Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.

Reasons for, and outcomes of patients who were referred for a ventricular assist device but were declined: the recent era forgotten ones.

BACKGROUND: Ventricular assist devices (VADs) have a proven survival benefit in select patients with advanced heart failure, yet many patients considered for implantation are declined for various reasons. The outcome of these patients is obscure owing to their exclusion from recent VAD studies. We aim to compare the outcomes of patients who received a VAD to those who did not. METHODS: For this study, the Artificial Heart Program's database at Intermountain Medical Center was queried from 2006 to 2012 for patients referred for a VAD. Kaplan-Meier survival analysis was performed with log-rank test determining significance. RESULTS: Of 232 patients included, 118 patients received a VAD and 114 patients did not. The prevailing reason for VAD decline in eligible and willing patients was due to pre-existing illness (39%). Mortality was higher in non-VAD vs. VAD patients (58.8% vs. 35.6%, p < 0.001) with a median time-to-death of 67 (IQR:12-314) and 301 (IQR:136-694) d, respectively (p = 0.007). CONCLUSIONS: In the current era of non-pulsatile VADs, mortality of patients who are considered but not implanted remains high. Additionally, mortality of these patients occurred much sooner. Educational efforts ensuring timely referral for VAD therapy are important to maximize the number of patients who may benefit.

Discovery of TITIN Gene Truncating Variant Mutations and 5-Year Outcomes in Patients With Nonischemic Dilated Cardiomyopathy.

Genetic factors play an important role in nonischemic dilated cardiomyopathy (NIDC). However, prime opportunities remain for genetic discovery and prognostic understanding. TITIN gene truncating variant mutations (TTNtv) are of interest because of their frequent appearance in NIDC series. We sought to discover known and novel TTNtv mutations in a NIDC cohort and assess 5-year outcomes. Patients with NIDC entered into the INSPIRE Registry with ≥3 years of follow-up were studied. Whole exome sequencing (WES) was performed using an Illumina Novaseq platform. Genetic analysis used Sentieon software and the GRCh38 human reference genome. Variant calls were annotated with ClinVar. Five-year outcomes were determined by functional assessment and ejection fraction (EF) as recovered (EF ≥50%), persistent (EF 21% to 49%), or progressive (left ventricular assist device, transplant, heart failure [HF] or arrhythmic death, or EF ≤20%). The study comprised 229 NIDC patients (age = 50 ± 15 years, 58% men). TTNtv's were discovered in 27 patients with 22 unique mutations; (7 known, 15 novel). TTNtv+ patients more frequently presented with severe NIDC (EF ≤20%) (p = 0.032). By 5-year, outcomes were worse in TTNtv+ patients (p = 0.027), and patients less often recovered (11% vs. 30%). Prognosis was similar with known and novel mutations. Nongenetic (e.g., environmental) cocausal risk factors for HF were frequently present, and these factors frequently appeared to act in concert with genetic variants to precipitate clinical HF. In conclusion, our study expands the library of likely pathogenic TTN mutations and increases our understanding of their clinical impact in association with other HF risk factors.

Mechanisms of Improved Mortality Following Ablation: Does Ablation Restore Beta-Blocker Benefit in Atrial Fibrillation/Heart Failure?

Observational trials have shown that atrial fibrillation ablation favorably impacts long-term outcomes in systolic heart failure. These outcomes have been confirmed by randomized prospective trials highlighting the favorable impact of ablation on left ventricular function and remodeling, risk of heart failure hospitalization, and mortality. Ablation along with established heart failure medications is new and supported conceptually by the value of restoring sinus rhythm, avoiding long-term antiarrhythmic drugs, and minimizing drug-drug interactions. Observational data suggest a potential long-term benefit of beta-blockers with ablation that becomes augmented as follow-up is extended from 1 to 5 years.

