Number 20, 2003
Hibernation preconditioning

Pathophysiology of chronic but reversible ischemic dysfunction*

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Jean-Louis J. Vanoverschelde, Jacques A. Melin
Divisions of Cardiology and Nuclear Medicine, Université Catholique de Louvain,
Louvain, Belgium
Correspondence: Dr Jean-Louis Vanoverschelde, Division of Cardiology, Cliniques Universitaires St Luc, Avenue Hippocrate 10 (2881), 1200 Brussels, Belgium.
Tel: +32 2 7642803, fax: +32 2 7642811, e-mail: vanoverschelde@card.ucl.ac.be

Introduction
Revascularization of chronically but reversibly dysfunctional myocardium, often referred to as viable, has recently emerged as an important alternative in the treatment of heart failure secondary to coronary artery disease [1]. Observational studies have indeed suggested that patients with ischemic left ventricular dysfunction and a significant amount of viable myocardium identified by various noninvasive imaging modalities have lower rates of perioperative mortality, greater improvements in regional and global left ventricular function, fewer heart failure symptoms, and improved long-term survival after revascularization compared with patients with large areas of nonviable myocardium [2, 3].
This short discussion will review some of the more recent advances in understanding the
pathophysiology of chronic but reversible ischemic left ventricular dysfunction. Emphasis will be placed on regional perfusion-contraction matching and on the peculiar morphological changes that have been shown to occur in reversibly dysfunctional myocardium.

Historical perspective
The spectrum of left ventricular dysfunction caused by atherosclerotic coronary artery disease expanded over the last quarter of the 20th century. Traditionally, it was assumed that heart failure arose from either reversible ischemia (anginal equivalent) or irreversible myocardial infarction. Insights gained from more recent functional, metabolic, and morphological studies have led to the concept of dysfunctional but viable myocardium (stunned and hibernating) and to that of ventricular remodeling.
The possible discordance between wall motion abnormalities and histopathological findings has been recognized clinically since the early 1970s. Chatterjee et al [4] reported improved regional myocardial wall motion abnormalities in the absence of myocardial scarring. In 1974, Horn et al [5] demonstrated improved regional wall motion with epinephrine infusion in patients with coronary artery disease and chronic asynergy. In 1978, Diamond et al [6] suggested that ischemic noninfarcted myocardium could exist in a state of functional hibernation. In the mid-1980s, Rahimtoola [7] used the term “myocardial hibernation” to describe a state of diminished resting ventricular function in the setting of coronary artery disease, which occurs in at least a third of coronary patients. He proposed that myocardial hibernation develops as a protective mechanism in which persistent myocardial hypoperfusion in the absence of myocardial necrosis leads to downregulation of myocardial contractility [8]. Ross [9] subsequently coined the term “perfusion-contraction matching” to characterize the adaptive response of the hibernating myocardium to diminished perfusion. The concept of evaluating perfusion and contraction simultaneously to characterize the mechanisms underlying contractile dysfunction has fostered considerable research interest and stimulated the use of perfusion imaging, not only to address basic pathophysiological mechanisms but also to detect viable myocardium clinically in coronary patients.

Pathophysiology
Observations in humans with chronic reversible ischemic dysfunction
Assessment of perfusion-contraction matching in patients with chronic left ventricular ischemic dysfunction requires the ability to measure regional myocardial blood flow in absolute terms and to correlate the findings with data on regional myocardial function, acquired simultaneously. In daily clinical practice, this has only become possible with the advent of PET and the use of either 13N-ammonia or 15O-water as flow tracers [10, 11]. PET is a truly quantitative method. It has a good spatial resolution; it allows for accurate correction of photon attenuation and, to some extent, of partial volume effects; and, when mathematically and physiologically appropriate models are used to describe the biological behavior of the radiotracers in blood and myocardium, it allows for computation of quantitative estimates of regional myocardial perfusion.
Resting PET flow measurements obtained in chronically dysfunctional but viable myocardium are summarized in Table I and Figure 1.

Table I. Resting myocardial blood flow in dysfunctional and remote myocardium in humans.

