Albert Y. Sun

A VGF-Derived Peptide Attenuates Development of Type 2 Diabetes via Enhancement of Islet β-Cell Survival and Function

Deterioration of functional islet β-cell mass is the final step in progression to Type 2 diabetes. We previously reported that overexpression of Nkx6.1 in rat islets has the dual effects of enhancing glucose-stimulated insulin secretion (GSIS) and increasing β-cell replication. Here we show that Nkx6.1 strongly upregulates the prohormone VGF in rat islets and that VGF is both necessary and sufficient for Nkx6.1-mediated enhancement of GSIS. Moreover, the VGF-derived peptide TLQP-21 potentiates GSIS in rat and human islets and improves glucose tolerance in vivo. Chronic injection of TLQP-21 in prediabetic ZDF rats preserves islet mass and slows diabetes onset. TLQP-21 prevents islet cell apoptosis by a pathway similar to that used by GLP-1, but independent of the GLP-1, GIP, or VIP receptors. Unlike GLP-1, TLQP-21 does not inhibit gastric emptying or increase heart rate. We conclude that TLQP-21 is a targeted agent for enhancing islet β-cell survival and function.

Outcomes of Atrioesophageal Fistula Following Catheter Ablation of Atrial Fibrillation Treated with Surgical Repair versus Esophageal Stenting: Management of Atrioesophageal Fistula Post-AF Ablation

Atrioesophageal fistula (AEF) is a rare but devastating complication of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). Surgical repair and esophageal stents are available treatment options for AEF. We report outcomes of these 2 management strategies.

The S1103Y Cardiac Sodium Channel Variant Is Associated With Implantable Cardioverter-Defibrillator Events in Blacks With Heart Failure and Reduced Ejection Fraction

Background—Risk-stratifying heart failure patients for primary prevention implantable cardioverter-defibrillators (ICDs) remains a challenge, especially for blacks, who have an increased incidence of sudden cardiac death but have been underrepresented in clinical trials. We hypothesized that the S1103Y cardiac sodium channel SCN5A variant influences the propensity for ventricular arrhythmias in black patients with heart failure and reduced ejection fraction. Methods and Results—Blacks (n=112) with ejection fractions <35% receiving primary prevention ICDs were identified from the Duke Electrophysiology Genetic and Genomic Studies (EPGEN) biorepository and followed for appropriate ICD therapy (either anti tachycardia pacing or shock) for documented sustained ventricular tachycardia or fibrillation. The S1103Y variant was overrepresented in patients receiving appropriate ICD therapy compared with subjects who did not (35% versus 13%, P=0.03). Controlling for baseline characteristics, the adjusted hazard ratio using a Cox proportional hazard model for ICD therapy in Y1103 allele carriers was 4.33 (95% confidence interval, 1.60 to 11.73, P=<0.01). There was no difference in mortality between carriers and noncarriers. Conclusions—This is the first report that the S1103Y variant is associated with a higher incidence of ventricular arrhythmias in blacks with heart failure and reduced ejection fraction.

Dissection of a Quantitative Trait Locus for PR Interval Duration Identifies Tnni3k as a Novel Modulator of Cardiac Conduction

Atrio-ventricular conduction disease is a common feature in Mendelian rhythm disorders associated with sudden cardiac death and is characterized by prolongation of the PR interval on the surface electrocardiogram (ECG). Prolongation of the PR interval is also a strong predictor of atrial fibrillation, the most prevalent sustained cardiac arrhythmia. Despite the significant genetic component in PR duration variability, the genes regulating PR interval duration remain largely elusive. We here aimed to dissect the quantitative trait locus (QTL) for PR interval duration that we previously mapped in murine F2 progeny of a sensitized 129P2 and FVBN/J cross. To determine the underlying gene responsible for this QTL, genome-wide transcriptional profiling was carried out on myocardial tissue from 109 F2 mice. Expression QTLs (eQTLs) were mapped and the PR interval QTL was inspected for the co-incidence of eQTLs. We further determined the correlation of each of these transcripts to the PR interval. Tnni3k was the only eQTL, mapping to the PR-QTL, with an established abundant cardiac-specific expression pattern and a significant correlation to PR interval duration. Genotype inspection in various inbred mouse strains revealed the presence of at least three independent haplotypes at the Tnni3k locus. Measurement of PR interval duration and Tnni3k mRNA expression levels in six inbred lines identified a positive correlation between the level of Tnni3k mRNA and PR interval duration. Furthermore, in DBA/2J mice overexpressing hTNNI3K, and in DBA.AKR.hrtfm2 congenic mice, which harbor the AKR/J “high-Tnni3k expression” haplotype in the DBA/2J genetic background, PR interval duration was prolonged as compared to DBA/2J wild-type mice (“low-Tnni3k expression” haplotype). Our data provide the first evidence for a role of Tnni3k in controlling the electrocardiographic PR interval indicating a function of Tnni3k in atrio-ventricular conduction.

