Recurrent Cardiogenic Shock Associated with Cannabis Use: Report of a Case and Review of the Literature.

BACKGROUND: The United States has recently undergone increases in the legalization and use of marijuana. There have been previous reports on the association of cannabis use and myocardial dysfunction, however, few on the association with acute stress cardiomyopathy and cardiogenic shock. CASE REPORT: This is a case of a 58-year-old female with a history of inhaled cannabis use, no history of diabetes, and no known history of cardiac disease, that illustrates an association between cannabis use and the recurrent development of stress cardiomyopathy and cardiogenic shock. A review of medical records was performed from two hospitalizations and subsequent outpatient follow-up for similar presentations 6 years apart and review of literature regarding cannabis use and its association with cardiac dysfunction. In separate hospitalizations, the patient presented with clinical findings of cardiogenic shock, severe left ventricular dysfunction with morphologic features of stress cardiomyopathy, and normal coronary angiography. Laboratory results included elevated cardiac biomarkers and urine tetrahydrocannabinol levels > 300 ng/mL. The patient required intensive cardiovascular support, but recovered with normal cardiac function after each event. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: As use of cannabis becomes more prevalent, it will be important for physicians to recognize the potential association of cannabis use and acute myocardial dysfunction, and how early treatment may contribute to salutary outcomes.

Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA2a) activity is deficient in the failing heart. Correction of this abnormality by gene transfer might improve cardiac function. We aimed to investigate the clinical benefits and safety of gene therapy through infusion of adeno-associated virus 1 (AAV1)/SERCA2a in patients with heart failure and reduced ejection fraction. METHODS: We did this randomised, multinational, double-blind, placebo-controlled, phase 2b trial at 67 clinical centres and hospitals in the USA, Europe, and Israel. High-risk ambulatory patients with New York Heart Association class II-IV symptoms of heart failure and a left ventricular ejection fraction of 0·35 or less due to an ischaemic or non-ischaemic cause were randomly assigned (1:1), via an interactive voice and web-response system, to receive a single intracoronary infusion of 1 × 10(13) DNase-resistant particles of AAV1/SERCA2a or placebo. Randomisation was stratified by country and by 6 min walk test distance. All patients, physicians, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was time to recurrent events, defined as hospital admission because of heart failure or ambulatory treatment for worsening heart failure. Primary efficacy endpoint analyses and safety analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01643330. FINDINGS: Between July 9, 2012, and Feb 5, 2014, we randomly assigned 250 patients to receive either AAV1/SERCA2a (n=123) or placebo (n=127); 243 (97%) patients comprised the modified intention-to-treat population. Patients were followed up for at least 12 months; median follow-up was 17·5 months (range 1·8-29·4 months). AAV1/SERCA2a did not improve time to recurrent events compared with placebo (104 vs 128 events; hazard ratio 0·93, 95% CI 0·53-1·65; p=0·81). No safety signals were noted. 20 (16%) patients died in the placebo group and 25 (21%) patients died in the AAV1/SERCA2a group; 18 and 22 deaths, respectively, were adjudicated as being due to cardiovascular causes. INTERPRETATION: CUPID 2 is the largest gene transfer study done in patients with heart failure so far. Despite promising results from previous studies, AAV1/SERCA2a at the dose tested did not improve the clinical course of patients with heart failure and reduced ejection fraction. Although we did not find evidence of improved outcomes at the dose of AAV1/SERCA2a studied, our findings should stimulate further research into the use of gene therapy to treat patients with heart failure and help inform the design of future gene therapy trials. FUNDING: Celladon Corporation.

How B-Type Natriuretic Peptide (BNP) and Body Weight Changes Vary in Heart Failure With Preserved Ejection Fraction Compared With Reduced Ejection Fraction: Secondary Results of the HABIT (HF Assessment With BNP in the Home) Trial.

