case study of hypertension

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Clinical management and treatment decisions, hypertension in black americans, pharmacologic treatment of hypertension in black americans.

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Suzanne Oparil, Case study, American Journal of Hypertension , Volume 11, Issue S8, November 1998, Pages 192S–194S, https://doi.org/10.1016/S0895-7061(98)00195-2

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Ms. C is a 42-year-old black American woman with a 7-year history of hypertension first diagnosed during her last pregnancy. Her family history is positive for hypertension, with her mother dying at 56 years of age from hypertension-related cardiovascular disease (CVD). In addition, both her maternal and paternal grandparents had CVD.

At physician visit one, Ms. C presented with complaints of headache and general weakness. She reported that she has been taking many medications for her hypertension in the past, but stopped taking them because of the side effects. She could not recall the names of the medications. Currently she is taking 100 mg/day atenolol and 12.5 mg/day hydrochlorothiazide (HCTZ), which she admits to taking irregularly because “... they bother me, and I forget to renew my prescription.” Despite this antihypertensive regimen, her blood pressure remains elevated, ranging from 150 to 155/110 to 114 mm Hg. In addition, Ms. C admits that she has found it difficult to exercise, stop smoking, and change her eating habits. Findings from a complete history and physical assessment are unremarkable except for the presence of moderate obesity (5 ft 6 in., 150 lbs), minimal retinopathy, and a 25-year history of smoking approximately one pack of cigarettes per day. Initial laboratory data revealed serum sodium 138 mEq/L (135 to 147 mEq/L); potassium 3.4 mEq/L (3.5 to 5 mEq/L); blood urea nitrogen (BUN) 19 mg/dL (10 to 20 mg/dL); creatinine 0.9 mg/dL (0.35 to 0.93 mg/dL); calcium 9.8 mg/dL (8.8 to 10 mg/dL); total cholesterol 268 mg/dL (< 245 mg/dL); triglycerides 230 mg/dL (< 160 mg/dL); and fasting glucose 105 mg/dL (70 to 110 mg/dL). The patient refused a 24-h urine test.

Taking into account the past history of compliance irregularities and the need to take immediate action to lower this patient’s blood pressure, Ms. C’s pharmacologic regimen was changed to a trial of the angiotensin-converting enzyme (ACE) inhibitor enalapril, 5 mg/day; her HCTZ was discontinued. In addition, recommendations for smoking cessation, weight reduction, and diet modification were reviewed as recommended by the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). 1

After a 3-month trial of this treatment plan with escalation of the enalapril dose to 20 mg/day, the patient’s blood pressure remained uncontrolled. The patient’s medical status was reviewed, without notation of significant changes, and her antihypertensive therapy was modified. The ACE inhibitor was discontinued, and the patient was started on the angiotensin-II receptor blocker (ARB) losartan, 50 mg/day.

After 2 months of therapy with the ARB the patient experienced a modest, yet encouraging, reduction in blood pressure (140/100 mm Hg). Serum electrolyte laboratory values were within normal limits, and the physical assessment remained unchanged. The treatment plan was to continue the ARB and reevaluate the patient in 1 month. At that time, if blood pressure control remained marginal, low-dose HCTZ (12.5 mg/day) was to be added to the regimen.

Hypertension remains a significant health problem in the United States (US) despite recent advances in antihypertensive therapy. The role of hypertension as a risk factor for cardiovascular morbidity and mortality is well established. 2–7 The age-adjusted prevalence of hypertension in non-Hispanic black Americans is approximately 40% higher than in non-Hispanic whites. 8 Black Americans have an earlier onset of hypertension and greater incidence of stage 3 hypertension than whites, thereby raising the risk for hypertension-related target organ damage. 1 , 8 For example, hypertensive black Americans have a 320% greater incidence of hypertension-related end-stage renal disease (ESRD), 80% higher stroke mortality rate, and 50% higher CVD mortality rate, compared with that of the general population. 1 , 9 In addition, aging is associated with increases in the prevalence and severity of hypertension. 8

Research findings suggest that risk factors for coronary heart disease (CHD) and stroke, particularly the role of blood pressure, may be different for black American and white individuals. 10–12 Some studies indicate that effective treatment of hypertension in black Americans results in a decrease in the incidence of CVD to a level that is similar to that of nonblack American hypertensives. 13 , 14

Data also reveal differences between black American and white individuals in responsiveness to antihypertensive therapy. For instance, studies have shown that diuretics 15 , 16 and the calcium channel blocker diltiazem 16 , 17 are effective in lowering blood pressure in black American patients, whereas β-adrenergic receptor blockers and ACE inhibitors appear less effective. 15 , 16 In addition, recent studies indicate that ARB may also be effective in this patient population.

Angiotensin-II receptor blockers are a relatively new class of agents that are approved for the treatment of hypertension. Currently, four ARB have been approved by the US Food and Drug Administration (FDA): eprosartan, irbesartan, losartan, and valsartan. Recently, a 528-patient, 26-week study compared the efficacy of eprosartan (200 to 300 mg/twice daily) versus enalapril (5 to 20 mg/daily) in patients with essential hypertension (baseline sitting diastolic blood pressure [DBP] 95 to 114 mm Hg). After 3 to 5 weeks of placebo, patients were randomized to receive either eprosartan or enalapril. After 12 weeks of therapy within the titration phase, patients were supplemented with HCTZ as needed. In a prospectively defined subset analysis, black American patients in the eprosartan group (n = 21) achieved comparable reductions in DBP (−13.3 mm Hg with eprosartan; −12.4 mm Hg with enalapril) and greater reductions in systolic blood pressure (SBP) (−23.1 with eprosartan; −13.2 with enalapril), compared with black American patients in the enalapril group (n = 19) ( Fig. 1 ). 18 Additional trials enrolling more patients are clearly necessary, but this early experience with an ARB in black American patients is encouraging.

Efficacy of the angiotensin II receptor blocker eprosartan in black American with mild to moderate hypertension (baseline sitting DBP 95 to 114 mm Hg) in a 26-week study. Eprosartan, 200 to 300 mg twice daily (n = 21, solid bar), enalapril 5 to 20 mg daily (n = 19, diagonal bar). †10 of 21 eprosartan patients and seven of 19 enalapril patients also received HCTZ. Adapted from data in Levine: Subgroup analysis of black hypertensive patients treated with eprosartan or enalapril: results of a 26-week study, in Programs and abstracts from the 1st International Symposium on Angiotensin-II Antagonism, September 28–October 1, 1997, London, UK.

Approximately 30% of all deaths in hypertensive black American men and 20% of all deaths in hypertensive black American women are attributable to high blood pressure. Black Americans develop high blood pressure at an earlier age, and hypertension is more severe in every decade of life, compared with whites. As a result, black Americans have a 1.3 times greater rate of nonfatal stroke, a 1.8 times greater rate of fatal stroke, a 1.5 times greater rate of heart disease deaths, and a 5 times greater rate of ESRD when compared with whites. 19 Therefore, there is a need for aggressive antihypertensive treatment in this group. Newer, better tolerated antihypertensive drugs, which have the advantages of fewer adverse effects combined with greater antihypertensive efficacy, may be of great benefit to this patient population.

1. Joint National Committee : The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure . Arch Intern Med 1997 ; 24 157 : 2413 – 2446 .

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4. Pooling Project Research Group : Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to the incidence of major coronary events: Final report of the pooling project . J Chronic Dis 1978 ; 31 : 201 – 306 .

5. Hypertension Detection and Follow-Up Program Cooperative Group : Five-year findings of the hypertension detection and follow-up program: I. Reduction in mortality of persons with high blood pressure, including mild hypertension . JAMA 1979 ; 242 : 2562 – 2577 .

6. Kannel WB , Dawber TR , McGee DL : Perspectives on systolic hypertension: The Framingham Study . Circulation 1980 ; 61 : 1179 – 1182 .

7. Hypertension Detection and Follow-Up Program Cooperative Group : The effect of treatment on mortality in “mild” hypertension: Results of the Hypertension Detection and Follow-Up Program . N Engl J Med 1982 ; 307 : 976 – 980 .

8. Burt VL , Whelton P , Roccella EJ et al.  : Prevalence of hypertension in the US adult population: Results from the third National Health and Nutrition Examination Survey, 1988–1991 . Hypertension 1995 ; 25 : 305 – 313 .

9. Klag MJ , Whelton PK , Randall BL et al.  : End-stage renal disease in African-American and white men: 16-year MRFIT findings . JAMA 1997 ; 277 : 1293 – 1298 .

10. Neaton JD , Kuller LH , Wentworth D et al.  : Total and cardiovascular mortality in relation to cigarette smoking, serum cholesterol concentration, and diastolic blood pressure among black and white males followed up for five years . Am Heart J 1984 ; 3 : 759 – 769 .

11. Gillum RF , Grant CT : Coronary heart disease in black populations II: Risk factors . Heart J 1982 ; 104 : 852 – 864 .

12. M’Buyamba-Kabangu JR , Amery A , Lijnen P : Differences between black and white persons in blood pressure and related biological variables . J Hum Hypertens 1994 ; 8 : 163 – 170 .

13. Hypertension Detection and Follow-up Program Cooperative Group : Five-year findings of the Hypertension Detection and Follow-up Program: mortality by race-sex and blood pressure level: a further analysis . J Community Health 1984 ; 9 : 314 – 327 .

14. Ooi WL , Budner NS , Cohen H et al.  : Impact of race on treatment response and cardiovascular disease among hypertensives . Hypertension 1989 ; 14 : 227 – 234 .

15. Weinberger MH : Racial differences in antihypertensive therapy: evidence and implications . Cardiovasc Drugs Ther 1990 ; 4 ( suppl 2 ): 379 – 392 .

16. Materson BJ , Reda DJ , Cushman WC et al.  : Single-drug therapy for hypertension in men: A comparison of six antihypertensive agents with placebo . N Engl J Med 1993 ; 328 : 914 – 921 .

17. Materson BJ , Reda DJ , Cushman WC for the Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents : Department of Veterans Affairs single-drug therapy of hypertension study: Revised figures and new data . Am J Hypertens 1995 ; 8 : 189 – 192 .

18. Levine B : Subgroup analysis of black hypertensive patients treated with eprosartan or enalapril: results of a 26-week study , in Programs and abstracts from the first International Symposium on Angiotensin-II Antagonism , September 28 – October 1 , 1997 , London, UK .

19. American Heart Association: 1997 Heart and Stroke Statistical Update . American Heart Association , Dallas , 1997 .

• hypertension
• blood pressure
• african american

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Newly diagnosed hypertension: case study

Affiliation.

• 1 Trainee Advanced Nurse Practitioner, East Belfast GP Federation, Northern Ireland.
• PMID: 37344134
• DOI: 10.12968/bjon.2023.32.12.556

The role of an advanced nurse practitioner encompasses the assessment, diagnosis and treatment of a range of conditions. This case study presents a patient with newly diagnosed hypertension. It demonstrates effective history taking, physical examination, differential diagnoses and the shared decision making which occurred between the patient and the professional. It is widely acknowledged that adherence to medications is poor in long-term conditions, such as hypertension, but using a concordant approach in practice can optimise patient outcomes. This case study outlines a concordant approach to consultations in clinical practice which can enhance adherence in long-term conditions.

Keywords: Adherence; Advanced nurse practitioner; Case study; Concordance; Hypertension.

• Diagnosis, Differential
• Hypertension* / diagnosis
• Hypertension* / drug therapy
• Nurse Practitioners*

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• Review Article
• Published: 05 July 2022

Update on Hypertension Research in 2021

• Masaki Mogi 1 ,
• Tatsuya Maruhashi 2 ,
• Yukihito Higashi 2 , 3 ,
• Takahiro Masuda 4 ,
• Daisuke Nagata 4 ,
• Michiaki Nagai 5 ,
• Kanako Bokuda 6 ,
• Atsuhiro Ichihara 6 ,
• Yoichi Nozato 7 ,
• Ayumi Toba 8 ,
• Keisuke Narita 9 ,
• Satoshi Hoshide 9 ,
• Atsushi Tanaka 10 ,
• Koichi Node 10 ,
• Yuichi Yoshida 11 ,
• Hirotaka Shibata 11 ,
• Kenichi Katsurada 9 , 12 ,
• Masanari Kuwabara 13 ,
• Takahide Kodama 13 ,
• Keisuke Shinohara 14 &
• Kazuomi Kario 9  

Hypertension Research volume  45 ,  pages 1276–1297 ( 2022 ) Cite this article

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In 2021, 217 excellent manuscripts were published in Hypertension Research. Editorial teams greatly appreciate the authors’ contribution to hypertension research progress. Here, our editorial members have summarized twelve topics from published work and discussed current topics in depth. We hope you enjoy our special feature, “Update on Hypertension Research in 2021”.

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Genome-wide association studies

Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Usefulness of vascular function tests for cardiovascular risk assessment and a better understanding of the pathophysiology of atherosclerosis in hypertension (see supplementary information  1 ).

Vascular function tests and vascular imaging tests are useful for assessing the severity of atherosclerosis. Since vascular dysfunction and vascular morphological alterations are closely associated with the maintenance and progression of atherosclerosis, vascular tests may provide additional information for cardiovascular risk assessment (Fig.  1 ) [ 1 , 2 , 3 , 4 , 5 ]. Measurement of the ankle-brachial index (ABI) has been performed not only for screening for peripheral artery disease but also for cardiovascular risk assessment in clinical practice [ 6 ]. However, the ABI method does not always provide reliable data because the ABI value is falsely elevated despite the presence of occlusive arterial lesions in the lower extremities of patients with noncompressible lower limb arteries, which can lead to incorrect cardiovascular risk assessment [ 7 , 8 , 9 ]. Tsai et al. [ 10 ] reported that a combination of an ABI value <0.9 and an interleg ABI difference ≥0.17 was more useful for predicting all-cause mortality and cardiovascular mortality than was an ABI value <0.9 alone. Therefore, attention should be given not only to the ABI value but also to the interleg ABI difference for more precise cardiovascular risk assessment. Sang et al. [ 11 ] conducted a systematic review and meta-analysis to investigate the usefulness of brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, for risk assessment and showed that higher baPWV was significantly associated with a higher risk of cardiovascular events, cardiovascular mortality, and all-cause mortality in patients with a history of coronary artery disease or stroke.

Vascular function tests and vascular imaging tests for the assessment of cardiovascular risk. CV cardiovascular

Vascular tests are also useful to achieve a better understanding of the underlying pathophysiology of cardiac disorders. Harada et al. [ 12 ] reported that short stature defined as height <155.0 cm was associated with low flow-mediated vasodilation (FMD), an index of endothelial function, in Japanese men, supporting the association between short stature and high risk of cardiovascular events [ 13 ]. Cassano et al. [Supplementary Information  1 - 1 ] reported that low levels of endothelial progenitor cells (EPCs) at baseline were associated with impaired endothelial function assessed by the reactive hyperemia index (RHI) and impaired arterial stiffness assessed by carotid-femoral PWV (cfPWV) at baseline and that EPC levels at baseline were also associated with longitudinal changes in RHI and cfPWV three years after the initiation of antihypertensive drug treatment in patients with hypertension. Murai et al. [Supplementary Information  1 - 2 ]. reported that a higher area under the curve value of insulin during a 75-g oral glucose tolerance test, but not insulin sensitivity indices, was significantly associated with higher baPWV in young Japanese subjects aged <40 years. Miyaoka et al. [ 14 ] reported that baPWV and central systolic blood pressure were significantly associated with renal microvascular damage assessed by using renal biopsy specimens in patients with nondiabetic kidney disease. Vila et al. [Supplementary Information  1 - 3 ] reported that carotid intima-media thickness (IMT) was significantly greater in male patients with autoimmune disease than in age-matched male controls without autoimmune disease, supporting a role for immune-mediated inflammation in the pathogenesis of atherosclerosis. Li et al. [Supplementary Information  1 - 4 ] showed in a cross-sectional study that increased carotid IMT was significantly associated with cognitive impairment assessed by the Mini-Mental State Examination in Chinese patients with hypertension, especially patients who were ≥60 years of age and patients with low high-density lipoprotein cholesterol levels (<40 mg/dL).

Vascular function is profoundly affected by habitual behavior. Fryer et al. [Supplementary Information  1 - 5 ] reported that central arterial stiffness and peripheral arterial stiffness assessed by cfPWV and PWV β were more deteriorated by uninterrupted prolonged sitting (180 min) combined with prior high-fat meal consumption (61 g fat, 1066 kcal) than by uninterrupted prolonged sitting combined with prior low-fat meal consumption (10 g fat, 601 kcal) in healthy nonsmoking male subjects, suggesting that high-fat meal consumption should be avoided before uninterrupted prolonged sitting to prevent the progression of arterial stiffening. Yamaji et al. [ 15 ] reported that endothelial function assessed by FMD and vascular smooth muscle function assessed by nitroglycerine-induced vasodilation of the brachial artery were more impaired in patients without daily stair climbing activity than in patients who habitually climbed stairs to the ≥3 rd floor among patients with hypertension. Funakoshi et al. [ 16 ] reported that eating within 2 h before bedtime ≥3 days/week was associated with the development of hypertension defined as blood pressure ≥140/90 mmHg or initiation of antihypertensive drug treatment during an average follow-up period of 4.5 years in the general Japanese population, suggesting that avoiding late dinners may be helpful for preventing the development of hypertension. These findings indicate the importance of lifestyle modifications for maintaining vascular function and preventing the development of hypertension and the progression of atherosclerosis.

(TM and YH)

Keywords : vascular function, endothelial function, arterial stiffness, carotid intimathickness, ankle-brachial index.

Advances in hypertension management for better renal outcomes (See Supplementary Information 2 )

In chronic kidney disease (CKD) patients, hypertension is a risk factor for end-stage renal disease (ESRD), cardiovascular events and mortality. Thus, the prevention and appropriate management of hypertension in CKD patients are important strategies for preventing ESRD and cardiovascular disease (Fig.  2 ).

