Clinical Trial of Pioglitazone for Prevention of Cardiac Allograft Vasculopathy After Heart Transplantation

CAV, a rapidly progressive obliterative disease involving the graft coronary arteries, is
the leading cause of morbidity and mortality beyond the first year after heart
transplantation. This common complication occurs in almost half of recipients within 3 years
after heart transplantation, and is associated with high rates of graft failure and
mortality. Clinical care of heart transplant recipients in the current era is greatly
limited by the lack of effective treatment options to prevent or retard the progression of
CAV. CAV appears to be strongly associated with the state of insulin resistance, which is
present in over half of heart transplant recipients and is characterized by metabolic
abnormalities including glucose intolerance, dyslipidemia, endothelial dysfunction, and high
levels of circulating inflammatory markers. Insulin resistance can be effectively treated
with pioglitazone, a TZD compound which directly affects tissue insulin sensitivity. In this
study, we will enroll 32 insulin-resistant heart transplant recipients and will randomize
them to pioglitazone or placebo for a one-year period. We will determine the efficacy of
pioglitazone for the treatment of insulin resistance and prevention of the development and
progression of CAV after heart transplantation. The data generated from this study will
provide important preliminary data for future, larger-scale clinical investigations.

Inclusion Criteria:

1. Heart transplant recipients, years 1-4 post-transplant

2. Age >= 18 years

3. Fasting TG/HDL ratio>=3.0 or Fasting TG>=150 mg/dL

Exclusion Criteria:

1. Diabetes mellitus

2. Severe liver dysfunction (ALT>=2.5 x upper limit of normal)

3. Severe renal dysfunction (GFR<30 or Stage IV CKD)

4. Moderate-severe fluid retention

5. Clinical or echocardiographic signs of left ventricular dysfunction

6. Contraindication to coronary angiography and/or IVUS