Pathology of Hypertension PDF

Pathology of Hypertension Pathology of Hypertension Dr. Aileen Azari-Yam M.D., Ph.D. _______________ 1 Page 489 2 Outline Normal blood pressure homeostasis Pathogenic mechanisms that underlie hypertension Hypertensio...

Pathology of Hypertension Pathology of Hypertension Dr. Aileen Azari-Yam M.D., Ph.D. _______________ 1 Page 489 2 Outline Normal blood pressure homeostasis Pathogenic mechanisms that underlie hypertension Hypertension-associated pathologic changes in vessels Etiology of secondary hypertension 3 Clinically significant hypertension Diastolic pressures > 80 mm Hg or Systolic pressures > 120 mm Hg 4 HTN, classification Secondary hypertension (10%)- identifiable underlying cause, e.g.: Adrenal disease, e.g.: Primary aldosteronism Cushing syndrome Pheochromocytoma Renal disease, e.g.: Renal artery stenosis Idiopathic (essential) hypertension (90%) 5 Hypertension complications Hypertension increases the risk of : Atherosclerosis Cardiac hypertrophy ♥ failure (hypertensive ♥ disease) Multi-infarct dementia Aortic dissection Renal failure Unfortunately, even severe hypertension can be clinically silent for years. 6 Malignant hypertension 5% of hypertensive persons show a rapidly rising blood pressure that, if untreated, leads to death within 1 to 2 years. Characteristics: Severe pressure elevations (i.e., systolic pressure > 200 mm Hg, diastolic pressure > 120 mm Hg) Renal failure Retinal hemorrhages and exudates 7  Blood pressure regulation Diverse influences on cardiac output (e.g., blood volume and myocardial contractility) and peripheral resistance (neural, humoral, and local effectors) impact the output blood pressure. 8 Cardiac output A function of stroke volume and ♥ rate The most important determinant of stroke volume is the filling pressure, which is regulated through sodium homeostasis ♥ rate and myocardial contractility both regulated by the α- and β-adrenergic systems, which also have important effects on vascular tone. 9 Peripheral resistance Regulated at the level of the arterioles by neural and hormonal inputs. Vascular tone reflects a balance between vasoconstrictors (including angiotensin II, catecholamines, and endothelin) and vasodilators (including kinins, prostaglandins, and NO). Resistance vessels show autoregulation, whereby increased blood flow induces vasoconstriction to protect tissues against hyperperfusion. Finally, blood pressure is fine-tuned by tissue pH and hypoxia to accommodate local metabolic demands. 10  Factors released from the kidneys, adrenals, and myocardium interact to influence vascular tone and to regulate blood volume by adjusting sodium balance. The kidneys and heart contain cells that sense changes in blood pressure or volume. 11 Renin A proteolytic enzyme Produced by renal juxtaglomerular cells (myoepithelial cells adjacent to the glomerular afferent arterioles) Released in response to Low blood pressure in afferent arterioles Elevated levels of circulating catecholamines Low sodium levels in the distal convoluted renal tubules Low cardiac output >>> ↓ GFR >>> ↑ sodium resorption by the prox. tubules 12  Renin Cleaves plasma angiotensinogen to angiotensin I, which in turn is converted to angiotensin II by ACE (a product of vascular endothelium) Angiotensin II raises blood pressure by (1) Inducing vascular contraction (2) Stimulating aldosterone secretion by the adrenal gland (3) Increasing tubular sodium resorption 13 The renal corpuscle 14 Adrenal glands Aldosterone >>> ↑ sodium resorption (and thus water) in the distal convoluted tubules >>> ↑ blood volume >>> ↑ blood pressure 15 Other factors The kidney also produces a variety of vascular relaxing substances (including prostaglandins and NO) that can counterbalance the vasopressor effects of angiotensin. 16 Myocardial natriuretic peptides Volume expansion >>> Released ANP from atrial and ventricular myocardium >>> inhibition of sodium resorption in the distal renal tubules >>> sodium excretion >>> diuresis ANP >>> systemic vasodilation 17 Key concepts, Blood Pressure Regulation
Blood pressure is determined by vascular resistance and cardiac output. Vascular resistance is regulated at the level of the arterioles, influenced by neural and hormonal inputs. Cardiac output is determined by heart rate and stroke volume, which is strongly influenced by blood volume. Blood volume is regulated mainly by renal sodium excretion or resorption. Renin, a major regulator of blood pressure, is secreted by the kidneys in response to decreased blood pressure in afferent arterioles. Renin cleaves angiotensinogen to angiotensin I; subsequent endothelial catabolism produces angiotensin II, which regulates blood pressure by increasing vascular SMC tone and by increasing adrenal aldosterone secretion, thereby increasing renal sodium resorption. 