Background The etiology of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or non-familial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality. Methods Based on this hypothesis, we have launched the NHLBI- and NHGRI-funded DCM Precision Medicine Study, which aims to enroll 1,300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2,600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12-14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity-ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of Family Heart Talk, an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives. Conclusions We anticipate this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives.
Background: The hypothesis of the Dilated Cardiomyopathy Precision Medicine Study is that most dilated cardiomyopathy has a genetic basis. The study returns results to probands and, when indicated, to relatives. While both the American College of Medical Genetics and Genomics/Association for Molecular Pathology and ClinGen’s MYH7 -cardiomyopathy specifications provide relevant guidance for variant interpretation, further gene- and disease-specific considerations were required for dilated cardiomyopathy. To this end, we tailored the ClinGen MYH7 -cardiomyopathy variant interpretation framework; the specifications implemented for the study are presented here. Methods: Modifications were created and approved by an external Variant Adjudication Oversight Committee. After a pilot using 81 probands, further adjustments were made, resulting in 27 criteria (9 modifications of the ClinGen MYH7 framework and reintroduction of 2 American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria that were deemed not applicable by the ClinGen MYH7 working group). Results: These criteria were applied to 2059 variants in a test set of 97 probands. Variants were classified as benign (n=1702), likely benign (n=33), uncertain significance (n=71), likely pathogenic (likely pathogenic; n=12), and pathogenic (P; n=3). Only 2/15 likely pathogenic/P variants were identified in Non-Hispanic African ancestry probands. Conclusions: We tailored the ClinGen MYH7 criteria for our study. Our preliminary data show that 15/97 (15.5%) probands have likely pathogenic/P variants, most of which were identified in probands of Non-Hispanic European ancestry. We anticipate continued evolution of our approach, one that will be informed by new insights on variant interpretation and a greater understanding of the genetic architecture of dilated cardiomyopathy. Clinical Trial Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03037632
Abstract:With the aging of the world's population and the rise of chronic illness such as heart failure (HF), the economic burden, number of hospitalizations, and penalties imposed for failure to meet hospital readmission expectations will continue to rise, thus increasing pressure on clinicians to utilize successful HF monitoring interventions to improve these measures. Telephone monitoring in patients with chronic HF utilizes a proactive approach in the care of such patients, and for this review is grouped into three categories, ie, structured telephone support, telemonitoring, and remote implantable device monitoring. Earlier studies on structured telephone support and telemonitoring suggested a clear benefit on mortality and HF admissions, although several recent large, randomized controlled studies have been neutral. Optimizing medical therapy requires an accurate assessment of volume status by the clinician; therefore, symptom report and weight monitoring alone are often challenging in the identification of true HF decompensation because they are not very sensitive markers. The use of remote monitoring technology for follow-up of patients with implantable devices, including implantable cardiac defibrillators and cardiac resynchronization therapy devices, can aid in identifying HF decompensation. Self-care or self-management is an essential component of a chronic illness such as HF, and it is important for such patients to be engaged in their health care to best utilize the telephone monitoring intervention. System design, adequate staffing, patient satisfaction, and treatment adherence are important for success of the telemonitoring system. Telephone monitoring seems to be an effective approach in the chronic HF population. In the future, large-scale telemonitoring programs may come into place as well as additional remote implantable monitoring devices.
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