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Objectives: This study sought to examine whether the cardioprotective effects of angiotensin-converting enzyme (ACE) inhibitor therapy by perindopril are modified by renal function in patients with stable coronary artery disease., Background: A recent study reported that an impaired renal function identified a subgroup of patients with stable coronary artery disease more likely to benefit from ACE inhibition therapy. In light of the growing interest in tailored therapy for targeting medications to specific subgroups, remarks on the consistency of the treatment effect by ACE inhibitors are highly important., Methods: The present study involved 12,056 patients with stable coronary artery disease without heart failure randomized to perindopril or placebo. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation. Cox regression analysis was used to estimate multivariable-adjusted hazard ratios., Results: The mean eGFR was 76.2 (+/-18.1) ml/min/1.73 m2. During follow-up, the primary end point (cardiovascular death, nonfatal myocardial infarction, or resuscitated cardiac arrest) occurred in 454 of 5,761 patients (7.9%) with eGFR > or =75 and in 631 of 6,295 patients (10.0%) with eGFR <75. Treatment benefits of perindopril were apparent in both patient groups either with eGFR > or =75 (hazard ratio 0.77; 95% confidence interval 0.64 to 0.93) or eGFR <75 (hazard ratio 0.84; 95% confidence interval 0.72 to 0.98). We observed no significant interaction between renal function and treatment benefit (p = 0.47). Using different cutoff points of eGFR at the level of 60 or 90 resulted in similar trends., Conclusions: The treatment benefit of perindopril is consistent and not modified by mild to moderate renal insufficiency.

Objectives: We explored whether vascular protection by carvedilol could contribute to its superior effects in the treatment of heart failure (HF) compared with metoprolol tartrate in the COMET (Carvedilol Or Metoprolol European Trial) study., Background: Full adrenergic blockade by carvedilol and additional (e.g., antioxidative) properties may lead to vascular protection relative to beta-1 blockade alone, and contribute to its efficacy in HF treatment., Methods: Three thousand twenty-nine patients with HF due to ischemic (51%) or idiopathic cardiomyopathy (44%) were randomized double-blind to carvedilol (n = 1,511) or metoprolol (n = 1,518) and followed for 58 months. Vascular end points were cardiovascular death, stroke, stroke death, myocardial infarction (MI), and unstable angina., Results: The effect of carvedilol on cardiovascular death improved consistently in subgroups with prespecified baseline variables. Myocardial infarctions were reported in 69 carvedilol and 94 metoprolol patients (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.52 to 0.97, p = 0.03). Cardiovascular death or nonfatal MI combined were reduced by 19% in carvedilol (HR 0.81, 95% CI 0.72 to 0.92, p = 0.0009 vs. metoprolol). Unstable angina was reported as an adverse event in 56 carvedilol and in 77 metoprolol patients (HR 0.71, 95% CI 0.501 to 0.998, p = 0.049). A stroke occurred in 65 carvedilol and 80 metoprolol patients (HR 0.79, 95% CI 0.57 to 1.10). Stroke or MI combined occurred in 130 carvedilol and 168 metoprolol patients (HR 0.75, 95% CI 0.60 to 0.95, p = 0.015), and fatal MI or fatal stroke occurred in 34 carvedilol and in 72 metoprolol patients (HR 0.46, 95% CI 0.31 to 0.69, p = 0.0002). Death after a nonfatal MI or stroke occurred in 61 of 124 carvedilol and in 106 of 160 metoprolol patients (HR 0.66, 95% CI 0.48 to 0.90, p = 0.0086)., Conclusions: Carvedilol improves vascular outcomes better than metoprolol. These results suggest a ubiquitous protective effect of carvedilol against major vascular events.

