Hypertension

Hemodynamics and physiologic components (eg, plasma volume, activity of the renin-angiotensin system) vary, indicating that primary hypertension is unlikely to have a single cause. Even if one factor is initially responsible, multiple factors are probably involved in sustaining elevated blood pressure (the mosaic theory). In afferent systemic arterioles, malfunction of ion pumps on sarcolemmal membranes of smooth muscle cells may lead to chronically increased vascular tone. Heredity is a predisposing factor, but the exact mechanism is unclear. Environmental factors (eg, dietary sodium, stress) seem to affect only people who are genetically susceptible at younger ages; however, in patients > 65 years, high sodium intake is more likely to precipitate hypertension.

Common causes include

• Obesity

• Primary aldosteronism (1)

• Obstructive sleep apnea

• Renal parenchymal disease (eg, chronic glomerulonephritis or pyelonephritis, polycystic renal disease, lupus nephritis, obstructive uropathy)

• Renovascular disease

Other, much rarer, causes include pheochromocytoma, Cushing syndrome, congenital adrenal hyperplasia, hyperthyroidism, hypothyroidism (myxedema), primary hyperparathyroidism, acromegaly, coarctation of the aorta, and mineralocorticoid excess syndromes other than primary aldosteronism.

Excessive alcohol intake and use of oral contraceptives are common reversible causes of hypertension.

Also, use of sympathomimetics, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, cocaine, or licorice may contribute to worsening of blood pressure control.

Although hypertension is common in patients with diabetes, diabetes is not considered a cause.

1. 1. Brown JM, Siddiqui M, Calhoun DA, et al: The unrecognized prevalence of primary aldosteronism: A cross-sectional study. Ann Intern Med 173(1):10–20, 2020. doi:10.7326/M20-0065

In many cases of hypertension, sodium transport across the cell wall is abnormal, because the sodium-potassium pump (Na+, K+-ATPase) is defective or inhibited or because permeability to sodium ions is increased. The result is increased intracellular sodium, which makes the cell more sensitive to sympathetic stimulation. Calcium follows sodium, so accumulation of intracellular calcium may be responsible for the increased sensitivity. Because Na+, K+-ATPase may pump norepinephrine back into sympathetic neurons (thus inactivating this neurotransmitter), inhibition of this mechanism could also enhance the effect of norepinephrine, increasing BP. Defects in sodium transport may occur in children who are normotensive but have a parent with hypertension.

Sympathetic stimulation increases blood pressure, usually more in patients with elevated BP and hypertension than in patients who are normotensive. Whether this hyperresponsiveness resides in the sympathetic nervous system or in the myocardium and vascular smooth muscle is unknown.

A high resting pulse rate, which may result from increased sympathetic nervous activity, is a well-known predictor of hypertension.

In some patients with hypertension, circulating plasma catecholamine levels during rest are higher than normal.

The renin-angiotensin-aldosterone system helps regulate blood volume and therefore blood pressure. Renin, an enzyme formed in the juxtaglomerular apparatus, catalyzes conversion of angiotensinogen to angiotensin I. This inactive product is cleaved by angiotensin-converting enzyme (ACE), mainly in the lungs but also in the kidneys and brain, to angiotensin II, a potent vasoconstrictor that also stimulates autonomic centers in the brain to increase sympathetic discharge and stimulates release of aldosterone and vasopressin. Aldosterone and vasopressin cause sodium and water retention, elevating BP. Aldosterone also enhances potassium excretion; low plasma potassium (< 3.5 mEq/L [< 3.5 mmol/L]) increases vasoconstriction through closure of potassium channels. Angiotensin III, present in the circulation, stimulates aldosterone release as actively as angiotensin II but has much less pressor activity. Because chymase enzymes also convert angiotensin I to angiotensin II, medications that inhibit ACE do not fully suppress angiotensin II production.

