A guinea-pig model of cardiac injury is used to show that human embryonic stem-cell-derived cardiomyocyte grafts can electrically integrate into the injured heart, improving mechanical function and reducing spontaneous and induced ventricular tachycardia; this is a major step towards clinical adoption of cell replacement therapies for cardiovascular diseases using human cardiomyocytes. This study extends previous findings that transplantation of fetal cardiomyocytes can improve the function of infarcted hearts, despite having only a modest effect on the organ's mechanical properties. The investigators developed a guinea pig model of cardiac injury, because the heart rate of these animals is at the upper end of what is tolerable to human cardiomyocytes, and much lower than that of the mice and rats often used as models. The authors show that cardiomyocytes derived from human embryonic stem cells can integrate electrically into the guinea pig heart and protect against arrhythmias. This is the first convincing evidence that cardiomyocytes generated from cultured human embryonic stem cells can integrate into the adult heart, and is therefore a major step towards the clinical adoption of cell-replacement therapies for cardiovascular disease. Transplantation studies in mice and rats have shown that human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts1,2,3, but two critical issues related to their electrophysiological behaviour in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear whether these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea-pig model to show that hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia. To assess the activity of hESC-CM grafts in vivo, we transplanted hESC-CMs expressing the genetically encoded calcium sensor, GCaMP3 (refs 4, 5). By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host–graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair.

Background: Phthalates are common plasticizers present in medical-grade plastics and other everyday products. They can also act as endocrine-disrupting chemicals and have been linked to the rise in metabolic disorders. However, the effect of phthalates on cardiac metabolism remains largely unknown. Objectives: We examined the effect of di(2-ethylhexyl)phthalate (DEHP) on the metabolic profile of cardiomyocytes because alterations in metabolic processes can lead to cell dysfunction. Methods: Neonatal rat cardiomyocytes were treated with DEHP at a concentration and duration comparable to clinical exposure (50–100 μg/mL, 72 hr). We assessed the effect of DEHP on gene expression using microarray analysis. Physiological responses were examined via fatty acid utilization, oxygen consumption, mitochondrial mass, and Western blot analysis. Results: Exposure to DEHP led to up-regulation of genes associated with fatty acid transport, esterification, mitochondrial import, and β-oxidation. The functional outcome was an increase in myocyte fatty acid–substrate utilization, oxygen consumption, mitochondrial mass, PPARα (peroxisome proliferator-activated receptor α) protein expression, and extracellular acidosis. Treatment with a PPARα agonist (Wy-14643) only partially mimicked the effects observed in DEHP-treated cells. Conclusions: Data suggest that DEHP exposure results in metabolic remodeling of cardiomyocytes, whereby cardiac cells increase their dependence on fatty acids for energy production. This fuel switch may be regulated at both the gene expression and posttranscription levels. Our findings have important clinical implications because chronic dependence on fatty acids is associated with an accumulation in lipid intermediates, lactate, protons, and reactive oxygen species. This dependence can sensitize the heart to ischemic injury and ventricular dysfunction.

Optical mapping of Ca²⁺-sensitive fluorescence probes has become an extremely useful approach and adopted by many cardiovascular research laboratories to study a spectrum of myocardial physiology and disease conditions. Optical mapping data are often displayed as detailed pseudocolor images, providing unique insight for interpreting mechanisms of ectopic activity, action potential and Ca²⁺transient alternans, tachycardia, and fibrillation. Ca²⁺-sensitive fluorescent probes and optical mapping systems continue to evolve in the ongoing effort to improve therapies that ease the growing worldwide burden of cardiovascular disease. In this technical review we provide an updated overview of conventional approaches for optical mapping of Ca_i²⁺within intact myocardium. In doing so, a brief history of Ca_i²⁺probes is provided, and nonratiometric and ratiometric Ca²⁺probes are discussed, including probes for imaging sarcoplasmic reticulum Ca²⁺and probes compatible with potentiometric dyes for dual optical mapping. Typical measurements derived from optical Ca_i²⁺signals are explained, and the analytics used to compute them are presented. Last, recent studies using Ca_i²⁺optical mapping to study arrhythmias, heart failure, and metabolic perturbations are summarized.