Cardiac remodeling is generally considered the most important pathophysiological mechanism determining the progressive development of heart failure in patients with extensive ventricular myocardial infarction or long-standing myocardial disease. In the year 2000, a consensus conference defined cardiac remodeling as the result of changes in the expression of the cellular genome of myocardial tissue that induces changes, at the molecular level, of cellular structure and interstitial matrix that produce changes in the weight, shape, and function of the heart. These anatomopathological alterations are caused by hemodynamic overload and/or cardiac damage, and the subsequent progressive cardiac remodeling is influenced by hemodynamic alterations and activation of the neuro-immune-hormonal system. Heart failure is the final common pathway of all cardiovascular diseases (of which coronary ischemia covers more than half of the cases in Western countries), so patients with a wide variety of clinical conditions can be affected. For this reason, they show a different propensity to develop ventricular remodeling and fibrosis.
Patients with HF are distinguished into two groups concerning the value of left ventricular systolic ejection fraction (LVEF), usually assessed by echocardiographic examination, which can be reduced (≤40%, Heart Failure with Reduced Ejection Fraction [HFrEF]) or preserved (≥50%, Heart Failure with Preserved Ejection Fraction [HFpEF]) (Table 1). The epidemiology, etiology, pathophysiologic mechanisms, anatomopathological picture, and clinical dis ease progression that characterize these two groups of patients are substantially different. Patients with HFpEF are generally older, female, and have comorbidities (hypertension, obesity, diabetes mellitus, atherosclerosis, atrial fibrillation, and renal failure) and diastolic dysfunction on echocardiographic examination. The number of patients with HFpEF has increased in recent years, reaching that of patients with HFrEF, whose incidence has decreased. Thus, the prevalence of the two different clinical conditions in the general population is estimated to be similar. Diagnosis and treatment are more complex in patients with HFpEF, for which the prognosis is more severe. In accordance with the 2016 ESC guidelines, the diagnosis of HFrEF is based only on the presence of clinical symptoms and the assessment of <40% LVEF reduction, whereas the diagnosis of heart failure with preserved or intermediate LVEF (LVEF between 40 and 50%) requires elevated natriuretic peptide values and structural or functional alterations in the ventricle, indicating the presence of diastolic dysfunction (Table 1).
Table1. Definition of heart failure with preserved (HFpEF), midrange (HFmrEF), and reduced (HFrEF) ventricular ejection fraction according to ESC guidelines 2016
Cardiac fibrosis, whose most evident aspect is ventricular wall thickening, occurs more frequently in patients with HFpEF than in those with HFrEF, representing the most important pathogenetic mechanism of diastolic dysfunction. This evidence has stimulated in recent years the research and clinical validation of reliable biomarkers of cardiac fibrosis for the diagnosis, risk stratification, and monitoring of patients with HFpEF. Considering the results obtained in these studies, the 2013 American College of Cardiology Foundation and American Heart Association guidelines included, for the first time, biomarkers of cardiac fibrosis, and in particular galectin-3 and the soluble IL-33 receptor, called sST2, among the biomarkers for risk stratification in patients with heart failure.
From a physiopathological point of view, these biomarkers have the critical limitation to not be cardio-specific since they can be produced by numerous immunocompetent cells, mature or immature fibroblasts, or even endothelial or epithelial cells, especially during local or even systemic inflammatory processes.
Thus, for the clinician, it is often impossible to link variations in the circulating levels of these biomarkers to possible pathophysiological processes specifically located in the myocardium (and not in other organs, such as kidney, liver, and lungs).
