A case of short QT-interval postventricular arrhythmia arrest from Torsade De Pointes, a new phenotype, or the result of tachycardia-mediated imbalance.

INTRODUCTION: We report the case of an 18-year-old female with recurrent syncope that was discovered to have congenital long QT syndrome (LQTS) and episodes of a transiently short QT interval after spontaneous termination of polymorphic ventricular tachycardia. METHODS & RESULTS: A cardiac event monitor revealed a long QT interval and initiation of polymorphic ventricular tachycardia by a premature ventricular complex on the preceding T-wave. After 1 minute of ventricular fibrillation, her arrhythmia spontaneously terminated with evidence of a short QT interval. CONCLUSIONS: A transient, potentially artificial, short QT interval following Torsades de Pointes can occur in patients with LQTS.

Vagal milieu or electrophysiologic substrate? The link between atrial fibrillation and obstructive sleep apnea.

Atrial fibrillation is the most common cardiac arrhythmia with its prevalence expected to increase to 12.1 million people in the United States by 2030. Chronic underlying conditions that affect the heart and lungs predispose patients to develop atrial fibrillation. Obstructive sleep apnea is strongly associated with atrial fibrillation. Several pathophysiological mechanisms have been proposed to elucidate this relationship which includes electrophysiological substrate modification and the contribution of the autonomic nervous system. In this comprehensive review, we highlight important relationships and plausible causality between obstructive sleep apnea and atrial fibrillation which will improve our understanding in the evaluation, management, and prevention of atrial fibrillation. This is the most updated comprehensive review of the relationship between obstructive sleep apnea and atrial fibrillation.

Beyond Ejection Fraction: Novel Clinical Approaches Towards Sudden Cardiac Death Risk Stratification in Patients with Dilated Cardiomyopathy.

Implantable Cardioverter-Defibrillator (ICD) therapy is indicated for patients at risk for sudden cardiac death due to ventricular tachyarrhythmia. The most commonly used risk stratification algorithms use Left Ventricular Ejection Fraction (LVEF) to determine which patients qualify for ICD therapy, even though LVEF is a better marker of total mortality than ventricular tachyarrhythmias mortality. This review evaluates imaging tools and novel biomarkers proposed for better risk stratifying arrhythmic substrate, thereby identifying optimal ICD therapy candidates.

Ablation Therapy for Persistent Atrial Fibrillation.

Atrial Fibrillation (AF) is the most common form of electrical disturbance of the heart and contributes to significant patient morbidity and mortality. With a better understanding of the mechanisms of atrial fibrillation and improvements in mapping and ablation technologies, ablation has become a preferred therapy for patients with symptomatic AF. Pulmonary Vein Isolation (PVI) is the cornerstone for AF ablation therapy, but particularly in patients with AF occurring for longer than 7 days (persistent AF), identifying clinically significant nonpulmonary vein targets and achieving durability of ablation lesions remains an important challenge.

N-terminal pro-B-type natriuretic peptide is a specific predictor of appropriate device therapies in patients with primary prevention implantable cardioverter-defibrillators.

