Obesity, cardiovascular risk and pharmacotherapy.
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Anti-Obesity Agents↗
Biomedical subjects
Luis M Ruilope
Publications and source records attributed to Luis M Ruilope.
Valsartan improves fibrinolytic balance in atherosclerotic rabbits.
OBJECTIVES: To examine the long-term effects of the angiotensin type I (AT1) receptor antagonist, valsartan, on fibrinolytic balance, coagulation parameters, endothelial function and structural alterations in atherosclerotic rabbits. METHODS: Animals were submitted to a 1% cholesterol-enriched diet for 10 weeks. Half of the animals were treated with valsartan (3 or 10 mg/kg per day). Systolic arterial pressure was directly measured in awake rabbits. Tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor (PAI-1) activities were measured. Plasma concentrations of cholesterol, D-dimer, factor VIII and fibrinogen, as well as thrombin time, were also determined. Responses to acetylcholine, sodium nitroprusside and angiotensin II were evaluated in aortic rings. Morphometric analysis of aortic segments was also performed to calculate atherosclerotic lesion. RESULTS: Cholesterol-fed rabbits presented systolic arterial pressure levels comparable to controls. These animals presented aortic atherosclerotic lesions. Treatment with valsartan did not alter plasma cholesterol levels or arterial pressure in any group. Acetylcholine-induced relaxations and D-dimer and t-PA activity were lower (P < 0.05) in atherosclerotic than in normal rabbits. In contrast, PAI-1 activity was higher (P < 0.05) in atherosclerotic rabbits than in controls. Valsartan increased (P < 0.05) acetylcholine-induced relaxations, D-dimer concentration and t-PA activity, and reduced intimal thickening and PAI-1 activity in cholesterol-fed rabbits. Fibrinogen concentrations and factor VIII concentrations were lower (P < 0.05) and thrombin time was higher (P < 0.05) in atherosclerotic rabbits compared to controls. Valsartan did not affect factor VIII in any group, but reduced fibrinogen levels only in hypercholesterolemic rabbits. Valsartan 10 mg/kg per day reduced (P < 0.05) thrombin time in cholesterol-fed rabbits. CONCLUSIONS: Impairment of fibrinolytic balance, associated with atherosclerosis in rabbits, appears to be related with angiotensin II via AT1receptors. The beneficial effect of valsartan on fibrinolysis seems to be related to the concomitant amelioration of endothelial dysfunction and reduction of intimal thickening, further supporting the importance of the blockade of angiotensin II actions to prevent thrombotic alterations associated with atherosclerosis.
Acetylcholine↗
Losartan titration versus diuretic combination in type 2 diabetic patients.
METHODS: We compared the effects of Losartan dose titration to 100 mg versus the addition of 12.5 mg of hydrochlorothiazide, in 90 type 2 diabetic patients with microalbuminuria and blood pressure > 130/85 mmHg, receiving losartan 50 mg as initial treatment during 4 weeks. RESULTS: With the first dose of losartan, systolic (SBP) and diastolic blood pressure (DBP) decreased from 154.5 (152.1-157.5) to 144.4 (141.3-147.5) mmHg (P < 0.001) and from 91.1 (89.4-92.8) to 84.6 (82.8-86.4) mmHg (P < 0.001), with 20 patients attaining the expected goal blood pressure (< 130/85 mmHg); albuminuria decreased from 109.8 (90.5-133.3) to 83.5 (63.6-109.5) mg per 24 h (P = 0.006). Patients not attaining the target blood pressure were randomly allocated to titration or to the combination arm. After an additional 4 weeks, patients titrated exhibited a fall in SBP and DBP from 157.1 (152.7-161.5) to 142.1 (136.4-147.8) mmHg (P < 0.001) and from 92.4 (89.5-95.3) to 83.6 (81.1-86.1) mmHg (P < 0.001); albuminuria decreased from 136.3 (97.8-189.9) to 99.7 (69.3-143.4) mg per 24 h (P = 0.002). In the combination arm, there were similar reductions in SBP and DBP from 155.3 (151.5-159.1) to 139.1 (132.1-146.1) mmHg (P < 0.001) and from 92.1 (89.3-94.9) to 80.9 (77.4-84.4) mmHg (P < 0.001); while albuminuria fell from 107.7 (82.2-141.0) to 64.2 (45.9-89.9) mg per 24 h (P = 0.001). CONCLUSIONS: Losartan 50 mg was effective in reducing blood pressure and albuminuria in type 2 diabetic patients. When the blood pressure target was not reached, the two strategies tested seem to contribute similarly to further reductions in blood pressure and albuminuria.
