Revascularization of chronic hibernating myocardium stimulates myocyte proliferation and partially reverses chronic adaptations to ischemia.

BACKGROUND: The time course and extent of recovery after revascularization of viable dysfunctional myocardium are variable. Although fibrosis is a major determinant, myocyte structural and molecular remodeling may also play important roles. OBJECTIVES: This study sought to determine whether persistent myocyte loss and/or irreversibility of protein changes that develop in hibernating myocardium have an impact on functional recovery in the absence of infarction. METHODS: Swine implanted with a chronic left anterior descending artery (LAD) stenosis to produce hibernating myocardium underwent percutaneous revascularization, with serial functional recovery evaluated for 1 month (n = 12). Myocardial tissue was evaluated to assess myocyte size, nuclear density, and proliferation indexes in comparison with those of normal animals and nonrevascularized controls. Proteomic analysis by 2-dimensional differential in-gel electrophoresis was used to determine the reversibility of molecular adaptations of hibernating myocytes. RESULTS: At 3 months, physiological features of hibernating myocardium were confirmed, with depressed LAD wall thickening and no significant infarction. Revascularization normalized LAD flow reserve, with no immediate change in LAD wall thickening. Regional LAD wall thickening slowly improved but remained depressed 1 month post-percutaneous coronary intervention. Surprisingly, revascularization was associated with histological evidence of myocytes re-entering the growth phase of the cell cycle and increases in the number of c-Kit(+) cells. Myocyte nuclear density returned to normal, whereas regional myocyte hypertrophy regressed. Proteomic analysis demonstrated heterogeneous effects of revascularization. Up-regulated stress and cytoskeletal proteins normalized, whereas reduced contractile and metabolic proteins persisted. CONCLUSIONS: Delayed recovery of hibernating myocardium in the absence of scar may reflect persistent reductions in the amounts of contractile and metabolic proteins. Although revascularization appeared to stimulate myocyte proliferation, the persistence of small immature myocytes may have contributed to delayed functional recovery.

Dissociation of hemodynamic and electrocardiographic indexes of myocardial ischemia in pigs with hibernating myocardium and sudden cardiac death.

Many survivors of sudden cardiac death (SCD) have normal global ventricular function and severe coronary artery disease but no evidence of symptomatic ischemia or infarction before the development of lethal ventricular arrhythmias, and the trigger for ventricular tachycardia (VT)/ventricular fibrillation (VF) remains unclear. We sought to identify the role of spontaneous ischemia and temporal hemodynamic factors preceding SCD using continuous telemetry of left ventricular (LV) pressure and the ECG for periods up to 5 mo in swine (n = 37) with hibernating myocardium who experience spontaneous VT/VF in the absence of heart failure or infarction. Hemodynamics and ST deviation at the time of VT/VF were compared with survivors with hibernating myocardium as well as sham controls. All episodes of VT/VF occurred during sympathetic activation and were initiated by single premature ventricular contractions, and the VT degenerated into VF in ∼ 30 s. ECG evidence of ischemia was infrequent and no different from those that survived. Baseline hemodynamics were no different among groups, but LV end-diastolic pressure during sympathetic activation was higher at the time of SCD (37 ± 4 vs. 26 ± 4 mmHg, P < 0.05) and the ECG demonstrated QT shortening (155 ± 4 vs. 173 ± 5 ms, P < 0.05). The week before SCD, both parameters were no different from survivors. These data indicate that there are no differences in the degree of sympathetic activation or hemodynamic stress when VT/VF develops in swine with hibernating myocardium. The transiently elevated LV end-diastolic pressure and QT shortening preceding VT/VF raises the possibility that electrocardiographically silent subendocardial ischemia and/or mechanoelectrical feedback serve as a trigger for the development of SCD in chronic ischemic heart disease.

11C-meta-hydroxyephedrine defects persist despite functional improvement in hibernating myocardium.

BACKGROUND: Regional cardiac sympathetic nerve dysfunction develops in hibernating myocardium and may play a role in its association with sudden cardiac death. Interventions to improve cardiac function (i.e., revascularization) improve survival, but the potential reversibility of sympathetic nerve dysfunction remains unclear. METHODS AND RESULTS: Pigs (n = 11) were chronically instrumented with a proximal left anterior descending coronary artery (LAD) stenosis to produce hibernating myocardium. Prior to therapeutic interventions, there was LAD occlusion with collateral-dependent myocardium, reduced regional function (echocardiographic LAD wall-thickening 23% +/- 4% vs 83% +/- 6% in Remote, P < .001), and large defects in (11)C-meta-hydroxyephedrine (HED) PET (48% +/- 4% of LV area, 26% +/- 2% integrated reduction). Successful PCI or pravastatin therapy improved regional (LAD wall-thickening 23% +/- 4% to 42% +/- 6%, P < .05) and global LV function (fractional shortening 24% +/- 2% to 31% +/- 2%, P < .01), but did not alter regional HED uptake, retention, defect size, or defect severity. CONCLUSIONS: Despite significant functional improvement of hibernating myocardium as a result of PCI or pravastatin therapy, there were no changes in HED defect size or severity. Thus, inhomogeneity in myocardial sympathetic innervation persisted, and the lack of plasticity suggests that even in the absence of significant infarction, structural rather than functional defects are responsible for reduced myocardial norepinephrine uptake in chronic ischemic heart disease.