Renin secretion is controlled by at least 4 mechanisms, which are not mutually exclusive:

• A renal vascular receptor responds to changes in tension in the afferent arteriolar wall

• A macula densa receptor detects changes in the delivery rate or concentration of sodium chloride in the distal tubule

• Circulating angiotensin has a negative feedback effect on renin secretion

• Sympathetic nervous system stimulates renin secretion mediated by beta-receptors (via the renal nerve)

Angiotensin is generally acknowledged to be responsible for renovascular hypertension, at least in the early phase, but the role of the renin-angiotensin-aldosterone system in primary hypertension is not established. However, in patients with African ancestry and older patients with hypertension, renin levels tend to be low (1). Older patients also tend to have low angiotensin II levels.

Hypertension due to chronic renal parenchymal disease (renoprival hypertension) results from the combination of a renin-dependent mechanism and a volume-dependent mechanism. In most cases, increased renin activity is not evident in peripheral blood. Hypertension is typically moderate and sensitive to sodium and water balance.

Deficiency of a vasodilator (eg, bradykinin, nitric oxide) rather than excess of a vasoconstrictor (eg, angiotensin, norepinephrine) may cause hypertension. Reductions in nitric oxide occur with aging, and this reduction contributes to salt sensitivity (ie, lesser amounts of salt ingestion will raise BP higher compared to younger people—2).

Reduction in nitric oxide due to stiff arteries is linked to salt-sensitive hypertension, an inordinate increase of > 10 to 20 mm Hg systolic BP after a large sodium load (eg, a salty meal).

If the kidneys do not produce adequate amounts of vasodilators (because of renal parenchymal disease or bilateral nephrectomy), blood pressure can increase.

Vasodilators and vasoconstrictors (mainly endothelin) are also produced in endothelial cells. Therefore, endothelial dysfunction greatly affects blood pressure.

No pathologic changes occur early in hypertension. Severe or prolonged hypertension damages target organs (primarily the cardiovascular system, brain, and kidneys), increasing risk of

• Coronary artery disease (CAD) and myocardial infarction (MI)

• Heart failure

• Stroke (particularly hemorrhagic)

• Renal failure

• Death

The mechanism involves development of generalized arteriolosclerosis and acceleration of atherogenesis. Arteriolosclerosis is characterized by medial hypertrophy, hyperplasia, and hyalinization; it is particularly apparent in small arterioles, notably in the eyes and the kidneys. In the kidneys, the changes narrow the arteriolar lumen, increasing TPR; thus, hypertension leads to more hypertension. Furthermore, once arteries are narrowed, any slight additional shortening of already hypertrophied smooth muscle reduces the lumen to a greater extent than in normal-diameter arteries. These effects may explain why the longer hypertension has existed, the less likely specific treatment (eg, renovascular surgery) for secondary causes is to restore blood pressure to normal.

Because of increased afterload, the left ventricle gradually hypertrophies, causing diastolic dysfunction. The ventricle eventually dilates, causing dilated cardiomyopathy and heart failure due to systolic dysfunction often worsened by arteriosclerotic coronary artery disease. Thoracic aortic dissection is typically a consequence of hypertension; almost all patients with abdominal aortic aneurysms have hypertension.

1. 1. Williams SF, Nicholas SB, Vaziri ND, Norris KC. African Americans, hypertension and the renin angiotensin system. World J Cardiol 6(9):878-889, 2014. doi:10.4330/wjc.v6.i9.878

2. 2. Fujiwara N, Osanai T, Kamada T, et al: Study on the relationship between plasma nitrite and nitrate level and salt sensitivity in human hypertension: modulation of nitric oxide synthesis by salt intake. Circulation 101:856–861, 2000.

The blood pressure used for formal diagnosis should be an average of 2 or 3 measurements taken at different times with the patient:

• Seated in a chair (not examination table) for > 5 minutes, feet on floor, back supported

• With their limb supported at heart level with no clothing covering the area of cuff placement

• Having had no exercise, caffeine, or smoking for at least 30 minutes

At the first visit, measure BP in both arms; subsequent measurements should use the arm that gave the higher reading.

A properly sized BP cuff is applied to the upper arm. An appropriately sized cuff covers two thirds of the biceps; the bladder is long enough to encircle > 80% of the arm, and bladder width equals at least 40% of the arm’s circumference. Thus, patients with obesity usually require large cuffs. The clinician inflates the cuff above the expected systolic pressure and gradually releases the air while listening over the brachial artery. The pressure at which the first heartbeat is heard as the pressure falls is systolic BP. Total disappearance of the sound marks diastolic BP. The same principles are followed to measure BP in a forearm (radial artery) and thigh (popliteal artery). Mechanical devices should be calibrated periodically; automated readers are often inaccurate (1).

