Kishan S. Parikh

Early Repolarization Associated With Ventricular Arrhythmias in Patients With Chronic Coronary Artery Disease

Background—Early repolarization, indicated on the standard 12-lead ECG, has recently been associated with idiopathic ventricular fibrillation in patients without structural heart disease. It is unknown whether there is an association between early repolarization and ventricular arrhythmias in the coronary artery disease (CAD) population. Methods and Results—Patients with CAD with implantable cardioverter-defibrillators in the healed phase of myocardial infarction were analyzed. In a case-control design, 60 patients who had ventricular arrhythmic events were matched for age and sex with 60 control subjects. ECGs were analyzed for early repolarization, defined as notching or slurring morphology of the terminal QRS complex or J-point elevation ≥0.1 mV above baseline in at least 2 lateral or inferior leads. Results were adjusted for left ventricular ejection fraction. Overall, early repolarization in 2 or more leads was more common in cases than control subjects (32% versus 8%, P=0.005). Early repolarization was noted more commonly in inferior leads (23% versus 8%, P=0.03), and a trend was noted in leads V4 through V6 (12% versus 3%, P=0.11). Early repolarization was uncommon in leads I and aVL in cases and control subjects (3% versus 0%). Notching was more common in cases than control subjects (28% versus 7%, P=0.008). Slurring and J-point elevation were not associated with ventricular arrhythmias. Conclusions—Early repolarization and, in particular, notching in the inferior leads is associated with increased risk of life-threatening ventricular arrhythmias in patients with CAD, even after adjustment for left ventricular ejection fraction. Our findings suggest early repolarization, and a notching morphology should be considered in a risk prediction model for arrhythmias in patients with CAD.

GRK2-Mediated Inhibition of Adrenergic and Dopaminergic Signaling in Right Ventricular Hypertrophy Therapeutic Implications in Pulmonary Hypertension

Background—The cause and consequences of impaired adrenergic signaling in right ventricular failure/hypertrophy (RVH) are poorly understood. We hypothesized that G protein–coupled receptor kinase-2 (GRK2)–mediated uncoupling of &bgr;-adrenergic receptor signaling impairs inotropic reserve. The implications of right ventricular (RV) adrenergic remodeling for inotrope selection and the therapeutic benefit of interrupting G&bgr;&ggr;–GRK2 interaction, using gallein, were tested. Methods and Results—Chamber-specificity and cellular localization of adrenergic remodeling were compared in rodent RVH associated with pulmonary arterial hypertension (PAH-RVH; SU5416+chronic-hypoxia or Monocrotaline) versus pulmonary artery banding–induced RVH (PAB-RVH). Results were corroborated in RV arrays from 10 PAH patients versus controls. Inotropic reserve was assessed in RV- and left ventricular–Langendorff models and in vivo. Gallein therapy (1.8 mg/kg/day ×2-weeks) was assessed. Despite similar RVH, cardiac output (58.3±4.9 versus 82.9±4.8 mL/min; P<0.001) and treadmill distance (41.5±11.6 versus 244.1±12.4 m; P<0.001) were lower in PAH-RVH versus PAB-RVH. In PAH-RVH versus PAB-RVH there was greater downregulation of &bgr;1-, &agr;1- and dopamine-1 receptors, more left ventricular involvement, and greater impairment of RV contractile reserve. RV GRK2 activity increased in parallel with a reduction in both adrenergic receptor expression and inotrope-stimulated cAMP levels (P<0.01). &bgr;1-receptor downregulation also occurred in human PAH-RVH. Dobutamine was superior to dopamine as an RV inotrope, both ex vivo and in vivo. Conclusions—GRK2-mediated desensitization-downregulation of adrenergic and dopaminergic receptors impairs inotropic reserve in PAH-RVH. Acute inotropic support in RVH is best accomplished by dobutamine, reflecting its better coupling to adenylyl cyclase and the reliance of dopamine on dopamine-1–receptor signaling, which is impaired in RVH. Inhibiting G&bgr;&ggr;–GRK2 interactions has therapeutic benefit in RVH.

Percutaneous Transcatheter Aortic Valve Closure Successfully Treats Left Ventricular Assist Device–Associated Aortic Insufficiency and Improves Cardiac Hemodynamics

OBJECTIVES This study sought to assess the effectiveness of a novel percutaneous method to treat left ventricular assist device (LVAD)-associated severe aortic insufficiency (AI) in a series of patients determined to be poor reoperative candidates. BACKGROUND The increased use of continuous-flow LVAD in advanced heart failure has led to marked changes in the management of patients with this condition. However, secondary AI can become a significant complication. METHODS Five patients with continuous-flow LVAD and severe post-LVAD AI underwent percutaneous transcatheter aortic valve closure from September to October 2011 at a single quaternary care academic medical center. All patients had LVAD implanted as destination therapy. LVAD parameters, hemodynamics, and echocardiographic measurements were obtained before and after aortic valve closure. RESULTS All patients underwent successful closure with the Amplatzer cribriform device (AGA Medical, Plymouth, Minnesota) via a percutaneous transcatheter femoral approach with a significant reduction of AI from severe to trivial. Cardiac hemodynamics improved, and the pulmonary capillary wedge pressure was reduced in all patients. There was no change in mitral or tricuspid regurgitation, LVAD power, or pulsatility index. CONCLUSIONS Percutaneous transcatheter closure of the aortic valve effectively treats LVAD-associated AI and reduces pulmonary capillary wedge pressure. This procedure should be considered to treat LVAD-associated AI in patients who are poor candidates for repeat operation. Further data are needed to assess long-term results.

