Pathophysiology of Hypertension

Updated: May 18, 2017
Author: Seyed Mehrdad Hamrahian, MD; Chief Editor: Vecihi Batuman, MD, FASN 

Pathogenesis of Essential Hypertension

The pathogenesis of essential hypertension is multifactorial and highly complex. The kidney is both the contributing and the target organ of the hypertensive processes,[1] and the disease involves the interaction of multiple organ systems and numerous mechanisms of independent or interdependent pathways. Factors that play an important role in the pathogenesis of hypertension include genetics, activation of neurohormonal systems such as the sympathetic nervous system and renin-angiotensin-aldosterone system, obesity, and increased dietary salt intake.

Arterial hypertension is the condition of persistent elevation of systemic blood pressure (BP). BP is the product of cardiac output and total peripheral vascular resistance. Multiple factors are involved in short-term and long-term regulation of BP for adequate tissue perfusion; these include the following:

  • Cardiac output and circulatory blood volume

  • Vascular caliber, elasticity, and reactivity

  • Humoral mediators

  • Neural stimulation

Over the course of its natural history, essential hypertension progresses from occasional to established hypertension. After a long, invariable, asymptomatic period, persistent hypertension develops into complicated hypertension, in which target organ damage to the aorta and small arteries, heart, kidneys, retina, and central nervous system is evident.

The progression of essential hypertension begins with prehypertension in persons aged 10-30 years (by increased cardiac output); then advances to early hypertension in persons aged 20-40 years (in which increased peripheral resistance is prominent); then progresses to established hypertension in persons aged 30-50 years; and finally advances to complicated hypertension in persons aged 40-60 years.

Go to Hypertension, Hypertensive Heart Disease, and Hypertensive Emergencies for more complete information on these topics.


Factors Influencing BP Regulation

Regulation of normal blood pressure (BP) is a complex process. Arterial BP is a product of cardiac output and peripheral vascular resistance. Cardiac output is the product of stroke volume and heart rate. The factors affecting cardiac output include sodium intake, renal function, and mineralocorticoids. The inotropic effects occur via extracellular fluid volume augmentation and an increase in heart rate and contractility.

Peripheral vascular resistance is dependent upon the sympathetic nervous system (SNS), humoral factors, and local autoregulation. The vasculature is highly innervated by sympathetic fibers. The SNS produces its effects via the vasoconstrictor alpha effect or the vasodilator beta effect. Along the same line, the renal artery is highly innervated, with the sympathetic activation promoting sodium retention via increased renin secretion.

The role of renal nerves in BP control and in the pathogenesis of hypertension has been made evident by the effect of renal denervation (RDN) in animal model experiments.[2] The initial two clinical trials of RDN using a percutaneous radiofrequency procedure suggested that the procedure resulted in a reduction of BP in drug-resistant patients.[3, 4] However, the SYMPLICITY HTN-3 trial, which included a sham surgery arm, failed to demonstrate significant reductions in 24-hour ambulatory BP after RDN.[5] The physiologic mechanisms that account for the heterogeneous decrease in arterial BP following RDN remain unclear and may indicate factors more than simply high renal sympathetic activity. Of all of the variables examined that could influence BP outcomes, the extent of the RDN seems to be of great significance. Respectively, RDN might work if done properly and if used in the appropriate patient population.

Similarly, the role of the arterial baroreflex system in moment-to-moment regulation of BP is well known. Although electrical stimulation of baroreceptors can cause significant reduction in BP in humans with treatment-resistant hypertension, its importance in long-term BP control remains controversial.[6] These studies confirm the role of the SNS as a component in the pathogenesis of hypertension.

The humoral actions on peripheral vascular resistance are a result of mediators, such as vasoconstrictors (eg, endothelin [ET], angiotensin II [Ang II], catecholamines) or vasodilators (eg, nitric oxide [NO], prostaglandins, kinins). In addition, blood viscosity, vascular wall shear conditions (rate and stress), and blood flow velocity (mean and pulsatile components) have potential relevance with regard to the regulation of BP in humans by vascular and endothelial function. Circulating blood volume is regulated by renal salt and water handling, a phenomenon that plays a particularly important role in salt-sensitive hypertension and in the setting of chronic kidney disease.

