Michael D. Banas

Hibernating Myocardium Chronically Adapted to Ischemia but Vulnerable to Sudden Death

Abstract— 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.

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.

Accelerated Mineralization of Prosthetic Heart Valves

Abstract The most common cause of prosthetic heart valve failure is severe regurgitation due to rupture of one or more valve cusps that have become mineralized and rigid. To assess the role of stress and strain in the mineralization initiation, in vitro, reference-grade, essentially lipid-free, glutaraldehyde-tanned bovine pericardium (developed as a standard reference material for bioprosthetic device testing) was exposed to a supersaturated calcium phosphate solution in a high-speed valve tester. The pericardium was tested as sheets constructed into tricuspid valves and dumbbell-shaped tensile-test specimens, and then tested at 720 cycles/min. for up to 18 million cycles. Mineralization was followed using X-ray photography, energy-dispersive X-ray analysis, field-emission scanning electron microscopy, and multiple-attenuated internal reflection infrared spectroscopy. Tensile strength of the tissue was determined using a chemomechanical testing apparatus. Phosphate-based tissue mineralization, first concentrated superficially in an annular distribution at the valve cusp bases, was followed by minimal diffuse calcification within the valve cusps. Small crystalline patches also appeared in the tissue compressed by the valve support rings. Mineralization occurred in a distribution similar to that found in clinically explanted prosthetic heart valves, in areas of maximal tensile and compressive stress and maximal strain. Infrared and tensile test data combine to show that tissue fatigue due to cyclic loading most likely caused breakage of collagen cross-links. Exposure of superficial broken cross-link sites, and unmasking of hydroxyproline binding sites, of the tissue collagen are thus implicated as the main factors in phosphate-radical nucleation events leading to valve mineralization, overshadowing previously cited contributions from tissue lipids and membranes. Mineralization first occurs at the surface regions subjected to the greatest stress and strain, and begins as amorphous phosphate-rich rather than crystalline calcium-rich deposits.

Reply to "Letter to the editor: 'The role of short QT interval and elevated LV end-diastolic pressure in the genesis of ventricular tachycardia and fibrillation'".

reply: We appreciate Dr. Karagueuzians ([3][1]) insight regarding the potential role of reduced cytosolic ATP (derived from glucose and glycogen) in explaining shortening of the QT interval (through activation of the ATP-sensitive K+ channel) as well as elevations in end-diastolic pressure (through