John H. Laragh

Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial

BACKGROUND The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test the hypothesis that for the same blood-pressure control, valsartan would reduce cardiac morbidity and mortality more than amlodipine in hypertensive patients at high cardiovascular risk. METHODS 15?245 patients, aged 50 years or older with treated or untreated hypertension and high risk of cardiac events participated in a randomised, double-blind, parallel-group comparison of therapy based on valsartan or amlodipine. Duration of treatment was event-driven and the trial lasted until at least 1450 patients had reached a primary endpoint, defined as a composite of cardiac mortality and morbidity. Patients from 31 countries were followed up for a mean of 4.2 years. FINDINGS Blood pressure was reduced by both treatments, but the effects of the amlodipine-based regimen were more pronounced, especially in the early period (blood pressure 4.0/2.1 mm Hg lower in amlodipine than valsartan group after 1 month; 1.5/1.3 mm Hg after 1 year; p<0.001 between groups). The primary composite endpoint occurred in 810 patients in the valsartan group (10.6%, 25.5 per 1000 patient-years) and 789 in the amlodipine group (10.4%, 24.7 per 1000 patient-years; hazard ratio 1.04, 95% CI 0.94-1.15, p=0.49). INTERPRETATION The main outcome of cardiac disease did not differ between the treatment groups. Unequal reductions in blood pressure might account for differences between the groups in cause-specific outcomes. The findings emphasise the importance of prompt blood-pressure control in hypertensive patients at high cardiovascular risk.

Relation of Left Ventricular Mass and Geometry to Morbidity and Mortality in Uncomplicated Essential Hypertension

OBJECTIVE To assess the prognostic significance of left ventricular mass and geometry in initially healthy persons with essential hypertension. DESIGN An observational study of a prospectively identified cohort. SETTING University medical center. PATIENTS Two hundred and eighty patients with essential hypertension and no pre-existing cardiac disease were evaluated using echocardiography between 1976 and 1981. Two hundred and fifty-three subjects or their family members (90%) were contacted for a follow-up interview an average of 10.2 years after the initial echocardiogram was obtained; the survival status of 27 patients lost to follow-up was ascertained using National Death Index data. MEASUREMENTS AND MAIN RESULTS Left ventricular mass exceeded 125 g/m2 in 69 of 253 patients (27%). Cardiovascular events occurred in a higher proportion of patients with than without left ventricular hypertrophy (26% compared with 12%; P = 0.006). Patients with increased ventricular mass were also at higher risk for cardiovascular death (14% compared with 0.5%; P less than 0.001) and all-cause mortality (16% compared with 2%; P = 0.001). Electrocardiographic left ventricular hypertrophy did not predict risk. Patients with normal left ventricular geometry had the fewest adverse outcomes (no cardiac deaths; morbid events in 11%), and those with concentric hypertrophy had the most (death in 21%; morbid events in 31%). In a multivariate analysis, only age and left ventricular mass--but not gender, blood pressure, or serum cholesterol level--independently predicted all three outcome measures. CONCLUSIONS Echocardiographically determined left ventricular mass and geometry stratify risk in patients with essential hypertension independently of and more strongly than blood pressure or other potentially reversible risk factors and may help to stratify the need for intensive treatment.

Value of Echocardiographic Measurement of Left Ventricular Mass in Predicting Cardiovascular Morbid Events in Hypertensive Men

To assess whether echocardiographic and electrocardiographic detection of left ventricular hypertrophy could predict cardiovascular morbid events in patients with uncomplicated essential hypertension, we followed 140 men for a mean of 4.8 years. Initial echocardiographic measurements of left ventricular mass were normal (less than 125 g/m2 body surface area) in 111 patients and revealed hypertrophy in 29 patients. Morbid events occurred in more patients with hypertrophy on echocardiography (7 of 29, 4.6/100 patient-years) than with normal ventricular mass (7 of 111, 1.4/100 patient-years; p less than 0.01). Electrocardiography showed hypertrophy in too few patients to be of predictive value. Multiple logistic regression analysis showed that left ventricular mass index had the highest independent relative risk for future events and that systolic and diastolic pressures and age had slightly lower relative risks. In men with mild uncomplicated hypertension, left ventricular hypertrophy detected by echocardiography identifies patients at high risk for cardiovascular morbid events and is a significant risk factor for future morbid events independent of age, blood pressure, or resting ventricular function.