Objectives: This study was designed to investigate the loss of well-being, in terms of life-years, overall and in patients randomized to metoprolol versus carvedilol in the Carvedilol Or Metoprolol European Trial (COMET)., Background: The ultimate objectives of treating patients with heart failure are to relieve suffering and prolong life. Although the effect of treatment on mortality is usually described in trials, the effects on patient well-being throughout the trials' courses are rarely reported., Methods: A total of 3,029 patients randomized in the COMET study were included in the analysis. "Patient journey" was calculated by adjusting days alive and out of hospital over four years using a five-point score completed by the patient every four months, adjusted according to the need for intensification of diuretic therapy. Scores ranged from 0% (dead or hospitalized) to 100% (feeling very well)., Results: Over 48 months, 17% of all days were lost through death, 1% through hospitalization, 23% through impaired well-being, and 2% through the need for intensified therapy. Compared with metoprolol, carvedilol was associated with fewer days lost to death, with no increase in days lost due to impaired well-being or days in hospital. The "patient journey" score improved from a mean of 54.8% (SD 26.0) to 57.4% (SD 26.3%) (p < 0.0068)., Conclusions: Despite treatment with beta-blockers, heart failure remains associated with a marked reduction in well-being and survival. Loss of quality-adjusted life-years through death and poor well-being seemed of similar magnitude over four years, and both were much larger than the loss that could be attributed to hospitalization.

Objectives: We sought to define the therapeutic dose range of levosimendan in patients with New York Heart Association class II-IV heart failure of ischemic origin., Background: Levosimendan is a calcium sensitizer for treatment of acute decompensated heart failure., Methods: A double-blind, placebo-controlled, randomized, multicenter, parallel-group study included 151 adult patients. Levosimendan was given as a 10-min intravenous bolus of 3, 6, 12, 24 or 36 microg/kg, followed by a 24-h infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 microg/kg/min, respectively. Dobutamine, for comparative purposes, was given as an open-label infusion (6 microg/kg/min). The primary efficacy variable was the proportion of patients achieving in each treatment group at least one of the following: 1) a > or =15% increase in stroke volume (SV) at 23 h to 24 h; 2) a > or =25% decrease in pulmonary capillary wedge pressure (PCWP) (and > or =4 mm Hg) at 23 h to 24 h; 3) a > or =40% increase in cardiac output (CO) (with change in heart rate [HR] <20%); 4) a > or =50% decrease in PCWP during two consecutive measurements., Results: The response rate to levosimendan ranged from 50% at the lowest dose to 88% at the highest dose (compared with placebo 14%, dobutamine 70%). A dose-response relationship was demonstrated for levosimendan on increases in CO and SV, and reductions in PCWP during the infusion (for all, p< or =0.001). Headache (9%), nausea (5%) and hypotension (5%) were the most frequently reported adverse events at higher dosages., Conclusions: Dosing of levosimendan with a 10-min bolus of 6 to 24 microg/kg followed by an infusion of 0.05 to 0.2 microg/kg/min is well tolerated and leads to favorable hemodynamic effects.

Heart failure is a clinical syndrome that is predominantly caused by cardiovascular disorders such as coronary heart disease and hypertension. However, several classes of drugs may induce heart failure in patients without concurrent cardiovascular disease or may precipitate the occurrence of heart failure in patients with preexisting left ventricular impairment. We reviewed the literature on drug-induced heart failure, using the MEDLINE database and lateral references. Successively, we discuss the potential role in the occurrence of heart failure of cytostatics, immunomodulating drugs, antidepressants, calcium channel blocking agents, nonsteroidal anti-inflammatory drugs, antiarrhythmics, beta-adrenoceptor blocking agents, anesthetics and some miscellaneous agents. Drug-induced heart failure may play a role in only a minority of the patients presenting with heart failure. Nevertheless, drug-induced heart failure should be regarded as a potentially preventable cause of heart failure, although sometimes other priorities do not offer therapeutic alternatives (e.g., anthracycline-induced cardiomyopathy). The awareness of clinicians of potential adverse effects on cardiac performance by several classes of drugs, particularly in patients with preexisting ventricular dysfunction, may contribute to timely diagnosis and prevention of drug-induced heart failure.

Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its value in patients with heart failure and sinus rhythm has often been questioned. In the 1980s, reports of some large-scale trials indicated that digoxin, with or without vasodilators or angiotensin-converting enzyme inhibitors, reduced signs and symptoms of congestive heart failure and improved exercise tolerance. This beneficial influence was mainly found in patients with more advanced heart failure and dilated ventricles, whereas the effect in those with mild disease appeared to be less pronounced. In the last few years, new data have shown that digoxin may also have clinical value in mild heart failure, either when used in combination with other drugs or when administered alone. As neurohumoral activation has increasingly been recognized to be a contributing factor in the disease progression of chronic heart failure, the modulating effects of digoxin on neurohumoral and autonomic status have received more attention. Also, there is evidence that relatively low doses of digoxin may be at least as effective as higher doses and have a lower incidence of side effects. Further, the recognition that the use of digoxin too early after myocardial infarction may be harmful and the development of other drugs, in particular angiotensin-converting enzyme inhibitors, have obviously changed the place of digoxin in the treatment of chronic heart failure. The large-scale survival trial by the Digitalis Investigators Group (DIG), whose preliminary results have recently been presented, has shown that although digoxin has a neutral effect on total mortality during long-term treatment, it reduces the number of hospital admissions and deaths due to worsening heart failure. The potentially new features of the old drug digoxin are discussed in this review.

