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1.  Calcium-Activated Potassium Current Modulates Ventricular Repolarization in Chronic Heart Failure 
PLoS ONE  2014;9(10):e108824.
The role of IKCa in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of IKCa blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The IKCa blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n = 5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n = 7). A group of age-matched canine controls were used (n = 8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by IKCa blockade in all of the groups studied. IKCa blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. IKCa blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, IKCa blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for IKCa in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.
PMCID: PMC4182742  PMID: 25271970
2.  A Promoter Polymorphism of the Endothelial Nitric Oxide Synthase Gene is Associated with Reduced mRNA and Protein Expression in Failing Human Myocardium 
Journal of cardiac failure  2010;16(4):314-319.
Alterations of endothelial nitric oxide synthase (eNOS) enzyme activity via eNOS gene polymorphisms have been associated with significant cardiovascular morbidity and mortality. Both the thymidine to cytosine transition mutation (T−786→C) in the promoter region and the missense mutation in the exon 7 coding region of the eNOS gene (G894→T) have been associated with several cardiovascular disease states. We hypothesized that heart transplant recipients who carried at least one allele of either of the polymorphisms would have reduced myocardial tissue expression of eNOS measured in the explanted heart.
Genomic DNA was isolated from myocardial tissue samples obtained from 43 explanted human hearts using standard methods. Regions of the eNOS gene were amplified from genomic DNA with a polymerase chain reaction using specific primers. Protein expression of eNOS was measured by Western blot analysis. There was a statistically significant decrease in mean eNOS expression in samples containing at least one allele for the T−786→C promoter polymorphism (p = 0.04) compared to patients homozygous for the T allele. There was no change in eNOS expression associated with the G894→T exonic polymorphisms. Conclusions: Our data show in failing human myocardium that the T−786→C promoter polymorphism is associated with reduced eNOS expression whereas the G894→T polymorphism of exon 7 is not associated with change in either eNOS mRNA or protein expression. Reduced eNOS expression associated with the promoter polymorphism may contribute to the vascular, contractile, and autonomic responses to ventricular failure.
PMCID: PMC2848179  PMID: 20350698
Nitric Oxide; Genetics; Cardiomyopathy; Pharmacogenetics
3.  Statin Pharmacogenomics: Pursuing Biomarkers for Predicting Clinical Outcomes 
Discovery medicine  2013;16(86):45-51.
Indicated for treating hyperlipidemias and for the prevention of cardiovascular disease (CVD), statins rank among the most commonly prescribed drug classes. While statins are considered to be highly effective in preventing atherosclerotic events, a substantial portion of treated patients still progress to overt CVD. Genetic factors are thought to contribute substantially to treatment outcome. Several candidate genes have been associated with statin dose requirements and treatment outcomes, but a clinically relevant pharmacogenomics test to guide statin therapy has not yet emerged. Here we define basic pharmacogenomics terminology, present strong candidate genes (CETP, HMGCR, SLCO1B1, ABCB1, and CYP3A4/5), and discuss the challenges in developing much-needed statin pharmacogenomics biomarkers for predicting treatment outcomes.
PMCID: PMC4039562  PMID: 23911231
5.  CaMKII-Based Regulation of Voltage-Gated Na+ Channel in Cardiac Disease 
Circulation  2012;126(17):10.1161/CIRCULATIONAHA.112.105320.
Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked with potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia variants remains undefined despite over a decade of investigation. Post-translational modulation of membrane proteins is essential for normal cardiac function. Importantly, aberrant myocyte signaling has been linked to defects in cardiac ion channel post-translational modifications and disease. We recently identified a novel pathway for post-translational regulation of the primary cardiac voltage-gated Na+ channel (Nav1.5) by CaMKII. However, a role for this pathway in cardiac disease has not been evaluated.