Microvascular Loss and Diastolic Dysfunction in Severe Symptomatic Cardiac Allograft Vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) remains an important source of mortality after heart transplant. The aim of our study was to identify structural and microvasculature changes in severe CAV. METHODS AND RESULTS: The study group included heart transplant recipients with severe CAV who underwent retransplantation (severe CAV, n=20). Control groups included time from transplant matched cardiac transplant recipients without CAV (transplant control, n=20), severe ischemic cardiomyopathy patients requiring left ventricular assist device implantation (ischemic control, n=18), and normal hearts donated for research (donor control, n=10). We collected baseline demographic information, echocardiography data, and performed histopathologic examination of myocardial microvasculature. Echocardiographic features of severe CAV included lack of eccentric remodeling and presence of significant diastolic dysfunction. In contrast, diastolic function was preserved in transplant control subjects. Histopathologic examination showed increased interstitial fibrosis among severe CAV, transplant controls, and ischemic control patients. Compared with transplant controls, severe CAV subjects had reduced capillary density and increased capillary wall thickness ( P<0.05). CONCLUSIONS: Our results suggest that the marked diastolic dysfunction and resultant symptoms in patients with severe CAV may be secondary to the loss of microvasculature and remodeling of remaining microvessels rather than a consequence of interstitial fibrosis. The clinical significance and potential therapeutic implications of these unique microvasculature characteristics warrant further investigation.

Return-to-Play in 2017 and the Role of Shared Decision-Making in Patients with Inherited and Acquired Channelopathies and Cardiomyopathies.

OPINION STATEMENT: Shared decision-making is based upon a physician-patient encounter in which there is adequate education using aids if needed, a mutual discussion of how to assist the patient in weighing risks and benefits, and a supportive environment that allows the patient to deliberate on the clinical decision and make their own choice. This decision-making paradigm centers on the principles of autonomy and self-determination. Physical activity is a critical part of healthy lifestyle choices that helps lower risk of cardiovascular disease or the progression of it. Exercise is also a significant contributor to quality of life in many patients in additional to the health benefits. In patients with inherited or acquired cardiovascular disease, exercise may increase risk of electrical and hemodynamic instability. There is a paucity of data to guide physicians and committees that create guidelines regarding athletic and fitness participation in these patients, particularly when the patient wants to participate in those activities that are considered moderate-severe in intensity. As a consequence, the principles of shared decision-making are critical for physicians to use to help patients with cardiovascular disease make the best decision regarding fitness participation that will minimize their risk of new disease or progression of their disease and enhance their quality of life.

Mixed cellular and antibody-mediated rejection in heart transplantation: In-depth pathologic and clinical observations.

BACKGROUND: Little is known about mixed cellular and antibody-mediated rejection (MR) in heart transplantation. It remains unclear whether cardiac MR has distinctive pathologic and clinical features beyond those of simultaneous cellular rejection (CR) and antibody-mediated rejection (AMR). In this study we systematically explore the pathologic and clinical characteristics of MR in heart transplantation. METHODS: The UTAH Cardiac Transplant Program database was queried for transplant recipients who survived long enough to have at least one endomyocardial biopsy (EMB) between 1985 and 2014. Only EMBs with both CR and AMR scores documented were included. In addition to detailed pathologic analyses, we also examined the incidence and prevalence of MR, the likelihood to transition from and to MR, and mortality associated with MR. RESULTS: Patients (n = 1,207) with a total of 28,484 EMBs met the study inclusion criteria. The overall prevalence of MR was 7.8% and it was nearly twice as frequent within the first year post-transplant. Mild MR was by far the most common occurrence and was typically preceded by an immune active state. When CR increased in severity, AMR tended to follow, but the reverse was not true. On pathology, individual features of CR and AMR were more easily separated in cases of mild MR, whereas they substantially overlapped in more severe cases. MR was associated with a significant cardiovascular death risk that was incremental with severity. CONCLUSIONS: MR is not common, usually occurs early after transplant, and is associated with worse outcomes. MR reflects a complex interplay between cellular and humoral processes, which varies with rejection severity.

Ultraviolet Radiation Affects Thoratec HeartMate II Driveline Mechanical Properties: A Pilot Experiment.

