DR JULIAN JOHNY THOTTIAN DM CARDIO RESIDENT CMC KOZHIKODE
Introduction Relatively modern disorder Prevalence Increases with age Environmental factors play role Genetic variation is possible
Highly prevalent in the industrialized world with readily available food Industrialization, environmentalisation & genetic factors play a role
Definition Essential, primary, or idiopathic hypertension is defined as high BP in which secondary causes such as renovascular disease, renal failure, pheochromocytoma, aldosteronism, or other causes of secondary hypertension or mendelian forms (monogenic) are not present.
Risk factors (1) Obesity (2) Insulin resistance (3) High alcohol intake (4) High salt intake (in salt-sensitive patients) (5) Aging (6) Sedentary lifestyle (7) Stress (8) Low Potassium intake (9) Low Calcium intake Furthermore, many of these factors are additive, such as obesity and alcohol intake Most commonly related to PH are overweight & obesity accounting for 65%
Blood pressure equation BP = cardiac output (CO) x total peripheral resistance (TPR) Cardiac Output = stroke volume (SV) x heart (HR) TPR depends on the tone of the resistance vessels = Mean BP Total Peripheral Resistance X Cardiac Output
Homeostatic control cycles MAPCOSV venous return aldosterone Blood volume baroreceptors Vasomotor centre HR Contractile force renin venous tone Peripheral resistance sympathetic nervous system angiotensin Renal blood pressure parasympathetic nervous system Neural RAAS Vasomotor Endocrine
10 Causes of hypertension = Increased Cardiac Output Intravascular Volume Glomerular filtration Sodium excretion Extracellular Fluid Renal Nerve Activity Myocardial Performance Adrenergic Activity Increased Vasoconstriction Adrenergic Stimuli Angiotensin II Endothelin Endothelium-derived Contracting Factors Thromboxane Decreased Vasodilation Prostacyclin Nitric oxide EDHF* Textor SC. Atlas of Diseases of the Kidney, *Endothelium-derived Hyperpolarizing Factors Mean BP Total Systemic Vascular Resistance X Cardiac Output
11 Mechanisms of essential hypertension Renal/Hormonal: Sodium & volume regulation Intrinsic renal pressure/naturesis system RAAS (renin angiotensin aldosterone system) Atrial/Brain naturetic peptides Vascular: tone of resistance vessel Abnormal cellular ion pumps Vascular remodelling Neural: Central Sympathetic Nervous system
12 Renal regulation of BP Intrinsic GFR > PT-Na > BP RAAS Angiotensin II > Constriction-----> BP DT-Na+ Naturetic factors BV > ANF > Dilation > BP DT-Na+ Aldosterone BP regulation by 3 renal mechanisms:
Intrinsic pressure naturiesis Sodium load Volume expansion Cardiac Output Excretion of sodium load Tissue overperfusion BP Tissue vasoconstriction Pressure naturiesis BP Simple loop, keeping BP stable
Resistance vessels Concept: Resistance vessels (arterioles) set peripheral resistance and blood pressure Microcirculation protects target organ from systemic blood pressure (damaging) autoregulation Systemic pressure microcirculation Resistance vessels Target organ
Cell ionic fluxes Implicated channels Na channel Na/H exchange channel Na+/K+/Cl- co-transport Na/Ca exchange Na/Li countertransport Unclear significance, may be epiphenomena, contributory or causal Target more likely in vascular smooth muscle Could increase Ca influx, increasing tone in wall
Ion fluxes trigger cell growth Modulated by Angiotensin II Stimulates cell growth, leading to hypertrophy
Abnormal autonomic NS in hypertension Concept of increased pressor responsiveness on resistance vessels
Hypertension a reset problem? Renal blood flow reduced in response to sodium in hypertensives (reset through RAAS? Or abnormal renal prostaglandins) Less flow allows more tubular sodium resorption Leads to higher blood volume and pressure Homeostasis in effect reset at a higher level RAAS should be suppressed at hypertensive levels, but rarely is, possibly further driving BP In predisposed individuals, other mechanisms maintain hypertension and leads to tissue damage
