Linda M. King

Energy Substrate Metabolism, Myocardial Ischemia, and Targets for Pharmacotherapy

Myocardial ischemia is essentially a metabolic event. In this review we will try to distill the essence of a complex series of molecular reactions triggered by the sudden reduction or cessation of blood flow to the heart. We recognize that it is difficult to describe even simple metabolic changes occurring in ischemia without a brief recap of pathways of energy transfer in the normal myocardium. We will therefore begin with a description of the energy substrate supply to a system that is best defined as the hearts remarkable ability for efficient conversion of chemical into mechanical energy. At the core of the system are rates of oxidative phosphorylation of adenosine diphosphate (ADP) that exactly match rates of adenosine triphosphate (ATP) hydrolysis. We will then describe the consequences of a sudden interruption to this balance, namely ischemia. At the same time we will explore metabolic strategies that may be employed to lessen the consequences of ischemia on contractile function, highlighting areas of future research and clinical investigation. The review is not meant to be comprehensive. Its main aim is to discuss the concept of pharmacotherapy as an intervention in altered cellular metabolism, akin to the concept of reperfusion therapy as an intervention in obstructed coronary arteries.

Coronary flow and glucose delivery as determinants of contracture in the ischemic myocardium.

Ischemic contracture may be avoided by the provision of glucose under low flow conditions (Owen et al., 1990). However, accumulation of harmful metabolic end products may inhibit glycolytic flux and lessen the benefit of glucose. We assessed whether during increasingly severe flow restriction, provision of glucose might be harmful rather than beneficial, using the Langendorff perfused rat heart. Ischemic contracture (resting tension expressed as percent of preischemic developed pressure) was measured via a left ventricular balloon. Reductions in flow to 0, 0.015, 0.03, 0.06, 0.1, 0.2 or 0.4 ml/min/g wet wt over 60 min were tested. At zero flow, peak contracture was 61.4 +/- 3.5% (+/- S.E.) but fell to 15.6 +/- 6.3% with 0.4 ml/min/g wet wt (P < 0.05) in the presence of 11 mmol/l glucose. Time-to-onset of contracture was significantly delayed by the higher coronary flows. At coronary flows down to zero, the effect of glucose was inconstant or absent, but not harmful. With the residual flow at 0.2 ml/min/g wet wt, a dose response to glucose in ischemia was elicited, using concentrations of 0, 2.5, 5.5, 11 or 22 mmol/l. Maximum protection against ischemic contracture was found with 11 mmol/l glucose. However, once contracture occurred, functional recovery was severely impaired in all cases. Reducing glycogen prior to low flow ischemia (0.2 ml/min/g wet wt) with 11 mmol/l glucose increased peak contracture, and reduced the time-to-onset of contracture. Increased preischemic glycogen had little effect on contracture. Glycolytic flux fell in proportion to the coronary flow. However, there was an increased glucose extraction at lower flows of 0.1 and 0.2 ml/min/g wet wt, suggesting that it is the rate of delivery (i.e. coronary flow) which is the rate limiting step rather than enzyme inhibition by accumulated metabolites. If flow were further reduced, metabolite accumulation would become more important, such that with no flow, this would be the determinant of glycolytic flux rate. In our model, the two requirements for optimal protection from ischemia were (i) provision of glucose (11 mmol/l was optimal) and (ii) an adequate coronary flow to deliver the glucose and remove end product inhibition (greater than 0.06 ml/min/g wet wt).

Preconditioning — a reappraisal of protection

Preconditioning has been described as the most potent form of protection against myocardial necrosis yet described (5). The protection conferred by preconditioning has been found against most of the deleterious effects induced by ischaemia and reperfusion, and in most animal models as well as in humans. While preconditioning undoubtedly delays infarct development, and offers intriguing mechanisms of endogenous protection, a word of caution is required before assuming that preconditioning could be the basis of a new-found therapy for patients. We attempt to take a critical look at the literature and to emphasise that the reduction of infarct size, often praised as an important consequence of preconditioning, has two important limitations. First, it is a delay in the development of necrosis that is achieved; thus preconditioning buys time but does not cheat death. Secondly, almost all the models used in the studies of infarct size reduction use regional ischaemia followed by reperfusion, so that the benefits of preconditioning could have occurred in either the ischaemic or in the reperfusion period, which is an important distinction. We will emphasise that preconditioning can have different end-points, and that not all of its effects are favourable. Specifically, there may be adverse effects during the ischaemic period, which differ from those on reperfusion.

Muscular dystrophy: from gene to patient

4. ConclusionsAltered expression of dystrophin led to a reduction in the myocardial PCr to ATP ratio in MD carriers and BMD patients. Decreased myocardial PCr was also observed in the mouse model of MD, themdx mouse, which had decreased myocardial glucose uptake in response to insulin and during ischaemia, with increased susceptibility to ischaemic damage. However, utrophin transgene expression corrected the functional and metabolic abnormalities in the dystrophin-deficient mouse heart. To our knowledge, this is the first report of beneficial effects resulting from the expression of a dystrophin-related transgene in heart, making the findings important for the use of gene therapy in the treatment of cardiomyopathy in dystrophic patients.