Aged↗
The Framingham prediction rule is not valid in a European population of treated hypertensive patients.
BACKGROUND: Stratification of population groups according to cardiovascular risk level is recommended for primary prevention. OBJECTIVE: To assess whether the Framingham models could accurately predict the absolute risk of coronary heart disease (CHD) and stroke in a large cohort of middle-aged European patients with hypertension, and rank individual patients according to actual risk. DESIGN: A prospective cohort study comparing the actual risk with that predicted by either the Framingham equations or models derived from the INSIGHT study. PATIENTS AND SETTING: From the INSIGHT prospective trial, conducted in eight countries of Western Europe and Israel, we selected 4407 European patients younger than 75 years without previous cardiovascular events. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Major cardiovascular events. RESULTS: In this population (45% men, mean age 64.1 years), 124 (2.8%) patients had CHD and 96 (2.2%) had strokes after a median follow-up of 3.7 years. Overestimation of absolute CHD risk by the Framingham equation was observed in all countries (from 2% in the UK to 7% in France), whereas predicted risk of stroke was close to the actual risk. However, patients in the highest risk quintile within each country had a threefold greater risk of a cardiovascular event than those in the lowest quintile. CONCLUSIONS: The Framingham models should not be used to predict absolute CHD risk in the European population as a whole. However, these models may be used within each country, provided that cut-off points defining high-risk patients have been determined within each country.
Age Factors↗
Antihypertensive treatment in patients with type-2 diabetes mellitus: what guidance from recent controlled randomized trials?
BACKGROUND: Patients with type-2 diabetes have a high prevalence of hypertension and show an elevated incidence of cardiovascular events and nephropathy. OBJECTIVES: Recent randomized trials of antihypertensive therapy providing information about cardiovascular and renal risk in diabetes, blood pressure goals and best suitable drugs were reviewed. FINDINGS: Evidence that association of type-2 diabetes with hypertension markedly increases cardiovascular and renal risk is incontrovertible: even blood pressure values in the high-normal range represent a more relevant risk than in non-diabetics. More versus less intensive blood pressure lowering or active versus placebo treatment can significantly prevent cardiovascular and renal events, with a particularly consistent reduction of proteinuria and microalbuminuria. Although several of the trials showing significant reduction of cardiovascular or renal risk achieved diastolic blood pressure (DBP) between 75 and 82 mmHg, systolic blood pressure (SBP) 140 mmHg was never achieved in trials showing cardiovascular benefits and SBP 130 mmHg was only achieved in two trials in normotensive subjects showing proteinuria reduction. The recommendation given by all major guidelines to lower SBP 130 mmHg appears to be difficult to comply with. Evidence of the superiority or inferiority of different drug classes (angiotensin-converting enzyme inhibitors, calcium antagonists, diuretics and beta-blockers) is rather vague, especially for cardiovascular protection. As to angiotensin-receptor antagonists, losartan has shown significant cardiovascular protection over a beta-blocker, and irbesartan, although not showing cardiovascular benefits over a calcium antagonist, was significantly better in retarding renal dysfunction and failure. CONCLUSIONS: In most trials on hypertensive diabetics, the large majority of patients were on two, three and even four-drug therapy. Therefore, it appears reasonable that all effective and well tolerated antihypertensive agents can be used in association to achieve DBP 80 mmHg and, whenever possible, SBP 130 or 135 mmHg, with the regular inclusion of an angiotensin-receptor antagonist for its proven renoprotective action. Hopefully, better guidance will be provided by further trials.
Antihypertensive Agents↗
Hypertension magnitude and management in the elderly population of Spain.