Genes and essential hypertension Jeunemaitre et al first reported a polymorphism in the angiotensinogen gene linked with essential hypertension in hypertensive siblings from Utah and France Substitution of methionine for threonine at position 235 (M235T) and is associated with increased concentrations of plasma angiotensinogen Corvol P, Jeunemaitre X. Molecular genetics of human hypertension: role of angiotensinogen. Endocr Rev. 1997;18:662–677
25 Rat models have had their genetic diversity pruned by selection, mostly major (homozygous) genes left Most human populations are outbred (exceptions) Polygenes are more important Pima African Americans Outbred populations Major genes Polygenes
26 Interaction genes & environment
27 Interactions in essential hypertension Environment Fetal Genetics Modifiable Na intake K intake Obesity Exercise Small effect Environment overwhelms genetics (migration studies) Large effect Modifiers & Magnifiers
Other potential genes Angiotensin-converting enzyme β 2 -adrenergic receptor α-adducin Angiotensinase C Renin-binding protein G-protein β 3 -subunit Atrial natriuretic factor Insulin receptor
CONCEPT OF SALT SENSITIVITY Concept of heterogeneity of blood pressure responsiveness to alterations in dietary sodium intake was first suggested by studies in 19 hypertensive subjects who were observed after a “normal” (109 mmol/d), “low” (9 mmol/d), and then “high” (249 mmol/d) sodium intake Kawasaki T, Delea CS, Bartter FC, Smith H. The effect of high-sodium and low-sodium intakes on blood pressure and other related variables in human subjects with idiopathic hypertension. Am J Med. 1978;64:
73% of black hypertensive patients were salt sensitive compared with 56% of a white hypertensive group; but in the normotensive population, the frequency of salt sensitivity among blacks (36%) was similar to that seen among whites (29%) In the large epidemiological INTERSALT study, the relationship between sodium excretion and blood pressure was most notable when examined on the basis of age. Rodriquez BL, Labarthe DR, Huang B, Lopez-Gomez J. Rise of blood pressure with age. Hypertension. 1994;24:
Salt-sensitive individuals had a rise in blood pressure over time that was significantly (P<.001) greater than in those who were salt resistant. A more consistent finding has been the alteration in salt sensitivity of blood pressure after weight loss in obese subjects Genetic- greater frequency of salt sensitivity among Japanese with the haptoglobin 1-2 genotype than among those who were homozygous for 2-2 Investigators were unable to identify differences in salt sensitivity based on the three different patterns (II, ID, and DD)
Salt-sensitive subjects were all blacks who demonstrated a decrease in renal blood flow in response to the high salt diet, whereas the salt-resistant group, which included all of the white subjects as well as some blacks, showed an increase in renal blood flow Observations in both experimental animals and humans have been cited that provide substantial indirect evidence that salt sensitivity is associated with a reduction in nephron number or glomerular surface area Myron H. Weinberger
Other hormones ANF -Salt-sensitive hypertensive men have lower levels of ANF after a high salt intake than subjects whose blood pressure is not salt sensitive. Gerdts E, Myking OL, Omvik P. Salt sensitive essential hypertension evaluated by 24 hour ambulatory blood pressure. Blood Pressure. 1994;3: KALLIKREIN KININ SYSTEM -Salt-sensitive hypertensive patients have lower levels of urinary kallikrein than those who are salt resistant Ferri C, Bellini C, Carlomagno A, Perrone A, Santucci A. Urinary kallikrein and salt sensitivity in essential hypertensive males Kidney Int. 1994;46:
INCREASED RENAL OXIDATIVE STRESS
OUTCOMES Kimura and Brenner have suggested that salt sensitivity is associated with an increased intraglomerular pressure and hence a higher risk of developing glomerulosclerosis and CRF. Furthermore, salt sensitivity is associated with several features known to confer a greater renal and cardiovascular risk such as microalbuminuria, high levels of LDL and Lp(a), insulin resistance, a lack of nocturnal decrease in blood pressure and an increased left ventricular mass. Morimoto et al. have followed a group of salt‐sensitive and salt‐resistant hypertensive patients for 17 years and could demonstrate that salt sensitivity is indeed an independent cardiovascular risk factor