Advantages of hypertension in CKD. CKD chronic kidney disease, GFR glomerular filtration rate, MR mineralocorticoid receptor, SGLT2 sodium–glucose cotransporter 2

Risk factors for hypertension

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that is mainly secreted by the liver. Circulating FGF21 levels are reported to be increased in CKD patients, while higher circulating FGF21 levels were reported to be associated with all-cause mortality in ESRD patients [ 17 , 18 ]. Additionally, Matsui et al. reported that higher circulating FGF21 levels partially mediate the association of elevated BP and/or aortic stiffness with renal dysfunction in middle-aged and older adults [ 19 ]. A study by Funakoshi et al. showed that eating before bed was correlated with the future risk of developing hypertension in the Iki Epidemiological Study of Atherosclerosis and Chronic Kidney Disease [Supplementary Information  2 - 1 ].

Prognostic markers

Several promising prognostic markers for renal and cardiovascular outcomes have been suggested. Matsukuma et al. reported that a higher urinary sodium-to-potassium ratio was independently associated with poor renal outcomes in patients with CKD [Supplementary Information  2 - 2 ]. Chinese hypertensive patients with higher albumin-to-creatinine ratios had a significantly increased risk of first ischemic stroke [Supplementary Information  2 - 3 ]. The number of nephrons in hypertensive patients was significantly lower than that in controls [ 20 ]. Tsuboi et al. suggested the usefulness of methods to estimate the total nephron count and single nephron GFR in living patients, which helped to tailor patient care depending on age or disease stage as well as to predict the response to therapy and the disease outcome [ 21 ].

Mineralocorticoid receptor (MR) blockers (e.g., esaxerenone) are used in the treatment of essential hypertension and hyperaldosteronism. Recently, a new MR antagonist, finerenone, has been introduced as a treatment for CKD patients with type 2 diabetes. However, hyperkalemia has been recognized as a potential side effect during treatment with MR blockers. A recent review article by Rakugi et al. suggested that being aware of at-risk patient groups, choosing appropriate dosages, and monitoring serum potassium during therapy are required to ensure the safe clinical use of these agents [Supplementary Information  2 - 4 ].

The clinical use of sodium–glucose cotransporter-2 inhibitors (SGLT2is) has recently been expanded to nondiabetic patients with CKD and heart failure as well as diabetic patients [ 22 , 23 ]. Several novel findings regarding the renal protective properties of SGTL2is were reported in 2021. In a real-world registry study of Japanese type 2 diabetes patients with CKD, SGLT2is were associated with significantly better kidney outcomes in comparison to other glucose-lowering drugs, irrespective of the presence or absence of proteinuria [ 24 ]. Kitamura et al. reported that the addition of metformin to SGLT2is blunts the decrease in eGFR but that the coadministration of RAS inhibitors ameliorates this response [Supplementary Information  2 - 5 ]. Thomson and Vallon reported that (1) SGLT2i treatment reduces glomerular capillary pressure that is mediated through tubuloglomerular feedback (TGF) and (2) the TGF response to SGLT2is involves preglomerular vasoconstriction and postglomerular vasorelaxation [ 25 ].

SGLT2is have an antihypertensive effect, which is greater in subjects with higher salt sensitivity and BMI [ 26 , 27 , 28 ]. Furthermore, the degree of BP change in patients undergoing SGLT2i therapy depends on the baseline BP; a larger reduction is observed in patients with higher baseline BP, and a smaller reduction or slight increase is observed in patients with lower baseline BP [ 29 ]. These BP regulation mechanisms may partially depend on body fluid homeostasis by SGLT2is. SGLT2is ameliorate fluid retention through osmotic diuresis and natriuresis but are associated with a low rate of hypovolemia [ 30 , 31 , 32 , 33 ], which is evident by the compensatory upregulation of renin and vasopressin levels [ 33 , 34 , 35 ]. These fluid homeostatic mechanisms exerted by SGLT2is may contribute to the stabilization of BP. Moreover, recent clinical studies have shown that SGLT2is reduce BP without changes in urinary sodium and fluid excretion or plasma volume [ 35 , 36 , 37 ], suggesting the role of other factors, such as the inhibition of the sympathetic nervous system, restoration of endothelial function, and reduction of arterial stiffness [ 38 , 39 ].

(TM and DN)

Keywords : fibroblast growth factor 21, nephron number, mineralocorticoid receptor blocker, SGLT2 inhibitor, fluid homeostasis.

Hypertension and heart disease-focusing on the relationship with HFpEF (See Supplementary Information 3 )

With the increasing longevity of ‘Westernized’ populations, heart failure (HF) in the elderly has become a problem of growing scale and complexity worldwide [ 40 ].

Stages of HF are classified from A to D [ 41 ]. HF patients are also divided into patients with preserved ejection fraction (EF) (HFpEF), those with mildly reduced EF and those with reduced EF (HFrEF). Persistent hypertension and increased arterial stiffness in stage A HF result in left ventricular (LV) hypertrophy (LVH), at which point it is classified as stage B HF. Although the etiology of HFpEF is diverse, patients with HFpEF have been reported to have a high prevalence of hypertension, which is closely associated with increased arterial stiffness, LVH and diastolic LV dysfunction [ 41 ].

In adult Sprague–Dawley rats, a novel flavoprotein, renalase, was increased in hypertrophic cardiac tissue, and recombinant renalase improved cardiac function and suppressed myocardial fibrosis in the HF model [ 42 ]. In stroke-prone spontaneously hypertensive rats, carboxypeptidase X 2 (Cpxm2) was identified as a locus that affects LV mass. Analysis of endomyocardial biopsies from LVH patients showed significant upregulation of CPXM2 expression [ 43 ]. In this way, basic research applied to humans has shown in detail the pathophysiology of LVH.

Left atrial (LA) enlargement (LAe) is also associated with HFpEF [ 44 ]. In response to proinflammatory mediators, microvascular endothelial cells become inappropriately activated, resulting in microvascular endothelial dysfunction, perpetuating the inflammatory process and LA fibrosis [ 45 ]. Manifestations of these mechanisms have been related to LAe, which can be detected prior to the incidence of atrial fibrillation. Sympathetic overdrive from the central autonomic network, including the insular cortex, causes LA-pulmonary vein (PV) border fibrosis. LA-PV border fibrosis was suggested to originate from local inflammation triggered by preganglionic fibers ending in ganglionated plexi [ 45 , 46 ].

In the SPRINT study, intensive BP management was not associated with LA abnormalities defined based on ECG [ 47 ]. Although LA volume (LAV) according to body surface area was recommended to assess LA size [ 48 ], LAV indexed for height 2 was shown to be more sensitive for detecting subclinical hypertensive organ damage in females [ 49 ]. In the ARIC study, the minimum but not the maximum LAV index was significantly associated with the risk of incident HFpEF or death [ 50 ].

In the 2021 European Society of Cardiology guidelines for the treatment of HFrEF, angiotensin receptor/neprilysin inhibitor (ARNI) and sodium–glucose cotransporter 2 inhibitor (SGLT2i) are newly recommended for first-line treatment. In contrast, no guideline-directed treatment has been shown to convincingly reduce mortality and morbidity in HFpEF patients [ 44 ].

BP control is important to prevent adverse events in HFpEF patients with high BP. In a randomized study of hypertension patients, a significant reduction in systolic blood pressure (BP) (SBP) and diastolic BP was observed during daytime and nighttime in the ARNI group compared to the placebo group [ 51 ]. ARNI was also associated with reduced BP in patients with refractory hypertension with HFpEF [ 52 ]. In the PARAGON-HF trial, a decrease in pulse pressure, a marker of large arterial stiffness, during ARNI run-in was associated with a significant improvement in the prognosis of HFpEF [ 53 ]. On the other hand, the SACRA study showed that a significant reduction in BP occurred after adding SGLT2i to existing antihypertensive and antidiabetic agents in nonsevere obese diabetic elderly with uncontrolled nocturnal hypertension [ 54 ]. Recently, in the EMPEROR-Preserved Trial, SGLT2i improved the prognosis of patients with HFpEF [ 55 ]. From the above, it is suggested that reducing nighttime BP and improving diurnal BP patterns improves the prognosis of HFpEF [ 56 , 57 ].

Accumulated evidence from basic and clinical studies suggests that hypertension is a crucial risk factor for HFpEF (Fig.  3 ). These data may contribute to future studies aimed at elucidating the more detailed pathophysiology of HFpEF in hypertension research and the development of therapeutic agents and/or strategies that improve the prognosis of HFpEF in hypertension.

A scheme of the relationship between hypertension and HFpEF. The dysregulation of the central autonomic network is associated with enhanced sympathetic nervous system activity in hypertension linked to HFpEF via left atrial remodeling, left ventricular hypertrophy and increased arterial stiffness. HFpEF heart failure with preserved ejection fraction, LA left atrium, PV pulmonary vein

Keywords : heart failure with preserved ejection fraction, arterial stiffness, leftventricular hypertrophy, diastolic left ventricular dysfunction, left atrial remodeling.

Up-to-date preeclampsia knowledge; what we should know for mother and child (See Supplementary Information 4 )

Diagnostic criterion.

In 2017, the American College of Cardiology/American Heart Association hypertension treatment guidelines identified hypertension as blood pressure (BP) ≥ 130/80 mmHg. The reference BP for hypertension during pregnancy as specified in international guidelines [e.g., the International Society for the Study of Hypertension in Pregnancy guidelines (ISSHP) [ 58 ] and the American College of Obstetricians and Gynecologists guidelines (ACOG) [ 59 , 60 ]] is ≥140/90 mmHg. A large number of studies have examined the incidence of PE and fetal outcomes according to BP levels. The meta-analysis of these studies has shown that BP ≥ 120/80 mmHg, particularly ≥130/80 mmHg, in early pregnancy is also associated with increased maternal and perinatal risks and proposed new BP categories of <120/80 mmHg (normal), 120–129/<80 mmHg (high normal), and 130–139/80–89 mmHg (elevated) for pregnant women [ 61 ].

Prognostic tools

The predictive value of BP and other clinical characteristics for PE is relatively low [ 62 , 63 ]. Soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio testing resulted in reduced unnecessary hospitalization [ 64 , 65 ]. Circulating cell-free DNA (cfDNA) and human suppression of tumorigenesis 2 (ST2) were increased in individual with gestational hypertension (GH) and PE and served as diagnostic biomarkers [Supplementary Information  4 - 1 ]. Nocturnal hypertension was a significant predictor of early-onset PE in high-risk pregnancies [ 66 ]. BP variability was higher in pregnant women with hypertensive disorders and was significantly associated with left ventricular mechanics [Supplementary Information  4 - 2 ]. Including these factors in multivariate models may improve the detection rates of PE and may identify women who could benefit from preventive interventions (Fig.  4 ).

Schematic presentation of the topics of preeclampsia 2021. HTN hypertension, PE preeclampsia, BP blood pressure, cfDNA cell-free DNA, ST2 human suppression of tumorigenesis 2, sFlt-1 soluble fms-like tyrosine kinase-1, PIGF placental growth factor, PRES posterior reversible encephalopathy syndrome, AKI acute kidney injury, ACE angiotensinogen converting enzyme, Ang angiotensin

The ISSHP recommends that BP ≥ 140/90 mmHg should be treated, with a goal BP of 110–140/85 mmHg, while the ACOG recommends antihypertensive medications when BP ≥ 160/110 mmHg, with goal BP below this threshold (Fig.  4 ). Systolic BP (sBP) < 130 mmHg within 14 weeks of gestation reduced the risk of developing early-onset superimposed PE in women with chronic hypertension [ 67 ]. The Chronic Hypertension and Pregnancy (CHAP) project also showed that BP control to <140/90 was associated with a reduction in composite adverse outcomes, with no significant increase in small for gestational age infants [ 68 ].

Long-term outcomes

PE is linked to major chronic diseases such as hypertension, type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease (Fig.  4 ). The American Heart Association lists hypertension during pregnancy as a major cardiovascular risk factor and recommends that affected women undergo cardiovascular risk screening within 3 months after giving birth [ 69 ]. Since many cardiovascular risk factors are modifiable and related to lifestyle, all women with prior PE should be followed up by physicians even after the resolution of PE.

COVID-19 and Pregnancy

Pregnancy could potentially affect the susceptibility to and severity of COVID-19. Severe cases of COVID-19 present with PE-like symptoms. PE mimicry by COVID-19 was confirmed following the alleviation of preeclamptic symptoms without delivery of the placenta [ 70 ]. In COVID-19, angiotensin-converting enzyme 2 (ACE 2) function decreases, and subsequently, angiotensin II (Ang) activity increases [ 71 ]. Similar to PE, COVID-19 results in an increase in the sFlt-1/PlGF ratio due to pathologic Ang II/Ang (1-7) imbalance [ 72 ] (Fig.  4 ). Most experts believe that SARS-CoV-2 is likely to become endemic, and continued collection of data on the effects of COVID-19 during pregnancy is needed.

Further investigation is needed to decrease PE-related maternal and fetal deaths and to reduce maternal risks for chronic diseases in later life. The participation of physicians is necessary to offer appropriate medical care to women with prior PE, and continued publications of issues regarding PE in Hypertension Research are expected.

(KB and AI)

Keywords : preeclampsia, gestational hypertension, chronic hypertension, soluble fms-like tyrosine kinase 1, placental growth factor.

Appropriate blood pressure assessment methods for the prevention of hypertension complications (See Supplementary Information 5 )

Blood pressure (BP) values can vary and fluctuate widely depending on the method and the environment of blood measurement. Via appropriate measurement and interpretation of BP values, hypertension can be correctly diagnosed, treated and guided [ 73 ]. To give an example, appropriate body posture is important for accurate BP measurement. Wan et al. [Supplementary Information  5 - 1 ] demonstrated that BP levels measured with the back in an unsupported position were 2.3/1.0 mmHg higher than those measured with the back in a supported position. Glenning et al. [Supplementary Information  5 - 2 ] demonstrated the feasibility of measuring diastolic blood pressure by the onset of the fourth Korotkoff phase (K4), when K5 is undetectable under exercise conditions in children and adolescents. In recent years, a variety of BP measurement devices and techniques have appeared, and accumulating evidence has shown the feasibility, reproducibility, and usefulness of these devices [ 74 , 75 ]. Kario et al. [ 76 ] demonstrated the relationship between BP by a newly released wrist-cuff oscillometric wearable BP device and left ventricular hypertrophy. They concluded the feasibility and usefulness of wearable BP devices to detect masked daytime hypertension. Automated office blood pressure (AOBP) measurement includes recording of several BP readings using a fully automated oscillometric sphygmomanometer with the patient resting alone in a quiet place, thereby potentially minimizing the white-coat effect. The most comprehensive meta-analysis [ 77 ] reported that AOBP is equivalent to home BP (HBP), but the diagnostic value and viability of AOBP are still controversial. Lee et al. [ 78 ] assessed the diagnostic accuracies of two AOBP machines and manual office blood pressure measurements (MOBP) in Chinese individuals and clarified the lower diagnostic significance of AOBP than that of MOBP. Recent studies strongly recommended the wide use of self-measured HBP [ 79 ] because HBP has better reproducibility than office BP (OBP), improves adherence to treatment, enables us to detect high-risk populations and has prognostic value for cardiovascular disease (CVD) events [ 80 , 81 , 82 ]. Both elevated morning and nocturnal BP values and disrupted circadian BP rhythm assessed by each BP measurement method or devices are associated with worsened cardiovascular outcomes (Fig.  5 ). Zhan et al. [ 83 ] demonstrated that HBP monitoring improved treatment adherence and BP control in stage 2 and 3 hypertension. Hoshide et al. [ 84 ] demonstrated the association of nighttime BP assessed by HBP and CVD events, independent of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, in the Japanese clinical population. Narita et al. [Supplementary Information  5 - 3 ] demonstrated that the elevated difference between morning and evening systolic BP was associated with a higher incidence of CVD events in the J-HOP study. Narita et al. [Supplementary Information  5 - 4 ] also demonstrated that treatment-resistant hypertension diagnosed by HBP monitoring was associated with increased CVD risk independent of cardiovascular damage in the same Japanese cohort. Oliveira et al. [Supplementary Information  5 - 5 ] demonstrated that the SAGE score calculated by systolic BP, age, fasting blood glucose and estimated glomerular filtration rate was associated with pulse wave velocity measured by oscillometric devices and concluded that a SAGE score ≥8 could be used to identify a high risk of CVD events. ABPM is currently regarded as the reference method for hypertension diagnosis in children and pregnancy. Salazar et al. [Supplementary Information  5 - 6 ] demonstrated nocturnal hypertension assessed by ABPM as a significant predictor of early-onset preeclampsia/eclampsia in high-risk pregnant women in a cohort study in Argentina. ABPM also helped us to notice abnormal circadian patterns in BP, which are associated with increased circulating volume, largely determined by salt sensitivity and salt intake. Understanding these pathogenic mechanisms under conditions of nocturnal hypertension and heart failure suggests several new antihypertensive pharmacotherapies, including sodium–glucose cotransporter 2 inhibitors, angiotensin receptor neprilysin inhibitors and mineralocorticoid receptor antagonists [ 56 , 85 , 86 ]. Kario et al. [Supplementary Information  5 - 7 ] demonstrated the effect of esaxerenone, a highly selective mineralocorticoid receptor blocker, for improving nocturnal hypertension and NT-proBNP levels. Esaxerenon could be an effective treatment option, especially for nocturnal hypertensive patients with a riser pattern.

Methods of measuring variable blood pressure and evaluating factors associated with the prognosis of cardiovascular disease

Keywords : hypertension management, BP measurement devices, BP variability, home BP, cardiovascular disease

Considering frailty and exercise in the management of hypertension and hypertensive organ damage (See Supplementary Information 6 )

Frailty is defined as physiological decline and a state of vulnerability to stress and results in adverse health outcomes [ 87 ]. Frailty consists of multiple domains, such as physical, social, and psychological factors. Cognitive decline is one of the factors related to frailty, and blood pressure (BP) control significantly reduced dementia or cognitive decline in a meta-analysis [ 88 ]. However, in the elderly population above 80 years, the positive effect of antihypertensive therapy for preventing dementia was not proven [ 89 , 90 , 91 ].