OBJECTIVE: The present study assessed the prevalence, awareness, treatment and control of hypertension among the elderly population of Spain. DESIGN: Based on a nationally representative sample of 4009 individuals aged 60 years, two sets of six blood pressure measurements were obtained by trained observers at each subject's home, using standardized methods. In each set, three mercury-based measurements were alternated with three automated measurements. RESULTS: The mean systolic blood pressure (SBP)/diastolic blood pressure (DBP) was 143/79 mmHg, and the pulse pressure was 64 mmHg. The prevalence rate of hypertension (SBP 140 mmHg, DBP 90 mmHg, or current drug treatment) was 68.3%. No result obtained was sensitive to a particular measurement device. Of the hypertensives, 65% were aware of their condition, 55.3% were treated and 16.3% were controlled. Among treated hypertensives, SBP control (32.2%) was much lower than DBP control (82.3%). Control was lower in men than in women, in older than in younger subjects, and in those with lowest than in those with higher educational levels. About 57% of uncontrolled treated hypertensives were on monotherapy. Weight loss was among the least heeded items of advice (39% among overweight hypertensives). CONCLUSIONS: Hypertension is a major public health problem in elderly Spaniards. Most hypertensives had their hypertension uncontrolled. Greater emphasis should be laid on the most disadvantaged (the older, men, and those with lowest education) in terms of hypertension management, and on reinforcing weight loss and combining drugs for enhanced hypertension control.
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The kidney as a sensor of cardiovascular risk in essential hypertension.
Renal damage as a consequence of uncontrolled arterial hypertension is well recognized. Antihypertensive therapy has come to very significantly decrease the vascular damage in the kidneys of hypertensive patients. However, prevalence of mild renal insufficiency remains present in a significant proportion of the hypertensive population. This is accompanied by a marked increase in cardiovascular risk, as a consequence of the clustering of other cardiovascular risk factors and of insufficiently controlled BP. Prevention and protection of renal and cardiovascular damage in these patients will be one of the most relevant tasks in the future.
Albuminuria↗
Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study.
This article reports further analyses of the Hypertension Optimal Treatment (HOT) Study data with the aim to describe (1) the value of baseline serum creatinine and its clearance (estimated by Cockroft and Gault formula) as predictors of cardiovascular events, (2) the effects of intensive lowering of BP on cardiovascular events and renal function in patients with reduced renal function, and (3) the effects on cardiovascular events of adding acetylsalicylic acid to antihypertensive therapy in patients with reduced renal function. The results show that (1) baseline elevation in serum creatinine and a reduction in estimated creatinine clearance are powerful predictors of cardiovascular events and death. (2) Reduced renal function at baseline did not preclude the desired control of BP. In contrast to patients with normal renal function, the incidence of major cardiovascular events did not differ in the three groups of patients with mild renal insufficiency randomized to different diastolic BP targets. No significant changes in serum creatinine were seen at the end of the 3.8-yr treatment period in the great majority of patients. However, there was a small group of patients (0.58% of the total study population) whose renal function deteriorated (increase > or =30% over baseline and final serum creatinine concentration > or =2 mg/dl) despite satisfactory reduction of diastolic BP. (3) The results of this reanalysis of the HOT Study suggest though do not prove that the association of acetylsalicylic acid with intensive antihypertensive therapy offers additional benefit in hypertensive patients with reduced renal function.
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Clinical significance of renal function in hypertensive patients at high risk: results from the INSIGHT trial.
BACKGROUND: Increasing evidence suggests renal involvement in hypertension-related cardiovascular and cerebrovascular complications. To assess this role of renal function in more detail, we studied the evolution of renal function and the relationship of renal function with mortality and morbidity in the Intervention as a Goal in Hypertension Treatment (INSIGHT) study. METHODS: The INSIGHT study was a double-blind, randomized, multicenter trial in patients with hypertension and at least 1 additional cardiovascular risk factor. Treatment consisted of nifedipine gastrointestinal therapeutic system, 30 mg/d, or hydrochlorothiazide-amiloride (25 mg/d of hydrochlorothiazide and 2.5 mg/d of amiloride hydrochloride). Primary outcome was a composite of cardiovascular death, myocardial infarction, heart failure, and stroke. Renal function was assessed by measuring creatinine clearance, serum creatinine level, and serum uric acid level and by the presence of proteinuria. RESULTS: Creatinine clearance fell more in nifedipine recipients than in hydrochlorothiazide-amiloride recipients. Renal insufficiency developed in 2% of nifedipine recipients and 5% of hydrochlorothiazide-amiloride recipients. Primary outcomes occurred in 15% of patients with increased serum creatinine levels and 6% of patients with normal levels (odds ratio [OR] 2.89; 95% confidence interval [CI], 1.92-4.36; P<.001). Primary outcomes were more likely in patients with low creatinine clearance (<60 mL/min) than in those with higher clearances (9% vs 5%, respectively [OR, 1.51, 95%CI, 1.22-1.88; P<.001]). CONCLUSIONS: Renal function is an important predictor of risk in hypertensive patients at high risk. Antihypertensive treatment with a long-acting dihydropyridine calcium channel blocker may better preserve renal function than would treatment with diuretics.
