hypertension case study

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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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3. Veterans Administration Cooperative Study Group on Antihypertensive Agents : Effects of treatment on morbidity in hypertension: II. Results in patients with diastolic blood pressures averaging 90 through 114 mm Hg . JAMA 1970 ; 213 : 1143 – 1152 .

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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Clinical pearls, case study: treating hypertension in patients with diabetes.

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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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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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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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• 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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2023 update and perspectives

Masaki Mogi, Atsushi Tanaka, … Kazuomi Kario

Annual reports on hypertension research 2020

Masaki Mogi, Yukihito Higashi, … Kazuomi Kario

Epidemiology of hypertension in Japan: beyond the new 2019 Japanese guidelines

Takashi Hisamatsu, Hiroyoshi Segawa, … Katsuyuki Miura

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

Department of Regenerative Medicine, Division of Radiation Medical Science, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan

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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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DOI : https://doi.org/10.1038/s41440-022-00967-4

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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 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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Pathophysiology and Pharmacotherapy of Cardiovascular Disease pp 635–653 Cite as

Hypertension: Introduction, Types, Causes, and Complications

• Yoshihiro Kokubo MD, PhD, FAHA, FACC, FESC, FESO 4 ,
• Yoshio Iwashima MD, PhD, FAHA 5 &
• Kei Kamide MD, PhD, FAHA 6  

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Hypertension remains one of the most significant causes of mortality worldwide. It is preventable by medication and lifestyle modification. Office blood pressure (BP), out-of-office BP measurement with ambulatory BP monitoring, and self-BP measurement at home are reliable and important data for assessing hypertension. Primary hypertension can be defined as an elevated BP of unknown cause due to cardiovascular risk factors resulting from changes in environmental and lifestyle factors. Another type, secondary hypertension, is caused by various toxicities, iatrogenic disease, and congenital diseases. Complications of hypertension are the clinical outcomes of persistently high BP that result in cardiovascular disease (CVD), atherosclerosis, kidney disease, diabetes mellitus, metabolic syndrome, preeclampsia, erectile dysfunction, and eye disease. Treatment strategies for hypertension consist of lifestyle modifications (which include a diet rich in fruits, vegetables, and low-fat food or fish with a reduced content of saturated and total fat, salt restriction, appropriate body weight, regular exercise, moderate alcohol consumption, and smoking cessation) and drug therapies, although these vary somewhat according to different published hypertension treatment guidelines.

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Sources of Funding

This study was supported by grants-in-aid from the Ministry of Education, Science, and Culture of Japan (Nos. 25293147 and 26670320), the Ministry of Health, Labor, and Welfare of Japan (H26-Junkankitou [Seisaku]-Ippan-001), the Rice Health Database Maintenance industry, Tojuro Iijima Memorial Food Science, the Intramural Research Fund of the National Cerebral and Cardiovascular Center (22-4-5).

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Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, 5-7-1, Fujishiro-dai, Suita, Osaka, 565-8565, Japan

Yoshihiro Kokubo MD, PhD, FAHA, FACC, FESC, FESO

Divisions of Hypertension and Nephrology, National Cerebral and Cardiovascular Center, 5-7-1, Fujishiro-dai, Suita, Osaka, 565-8565, Japan

Yoshio Iwashima MD, PhD, FAHA

Division of Health Science, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Kei Kamide MD, PhD, FAHA

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Correspondence to Yoshihiro Kokubo MD, PhD, FAHA, FACC, FESC, FESO .

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Kokubo, Y., Iwashima, Y., Kamide, K. (2015). Hypertension: Introduction, Types, Causes, and Complications. In: Jagadeesh, G., Balakumar, P., Maung-U, K. (eds) Pathophysiology and Pharmacotherapy of Cardiovascular Disease. Adis, Cham. https://doi.org/10.1007/978-3-319-15961-4_30

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Hypertension Case Study

Ashley Barczok Amanda Bliemeister Josh Bryant Myungsun Lipthratt Nancy Schmelzer

Our Rationale for Choosing this Condition

We chose hypertension as a case study topic because regardless of career trajectory, every nurse practitioner will treat patients who display symptoms or have been diagnosed previously with hypertension.

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Nursing case management for people with hypertension

To explore the effect of management of nursing case on blood pressure control in hypertension patients.

