Anthracycline cardiotoxicity

Three types of anthracycline induced cardiotoxicity: acute changes that occur within 1 week of infusion, early onset chronic cardiotoxicity occurring within the first year of treatment, and late onset cardiotoxicity occurring after the first year of exposure.

Suspected myocardial damage is mediated through the formation of iron dependent oxygen free radicals and peroxidation of lipids in the membranes of myocardial mitochondria, reduced myocardial ATP production, decreased mRNA coding for calcium ion,-ATPase in the sarcoplasmic reticulum, lowered cardiac glutathione peroxidase activity ad mitochondrial DNA damage.

Cardiomyopathy is a result of myocyte death at the time of treatment, followed by cardiac remodeling in the years following completion of therapy, and eventually leading to heart failure.

Myocytes undergo apoptosis when exposed to anthracyclines.

Left ventricular injury and reduced left ventricular ejection fraction and precipitation of congestive heart failure can occur within weeks to months after receiving such therapy.

Latent cardiovascular disease may occur in surviving patients 5 to 10 years after receiving such agents.

Myocyte loss and damage occurs with treatment can lead to progressive left ventricular wall thinning and decrease in cardiac contractility.

With chronic changes an elevation of the left ventricle wall stress increased leading to further left ventricular impairment.

Left ventricular dysfunction, impaired exercise capacity and CHF may occur.

Late onset disease usually asymptomatic.

Within 12 months after administration of anthracyclines, more than 20% of patients with lymphoma, have a greater than a 10% decline in left ventricular ejection fraction, and that at five years up to 20% develop heart failure.

Anthracycline -Induced heart failure may take years or decades to manifest.

Smaller bolus doses and continuous intravenous infusion reduces cardiotoxicity in adults, but this has not been confirmed in children.

Early intervention with cardioprotective medications results in better long term cardiac function, and may,in fact, allow for partial recovery of LVEF in this population.

Pinder et al report increased risk of congestive heart failure in older women who had more than 10 years of follow up following adjuvant anthracyclines for breast cancer: with women aged 66-70 years at 10 years of follow up CHF noted in 38.4%, 32.5% and 29% for anthracycline, nonanthracycline and no chemotherapy groups.

Incidence of clinical congestive heart failure year after anthracycline-based chemotherapy for adult cancer is less than 5%.

A significantly higher percentage of patients have evidence of sub clinical heart failure with reports of asymptomatic left ventricular ejection fraction decline being 9-50% in various studies.

Advanced age, African American race, hypertension, coronary artery disease, diabetes are significant predictors of congestive heart failure in patients who received adjuvant treatment at 10 years of follow up.

Cardotoxicity related to cumulative anthracycline dose administered, pre-existing heart disease, a history of mediastinal irradiation and coadminstration of palclitaxel and trastuzumab.

In the Pinder study African American women has a relative 49% higher risk of developing CHF compared to white females that received adjuvant chemotherapy for breast cancer.

A 0.8% incidence of congestive heart failure has been reported with older adjutant regimens for breast cancer incorporating doxorubicin (Valagussa P).

Adjuvant breast cancer trial CALGB 9344 founf a 16% rate of cardiotoxicity with a doxorubicin dose of 90 mg/m2 versus 11% with 60 mg/m2.

In a 14 year follow-up in adjuvant anthracycline regimens a 0.4% cardiac death reported (Zambetti M et al).

The French Adjutant Study Group (FASG) reviewed its experience with adjuvant epirubicin and found a 1.3% incidence of clinical cardiac dysfunction (Fumoleau P).

Among patients with lymphoma treated with anthracycline-based chemotherapy, atrovastatin reduces the incidence of cardiac dysfunction.

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