BP is measured in both arms because BP that is > 15 mm Hg higher in one arm than the other requires evaluation of the upper vasculature.

BP is measured in a thigh (with a much larger cuff) to rule out coarctation of the aorta, particularly in patients with diminished or delayed femoral pulses; with coarctation, BP is significantly lower in the legs.

If BP is in the stage 1 hypertensive range or is markedly labile, more BP measurements are desirable. BP measurements may be sporadically high before hypertension becomes sustained; this phenomenon probably accounts for “white coat hypertension,” in which BP is elevated when measured in the physician’s office but normal when measured at home or by ambulatory BP monitoring.

Home or ambulatory BP monitoring is indicated when "white coat hypertension" is suspected. In addition, ambulatory BP monitoring also may be indicated when "masked hypertension" (a condition in which BP measured at home is higher than values obtained in the clinician's office) is suspected, typically in patients who demonstrate sequelae of hypertension without evidence of hypertension according to in-office measurements.

The history includes the

• Duration of hypertension and previously recorded BP levels

• History or symptoms of coronary artery disease, heart failure, or obstructive sleep apnea

• Symptoms of or personal or family history of other relevant coexisting disorders (eg, stroke, renal dysfunction, peripheral arterial disease, dyslipidemia, diabetes, gout)

• Use of medications that predispose to hypertension (eg, NSAIDs, estrogen-containing oral contraceptives)

• Sleep duration

Social history includes exercise levels and use of tobacco, alcohol, and stimulants (including medications and illicit drugs).

A dietary history focuses on intake of salt and stimulants (eg, tea, coffee, caffeine-containing sodas, energy drinks).

The physical examination includes measurement of height, weight, and waist circumference; funduscopic examination for retinopathy; auscultation for bruits in the neck and abdomen; and a full cardiac, respiratory, and neurologic examination. The abdomen is palpated for kidney enlargement and abdominal masses. Peripheral arterial pulses are evaluated; diminished or delayed femoral pulses suggest aortic coarctation, particularly in patients < 30 years. A unilateral renal artery bruit may be heard in thin patients with renovascular hypertension.

After hypertension is diagnosed based on blood pressure measurements, testing is needed to

• Detect target-organ damage

• Identify cardiovascular risk factors

The more severe the hypertension and the younger the patient, the more extensive is the evaluation. Tests may include

• Urinalysis and urinary albumin:creatinine ratio; if abnormal, consider renal ultrasonography

• Lipid panel, complete metabolic panel (including creatinine, potassium, and calcium), fasting plasma glucose

• ECG

• Sometimes measurement of thyroid-stimulating hormone levels

• Sometimes measurement of plasma free metanephrines (to detect pheochromocytoma)

• Sometimes a sleep study

Depending on results of the examination and initial tests, other tests may be needed.

Renal ultrasonography to evaluate kidney size may provide useful information if urinalysis detects albuminuria (proteinuria), casts, or microhematuria, or if serum creatinine or cystatin C is elevated.

Patients with hypokalemia unrelated to diuretic use are evaluated for high salt intake and for primary aldosteronism by measuring plasma aldosterone levels and plasma renin activity. Primary aldosteronism is present in about 10 to 20% of patients with resistant hypertension, which is much higher than previous estimates (2, 3).

On ECG, a broad, notched P-wave indicates atrial hypertrophy and, although nonspecific, may be one of the earliest signs of hypertensive heart disease. Elevated QRS voltage with or without evidence of ischemia, may occur later and indicates left ventricular hypertrophy (LVH). When LVH is seen on ECG, echocardiography is often done.

If coarctation of the aorta is suspected, echocardiography, CT, or MRI helps confirm the diagnosis.

Patients with labile, significantly elevated BP and symptoms such as headache, palpitations, tachycardia, excessive perspiration, tremor, and pallor are screened for pheochromocytoma by measuring plasma free metanephrines and for hyperthyroidism, first by measuring thyroid-stimulating hormone (TSH). A sleep study should also be strongly considered in those whose history suggests sleep apnea.

