Background— Inflammatory mechanisms have been proposed to be important in heart failure (HF), and cytokines have been implicated to add to the progression of HF. However, it is unclear whether such mechanisms are already activated when hypertrophied hearts still appear well-compensated and whether such early mechanisms contribute to the development of HF. Methods and Results— In a comprehensive microarray study, galectin-3 emerged as the most robustly overexpressed gene in failing versus functionally compensated hearts from homozygous transgenic TGRmRen2-27 (Ren-2) rats. Myocardial biopsies obtained at an early stage of hypertrophy before apparent HF showed that expression of galectin-3 was increased specifically in the rats that later rapidly developed HF. Galectin-3 colocalized with activated myocardial macrophages. We found galectin-3-binding sites in rat cardiac fibroblasts and the extracellular matrix. Recombinant galectin-3 induced cardiac fibroblast proliferation, collagen production, and cyclin D1 expression. A 4-week continuous infusion of low-dose galectin-3 into the pericardial sac of healthy Sprague-Dawley rats led to left ventricular dysfunction, with a 3-fold differential increase of collagen I over collagen III. Myocardial galectin-3 expression was increased in aortic stenosis patients with depressed ejection fraction. Conclusions— This study shows that an early increase in galectin-3 expression identifies failure-prone hypertrophied hearts. Galectin-3, a macrophage-derived mediator, induces cardiac fibroblast proliferation, collagen deposition, and ventricular dysfunction. This implies that HF therapy aimed at inflammatory responses may need to be targeted at the early stages of HF and probably needs to antagonize multiple inflammatory mediators, including galectin-3.

If and how the heart regenerates after an injury event is highly debated. c-kit-expressing cardiac progenitor cells have been reported as the primary source for generation of new myocardium after injury. Here we generated two genetic approaches in mice to examine whether endogenous c-kit⁺ cells contribute differentiated cardiomyocytes to the heart during development, with ageing or after injury in adulthood. A complementary DNA encoding either Cre recombinase or a tamoxifen-inducible MerCreMer chimaeric protein was targeted to the Kit locus in mice and then bred with reporter lines to permanently mark cell lineage. Endogenous c-kit⁺ cells did produce new cardiomyocytes within the heart, although at a percentage of approximately 0.03 or less, and if a preponderance towards cellular fusion is considered, the percentage falls to below approximately 0.008. By contrast, c-kit⁺ cells amply generated cardiac endothelial cells. Thus, endogenous c-kit⁺ cells can generate cardiomyocytes within the heart, although probably at a functionally insignificant level.

Cardiovascular disease is the number one cause of mortality in the Western world. The heart responds to many cardiopathological conditions with hypertrophic growth by enlarging individual myocytes to augment cardiac pump function and decrease ventricular wall tension. Initially, such cardiac hypertrophic growth is often compensatory, but as time progresses these changes become maladaptive. Cardiac hypertrophy is the strongest predictor for the development of heart failure, arrhythmia, and sudden death. Here we discuss therapeutic avenues emerging from molecular and genetic studies of cardiovascular disease in animal models. The majority of these are based on intracellular signaling pathways considered central to pathologic cardiac remodeling and hypertrophy, which then leads to heart failure. We focus our discussion on selected therapeutic targets that have more recently emerged and have a tangible translational potential given the available pharmacologic agents that could be readily evaluated in human clinical trials.