Hypertrophic Regression With N-Acetylcysteine in HCM

The primary objective is to perform a pilot study in patients with hypertrophic
cardiomyopathy (HCM) and mutations in genes encoding sarcomere proteins to assess safety and
gather the pre-requisite data for subsequent robust randomized placebo-controlled efficacy
studies with N-acetylcysteine (NAC). We will gather data on the recruitment, accrual,
retention, and compliance rates of HCM patients randomized to treatment with a placebo or
two escalating doses of NAC. Likewise, we will determine any potential side effects and
estimate the effect size of NAC on indices of cardiac hypertrophy.

HCM, the main focus of our research during the past two decades, is the most common cause of
sudden cardiac death (SCD) in the young and an important cause of morbidity in the elderly.
Despite its clinical impact, there is no effective pharmacological therapy for HCM. None of
the current pharmacological therapies reverses or attenuates cardiac hypertrophy or reduces
the risk of SCD in adults. Cardiac hypertrophy, the quintessential clinical feature of human
HCM, is a major determinant of morbidity and the risk of SCD. Regression of cardiac
hypertrophy is expected to improve morbidity and decrease the risk of SCD in HCM, as
observed upon regression of load-dependent cardiac hypertrophy.

We have generated transgenic rabbit and mouse models of HCM and shown that cardiac
hypertrophy and fibrosis could be reversed through genetic or pharmacological interventions.
Results with NAC, a precursor to glutathione; the largest intracellular thiol pool against
oxidative stress, were most promising. In three independent studies in two different
transgenic models of HCM (rabbits and mouse), treatment with NAC completely reversed cardiac
hypertrophy and fibrosis and improved indices of diastolic function. The ultimate goal of
every physician-scientist is to apply the bench discoveries at the bedside. We propose to
test our findings in the animal models in humans with HCM caused by sarcomere protein
mutations. The use of NAC is also supported by data showing increased oxidative stress in
human HCM. Moreover, NAC has been used extensively in humans and has a well-established
safety profile. Resources including patients with sarcomere protein mutations are available
to successfully complete a randomized placebo-controlled (N=25) pilot study to test two
escalating doses of NAC (N=50), administered for one year. We will determine recruitment,
accrual, retention and compliance rates; tolerability, safety and side effects; and estimate
the effect size of NAC on the indices of cardiac hypertrophy, as determined by serial
cardiac magnetic resonance imaging (MRI) at the baseline and after one year of treatment.
Only HCM patients with sarcomere proteins mutations will be included to exclude phenocopy.
The Core centers will interpret the phenotypic data to assure homogeneity. Data Coordinating
Center will assist in the research design, planning and conduct of the study and analysis of
the data. The findings will set the stage for large-scale robust randomized placebo-control
efficacy studies.

Inclusion Criteria:

- Patients with primary cardiac hypertrophy, non-dilated LV cavity and preserved LV
systolic function, hence, the diagnosis of HCM, who have at least an LV end diastolic
(LVSD) wall thickness of at least 15 mm on a 2D echocardiogram and

- Known to have mutations in genes encoding sarcomeric proteins

Exclusion Criteria:

- Hypersensitivity to NAC

- Individuals younger than 18 years old (in the pilot study)

- Phenocopy conditions, diagnosed clinically or genetically

- Patients who have undergone transcatheter (alcohol) septal ablation within 6 months.

- Individuals (typically family members) with causal mutations but an LVSD wall
thickness of <15 mm

- Patients with concomitant diseases such as:

- Significant coronary artery disease >70% luminal diameter stenosis in ny of the
major coronary arteries (if known);

- Valvular heart diseases (more than mild aortic stenosis and mitral
regurgitation, the latter judged to be due to primary mitral valve
abnormalities);

- Uncontrolled hypertension, defined as systolic blood pressure of

- 140 mmHg and diastolic blood pressure of ≥90 mmHg on medication, mean of
three measurements at rest);

- Other significant medical problems, such as moderate to severe chronic renal
failure (GFR<45 ml/min/1.73m2), advanced liver disease, cancer, or other
disabling conditions

- Pregnant women, nursing mothers and those who plan pregnancy during the study period

- Those with active asthma (albeit the concern is relevant to nebulizer form but not
oral formulations)