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Left ventricular hypertrophy [LVH, high left ventricular mass (LVM)] is traditionally classified as concentric or eccentric based on left ventricular relative wall thickness. We evaluated left ventricular systolic function in a new four-group LVH classification based on left ventricular dilatation [high left ventricular end-diastolic volume (EDV) index and concentricity (LVM/EDV)] in hypertensive patients.Nine hundred thirty-nine participants in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiography substudy had measurable LVM at enrolment. Patients with LVH (LVM/body surface area ≥116 g/m in men and ≥96 g/m in women) were divided into four groups; 'eccentric nondilated' (normal LVM/EDV and EDV), 'eccentric dilated' (increased EDV, normal LVM/EDV), 'concentric nondilated' (increased LVM/EDV with normal EDV), and 'concentric dilated' (increased LVM/EDV and EDV) and compared to patients with normal LVM. At baseline, 12% had eccentric nondilated, 20% eccentric dilated, 29% concentric nondilated, and 14% concentric dilated LVH, with normal LVM in 25%. Compared with the concentric nondilated LVH group, those with concentric dilated LVH had significantly lower pulse pressure/stroke index and ejection fraction; higher LVM index, stroke volume, cardiac output, left ventricular midwall shortening, left atrial volume and isovolumic relaxation time; and more had segmental wall motion abnormalities (all P 0.05). Similar differences existed between patients with eccentric dilated and those with eccentric nondilated LVH (all P 0.05). Compared with patients with normal LVM, the eccentric nondilated had higher LV stroke volume, pulse pressure/stroke index, Cornell voltage product and SBP, and lower heart rate and fewer were African-American (all P 0.05).The new four-group classification of LVH identifies dilated subgroups with reduced left ventricular function among patients currently classified with eccentric or concentric LVH.

It remains to be determined whether the evidence in Western countries for blockade of the renin-angiotensin System in cardiovascular diseases could be directly applied to East Asian races including the Japanese population as a long-term strategy. The KYOTO HEART Study (KHS) is designed to investigate the add-on effect of valsartan versus conventional anti-hypertensive treatment on cardiovascular morbidity and mortality in Japanese hypertensive patients with uncontrolled blood pressure and with high cardiovascular risk. Over 3000 high-risk Japanese patients with uncontrolled hypertension were randomised to receive either additional treatment with valsartan or conventional non-angiotensin receptor blocker therapies, and the follow-up period will be at least 3 years. The primary end point is a composite of defined cardio- or cerebro-vascular events. Secondary end points include all causes of mortality, worsening of cardiac function, new onset or worsening of arrhythmias or diabetes mellitus. The KHS will provide new evidence for the management of blood pressure in hypertensive patients with high risk.

To investigate whether a threshold exists for cardiovascular risk in type 2 diabetic patients with hypertension, the association between renal function and cardiovascular risk was examined across the entire physiological range of serum creatinine.The RENAAL and LIFE studies enrolled 1513 and 1195 patients with type 2 diabetes and hypertension, respectively. The relationship between baseline serum creatinine and the risk for a composite outcome of myocardial infarction, stroke or cardiovascular death was examined using Cox regression models. To adjust for heterogeneity between studies and treatment groups, these factors were included as strata when applicable. The analyses were conducted with adjustment for age, gender, smoking, alcohol use, blood pressure, heart rate, total and high-density lipoprotein (HDL) cholesterol, hemoglobin, albuminuria and prior cardiovascular disease.The hazard ratios across the baseline serum creatinine categories0.9 mg/dl, 0.9-1.2 mg/dl, 1.2-1.6 mg/dl, 1.6-2.8 mg/dl andor= 2.8 mg/dl were 0.51 (95% confidence interval 0.34, 0.74), 0.74 (0.55, 1.00), 1.00 (reference), 1.24 (0.96, 1.59) and 1.67 (1.17, 2.91), respectively. Baseline serum creatinine (per mg/dl) strongly predicted the composite cardiovascular endpoint in LIFE [2.82(1.74,4.56), P0.001], RENAAL [1.41(1.12,1.79), P0.001], as well as the combined studies [1.51(1.21,1.87), P0.001].A progressively higher risk for the composite cardiovascular endpoint was observed with incremental baseline serum creatinine in type 2 diabetic patients with hypertension, even within the normal range. Thus, there appears to be no serum creatinine threshold level for an increased cardiovascular risk. Baseline serum creatinine was a major independent risk factor for cardiovascular disease (www.ClinicalTrials.gov number NCT00308347).

To determine whether or not the lower rate of coronary disease in France, in comparison with Sweden, might be explained by different cardiovascular risk profiles, a cross-sectional analysis (first step of a longitudinal study) of comparable samples of automotive workers was carried out in corporate occupational health clinics of Renault and Volvo. Traditional cardiovascular risk factors were evaluated and the Framingham coronary risk was estimated for 1000 randomly selected 45-50 years old Caucasian males from each company. Compared with the Frenchmen, the Swedish men consisted of more white collar workers and were slightly older. After adjustment for age and blue/white collar status, the Swedish men showed lower body mass indexes, waist to hip rations and heart rates, lower frequency of treatment of hypercholesterolemia and diabetes than the Frenchmen. The Swedish males also exhibited higher averages of blood cholesterol, low density lipoprotein (LDL) cholesterol and glucose, but lower frequencies of hypercholestrolemia and diabetes, and a higher frequency of family histories of cardiovascular disease. Blood pressure, hypertension prevalence, triglycerides level, and high density lipoprotein (HDL) did not differ between the groups. The average number of traditional risk factors was 1.1/person for the Frenchmen and 0.8/person for the Swedes. However, the coronary risk as estimated using the Framingham index was not different between the groups. This, together with the more frequent family history of cardiovascular disease in Swedish men, suggests a lower susceptibility to risk factors as a possible explanation for the lower cardiovascular disease prevalence reported in France, and/or the possibility that factors not measured were involved.

To evaluate, in hypertensive patients, whether the metabolic syndrome is a better predictor of new-onset diabetes compared with impaired fasting glucose, obesity or its other individual components alone, or collectively.Cox models were developed to assess the risk of new-onset diabetes associated with the metabolic syndrome after adjusting for a priori confounders (age, sex, ethnicity and concomitant use of non-cardiovascular medications), its individual components and other determinants of new-onset diabetes. Area under receiver operator curves using the metabolic syndrome or models of impaired fasting glucose were compared, and the ability of these models to correctly identify those who (after 5-years of follow-up) would or would not develop diabetes was assessed.The metabolic syndrome adjusted for a priori confounders and its individual components, and further adjusted for other determinants, was associated with significantly increased risk of new-onset diabetes [1.19 (1.00-1.40), P = 0.05 and 1.22 (1.03-1.44), P = 0.02, respectively]. The discriminative ability of the metabolic syndrome model [area under receiver operating curve: 0.764 (0.750-0.778)] was significantly better than the model of impaired fasting glucose [0.742 (0.727-0.757)] (P0.001). The metabolic syndrome correctly allocates the risk of new-onset diabetes in a significantly higher proportion of patients (62.3%) than impaired fasting glucose status (37.7%) (P0.001). The presence of both the metabolic syndrome and impaired fasting glucose were associated with an approximately 9-fold (7.47-10.45) increased risk of new-onset diabetes. Among normoglycaemic patients, the metabolic syndrome was also associated with significantly increased risk of new-onset diabetes, after adjusting for BMI and a priori confounders [1.66 (1.29-2.13)].Both impaired fasting glucose and the metabolic syndrome predict the risk of new-onset diabetes; however, the metabolic syndrome is a better predictor than impaired fasting glucose in assigning the risk of new-onset diabetes in hypertensive patients, and among those with normoglycaemia.

