Body sodium works together with the plasma renin-angiotensin system to ensure adequate blood flow to the tissues. Body sodium content determines the extracellular fluid (ECF) volume ensuring that, ...with each heart beat, a sufficient volume of fluid is delivered into the arterial space. At the same time the kidneys monitor ECF volume and blood pressure (BP), so that the juxtaglomerular cells can adjust their net secretion rate of renin to maintain an appropriate plasma renin activity (PRA) level. Plasma renin produces angiotensin II (Ang II) to constrict the arterioles and thereby ensure sufficient BP to deliver an appropriate rate of flow for cardiovascular homeostasis. The low renin, sodium-volume dependent (V) form of essential hypertension occurs whenever body sodium content increases beyond the point where plasma renin-angiotensin vasoconstrictor activity is turned off. In contrast, medium to high renin (R) hypertension occurs when too much renin is secreted relative to the body sodium content. Thus, BP = V × R. This volume-vasoconstriction dual support of long-term hypertension is validated by the fact that all effective long-term antihypertensive drug types are either (i) natriuretic to reduce body salt and volume content (anti-V), or (ii) antirenin to reduce or block the activity of the circulating renin-angiotensin system (anti-R). The PRA test defines the relative participation of the concurrent volume and vasoconstrictor factors. In the hypertensive patient PRA testing can guide initiation, addition or subtraction of anti-V or anti-R antihypertensive drug types to thereby improve BP control and prognosis while reducing drug type usage and cost.
American Journal of Hypertension, advance online publication 22 September 2011; doi:10.1038/ajh.2011.171
Background Suppressed baseline plasma renin activity (PRA) levels or large reactive increases in renin secretion are two possible reasons for treatment failure with antirenin system drugs. Methods To ...investigate their prevalence we reanalyzed data from three published clinical trials of the renin inhibitor aliskiren. Results Aliskiren failed to lower systolic blood pressure (SBP) by at least 10 mm Hg in half of all patients. It was very effective in two-thirds of medium- to high-renin patients (‐19 mm Hg). But BP did not fall in most low-renin patients, or in 30% of medium- to high-renin patients. BP actually rose by >10 mm Hg in 5% of patients taking aliskiren and in >10% of patients when aliskiren was added to an angiotensin receptor blocker (ARB) or angiotensin converting enzyme inhibitor (ACEI). PRA changed in parallel with BP. Although PRA fell in most patients, it actually rose in 5% and in up to 30% when aliskiren was added to an ARB or ACEI. Conclusions There are two reasons for treatment failure with aliskiren. Many hypertensive patients have large BP falls. But, BP does not fall in most low-renin patients or in medium- to high-renin patients whose PRA levels do not fall sufficiently. If the concept of that treatment resistance is caused by excessive reactive increases in renin secretion is confirmed, then a PRA determination during treatment could be used to guide subsequent addition or subtraction of either natriuretic or antirenin drug types, to thereby correct BP and reduce cardiovascular risk. American Journal of Hypertension (2009). doi:10.1038/ajh.2008.275
Although it is recognized that both hypertension and obesity are associated with increased left ventricular mass, the relative impacts of obesity, arterial hypertension, and gender on the prevalence ...of ventricular hypertrophy remain uncertain. Accordingly, echocardiographic left ventricular mass normalized for height to the power of the allometric or growth relation between ventricular mass and height was compared in 164 normotensive subjects (85 men 24 obese and 79 women 28 obese, aged 45 +/- 12 years) and 475 hypertensive patients (325 men 126 obese and 150 women 85 obese, aged 54 +/- 10 years) from an adult employed population. Gender-specific upper normal limits were used to identify ventricular hypertrophy. Left ventricular mass/height 2.7 was higher in obese than normal-weight normotensive subjects (P < .004) independently of the level of blood pressure and identified a higher prevalence of hypertrophy (mainly eccentric) in obese than in normal-weight normotensive subjects (14% versus 5%, P < .04), a difference that was not detected by left ventricular mass/body surface area. Left ventricular mass/height identified hypertrophy in 52% of obese and 30% of normal-weight hypertensive patients (P < .0001) because of higher prevalences in obese than normal-weight patients of both eccentric (34% versus 20%) and concentric ventricular hypertrophy (18% versus 10%). The increase in left ventricular mass was independent of blood pressure values in obese normotensive women (but not men), and the prevalence of supranormal left ventricular mass/height 2.7 was even higher in hypertensive obese women (58%) than men (49%).