BACKGROUND: Heart failure is a common cause of hospitalization and can be divided into types with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). In this subanalysis of the HABIT (Heart Failure Assessment With BNP in the Home) trial, we examined the differences between home B-type natriuretic peptide (BNP) testing and weight monitoring in patients with HFpEF and with HFrEF before decompensation. METHODS AND RESULTS: This was a retrospective review of patients with HFpEF and HFrEF from the HABIT trial. The HFpEF patients compared with HFrEF patients were older and more obese and had lower baseline BNP values. Intra-individual BNP dispersion (spread of distribution over time) was greater in HFpEF than in HFrEF owing to rapid fluctuations (within 3 days). Slowly varying changes in BNP (estimated by a moving average) were equally predictive of ADHF risk in both HFpEF and HFrEF. However, in HFpEF, a rapid rise in BNP >200 pg/mL within 3 days was associated with an increased risk of acute decompensated heart failure (ADHF; hazard ratio 4.0), whereas a similar association was not observed in HFrEF. Weight gain ≥5 lb in 3 days had a high specificity but low sensitivity for ADHF in both HFpEF and HFrEF, whereas a lower threshold of ≥2 lb weight gain over 3 days in patients with HFpEF (but not HFrEF) was a moderately sensitive cutoff associated with decompensation (60% sensitivity). CONCLUSIONS: Patients with HFpEF and HFrEF have variations in their BNP and weight before decompensation. The rapid time scale behaves differently between the groups. In those with HFpEF, a 3-day period characterized by ≥2 lb weight gain and/or >200 pg/mL BNP rise was significantly associated with decompensation. Future prospective studies investigating different weight and BNP cutoffs for home monitoring of HFpEF and HFrEF patients should be performed to fully learn the value of BNP changes before clinical deompensation.

Factors Associated With Ineligibility for PCI Differ Between Inpatient and Outpatient ST-Elevation Myocardial Infarction.

OBJECTIVES: Without early revascularization, both inpatient and outpatient STEMIs have poor outcomes. Reasons for denying PCI for STEMI, however, remain uncertain. This single-center retrospective cohort study compares factors and outcomes associated with ineligibility for PCI between inpatients and outpatients following ST-elevation myocardial infarction (STEMI). METHODS: A total of 1,759 STEMI patients between June 2009 and January 2015 were assessed. Individual medical records were reviewed to obtain reasons for PCI ineligibility for STEMI patients who did not receive reperfusion therapy. RESULTS: Compared to outpatients with STEMI (n = 1,688), inpatients (n = 71) were less likely to receive coronary angiography (60.6% vs 95.9%; P < 0.001) or PCI (50.7% vs 80.9%; P < 0.001), with longer ECG/door to first device activation times (97 [78, 131] vs 63 [49, 78] minutes; P < 0.001). When coronary angiography was performed, however, similar rates of PCI and procedural success were seen in both groups. Principal contraindication for PCI was risk of bleeding within the inpatient population and complex coronary artery disease within the outpatient population. Total in-hospital mortality was higher in inpatient STEMIs compared to outpatients (42.2% vs 10.0%; P < 0.001), but lower for patients eligible for PCI in both groups. CONCLUSIONS: Reasons for PCI ineligibility differ between inpatient and outpatient STEMIs. Inpatients have increased risks of bleeding, lower coronary angiography and PCI use, and higher in-hospital mortality. Especially for inpatients, specific PCI STEMI protocols that anticipate and overcome types of ineligibility and delay for cardiac catheterization may improve outcomes.

Rationale and design of the Aquapheresis Versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-HF) trial.