Autoregulation of BP

Autoregulatory mechanisms maintain the blood flow of most tissues over a wide range of BP according to their specific needs.[7]  Autoregulation of BP occurs by way of intravascular volume contraction and expansion regulated by the kidney, as well as via transfer of transcapillary fluid. Through the mechanism of pressure natriuresis, salt and water balance is achieved at heightened systemic pressure, as proposed by Guyton et al.[8] Interactions between cardiac output and peripheral vascular resistance are autoregulated to maintain a set BP in an individual. For example, constriction of the arterioles elevates arterial pressure by increasing total peripheral vascular resistance, whereas venular constriction leads to redistribution of the peripheral intravascular volume to the central circulation, thereby increasing preload and cardiac output.

Vasoreactivity and the role of the vascular endothelium

The vasoreactivity of the vascular bed, an important phenomenon mediating changes of hypertension, is influenced by the activity of vasoactive factors, reactivity of the smooth muscle cells, and structural changes in the vessel wall and vessel caliber, expressed by a lumen-to-wall ratio.

The vascular endothelium is considered to be a vital organ, in which synthesis of various vasodilating and constricting mediators occurs. The interaction of autocrine and paracrine factors takes place in the vascular endothelium, leading to growth and remodeling of the vessel wall and to the hemodynamic regulation of BP.

Numerous hormonal, humoral vasoactive, and growth and regulating peptides are produced in the vascular endothelium. These mediators include ET, Ang II, bradykinin, NO, and several other growth factors.

ET is a potent vasoconstrictor in humans and impairs renal pressure natriuresis. ET-1 is the predominant isoform and stimulates ET type A (ETA) receptor. Chronic ET-1 activation of ETA receptors in the kidneys may play a major role in the pathogenesis of hypertension. Bosentan and other ET-1 receptor antagonists have been beneficial in patients with pulmonary arterial hypertension; however, their role in the management of essential hypertension is limited because of their side effects, which include fluid retention and edema.

Ang II is a potent vasoconstrictor synthesized from angiotensin I with the help of an angiotensin-converting enzyme. Ang II also plays a key role in chronic BP regulation via activation of the Ang II type1 (AT1) receptor. It has direct sodium-retaining effects by increasing activities of the Na+/H+ exchanger and Na+/K+ ATPase in the proximal tubule, the Na+/K+/2Cl− transport in the loop of Henle, and multiple ion transporters in the distal nephron and collecting tubules. 

NO is another vasoactive substance manufactured in the endothelium. NO is produced mainly from L-arginine by endothelial NO synthase (eNOS). It is an extremely potent vasodilator that influences local autoregulation and other vital organ functions. Additionally, several growth factors are manufactured in the vascular endothelium; each of these plays an important role in atherogenesis and target organ damage. These factors include platelet-derived growth factor, fibroblast growth factor, and  insulin growth factor.


Etiology of Essential Hypertension

Essential hypertension (also called idiopathic hypertension) may be attributed to multiple factors, including genetic predisposition, excess dietary salt intake, and adrenergic tone, that may interact to produce hypertension. Essential hypertension accounts for 90% of human hypertension and can evolve into secondary hypertension, as renal function decreases. Thus, the distinction between primary and secondary forms of hypertension is not always clear in patients who have had uncontrolled hypertension for many years. 

Long-term regulation of daily blood pressure (BP) is closely linked with salt and water homeostasis. Increased BP raises renal sodium and water excretion, often called renal-pressure natriuresis or diuresis. Increased salt intake in persons who have normal kidney and neurohormonal functions has an insignificant effect on BP changes. These individuals are called “salt resistant.” In contrast, in “salt-sensitive” individuals with impaired kidney function, because of abnormal neurohormonal control or intrinsic kidney abnormalities, increased BP and subsequent pressure natriuresis or diuresis provide another means of maintaining salt and water balance. That is, sodium balance is maintained at a higher BP in patients with primary hypertension, indicating that pressure natriuresis has been reset.

There are two types of genetic causes of hypertension: rare familial monogenic hypertensive disorders and classic quantitative trait form. 

The rare monogenic disorders, which account only for a very small percentage of hypertension in humans, increase renal sodium reabsorption and induce low renin hypertension due to volume expansion. They compromise eight monogenic hypertensive syndromes that are subdivided based on aldosterone level and the presence of special features.[9]

Syndromes with elevated aldosterone level include the following:

  • Glucocorticoid remediable aldosteronism (GRA) or familial hyperaldosteronism type I (FH1). The underlying gene is CYP11B2.
  • Gordon hyperkalemia-hypertension syndrome or pseudohypoaldosteronism type II (PHA2). The genes involved are WNK kinases 1 and 4 ( WNK1, WNK4) or KLHL3 and CUL3.
  • Familial hyperaldosteronism type III (FH3). The mutated gene is KCNJ5.