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Long-term cardiovascular consequences of diuretics vs calcium channel blockers vs angiotensin-converting enzyme inhibitors.
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Angiotensin-Converting Enzyme Inhibitors↗
Renal endpoints in hypertension trials.
A growing interest in the investigation of renal function has developed in recent years in big trials. This is justified by the high prevalence of nephrosclerosis as a cause of end-stage renal disease and the capacity of minor alterations of renal function to predict poor outcome for the patients. The finding of a small increase in serum creatinine values, a diminished estimated glomerular filtration rate, microalbuminuria and/or proteinuria, heralds a significant elevation in cardiovascular events and death as well as in total mortality. This paper describes the detection, prevalence and relevance of minor alterations in the stratification of cardiovascular risk in the hypertensive patient.
Antihypertensive Agents↗
Factors influencing the systolic blood pressure response to drug therapy.
In the early stage of hypertension, diastolic blood pressure has greater prognostic importance, but in the elderly, systolic blood pressure is the most important marker of cardiovascular complications. Therefore, the need for more strict control of this component of blood pressure must be reconsidered. The benefit obtained in different studies in the elderly suggests that the treatment of isolated systolic hypertension is associated with a reduction in overall cardiovascular mortality of 22%, in coronary heart disease mortality of 26%, and in stroke mortality of 33%. However, a higher percentage of patients (73%) attain the diastolic goal of <90 mm Hg, while only 34% have systolic pressure reduced to <140 mm Hg. In a review of randomized trials comparing at least four different antihypertensive drugs, significant differences in systolic blood pressure reduction have not been demonstrated, except in black populations, in whom calcium channel blockers and diuretics seem to be more effective. In patients with isolated systolic hypertension, data are inconclusive, but calcium channel blockers and diuretics appear to lower blood pressure to a greater degree than do other antihypertensive drugs. Two main predictors of difficulty in controlling systolic blood pressure are the baseline blood pressure and the presence of diabetes. Other predictors are the duration of arterial hypertension, older age, the presence of target organ damage and associated clinical conditions (myocardial infarction, stroke, chronic renal failure), and an elevated serum uric acid level. It appears that the profile of patients with a poorer therapeutic response includes a greater severity of hypertension and/or the presence of cardiovascular disease.
Antihypertensive Agents↗
How relevant and frequent is the presence of mild renal insufficiency in essential hypertension?
Recent analyses of the influence of renal function on the cardiovascular outcome in essential hypertensive patients have confirmed the relevance of the kidney in cardiovascular prognosis even in the initial stages of renal failure. The evaluation of renal function in clinical practice is based mainly on the finding of changes in serum creatinine, but the estimation of creatinine clearance or its determination after 24-hour urine collection is not usually performed. The objective of this study was to analyze the prevalence of mild chronic renal insufficiency (MCRI) through the determination of creatinine clearance in patients with essential hypertension to reinforce the need to consider using this parameter in daily clinical practice. We analyzed clinical and biochemical data from 2686 essential hypertension patients referred to our unit from 1979-1999. MCRI was defined as a serum creatinine > or =1.5 mg/dL in men and > or =1.4 mg/dL in women, or a creatinine clearance estimated by the Cockroft-Gault formula or by a 24-hour urine collection of <60 mL/min. A prevalence of MCRI was found in 7.6% according to serum creatinine levels. This prevalence increased to 22.3% and 21.5% respectively when the diagnostic criteria for MCRI was the estimation of 24-hour creatinine clearance in urine, or its estimation using the Cockroft-Gault formula. When classified by creatinine clearance values, patients with MCRI were characterized by older age, elevated systolic blood pressure, higher serum total cholesterol, low-density lipoprotein cholesterol, and triglycerides, lower levels of high-density lipoprotein cholesterol, higher serum uric acid, fasting serum glucose, serum potassium, and higher levels of urinary albumin excretion. In summary, MCRI is more prevalent in essential hypertension than previously thought, particularly if the estimated creatinine clearance is used to define MCRI. The finding of an altered renal function is associated with a significant increase in cardiovascular risk. This fact reinforces the need to pay attention to any of the manifestations of renal damage observed in the usual clinical assessment of any hypertensive patient.
Adult↗