Efficacy and safety of high-dose lisinopril in chronic heart failure patients at high cardiovascular risk, including those with diabetes mellitus. Results from the ATLAS trial.

AIMS: An analysis was designed to determine whether chronic heart failure patients at high cardiovascular risk benefited to the same extent from high-dose lisinopril as the whole ATLAS population. METHODS AND RESULTS: A retrospective analysis was performed on high-risk heart failure patients in the Assessment of Treatment with Lisinopril And Survival (ATLAS) trial (total number of patients 3164) comparing highdose (32.5-35 mg. day(-1)) vs low-dose (2.5-5 mg. day(-1)) lisinopril for a median of 46 months. These high-risk patients included those with hypotension, hyponatraemia, compromised renal function, the elderly and patients with diabetes mellitus at baseline. In the whole study population, high-dose lisinopril led to a trend in risk reduction of all-cause mortality (primary end-point P=0.128) and a significant risk reduction in all-cause mortality plus hospitalization (principal secondary end-point P=0.002). Subgroup analyses were performed for these end-points. There were no consistent interactions between age, baseline sodium, creatinine or potassium values, and treatment effect. Diabetics showed a beneficial response to high-dose therapy that was at least as good as that in non-diabetics. The underlying higher morbidity/mortality rates in diabetics mean that high-dose lisinopril has potential for a larger absolute clinical impact in these patients. CONCLUSION: Long-term high-dose lisinopril was as effective and well-tolerated in high-risk patients, including those with diabetes mellitus, as for the ATLAS study population as a whole.

Design and current status of ACTION: A Coronary disease Trial Investigating Outcome with Nifedipine GITS. Gastro-Intestinal Therapeutic System.

AIMS: To present the design of ACTION (A Coronary disease Trial Investigating Outcome with Nifedipine GITS), an ongoing multicentre clinical outcome trial with nifedipine GITS (Gastro-Intestinal Therapeutic System) in patients with stable angina pectoris. METHODS: At least 6000 patients with optimally treated stable angina without depressed left ventricular function are randomized in equal proportions to either nifedipine GITS or matching placebo (starting dose 30 mg, maintenance dose 60 mg once daily). Patients are followed for at least four years. The primary end-point, to be analyzed by assigned treatment, includes all-cause mortality, acute myocardial infarction, emergency coronary angiography for refractory angina, overt heart failure, debilitating stroke and peripheral revascularization. For this end-point, the trial has a power of 95% to detect a relative risk reduction of 18% at the 5%, level of significance, and is large enough to exclude an excess mortality caused by nifedipine GITS of 3.1 deaths per 1000 years of treatment or greater. The pre-specified early termination rule is more conservative in the case of a beneficial effect than in the case of an adverse effect of nifedipine GITS. The first patient was randomized on 29 November, 1996. By the end of April 1998, about 5200 patients had been started on study medication. CONCLUSIONS: Results will be available in the autumn of 2003.

Deficient insulin-like growth factor I in chronic heart failure predicts altered body composition, anabolic deficiency, cytokine and neurohormonal activation.