Left Ventricular Hypertrophy on ECG

Image

© Springer Science+Business Media

Patients with symptoms suggesting Cushing syndrome, systemic rheumatic diseases, eclampsia, acute porphyria, hyperthyroidism, myxedema, acromegaly, or central nervous system (CNS) disorders also require further evaluation.

1. 1. Muntner P, Shimbo D, Carey RM, et al: Measurement of blood pressure in humans: A scientific statement from the American Heart Association. Hypertension 73:e35–e66, 2019.

2. 2. Burrello J, Monticone S, Losano I, et al: Prevalence of Hypokalemia and Primary Aldosteronism in 5100 Patients Referred to a Tertiary Hypertension Unit. Hypertension 2020;75(4):1025-1033. doi:10.1161/HYPERTENSIONAHA.119.14063

3. 3. Mulatero P, Stowasser M, Loh KC, et al: Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents. J Clin Endocrinol Metab 2004;89(3):1045-1050. doi:10.1210/jc.2003-031337

Lifestyle modifications are recommended for all patients with elevated BP or any stage hypertension (see also Table 15. Nonpharmacological Interventions in 2017 Hypertension Guidelines). The best proven nonpharmacologic interventions for prevention and treatment of hypertension include the following:

• Increased physical activity, ideally with a structured exercise program

• Weight loss if the patient has overweight or obesity

• Healthy diet rich in fruits, vegetables, whole grains, and low-fat dairy products, with reduced saturated and total fat content

• Reduced dietary sodium to < 1500 mg/day (< 3.75 g sodium chloride) optimally, but at least a 1000 mg/day reduction

• Enhanced dietary potassium intake, unless contraindicated due to chronic kidney disease or use of medications that reduce potassium excretion

• Moderation in alcohol intake in those who drink alcohol to ≤ 2 drinks daily for men and ≤ 1 drink daily for women (one drink is about 355 mL [12 oz] of beer, 148 mL [5 oz] of wine, or 44 mL [1.5 oz] distilled spirits)

• Smoking cessation

Adequate sleep duration (> 6 hours/night) is also recommended. Short sleep duration (typically defined as < 5 or 6 hours per night in adults, has been associated with hypertension (4). For example, data suggest that optimizing sleep quality and duration (> 6 hours/night) improves blood pressure control in patients with chronic kidney disease (5).

Dietary modifications can also help control diabetes, obesity, and dyslipidemia. Patients with uncomplicated hypertension do not need to restrict their activities as long as blood pressure is controlled.

(See also Medications for Hypertension.)

The decision to treat with medication is based on the BP level and the presence of atherosclerotic cardiovascular disease (ASCVD) or its risk factors (see table Initial Approach to Management of High Blood Pressure). The presence of diabetes or kidney disease is not factored in separately because these diseases are part of ASCVD risk assessment.

An important part of management is continued reassessment. If patients are not at goal BP, clinicians should strive to optimize adherence before switching or adding medications.

Medication selection is based on several factors, including comorbidities and contraindications. For most patients, when selecting an agent for monotherapy, initial treatment may be with any of the following medication classes:

• Angiotensin-converting enzyme (ACE) inhibitor

• Angiotensin II receptor blocker (ARB)

• Dihydropyridine calcium channel blocker

In addition, some experts recommend that for patients of African ancestry who are candidates for monotherapy, a calcium channel blocker or a thiazide diuretic should be used initially (unless patients also have stage 3 or higher chronic kidney disease). The preference for a calcium channel blocker or a thiazide diuretic in patients of African ancestry is based on evidence from randomized trials showing that these classes of medications have superior efficacy in lowering blood pressure and rates of cardiovascular events than ACE inhibitors or ARBs (6, 7, 8, 9). However, subsequent data suggest that despite the use of this race-based approach, control of hypertension and racial disparities in blood pressure control have not improved (10). Thus, some experts favor an individualized approach to therapeutic selection rather than a race-based approach. In addition, there is substantial variability in blood pressure response within racial groups (11).

When combination therapy with 2 antihypertensive agents is selected, options include either an ACE inhibitor or ARB combined with either a diuretic or a calcium channel blocker. Many combinations are available as single pills, which are preferable to improve patient adherence (12, 13).

