miRNAs at the heart of the matter

Cardiovascular disease is among the main causes of morbidity and mortality in developed countries. The pathological process of the heart is associated with altered expression profile of genes that are important for cardiac function. MicroRNAs (miRNAs) have emerged as one of the central players of gene expression regulation. The implications of miRNAs in the pathological process of cardiovascular system have recently been recognized, representing the most rapidly evolving research field. Here, we summarize and analyze the currently available data from our own laboratory and other groups, providing a comprehensive overview of miRNA function in the heart, including a brief introduction of miRNA biology, expression profile of miRNAs in cardiac tissue, role of miRNAs in cardiac hypertrophy and heart failure, the arrhythmogenic potential of miRNAs, the involvement of miRNAs in vascular angiogenesis, and regulation of cardiomyocyte apoptosis by miRNAs. The target genes and signaling pathways linking the miRNAs to cardiovascular disease are highlighted. The applications of miRNA interference technologies for manipulating miRNA expression, stability, and function as new strategies for molecular therapy of human disease are evaluated. Finally, some specific issues related to future directions of the research on miRNAs relevant to cardiovascular disease are pinpointed and speculated

Effects of Heart Rate and Ventricular Wall Thickness on Non-invasive Mapping: An in silico Study

Background: Non-invasive cardiac mapping—also known as Electrocardiographic imaging (ECGi)—is a novel, painless and relatively economic method to map the electrical activation and repolarization patterns of the heart, providing a valuable tool for early identification and diagnosis of conduction abnormalities and arrhythmias. Moreover, the ability to obtain information on cardiac electrical activity non-invasively using ECGi provides the potential for a priori information to guide invasive surgical procedures, improving success rates, and reducing procedure time. Previous studies have shown the influence of clinical variables, such as heart rate, heart size, endocardial wall, and body composition on surface electrocardiogram (ECG) measurements. The influence of clinical variables on the ECG variability has provided information on cardiovascular control and its abnormalities in various pathologies. However, the effects of such clinical variables on the Body Surface Potential (BSP) and ECGi maps have yet to be systematically investigated. Methods: In this study we investigated the effects of heart size, intracardiac thickness, and heart rate on BSP and ECGi maps using a previously-developed 3D electrophysiologically-detailed ventricles-torso model. The inverse solution was solved using the three different Tikhonov regularization methods. Results: Through comparison of multiple measures of error/accuracy on the ECGi reconstructions, our results showed that using different heart geometries to solve the forward and inverse problems produced a larger estimated focal excitation location. An increase of ~2 mm in the Euclidean distance error was observed for an increase in the heart size. However, the estimation of the location of focal activity was still able to be obtained. Similarly, a Euclidean distance increase was observed when the order of regularization was reduced. For the case of activation maps reconstructed at the same ectopic focus location but different heart rates, an increase in the errors and Euclidean distance was observed when the heart rate was increased. Conclusions: Non-invasive cardiac mapping can still provide useful information about cardiac activation patterns for the cases when a different geometry is used for the inverse problem compared to the one used for the forward solution; rapid pacing rates can induce order-dependent errors in the accuracy of reconstruction

Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT

Enhanced dispersion of repolarization (DR) and refractoriness may be a unifying mechanism central to arrhythmia genesis in the long QT (LQT) syndrome. The role of DR in promoting arrhythmias was investigated in several strains of molecularly engineered mice: (a) Kv4.2 dominant negative transgenic (Kv4.2DN) that lacks the fast component of the transient outward current, Ito,f, have action potential (AP) and QT prolongation, but no spontaneous arrhythmias, (b) Kv1.4 targeted mice (Kv1.4−/−) that lack the slow component of Ito (Ito,s), have no QT prolongation and no spontaneous arrhythmias, and (c) double transgenic (Kv4.2DN×Kv1.4−/−) mice that lack both Ito,f and Ito,s, have AP and QT prolongation, and spontaneous ventricular tachyarrhythmias. Hearts were perfused, stained with di-4-ANEPPS and optically mapped. Activation patterns and conduction velocities were similar between the strains but AP duration at 75% recovery (APD75) was longer in Kv4.2DN (28.0 ± 2.5 ms, P < 0.01, n = 6), Kv1.4−/− (28.4 ± 0.4 ms, P < 0.01, n = 5) and Kv4.2DN×Kv1.4−/− (34.3 ± 2.6 ms, P < 0.01, n = 6) mice than controls (20.3 ± 1.0 ms, n = 5). Dispersion of refractoriness between apex and base was markedly reduced in Kv4.2DN (0.3 ± 0.5 ms, n = 6, P < 0.05) but enhanced in Kv1.4−/− (14.2 ± 2.0 ms, n = 5, P < 0.05) and Kv4.2DN×Kv1.4−/− (15.0 ± 3 ms, n = 5, P < 0.5) mice compared with controls (10 ± 2 ms, n = 5). A premature pulse elicited ventricular tachycardia (VT) in Kv1.4−/− (n = 4/5) and Kv4.2DN×Kv1.4−/− hearts (n = 5/5) but not Kv4.2DN hearts (n = 0/6). Voltage-clamp recordings showed that Ito,f was 30% greater in myocytes from the apex than base which may account for the absence of DR in Kv4.2DN mice. Thus, dispersion of repolarization (DR) appears to be an important determinant of arrhythmia vulnerability

Action Potential Duration Dispersion and Alternans in Simulated Heterogeneous Cardiac Tissue with a Structural Barrier

Structural barriers to wave propagation in cardiac tissue are associated with a decreased threshold for repolarization alternans both experimentally and clinically. Using computer simulations, we investigated the effects of a structural barrier on the onset of spatially concordant and discordant alternans. We used two-dimensional tissue geometry with heterogeneity in selected potassium conductances to mimic known apex-base gradients. Although we found that the actual onset of alternans was similar with and without the structural barrier, the increase in alternans magnitude with faster pacing was steeper with the barrier—giving the appearance of an earlier alternans onset in its presence. This is consistent with both experimental structural barrier findings and the clinical observation of T-wave alternans occurring at slower pacing rates in patients with structural heart disease. In ionically homogeneous tissue, discordant alternans induced by the presence of the structural barrier arose at intermediate pacing rates due to a source-sink mismatch behind the barrier. In heterogeneous tissue, discordant alternans occurred during fast pacing due to a barrier-induced decoupling of tissue with different restitution properties. Our results demonstrate a causal relationship between the presence of a structural barrier and increased alternans magnitude and action potential duration dispersion, which may contribute to why patients with structural heart disease are at higher risk for ventricular tachyarrhythmias