A systematic review and meta-analysis of the prevalence of mild cognitive impairment (MCI) among hypertensive patients was conducted by Quin et al. The prevalence of MCI was 30% in a sample of 47,179 hypertensive patients. Heterogeneity was seen due to ethnicity, study design (cross-sectional or cohort study), and cognition assessment tools [ 92 ]. Li. et al. investigated the association between carotid intima thickness (CIMT) and cognitive function in hypertensive patients [Supplementary Information  6 - 1 ]. CIMT was significantly and negatively associated with MMSE scores in people aged ≥60 years but not in those aged <60 years.

BP guidelines in various countries suggest that BP management should be carried out in the context of frailty or end of life, and careful observation, including personalized BP control among elderly individuals, is essential (Fig.  6 ). A total of 535 patients with hypertension (age 78 [ 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ] years, 51% men, 37% with frailty) were prospectively followed for 41 months, and mortality associated with frailty and BP was evaluated by Inoue et al. [ 93 ]. Frailty was assessed by the Kihon checklist. Among 49 patients who died, mortality rates were lowest in those with systolic BP < 140 mmHg and nonfrailty and highest in those with systolic BP < 140 mmHg and frailty. The results indicate that frail patients have a higher risk of all-cause mortality than nonfrail patients, and BP should be managed considering frailty status, which is in line with previous reports [ 94 ]. Our latest study showed that in patients with preserved MMSE scores, higher BP was associated with cognitive impairment, and those with MMSE scores below 24 points had the opposite results [ 95 ]. Elderly individuals with hearing impairment have higher rates of hospitalization, mortality, falls, frailty, dementia, and depression. Miyata et al. performed a study using data from medical records from health checkups: higher SBP levels were associated with an increased risk of objective hearing impairment at 1 kHz [Supplementary Information  6 - 2 ].

Hypertension management in frail patients. ADL activities of daily living, IADL instrumental activities of daily living

In the era of technical advancement, people are spending less time being active, which leads to cardiovascular risks, including hypertension. However, guidelines emphasize the importance of nonpharmacological strategies such as lifestyle modification and exercise to prevent diseases [ 96 ].

Sardeli et al. compared types of exercise that are beneficial to health. The study compared the effects of aerobic training (AT), resistance training (RT), and combined training (CT) in hypertensive older adults aged >50 years. There were extensive health benefits associated with exercise training, and CT was the most effective intervention at improving a wide spectrum of health conditions, including cardiorespiratory fitness, muscle strength BMI, fat mass, glucose, TC and TGs [ 97 ]. J Almeida et al. showed that isometric handgrip exercise training reduced systolic BP in treated hypertensive patients [Supplementary Information  6 - 3 ]. Stair climbing and vascular function were assessed by Yamaji et al. There was a significant difference in nitroglycerine-induced vasodilatation between the group with no habits of climbing stairs and the other groups with two or more climbing habits [Supplementary Information  6 - 4 ].

The safety of resistance training was studied by Hansford et al who concluded that isometric resistance training (IRT) was safe and led to a potentially clinically meaningful reduction in BP [Supplementary Information  6 - 5 ].

Keywords : physical and social frailty, elderly, cognitive function, resistance training, cardiorespiratory function

Blood pressure variability—therapeutic target for the prevention of cardiovascular disease (See Supplementary Information 7 )

In the past three decades, there have been many reports on the associations of various parameters of blood pressure (BP) variability with increased risk of cardiovascular disease (CVD) events; these parameters include short-term BP variability (BPV), i.e., beat-by-beat BPV and ambulatory BPV, abnormality of nocturnal BP dipping pattern, and mid- to long-term BPV, i.e., day-by-day BPV, visit-to-visit BPV, and seasonal variations in BP [ 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 ]. In addition, BPV has been associated with the progression of endovascular organ damage related to heart failure, chronic kidney disease, and cognitive function [ 107 , 108 , 109 , 110 , 111 ] [Supplementary Information  7 - 1 ]. Several factors that are associated with abnormal BPV [ 112 ], as well as environmental factors such as cold or warm temperatures and seasonal changes in climate, increase fluctuations in BP. Individual intrinsic factors, such as sympathetic nervous tone, arterial stiffness, physical activity, and mental stress, also contribute to elevated BPV. According to evaluations of BPV abnormalities, out-of-office BP measurements, such as ambulatory and home BP monitoring, are needed. To evaluate nighttime BP levels, home BP monitoring devices equipped with a function for nighttime BP readings and new wrist-type nocturnal BP monitoring devices are available [ 76 ]. Although there are issues regarding measurement accuracy, cuffless BP monitoring devices, for example, those using pulse transit time, may be used to estimate nighttime BP levels [Supplementary Information  7 - 2 ]. Such cuffless BP devices can also evaluate beat-by-beat BPV. Moreover, by using the multisensor-equipped ambulatory BP monitoring device developed by our research group, it is possible to evaluate BPV associated with changes in temperature, physical activity, and/or atmospheric pressure [ 113 ].

Based on the mechanism(s) underlying a given patient’s BPV abnormality, several methods may be considered for the management of that abnormality (Fig.  7 ). For example, improving excessive sympathetic nervous system activation may be useful in the management of BPV abnormalities [ 114 ], and renal denervation has been reported to decrease ambulatory BPV [ 115 ]. Abnormal nocturnal BP dips may be treated by decreasing nighttime BP. In patients with sleep apnea, improving sleep quality and implementing continuous positive airway pressure are recognized to be useful for nighttime BP control [ 116 ]. Moreover, early adjustment of antihypertensive drugs has been reported to be useful in suppressing seasonal variations in BP, leading to a decreased risk of CVD events [ 99 ]. Furthermore, housing conditions and room temperature are closely related to BP levels, and adaptive control of room temperature would be useful to suppress winter increases in BP [ 117 , 118 ]. In clinical practice, we must not forget that BPV parameters are interrelated. For instance, frequent evaluation of BP levels and adjustment of antihypertensive drugs can suppress visit-to-visit BPV, which in turn leads to the suppression of seasonal variations in BP.

Current and future perspectives in the management of blood pressure variability. Short- and long-term BP variability is associated with CVD event risk independent of each BP level. Out-of-office BP measurements, such as ABPM and home BP monitoring, and other new BP devices are useful for evaluating the various types of BP variability. To suppress BP variability, several management methods, including new antihypertensive medications, chronotherapy, housing condition, and sympathetic nervous denervation, are considered. ABPM ambulatory blood pressure monitoring, ABPV ambulatory blood pressure variability, ARNI angiotensin receptor neprilysin inhibitor, BP blood pressure, BPV blood pressure variability, CVD cardiovascular disease, ICT information and communication technology, SGLT2i sodium–glucose cotransporter 2 inhibitor

Over the next decade, more data on how to manage and control BPV need to be accumulated. Additionally, future studies should be conducted to verify whether the different types of BVP management are useful in preventing CVD events.

(KN, SH and KK)

Keywords : blood pressure variability, out-of-office blood pressure monitoring, cardiovascular disease prevention, wearable blood pressure monitoring device, environmental factors.

Optimal therapy and clinical management of obesity/diabetes (See Supplementary Information 8 )

Obesity/diabetes is a major comorbidity in patients with hypertension, and these conditions often share common pathological conditions, such as insulin resistance and the risk of cardiovascular diseases (CVD). One of the biggest highlights of recent years in the area of obesity/diabetes has been the remarkable benefits of newer glucose-lowering agents seen in large-scale clinical trials on cardiorenal outcomes (Fig.  8 ), followed by the relevant clinical guideline updates and the expansion of the clinical application of those agents [ 119 ]. In particular, sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists are now preferentially recommended in patients with type 2 diabetes (T2D) and specific cardiorenal risk, independent of diabetes status or background use of metformin [ 120 ]. It is noteworthy, of course, that those agents reduced the risk of cardiorenal events, and their multifaceted effects beyond hypoglycemic effects are also attracting clinical attention. In a review series ‘New Horizons in the Treatment of Hypertension’ in Hypertension Research, Tanaka and Node [ 121 ] discussed the modest effects of those agents on blood pressure (BP)-reduction and the clinical perspectives. They also proposed a new-normal style care for diabetes and its complications using such evidence-based agents with multidisciplinary effects, partly aiming at reduced polypharmacy and avoidance of its possible harm. This action will improve the quality of hypertension care in patients with obesity/diabetes; however, a substantial population with treated hypertension still has inadequate blood pressure control, which is recognized as resistant hypertension (RH). Due to the difficulty in distinguishing true RH from pseudo-RH due to nonadherence, little is known about the clinical characteristics of true RH. Chiu et al. from Boston [Supplementary Information  8 - 1 ] reported a notable prevalence (26.6%) of true RH in patients with T2D registered in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure trial and identified several independent predictors, such as higher baseline BP, higher number of baseline antihypertensives, macroalbuminuria, chronic kidney disease, and history of stroke. Moreover, patients with true RH exhibited poorer prognosis than those without, suggesting an emerging need for effective screening and intensified treatment for patients with true RH.

Schematic presentation of the topic ‘Obesity/Diabetes’ in 2021

The BP treatment goal in patients with diabetes and hypertension is less than 130/80 mmHg [ 122 ], and intensified BP control was associated with reduced stroke risk [ 123 , 124 , 125 ]. Intensive lipid-lowering therapy is also recommended for patients with T2D at risk of CVD [ 126 ]; however, an original EMPATHY study investigating the effect of intensive lipid-lowering therapy (target of low-density lipoprotein cholesterol [LDL-C] < 70 mg/dL) on cardiovascular outcomes failed to show the clinical benefits of intensive statin therapy in patients with T2D, diabetic retinopathy, elevated LDL-C levels, and no known CVD [ 127 ]. In a subanalysis of the EMPATHY study, Shinohara et al. [ 128 ] revealed for the first time that intensive statin therapy was associated with a reduced risk of cardiovascular events compared with standard therapy (target of ≥100 to <120 mg/dL) in a subgroup with baseline BP ≥ 130/80 mmHg but not in another subgroup with baseline BP < 130/80 mmHg. Their findings suggest that baseline BP is also a possible determinant of the target LDL-C in that patient population, although the precise reasons for the difference in the clinical benefits of intensive statin therapy between subgroups according to baseline BP levels are still uncertain.

Obesity is a crucial global health concern across generations. Obesity and insulin resistance cause several cardiometabolic disorders, including hypertension, and increase the risk of subsequent CVD. Hence, further actions against obesity and cardiometabolic disorders are urgently needed for individuals of all generations [ 129 , 130 ]. In this context, Fernandes et al. from Brazil [Supplementary Information  8 - 2 ] revealed for the first time that Ang-(1-7) and des-Arg9BK metabolites were novel biological markers of adolescent obesity and relevant cardiovascular risk profiles, such as elevated BP, lipids, and inflammation. Thu et al. from Singapore [Supplementary Information  8 - 3 ] found a positive association between accumulated visceral adipose tissue and systolic BP in midlife-aged women, independent of burdens of inflammatory markers. Intriguingly, Haze et al. [ 131 ] clearly demonstrated that an increased ratio of visceral-to subcutaneous fat volume was an independent risk factor for renal dysfunction in Japanese patients with primary aldosteronism. These findings should highlight the clinical importance and the need for further research to explore surrogate markers of obesity in the care of hypertension and its related conditions (Fig.  8 ).

Finally, we briefly introduce some exciting progress in vascular function in the area of “Obesity/Diabetes” (Fig.  8 ). Murai et al. [ 132 ] elegantly showed that postload hyperinsulinemia was independently associated with increased arterial stiffness as assessed by brachial-ankle pulse wave velocity (PWV) in young medical students at Jichi Medical University. Given the close pathological relationship between hyperinsulinemia and most CVDs, including heart failure [ 133 , 134 ], their findings suggest that hyperinsulinemia-induced vascular failure is one of the key drivers of that pathological link. Interestingly, Fryer et al. from the UK [Supplementary Information  8 - 4 ] also found that arterial stiffness as assessed by carotid-femoral PWV was exacerbated by the consumption of a high-fat meal relative to a low-fat meal prior to 180 min of uninterrupted sitting. Importantly, arterial stiffness testing could accurately reflect even such a combination of unfavorable behaviors, and thus vascular function assessment has the potential to reflect a wide spectrum of cardiovascular risk and provide a clinical opportunity for better risk stratification and optimal modification [ 135 ]. We look forward to accumulating and consolidating evidence of vascular function tests and further applying them to actual cardiovascular care [ 136 ].

(AT and KN)

Keywords : glucose-lowering agent, resistant hypertension, statin, surrogate marker, vascular function

A new era of progress in primary aldosteronism treatment: mineralocorticoid receptor antagonists, a new aldosterone assay, and a clinical practice guideline (See Supplementary Information 9 )

A hot topic in 2021 was advances in the treatment of mineralocorticoid receptor (MR)-associated hypertension [ 137 ], particularly primary aldosteronism (PA). The nonsteroidal MR antagonist (MRA) esaxerenone is now widely used in Japan. Kario et al. [ 138 ] reported that esaxerenone reduced nocturnal blood pressure in patients with essential hypertension, according to ambulatory blood pressure assessment and N-terminal pro-brain natriuretic peptide assays. Yoshida et al. [ 139 ] reported that MRAs such as esaxerenone improved quality of life in PA patients. Ito et al. [ 140 ] reported that add-on treatment using esaxerenone with maximal tolerable doses of a renin-angiotensin system (RAS) inhibitor reduced the urinary albumin-creatinine ratio in patients with type 2 diabetes mellitus (ESAX-DN), suggesting a renoprotective effect against diabetic nephropathy. Several clinical studies of another nonsteroidal MRA, finerenone (FIDELIO-DKD [ 141 ], FIGARO-DKD [ 142 ], and FIDELITY [ 143 ]), have shown its renoprotective effect against diabetic nephropathy as well as cardiovascular events, particularly hospitalization for heart failure in patients with type 2 diabetes and chronic kidney disease. Although there are no reports of clinical studies on finerenone for PA, finerenone may be used in the future for type 2 diabetes patients with PA, as obesity, glucose intolerance, and sleep apnea are common complications in patients with PA [ 144 ]. Similarly, sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to improve the prognosis of cardiovascular disease and chronic kidney disease in individuals with type 2 diabetes (EMPA-REG OUTCOME [ 145 ], DECLARE–TIMI 58 [ 146 ], DAPA-HF[ 147 ], and DAPA-CKD [ 22 ]). As steroidal MRAs such as spironolactone and eplerenone are effective in the treatment of mild to severe stages of heart failure (RALES, EPHESUS [ 148 ], and EPHESUS-HF [ 149 ]), combined treatment with MRA and SGLT2i, in addition to an RAS inhibitor, may be a novel effective treatment for cardiac and renal protection in type 2 diabetic patients (Fig.  9 ). Second, radiofrequency ablation of macroscopic adrenal tumors [ 150 , 151 , 152 ] has been reported as an alternative treatment for PA to lower blood pressure and plasma aldosterone levels. This treatment has been covered by health insurance providers in Japan since April 2022, but long-term outcomes need to be validated.

Potential drug therapy regimen. Combined administration of an MRA and an SGLT2i may afford cardiac and renal protection. MRA mineralocorticoid receptor antagonist, SGLT2i sodium–glucose cotransporter 2 inhibitor

Another hot topic was the launch of serum aldosterone measurement using a chemiluminescent enzyme immunoassay (CLEIA), which utilizes a two-step sandwich method. Previously, low aldosterone levels may have been measured incorrectly [ 153 ]. The new CLEIA figures are closely correlated with liquid chromatography/tandem mass spectrometry values; the new assay is more accurate than the previous radioimmunoassay, which overestimated serum aldosterone levels [ 154 , 155 , 156 ]. Thus, the Japan Endocrine Society issued a Primary Aldosteronism Clinical Guideline in 2021 [ 157 ]. The CLEIA method is also used to measure urinary aldosterone levels; Ozeki et al. [ 158 ] proposed a PA diagnostic cutoff of ≥3 μg/day for the oral salt loading test. The CLEIA method is currently available only in Japan.

Exosomes may serve as biomarkers of MR activity. Ochiai-Homma et al. [ 159 ] focused on pendrin, a Cl – /HCO3 – exchanger that is only expressed by renal intercalated cells. In a rat model, the pendrin level in the urinary exosome was reduced by therapeutic interventions favored for PA patients; the urinary level was correlated with the renal level. This model may help to elucidate the pathophysiology of PA-induced organ injury [ 160 ].

Finally, Haze et al. [Supplementary Information  9 - 1 ], Segawa et al. [Supplementary Information  9 - 2 ], Nishimoto et al. [Supplementary Information  9 - 3 ], Chen et al. [Supplementary Information  9 - 4 ], and Liu et al. [Supplementary Information  9 - 5 ] have conducted intriguing clinical studies regarding PA.

(YY and HS)

Keywords : mineralocorticoid receptor-associated hypertension, mineralocorticoid receptor antagonist, hypertension, primary aldosteronism, chemiluminescent enzyme immunoassay

Advances in renal denervation for treating hypertension: current evidence and future perspectives (See Supplementary Information 10 )

It is well established that renal denervation (RDN) decreases blood pressure (BP) in various models of hypertension in animals and in humans [ 161 , 162 , 163 , 164 , 165 ]. Here, we reviewed studies related to RDN published in Hypertension Research in 2021 (Fig.  10 ). The antihypertensive effect of RDN is mediated by interrupting both the efferent outputs from the brain to the kidney and the afferent inputs from the kidney to the brain, suppressing systemic sympathetic outflow [ 165 , 166 ]. In basic research, there are two methods of RDN: total RDN (TRDN) performed by surgical cutting of renal nerves to ablate both efferent and afferent nerves and selective afferent RDN (ARDN) performed via capsaicin application to renal nerves to specifically ablate afferent nerves expressing capsaicin receptors [ 167 , 168 ]. Katsurada et al. [ 169 ] reviewed previous reports that address the different effects of TRDN and ARDN in different animal models of hypertension, suggesting potentially complicated and diversified origins of hypertension. The potential therapeutic effects of TRDN and ARDN have also been reported in animal models of heart failure [ 170 ].

