Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy

Condition(s) targeted: Myocardial Fibrosis; Hypertrophic Cardiomyopathy

Intervention: spironolactone (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Tufts Medical Center

Overall contact:
Martin S Maron, MD, Phone: 617 636-8066, Email: mmaron@tuftsmedicalcenter.org

Hypertrophic Cardiomyopathy (HCM) is the most common genetic cardiomyopathy and remains the leading cause of sudden cardiac death in young people and an important cause of heart failure symptoms and death at any age. In HCM, pathological remodeling of the left ventricle involving myocardial fibrosis is likely a major contributor to cardiac dysfunction and also a nidus for the generation of ventricular arrhythmias. Serum markers of collagen turnover have been shown to reliably reflect the magnitude of myocardial fibrosis in a variety of cardiovascular diseases. In addition, aldosterone antagonist drugs have been shown to decrease fibrous tissue formation in the myocardium in certain pathologic cardiovascular states in which aldosterone production is increased. In HCM, aldosterone production is up-regulated and has been implicated in the formation of myocardial fibrosis.

Therefore, the specific aims of this proposal are to:

1. assess serum markers of collagen turnover at baseline and correlate these findings with a variety of clinical and morphologic disease parameters

2. examine the effects of a 12-month treatment with the aldosterone antagonist spironolactone on magnitude of fibrosis as measured by serum markers of collagen turnover as well as changes in clinical and morphologic disease parameters.

The results of this proposal will offer important insights into the clinical significance of myocardial fibrosis in this primary genetic cardiomyopathy. The demonstration that spironolactone decreases fibrosis and improves clinical course would provide the rational for a larger multicenter clinical trial evaluating this novel therapy for improving clinical outcome in patients with HCM.

Official title: Clinical and Therapeutic Implications of Fibrosis in Hypertrophic

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: changes in serum markers of collagen turnover

Secondary outcome:

measures of diastolic function by echocardiography

cardiac mass and fibrosis by cardiac magnetic resonance imaging (CMR)

exercise tolerance by exercise VO2max and Holter

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Hypertrophic cardiomyopathy

2. Able to swallow pills

3. No prior septal reduction therapy

4. Negative serum or hCG pregnancy test

Exclusion Criteria:

1. Unable or unwilling to perform treadmill cardiopulmonary exercise test

2. Prior surgical myectomy or alcohol septal ablation

3. Known or suspected infiltrative or glycogen storage disease

4. Significant coronary artery disease, defined as atherosclerotic coronary artery narrowing >70% of the luminal diameter by coronary angiography

5. Severe obstructive pulmonary disease, defined as forced expiratory volume in 1 second (FEV1) <50% of predicted.

6. Prior intolerance or adverse reaction to aldosterone receptor antagonist.

7. History of hyper or hypoaldosteronism

8. Baseline serum potassium >5. 0 mmol/L.

9. Calculated creatinine clearance <30 ml/min using Cockcroft-Gault formula.

10. Pregnant or breast feeding

11. Poorly controlled systemic hypertension, defined as systolic blood pressure ≥150 mmHg or diastolic pressure ≥100 mmHg, during 2 clinic visits.

12. Known conditions associated with elevated serum concentrations of PIIINP (e. g., chronic liver disease, diabetes mellitus, tumors, pulmonary fibrosis, bone and rheumatoid diseases, extensive wounds) or PINP (e. g., alcoholic liver disease, metabolic bone disease, thyroid disorders), including recent trauma (≤2 weeks) or surgery (≤6 months)

13. Taking drugs known to directly influence collagen metabolism including, amiodorone, ACE or angiotensin II inhibitors, aldosterone antagonists, statins, glucocorticoids and estrogens

14. Patients with ICDs/pacemakers will be recruited in the study, but will be excluded from the CMR component.

Martin S Maron, MD, Phone: 617 636-8066, Email: mmaron@tuftsmedicalcenter.org

Tufts Medical Center, Boston, Massachusetts 02111, United States; Recruiting
Martin S Maron, MD, Phone: 617-636-8066, Email: mmaron@tuftsmedicalcenter.org
James E Udelson, MD, Phone: 6176368066, Email: judelson@tuftsmedicalcenter.org
Martin S Maron, MD, Principal Investigator

Starting date: November 2007
Ending date: November 2012
Last updated: April 8, 2009