Altered Cross-Bridge Relaxation Kinetics in Guinea Pig Cardiac Hypertrophy

Abstract

Cardiac hypertrophy is associated with Diastolic Heart Failure (DHF), a syndrome in which systolic function is preserved, but cardiac filling dynamics are depressed. The molecular mechanisms underlying DHF and the potential role of altered cross-bridge cycling in this syndrome are poorly understood. Accordingly, we induced chronic pressure overload by surgically banding the thoracic ascending aorta in female Dunkin Hartley Guinea pigs weighing 400g, for 12-16 weeks. Guinea pigs were chosen to avoid the confounding effects of myosin isoform switch that occurs in other small rodent models. Left ventricular (LV) samples were frozen in liquid N2. Aortic banding resulted in (+31%) LV hypertrophy (LV/BW ratio) and reduced diastolic cardiac function, but normal systolic function. Single myofibrils were prepared by mechanical dissociation and subsequently attached between two glass micro-needles that were positioned on the stage of an inverted phase-contrast microscope. While the maximum calcium saturated force development was depressed (−18%), the time required for force relaxation was increased (+8%) in parallel to a significant decrease in the rate of relaxation (−25%) in DHF myofibrils; Myosin Heavy Chain (MHC) isoform distribution was unaltered. We conclude that slower cross-bridge relaxation kinetics contribute to diastolic dysfunction in cardiac hypertrophy.