Study Looking at the Recovery of New Onset Cardiomyopathy

After presenting with new onset idiopathic dilated cardiomyopathy, one third of patients
experience dramatic recovery of left ventricular function, while for the majority chronic
heart failure and left ventricular dysfunction persist. This marked variation in clinical
outcomes is determined in part by genetic heterogeneity of the systemic response to
myocardial injury. This population has been excluded from most clinical trials and few
studies have examined the role of cytokine and neurohormonal mediators in modulating the
balance between left ventricular recovery and remodeling in early cardiomyopathy. This
proposal will investigate whether genetic polymorphisms of inflammatory and neurohormonal
mediators influence subsequent clinical outcomes for patients with recent onset primary
(idiopathic) dilated cardiomyopathy. The study will enroll 500 patients with recent onset
left ventricular dysfunction (LVEF < 0.40) due to non-ischemic primary cardiomyopathy at
eleven centers and follow these patients prospectively to evaluate subsequent left
ventricular recovery and freedom from clinical events.

Specific aim 1 will be to determine the correlation of echocardiographic parameters of
systolic and diastolic functional entry with circulating inflammatory mediators: TNF, IL-6
and TNF receptors 1 and 2. Specific aim 2 will be to determine the predictive value of early
plasma TNFα levels and of left ventricular size by transthoracic echo at baseline in
predicting improvements in left ventricular ejection function (LVEF) at 6 months. Specific
aim 3 will evaluate the effects of the TNFA 1/2 promoter polymorphism on circulating plasma
TNF levels and its influence on subsequent improvement in LVEF. Specific aim 4 will look at
the impact of the deletion allele of the angiotensin-converting enzyme and the genetic
variation of beta 1 and beta 2 adrenergic receptors on left ventricular recovery.

Inclusion Criteria:

1. Patients must be 18 years or over, and may be of either gender and of any race.

2. Patients must have significantly systolic dysfunction, defined as a left ventricular
ejection fraction of less than or equal to 40% by transthoracic echocardiography.

3. The patients must have a recent onset of dilated cardiomyopathy. Specifically, the
initial signs or symptoms of cardiomyopathy should not pre-date the time of
evaluation for the study by more than six months.

4. Subjects diagnosed during with peripartum cardiomyopathy (PPCM) are allowed as long
as they are enrolled within six months of cardiac symptoms.

5. Subjects presenting with acute heart failure with a positive familial history of
cardiomyopathy are included. Subjects who are asymptomatic, but are diagnosed with a
cardiomyopathy of unknown duration during screening for known familial disease are
excluded

6. Patients must be competent to give informed consent.

Exclusion Criteria:

1. Coronary artery disease as defined as a single coronary artery stenosis of a major
epicardial vessel greater than 50% or a previous history of myocardial infarction.

2. Patients with a history of familial cardiomyopathy, or a primary relative defined as
parents, siblings or children with a dilated cardiomyopathy are excluded.

3. Past or present history of alcoholism, or in whose current alcohol consumption
exceeds an average of three drinks per day. A past history of cocaine or IV drug
abuse as a possible explanation for their cardiomyopathy as well as substance abuse
of prescription pain relievers or any illicit drug that may hinder the participant's
ability to complete study follow-up.

4. Patients who are post cardiac transplant.

5. Patients whose heart failure is felt to be secondary to primary valvular disease,
uncorrected thyroid disease, uncontrolled hypertension despite medical therapy,
obstructive or hypertrophic cardiomyopathy, pericardial disease, or a systemic
illness such as sarcoidosis.

6. Patients whose history of cardiac symptoms or signs of cardiac disease predate the
time of evaluation by more than six months are excluded.

7. Evidence of ongoing bacteremia or sepsis. Patient with a febrile illness felt to be
secondary to myocarditis can be included (even with a non-diagnostic biopsy) if a
bacteriologic cause of the illness is excluded.

8. Patients with other life threatening diseases such as malignancy which would likely
decrease their life expectancy over the next three years. Any history of malignancy
treated with either chest radiation or chemotherapy.

9. The following patients are excluded for medical reasons: Patients with evidence of
chronic liver disease (total bilirubin >3.0mg%) or chronic renal disease (creatinine
> or equal to 2.5mg%) are excluded from the study. Subjects who present with an acute
worsening of renal function or liver function tests in the setting of potentially
fulminant myocarditis can be enrolled. Patients whose hepatic abnormalities are
secondary to hypoperfusion can also be considered.

10. Patients with previous history of diabetes and with evidence of multisystem end organ
damage (i.e. end stage renal disease and cardiomyopathy) or with evidence of any
coronary disease. Patient with diabetes without significant end organ damage is
allowed.

11. Patients enrolled in other placebo controlled experimental trials.

12. Patients who have had a myocardial biopsy, which reveals evidence of hemochromatosis,
amyloid, sarcoidosis, or giant cell myocarditis, are excluded.