Adherence to lipid-lowering therapy in clinical practice is less than ideal. Analysis of registry data has indicated that this is associated with poor outcomes. The objective of the present analysis was to assess the impact of high adherence to drug (defined as80% of days covered), compared with low adherence to drug (50% of days covered) in terms of risk of events and long-term economic consequences.Open-label follow up of a randomised placebo-controlled trial in hypertensive patients.Cox proportional hazards and Poisson regression models were used to assess the hazard ratio of patients with high adherence compared with low adherence while controlling for cardiovascular risk. A Markov model was used to predict the long-term costs and health outcomes associated with poor adherence during the follow-up period.Both statistical models indicated that high adherence is associated with improved prognosis [Cox model: 0.75; 95% confidence interval (CI): 0.56-0.98, Poisson model hazard ratio: 0.73; 95% CI: 0.58-0.98]. Discounted at 3.5% per year, the Markov model predicts that as a consequence of higher adherence during the follow-up period, costs would be higher (1689 pounds per patient compared with 1323 pounds per patient) because of higher drug costs, but the projected survival and quality-adjusted survival (QALY) would also be longer (10.83 compared with 10.81 life years and 8.13 compared with 8.11 QALYs).Given the higher risk of cardiovascular events associated with low adherence shown here, measures to improve adherence are an important part of the prevention of cardiovascular disease.

Echocardiographically determined left ventricular mass (LVM) is currently considered to be the most powerful risk indicator for cardiovascular disease, yielding prognostic information beyond that provided by the evaluation of traditional cardiovascular risk factors, high blood pressure included. It has been considered logical to try to obtain regression of cardiac hypertrophy, even though the risk-reducing implications of such a measure remain to be fully established. Experimental and clinical studies have shown that some classes of antihypertensive compounds are less effective than others in causing reversal of left ventricular hypertrophy (LVH) in spite of being similarly efficacious in lowering blood pressure. In order to extract the maximum amount of information from clinical studies, a meta-analysis was performed. This analysis included 109 treatment studies, each conformed to strict present rules. Only studies with pharmacological antihypertensive therapy and echocardiographically determined LVM were included. An analysis of the effect of the four first-hand antihypertensive treatment principles, adjusted for differences between studies with ANCOVA, showed that the ACE inhibitors, beta-blockers and calcium antagonists all reduce LVM by reversing wall hypertrophy and that the effect is most pronounced with ACE inhibitors. Diuretics reduce LVM mainly by a reduction in left ventricular diameter. If the difference in ability to reverse LVH, between ACE inhibitors and beta-blockers/diuretics would correspond to a difference in prognosis, then the outcome of antihypertensive therapy might be expected to improve. This hypothesis is currently under investigation.

Endothelin-1 was infused into the non-dominant brachial artery in two male subjects. We then monitored intra-arterial mean blood pressure, right atrial pressure, the heart rate and forearm blood flow (by plethysmography). Endothelin-1 at a dose of 5 x 10(-14) to 5 x 10(-9) mol, infused over 5 min periods, elicited no major changes in mean arterial pressure, heart rate and right atrial pressure. We observed an initial increase in forearm blood flow, followed by dose-dependent decreases of 25, 34 and 42% at 5 x 10(-11) to 5 x 10(-9) mol. A higher dose of endothelin-1, 5 x 10(-8) mol, given to only one of the subjects, elicited sweating and vomiting. In this subject, mean arterial pressure, right atrial pressure and the heart rate did not change, while forearm blood flow increased transiently. A deep muscular pain developed in the forearm receiving the endothelin-1 infusion after 30 min (maximum 2 h, duration 10 h), and this pain was intensified by touch and muscle contractions. The force of muscle contractions in the forearm was markedly reduced and a visible oedema developed. In order to investigate the mechanisms of oedema formation, endothelin-1 (10(-10) to 5 x 10(-8) mol/l) was given intra-arterially in a rat hindquarter preparation which was perfused at a constant flow rate. In the rat, endothelin-1 increased both pre- and postcapillary resistance, leading to an increase in capillary hydrostatic pressure and a marked net transcapillary fluid transfer from the perfusate to tissue. There was no sign of increased vascular permeability.(ABSTRACT TRUNCATED AT 250 WORDS)

The aim of the Nordic Diltiazem (NORDIL) Study was to compare patients with essential hypertension receiving calcium-antagonist-based treatment with diltiazem and similar patients receiving conventional diuretic/beta-blocker-based treatment, with respect to cardiovascular morbidity and mortality.To assess the influence of age, sex, severity of hypertension and heart rate on treatment effects, in a sub-analysis.The NORDIL study was prospective, randomized, open and endpoint-blinded. It enrolled, at health centres in Norway and Sweden, 10 881 patients aged 50-74 years who had diastolic blood pressure (DBP) of 100 mmHg or more. Systolic blood pressure (SBP) and DBP were decreased by 20.3/18.7 mmHg in the diltiazem group and by 23.3/18.7 mmHg in the diuretic/beta-blocker group - a significant difference in SBP (P0.001).The incidence of the primary endpoint - a composite of cardiovascular death, cerebral stroke and myocardial infarction - was similar for the two treatments. Fatal and non-fatal stroke occurred in 159 patients in the diltiazem group and in 196 patients in the conventional treatment group [relative risk (RR) 0.80, 95% confidence interval (CI) 0.65 to 0.99; P = 0.040], whereas there was a non-significant inverse tendency with respect to all myocardial infarction. There were significantly fewer cerebral strokes in patients receiving diltiazem in the subgroups with baseline SBP170 mmHg (n = 5420, RR 0.75, 95% CI 0.58 to 0.98; P = 0.032), DBP/= 105 mmHg (n = 5881, RR 0.74, 95% CI 0.57 to 0.97; P = 0.030) and pulse pressure/= 66 mmHg (n = 5461, RR 0.76, 95% CI 0.58 to 0.99, P = 0.041), and more myocardial infarctions in those with heart rate less than 74 beats/min (n = 5303, RR 1.13, 95% CI 1.01 to 1.87; P = 0.040). However, the tendencies for fewer strokes and greater incidence of myocardial infarction were present across subgroups when results were analysed for age, sex, severity of hypertension and heart rate, and treatment-subgroup interaction analyses were not statistically significant.Compared with a conventional diuretic/beta-blocker-based antihypertensive regimen, there were additional 25% reductions in stroke in the diltiazem-treated patients with blood pressure or pulse pressure greater than the medians, and an increase in myocardial infarction in those with heart rate less than the median. Such findings may be attributable to chance, but the consistency of, in particular, the stroke findings may also suggest an ability of diltiazem, beyond conventional treatment, to prevent cerebral stroke in hypertensive patients with the greatest cardiovascular risk.

In the Losartan Intervention For Endpoint reduction (LIFE) study left ventricular (LV) hypertrophy was associated with increased urine albumin/creatinine ratio (UACR) at baseline. To evaluate whether this association was due only to parallel blood pressure (BP)-induced changes we re-examined the patients after 1 year of antihypertensive treatment to investigate whether changes in LV hypertrophy and UACR were related independently of changes in BP. In 7,142 hypertensive patients included in the LIFE study, we measured UACR, LV hypertrophy by electrocardiography, plasma glucose and BP after 2 weeks of placebo treatment and again after 1 year of antihypertensive treatment with either an atenolol or a losartan based regime. At baseline and still after 1 year of treatment logUACR (R = 0.28, P0.001) was still correlated to LV hypertrophy (beta = 0.05) assessed by ECG independently of systolic BP (beta = 0.16), plasma glucose (beta = 0.19) and age (beta = 0.08). Change in logUACR (R = 0.19, P0.001) during treatment was correlated to change in LV hypertrophy (beta = 0.10) independently of reduction in systolic BP (beta = 0.13) and change in plasma glucose (beta = 0.06). After 1 year of antihypertensive treatment UACR was still related to LV hypertrophy independently of systolic BP, and the reduction in UACR during that first year of treatment was related to regression of LV hypertrophy independently of reduction in systolic BP. This suggests that the relationship between LV hypertrophy and glomerular albumin leakage is not just due to parallel BP-induced changes. As glomerular albumin leakage may represent generalised vascular damage we hypothesise a vascular relationship between cardiac and glomerular damage.

