A unified view of ventricular remodelling

The association between cardiac enlargement and heart failure (HF) has long been recognized. In 1975, Grossman et al. hypothesized a fundamental relationship between myocardial wall stress and ventricular hypertrophy and chamber enlargement in which pressure overload would be associated with sarcomere replication in parallel and increased wall thickness-to-chamber radius ratio (concentric hypertrophy), allowing for normalization of left ventricular (LV) peak systolic meridional wall stress. Conversely, volume overload has been associated with sarcomere replication in series and preserved wall thickness-to-chamber radius ratio (eccentric hypertrophy). The term ‘ventricular remodelling’ was first coined to describe the progressive cavity dilatation following chronic myocardial infarction (MI), but has come to be used more generally to refer to changes in LV structure in response to physiological and pathological haemodynamic stress. Numerous studies have demonstrated not only the prognostic importance of increased LV volume in response to acute myocyte loss, but also the prognostic importance of architectural changes that occur in response to more chronic myocardial stressors, such as hypertension and diabetes. Increased LV mass is a powerful predictor of cardiovascular morbidity and mortality, and the relationship between LV mass and chamber size—LV geometry—provides incremental prognostic information beyond either parameter alone. Importantly, these characteristic patterns of response, eccentric and concentric remodelling, often coexist and interact with regard to patient risk. Among patients who sustained an MI complicated by LV dysfunction or HF, specific patterns of LV geometry have been associated with death or HF hospitalization, even after adjusting for ejection fraction (EF) and LV end-diastolic volume. Additionally, concentric hypertrophy at baseline predisposes to LV enlargement post-MI. Thus, a more comprehensive understanding of ventricular remodelling, incorporating not only chamber enlargement but also the pattern of ventricular hypertrophy, is essential to understanding the myocardial response to insult and its prognostic implications (Figure 1). Patients with diabetes and hypertension, for example, have worse outcomes following MI for the same degree of ventricular function or enlargement compared with patients without these disorders. Indeed, the relationship between ventricular size and outcome in diabetics is different from that relationship in non-diabetics, suggesting that we must incorporate more sophisticated measures of structure to fully understand the remodelling process and to identify the patients at highest risk. In this month’s issue of the European Journal of Heart Failure, Mann et al. present a timely review highlighting the importance of LV structure in the management of patients with HF. Specifically, they question the emphasis generally placed on EF at the expense of parameters of ventricular structure and the resulting missed opportunities to potentially better select HF patients for medical and device therapies. One example of where this emphasis on EF, to the exclusion of LV structure, is particularly problematic is the population of patients with HF and a normal or near-normal EF. Surprisingly, little is known about the spectrum of abnormalities in cardiac structure that characterize the heterogeneous syndrome of HF with preserved EF (HFpEF). As reflected in recent guidelines, it is believed to be primarily a disorder of diastolic function, with preserved to decreased LV cavity size. However, HFpEF patients encountered in clinical practice represent a much more heterogeneous group. No single EF cut-off defines a distinct HFpEF syndrome. Rather, EF has a unimodal distribution in patientswith HF and falls below the clearly normal range in a sizeable minority of subjects enrolled in large clinical trials. A relatively high prevalence of concomitant ischaemic disease is also noted in these studies. Just as structural changes typical of patients with HFpEF (e.g. hypertrophy) are also present in HF with reduced EF patients, these findings suggest that many HFpEF patients share, to varying degrees, pathophysiological features of both concentric and eccentric remodelling. A better understanding of the spectrum of perturbations in cardiac structure underlying HFpEF, and particularly of the interaction between concentric and eccentric patterns of remodelling, may improve our ability to identify relevant patient subgroups and to develop effective disease-specific therapies to improve prognosis.