cardiovascular disorders
Hypertension
Pathophysiology of Hypertension
Because blood pressure equals cardiac output (CO) × total peripheral vascular resistance (TPR), pathogenic mechanisms involve Increased CO Increased TPR Both In most patients, CO is normal or slightly increased, and TPR is increased. This pattern is typical of primary hypertension and hypertension due to Primary Aldosteronism , In other patients, CO is increased (possibly because of venoconstriction in large veins), and TPR is inappropriately normal for the level of CO. Later in the disorder, TPR increases and CO returns to normal, probably because of autoregulation. Some disorders that increase CO (eg, Hyperthyroidism , Plasma volume tends to decrease as BP increases; rarely, plasma volume remains normal or increases. Plasma volume tends to be high in hypertension due to primary aldosteronism or renal parenchymal disease and may be quite low in hypertension due to pheochromocytoma. Renal blood flow gradually decreases as diastolic BP increases and arteriolar sclerosis begins. Glomerular filtration rate (GFR) remains normal until late in the disorder; as a result, the filtration fraction is increased. Coronary, cerebral, and muscle blood flow is maintained unless severe atherosclerosis coexists in these vascular beds. 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 pumpnorepinephrineback into sympathetic neurons (thus inactivating this neurotransmitter), inhibition of this mechanism could also enhance the effect ofnorepinephrine, 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, toangiotensin II, a potent vasoconstrictor that also stimulates autonomic centers in the brain to increase sympathetic discharge and stimulates release of aldosterone andvasopressin. Aldosterone andvasopressincause 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 asangiotensin IIbut has much less pressor activity. Because chymase enzymes also convert angiotensin I toangiotensin II, medications that inhibit ACE do not fully suppressangiotensin IIproduction. 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 ofsodium chloridein 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 ( 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. ) 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— Pathophysiology references ). 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 Overview of Coronary Artery Disease (CAD) and Heart Failure (HF) None Overview of Stroke (particularly hemorrhagic) Chronic Kidney Disease None Death The mechanism involves development of generalized Atherosclerosis 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 1.Williams SF, Nicholas SB, Vaziri ND, Norris KC. African Americans, hypertension and the renin angiotensin system.World J Cardiol6(9):878-889, 2014. doi:10.4330/wjc.v6.i9.878 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.Circulation101:856–861, 2000. 