Objective The Verapamil in Hypertension and Atherosclerosis Study (VHAS) is a prospective randomized study the objective of which was to compare the long-term effects of verapamil and chlorthalidone on the blood pressure, clinical safety, and the progression/regression of carotid wall lesions in members of a large population of hypertensive patients. Design After a 3-week placebo run-in period, 1414 hypertensive patients [692 men and 722 women, aged 53.2 ± 7 years, blood pressure 168.9 ± 10.5/ 102.2 ± 5.0 mmHg (means ± SD)] were assigned randomly to be administered either 240 mg sustained- release verapamil (n = 707) or 25 mg chlorthalidone (n = 707) once a day for 2 years. The study design was double blind for the first 6 months and open thereafter. 25–50 mg/day captopril were added to the treatment of non-responding patients; subsequently, patients not responding to combined therapy were switched to any therapy chosen by the treating doctors (free therapy). The blood pressure of the sitting subject, heart rate, and a standard clinical safety profile (electrocardiogram, laboratory tests, adverse events, cardiovascular events, and deaths) were assessed regularly throughout the study. Results After 2 years the systolic and diastolic blood pressures were reduced significantly in members of both treatment groups (by 16.3/16.6% with verapamil and by 16.9/16.2% with chlorthalidone, both by analysis of variance, P < 0.0001). The patients for whom we added captopril treatment constituted 22.6% of the verapamil and 26.2% of the chlorthalidone group; while 11.6 and 12.2% of patients in these groups, respectively, were administered free therapy. Normalization of the diastolic blood pressure (to ≤ 90 mmHg or to ≤ 95 mmHg with a ≥ 10% decrease) was achieved for 69.3% of the verapamil and 66.9% of the chlorthalidone group. A decrease in heart rate (by 5.8%) occurred in members of the verapamil group only. A decrease in total serum cholesterol (from 223.6 to 216.9 mg/dl, P < 0.01) and in the total cholesterol : high-density lipoprotein cholesterol ratio (from 4.9 to 4.5, P < 0.01) was noted for the verapamil group only, whereas significantly greater rates of hyperuricemia (plasma urate > 7.0 mg/dl; 10.8 versus 3.9%) and hypokalemia (serum K < 3.5 mmol/l; 24.6 versus 4.4%) were observed for the chlorthalidone group (P < 0.01, versus verapamil for both). Adverse events were reported by 32.5% of patients treated with verapamil and by 33.4% of those treated with chlorthalidone. The most frequent adverse events were constipation in members of the verapamil group (13.7%) and asthenia in members of the chlorthalidone group (8.5%). In total 315 dropped out (153 from the verapamil and 162 from the chlorthalidone group). The occurrence of cardiovascular events was similar for both treatments (42 events for verapamil and 43 for chlorthalidone, NS). Conclusion Similar antihypertensive efficacies, tolerabilities and cardiovascular event rates were observed with verapamil and with chlorthalidone. However, treatment with chlorthalidone was associated with significantly higher incidences of hyperuricemia and hypokalemia than was treatment with verapamil.

OBJECTIVES:To compare the effect of the angiotensin converting enzyme (ACE) inhibitor ramipril with that of the beta-blocker atenolol on reversal of left ventricular hypertrophy, on blood pressure and on other echocardiographic parameters.DESIGN:The study was conducted in accord with the PROBE (prospective randomized open blinded endpoint) design. Randomized treatment either with ramipril or with atenolol was continued for 6 months, and echocardiograms were recorded before and after 3 and 6 months of treatment. The echo tracings were blindly evaluated in a single reading centre.METHODS:M-mode, two-dimensional guided echocardiography was used to measure left ventricular wall thicknesses and dimensions, from which left ventricular mass was calculated, according to the Penn convention.RESULTS:Of 193 patients at 16 centres, 111 had echocardiograms that could be quantitatively evaluated. The primary analysis of the study was performed using data from those patients. In addition, echocardiograms of 88 patients were analysed on an 'according to protocol' basis (patients with preset values of left ventricular mass). Systolic and diastolic blood pressures were significantly reduced both by ramipril and by atenolol without any significant difference between the two drug treatments. The heart rate was significantly reduced by atenolol only. Both the 'primary' and the 'according to protocol' analyses showed that the left ventricular mass was significantly reduced by ramipril only. Comparison between treatments according to a multivariate analysis demonstrated a significantly greater reduction in left ventricular mass during ramipril than during atenolol treatment.CONCLUSIONS:The present study is the first of suitably large size in which a direct comparison of the effects of an ACE inhibitor and a beta-blocker on echocardiographic left ventricular mass has been performed. It has demonstrated that ramipril is more effective than atenolol in reversing left ventricular hypertrophy in essential hypertensive patients.

