Cardiac Hypertrophy Postliver Transplantation: A Role for Fk506 and Cyclosporine A?

Asymmetric cardiac hypertrophy at autopsy in patients who receive FK506 (tacrolimus) or cyclosporine A after liver transplant. Transplantation 2002; 74: 817. It is well recognized that orthotopic liver transplantation is associated with a high incidence of cardiovascular complications. One puzzling and somewhat controversial complication is that of cardiac hypertrophy seen in association with FK506 treatment (1–3). Roberts et al., reporting in this issue of Transplantation, document an increased incidence of asymmetric cardiac hypertrophy seen at autopsy in both children and adults after orthotopic liver transplantation, treated with either FK506 (tacrolimus) or cyclosporin A (CsA). This study is significant in that it represents the largest series of its kind yet published and because it contains detailed pathologic demonstration of cardiac, primarily left ventricular, hypertrophy. It is also significant that, unlike previous reports, Roberts et al. observed no difference in the association of cardiac hypertrophy with FK506 or CsA immunosuppressive therapy. The authors suggest, as others have previously, that the cardiac hypertrophy is related somehow to the use of FK506 (or CsA). The immunosuppressant macrolide FK506, derived from Streptomycestsukubaensis, and oligopeptide CsA, derived from Tolypocladium inflatum Gams, form intracellular complexes with FKBP12 and cyclophilin, respectively, and inhibit calcineurin-dependent T-cell activation (4,5). Calcineurin, a calmodulin-activated phosphatase, dephosphorylates the transcription factor nuclear factor of activated T cells (NFAT), which translocates to the nucleus and, in concert with AP-1 transcription factors, regulates gene expression. Calcium, which binds to and activates calmodulin, calmodulin, calcineurin, and NFAT have all been implicated in cardiac hypertrophy in animal models (6–8). The calcineurin-inhibitor CsA blocks agonist-induced cardiac myocyte hypertrophy in vitro (7), and both CsA and FK506 have been shown to at least partially prevent cardiac hypertrophy induced by aortic restriction in lab animals (9,10). Thus, from these experimental studies it appears that the calcium-calmodulin-calcineurin-NFAT signaling pathway is involved in cardiac hypertrophy. However, as compelling as this conclusion may seem, doubt remains because in other studies CsA and FK506 have proven ineffective in preventing cardiac hypertrophy (11,12). The original findings in the clinical literature that seem to have been confirmed by Roberts et al. in this issue are that liver transplantation is associated with an increased incidence of cardiac hypertrophy. Although several authors have implicated FK506 and CsA in this process, the outcome contrasts sharply with what is predicted by most of the experimental results outlined above (assuming the mechanism is calcineurin inhibition). Perhaps either the mechanism (whereby FK506 and CsA promote cardiac hypertrophy in liver transplant recipients) is unrelated to calcineurin inhibition, or confounding factors associated with liver transplantation (other than FK506 and CsA) are causal. In addition to calcineurin, CsA and FK506 target other signaling and transcription factors that may influence cardiac myocytes (13,14). One particularly intriguing candidate factor is myocyte enhancer factor(MEF)-2, which is up-regulated in experimentally induced cardiac hypertrophy (15). It would be interesting to know what effect, if any, CsA and FK506 have on cardiac MEF-2 activity. Another interesting factor that might play a role is myocyte-enriched calcineurin interacting protein (MCIP)-1, a possible endogenous calcineurin inhibitor. Over-expression of MCIP-1 in a transgenic mouse model has been shown to prevent experimentally induced cardiac hypertrophy (16). Another alternative mechanism of cardiac hypertrophy in liver transplantation may be FK506 and CsA-mediated hypertension (17–20). Notably, at least in cardiac transplant patients, the hypertrophic response to CsA exceeds that of essential hypertension (19). One author characterized the hypertensive effects of these compounds as “. . . outweighing any putative protective effects on cardiac hypertrophy” (21). Another hint that CsA may be more directly involved in cardiac hypertrophy than is currently understood is a study in which the increase in left ventricular mass correlated with the CsA levels in cardiac transplant patients with diuretic (but not felodipine)-treated hypertension (20). Two related but distinct alternative mechanisms that may be operative in some cases of cardiac hypertrophy in adult (but not pediatric) liver transplant candidates are cirrhotic cardiomyopathy and alcoholic cardiomyopathy (22). In fairness, by excluding adult transplant patients with a history of excessive alcohol use, Roberts and colleagues have minimized the confounding influence of these processes. However, it has been stressed that cirrhotic cardiomyopathy may be under-recognized in liver transplant candidates (23). Cirrhotic cardiomyopathy is often associated with left ventricular hypertrophy. The significant hemodynamic changes induced by cirrhosis and increases in cardio-depressant substances such as bile acids and endotoxin seen in liver failure likely conspire to induce the cardiomyopathy (24–26). In contrast, the disease known as alcoholic cardiomyopathy may or may not be associated with cirrhosis and is more likely because of the direct cytotoxic effects of alcohol or alcohol metabolites (e.g. acetaldehyde) and reduced contractile protein synthesis (27). Although after liver transplantation the hemodynamic changes associated with cirrhosis normalize (28), the effect of liver transplantation on reversal of cirrhotic cardiomyopathy has not been reported. Another important confounding factor may be corticosteroids. The response of cardiac muscle to glucocorticoids (GC) is quite distinct from that of skeletal muscle. Skeletal muscle mass is decreased in patients treated with corticosteroids, while, at least in animals, GC treatment is associated with a rapid increase in cardiac muscle mass ranging from 6 to 20% (29). As a matter of interest, after prolonged treatment the cardiac mass returns to normal. Although GC reportedly induces a proportional increase in myosin β-heavy chain and the V3 myosin isoform (30,31), it has been suggested that the increase in cardiac mass is due less to increased protein synthesis and more to decreased protein degradation (32). Roberts and coworkers have made a significant contribution by confirming the phenomenon of cardiac hypertrophy in liver transplantation. There is clearly much work to be done to further define the clinical significance and the true etiology of posttransplant cardiac hypertrophy.