Topics on renal denervation. BP blood pressure, RDN renal denervation

In clinical practice, radiofrequency, ultrasound, and alcohol-based RDN devices have been developed as second-generation catheter devices and evaluated in randomized control trials. Ogoyama et al. [ 171 ] reported a meta-analysis of nine randomized sham-controlled trials of RDN that showed that RDN significantly reduced a range of office, home and 24 h BP parameters in patients with resistant, uncontrolled, and drug-naïve hypertension. There were no significant differences in the magnitude of BP reduction between radiofrequency-based and ultrasound-based devices.

The Global SYMPLICITY Registry (GSR) is a prospective all-comer registry to evaluate the safety and efficacy of RDN in a real-world population [ 172 ]. The overall GSR has enrolled over 2700 patients, and more than 2300 of these have now been followed for 3 years [ 173 ]. GSR Korea is a Korean registry substudy of GSR ( N  = 102) [ 174 ]. Kim et al. [Supplementary Information  10 - 1 ] reported the 3-year follow-up outcomes from the GSR Korea showing that RDN led to sustained reductions in office systolic BP at 12, 24 and 36 months (−26.7 ± 18.5, −30.1 ± 21.6, and −32.5 ± 18.8 mmHg, respectively) without safety concerns. Recently, the efficacy and safety of second-generation radiofrequency RDN up to 36 months have been reported [ 175 ].

The REQUIRE trial by Kario et al. [Supplementary Information  10 - 2 ] is the first trial of ultrasound RDN in Asian patients from Japan and South Korea with hypertension receiving antihypertensive therapy. The study findings were neutral for the primary endpoint, with similar reductions in 24 h systolic BP at 3 months in the RDN (−6.6 mmHg) and sham control groups (−6.5 mmHg). Although BP reduction after RDN was similar to other sham-controlled studies [ 161 , 162 , 164 , 176 ], the sham group in this study showed much greater reduction. Unlike RADIANCE-HTN TRIO that used an ultrasound catheter system to measure its primary endpoint, REQUIRE did not standardize medications or measure medication adherence, which may lead to increased variability in BP outcome; moreover, REQUIRE was not a double-blind study, which may result in a substantial bias. Another important factor is that 32.4% of patients showed hyperaldosteronism in the REQUIRE trial. Patients with primary aldosteronism have decreased sympathetic nerve activity and are likely to respond poorly to RDN [ 177 ]. The lessons from REQUIRE will enable us to design a follow-up trial to make a definitive evaluation of the effectiveness of RDN in Asian patients with hypertension.

Another topic is the patient preference for RDN. Kario et al. [Supplementary Information  10 - 3 ] conducted a nationwide web-based survey in Japan and reported that preference for RDN was expressed by 755 of 2392 Japanese patients (31.6%) and was higher in males, in younger patients, in those with higher BP, in patients who were less adherent to antihypertensive drug therapy, in those who had antihypertensive drug-related side effects, and in those with comorbid heart failure. This should be taken into account when making shared decisions about antihypertensive therapy.

Keywords : renal nerves, hypertension, renal denervation, patient preference, heart failure

Hot topics in uric acid research: the difficulties of managing hyperuricemia (See Supplementary Information 11 )

The mechanisms linking hyperuricemia, arteriosclerosis, hypertension, chronic kidney disease, and cardiovascular disease are becoming clearer (Fig.  11 ) [ 178 , 179 , 180 , 181 ]. However, it remains unclear whether treatment of hyperuricemia improves these diseases. Some recent topics of uric acid research are introduced below.

Mechanisms linking hyperuricemia and arteriosclerosis, hypertension, chronic kidney disease, and cardiovascular disease. ATP adenosine triphosphate, CKD chronic kidney disease

First, urate-lowering treatment with allopurinol, a xanthine oxidase (XO) inhibitor, did not slow the decline in eGFR compared with placebo in either the PERL (Preventing Early Renal Loss in Diabetes) trial [ 182 ] or CKD-FIX (Controlled Trial of Slowing of Kidney Disease Progression from the Inhibition of Xanthine Oxidase) [ 183 ]. These results were similar to the results of FEATHER (Febuxostat Versus Placebo Randomized Controlled Trial Regarding Reduced Renal Function in Patients with Hyperuricemia Complicated by Chronic Kidney Disease Stage 3) from Japan [ 184 ]. Moreover, the PRIZE (Program of Vascular Evaluation Under Uric Acid Control by the Xanthine Oxidase Inhibitor Febuxostat: Multicenter, Randomized, Controlled) study showed that febuxostat did not delay the progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia [ 185 ]. These results suggest the difficulties of managing hyperuricemia for preventing chronic kidney disease (CKD) and/or arteriosclerosis.

Second, FAST (the Febuxostat versus Allopurinol Streamlined Trial) showed that febuxostat was noninferior to allopurinol therapy with respect to the primary cardiovascular endpoint, all-cause or cardiovascular deaths [ 186 ]. The results of FAST were different from the results of the CARES (The Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities) trial [ 187 ], and the authors summarized that regulatory advice to avoid the use of febuxostat in patients with cardiovascular disease should be reconsidered and modified [ 186 ].

In Hypertension Research 2021, several important articles on uric acid research were published. Mori et al. reported that a high serum uric acid level is associated with an increase in systolic blood pressure in women but not in men in subjects who underwent annual health checkups [ 188 ]. Their group also reported that a low uric acid level is a significant risk factor for CKD over 10 years in only women, and an elevated UA level increases the risk of CKD in both sexes [Supplementary Information  11 - 1 ]. Moreover, Li et al. reported that elevated serum uric acid levels in subjects without stroke, coronary heart disease, and medication for hyperuricemia or gout aged 40–79 years were independent predictors of total stroke, especially ischemic stroke, in women but not in men in a 10-year cohort study [Supplementary Information  11 - 2 ]. These results suggested the possibility that both hyperuricemia and hypouricemia in women could be associated with a higher risk for hypertension, CKD, and stroke than those in men.

Azegami et al. reported a prediction model of high blood pressure in young adults aged 12–13 years followed up for an average of 8.6 years. The results showed that uric acid was an important predictor of high blood pressure [ 189 ].

Kawasoe et al. reported that high (4.1–5.0, 5.1–6.0, and >/=6.1 mg/dL) and low (</=2.0 mg/dL) serum uric acid levels were significantly associated with an increased prevalence of high blood pressure compared to 2.1–4.0 mg/dL serum uric acid in subjects who underwent health checkups [ 190 ]. The results were compatible with a previous report stratified by sex [ 191 ]. Serum uric acid levels and the risks for diseases are largely different between men and women, and it is desirable to conduct every analysis by sex when conducting uric acid research.

Furuhashi et al. reported that plasma xanthine oxidoreductase (XOR) activity was associated with hypertension in 271 nondiabetic subjects in the Tanno–Sobetsu Study [ 192 ]. Kusunose et al. reported that additional febuxostat treatment in patients with asymptomatic hyperuricemia for 24 months might have potential prevention effects on impaired diastolic dysfunction in the subanalysis of the PRIZE study [ 193 ]. These reports suggested the potential direct antioxidant effects of the treatment as reflected in serum uric acid levels as well as its xanthine-oxidase-lowering properties in tissue [Supplementary Information  11 - 3 ]. Whether the preferential use of xanthine oxidoreductase XO inhibitors becomes a new therapeutic strategy for the prevention of cardiovascular disease in patients with asymptomatic hyperuricemia awaits further high-quality trials [Supplementary Information  11 - 4 ].

Finally, Nishizawa et al. reported a mini review article focusing on the relationship between hyperuricemia and CKD or cardiovascular diseases, and they summarized that high-quality and detailed clinical and basic science studies of hyperuricemia and purine metabolism are needed [Supplementary Information  11 - 5 ].

(MK and TK)

Keywords : uric acid, cardiovascular disease, chronic kidney disease, arteriosclerosis, xanthine oxidase

Basic research: elucidation of the “mosaic” pathogenesis of hypertension (See Supplementary Information 12 )

The pathogenesis of hypertension is multifactorial and highly complex, as described by the “mosaic theory” of hypertension. Basic research plays critical roles in elucidating the “mosaic” pathogenesis of hypertension and developing its treatment (Fig.  12 ).

Topics in basic research. Each ref. number indicates the reference paper cited in the text. AT1R angiotensin type 1 receptor, EV extracellular vesicles, KO knockout, RAS renin-angiotensin system, Snx1 soring nexin 1, SIRT6 sirtuin 6, TWIST1 twist-related protein 1

In the field of the brain and autonomic nervous system, Chen et al. demonstrated that mild cold exposure elicits autonomic dysregulation, such as increased sympathetic activity, decreased baroreflex sensitivity, and poor sleep quality, causing blood pressure (BP) elevation in normotensive rats [ 194 ]. This finding may have critical implications for cardiovascular event occurrence at low ambient temperatures. In addition, Domingos-Souza et al. showed that the ability of baroreflex activation to modulate hemodynamics and induce lasting vascular adaptation is critically dependent on the electrical parameters and duration of carotid sinus stimulation in spontaneously hypertensive rats (SHRs) [ 195 ], proposing a rationale for improving baroreflex activation therapy in humans. Although only normotensive and hypertensive rats were used in these two studies, without comparing the two strains, previous studies have shown that neuronal function and activity in the cardiovascular sympathoregulatory nuclei, including the nucleus tractus solitarius and rostral ventrolateral medulla, which are involved in baroreflex regulation, are different between normotensive and hypertensive rats [ 196 , 197 ]. Further studies comparing normotensive and various hypertensive animal models would be interesting.

In the kidney, Kasacka et al. showed that the activity of the Wnt/β-catenin pathway is increased in SHRs and two-kidney, one-clip (2K1C) hypertensive rats, while it is inhibited in deoxycorticosterone acetate (DOCA)-salt rats according to kidney immunohistochemistry [ 198 ]. The intrarenal renin-angiotensin system (RAS) is also involved in BP regulation. In renal damage with an impaired glomerular filtration barrier, liver-derived angiotensinogen filtered through damaged glomeruli regulates intrarenal RAS activity [ 199 ]. Matsuyama et al. further showed that the glomerular filtration of liver-derived angiotensinogen depending on glomerular capillary pressure causes circadian rhythm of the intrarenal RAS with in vivo imaging using multiphoton microscopy [ 200 ]. Fukuda and his colleagues have shown that complement 3 (C3) is a primary factor that activates intrarenal RAS [Supplementary Information  12 - 1 , 2 ]. Otsuki and Fukuda et al. additionally demonstrated that TWIST1, a transcription factor that regulates mesodermal embryogenesis, transcriptionally upregulates C3 in glomerular mesangial cells from SHRs [ 201 ].

The RAS in the vascular system, as well as in other organ systems, plays a major role in BP regulation. Soring nexins (SNXs) are cellular sorting proteins that can regulate the expression and function of G protein-coupled receptors (GPCRs) [Supplementary Information  12 - 3 , 4 , 5 ]. Liu C et al. demonstrated that SNX1 knockout mice exhibit hypertension through vasoconstriction mediated by increased expression of AT1R, a GPCR mediating most of the effects of angiotensin II (Ang II), within the arteries [ 202 ]. Moreover, in vitro studies suggest that SNX1 sorts arterial AT1R for proteasomal degradation. These findings indicate that SNX1 impairment increases arterial AT1R expression, leading to vasoconstriction and hypertension. Liu X et al. found that sirtuin 6 (SIRT6) expression is downregulated in the aortae of aged rats and showed that SIRT6 knockdown enhances Ang II-induced vascular adventitial aging by activating the NF-κB pathway in vitro [ 203 ]. This study suggests that SIRT6 may be a biomarker of vascular aging and that activating SIRT6 can be a therapeutic strategy for delaying vascular aging.

Several reports indicate the potential treatment for hypertension and the associated organ damage. Narita et al. showed that rivaroxaban exerts a protective effect against cardiac hypertrophy by inhibiting protease-activated receptor-2 signaling in renin-overexpressing hypertensive mice [Supplementary Information  12 - 6 ]. In addition, the efficacy of nebivolol (a third-generation β-blocker), maximakinin (a bradykinin agonist peptide extracted from the skin venom of toad), and Pinggan-Qianyang decoction (a traditional Chinese medicine) were also shown in hypertensive animal models [Supplementary Information  12 - 7 , 8 , 9 ]. In animal models of gestational hypertension, melatonin and crocin have each exhibited an antihypertensive effect [Supplementary Information  12 - 10 , 11 ].

Studies investigating extracellular vesicles (EVs) have increased. Ochiai-Homma et al. showed that pendrin in urinary EVs can be a useful biomarker for the diagnosis and treatment of primary aldosteronism, which was supported by studies using a rat model of aldosterone excess [ 159 ]. Another report indicated that pulmonary arterial hypertension induces the release of circulating EVs with oxidative content and alters redox and mitochondrial homeostasis in the brains of rats [Supplementary Information  12 - 12 ]. Studies on the role of gut microbiota in BP regulation have also been accumulating. Wu et al. demonstrated that captopril has the potential to rebalance the dysbiotic gut microbiota of DOCA-salt hypertensive rats, suggesting that the alteration of the gut flora by captopril may contribute to the hypotensive effect of this drug [ 204 ]. Moreover, important basic studies, including review papers, have been reported in Hypertension Research. See Supplementary Information.

Keywords : autonomic nervous system, kidney, vascular system, renin-angiotensin system, extracellular vesicles, gut microbiota.

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Masaki Mogi

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Mogi, M., Maruhashi, T., Higashi, Y. et al. Update on Hypertension Research in 2021. Hypertens Res 45 , 1276–1297 (2022). https://doi.org/10.1038/s41440-022-00967-4

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• Published: 15 September 2020

Treatment adherence among patients with hypertension: findings from a cross-sectional study

• Fahad M. Algabbani 1 &
• Aljoharah M. Algabbani 2  

Clinical Hypertension volume  26 , Article number:  18 ( 2020 ) Cite this article

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Metrics details

Hypertension is a major risk factor for cardiovascular disease, which is the leading cause of mortality globally. Patient’s adherence to treatment is a cornerstone factor in controlling hypertension and its complications. This study assesses hypertension patients’ adherence to treatment and its associated factors.

This cross-sectional study conducted in Riyadh, Saudi Arabia. The study targeted outpatients aged ≥18 years who were diagnosed with hypertension. Participants were recruited using a systemic sampling technique. The two main measurements were assessing adherence rate of antihypertensive medications using Morisky scale and identifying predictors of poor medication adherence among hypertensive patients including socio-economic and demographic data, health status, clinic visits, medication side effects, medications availability, and knowledge. Descriptive and logistic regression analyses were performed to assess factors associated with poor adherence.

A total of 306 hypertensive outpatients participated in this study. 42.2% of participants were adherent to antihypertensive medications. Almost half of participants (49%) who reported having no comorbidities were adherent to antihypertensive medications compared to participants with one or more than one comorbidities 41, 39% respectively. The presence of comorbid conditions and being on multiple medications were significantly associated with medication adherence ( P -values, respectively, < 0.004, < 0.009). Patients with good knowledge about the disease and its complications were seven times more likely to have good adherence to medication ( P  <  0.001).

Conclusions

Non-adherence to medications is prevalent among a proportion of hypertensive patients which urges continuous monitoring to medication adherence with special attention to at risks groups of patients. Patients with comorbidities and on multiple medications were at high risk of medication non-adherence. Patients’ knowledge on the disease was one of the main associated factors with non-adherence.

Hypertension is one of the most common chronic diseases in Saudi Arabia and a rising health burden, affecting 26.1% adult population [ 1 ]. Hypertension is a major risk factor for heart failure, myocardial infarction, cerebrovascular disease, and renal failure [ 2 ]. Controlling hypertension reduces the risk of cerebrovascular accident (CVA), coronary heart disease, congestive heart failure, and mortality [ 2 , 3 ]. There are several factors that affect blood pressure control. Patients’ adherence to treatment is one of the major factors in controlling blood pressure and preventing hypertension complications [ 3 ]. The World Health Organization (WHO) defines adherence to long-term therapy as “the extent to which a person’s behavior-taking medication, following a diet, and/or executing lifestyle changes-corresponds with agreed recommendations from a healthcare provider” [ 3 ]. Patients with a high level of medication adherence were found to have better blood pressure control [ 4 ]. Still, adherence to hypertension treatment is challenging, due to the asymptomatic nature of the disease [ 5 ].

Several studies investigated the adherence rate among hypertension patients and sociodemographic factors affecting medication adherence including age, gender, comorbidities, patients’ knowledge about the disease, the number of medications. A study conducted in Saudi Arabia showed that only 34.7% of male hypertensive patients were found to be adherent to their medication [ 6 ]. The study reported a negative association between the presence of comorbidities and the adherence level [ 6 ]. A cross-sectional study on medication adherence among patients with hypertension in Malaysia, found an association between adherence and good knowledge of the medications and disease [ 7 ]. The study also found that the increase in the number of drugs patients taking has a negative effect on medication adherence [ 7 ]. Other studies had similar findings regarding the association between the number of medications and adherence [ 8 , 9 , 10 ]. In a cross-sectional study conducted in Iran, older patients reported high adherence to antihypertensive medication and better knowledge of their disease than younger patients [ 9 ]. However, number of studies reported no significant associations between age and medication adherence [ 8 , 11 ]. Female patients were more likely to adhere to their medication, compared to males [ 12 ]. Another study on the prevalence and predictors of poor antihypertensive reported that male patients were more adherent than female patients [ 13 ]. Some studies reported no relationship between gender and adherence [ 9 , 11 ].

Educational level and health literacy were shown to be associated with medication adherence. A cross-sectional study conducted in Iraq showed that adherence decreased in patients with primary and secondary school education, while no significant difference among patients with higher education and undereducated patients [ 14 ]. Similar results found in a systematic review conducted in hypertension management and medication adherence [ 15 ]. On the other hand, no association between educational level and adherence was found in a study conducted in Saudi Arabia [ 8 ]. However, good health knowledge of hypertension shown to be associated with good adherence to medication treatment in several studies [ 7 , 11 ]. Two cross-sectional studies conducted in Turkey and Algeria showed a significant association between knowledge of complications related to hypertension and good adherence to antihypertensive therapy [ 16 , 17 ].

