Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy

March 31, 2021 updated by: Tufts Medical Center

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Study Type

Interventional

Enrollment (Actual)

53

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02111
        • Tufts Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Spironolactone
Experimental group includes individuals diagnosed with HCM between the ages of 18-55 (up to 50 for men). At time of randomization subjects randomized to experimental group will be initiated on 25mg of spironolactone. If at week 4, serum potassium is <5.5 mmol/L and serum creatinine-baseline creatinine is <0.5 mg/dl, the study drug will be increased to the target dose of 50mg once daily.
Drug: Spironolactone
spironolactone 50mg daily
Other Names:
  • Aldactone
Placebo Comparator: Placebo Control
Placebo group includes individuals diagnosed with HCM between the ages of 18-55 (up to 50 for men). At time of randomization subjects randomized to placebo group will be initiated on an inactive placebo pill.
Drug: Placebo
inactive placebo pill daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Absolute Change in Serum Markers of Collagen Turnover (Micrograms/L) Over a One-year Follow-up Period in the Spironolactone Group Compared to Placebo.
Time Frame: The time points measured were at Baseline and at 12 Months (Follow-Up).
Specific variables of collagen turnover markers that will be evaluated include markers of collagen synthesis (PINP, PIIINP), and marker of collagen degradation (ICTP). A two-sample t-test was used to compare the differences between these collagen turnover markers at baseline and the absolute differences in change from baseline to 12 months of follow-up.
The time points measured were at Baseline and at 12 Months (Follow-Up).

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Measure of Functional Capacity: Peak Oxygen Consumption With Exercise
Time Frame: The time points measured were at Baseline and at 12 Months (Follow-Up).
This data was collected at baseline, prior to drug administration, and again at 12-months of follow-up to determine if spironolactone improves a subject's functional capacity during exercise (peak oxygen consumption levels/peak VO2). Peak VO2 levels were measured in ml/kg/min.
The time points measured were at Baseline and at 12 Months (Follow-Up).
Measure of Heart Failure Symptoms According to the New York Heart Association Functional Class
Time Frame: Time points were measured at Baseline and again at 12 months (follow-up)
This data was collected at baseline, prior to drug administration, and again at 12-months of follow-up to assess heart failure symptoms according to the New York Heart Association (NYHA) functional class, which is an estimate of a patients functional ability. The NYHA functional classes include: Class I (no limitation of physical activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity), and Class IV (unable to carry out any physical acitivity without discomfort).
Time points were measured at Baseline and again at 12 months (follow-up)
Measure of Indices of Diastolic Function by Tissue Doppler Echocardiography (Septal E/e')
Time Frame: The time points measured were at Baseline and at 12 Months (Follow-Up).
This data was collected at baseline, prior to drug administration, and again at 12-months of follow-up to measure indices of diastolic function by Tissue Doppler Echocardiography using the Septal E/e' ratio.
The time points measured were at Baseline and at 12 Months (Follow-Up).
Assessment of Cardiac Mass and Fibrosis by Cardiac Magnetic Resonance Imaging (CMR) - Percentage of Left Ventricular Mass (%LV)
Time Frame: The time points measured were at Baseline and at 12 Months (Follow-Up).
CMR will be utilized as it has superior reproducibility (as compared to 2-D echocardiography). Late Gadolinium Enhancement (LGE) Assessment of myocardial fibrosis by CMR will be expressed as a percentage of left ventricular mass (%LV), maximum left ventricular wall thickness (in mm), left ventricular end-diastolic cavity size (in mm/m^2), and left atrial dimension (in mm).
The time points measured were at Baseline and at 12 Months (Follow-Up).
Assessment of Cardiac Mass and Fibrosis by Cardiac Magnetic Resonance Imaging (CMR) - Maximum Left Ventricular Wall Thickness (in mm)
Time Frame: The time points measured were at Baseline and at 12 Months (Follow-Up).
CMR will be utilized as it has superior reproducibility (as compared to 2-D echocardiography). Late Gadolinium Enhancement (LGE) Assessment of myocardial fibrosis by CMR will be expressed as a percentage of left ventricular mass (%LV), maximum left ventricular wall thickness (in mm), left ventricular end-diastolic cavity size (in mm/m^2), and left atrial dimension (in mm).
The time points measured were at Baseline and at 12 Months (Follow-Up).
Assessment of Cardiac Mass and Fibrosis by Cardiac Magnetic Resonance Imaging (CMR) - Left Ventricular End-Diastolic (LVED) Cavity Size (in mm/m^2)
Time Frame: The time points measured were at Baseline and at 12 Months (Follow-Up)
CMR will be utilized as it has superior reproducibility (as compared to 2-D echocardiography). Late Gadolinium Enhancement (LGE) Assessment of myocardial fibrosis by CMR will be expressed as a percentage of left ventricular mass (%LV), maximum left ventricular wall thickness (in mm), left ventricular end-diastolic (LVED) cavity size (in mm/m^2), and left atrial dimension (in mm).
The time points measured were at Baseline and at 12 Months (Follow-Up)
Assessment of Cardiac Mass and Fibrosis by Cardiac Magnetic Resonance Imaging (CMR) - Left Atrial Dimension (in mm)
Time Frame: The time points measured were at Baseline and at 12 Months (Follow-Up)
CMR will be utilized as it has superior reproducibility (as compared to 2-D echocardiography). Late Gadolinium Enhancement (LGE) Assessment of myocardial fibrosis by CMR will be expressed as a percentage of left ventricular mass (%LV), maximum left ventricular wall thickness (in mm), left ventricular end-diastolic cavity size (in mm/m^2), and left atrial dimension (in mm).
The time points measured were at Baseline and at 12 Months (Follow-Up)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Tufts Medical Center

Investigators

  • Principal Investigator: Martin S Maron, MD, Tufts Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2007

Primary Completion (Actual)

November 1, 2011

Study Completion (Actual)

November 1, 2012

Study Registration Dates

First Submitted

April 8, 2009

First Submitted That Met QC Criteria

April 8, 2009

First Posted (Estimate)

April 9, 2009

Study Record Updates

Last Update Posted (Actual)

April 27, 2021

Last Update Submitted That Met QC Criteria

March 31, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • K23HL086745-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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