Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
Condition: Myocardial Fibrosis; Hypertrophic Cardiomyopathy
MeSH terms: Cardiomyopathies; Cardiomyopathy, Hypertrophic; Fibrosis; Hypertrophy
Intervention: Spironolactone; Placebo
Intervention description: spironolactone 50mg daily; inactive placebo pill daily
Intervention MeSH terms: Spironolactone
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 53.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Fibrosis; Hypertrophic cardiomyopathy; MRI; Myocardial Fibrosis; Spironolactone

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.
    

Eligibility 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.