BACKGROUND: Recent studies of growth hormone supplementation in chronic heart failure have been associated with variable results. Acquired abnormalities of biochemical parameters of the growth hormone insulin-like growth factor I axis have been associated with severe chronic heart failure. There are suggestions of an acquired growth hormone resistance with deficient insulin-like growth factor I in some patients. OBJECTIVES: Therefore, we set out to investigate the clinical and functional status and the degree of cytokine and neurohormonal alteration of chronic heart failure patients with deficient insulin-like growth factor I responses. METHODS: Patients with chronic heart failure were divided into two groups according to their insulin-like growth factor I levels (classified according to the manufacturer's assay range in normal controls): low insulin-like growth factor I <104 (n = 20; 89 +/- 9.6 ng/ml), and normal/high >104 ng/ml (n = 32; 169 +/- 52 ng/ml). Between groups there was no difference in age (low versus high: 65.3 +/- 12.1 versus 61.6 +/- 9.1 years, p = 0.21), body mass index, aerobic capacity (peak oxygen consumption: low versus high: 15.5 +/- 5.2 versus 17.3 +/- 6.3 mL/kg/min, p = 0.23), left ventricular ejection fraction, New York Heart Association classification. RESULTS: During quadriceps strength testing, patients with low insulin-like growth factor I had reduced absolute strength (-24%), and strength per unit area muscle (- 14%) than patients with normal/high insulin-like growth factor I. Leg muscle cross-sectional area was lower in the low insulin-like growth factor I group (-12% and -13% for right and left legs, respectively). These alterations were accompanied by increased levels of growth hormone (+145%), tumor necrosis factor-alpha (+46%), cortisol/ dehydroepiandrosterone ratio (+60%), noradrenaline (+49%) and adrenaline (+136%) (all at least p < 0.05). CONCLUSIONS: Patients with low insulin-like growth factor I levels show signs of altered body composition, cytokine and neuroendocrine activation, to a greater extent than patients with normal/high levels.

Endothelin-1 is involved in norepinephrine-induced ventricular hypertrophy in vivo. Acute effects of bosentan, an orally active, mixed endothelin ETA and ETB receptor antagonist.

BACKGROUND: Endothelin-1 (ET-1) has potent effects on cell growth and induces hypertrophy of cultured ventricular myocytes. Catecholamines increase expression of ET-1 mRNA by cultured myocytes. We investigated the role of endogenous ET-1 in catecholamine-induced hypertrophy in vivo by studying the effects of continuous norepinephrine infusion on physical and molecular markers of ventricular hypertrophy, ventricular and noncardiac expression of ET-1 mRNA, and the acute effects of bosentan, an orally active ETA and ETB receptor antagonist. METHODS AND RESULTS: Seventy male Sprague-Dawley rats (175 to 200 g) were divided into four groups: (1) sham-operated rats, (2) norepinephrine-infused rats (600 micrograms.kg-1.h-1 by subcutaneous osmotic pump, up to 7 days), (3) sham-operated rats given bosentan, and (4) norepinephrine-infused rats given bosentan. Bosentan (100 mg/kg once daily) was administered by gavage for 6 days starting 1 day before operation. Norepinephrine caused increases in absolute ventricular weight and ratios of ventricular weight to body weight and ventricular RNA to protein. Ventricular expression of mRNAs for atrial natriuretic factor, skeletal alpha-actin, and beta-myosin heavy chain, which in adult rat ventricle are indicators of hypertrophy, also increased. Ventricular expression of ET-1 mRNA was elevated in the norepinephrine group at 1, 2, and 3 days. By 5 days, this had fallen to control levels. In lung, kidney, and skeletal muscle, norepinephrine did not significantly increase expression of ET-1 mRNA. Bosentan attenuated norepinephrine-induced increases in ventricular weight, ratio of RNA to protein, and expression of skeletal alpha-actin mRNA and beta-myosin heavy chain mRNA at 5 days, but it did not attenuate increased ventricular expression of atrial natriuretic factor mRNA. CONCLUSIONS: These data suggest that endogenous ET-1 plays a direct role in mediating norepinephrine-induced ventricular hypertrophy in vivo.

The DEFIANT study of left ventricular function and exercise performance after acute myocardial infarction. Doppler Flow and Echocardiology in Functional Cardiac Insufficiency: Assessment of Nisoldipine Therapy Study Group.

