Atrial fibrillation is a rhythm disorder characterized by chaotic electrical activity of cardiac atria. Predisposing to stroke and heart failure, this common condition is increasingly recognized as a heritable disorder. To identify genetic defects conferring disease susceptibility, patients with idiopathic atrial fibrillation, lacking traditional risk factors, were evaluated. Genomic DNA scanning revealed a nonsense mutation in KCNA5 that encodes Kv1.5, a voltage-gated potassium channel expressed in human atria. The heterozygous E375X mutation, present in a familial case of atrial fibrillation and absent in 540 unrelated control individuals, introduced a premature stop codon disrupting the Kv1.5 channel protein. The truncation eliminated the S4–S6 voltage sensor, pore region and C-terminus, preserving the N-terminus and S1–S3 transmembrane domains that secure tetrameric subunit assembly. Heterologously expressed recombinant E375X mutant failed to generate the ultrarapid delayed rectifier current I_Kur vital for atrial repolarization and exerted a dominant-negative effect on wild-type current. Loss of channel function translated into action potential prolongation and early after-depolarization in human atrial myocytes, increasing vulnerability to stress-provoked triggered activity. The pathogenic link between compromised Kv1.5 function and susceptibility to atrial fibrillation was verified, at the organism level, in a murine model. Rescue of the genetic defect was achieved by aminoglycoside-induced translational read-through of the E375X premature stop codon, restoring channel function. This first report of Kv1.5 loss-of-function channelopathy establishes KCNA5 mutation as a novel risk factor for repolarization deficiency and atrial fibrillation.

Members of the transforming growth factor pβ (TGF‐β) superfamily‐namely, TGF‐β and BMP2—applied to undifferentiated murine embryonic stem cells up‐regulated mRNA of mesodermal (Brachyury) and cardiac specific transcription factors (Nkx2.5, MEF2C). Embryoid bodies generated from stem cells primed with these growth factors demonstrated an increased potential for cardiac differentiation with a significant increase in beating areas and enhanced myofibrillogenesis. In an environment of postmitotic cardiomyocytes, stem cells engineered to express a fluorescent protein under the control of a cardiac promoter differentiated into fluorescent ventricular myocytes beating in synchrony with host cells, a process significantly enhanced by TGF‐β or BMP2. In vitro, disruption of the TGF‐β/BMP signaling pathways by latency‐associated peptide and/or noggin prevented differentiation of stem cells. In fact, only host cells that secrete a TGF‐β family member induced a cardiac phenotype in stem cells. In vivo, transplantation of stem cells into heart also resulted in cardiac differentiation provided that TGF‐β/BMP2 signaling was intact. In infarcted myocardium, grafted stem cells differentiated into functional cardiomyocytes integrated with surrounding tissue, improving contractile performance. Thus, embryonic stem cells are directed to differentiate into cardiomyocytes by signaling mediated through TGF‐β/BMP2, a cardiac paracrine pathway required for therapeutic benefit of stem cell transplantation in diseased heart.—Behfar, A., Zingman, L. V., Hodgson, D. M., Rauzier, J.‐M., Kane, G. C., Terzic, A., Pucéat, M. Stem cell differentiation requires a paracrine pathway in the heart. FASEB J . 16, 1558–1566 (2002)

Stress tolerance of the heart requires high-fidelity metabolic sensing by ATP-sensitive potassium (K_ATP) channels that adjust membrane potential–dependent functions to match cellular energetic demand. Scanning of genomic DNA from individuals with heart failure and rhythm disturbances due to idiopathic dilated cardiomyopathy identified two mutations in ABCC9, which encodes the regulatory SUR2A subunit of the cardiac K_ATP channel. These missense and frameshift mutations mapped to evolutionarily conserved domains adjacent to the catalytic ATPase pocket within SUR2A. Mutant SUR2A proteins showed aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle, translating into abnormal K_ATP channel phenotypes with compromised metabolic signal decoding. Defective catalysis-mediated pore regulation is thus a mechanism for channel dysfunction and susceptibility to dilated cardiomyopathy.

Atrial fibrillation is a common arrhythmia that is hereditary in a small subgroup of patients. In a family with 11 clinically affected members, we mapped an atrial fibrillation locus to chromosome 1p36-p35 and identified a heterozygous frameshift mutation in the gene encoding atrial natriuretic peptide. Circulating chimeric atrial natriuretic peptide (ANP) was detected in high concentration in subjects with the mutation, and shortened atrial action potentials were seen in an isolated heart model, creating a possible substrate for atrial fibrillation. This report implicates perturbation of the atrial natriuretic peptide–cyclic guanosine monophosphate (cGMP) pathway in cardiac electrical instability.

Transduction of energetic signals into membrane electrical events governs vital cellular functions, ranging from hormone secretion and cytoprotection to appetite control and hair growth. Central to the regulation of such diverse cellular processes are the metabolism sensing ATP-sensitive K ⁺ (K _ATP ) channels. However, the mechanism that communicates metabolic signals and integrates cellular energetics with K _ATP channel-dependent membrane excitability remains elusive. Here, we identify that the response of K _ATP channels to metabolic challenge is regulated by adenylate kinase phosphotransfer. Adenylate kinase associates with the K _ATP channel complex, anchoring cellular phosphotransfer networks and facilitating delivery of mitochondrial signals to the membrane environment. Deletion of the adenylate kinase gene compromised nucleotide exchange at the channel site and impeded communication between mitochondria and K _ATP channels, rendering cellular metabolic sensing defective. Assigning a signal processing role to adenylate kinase identifies a phosphorelay mechanism essential for efficient coupling of cellular energetics with K _ATP channels and associated functions.

Reaction to stress requires feedback adaptation of cellular functions to secure a response without distress, but the molecular order of this process is only partially understood. Here, we report a previously unrecognized regulatory element in the general adaptation syndrome. Kir6.2, the ion-conducting subunit of the metabolically responsive ATP-sensitive potassium (K _ATP ) channel, was mandatory for optimal adaptation capacity under stress. Genetic deletion of Kir6.2 disrupted K _ATP channel-dependent adjustment of membrane excitability and calcium handling, compromising the enhancement of cardiac performance driven by sympathetic stimulation, a key mediator of the adaptation response. In the absence of Kir6.2, vigorous sympathetic challenge caused arrhythmia and sudden death, preventable by calcium-channel blockade. Thus, this vital function identifies a physiological role for K _ATP channels in the heart.