Mutant ANP induces mitochondrial and ion channel remodeling in a human iPSC-derived atrial fibrillation model.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) can model heritable arrhythmias to personalize therapies for individual patients. Although atrial fibrillation (AF) is a leading cause of cardiovascular morbidity and mortality, current platforms to generate iPSC-atrial (a) CMs are inadequate for modeling AF. We applied a combinatorial engineering approach, which integrated multiple physiological cues, including metabolic conditioning and electrical stimulation, to generate mature iPSC-aCMs. Using the patient's own atrial tissue as a gold standard benchmark, we assessed the electrophysiological, structural, metabolic, and molecular maturation of iPSC-aCMs. Unbiased transcriptomic analysis and inference from gene regulatory networks identified key gene expression pathways and transcription factors mediating atrial development and maturation. Only mature iPSC-aCMs generated from patients with heritable AF carrying the non-ion channel gene (NPPA) mutation showed enhanced expression and function of a cardiac potassium channel and revealed mitochondrial electron transport chain dysfunction. Collectively, we propose that ion channel remodeling in conjunction with metabolic defects created an electrophysiological substrate for AF. Overall, our electro-metabolic approach generated mature human iPSC-aCMs that unmasked the underlying mechanism of the first non-ion channel gene, NPPA, that causes AF. Our maturation approach will allow for the investigation of the molecular underpinnings of heritable AF and the development of personalized therapies.

Current and future therapy for pulmonary hypertension in patients with right and left heart failure.

Pulmonary hypertension (PH) is a devastating condition that without proper management can deteriorate progressively. Elevated pulmonary artery pressure without an identifiable etiology is called IPAH. PH resulting from a specific disease is referred to as secondary PH; left-sided cardiac disease can lead to an increase in pulmonary artery pressure resulting in increased vascular resistance and subsequent structural remodeling. If left-sided failure progresses to right-sided failure with high pulmonary artery pressure, the outcome is ominous. It has been clearly proven that early diagnosis and effective medical therapy can markedly decrease morbidity and mortality. In this review, we discuss the current treatment modalities and their limitations for PH secondary to heart failure. Conventional therapy in patients with pulmonary arterial hypertension as well as recent advances in the medical management of PH in general, are also described. Last, the surgical management of these patients and other promising interventional modalities are reviewed.