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Progress in precision medicine is limited by insufficient knowledge of transcriptomic or proteomic features in involved tissues that define pathobiological differences between patients. Here, myectomy tissue from patients with obstructive hypertrophic cardiomyopathy and heart failure is analyzed using RNA-Seq, and the results are used to develop individualized protein-protein interaction networks. From this approach, hypertrophic cardiomyopathy is distinguished from dilated cardiomyopathy based on the protein-protein interaction network pattern. Within the hypertrophic cardiomyopathy cohort, the patient-specific networks are variable in complexity, and enriched for 30 endophenotypes. The cardiac Janus kinase 2-Signal Transducer and Activator of Transcription 3-collagen 4A2 (JAK2-STAT3-COL4A2) expression profile informed by the networks was able to discriminate two hypertrophic cardiomyopathy patients with extreme fibrosis phenotypes. Patient-specific network features also associate with other important hypertrophic cardiomyopathy clinical phenotypes. These proof-of-concept findings introduce personalized protein-protein interaction networks (reticulotypes) for characterizing patient-specific pathobiology, thereby offering a direct strategy for advancing precision medicine. Understanding patient-specific pathobiological pathways is a critical step for advancing precision medicine. Here the authors show that individualized protein-protein interaction networks provide key insight on patient-level pathobiology and clinically relevant pathophenotypic characteristics in a complex disease.

The genetic etiology of hypertrophic cardiomyopathy (HCM) and the critical role of sarcomeric variants in its pathogenesis are well recognized (1). Among these, loss-of-function variants in the myosin binding protein C gene ( ) are the most prevalent, resulting in protein insufficiency when compared to healthy controls (1). Preclinical studies have shown that recombinant adeno-associated virus serotype 9 (rAAV9) carrying the full-length transgene can increase protein expression and improve cardiac function. However, pre-existing anti-AAV9 antibodies-neutralizing (NAb) and total (TAb)-may limit gene transfer efficacy and eligibility for gene therapy. We sought to evaluate the prevalence of anti-AAV9 antibodies in patients with -associated HCM to optimize patient selection for MyPEAK-1, an ongoing trial evaluating the safety, tolerability, and pharmacodynamics of TN-201, an AAV9: gene therapy. This was a prospective, cross-sectional study of 100 adults (aged 18-65 years) with symptomatic -associated HCM (NYHA II-IV). Blood samples were analyzed for anti-AAV9 NAb (transduction inhibition assay) and TAb (electrochemiluminescence assay). Titers ≥1:10 were considered positive. Associations between antibody levels and demographic and clinical characteristics were explored using statistical tests. Pre-existing anti-AAV9 NAb were undetectable in 50% of patients. Among those with detectable titers (range: 1:10-1:720), only 16% exceeded 1:40. TAb were undetectable in 53%; titers ranged from 1:10 to 1:65,600. A strong correlation was observed between NAb and TAb titers (r = 0.671,  < 0.001). Serostatus was not significantly associated with age, sex, NYHA class, or ethnicity (all  > 0.05). Pre-existing immunity to AAV9 was absent or low in most -associated HCM patients, with only a small proportion exceeding standard NAb thresholds for AAV gene therapy trials. These findings support the feasibility of a clinical trial of TN-201, an AAV9-based gene replacement therapy, in this population. Given the concordance between NAb and TAb assays, either may be suitable for screening.

Sudden cardiac death (SCD) in young athletes is generally caused by inherited cardiac disorders. While these events are relatively few compared to other cardiac deaths, they are tragic in that death occurs in a young, otherwise healthy person. The genetic abnormalities most associated with SCD are hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. As a result of growing awareness that these deaths can be prevented, guidelines have been issued in both Europe and the United States to help screen and determine qualification for young persons who want to participate in competitive athletics. There remains debate on the how extensive screening should be, in particular over the use of the 12-lead electrocardiogram (ECG), with European guidelines mandating ECG and United States guidelines not recommending routine use of the ECG.

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. 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. 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. 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. MyoKardia.