Essential Hypertension: Renin and Aldosterone, Heart Attack and Stroke

Abstract In 219 patients with essential hypertension, aldosterone excretion and plasma renin activity were related to daily sodium excretion and compared to a nomogram drawn from 52 normal volunteers studied over the same continuous range of sodium balance. Plasma renin activity was subnormal in 27 per cent, normal in 57 per cent and elevated in 16 per cent. Further study showed eight patterns of renin and aldosterone secretion. Patients with normal or high renin had an 11 and 14 per cent frequency respectively of heart attacks or strokes. However, during a similar period of observation, none of 59 low renin patients had any of these complications. They appear protected despite similar hypertension, similar left ventricular enlargement, and despite higher mean age. Plasma renin activity emerges as a potential risk factor for patients with essential hypertension — useful for identifying etiologies, determining prognosis and applying therapy.

Effect of Growth on Variability of Left Ventricular Mass: Assessment of Allometric Signals in Adults and Children and Their Capacity to Predict Cardiovascular Risk

OBJECTIVES 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. BACKGROUND 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. METHODS Residuals of left ventricular mass-height2.7 relations 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. RESULTS The dispersion of residuals of ventricular mass versus height2.7 increased 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 x height2.13, r = 0.48) and children (32.3 x 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, height2.13 and body surface area (all p < 0.01) and 1.7 times the risk with ventricular mass/weight (p > 0.1). CONCLUSIONS 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.

Standardization of M-mode echocardiographic left ventricular anatomic measurements

To improve standardization of echocardiographic left ventricular anatomic measurements, echographic left ventricular dimensions and mass were related to body size indexes, sex, age and blood pressure. Independent normal populations comprised 92 hospital-based subjects (64 women, 28 men) and 133 subjects from a population sample (55 women, 78 men). All measurements of chamber size, wall thickness and mass differed between men and women in both series (p less than 0.01 to p less than 0.001). Left ventricular mass was related most closely to body surface area among measurements of body size (r = 0.37, p less than 0.01 to r = 0.57, p less than 0.001) in all four groups. Indexation by body surface area eliminated sex differences in wall thicknesses and internal dimension, but a significant sex difference in left ventricular mass index persisted (89 +/- 21 g/m2 in men versus 69 + 19 g/m2 in women in the entire series, p less than 0.0001). The 97th percentile of left ventricular mass index was identical in both groups of men (136 and 132 g/m2) and women (112 and 109 g/m2). A highly significant difference in lean body mass, estimated from 24 hour urine creatine excretion, was observed between men and women (58 +/- 15 versus 40 +/- 13 kg, p less than 0.001) and no sex difference existed in left ventricular mass indexed by lean body mass (3.4 +/- 1.3 versus 3.5 +/- 1.5 g/kg). Weak correlations were observed between left ventricular mass/lean body mass and systolic or diastolic blood pressure (r = 0.25, p less than 0.05 and r = 0.28, p less than 0.01, respectively) but not age (18 to 72 years).(ABSTRACT TRUNCATED AT 250 WORDS)

Association of the Renin-Sodium Profile with the Risk of Myocardial Infarction in Patients with Hypertension

