UTSW HP [13-C] Pyruvate Injection in HCM

In this study the investigators propose to detect early mitochondrial metabolic changes in
the heart in patients with a positive genotype and phenotype for HCM using a novel
hyperpolarized [1-13C]pyruvate MRI methodology. Carbon-13 is a stable isotope (not
radioactive) that makes up approximately 1.1% of all natural carbon. Carbon-13 has a non-zero
spin quantum number that allows the investigation of carbon containing substances using
magnetic resonance. However, compared with other analytical methods, carbon-13 magnetic
resonance has been limited by an intrinsically low sensitivity [2}.

Recent experimental studies suggest that altered energy substrate metabolism may precede
structural changes in myocardial hypertrophy. A better understanding of the myocardial
metabolic changes in HCM is important, as the elucidation of such changes may precede the
clinical development of myocardial fibrosis and malignant arrhythmias. Hyperpolarized
[1-13C]pyruvate and its cellular metabolic flux can be assessed with a more than 10,000-fold
higher sensitivity compared to traditional methods. The aim of this pilot study is to test
the hypothesis that patients with HCM present focal alterations in myocardial hyperpolarized
[1-13C]pyruvate flux.

To achieve this aim the investigators will assess myocardial metabolic changes in HCM
subjects with a positive HCM genotype and phenotype (n=5) and in healthy control subjects
(n=5) who are matched for age, sex, and Body Mass Index (BMI). Total target enrollment will
be set at 15 subjects to allow for attrition and screen failures.

Cardiac function and structure will be evaluated with MRI (proton imaging) before and after
contrast administration. Then myocardial metabolism will be assessed utilizing MRS (carbon
spectroscopy) before and after intravenous injection with hyperpolarized [1-13C]pyruvate. The
study agent, hyperpolarized [1-13C]pyruvate, will be administered under a Food and Drug
Administration (FDA) Investigational New Drug (IND), currently in review process, PI Dr.
Craig Malloy.

Human preliminary data are essential to secure larger scale funding required for clinical
studies. The identification of mitochondrial metabolic changes preceding replacement fibrosis
and malignant arrhythmias may generate a paradigm shift to early detection and more targeted
treatment of HCM with potentially improved clinical outcomes. Cardiac focused applications at
the Advanced Imaging Research Center, genetic disease diagnosis at the Eugene McDermott
Center for Human Genetics and the development of a dedicated HCM Clinic at the UT
Southwestern Medical Center offer today a unique opportunity to lead globally the
translational scientific efforts in this field.

Inclusion Criteria:

- Subjects who are 18 through 60 years of age.

- Subjects who have the ability to understand and the willingness to sign a written
informed consent.

- While all races and ethnicities will be included, subjects must be able to read and
speak the English language. Once the protocol is established, Spanish-speaking
participants will be included.

- Women of child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, for the duration of
study participation. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.

HCM subjects:

- Definitive diagnosis of HCM by genotype and imaging which demonstrates abnormal Left
Ventricular (LV) wall thickness in the absence of other cause (Unexplained maximal
wall thickness >15 mm in any myocardial segment [6-8]).

- Subjects who are 18 through 60 years of age.

- Subjects who have the ability to understand and the willingness to sign a written
informed consent.

- While all races and ethnicities will be included, subjects must be able to read and
speak the English language. Once the protocol is established, Spanish-speaking
participants will be included.

- Women of child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation. Should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately.

Criteria for Exclusion of Subjects:

Controls and HCM subjects:

- Subjects who are receiving any other investigational agents.

- Intercurrent illness including, but not limited to, ongoing or active infection,
uncontrolled chronic diseases such as hypertension, lung disease, liver disease,
kidney disease, diabetes, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements.

- Subjects who are taking thyroid hormone replacements, have a history of alcohol abuse
or illicit drug use.

- Subjects who have contraindication to contrast enhanced MRI examination.

Contraindications to MRI examinations include:

- Medically unstable

- Heart failure

- Severe Left Ventricular Outflow Tract (LVOT) obstruction

- Unstable angina

- Child bearing

- Lactating

- Any contraindication per MRI Screening Form including

- Implants contraindicated at 3Tesla, pacemakers

- Implantable Cardioverter Defibrillator (ICD)

- Claustrophobia

- Since each subject is receiving a gadolinium based contrast agent intravenously:

- eGFR ≤ 30 mL/min/1.73m2

- Sickle cell disease

- Hemolytic anemia