Cardiotoxicity of chemotherapeutic agents

The successful treatment of cancer with chemotherapeutic agents has led to a new set of cardiac problems related to their acute and chronic cardiac toxicity. It should not be surprising that drugs that impact so potently on intrinsic cell function and energy production to cause tumor cell death also impact on other systems, including the heart. An unfortunate by-product of the success of adjuvant therapy has been development of cardiomyocyte dysfunction and death and the development of heart failure.

Current estimates indicate that cardiovascular disease has become a competing comortality risk in women undergoing cancer chemotherapy. Cohort studies indicate that breast cancer patients who have undergone chemotherapy are at an increased cardiovascular mortality risk, compared with age matched controls. The National Cancer Institute and the Centers for Disease Control and Prevention estimate that there are more than 10 million cancer survivors in the United States and that 60% of adults newly diagnosed with cancer will be alive 5 or more years later. Many of these survivors will have significant heart failure as a result of their "successful" chemotherapy (J. Clin. Oncol. 2007;25:3991-4008).

Most of these survivors will have been treated either acutely or chronically with anthracycline drugs (such as doxorubicin), drugs directed at HER2 monoclonal antibodies (trastuzumab), or endocrine-like drugs (tamoxifen). Treatment protocols vary widely and have focused primarily on the acute, chronic, and recurrent therapy for tumor eradication with limited regard – until recently – for the acute or chronic cardiotoxic effects of the drugs. The precise incidence of cardiac toxicity is poorly understood since there are very few long-term follow-up data regarding cardiac morbidity and mortality. In these long-term survivors, cardiovascular mortality will be the predominant cause of death in women over age 60 treated for breast cancer (Circulation 2012;126:2749-63). It is estimated that half of the patients treated with anthracyclines will exhibit some cardiac dysfunction within 10-20 years and 5% will develop overt heart failure.

The mechanism by which cardiac dysfunction occurs varies depending upon the drug used. Anthracycline drugs cause ultrastructural cell changes, vacuolar degeneration, myofibrillar loss, and apoptosis. This change can be observed during early administration but may manifest years later, seemingly without any early evidence of dysfunction. Trastuzumab causes cardiac function as a result of deletion of HER2, which is essential for cardiomyocyte survival and stress adaptation. Tamoxifen-like drugs can lead to the acceleration of typical cardiac risk factors. Interaction of any of these classes of drugs when used in combination for recurrent or resistant disease can accelerate the occurrence of cardiac pathology.

The degree of adverse acute and chronic cardiac effects is related to the dose and duration of therapy. Early recognition of cardiac toxicity appears to be critical in order to mitigate the toxic drug effects. Clinical data suggest that early administration of ACE inhibitors or beta-blockers may limit or reverse cardiac dysfunction (Circulation 2006;114:2474-81). The measurement of LVEF has been used to identify early cardiac dysfunction. A symptomatic decrease in LVEF from 5% to 55% or an asymptomatic decrease of 10% is considered to be diagnostic of cardiac toxicity. Serum troponin I of greater than 0.08% also has been reported to increase the occurrence of cardiac toxicity 24-fold. Recent studies suggest that measurement of myocardial contractile velocity and strain and rate of strain by tissue Doppler imaging may provide earlier identification of myocardial dysfunction than that achieved with LVEF alone (Circulation 2012;126:2749-63).

The increased development of heart failure as a result of cancer chemotherapy has largely slipped under the cardiologist’s radar. The recent awareness of the adverse cardiac effect of these agents has generated investigation into the development of early and more sensitive biological markers and methods of mitigating cell dysfunction with concomitant medical therapy.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The successful treatment of cancer with chemotherapeutic agents has led to a new set of cardiac problems related to their acute and chronic cardiac toxicity. It should not be surprising that drugs that impact so potently on intrinsic cell function and energy production to cause tumor cell death also impact on other systems, including the heart. An unfortunate by-product of the success of adjuvant therapy has been development of cardiomyocyte dysfunction and death and the development of heart failure.

Current estimates indicate that cardiovascular disease has become a competing comortality risk in women undergoing cancer chemotherapy. Cohort studies indicate that breast cancer patients who have undergone chemotherapy are at an increased cardiovascular mortality risk, compared with age matched controls. The National Cancer Institute and the Centers for Disease Control and Prevention estimate that there are more than 10 million cancer survivors in the United States and that 60% of adults newly diagnosed with cancer will be alive 5 or more years later. Many of these survivors will have significant heart failure as a result of their "successful" chemotherapy (J. Clin. Oncol. 2007;25:3991-4008).

Most of these survivors will have been treated either acutely or chronically with anthracycline drugs (such as doxorubicin), drugs directed at HER2 monoclonal antibodies (trastuzumab), or endocrine-like drugs (tamoxifen). Treatment protocols vary widely and have focused primarily on the acute, chronic, and recurrent therapy for tumor eradication with limited regard – until recently – for the acute or chronic cardiotoxic effects of the drugs. The precise incidence of cardiac toxicity is poorly understood since there are very few long-term follow-up data regarding cardiac morbidity and mortality. In these long-term survivors, cardiovascular mortality will be the predominant cause of death in women over age 60 treated for breast cancer (Circulation 2012;126:2749-63). It is estimated that half of the patients treated with anthracyclines will exhibit some cardiac dysfunction within 10-20 years and 5% will develop overt heart failure.