BACKGROUND: In patients hospitalized with acutely decompensated heart failure, unresolved signs and symptoms of fluid overload have been consistently associated with poor outcomes. Regardless of dosing and type of administration, intravenous loop diuretics have not reduced heart failure events or mortality in patients with acutely decompensated heart failure. The results of trials comparing intravenous loop diuretics to mechanical fluid removal by isolated venovenous ultrafiltration have yielded conflicting results. Studies evaluating early decongestive strategies have shown that ultrafiltration removed more fluid and was associated with fewer heart failure-related rehospitalization than intravenous loop diuretics. In contrast, when used in the setting of worsening renal function, ultrafiltration was associated with poorer renal outcomes and no reduction in heart failure events. METHODS: The AVOID-HF trial seeks to determine if an early strategy of ultrafiltration in patients with acutely decompensated heart failure is associated with fewer heart failure events at 90 days compared with a strategy based on intravenous loop diuretics. Study subjects from 40 highly experienced institutions are randomized to either early ultrafiltration or intravenous loop diuretics. In both treatment arms, fluid removal therapies are adjusted according to the patients' hemodynamic condition and renal function. The study was unilaterally terminated by the sponsor in the absence of futility and safety concerns after the enrollment of 221 subjects, or 27% of the originally planned sample size of 810 patients. CONCLUSIONS: The AVOID-HF trial's principal aim is to compare the safety and efficacy of ultrafiltration vs that of intravenous loop diuretics in patients hospitalized with acutely decompensated heart failure. Because stepped treatment approaches are applied in both ultrafiltration and intravenous loop diuretics groups and the primary end point is time to first heart failure event within 90 days, it is hoped that the AVOID-HF trial, despite its untimely termination by the sponsor, will provide further insight on how to optimally decongest patients with fluid-overloaded heart failure.

Use of a Pulmonary Artery Pressure Sensor to Manage Patients With Left Ventricular Assist Devices.

BACKGROUND: Hemodynamic-guided management with a pulmonary artery pressure sensor (CardioMEMS) is effective in reducing heart failure hospitalization in patients with chronic heart failure. This study aims to determine the feasibility and clinical utility of the CardioMEMS heart failure system to manage patients supported with left ventricular assist devices (LVADs). METHODS: In this multicenter prospective study, we followed patients with HeartMate II (n=52) or HeartMate 3 (n=49) LVADs and with CardioMEMS PA Sensors and measured pulmonary artery pressure, 6-minute walk distance, quality of life (EQ-5D-5 L scores), and heart failure hospitalization rates through 6 months. Patients were stratified as responders (R) and nonresponders to reductions in pulmonary artery diastolic pressure (PAD). RESULTS: There were significant reductions in PAD from baseline to 6 months in R (21.5-16.5 mm Hg; P<0.001), compared with an increase in NR (18.0-20.3; P=0.002), and there was a significant increase in 6-minute walk distance among R (266 versus 322 meters; P=0.025) compared with no change in nonresponder. Patients who maintained PAD <20 compared with PAD ≥20 mm Hg for more than half the time throughout the study (averaging 15.6 versus 23.3 mm Hg) had a statistically significant lower rate of heart failure hospitalization (12.0% versus 38.9%; P=0.005). CONCLUSIONS: Patients with LVAD managed with CardioMEMS with a significant reduction in PAD at 6 months showed improvements in 6-minute walk distance. Maintaining PAD <20 mm Hg was associated with fewer heart failure hospitalizations. Hemodynamic-guided management of patients with LVAD with CardioMEMS is feasible and may result in functional and clinical benefits. Prospective evaluation of ambulatory hemodynamic management in patients with LVAD is warranted. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03247829.

Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure.