Methods and Results
We evaluated the role of CaMKII-dependent phosphorylation in human genetic and acquired disease. We report an unexpected link between a short motif in the Nav1.5 DI-DII loop, recently shown to be critical for CaMKII-dependent phosphorylation, and Nav1.5 function in monogenic arrhythmia and common heart disease. Experiments in heterologous cells and primary ventricular cardiomyocytes demonstrate that human arrhythmia susceptibility variants (A572D and Q573E) alter CaMKII-dependent regulation of Nav1.5 resulting in abnormal channel activity and cell excitability. In silico analysis reveals that these variants functionally mimic the phosphorylated channel resulting in increased susceptibility to arrhythmia-triggering afterdepolarizations. Finally, we report that this same motif is aberrantly regulated in a large animal model of acquired heart disease and in failing human myocardium.
We identify the mechanism for two human arrhythmia variants that affect Nav1.5 channel activity through direct effects on channel post-translational modification. We propose that the CaMKII phosphorylation motif in the Nav1.5 DI-DII cytoplasmic loop is a critical nodal point for pro-arrhythmic changes to Nav1.5 in congenital and acquired cardiac disease.
PMCID: PMC3811023  PMID: 23008441
arrhythmia (mechanisms); calmodulin dependent protein kinase II; heart failure; ion channels; long-QT syndrome; myocardial infarction
6.  The Role of Repeat Transesophageal Echocardiography in Patients without Atrial Thrombus Prior to Cardioversion or Ablation 
Cardioversion (CV) and radiofrequency catheter ablation (RFA) are often used to restore sinus rhythm in patients with atrial fibrillation (AF). These procedures are associated with a risk for stroke. The use of transesophageal echocardiography (TEE) to guide the management of AF is a validated strategy for patients in whom CV is planned, as well patients before RFA. For patients in whom the initial procedure fails, repeat TEE is often performed before repeat CV or RFA. The aim of this study was to test the hypothesis that patients with initial negative results on TEE would be unlikely to have thrombi detected on subsequent TEE and thus may avoid repeat procedures.
A total of 2,999 patients with AF were identified via retrospective review who had undergone TEE before CV or RFA, and 418 of these individuals underwent repeat TEE. After excluding patients who underwent repeat TEE >365 days from the initial study (n= 135) and those with thrombi on initial TEE (n= 20), 263 patients who had underwent two or more examinations were identified and analyzed.
Of 263 eligible patients, two (0.8%; 95% confidence interval,0.21–2.7%)had thrombion subsequent TEE.
Fewer than 1% of patients with AF with negative results on baseline TEE had thrombi detected on repeat TEE before subsequent CV or RFA. Thus, it may be possible to selectively screen patients to identify those at low risk for developing thrombi subsequent to negative results on initial TEE, especially if patients are in sinus rhythm. These results suggest the need for a prospective trial to definitively answer the question regarding repeat TEE in low-risk patients. (J Am Soc Echocardiogr 2012;25:1106-12.)
PMCID: PMC3742543  PMID: 22749434
Atrial fibrillation; Atrial flutter; Electrical cardioversion; Transesophageal echocardiography
7.  Evidence for the Role of Epstein Barr Virus Infections in the Pathogenesis of Acute Coronary Events 
PLoS ONE  2013;8(1):e54008.
The role of viral infections in the pathogenesis of atherosclerosis remains controversial largely due to inconsistent detection of the virus in atherosclerotic lesions. However, viral infections elicit a pro-inflammatory cascade known to be atherogenic and to precipitate acute ischemic events. We have published in vitro data that provide the foundation for a mechanism that reconciles these conflicting observations. To determine the relation between an early viral protein, deoxyuridine triphosphate nucleotidohydrolase (dUTPase), produced following reactivation of Epstein Barr Virus (EBV) to circulating pro-inflammatory cytokines, intercellular adhesion molecule-1 (ICAM-1) and acute coronary events.
Methodology/Principal Findings
Blood samples were obtained from 299 patients undergoing percutaneous coronary intervention for stable angina (SA), unstable angina (UA), or acute myocardial infarction (AMI). Plasma concentrations of pro-inflammatory cytokines and neutralizing antibody against EBV-encoded dUTPase were compared in the three patient groups. AMI was associated with the highest measures of interleukin-6 (ANOVA p<0.05; 4.6±2.6 pg/mL in patients with AMI vs. 3.2±2.3 pg/mL in SA). ICAM-1 was significantly higher in patients with AMI (ANOVA p<0.05; 304±116 pg/mL in AMI vs. 265±86 pg/mL SA). The highest values of ICAM-1 were found in patients having an AMI and who were antibody positive for dUTPase (ANOVA p = 0.008; 369±183 pg/mL in AMI and positive for dUTPase vs. 249±70 pg/mL in SA negative for dUTPase antibody).