Background Normal exercise single-photon emission computed tomography (SPECT) studies are associated with a low event rate (<1.0%/year) during short-term follow-up. The influence of cardiac risk factors on long-term outcomes in such patients has not been well studied. Material and Methods 2,597 patients (55 ± 12 years, male 41%) without a history of heart disease and a normal exercise SPECT between the years 1995 and 2006 were followed for a mean 6.8 ± 3.1 years for all-cause mortality assessed for using the Social Security Death Index. Baseline clinical risk factors and other clinical information were recorded for each patient and compared to outcomes. Results The mortality rate was 0.9%/year for our overall study population but varied according to individual baseline risk factors. Three coronary artery disease (CAD) risk factors were significant predictors of all-cause mortality: hypertension, diabetes, and smoking. When all three were absent, long-term all-cause mortality rate averaged 0.2%/year and when all three were present, all-cause mortality averaged 1.8%/year, constituting a 5.7-fold adjusted increase in risk (95% CI 2.7-12.8, P  < .0001). Conclusions During follow-up, annualized mortality rate varies markedly according to the number of CAD risk factors in patients without known heart disease and a normal exercise SPECT stress. Despite overall excellent long-term prognosis of a normal exercise SPECT, the burden of traditional CAD risk factors exert a strong synergistic influence on long-term survival and warrant aggressive treatment in this patient population.

Sudden cardiac death (SCD) in young athletes is generally caused by inherited cardiac disorders. While these events are relatively few compared to other cardiac deaths, they are tragic in that death occurs in a young, otherwise healthy person. The genetic abnormalities most associated with SCD are hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. As a result of growing awareness that these deaths can be prevented, guidelines have been issued in both Europe and the United States to help screen and determine qualification for young persons who want to participate in competitive athletics. There remains debate on the how extensive screening should be, in particular over the use of the 12-lead electrocardiogram (ECG), with European guidelines mandating ECG and United States guidelines not recommending routine use of the ECG.

Transcriptomic changes in heart failure (HF) patients prior to and following left ventricular assist device (LVAD) support have been extensively studied. Recent studies focused on understanding DNA methylation changes in patients with cardiovascular diseases (CVD) and the role of circulating markers of DNA methylation as clinical predictors of the risk of CVD related morbidity and mortality. In this study, we used paired (pre- and post-LVAD) myocardial samples to examine changes in DNA methylation alongside RNA and protein expression. Our data suggests that patients with no improvement in cardiac function after LVAD therapy, despite showing an improvement in energy production (increased β-oxidation of fatty acid) exhibited persistent activation of profibrotic signaling, increased collagen deposition and cytoskeletal disarray evident from abnormal increase in sarcomeric distance following LVAD support. Contrarily, patients with improvement in cardiac function after LVAD therapy showed activation of pro-inflammatory signaling, collagen degradation and myogenesis. Both RNA sequencing and western blot data showed increased COL1A1 and decreased TPPP3 in post-NR thereby suggesting increased fibrosis and disrupted cytoskeletal signaling as potential barriers to myocardial recovery. Additionally, responders to LVAD therapy showed a significant reversal in myocardial interstitial fibrosis with a preserved sarcomeric architecture. Mice model of HF and recovery also confirmed our human findings, with reduced fibrotic signaling and improved cytoskeletal remodeling signaling observed in mice that showed improvement in cardiac function compared to mice with HF. Overall, our data suggests that altering extracellular matrix regulation and cytoskeletal signaling pathways may contribute to myocardial recovery. Further studies targeting these pathways are required to identify new HF therapeutic targets.

Mechanical unloading and circulatory support with left ventricular assist devices (LVADs) mediate significant myocardial improvement in a subset of advanced heart failure (HF) patients. The clinical and biological phenomena associated with cardiac recovery are under intensive investigation. Left ventricular (LV) apical tissue, alongside clinical data, were collected from HF patients at the time of LVAD implantation (n=208). RNA was isolated and mRNA transcripts were identified through RNA sequencing and confirmed with RT-qPCR. To our knowledge this is the first study to combine transcriptomic and clinical data to derive predictors of myocardial recovery. We used a bioinformatic approach to integrate 59 clinical variables and 22,373 mRNA transcripts at the time of LVAD implantation for the prediction of post-LVAD myocardial recovery defined as LV ejection fraction (LVEF) ≥40% and LV end-diastolic diameter (LVEDD) ≤5.9cm, as well as functional and structural LV improvement independently by using LVEF and LVEDD as continuous variables, respectively. To substantiate the predicted variables, we used a multi-model approach with logistic and linear regressions. Combining RNA and clinical data resulted in a gradient boosted model with 80 features achieving an AUC of 0.731±0.15 for predicting myocardial recovery. Variables associated with myocardial recovery from a clinical standpoint included HF duration, pre-LVAD LVEF, LVEDD, and HF pharmacologic therapy, and LRRN4CL (ligand binding and programmed cell death) from a biological standpoint. Our findings could have diagnostic, prognostic, and therapeutic implications for advanced HF patients, and inform the care of the broader HF population.