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Biomedical subjects

John H Laragh

Publications and source records attributed to John H Laragh.

16 recordsLinked to original sources
PubMed2006

Outcomes in subgroups of hypertensive patients treated with regimens based on valsartan and amlodipine: An analysis of findings from the VALUE trial.

BACKGROUND: In the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial the primary outcome (cardiac morbidity and mortality) did not differ between valsartan and amlodipine-based treatment groups, although systolic blood pressure (SBP) and diastolic blood pressure reductions were significantly more pronounced with amlodipine. Stroke incidence was non-significantly, and myocardial infarction was significantly lower in the amlodipine-based regimen, whereas cardiac failure was non-significantly lower on valsartan. OBJECTIVES: The study protocol specified additional analyses of the primary endpoint according to: sex; age; race; geographical region; smoking status; type 2 diabetes; total cholesterol; left ventricular hypertrophy; proteinuria; serum creatinine; a history of coronary heart disease; a history of stroke or transient ischemic attack; and a history of peripheral artery disease. Additional subgroups were isolated systolic hypertension and classes of antihypertensive agents used immediately before randomization. METHODS: The 15,245 hypertensive patients participating in VALUE were divided into subgroups according to baseline characteristics. Treatment by subgroup interaction analyses were carried out by a Cox proportional hazard model. Within each subgroup, treatment effects were assessed by hazard ratios and 95% confidence intervals. RESULTS: For cardiac mortality and morbidity, the only significant subgroup by treatment interaction was of sex (P = 0.016), with the hazard ratio indicating a relative excess of cardiac events with valsartan treatment in women but not in men, but SBP differences in favour of amlodipine were distinctly greater in women. No other subgroup showed a significant difference in the composite cardiac outcome between valsartan and amlodipine-based treatments. For secondary endpoints, a sex-related significant interaction was found for heart failure (P < 0.0001), with men but not women having a lower incidence of heart failure with valsartan. CONCLUSION: As in the whole VALUE cohort, in no subgroup of patients were there differences in the incidence of the composite cardiac endpoint with valsartan and amlodipine-based treatments, despite a greater blood pressure decrease in the amlodipine group. The only exception was sex, in which the amlodipine-based regimen was more effective than valsartan in women, but not in men, whereas the valsartan regimen was more effective in preventing cardiac failure in men than in women.

Aged↗
PubMed2005

Low renin hypertensive states: perspectives, unsolved problems, future research.

Some causes of low renin hypertension are familial with known genetic bases. One of them, primary aldosteronism, is specifically treatable by mineralocorticoid receptor blockers or by surgery, and has at least two different familial varieties. These have provided insights into its natural history, with long normotensive and normokalemic phases, and variable expression within the same family. Primary aldosteronism was considered rare, but recent work beginning in 1992 suggests that it might be the most common curable cause of hypertension, worth screening for in every hypertensive. Evidence is now compelling that inappropriate aldosterone for salt status can cause not only hypertension, but vascular inflammation and end-organ damage, preventable by mineralocorticoid receptor blockade.

Cardiology↗
PubMed2004

Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.

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.

Amlodipine↗
PubMed2004

Plasma renin activity levels in hypertensive persons: their wide range and lack of suppression in diabetic and in most elderly patients.

BACKGROUND: The renin-angiotensin system (RAS) maintains hemodynamic integrity by modulating both volume and vasoconstriction through a cybernetic feedback control mechanism. In addition, angiotensin II, the active component of the RAS, can be vasculotoxic and, in hypertensive individuals, is associated with increased cardiovascular morbidity and mortality. The objective of this study was to determine the distribution and determinants of plasma renin activity (PRA) in a representative sample of hypertensive persons. METHODS: We systematically measured PRA in 4170 untreated participants in a systematic work site-based, hypertension treatment program. RESULTS: In this multiethnic employed population, patients were classified as follows: low renin, <0.65 ng/mL/h (30% of the sample); medium renin, 0.66 to 4.5 mg/mL/h (60%); or high renin, >4.5 ng/mL/h (10%). Low renin patients were more likely to be African American, female, and slightly older. However, the majority of women and African American individuals were not low renin. The 469 diabetic subjects distributed across renin categories, as did the group as a whole. CONCLUSIONS: This systematic study of PRA in a large community sample of hypertensive patients reveals a wide distribution of activity level, with identifiable differences according to ethnicity, age, and sex but not diabetic status. However, these demographic differences were more quantitative than qualitative and do not provide a useful basis for estimation of the activity of the RAS. Instead, in hypertensive subjects, direct measurement of PRA is necessary, both for prognosis and for guiding hypertensive therapy.

Age Factors↗
PubMed2004

Acute vascular effects of the angiotensin II receptor antagonist olmesartan in normal subjects: relation to the renin-aldosterone system.