Objectives: The purpose of this study was to assess the effect of different degrees of ischemia on circulating and cardiac neurohormones and vasotone., Background: Neuroendocrine activation and subsequent systemic vasoconstriction may complicate ischemia. Whether this relates to severity of ischemia and subsequent cardiac dysfunction, and whether neurohormonal balance in the ischemic area changes, is unknown., Methods: Fifty-six normotensive patients with coronary artery disease were evaluated during incremental atrial pacing. On the basis of ST segment changes, patients were classified in a nonischemic (n = 11) or ischemic group (n = 45), the latter patients were subsequently classified as lactate (n = 28) or nonlactate (n = 17) producing, to identify neurohormonal changes in the effluent of the ischemic myocardium., Results: Angina occurred in 55%, 82% and 82% of patients in the nonischemic, lactate- and nonlactate-producing groups, respectively. Baseline hemodynamic variables and neurohormones were comparable in all groups, as were heart rate, rate-pressure product and coronary hemodynamic variables during pacing. In lactate producers, contractility did not improve, relaxation deteriorated, left ventricular filling pressure increased and cardiac output decreased during pacing, indicating more severe ischemia compared with that in nonlactate producers. Neurohormones did not change in the nonischemic group. In contrast, arterial and coronary venous catecholamines increased significantly more in lactate producers than in nonlactate producers (arterial norepinephrine by 68% vs. 36%, respectively). Moreover, arterial angiotensin II increased in lactate producers from a baseline mean +/- SEM of 6.8 +/- 0.9 to 9.7 +/- 1.6 pmol/liter (p < 0.05), accompanied by a sustained 23% increase in systemic resistance and arterial pressures. In lactate producers, baseline net cardiac norepinephrine release changed to net uptake during pacing (-0.05 +/- 0.02 vs. 0.06 +/- 0.05 nmol/min, p < 0.05). Epinephrine uptake increased in all patients with ischemia, albeit more in lactate producers., Conclusions: Circulating catecholamines and renin-angiotensin levels are activated, and systemic vasotone is increased in relation to the degree of ischemia. Cardiac epinephrine uptake increases, whereas net baseline norepinephrine release from the ischemic myocardium changes to net uptake. Modulation of this neurohormonal activation may provide an alternative mode to limit ischemia.

Objectives: This study was designed to compare the acute systemic and coronary hemodynamic effects of high doses of intravenous diltiazem in patients with normal versus impaired left ventricular function, investigate the safety of this drug and compare its anti-ischemic potential in these two patient groups during pacing-induced stress., Background: Because coronary hemodynamic effects and negative inotropic properties of diltiazem are dose related, high dose intravenous diltiazem may improve anti-ischemic efficacy but may not be tolerated in patients with impaired cardiac function., Methods: High dose intravenous diltiazem, 0.4 mg/kg for 5 min followed by 0.4 mg/kg for 10 min, was administered to 23 normotensive patients with coronary artery disease, 11 (group A) with normal and 12 (group B) with impaired ventricular function (ejection fraction < 45%) during two identical arterial pacing stress tests performed 30 min before (pacing test I) and immediately after diltiazem (pacing test II)., Results: Diltiazem was well tolerated despite high peak plasma levels, 869 +/- 152 micrograms/liter (group A) and 926 +/- 169 micrograms/liter (group B). It resulted in immediate but similar reductions in systemic resistance from 1,321 +/- 136 (control value) to 963 +/- 113 dynes.s.cm-5 (group A) and from 1,267 +/- 106 to 865 +/- 58 dynes.s.cm-5 (group B) and in mean arterial pressure from 107 +/- 3 to 93 +/- 4 mm Hg (group A) and from 103 +/- 4 to 86 +/- 4 mm Hg (group B), at 5 min after diltiazem (all p < 0.05 vs. control value). Diltiazem improved stroke output from 36 +/- 3 (control value) to 46 +/- 4 ml/beat per m2 in group B and from 44 +/- 4 (control value) to 49 +/- 5 ml/beat per m2 in group A, an effect that was significantly greater and more prolonged in group B than in group A. Although neither heart rate nor contractility was affected in either group, left ventricular end-diastolic pressure increased in group A (9 +/- 2 mm Hg to 12 +/- 1 mm Hg, p < 0.05) but not in group B. Despite similar reductions in coronary resistance and improvements in coronary flow, diltiazem consistently reduced myocardial oxygen extraction, but only in group B. Also, the anti-ischemic effects of diltiazem were more pronounced in group B. During pacing test II, myocardial lactate extraction normalized in group B (7 +/- 5% vs. -6 +/- 12% [pacing test I]) but not in group A, contractility indexes improved more and the increase in left ventricular filling pressure was reduced to a greater extent in group B. Moreover, the ischemia-induced increase in arterial pressures, observed in both groups during pacing test I, was prevented in group B but recurred in group A during pacing test II., Conclusions: High dose intravenous diltiazem is well tolerated, augments coronary flow and improves left ventricular pump function, particularly in patients with preexisting ventricular dysfunction. As its anti-ischemic effects also appear more pronounced in the latter group, high dose diltiazem may be particularly useful when ventricular function is depressed, for example, during prolonged ischemia at rest.

