Introduction

Chronic congestive heart failure (CHF) has become one of the major medical problems in the Western world, and its incidence and prevalence are still increasing. Although many advances have been made in understanding the pathophysiology of this syndrome, morbidity and mortality remain high. Drug treatment in CHF must focus on improvement of quality of life (≈ reduction of morbidity) and improvement of survival. Until the mid-1970s, the only drugs available for CHF were digoxin and diuretics. At that time, vasodilators were first suggested for the treatment of CHF, but it was not until 1986 that, for the first time, this concept was found to be correct, when the results of the V-HeFT 1 trial showed that the combination of an arterial and a venous vasodilator reduced mortality in patients with CHF (1). An even greater breakthrough came in 1987, when the angiotensin-converting enzyme (ACE) inhibitor enalapril was found to cause a much more pronounced reduction in mortality in the CONSENSUS Trial(2). Since then, a large number of drugs have been developed for CHF (including many drugs with some positive inotropic action and many vasodilators), but almost none of these drugs was found to be of substantial additional benefit to the regimen of diuretics, digoxin, and ACE inhibitors (or, when not tolerated, conventional vasodilators) (3). The only exception to these disappointing results were the findings with β-blockers. As early as 1986, a follow-up analysis of the BHAT study showed that propranolol, when given to patients with CHF after myocardial infarction (MI), caused a significant reduction in mortality (4). In the beginning of the 1990s, two studies in patients with CHF examining the β1-selective blockers metoprolol (5) and bisoprolol (6) showed that the concept of β-blockade in CHF (7) was valid. Interestingly, however, these compounds were mainly effective in patients with idiopathic dilated cardiomyopathy. In 1996, the US Carvedilol Trial was published (8), which showed for the first time that β-blockade (with carvedilol) significantly reduced mortality in all classes of CHF. Furthermore, in contrast to ACE inhibitors, which reduced mortality only from progressive pump failure (2), carvedilol also reduced the incidence of sudden death (8). These effects were recently more or less confirmed in the Australian-New Zealand Trial(9), in which the favorable effects of carvedilol on the combined end point death/hospital admission were maintained for at least 1 year. Because of these results and previous data, the drug was recently approved for CHF in a large number of countries, including The Netherlands. A symposium was held for this occasion on May 31, 1997 in Apeldoorn, The Netherlands to discuss current insights and new treatment options in CHF, with the focus on carvedilol, the proceedings of which are published in this supplement. In most patients in the Western world, CHF is due to coronary artery disease and (recurrent) myocardial infarction (MI). Preventing dilatation after MI is therefore one of the most important goals in preventing or slowing the progression of CHF, as was discussed by van Gilst and co-workers. Hypertension remains another very important cause of CHF, although drug treatment has certainly been effective in many patients to avoid left ventricular hypertrophy and CHF. De Leeuw discusses the pathophysiology of these abnormalities and focuses on both systolic and diastolic dysfunction in this disorder. Although disease progression in patients with CHF is gradual, it occurs in most if not all patients. In the past, many physicians believed that the hemodynamic abnormalities in CHF (increased pre- and afterload) could explain this progression. In recent years, however, other (additional) factors have been identified that contribute to this progression. Neurohumoral activation has been proved to play an important role in this respect, as is highlighted by Francis. More recently, it has been shown that formation of oxygen free radicals may also play a role. Furthermore, myocardial cell damage in CHF may not always be synonymous with necrosis but may also be due to apoptosis, or programmed cell death, which sheds important new light on the pathophysiology of CHF (10), as is discussed by Ruffolo. Impairment of exercise capacity is one of the hallmarks of CHF, and exercise testing (both maximal and submaximal), including measurement of peak oxygen consumption, is important to assess severity of disease and effects of drug treatment, as discussed by Metra. Myocardial ischemia leads to left ventricular dysfunction amd CHF, but whether the opposite is also true is less well established. van Veldhuisen discusses this issue and provides evidence for this hypothesis by showing recent data from studies with positron emission tomography (PET). In the final presentation, Cleland reviews the currently available data on β-blockers in general and carvedilol in particular. He emphasizes that it is difficult to persuade physicians that β-blockers should earn a place in the treatment of CHF, when in the past we were told to avoid these drugs. The treatment of CHF remains a great challenge, but with the introduction of carvedilol, a truely new tool has come available for the first time in almost 10 years. Carvedilol has an attractive but complex mechanism of action, with primarily β-blocking and vasodilating(α-blocking) properties, which makes it very useful in patients with CHF (11,12). Future studies, however, of larger size and duration will determine whether carvedilol, together with ACE inhibitors, can become first-line therapy for CHF.