Syndromes with low aldosterone level include the following:

  • Liddle syndrome or pseudoaldosteronism. The mutated genes are SCNN1B and SCNN1G.
  • Syndrome of apparent mineralocorticoid excess. HSD11B2 is the involved gene.

Syndromes with low aldosterone level with special features include the following:

  • Congenital adrenal hyperplasia, due to 11-beta-hydroxylase deficiency (gene defect in  CYP11B1) CAH type IV or 17-alpha-hydroxylase deficiency (mutated  CYP17A1) CAH type V.
  • Autosomal dominant hypertension with exacerbation in pregnancy. The defect is in gene NR3C2.
  • Hypertension and brachydactyly syndrome. The mutated gene is PDE3A.

Gene linkage studies performed over recent decades have yielded only a few reproducible results. To understand the genetic basis of primary hypertension, one requires genotyping of hundreds of thousands of variants, a process made possible by genome-wide association studies (GWAS). This method searches the genome for small variations, called single nucleotide polymorphisms (SNPs) that occur more frequently in people with a particular disease than in people without that disease. Researchers using GWAS to search for gene variants that lead to primary hypertension have identified a large number of small-effect size genetic variants. In general, the effect size of a variant is inversely proportional to the frequency of the variant. That is, the rare monogenic familial gene-variants have large effect sizes, whereas the frequent BP-GWAS variants have too small of an effect size to be of any individual significance.

Although the SNP type is the most frequent kind of variant, other types exist as well, including gene polymorphism. A gene is polymorphic if more than one allele occupies that gene’s locus within a population. A polymorphic variant of a gene may lead to the abnormal expression of a gene or to the production of an abnormal form of the gene that may cause or be associated with a disease. Many studies have shown associations of gene polymorphisms and BP, but the genetic variants that contribute to essential hypertension remain unknown. One of the most widely studied polymorphisms is the angiotensine converting enzyme (ACE) gene insertion/deletion (I/D). ACE is the core enzyme in the renin-angiotensin-aldosterone system (RAAS). The II, ID and DD genotypes are associated with low, intermediate, and high ACE levels, respectively.[10] But studies searching for an association between the DD genotype and hypertension have had conflicting results. Despite these inconsistent findings, it is believed that genetic factors may account for up to 30- 50% of BP variance.[11]

Patients who develop hypertension are known to develop a systemic hypertensive response secondary to vasoconstrictive stimuli. Alterations in structural and physical properties of resistance arteries, as well as changes in endothelial function, are probably responsible for this abnormal behavior of the vasculature. Furthermore, vascular remodeling occurs over the years as hypertension evolves, thereby maintaining increased vascular resistance irrespective of the initial hemodynamic pattern.

Changes in vascular wall thickness affect the amplification of peripheral vascular resistance in hypertensive patients and result in the reflection of waves back to the aorta, increasing systolic BP.

One form of essential hypertension, termed high-output hypertension, results from decreased peripheral vascular resistance and concomitant cardiac stimulation by adrenergic hyperactivity and altered calcium homeostasis. A second mechanism manifests with normal or reduced cardiac output and elevated systemic vascular resistance (SVR) due to increased vasoreactivity. Another (and overlapping) mechanism is increased salt and water reabsorption (salt sensitivity) by the kidney, which increases circulating blood volume.

Finally, over the past several years, it has become apparent that an inflammatory process often accompanies hypertension. Activated immune cells infiltrate and alter the function and structure of various organs, including the vasculature and the kidney. The inflammatory process is not thought to cause hypertension on its own, but rather to intensify dysfunction of the kidney and the vasculature. That is, it promotes BP elevation as well as the end-organ damage associated with hypertension.[12, 13]


