Mariell Jessup

Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID Trial), a First-in-Human Phase 1/2 Clinical Trial

BACKGROUND SERCA2a deficiency is commonly seen in advanced heart failure (HF). This study is designed to investigate safety and biological effects of enzyme replacement using gene transfer in patients with advanced HF. METHODS AND RESULTS A total of 9 patients with advanced HF (New York Heart Association [NYHA] Class III/IV, ejection fraction [EF] < or = 30%, maximal oxygen uptake [VO2 max] <16 mL.kg.min, with maximal pharmacological and device therapy) received a single intracoronary infusion of AAV1/SERCA2a in the open-label portion of this ongoing study. Doses administered ranged from 1.4 x 10(11) to 3 x 10(12) DNase resistant particles per patient. We present 6- to 12-month follow-up data for these patients. AAV1/SERCA2a demonstrated an acceptable safety profile in this advanced HF population. Of the 9 patients treated, several demonstrated improvements from baseline to month 6 across a number of parameters important in HF, including symptomatic (NYHA and Minnesota Living with Heart Failure Questionnaire, 5 patients), functional (6-minute walk test and VO2 max, 4 patients), biomarker (NT-ProBNP, 2 patients), and LV function/remodeling (EF and end-systolic volume, 5 patients). Of note, 2 patients who failed to improve had preexisting anti-AAV1 neutralizing antibodies. CONCLUSIONS Quantitative evidence of biological activity across a number of parameters important for assessing HF status could be detected in several patients without preexisting neutralizing antibodies in this open-label study, although the number of patients in each cohort is too small to conduct statistical analyses. These findings support the initiation of the Phase 2 double-blind, placebo-controlled portion of this study.

Risk Score Derived from Pre-operative Data Analysis Predicts the Need for Biventricular Mechanical Circulatory Support

BACKGROUND Right ventricular (RV) failure after left ventricular assist device (LVAD) placement is a serious complication and is difficult to predict. In the era of destination therapy and the total artificial heart, predicting post-LVAD RV failure requiring mechanical support is extremely important. METHODS We reviewed patient characteristics, laboratory values and hemodynamic data from 266 patients who underwent LVAD placement at the University of Pennsylvania from April 1995 to June 2007. RESULTS Of 266 LVAD recipients, 99 required RV assist device (BiVAD) placement (37%). We compared 36 parameters between LVAD (n = 167) and BiVAD patients (n = 99) to determine pre-operative risk factors for RV assist device (RVAD) need. By univariate analysis, 23 variables showed statistically significant differences between the two groups (p < or = 0.05). By multivariate logistic regression, cardiac index < or =2.2 liters/min/m(2) (odds ratio [OR] 5.7), RV stroke work index < or =0.25 mm Hg . liter/m(2) (OR 5.1), severe pre-operative RV dysfunction (OR 5.0), pre-operative creatinine > or =1.9 mg/dl (OR 4.8), previous cardiac surgery (OR 4.5) and systolic blood pressure < or =96 mm Hg (OR 2.9) were the best predictors of RVAD need. CONCLUSIONS The most significant predictors for RVAD need were cardiac index, RV stroke work index, severe pre-operative RV dysfunction, creatinine, previous cardiac surgery and systolic blood pressure. Using these data, we constructed an algorithm that can predict which LVAD patients will require RVAD with >80% sensitivity and specificity.

Design of a Phase 1/2 Trial of Intracoronary Administration of AAV1/SERCA2a in Patients With Heart Failure

BACKGROUND Heart failure (HF) remains a major cause of morbidity and mortality in North America. With an aging population and an unmet clinical need by current pharmacologic and device-related therapeutic strategies, novel treatment options for HF are being explored. One such promising strategy is gene therapy to target underlying molecular anomalies in the dysfunctional cardiomyocyte. Prior animal and human studies have documented decreased expression of SERCA2a, a major cardiac calcium cycling protein, as a major defect found in HF. METHODS AND RESULTS We hypothesize that increasing the activity of SERCA2a in patients with moderate to severe HF will improve their cardiac function, disease status, and quality of life. Gene transfer of SERCA2a will be performed via an adeno-associated viral (AAV) vector, derived from a nonpathogenic virus with long-term transgene expression as well as a clinically established favorable safety profile. CONCLUSIONS We describe the design of a phase 1 clinical trial of antegrade epicardial coronary artery infusion (AECAI) administration of AAVI/SERCA2a (MYDICAR) to subjects with HF divided into 2 stages: in Stage 1, subjects will be assigned open-label MYDICAR in one of up to 4 sequential dose escalation cohorts; in Stage 2, subjects will be randomized in parallel to 2 or 3 doses of MYDICAR or placebo in a double-blinded manner.

