B-Receptor Signaling in Cardiomyopathy

There is a strong correlation between total doxorubicin dose and anti-tumor efficacy,
however, the clinical utility of doxorubicin is severely limited by its cardiotoxicity. With
improved methods of detecting subtle changes in cardiac function, e.g. alterations in left
ventricular wall stress (1), the incidence of doxorubicin cardiotoxicity is now appreciated
to be much higher than previously suspected, documented in 65% of long-term survivors of
childhood cancer, even at doses as low as 228 mg/m2. This cardiotoxicity is dose-related,
and higher doses are related to a higher incidence of clinical heart failure (2).
Doxorubicin's cardiotoxicity is thought to be mediated through the generation of free
radicals and through mitochondrial and membrane damage.

We wish to determine whether beta-receptor genotype affects anthracycline-induced
cardiomyopathy. We will correlate beta-receptor genotype with difference in wall stress
post-anthracycline exposure, and with difference in shortening fraction. We plan to recruit
300 patients over a two-year period. Inclusion criteria includes past exposure to
anthracycline for cancer treatment and an echocardiogram 6 - 48 months after exposure to
anthracyclines.

The mean difference in 1.) wall stress and 2.) shortening fraction between each minor allele
subgroup and wild type subgroup, for both beta-1 and beta-2 will be assessed using unpaired
t-test analyses . We will assess through multivariate linear regression whether there are
interactions between differences in wall stress or fractional shortening and other variables
such as age, gender, dose of anthracycline, type of anthracycline given, and time between
anthracycline exposure and echocardiogram. Those who receive other cardiotoxic drugs (such
as trastuzumab for breast cancer) will be analyzed separately.

Inclusion Criteria:1.) Past exposure to anthracycline chemotherapy for cancer

2.) Echocardiogram at least six months after exposure to anthracyclines (in patients over
the age of 40, the echocardiogram must be obtained within 6 - 48 months of anthracycline
exposure)

3.) Ability to understand and the willingness to sign a written informed consent document.

We have no age, gender, or ethnic background limitations. Due to the increased frequency
of cardiovascular disease from other causes in adults over 40 years, we will limit
enrollment to those patients with an echocardiogram 6 - 48 months after the completion of
anthracycline exposure. Children will be included and will be eligible if they have an
echocardiogram at least 6 months after completion of anthracycline treatment..

Exclusion Criteria:1.) Congenital heart disease (other than patent foramen ovale)

2.) Pre-existing cardiomyopathy before anthracycline administration

3.) Patients with Down syndrome

4.) Patients receiving B-blocker therapy at the time of anthracycline exposure

5.) Pregnant patients (if their echocardiogram was obtained either during pregnancy or
within three months of pregnancy)

All participants will be cancer survivors. To minimize bias from post-partum
cardiomyopathy, pregnant patients will be excluded if their echocardiogram was obtained
during pregnancy or within three months of pregnancy. HIV-positive persons will not be
excluded from the study.

Of note, some patients receive a MUGA (multigated acquisition) study to evaluate left
ventricular ejection fraction. Patients who receive only a MUGA scan will NOT be included
in the study - an echocardiogram is necessary