Objectives. This study examined left ventricular performance in relatively unselected hypertensive patients by use of physiologically appropriate midwall shortening/end-systolic stress relations.
...Background. Supranormal left ventricular function has been reported in hypertensive patients, possibly due to an artifact of mismatching endocardial rather than midwall fractional shortening to mean left ventricular end-systolic stress.
Methods. Samples of 474 hypertensive patients (150 women, 324 men) and 140 normal subjects (68 women, 72 men) were drawn from a large urban employed population. The inverse relations (p < 0.0001) of both echocardiographic endocardial and midwall fractional shortening to end-systolic stress in normal subjects were used to calculate the ratios of observed to predicted endocardial and midwall fractional shortening in hypertensive patients. Midwall shortening was calculated from an elliptic model, taking into account the epicardial migration of the midwall during systole.
Results. Use of midwall fractional shortening in hypertensive patients reduced the proportion of patients with function above the 95th percentile of normal from 22% to 4% (p < 0.0001) and fractional shortening as a percent of predicted from 107% (p < 0.001 vs. 100% in normotensive control subjects) to 95% (p < 0.0001; p < 0.001 vs. 101% in normotensive control subjects). Midwall shortening was below the 5th percentile of normal in 16% of hypertensive patients instead of 2% with endocardial shortening (p < 0.0001): They tended to be older than other hypertensive patients and had concentric left ventricular hypertrophy. Among hypertensive patients, these with concentric left ventricular hypertrophy or remodeling had reduced midwall shortening as a percent of predicted from end-systolic stress (p < 0.0001).
Conclusions. Use of the physiologically more appropriate mid-wall shortening/end-systolic stress relation 1) markedly reduces the proportion of hypertensive subjects identified as having high endocardial left ventricular functions; and 2) identifies a substantial subgroup of patients with reduced left ventricular function who have concentric geometry of the left ventricle, a pattern associated with high cardiovascular risk.
We sought to determine whether growth influences the relation between left ventricular mass and body size and whether use of different body size indexes affects the ability of ventricular mass to ...predict complications of hypertension.
Allometric (or growth) signals between left ventricular mass and height have recently been reported to improve previous approaches for normalization of ventricular mass for body size.
Residuals of left ventricular mass—height2.7relations were analyzed in a learning series of 611 normotensive, normal-weight subjects 4 months to 70 years old and, separately, in 383 children (<17 years old) and 228 adults. Ten-year cardiovascular morbidity in a test series of 253 hypertensive adults was compared with groups with normal or high baseline left ventricular mass normalized for body weight, height, body surface area and allometric powers of height.
The dispersion of residuals of ventricular mass versus height2.7increased with increasing height or age in children but not in adults, suggesting that the effect of other variables on ventricular growth increases during body growth and stabilizes in adulthood. Therefore, we derived separate allometric signals for adults (predicted ventricular mass = 45.4 × height2.13, r = 0.48) and children (32.3 × height2.3, r = 0.85) (both p < 0.0001). Patients with left ventricular hypertrophy had 3.3 times higher cardiac risk with elevated left ventricular mass/height2.7(p < 0.001), 2.6 to 2.7 times higher risk with left ventricular mass indexed for height, height2.13and body surface area (all p < 0.01) and 1.7 times the risk with ventricular mass/weight (p > 0.1).