Implant Strategies Change Over Time and Impact Outcomes : Insights From the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support)

OBJECTIVES This study investigated how the initial intended strategy at left ventricular assist device (LVAD) implantation influenced patient outcomes. BACKGROUND Left ventricular assist device implantation strategy impacts candidate selection, reimbursement, and clinical trial design; however, concepts of device strategy are continuing to evolve. METHODS For patients entered in the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) receiving a primary continuous flow LVAD between March 2006 and March 2011, initial strategies were bridge to transplant (BTT), bridge to candidacy (BTC) for transplant, and destination therapy (DT). Primary analyses compared BTT, BTC, and DT outcomes at 6, 12, and 24 months. RESULTS Among 2,816 primary LVAD recipients, implant strategy was 1,060 (38%) BTT, 1,162 (42%) BTC (likely to be listed 796, moderately likely 282, unlikely 84), and 553 (20%) DT. Compared with BTC/DT, those listed at implant (BTT) had similar degrees of ventricular dysfunction and hemodynamic derangement but generally less comorbidity. Survival (alive with LVAD or transplanted) was superior at 24 months for BTT versus BTC versus DT (77.7% vs.70.1% vs. 60.7%, respectively, p < 0.0001). Strategic intent changed over time, at 2 years 43.5% of BTT patients were no longer listed for transplant, but 29.3% of BTC patients were listed for transplant. CONCLUSIONS The currently accepted indications only account for 58% of LVAD implants. Across indications, patients differ by the number and types of comorbidities rather than the need for hemodynamic support. Regardless of initial implant strategy, patients often have long durations of support, and strategies often change over time, challenging the regulatory categorization of LVAD recipients as either BTT or DT.

Management of prosthetic valves during ventricular assist device implantation.

Abstract  Background: An increasing number of patients requiring ventricular assist devices (VAD) have had previous valvular corrections, including valve repair and valve replacement with mechanical or bioprosthetic valves. The operative and peri‐operative management of these patients has been varied. Methods: A retrospective study of VADs between January 1994 and June 2008 revealed 10 patients with previous prosthetic valves requiring management during and after VAD placement. Three patients were supported postcardiotomy after valve surgery. Two patients were supported due to cardiogenic shock postoperatively. Four patients were supported as a bridge to transplantation. One patient was supported as a destination therapy (DT). Results: The mitral, valve was left untreated during VAD implantation regardless of valve repair or replacement. For aortic valves, the mechanical aortic valve was replaced with tissue valve in two patients and left untreated in one case. One patient had tricuspid valve repair previously and was left untouched. All patients with prosthetic valves in aortic, mitral and tricuspid position during VAD support received anticoagulation therapy. There were four deaths, and four went on to transplantation. One patient was weaned from VAD and discharged from the hospital. One patient received HeartMate I as DT. The most common causes of death were multisystem organ failure (MSOF) and sepsis. One patient had a thromboembolic event. Conclusions: The survival rate of 60% is encouraging when compared to overall survival rates. The most common cause of death was MSOF. Patients with prosthetic valves may be safely managed during VAD support. (J Card Surg 2010;25:601‐605)

End-Stage Diastolic and Systolic Heart Failure: Evaluation and Timing of Heart Transplantation

End stage hypertrophic cardiomyopathy occurs in an estimated 3–15 % of patients and can present as either systolic or diastolic dysfunction. Risk factors for developing end stage disease include a family history of end stage disease, younger age at initial diagnosis, increased wall thickness and persistent arrhythmia. The classic form of adverse remodeling includes left ventricular cavity dilation with regression of hypertrophy and decrease in ejection fraction. Standard medical therapy for systolic heart failure and consideration of prophylactic defibrillator is indicated when LVEF is less than 50 %. Heart transplant is a viable option for patients with end stage hypertrophic cardiomyopathy, including those with systolic heart failure, diastolic heart failure or refractory arrhythmia. Strategies used to bridge patients to transplant include continuous inotropic infusion, left ventricular assist device, intra-aortic balloon pump, and in rare cases extracorporeal membrane oxygenation. Survival after heart transplant for hypertrophic cardiomyopathy is equal to or better than survival for patients who have other types of cardiomyopathies.