Hypertension is one of the major health issues in Saudi Arabia; affecting more than a quarter of the Saudi adult population [ 1 ]. Only 37% of hypertensive patients on medication have their blood pressure controlled [ 18 ]. Non-adherence to antihypertensive medications is a potential contributing factor to uncontrolled hypertension. With limited studies conducted to investigate this challenging issue, this cross-sectional study aims to assess the adherence rate among hypertensive patients and associated factors affecting adherence to antihypertensive medications.

Study design and sampling

This cross-sectional study was conducted to determine the adherence rate of antihypertensive medications and the predictors of poor medication adherence among hypertensive patients at primary health clinics (PHCs) in Prince Sultan Medical City (PSMMC) in Riyadh the capital city of Saudi Arabia. Single population proportion formula was used to calculate the sample size based on the prevalence of hypertension in Saudi Arabia (26.1%) [ 1 ]. With a 95% confidence level and a 5% margin of error, a total of 306 randomly selected outpatients with hypertension following up at primary health clinics were included in this study.

Participants recruitment

Participants in this study were recruited using a systemic sampling technique. Every fourth consecutive patient who fits the criteria was included. Arabic speaker patients older than 18 years who have been diagnosed with hypertension for more than three months were included in this study. Patients who do not speak Arabic had mental retardation, secondary hypertension, or who were younger than 18 years old were excluded from the study. The data was collected using a self-administered questionnaire that was distributed in the waiting area of the pharmacy. Illiterate participants were interviewed by a trained data collector. Before participants’ recruitment in the study, informed consent was obtained from all patients after a full explanation of the study. The study was approved and supervised by the institution review board (IRB) of Prince Sultan Medical City.

Measurements

The questionnaire consists of four main sections. The first section assesses participants’ socio-economic factors including age, gender, marital status, occupation, the highest level of education currently attained, occupation, and monthly income. The second section assesses the factors affecting medication adherence including comorbidities, number of medications, number of daily doses, number of clinic visits, the distance to the clinic, medication side effects, medication availability at the pharmacy. The third section aimed to assess patients’ adherence to treatment. The fourth part assesses the patients’ knowledge about hypertension.

Medication adherence was assessed using the 8- items Morisky scale [ 19 ]. Morisky scale has been validated and found to be reliable (α = .83) [ 20 ]. The scale is based on the patients’ self-response and consists of eight questions, seven items with yes or no response, and one item with a 5-point Likert scale response option. The total score ranges from 1 to 8, the patient whose adherence score was six or more is considered adherent. For linguistic validation, questions were translated forward and backward into Arabic by an independent translator.

The participant’s knowledge about hypertension was assessed using nine structured questions. The questions focused on different aspects of hypertension, namely blood pressure target, lifestyle modification effect, complications, treatment, and cure. During analysis, patients who answered < 70% were considered to have low knowledge and patient how answered ≥70% of the questions were considered to have good knowledge. The 70 % cut-off is based on the minimally acceptable level of quality control at PSMMC [ 21 ].

The questionnaire was pre-tested and then a pilot survey was conducted on 20 patients for clarity and feasibility. The questionnaire was also evaluated and reviewed by two independent family medicine consultants at Prince Sultan Medical City for validation.

Data analysis

Frequencies and percentages were used to assess participants’ characteristics. Chi-square analysis was used to determine the association between demographic, socioeconomic, and clinical factors with medication adherence. Logistic regression analysis was performed to assess factors associated with poor adherence. The variables were analyzed collectively using logistic regression to study the potential factors to avoid confounding bias. The association was considered statistically significant if the P -value was less than 0.05. Statistical Package for Social Sciences version 25 and Statistical Analysis System version 9.4 was used for data analysis.

A total of 306 outpatients who have hypertension participated in this study. Approximately 43% of the participants’ ages range was between 56 and 65. The majority of participants were married (92%), employed (61%), and had a high school diploma or above (80%). Most of the participants were middle income in the 5000–10,000 Saudi Riyal range of monthly income. Nearly one-third (28.1%) of the respondents in this study had no comorbidities while two-thirds reported having one or more comorbidities. The demographic, and socioeconomic clinical characteristics of the participants are presented in Table  1 .

Only 13% of the respondents live at a distance of less than half an hour from the clinic. Of the total participants, 14.1% reported visiting the primary health clinic once in the last year, 29.4% twice, 24.2% three times. The majority of participants reported taking less than four medications a day and 31.4% reported taking four or more medications a day. As to antihypertensive medication side effects, 19.6% reported having medication side effects. Only 4.9% of the participants reported that they stop taking their antihypertensive medications when they get sick. Approximately 9% of the participants reported that they stop taking their medications when it is not available at the pharmacy. Findings show that half (50.7%) of the participants were knowledgeable about the disease. The clinical characteristics of the participants are presented in Table 1 .

Figure  1 presents the percentage of participants’ adherence to antihypertensive treatment. Based on Morisky scale test results, 42.2% of the participants in this study were adherent to antihypertensive medications, while 57.8% were not adherent.

Distribution of patients according to their medication adherence status*

Table  2 presents the adherence rate in relation to the participants’ demographic, socioeconomic, and clinical characteristics. The presence of comorbid conditions is significantly associated with medication adherence ( P  <  0.001). Almost half of participants (49%) who reported having no comorbidities were adherent to antihypertensive medications compared to the participants with one or more than one comorbidities 41, 39% respectively. As for the number of medications, the adherence rate was found to be better among patients who were taking less than four medications (47.1%) compared to patients who were taking four or more medications (31.3%). Patients who visited the clinic once in the last year were more adherent than those who visited the clinic more than once ( p  < 0.05). No significant association between age, gender, income, educational level, and distance from home to the clinic.

The participants were asked eight questions about hypertension. Table  3 shows the distribution of the correct and incorrect answers giving by the participants. Most participants (64.4%) knew the target blood pressure for hypertensive patients and 40.8% think that hypertension can be cured. The majority (78%) knew that a low salt diet helps in lowering high blood pressure. Only 61% knew that hypertension can affect eyes and 13.4% reported that they stop taking their medication when they feel their blood pressure under control.

Adherence to antihypertensive medications among patients with good and poor knowledge levels about hypertension was assessed based on nine structured questions. Figure  2 shows the adherence to hypertension treatment among patients with good and poor knowledge level. 57.4% of patients with good knowledge levels were adherent compared to 42.6% who were not adherent. The majority (73.5%) of patients with poor knowledge levels were not adherent to treatment.

Adherence to hypertension treatment among patients with good and poor knowledge level*

Table  4 presents the factors associated with good adherence. When conducting binary logistic regression, knowledge about the disease was found to be significantly associated with adherence. Patients with good knowledge about the disease were seven times more likely to have good adherence to antihypertensive medications than those with poor knowledge (AOR 7.4 [95% CI: 4.177–13.121], p  < 0.001).

Several studies have investigated factors affecting medication adherence. This study shows that the level of adherence to antihypertensive medications is low. In this sample the adherence rate to hypertension treatment was found to be only 42%, which is similar to the study conducted in Al-Khobar and higher than the study conducted in Taif where adherence rate was found to be 47 and 34.7%, respectively [ 6 , 8 ]. Other studies conducted in different countries reported adherence rates ranging from 15 to 88% [ 22 , 23 , 24 , 25 ]. This discrepancy in adherence rate is potentially due to the differences in population characteristics, medication adherence assessment tools, and healthcare systems.

The association between sociodemographic and socioeconomic factors and adherence level has been investigated in several studies. In a study done in Hong Kong, older patients were found to be more adherent. However, in this study, there was no association between age and adherence. In another study done in the United States, female patients were less adherent to hypertension medication compared to male patients [ 13 ]. A study conducted in Malaysia reported that female patients were more adherent than male patients [ 22 ]. Our study showed that there was no significant relationship between gender and adherence. A meta-analysis suggested that the association between age, gender, and adherence level is weak [ 26 ]. The results of our study also demonstrate no significant relationship between marital status and educational level with adherence, which is similar to findings reported by other studies [ 9 , 27 ].

Previous research found that shorter traveling time from residence to the healthcare facility could increase patients’ adherence [ 28 ]. A study in Ethiopia found that the adherence level was lower in patients who lived more than 10 km from healthcare facilities [ 29 ]. A cross-sectional observational study done in Northwest Ethiopia indicated that patients who live less than 10 km from the healthcare facility had an adherence rate of 74% compared to 58% for patients who live far from the healthcare facility [ 29 ]. As the authors attributed this problem to poor infrastructure and lack of transportation in Ethiopia, the study suggested that shorter traveling time from residence to the healthcare facility could increase patients’ adherence [ 29 ]. In this study, distance from home to the clinic was not associated with hypertensive treatment. These differences may be due to the higher level of car ownership in Saudis Arabia which makes it easier to access health care facilities [ 30 ].

Only 8.8% of the participants reported not taking their medication when it is not available at the hospital pharmacy. This low percentage may be explained by the multiple community health centers in Saudi Arabia which provide free health care including medications dispensing. Moreover, the medication cost at private pharmacies in Saudi Arabia is affordable for most patients. According to the published Saudi Hypertension Management Guidelines the prices of the antihypertensive medications ranges between 7 to 118 Saudi Riyal (about 2 to 31 US Dollar) [ 31 ].

Many patients with hypertension will need two or more antihypertensive medications to achieve goal blood pressure [ 2 ]. In this sample significant association was observed between the number of medications and adherence level. The adherence rate among patients taking less than four medications was 47.1% compared to 31.3% to those who take four or more medications. Similarly, other studies reported the negative association between the number of medication and adherence levels [ 29 , 32 ].

Findings indicate that patients with multiple comorbidities were less adherent to antihypertensive medication, which is inconsistent with a previous study done in Taif which showed a negative association between the presence of comorbidity and adherence level [ 6 ]. This may be related to the fact that most patients with multiple comorbidities require taking multiple complex medications.

The result of our study showed that the patient who visited the clinic once in the last year were more adherent than the patient who visited the clinic more than once. This could be explained by that most patients with multiple comorbidities and on multiple medications frequently visit the clinic for issues related to their disease and to refill prescriptions.

Our study demonstrated the positive association between knowledge and adherence levels. Patients who had good knowledge were more adherent to the treatment [ 29 ]. Previous studies showed that patients who know the ideal target blood pressure level were more adherent to their medications [ 16 , 20 ]. In this study, only 64.4% of the participants knew the ideal target of blood pressure and 40.8% of the patients believe that hypertension can be cured. A study conducted in Rajshahi, Bangladesh found that 65.8% of the patients believe that hypertension is curable. Patients how have been educated by their physicians and healthcare providers were more adherents to treatment as they have a better understanding of the disease nature, the ideal target of blood pressure, and the complications of hypertension [ 33 ]. Therefore, patient education in disease nature and management is considered a key factor in the treatment of hypertension.

The study findings were based on self-reported survey. Self-reported data is a common method used in a cross-sectional study. However, self-reported data is subjected to biases such as response and recall biases that can lead to under- or overestimation of findings. On the other hand, adherence in this study was measured based on a validated self-report adherence scale and knowledge was tested based on evaluated and reviewed assessment items by two independent family medicine consultants. Moreover, this study conducted in one of the largest medical cities that serves a large community in the capital city Riyadh. Due to the study design and sampling method, study findings cannot be generalized and temporal relationships cannot be established between risk factors and adherence. Nevertheless, this study provides a snapshot of adherence to antihypertensive medication status and associated determinates among outpatients. Future large scale longitudinal studies will contribute to a better understanding of adherence status and associated factors among hypertensive patients.

Non-adherence to medications is prevalent in proportion of patients with hypertension. Therefore, there is an urge to continually monitor patients’ adherence to antihypertensive medication using a standardized scale. Patients with comorbidities and on multiple medications were at higher risk of non-adherence. There is a need to encourage patients on multiple medications to use adherence aids such as weekly pill organizers and medication alarm devices. Hypertensive patients’ knowledge of the disease and its complications was one of the main factors affecting patients’ adherence to treatment. Implementation of health awareness interventions and education programs intended for hypertensive patients will help improve medication adherence.

Availability of data and materials

The data sets generated during and/or analyzed during the current study are available from the corresponding authors on reasonable request.

Abbreviations

Adjusted odd ratio

Confidence interval

Blood pressure

Prince Sultan Medical City

primary health clinic

institution review board

Cerebrovascular accident

The World Health Organization

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The study design was conceptualized by FA and AA. Data collection was managed by FA and data analysis and interpretation were conducted by FA and AA. All authors participated in writing and editing the manuscript. All authors read and approved the final manuscript.

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Algabbani, F.M., Algabbani, A.M. Treatment adherence among patients with hypertension: findings from a cross-sectional study. Clin Hypertens 26 , 18 (2020). https://doi.org/10.1186/s40885-020-00151-1

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Evan M. Benjamin; Case Study: Treating Hypertension in Patients With Diabetes. Clin Diabetes 1 July 2004; 22 (3): 137–138. https://doi.org/10.2337/diaclin.22.3.137

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L.N. is a 49-year-old white woman with a history of type 2 diabetes,obesity, hypertension, and migraine headaches. The patient was diagnosed with type 2 diabetes 9 years ago when she presented with mild polyuria and polydipsia. L.N. is 5′4″ and has always been on the large side,with her weight fluctuating between 165 and 185 lb.

Initial treatment for her diabetes consisted of an oral sulfonylurea with the rapid addition of metformin. Her diabetes has been under fair control with a most recent hemoglobin A 1c of 7.4%.

Hypertension was diagnosed 5 years ago when blood pressure (BP) measured in the office was noted to be consistently elevated in the range of 160/90 mmHg on three occasions. L.N. was initially treated with lisinopril, starting at 10 mg daily and increasing to 20 mg daily, yet her BP control has fluctuated.

One year ago, microalbuminuria was detected on an annual urine screen, with 1,943 mg/dl of microalbumin identified on a spot urine sample. L.N. comes into the office today for her usual follow-up visit for diabetes. Physical examination reveals an obese woman with a BP of 154/86 mmHg and a pulse of 78 bpm.

What are the effects of controlling BP in people with diabetes?

What is the target BP for patients with diabetes and hypertension?

Which antihypertensive agents are recommended for patients with diabetes?

Diabetes mellitus is a major risk factor for cardiovascular disease (CVD). Approximately two-thirds of people with diabetes die from complications of CVD. Nearly half of middle-aged people with diabetes have evidence of coronary artery disease (CAD), compared with only one-fourth of people without diabetes in similar populations.

Patients with diabetes are prone to a number of cardiovascular risk factors beyond hyperglycemia. These risk factors, including hypertension,dyslipidemia, and a sedentary lifestyle, are particularly prevalent among patients with diabetes. To reduce the mortality and morbidity from CVD among patients with diabetes, aggressive treatment of glycemic control as well as other cardiovascular risk factors must be initiated.

Studies that have compared antihypertensive treatment in patients with diabetes versus placebo have shown reduced cardiovascular events. The United Kingdom Prospective Diabetes Study (UKPDS), which followed patients with diabetes for an average of 8.5 years, found that patients with tight BP control (< 150/< 85 mmHg) versus less tight control (< 180/< 105 mmHg) had lower rates of myocardial infarction (MI), stroke, and peripheral vascular events. In the UKPDS, each 10-mmHg decrease in mean systolic BP was associated with a 12% reduction in risk for any complication related to diabetes, a 15% reduction for death related to diabetes, and an 11% reduction for MI. Another trial followed patients for 2 years and compared calcium-channel blockers and angiotensin-converting enzyme (ACE) inhibitors,with or without hydrochlorothiazide against placebo and found a significant reduction in acute MI, congestive heart failure, and sudden cardiac death in the intervention group compared to placebo.

The Hypertension Optimal Treatment (HOT) trial has shown that patients assigned to lower BP targets have improved outcomes. In the HOT trial,patients who achieved a diastolic BP of < 80 mmHg benefited the most in terms of reduction of cardiovascular events. Other epidemiological studies have shown that BPs > 120/70 mmHg are associated with increased cardiovascular morbidity and mortality in people with diabetes. The American Diabetes Association has recommended a target BP goal of < 130/80 mmHg. Studies have shown that there is no lower threshold value for BP and that the risk of morbidity and mortality will continue to decrease well into the normal range.

Many classes of drugs have been used in numerous trials to treat patients with hypertension. All classes of drugs have been shown to be superior to placebo in terms of reducing morbidity and mortality. Often, numerous agents(three or more) are needed to achieve specific target levels of BP. Use of almost any drug therapy to reduce hypertension in patients with diabetes has been shown to be effective in decreasing cardiovascular risk. Keeping in mind that numerous agents are often required to achieve the target level of BP control, recommending specific agents becomes a not-so-simple task. The literature continues to evolve, and individual patient conditions and preferences also must come into play.

While lowering BP by any means will help to reduce cardiovascular morbidity, there is evidence that may help guide the selection of an antihypertensive regimen. The UKPDS showed no significant differences in outcomes for treatment for hypertension using an ACE inhibitor or aβ-blocker. In addition, both ACE inhibitors and angiotensin II receptor blockers (ARBs) have been shown to slow the development and progression of diabetic nephropathy. In the Heart Outcomes Prevention Evaluation (HOPE)trial, ACE inhibitors were found to have a favorable effect in reducing cardiovascular morbidity and mortality, whereas recent trials have shown a renal protective benefit from both ACE inhibitors and ARBs. ACE inhibitors andβ-blockers seem to be better than dihydropyridine calcium-channel blockers to reduce MI and heart failure. However, trials using dihydropyridine calcium-channel blockers in combination with ACE inhibitors andβ-blockers do not appear to show any increased morbidity or mortality in CVD, as has been implicated in the past for dihydropyridine calcium-channel blockers alone. Recently, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) in high-risk hypertensive patients,including those with diabetes, demonstrated that chlorthalidone, a thiazide-type diuretic, was superior to an ACE inhibitor, lisinopril, in preventing one or more forms of CVD.

L.N. is a typical patient with obesity, diabetes, and hypertension. Her BP control can be improved. To achieve the target BP goal of < 130/80 mmHg, it may be necessary to maximize the dose of the ACE inhibitor and to add a second and perhaps even a third agent.

