Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
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.

 3. explore the effects of a 12-month treatment with aldosterone antagonist spironolactone
 on heart failure status, diastolic function, arrhythmic burden, and total LV mass and
 quantity of fibrosis by CMR.

 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.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease in the general
 population. Myocardial fibrosis has become a prominent and clinically relevant
 pathophysiologic component of this complex genetic disease, related to the risk for both
 sudden death and heart failure. For example, left ventricular replacement fibrosis and
 scarring has been implicated in triggering life threatening ventricular
 tachycardia/fibrillation and most recently has become a novel risk marker for sudden death,
 based on in vivo demonstration of extensive late gadolinium enhancement (LGE) with
 cardiovascular magnetic resonance (CMR). Extensive LGE identifies patients who benefit from
 primary prevention of sudden death with the implantable cardioverter-defibrillators (ICD), or
 who evolve to the end-stage of this disease with systolic dysfunction and consideration for
 heart transplant.

 The mineralocorticoid aldosterone has been shown to be a mediator of myocardial fibrosis, and
 blockade with spironolactone normalizes collagen content in HCM murine models. In addition,
 aldosterone antagonists have favorable clinical effects in patients with a variety of
 diseases associated with myocardial scarring such as congestive heart failure, systemic
 hypertension, and atherosclerotic coronary artery disease. However, it is uncertain whether
 spironolactone would have similar effects on the clinical and phenotypic expression of a
 genetic disease such as HCM. Therefore, we investigated whether mineralocorticoid receptor
 blockade with spironolactone would reduce measures reflecting myocardial fibrosis, producing
 favorable LV remodeling and ultimately leading to positive clinical effects for patients with
 HCM.

 The general aim of this study is to explore the role of fibrosis in HCM by testing the
 hypothesis that: the presence of magnitude of myocardial fibrosis bears clinical relevance
 for patients with HCM, and that mineralocorticoid receptor blockade will reduce myocardial
 fibrosis and thereby alter the natural history of the disease.

 Experimental design: prospective, randomized, double-blind, placebo-controlled trial in a
 consecutive HCM population at a single clinical center (Tufts Medical Center HCM
 Institution).

 Study procedures: HCM patients were recruited from Tufts Medical Center HCM Institution
 population from November 2007 to June 2009. Enrolled patients were randomized into two arms;
 treatment arm received 25mg at the start of study and then increased to target dose of 50mg
 if serum potassium was <5.5mmol/L and serum creatinine-baseline creatinine was <0.5mg/dl.
 This arm was then followed for 12 months. The control arm of the study received 25mg of
 placebo over 12 months. There was an additional control arm of age and gender-matched
 controls without HCM in the control arm to evaluate the serum markers of collagen turnover at
 baseline. These controls had a one time blood draw of 15mL (3 teaspoons) to assess serum
 biomarkers of interest and were not be followed for 12 months.

 Specific outcome measures:

 Primary Outcome: 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.

 Secondary Outcomes: explore the effects of a 12-month treatment with aldosterone antagonist
 spironolactone on heart failure status, diastolic function, arrhythmic burden, and total LV
 mass and quantity of fibrosis by CMR.

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