Patient case: 32-year-old male with dilated cardiomyopathy; genetic feature: LMNA

Clinical trial: DCM Precision Medicine Study

Summary: The aims of the DCM Precision Medicine Study are to test the hypothesis that DCM has substantial genetic basis and to evaluate the effectiveness of a family communication intervention in improving the uptake and impact of family member clinical screening.

Detailed description: Dilated cardiomyopathy of unknown cause (DCM), known clinically as idiopathic dilated cardiomypathy, is the most common cardiomyopathy and is the leading cause of heart transplantation. DCM affects approximately one million individuals, and so has a major impact on US public health. DCM is commonly asymptomatic until very late in its course when it causes heart failure, disability, and death. Because of its clinical course, any means to identify patients at risk for DCM or to detect DCM in its asymptomatic phase could provide enormous opportunity for intervention to extend lives and prevent late-stage disease. Within this paradigm precision medicine for DCM could greatly impact health care outcomes and costs. Recent advances in DCM genetics have introduced these possibilities, but unresolved questions of familial recurrence risk, genetic etiology, racial differences, and family-based screening must be addressed to move ahead. The central hypothesis of this study, based on published studies of the investigative group, states that DCM has substantial genetic basis. For this study the investigators hypothesize that: (a) 35% of probands of both European and African ancestry (EA/AA) will be classified as familial in a cohort recruited in a multicenter US consortium and given explicit recommendations and assistance to achieve the clinical screening of relatives; (b) approximately 40% of DCM probands, whether categorized as familial or non-familial, or as EA or AA, will have pathogenic or likely pathogenic variants in genes previously implicated in DCM; and (c) a tailored intervention to help DCM probands communicate DCM risk to their family members will improve the uptake and impact of necessary clinical and genetic testing. To test these hypotheses, the investigators propose to: (1) estimate and compare the frequencies of EA and AA DCM probands classified as having familial DCM; (2) estimate and compare the proportions of probands with an identifiable genetic cause of DCM in groups defined by proband classification (familial/non-familial) and ancestry (EA/AA); and (3) evaluate the impact of a randomized intervention to aid and direct family communication on participation of at-risk family members in clinical screening and appropriate follow-up surveillance for DCM. These aims will be accomplished by recruiting a cohort of 1300 DCM probands (600 EA, 600 AA, 100 Hispanic ethnicity), performing cardiovascular clinical screening of 2600 family members, performing genetic testing of probands and affected family members by exome sequencing, returning genetic results, and randomizing probands to an intervention to improve family communication regarding DCM risk. Proving these hypotheses would be transformative for the field: rather than viewing DCM as only a clinical diagnosis, cardiovascular professionals would understand DCM as a genetic disease that should be managed using genetic diagnostic and family-based preventive strategies. These study results would make precision medicine for DCM a reality.

Eligibility: Inclusion Criteria:
  -  Meeting criteria for dilated cardiomyopathy (DCM) :
  -  Left ventricular ejection fraction <50%
  -  Left ventricular enlargement (A left ventricular end-diastolic dimension > 95%tile population standard based on gender and height).
  -  Detectable causes of cardiomyopathy, except genetic, excluded beyond a reasonable doubt at the time of DCM diagnosis (that is, meeting clinical criteria for idiopathic DCM)
  -  Any age (including children)
  -  Non-Hispanic and Hispanic ethnicity
  -  All races (PI pre-approval required for recruitment beyond pre-specified recruitment targets).
  -  Ability to give informed consent
  -  Ability to communicate in English (except Spanish language at sites approved to recruit individuals of Hispanic ethnicity)
  -  Willingness to participate in a family-based study (patient willing to work with a clinical site and/or OSU to facilitate the recruitment and enrollment of family members to the study).
  Exclusion Criteria:
  -  Coronary artery disease (CAD) causing ischemic cardiomyopathy (> 50% narrowing, any major epicardial coronary artery)
  -  Primary valvular disease
  -  Adriamycin or other cardiotoxic drug exposure
  -  Other forms of cardiomyopathy: Hypertrophic, Restrictive, or Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
  -  Congenital heart disease
  -  Other detectable causes of dilated cardiomyopathy, including sarcoid and hemochromatosis.
  -  Other active multi-system disease that may cause DCM (e.g., active connective tissue disease).
  -  Severe and untreated or untreatable hypertension (systolic blood pressures routinely greater than 180 mm Hg and/or diastolic blood pressures greater than 120 mm Hg, and if resistant to multidrug treatment).
  -  However, conventional risk factors for DCM, including obesity, routinely treated hypertension, alcohol use, pregnancy or the peri-partum period, or left ventricular noncompaction, will NOT be considered exclusion criteria.

Relevance to patient case: not relevant