Diuretics have been shown to have synergistic effects with ACE inhibitors,and one could be added. Because L.N. has migraine headaches as well as diabetic nephropathy, it may be necessary to individualize her treatment. Adding a β-blocker to the ACE inhibitor will certainly help lower her BP and is associated with good evidence to reduce cardiovascular morbidity. Theβ-blocker may also help to reduce the burden caused by her migraine headaches. Because of the presence of microalbuminuria, the combination of ARBs and ACE inhibitors could also be considered to help reduce BP as well as retard the progression of diabetic nephropathy. Overall, more aggressive treatment to control L.N.'s hypertension will be necessary. Information obtained from recent trials and emerging new pharmacological agents now make it easier to achieve BP control targets.

Hypertension is a risk factor for cardiovascular complications of diabetes.

Clinical trials demonstrate that drug therapy versus placebo will reduce cardiovascular events when treating patients with hypertension and diabetes.

A target BP goal of < 130/80 mmHg is recommended.

Pharmacological therapy needs to be individualized to fit patients'needs.

ACE inhibitors, ARBs, diuretics, and β-blockers have all been documented to be effective pharmacological treatment.

Combinations of drugs are often necessary to achieve target levels of BP control.

ACE inhibitors and ARBs are agents best suited to retard progression of nephropathy.

Evan M. Benjamin, MD, FACP, is an assistant professor of medicine and Vice President of Healthcare Quality at Baystate Medical Center in Springfield, Mass.

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Chapter 6:  10 Real Cases on Hypertensive Emergency and Pericardial Disease: Diagnosis, Management, and Follow-Up

Niel Shah; Fareeha S. Alavi; Muhammad Saad

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Case review, case discussion.

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Case 1: Management of Hypertensive Encephalopathy

A 45-year-old man with a 2-month history of progressive headache presented to the emergency department with nausea, vomiting, visual disturbance, and confusion for 1 day. He denied fever, weakness, numbness, shortness of breath, and flulike symptoms. He had significant medical history of hypertension and was on a β-blocker in the past, but a year ago, he stopped taking medication due to an unspecified reason. The patient denied any history of tobacco smoking, alcoholism, and recreational drug use. The patient had a significant family history of hypertension in both his father and mother. Physical examination was unremarkable, and at the time of triage, his blood pressure (BP) was noted as 195/123 mm Hg, equal in both arms. The patient was promptly started on intravenous labetalol with the goal to reduce BP by 15% to 20% in the first hour. The BP was rechecked after an hour of starting labetalol and was 165/100 mm Hg. MRI of the brain was performed in the emergency department and demonstrated multiple scattered areas of increased signal intensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images in both the occipital and posterior parietal lobes. There were also similar lesions in both hemispheres of the cerebellum (especially the cerebellar white matter on the left) as well as in the medulla oblongata. The lesions were not associated with mass effect, and after contrast administration, there was no evidence of abnormal enhancement. In the emergency department, his BP decreased to 160/95 mm Hg, and he was transitioned from drip to oral medications and transferred to the telemetry floor. How would you manage this case?

The patient initially presented with headache, nausea, vomiting, blurred vision, and confusion. The patient’s BP was found to be 195/123 mm Hg, and MRI of the brain demonstrated scattered lesions with increased intensity in the occipital and posterior parietal lobes, as well as in cerebellum and medulla oblongata. The clinical presentation, elevated BP, and brain MRI findings were suggestive of hypertensive emergency, more specifically hypertensive encephalopathy. These MRI changes can be seen particularly in posterior reversible encephalopathy syndrome (PRES), a sequela of hypertensive encephalopathy. BP was initially controlled by labetalol, and after satisfactory control of BP, the patient was switched to oral antihypertensive medications.

Hypertensive emergency refers to the elevation of systolic BP >180 mm Hg and/or diastolic BP >120 mm Hg that is associated with end-organ damage; however, in some conditions such as pregnancy, more modest BP elevation can constitute an emergency. An equal degree of hypertension but without end-organ damage constitutes a hypertensive urgency, the treatment of which requires gradual BP reduction over several hours. Patients with hypertensive emergency require rapid, tightly controlled reductions in BP that avoid overcorrection. Management typically occurs in an intensive care setting with continuous arterial BP monitoring and continuous infusion of antihypertensive agents.

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Newly diagnosed hypertension: case study

Angela Brown

Trainee Advanced Nurse Practitioner, East Belfast GP Federation, Northern Ireland

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The role of an advanced nurse practitioner encompasses the assessment, diagnosis and treatment of a range of conditions. This case study presents a patient with newly diagnosed hypertension. It demonstrates effective history taking, physical examination, differential diagnoses and the shared decision making which occurred between the patient and the professional. It is widely acknowledged that adherence to medications is poor in long-term conditions, such as hypertension, but using a concordant approach in practice can optimise patient outcomes. This case study outlines a concordant approach to consultations in clinical practice which can enhance adherence in long-term conditions.

Hypertension is a worldwide problem with substantial consequences ( Fisher and Curfman, 2018 ). It is a progressive condition ( Jamison, 2006 ) requiring lifelong management with pharmacological treatments and lifestyle adjustments. However, adopting these lifestyle changes can be notoriously difficult to implement and sustain ( Fisher and Curfman, 2018 ) and non-adherence to chronic medication regimens is extremely common ( Abegaz et al, 2017 ). This is also recognised by the National Institute for Health and Care Excellence (NICE) (2009) which estimates that between 33.3% and 50% of medications are not taken as recommended. Abegaz et al (2017) furthered this by claiming 83.7% of people with uncontrolled hypertension do not take medications as prescribed. However, leaving hypertension untreated or uncontrolled is the single largest cause of cardiovascular disease ( Fisher and Curfman, 2018 ). Therefore, better adherence to medications is associated with better outcomes ( World Health Organization, 2003 ) in terms of reducing the financial burden associated with the disease process on the health service, improving outcomes for patients ( Chakrabarti, 2014 ) and increasing job satisfaction for professionals ( McKinnon, 2013 ). Therefore, at a time when growing numbers of patients are presenting with hypertension, health professionals must adopt a concordant approach from the initial consultation to optimise adherence.

Great emphasis is placed on optimising adherence to medications ( NICE, 2009 ), but the meaning of the term ‘adherence’ is not clear and it is sometimes used interchangeably with compliance and concordance ( De Mauri et al, 2022 ), although they are not synonyms. Compliance is an outdated term alluding to paternalism, obedience and passivity from the patient ( Rae, 2021 ), whereby the patient's behaviour must conform to the health professional's recommendations. Adherence is defined as ‘the extent to which a person's behaviour, taking medication, following a diet and/or executing lifestyle changes, corresponds with agreed recommendations from a health care provider’ ( Chakrabarti, 2014 ). This term is preferred over compliance as it is less paternalistic ( Rae, 2021 ), as the patient is included in the decision-making process and has agreed to the treatment plan. While it is not yet widely embraced or used in practice ( Fawcett, 2020 ), concordance is recognised, not as a behaviour ( Rae, 2021 ) but more an approach or method which focuses on the equal partnership between patient and professional ( McKinnon, 2013 ) and enables effective and agreed treatment plans.

NICE last reviewed its guidance on medication adherence in 2019 and did not replace adherence with concordance within this. This supports the theory that adherence is an outcome of good concordance and the two are not synonyms. NICE (2009) guidelines, which are still valid, show evidence of concordant principles to maximise adherence. Integrating the theoretical principles of concordance into this case study demonstrates how the trainee advanced nurse practitioner aimed to individualise patient-centred care and improve health outcomes through optimising adherence.

Patient introduction and assessment

Jane (a pseudonym has been used to protect the patient's anonymity; Nursing and Midwifery Council (NMC) 2018 ), is a 45-year-old woman who had been referred to the surgery following an attendance at an emergency department. Jane had been role-playing as a patient as part of a teaching session for health professionals when it was noted that her blood pressure was significantly elevated at 170/88 mmHg. She had no other symptoms. Following an initial assessment at the emergency department, Jane was advised to contact her GP surgery for review and follow up. Nazarko (2021) recognised that it is common for individuals with high blood pressure to be asymptomatic, contributing to this being referred to as the ‘silent killer’. Hypertension is generally only detected through opportunistic checking of blood pressure, as seen in Jane's case, which is why adults over the age of 40 years are offered a blood pressure check every 5 years ( Bostock-Cox, 2013 ).

Consultation

Jane presented for a consultation at the surgery. Green (2015) advocates using a model to provide a structured approach to consultations which ensures quality and safety, and improves time management. Young et al (2009) claimed that no single consultation model is perfect, and Diamond-Fox (2021) suggested that, with experience, professionals can combine models to optimise consultation outcomes. Therefore, to effectively consult with Jane and to adapt to her individual personality, different models were intertwined to provide better person-centred care.

The Calgary–Cambridge model is the only consultation model that places emphasis on initiating the session, despite it being recognised that if a consultation gets off to a bad start this can interfere throughout ( Young et al, 2009 ). Being prepared for the consultation is key. Before Jane's consultation, the environment was checked to minimise interruptions, ensuring privacy and dignity ( Green, 2015 ; NMC, 2018 ), the seating arrangements optimised to aid good body language and communication ( Diamond-Fox, 2021 ) and her records were viewed to give some background information to help set the scene and develop a rapport ( Young et al, 2009 ). Being adequately prepared builds the patient's trust and confidence in the professional ( Donnelly and Martin, 2016 ) but equally viewing patient information can lead to the professional forming preconceived ideas ( Donnelly and Martin, 2016 ). Therefore, care was taken by the trainee advanced nurse practitioner to remain open-minded.

During Jane's consultation, a thorough clinical history was taken ( Table 1 ). History taking is common to all consultation models and involves gathering important information ( Diamond-Fox, 2021 ). History-taking needs to be an effective ( Bostock-Cox, 2019 ), holistic process ( Harper and Ajao, 2010 ) in order to be thorough, safe ( Diamond-Fox, 2021 ) and aid in an accurate diagnosis. The key skill for taking history is listening and observing the patient ( Harper and Ajao, 2010 ). Sir William Osler said:‘listen to the patient as they are telling you the diagnosis’, but Knott and Tidy (2021) suggested that patients are barely given 20 seconds before being interrupted, after which they withdraw and do not offer any new information ( Demosthenous, 2017 ). Using this guidance, Jane was given the ‘golden minute’ allowing her to tell her ‘story’ without being interrupted ( Green, 2015 ). This not only showed respect ( Ingram, 2017 ) but interest in the patient and their concerns.

Once Jane shared her story, it was important for the trainee advanced nurse practitioner to guide the questioning ( Green 2015 ). This was achieved using a structured approach to take Jane's history, which optimised efficiency and effectiveness, and ensured that pertinent information was not omitted ( Young et al, 2009 ). Thomas and Monaghan (2014) set out clear headings for this purpose. These included:

• The presenting complaint
• Past medical history
• Drug history
• Social history
• Family history.

McPhillips et al (2021) also emphasised a need for a systemic enquiry of the other body systems to ensure nothing is missed. From taking this history it was discovered that Jane had been feeling well with no associated symptoms or red flags. A blood pressure reading showed that her blood pressure was elevated. Jane had no past medical history or allergies. She was not taking any medications, including prescribed, over the counter, herbal or recreational. Jane confirmed that she did not drink alcohol or smoke. There was no family history to note, which is important to clarify as a genetic link to hypertension could account for 30–50% of cases ( Nazarko, 2021 ). The information gathered was summarised back to Jane, showing good practice ( McPhillips et al, 2021 ), and Jane was able to clarify salient or missing points. Green (2015) suggested that optimising the patient's involvement in this way in the consultation makes her feel listened to which enhances patient satisfaction, develops a therapeutic relationship and demonstrates concordance.

During history taking it is important to explore the patient's ideas, concerns and expectations. Moulton (2007) refers to these as the ‘holy trinity’ and central to upholding person-centredness ( Matthys et al, 2009 ). Giving Jane time to discuss her ideas, concerns and expectations allowed the trainee advanced nurse practitioner to understand that she was concerned about her risk of a stroke and heart attack, and worried about the implications of hypertension on her already stressful job. Using ideas, concerns and expectations helped to understand Jane's experience, attitudes and perceptions, which ultimately will impact on her health behaviours and whether engagement in treatment options is likely ( James and Holloway, 2020 ). Establishing Jane's views demonstrated that she was eager to engage and manage her blood pressure more effectively.

Vincer and Kaufman (2017) demonstrated, through their case study, that a failure to ask their patient's viewpoint at the initial consultation meant a delay in engagement with treatment. They recognised that this delay could have been avoided with the use of additional strategies had ideas, concerns and expectations been implemented. Failure to implement ideas, concerns and expectations is also associated with reattendance or the patient seeking second opinions ( Green, 2015 ) but more positively, when ideas, concerns and expectations is implemented, it can reduce the number of prescriptions while sustaining patient satisfaction ( Matthys et al, 2009 ).

Physical examination

Once a comprehensive history was taken, a physical examination was undertaken to supplement this information ( Nuttall and Rutt-Howard, 2016 ). A physical examination of all the body systems is not required ( Diamond-Fox, 2021 ) as this would be extremely time consuming, but the trainee advanced nurse practitioner needed to carefully select which systems to examine and use good examination technique to yield a correct diagnosis ( Knott and Tidy, 2021 ). With informed consent, clinical observations were recorded along with a full cardiovascular examination. The only abnormality discovered was Jane's blood pressure which was 164/90 mmHg, which could suggest stage 2 hypertension ( NICE, 2019 ; 2022 ). However, it is the trainee advanced nurse practitioner's role to use a hypothetico-deductive approach to arrive at a diagnosis. This requires synthesising all the information from the history taking and physical examination to formulate differential diagnoses ( Green, 2015 ) from which to confirm or refute before arriving at a final diagnosis ( Barratt, 2018 ).

Differential diagnosis

Hypertension can be triggered by secondary causes such as certain drugs (non-steroidal anti-inflammatory drugs, steroids, decongestants, sodium-containing medications or combined oral contraception), foods (liquorice, alcohol or caffeine; Jamison, 2006 ), physiological response (pain, anxiety or stress) or pre-eclampsia ( Jamison, 2006 ; Schroeder, 2017 ). However, Jane had clarified that these were not contributing factors. Other potential differentials which could not be ruled out were the white-coat syndrome, renal disease or hyperthyroidism ( Schroeder, 2017 ). Further tests were required, which included bloods, urine albumin creatinine ratio, electrocardiogram and home blood pressure monitoring, to ensure a correct diagnosis and identify any target organ damage.

Joint decision making

At this point, the trainee advanced nurse practitioner needed to share their knowledge in a meaningful way to enable the patient to participate with and be involved in making decisions about their care ( Rostoft et al, 2021 ). Not all patients wish to be involved in decision making ( Hobden, 2006 ) and this must be respected ( NMC, 2018 ). However, engaging patients in partnership working improves health outcomes ( McKinnon, 2013 ). Explaining the options available requires skill so as not to make the professional seem incompetent and to ensure the patient continues to feel safe ( Rostoft et al, 2021 ).

Information supported by the NICE guidelines was shared with Jane. These guidelines advocated that in order to confirm a diagnosis of hypertension, a clinic blood pressure reading of 140/90 mmHg or higher was required, with either an ambulatory or home blood pressure monitoring result of 135/85 mmHg or higher ( NICE, 2019 ; 2022 ). However, the results from a new retrospective study suggested that the use of home blood pressure monitoring is failing to detect ‘non-dippers’ or ‘reverse dippers’ ( Armitage et al, 2023 ). These are patients whose blood pressure fails to fall during their nighttime sleep. This places them at greater risk of cardiovascular disease and misdiagnosis if home blood pressure monitors are used, but ambulatory blood pressure monitors are less frequently used in primary care and therefore home blood pressure monitors appear to be the new norm ( Armitage et al, 2023 ).

Having discussed this with Jane she was keen to engage with home blood pressure monitoring in order to confirm the potential diagnosis, as starting a medication without a true diagnosis of hypertension could potentially cause harm ( Jamison, 2006 ). An accurate blood pressure measurement is needed to prevent misdiagnosis and unnecessary therapy ( Jamison, 2006 ) and this is dependent on reliable and calibrated equipment and competency in performing the task ( Bostock-Cox, 2013 ). Therefore, Jane was given education and training to ensure the validity and reliability of her blood pressure readings.

For Jane, this consultation was the ideal time to offer health promotion advice ( Green, 2015 ) as she was particularly worried about her elevated blood pressure. Offering health promotion advice is a way of caring, showing support and empowerment ( Ingram, 2017 ). Therefore, Jane was provided with information on a healthy diet, the reduction of salt intake, weight loss, exercise and continuing to abstain from smoking and alcohol ( Williams, 2013 ). These were all modifiable factors which Jane could implement straight away to reduce her blood pressure.

Safety netting

The final stage and bringing this consultation to a close was based on the fourth stage of Neighbour's (1987) model, which is safety netting. Safety netting identifies appropriate follow up and gives details to the patient on what to do if their condition changes ( Weiss, 2019 ). It is important that the patient knows who to contact and when ( Young et al, 2009 ). Therefore, Jane was advised that, should she develop chest pains, shortness of breath, peripheral oedema, reduced urinary output, headaches, visual disturbances or retinal haemorrhages ( Schroeder, 2017 ), she should present immediately to the emergency department, otherwise she would be reviewed in the surgery in 1 week.

Jane was followed up in a second consultation 1 week later with her home blood pressure readings. The average reading from the previous 6 days was calculated ( Bostock-Cox, 2013 ) and Jane's home blood pressure reading was 158/82 mmHg. This reading ruled out white-coat syndrome as Jane's blood pressure remained elevated outside clinic conditions (white-coat syndrome is defined as a difference of more than 20/10 mmHg between clinic blood pressure readings and the average home blood pressure reading; NICE, 2019 ; 2022 ). Subsequently, Jane was diagnosed with stage 2 essential (or primary) hypertension. Stage 2 is defined as a clinic blood pressure of 160/100 mmHg or higher or a home blood pressure of 150/95 mmHg or higher ( NICE, 2019 ; 2022 ).

