DCM Precision Medicine Study

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.

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.