BACKGROUND: Adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase was assessed in a randomized, double-blind, placebo-controlled, phase 2 study in patients with advanced heart failure. METHODS AND RESULTS: Thirty-nine patients received intracoronary adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase or placebo. Seven efficacy parameters were assessed in 4 domains: symptoms (New York Heart Association class, Minnesota Living With Heart Failure Questionnaire), functional status (6-minute walk test, peak maximum oxygen consumption), biomarker (N-terminal prohormone brain natriuretic peptide), and left ventricular function/remodeling (left ventricular ejection fraction, left ventricular end-systolic volume), plus clinical outcomes. The primary end point success criteria were prospectively defined as achieving efficacy at 6 months in the group-level (concordant improvement in 7 efficacy parameters and no clinically significant worsening in any parameter), individual-level (total score for predefined clinically meaningful changes in 7 efficacy parameters), or outcome end points (cardiovascular hospitalizations and time to terminal events). Efficacy in 1 analysis had to be associated with at least a positive trend in the other 2 analyses. This combination of requirements resulted in a probability of success by chance alone of 2.7%. The high-dose group versus placebo met the prespecified criteria for success at the group-level, individual-level, and outcome analyses (cardiovascular hospitalizations) at 6 months (confirmed at 12 months) and demonstrated improvement or stabilization in New York Heart Association class, Minnesota Living With Heart Failure Questionnaire, 6-minute walk test, peak maximum oxygen consumption, N-terminal prohormone brain natriuretic peptide levels, and left ventricular end-systolic volume. Significant increases in time to clinical events and decreased frequency of cardiovascular events were observed at 12 months (hazard ratio=0.12; P=0.003), and mean duration of cardiovascular hospitalizations over 12 months was substantially decreased (0.4 versus 4.5 days; P=0.05) on high-dose treatment versus placebo. There were no untoward safety findings. CONCLUSIONS: The Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) study demonstrated safety and suggested benefit of adeno-associated virus type 1/sarcoplasmic reticulum Ca(2+)-ATPase in advanced heart failure, supporting larger confirmatory trials. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00454818.

Emergency department initiation of cardiopulmonary bypass: a case report and review of the literature.

BACKGROUND: Out-of-hospital cardiac arrest carries a dismal prognosis. Percutaneous extracorporeal membrane oxygenation (ECMO) has been used with success for in-hospital arrests, and some literature suggests improvement in long-term survival for out-of-hospital arrests as well. OBJECTIVES: This case highlights the use of ECMO in the emergency department. CASE REPORT: We report a case in which emergency physician-initiated ECMO was used as a bridge to definitive care in an out-of- hospital cardiac arrest in the United States. CONCLUSIONS: ECMO is a novel adjunct for patients in cardiac arrest in whom the usual advanced life support techniques have failed.

Transaxillary Stenting of LVAD Outflow Graft Obstruction.

An 82-year-old man with a HeartMate II left ventricular assist device presented with low-flow alarms and cardiogenic shock secondary to left ventricular assist device outflow graft obstruction. Given high risk for redo sternotomy, the heart team decided on percutaneous intervention with peripheral stents, a procedure that is currently limited to case reports. (Level of Difficulty: Advanced.).

Cardiac resynchronization therapy reduces the risk of hospitalizations in patients with advanced heart failure: results from the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial.

BACKGROUND: In the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial, 1520 patients with advanced heart failure were assigned in a 1:2:2 ratio to optimal pharmacological therapy or optimal pharmacological therapy plus cardiac resynchronization therapy (CRT-P) or CRT with defibrillator (CRT-D). Use of CRT-P and CRT-D was associated with a significant reduction in combined risk of death or all-cause hospitalizations. Because mortality also was significantly reduced (optimal pharmacological therapy versus CRT-D only), an assessment of the true reduction in hospitalization rates must consider the competing risk of death and varying follow-up times. METHODS AND RESULTS: To overcome the challenges of comparing treatment groups, we used a nonparametric test of right-censored recurrent events that accounts for multiple hospital admissions, differential follow-up time between treatment groups, and death as a competing risk. An end-point committee adjudicated and classified all hospitalizations. Compared with optimal pharmacological therapy, CRT-P and CRT-D were associated with a 21% and 25% reduction in all-cause, 34% and 37% reduction in cardiac, and 44% and 41% reduction in heart failure hospital admissions per patient-year of follow-up, respectively. Similar reductions were seen in hospitalization days per patient-year. The reduction in hospitalization rate for heart failure in the CRT groups appeared within days of randomization and remained sustained. Noncardiac hospitalization rates were not different between groups. CONCLUSIONS: Use of CRT with or without a defibrillator in advanced heart failure patients was associated with marked reductions in all-cause, cardiac, and heart failure hospitalization rates in an analysis that accounted for the competing risk of mortality and unequal follow-up time.