A diagnosis of hypertension can be difficult for patients as they obtain a ‘sick label’ despite feeling well ( Jamison, 2006 ). This is recognised as a deterrent for their motivation to initiate drug treatment and lifestyle changes ( Williams, 2013 ), presenting a greater challenge to health professionals, which can be addressed through concordance strategies. However, having taken Jane's bloods, electrocardiogram and urine albumin:creatinine ratio in the first consultation, it was evident that there was no target organ damage and her Qrisk3 score was calculated as 3.4%. These results provided reassurance for Jane, but she was keen to engage and prevent any potential complications.

Agreeing treatment

Concordance is only truly practised when the patient's perspectives are valued, shared and used to inform planning ( McKinnon, 2013 ). The trainee advanced nurse practitioner now needed to use the information gained from the consultations to formulate a co-produced and meaningful treatment plan based on the best available evidence ( Diamond-Fox and Bone, 2021 ). Jane understood the risk associated with high blood pressure and was keen to begin medication as soon as possible. NICE guidelines ( 2019 ; 2022 ) advocate the use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blockers in patients under 55 years of age and not of Black African or African-Caribbean origin. However, ACE inhibitors seem to be used as the first-line treatment for hypertensive patients under the age of 55 years ( O'Donovan, 2019 ).

ACE inhibitors directly affect the renin–angiotensin-aldosterone system which plays a central role in regulation of blood pressure ( Porth, 2015 ). Renin is secreted by the juxtaglomerular cells, in the kidneys' nephrons, when there is a decrease in renal perfusion and stimulation of the sympathetic nervous system ( O'Donovan, 2018 ). Renin then combines with angiotensinogen, a circulating plasma globulin from the liver, to form angiotensin I ( Kumar and Clark, 2017 ). Angiotensin I is inactive but, through ACE, an enzyme present in the endothelium of the lungs, it is transformed into angiotensin II ( Kumar and Clark, 2017 ). Angiotensin II is a vasoconstrictor which increases vascular resistance and in turn blood pressure ( Porth, 2015 ) while also stimulating the adrenal gland to produce aldosterone. Aldosterone reduces sodium excretion in the kidneys, thus increasing water reabsorption and therefore blood volume ( Porth, 2015 ). Using an ACE inhibitor prevents angiotensin II formation, which prevents vasoconstriction and stops reabsorption of sodium and water, thus reducing blood pressure.

When any new medication is being considered, providing education is key. This must include what the medication is for, the importance of taking it, any contraindications or interactions with the current medications being taken by the patient and the potential risk of adverse effects ( O'Donovan, 2018 ). Sharing this information with Jane allowed her to weigh up the pros and cons and make an informed choice leading to the creation of an individualised treatment plan.

Jamison (2006) placed great emphasis on sharing information about adverse effects, because patients with hypertension feel well before commencing medications, but taking medication has the potential to cause side effects which can affect adherence. Therefore, the range of side effects were discussed with Jane. These include a persistent, dry non-productive cough, hypotension, hypersensitivity, angioedema and renal impairment with hyperkalaemia ( Hitchings et al, 2019 ). ACE inhibitors have a range of adverse effects and most resolve when treatment is stopped ( Waterfield, 2008 ).

Following discussion with Jane, she proceeded with taking an ACE inhibitor and was encouraged to report any side effects in order to find another more suitable medication and to prevent her hypertension from going untreated. This information was provided verbally and written which is seen as good practice ( Green, 2015 ). Jane was followed up with fortnightly blood pressure recordings and urea and electrolyte checks and her dose of ramipril was increased fortnightly until her blood pressure was under 140/90 mmHg ( NICE, 2019 ; 2022 ).

Conclusions

Adherence to medications can be difficult to establish and maintain, especially for patients with long-term conditions. This can be particularly challenging for patients with hypertension because they are generally asymptomatic, yet acquire a sick label and start lifelong medication and lifestyle adjustments to prevent complications. Through adopting a concordant approach in practice, the outcome of adherence can be increased. This case study demonstrates how concordant strategies were implemented throughout the consultation to create a therapeutic patient–professional relationship. This optimised the creation of an individualised treatment plan which the patient engaged with and adhered to.

• Hypertension is a growing worldwide problem
• Appropriate clinical assessment, diagnosis and management is key to prevent misdiagnosis
• Long-term conditions are associated with high levels of non-adherence to treatments
• Adopting a concordance approach to practice optimises adherence and promotes positive patient outcomes

CPD reflective questions

• How has this article developed your assessment, diagnosis or management of patients presenting with a high blood pressure?
• What measures can you implement in your practice to enhance a concordant approach?

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Differential Diagnoses

Hypertension differential diagnosis.

One of the most dangerous aspects of hypertension is that it may be asymptomatic. The early stages of hypertension may present with no clinical manifestations other than elevated blood pressure.

Diagnosis of hypertension requires blood pressure measurement on at least two separate occasions. These two measurements are then averaged. Requirements for these measurements include no smoking or caffeine intake within the previous thirty minutes and that the two blood pressure readings must be at least 2 minutes apart (Mayo Clinic, 2014a).

Differential Diagnosis I: Primary Hypertension

Due to patient’s age, BMI, lifestyle, consecutive hypertensive blood pressures, and description of headaches (bilateral temporal throbbing – occurring throughout day with decreased intensity as the day progresses), lower extremity edema, and knowledge that primary hypertension is the most common form of hypertension and mild to moderate primary (essential) hypertension is largely asymptomatic for many years, combined provide rationale for this differential diagnosis.

Differential Diagnosis II: Secondary Hypertension

Patient’s description of headaches, consecutive hypertensive blood pressures, combined with the knowledge that secondary hypertension is the second most common type of hypertension provides rationale for this differential diagnosis. Presentation of secondary hypertension is similar to primary hypertension in that it may be asymptomatic despite a dangerously elevated blood pressure (Mayo Clinic, 2014b).

Differential Diagnosis III: Complicated Hypertension

Patient’s description of headaches, swelling of the lower extremities, consecutive uncontrolled hypertensive blood pressures, combined with the potential for chronic hypertensive damage leading to organ dysfunction, provides rationale for this differential diagnosis. Potential organ damage and/or dysfunction include: heart, kidney, eyes, arteries, brain, bone loss, difficulty sleeping, and sexual dysfunction (Mayo Clinic 2014c).

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• Open access
• Published: 04 May 2024

Factors associated with non-fatal heart failure and atrial fibrillation or flutter within the first 30 days post COPD exacerbation: a nested case-control study

• Emily L. Graul 1 ,
• Clementine Nordon 2 ,
• Kirsty Rhodes 2 ,
• Shruti Menon 3 ,
• Mahmoud Al Ammouri 1 ,
• Constantinos Kallis 1 ,
• Anne E. Ioannides 1 ,
• Hannah R. Whittaker 1 ,
• Nicholas S. Peters 4 &
• Jennifer K. Quint 1  

BMC Pulmonary Medicine volume  24 , Article number:  221 ( 2024 ) Cite this article

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An immediate, temporal risk of heart failure and arrhythmias after a Chronic Obstructive Pulmonary Disease (COPD) exacerbation has been demonstrated, particularly in the first month post-exacerbation. However, the clinical profile of patients who develop heart failure (HF) or atrial fibrillation/flutter (AF) following exacerbation is unclear. Therefore we examined factors associated with people being hospitalized for HF or AF, respectively, following a COPD exacerbation.

We conducted two nested case-control studies, using primary care electronic healthcare records from the Clinical Practice Research Datalink Aurum linked to Hospital Episode Statistics, Office for National Statistics for mortality, and socioeconomic data (2014-2020). Cases had hospitalization for HF or AF within 30 days of a COPD exacerbation, with controls matched by GP practice (HF 2:1;AF 3:1). We used conditional logistic regression to explore demographic and clinical factors associated with HF and AF hospitalization.

Odds of HF hospitalization (1,569 cases, 3,138 controls) increased with age, type II diabetes, obesity, HF and arrhythmia history, exacerbation severity (hospitalization), most cardiovascular medications, GOLD airflow obstruction, MRC dyspnea score, and chronic kidney disease. Strongest associations were for severe exacerbations (adjusted odds ratio (aOR)=6.25, 95%CI 5.10-7.66), prior HF (aOR=2.57, 95%CI 1.73-3.83), age≥80 years (aOR=2.41, 95%CI 1.88-3.09), and prior diuretics prescription (aOR=2.81, 95%CI 2.29-3.45).

Odds of AF hospitalization (841 cases, 2,523 controls) increased with age, male sex, severe exacerbation, arrhythmia and pulmonary hypertension history and most cardiovascular medications. Strongest associations were for severe exacerbations (aOR=5.78, 95%CI 4.45-7.50), age≥80 years (aOR=3.15, 95%CI 2.26-4.40), arrhythmia (aOR=3.55, 95%CI 2.53-4.98), pulmonary hypertension (aOR=3.05, 95%CI 1.21-7.68), and prescription of anticoagulants (aOR=3.81, 95%CI 2.57-5.64), positive inotropes (aOR=2.29, 95%CI 1.41-3.74) and anti-arrhythmic drugs (aOR=2.14, 95%CI 1.10-4.15).

Conclusions

Cardiopulmonary factors were associated with hospitalization for HF in the 30 days following a COPD exacerbation, while only cardiovascular-related factors and exacerbation severity were associated with AF hospitalization. Understanding factors will help target people for prevention.

Peer Review reports

Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) are associated with an increased risk of cardiovascular disease (CVD) [ 1 ] likely due to linked pathophysiology, hypoxic state, and an amplified systemic inflammatory response [ 2 , 3 ]. Previous studies have demonstrated an increased, immediate period of risk for hospitalized cardiovascular events following a COPD exacerbation compared with non-exacerbating patients, [ 1 , 4 ] with the risk highest within the first month and following a severe (hospitalized) exacerbation [ 1 , 5 , 6 ]. The 30 day risk of arrhythmias and heart failure (HF) following an exacerbation, [ 6 , 7 , 8 ] approach [ 4 , 6 ] or even surpass [ 7 , 9 ] 3-fold, compared to those who did not have an exacerbation.

Globally, the prevalence of HF in COPD is high, [ 10 ] and, of patients hospitalized for exacerbation, 20% have existing, undertreated HF [ 11 ]. Incident HF attributed to exacerbations is thought to come from the increase in pulmonary arterial pressures, low blood oxygen levels [ 12 ] and activation of adrenoceptors of the autonomic nervous system [ 12 , 13 ]. However, shared symptomology of HF and COPD exacerbations makes new HF diagnosis difficult, with HF often missed [ 3 , 12 , 14 ] or occurring in tandem; approximately 8% of people primarily diagnosed with HF also have a secondary diagnosis of exacerbation [ 15 ]. Studies have investigated COPD progression in HF [ 12 ] and conversely, HF progression across COPD phenotypes, [ 12 , 16 ] but few have focused on exacerbating COPD alone [ 15 ] and no studies have examined factors associated with hospitalization with a HF diagnosis following a COPD exacerbation.

Arrhythmias are also common among people with COPD, with prevalence ranging from 5 to 15% globally, [ 10 ] and atrial fibrillation (AF) is the most common arrhythmia [ 17 ]. AF diagnoses at the time of an exacerbation are also common, with estimates around 17% [ 18 ], but due to shared, nonspecific symptoms between AF and COPD, differential diagnosis can be difficult [ 19 ]. During a COPD exacerbation, changes in blood gases from hypoxia and rising pulmonary pressure can lead to electrophysiological and structural changes of the atrium, and together are thought to contribute to exacerbation-related disturbances in rhythm and progression of AF [ 6 , 10 , 19 , 20 , 21 ] The understanding of COPD progression alongside AF progression is unclear [ 19 ]. Few studies have examined factors associated with hospitalization for incident AF after an exacerbation, with the focus on the short-term [ 21 , 22 ]. Several have however investigated factors associated with concurrent AF at time of an exacerbation [ 18 , 23 ].

Therefore, using a primary-care defined COPD cohort from the Clinical Practice Research Datalink (CPRD) Aurum database linked with hospital, mortality, and socioeconomic deprivation data, we explored factors associated with incident hospitalization for non-fatal HF, or AF or atrial flutter, within the 30 days following a COPD exacerbation.

Study design and methods

Data source.

We obtained pseudonymized, routinely-collected electronic healthcare record data from CPRD Aurum, [ 24 ] a primary care database broadly representative by age, sex, deprivation, and regional distribution, [ 25 ] and covering approximately 20% of GP-registered patients in England [ 24 ]. Primary care data from the May 2022 build [ 24 ] were linked to the Office for National Statistics (ONS) for mortality, socioeconomic data from the 2015 Index of Multiple Deprivation (IMD), and secondary care data from NHS England’s Hospital Episode Statistics (HES) Admitted Patient Care (APC) database.

Source population

The source population were people with a COPD diagnosis who had been included in the Exacerbations of COPD and their OutcomeS on CardioVascular diseases (EXACOS-CV) observational open cohort study [ 4 ]. People were eligible for inclusion in that original cohort study if they met the following criteria: 1) aged 40 years or older, 2) had a COPD diagnosis using a validated algorithm (86.5% PPV) [ 26 ] 3) were eligible for linkage with HES, ONS, and IMD data, 4) had a smoking history (i.e., current or ex-smoker), 5) had continuous GP practice registration with acceptable quality data in the year before start of follow up, and 6) had data recorded after 1 st of January 2014.

Study design and population

We conducted two nested-case control studies, in parallel. The study population for each study consisted of COPD patients in the EXACOS-CV source population, who 1) experienced an exacerbation within cohort follow-up, 2) among the pool of eligible controls had at least 30 days of contributing data post-exacerbation, and 3) had no evidence of HF or arrhythmias in the year before exacerbation. People were excluded from the AF/flutter study population if, within the 30 days post-exacerbation, they had evidence of other non-AF arrhythmias (e.g., cardiac arrest) (Fig. 1 for study designs; Supplementary Figures 1 and 2 for HF and AF/flutter eligibility diagram respectively).

Study design for the parallel, nested case control studies. Abbreviations: HF=heart failure, AF/f = atrial fibrillation/flutter, GP=general practice, CV=cardiovascular. Two nested case control studies, for HF and AF/f respectively, were conducted among all patients who experienced an exacerbation at start of cohort follow up. Full definitions of demographic and clinical factors of interest are in the Supplementary materials

Cases were individuals with a hospitalized, cardiovascular event (HF or AF/flutter, respectively) within 1-30 days post COPD exacerbation. Cases were determined in the HES database using ICD-10 codes in the primary diagnostic position across all episodes in a single hospitalization. The date of admission was the date of the case (index date, HF or AF/flutter, respectively). Extended case definitions are in Supplementary Table 3 .

The set of controls per case was drawn among individuals in the study population who had no in-hospital diagnosis of the cardiovascular event-of-interest (HF or AF/flutter, respectively) and who had 30 days of contributing data post-exacerbation. Controls were assigned a pseudo-end date (i.e., 30 days post-exacerbation) on which to match. Controls were individually matched to cases on GP practice to account for unmeasurable potential clinical differences in disease management by clinicians, within a 30-day window of the index date, and could be used as a control for more than one case. For the HF analysis, controls were matched 2:1 and for the AF/flutter analysis, 3:1.

The choice of matching factors and ratios were chosen based on considerations of 1) maximizing the ratio itself for reasons of power and precision while 2) minimizing cases lost without a full set of controls. Only case sets with the full ratio of controls per case were included for analysis.

We examined factors potentially associated with hospitalization for HF or AF/flutter in the 30 days following an exacerbation of COPD. Factors included demographic characteristics: age (categorized into four age bands; 40-69, 70-74, 75-79, ≥80), sex, IMD quintiles, and ethnicity; and smoking status. Comorbidities included (hypertension, anxiety, depression and depressive symptoms, type II diabetes, chronic kidney disease (CKD), BMI [body mass index; using World Health Organization classification]). COPD factors included GOLD grade of airflow limitation (defined as 1 mild, 2 moderate, 3-4 severe/very severe), Medical Research Council (MRC) dyspnea score (1-2; 3; 4-5), exacerbation severity at cohort entry (moderate/severe) prior exacerbation frequency (infrequent (≤1) versus frequent (≥2) history in a year window preceding one year to cohort entry). Prior CVD history was evidence of the following anytime preceding the year before exacerbation date [acute coronary syndrome (ACS), arrhythmias, HF, ischemic stroke, pulmonary hypertension PH], COPD inhaled therapies, and major classes of cardiovascular medications (prescriptions defined two years before cohort entry). Covariate definitions are in Supplementary Table 4 .

We used validated definitions for COPD exacerbations. A moderate exacerbation was defined as a COPD-related primary care (GP) visit with either a code for exacerbation (including Lower Respiratory Tract Infection (LRTI) SNOMED-CT codes) and/or prescription for respiratory antibiotics and oral systemic corticosteroids not on the same day as an annual review, as validated in CPRD [ 27 ]. A severe exacerbation was defined as a hospitalization with an acute respiratory event code including COPD or bronchitis as a primary diagnosis, or a secondary diagnosis of COPD, as validated in HES [ 28 ]. We considered exacerbations to be the same event if recorded within 14 days in which case the highest level of severity was chosen.

We checked covariate missingness to assess use in adjusted models. Imputation was not considered for covariates with missing data, given the missingness mechanism was Missing-Not-At-Random (MNAR), violating the Missing-Completely-At-Random (MCAR) assumption premising imputation [ 29 ].

Codelists for primary care factors were generated using SNOMED-CT and British National Formulary ontologies; we used our standardizable, reproducible methodology, available on GitHub: for drug [ 30 ] and medical/phenotype codelists , respectively. Codelists for hospitalizations used ICD-10 codes. Codelists are available on our EXACOS-CV GitHub repository .

Statistical analysis

We compared separately the odds of hospitalization for HF or AF/flutter between the comparator groups for each factor, using conditional logistic regression. Our final model was adjusted for all covariates without substantial amount of missing data, including demographic factors, comorbidities, and COPD inhaled therapies and cardiovascular medications. In three sensitivity analyses, we repeated main analyses additionally adjusting for variables-of-interest with substantial missing data, respectively: GOLD, MRC, and CKD.

Analyses were performed using STATA v17.

These data were collected and provided by CPRD. Ethical approval was obtained through CPRD’s Research Data Governance Process (protocol number: 22_002377). The RECORD checklist for observational studies is in Supplementary Table 5 .