In hypertensive patients, left ventricular hypertrophy (LVH) predicts increased mortality, in part due to an increased incidence of sudden death. Repolarization-related arrhythmogenesis may be an important mechanism of sudden death in hypertensive patients with LVH. Increased QT interval and QT dispersion are electrocardiographic (ECG) measures of ventricular repolarization, and also risk markers for ventricular tachyarrhythmias. We assessed the relation of QT intervals and QT dispersion to echocardiographically determined left ventricular (LV) mass and geometry in a large population of hypertensive patients with ECG evidence of LVH.QT intervals and QT dispersion were determined from baseline 12-lead ECGs in 577 (57% male; mean age 65 +/- 7 years) participants in the LIFE study. LV mass index (LVMI) and geometric pattern were determined by echocardiography and QT interval duration and QT dispersion were assessed in relation to gender-specific LVMI quartiles.In both genders, increasing LVMI was associated with longer rate-adjusted QT intervals. QT dispersion measures showed a weaker association with LVMI quartiles. Both concentric and eccentric LVH were associated with increased QT interval duration and QT dispersion. These relations remained significant after controlling for relevant clinical variables.In hypertensive patients with ECG evidence of LVH, increased LVMI and LVH are associated with a prolonged QT interval and increased QT dispersion. These findings suggest that an increased vulnerability to repolarization-related ventricular arrhythmias might in part explain the increased risk of sudden death in hypertensive patients with increased LV mass.

This study was designed to assess the relation of electrocardiographic (ECG) strain to increased left ventricular (LV) mass, independent of its relation to coronary heart disease (CHD).The classic ECG strain pattern, ST depression and T-wave inversion, is a marker for left ventricular hypertrophy (LVH) and adverse prognosis. However, the independence of the relation of strain to increased LV mass from its relation to CHD has not been extensively examined.Electrocardiograms and echocardiograms were examined at study baseline in 886 hypertensive patients with ECG LVH by Cornell voltage-duration product and/or Sokolow-Lyon voltage enrolled in the Losartan Intervention For End point (LIFE) echocardiographic substudy. Strain was defined as a downsloping convex ST segment with inverted asymmetrical T-wave opposite to the QRS axis in leads V5 and/or V6.Strain occurred in 15% of patients, more commonly in patients with than without evident CHD (29%, 51/175 vs. 11%, 81/711, p0.001). When differences in gender, race, diabetes, systolic pressure, serum creatinine and high density lipoprotein cholesterol were controlled, strain on baseline ECG was associated with greater indexed LV mass in patients with (152 +/- 33 vs. 131 +/- 32 g/m2, p0.001) or without CHD (131 +/- 24 vs. 119 +/- 22 g/m2, p0.001). In logistic regression analyses, strain was associated with an increased risk of anatomic LVH in patients with CHD (relative risk 5.14, 95% confidence interval [CI] 1.16 to 22.85, p = 0.0315), without evident CHD (relative risk 2.91, 95% CI 1.50 to 5.65, p = 0.0016), and in the overall population when CHD was taken into account (relative risk 2.98, 95% CI 1.65 to 5.38, p = 0.0003).When clinical evidence of CHD is accounted for, ECG strain is likely to indicate the presence of anatomic LVH. Greater LV mass and higher prevalence of LVH in patients with strain offer insights into the known association of the strain pattern with adverse outcomes.

To test the primary hypothesis that a newer antihypertensive treatment regimen (calcium channel blocker +/- an angiotensin converting enzyme inhibitor) is more effective than an older regimen (beta-blocker +/- a diuretic) in the primary prevention of coronary heart disease (CHD). To test a second primary hypothesis that a statin compared with placebo will further protect against CHD endpoints in hypertensive subjects with a total cholesterolor = 6.5 mmol/l.Prospective, randomized, open, blinded endpoint trial with a double-blinded 2 x 2 factorial component.Patients were recruited mainly from general practices.Men and women aged 40-79 were eligible if their blood pressure wasor = 160 mmHg systolic oror = 100 mmHg diastolic (untreated) oror = 140 mmHg systolic oror = 90 mmHg diastolic (treated) at randomization.Patients received either amlodipine (5/ 10 mg) +/- perindopril (4/8 mg) or atenolol (50/ 100 mg) +/- bendroflumethiazide (1.25/2.5 mg) +K+ with further therapy as required to reach a blood pressure ofor = 140 mmHg systolic and 90 mmHg diastolic. Patients with a total cholesterol ofor = 6.5 mmol/l were further randomized to receive either atorvastatin 10 mg or placebo daily.Non-fatal myocardial infarction (MI) and fatal coronary heart disease (CHD).19 342 men and women were initially randomized, of these 10297 were also randomized into the lipid-lowering limb. All patients had three or more additional cardiovascular risk factors.The study has 80% power (at the 5% level) to detect a relative difference of 20% in CHD endpoints between the calcium channel blocker-based regimen and the beta-blocker-based regimen. The lipid-lowering limb of the study has 90% power at the 1% level to detect a relative difference of 30% in CHD endpoints between groups.

To clarify the relations of systemic hemodynamics to left ventricular (LV) geometric patterns in patients with moderate hypertension and target organ damage.LV geometry stratifies risk in hypertension, but relations of LV geometry to systemic hemodynamic patterns in moderately severe hypertension have not been fully elucidated.Cross-sectional case-control study.Baseline findings in the echocardiographic substudy of the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE) and in a normotensive reference group.Nine hundred and sixty-four patients with Stage I-II hypertension and LV hypertrophy by Cornell voltage duration criteria ((SV3 + RaVL [+ 6 mm in women]) x QRS2440 mm x ms) or modified Sokolow- Lyon voltage criteria (SV1 + RV5/RV638 mm), and 366 apparently normal adults.None.Two-dimensional and Doppler echocardiograms were used to classify hypertensive patients into groups with normal geometry, concentric remodelling and concentric and eccentric hypertrophy, and to measure stroke volume (SV), cardiac output, peripheral resistance and pulse pressure/SV as a measure of arterial stiffness. Comparisons were adjusted for covariates by general linear model with the Sidak post-hoc testMean SV was higher in patients with eccentric hypertrophy (83 ml/beat) and lower with concentric remodeling (68 ml/beat) than in normal adults (73 ml/ beat). Cardiac output was highest in patients with eccentric LV hypertrophy and lower with concentric remodeling than eccentric hypertrophy; mean pressure and peripheral resistance were equally high in all hypertensive subgroups, whereas pulse pressure/SV was most elevated (by a mean of 47% versus reference subjects) with concentric remodeling and least so (mean + 15%) with eccentric hypertrophy. In multivariate analysis (Multiple R + 0.68), LV mass was independently related to higher systolic pressure, older age, SV, male gender and body mass index (all P0.001). Relative wall thickness was independently related (Multiple R + 0.50) to older age, higher systolic pressure, lower SV (all P0.001) and higher body mass index (P + 0.007). SV and cardiac output were lower in patients with low stress-corrected midwall shortening.In patients with moderate hypertension and ECG LV hypertrophy, the levels of SV and pulse pressure/ SV, are associated with, and may be stimuli to different LV geometric phenotypes.

