Pathomechanisms in heart failure: the contractile connection

Abstract

Heart failure is a multi-factorial progressive disease in which eventually the contractile performance of the heart is insufficient to meet the demands of the body, even at rest. A distinction can be made on the basis of the cause of the disease in genetic and acquired heart failure and at the functional level between systolic and diastolic heart failure. Here the basic determinants of contractile function of myocardial cells will be reviewed and an attempt will be made to elucidate their role in the development of heart failure. The following topics are addressed: the tension generating capacity, passive tension, the rate of tension development, the rate of ATP utilisation, calcium sensitivity of tension development, phosphorylation of contractile proteins, length dependent activation and stretch activation. The reduction in contractile performance during systole can be attributed predominantly to a loss of cardiomyocytes (necrosis), myocyte disarray and a decrease in myofibrillar density all resulting in a reduction in the tension generating capacity and likely also to a mismatch between energy supply and demand of the myocardium. This leads to a decline in the ejection fraction of the heart. Diastolic dysfunction can be attributed to fibrosis and an increase in titin stiffness which result in an increase in stiffness of the ventricular wall and hampers the filling of the heart with blood during diastole. A large number of post translation modifications of regulatory sarcomeric proteins influence myocardial function by altering calcium sensitivity of tension development. It is still unclear whether in concert these influences are adaptive or maladaptive during the disease process.

Physiologically inspired cardiac scaffolds for tailoredin vivofunction and heart regeneration

“…Diseased myocardium that exhibits decreased contractility has been clinically associated with decreased heart performance in the form of reduced ejection fraction, defined clinically as systolic dysfunction. Conversely, diseased myocardium that exhibits increased stiffness has been associated with decreased performance in the form of reduced chamber filling during diastole [17, 18]. Both reduced contractility and increased myocardial stiffness are associated with the local ischemia, injury, and remodeling that occurs in the heart after a myocardial infarction, which is a well-recognized target of tissue engineering therapies due to its prevalence.…”

Atomic force microscopy combined with human pluripotent stem cell derived cardiomyocytes for biomechanical sensing

“…Most of them have hidden cause at the cellular and genetic levels (Aistrup et al, 2009;Stienen, 2015) not easily accessible for diagnostics, as heart biopsy is invasive procedure with significant risk (Holzmann et al, 2008;Imamura et al, 2015). Since the discovery of pluripotent stem cells (PSCs), such as human embryonic stem cells (hESC) (Thomson et al, 1998) and especially disease specific induced pluripotent stem cells (hiPSC) (Takahashi et al, 2007) and their differentiation into cardiomyocytes (Mummery et al, 2002), these cell types represent an important cellular model in drug and disease screening (reviewed in Acimovic et al, 2014).…”

Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment

“…Further study is needed to determine which extracellular matrix or cellular changes are altered by rapamycin in the myocardium. Another potential source of increased passive stiffness is changes in myofilaments and their posttranslational modification, especially phosphorylation of key sites (Stienen, ); these also remain open for future study.…”

“…Another potential source of increased passive stiffness is changes in myofilaments and their posttranslational modification, especially phosphorylation of key sites (Stienen, 2015); these also remain open for future study.…”