Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
| Status: | Completed |
|---|---|
| Conditions: | High Cholesterol, Cardiology, Orthopedic |
| Therapuetic Areas: | Cardiology / Vascular Diseases, Orthopedics / Podiatry |
| Healthy: | No |
| Age Range: | 18 - 70 |
| Updated: | 4/2/2016 |
| Start Date: | November 2007 |
| End Date: | November 2012 |
| Contact: | Martin S Maron, MD |
| Email: | mmaron@tuftsmedicalcenter.org |
| Phone: | 617 636-8066 |
Clinical and Therapeutic Implications of Fibrosis in Hypertrophic
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.
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.
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.
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