This is a randomized controlled study which will be carried out from May 2021 to May 2022. The experiment was granted through the Research Ethics Committee of the People's Hospital of Chengyang District (03982808). Our research includes 200 patients. Patients who meet the following conditions will be included in this experiment: the patients aged 18 to 60 years; the patients had the diagnosis of hypertension; and the urban residents. While patients with the following conditions will be excluded: having renal failure, liver failure, heart and respiratory failure; and known pregnancy. Primary result is blood pressure, while secondary results are treatment compliance, waist circumference, body mass index (BMI), type and number of antihypertensive agents used, and the existence of metabolic and cardiovascular comorbidities.

Table 1 shows the clinical outcomes between the two groups.

Conclusion:

Nursing case management is effective to improve the prognosis of hypertension patients.

1. Introduction

Hypertension is one of the cause of death worldwide, which is preventable. [ 1 , 2 ] It is also a significant risk factor for myocardial infarction, heart failure, stroke, as well as other serious renal and cardiovascular diseases. [ 3 – 5 ] The incidence rate of hypertension rises with the age of adults. It is reported that 36% of the adults aged 40 to 64 suffer from hypertension; among adults aged 65 and above, the proportion has increased to 70%. [ 6 , 7 ] It has become a serious problem of public health. Since the hypertension is asymptomatic, its detection and control remains a challenge. The hypertension patients are managed via the primary health care provider. [ 8 ] Nevertheless, although the progress has been made in the management of chronic diseases, the hypertensive patients who receive regular treatment from primary care providers do not meet their targets of blood pressure.

In recent years, more and more researches begin to pay attention to the significant role of the management of nursing case in treating hypertension. [ 9 , 10 ] It requires a complex care, involving major lifestyle changes such as adherence to medication, reduced salt intake, the measurement of blood pressure and exercise. Nevertheless, the hypertension patients have poor self-management behaviors. The self-care and self-efficacy behavior of uncontrolled hypertension patients are lower. Case management is a kind of healthcare strategy that determines patients at high risk, prevents complications and disease progression, and promotes the patients participation in self-care. Other targets involve caring for the perspectives and needs of patients, developing personalized care programs, improving the quality of health care, and decreasing decentralized patient care. The former researches have suggested that management of case may have a positive effect on hypertension. [ 11 – 13 ] In addition, it can increase the knowledge about the disease; adhere to the treatment plans and help the patients improve their own lifestyle. Although it has achieved positive results in the case management of chronic disease, it has not been applied in patients with hypertension. Hence, we conduct the randomized controlled study protocol to explore the effect of management of nursing case on blood pressure control in hypertension patients.

2. Materials and methods

This is a randomized controlled study which will be carried out from May 2021 to May 2022 at the People's Hospital of Chengyang District. The experiment was granted through the Research Ethics Committee of the People's Hospital of Chengyang District (03982808) and recorded in research registry (researchregistry6244).

2.1. Inclusion criteria and exclusion criteria

Patients who meet the following conditions will be included in this experiment: the patients aged 18 to 60 years; the patients had the diagnosis of hypertension; and the urban residents. While patients with the following conditions will be excluded: having renal failure, liver failure, heart and respiratory failure; and known pregnancy. All the patients are randomly assigned to the random number through utilizing a random-number table, and the result of distribution is kept in a random envelope and is invisible. All the patients are randomly divided to the control group and study group, and there are 100 patients in each group.

2.2. Nursing case management

The nursing standards of the control group are as follows: renewal of prescriptions in meetings, free distribution of hypertension medication, and the monitor of blood pressure every 2 months, nursing and medical appointments, and consultation with psychologists and nutritionists based on the needs of patients.

In intervention group, patients are given management of nursing case. From the existing management activities, the arrangements are as follows: telephone contacts, nursing consultations, personal health education activities, and home visits. The nursing consultations are implemented every 6 months. The purpose of the consultation is to gather information that can be utilized to draft personal care plans and to set mutually agreed targets. The consultation lasts about an hour, involving the targeted health education, the measurement of waist circumference and blood pressure, and the calculation of BMI. Telephone contact is conducted every 1 month to reassess the healthcare plans of patients and remind the patients to consult the agendas in a timely manner. WeChat is a kind of instant messaging tool, which allows the voice calls through using the mobile phone, and it is also utilized for communication. Each telephone meeting lasts about 10 min. In the process of home visits, the case manager will observe the home environment, for instance, the living conditions and family's interaction. They offer the health education, check the weight of patient and their blood pressure, and then review the targets and medical plans. All the verbal instructions will be recorded and the patients will be provided the copy for consultation if needed. For the home visits, it lasts about 45 min. And the group activities contain the interactive activities and informational lectures. The focus of these activities is to develop healthy habits. The theme of educational activities is selected according to patients’ main needs. The activities of collective health education are carried out in community space. These group activities last about 1 h. Personalized educational activities are offered in the process of nursing consultation, telephone consultation, and home visit. All information acquired in the process of nursing management will be recorded.