Race, common genetic variation, and therapeutic response disparities in heart failure.

Because of its comparatively recent evolution, Homo sapiens exhibit relatively little within-species genomic diversity. However, because of genome size, a proportionately small amount of variation creates ample opportunities for both rare mutations that may cause disease as well as more common genetic variations that may be important in disease modification or pharmacogenetics. Primarily because of the East African origin of modern humans, individuals of African ancestry (AA) exhibit greater degrees of genetic diversity than more recently established populations, such as those of European ancestry (EA) or Asian ancestry. Those population effects extend to differences in frequency of common gene variants that may be important in heart failure natural history or therapy. For cell-signaling mechanisms important in heart failure, we review and present new data for genetic variation between AA and EA populations. Data indicate that: 1) neurohormonal signaling mechanisms frequently (16 of the 19 investigated polymorphisms) exhibit racial differences in the allele frequencies of variants comprising key constituents; 2) some of these differences in allele frequency may differentially affect the natural history of heart failure in AA compared with EA individuals; and 3) in many cases, these differences likely play a role in observed racial differences in drug or device response.

STIM1–Ca2+ signaling modulates automaticity of the mouse sinoatrial node

Significance Each heartbeat originates in the sinoatrial node (SAN), a collection of specialized cardiomyocytes (SANCs), which exhibit rhythmic action potentials and spontaneous Ca2+ transients. We have found that the Ca2+ sensor protein stromal interaction molecule 1 (STIM1) is enriched in the SANCs. Here we show that STIM1 Ca2+ signaling is important in SANCs to maintain the Ca2+ content of intracellular Ca2+ stores and that this contributes to maintaining the regular sinus rhythm of the heart. Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca2+ release from internal Ca2+ stores (Ca2+ clock) to adjust heart rate to meet hemodynamic demand. Here, we report that stromal interaction molecule 1 (STIM1) and Orai1 channels, key components of store-operated Ca2+ entry, are selectively expressed in SANCs. Cardiac-specific deletion of STIM1 in mice resulted in depletion of sarcoplasmic reticulum (SR) Ca2+ stores of SANCs and led to SAN dysfunction, as was evident by a reduction in heart rate, sinus arrest, and an exaggerated autonomic response to cholinergic signaling. Moreover, STIM1 influenced SAN function by regulating ionic fluxes in SANCs, including activation of a store-operated Ca2+ current, a reduction in L-type Ca2+ current, and enhancing the activities of Na+/Ca2+ exchanger. In conclusion, these studies reveal that STIM1 is a multifunctional regulator of Ca2+ dynamics in SANCs that links SR Ca2+ store content with electrical events occurring in the plasma membrane, thereby contributing to automaticity of the SAN.

Predictors of mortality in patients with chronic kidney disease and an implantable defibrillator: an EPGEN substudy.

