Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM

Inclusion Criteria:

1. All subjects must have a Pathogenic or Likely Pathogenic HCM Sarcomere Mutation

a. The following categories of mutations are considered acceptable for subjects who have
previously undergone clinical genetic testing. If results are ambiguous, they will be
reviewed by the Clinical Coordinating Center to determine eligibility.

   - Laboratory for Molecular Medicine (Pathogenic, Likely Pathogenic)

   - Transgenomics/ PGXHealth (Class I)

   - GeneDx (Disease causing; Variant; likely disease-causing; Published, disease-causing
   mutation; Novel, likely disease-causing, mutation)

   - Correlagen (Associated; Probably Associated)

Group 1 (Overt HCM Cohort)

   1. LV wall thickness ≥12 mm and ≤25 mm or z score ≥3 and ≤18 as determined by rapid
   assessment by the echocardiographic core laboratory

   2. NYHA functional class I or II; no perceived or only slight limitations in physical
   activities

   3. No resting or provokable LV obstruction (peak gradient ≤ 30 mmHg) on
   clinically-obtained Exercise Tolerance Test (ETT)-echo within the past 24 months or
   transthoracic echo with Valsalva maneuver within the past 12 months

   4. Age 8-45 years

   5. Able to attend follow-up appointments, complete all study assessments, and provide
   written informed consent

Group 2 (Preclinical HCM Cohort (G+/LVH-))

   1. LV Wall Thickness <12 mm and z score <3 , as determined by rapid assessment by the
   echocardiographic core laboratory

   2. Age 10-25 years

   3. E' z score ≤ -1.5 OR ECG abnormalities other than NSSTW changes (Q waves, T wave
   inversion, repolarization changes) OR LV wall thickness z-score 1.5-2.9 combined with
   LV thickness to dimension ratio ≥0.19 (as determined by rapid assessment by the
   echocardiographic core laboratory)

   4. Able to attend follow-up appointments, complete all study assessments, and provide
   written informed consent

Subject Exclusion Criteria

   1. Contraindication to angiotensin receptor blocker (ARB) administration, including
   impaired renal function, hyperkalemia (serum K>5.0 mmol/L), prior history of
   angioedema

   2. Medical conditions associated with increased collagen turnover that may confound
   interpretation of biomarkers of collagen synthesis (liver, pulmonary or renal
   fibrosis, inflammatory states, cancer, trauma or surgery within 6 months of
   enrollment)

   3. Concomitant use of Spironolactone, Lithium, or Aliskiren, ARB or ACE-inhibitors. If
   these drugs are in active use but not necessary for medical care, they may be
   discontinued and baseline studies can be performed after a 2-week washout period.

   4. Pregnant or breastfeeding females - Females of childbearing potential with no
   effective contraceptive method (including abstinence)

   5. Uncontrolled systemic HTN [persistent SBP>160 and/or DBP>90 in adult or equivalent in
   children (e.g., SBP>99th or DBP>95th percentile for sex, age, and height centile based
   on the American Academy of Pediatrics normal values)]

   6. Obstructive physiology, defined by resting, Valsalva-provoked or exercise-induced
   gradient >30mmHg within the past 24 months

   7. Prior septal myectomy or alcohol septal ablation

   8. Known, suspected, or symptomatic coronary artery disease or evidence of prior
   myocardial infarction based on symptoms or cardiac imaging

   9. More than mild valvular heart disease or clinically significant congenital heart
   disease. Allowable conditions include bicuspid aortic valve without clinically
   significant stenosis or regurgitation; spontaneously closed ventricular septal
   defects; patent foramen ovale, small (≤ 2 mm) restrictive ventricular septal defects
   with normal ventricular size, and other minor defects that are considered allowable
   after [review and consensus by participating pediatric cardiologists, overall study PI
   and] adjudication by the echocardiographic core laboratory.

10. Left ventricular ejection fraction (LVEF) <55%

11. Concomitant medical conditions that would preclude performance of or confound
   interpretation of echocardiography, exercise testing, or CMR (e.g., renal
   insufficiency, lung disease, orthopedic/rheumatologic conditions, atrial fibrillation)

12. Secondary prevention implantable cardioverter-defibrillator device (ICD; primary
   prevention ICDs without a history of appropriate therapy, including shock or ATP, are
   allowable).

13. Prior treatment or hospitalization for symptomatic heart failure

14. Participation in a clinical trial (except observational studies) involving
   investigational medications within the previous 30 days.