Signs of hypertensive emergencies require immediate blood pressure reduction with parenteral antihypertensives.

Some antihypertensives are avoided in certain disorders (eg, ACE inhibitors in severe aortic stenosis) whereas others are preferred for certain disorders (eg, calcium channel blockers for angina pectoris, ACE inhibitors or ARBs for diabetes with proteinuria—see tables Initial Choice of Antihypertensive Medication Class and Antihypertensives for Patients With Comorbidities).

If the goal BP is not achieved within 1 month, assess adherence and reinforce the importance of following treatment. If patients are adherent, the dose of the initial medication can be increased or a second medication added (selected from among the medications recommended for initial treatment). Note that an ACE inhibitor and an ARB should not be used together. Therapy is titrated frequently. If target BP cannot be achieved with 2 medications, a third medication from the initial group is added. If such a third medication is not tolerated or is contraindicated, a medication from another class (eg, aldosterone antagonist) can be used. Patients with such difficult to control BP may benefit from consultation with a hypertension specialist.

If initial systolic BP is > 160 mm Hg, 2 medications should be initiated regardless of cardiovascular disease risk. An appropriate combination and dose are determined. For resistant hypertension (BP remains above goal despite use of 3 different antihypertensive medications), 4 or more medications are commonly needed.

Achieving adequate blood pressure control often requires several evaluations and changes in pharmacotherapy. Reluctance to titrate or add medications to control BP must be overcome. Nonadherence to therapy, particularly because lifelong treatment is required, can interfere with adequate BP control. Education, with empathy and support, is essential for success.

Percutaneous catheter-based radiofrequency ablation of the sympathetic nerves in the renal artery is used in Europe and Australia for resistant hypertension. Several industry-funded sham-controlled studies with different patient populations (eg, those with untreated hypertension [14], treated hypertension [15], or resistant hypertension [16]) have demonstrated statistically and/or clinically significant reductions in systolic blood pressure. However, whether these devices reduce major cardiovascular events remains uncertain. Thus, sympathetic ablation should be considered experimental and used only in centers with extensive experience.

A physical intervention to lower blood pressure involves stimulating the carotid baroreceptor with a device surgically implanted around the carotid body. A battery attached to the device, much like a pacemaker, is designed to stimulate the baroreceptor and, in a dose-dependent manner, lower blood pressure. Long-term follow-up of patients with resistant hypertension who were included in earlier pivotal trials suggests that baroreflex activation therapy maintained its efficacy for persistent reduction of office BP without major safety issues (17). However, the 2017 American College of Cardiology/American Heart Association guidelines concluded that studies have not provided sufficient evidence to recommend the use of these devices in managing resistant hypertension (18).

1. 1. Gomadam P, Shah A, Qureshi W, et al. Blood pressure indices and cardiovascular disease mortality in persons with or without diabetes mellitus. J Hypertens 36(1):85-92, 2018. doi:10.1097/HJH.0000000000001509

2. 2. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years: A Randomized Clinical Trial. JAMA 315(24):2673-2682, 2016. doi:10.1001/jama.2016.7050

3. 3. White WB, Wakefield DB, Moscufo N, et al. Effects of Intensive Versus Standard Ambulatory Blood Pressure Control on Cerebrovascular Outcomes in Older People (INFINITY). Circulation 140(20):1626-1635, 2019. doi:10.1161/CIRCULATIONAHA.119.041603

4. 4. Thomas SJ, Calhoun D. Sleep, insomnia, and hypertension: current findings and future directions. J Am Soc Hypertens 11(2):122-129, 2017. doi:10.1016/j.jash.2016.11.008

5. 5. Ali W, Gao G, Bakris GL. Improved Sleep Quality Improves Blood Pressure Control among Patients with Chronic Kidney Disease: A Pilot Study. Am J Nephrol 51(3):249-254, 2020. doi:10.1159/000505895

6. 6. Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents [published correction appears in N Engl J Med 1994 Jun 9;330(23):1689]. N Engl J Med 1993;328(13):914-921. doi:10.1056/NEJM199304013281303