BACKGROUND To test the prognostic value of plasma renin activity prospectively, we determined the pretreatment renin-sodium profile of 1717 subjects with mild-to-moderate hypertension (mean age, 53 years; 36 percent white; 67 percent men) in a systematic work-site treatment program. METHODS Renin profiles, obtained by plotting plasma renin activity against the urinary excretion of sodium, were classified as high (12 percent of the subjects), normal (56 percent), and low (32 percent), and there were expected variations according to age, sex, and race. Modified stepped-care treatment for hypertension, prescribed without reference to the renin profile, was similar in the three renin groups. RESULTS Mean (+/- SD) blood pressure at entry was 151 +/- 19/100 +/- 10 mm Hg in the subjects with a high renin profile, 151 +/- 19/97 +/- 10 mm Hg in those with a normal profile, and 151 +/- 20/96 +/- 11 mm Hg in those with a low profile. During 8.3 years of follow-up, there were 27 myocardial infarctions. As adjusted for age, sex, and race, the incidence of myocardial infarction per 1000 person-years was 14.7 among the subjects with a high renin profile, 5.6 among those with a normal profile, and 2.8 among those with a low profile (rate ratio for high vs. low, 5.3; 95 percent confidence interval, 3.4 to 8.3). The rate of mortality from all causes was 9.3 in the high-profile group, 5.3 in the normal-profile group, and 3.9 in the low-profile group. The independent association of a high renin profile with myocardial infarction (but not with stroke or noncardiovascular events) was affirmed by Cox analyses (rate ratio for high vs. normal plus low, 3.2; 95 percent confidence interval, 1.2 to 8.4) after adjustment for race, sex, age at entry, serum cholesterol level, smoking status, electrocardiographic evidence of left ventricular hypertrophy, blood glucose level, body-mass index, history of cardiovascular disease or treatment, blood pressure, and use of beta-blockers. CONCLUSIONS In the study population, whose blood pressure before and during treatment was in a narrow range, and after other cardiovascular risk factors had been considered, the renin profile before treatment remained independently associated with the subsequent risk of myocardial infarction.

Propranolol inhibition of renin secretion. A specific approach to diagnosis and treatment of renin-dependent hypertensive diseases.

Abstract The antihypertensive effect and mechanism of propranolol were studied in 47 hypertensive patients classified according to high, normal, or low plasma renin activity. The drug was uniformly effective in 13 patients with high renin activity and malignant, renovascular, or essential hypertension, producing a mean fall in diastolic pressure of 30 mm of mercury. In 22 with normal renin, propranolol reduced mean diastolic pressure by 20 mm of mercury, but individual responses were less consistent. In contrast, the drug was uniformly ineffective in the 12 patients with low-renin essential hypertension. In all three groups, the action of propranolol closely correlated with both the control renin levels and the degree of renin suppression produced. Propranolol usually suppressed aldosterone secretion but to a lesser extent than it did renin, perhaps because of a hyperkalemic effect of the drug. These special effects of propranolol in renin-dependent hypertensions point to the possibility of an associated ...

Atrial natriuretic factor in normal subjects and heart failure patients. Plasma levels and renal, hormonal, and hemodynamic responses to peptide infusion.

We investigated atrial natriuretic factor (ANF) in humans, measuring plasma immunoreactive (ir) ANF (in femtomoles per milliliter), and renal, hormonal, and hemodynamic responses to ANF infusion, in normal subjects (NL) and congestive heart failure patients (CHF). Plasma irANF was 11 +/- 0.9 fmol/ml in NL and 71 +/- 9.9 in CHF (P less than 0.01); the latter with twofold right ventricular increment (P less than 0.05). In NL, ANF infusion of 0.10 microgram/kg per min (40 pmol/kg per min) induced increases (P less than 0.05) of absolute (from 160 +/- 23 to 725 +/- 198 mueq/min) and fractional (1-4%) sodium excretion, urine flow rate (from 10 +/- 1.6 to 20 +/- 2.6 ml/min), osmolar (from 3.2 +/- 0.6 to 6.8 +/- 1.2 ml/min) and free water (from 6.8 +/- 1.6 to 13.6 +/- 1.6 ml/min) clearances, and filtration fraction (from 20 +/- 1 to 26 +/- 2%). Plasma renin and aldosterone decreased 33% and 40%, respectively (P less than 0.01). Systolic blood pressure fell (from 112 +/- 3 to 104 +/- 5 mmHg, P less than 0.05) in seated NL; but in supine NL, the only hemodynamic response was decreased pulmonary wedge pressure (from 11 +/- 1 to 7 +/- 1 mmHg, P less than 0.05). In CHF, ANF induced changes in aldosterone and pulmonary wedge pressure, cardiac index, and systemic vascular resistance (all P less than 0.05); however, responses of renin and renal excretion were attenuated. ANF infusion increased hematocrit and serum protein concentration by 5-7% in NL (P less than 0.05) but not in CHF.

Assessment of left ventricular function by the midwall fractional shortening/end-systolic stress relation in human hypertension☆

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, those 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 midwall shortening/end-systolic stress relation 1) markedly reduces the proportion of hypertensive subjects identified as having high endocardial left ventricular function; 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.