Excessive weight gain Current estimates indicate that more than 1 billion people in the world are overweight or obese Framingham Heart Study, for example, suggest that approximately 78% of primary hypertension in men and 65% in women can be ascribed to excess weight gain Each 10% weight gain is associated with a 6.5 mm Hg increase in systolic BP
A BMI of 1000%. BP in obese adolescents is sodium-sensitive, and fasting insulin is the best predictor of this sensitivity. Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V, Martin M. The effect of weight loss on the sensitivity of blood pressure to sodium in obese adolescents. N Engl J Med. 1989;321:580–585
Effect of Obesity on Tissue Blood Flow and Cardiac Output Expansion of extracellular fluid volume, as well as increased tissue blood flow and cardiac output Increased flow leads to tissue growth due to increased workload and metabolic demands Despite higher resting blood flows in many tissues, there appears to be reduced blood flow "reserve" during exercise in obese, compared with lean, individuals. Cardiac reserve is also reduced
Mechanisms of Impaired Renal Pressure Natriuresis in Obesity Hypertension
Sympathetic Nervous System Activation in Obesity Hypertension Evidence of increased SNS activity in obesity- (1) SNS activation, especially renal sympathetic activity, is increased in obese subjects (2) Pharmacologic blockade of adrenergic activity lowers blood pressure to a greater extent in obese, compared with lean, individuals (3) Renal denervation markedly attenuates sodium retention and hypertension associated with a high-fat diet
SNS activity is highly differentiated Cardiac sympathetic activation is not so much elevated when compared to kidney and skeletal muscles But SNS activity in kidney is not so much activated to cause vasoconstriction but surely increases renin and increased tubular absorption
Genetic factors and SNS activity In Pima Indians who have a high prevalence of obesity but a relatively low prevalence of hypertension. In black men, SNS activity is higher, and hypertension is more prevalent than in white men despite comparable levels of obesity. In young, overweight, black women, adiposity is associated with sympathetic hyperactivity. Factors such as differences in fat mass distribution may contribute to some of the racial variation in SNS responses to increasing adiposity. Abdominal obesity elicits a much greater sympathetic activation than does subcutaneous or lower body obesity. 207
Several potential mediators of SNS activation (1) Hyperinsulinemia (2) Ang II (3) Increased levels of free fatty acids (4) Impaired baroreceptor reflexes (5) Activation of chemoreceptor-mediated reflexes associated with sleep apnea (6) Cytokines released from adipocytes (ie, "adipokines") such as leptin, TNF-, and IL-6
Hyperleptinemia Leptin released from adipocytes It increases SNS activity and decreases appetite It acts on the hypothalamus The hypertensive effects of leptin are enhanced when NO synthesis is inhibited as often occurs in obese subjects with endothelial dysfunction.
How leptin acts….
RAAS Obese subjects- visceral obesity, often have mild to moderate increases in plasma renin activity, angiotensinogen, ACE activity, Ang II, and aldosterone levels. Activation of the RAS in obese subject occurs despite sodium retention, volume expansion, and hypertension, all of which would normally tend to suppress renin secretion and Ang II formation.
There have been no large-scale clinical studies comparing the effectiveness of RAS blockers in obese and lean hypertensive patients, although smaller clinical trials have shown that both ARBs and ACE inhibitors are effective in lowering blood pressure in obese hypertensive patients.