2.3. Outcomes

Primary result is blood pressure, while secondary results are treatment compliance, waist circumference, BMI, type and number of antihypertensive agents used, and the existence of metabolic and cardiovascular comorbidities.

2.4. Statistical analysis

The analysis of all the data are conducted with the software of IBM SPSS Statistics for Windows, version 20 (IBM Corp, Armonk, NY). Afterwards, all the data acquired are represented through the appropriate characteristics, for example, standard deviation, and mean, median as well as percentage. And independent t tests and χ 2 -tests are respectively utilized to analyze the categorical variable and continuous variable. P value < .05 indicates that there is statistical significance.

Table ​ Table1 1 shows the clinical outcomes between the two groups.

The clinical outcomes between the two groups.

4. Discussion

Hypertension is the most significant risk factor for disability and death worldwide, which affects more than one billion people and causes ∼9.4 million deaths each year. [ 14 ] On the basis of a report by the World Health Organization, hypertension is the single most significant risk factor, which accounts for 13% of global mortality. Human hypertension may be the result of lifestyle and genetic factors. [ 15 , 16 ] The current evidence-based treatment for the hypertension is a key intervention measure to reduce the incidence rate and mortality of cardiovascular diseases. Researches have determined a variety of barriers to the control of hypertension in routine care that are composed of factors related to patients, physicians, healthcare system, and healthcare services.

People with lower income and education levels are more likely to be insufficiently physically active, which predisposes them to the risk of complications associated with chronic diseases, particularly the hypertension. [ 17 ] In contrast, people with higher educational and economic levels tend to be more effective at controlling the levels of blood pressure. Therefore, it is essential to consider the effect of these variables and then incorporate these variables into the development of nursing planning and educational activities for hypertension patients. Case management can be utilized for this objective by providing a personalized plan based on each person's needs.

5. Conclusion

Author contributions.

Shiqiang Song designs the protocol. Xianhong Li reviews the protocol. Xueling Ning performs the data collection. Chunjing Song finishes the manuscript. All of the authors approved the submission.

Conceptualization: Xianhong Li.

Data curation: Xianhong Li.

Funding acquisition: Shiqiang Song.

Investigation: Xueling Ning.

Methodology: Xueling Ning.

Writing – original draft: Chunjing Song.

Abbreviations: BMI = body mass index, Trial registration = The protocol was registered in Research Registry (researchregistry6244).

How to cite this article: Song C, Li X, Ning X, Song S. Nursing case management for people with hypertension: A randomized controlled trial protocol. Medicine . 2020;99:52(e23850).

Qingdao Health Bureau project (2013-WSZD120).

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the present study are publicly available.

• Open access
• Published: 10 April 2024

Association of serum sodium minus chloride level at initiation of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and hyperkalemia in patients with CKD: a case control study

• Haruki Mae 1 ,
• Takuya Fujimaru   ORCID: orcid.org/0000-0002-6825-3456 1 ,
• Koutarou Shimoyama 1 ,
• Nozomi Kadota 1 ,
• Kasumi Konishi 1 ,
• Yugo Itou 1 ,
• Masahiko Nagahama 1 ,
• Fumika Taki 1 &
• Masaaki Nakayama 1  

Renal Replacement Therapy volume  10 , Article number:  24 ( 2024 ) Cite this article

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Metrics details

Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) exert a renoprotective effect on patients with chronic kidney disease (CKD). Despite their benefit, one of their side effects is hyperkalemia, and it is one of the most common reasons for discontinuation of these drugs. Hyperchloremic metabolic acidosis is a known risk factor for hyperkalemia in patients with CKD. However, whether it is a risk factor for hyperkalemia after initiating ACE-I or ARB remains unclear.

In a previous study, serum sodium minus chloride level ([Na + ) − (Cl − ]) was identified as useful for diagnosing metabolic acidosis. To estimate the baseline acid–base status, we determined for the cutoff value of [Na + ] − [Cl − ] that correlates with [HCO 3 − ] below 24 mEq/L in patients with CKD. We then investigated whether this cutoff value was associated with hyperkalemia (serum potassium level ≥ 5.0 mEq/L) after initiating ACE-I or ARB in patients with CKD.