Left ventricular (LV) ejection fraction is normal in most patients with uncomplicated hypertension, but the prevalence and correlates of decreased LV systolic chamber and myocardial function, as assessed by midwall mechanics, in hypertensive patients identified as being at high risk by the presence of LV hypertrophy on the electrocardiogram has not been established. Therefore echocardiograms were obtained in 913 patients with stage I to III hypertension and LV hypertrophy determined by electrocardiographic (Cornell voltage duration or Sokolow-Lyon voltage) criteria after 14 days' placebo treatment. The 913 patients' mean age was 66 years, and 42% were women. Fourteen percent had subnormal LV endocardial shortening, 24% had subnormal midwall shortening, and 13% had reduced stress-corrected midwall shortening. Nineteen percent had normal LV geometry, 11% had concentric remodeling, 47% had eccentric hypertrophy, and 23% had concentric hypertrophy. LV systolic performance evaluated by LV endocardial shortening and midwall shortening was impaired in 10% of patients with normal geometry, 20% with concentric remodeling, 27% with eccentric hypertrophy, and 42% with concentric hypertrophy. Relative wall thickness, an important independent correlate of LV chamber function, was related directly to endocardial shortening and negatively to midwall shortening and stress-corrected midwall shortening. LV mass was the strongest independent correlate of impaired endocardial shortening, midwall shortening, or both. In hypertensive patients with electrocardiographic LV hypertrophy, indexes of systolic performance are subnormal in 10% to 42% with different LV geometric patterns. Depressed endocardial shortening is most common in patients with eccentric LV hypertrophy, whereas impaired midwall shortening is most prevalent in patients with concentric remodeling or hypertrophy. Thus, in hypertensive patients with electrocardiographic LV hypertrophy, impaired LV performance occurs most often, and is associated with greater LV mass and relative wall thickness and may contribute to the high rate of cardiovascular events.

The benefits of treating hypertension in elderly diabetic patients, in terms of achieving reductions in cardiovascular morbidity and mortality, have been documented in several recent prospective trials. There has, however, been some controversy regarding the effect of different antihypertensive drugs on the frequency of myocardial infarction in this group of patients.STOP Hypertension-2 was a prospective, randomized, open trial with blinded endpoint evaluation.We studied 6614 elderly patients aged 70-84 years; 719 of them had diabetes mellitus at the start of the study (mean age 75.8 years). Patients were randomly assigned to one of three treatment strategies: conventional antihypertensive drugs (diuretics or beta-blockers), calcium antagonists, or angiotensin converting enzyme (ACE) inhibitors.Reduction in blood pressure was similar in the three treatment groups of diabetics. The prevention of cardiovascular mortality was also similar; the frequency of this primary endpoint did not differ significantly between the three groups. There were, however, significantly fewer (P = 0.025) myocardial infarctions during ACE inhibitor treatment (n = 17) than during calcium antagonist treatment (n = 32; relative risk 0.51, 95% confidence interval 0.28-0.92); but a (non-significant) tendency to more strokes during ACE inhibitor treatment (n = 34 compared with n = 29; relative risk 1.16, 95% confidence interval 0.71-1.91).Treatment of hypertensive diabetic patients with conventional antihypertensive drugs (diuretics, beta-blockers, or both) seemed to be as effective as treatment with newer drugs such as calcium antagonists or ACE inhibitors.

The Losartan Intervention For Endpoint (LIFE) reduction in hypertension study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of atenolol on the reduction of cardiovascular morbidity and mortality. A total of 9194 patients with hypertension and ECG left ventricular hypertrophy (LVH) by Cornell voltage-duration product and/or Sokolow-Lyon voltage criteria were enrolled in the study, with baseline clinical and ECG data available in 8785 patients (54% women; mean age, 67+/-7 years). ECG LVH by Cornell voltage-duration product criteria was present in 5791 patients (65.9%) and by Sokolow-Lyon voltage in 2025 patients (23.1%). Compared with patients without ECG LVH by Cornell voltage-duration product criteria, patients with ECG LVH by this method were older; more obese; more likely to be female, white, and to have never smoked; more likely to be diabetic and have angina; and had slightly higher systolic, diastolic, and pulse blood pressures. In contrast, patients with ECG LVH by Sokolow-Lyon criteria were slightly younger; less obese; more likely to be male, black, and current smokers; less likely to have diabetes; more likely to have angina and a history of cerebrovascular disease; and had higher systolic and pulse blood pressure but slightly lower diastolic blood pressure than patients without ECG LVH by this method. By use of multivariate logistic regression analyses, presence of ECG LVH by Cornell voltage-duration product criteria was predominantly associated with higher body mass index, increased age, and female gender, whereas presence of ECG LVH by Sokolow-Lyon voltage criteria was predominantly related to lower body mass index, male gender, and black race. Thus, hypertensive patients who meet Cornell product and Sokolow-Lyon voltage criteria are associated with different, but potentially equally adverse, risk factor profiles.

Left ventricular (LV) hypertrophy on echocardiogram (ECG) strongly predicts coronary heart disease events, but the mechanisms linking increased LV mass to ischemic vascular events is uncertain.Variables related to myocardial oxygen demand were compared among normotensive adults and patients with mild and more severe hypertension, and among groups of moderately hypertensive patients with target organ damage in relation to gender, LV geometry and LV systolic function.The Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial, in which hypertensive patients with ECG LV hypertrophy (Cornell voltage-duration product,2440 mm x ms and/or SV1 + RV(5-6)38 mm) were randomized toor = 4 years double-blinded treatment with losartan or atenolol.A total of 964 LIFE participants enrolled in an echocardiographic substudy, and groups of 282 employed hypertensive and 366 apparently normal adults.None.ECG LV parameters contributing to myocardial oxygen demand (wall stresses, LV mass, heart rate and wall stress-mass-heart rate products).In both women and men, stepwise increases from reference subjects to employed hypertensives to LIFE patients were observed for LV wall stresses, mass and stress-mass-heart rate products. LIFE men patients had slightly higher wall stresses and significantly higher triple products than women. Wall stresses were increased in patients with normal LV geometry, eccentric or concentric hypertrophy; triple products were about three and two times normal with eccentric and concentric hypertrophy, with smaller increases in other geometric groups. Patients with decreased LV fractional shortening had two times normal end-systolic stresses and three or four times normal triple products; smaller increases in stresses and triple products occurred with decreased LV midwall function.Hypertensive patients with ECG LV hypertrophy have increased LV wall stresses and stress-mass-heart rate products, suggesting a contribution of high myocardial oxygen demand to increased risk in such patients. Particularly high stresses and triple products were associated with echocardiographic LV hypertrophy, and subnormal LV chamber and midwall function.