Based on the results of these studies, it appears that the transmural blood flow to dysfunctional but viable segments is remarkably variable, about one half of the segments showing reduced perfusion, as predicted by Rahimtoola, whereas the other half displays only minor and often no reduction in transmural myocardial blood flow.
Irrespective of resting flow, perfusion reserve is always reduced in dysfunctional but viable myocardium [12, 13, 24, 29], albeit more severely in segments with low resting perfusion than in those with normal resting perfusion [24]. The severity of flow reserve reduction directly impacts on the ability of dysfunctional but viable myocardium to improve in contraction upon inotropic stimulation, as this requires increased myocardial blood flow and oxygen consumption. Accordingly, viable segments without recruitable inotropic reserve usually have lower residual myocardial flow reserve than viable segments with recruitable inotropic reserve [29].
Besides the changes in resting myocardial blood flow and flow reserve, several structural alterations that affect both the cardiomyocytes and the extracellular matrix have been described in chronically but reversibly dysfunctional segments [12, 30–32]. Most of the available information on these structural changes has been gathered from studies in which human myocardial biopsy specimens were harvested at the time of bypass surgery. The primary alterations include depletion of contractile elements [32]. In some cells, this is limited to the vicinity of the nucleus, whereas in others it is very extended, leaving only few or no sarcomeres at the cell periphery. Myofibrillar loss is not accompanied by major cell volume changes, which is clearly different from atrophic degeneration. The space previously occupied by the myofilaments is filled with an amorphous, strongly PAS-positive material, typical of glycogen (Figuur 2).

Figure 2. (Panel A): Light micrograph of a normal myocardium. (Panel B): Representative light micrograph of hibernating myocardium. The myolytic cytoplasm is filled with PAS-positive material typical of glycogen. Magnification ´320.

At the ultrastructural level, adaptive rather than degenerative ischemic changes are observed. The mitochondria are increased in number and they display alterations in size and shape. They are unevenly distributed within the cytoplasm. Most appear doughnut-shaped and show loss of contact sites between inner and outer mitochondrial membranes or decreased numbers of cristae. The nuclear alterations range from irregular tortuous nuclear outlines, with even distribution of heterochromatin over the nucleoplasm, to chromatin clumping near the nuclear membrane and throughout the whole nucleoplasm. Loss of sarcoplasmic reticulum, T tubules, and sarcomeres, but increased endoplasmic reticulum, provides additional support for an adaptive phenomenon. The contractile protein myosin, the thin filament complex, titin, and a-actinin are reduced, and the distribution of titin within the cardiomyocyte is altered [33, 34]. Cytoskeletal proteins such as desmin, tubulin, and vinculin are disorganized. The expression of connexin 43, a major gap junction protein [35], and that of nuclear A-type lamins [36] are also reduced. From a biochemical point of view, the tissue content of ATP, total adenine nucleotides, and phosphocreatine (PCr) usually remain nearly normal [32], and mitochondrial function, as reflected by the ADP/ATP and PCr/ATP ratios, also remains nearly intact [32]. The interstitial alterations consist of increased amounts of collagen deposition [37, 38]. Within the widened interstitium are variable numbers of fibroblasts and macrophages, and scant increased amounts of elastic fibers. Importantly, acute ischemic changes such as endothelial swelling of the microvasculature are absent. Given their severity, the structural changes that affect chronically dysfunctional myocardium are likely to impact on its ability to respond to an inotropic stimulus [39] and on the speed at which it may or may not recover after revascularization [20]. Not surprisingly, segments with less fibrosis or with less severe cardiomyocyte alteration and remodeling are more likely to improve function following the administration of dobutamine or after revascularization [17].
Recent studies have suggested that the structural changes occurring in hibernating myocardium were the consequence of a dedifferentiation process [40]. The hibernating cardiomyocytes indeed show many features of neonatal cardiomyocytes, including: (1) depletion of contractile filaments, (2) presence of rough sarcoplasmic reticulum, (3) accumulation of glycogen, (4) occurrence of irregularly shaped nuclei with peculiar distribution of chromatin, (5) loss of organized sarcoplasmic reticulum, (6) lack of T tubules, and (7) vesiculization of the sarcolemma. Not all the characteristics of altered cardiomyocytes resemble those of embryonic cells, however. For instance, the remaining sarcomeres in the altered cells often retain their orderly arrangement at the cell periphery, while they are randomly distributed in embryonic cells. Also, the amount of glycogen seen in altered cardiomyocytes far exceeds that reported in the embryo. The hypothesis of dedifferentiation is further substantiated by immunohistological studies showing that hibernating cardiomyocytes re-express contractile proteins that are specific to the fetal heart, such as the a-smooth muscle actin, while at the same time they exhibit the same organization of structural proteins such as titin as developing cardiomyocytes. In addition, cardiotin, a recently described high molecular weight protein absent in fetal cells, is also absent in the altered cells. These findings reinforce the thesis that hibernating cardiomyocytes undergo partial dedifferentiation.