In the investigation of the cutoff value of [Na + ] − [Cl − ], 612 patients were examined, and [Na + ] − [Cl − ] showed a good correlation with [HCO 3 − ] ( r  = 0.67, p  < 0.001). Based on receiver operating curve analysis, we derived a cut-off value of [Na + ] − [Cl − ] below 33.5 mEq/L. Using this cut off value, the sensitivity and specificity of [Na + ] − [Cl − ] for metabolic acidosis were 75.2% and 75.0%, respectively. To explore whether metabolic acidosis is associated with hyperkalemia after initiating ACE-I or ARB, we examined 1143 patients with CKD. Among this cohort, 403 (35.3%) patients had [Na + ] − [Cl − ] < 33.5 mEq/L at baseline, and the incidence of hyperkalemia was significantly higher in univariate analysis (9.2% versus 4.2%, p  = 0.03). However, in multivariate analysis, [Na + ] − [Cl − ] < 33.5 mEq/L was not associated with hyperkalemia (odds ratio 1.13; 95% confidence interval 0.65–1.95).

Conclusions

Hyperchloremic metabolic acidosis was not associated with hyperkalemia after initiation of ACE-I or ARB in patients with CKD.

Angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) are well known for their ability to reduce cardiovascular events and exert renoprotective effects in patients with chronic kidney disease (CKD) [ 1 ]. However, hyperkalemia defined as serum potassium level ([K + ]) ≥ 5.0 mEq/L is one of the major side effects associated with these drugs. Since hyperkalemia adversely affects long term prognosis in patients with CKD [ 2 ], preventing the development of hyperkalemia after initiation of ACE-I or ARB is crucial in CKD management. Few risk factors for developing hyperkalemia following initiation of ACE-I or ARB include patient age, baseline estimated glomerular filtration rate (eGFR), doses of ACE-I or ARB, and diabetes [ 3 , 4 ]. Although hyperchloremic metabolic acidosis is one of the risk factors for hyperkalemia in patients with CKD, it is unclear whether this is also a risk factor for hyperkalemia after initiation of ACE-I or ARB in patients with CKD.

Blood gas analysis is required for diagnosing hyperchloremic metabolic acidosis. Another method to assess serum bicarbonate level ([HCO 3 − ]) is total CO 2 (tCO 2 ) measurement. However, because measuring tCO 2 requires specialized testing equipment, it is thought that it is not as popular in Japan as it is in the USA [ 5 ]. Since a Kidney Disease: Improving Global Outcomes and Japanese CKD guideline recommend measuring [HCO 3 − ] in the management of patients with CKD [ 6 , 7 ], it is likely that nephrologists evaluate [HCO 3 − ] in daily practice even in Japan. On the other hand, ACE-I and ARB are also used in patients with heart failure and hypertension, so these drugs are prescribed in medical departments other than nephrology. Therefore, such medical departments may not routinely assess [HCO 3 − ]. Interestingly, serum sodium level ([Na + ]) minus serum chloride level ([Cl − ]) enables prediction of metabolic acidosis [ 8 ]. Therefore, if measurement of [Na + ] minus [Cl − ] ([Na + ] − [Cl − ]) could predict the development of hyperkalemia after initiation of ACE-I or ARB, it would subsequently be beneficial in CKD management.

In this study, to assess the association between baseline acid–base status and hyperkalemia after initiation of these drugs, we initially investigated the cutoff value of [Na + ] − [Cl − ] that correlates with [HCO 3 − ] below 24 mEq/L in patients with CKD. Then, using this cutoff value, we examined whether it was useful for predicting hyperkalemia after the initiation of ACE-I or ARB in patients with CKD.

Study design and population

This was a single center retrospective case control study. Patients with CKD not on dialysis on an outpatient or inpatient basis, who were newly initiated on ACE-I or ARB from January 2011 to December 2021 at St. Luke’s International Hospital in Japan, were included in the study. Since we defined hyperkalemia as [K + ] ≥ 5.0 mEq/L, we only included the patients with CKD whose [K + ] were below 5.0 mEq/L at the initiation of ACE-I or ARB. CKD was defined as eGFR less than 60 mL/min/1.73 m 2 at or before initiation of ACE-I or ARB. Serum creatinine, age, and sex were used for determining eGFR [ 9 ]. Exclusion criteria were: patients who had medical record of taking ACE-I or ARB before the initiation of ACE-I or ARB; patients who had medical record of dialysis before the initiation of ACE-I or ARB; patients who had baseline eGFR < 8 mL/min/1.73 m 2 ; and patients whose baseline [Na + ], [K + ], [Cl − ], and serum albumin level were not measured on the same day. We also excluded patients who were prescribed ACE-I or ARB within 7 days of hospitalization and patients ≥ 75 years old with an eGFR < 30 mL/min/1.73 m 2 , as the Japanese CKD guideline does not recommend initiating ACE-I or ARB to this population. For the investigation of whether [Na + ] − [Cl − ] correlates with [HCO 3 − ] in patients with CKD, we only included the patients whose [HCO 3 − ] were measured at the initiation of ACE-I or ARB.