Characteristics of study participants

The HF dataset consisted of 1,569 cases experiencing an HF event within the first 30 days post-exacerbation, matched to 3,138 controls. The AF/flutter dataset consisted of 841 cases experiencing an AF/flutter event within the first 30 days post-exacerbation, matched to 2,523 controls. Tables 1 and 2 show the characteristics of the participants for HF and AF/flutter, respectively.

Across both study populations, cases tended to have had a severe exacerbation, were more likely to be older, male, an ex-smoker, have comorbidities including prior prevalent cardiovascular disease, and be prescribed cardiovascular medications. Cases and controls both tended to have infrequent exacerbation history, have prescriptions for long-acting therapies, but tended to not have prescriptions for short-acting inhaled therapies.

Factors associated with HF hospitalization 1-30 days post exacerbation

Age, type II diabetes, obesity, prior HF diagnosis, prior arrhythmia diagnosis, having a severe exacerbation, and most cardiovascular medications were associated with increased odds of being hospitalized for HF within 30 days of a COPD exacerbation (Table 1 ). The factors most strongly associated with HF were exacerbation severity (aOR=6.25, 95%CI 5.10-7.66), a prior HF diagnosis (aOR=2.57, 95%CI 1.73-3.83), age at least 80 years (≥80 vs. 40-69; aOR=2.41, 95%CI 1.88-3.09), and, of the cardiovascular medications, diuretics (aOR=2.81, 95%CI 2.29-3.45).

In sensitivity analyses, GOLD grade, MRC score, and history of CKD were all associated with an increased odds of being hospitalized for HF within the month post exacerbation.(Supplementary Table 1 ) The strongest associations were for CKD (aOR=1.85, 95%CI 1.46-2.35) and higher levels of airflow limitation and breathlessness (GOLD grade 3-4 Severe/Very Severe aOR=1.83, 95%CI 1.32-2.54, versus GOLD grade 1 Mild) (Score 4-5 MRC aOR=1.87, 95%CI 1.42-2.46, versus MRC 1-2).

Factors associated with AF/flutter hospitalization 1-30 days post exacerbation

Age, male sex, prior arrhythmia, prior PH, and having a severe exacerbation were associated with AF/flutter in the 30 days following an exacerbation. Most cardiovascular medications were also associated with AF/flutter (Table 2 ). The factors most strongly associated with AF were exacerbation severity (aOR=5.78 95%CI 4.45-7.50), age ≥80 years (aOR=3.15 95%CI 2.26-4.40), prior arrhythmia and PH (aOR=3.55, 95%CI 2.53-4.98; aOR=3.05, 95%CI 1.21-7.68), and of the cardiovascular medications, anticoagulants (aOR=3.81, 95%CI 2.57-5.64), positive inotropes (aOR=2.29, 95%CI 1.41-3.74) and anti-arrhythmic drugs (aOR=2.14, 95%CI 1.10-4.15).

In sensitivity analyses, GOLD grade, MRC score, and CKD had no association with AF/flutter (Supplementary Table 2 ).

In a primary care defined COPD population, this study examined the clinical profiles of people hospitalized for HF and for AF within a month post exacerbation. We observed that the odds of HF and of AF hospitalization were higher for people with severe, hospitalized exacerbations and with cardiovascular-related history. For HF analyses only, the odds of HF were also higher for people with microvascular factors (i.e., type II diabetes; obesity; CKD) and for people with pulmonary factors, namely those with worse GOLD grade of airflow limitation and higher levels of MRC breathlessness scores.

Heart failure

The pathophysiological links between COPD exacerbations and HF are recognized [ 31 , 32 , 33 ]. Upon exacerbation, dynamic lung hyperinflation from airflow limitation alongside heightened inflammation and hypoxia, can lead to increased strain on both the lungs and heart. The increased cardiopulmonary pressure can then lead to impaired contraction or filling of the left ventricle, namely HF with preserved or with reduced ejection fraction, respectively [ 31 , 32 , 33 ].

Few studies have investigated factors associated with HF in COPD alone, [ 15 , 34 , 35 , 36 ] of which only one [ 15 ] investigated hospitalized exacerbation with concurrent HF, but did not quantify this relationship with ORs, and was conducted in the US National Inpatient Sample (NIS) database. The remaining were post-hoc analyses of trials focused on stable COPD [ 34 , 35 , 36 ].

The strong magnitude of the association for exacerbation severity (hospitalization) but not for exacerbation frequency, suggests two points. First, from a healthcare service-level standpoint, patients hospitalized for exacerbations are more likely to be hospitalized for a future HF (i.e., re-admission) compared with patients whose exacerbation was managed in primary care. Second, clinically, exacerbation severity (e.g., greater intensity of inflammation) has a greater indication of a patients’ future cardiac state, rather than past exacerbation occurrence and management. Findings for older age were anticipated and align with previous studies [ 15 , 34 , 35 , 36 ].

The associations for history of HF, arrhythmia, type II diabetes, and CKD with post-exacerbation HF are unsurprising given their known independent relationships each with HF and exacerbations alone. Chronic, unmanaged HF can lead to future health service utilization for HF [ 16 , 37 ]. Arrhythmia-attributed cardiac remodeling can contribute to development of cardiomyopathy [ 38 ]. Diabetes is a risk factor for substantial HF progression [ 16 , 39 ], and separately a population-based study in COPD patients demonstrated an increased risk of cardiovascular mortality with type II diabetes [ 40 ]. Impaired renal hemodynamics and activation of the renin-angiotensin-aldosterone system (RAAS) can lead to HF, [ 41 ] and separately reduced kidney function is associated with future HF [ 42 ].

Our findings for cardiovascular medications indicate a certain treatment profile in primary care, leading up to the post-exacerbation HF hospitalization. The strongest association for diuretics suggests that leading up to future HF, patients perhaps are receiving treatment indicated for uncontrolled edema from existing HF, diabetic cardiomyopathy, or CKD for example.

GOLD and MRC as factors for post-exacerbation HF likewise were expected. Increased breathlessness and reduced lung function are not only symptoms of an imminent exacerbation or HF; equally, these factors can also indicate delayed diagnosis of unstable COPD or HF, [ 16 , 43 ] given their shared symptomology [ 3 , 12 , 14 ]. Reduced lung function can contribute to worsening prognosis and precipitate a future exacerbation or HF [ 16 , 43 ].

Atrial fibrillation

The pathophysiological mechanisms implicating AF post COPD exacerbation are also established [ 19 , 44 ]. At time of exacerbation, drastic increases in lung hyperinflation and impaired intrathoracic pressures can cause increased pulmonary vascular resistance and damage, leading to alterations to atrial electrophysiology [ 19 , 44 ]. Compromised gas exchange in the lungs can induce systemic inflammation and oxidative stress too, and also put strain on pulmonary vasculature, leading to abnormal atrial structure and ion-channel remodeling, [ 19 , 44 ] while certain treatments prescribed upon exacerbation are arrhythmogenic [ 19 , 44 ].

Only four studies have investigated patient profiles for AF development in unstable COPD, all hospital-based [ 18 , 21 , 22 , 23 ], of which two conducted in the US National Inpatient Sample (NIS) database [ 18 , 22 ]. Two examined factors associated with AF diagnosis after exacerbation [ 21 , 22 ] one of which patients had existing AF [ 21 ]. Two failed to quantify with ORs, only comparing baseline characteristics of exacerbating patients by status of concurrent AF [ 18 , 23 ].

Our findings for older age and male gender are not unexpected; studies similarly found these associations in exacerbating [ 18 , 22 ] and in stable COPD [ 45 ]. Unsurprisingly, exacerbation severity associated with future AF, again adding to the existing evidence of stronger associations for hospitalized exacerbation [ 1 , 6 ] and again, likewise to HF, suggests a distinction between healthcare service-level patient pathways, and intensity versus frequency.

The associations we found for history of PH and arrhythmias aligns with what was anticipated clinically. Electrophysiological and structural changes to the atrium over time, from either AF itself [ 20 ] or from chronic atrial stretching and fibrosis attributed to PH, [ 46 ] can lead to future AF. While a study using Euro Heart Survey data showed COPD as a factor for progression of paroxysmal to persistent AF (aOR=1.51, 95%CI 0.95-2.39) [ 20 ], neither of the two studies looking at patient profiles for post-exacerbation AF, looked at chronic, prevalent arrhythmias itself as a factor [ 21 , 22 ]. No studies have looked at PH, although the study among end-stage COPD patients in the NIS database found a weak association for pulmonary circulatory disorders (aOR=1.44, 95%CI 1.37-1.52) [ 22 ], compared the OR of about 3 for PH. A study found raised pulmonary artery pressure to be associated with AF (p<0.05), but failed to quantify, and it was small, underpowered, and not generalizable as it restricted to hospitalized COPD patients with existing AF [ 21 ].

The lack of associations for prior ACS, ischemic stroke, HF, and hypertension somewhat contradict the study among hospitalized, end-stage COPD patients, [ 22 ] where an association was found for HF (aOR=2.42; 95%CI: 2.36-2.48) and coagulopathy (aOR=1.23; 95%CI:1.16-1.31), but again this may reflect the more severe prognosis of these patients versus those in our study.

Likewise to HF, findings for cardiovascular medications indicate a certain treatment profile in primary care, leading up to the post-exacerbation AF hospitalization. Although we were unable to adjudicate by specific subtype of AF,(e.g., paroxysmal, persistent) the strongest associations for positive inotropes, anti-arrhythmic drugs, and anticoagulants may suggest that leading up to future AF, patients perhaps are receiving treatment to manage abnormal heart rate and/or rhythm, and/or to prevent clotting. Future research could investigate the respective treatment profile relative to paroxysmal AF and to persistent AF [ 47 ] to confirm and extend our findings.

Our null results for other comorbidities (i.e., depression and depressive symptoms, anxiety, BMI, CKD, and type-II diabetes) goes against studies finding an association for diabetes, [ 18 , 22 ] mixed findings for depression, [ 18 , 22 ] among other comorbidities. Yet these observed associations could be due to differing context; using the NIS database in a study population of only hospitalized, exacerbating, insured payors. GOLD airflow obstruction and MRC dyspnea score were not associated with post-exacerbation AF hospitalization, possibly as AF is often associated with vague symptoms of onset and not necessarily immediately thought about as a cause of increasing breathlessness in someone with COPD [ 44 , 48 , 49 ].

Methodological considerations

A key strength is our generalizable COPD cohort, defined within the electronic healthcare record with detailed data to examine and adjust for a range of factors. Unlike other studies, this allowed us to look at two patient pathways: cardiovascular-related hospitalizations post primary-care exacerbation, and re-admissions post hospitalized exacerbation. Our exclusion criteria allowed us to quantify the odds of new onset HF and AF hospitalizations following exacerbation, by ensuring no evidence of AF or HF in the year prior to exacerbation. We chose to study two common cardiovascular conditions in COPD, AF and HF. We could not subdivide HF and AF more granularly, because of insufficient statistical power and the inability to obtain electrocardiogram or echocardiogram results to adjudicate.

We used validated codes to define COPD [ 26 ] and COPD exacerbations [ 27 , 28 ] so misclassification is unlikely. Where possible, we used previously tested methods [ 30 ] and codes to define our factors-of-interest and codes were checked by a pulmonologist and/or cardiologist. The nested case control matched design allowed us to control for unmeasurable potential clinical differences in disease management by clinicians, by matching patients on GP practice.

To minimize selection bias among patients with measured factors only, we adjusted only for covariates without substantial missing data. We reserved GOLD, MRC, and CKD for sensitivity analyses; the associations of these factors with HF are generalizable only to patients with measurements (e.g., patients with greater healthcare monitoring, provision, or access). For this reason, the relationship for ethnicity could not be quantified, and given the data sparsity. For the HF analysis, we were unable to quantify B-type natriuretic peptide testing as a factor (BNP or NT-proBNP) because of 90% missing data for BNP (data not shown).

Confounding by indication is possible, particularly for the associations observed for cardiovascular medications (cases could have been more likely prescribed cardiovascular medications to manage a prevalent co-morbidity (perhaps with delayed diagnosis) that posed future cardiovascular risk, compared with controls) [ 50 ]. For example, although 12.8% of HF cases had prevalent HF diagnoses at baseline (201/1569), over 70% of HF cases were prescribed diuretics (1122/1569). Diuretics, particularly extended use of loop diuretics, can indicate possible, pre-HF diagnoses [ 51 ], given HF diagnoses tend to be delayed in COPD patients [ 14 , 37 , 51 ]. Taking this information together, this suggests a substantial proportion of cases could have been prescribed diuretics to manage possible-yet-undiagnosed HF, in which case, the later case-defining hospitalization was the delayed, first-time diagnosis of HF.

Our results for cardiovascular medications do not imply these medications are increasing the cardiovascular risk, rather they add to an understanding of the exacerbating patient profile. Furthermore, although these medications could indicate delayed CVD diagnosis, alternatively they could be medically indicated for management of a co-morbidity we did not adjust for, e.g., beta-blockers can be prescribed for thyroid conditions [ 52 ].

Implications for clinical practice

Within the month-window following an exacerbation, largely exacerbation intensity and cardiovascular-related management and disease history were associated with odds of incident HF and AF. For HF specifically, existing type II diabetes, CKD, lung function (GOLD grade), and levels of breathlessness (MRC) had an association too—but not for AF. These factors can help better identify patients most at-risk for HF and AF, to streamline efforts to allocate screening, vigilant monitoring, and prevention.

At the time of a COPD exacerbation, particularly hospitalized exacerbation, we recommend preemptively monitoring markers of possible HF, through taking medication history of loop diuretics, [ 51 ] and through BNP testing [ 53 ]. At present however, HF prevention is narrow in scope, with guidelines for early identification of HF not explicitly considering unstable COPD [ 53 , 54 ]. Our results suggest that HF monitoring should widen to include patients with COPD exacerbations.

Upon exacerbation, particularly hospitalized exacerbation, we recommend proactively screening for AF (e.g., electrocardiogram) [ 19 ] as AF commonly presents subclinically [ 17 ]. Still, at present, AF screening is narrow in scope; it is primarily conducted in patients with existing or suspected AF with the goal of preventing stroke, with AF guidelines not explicitly considering unstable COPD [ 17 , 55 ]. Our results suggest that AF screening should widen to include patients with COPD exacerbations, to help prevent future AF—even before stroke.

Cardiopulmonary factors were associated with hospitalization for HF in the 30 days following a COPD exacerbation, while only cardiovascular-related factors and exacerbation severity were associated with AF hospitalization. Understanding risk factors will help to target people for prevention. Future studies with the intent of improving risk prediction for HF and AF should consider exacerbations of COPD.

Availability of data and materials

Data are available on request from the CPRD. Their provision requires the purchase of a license, and this license does not permit the authors to make them publicly available to all. This work used data from the CPRD Aurum version collected in May 2022 and have clearly specified the data selected within the Methods section, and linked data in the Supplementary Materials . To allow identical data to be obtained by others, via the purchase of a license, the code lists will be provided upon request. Licenses are available from the CPRD ( http://www.cprd.com ): The Clinical Practice Research Datalink Group, The Medicines and Healthcare products Regulatory Agency, 10 South Colonnade, Canary Wharf, London E14 4PU.

Abbreviations

Chronic Obstructive Pulmonary Disease

Clinical Practice Research Datalink

• Cardiovascular Disease

General practice

Hospital Episode Statistics

Index of Multiple Deprivation

Medical Research Council

• Heart Failure
• Atrial Fibrillation

Chronic Kidney Disease

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Acknowledgements

This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data is provided by patients and collected by the National Health Service (NHS) as part of their care and support. The interpretation and conclusions contained in this study are those of the author/s alone.

This study was funded by AstraZeneca UK. CN, KR, and SM of the funding source took part in initial conceptualization and protocol design and the interpretation of results.

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JQ takes responsibility for the content of the manuscript, including the data and analysis. EG, JQ, CN, KR, and SM conceptualized the study and designed the protocol. JQ, NP and EG contributed to the development of the codelists that defined the study variables. EG, CK contributed to the methodology. EG, HW, CK and AI accessed and verified the data. EG, CK and AI were responsible for data curation and management. EG, CK were responsible for formal analysis. EG wrote the original draft of the manuscript. EG, MA, JQ contributed to the literature review and clinical implications. All authors contributed and approved the final manuscript. All authors had final responsibility for the decision to submit for publication.

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CPRD has NHS Health Research Authority (HRA) Research Ethics Committee (REC) approval to allow the collection and release of anonymized primary care data for observational research [NHS HRA REC reference number: 05/MRE04/87]. Each year CPRD obtains Section 251 regulatory support through the HRA Confidentiality Advisory Group (CAG), to enable patient identifiers, without accompanying clinical data, to flow from CPRD contributing GP practices in England to NHS Digital, for the purposes of data linkage [CAG reference number: 21/CAG/0008]. The protocol for this research was approved by CPRD’s Research Data Governance (RDG) Process (protocol number: 22_002377 ) and the approved protocol is available upon request. Linked pseudonymized data was provided for this study by CPRD. Data is linked by NHS Digital, the statutory trusted third party for linking data, using identifiable data held only by NHS Digital. Select general practices consent to this process at a practice level with individual patients having the right to opt-out.

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Competing interests

JQ reports grants from GlaxoSmithKline, Health Data Research UK, MRC, Asthma+Lung UK, Bayer, BI, AZ and Chiesi, outside this work and AZ for the conduct of this study. JQ has received personal fees for advisory board participation, consultancy or speaking fees from GlaxoSmithKline, Evidera, AstraZeneca, and Insmed. CN, KR, and SM are employees of AZ and hold stock and/or options in the company. HW reports grants from Health Data Research UK outside the submitted work. EG, CK, AI, and MA have nothing to disclose.

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Graul, E.L., Nordon, C., Rhodes, K. et al. Factors associated with non-fatal heart failure and atrial fibrillation or flutter within the first 30 days post COPD exacerbation: a nested case-control study. BMC Pulm Med 24 , 221 (2024). https://doi.org/10.1186/s12890-024-03035-4

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Received : 22 December 2023

Accepted : 24 April 2024

Published : 04 May 2024

DOI : https://doi.org/10.1186/s12890-024-03035-4

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