Mortality differences among patients with in-hospital ST-elevation myocardial infarction.

BACKGROUND: In-hospital ST-elevation myocardial infarction (STEMI) is associated with a higher mortality rate than out-of-hospital STEMI. Quality measures and universal protocols for treatment of in-hospital STEMI do not exist, likely contributing to delays in recognition and treatment. HYPOTHESIS: To analyze differences in mortality among three subsets of patients who develop in-hospital STEMI. METHODS: This was a multicenter, retrospective observational study of patients who developed in-hospital STEMI at six United States medical centers between 2008 and 2017. Patients were stratified into three groups: (1) cardiac, (2) periprocedure, or (3) noncardiac/nonpostprocedure. Outcomes examined include time from electrocardiogram (ECG) acquisition to cardiac catheterization lab arrival (ECG-to-CCL) and survival to discharge. RESULTS: We identified 184 patients with in-hospital STEMI (mean age 68.7 years, 58.7% male). Group 1 (cardiac) patients had a shorter average ECG-to-CCL time (69 minutes) than group 2 (periprocedure, 215 minutes) and group 3 (noncardiac/nonpostprocedure, 199 minutes). Compared to group 1, survival to discharge was lower for group 2 (OR 0.33, P = .102) and group 3 (OR 0.20, P = .016). After adjusting for prespecified covariates, the relationship between group and survival showed a similar trend but did not reach statistical significance. CONCLUSIONS: Patients who develop in-hospital STEMI in the context of a preceding procedure or noncardiac illness appear to have longer reperfusion times and higher in-hospital mortality than patients admitted with cardiac diagnoses. Larger studies are warranted to further investigate these observations. Health systems should place an increased emphasis on developing quality metrics and implementing quality improvement initiatives to improve outcomes for in-hospital STEMI.

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.

Effects of cardiac resynchronization therapy with or without a defibrillator on survival and hospitalizations in patients with New York Heart Association class IV heart failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) alone or combined with an implantable defibrillator (CRT-D) has been shown to improve exercise capacity and quality of life and to reduce heart failure (HF) hospitalizations and mortality in patients with New York Heart Association (NYHA) class III and IV HF. There is concern that the device procedure may destabilize these very ill class IV patients. We sought to examine the outcomes of NYHA class IV patients enrolled in the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial to assess the potential benefits of CRT and CRT-D. METHODS AND RESULTS: The COMPANION trial randomized 1520 patients with NYHA class III and IV HF to optimal medical therapy, CRT, or CRT-D. In the class IV patients (n=217), the primary end point of time to death or hospitalization for any cause was significantly improved by both CRT (hazard ratio [HR], 0.64; 95% CI, 0.43 to 0.94; P=0.02) and CRT-D (HR, 0.62; 95% CI, 0.42 to 0.90; P=0.01). Time to all-cause death and HF hospitalization was also significantly improved in both CRT (HR, 0.57; 95% CI, 0.37 to 0.87; P=0.01) and CRT-D (HR, 0.49; 95% CI, 0.32 to 0.75; P=0.001) Time to all-cause death trended to an improvement in both CRT (HR, 0.67; 95% CI, 0.41 to 1.10; P=0.11) and CRT-D (HR, 0.63; 95% CI, 0.39 to 1.03; P=0.06). Time to sudden death appeared to be significantly reduced in the CRT-D group (HR, 0.27; 95% CI, 0.08 to 0.90; P=0.03). There was a nonsignificant reduction in time to HF deaths for both CRT (HR, 0.68; 95% CI, 0.34 to 1.37; P=0.28) and CRT-D (HR, 0.79; 95% CI, 0.41 to 1.52; P=0.48). CONCLUSIONS: CRT and CRT-D significantly improve time to all-cause mortality and hospitalizations in NYHA class IV patients, with a trend for improved mortality. These devices should be considered in ambulatory NYHA class IV HF patients similar to those enrolled in COMPANION.