BACKGROUND: Sudden death risk stratification of patients with left ventricular systolic dysfunction remains challenging. Retrospective studies have suggested N-terminal pro-B-type natriuretic peptide (NT-proBNP) may be a useful risk stratification tool. OBJECTIVE: The purpose of this study was to ascertain the utility of NT-proBNP as a predictor of appropriate implantable cardioverter-defibrillator (ICD) therapies in primary prevention ICD recipients. METHODS: This was a prospective study of 342 stable patients with left ventricular ejection fraction ≤40% who received a primary prevention ICD. NT-proBNP assay was performed at the time of device implant and used as a dichotomized variable (1st-3rd NT-proBNP quartiles vs 4th NT-proBNP quartile) to predict primary (appropriate ICD therapies) and secondary (death, ICD-deactivation, chronic inotropic support, transplant) outcomes. RESULTS: Median follow-up was 35.0 months (interquartile range 15.2-55.3). In unadjusted analyses, NT-proBNP predicted both primary (hazard ratio [HR] 1.89; 95% confidence interval [CI] 1.00-3.56); P = .049) and secondary outcomes (HR 2.13; 95% CI 1.18-3.85; P =.012). Multivariable analysis reaffirmed NT-proBNP as a primary outcome predictor (HR 4.31; 95% CI 1.92-9.70; P <.001) but not as a secondary outcome predictor (HR 1.23; 95% CI 0.61-2.50; P = .564). Instead, secondary outcome was predicted by patient age and renal function. In an unadjusted subanalysis limited to patients with blood urea nitrogen <30 mg/dL, NT-proBNP remained a primary endpoint predictor (HR 2.51; 95% CI 1.25-5.05; P = .010) but not a secondary endpoint predictor (HR 1.34; 95% CI 0.52-3.44; P = .541). Receiver operating analyses at 2- and 3-year follow-up timepoints confirmed that NT-proBNP significantly improved the performance of multivariable models designed to predict future appropriate ICD therapies. CONCLUSION: In multivariable analysis, NT-proBNP is a reasonable and specific predictor of future appropriate device therapies in primary prevention ICD recipients. In contrast, adjusted NT-proBNP does not predict all-cause mortality.

Ticagrelor or prasugrel vs. clopidogrel in combination with anticoagulation for treatment of acute coronary syndrome in patients with atrial fibrillation.

For patients with atrial fibrillation (AF) and acute coronary syndrome (ACS), it is often challenging to find the optimal balance between the risk for ischemic and hemorrhagic complication when using both antiplatelet therapy and oral anticoagulation (OAC) with vitamin K antagonist (VKA) or direct oral anticoagulants (DOACs). Current guidelines recommended: (I) double therapy with a P2Y12 inhibitor and dose adjusted VKA is reasonable post-stenting; (II) double therapy with clopidogrel and low-dose rivaroxaban (15 mg daily) may be reasonable post-stenting; (III) double therapy with a P2Y12 inhibitor and dabigatran 150 mg twice daily is reasonable post-stenting. In the AUGUSTUS trial, most patients were given clopidogrel as part a DAPT regimen, however prasugrel and ticagrelor use allowed albeit in a small percentage of the trial population, underestimating its effect. Ticagrelor and prasugrel are known to have a stronger antiplatelet effect compared to clopidogrel, however randomized studies have not been adequately powered to date allowing comparisons between ticagrelor, prasugrel and clopidogrel together in the setting of anticoagulation for the treatment of patients with ACS and AF. Careful consideration should be given to this scenario to avoid falling into the concept of sacrificing efficacy for safety.

Cardiac physiology in post myocardial infarction patients: the effect of cardiac rehabilitation programs-a systematic review and update meta-analysis.

Cardiac rehabilitation program (CRP) is a recognized non-pharmacological modality to decrease mortality after acute myocardial infarction (AMI) events. We aimed to evaluate the effect of CRP on the cardiac physiology in patients post myocardial infarction (MI). Online database search of PubMed, MEDLINE, EMBASE, SCOPUS, COCHRANE, and GOOGLE SCHOLAR were performed (1988-Mar 2016); key bibliographies were reviewed. Studies comparing post MI patients who were enrolled in a CRP to those who were not, were included. Standardized mean difference (SMD) with the corresponding 95% confidence intervals (CI) by random and fixed effects models of pooled data were calculated. Study quality was assessed using CONSORT criteria. Outcomes of interest measured included resting and maximum heart rate (HR), peak VO2, ejection fraction (EF%), wall motion score index (WMSI), left ventricular end diastolic volume (LVEDV) in cardiac rehabilitation patients versus control. Search strategy yielded 147 studies, 23 studies fulfilled the selection criteria, 19 of which were RCTs. These included a total of 1,683 patients; 827 were enrolled in a CRP while 855 did not receive the intervention. Median age was 58 years. There was no significant difference between the two groups in terms of age, comorbidities, severity of CAD, baseline EF or HR. Meta-analysis of data included demonstrated that CRP patients had lower post-intervention resting HR than non-CRP patients (SMD: -0.59; 95% CI: -0.73 to -0.46, fixed effect model P<0.05). EF% was significantly improved after CRP compared to control (SMD: 0.21; 95% CI: 0.02 to 0.40, P=0.03). Peak VO2 was significantly improved by CRP (SMD: 1.00; 95% CI: 0.56 to 1.45; P<0.0001). LVEDV was significantly less in CRP patients (SMD: -0.31; 95% CI: -0.59 to -0.02, fixed effect model P<0.05). WMSI was significantly less in CRP patients (SMD: -0.41; 95% CI: -0.78 to -0.05, P=0.024). CRP improves cardiac function in post MI patients. This may explain the reported improvement of functionality and mortality among those patients. Further randomized trials may help evaluate the long-term benefits of CRP.