Determinants of contractile reserve in viable, chronically dysfunctional myocardium.

There is considerable variability in the sensitivity of inotropic reserve to identify viability in chronically dysfunctional myocardium. This is partially related to the underlying pathophysiology, with more frequent contractile reserve in chronically stunned (with normal resting perfusion) than hibernating myocardium (with reduced flow). This study was undertaken to determine the physiological responses to transient and graded stimulation in chronically stunned and hibernating myocardium to define the relative roles of acute catecholamine desensitization and biphasic responses. Pigs were chronically instrumented with a fixed left anterior descending artery stenosis that resulted in chronically stunned myocardium after 2 mo. One month later, hibernating myocardium was confirmed by regional dysfunction (wall thickening, 3.2 +/- 0.3 vs. 5.5 +/- 5 mm in remote, P=0.01) with reduced resting flow (0.70 +/- 0.07 vs. 0.92 +/- 0.09 ml x min(-1) x g(-1) in remote, P=0.01) without infarction. Wall thickening in dysfunctional regions significantly increased during both graded and transient epinephrine stimulation in chronically stunned (from 3.6 +/- 0.3 to 5.6 +/- 0.5 and 4.9 +/- 0.5 mm, respectively) and hibernating myocardium (from 3.3 +/- 0.3 to 5.4 +/- 0.6 and 5.0 +/- 0.7 mm, respectively) and returned to baseline within 15 min. Although a biphasic response during graded stimulation was common, the subsequent decrement in function was small and similar in both groups (stunned, 0.7 +/- 0.2 mm; hibernating, 1.1 +/- 0.3 mm, P=0.25). We conclude that 1) the extent of contractile reserve during beta-adrenergic stimulation is similar in chronically stunned and hibernating myocardium, 2) there are no significant differences between the responses to transient compared with graded catecholamine stimulation, and 3) submaximal catecholamine stimulation does not induce additional stunning in either chronically stunned or hibernating myocardium.

Brief sympathetic activation precedes the development of ventricular tachycardia and ventricular fibrillation in hibernating myocardium.

BACKGROUND: Hibernating myocardium develops inhomogeneity in myocardial sympathetic innervation with spontaneous sudden cardiac death (SCD) because of ventricular fibrillation (VF). The triggers and prodromal arrhythmias initiating SCD in this substrate are unknown. METHODS: Swine chronically instrumented with a proximal left anterior descending coronary artery stenosis underwent placement of an implantable telemetry unit capable of continuously recording digitized electrocardiogram and left ventricular pressure signals at 1 kHz in conscious unrestrained animals for periods of up to 5 months. RESULTS: Spontaneous SCD (n = 10) was initiated by a close-coupled premature ventricular contraction followed by ventricular tachycardia (VT) that degenerated into VF during brief sympathetic activation. Peak heart rates were similar in animals that developed SCD vs survivors (250 +/- 12 vs 261 +/- 6 bpm). Electrocardiogram evidence of ischemia preceding VT/VF occurred in only 1 animal, and there was no significant infarction. CONCLUSIONS: Spontaneous VT/VF in hibernating myocardium develops during brief sympathetic activation with only rare evidence of acute ischemia. This supports the notion that the regional remodeling accompanying hibernating myocardium may be a novel substrate for the development of SCD in chronic ischemic heart disease.

Hibernating myocardium: chronically adapted to ischemia but vulnerable to sudden death.

The inability to reproduce spontaneous ventricular fibrillation in an animal model of chronic coronary artery disease has limited advances in understanding mechanisms of sudden cardiac death (SCD). Swine with hibernating myocardium arising from a chronic left anterior descending coronary artery (LAD) occlusion have a high rate of SCD that parallels the poor clinical survival of medically treated patients with hibernating myocardium. Kaplan-Meier analysis (n=426) demonstrated a cumulative mortality of 49% after 5 months that was almost entirely attributable to spontaneous SCD. Using implantable loop recorders, ventricular fibrillation was documented as the arrhythmic mechanism of death in all animals (n=10) and was usually preceded by ventricular tachycardia (n=8). Physiological studies before SCD (n=7) demonstrated total LAD occlusion and collateral-dependent myocardium (n=5), excluding acute occlusion as a major trigger of arrhythmia. The physiological substrate of hibernating myocardium was present before SCD, with reductions in LAD perfusion (SCD 0.79+/-0.13 versus 0.80+/-0.08 mL/min per g) and wall thickening (SCD 28+/-3% versus 22+/-3%) that were similar to survivors (n=14). Triphenyltetrazolium chloride infarcts among animals with SCD were infrequent (4 of 32) and small, averaging 4.6% of LV mass. Histology (n=4) showed postmortem changes but no acute inflammation nor contraction band necrosis. These data support the notion that hibernating myocardium is a pathophysiological substrate at high risk of SCD. This is independent of changes in functional stenosis severity, acute myocardial necrosis, or fibrotic scar. Thus, regional adaptations that promote myocyte survival in the setting of chronic repetitive ischemia result in a substrate with enhanced vulnerability to lethal arrhythmias and SCD.