Exercise Training in Transthyretin Cardiac Amyloidosis

Inclusion Criteria:

* Diagnosis and typing of ATTR-CM by endomyocardial biopsy or by Grade 2 or Grade 3 pyrophosphate (PYP) positivity (exception: nonamyloid control arm in aim 1).

  * Diagnosis of heart failure, with prior or current need of diuretics and increased N-terminal prohormone B-natureitic peptide (BNP) (≥450 pg/ml).
  * Peak VO2 \<80% predicted, indicating impaired aerobic capacity (for aim 2 only).
  * Taking tafamidis (for aim 2 only)
  * Able to walk 4 meters (with or without the use of an assistive device) and independent with basic activities of daily living at the time of enrolment.
  * Adequate clinical stability has been achieved in the judgment of the investigator to allow participation in study assessments and the intervention.
  * Signed informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study.

Exclusion Criteria:

* Acute myocardial infarction (Note: given that cardiac biomarkers such as troponin are frequently elevated in ATTR-CM patients, the diagnosis of acute myocardial infarction should be based on clinical diagnosis, not biomarkers alone)

  * \>70% obstructive coronary artery disease
  * Severe aortic valve stenosis
  * Already actively participating in formal, facility-based cardiac exercise
  * Already engaging in regular moderate to vigorous exercise conditioning defined as \> 30 minutes per day, ≥ twice per week consistently during the previous 6 weeks
  * Ventricular assist device
  * Light chain amyloidosis or other form of non-ATTR amyloidosis
  * Advanced chronic kidney disease defined as estimated glomerular filtration rate \<20 mL/min/1.73m2
  * Any organ transplantation
  * Terminal illness other than HF with life expectancy \< 1 year
  * Pacemaker or implantable cardioverter-defibrillato (ICD) with heart rate limits \< expected heart rates for exercise and unable to be reprogrammed
  * Neuropathy due to transthyretin (TTR) mutation
  * Impairment from stroke, injury or other medical disorder that precludes participation in the intervention
  * Abnormal cardiopulmonary exercise testing (CPET) finding that requires further investigation and management
  * Dementia that precludes ability to participate in exercise and follow study protocols
  * High risk for non-adherence as determined by screening evaluation
  * Inability or unwillingness to comply with the study requirements