Directed differentiation protocols enable derivation of cardiomyocytes from human pluripotent stem cells (hPSC) and permit engineering of human myocardium in vitro. However, hPSC-derived cardiomyocytes are reflective of very early human development, limiting their utility in the generation of in vitro models of mature myocardium. Here, we developed a new platform that combines three-dimensional cell cultivation in a microfabricated system with electrical stimulation to mature hPSC-derived cardiac tissues. We utilized quantitative structural, molecular and electrophysiological analyses to elucidate the responses of immature human myocardium to electrical stimulation and pacing. We demonstrated that the engineered platform allowed for the generation of 3-dimensional, aligned cardiac tissues (biowires) with frequent striations. Biowires submitted to electrical stimulation markedly increased myofibril ultrastructural organization, displayed elevated conduction velocity and altered both the electrophysiological and Ca2+ handling properties versus non-stimulated controls. These changes were in agreement with cardiomyocyte maturation and were dependent on the stimulation rate.

We report the fabrication of a scaffold (hereafter referred to as AngioChip) that supports the assembly of parenchymal cells on a mechanically tunable matrix surrounding a perfusable, branched, three-dimensional microchannel network coated with endothelial cells. The design of AngioChip decouples the material choices for the engineered vessel network and for cell seeding in the parenchyma, enabling extensive remodelling while maintaining an open-vessel lumen. The incorporation of nanopores and micro-holes in the vessel walls enhances permeability, and permits intercellular crosstalk and extravasation of monocytes and endothelial cells on biomolecular stimulation. We also show that vascularized hepatic tissues and cardiac tissues engineered by using AngioChips process clinically relevant drugs delivered through the vasculature, and that millimeter-thick cardiac tissues can be engineered in a scalable manner. Moreover, we demonstrate that AngioChip cardiac tissues implanted via direct surgical anastomosis to the femoral vessels of rat hindlimbs establish immediate blood perfusion.

Significance Robust and predictive in vitro models of human cardiac tissue function could have transformative impact on our ability to test new drugs and understand cardiac disease. Despite significant effort, the generation of high-fidelity adult-like human cardiac tissue analogs remains challenging. In this paper, we systematically explore the design criteria for pluripotent stem cell-derived engineered cardiac tissue. Parameters such as biomechanical stress during tissue remodeling, input-cell composition, electrical stimulation, and tissue geometry are evaluated. Our results suggest that a specified combination of a 3D matrix-based microenvironment, uniaxial mechanical stress, and mixtures of cardiomyocytes and fibroblasts improves the performance and maturation state of in vitro engineered cardiac tissue.

Summary Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) show considerable promise for regenerating injured hearts, and we therefore tested their capacity to stably engraft in a translationally relevant preclinical model, the infarcted pig heart. Transplantation of immature hESC-CMs resulted in substantial myocardial implants within the infarct scar that matured over time, formed vascular networks with the host, and evoked minimal cellular rejection. While arrhythmias were rare in infarcted pigs receiving vehicle alone, hESC-CM recipients experienced frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. Electroanatomical mapping and pacing studies implicated focal mechanisms, rather than macro-reentry, for these graft-related tachyarrhythmias as evidenced by an abnormal centrifugal pattern with earliest electrical activation in histologically confirmed graft tissue. These findings demonstrate the suitability of the pig model for the preclinical development of a hESC-based cardiac therapy and provide new insights into the mechanistic basis of electrical instability following hESC-CM transplantation.

Background-Atrial fibrillation (AF) may recur after pulmonary vein isolation (PVI) as the result of either recurrent PV conduction or non-PV foci. This study characterized the electrophysiological findings of patients with recurrent AF after initially successful PVI and the clinical outcome after a repeat procedure. Methods and Results-Among 185 patients undergoing PVI, 52 reported no significant improvement in their clinical course. We analyzed PV conduction in 51 PVs (15 patients) at repeat PVI. All PVs were isolated with either RF (30 W, 50°C, 60 seconds) or cryoablation (Ϫ80°C for 5 minutes). At repeat study, 42 of the previously isolated 51 PVs had return of conduction. All patients had recurrent conduction in Ն2 PVs, with only 1 non-PV focus identified. The mean number of RF applications required to re-isolate the PVs was fewer at the repeat compared with the initial procedure (10Ϯ6 versus 4Ϯ2, PϽ0.005). Over a period of 15Ϯ6 months, all but 1 patient was clinically improved by the second procedure. Conclusions-In patients with recurrent AF after PVI, return of PV conduction can be expected. Repeat PVI provides significant clinical benefit for these patients. These results suggest that if permanent PV isolation is the ablation strategy, different techniques may be required to improve long-term efficacy.