AIMS Chronic kidney disease (CKD) is increasingly prevalent, and is an independent risk factor for cardiovascular mortality. Clinical trials of the implantable cardioverter-defibrillator (ICD) have demonstrated a survival benefit over medical therapy for the prevention of sudden cardiac death, but its benefit in patients with concomitant CKD is unclear. METHODS AND RESULTS We studied 199 subjects with CKD, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2), who underwent ICD implantation in the Duke Electrophysiology Genetic and Genomic Studies (EPGEN) biorepository. The mean age of the cohort was 67.8 ± 9.3 years, and the mean eGFR was 41.1 ± 13.2 mL/min/1.73 m(2). There were 63 deaths over a mean follow-up of 31.1 ± 18.8 months, corresponding to an annual mortality rate of 12.2%. Additionally, there was a 7% annual rate of appropriate ICD therapy. Using Cox regression analysis, older age, lower ejection fraction, and lower eGFR were found to be significant predictors of mortality. There was a gradient of risk associated with lower renal function: a 10 mL/min reduction in eGFR conferred a 48% increase in the risk of death (P < 0.001). Further adjustment for appropriate ICD therapy did not modify these associations. CONCLUSION In patients with CKD treated with a defibrillator, more advanced renal dysfunction is associated with reduced survival despite appropriate defibrillator therapy. This may be due to competing mortality risks in this population that attenuate the benefit of the ICD in reducing arrhythmic death. Age, ejection fraction, and kidney disease severity can be used to risk stratify patients before device implantation.

Rationale and design of the Duke Electrophysiology Genetic and Genomic Studies (EPGEN) biorepository

BACKGROUND Disturbances in cardiac rhythm can lead to significant morbidity and mortality. Many arrhythmias are known to have a heritable component, but the degree to which genetic variation contributes to disease risk and morbidity is poorly understood. METHODS AND RESULTS The EPGEN is a prospective single-center repository that archives DNA, RNA, and protein samples obtained at the time of an electrophysiologic evaluation or intervention. To identify genes and molecular variants that are associated with risk for arrhythmic phenotypes, EPGEN uses unbiased genomic screening; candidate gene analysis; and both unbiased and targeted transcript, protein, and metabolite profiling. To date, EPGEN has successfully enrolled >1,500 subjects. The median age of the study population is 62.9 years; 35% of the subjects are female and 21% are black. To this point, the study population has been composed of patients who had undergone defibrillator (implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator) implantation (45%), electrophysiology studies or ablation procedures (35%), and pacemaker implantation or other procedures (20%). The cohort has a high prevalence of comorbidities, including diabetes (33%), hypertension (73%), chronic kidney disease (26%), and peripheral vascular disease (13%). CONCLUSIONS We have established a biorepository and clinical database composed of patients with electrophysiologic diseases. EPGEN will seek to (1) improve risk stratification, (2) elucidate mechanisms of arrhythmogenesis, and (3) identify novel pharmacologic targets for the treatment of heart rhythm disorders.

Pinning down the CaMKII targets in the L-type Ca2+ channel: An essential step in defining CaMKII regulation

With each heartbeat, intracellular Ca2+ in a myocyte transiently increases about 10-fold, from ~ 100 nM to a peak of ~ 1 μM. In subcellular domains, such as near the mouth of an L-type Ca2+ channel (LTCC), the peak is even higher. These rapid oscillations in Ca2+, commencing with Ca2+ entry through the LTCC that in turn triggers the release of intracellular Ca2+ stores from the sarcoplasmic reticulum via the ryanodine receptor type 2, are central to excitation–contraction coupling. In the midst of these large beat-to-beat changes in internal Ca2+, comparatively subtle Ca2+ signals control so much more than excitation–contraction coupling. A decade of research has shown that Ca2+ signals also trigger arrhythmogenic afterdepolarizations, initiate gene expression that leads to hypertrophy, and induce apoptosis. So, how does Ca2+ control all this among the waves of the beat-to-beat Ca2+ changes driving excitation–contraction coupling?

Stellate ganglion blockade for the treatment of refractory ventricular arrhythmias: A systematic review and meta-analysis: FUDIM et al .

Treatment refractory ventricular arrhythmias (VAs) are often driven and exacerbated by heightened sympathetic tone. We aim to conduct a systematic review and meta‐analysis of published studies of a temporary percutaneous stellate ganglion block (SGB) on VA burden and defibrillation episodes in patients with treatment refractory VAs.