title: Alterations in myofilament properties in a rabbit coronary artery ligation model of left ventricular dysfunction
Creators: name: Wilson, Gayle
Publisher: name: University of Glasgow
Year: 1998
Subjects: subject: Physiology.

description: The work reported in this thesis examines alterations in the properties of the myofilaments in a rabbit coronary artery ligation model of heart failure. Heart failure is characterised by abnormalities of myocardial systolic and diastolic function. While much research in this field focuses on alterations in Ca+2 handling by the sarcoplasmic reticulum, fewer studies have purely examined alterations in the properties of the myofilaments, particularly so in this model of heart failure. This particular model has clinical relevance in that it produces a well defined region of infarcted tissue which induces ventricular remodelling in a similar way to that seen after infarction in the human. Treatment of ventricular trabeculae with the non-ionic detergent Triton X-100, results in the complete disruption of surface and intracellular membrane diffusion barriers, but leaves the myofilaments functionally intact. After this chemical 'skinning', the bathing solution essentially becomes an extension of the intracellular environment. Therefore, chemical interventions that produce an alteration in the mechanical activity of the preparation can be directly attributed to an effect on the myofilaments. The technique of applying small sinusoidal length changes to chemically-skinned trabeculae is ideal for examining both resting and dynamic properties of the myocardium as it allows both mechanical and chemical perturbations to be applied and studied simultaneously. Chapter 3 reports upon the alterations in the contractile activity of the myofilaments found in this model of heart failure using the technique of sinusoidal analysis. The results presented show that there is a significant decrease in the intrinsic cycling rate of the crossbridges (as indicated by a reduction in fmin, the frequency at which dynamic stiffness is lowest), without a decrease in maximal force generation or Ca+2-sensitivity of the muscle. Chapter 4 reports the alterations in the maximal work and power generating capacity of the myocardium found to be associated with heart failure using the sinusoidal analysis method. Chapter 5 reports the alterations in the relaxation properties of the myocardium in this model of heart failure using an 'EGTA'-jump protocol. Chapter 6 investigates the effects of the hypochlorite anion, a reactive oxygen species, on the mechanical functioning of the myocardium. The reason for investigating the effects of this compound is that increased oxidative stress is one detrimental factor to which the myocardium is subjected during the progression of heart failure. The oxidative stress results from an increase in the production of oxygen-derived free radicals and reactive oxygen species and/or a decrease in the antioxidant capacity of the myocardium. All the parameters mentioned so far were re-examined in tissues acutely exposed to the hypochlorite anion. The results show that exposure to the hypochlorite anion significantly reduced maximum Ca+2-activated force, fmin, positive and negative work/power generation and the relaxation rate of both sham and ligated trabeculae, whereas myocardial resting and dynamic stiffness was increased. The contractile proteins of the sham animals demonstrated an increased susceptibility to oxidant damage for all of these parameters just described. The relationship between the frequency of maximum positive and negative work/power generation and fmin was unchanged after hypochlorite anion exposure, though the frequencies at which all of these parameters were observed occurred at a lower frequency than pre-exposure. On examination of the results presented in Chapter 6 for the control animals, with the exception of a decrease in maximal force generation, the alterations in mechanical functioning that occur after free radical exposure closely resemble the changes seen in the mechanical functioning between sham and ligated animals described in the three preceding results chapters. The results presented in this chapter are consistent with the idea that pre-exposure to this reactive oxygen species has occurred in the intact myocardium in vivo in the ligated animals used in this study. (Abstract shortened by ProQuest.).