Hypertensive Emergencies and Target Organ Damage

Hypertensive emergencies are defined as a major sudden elevation in blood pressure (BP) associated with progressive and acute target-organ dysfunction. They are true medical emergencies requiring prompt treatment to reduce BP. The pathophysiology of hypertensive emergencies is not well understood. Failure of normal autoregulation and an abrupt rise in systemic vascular resistance (SVR) are typically the initial steps in the disease process. Increases in SVR are thought to occur from the release of humoral vasoconstrictors from the wall of a stressed vessel. The increased pressure within the vessel then starts a cycle of endothelial damage, local intravascular activation of the clotting cascade, fibrinoid necrosis of small blood vessels, and the release of more vasoconstrictors. If the process is not stopped, a cycle of further vascular injury, tissue ischemia, and autoregulatory dysfunction ensues.[14, 15]

The clinical presentation is easily classified according to the target organ involved. Single-organ involvement is found in approximately 83% of patients presenting with hypertensive emergencies. Two-organ involvement is found in 14% of patients, and multiorgan involvement (>3 organ systems) is found in approximately 3% of patients presenting with a hypertensive emergency.[16]

Hypertension and cardiovascular disease

During hypertensive emergencies, the left ventricle is unable to compensate for an acute rise in SVR. This leads to left ventricular failure and pulmonary edema or myocardial ischemia.

Chronic hypertension increases arterial stiffness, increases systolic BP, and widens pulse pressures. These factors decrease coronary perfusion pressures, increase myocardial oxygen consumption, and lead to the development of left ventricular hypertrophy (LVH).[17] In LVH, the myocardium undergoes structural changes in response to increased afterload. Cardiac myocytes respond with hypertrophy, allowing the heart to pump more strongly against the elevated pressure. However, the contractile function of the left ventricle remains normal until later stages. Eventually, LVH reduces the chamber lumen, limiting diastolic filling and stroke volume. The left ventricular diastolic function is markedly compromised in long-standing hypertension.

The mechanisms of diastolic dysfunction apparently include an aberration in the passive relaxation of the left ventricle during diastole. Over time, fibrosis may occur, further contributing to the poor compliance of the ventricle. As the left ventricle does not relax during early diastole, left ventricular end-diastolic pressure increases, further increasing left atrial pressure in late diastole. The exact determinants of left ventricular diastolic dysfunction have not been well studied; possibly, the abnormality is governed by abnormal calcium kinetics.

Cardiac involvement in hypertension manifests as LVH, left atrial enlargement, aortic root dilatation, atrial and ventricular arrhythmias, systolic and diastolic heart failure, and ischemic heart disease. LVH is associated with an increased risk of premature death and morbidity. A higher frequency of cardiac atrial and ventricular dysrhythmias and sudden cardiac death may exist. Possibly, increased coronary arteriolar resistance leads to reduced blood flow to the hypertrophied myocardium, resulting in angina despite clean coronary arteries. Hypertension, along with reduced oxygen supply and other risk factors, accelerates the process of atherogenesis, thereby further reducing oxygen delivery to the myocardium. Hypertension has also been associated with higher mortality in patients with ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI)/unstable angina (UA) or stable angina pectoris who undergo percutaneous coronary intervention.[18]

Hypertension and cerebrovascular disease

Cerebral autoregulation is the inherent ability of the cerebral vasculature to maintain a constant cerebral blood flow (CBF) across a wide range of perfusion pressures. Rapid rises in BP can cause hyperperfusion and increased CBF, which can lead to increased intracranial pressure and cerebral edema.[19] Patients with chronic hypertension can tolerate higher mean arterial pressures before they suffer disruption of their autoregulatory system. However, such patients also have increased cerebrovascular resistance and are more prone to cerebral ischemia when flow decreases, especially if the BP is lowered into normotensive ranges.[20]

Hypertension and renal disease

Hypertension is commonly observed in patients with kidney disease, with chronic hypertension causing pathologic changes to the small arteries of the kidney. As hypertensive damage occurs, the renal arteries develop endothelial dysfunction and impaired vasodilation, which alter renal autoregulation. When the renal autoregulatory system is disrupted, the intraglomerular pressure starts to vary directly with the systemic arterial pressure, thus offering no protection to the kidney during BP fluctuations. During a hypertensive crisis, this can lead to acute renal ischemia.

Volume expansion is the main cause of hypertension in patients with glomerular disease (nephrotic and nephritic syndrome). Hypertension in patients with vascular disease is the result of the activation of the renin-angiotensin system (RAS), which is often secondary to ischemia. The combination of volume expansion and the activation of the RAS is believed to be the main factor behind hypertension in patients with chronic renal failure.