The effect of early myocardial reperfusion (within 4 hours after onset of symptoms) on regional left ventricular function in patients with acute myocardial infarction has been quantitated by analysis of segmental wall motion. Of 533 patients randomized either to conventional coronary care unit therapy or to a reperfusion strategy, in 332 high quality angiograms were obtained 2 to 8 weeks after the onset of myocardial infarction. In those assigned to thrombolytic therapy, angiographic data were also available after acute reperfusion. Analysis on an "intention to treat" basis revealed significant preservation of left ventricular function after thrombolytic therapy (ejection fraction 53%) compared with conventional treatment (ejection fraction 47%). In addition, wall motion analysis showed significant improvement of regional function in the infarct zone in both inferior and anterior infarction. In addition, significant changes occurred in regional function of the remote "noninfarct zone" in the acute as well as the chronic stage. It is concluded that improved regional and global left ventricular function can be achieved with early reperfusion and that this is the likely explanation for the reduction of early and late mortality after thrombolysis observed in this study.

The effect of thrombolysis in acute myocardial infarction on infarct size, left ventricular function, clinical course and patient survival was studied in a randomized trial comparing thrombolysis (269 patients) with conventional treatment (264 control patients). All 533 patients were admitted to the coronary care unit within 4 hours after the onset of symptoms related to the infarction. Baseline characteristics were similar in both groups. Informed consent was requested only of patients allocated to thrombolysis; no angiography was performed in 35. The infarct-related artery was patent in 65 patients and occluded in 169. Recanalization was achieved in 133 patients. The median time to angiographic documentation of vessel patency was 200 minutes after the onset of symptoms. The clinical course in the coronary care unit was more favorable after thrombolysis. Infarct size, estimated from myocardial enzyme release, was 30% lower after thrombolysis. In patients admitted within 1 hour after the onset of symptoms the reduction of infarct size was 51%, in those admitted between 1 and 2 hours it was 31% and in those admitted later than 2 hours it was 13%. Left ventricular function measured by radionuclide angiography before hospital discharge was better after thrombolysis (ejection fraction 48 +/- 15%) than in control patients (44 +/- 15%). Similar improvement was observed in patients with a first infarct only (thrombolysis 50 +/- 14%, control subjects 46 +/- 15%), in patients with anterior infarction (thrombolysis 44 +/- 16%, control subjects 35 +/- 14%) and in those with inferior infarction (thrombolysis 52 +/- 12%, control subjects 49 +/- 12%). Similar results were obtained by contrast angiography. Mortality was lower after thrombolysis. After 28 days 16 patients allocated to thrombolysis and 31 control patients had died. One year survival rates were 91 and 84%, respectively. On the other hand, nonfatal reinfarction occurred more frequently after thrombolysis (36 patients) than in control subjects (16 patients). Early thrombolysis by intracoronary streptokinase leads to a smaller infarct size estimated by enzyme release, preserves left ventricular function at the second week and leads to improved 1 year survival.