The mechanism by which cardiac dysfunction occurs varies depending upon the drug used. Anthracycline drugs cause ultrastructural cell changes, vacuolar degeneration, myofibrillar loss, and apoptosis. This change can be observed during early administration but may manifest years later, seemingly without any early evidence of dysfunction. Trastuzumab causes cardiac function as a result of deletion of HER2, which is essential for cardiomyocyte survival and stress adaptation. Tamoxifen-like drugs can lead to the acceleration of typical cardiac risk factors. Interaction of any of these classes of drugs when used in combination for recurrent or resistant disease can accelerate the occurrence of cardiac pathology.

The degree of adverse acute and chronic cardiac effects is related to the dose and duration of therapy. Early recognition of cardiac toxicity appears to be critical in order to mitigate the toxic drug effects. Clinical data suggest that early administration of ACE inhibitors or beta-blockers may limit or reverse cardiac dysfunction (Circulation 2006;114:2474-81). The measurement of LVEF has been used to identify early cardiac dysfunction. A symptomatic decrease in LVEF from 5% to 55% or an asymptomatic decrease of 10% is considered to be diagnostic of cardiac toxicity. Serum troponin I of greater than 0.08% also has been reported to increase the occurrence of cardiac toxicity 24-fold. Recent studies suggest that measurement of myocardial contractile velocity and strain and rate of strain by tissue Doppler imaging may provide earlier identification of myocardial dysfunction than that achieved with LVEF alone (Circulation 2012;126:2749-63).

The increased development of heart failure as a result of cancer chemotherapy has largely slipped under the cardiologist’s radar. The recent awareness of the adverse cardiac effect of these agents has generated investigation into the development of early and more sensitive biological markers and methods of mitigating cell dysfunction with concomitant medical therapy.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.

The successful treatment of cancer with chemotherapeutic agents has led to a new set of cardiac problems related to their acute and chronic cardiac toxicity. It should not be surprising that drugs that impact so potently on intrinsic cell function and energy production to cause tumor cell death also impact on other systems, including the heart. An unfortunate by-product of the success of adjuvant therapy has been development of cardiomyocyte dysfunction and death and the development of heart failure.

Current estimates indicate that cardiovascular disease has become a competing comortality risk in women undergoing cancer chemotherapy. Cohort studies indicate that breast cancer patients who have undergone chemotherapy are at an increased cardiovascular mortality risk, compared with age matched controls. The National Cancer Institute and the Centers for Disease Control and Prevention estimate that there are more than 10 million cancer survivors in the United States and that 60% of adults newly diagnosed with cancer will be alive 5 or more years later. Many of these survivors will have significant heart failure as a result of their "successful" chemotherapy (J. Clin. Oncol. 2007;25:3991-4008).

Most of these survivors will have been treated either acutely or chronically with anthracycline drugs (such as doxorubicin), drugs directed at HER2 monoclonal antibodies (trastuzumab), or endocrine-like drugs (tamoxifen). Treatment protocols vary widely and have focused primarily on the acute, chronic, and recurrent therapy for tumor eradication with limited regard – until recently – for the acute or chronic cardiotoxic effects of the drugs. The precise incidence of cardiac toxicity is poorly understood since there are very few long-term follow-up data regarding cardiac morbidity and mortality. In these long-term survivors, cardiovascular mortality will be the predominant cause of death in women over age 60 treated for breast cancer (Circulation 2012;126:2749-63). It is estimated that half of the patients treated with anthracyclines will exhibit some cardiac dysfunction within 10-20 years and 5% will develop overt heart failure.

The mechanism by which cardiac dysfunction occurs varies depending upon the drug used. Anthracycline drugs cause ultrastructural cell changes, vacuolar degeneration, myofibrillar loss, and apoptosis. This change can be observed during early administration but may manifest years later, seemingly without any early evidence of dysfunction. Trastuzumab causes cardiac function as a result of deletion of HER2, which is essential for cardiomyocyte survival and stress adaptation. Tamoxifen-like drugs can lead to the acceleration of typical cardiac risk factors. Interaction of any of these classes of drugs when used in combination for recurrent or resistant disease can accelerate the occurrence of cardiac pathology.

The degree of adverse acute and chronic cardiac effects is related to the dose and duration of therapy. Early recognition of cardiac toxicity appears to be critical in order to mitigate the toxic drug effects. Clinical data suggest that early administration of ACE inhibitors or beta-blockers may limit or reverse cardiac dysfunction (Circulation 2006;114:2474-81). The measurement of LVEF has been used to identify early cardiac dysfunction. A symptomatic decrease in LVEF from 5% to 55% or an asymptomatic decrease of 10% is considered to be diagnostic of cardiac toxicity. Serum troponin I of greater than 0.08% also has been reported to increase the occurrence of cardiac toxicity 24-fold. Recent studies suggest that measurement of myocardial contractile velocity and strain and rate of strain by tissue Doppler imaging may provide earlier identification of myocardial dysfunction than that achieved with LVEF alone (Circulation 2012;126:2749-63).

The increased development of heart failure as a result of cancer chemotherapy has largely slipped under the cardiologist’s radar. The recent awareness of the adverse cardiac effect of these agents has generated investigation into the development of early and more sensitive biological markers and methods of mitigating cell dysfunction with concomitant medical therapy.

Dr. Goldstein, medical editor of Cardiology News, is professor of medicine at Wayne State University and division head emeritus of cardiovascular medicine at Henry Ford Hospital, both in Detroit. He is on data safety monitoring committees for the National Institutes of Health and several pharmaceutical companies.