Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
Condition: Myocardial Fibrosis; Hypertrophic Cardiomyopathy
MeSH terms: Cardiomyopathies; Cardiomyopathy, Hypertrophic; Fibrosis; Hypertrophy
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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
    

Intervention name(s): Spironolactone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): spironolactone 50mg daily; inactive placebo pill daily
Other intervention name(s): Aldactone
Intervention MeSH terms: Spironolactone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Fibrosis; Hypertrophic cardiomyopathy; MRI; Myocardial Fibrosis; Spironolactone