Pathophysiology is a study which explains the function of the body as it relates to diseases and conditions. Thepathophysiology of hypertension is an area which attempts to explain mechanistically the causes ofhypertension, which is a chronic disease characterized by elevation ofblood pressure. Hypertension can be classified by cause as eitheressential (also known as primary oridiopathic) orsecondary. About 90–95% of hypertension is essential hypertension.[1][2][3][4] Some authorities define essential hypertension as that which has no known explanation, while others define its cause as being due to overconsumption of sodium and underconsumption of potassium.Secondary hypertension indicates that the hypertension is a result of a specific underlying condition with a well-known mechanism, such as chronic kidney disease, narrowing of the aorta or kidney arteries, or endocrine disorders such as excessaldosterone,cortisol, orcatecholamines. Persistent hypertension is a major risk factor for hypertensive heart disease, coronary artery disease, stroke, aortic aneurysm, peripheral artery disease, and chronic kidney disease.[5]
Single gene mutations can causeMendelian forms ofhigh blood pressure;[7] ten genes have been identified which cause these monogenic forms ofhypertension.[7][8] These mutations affect blood pressure by alteringkidney salt handling.[9][10] There is greater similarity inblood pressure within families than between families, which indicates a form ofinheritance,[11] and this is not due to shared environmental factors.[12] With the aid ofgenetic analysis techniques, astatistically significant linkage of blood pressure to severalchromosomal regions, including regions linked to familial combinedhyperlipidemia, was found.[13][14][15][16][17] These findings suggest that there are manygenetic loci, in the general population, each with small effects on blood pressure. Approximately 280 genetic variants are affiliated with being at risk for high blood pressure, and they lead to other cardiovascular diseases such as hypertension or coronary artery disease as well. Overall, however, identifiable single-gene causes of hypertension are uncommon, consistent with a multifactorial cause of essential hypertension.[2][10][18][19]
The mechanisms of increased sympathetic nervous system activity in hypertension involve alterations inbaroreflex andchemoreflex pathways at both peripheral and central levels.Arterial baroreceptors are reset to a higher pressure in hypertensive patients, and this peripheral resetting reverts to normal when arterial pressure is normalized.[25][26][27] Furthermore, there iscentral resetting of theaortic baroreflex in hypertensive patients, resulting in suppression of sympathetic inhibition after activation of aortic baroreceptor nerves. This baroreflex resetting seems to be mediated, at least partly, by a central action ofangiotensin II.[28][29][30] Additional small-moleculemediators that suppress baroreceptor activity and contribute to exaggerated sympathetic drive in hypertension includereactive oxygen species andendothelin.[31][32] Some studies have shown that hypertensive patients manifest greatervasoconstrictor responses to infusednorepinephrine thannormotensive controls.[33] And that hypertensive patients do not show the normal response to increased circulating norepinephrinelevels which generally induces downregulation ofnoradrenergic receptor, and it is believed that this abnormal response isgeneticallyinherited.[34]
Exposure tostress increases sympathetic outflow, and repeated stress-induced vasoconstriction may result invascular hypertrophy, leading to progressive increases inperipheral resistance and blood pressure.[2] This could partly explain the greater incidence of hypertension inlower socioeconomic groups, since they must endure greater levels of stress associated with daily living. Persons with a family history of hypertension manifest augmented vasoconstrictor and sympathetic responses to laboratory stressors, such ascold pressor testing andmental stress, that may predispose them to hypertension. This is particularly true of young African Americans. Exaggerated stress responses may contribute to the increased incidence of hypertension in this group.[35] For patients having hypertension, higherheart rate variability (HRV) is a risk factor foratrial fibrillation.[36]
Resistant hypertension can be treated by electrically stimulating thebaroreflex with a pacemaker-like device.[37]