Outcomes of volume-overloaded cardiovascular patients treated with ultrafiltration.

BACKGROUND: Ultrafiltration (UF) can rapidly and predictably remove extracellular and intravascular fluid volume. To date, assessment of UF in patients with cardiovascular disease has been confined to short- and medium-term studies in patients with a principal diagnosis of acute heart failure. METHODS: In-hospital and long-term outcomes were reviewed from consecutive patients with cardiovascular disorders and recognized pulmonary and systemic volume overload treated with a simplified UF system with the capability for peripheral venovenous access. Trained abstractors reviewed both paper and electronic medical records. Patients with a principal diagnosis of heart failure versus other primary hospital discharge diagnoses were identified according to International Classification of Diseases, 9th Revision standards by independent coders. RESULTS: For a period of 43 months, 100 patients (76 male/24 female, 65 +/- 14.0 years of age, systolic dysfunction 64%) were treated with UF during 130 hospitalizations. Baseline systolic blood pressure was 119 +/- 23 mm Hg. Before UF, 53% were receiving intravenous vasoactive therapy. By using UF, 7.1 +/- 3.9 L of ultrafiltrate were removed during 2.0 +/- 1.2 treatments per hospitalization. Baseline creatinine was 1.8 +/- 0.8 and 1.9 +/- 1.2 (not significant) at discharge. Of the 15 in-hospital deaths, 14 occurred during the initial hospitalization. Left ventricular dysfunction was related to 13 (87%) of the 15 deaths; no deaths were related to UF use. In hospitalizations with a principal diagnosis of heart failure (n = 79), in-hospital mortality was 7.6% compared with an ADHERE risk tree estimated mortality of 7.5%. Multivariate logistic regression identified a trend for decreased systolic blood pressure to predict patient initial hospitalization mortality (P = .06). Kaplan-Meier survivals for all patients were 71% at 1 year and 67% at 2 years. Cox regression found decreased systolic blood pressure as a predictor of long-term mortality (P = .025). Total volume of ultrafiltrate removed, ejection fraction, history of coronary artery disease, creatinine clearance, gender, age, and principal diagnosis of heart failure were not significantly associated with long-term mortality. CONCLUSION: This series extends the spectrum of patients previously reported to be treated with UF. Despite marked volume overload, UF-treated patients with a principal diagnosis of heart failure had inpatient outcomes similar to the ADHERE registry. UF should be considered for a broad range of patients who present with volume overload.

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.

Adjudication of mortality events in a heart failure-arrhythmia trial by a multiparameter descriptive method: comparison with methods used in heart failure trials and methods used in arrhythmia trials.

INTRODUCTION: Mortality events in studies of cardiovascular disease are currently adjudicated using different methodologies depending on the investigators' preferences. Traditionally, deaths have been categorized by a single term, such as sudden, ischemic, or pump failure, a method that can be referred to as "categorical". In contrast, deaths may be categorized using several specific pieces of information about the event, a method that can be referred to as "multiparameter descriptive." Herein, we describe an adaptation of this descriptive method in a trial of patients with heart failure and arrhythmias. METHODS AND RESULTS: Case examples were selected from two clinical trials of an investigational implantable cardioverter-defibrillator (ICD)-biventricular pacing system in patients with symptomatic heart failure and a class I indication for ICD implantation, and the complete results for one of the trials are given. Deaths were classified according to the new descriptive method, and also according to published categorical methods for heart failure and arrhythmia trials. The descriptive method preserved traditional arrhythmia and heart failure trial single category classifications of death. Furthermore, there was agreement between the arrhythmia and heart failure category classifications in 126 of the 148 of the mortality events adjudicated (85%). CONCLUSION: A descriptive method for the classification of death retains more data and allows for comparison among trials using different classification schemes. This may allow greater mechanistic insight into study populations that have diverse and frequently multiple etiologies of death.