The antihypertensive efficacy of slow-release oral (SRO) isradipine was evaluated in 392 patients (mean age, 53 ± 9 years) with mild-to-moderate essential hypertension (diastolic blood pressure [DBP] 96 to 110 mm Hg). Patients from 35 hospitals throughout Italy participated in this 26-week study. After a 2-week placebo run-in period, patients were treated with 5 mg/d of isradipine; 6 weeks later, 10 to 20 mg of enalapril was added if DBP was not adequately reduced. At baseline and after 6 and 26 weeks of treatment, ambulatory 24-hour blood pressure (BP) recordings were made with measurements every 15 minutes during waking hours (7 am to 11 pm) and every 30 minutes during nighttime (11 pm to 7 am). Seated office BP was significantly reduced by isradipine alone and in combination with enalapril: mean overall group casual BP measurements fell by 15 mm Hg (systolic blood pressure [SBP]) and 10 mm Hg (DBP) at 6 weeks and 22 mm Hg (SBP) and 16 mm Hg (DBP) at 26 weeks compared with baseline. There was no significant difference between the two regimens. Mean 24-hour ambulatory BP of all 392 patients was lower with isradipine treatment at weeks 6 and 26, without changes in 24-hour BP profiles. The most frequent side effects observed were headache, flushing, ankle edema, and palpitations. These were responsible for a 4.8% dropout rate. No clinically important variations were observed in blood chemistries. The results of this large-scale study confirm that 5 mg/d of isradipine SRO is effective and well tolerated in the treatment of patients with mild-to-moderate essential hypertension. Analysis of BP profiles showed that, despite the marked antihypertensive effect persisting over 24 hours, the physiologic circadian BP rhythm was maintained.

It has been proposed, therefore, that hyperinsulinemia may favor the development of hypertension through sodium retention, sympathetic nervous system activation, and vascular hypertrophy. In insulin-resistant hypertensive subjects, insulin infusion during euglycemic clamp promotes a transient sodium retention by stimulating proximal tubular Na+ reabsorption, but chronic hypertension usually is not associated with extracellular fluid and plasma volume expansion. In essential hypertensive subjects, intracellular potassium is decreased and intracellular sodium increased, which is consistent with insulin resistance. The latter is also associated with high red blood cell Li+/Na+ exchange, and chronic insulin treatment in insulin-dependent diabetics induces a slight increase in Li+/Na+ CT. This is a functioning mode of the Na+/H+ exchange, and its increase may reflect either an increased number of transport units or abnormal kinetic properties. Experiments in vitro and in vivo suggested that any change in insulin concentration and insulin sensitivity may affect Li+/Na+ and Na+/H+ counter-transport. High Li+/Na+ and Na+/H+ CT are associated with a significant cardiac and vascular remodeling in essential hypertension, insulin-dependent diabetes, and familiar hypertrophic cardiomyopathy. Reduced insulin sensitivity is associated with salt-sensitive hypertension. Finally, insulin potentiates the effects of other agonists (eg, thromboxane A2, angiotensin II) on vascular contraction and cell growth. These data indicate that insulin may play a role in the pathogenesis of hypertension and its major complications by amplifying the effects of sodium, vasoconstrictors, and growth factors.

