Doxorubicin-Induced Cardiomyopathy: From the Cardiotoxic Mechanisms to Management
Section snippets
Morphological Aspects of DOX-Induced Cardiomyopathy
As with other forms of dilated cardiomyopathy, hearts affected by DOX's cardiotoxicity are enlarged with dilation of all chambers, and mural thrombi are seen frequently in both ventricles. At the light microscope level, there are multifocal areas of patchy and interstitial fibrosis and scattered cardiomyocytes with vacuolation (Fig 2). Vacuolated cardiomyocytes are occasionally observed adjacent to areas of fibrosis (Adria cells). Fibrotic foci generally predominate, whereas areas of acute
Pathogenic Mechanisms of DOX-Induced Cardiomyopathy
The mechanism responsible for DOX-induced cardiomyopathy remains unclear, but it seems very different from that underlying DOX's antitumor activity. This has raised hopes that treatment protocols can be designed that protect the heart without diminishing the drug's antitumor activity.
Although numerous mechanisms have been proposed (Table 1), most studies support the view that an increase in oxidative stress, evidenced increases in the levels of ROS,36, 37, 38 and lipid peroxidation,20, 36, 39
Epidemiology and Clinical Features
Doxorubicin exerts both acute and chronic effects on the cardiovascular system. Its acute effects include arrhythmias (eg, supraventricular tachycardia, ventricular premature beats), hypotension, and various electrocardiographic changes (eg, nonspecific ST-T change, left axial deviation, low voltage).2, 121, 122 These effects occur in approximately 11% of patients during or soon after (within a couple of days) DOX administration and are generally reversible and clinically manageable.2 Acute
Monitoring of Patients and Diagnostic Procedures
The monitoring of patients receiving DOX includes (1) assessment of baseline cardiac performance before DOX therapy begins (to exclude contraindicated patients), (2) regular assessments during treatment (to prevent overdosage or to determine when DOX should be terminated), and (3) follow-up after therapy has been completed (to watch for insidious progression of cardiomyopathy). Various diagnostic procedures are listed in Table 6.
Management: Prevention of DOX-induced cardiomyopathy
Limiting the cumulative dose of DOX to less than 450 mg/m2 is the first line of defense against cardiotoxicity.152 To minimize the total amount of DOX used, it is administered concurrently with other antitumor drugs such as vincristine, procarbazine, cisplatin and cyclophosphamide.127, 152 Additional strategies that have been used in an attempt to prevent DOX-induced cardiomyopathy include the use of DOX analogues, alternative drug-delivery methods, antioxidants, and the iron chelator
Management: Treatment of DOX-induced cardiomyopathy
At present, there is no specific treatment for DOX cardiomyopathy. Typically, DOX cardiomyopathy and heart failure are refractory to conventional therapy.179β-Blockers (eg, metoprolol) and angiotensin-converting enzyme inhibitors (eg, enalapril and captopril) may be useful in patients with congestive heart failure.180, 181 Malignant arrhythmias may also require treatment. Cardiac transplantation remains a vital option for patients with end-stage heart failure due to DOX cardiomyopathy.181, 182,
Conclusions
Anthracyclines, including DOX, rank among the most effective anticancer drugs ever developed, despite their dose-dependent cardiotoxic effects.1, 185 Contributors to DOX-induced cardiomyopathy include free radical formation, apoptosis, inhibited expression of cardiomyocyte-specific genes, and altered molecular signaling pathways.186 A variety of approaches to preventing this cardiotoxicity have be tried, but so far, the ability of these treatments to protect the heart from DOX-induced damage
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