Recent Updates in the Role of Wearable Cardioverter Defibrillator for Prevention of Sudden Cardiac Death.

PURPOSE OF REVIEW: The wearable cardioverter defibrillator (WCD) or LifeVest may protect against sudden cardiac death (SCD) in patients awaiting insertion of an implantable cardioverter defibrillator (ICD). The purpose of this communication is to review the rationale behind WCD therapy and to critically analyze recent data regarding its clinical efficacy. We seek to provide evidence-based recommendations regarding the potential role of the WCD in certain populations. RECENT FINDINGS: The only randomized controlled trial that evaluated WCD therapy did not demonstrate a reduced rate of arrhythmic death in patients prescribed the WCD during the first 90-day post-myocardial infarction (MI). However, when considering trial results alongside previous retrospective data, patient noncompliance with WCD therapy-rather than ineffectiveness of WCD therapy-remains an important theme. The uncertainty of data regarding the use of WCD therapy in patients during ICD waiting periods should be considered as part of the shared decision processes between healthcare providers and patients. Higher rates of adherence are needed to ensure efficiency. Well-designed future studies with appropriate cost-effectiveness analyses are indicated to define the clinical efficacy of WCD therapy on arrhythmic and non-arrhythmic morbidity and mortality in patients who are not yet candidates for ICDs.

Left ventricular sphericity independently predicts appropriate implantable cardioverter-defibrillator therapy.

BACKGROUND: Whether echocardiographic markers of remodeling are associated with ventricular tachyarrhythmias is unknown. OBJECTIVE: The purpose of this study was to determine whether a transthoracic echocardiographic (TTE) marker of spherical left ventricular (LV) remodeling is associated with appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with primary prevention ICDs. METHODS: From TTE images, we calculated sphericity index (SI), the ratio of biplane LV end-diastolic volume to the volume of a hypothetical sphere with a diameter of the LV end-diastolic length, and examined the relation between SI and therapy for ventricular tachyarrhythmias in 278 patients with primary prevention ICDs and in 50 controls without structural heart disease or ventricular arrhythmias. RESULTS: SI in normal healthy adult subjects and in subjects receiving ICDs was 0.44 ± 0.02 and 0.65 ± 0.04, respectively (P <.001). Median time to first appropriate ICD therapy was significantly shorter in ICD patients with SI in the upper vs lower 50% of SI values (1.40 vs 2.38 years, P = .02 for conventional ICD patients; 1.54 vs 2.65 years, P = .02 for cardiac resynchronization therapy-defibrillator [CRT-D] patients). In multivariable Cox regression analysis, SI in the upper 50% was independently associated with appropriate ICD therapy after multivariable adjustment (hazard ratio 2.2, P = .03 for ICD cohort; hazard ratio 4.4, P = .01 for CRT-D cohort). SI was not associated with total mortality in either cohort. CONCLUSION: SI is associated with appropriate ICD therapy, but not total mortality, in patients receiving primary prevention ICDs. These observations suggest spherical LV remodeling may predispose to ventricular arrhythmias. Furthermore, SI appears to add predictive accuracy for appropriate ICD therapy in patients with reduced ejection fraction.