This double-blind, randomized, multicenter study was designed to compare the efficacy and tolerability of lisinopril and hydrochlorothiazide (HCTZ) in elderly patients (≥65 years old) with either mild-to-moderate systolic/diastolic hypertension (SDBP ≥ 95 ≤ 120 mmHg) or isolated systolic hypertension (SSBP > 160 mmHg, SDBP < 90 mmHg) and creatinine clearance levels ≥ 30 ml/min. At the end of a 2-week placebo run-in period, 96 patients were randomized in a 1:1 mode to receive either lisinopril 10 mg/day or HCTZ 12.5 mg/day. During the 12-week study, the doses of lisinopril and HCTZ were doubled every 4 weeks for nonresponders to a maximum of 40 and 50 mg/day, respectively. A positive response was defined as sitting diastolic blood pressure ≤ 90 mmHg for systolic/diastolic hypertension and as sitting systolic blood pressure ≤ 140 mmHg for isolated systolic hypertension. Mean decreases from baseline in systolic and diastolic blood pressures were significant (P ≤ 0.01) in both treatment groups. Both drugs were generally well tolerated; however, patients treated with HCTZ experienced more adverse effects. Moreover, mean serum potassium levels decreased significantly in the HCTZ group. No serious adverse events were reported in either group. Lisinopril has been shown to be an effective, well-tolerated angiotensin-converting enzyme inhibitor in elderly patients.

I N WESTERN SOCIETIES arterial hypertension is a common finding in people over the age of 65. In fact the elderly hypertensive population is made up not only of hypertensive persons who have aged, but also of those who have developed hypertension (mainly systolic) as a consequence of the vascular changes that are characteristic of old age. Ever since the epidemiologic studies conducted in the 60s and the 70s it is known that in the elderly the prevalence of hypertension is very high: 60% for systodiastolic hypertension and 15% to 45% for isolated systolic hypertension. However this particularly high figure may be due to the fact that most studies were based on a single blood pressure (BP) measurement. This may lead to an overestimation of the prevalence of hypertension, as we ourselves have been able to discover with repeated BP measurements over a period of 3 to 5 months of observation.1,2 Other trials have demonstrated a slightly lower prevalence,3,4 but confirm the importance of the phenomenon of hypertension in the elderly, particularly considering that in western countries the number of persons over the age of 65 increases by 4% each year; it has been calculated that by the year 2020 in Italy there will be some 11 million. It is well established that hypertension represents a major risk factor for cardiovascular diseases. This applies particularly to the elderly population where age itself represents a key factor in predicting the risk of atherosclerosis and its complications. Besides, the almost constant association with a deranged cerebral circulation and impaired cardiac and renal function exponentially increases the risk itself.

Exercise training is currently recommended in the management of mild hypertension, but the relationship between training and ventricular arrhythmias has never been investigated in hypertensive subjects. Forty hypertensive sportsmen were studied by means of 24-h ECG Holter monitoring and the results were compared with those obtained in 40 sedentary hypertensives, 40 normotensive sportsmen and 40 normotensive sedentary subjects. Among the hypertensive sportsmen 82.5% exhibited at least one ventricular extrasystole and 32.5% complex forms of ectopy, a prevalence higher than that observed in the sedentary hypertensives (50% and 17.5%; P = 0.002). In the normotensive sportsmen the prevalence of ventricular arrhythmias (62.5% and 22.5%) was lower than that in the hypertensive sportsmen, but the difference was not statistically significant. During a training session the prevalence of ventricular ectopy was similar in the two groups of trained individuals. Among the hypertensive sportsmen no correlation was found between the severity of ventricular arrhythmias and the degree of left ventricular hypertrophy and performance. The results of the present study suggest that exercise training may enhance left ventricular vulnerability in hypertensive subjects. Whether subjects who manifest complex ventricular arrhythmias should continue to train remains a matter for individual judgement.

