Adverse remodeling of the electrophysiological response to ischemia-reperfusion in human heart failure is associated with remodeling of metabolic gene expression.

Background: Ventricular arrhythmias occur more frequently in heart failure during episodes of ischemia-reperfusion although the mechanisms underlying this in humans are unclear. We assessed, in explanted human hearts, the remodeled electrophysiological response to acute ischemia-reperfusion in heart failure and its potential causes, including the remodeling of metabolic gene expression.

Methods And Results: We optically mapped coronary-perfused left ventricular wedge preparations from 6 human end-stage failing hearts (F) and 6 donor hearts rejected for transplantation (D).

How to build an integrated biobank: the Washington University Translational Cardiovascular Biobank & Repository experience.

Translational studies that assess and extend observations made in animal models of human pathology to elucidate relevant and important determinants of human diseases require the availability of viable human tissue samples. However, there are a number of technical and practical obstacles that must be overcome in order to perform cellular and electrophysiological studies of the human heart. In addition, changing paradigms of how diseases are diagnosed, studied and treated require increasingly complex integration of rigorous disease phenotyping, tissue characterization and detailed delineation of a multitude of "_omics".

Mechanisms of cardiac and renal dysfunction in patients dying of sepsis.

Rationale: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined.

Objectives: To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death.

Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling.

Increased dispersion of repolarization has been suggested to underlie increased arrhythmogenesis in human heart failure (HF). However, no detailed repolarization mapping data were available to support the presence of increased dispersion of repolarization in failing human heart. In the present study, we aimed to determine the existence of enhanced repolarization dispersion in the right ventricular (RV) endocardium from failing human heart and examine its association with arrhythmia inducibility.

Conduction remodeling in human end-stage nonischemic left ventricular cardiomyopathy.

Background: Several arrhythmogenic mechanisms have been inferred from animal heart failure models. However, the translation of these hypotheses is difficult because of the lack of functional human data. We aimed to investigate the electrophysiological substrate for arrhythmia in human end-stage nonischemic cardiomyopathy.

Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts.

This study compared the effects of ATP-regulated potassium channel (K(ATP)) openers, diazoxide and pinacidil, on diseased and normal human atria and ventricles. We optically mapped the endocardium of coronary-perfused right (n=11) or left (n=2) posterior atrial-ventricular free wall preparations from human hearts with congestive heart failure (CHF, n=8) and non-failing human hearts without (NF, n=3) or with (INF, n=2) infarction. We also analyzed the mRNA expression of the K(ATP) targets K(ir)6.

Multiscale imaging of the human heart: Building the foundation for human systems physiology and translational medicine.

The development of human cardiovascular systems physiology is inhibited by the lack of multiscale functional physiological data, which represents human heart physiology at the molecular, cellular, tissue, organ, and system levels. We have developed an experimental approach to study explanted human hearts in vitro at multiple physiological scales with a wide array of imaging modalities. This approach has already yielded data indicating significant differences between animal models of diseases and actual human heart disease.

Complex interactions between the sinoatrial node and atrium during reentrant arrhythmias in the canine heart.

Background: Numerous studies implicate the sinoatrial node (SAN) as a participant in atrial arrhythmias, including atrial flutter (AFL) and atrial fibrillation (AF). However, the direct role of the SAN has never been described.

Methods And Results: The SAN was optically mapped in coronary perfused preparations from normal canine hearts (n=17).

The temporal variability of dominant frequency and complex fractionated atrial electrograms constrains the validity of sequential mapping in human atrial fibrillation.

Background: It has been proposed that sequential mapping of dominant frequency (DF) and complex fractionated atrial electrograms (CFAE) can identify target sites for ablation of atrial fibrillation (AF). These mapping strategies are valid only if DF and CFAE are temporally stable on the timescale of the mapping procedure. We postulate that DF and CFAE are temporally variable; consequently, sequential mapping can be misleading.

Simulations of optical mapping during electroporation.

Experiments using optical mapping suggest that electroporation occurs in cardiac tissue when the transmembrane potential, Vm, is observed to be significantly less than +/- 400 mV. Our hypothesis, which we test by numerical simulation, is that Vm is greater than +/- 400 mV at the tissue surface, but optical mapping underestimates Vm because it averages over depth. Results indicate a significant underestimation of Vm.

Quatrefoil reentry caused by burst pacing.

Background: Experiments and clinical studies have shown that high-frequency (burst) pacing can induce reentry and fibrillation without a strong shock. We hypothesize that a train of weak stimuli induces quatrefoil reentry, and investigate the mechanism and threshold for this mode of reentry induction.

Methods: We apply a train of weak stimuli at different pacing rates to determine the threshold necessary to induce quatrefoil reentry.

Cardiac optical mapping under a translucent stimulation electrode.

Major effects of stimulation on cardiac transmembrane potentials (Vm) are thought to occur under the electrode, however these have not been optically mapped due to blockage of light by electrodes. Here we optically mapped under translucent indium tin oxide (ITO) electrodes in hearts stained with transmembrane voltage sensitive fluorescent dye, di-4-ANEPPS excited at 488 nm. Emissions in wavelength bands 510-570 nm and >590 nm were similarly affected by changes in ITO transmittance due to electrochemical effects of current at the electrode interface.

Averaging over depth during optical mapping of unipolar stimulation.

Numerical simulations have predicted the distribution of transmembrane potential during electrical stimulation of cardiac tissue. When comparing these predictions to measurements obtained using optical mapping techniques, the optical signal should not be compared to the transmembrane potential calculated at the surface of the tissue, but instead to the transmembrane potential averaged over depth. In this paper, the bidomain model is used to calculate the transmembrane potential in a three-dimensional slab of cardiac tissue, stimulated by a unipolar electrode on the tissue surface.