Structural remodelling in heart failure

In the development of heart failure, extensive remodelling of the entire myocardium takes place. In this paper, findings on structural remodelling occurring in patients with severely reduced left ventricular function due to dilated cardiomyopathy are presented. This process involves all structural proteins of the myocytes; some of them are reduced (contractile proteins and most of the sarcomeric skeleton) and others are increased (cytoskeleton and membrane-associated proteins). Likewise, the connexin43 content of gap junctions is significantly reduced. The myocyte nuclei are enlarged by 20%, but the ratio of nuclear volume to cell volume is decreased. Nuclei contain less DNA and less of the splicing factor Sc-35 than normal myocardium, which might explain the depressed transcription and translation observed in failing hearts. The connective tissue including fibronectin, laminin and the different types of collagen is augmented, whereas the number of microvessels is decreased. This results in replacement fibrosis. Cell loss is caused by either ubiquitin-related autophagic cell death (most frequent) or by acute ischemic cell death (oncosis) but to a lesser degree by apoptosis. All of these modes of cell death contribute significantly to the loss of contractile function. The morphological alterations described here are the structural correlates of the typical clinical characteristics of heart failure in humans: reduced contractile function, increased ventricular stiffness and ventricular arrhythmias.