TCT-379 Percutaneous Transcatheter Aortic Valve Closure Successfully Treats Left Ventricular Assist Device-Associated Aortic Insufficiency and Improves Cardiac Hemodynamics

The increased use of continuous-flow LVADs in advanced heart failure has led to marked changes in the management of patients with this condition. However, secondary AI can become a significant complication. Our objective was to assess the effectiveness of a novel percutaneous method to treat left

Wellens syndrome: a life-saving diagnosis

The diagnosis of acute coronary syndrome relies on clinical history, electrocardiographic (ECG) changes, and cardiac biomarkers; but within the spectrum of acute coronary syndrome, there exist subtle presentations that cannot afford to be overlooked. Wellens syndrome is one such example, in which a patient can present with both ECG changes that are not classic for myocardial ischemia and negative cardiac biomarkers. The characteristic ECG findings associated with Wellens syndrome consist of deep, symmetric T-wave inversions in the anterior precordial leads. However, Wellens syndrome can also present as biphasic T-wave inversions in those same ECG leads. The associated critical stenosis of the proximal left anterior descending artery carries an immediately life-threatening prognosis if not recognized promptly (Am Heart J. 1982;103[4 Pt 2]:730-736). We describe a case of a less common manifestation of Wellens syndrome (type 1) followed by a discussion of its implications and management.

Mode of Death After Acute Heart Failure Hospitalization – A Clue to Possible Mechanisms –

Heart failure continues to be a leading cause of hospitalization worldwide, and acute heart failure (AHF) carries significant risk for short-term morbidity and mortality. Despite many trials of potential new therapies for AHF, there have been very few advances over the recent decades. In this review, we will examine mortality during and after AHF hospitalization, with an emphasis on available data on mode of death (MOD). We will also review data on the timing of different MOD after AHF and the effect of specific therapies, as well as what is known about the contribution of specific pathophysiological mechanisms. Finally, we discuss the potential utility of further study of MOD data for AHF and its application to drug development, risk stratification, and therapeutic tailoring to improve short- and long-term outcomes in AHF.

Use of outcome measures in pulmonary hypertension clinical trials.

OBJECTIVES To evaluate the use of surrogate measures in pulmonary hypertension (PH) clinical trials and how it relates to clinical practice. BACKGROUND Studies of pulmonary arterial hypertension (PAH) employ a variety of surrogate measures in addition to clinical events because of a small patient population, participant burden, and costs. The use of these measures in PH drug trials is poorly defined. METHODS We searched PubMed/MEDLINE/Embase for randomized or prospective cohort PAH clinical treatment trials from 1985 to 2013. Extracted data included intervention, trial duration, study design, patient characteristics, and primary and secondary outcome measures. To compare with clinical practice, we assessed the use of surrogate measures in a clinical sample of patients on PH medications at Duke University Medical Center between 2003 and 2014. RESULTS Between 1985 and 2013, 126 PAH trials were identified and analyzed. Surrogate measures served as primary endpoints in 119 trials (94.0%). Inclusion of invasive hemodynamics decreased over time (78.6%, 75.0%, 52.2%; P for trend = .02), while functional testing (7.1%, 60.0%, 81.5%; P for trend < .0001) and functional status or quality of life (0%, 47.6%, 62.8%; P for trend < .0001) increased in PAH trials over the same time periods. Echocardiography data were reported as a primary or secondary outcome in 32 trials (25.4%) with increased use from 1985-1994 to 1995-2004 (7.1% vs 35.0%, P = .04), but the trend did not continue to 2005-2013 (25.0%). In comparison, among 450 patients on PAH therapies at our institution between 2003 and 2013, clinical assessments regularly incorporated serial echocardiography and 6-minute walk distance tests (92% and 95% of patients, respectively) and repeat measurement of invasive hemodynamics (46% of patients). CONCLUSIONS The majority of PAH trials have utilized surrogate measures as primary endpoints. The use of these surrogate endpoints has evolved significantly over time with increasing use of patient-centered endpoints and decreasing or stable use of imaging and invasive measures. In contrast, imaging and invasive measures are commonly used in contemporary clinical practice. Further research is needed to validate and standardize currently used measures.

Resting Heart Rate and Long-term Outcomes Among the African American Population: Insights From the Jackson Heart Study.