These results show the following: 1) Variability of left ventricular mass in relation to height increases during human growth; 2) allometric signals of left ventricular mass versus height are lower in adults and children than those obtained across the entire age spectrum; 3) height-based indexes of left ventricular mass at least maintain and may enhance prediction of cardiac risk by hypertensive left ventricular hypertrophy; and 4) the allometric signal derived across the entire spectrum of age appears to be more useful for prediction of cardiovascular risk than that computed in adults.
These 25 lessons 1) review the roles of plasma renin levels for causing malignant and most essential hypertension and their related vascular injuries (heart attack, heart failure, kidney failure and ...stroke); 2) review how antihypertensive anti-R drugs that block renin activity (beta blockers, the first converting enzyme inhibitor from venom, and the first angiotensin receptor blocker) were used to reveal plasma renin involvement in the hypertension of medium and high renin patients and to show; 3) that the 30% with low renin essential hypertension do not respond to R drugs, are not prone to heart attack or stroke, and BP is corrected instead by the natriuretic anti-V drugs (diuretics, spironolactone, CCB, alpha blockers); 4) thus, all hypertensives can be divided into R patients who have too much renin vasoconstriction or V patients who instead have predominant sodium-volume mediation. Furthermore, all antihypertensive drug classes can be divided into R drugs that block the renin factor, or V drugs that reduce body sodium volume; 5) these findings document our conception of two biochemically and physiologically different final factors that sustain all BP in which the sodium-volume factor continuously sustains cardiac output and flow while plasma renin-angiotensin sets total peripheral resistance (TPR), which, within the Poiseuille Equation (BP = cardiac output CO × TPR) describes our Na
+-volume × renin-angiotensin vasoconstriction model that supports all normotension or hypertension; 6) in this light, we designed a visit-by-visit method for treating untreated hypertensives using the ambient plasma renin level and BP responses to guide primary drug therapy against either the V or R factor; and 7) for also correcting nonresponders receiving multiple drugs where renin testing correctly guides addition or subtraction of drugs depending on whether the test indicates unresponsiveness due to a reactive sodium-volume excess, or to lack of effectiveness of an R drug in a V patient or of a V drug in an R patient, or from large reactive increases in renin that override the R drug, calling for strengthening the R and/or removing V drugs. This objective, biochemically based method results in effective longterm BP control of nearly all patients using fewer, but the correct drug(s) for each individual.
An appreciable proportion of asymptomatic hypertensive patients have depressed left ventricular (LV) performance that is identified by midwall shortening/endsystolic stress relations but not by ...indexes that use endocardial shortening. It has not been established, however, whether depressed midwall ventricular performance has prognostic implications.
Echocardiographic endocardial and midwall LV fractional shortening/circumferential end-systolic stress relations in 294 hypertensive patients were analyzed as predictors of the occurrence of cardiovascular morbid events that occurred in 50 patients (including 14 deaths) during a 10-year mean follow-up. Patients with initially lower midwall but not endocardial shortening, either in absolute terms or as a percentage of predicted from observed end-systolic stress, were more likely to suffer morbid events than those with initially normal values (P < .004). Cardiovascular events occurred in 29 of 100 patients (29%) and death in 10 of 100 patients (10%) among those who were in both the two highest quartiles of LV mass index and the two lowest quartiles of midwall shortening, as opposed to 21 of 194 (11%) and 4 of 194 (2.1%) of the remaining patients (odds ratio, 3.4; 95% CI, 1.8 to 6.3; P < .0001; and odds ratio, 5.3; 95% CI, 1.6 to 17.3; P < .006, respectively). In logistic analysis, increasing age, high LV mass, high systolic blood pressure, and low values for an interaction term between LV mass index and midwall shortening independently predicted cardiovascular events (.04 < P < .001); increasing age, low midwall LV shortening as a percentage of predicted, and high value of the interaction term predicted the occurrence of cardiac death (.004 < P < .0002). Survival analysis controlling for age confirmed that low midwall shortening independently predicted cardiac morbidity or death, especially in the subgroup of patients with LV hypertrophy.
