Do we understand why the heart fails?

In Western countries, heart failure has become one of the most prominent health care problems. Increased prevalence of coronary artery disease (CAD), improvements in CAD and hypertension treatment, and ageing of the population are major factors contributing to the fact that 1–2% of the Western populations suffer from heart failure, with a prevalence of 10% or more in the very elderly. Despite advances in heart failure therapy, morbidity and mortality remain high and quality of life is severely impaired. Heart failure is a leading cause of hospital admissions, and hospitalizations for heart failure are often of long duration, resulting in enormous health care costs. It is estimated that they account for 2% of the total health care budget in these countries. Despite the importance of heart failure, both to the affected patients and to the health care providers, and much effort in basic as well as clinical research, many aspects in heart failure are still incompletely understood. For a long time, the focus was almost exclusively on systolic dysfunction. Heart failure was considered as the final common pathway of different cardiac disorders and, as a consequence, difficult to reverse. Once left ventricular systolic function is significantly depressed, uniform therapeutic response and results from human and animal studies suggested that the underlying cause is of lesser relevance. Therapy focuses primarily on delay of disease progression and complications of heart failure, whereas treatment of underlying diseases or risk factors is the main focus in prevention of heart failure only. In the 1990s, it was recognized that many patients with the clinical symptom of heart failure do not have left ventricular systolic dysfunction, particularly in the elderly population, where at least half of the heart failure patients have preserved left ventricular systolic function. Various population-based studies such as the Cardiovascular Health Study have contributed significantly to this understanding. In heart failure with preserved left ventricular systolic function, diastolic dysfunction is considered to be the main cause, but the pathophysiology behind it is still incompletely understood. Different factors are believed to contribute to this. Traditional cardiovascular risk factors were found to be related to the development of heart failure with preserved left ventricular systolic function. Various other factors, some associated with the traditional risk factors, are recognized to be of importance. Among those, left ventricular hypertrophy may be of particular significance, as it is considered not only to be the result of risk factors, particularly arterial hypertension, but also to be an independent risk factor of both systolic and diastolic left ventricular dysfunction. As a consequence, left ventricular hypertrophy is now considered a pre-clinical disease. However, to differentiate between left ventricular hypertrophy being the cause or the result of heart failure may be difficult as all these factors interact significantly. Thus, little is known about whether left ventricular hypertrophy is related to incident heart failure independent of coronary vascular events. de Simone et al. have provided strong evidence that this is indeed the case. They analysed a subgroup of .2000 patients of the Cardiovascular Health Study cohort, who did not have evidence of previous myocardial infarction. They show that not only load-dependent, but, possibly more importantly, also load-independent concentric left ventricular hypertrophy is a strong risk factor for the development of heart failure during the upcoming years, independently of other risk factors. This increased risk was independent of incident myocardial infarction, suggesting that mechanisms other than myocardial ischaemia and haemodynamic load may play an important role in the development of heart failure in patients with left ventricular hypertrophy. In addition, this study supports the shifting paradigm that left ventricular hypertrophy may be detrimental already in its early stage, and prevention of the hypertrophic response is actually associated with preserved ventricular function. Why is this finding important? The pathophysiological understanding of incident heart failure may be enhanced, although data from a cohort study do not allow direct conclusions. de Simone et al. discuss potential mechanisms, amongst which myocardial fibrosis may be the central one, also potentially having therapeutic implications. However, there are numerous other potential mechanisms, and a huge variety of pathways were found to be involved