B-Receptor Signaling in Cardiomyopathy
B-Receptor Signaling in Cardiomyopathy
We hope to determine the importance of different genes (including B receptors) in
 anthracycline-induced cardiomyopathy. This has important benefits to patients exposed to
 anthracyclines, as this could help determine whether certain individuals have increased
 susceptibility to cardiac injury.
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