The Losartan Intervention For Endpoint (LIFE) reduction in hypertension study is a double-blind, prospective, parallel-group study comparing the effects of losartan with those of atenolol on the reduction of cardiovascular complications in patients (n = 9,194) with essential hypertension and with electrocardiographically (ECG) documented left ventricular hypertrophy (LVH). Baseline blood pressure was 174.4/97.8 mm Hg (mean), age 66.9 years, body mass index 28.0 kg/m2; 54.1% were women and 12.5% had diabetes mellitus. This population will be treated until at least 1,040 have a primary endpoint. After five scheduled visits and 12 months of follow-up, blood pressure decreased by 23.9/12.8 mm Hg to 150.5/85.1 mm Hg (target140/90 mm Hg). The mandatory titration level ofor = 160/95 mm Hg was reached by 72.1% of the patients. At the 12-month visit, 22.7% of all patients were taking blinded study drug alone, 44.3% were taking blinded drug plus hydrochlorothiazide (HCTZ), and 17.7% were taking blinded drugs plus HCTZ and additional drugs. Controlling for all other variables, patients in the US received more medication and had 2.4 times the odds of achieving blood pressure control than patients in the rest of the study (P.001). Previously untreated patients (n = 2,530) had a larger initial decrease in blood pressure compared with those previously treated. Diabetics (n = 1,148) needed more medication than nondiabetics to gain blood pressure control. Only 13.9% of the patients had discontinued blinded study drug and 1.4% missed the revisit at 12 months. These data demonstrate both the successful lowering of blood pressure during 12 months of follow-up in a large cohort of patients with hypertension and LVH on ECG, but also emphasize the need for two or more drugs to control high blood pressure in most of these patients. Being previously treated and having diabetes were associated with less blood pressure response, whereas living in the US indicated better blood pressure control. It has been possible to keep most of these patients with complicated hypertension taking blinded study drug for 12 months.

During the last two decades several large clinical trials have documented beneficial eVects of diVerent pharmacological interventions on morbidity and mortality in various cardiovascular conditions. Based on the results of these trials physicians in general feel convinced that there is a considerable reduction of mortality and morbidity as a result of treatment with: (a) ‚ receptor blockers in patients with acute myocardial infarction as well as in the postinfarction period; (b) acetylsalicylic acid (ASA; aspirin) and thrombolytic drugs in patients with acute myocardial infarction; (c) angiotensin converting enzyme (ACE) inhibitors in patients with left ventricular systolic dysfunction irrespective of symptoms of heart failure and, as recently shown in the HOPE study, in patients with high cardiovascular risk but without heart failure or obvious left ventricular systolic dysfunction; (d) ‚ receptor blockers and spironolactone in addition to an ACE inhibitor in patients with chronic heart failure; (e) diuretics, ‚ receptor blockers, calcium channel blockers, and ACE inhibitors in hypertension; and (f) statins in secondary pre

Abnormal left ventricular (LV) filling may exist in early stages of hypertension. Whether this finding is related to LV hypertrophy is currently controversial. This study was undertaken to assess relations between abnormal diastolic LV filling and LV geometry in a large series of hypertensive patients with electrocardiographic LV hypertrophy. M-mode, 2-dimensional, and pulsed Doppler echocardiographic recordings of mitral inflow velocity and isovolumetric relaxation time (IVRT) were obtained in 750 patients with stage I to III hypertension and LV hypertrophy determined by electrocardiography (sex-adjusted Cornell voltage duration criteria or Sokolow-Lyon voltage criteria) after 14 days of placebo treatment. The patients' mean age was 67+/-7 years and 44% were women. One hundred forty patients (19%) had normal LV geometric pattern, 79 (11%) had concentric remodeling, 342 (45%) had eccentric LV hypertrophy, and 189 (25%) had concentric LV hypertrophy. A normal LV filling pattern was found in 116 patients (16%), abnormal relaxation in 519 (69%), "pseudonormal" filling was found in 83 (11%), and a restrictive filling pattern in 32 (4%). Prolonged IVRT was associated with LV hypertrophy (p0.01) as well as elevated relative wall thickness (p0.05). A stronger difference (p0.01) in IVRT was found between groups with and without LV hypertrophy. Multiple regression analysis revealed that increased LV mass correlated with prolonged IVRT, whereas LV mass and geometry were not associated with peak early LV filling velocity (E), peak atrial filling velocity (A) ratio or mitral valve E-peak deceleration time, although IVRT was found to be an independent correlate of E/A ratio and deceleration time. Thus, abnormal IVRT was highly prevalent in all LV geometric subgroups among hypertensive patients with electrocardiographic LV hypertrophy, even in those with normal LV geometry determined by echocardiography. We found that IVRT differed significantly among patient groups with different LV geometric patterns, primarily because of the association of IVRT to LV mass.

The study was done to evaluate reliability of echocardiographic left ventricular (LV) mass.Echocardiographic estimation of LV mass is affected by several sources of variability.We assessed intrapatient reliability of LV mass measurements in 183 hypertensive patients (68% men, 65 +/- 9 years) enrolled in the Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement (PRESERVE) trial after a screening echocardiogram (ECHO) showed LV hypertrophy. A second ECHO was repeated at randomization (45 +/- 25 days later). Two-dimensional (2D)-guided M-mode or 2D linear measurements of LV cavity and wall dimensions were verified by one experienced reader.Mean LV mass was similar at first and second ECHO (243 +/- 53 vs. 241 +/- 54 g) and showed high reliability as estimated by intraclass correlation coefficient (RHO) = 0.93. Within-patient 5th, 10th, 90th and 95th percentiles of between-study difference in LV mass were -32 g, -28 g, +25 g and +35 g. Mean LV mass fell less from the first to the second ECHO than expected from a formula to predict regression to the mean (2 +/- 19 vs. 17 +/- 12 g, p0.001). Reliability was also high for LV internal diameter (RHO = 0.87), septal (RHO = 0.85) and posterior wall thickness (RHO = 0.83). Substantial or moderate reliability was observed for measures of LV systolic function and diastolic filling (RHO from 0.71 to 0.57).Left ventricular mass had high reliability and little regression to the mean; between-study LV mass change of +/-35 g or +/-17 g hador = 95% oror = 80% likelihood of being true change.

Losartan was the first available orally administered selective antagonist of the angiotensin II type 1 receptor developed for the treatment of hypertension. The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality. Patients with essential hypertension, aged between 55 and 80 years, and ECG-documented left ventricular hypertrophy (LVH) were included. Altogether, 9223 patients in Scandinavia, the United Kingdom, and the United States were randomized from June 1995 through April 1997, and 9194 remain after exclusion of a study center at which irregularities were discovered. This population of hypertensives (mean systolic/diastolic blood pressure, 174.4/97.8 mm Hg) with LVH comprises women (54.1%) and men, mostly retired from active work (mean age, 66.9 years), with a high prevalence of overweight (mean body mass index, 28.0 kg/m2), diabetes mellitus (12.3%), lipid disorders (18.0%), and symptoms or signs of coronary heart disease (15.1%). There were fewer current smokers (17%) than in the general population, and approximately 7% were nonwhite. Almost 30% of participants had been untreated for at least 6 months when screened for the study. Only 1557 persons who entered the placebo run-in period of 14 days were excluded, predominantly because of sitting blood pressures above or below the predetermined range of 160-200/95-115 mm Hg and ECG-LVH criteria not met. By application of simple 12-lead ECG criteria for LVH (Cornell voltage QRS duration product formula plus Sokolow-Lyon voltage read by a core laboratory), hypertensive patients with LVH with an average 5-year coronary heart disease risk of 22.3% according to the Framingham score were identified. This population is now being treated (goal,140/90 mm Hg) in adherence with the protocol for at least 4 years after final enrollment (ie, through April 2001) and until at least 1040 patients suffer myocardial infarction, stroke, or cardiovascular death.