Data sources

All the laboratory data were extracted from venous blood samples and were measured at the St.Luke’s International Hospital specimen laboratory. Serum albumin levels were measured by a bromocresol purple method. Serum creatine levels were measured by an enzyme method. [HCO 3 − ] was measured by tCO 2 detection using a dry chemistry method. [Na + ], [Cl – ], and [K + ] levels were measured by electrode method.

Cutoff value for serum sodium minus chloride level

Linear regression analysis was performed to evaluate the relationship between [Na + ] − [Cl − ] and [HCO 3 − ]. Furthermore, receiver operating curve (ROC) analysis and the Yoden index were established to evaluate diagnostic sensitivity, specificity, and the cutoff value for [Na + ] − [Cl − ] to predict metabolic acidosis ([HCO 3 − ] < 24 mEq/L).

Association of serum sodium minus chloride level at baseline and hyperkalemia after initiation

Using the cutoff value of [Na + ] − [Cl − ] that correlates with [HCO 3 − ] < 24 mEq/L, which was derived from our cohort, we divided all eligible patients into two groups: those with [Na + ] − [Cl − ] below the cutoff value and those with [Na + ] − [Cl − ] at or above the cutoff value. The outcome was [K + ] ≥ 5.0 mEq/L at the first blood test after the initiation of ACE-I or ARB. All blood tests were performed within 1 year after the initiation of ACE-I or ARB.

Statistical analyses

Univariate analyses were conducted using the χ 2 test and Fisher’s exact test. A multivariate analysis was performed by conducting a logistic regression analysis adjusted in accordance with the baseline data; age, sex, diabetes mellitus, eGFR, [K + ], complication of hypoalbuminemia, and concomitant use of drugs that can increase [K + ] or decrease [K + ]. Hypoalbuminemia was defined as serum albumin level < 4 g/dL. These covariates were selected based on prior studies and clinical plausibility [ 3 , 4 ]. Mineralocorticoid receptor antagonists and tolvaptan were defined as the drugs that increase [K + ] and gastrointestinal cation exchangers, loop diuretics, thiazide diuretics, acetazolamide, and bicarbonate supplementation agents were defined as the drugs that decrease [K + ]. A significant difference was defined as p -value < 0.05. All the analyses were conducted using RStudio version 4.2.0. (RStudio Team (2020). RStudio: Integrated Development for R. RStudio, PBC, Boston, MA URL http://www.rstudio.com/ ), and the study was approved by the ethical review board of St. Luke’s International Hospital.

During the observation period, 4385 patients with CKD were initiated on either ACE-I or ARB. After applying the exclusion criteria, 612 patients had their [HCO 3 − ] measured at baseline and were included in the investigation of whether [Na + ] − [Cl − ] correlates with [HCO 3 − ]. A significant relationship was detected between [Na + ] − [Cl − ] and [HCO 3 − ] ( r  = 0.67, p  < 0.001) through regression analysis (Fig.  1 A). ROC analysis indicated that [Na + ] − [Cl − ] of 33.5 mEq/L had the highest Yoden indices (sensitivity + specificity − 1) to predict metabolic acidosis ([HCO 3 − ] < 24 mEq/L) (Fig.  1 B). Using this cutoff value, the sensitivity and specificity of [Na + ] − [Cl − ] for metabolic acidosis were 75.2% and 75.0%, respectively, while the area under the ROC curve was 0.81 (95% confidential interval 0.78–0.85).

Relationship between [HCO 3 − ] and [Na + ] − [Cl − ] at the initiation of ACE-I or ARB. A . Scatter plot of [HCO 3 − ] and [Na + ] − [Cl − ]. From the linear regression analysis, [Na + ] − [Cl − ] was significantly related with [HCO 3 − ] ( r  = 0.67 and p  < 0.001). B . Receiver operating curve analysis for [Na + ] − [Cl − ] for predicting metabolic acidosis ([HCO 3 − ] < 24 mEq/L). From this analysis, 33.5 mEq/L had the highest Yoden indices (sensitivity + specificity − 1). Using this cutoff value, the sensitivity and specificity of [Na + ] − [Cl − ] for metabolic acidosis was 75.2% and 75.0%, respectively, while the area under the ROC curve was 0.81 (95% confidential interval 0.78–0.85). [HCO 3 − ], serum bicarbonate level; [Na + ], serum sodium level; [Cl − ], serum chloride level; ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker

By using the cutoff value of [Na + ] − [Cl − ], we then investigated whether this cutoff value was associated with hyperkalemia after initiation of ACE-I or ARB. In this cohort, 1143 patients were enrolled, among which there were 960 outpatients and 183 inpatients. The distribution of [Na + ] − [Cl − ] at the initiation of ACE-I or ARB in 1143 patients is depicted in Fig.  2 . At the initiation of ACE-I or ARB, [Na + ] − [Cl − ] was almost normally distributed. Using the cutoff value of [Na + ] − [Cl − ] at 33.5 mEq/L, the 1143 patients were divided into two groups: those with [Na + ] − [Cl − ] < 33.5 mEq/L (Na − Cl < 33.5 group) and those with [Na + ] − [Cl − ] ≥ 33.5 mEq/L (Na − Cl ≥ 33.5 group). The Na − Cl < 33.5 group consisted of 403 patients, while the Na − Cl ≥ 33.5 group consisted of 740 patients.

Distribution of serum sodium minus chloride level at the initiation of ACE-I or ARB. At the initiation of ACE-I or ARB, [Na + ] − [Cl − ] was almost normally distributed. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; [Na + ], serum sodium level; [Cl − ], serum chloride level

Table 1 demonstrates the clinical characteristics of the patients at initiation of ACE-I or ARB for each group. Baseline eGFR was observed to be significantly lower, baseline [K + ] was significantly higher, hypoalbuminemia was significantly more prevalent, and the incidence of hyperkalemia after the initiation of ACE-I or ARB was significantly higher in the Na − Cl < 33.5 group as compared with the Na − Cl ≥ 33.5 group.

Table 2 demonstrates the results of the univariate analysis for association of hyperkalemia after the initiation of ACE-I or ARB with baseline clinical characteristics. According to the univariate analysis, baseline [Na + ] − [Cl − ] < 33.5 mEq/L, baseline eGFR, baseline [K + ], and concomitant use of drugs which decrease [K + ] were observed to be significantly associated with hyperkalemia. However, multivariate analysis indicated that only baseline eGFR and baseline [K + ] were significantly associated with hyperkalemia after the initiation of ACE-I or ARB (Table  3 ).

In this study, we investigated the association between [Na + ] − [Cl − ] and [HCO 3 − ] and derived the cut-off value of [Na + ] − [Cl − ] < 33.5 mEq/L as a surrogate for [HCO 3 − ] < 24 mEq/L. Then, we explored whether [Na + ] − [Cl − ] < 33.5 mEq/L at the initiation of ACE-I or ARB was associated with the development of hyperkalemia in patients with CKD. A significant association between [Na + ] − [Cl − ] at initiation of ACE-I or ARB and hyperkalemia was observed in univariate analysis. However, no such significance was observed in multivariate analysis adjusted by age, sex, diabetes mellitus, eGFR, [K + ], complication of hypoalbuminemia, and concomitant use of drugs that increase [K + ] or decrease [K + ].

In this study, we identified a significant relationship between [Na + ] − [Cl − ] and [HCO 3 − ]. A study that examined whether [Na + ] − [Cl − ] could predict metabolic acidosis included 341 patients in the intensive care unit (ICU) and defined metabolic acidosis based on the strong ion difference (SID) [ 8 ]. According to this study, metabolic acidosis was defined as SID < 42.7 mEq/L using data from healthy volunteers. Our study revealed that [Na + ] − [Cl − ] is useful not only for SID-defined metabolic acidosis,but also for [HCO 3 − ]-defined metabolic acidosis. Furthermore, to the best of our knowledge, this is the first study to demonstrate that [Na + ] − [Cl − ] is useful for assessing metabolic acidosis in patients with CKD.

We adopted serum [Na + ] − [Cl − ] as a possible predictive value for developing hyperkalemia because we anticipated it would correlate with hyperchloremic metabolic acidosis. We specifically focused on hyperchloremic metabolic acidosis, as opposed to high anion gap metabolic acidosis, because we expected that the effect of serum [HCO 3 − ] on [K + ] was primarily related to the degree of hyperchloremic metabolic acidosis. From a physiological standpoint, the serum anion gap can be calculated using the equation:

We then rearranged this equation as follows:

Since hyperchloremic metabolic acidosis does not alter the serum anion gap, [Na + ] − [Cl − ] is lower in patients with hyperchloremic metabolic acidosis. In contrast, in patients diagnosed with high anion gap metabolic acidosis, an increase in serum anion gap would exactly match the decrease in [HCO 3 − ] caused by buffering of hydrogen ions, resulting in [Na + ] − [Cl − ] remaining constant in these patients. Therefore, a decrease in [Na + ] − [Cl − ] suggests hyperchloremic metabolic acidosis but not high anion gap acidosis. Additionally, although hyperchloremic metabolic acidosis is known as a risk factor for hyperkalemia, high anion gap metabolic acidosis is not considered a risk factor for hyperkalemia according to previous studies [ 10 , 11 , 12 ]. The explanation for this difference is that organic acids, unlike mineral acids, can freely penetrate cell membranes and cause less efflux of potassium from the intracellular compartment [ 10 ]. Furthermore, organic acids are actively absorbed into the intracellular compartment via transporters on the cell membrane, causing greater decrease in cell pH [ 11 ]. This leads to the influx of Na + and efflux of H + via the Na + –H + exchanger to mitigate the decrease in cell pH, subsequently enhancing the Na + -K + -ATPase, which causes an influx of potassium from the extracellular compartment. From this perspective, the association between acid–base disorders and hyperkalemia in patients with CKD may be assessed solely by the degree of hyperchloremic metabolic acidosis, which can be predicted by [Na + ] − [Cl − ]. Although high anion gap metabolic acidosis may occur in conjunction with hyperchloremic metabolic acidosis as the CKD stages progress, the accumulation of organic acid would theoretically not have an effect on [K + ].

Considering the normal value of 24 mEq/L for [HCO 3 − ] and 12 mEq/L for serum anion gap, [Na + ] − [Cl − ] < 36 mEq/L would theoretically be correlated with [HCO 3 − ] < 24 mEq/L. However, from the ROC analysis of our cohort, [Na + ] − [Cl − ] of 33.5 mEq/L had the highest Yoden indices (sensitivity + specificity − 1) for predicting metabolic acidosis. Interestingly, the best cutoff value according to the previous study of [Na + ] − [Cl − ] for diagnosing SID-defined metabolic acidosis was 34 mEq/L [ 8 ]. As mentioned above, we transformed the equation of serum anion gap as follows:

[Na + ] (mEq/L) − [Cl − ] (mEq/L) = serum anion gap (mEq/L) + [HCO 3 − ] (mEq/L).

Additionally, serum anion gap is defined as follows:

Serum anion gap (mEq/L) = all unmeasured anions (mEq/L) − all unmeasured cations (mEq/L).

Since the major unmeasured anion is albumin, patients with hypoalbuminemia have a lower anion gap. In general, for each 1 g/dL decrease in serum albumin concentration below 4 g/dL, the serum anion gap decreases by approximately 2.5 mEq/L [ 13 , 14 ]. Therefore, hypoalbuminemia was suggested as the reason why the ROC cutoff value for [Na + ] − [Cl − ] was lower than the physiologically determined value. Almost half of patients with CKD enrolled in our study had hypoalbuminemia (511 of 1143 patients). Furthermore, in the previous study according to which the best cutoff value of [Na + ] − [Cl − ] to diagnose SID defined metabolic acidosis was 34 mEq/L, the median serum albumin of patients in the ICU was 2.4 g/dL [ 8 ].

In this study, at the initiation of ACE-I or ARB, [Na + ] − [Cl − ] was not associated with the development of hyperkalemia. We consider that the patients who were not hypoaldosteronism at the initiation of ACE-I or ARB may be more susceptible to these drugs. As presented in Table  1 , patients belonging to the Na − Cl < 33.5 group had significantly impaired renal function and higher [K + ] compared with the Na − Cl ≥ 33.5 group. Previous study indicated that hypoaldosteronism was observed in most patients with hyperkalemia and impaired renal function [ 15 ]. Therefore, the Na − Cl < 33.5 group could be hypoaldosteronism. ACE-I and ARB are known to inhibit the excretion of hydrogen and potassium at the collecting duct via the suppression of renin–angiotensin–aldosterone system, thereby inducing hyperchloremic acidosis [ 16 ]. In our view, patients without acidosis at the time of initiation of ACE-I or ARB were those who had higher eGFR and lower [K + ] and were suspected to have normal activity level of renin–angiotensin–aldosterone system. Thus, they were more susceptible to developing metabolic acidosis after the initiation of ACE-I or ARB. Therefore, the acid–base status at the initiation of ACE-I or ARB may not be associated with the development of hyperkalemia.