7. 7. Yamal JM, Oparil S, Davis BR, et alJ Am Soc Hypertens 2014;8(11):808-819. doi:10.1016/j.jash.2014.08.003

8. 8. Wright JT Jr, Harris-Haywood S, Pressel S, et al. Clinical outcomes by race in hypertensive patients with and without the metabolic syndrome: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2008;168(2):207-217. doi:10.1001/archinternmed.2007.66

9. 9. Hall WD, Reed JW, Flack JM, Yunis C, Preisser J. Comparison of the efficacy of dihydropyridine calcium channel blockers in African American patients with hypertension. ISHIB Investigators Group. International Society on Hypertension in Blacks. Arch Intern Med 158(18):2029-2034, 1998. doi: 10.1001/archinte.158.18.2029

10. 10. Egan BM, Li J, Sutherland SE, Rakotz MK, Wozniak GD. Hypertension Control in the United States 2009 to 2018: Factors Underlying Falling Control Rates During 2015 to 2018 Across Age- and Race-Ethnicity Groups. Hypertension 78(3):578-587, 2021. doi:10.1161/HYPERTENSIONAHA.120.16418

11. 11. Mokwe E, Ohmit SE, Nasser SA, et al. Determinants of blood pressure response to quinapril in black and white hypertensive patients: the Quinapril Titration Interval Management Evaluation trial. Hypertension 2004;43(6):1202-1207. doi:10.1161/01.HYP.0000127924.67353.86

12. 12. Parati G, Kjeldsen S, Coca A, Cushman WC, Wang J. Adherence to Single-Pill Versus Free-Equivalent Combination Therapy in Hypertension: A Systematic Review and Meta-Analysis. Hypertension 77(2):692-705, 2021. doi:10.1161/HYPERTENSIONAHA.120.15781

13. 13. Williams B, Mancia G, Spiering W, et al. 2018 Practice Guidelines for the management of arterial hypertension of the European Society of Hypertension and the European Society of Cardiology: ESH/ESC Task Force for the Management of Arterial Hypertension [published correction appears in J Hypertens 2019 Feb;37(2):456]. J Hypertens 8;36(12):2284-2309, 2018. doi:10.1097/HJH.0000000000001961

14. 14. Böhm M, Kario K, Kandzari DE, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial. Lancet 395(10234):1444-1451, 2020. doi:10.1016/S0140-6736(20)30554-7

15. 15. Mahfoud F, Kandzari DE, Kario K, et al. Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial. Lancet 399(10333):1401-1410, 2022. doi:10.1016/S0140-6736(22)00455-X

16. 16. Bhatt DL, Vaduganathan M, Kandzari DE, et al. Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 Trial. Lancet 400(10361):1405-1416, 2022. doi:10.1016/S0140-6736(22)01787-1

17. 17. de Leeuw PW, Bisognano JD, Bakris GL, Nadim MK, Haller H, Kroon AA, DEBuT-T and Rheos Trial Investigators: Sustained reduction of blood pressure with baroreceptor activation therapy: Results of the 6-year open follow-up. Hypertension 69:836–843, 2017.

18. 18. Whelton PK, Carey RM, Aronow WS, et al: 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 71(6):e13–e115, 2018. doi: 10.1161/HYP.0000000000000065

1. 1. Bourdillon MT, Song RJ, Musa Yola I, Xanthakis V, Vasan RS. Prevalence, Predictors, Progression, and Prognosis of Hypertension Subtypes in the Framingham Heart Study. J Am Heart Assoc 11(6):e024202, 2022. doi:10.1161/JAHA.121.024202

2. 2. Kannel WB, Gordon T, Schwartz MJ. Systolic versus diastolic blood pressure and risk of coronary heart disease. The Framingham study. Am J Cardiol 27(4):335-346, 1971. doi:10.1016/0002-9149(71)90428-0

3. 3. Dziedziak J, Zaleska-Żmijewska A, Szaflik JP, Cudnoch-Jędrzejewska A. Impact of Arterial Hypertension on the Eye: A Review of the Pathogenesis, Diagnostic Methods, and Treatment of Hypertensive Retinopathy. Med Sci Monit 28:e935135, 2022. doi:10.12659/MSM.935135