Increased aldosterone and MR activation also appear to contribute to obesity-induced hypertension Combined blockade of MR and Ang II might be especially effective in treating patients with obesity hypertension. The observation that MR antagonism attenuated glomerular hyperfiltration may also have important implications for renal protection in obesity. Administration of the MR antagonists also provides significant antihypertensive benefit in resistant obese patients. The reductions in blood pressure caused by MR antagonism in obese patients with resistant hypertension occurred despite concurrent therapy with ACE inhibitor or ARB, calcium channel blocker, and thiazide diuretic, suggesting that MR activation in obesity may occur independently of Ang II–mediated stimulation of aldosterone secretion
RENIN HYPERTENSION Renin-sodium profiling in patients with essential (primary) hypertension reveals that the plasma renin activity (PRA) is increased in 15 percent, normal in 60 percent, and reduced in approximately 25 percent. Low renin levels are found more frequently in blacks and in the elderly Although it is likely that patients with low-renin essential hypertension (LREH) represent part of a continuum of hypertensives, this subgroup may have some relatively unique characteristics: 1. The elevation in blood pressure is more likely to be salt-sensitive. 2. The response to nonpharmacologic therapy, particularly weight reduction, may be less pronounced. 3. The antihypertensive response may be greatest with a diuretic or calcium channel blocker.
Non modulators A subgroup of hypertensive patients has been described in whom the “normal” alterations in renal blood flow associated with a high dietary sodium intake and a “normal” response of plasma aldosterone to administered angiotensin II are not seen. This subgroup has been defined as non-modulators, and many but not all of the subjects in this subgroup have been characterized as salt sensitive in terms of their blood pressure response to alterations in dietary sodium intake
RENAL COMPRESSION IN OBESITY Compression of the kidneys---- increased intrarenal pressures impaired renal pressure natriuresis and hypertension. Increased intrarenal hydrostatic pressure may, in turn, cause compression of the loops of Henle and vasa recta, thereby increasing tubular sodium and water reabsorption. Renal medullary histology shows increased extracellular matrix that exacerbates intrarenal compression.
Glomerular injury and nephron loss Proteinuria in the nephrotic range folowed by progressive loss of kidney function is seen Glomerulomegaly and focal/segmental glomerular sclerosis is seen Increased expression of TGF-beta and inreased mesangial matrix Praga and coworkers reported that of patients with a BMI greater than 30 who had undergone unilateral nephrectomy, 92% developed proteinuria or renal insufficiency, but only 12% of patients with a BMI less than 30 developed these disorders.
Role of insulin resistance or metabolic syndrome Supporting a role for hyperinsulinemia in hypertension comes mainly from epidemiologic studies showing correlations between insulin resistance, hyperinsulinemia, and blood pressure and from short- term studies indicating that insulin has sympathetic effects that, if sustained, could theoretically increase blood pressure. However, chronic hyperinsulinemia, in the absence of obesity, does not raise blood pressure in either dogs or humans - Hall et al
Chronic infusion of insulin reduced BP in humans even in patients with renal dysfunction due to peripheral vasodilator effects. It did not enhance the hypertensive effects of other pressor substances such as norepinephrine or Ang II. These observations suggest that hyperinsulinemia per se is insufficient to cause chronic hypertension.
Insulin Resistance - Hypertension Independent of Hyperinsulinemia? Insulin resistance has also been suggested to cause hypertension by increasing TPR through mechanisms that are independent of hyperinsulinemia. Antihyperglycemic agents that increase insulin sensitivity, - thiazolidinediones, also lower BP as they influence the expression of multiple genes by binding to the peroxisome proliferator-activated receptor- (PPAR), a nuclear receptor. Thiazolidinediones may also inhibit L-type calcium channels, and they reduce blood pressure in renovascular hypertension that is not associated with insulin resistance or hyperinsulinemia.
Direct causal relationship between insulin resistance and hypertension has not been established. Abnormalities of glucose and lipid metabolism associated with insulin resistance may, over a period of many years, lead to vascular and renal injury and in this way contribute indirectly to increased blood pressure.