Percutaneous Repair of Postoperative Mitral Regurgitation After Left Ventricular Assist Device Implant.

Mitral regurgitation commonly improves after implantation of a left ventricular assist device without concomitant valvular repair owing to the mechanical unloading of the left ventricle. However, the development (or persistence) of significant mitral regurgitation after implantation of a left ventricular assist device is associated with adverse clinical events. We present a case of a left ventricular assist device patient who successfully underwent a percutaneous MitraClip procedure for repair of persistent late postoperative mitral insufficiency with demonstrable clinical and hemodynamic improvement.

In-Hospital ST-Segment Elevation Myocardial Infarction: Improving Diagnosis, Triage, and Treatment.

Importance: In-hospital ST-segment elevation myocardial infarction (STEMI) is a unique clinical entity with epidemiology, incidence, and outcomes distinct from that of out-of-hospital STEMI and has only within the past 10 years begun to receive increased attention and research. Patients with in-hospital STEMI are older, have more comorbidities, and more frequently have coagulopathies and contraindications for anticoagulation and fibrinolytic therapy. A standardized clinical definition of in-hospital STEMI is lacking. The objectives of this special communication are to (1) summarize the knowledge base regarding in-hospital STEMI; (2) review the challenges of diagnosis and treatment of patients with in-hospital STEMI; (3) present a standardized clinical definition for in-hospital STEMI; and (4) provide a quality improvement protocol to improve diagnosis, triage, and treatment of patients with in-hospital STEMI. Observations: Patients with in-hospital STEMI less frequently present with typical angina symptoms, and an electrocardiogram is often obtained owing to changes in clinical status, changes on telemetry, or a finding of elevated cardiac biomarker. The frequent nontypical presentations often lead to substantial delays in the diagnosis of STEMI. Only 34% to 71% of patients with in-hospital STEMI undergo diagnostic catheterization, and only 22% to 56% undergo percutaneous coronary intervention. Even in contemporary reports, some studies report in-hospital mortality in the range of 31% to 42%. Three areas of delay in the treatment of patients with in-hospital STEMI that merit particular attention are (1) delays in electrocardiogram acquisition, (2) delays in electrocardiogram interpretation, and (3) delays in activation of existing STEMI systems of care. Conclusions and Relevance: Treatment of patients with in-hospital STEMI is more complex and challenging than treatment of patients who develop out-of-hospital STEMI, leading to delays in diagnosis and triage and less frequent use of reperfusion therapy. Quality improvement programs targeted at decreasing delays and streamlining treatment of such patients may improve treatment and outcome.

Extracorporeal Ultrafiltration for Fluid Overload in Heart Failure: Current Status and Prospects for Further Research.

More than 1 million heart failure hospitalizations occur annually, and congestion is the predominant cause. Rehospitalizations for recurrent congestion portend poor outcomes independently of age and renal function. Persistent congestion trumps serum creatinine increases in predicting adverse heart failure outcomes. No decongestive pharmacological therapy has reduced these harmful consequences. Simplified ultrafiltration devices permit fluid removal in lower-acuity hospital settings, but with conflicting results regarding safety and efficacy. Ultrafiltration performed at fixed rates after onset of therapy-induced increased serum creatinine was not superior to standard care and resulted in more complications. In contrast, compared with diuretic agents, some data suggest that adjustment of ultrafiltration rates to patients' vital signs and renal function may be associated with more effective decongestion and fewer heart failure events. Essential aspects of ultrafiltration remain poorly defined. Further research is urgently needed, given the burden of congestion and data suggesting sustained benefits of early and adjustable ultrafiltration.