Whether or not some classes of antihypertensive drugs have an anti-atherogenic action independent of the antihypertensive one has been investigated through a large series of experimental studies, primarily involving calcium antagonists. Most experimental investigations have shown a significant anti-atherogenic action of calcium antagonists, but only when the drug is administered simultaneously with the atherogenic stimulus (mainly cholesterol feeding). When the drug is administered weeks or months after the beginning of the atherosclerotic process (as in the Watanabe heritable hyperlipidemic rabbit), with a single exception, no antiatherogenic effect has been shown. The few clinical studies completed so far have been on symptomatic coronary patients. Little is known of the effects of calcium antagonists on asymptomatic lesions in the carotid arteries of hypertensive patients, in whom carotid plaques can be identified and followed-up by non-invasive ultrasound techniques. However, two such trials are underway. The Verapamil in Hypertension Atherosclerosis Study (VHAS) is an ongoing randomized trial, comparing the antihypertensive efficacy of verapamil 240 mg SR with chlorthalidone 25 mg in 1,464 essential hypertensives aged 40-65 years. In a random subgroup of patients (500), who will be followed for three years, B-mode ultrasonography is being carried out blindly to evaluate the effect of the two drugs on carotid wall thickness and on carotid plaques, when present. Preliminary baseline data are available in 440 of the hypertensive patients in whom ultrasound investigation was performed. The mean (+/- SD) age of these patients was 53.7 +/- 6.9 years; 32.5% had echocardiographically normal carotid walls; 30.9% showed intima-media thickening; and 36.6% had one or more plaques.(ABSTRACT TRUNCATED AT 250 WORDS)

Three large-scale epidemiological surveys covering some major coronary risk factors were conducted in Italy in population samples of men and women aged 30-59 years. The first survey was carried out in 1978-1979 (RF2 study; nine samples in eight regions; 2561 men and 2912 women); the second in 1983-1984 (OB43 study; nine samples in the same eight regions; 2267 men and 2398 women); and the third one in 1985-1987 (MICOL study; 18 samples in 10 regions; 14411 men and 12611 women). Time trends in mean age standardized risk factors levels showed slight but systematic decreases in blood pressure, cigarette smoking (only in men), and body mass index (only in women); whereas no substantial changes were observed in serum cholesterol levels. The combined multiple coronary risk estimated by a model produced in a previous study, showed a decline between 1978-1979 and 1983-1984 of 5.5% in men and 13.4% in women. These changes were compared with the official coronary death rates between 1984 and 1987 in the whole country and in the regions where the samples were located. The expected/observed ratio computed in different ways ranged from 0.54 to 0.88 for men and was over 1 for women. Changes in the levels of major risk factors and changes in coronary mortality seem biologically coherent at least in men.

To evaluate the effects of a soybean-rich diet on blood lipids, 50 g soybean oil, 500 mL soybean milk, and 10 g soybean lecitine were given daily to 109 adult subjects in place of the normal dietary fats for 4 months. In 20 comparable subjects (control group), the usual diet was continued for the same period. At the end of 4 months, the soybean-rich diet was associated with the following changes: blood cholesterol decreased by 5.7% (p = 0.0001), triglycerides by 6.9%, and apolipoprotein B100 by 28.3% (p = 0.0001). Hemodynamic changes included decreases of 4.5% in systolic blood pressure (p = 0.0001), 6.9% in diastolic blood pressure (p = 0.0001), and 5.9% in heart rate (p = 0.001). In 17 subjects who underwent plethysmography, rest flow increased by 9.7% and peripheral resistance decreased by 4.3%. No changes were observed in the control group.

In INTERSALT, an international cooperative study on electrolytes and blood pressure, significant associations were found, in the pooled data for 52 centres, between systolic BP and sodium (Na) excretion, body mass index (BMI), high alcohol intake and low potassium (K) excretion. We have assessed the status of the four Italian centres (Mirano, Gubbio, Bassiano, Naples) on these variables. The four centres examined a total of 794 men and women aged 20-59 years. Combined values were similar to overall INTERSALT levels for daily Na excretion (170 mmol) and BMI (25 kg/m2). The Italian centres had slightly higher potassium excretions (57 vs. 55 mmol/day), a higher prevalence of drinkers and a greater average alcohol consumption. Participants were divided into those below or above median levels of Na, K, BMI, and by alcohol intake (below or above 300 ml/week). Both systolic BP and diastolic BP were found to be lower in the more favourable stratum, for each variable. When all four factors were combined, those below median Na excretion and BMI, above median K, and with alcohol intake less than 300 ml/week had age-adjusted systolic BP 7.5 mmHg lower than those with less favourable levels of all four variables. The difference in adjusted diastolic BP was 4.3 mmHg. The data indicate the potential for lower population average BP with improved lifestyles.