To determine whether or not the lower rate of coronary disease in France, in comparison with Sweden, might be explained by different cardiovascular risk profiles, a cross-sectional analysis (first step of a longitudinal study) of comparable samples of automotive workers was carried out in corporate occupational health clinics of Renault and Volvo. Traditional cardiovascular risk factors were evaluated and the Framingham coronary risk was estimated for 1000 randomly selected 45-50 years old Caucasian males from each company. Compared with the Frenchmen, the Swedish men consisted of more white collar workers and were slightly older. After adjustment for age and blue/white collar status, the Swedish men showed lower body mass indexes, waist to hip rations and heart rates, lower frequency of treatment of hypercholesterolemia and diabetes than the Frenchmen. The Swedish males also exhibited higher averages of blood cholesterol, low density lipoprotein (LDL) cholesterol and glucose, but lower frequencies of hypercholestrolemia and diabetes, and a higher frequency of family histories of cardiovascular disease. Blood pressure, hypertension prevalence, triglycerides level, and high density lipoprotein (HDL) did not differ between the groups. The average number of traditional risk factors was 1.1/person for the Frenchmen and 0.8/person for the Swedes. However, the coronary risk as estimated using the Framingham index was not different between the groups. This, together with the more frequent family history of cardiovascular disease in Swedish men, suggests a lower susceptibility to risk factors as a possible explanation for the lower cardiovascular disease prevalence reported in France, and/or the possibility that factors not measured were involved.

To compare two losartan regimens (with and without hydrochlorothiazide) and amlodipine in treating mild-to-moderate hypertension regarding their blood-pressure-lowering effect, drug tolerability and quality of life.A 12-week, randomized, double-blind, parallel-group, multi-centre study. After 4 weeks of placebo, patients with a diastolic blood pressure (DBP) in the range 95-115 mmHg were allocated randomly to be administered 50 mg losartan (increased to 100 mg if the DBP was 90 mmHg or more after 6 weeks), 50 mg losartan (plus 12.5 mg hydrochlorothiazide under the above conditions), or 5 mg amlodipine (increased to 10 mg under the above condition). The tolerability of the treatment and the quality of life were evaluated by spontaneous reporting, active questioning and the Psychological General Well-Being (PGWB) index.In total 898 hypertensives, mainly referred from primary health care (mean age 57.8 years) of whom 52% were men.Administration of 50 mg losartan (plus 12.5 hydrochlorothiazide if necessary) and of 5 mg amlodipine (or 10 mg if necessary) lowered the blood pressure as well as or better than did 50 mg losartan (or 100 mg if necessary). The incidence of 'any discomfort' and 'swollen ankles' increased with amlodipine but not with losartan treatment. The opposite was found for 'dizziness upon standing'. The incidence of drug-related adverse events and the number of patients withdrawn from therapy were higher with amlodipine than they were with losartan treatment. The PGWB index at week 12 indicated that improvements from baseline had occurred in some domains for the losartan groups whereas it remained unchanged for the amlodipine group.Both losartan and amlodipine were effective in lowering the blood pressure and were tolerated well. Administration of 50 mg losartan (plus 12.5 mg hydrochlorothiazide if necessary) and of 5 mg amlodipine (or 10 mg if necessary) lowered the blood pressure equally well or better than did 50 mg losartan (or 100 mg if necessary). Drug-related adverse effects and withdrawal from the study were more common for the amlodipine group. The clinical significance of the improvements in the PGWB index with losartan needs to be studied further.

The treatment of hypertension mainly with diuretics and beta blockers reduces cardiovascular mortality and morbidity, largely due to a decreased incidence of stroke, whereas the beneficial effects of antihypertensive therapy on the occurrence of coronary events have been less than expected from epidemiological studies. Furthermore, treated hypertensive patients still have a higher cardiovascular complication rate, compared with matched normotensives. This is particularly evident in patients with left ventricular hypertrophy (LVH), a major independent risk indicator for cardiovascular disease. In addition to elevating blood pressure, angiotensin II (A-II) exerts an important influence on cardiac structure and function, stimulating cell proliferation and growth. Thus, to further reduce morbidity and mortality when treating hypertensive patients, it may be important to effectively block the effects of A-II. This can be achieved directly at the A-II receptor level by losartan, the first of a new class of antihypertensive agents. It therefore seems pertinent to investigate whether selective A-II receptor blockade with losartan not only lowers blood pressure but also reduces LVH more effectively than current therapy, and thus improves prognosis. The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality in approximately 8,300 hypertensive patients (initial sitting diastolic blood pressure 95 to 115 mm Hg or systolic blood pressure 160 to 200 mm Hg) with electrocardiographically documented LVH. The study, which will continue for at least 4 years and until 1,040 patients experience one primary endpoint, has been designed with a statistical power that will detect a difference of at least 15% between groups in the incidence of combined cardiovascular morbidity and mortality. It is also the first prospective study with adequate power to link reversal of LVH to reduction in major cardiovascular events. The rationale of the study, which will involve more than 800 clinical centers in Scandinavia, the United Kingdom, and the United States, is discussed, and the major features of its design and general organization are described. On April 30, 1997, when inclusion was stopped, 9,218 patients had been randomized.

Resume Une relation bien etablie Il existe un seuil au-dela duquel le risque de deces vasculare augmente avec la pression arterielle, celle-ci etant un puissant determinant du risque d’accident vasculaire cerebral chez le sujet âge. En outre, une relation lineaire a pu etre etablie entre hypertension arterielle et risque de recidive d’accident vasculaire cerebral. L’efficacite des traitements antihypertenseurs Deux meta-analyses ont montre l’efficacite des traitements antihypertenseurs a l’egard des accidents vasculaires cerebraux en prevention primaire. Un benefice comparable a ete mis en evidence en prevention secondaire. Cependant, avec un abaissement similaire des chiffres tensionnels, l’efficacite preventive des differentes classes medicamenteuses varie. Les resultats de l’etude Life Dans cette etude realisee chez des patients ayant une hypertension arterielle avec hypertrophie ventriculaire gauche, le losartan, antagoniste selectif des recepteurs de type 1 de l’angiotensine II s’est montre superieur de maniere significative a l’atenolol, un betabloquant dans la prevention des accidents vasculaires cerebraux, l’abaissement des chiffres tensionnels etant pourtant comparable. En pratique En raison des differences dans la prevention des risques, il importe de mieux definir, avant traitement antihypertenseur, les risques (cœur, vaisseaux, rein) pour chaque patient afin de realiser une prise en charge specifique.

Activation of the renin-angiotensin system both systemically and locally seems to be of importance for cardiovascular hypertrophy and remodelling. The octapeptide angiotensin II definitively plays a central role. In the reversal, for example, of left ventricular hypertrophy, so far the most important independent risk factor for an adverse outcome, blocking of the renin-angiotensin system with ACE inhibition has been shown to be particularly effective. In cardiac tissue, however, ACE inhibition has been suggested to inhibit only a fraction of angiotensin II formed, indicating that other enzymatic pathways can be of importance. From a theoretical point of view a more complete blockade of the angiotensin II type 1 receptor would offer a more effective attenuation of the unfavourable effect of angiotensin II. Experimentally, losartan, a novel selective angiotensin II receptor type 1 antagonist has been shown to decrease cardiac hypertrophic response in models of both hypertension and volume cardiac hypertrophy as well as reverse hypertrophy in spontaneously hypertensive rats. TCV-116, another selective angiotensin II antagonist, also effectively reverses cardiac hypertophy and interstitial fibrosis in the rat. The only report so far regarding the effect of angiotensin II blockade on cardiac hypertrophy in essential hypertension suggests a more favourable short-term effect on cardiac hypertrophy for the same blood pressure reduction with losartan compared with atenolol in a small population of mild to moderate hypertensives. In the perspective of the well-established positive effects of ACE inhibition on the remodelling process in the remaining viable myocardium after myocardial infarction, involving myocyte hypertrophy, interstitial fibrosis and progressive dilatation, it is reassuring that angiotensin II blockade has been shown to perform equally well as ACE inhibition after experimental coronary ligation. In summary, the development of cardiovascular hypertrophy in hypertension is a serious prognostic indicator and selective angiotensin II blockade is a new anti-hypertensive treatment modality with promising properties, especially for prevention and reversal of cardiac hypertrophy including pathological fibrosis and cardiac remodelling after myocardial infarction. Thus, taking into account the shortcomings of today's anti-hypertensive treatment to achieve normalisation of excessive cardiovascular morbidity and mortality, as well as the seemingly great importance of the renin-angiotensin system for hypertension-induced functional and structural abnormalities, a therapy based on a specific All antagonist could offer obvious advantages in a high risk hypertensive patient with cardiovascular hypertrophy. This hypothesis will be investigated in a large prospective trial (Losartan Intervention For End-point reduction in hypertension: The LIFE Study).