These clinical data support a model, based on in vitro studies, by which EBV may precipitate AMI even under conditions of low viral load through the pro-inflammatory action of the early protein dUTPase that is produced even during incomplete viral replication. They further support the putative role of viral infections in the pathogenesis of atherosclerosis and coronary artery events.
PMCID: PMC3547968  PMID: 23349778
8.  Myocardial Viability and Survival in Ischemic Left Ventricular Dysfunction 
The New England Journal of Medicine  2011;364(17):1617-1625.
The assessment of myocardial viability has been used to identify patients with coronary artery disease and left ventricular dysfunction in whom coronary-artery bypass grafting (CABG) will provide a survival benefit. However, the efficacy of this approach is uncertain.
In a substudy of patients with coronary artery disease and left ventricular dysfunction who were enrolled in a randomized trial of medical therapy with or without CABG, we used single-photon-emission computed tomography (SPECT), dobutamine echocardiography, or both to assess myocardial viability on the basis of pre-specified thresholds.
Among the 1212 patients enrolled in the randomized trial, 601 underwent assessment of myocardial viability. Of these patients, we randomly assigned 298 to receive medical therapy plus CABG and 303 to receive medical therapy alone. A total of 178 of 487 patients with viable myocardium (37%) and 58 of 114 patients without viable myocardium (51%) died (hazard ratio for death among patients with viable myocardium, 0.64; 95% confidence interval [CI], 0.48 to 0.86; P = 0.003). However, after adjustment for other baseline variables, this association with mortality was not significant (P = 0.21). There was no significant interaction between viability status and treatment assignment with respect to mortality (P = 0.53).
The presence of viable myocardium was associated with a greater likelihood of survival in patients with coronary artery disease and left ventricular dysfunction, but this relationship was not significant after adjustment for other baseline variables. The assessment of myocardial viability did not identify patients with a differential survival benefit from CABG, as compared with medical therapy alone. (Funded by the National Heart, Lung, and Blood Institute; STICH number, NCT00023595.)
PMCID: PMC3290901  PMID: 21463153
9.  Highly variable mRNA expression and splicing of L-type voltage-dependent calcium channel alpha subunit 1C in human heart tissues 
Pharmacogenetics and genomics  2006;16(10):735-745.
The voltage-dependent L-type calcium channel α-subunit 1c (Cav1.2, CACNA1C) undergoes extensive mRNA splicing, leading to numerous isoforms with different functions. L-type calcium channel blockers are used in the treatment of hypertension and arrhythmias, but response varies between individuals. We have studied the interindividual variability in mRNA expression and splicing of CACNA1C, in 65 heart tissue samples, taken from heart transplant recipients.
Splice variants were measured quantitatively by polymerase chain reaction in 12 splicing loci of CACNA1C mRNA. To search for functional cis-acting polymorphisms, we determined allelic expression ratios for total CACNA1C mRNA and several splice variants using marker single nucleotide polymorphisms in exon 4 and exon 30.
Total CACNA1C mRNA levels varied ∼50-fold. Substantial splicing occurred in six loci generating two or more splice variants, some with known functional differences. Splice patterns varied broadly between individuals. Two heart tissues expressed predominantly the dihydropyridine-sensitive smooth muscle isoform of CACNA1C (containing exon 8), rather than the cardiac isoform (containing exon 8a). Lack of significant allelic expression imbalance, observed with total mRNA and several splice variants, argued against CACNA1C polymorphisms as a cause of variability. Taken together, highly variable splicing can cause profound phenotypic variations of CACNA1C function, potentially associated with disease susceptibility and response to L-type calcium channel blockers.
PMCID: PMC2688811  PMID: 17001293
cis-acting polymorphism; L-type calcium channel α-subunit 1c; mRNA splicing

Results 1-9 (9)