Abstract-Heart failure (HF) commonly results in atrial fibrillation (AF) and fibrosis, but how the distribution of fibrosis impacts AF dynamics has not been studied. HF was induced in sheep by ventricular tachypacing (220 bpm, 6 to 7 weeks). Optical mapping (Di-4-ANEPPS, 300 frames/sec) of the posterior left atrial (PLA) endocardium was performed during sustained AF (burst pacing) in Langendorff-perfused HF (nϭ7, 4 mol/L acetylcholine; nϭ3, no acetylcholine) and control (nϭ6) hearts. PLA breakthroughs were the most frequent activation pattern in both groups (72.0Ϯ4.6 and 90.2Ϯ2.7%, HF and control, respectively). However, unlike control, HF breakthroughs preferentially occurred at the PLAs periphery near the pulmonary vein ostia, and their beat-to-beat variability was greater than control (
Background-Styryl voltage-sensitive dyes (e.g. di-4-ANEPPS) have been successfully used for optical mapping in cardiac cells and tissues. However, their utility for probing electrical activity deep inside the myocardial wall and in blood-perfused myocardium has been limited because of light scattering and high absorption by endogenous chromophores and hemoglobin at blue-green excitation wavelengths.
Smyd1, a muscle-specific histone methyltransferase, has established roles in skeletal and cardiac muscle development, but its role in the adult heart remains poorly understood. Our prior work demonstrated that cardiac-specific deletion of Smyd1 in adult mice (Smyd1-KO) leads to hypertrophy and heart failure. Here we show that down-regulation of mitochondrial energetics is an early event in these Smyd1-KO mice preceding the onset of structural abnormalities. This early impairment of mitochondrial energetics in Smyd1-KO mice is associated with a significant reduction in gene and protein expression of PGC-1α, PPARα, and RXRα, the master regulators of cardiac energetics. The effect of Smyd1 on PGC-1α was recapitulated in primary cultured rat ventricular myocytes, in which acute siRNA-mediated silencing of Smyd1 resulted in a greater than twofold decrease in PGC-1α expression without affecting that of PPARα or RXRα. In addition, enrichment of histone H3 lysine 4 trimethylation (a mark of gene activation) at the PGC-1α locus was markedly reduced in Smyd1-KO mice, and Smyd1-induced transcriptional activation of PGC-1α was confirmed by luciferase reporter assays. Functional confirmation of Smyd1's involvement showed an increase in mitochondrial respiration capacity induced by overexpression of Smyd1, which was abolished by siRNA-mediated PGC-1α knockdown. Conversely, overexpression of PGC-1α rescued transcript expression and mitochondrial respiration caused by silencing Smyd1 in cardiomyocytes. These findings provide functional evidence for a role of Smyd1, or any member of the Smyd family, in regulating cardiac energetics in the adult heart, which is mediated, at least in part, via modulating PGC-1α.
Zaitsev AV. Three distinct phases of VF during global ischemia in the isolated blood-perfused pig heart. Am J Physiol Heart Circ Physiol 293: H1617-H1628, 2007. First published June 1, 2007; doi:10.1152/ajpheart.00130.2007.-Changes in ventricular fibrillation (VF) organization occurring after the onset of global ischemia are relevant to defibrillation and survival but remain poorly understood. We hypothesized that ischemia-specific dynamic instability of the action potential (AP) causes a loss of spatiotemporal periodicity of propagation and broadening of the electrocardiogram (ECG) frequency spectrum during VF in the ischemic myocardium. We recorded voltage-sensitive fluorescence of di-4-ANEPPS (anterior left ventricle, 35 ϫ 35 mm, 64 ϫ 64 pixels) and the volumeconducted ECG in six blood-perfused hearts during 10 min of VF and global ischemia. We used coefficient of variation (CV) to estimate variability of AP amplitude, AP duration, and diastolic interval (CV-APA, CV-APD, and CV-DI, respectively). We computed excitation median frequency (Median_F), spectral width of the AP and ECG (SpW-AP and SpW-ECG, respectively), wavebreak incidence (WBI), and recurrence of propagation direction (RPD). We found three distinct phases of local VF dynamics: "relatively periodic" (Յ1 min, high Median_F, moderate AP variability, high WBI, low RPD), "highly periodic" (1-2 min, reduced Median_F, low AP variability, low WBI, high RPD), and "aperiodic" (3-10 min, low Median_F, high AP variability, high WBI, low RPD). In one experiment, spontaneous conversion from the aperiodic to the highly periodic phase occurred after 5 min of ischemia. The SpW-ECG was correlated with SpW-AP, CV-APD, and CV-APA. We conclude that 1) at least three distinct phases of VF dynamics are present in our model, and 2) the newly described aperiodic phase is related to ischemia-specific dynamic instability of the AP shape, which underlies broadening of the ECG spectrum during VF evolution. ventricular fibrillation; action potential; electrocardiogram ONE IMPORTANT DECISION that an emergency care professional faces at the scene of cardiac arrest is whether to initiate cardiopulmonary resuscitation (CPR) before the application of a shock, or to defibrillate first. Population studies indicate that the "CPR first" strategy improves survival if the ventricular fibrillation (VF) duration exceeds 3-4 min ("circulatory phase") but not at the earlier "electrical" phase of VF (18). This observation motivated recent studies aimed at estimating VF duration based on the structure and spectral content of the electrocardiogram (ECG) waveform (6, 27, 34). Furthermore, various quantitative measures of "order" in the ECG waveform can predict the likelihood of rescue shock success, restoration of circulation, and survival to hospital discharge (4, 6). However, the relationship between the structure of the ECG waveform and the spatiotemporal dynamics of the fibrillatory waves in the myocardium remains unknown.VF organization evolves naturally after its onset as a result of glo...
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