The current failure of antihypertensive therapy to control BP in many hypertensive patients highlights the need for new treatment strategies. Ideally, these new strategies should provide reliable, effective 24 h BP control in all types of patients with a convenient, well-tolerated regimen. Logimax, an extended-release tablet containing felodipine and metoprolol, has been developed, which provides more effective control of BP in a wider range of patients than either component as monotherapy, without compromising tolerability. This combination increases the likelihood of achieving target BP and is therefore likely to provide further reductions in cardiovascular risk.

In a randomized, double blind, parallel-group, multicentre study in Norway, 97 patients with mild to moderate hypertension (mean blood pressure 159/104 mm Hg) were treated with either lisinopril 10-40 mg or nifedipine 20-80 mg and the effects on blood lipids were evaluated. Complete results of laboratory analyses are given for 80 patients. After a 4 week run-in and placebo period, antihypertensive treatment was given for the next 10 weeks. During treatment with lisinopril the changes in lipids were +2.1% for total cholesterol, +0.7% for HDL-cholesterol, +3.8% for triglycerides and -6.1% for ratio HDL/cholesterol-HDL. For nifedipine the corresponding values were -2.4% for cholesterol, -5.8% for HDL-cholesterol, +8.0% for triglycerides and +3.2% for ratio. None of these changes was statistically significant. Both lisinopril and nifedipine lowered the blood pressure significantly, 18.1/12.0 mm Hg with lisonopril (p0.01 for both systolic and diastolic pressure) and 8.0/8.5 mm Hg with nifedipine (p0.01 for both respectively). Both drugs were well tolerated. In conclusion, neither lisinopril nor nifedipine had any negative impact on lipid levels.

To investigate the effects of enalapril and hydrochlorothiazide on erythrocyte sodium and potassium in relation to their effects on BP, 28 men (mean age 46 years, range 22-64 years) with previously untreated essential hypertension (casual DBPor = 95 mmHg) were randomised to enalapril (n = 14) or hydrochlorothiazide (n = 14) treatment. BP was also measured intraarterially (brachial artery) and the mean arterial pressure (MAP) recorded. Intraerythrocyte sodium and potassium were measured by flame photometry at baseline and after 26 weeks of active treatment in the hypertensive patients and also in 28 age- and sex-matched normotensive control subjects. There was a significant positive relationship between intra-arterial BP and intraerythrocyte sodium in untreated hypertensives, but there was no significant difference in mean intraerythrocyte sodium or potassium content between hypertensive and normotensive subjects at baseline. The distribution of values of intraerythrocyte sodium, however, differed between hypertensive and normotensive subjects. Supine MAP was lowered from 113 +/- 4 to 97 +/- 3 mmHg and from 110 +/- 3 to 102 +/- 2 mmHg on enalapril and hydrochlorothiazide treatment, respectively. BP reduction with enalapril was associated with a significant decrease in intraerythrocyte sodium (P = 0.02), while hydrochlorothiazide had no effect. There was no significant correlation between delta MAP and delta intraerythrocyte sodium after 26 weeks in any of the groups. Intraerythrocyte potassium did not change on treatment with either drug. In conclusion, there wa a significant relationship between intra-arterial BP and intraerythrocyte sodium in untreated hypertensives. Both enalapril and hydrochlorothiazide reduced BP effectively while enalapril only reduced intraerythrocyte sodium.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular hypertrophy (LVH) is a recognized complication of, rather than a physiological response to, hypertension, being a powerful independent indicator of cardiovascular disease risk. In addition, it is reasonable to assume that the reversal of LVH is a desirable therapeutic goal in the treatment of hypertension. Furthermore, the renin-angiotensin system plays an important role in LVH and, in particular, in the development of cardiac interstitial fibrosis. Therefore, the effect of angiotensin-converting enzyme (ACE) inhibition on LVH is of particular interest. In both experimental and human studies, ACE inhibitors appear to perform better than other antihypertensive agents in reversing cardiac structural changes. A recent meta-analysis showed ACE inhibitors to be more efficacious than other first-line antihypertensives in reducing left ventricular mass. A controlled long-term study of previously untreated men showed that enalapril reversed LVH significantly better than did hydrochlorothiazide and that the regression of LVH was independently related to blockade of the renin-angiotensin system. Indeed, there have been studies showing that ACE inhibitors can affect LVH without lowering blood pressure. Moreover, ACE inhibitors have shown cardioprotective and cardioreparative properties in experimental models of hypertensive LVH. In conclusion, ACE inhibitors are effective in reversing LVH as well as interstitial fibrosis. The prognostic implications of this remain to be seen. So far, the experience with spirapril on LVH is limited, but the accumulated data are promising.

Objectives. To assess the peripheral and central haemodynamics, in particular the effect on minimal resistance in the hand, with an ACE inhibitor in comparison with a diuretic. Design. Double-blind randomized parallel group study. Subjects. Twenty-eight previously untreated men with essential hypertension (supine diastolic blood pressure > 95 mmHg repeatedly on placebo). Methods/intervention. Casual and intra-arterial blood pressure, dye-dilution technique, water plethysmography at rest and at ischaemia, enalapril (n = 14), hydrochlorothiazide (n = 14). Results. After 6 months the mean arterial pressure was reduced from 112.7 to 96.9 mmHg (change –15.9 mmHg; 95% confidence interval (CI) –21.9, –9.8) on enalapril and from 110.1 to 101.5 mmHg (change –8.6 mmHg; CI –14.4, –2.8). Heart rate did not change on any of the therapies. Enalapril reduced blood pressure mainly through a reduction in total peripheral resistance (Δ –3.0 PRU100; CI –5.6, –0.4) while hydrochlorothiazide reduced blood pressure mainly through a reduction in cardiac output (Δ –0.8 l/min−1 CI –1.5, –0.07). Minimal vascular resistance (mean of right and left hand) displayed a significant time × treatment interaction indicating a different trend with enalapril than hydrochlorothiazide with a change of –0.12 PRU100 (CI –0.33, 0.05) on enalapril and a change of 0.14 (CI –0.29, 0.56) on hydrochlorothiazide. The resistance level after 6 months was significantly higher on hydrochlorothiazide than on enalapril (P = 0.0105). Conclusion. Enalapril reduced blood pressure through vasodilatation and hydrochlorothiazide through decreased cardiac output. The two therapies also affected minimal vascular resistance (an indirect measure of vascular wall thickness) differently; with enalapril showing a favourable response in contrast to hydrochlorothiazide.

It is well established that hypertensive patients benefit from drug treatment of their disorder. In recent years three major out-come studies of antihypertensive treatment in elderly hypertensives have shown substantial benefits, i.e. a reduction in the risk of stroke and other cardiovascular mortality and morbidity. In all these studies beta-blockers and/or diuretics were used in comparison with placebo. Newer therapeutic alternatives have, however, at least theoretically, many advantages which could result in further improvements in prognosis. The initial Swedish Trial in Old Patients with Hypertension (STOP-Hypertension 1) was conducted in men and women aged 70-84 years. STOP-Hypertension 2 will evaluate the therapy used in STOP-Hypertension 1 against therapy based on either ACE-inhibitors (enalapril and lisinopril) or on calcium antagonists (isradipine and felodipine), using the PROBE design (Prospective, Randomised, Open, Blinded Endpoint evaluation). The primary aim will be to assess the effect on cardiovascular mortality. Statistical calculations indicate that 6,600 patients, followed for four years will be needed (2p0.05, power 90%) to obtain significance if there is a 25% difference between the new and the established therapy. Patients in primary health care (300 centres) will be included if their supine blood pressure isor = 180/105 mmHg (and/or). Recruitment of patients started in September 1992 and so far more than 100 patients/week have been included.