The renin-angiotensin system

The activities of the RAS influence the progression of renal disease. Angiotensin II (Ang II) acts on the afferent and efferent arterioles, but more so on the efferent arterioles, leading to increased intraglomerular pressure and, in turn, to microalbuminuria. Reducing intraglomerular pressure using an angiotensin-converting enzyme (ACE) inhibitor or an Ang II receptor blocker (ARB) has been shown to be beneficial in patients with diabetic nephropathy, even if they are not hypertensive. The beneficial effect of ACE inhibitors on the progression of renal insufficiency in patients who are nondiabetic is less clear. The benefit of ACE inhibitors is greater in patients with more pronounced proteinuria.

Renovascular hypertension

The term renovascular hypertension (RVHT) denotes the causal relationship between anatomically evident arterial occlusive disease and elevated BP. RVHT is the clinical consequence of renin-angiotensin-aldosterone system (RAAS) activation. As demonstrated by Goldblatt et al,[21] renal artery occlusion creates ischemia, which triggers the release of renin and a secondary elevation in BP. Hyperreninemia promotes conversion of Ang I to Ang II, causing severe vasoconstriction and aldosterone release.

The ensuing cascade of events varies, depending on the presence of a functioning contralateral kidney. In the setting of two kidneys, with unilateral renal artery stenosis, aldosterone-mediated sodium and water retention is handled properly by the nonstenotic kidney, precluding volume from contributing to the Ang II–mediated hypertension. By contrast, in bilateral renal artery stenosis or in a solitary, ischemic kidney, there is little or no capacity for sodium and water excretion; hence, volume plays an additive role in the hypertension.

Hypertension and end-stage renal disease

Despite widespread treatment of hypertension in the United States, the incidence of end-stage renal disease continues to rise. The explanation for this rise may be concomitant diabetes mellitus, the progressive nature of hypertensive renal disease despite therapy, or a failure to reduce BP to a protective level. A reduction in renal blood flow in conjunction with elevated afferent glomerular arteriolar resistance increases glomerular hydrostatic pressure secondary to efferent glomerular arteriolar constriction. The result is glomerular hyperfiltration, followed by development of glomerulosclerosis and further impairment of renal function.

Hypertension and ocular changes

The pathophysiologic effects of hypertensive ocular changes can be divided into acute changes from malignant hypertension and chronic changes from long-term, systemic hypertension.

Optic changes that can result from malignant hypertension include the development of the following acute retinal lesions:

  • Focal intraretinal periarteriolar transudates

  • Inner retinal ischemic spots (cotton-wool spots)

  • Microaneurysms

  • Shunt vessels

  • Collaterals

Chronic hypertensive retinal changes include the following:

  • Arteriolosclerosis: Localized or generalized narrowing of vessels

  • Copper wiring and silver wiring of arterioles as a result of arteriolosclerosis

  • Arteriovenous (AV) nicking as a result of arteriolosclerosis

  • Retinal hemorrhages

  • Nerve fiber layer losses

  • Increased vascular tortuosity

  • Remodeling changes due to capillary nonperfusion, such as shunt vessels and microaneurysms

Hypertension and metabolic syndrome

The metabolic syndrome is an assemblage of metabolic risk factors that directly promote the development of atherosclerotic cardiovascular disease.[22, 23] Dyslipidemia, hypertension, and hyperglycemia are the most widely recognized metabolic risk factors. The combination of these risk factors leads to a prothrombotic, proinflammatory state in humans and identifies individuals who are at elevated risk for atherosclerotic cardiovascular disease.

Obesity is a growing major healthcare problem. The relationship between body mass index and BP is linear.[24]  Other predictors of obesity-associated hypertension are the visceral or retroperitoneal fat distribution.[25]  Hypertensive patients who are obese have a sympathetic overdrive, higher cardiac output due to increased renal sodium reabsorption and impaired renal-pressure natriuresis, and a rise in peripheral vascular resistance due to reduced endothelium-dependent vasodilation. Plasma aldosterone and endothelin are increased. The increase in cardiac output manifests secondary to increased preload. This results in elevated end-diastolic volume and pressure, leading to left ventricular dilatation. Left ventricular wall thickening occurs secondary to increased afterload, heightening the risk of congestive heart failure. The concomitant diabetes that is often present in patients who are obese produces a devastating effect on the kidneys and leads to a much higher incidence of renal failure. This can result in the complex and bidirectional relationship between chronic kidney disease and hypertension. Finally, obstructive sleep apnea confers an additional risk of resistant hypertension.