We evaluated the ability of the Ca2+ channel blocker nifedipine to influence the severity of atherosclerotic lesions and the pattern of aortic smooth muscle cell (SMC) differentiation in cholesterol-fed New Zealand White rabbits. The animals were fed a 1% cholesterol-enriched diet for 12 weeks. After 4 weeks of the diet, some rabbits were given nifedipine (20 mg b.i.d.) for another 8 weeks without discontinuation of the cholesterol-enriched diet (experiment 1). Another group of rabbits was treated with nifedipine from the beginning of the cholesterol-enriched diet for the entire 12 weeks (experiment 2). The severity of ahterosclerotic lesions was determined by computerized planimetry, and qualitative effects of nifedipine on SMCs were studied by monoclonal antibodies specific for smooth muscle and nonmuscle myosins. In the aortic media of normal rabbits, these antibodies can identify an SMC population with an "immature" type of myosin pattern; a marked increase in the number of these cells is observed during atherogenesis. In experiment 1, we observed a marked decrease of medial SMCs with the immature type of myosin pattern, without any significant reduction in atherosclerosis severity. In experiment 2, disappearance of the previously mentioned medial SMC population was accompanied by a dramatic slowing of intimal lesion development. These results indicate that nifedipine treatment is effective in reducing atherosclerotic lesions only when given from the beginning of a cholesterol-enriched diet. Delay of nifedipine administration until the fourth week of the cholesterol-enriched diet fails to halt progression of the disease. The observed antiatherosclerotic activity can be attributable to a direct effect of the drug on the medial SMC population, which increases during the course of experimental atherogenesis.

Blood pressure variability has long been a subject of intense interest [1, 2] even though its clinical significance has not been completely established [3, 4]. Physical activity has been shown to represent one of the predominant determinants of blood pressure variability [5] and the blood pressure changes determined by both isotonic and isometric exercise have been studied extensively by means of laboratory tests. Everyday physical activities, as well as sports activities, differ in many respects from stress testing, however, so that a direct comparison cannot be made [6]. In fact, during such activities the dynamic and the static components of the exercise are not as clearly separated as in laboratory tests, but there is a parallel, though different, contribution of each one of them.

This paper deals with some changes at the cardiac and aortic levels observed in normotensive rats and in hypertensive rats and turkeys by using two different beta-blockers, namely propranolol and oxprenolol. Chronic treatment with propranolol induced in the heart of normotensive rats a shift in the ventricular myosin pattern toward the "slow" V2 and V3 isoforms which are characterized by a reduced oxygen consumption. Oxprenolol treatment did not modify the blood pressure levels in the renal hypertensive rats nor in the spontaneously hypertensive turkeys. Nevertheless, in both experimental models a substantial modification of the media and intima, respectively, took place. In untreated hypertensive and normal rats the thickness of the aortic media was significantly higher than that of the treated ones, therefore suggesting a direct effect of oxprenolol on the smooth muscle cells of the aortic media. In the spontaneously hypertensive turkeys the atherosclerotic plaques appeared to be more frequent and thicker than those found in the oxprenolol-treated animals. These two experiments demonstrate that beta-blockers can prevent the development of hypertrophy of the media and decrease both the incidence and severity of intimal proliferations independently of blood pressure control. It therefore appears that the well-known myocardial protective effect played by beta-blockers, which mainly consists of a reduced myocardial oxygen consumption, is certainly obtained by reducing blood pressure and heart rate but also by changing the contractile protein pattern. In addition, an indirect myocardial protective effect could be exerted by beta-blockers at the vascular level by preventing medial hypertrophy and the development of atherosclerosis.