Myocardial blood flow and metabolism in left ventricular ischemic dysfunction
(1995)
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- (en) Due to its inherent truly quantitative capabilities, its noninvasive nature and its nondestructive characteristics, PET has emerged as a unique investigative tool for the assessment and quantification of myocardial blood flow and metabolism in man. The present thesis reviews some of the insights gained with the use of PET into the pathophysiology of regional left ventricular ischemic dysfunction. Chapters 1 and 2 dealt with definitions and specific issues pertinent to the pathophysiological background of our studies and to the PET technology that was used to assess myocardial blood flow and metabolism. In Chapter 3, I have concentrated on the study of the flow and metabolic correlates of myocardial infarction, myocardial stunning and myocardial hibernation in humans as well as on the structural changes shown to occur in the hibernating myocardium. In reperfused myocardial infarction, studied at an average of 40 days after the acute event, flow and function were found to be significantly reduced and appropriately matched (chronic perfusion-contraction matching). Regional myocardial oxidative metabolism was also reduced, in proportion to the reduction in myocardial blood flow, while glucose metabolism was highly variable. In subsequent studies, the severity of flow reduction was found to be dependent on the severity of tissue fibrosis, providing an anatomical substrate for the noninvasive evaluation of the transmural extension of the fibrotic scar across the left ventricular wall. In the stunned myocardium, our results confirmed those previously demonstrated in the experimental lab, namely that regional perfusion and oxygen consumption were largely restored despite the continuing loss of regional contraction. The most unexpected observations were made in the hibernating myocardium. It had been initially postulated that myocardial hibernation resulted from the spontaneous adaptation of the ischemic myocardium to chronic underperfusion, whereby the heart downgrades its myocardial function to the extent that flow and function are once again matched and, as a consequence, no myocardial necrosis ensues. Surprisingly, quantification of myocardial perfusion and metabolism in absolute terms by the use of PET in patients with chronic hibernation failed to demonstrate any significant reduction of resting blood flow to the dysfunctional segments. Reduced blood flow values could only be measured in less than 25% of the patients with myocardial hibernation, the remaining patients showing normal levels of resting perfusion. Obviously, in these latter patients, the dysfunction could not be explained on the basis of a permanent, chronic reduction of transmural perfusion. The observation that regional dysfunction correlated closely with the severity of impairment of the coronary vasodilatory reserve raised the possibility that frequent, repeated and incompletely resolutive episodes of ischemia followed by stunning could be the primary mechanisms. Accordingly, myocardial hibernation would rather be the result of repetitive ischemia and stunning than the consequence of chronic and permanent underperfusion. It is therefore an unstable condition, which, in the absence of coronary recanalization, could eventually lead to tissue necrosis. Although such instability had not been anticipated in earlier studies, recent retrospective studies have confirmed that patients with hibernating myocardium indeed had a poor outcome if given only medical treatment. Although suggestive evidence thus indicates that repetitive ischemia with a persistent stunning effect probably sets the stage to chronic hibernation, definite proof that more frequent, more prolonged and more severe episodes of ischemia do indeed occur in patients with chronic dysfunction is still lacking. Future research should therefore aim at evaluating the total ischemic burden in these patients, for instance by use of quantitative Holter monitoring. The study of myocardial structure provided important clues as to the pathophysiology of the hibernating myocardium. Although stunning does not usually result in significant structural changes, marked alterations were noted in about half the cardiomyocytes in hibernating segments, including the loss of myofibrillar content and the accumulation of glycogen. Interestingly, these structural changes were accompanied by qualitative changes in the isoform expression of various contractile and cytoskeleton proteins, including the re-expression of the α-smooth-muscle actin and of the GLUT-1 glucose transporter, or changes in the organization pattern of titin and cardiotin towards a fetal phenotype. These observations, which are reminiscent of cell dedifferentiation, will likely stimulate the study of the molecular mechanisms underlying hibernation, and promote the development of relevant animal models for hibernation. Finally, definite proof that the structural changes directly contribute to the pathophysiology of myocardial hibernation was provided by studies on the time course of recovery of contractile function following revascularization, which showed that the rate of functional return after revascularization was intimately related to the severity of the preexisting structural changes. The finding that abnormal glucose uptake by previously hibernating myocardium can persist for prolonged periods of time after successful coronary recanalization further supports this contention. Unfortunately, for obvious ethical reason, confirmation of structural reversibility has not been possible, although it can be inferred from the return of function over time. Obviously, a better understanding of the genetic mechanisms controlling the processes of dedifferentiation and redifferentiation in the setting of hibernation is needed to develop appropriate pharmacological or genetic tools to hasten the recovery of function in these patients. In Chapter 4, we have attempted to apply the concepts derived from our previous studies to the clinical identification of which patient is most likely to resume satisfactory contractile function and thus benefit from coronary revascularization. We first characterized the flow, metabolic and structural factors associated with the return of regional contraction after revascularization, in patients with left ventricular dysfunction and a previous myocardial infarction. These studies largely confirmed our previous observations, namely that functional reversibility only occurs in segments with preserved flow, further supporting the concept that a permanent reduction of coronary blood flow is not needed to explain the dysfunction. These studies further indicated that the extent of recovery of regional contraction after revascularization was linked to both the extent and severity of tissue fibrosis, and thus irreversible injury. The ability to identify reversible dysfunction before revascularization by use of PET flow-metabolic imaging was then evaluated in 2 cohorts of patients with varying degrees of left ventricular ischemic dysfunction. By use of a multivariate approach, an equation which combined flow and normalized glucose extraction was generated that allowed prediction of functional recovery in 80 - 85% of the patients, irrespective of the severity of the underlying dysfunction. Finally, we examined the potential role of assessing residual inotropic reserve in dysfunctional segment to predict the reversibility of LV ischemic dysfunction after revascularization. We used the ß1-receptor agonist dobutamine as the inotropic agent and evaluated the diagnostic significance of an enhancement of regional function at echocardio-graphy during infusion of a low-dose of dobutamine for the prediction of functional recovery after revascularization. The results showed that dobutamine-echocardiography provides a potentially useful alternative to the use of PET to delineate myocardial viability in most patients with LV ischemic dysfunction.
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Vanoverschelde, J.-L. (1995). Myocardial blood flow and metabolism in left ventricular ischemic dysfunction. https://hdl.handle.net/2078.5/158958