Prevalence and outcomes of patients receiving implantable cardioverter-defibrillators for primary prevention not based on guidelines.

Implantable cardioverter-defibrillator (ICD) implantation outside practice guidelines remains contentious, particularly during the mandated waiting periods in patients with recent cardiac events. We assessed the prevalence and outcomes of non-guideline-based (NGB) ICD implantations in a tertiary academic medical center, with a specific focus on adjudication of arrhythmia events. All patients who underwent initial primary prevention ICD implantation at our institution from 2004 to 2012 were categorized as having received guideline-based (GB) or NGB implants and were retrospectively assessed for first episode of appropriate ICD therapy and total mortality. Of 807 patients, 137 (17.0%) received NGB implants. During a median follow-up of 2.9 years, patients with NGB implants had similar times to first appropriate ICD therapy (median time to event 1.94 vs 2.17 years in patients with GB implants, p = 0.20). After multivariable analysis, patients with NGB implants remained at higher risk for death (hazard ratio 1.54, 95% confidence interval 1.1 to 2.2, p = 0.03) but not appropriate ICD therapy (hazard ratio 0.83, 95% confidence interval 0.5 to 1.3, p = 0.51). Furthermore, only 1 of 125 patients who underwent implant within the 40-day waiting period after myocardial infarction or 3-month waiting period after revascularization or cardiomyopathy diagnosis received an appropriate therapy within this period. In conclusion, few patients received NGB ICD implants in our academic medical center. Although these patients have similar long-term risk of receiving appropriate ICD therapy compared with patients with GB implants, this risk is very low during the waiting periods mandated by clinical practice guidelines. These results suggest that there is little need to rush into implanting ICDs during these waiting periods.

B-type natriuretic peptide is a major predictor of ventricular tachyarrhythmias.

BACKGROUND: The cost-effective use of implantable cardioverter-defibrillators (ICDs) for the prevention of sudden cardiac death requires identification of patients at risk for ventricular tachyarrhythmias, not just for total mortality. OBJECTIVE: To determine whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) or B-type natriuretic peptide (BNP) are independent predictors of ventricular arrhythmias in patients receiving primary prevention ICDs. METHODS: One hundred sixty-one patients with NT-proBNP levels and 403 patients with BNP levels at the time of ICD implantation were retrospectively assessed for the occurrence of first appropriate ICD therapy and mortality. RESULTS: In multivariable Cox proportional hazards regression analysis, NT-proBNP or BNP levels in the upper 50th percentile were the strongest predictor of ICD therapy after adjustment for sex, age, left ventricular ejection fraction, New York Heart Association class, history of coronary artery disease, blood urea nitrogen, creatinine clearance, and history of atrial fibrillation (hazard ratio [HR] 5.75, P < .001 for NT-proBNP; HR 3.40, P = .01 for BNP). Patients were divided into quartiles on the basis of NT-proBNP or BNP levels. The adjusted HR for ICD therapy in the highest and second highest quartiles of NT-proBNP levels (HR 12.9, P < .001, and HR 4.6, P = .03, respectively) were higher than the adjusted HR for total mortality in these 2 quartiles (HR 3.4, P = .021 and HR 2.3, P = .13, respectively). Similarly, the adjusted HR for ICD therapy in the highest and second highest quartiles of BNP levels (HR 4.74, P = .01 and HR 2.17, P = .04, respectively) were higher than the adjusted HR for total mortality in these 2 quartiles (HR 3.05, P = .01 and HR 1.07, P = .3, respectively). CONCLUSION: In this study, elevated baseline NT-proBNP and BNP levels are independently associated with the risk for ventricular tachyarrhythmias, which significantly exceeds the risk for total mortality, in multivariable analysis.

Atrial natriuretic peptide-initiated cGMP pathways regulate vasodilator-stimulated phosphoprotein phosphorylation and angiogenesis in vascular endothelium.