The extent to which the clinical effects of angiotensin receptor blockers (ARB) are related to ambient renin system activity remains poorly defined. Therefore, we measured blood pressure (BP), large (C1) and small (C2) arterial compliance, systemic vascular resistance (SVR), plasma renin activity (PRA), and the 24-h urinary excretion of sodium (UNaV) and aldosterone before and 1, 2, 4, and 24 h after administration of single doses of placebo, and 5, 20, and 40 mg of the ARB olmesartan medoximil to 12 unmedicated normotensive subjects. In the basal state, SVR was inversely related to UNaV (r = -0.3, P =.04); the greater the UNaV, the more vasodilated the subject. Indices of arterial compliance, both C1 (r = -0.32, P =.03) and C2 (r = -0.35, P =.02) were inversely related to the basal PRA. Renin also predicted olmesartan-induced changes in C1 (r = 0.43, P =.004) and C2 (r = 0.33, P =.04). The greater the basal PRA, the less the arterial compliance, and the more compliance improved after olmesartan. Both systolic (P =.003) and diastolic (P <.0001) BP fell significantly on olmesartan compared with placebo (MANOVA with time), and relations were observed between the basal PRA and olmesartan-induced changes in pressure (systolic BP: r = -0.414, P =.012; diastolic BP: r = -0.561 P <.0001)-the greater the initial PRA, the more olmesartan lowered BP. Furthermore, the more pressure fell, the more PRA rose reciprocally (r = -0.44, P =.007). Finally, aldosterone excretion fell (sig = 0.05) on each dose of olmesartan compared with placebo. We conclude that 1) the inverse relation of UNaV and SVR illustrates the reciprocal role of volume versus constrictor factors in maintaining normal BP; and 2) PRA is a physiologic determinant of arterial compliance in normal individuals and of the response to the ARB olmesartan. Measurement of PRA may help to predict clinical ARB responses in individual subjects.

Adult↗
PubMed2004

Nitric oxide synthase inhibition accelerates the pressor response to low-dose angiotensin II, exacerbates target organ damage, and induces renin escape.

Because nitric oxide may attenuate both the pressor and cytotoxic effects of angiotensin II (Ang II), we investigated whether nitric oxide synthase (NOS) inhibition might accelerate the slow pressor effect of Ang II, and augment target organ damage. Using conscious, chronically catheterized rats, we previously observed that low-dose Ang II (10 ng/kg/min) rapidly increased mean arterial pressure (MAP) by approximately 25 mm Hg. The MAP then remained at this level for 2 to 4 days, and then increased again during the next 5 days by a further 25 mm Hg to a second plateau. In the present study, 7 days of N(omega)-nitro-l-arginine methyl ester (L-NAME; 10 microg/kg/min) alone increased MAP by 16 mm Hg. When Ang II was added to L-NAME, MAP increased as much as with Ang II alone, but then continued to increase until day 4, reaching a plateau as high as that reached only on day 9 of Ang II alone. In approximately half the rats infused with L-NAME + Ang II, plasma renin escaped from Ang II-induced suppression after day 4 of Ang II, and continued to increase for the duration of the study. On the first day that Ang II was added to L-NAME, urinary protein excretion and plasma cardiac troponin T increased, indicating early target organ damage. By the end of the study, all rats treated with L-NAME + Ang II developed tubulointerstitial and glomerular injuries, fibrosis of the renal and cardiac arteries, and cardiac interstitial fibrosis. Target organ damage was greater in rats that developed renin escape than in those in which plasma renin remained suppressed, but was minimal in rats infused with Ang II or L-NAME alone. Taken together, these findings suggest that endogenous NO normally attenuates the pressor response to low-dose Ang II for several days, and protects from Ang II-induced target organ damage. Under conditions of reduced NO bioavailability, which may result from endothelial insufficiency, relatively small changes in circulating Ang II levels may damage target organs. Moreover, renal damage leading to renin escape may initiate a vicious cycle of elevated Ang II production, leading to higher blood pressure and greater target organ damage.

Angiotensin II↗
PubMed2004

Beyond hypertension toward guidelines for cardiovascular risk reduction.

BACKGROUND: Most current clinical guidelines focus primarily on the management of individual cardiovascular risk factors, such as high blood pressure (BP), hypercholesterolemia, or diabetes. A more appropriate clinical approach to reducing cardiovascular disease risk would be based on a comprehensive evaluation of risk profile, and accurate stratification of global (absolute) risk in individual patients. We propose that global risk should be used as the main determinant of whom to treat, how to treat, and how much to treat. METHODS: In this article we use a series of case studies to demonstrate the implications of replacing the traditional "single risk factor-based" approach to managing hypertension by one based on global risk assessment. In some situations patients with mildly elevated BP levels would not be recommended for antihypertensive drug treatment whereas others with lower BP would be treated, depending upon the entire risk profile. CONCLUSION: We propose to replace the single risk factor-based approach with the assessment of global cardiovascular risk, both in the clinical management of individual patients and in guidelines.