Another system maintaining theextracellular fluid volume,peripheral resistance, and that if disturbed may lead to hypertension, is therenin–angiotensin–aldosterone system.Renin is a circulatingenzyme that participates in maintainingextracellular volume and arterialvasoconstriction, therefore contributing to regulation ofblood pressure. It performs this function by breaking down (hydrolysing)angiotensinogen, secreted from the liver, into the peptideangiotensin I. Angiotensin I is further cleaved by an enzyme that is located primarily but not exclusively in thepulmonary circulation bound toendothelium; that enzyme isangiotensin converting enzyme (ACE). This cleavage producesangiotensin II, the most vasoactive peptide.[38][39] Angiotensin II is a potent constrictor of all blood vessels. It acts on the musculature of arteries, raising peripheral resistance and thereby elevating blood pressure. Angiotensin II also causes the adrenal glands to releasealdosterone, which stimulates the epithelial cells of the kidneys to increase re-absorption of salt and water, leading to raised blood volume and raised blood pressure. So elevatedrenin levels in the blood (normally 1.98-2.46 ng/ml in the upright position)[40] leads to hypertension.[2][41]
Theendothelium of blood vessels produces an extensive range of substances that influenceblood flow and, in turn, is affected by changes in the blood and the pressure of blood flow. For example, localnitric oxide andendothelin, which are secreted by the endothelium, are the major regulators of vascular tone and blood pressure. In patients with essential hypertension, the balance between thevasodilators and thevasoconstrictors is upset, which leads to changes in the endothelium and sets up a "vicious cycle" that contributes to the maintenance of high blood pressure. In patients with hypertension,endothelial activation and damage also lead to changes invascular tone, vascular reactivity, andcoagulation andfibrinolytic pathways. Alterations in endothelial function are a reliable indicator of target organ damage and atherosclerotic disease, as well as prognosis.[45]
Endothelin is a potent vasoactive peptide produced by endothelial cells that has bothvasoconstrictor and vasodilator properties. Circulating endothelin levels are increased in some hypertensive patients,[50][51] particularlyAfrican Americans and persons with hypertension.[50][52][53][54]
Sodium/potassium ratio hypothesis of essential hypertension
A 2007 review article states that while excessive sodium consumption has long been recognized as contributing to the risk of hypertension, "potassium, the main intracellular cation, has usually been viewed as a minor factor in the pathogenesis of hypertension. However, abundant evidence indicates that a potassium deficit has a critical role in hypertension and its cardiovascular sequelae." The authors state that modern, western, high sodium, low potassium diets result in corresponding changes in intracellular concentration of these, the two most important cations in animal cells. This imbalance leads to contraction of vascular smooth muscle, restricting blood flow and so driving up blood pressure. The authors cite studies which show that potassium supplementation is effective in reducing hypertension.[55]
Epidemiological support for this hypothesis can be found in a 2014 meta-analysis which states that "the sodium-to-potassium ratio appears to be more strongly associated with blood pressure outcomes than either sodium or potassium alone in hypertensive adult populations.".[56]
Basic science discoveries have implicated the immune system as in the development of hypertension in animal models.[57] Population studies in humans have reported that higher levels of certain inflammatory cytokines are associated with greater risk of hypertension development.[58][59][60]
^Mark AL (December 1996). "The sympathetic nervous system in hypertension: a potential long-term regulator of arterial pressure".Journal of Hypertension Supplement.14 (5): S159–65.PMID9120673.
^Sesso, Howard D.; Wang, Lu; Buring, Julie E.; Ridker, Paul M.; Gaziano, J. Michael (February 2007). "Comparison of interleukin-6 and C-reactive protein for the risk of developing hypertension in women".Hypertension.49 (2):304–310.doi:10.1161/01.HYP.0000252664.24294.ff.ISSN1524-4563.PMID17159088.
Riyaz S. Patel, Stefano Masi, Stefano Taddei, Understanding the role of genetics in hypertension, European Heart Journal, Volume 38, Issue 29, 01 August 2017, Pages 2309–2312,https://doi.org/10.1093/eurheartj/ehx273