There is a normal range for [HCO 3 − ], which has been reported to be between 22 and 28 mEq/L [ 17 , 18 ]. From this perspective, we conducted another analysis in which we adopted 22 mEq/L as the normal value for [HCO 3 − ] instead of 24 mEq/L. Through this analysis, [Na + ] − [Cl − ] of 32.5 mEq/L had the highest Yoden indices for predicting metabolic acidosis (Additional file 1 : Figure S1). Additional file 1 : Table S1 presents a comparison of patient characteristics between the two groups with [Na + ] − [Cl − ] < 32.5 mEq/L and ≥ 32.5 mEq/L at the initiation of ACE-I or ARB. Additional file 1 : Table S2 presents the results of the multivariate analysis for association of hyperkalemia after the initiation of ACE-I or ARB with baseline clinical characteristics. This multivariate analysis was performed by changing the cutoff value for [Na + ] − [Cl − ] to 32.5 mEq/L and leaving other covariates unchanged. Interestingly, similar to the results of multivariate analysis using a cutoff value predicting [HCO 3 − ] < 24 mEq/L (Table  3 ), baseline eGFR and baseline serum potassium level were associated with hyperkalemia after the initiation of ACE-I or ARB.

There are several limitations in this study. First, our research was a single-center retrospective study conducted at a regional core hospital. This may introduce selection bias of the patient population. Second, although the doses of ACE-I or ARB were identified as a risk factor for hyperkalemia in a previous study [ 3 ], we could not assess the dosages of these drugs. Third, the acid–base status was not evaluated through blood gas analysis. However, to the best of our knowledge, this is the first study to demonstrate that [Na + ] − [Cl − ] is useful for assessing metabolic acidosis in patients with CKD and to investigate the relationship between [Na + ] − [Cl − ] at the initiation of ACE-I or ARB and the new onset of hyperkalemia in patients with CKD.

[Na + ] − [Cl − ] showed a strong correlation with [HCO 3 − ] and may serve as a reliable surrogate for [HCO 3 − ] in patients with CKD. However, the baseline acid–base status was not found to be associated with hyperkalemia after the initiation of ACE-I or ARB.

Availability of data and materials

The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. The data will be shared on reasonable request to the corresponding author.

Abbreviations

• Angiotensin-converting enzyme inhibitor
• Angiotensin receptor blocker
• Chronic kidney disease

Estimated glomerular filtration rate

Intensive care unit

Receiver operating curve

Strong ion difference

Renin–angiotensin–aldosterone system

Serum sodium level

Serum chloride level

Serum bicarbonate level

Serum potassium level

[Na + ] − [Cl − ] ≥ 33.5 mEq/L

[Na + ] − [Cl − ] < 33.5 mEq/L

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Acknowledgements

Not applicable.

No funding was received for conducting this study.

Author information

Authors and affiliations.

Department of Nephrology, St.Luke’s International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan

Haruki Mae, Takuya Fujimaru, Koutarou Shimoyama, Nozomi Kadota, Kasumi Konishi, Yugo Itou, Masahiko Nagahama, Fumika Taki & Masaaki Nakayama

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Research idea and study design: H.M. and T.F.; data acquisition: H.M. and T.F.; data analysis/interpretation: H.M. and T.F.; statistical analysis: H.M. and T.F.; supervision or mentorship: T.F., K.S., N.K., K.K., Y.I., M.N., F.T., and M.N. Each author contributed important intellectual content during manuscript drafting and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

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Correspondence to Takuya Fujimaru .

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This study protocol was reviewed and approved by the ethical review board of St. Luke’s International Hospital. Because of the anonymity of the patients studied and the nonintrusive nature of the research, the requirement for written consent was waived via the opt-out method on the hospital’s information website.

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Because of the anonymity of the patients studied and the nonintrusive nature of the research, the requirement for written consent was waived via the opt-out method on the hospital’s information website.

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The authors declare that they have no competing interests.

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Supplementary Information

Additional file 1:.

Supplementary Table S1. Clinical characteristics of the cohort adopting 22 mEq/L as the normal value for serum bicarbonate level. Supplementary Table S2. Multivariate analysis for association of hyperkalemia after the initiation of ACE-I or ARB with baseline clinical characteristics. Supplementary Figure S1. Receiver operating curve analysis for [Na + ] − [Cl − ] for predicting [HCO − ] < 22 mEq/L.

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Mae, H., Fujimaru, T., Shimoyama, K. et al. Association of serum sodium minus chloride level at initiation of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and hyperkalemia in patients with CKD: a case control study. Ren Replace Ther 10 , 24 (2024). https://doi.org/10.1186/s41100-024-00541-3

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Received : 23 November 2023

Accepted : 22 March 2024

Published : 10 April 2024

DOI : https://doi.org/10.1186/s41100-024-00541-3

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