Aged↗
PubMed2003

VALUE trial: Long-term blood pressure trends in 13,449 patients with hypertension and high cardiovascular risk.

BACKGROUND: The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study compares cardiovascular outcomes in 15,314 eligible patients from 31 countries randomized to valsartan or amlodipine-based treatment. METHODS: The blood pressure (BP) trends are analyzed in 13,449 of VALUE study patients who had baseline BP and 24 months BP and treatment data. RESULTS: In a cohort of 12,570 patients, baseline 24 and 30 months BP, but not 30 months treatment data, were available. Of 13,449 patients, 92% (N = 12,398) received antihypertensive therapy at baseline. The baseline BP was 153.5/86.9 mm Hg in treated compared to 168.1.8/95.3 mm Hg in 1051 untreated patients. After 6 months both groups had indistinguishable BP values. At 12 months the BP decreased to 141.2/82.9 mm Hg (P <.0001 for systolic BP and diastolic BP versus baseline), at 24 months to 139.1/80 mm Hg (P <.0001 v 12 months), and to 138/79 mm Hg at 30 months (P <.0001 v 24 months). The systolic BP control (<140 mm Hg) at 30 months increased from 21.9% at baseline to 62.2%, the diastolic BP (< 90 mm Hg) from 54.2% to 90.2% and the combined control (<140 and <90 mm Hg) from 18.9% to 60.5%. At 24 months 85.8% of patients were on protocol drugs: monotherapy = 39.7%, added hydrochlorothiazide = 26.6%, add-on drugs = 15.1%, and protocol drugs in nonstandard doses = 4.3%. CONCLUSIONS: The achieved BP control exceeds values reported in most published large-scale trials. The VALUE study is executed in regular clinical settings and 92% of the patients received antihypertensive drugs at baseline. When an explicit BP goal is set, and a treatment algorithm is provided, the physicians can achieve better control rates than in their regular practice.

Algorithms↗
PubMed2002

Hypertension guidelines: criteria that might make them more clinically useful.

Cardiovascular disease prevention depends on reduction of risk factors, including hypertension. Guidelines designed to improve management of hypertension are widely available. Their purpose is to assemble the available data from basic biomedical science, epidemiology, and clinical science in an accessible form with which physicians and patients can make reasoned decisions for individual cases. However, guidelines have been neither widely accepted, nor effectively implemented. We recommend a strategy for guideline preparation designed to yield a product more user friendly, accessible, and effective. Guideline recommendations and the evidence used to make them should be based on an explicit grading system. Relevant clinical as well as nonclinical factors must be considered. Moreover, because the goal of antihypertensive therapy is to prevent cardiovascular events, and the likelihood of such events is determined by multifactor or absolute risk assessment, risk, rather than level of blood pressure (BP), should determine the need for therapy. Similarly, the benefit of therapy must be assessed by reduction in cardiovascular disease morbidity and mortality.

Humans↗
PubMed2002

Left ventricular mass change during treatment and outcome in patients with essential hypertension.

BACKGROUND: It is uncertain whether reduction of left ventricular (LV) mass during antihypertensive treatment predicts reduces cardiovascular complications of hypertension. METHODS: A total of 172 prospectively identified patients with essential hypertension without complications of hypertension at baseline and follow-up echocardiograms 5.5 +/- 3.0 years apart, were followed an additional 4.8 +/- 2.9 years. Antihypertensive treatment was determined by primary physicians. RESULTS: After the second echocardiograms, cardiovascular events occurred in 24 patients (14%). Fewer of the 91 patients with unchanged or decreased LV mass experienced cardiovascular events than of the 81 patients whose LV mass increased during follow-up (8.8% [95% confidence interval (CI): 3.9%-13.7%] v 19.8% [95% CI 12.6%-27.0%]; P =.04) despite greater baseline LV mass in the former group (118 g/m(2) [95% CI 111-125] v 95 g/m(2) [95% CI 88-102]; P <.0001). Absence or presence of LV hypertrophy on the follow-up echocardiogram was the strongest predictor of relatively low (9.2% [95% CI 5%-13.4%]) v high (28.6% [95% CI 17.1%-40.1%]; P =.004) rates of subsequent morbid events. In multivariate analyses, only LV mass index at follow-up consistently predicted adverse outcomes. CONCLUSIONS: The LV mass reduction during antihypertensive treatment is associated with reduced rate of complications of essential hypertension. Our data further suggest that development or regression of LV hypertrophy during antihypertensive treatment may be more closely linked to prognosis than are changes in clinic blood pressure.

Adult↗