Nitric oxide (NO)- and atrial natriuretic peptide (ANP)-initiated cGMP signaling cascades are important in the maintenance of cardiovascular homeostasis. The molecular signaling mechanisms downstream of cGMP are not well understood, however. We have used small interfering RNA (siRNA) approaches to specifically knock down a series of signaling proteins in bovine aortic endothelial cells, and we have combined biochemical analyses with physiological assays to investigate cGMP-mediated signal transduction pathways. Activation of particulate guanylate cyclase (GC-A) by ANP leads to a substantial, dose-dependent, rapid, and sustained increase in intracellular cGMP. In contrast, stimulation of soluble guanylate cyclase by NO yields only a weak and transient increase in cGMP. ANP-induced cGMP production is selectively suppressed by siRNA-mediated knockdown of GC-A. ANP greatly enhances the phosphorylation at Ser-239 of the vasodilator-stimulated phosphoprotein (VASP), a major substrate of cGMP-dependent protein kinase (PKG) that significantly influences actin dynamics. Moreover, the ANP-induced phosphorylation of VASP at Ser-239 is accompanied by increased actin stress fiber formation and enhanced endothelial tube formation. siRNA-mediated knockdown of GC-A, VASP, or PKG abolishes ANP-induced VASP Ser-239 phosphorylation, stress fiber formation, and endothelial tube formation. We have demonstrated similar findings in human umbilical vein endothelial cells, where ANP substantially enhances intracellular cGMP content, phosphorylation of VASP at Ser-239, and endothelial tube formation. Taken together, our findings suggest that ANP-mediated cGMP signal transduction pathways regulate PKG phosphorylation of VASP Ser-239 in endothelial cells, resulting in reorganization of the actin cytoskeleton and enhancement of angiogenesis.

Agonist-modulated regulation of AMP-activated protein kinase (AMPK) in endothelial cells. Evidence for an AMPK -> Rac1 -> Akt -> endothelial nitric-oxide synthase pathway.

The endothelial isoform of nitric-oxide synthase (eNOS), a key determinant of vascular homeostasis, is a calcium/calmodulin-dependent phosphoprotein regulated by diverse cell surface receptors. Vascular endothelial growth factor (VEGF) and sphingosine 1-phosphate (S1P) stimulate eNOS activity through Akt/phosphoinositide 3-kinase and calcium-dependent pathways. AMP-activated protein kinase (AMPK) also activates eNOS in endothelial cells; however, the molecular mechanisms linking agonist-mediated AMPK regulation with eNOS activation remain incompletely understood. We studied the role of AMPK in VEGF- and S1P-mediated eNOS activation and found that both agonists led to a striking increase in AMPK phosphorylation in pathways involving the calcium/calmodulin-dependent protein kinase kinase beta. Treatment with tyrosine kinase inhibitors or the phosphoinositide 3-kinase inhibitor wortmannin demonstrated differential effects of VEGF versus S1P. Small interfering RNA (siRNA)-mediated knockdown of AMPKalpha1or Akt1 impaired the stimulatory effects of both VEGF and S1P on eNOS activation. AMPKalpha1 knockdown impaired agonist-mediated Akt phosphorylation, whereas Akt1 knockdown did not affect AMPK activation, thus suggesting that AMPK lies upstream of Akt in the pathway leading from receptor activation to eNOS stimulation. Importantly, we found that siRNA-mediated knockdown of AMPKalpha1 abrogates agonist-mediated activation of the small GTPase Rac1. Conversely, siRNA-mediated knockdown of Rac1 decreased the agonist-mediated phosphorylation of AMPK substrates without affecting that of AMPK, implicating Rac1 as a molecular link between AMPK and Akt in agonist-mediated eNOS activation. Finally, siRNA-mediated knockdown of caveolin-1 significantly enhanced AMPK phosphorylation, suggesting that AMPK is negatively regulated by caveolin-1. Taken together, these results suggest that VEGF and S1P differentially regulate AMPK and establish a central role for an agonist-modulated AMPK --> Rac1 --> Akt axis in the control of eNOS in endothelial cells.