The DEFIANT-I study (Doppler Flow and Echocardiography in Functional cardiac Insufficiency: Assessment of Nisoldipine Therapy) was a multicenter, multinational double-blind randomized study of the effects of the new calcium channel blocking drug nisoldipine on left ventricular (LV) size and function after acute myocardial infarction. Randomization to placebo or to long-acting nisoldipine core coat (20 mg once daily) was performed in 135 eligible patients with mild to moderate systolic LV dysfunction (LV ejection fraction < or = 50%) 20 days (range 7-35) after infarction, with serial clinical, echocardiographic, and Doppler cardiographic measurements during a 4 week follow-up period. At the end of the follow-up period, exercise capacity was determined by bicycle ergometry. Nisoldipine improved indices of diastolic LV function. Early diastolic transmitral blood flow velocity increased, with an increase in peak E wave of 0.06 m/sec (95% confidence intervals [CI], 0.01, 0.11) and an increase in time velocity integral of 1.2 cm (95% CI, 0.16, 2.27). Isovolumic relaxation time was reduced by 14.7 msec (95% CI, -22.5, -6.9), a change not explained by the very small (and not significant) changes in systemic arterial pressure, heart rate, or cardiac output. There was no change in systolic and diastolic LV volume, nor in LV ejection fraction. Exercise capacity was greater by 12 watts (95% CI, 0.8, 23.3) in patients receiving nisoldipine, while the incidence of > or = 1 mm ST-segment depression (relative occurrence 0.54, 95% CI, 0.30-0.97) and the incidence of angina pectoris (relative occurrence 0.67, 95% CI, 0.42-1.08) during exercise testing tended to be lower in this group. Although the relations were not exact, peak exercise workload 7 weeks after infarction correlated with resting measurements of diastolic LV function. Exercise workload was inversely related to peak late diastolic transmitral blood flow velocity (A wave, slope, -86.6; 95% CI, -120.9, -52.2) and directly to the E/A ratio (slope, 20.5, 95% CI, 6.0, 35.1). The relations between exercise workload and peak late diastolic flow velocity remained significant after correction for age, sex, resting heart rate, and usage of beta-blocking drugs or nisoldipine. Exercise capacity was not related to measurements of systolic LV function (LV end-diastolic and end-systolic volume, LV ejection fraction, stroke volume, cardiac index). In summary, the calcium channel blocker nisoldipine improved measurements of diastolic LV function in patients recovering from acute myocardial infarction. Exercise capacity was higher in patients receiving the drug, and there was less exercise induced ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Changing ideas in the treatment of heart failure--an overview.

Patients with heart failure should stop smoking, maintain an optimal weight and limit their intake of salt. Alcohol abuse should be avoided. The detection and early treatment of hypertension appears to have had a major impact in preventing heart failure. Diuretics revolutionized the treatment of congestive heart failure and their proper and appropriate use can alleviate peripheral and pulmonary oedema. Diuretics should not be overused and care should be taken to avoid hypokalaemia. Controversy surrounds the use of digoxin in patients in sinus rhythm; the drug should be used in patients in atrial fibrillation. The use of an inotropic drug may be harmful in the presence of coronary artery disease. A reduction in the current use of digoxin might be of benefit to many patients with heart failure. When the drug is prescribed it should be used in a therapeutic and not homeopathic dose. Recent interest has been directed toward the use of vasodilators and the angiotensin-converting enzyme inhibitors in patients with heart failure. In my opinion, these drugs should be used after patients have been treated with thiazide and loop diuretics. Vasodilators are particularly beneficial in acute heart failure or in patients with chronic heart failure when the symptoms are related to fluid overload and volume expansion. The cause of symptoms in patients with chronic heart failure optimally treated with diuretics is controversial. Shortness of breath may not be simply related to the left atrial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of nicardipine on left ventricular function and on angina induced by atrial pacing in patients with coronary artery disease.

The effect of intravenous nicardipine, a new calcium antagonist, on haemodynamics, left ventricular function and angina induced by atrial pacing has been investigated in patients with coronary artery disease. Patients were treated with beta-blockers and measurements were made at a fixed heart rate. Nicardipine produced a 24% fall in mean systemic blood pressure (P less than 0.02) and a 37% increase in cardiac index (P less than 0.02). Cardiac filling pressures, dp/dt max and left ventricular ejection fraction were unaltered. The time to pacing induced angina was prolonged (P less than 0.05) when the dose of nicardipine (0.75 mg X min-1) was selected not to cause an excessive fall in blood pressure. Nicardipine is a powerful arteriodilator without detectable negative inotropic effects and prolongs the time to pacing induced angina.