Longevity and quality of life for left ventricular assist device (LVAD) patients are plagued by driveline exit site infections. Ultraviolet (UV) radiation, a current treatment in wound healing clinics, could potentially treat LVAD exit site infections. However, the effect of UV radiation on the tensile properties of HeartMate II (HMII) driveline material is unknown. The sleeve of a single HMII driveline was distributed into six exposure groups (n = 10/group). The six groups were further divided into two treatment cohorts designed to replicate wound treatment schedules of postimplant LVAD patients. Strip biaxial tensile tests were performed on both unexposed and exposed samples to analyze changes in material elasticity (Young's modulus), point of deformation (yield strength), and breaking point. Our data suggest that UV exposure changes the elasticity of the HMII driveline. However, the material endured aberrantly large forces and the properties remained within the safety threshold of device performance. This study warrants further examination of the effect of UV light on driveline material, to determine safety, reliability, and efficacy of UV treatment on exit site infections.

Effect of the 2011 vs 2003 duty hour regulation-compliant models on sleep duration, trainee education, and continuity of patient care among internal medicine house staff: a randomized trial.

IMPORTANCE: On July 1, 2011, the Accreditation Council for Graduate Medical Education implemented further restrictions of its 2003 regulations on duty hours and supervision. It remains unclear if the 2003 regulations improved trainee well-being or patient safety. OBJECTIVE: To determine the effects of the 2011 Accreditation Council for Graduate Medical Education duty hour regulations compared with the 2003 regulations concerning sleep duration, trainee education, continuity of patient care, and perceived quality of care among internal medicine trainees. DESIGN AND SETTING: Crossover study design in an academic research setting. PARTICIPANTS: Medical house staff. INTERVENTION: General medical teams were randomly assigned using a sealed-envelope draw to an experimental model or a control model. MAIN OUTCOME MEASURES: We randomly assigned 4 medical house staff teams (43 interns) using a 3-month crossover design to a 2003-compliant model of every fourth night overnight call (control) with 30-hour duty limits or to one of two 2011-compliant models of every fifth night overnight call (Q5) or a night float schedule (NF), both with 16-hour duty limits. We measured sleep duration using actigraphy and used admission volumes, educational opportunities, the number of handoffs, and satisfaction surveys to assess trainee education, continuity of patient care, and perceived quality of care. RESULTS The study included 560 control, 420 Q5, and 140 NF days that interns worked and 834 hospital admissions. Compared with controls, interns on NF slept longer during the on call period (mean, 5.1 vs 8.3 hours; P = .003), and interns on Q5 slept longer during the postcall period (mean, 7.5 vs 10.2 hours; P = .05). However, both the Q5 and NF models increased handoffs, decreased availability for teaching conferences, and reduced intern presence during daytime work hours. Residents and nurses in both experimental models perceived reduced quality of care, so much so with NF that it was terminated early. CONCLUSIONS AND RELEVANCE: Compared with a 2003-compliant model, two 2011 duty hour regulation-compliant models were associated with increased sleep duration during the on-call period and with deteriorations in educational opportunities, continuity of patient care, and perceived quality of care.

Blood cultures for community-acquired pneumonia: are they worthy of two quality measures? A systematic review.

BACKGROUND: Obtaining blood cultures (BCs) for patients hospitalized with community-acquired-pneumonia (CAP) has been recommended by experts and used as a measure of quality of care. However, BCs are infrequently positive in these patients and their effect on clinical management has been questioned. PURPOSE: We performed a systematic review of the literature to determine the impact of BCs on clinical management in CAP requiring hospitalization and thus its appropriateness as a quality measure. DATA SOURCES: We searched MEDLINE, MEDLINE In-Process, and the Cochrane databases for English-language studies that reported the effect of BCs on management of adults hospitalized with CAP. We also searched the reference lists of included studies and background articles and asked experts to review our list for completeness. STUDY SELECTION: Studies were chosen if they included adults admitted to the hospital with CAP, BCs were obtained at admission, and BC-directed management changes were reported. DATA EXTRACTION: We abstracted study design, BC positivity, and frequency of BC-directed management changes. DATA SYNTHESIS: Fifteen studies, all with observational cohort design, were identified and reviewed. Two included only patients with BCs positive for pneumococcus, yielding 13 studies for the primary analysis. BCs were true-positive in 0% to 14% of cases. They led to antibiotic narrowing in 0% to 3% of patients and to antibiotic broadening ultimately associated with a resistant organism in 0% to 1% of patients. CONCLUSIONS: BCs have very limited utility in immunocompetent patients hospitalized with CAP. Pneumonia quality measures that include BCs should be reassessed.