Congestive heart failure doxorubicin

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

When the heart can no longer pump an adequate supply of blood to meet the metabolic needs of the tissues or in relation to venous return, cardiac failure may ensue. The causes of cardiac failure are complex, but stem from mechanical abnormalities (e.g., pericardial tamponade), myocardial failure (e.g., cardiomyopathy and inflammation), and arrhythmias. In high-output failure, the cardiac output, which may be normal or even higher than normal, is not sufficient to meet the metabolic requirement of the body. Cardiac failure may predispose a patient to congestive heart failure, which is a state of circulatory congestion. Toxic injury, caused by agents such as doxorubicin, the alkaloid emetine in ipecac syrup, cocaine, or ethyl alcohol, is another way by which the functional integrity of the heart may also be compromised. 

Cardiotoxicity, which can lead to congestive heart failure and death, is a toxic effect of the anticancer drug, doxorubicin. A cumulative dose-effect analysis demonstrated that doxorubicin cardiotoxicity is related to the lifetime dose of the drug (Figure 18.12) and provided the basis for the definition of safe lifetime dose levels (7). The lifetime dose of doxorubicin is now limited to less than 400-450 mg/m, which is associated with a <5% risk of developing congestive heart failure. 

FIGURE 18.12 Cumulative risk of developing congestive heart failure (chfi as a function of the lifetime dose of doxorubicin. (Reproduced with permission from Van Hoff DD, Layard MW, Basa P et al. Ann Intern Med 1979 91 710-7.)... 

Of 682 patients, 144 who were over 65 years of age all had doses up to but not exceeding the usual cumulative dose for doxorubicin (14). The authors concluded that older patients without cardiovascular co-morbidity are at no greater risk of congestive heart failure. 

The authors of a study of the use of MRI scans to assess the subclinical effects of the anthracyclines concluded that increased MRI enhancement equal to or greater than 5 on day 3 compared with the baseline predicted significant reduction in ejection fraction at day 28 (32). In 1000 patients given doxorubicin chemotherapy and irradiation there were six cases of congestive heart failure and three cases of myocardial infarction there was a cumulative cardiac mortality of 0.4% in all anthracycUne-exposed patients (33). 

Ibrahim NK, Hortobagyi GN, Ewer M, Ah MK, Asmar L, Theriault RL, Fraschini G, Frye DK, Buzdar AU. Doxorubicin-induced congestive heart failure in elderly patients with metastatic breast cancer, with long-term... 

The combination of doxorubicin plus paclitaxel is cardio-toxic. Various authors have suggested that after a median cumulative dose of 480 mg/m, 50% of patients will have a reduced left ventricular ejection fraction and 20% will develop congestive heart failure. 

Doxorubicin (adriamycin) An increased incidence of late onset congestive heart failure has been seen in patients treated with mitomycin that had previously been given doxorubicin. 

These toxicides are not related to the mechanism of antitumor activity and in point of fact are not completely understood. What is known is that patients treated with doxorubicin can display an acute type of cardiac alteration and/or a chronic type of cardiac toxicity. The acute toxicides are most often expressed as myocardial arrhythmias and decreased left ventricular ejection fraction. Both effects are reversible once drug administration stops and are not considered to be a reason to discontinue the use of doxorubicin. Whether there is a correlation between these acute events and subsequent chronic cardiac toxicity is not known since individuals who never displayed acute toxicides ultimately developed chronic toxicides including fatal congestive heart failure. A reversible... 

Numerous neuroendocrine biomarkers correlate with severity of cardiac dysfunction. Heart failure is associated with increase in peripheral vascular resistance due to increases in sympathetic tone, norepinephrine, renin, angiotensin II, arginine vasopressin, and endothelin-1. The increased venous pressure causes atrial distension that stimulates production and release of atrial and brain natriuretic peptides (ANP, BNP) from the atria and ventricles, respectively. ANP inhibits the renin-angiotensin-aldosterone system. In humans and mammals, BNP has been found to be an early biomarker of left ventricular hypertrophy developing with doxorubicin cardiotoxicity, congestive heart failure, or occult dilated cardiomyopathy (Erkus et al. 2006 Walker 2006 Oyama, Sisson, and Solter 2007). 

---