BackgroundThe cardiovascular complications of cancer therapeutics are the focus of the burgeoning field of cardio‐oncology. A common challenge in this field is the impact of cancer drugs on cardiac repolarization (ie, QT prolongation) and the potential risk for the life‐threatening arrhythmia torsades de pointes. Although QT prolongation is not a perfect marker of arrhythmia risk, this has become a primary safety metric among oncologists. Cardiologists caring for patients receiving cancer treatment should become familiar with the drugs associated with QT prolongation, its incidence, and appropriate management strategies to provide meaningful consultation in this complex clinical scenario.Methods and ResultsIn this article, we performed a systematic review (using Preferred Reporting Items of Systematic Reviews and Meta‐Analyses (PRISMA) guidelines) of commonly used cancer drugs to determine the incidence of QT prolongation and clinically relevant arrhythmias. We calculated summary estimates of the incidence of all and clinically relevant QT prolongation as well as arrhythmias and sudden cardiac death. We then describe strategies to prevent, identify, and manage QT prolongation in patients receiving cancer therapy. We identified a total of 173 relevant publications. The weighted incidence of any corrected QT (QTc) prolongation in our systematic review in patients treated with conventional therapies (eg, anthracyclines) ranged from 0% to 22%, although QTc >500 ms, arrhythmias, or sudden cardiac death was extremely rare. The risk of QTc prolongation with targeted therapies (eg, small molecular tyrosine kinase inhibitors) ranged between 0% and 22.7% with severe prolongation (QTc >500 ms) reported in 0% to 5.2% of the patients. Arrhythmias and sudden cardiac death were rare.ConclusionsOur systematic review demonstrates that there is variability in the incidence of QTc prolongation of various cancer drugs; however, the clinical consequence, as defined by arrhythmias or sudden cardiac death, remains rare.

Atrial fibrillation (AF) is the most common supraventricular arrhythmia that, for unknown reasons, is linked to intense endurance exercise. Our studies reveal that 6 weeks of swimming or treadmill exercise improves heart pump function and reduces heart-rates. Exercise also increases vulnerability to AF in association with inflammation, fibrosis, increased vagal tone, slowed conduction velocity, prolonged cardiomyocyte action potentials and RyR2 phosphorylation (CamKII-dependent S2814) in the atria, without corresponding alterations in the ventricles. Microarray results suggest the involvement of the inflammatory cytokine, TNFα, in exercised-induced atrial remodelling. Accordingly, exercise induces TNFα-dependent activation of both NFκB and p38MAPK, while TNFα inhibition (with etanercept), TNFα gene ablation, or p38 inhibition, prevents atrial structural remodelling and AF vulnerability in response to exercise, without affecting the beneficial physiological changes. Our results identify TNFα as a key factor in the pathology of intense exercise-induced AF.

Phase is a descriptor that tracks the progression of a defined region of myocardium through the action potential and has been demonstrated to be an effective parameter in analyzing spatiotemporal changes during fibrillation. In this review, the basic principles behind phase mapping are presented mainly in the context of ventricular fibrillation (VF), atrial fibrillation (AF), and fibrillation from experimental monolayer data. During fibrillation, the phase distribution changes over time, depending on activation patterns. Analyzing these phase patterns provides us insight into the fibrillatory dynamics and helps clarify the mechanisms of cardiac fibrillation and modulation by interventions. Winfree 1 introduced the phase analysis to study cardiac fibrillation in the late eighties. This time-encoding technique deals with a scenario where the activation periods are the same over the surface being mapped. To deal with the scenario of varying activation period over the mapped surface (common in animal and human fibrillation models), Gray et al 2,3 introduced the state-space encoding concept from nonlinear dynamics.In analyzing spatiotemporal phase maps constructed from electric or optical mapping of the surface of heart during VF, points around which the phase progresses through a complete cycle from Ϫ to ϩ are of great interest. At these points, the phase becomes indeterminate and the activation wave fronts hinge to these points and rotate around them in an organized fashion. These points in the phase map are called phase singularity (PS) points. Bray et al 4 developed a procedure to locate PS points in a phase map. Nash et al 5 used phase mapping to study the entire ventricular epicardium of human hearts with a sock containing 256 unipolar contact electrodes. The development of this phase mapping tool has led to better understanding of fibrillation dynamics as evidenced by the use of phase mapping in detecting PS and their role in demonstrating organization during VF. Some of these works and their findings are (1) PS colocalize with anatomic heterogeneities, and their spatial meandering is modulated by these heterogeneities, 6 (2) PS correlates with the locations of wave breaks, 7 (3) in myopathic human hearts, phase maps were used to show that the organization of electric activity were characterized by wave fronts emanating from a few rotors, 8 and (4) phase mapping technique has also been applied to investigate the mechanism of fibrillation. 7-9 Clinical electrophysiologists innovating therapies for both AF and VF are commonly not aware of phase mapping. This review addresses this shortcoming with the hope that by introducing the basic concepts of phase mapping to a greater audience, there will be an opportunity to devise therapies for these arrhythmias on a mechanistic basis.