Insulin causes decreased mobilization of fatty acids When adipocyte become resistant to insulin - decreasing lipid storage and increasing plasma concentration of fatty acids. These changes, if prolonged, could contribute to atherosclerosis and increased blood pressure, especially if the renal blood vessels and glomeruli are damaged
Glucotoxicity- could cause glycosylation of glomerular proteins, increased production of extracellular matrix, and loss of nephron function. The metabolic disturbances associated with severe insulin resistance could exacerbate hypertension by causing renal injury, although the importance of these effects in the absence of diabetes is still unclear
Hypertension and insulin resistance Insulin resistance is secondary to vascular changes that occur in hypertension Insulin resistance may occur as a result of increased peripheral vascular resistance, decreased tissue blood flow, and vascular rarefaction, which decrease the delivery of insulin and glucose and therefore impair glucose uptake
Although peripheral vascular resistance is elevated in hypertension, most tissues, including skeletal muscles, do not appear to be underperfused. Also, multiple studies indicate that underperfusion of peripheral tissues cannot explain, quantitatively, chronic hyperinsulinemia Hall et al
INFLAMMATORY CYTOKINES The RAS and SNS, interact with the proinflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor- (TNF- alpha). The SNS stimulates the release of proinflammatory cytokines, and sympathetic nerves may also serve as a source of cytokines. Experimental evidence also suggests that proinflammatory cytokines may activate the SNS.
EICOSANOIDS The largest production of PGE 2 occurs in the renal medulla with decreasing synthesis in the cortex. PGE 2 is synthesized and rapidly inactivated, and after it is synthesized, it is released, not stored. After it has been released, PGE 2 inhibits sodium reabsorption by several mechanisms, including direct effects on the renal tubules
Vitamin D deficiency Associated with cardiovascular risk factors. It has been observed that individuals with a vitamin D deficiency have higher systolic and diastolic blood pressures than average. Vitamin D inhibits renin secretion and its activity, it therefore acts as a "negative endocrine regulator of the renin-angiotensin system". Hence a deficiency in vitamin D leads to an increase in renin secretion. This is one possible mechanism of explaining the observed link between hypertension and vitamin D levels in the blood. Forman JP, Giovannucci E, Holmes MD, et al. (May 2007). "Plasma 25-hydroxyvitamin D levels and risk of incident hypertension". Hypertension 49 (5): 1063–9
1. All are acute BP control mechanisms except? a. CNS ischaemic response b. Chemoreceptors c. Baroreceptors d. Renal
2. False about salt sensitivity a. More common in blacks b. Associated with reduced nephrons and glomerular surface area c. Salt sensitivity decreases with age d. Salt sensitivity varies with weight loss
3. Which condition causes parallel shift of pressure natriuresis curve a. Increased preglomerular resistance b. Decreased renal mass c. Decreased renal glomerular capillary filtration coefficient d. Increased distal collecting tubule reabsorption
4. Obesity causes all except a. Increase SNS activation b. Increase RAAS activity c. Decrease in PAI-1 d. Causes insulin resistance
5.False about leptin a. It synthesized from liver b. It acts on the hypothalamus c. It increases SNS activity d. It suppresses hunger
6. Renin hypertension – which is false a. The elevation in blood pressure is more likely to be salt-sensitive. b. The response to nonpharmacologic therapy, particularly weight reduction, may be less pronounced c. The antihypertensive response may be greatest with a diuretic or calcium channel blocker. d. Low renin in EHT is seen in 60% of subjects.
7.Salt sensitivity in hypertension. False statement a. Increased intraglomerular pressure and hence a higher risk of developing glomerulosclerosis and CRF b. Increase LDL c. Increased urinary kallikrein d. Increases Lp(a)
8 In obesity which is false a) Increase in HR b) Increase in sympathetic activity c) Increase in cardiac output d) Increase in cardiac reserve
9) False regarding insulin resistance a)Insulin infusion causes fall in BP b) Thiazolidinediones causes fall in BP by increasing insulin sensitivity c) Insulin resistance has role in pathogenesis of EHT d) Hypertension causes insulin resistance and vice versa.
10) All are seen in EHT except a) Haptoglobin mutation b) Angiotensinogen gene mutation c) Polygenic inheritance d) IP3/DAG cascade