The Sod2 gene for Mn-superoxide dismutase (MnSOD), an intramitochondrial free radical scavenging enzyme that is the first line of defense against superoxide produced as a byproduct of oxidative phosphorylation, was inactivated by homologous recombination. Homozygous mutant mice die within the first 10 days of life with a dilated cardiomyopathy, accumulation of lipid in liver and skeletal muscle, and metabolic acidosis. Cytochemical analysis revealed a severe reduction in succinate dehydrogenase (complex II) and aconitase (a TCA cycle enzyme) activities in the heart and, to a lesser extent, in other organs. These findings indicate that MnSOD is required for normal biological function of tissues by maintaining the integrity of mitochondrial enzymes susceptible to direct inactivation by superoxide.

The electrophysiologic and anatomic basis for fractionated electrograms were investigated in superfused epicardial preparations from infarcted canine hearts. Fractionated bipolar electrograms were frequently recorded in preparations from infarcts 2 weeks to 18 months old but only rarely in preparations from 5-day-old infarcts. The fractionated electrograms were not caused by movement artifacts. They were not associated with depressed transmembrane resting or action potentials (which were found in the 5-day-old infarcts), but rather transmembrane potentials recorded in the vicinity of the bipolar electrodes were normal. Despite the normal transmembrane potentials, activation time in regions where fractionated electrograms occurred was prolonged. However, prolonged activation time by itself did not cause fractionation, since fractionated electrograms were not recorded from normal preparations in which conduction was markedly slowed by a superfusate containing 16 mM potassium and epinephrine. Unipolar electrograms recorded with glass microelectrodes (tip size 1 to 5 ,m) showed that activation in regions where fractionated electrograms were recorded was inhomogeneous. Prepotentials were found preceding the upstrokes of some action potentials in regions where double potentials were recorded, suggesting the possibility of electrotonic transmission across high resistance or inexcitable gaps, but no electrotonic potentials were seen in regions with multicomponent fractionated electrograms. Fractionated electrograms were recorded in regions where infarct healing caused wide separation of individual myocardial fibers while distorting their orientation. The anatomic changes probably caused slow and inhomogeneous activation. Circulation 72, No. 3, 596 611, 1985. FRACTIONATED electrograms, 1-1l consisting of either two discrete deflections separated by an isoelectric interval (double potentials or split deflections4' 7, 8. 12) or comprised of many components'6 7 have been recorded during mapping studies on patients with ischemic heart disease and a history of chronic ventricular tachycardia. These kinds of electrograms have been found during sinus rhythm2'6 7'9-1 as well as during tachycardia. [1][2][3] It is important to determine why fractionated electrograms occur and what they mean. Their occurrence during sinus rhythm might sometimes assist in identifying patients who can develop ventricular tachycardia.6' 8 The site at which these electrograms are recordFrom the

Excitation in the epicardial border zone of 3-5-day-old canine infarcts was mapped with an array of 192 bipolar electrodes during sustained ventricular tachycardia. Reentrant circuits were found in which activation occurred around long lines of apparent conduction block based on the criterion that excitation on opposite sides of the lines occurred with marked disparity in time. When the lines of apparent block were functional (i.e., occurred only during tachycardia and not during sinus rhythm or ventricular pacing) they were oriented parallel to the long axis of epicardial muscle fiber bundles. Isochrones distal to the lines were oriented parallel to them because widely separate sites within these isochrones were activated nearly simultaneously. This suggested that excitation not only occurred around the lines of block but also slowly across them. This slow activation occurred transverse to the long axis of the myocardial fibers and therefore might result because of the anisotropic tissue properties. To test this hypothesis, the epicardial border zone was stimulated during sinus rhythm through electrodes around its margin and at the center of the recording array. Activation transverse to the myocardial fibers in regions where lines of block occurred during tachycardia was slow, whereas it was rapid parallel to fibers' orientation. During tachycardia electrograms along the lines of apparent block had long durations and were fractionated, a characteristic that can also result from activation transverse to the myocardial fiber long axis. Therefore, we propose that the parallel orientation of the muscle bundles in the epicardial border zone is an important cause of ventricular tachycardia because activation transverse to myocardial fibers is sufficiently slow to permit the occurrence of reentry.

SUMMARY. Structural and electrophysiological properties of the epicardial muscle which survives on the surface of transmural infarcts of the canine heart (epicardial border zone) were studied at different times after occlusion of the left anterior coronary artery (LAD). Isolated preparations were superfused in vitro, transmembrane potentials recorded, and impulse propagation mapped. In preparations from subacute infarcts (1 and 5 days), resting potential, action potential amplitude, upstroke velocity, and duration were all significantly reduced. Well-defined directional differences in propagation occurred. Propagation was more rapid in the direction perpendicular to the left anterior coronary artery than in the direction perpendicular to the base of the heart, because of the uniform anisotropic structure of the surviving muscle fibers which were arranged in tightly packed bundles oriented perpendicular to the left anterior coronary artery. The only ultrastructural abnormalities found in these muscle fibers was an accumulation of large amounts of lipid droplets. As the infarcts healed, resting potential, action potential amplitude, and upstroke velocity returned to normal by 2 weeks, although action potential duration decreased further. Lipid droplets had disappeared, and connective tissue had invaded the epicardial border zone, separating the muscle bundles. By 2 months, action potentials were normal, but the muscle fibers were widely separated and disoriented by the connective tissue (parallel bundles no longer were found). In these regions with a nonuniform anisotropic structure, the well-defined directional differences in impulse propagation were lost. However, activation was very slow, perhaps because of diminished connections between cells. The persistence of slow conduction in healed infarcts may contribute to the occurrence of chronic arrhythmias. {Circ Res 56: 436-451, 1985)

In this model, unregulated continuous expression of VEGF is associated with (1) a high rate of failure to thrive/death and (2) formation of endothelial cell-derived intramural vascular tumors in the implantation site. These results underscore the importance of regulating VEGF expression for therapeutic angiogenesis.

Forty percent of deaths attributed to stated cardiac arrest were not sudden or unexpected, and nearly half of presumed SCDs were not arrhythmic. These findings have implications for the accuracy of SCDs as defined by WHO criteria or emergency medical services records in aggregate mortality data, clinical trials, and cohort studies.

The fDV of MR contrast material in the periinfarcted rim was significantly (P <. 05) greater than that in the normal myocardium, but significantly less than that in the core of infarcted myocardium.

Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single nucleotide variants in the MKL2, MYH7 and NKX2–5 genes. The MYH7 and MKL2 variants were inherited from the affected-asymptomatic father and the rare NKX2–5 variant (minor allele frequency=0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell–derived cardiomyocytes provided histologic and molecular evidence for the NKX2–5 variant’s contribution as a genetic modifier.