Importance Increased resting heart rate is associated with worse outcomes in studies of mostly white populations, but its significance is not well established in African Americans persons whose cardiac comorbidities and structural abnormalities differ. Objective To study the prognostic utility of heart rate in a community-based African American cohort in the Jackson Heart Study. Design, Setting, and Participants A total of 5261 participants in the Jackson Heart Study, a prospective, community-based study in Jackson, Mississippi, were evaluated. Baseline heart rate was assessed by quintiles and as a continuous variable. All participants with baseline heart rate documented by a 12-lead electrocardiogram without pacing or atrial fibrillation noted on their baseline Jackson Heart Study examination were included in the study. Follow-up began September 26, 2000, and was completed December 31, 2011. Data analysis was performed from July to October 2015. Main Outcomes and Measures Unadjusted and adjusted associations between heart rate and all-cause mortality and heart failure hospitalization using Cox proportional hazards regression models. Results Of the 5261 individuals included in the analysis, 1921 (36.5%) were men; median (25th-75th percentile) age was 55.7 (45.4-64.8) years. Median (25th-75th percentile) baseline heart rate was 63 beats per minute (bpm) (57-71 bpm). The highest heart rate quintile (73-118 bpm) had higher rates of diabetes (398 [37.4%]; P < .001) and hypertension (735 [69.1%]; P < .001), higher body mass index (median [IQR], 32.4 [28.1-38.3]; P < .001), less physical activity (0 hours per week, 561 [52.8%]; P < .001), and lower &bgr;-blocker use (73 [6.9%]; P < .001) compared with lower quintiles. Caffeine intake (from 80.7 to 85.5 mg/d; P = .57) and left ventricular ejection fraction (from 62% to 62.3%; P = .01) were similar between groups. As a continuous variable, elevated heart rate was associated with increased mortality and heart failure hospitalizations, with adjusted hazard ratios for every 5-bpm increase of 1.14 (95% CI, 1.10-1.19) and 1.10 (95% CI, 1.05-1.16), respectively. Similar patterns were observed in comparisons between the highest and lowest quintiles. Conclusions and Relevance Higher baseline heart rate was associated with increased mortality and heart failure hospitalizations among African American participants in the Jackson Heart Study. These findings are similar to those seen in white populations, but further study is needed to understand whether African American individuals benefit from interventions targeting heart rate reduction.

Safety and Tolerability of High-dose Inhaled Treprostinil in Pulmonary Hypertension.

Abstract: Pulmonary arterial hypertension (PAH) has emerging therapeutic options including prostacyclin analogs. Inhaled therapy offers advantages compared with alternative routes of administration. We aimed to determine the safety and tolerability of inhaled treprostinil (iTRE) titrated to target maintenance dose higher than the labeled dose for PAH. Our study included 80 consecutive patients (69% female, 70% White) followed at the Duke University Medical Center prescribed iTRE at dose >9 breaths (54 &mgr;g). Etiology of pulmonary hypertension was most frequently PAH (51%) or secondary to lung disease (35%). Median follow-up was 20.3 months (interquartile range 14.2–33.2). Most patients (91%) had titrated iTRE dose to 12 breaths (72 &mgr;g) four times daily. Common side effects reported with drug initiation were cough (41%), headache (28%), and throat irritation (8%); most of the side effects improved at follow-up. Overall, 25% patients discontinued iTRE: 9 transitioned to parenteral therapy, 4 had untolerable side effects, 3 died, and 4 had other reasons. Overall, iTRE taken at a higher dose than approved for use in PAH was safe and well-tolerated in our cohort of pulmonary hypertension patients.

Scope of Sacubitril/Valsartan Eligibility After Heart Failure Hospitalization: Findings From the GWTG-HF Registry (Get With The Guidelines-Heart Failure)

Sacubitril/valsartan was compared to enalapril in the PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] with ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure [HF]), which was stopped early after an observed 20% reduction in the composite end point of cardiovascular death or HF hospitalization.1 The US Food and Drug Administration (FDA) approved sacubitril/valsartan for patients with HF with reduced ejection fraction (HFrEF) in July 2015. However, FDA labeling is broader than trial entry criteria, and the scope of potential sacubitril/valsartan use in HFrEF is not well understood. We used the GWTG-HF registry (Get With The Guidelines-Heart Failure) to characterize patients’ eligibility and potential barriers for sacubitril/valsartan initiation according to criteria set forth in FDA labeling and PARADIGM-HF. The GWTG-HF registry was started in 2005 by the American Heart Association to improve adherence to quality of care guidelines for patients hospitalized for HF. Patients were eligible for inclusion in the registry if they were admitted for worsening HF or developed significant HF symptoms during a hospitalization.2 We included GWTG-HF registry participants ≥18 years of age hospitalized with HFrEF (EF ≤40%) between January 1, 2011, and December 31, 2013. Patients were excluded if they had in-hospital death or any missing information for variables needed to determine …