The renin-angiotensin system has an important effect on the development of cardiac hypertrophy and the regulation of left ventricular function, in particular by promoting cardiac interstitial fibrosis.In both experimental and human studies, ACE inhibitors have shown a clear tendency to perform better than other types of antihypertensive therapy in reversing cardiac structural changes. A recent meta-analysis of 109 studies showed that ACE inhibitors were more effective than beta-blockers, calcium antagonists and diuretics in reducing left ventricular mass. Furthermore, cardiac hypertrophy was reversed to a significantly greater extent with enalapril than hydrochlorothiazide in a long-term study of previously untreated men. Multivariate analyses of the results from that study showed that the reversal of cardiac hypertrophy was independently related to the blockade of the circulating renin-angiotensin system. Furthermore, experimental studies have shown that ACE inhibition can induce reversal of left ventricular hypertrophy even without a fall in blood pressure.The novel angiotensin II blocker losartan has, like ACE inhibitors, shown significant effects on cardiovascular structure in animal models.Blockade of the renin-angiotensin system with ACE inhibitors seems to have independent significance for the reversal of cardiac hypertrophy. However, we still do not know whether it is the attenuation of angiotensin II (locally or systemically), apart from a fall in blood pressure, that is the most important effect of ACE inhibition. Therefore, results from future studies on the ability of angiotensin II antagonists to affect left ventricular hypertrophy, in comparison with ACE inhibitors, are awaited with great interest, especially regarding the differential effects on myocyte hypertrophy and interstitial fibrosis.

In this double-blind, randomised, three-way crossover (latin square design), multicentre study, the aim was to compare the efficacy and tolerability of the fixed combination of felodipine and metoprolol with the individual components as monotherapy. A total of 58 patients with supine diastolic blood pressure of 100-115 mmHg were treated with (1) a fixed combination of felodipine plus metoprolol 5/50-10/100 mg (FM), (2) felodipine 5-10 mg (F) or (3) metoprolol 50-100 mg (M), for 12 weeks each. All treatments were extended-release formulations administered once daily and blood pressure was measured 24 h after dosing. Dose titration was performed after 6 weeks if diastolic blood pressure was90 mmHg. After 12 weeks of active treatment, the mean supine blood pressures were 153/89, 159/93 and 163/94 mmHg with FM, F and M, respectively. The mean differences in systolic/diastolic blood pressure were -5.6/-3.1 mmHg (p = 0.007/p = 0.002), -10.2/-4.4 mmHg (p0.0001/p0.0001) and -4.6/-1.4 mmHg (p = 0.03/p = 0.15) for FM vs F, FM vs M, and F vs M, respectively. Blood pressure control (supine diastolic blood pressureor = 90 mmHg) after 12 weeks was achieved in a significantly greater proportion of patients during treatment with FM than with F or M; 71%, 45% and 40% were controlled with the respective treatments. With FM, 45% of the patients were taking the higher dose after 12 weeks of treatment. The corresponding figures for F and M were 60% and 67%, respectively. Thirteen of the 58 patients (22%) were controlled only with FM.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind, randomised, parallel-group study was performed to compare the efficacy and tolerability of a new extended-release tablet containing felodipine and metoprolol with each constituent agent as monotherapy. After a 4-week placebo period, 159 patients with mild-to-moderate essential hypertension were randomised to receive either the combination tablet of felodipine and metoprolol 10/100 mg, felodipine 10 mg or metoprolol 100 mg once daily if supine diastolic blood pressure wasor = 95 mmHg. After 12 weeks of active treatment, reductions in supine systolic/diastolic blood pressure 24 h after dosing were 20/14, 13/10 and 11/8 mmHg with felodipine-metoprolol, felodipine and metoprolol, respectively. The differences in blood pressure changes were 7/4 mmHg (p = 0.004/0.006) and 8/5 mmHg (p = 0.0002/0.0001) between the fixed combination and felodipine and metoprolol, respectively. Blood pressure response (defined as a diastolic blood pressureor = 90 mmHg and/or a reductionor = 10 mmHg) after 12 weeks of treatment was greater with the combination than with felodipine or metoprolol alone: 85% vs 72% (p = 0.06) and 54% (p = 0.001), respectively. Treatments were well tolerated and adverse events were as expected from previous studies with each agent and did not differ in frequency between groups. In conclusion, the extended-release tablet formulation of felodipine-metoprolol 10/100 mg produces a clinically relevant and significantly greater blood pressure reduction 24 h after dosing than either agent as monotherapy without decreasing tolerability.

Our study attempted to evaluate the importance of changes in the circulating renin-angiotensin-aldosterone system (RAAS) and in hemodynamics in relation to observed changes in cardiovascular structure. We studied previously untreated men (n = 28) with essential nonmalignant hypertension and a supine casual diastolic blood pressure95 mm Hg on three to four separate (1-week interval) occasions measured in triplicate. We used intraarterial blood pressure, dye-dilution technique, plethysmography (hands), eye-ground photos, M-mode echocardiography, radio immunoassays, and multiple regression analysis. Patients were randomized to 6 months of double-blind treatment with either enalapril or hydrochlorothiazide, following 4 to 6 weeks on placebo. We found that enalapril blocked the plasma angiotensin converting enzyme (ACE) with a secondary increment in plasma renin activity (PRA) and reductions in angiotensin II (AII) and aldosterone. Blood pressure was lowered through a reduction in total peripheral resistance (TPR). Hydrochlorothiazide increased PRA, AII, and aldosterone, and lowered blood pressure mainly through a reduction in cardiac output. Enalapril was significantly more effective than hydrochlorothiazide in reversing structural changes in the retinal and hand vasculature as well as in the heart. A reduction in cardiac hypertrophy was seen even in the occasional enalapril-treated patient, in whom little or no reduction in blood pressure occurred. In the stepwise regression analyses, the changes in retinal and hand vascular structure were most strongly related to various changes in the RAAS, explaining 15 to 34% of the variance. For the changes in cardiac structure, the type of therapy (enalapril or hydrochlorothiazide) appeared to be the most important factor, explaining between 29 and 50% of the variance. The changes in cardiac structure were even more strongly related to changes in the RAAS for the enalapril treated patients and explained up to 55% of the variance in cardiac structure. It can be concluded that the reversal of structural vascular changes during antihypertensive therapy was more dependent on the blockade of the RAAS than on lowering of the blood pressure.

In a Norwegian, double-blind, double-dummy multicenter study, 828 patients with mild to moderate hypertension were randomized to treatment by either lisinopril or nifedipine. One of the aims of the study was to specifically investigate the frequency of side effects. Spontaneously reported coughing reached 8.5% for lisinopril, as against 3.1% for nifedipine. In two patients coughing led to withdrawal from the study, and in another three it contributed partially to discontinuation of the treatment. A significant sex difference was found for spontaneously reported coughing among patients on lisinopril; 12.6% of the women and 4.4% of the men. A similar difference between the sexes was found for specific questioning about coughing. Use of a visual analogue scale by both patient and spouse revealed similar frequency of coughing as when reported spontaneously. The reason for sex being an important determinant for lisinopril-induced coughing remains obscure.