Clinical trial NCT00575211: Study Looking at the Recovery of New Onset Cardiomyopathy
Official title: Genetic Modulation of Left Ventricular Recovery in Recent Onset Cardiomyopathy
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Cardiomyopathy
Keywords: New onset cardiomyopathy
Onset of symptoms less than 6 months
LVEF < 40%
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2007-12-18
Enrollment: 373
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: New onset Cardiomyopathy patient with symptoms less than 6 months

Brief summary: This is a multi-center, prospective evaluation of left ventricular recovery on conventional therapy in patients with the recent onset of dilated cardiomyopathy. In some subjects with this disorder, the heart will recover significantly over the first year, while others will be left with a chronically weak heart. The proteins that help the heart recover are encoded by genes, which can differ markedly between individuals. The goal of the current study is to determine whether variation in these genes involved affect the probability that the heart will recover. We will also look at which genes are involved in inflammation and which ones are "turned on" (producing proteins) in circulating white blood cells.{These statements will only be added if the site has chosen to participate in RNA analysis}. In addition, this study will look at how levels of proteins in the blood, proteins called "cytokines' which control inflammation and proteins called "neurohormones" which are released when the heart weakens, affect the likelihood of recovery.

Enrollment will take place at 15 centers. The goal is to enroll approximately 500 adult subjects (age 18 years or older, both men and women) over the course of approximately 48 months.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: The primary objective of this study is to determine whether variation in genetic background influences clinical outcomes in new onset cardiomyopathy.
timeFrame: 5 years
Secondary outcomes:
measure: Determine whether cytokine or echo parameters can predict who will have significant recovery left ventricular function.
timeFrame: 5 years
Other outcomes:
Locations:
city: Orange
country: United States
facility: University of California - Irvine
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Newark
country: United States
facility: Newark Beth Israel Medical Center
state: New Jersey
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Univesity Health Sciences
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Hershey
country: United States
facility: Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Dalls
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Montreal
country: Canada
facility: SBMB Jewish General Hospital
state: Quebec
Study officials:
affiliation: University of Pittsburgh
name: Dennis McNamara, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: McNamara DM, Starling RC, Cooper LT, Boehmer JP, Mather PJ, Janosko KM, Gorcsan J 3rd, Kip KE, Dec GW; IMAC Investigators. Clinical and demographic predictors of outcomes in recent onset dilated cardiomyopathy: results of the IMAC (Intervention in Myocarditis and Acute Cardiomyopathy)-2 study. J Am Coll Cardiol. 2011 Sep 6;58(11):1112-8. doi: 10.1016/j.jacc.2011.05.033.