What are the cardiac effects of Zidovudine (AZT)?

Cardiac Effects of Zidovudine (AZT)

Zidovudine (AZT) can cause cardiomyopathy, particularly in children and those with predisposing factors, and should be avoided in patients with pre-existing cardiac disease when alternative antiretrovirals are available. 1, 2

Primary Cardiac Effects of AZT

AZT has been associated with several cardiac effects:

1. Cardiomyopathy and Heart Failure

   • Children treated with AZT have 8.4 times greater odds of developing cardiomyopathy compared to those who never took AZT 2
   • Decreased left ventricular function has been temporally associated with AZT use 2
   • The FDA label reports congestive heart failure and left ventricular dilation as adverse reactions in pediatric patients 1

2. Mitochondrial Toxicity

   • AZT induces oxidative damage to cardiac mitochondria 3
   • Causes increased production of reactive oxygen species in mitochondria 3
   • Leads to mitochondrial lipid peroxidation and oxidation of mitochondrial glutathione 3

3. Molecular Mechanisms

   • Increases sarcolemmal expression of Fas and FasL 4
   • Activates caspase 3 and causes translocation of calpain 1 to the sarcolemma 4
   • Increases apoptosis in cardiac cells 4
   • Alters cardiac gene expression through mitochondrially derived reactive oxygen species 5

Risk Factors for AZT-Induced Cardiac Effects

Certain populations appear to be at higher risk for AZT-related cardiac complications:

• Pediatric patients: More susceptible to AZT-induced cardiomyopathy 2
• Patients with pre-existing heart disease: Higher risk for cardiac complications 6, 1
• Magnesium deficiency: Exacerbates AZT cardiac toxicity 7
• Patients with Fas ligand expression in myocardium: Increased susceptibility to AZT-induced cardiomyopathy 4

Clinical Implications and Management

When considering AZT therapy:

• Cardiac monitoring: Perform baseline and follow-up cardiac evaluations in patients receiving AZT, particularly in children 2
• Alternative agents: Consider tenofovir-based regimens which have higher completion rates than AZT-containing regimens (adjusted OR = 2.80) 6
• Antioxidant supplementation: Vitamins C and E may protect against AZT-induced mitochondrial oxidative stress in experimental models 3
• Magnesium status: Consider evaluating and correcting magnesium deficiency in patients receiving AZT 7

Comparison with Other Antiretrovirals

• Didanosine (ddI): Does not appear to increase the risk of cardiomyopathy compared to AZT 2
• Tenofovir-based regimens: Associated with significantly higher completion rates than AZT-containing regimens 6
• TAF-containing regimens: Completion rates range from 82% to 96% without HIV seroconversions 6

Important Considerations for Clinical Practice

• For post-exposure prophylaxis, the CDC recommends tenofovir-based regimens over AZT-containing regimens due to better tolerability 6
• When AZT must be used, monitor for signs of cardiac dysfunction, particularly in pediatric patients 1, 2
• The risk of cardiac effects appears to be dose and duration dependent with a nonlinear relationship between days of AZT use and decrease in cardiac fractional shortening 2

AZT's cardiac effects are significant enough that they should be carefully considered when selecting antiretroviral therapy, especially for patients with pre-existing cardiac risk factors or disease.