18 Mechanisms of Secondary Hypertension Renovascular hypertension ↓ ↑ ↑ Renal artery stenosis >>> glomerular flow and pressure in the afferent arteriole >>> renin secretion >>> blood volume and vascular tone (via angiotensin and aldosterone pathways) Primary hyperaldosteronism One of the most common causes of secondary hypertension. It may be idiopathic or less commonly caused by aldosterone-secreting adrenal adenomas. Single-gene disorders Severe but rare forms of hypertension Enzyme gene mutations involved in aldosterone metabolism (e.g., aldosterone synthase, 11β-hydroxylase, 17α-hydroxylase) Mutations affecting proteins that influence sodium reabsorption ↑ Liddle syndrome, caused by activating mutations in an epithelial Na+ channel protein >>> distal tubular reabsorption of sodium in response to aldosterone 19  Re me mb er Primary hyperaldosteronism fro m ad ren al lec tur e A group of conditions with chronic excess aldosterone secretion Primary from an autonomous overproduction of aldosterone >>> hypertension >>> suppression of the renin-angiotensin system Bilateral idiopathic hyperaldosteronism Adrenocortical neoplasm Familial hyperaldosteronism Secondary to an extra-adrenal cause such as: Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis) Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome) Pregnancy (due to estrogen-induced increases in plasma renin substrate) 20 Essential Hypertension, Mechanisms Vast majority of hypertension cases results from complex interactions between multiple genetic and environmental factors. 21 Essential Hypertension, Genetic factors Evidence: Comparisons of monozygotic and dizygotic twins Comparisons of genetically related versus adopted children Several single-gene disorders cause relatively rare forms of hypertension (and hypotension) by altering net sodium reabsorption Genome-wide association studies point to > 60 genetic loci in which variants individually contribute minimally to blood pressure levels but in sum have larger effects. 22 Essential hypertension, insufficient renal sodium excretion Insufficient renal sodium excretion in the presence of normal arterial pressure may be a key initiating event in essential hypertension and, indeed, a final common pathway for the pathogenesis of hypertension. ↑ In normal arterial pressure >>> insufficient sodium excretion >>> fluid ↑ volume >>> cardiac output, and peripheral vasoconstriction >>> hypertension At the higher blood pressure, enough additional sodium is excreted by the kidneys to equal intake and prevent further fluid retention. Thus a new steady state of sodium balance is achieved (“resetting of pressure natriuresis”), but at the expense of an increase in blood pressure. 23 Essential hypertension, Vasoconstrictive influences Factors that induce vasoconstriction or Stimuli that cause structural changes in the vessel wall ↑ >>> peripheral resistance and may also play a role in essential hypertension. 24 Essential hypertension, Environmental factors Implicated in hypertension: Stress Obesity Smoking Physical inactivity Heavy salt consumption 25 Vascular Pathology in Hypertension
Hypertension not only accelerates atherogenesis but also causes degenerative changes in the walls of large and medium arteries that can lead to Aortic dissection & Cerebrovascular hemorrhage Three forms of small vessel disease are hypertension-related 26 Hypertension-related small vessel disease
Three forms of small vessel disease are hypertension-related: Hyaline arteriolosclerosis Hyperplastic arteriolosclerosis Pulmonary hypertension 27 Vascular pathology in hypertension, Hyaline arteriolosclerosis Arterioles show homogeneous, pink hyaline thickening and luminal narrowing. Cause: Plasma protein leakage across injured ECs Increased SMC matrix synthesis in response to the chronic hemodynamic pressure The vessels of the elderly also exhibit hyaline arteriosclerosis, but it is less generalized and severe compared to patients with hypertension and diabetes. Chronic hypertension >>> renal arteriolar narrowing >>> diffuse impairment of blood supply >>> glomerular scarring >>> nephrosclerosis 28 Hyaline arteriolosclerosis The arteriolar wall is thickened with increased protein deposition (hyalinized), and the lumen is markedly narrowed. 29 Vascular pathology in hypertension, Hyperplastic arteriolosclerosis Occurs in severe hypertension Vessels exhibit concentric, laminated (“onionskin”) thickening of the walls with luminal narrowing The laminations consist of SMCs with thickened, reduplicated basement membrane In malignant hypertension, onionskinning is accompanied by fibrinoid deposits and vessel wall necrosis (necrotizing arteriolitis), particularly in the kidney 30  Hyperplastic arteriolosclerosis Onion-skinning causing luminal obliteration (arrow) (periodic acid-Schiff stain) 31  Pulmonary hypertension Cause: ♥ ♥ Left failure Congenital disease Valve disorders (mitral regurgitation) Obstructive or interstitial lung disease Recurrent thromboemboli The arterioles in such affected lungs typically show fibrotic intimal thickening to medial hyperplasia. 32 Hypertension, key concepts Very common, affects half of adults in the US A major risk factor for Atherosclerosis Congestive heart failure Renal failure Essential hypertension represents 90% of cases and is a complex, multifactorial disorder involving both environmental influences and genetic polymorphisms that influence sodium resorption, aldosterone pathways, and the renin-angiotensin-aldosterone system. Hypertension is occasionally caused by single-gene disorders Hypertension is occasionally secondary to diseases of the kidney, adrenal, or other endocrine organs. 33 Hypertension, key concepts Sustained hypertension requires participation of the kidney, which normally responds to hypertension by eliminating salt and water. In established hypertension, both increased blood volume and increased peripheral resistance contribute to the increased pressure. Histologically, hypertension is associated with thickening of arterial walls caused by hyaline deposits and, in severe cases, by proliferation of ECs or SMCs and replication of the basement membrane. 34 Thanks! Bafgh desert, Yazd, Iran 35