High Intensity Exercise for Increasing Fitness in Patients With Hypertrophic Cardiomyopathy

Regular exercise reduces the risk of all-cause and cardiovascular mortality in the general
population. Specifically, higher cardiorespiratory fitness is associated with a 10 - 20 %
reduction in mortality risk for every 1 MET (metabolic equivalent tasks) improvement in
fitness. A high degree of fitness is also protective against the development of heart failure
and exercise training has become the standard of care for most patients with cardiovascular
disease to improve functional capacity, and reduce morbidity and mortality. However,
hypertrophic cardiomyopathy, the most common inherited cardiovascular disease, may be an
exception. For more than 30 years, hypertrophic cardiomyopathy (HCM) has been identified as
the most common cause of death in young athletes, and patients with HCM are excluded from
participation in competitive sports. The fear of provocation of sudden cardiac death has
often been extended to non-competitive athletic activities in such patients, though there is
a distinct lack of evidence about the safety of exercise in this population. A recent
multicenter clinical trial provided evidence that moderate intensity exercise (MIE) may be
safe in this population, though the increase in fitness with this training paradigm was
modest. Alternatively, an extensive series of reviews published over the last five years
advocate for high intensity interval training (HIIT) as an efficacious stimulus for
increasing cardiorespiratory fitness in clinical adult populations, including those with
heart failure. While a pilot investigation and preliminary findings suggest that moderate to
vigorous intensity exercise may be safe and efficacious in patients with HCM, and even
protective in animal models, there is no Level A or B evidence comparing the efficacy or
safety of MIE and high intensity exercise (HIE) training in this patient population to guide
exercise prescription. Therefore, the primary purpose of this exercise trial is to compare
the efficacy and safety of supervised MIE and HIE training in adults with HCM. Specific aims
and hypotheses of the project are as follows:

Aim 1: Compare the efficacy of a high intensity and moderate intensity exercise intervention
to improve cardiorespiratory fitness and functional diastolic reserve in patients with HCM.

- Primary hypothesis: HIE will result in greater increases in maximal oxygen uptake
(V̇O2max) than MIE in patients with HCM.

- Secondary hypothesis: HIE will improve stroke volume reserve to a greater degree than
MIE in patients with HCM.

Aim 2: To evaluate the safety of HIE training in patients with HCM.

- Hypothesis: Regular exercise training of a high or moderate intensity will be safe (no
serious adverse events) in this patient population. Specifically, it is hypothesised
that HIE will not increase arrhythmia burden in patients with HCM.

Inclusion Criteria:

- Male and female patients aged 18 - 80 years old

- Diagnosed HCM defined by the presence of unexplained left-ventricular hypertrophy with
end-diastolic wall thickness ≥ 15 mm on 2D echocardiography or wall thickness between
13 and 15 mm along with at least one other piece of evidence of hypertrophic
cardiomyopathy, such as systolic anterior motion of the mitral valve leaflets, family
history of hypertrophic cardiomyopathy, or positive genetic test result.

Exclusion Criteria:

- A history of exercise-induced syncope or arrhythmias (ventricular tachycardia;
sustained or non-sustained)

- Left ventricular outflow obstruction (≥ 50 mm Hg at rest)

- Less than 3 months post septal reduction therapy (surgery or catheter based
intervention)

- Pregnancy

- Worsening clinical status or advanced heart failure (New York Heart Association class
IV symptoms)

- A hypotensive responsive to exercise (an increase in exercise systolic BP throughout
the exercise test of < 20mmHg compared with resting values, or an initial increase in
systolic BP > 20mmHg with a subsequent fall by peak exercise of > 20mmHg, or a
continuous decrease in systolic BP throughout the test of > 20mmHg, compared with
baseline BP)

- Left ventricular systolic dysfunction (left ventricular ejection fraction < 55 % by
echocardiography)

- Coronary artery disease as evidenced by prior myocardial infarction or angina

- Cerebrovascular disease as evidenced by prior transient ischemic attack or stroke

- A chronic orthopaedic injury which limits the ability to exercise

- Subjects unable to speak English will not be recruited because of the complex
experimental studies and the need for precise communication between the volunteers and
the research staff to ensure safety.