Homocysteine‐Lowering Therapy and Early Progression of Transplant Vasculopathy: A Prospective, Randomized, IVUS‐Based Study

Abstract

Although observational studies suggest that hyperhomocysteinemia may be a risk factor for coronary allograft vasculopathy (CAV), prospective data on homocysteine-lowering interventions and CAV development are lacking. We, therefore, randomized 44 de novo heart transplant (HT) recipients to 15 mg/day of 5-methyl-tetrahydrofolate (n = 22), or standard therapy (control group, n = 22) to investigate the effect of homocysteine lowering on the change in coronary intimal hyperplasia during the first 12 months after transplant, as detected by intra-vascular ultrasound (IVUS). Although 12 months after HT, homocysteinemia was lower in folate-treated patients (p < 0.001), coronary intimal area increased similarly in the two groups (p > 0.4). Conversely, hypercholesterolemia and cytomegalovirus infection were both associated with increased intimal hyperplasia (p < 0.04), independently from folate intake. Sub-group analysis revealed that folate therapy reduced intimal hyperplasia in patients with hyperhomocysteinemia before randomization (n = 19; p = 0.02), but increased intimal hyperplasia in patients with normal homocysteine plasma concentrations (p = 0.02). This bimodal effect of folate therapy persisted significantly after adjusting for cytomegalovirus infection and hypercholesterolemia.Despite effective in prevent hyperhomocysteinemia after heart transplantation, folate therapy does not seem to affect early CAV onset. However, sub-group analysis suggests that folate therapy may delay CAV development only in patients with baseline hyperhomocysteinemia, while may favor CAV progression in recipients with normal baseline homocysteinemia.

The Many Flavors of Hyperhomocyst(e)inemia: Insights from Transgenic and Inhibitor-Based Mouse Models of Disrupted One-Carbon Metabolism

“…It is now well established that administration of folic acid results in significant lowering of plasma total homocyst(e)ine (2,47,64,67), but the results of several large folate therapy clinical trials to reduce the progression of cardiovascular disease have been disappointing (1,12,31,34,43,64), while showing promise in others (48,53,58). These findings argue against the hypothesis that homocysteine itself is the causative agent of disease, per se.…”

Subclinical Inflammation and Prothrombotic State in Heart Transplant Recipients: Impact of Cyclosporin Microemulsion vs. Tacrolimus

“…Potena et al have reported a significant decrease in coronary intimal hyperplasia with folate supplementation in de novo heart transplant patients with hyperhomocysteinemia. Interestingly intimal hyperplasia increased in patients receiving folate without baseline hyperhomocysteinemia (53). The metabolic and/or physiological mechanisms involved with the development of homocystinemia and the benefits of reducing this state, will require additional investigations in cardiac transplant recipients.…”

Allograft Vasculopathy Versus Atherosclerosis

“…A more recent randomized trial of the folate therapy on de novo heart transplant recipients during the first 12 months after transplant, as detected by IVUS, does not seem to affect on early CAV onset. 41 Numerous studies suggest that homocysteine is a modifiable risk factor for atherosclerotic diseases. In general, epidemiologic studies show an independent and graded association between homocysteine levels and cardiovascular risk.…”