Depressed midwall shortening is a predictor of adverse outcome in arterial hypertension; the combination of higher LV mass and lower midwall shortening identifies individuals at markedly increased risk.
The spectrum of left ventricular geometric adaptation to hypertension was investigated in 165 patients with untreated essential hypertension and 125 age- and gender-matched normal adults studied by ...two-dimensional and M-mode echocardiography. Among hypertensive patients, left ventricular mass index and relative wall thickness were normal in 52%, whereas 13% had increased relative wall thickness with normal ventricular mass (“concentric remodeling”), 27% had increased mass with normal relative wall thickness (eccentric hypertrophy) and only 8% had “typical” hypertensive concentric hypertrophy (increase in both variables).
Systemic hemodynamics paralleled ventricular geometry, with the highest peripheral resistance in the groups with concentric remodeling and hypertrophy, whereas cardiac index was supernormal in those with eccentric hypertrophy and low normal in patients with concentric remodeling. The left ventricular shortaxis/long-axis ratio was positively related to stroke volume (r = 0.45, p < 0.001), with cavity shape most elliptic in patients with concentric remodeling and most spheric in those with eccentric hypertrophy. Normality of left ventricular mass in concentric remodeling appeared to reflect offsetting by volume “underload” of the effects of pressure overload, whereas eccentric hypertrophy was associated with concomitant pressure and volume overload.
Thus, arterial hypertension is associated with a spectrum of cardiac geometric adaptation matched to systemic hemodynamics and ventricular load. Concentric left ventricular remodeling and eccentric hypertrophy are more common than the typical pattern of concentric hypertrophy in untreated hypertensive patients.
The spectrum of disorders associated with an elevated blood pressure (BP) encompasses chronic uncomplicated hypertension and the hypertensive crises, including hypertensive urgencies and emergencies. ...Although these syndromes vary widely in their presentations, clinical courses, and outcomes they share pathophysiologic mechanisms and, consequently, therapeutic responses to specifically targeted antihypertensive drug types. Nevertheless, hypertensive crises are often treated with drugs which, in that setting are either unsafe or are of unsubstantiated efficacy. The purpose of this review is to examine the pathophysiology of commonly encountered hypertensive crises, including stroke, hypertensive encephalopathy, aortic dissection, acute pulmonary edema, and preeclampsia-eclampsia and to provide a rational approach to their treatment based upon relevant pathophysiologic and pharmacologic principles. Measurement of plasma renin activity (PRA) level often provides insight regarding pathophysiology and predicts efficacy of antihypertensive treatments in the individual patient. However, in hypertensive crises, drug therapy is initiated before the PRA level is known. Nevertheless, the renin-angiotensin dependence (R-type) or volume dependence (V-type) of hypertension can often be deduced by the BP response to drugs that interrupt the renin system (R-drugs) or that decrease body volume (V-drugs). Based upon these considerations, a treatment algorithm is provided to guide drug selection in patients presenting with a hypertensive crisis.
The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test whether, for the same achieved blood pressures, regimens based on valsartan or amlodipine would have ...differing effects on cardiovascular endpoints in high risk hypertension. But inequalities in blood pressure, favouring amlodipine, throughout the multiyear trial precluded comparison of outcomes. A technique of serial median matching, applied at 6 months when treatment adjustments intended to achieve control of blood pressure were complete, created 5006 valsartan-amlodipine patient pairs matched exactly for systolic blood pressure, age, sex, and the presence or absence of previous coronary disease, stroke, or diabetes. Subsequent combined cardiac events, myocardial infarction, stroke, and mortality were almost identical in the two cohorts, but admission to hospital for heart failure was significantly lower with valsartan. Reaching blood pressure control (systolic <140 mm Hg) by 6 months, independent of drug type, was associated with significant benefits for subsequent major outcomes; the blood pressure response after just 1 month of treatment predicted events and survival.
Published online June 14, 2004 http://image.thelancet.com/extras/04let5020web.pdf
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