Insights gained from animal models of chronic reversible ischemic dysfunction
Recently, chronic coronary stenosis and progressive ameroid occlusion models have shed new light on both the mechanisms and the temporal progression of reversible ischemic dysfunction [41–49]. During the first weeks after the onset of dysfunction, endocardial blood flow is consistently found to be either normal or only marginally decreased [45–49]. Chronic myocardial stunning is thus the most likely mechanism of the observed dysfunction, a hypothesis which is further supported by the strong relation between the reduction in subendocardial flow reserve and the severity of dysfunction [45, 49]. With time, and probably also increases in the physiological significance of the underlying coronary narrowing, some of the dysfunctional segments which appeared “chronically stunned” on early examination eventually become underperfused [46, 49]. It is noteworthy that the transition from chronic stunning to chronic hibernation only occurs for threshold reductions in myocardial flow reserve. The critical nature of coronary flow reserve reduction required to produce hibernating myocardium likely explains why not all studies have demonstrated a progression to hibernating myocardium distal to a chronic stenosis. For example, circumflex ameroid models (rapidly progressing stenoses) in dogs usually have normal resting perfusion, with a well-developed collateral circulation [48], yet hibernating myocardium can develop when source collateral flow is limited [48]. The experimental data thus suggest that chronic reversible myocardial ischemic dysfunction is a complex, progressive, and dynamic phenomenon that is initiated by repeated episodes of ischemia, and in which resting perfusion, although initially preserved, may subsequently become reduced, probably in response to the decrease in myocyte energy demand. Indeed, the persistence of some degree of flow reserve, even when resting myocardial blood flow is reduced, suggests that the reduction in resting flow is somehow secondary to that in resting contractile function, and could serve as a way to increase residual myocardial perfusion reserve.
Animal models have also improved our understanding of the morphological alterations seen in reversible ischemic dysfunction. Several studies have indeed indicated that myofibrillar disassembly, myofibrillar loss, and increased glycogen content develop rapidly after a critical limitation in flow reserve. Interestingly, these changes seem to take place similarly in dysfunctional and in normally perfused remote regions of dysfunctional hearts. Thus, the pathological changes described in humans with chronic but reversible dysfunction do not appear to reflect the chronicity of left ventricular dysfunction nor do they appear to arise as a direct consequence of ischemia. The fact that myolysis occurs globally in ischemic cardiomyopathy raises the possibility that these morphological changes reflect a response to chronic elevations in preload or stretch [50].

Implications for the clinical identification of reversible dysfunction
Taken together, the currently available data suggest that a spectrum of myocardial dysfunction exists in patients with coronary disease (Table II).

Table II. The patterns of chronic left ventricular ischemic dysfunction.

The initial stages of dysfunction are most likely characterized by normal resting perfusion but reduced flow reserve, mild myocyte alterations, maintained membrane integrity (allowing the transport of both thallium and glucose), preserved capacity to respond to an inotropic stimulus, and no or little tissue fibrosis. Following revascularization, functional recovery is likely to be rapid and complete. At the opposite end of the scale, more advanced stages of dysfunction are probably associated with reduced resting perfusion, increased tissue fibrosis, perhaps more severe myocyte remodeling, and a decreased ability to respond to inotropic stimuli. Nonetheless, membrane function and glucose metabolism may long remain preserved. Following revascularization, functional recovery, if any, is usually delayed and, ultimately, mostly incomplete.

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