tacrolimus and Cardiomyopathy--Hypertrophic

To clarify the incidence and pathophysiological mechanism of cardiovascular adverse effects of tacrolimus, the present prospective study performed scheduled cardiovascular examinations at 1, 2, 4, 8, 16, 20, and 24 weeks after starting the tacrolimus therapy in 68 consecutive kidney transplantation recipients enrolled from 26 institutes in Japan. Patients with previous coronary artery disease or congestive heart failure were excluded. The examinations included any subjective symptoms, changes in resting ECG, ambulatory Holter's dynamic ECG, two-dimensional echocardiography, and monitoring of serum drug concentrations and cardiac troponin T levels. Cardiac nuclear imaging and/or coronary angiography were performed in the case of suspicious coronary events. During the investigation, chest pain in 9 (13.2%) and palpitation in 6 patients (8.8%) were reported, both closely related to elevated blood drug concentrations (37.2 +/- 18.7 ng/mL, mean +/- SD). Cardiovascular examinations detected development of resting ECG abnormalities in 12 patients (17.6%), asymptomatic ST depression following increased heart rate in 11 (16.2%) and ventricular arrhythmias in 7 patients (10.3%) on Holter's dynamic ECG. Elevation of troponin T was detected in 3 patients (4.4%), which was also closely related to elevated drug concentrations and interpreted as myocardial damage associated with the therapy. Assessments by thallium(Tl)-201 myocardial scintigraphy and/or coronary angiography in patients with suspicious coronary events revealed only two patients (2.9%) were considered to be myocardial ischemia associated with coronary vasospasm or microcirculatory disturbance. Sequential evaluations on echocardiography revealed significant (p<0.05) decrease in LV end-diastolic dimension (4, 8, 18 and 24 weeks) and LV end-systolic dimension (from 1 to 24 weeks), and significant (p<0.05) increase in LV ejection fraction 1 to 4 weeks after the kidney transplantation. Thickening of LV wall (>2 mm compared with baseline) was detected in only one patient. The present prospective study detected totally 30.9% incidence of cardiovascular adverse events. Symptomatic events and troponin T elevation were closely related to elevated blood drug concentrations (>20 ng/ml). Coronary vasomotor dysfunction seemed to be related to these adverse events especially when the blood drug concentration was exceeding 20 ng/ml.

Topics: Adolescent; Adult; Body Weight; Cardiomyopathy, Hypertrophic; Cardiovascular Diseases; Dose-Response Relationship, Drug; Echocardiography; Electrocardiography; Electrocardiography, Ambulatory; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus; Time Factors; Troponin T

Hypertrophic cardiomyopathy in the newborn is a rare entity with heterogeneous etiology. Transient forms have been described in children of mothers with gestational diabetes and in preterm infants exposed both to prenatal and postnatal corticosteroids. We report a case of a preterm infant son of a mother who received renal transplant in whom hypertrophic cardiomyopathy was detected. He had been prenatally exposed to corticosteroids and tacrolimus that received the mother as immunosuppressive therapy. Both drugs cross the placental barrier and, on reaching the fetus, could have favored its development. Hypertrophic cardiomyopathy may be an uncommon side effect of treatment with tacrolimus in adults and children and it is reversible upon withdrawal. To our knowledge, it is the first published case of transient hypertrophic cardiomyopathy after fetal exposure to both corticosteroids and tacrolimus in the son of a renal transplanted mother.. La miocardiopatía hipertrófica en el recién nacido es una entidad poco frecuente y de etiología heterogénea. Se han descrito formas transitorias en hijos de madres con diabetes gestacional y en recién nacidos pretérminos expuestos a corticoides tanto prenatal como posnatalmente. Se presenta un caso de un recién nacido pretérmino, hijo de madre trasplantada renal al que se le detectó una miocardiopatía hipertrófica y que había estado expuesto prenatalmente a corticoides y tacrolimus que recibía la madre como tratamiento inmunosupresor. Ambos fármacos cruzan la barrera placentaria y, al llegar al feto, podrían haber favorecido su desarrollo. La miocardiopatía hipertrófica puede ser un efecto secundario poco común del tratamiento con tacrolimus en adultos y niños, y es reversible al retirarlo. En nuestro conocimiento, es el primer caso publicado de miocardiopatía hipertrófica transitoria tras la exposición fetal tanto a corticoides como a tacrolimus en un hijo de madre trasplantada renal.

Topics: Cardiomyopathy, Hypertrophic; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infant, Newborn; Infant, Premature; Kidney Transplantation; Male; Mothers; Placenta; Pregnancy; Tacrolimus

Topics: Cardiomyopathy, Hypertrophic; Dermatomyositis; Female; Humans; Immunosuppressive Agents; Middle Aged; Tacrolimus

Left ventricular hypertrophy associated with the use of tacrolimus is a rare complication of solid organ transplantation in adult recipients. We present a cardiac transplant recipient who developed severe concentric left ventricular hypertrophy with congestive heart failure related to myocardial hypertrophy on tacrolimus. Hypertrophy improved when the drug was discontinued and replaced with sirolimus.

Topics: Adult; Cardiomyopathy, Hypertrophic; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Middle Aged; Tacrolimus

Recently there are a number of reports on the cardiotoxicity of tacrolimus in post-transplant patients. There is no protocol for cardiovascular evaluation in these patients. This study was performed to evaluate the cardiotoxicity of tacrolimus in liver transplant recipients.. We evaluated 63 post-liver transplant patients who received tacrolimus. They were evaluated for cardiovascular complications by physical examination, electrocardiographic and echocardiographic examinations within three and six months following liver transplantation. Serum tacrolimus levels were checked by ELISA. For comparison, we selected 50 post-liver transplant patients who received no tacrolimus and evaluated them for cardiovascular function identically.. Among 63 patients, 42 were male (66.7%) and 21 were female (33.3%); 70% of the patients were adults, and 19 (30%) were within the pediatric age group. The cardiovascular examinations, electrocardiogram and echocardiography of all patients three months post-transplantation were normal except for two children who developed tacrolimus related cardiac complications. Both had high serum tacrolimus levels. No adults developed cardiovascular complications. In the control group, the results of the cardiovascular evaluations were normal in all cases.. The cardiovascular toxicity of tacrolimus, such as hypertrophic cardiomyopathy, may be observed in pediatric patients. Therefore, we recommend routine regular cardiovascular evaluation of children after liver transplantation.

Topics: Adolescent; Adult; Cardiomyopathy, Hypertrophic; Child; Child, Preschool; Echocardiography; Electrocardiography; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Tacrolimus; Young Adult

Tacrolimus (Tac)-related hypertrophic cardiomyopathy (HCM) has been reported to be an unusual but serious complication affecting pediatric patients after solid organ transplantation. Herein, we present a case of young liver transplant recipient with Tac-induced HCM, treated by discontinuation of Tac followed by conversion to rapamycin (Rap). Our case report points out the potential but rather low risk of HCM during Tac immunosuppression in pediatric liver transplants and demonstrates that replacement of calcineurin inhibitors with mammalian target of Rap (mTOR) inhibitors may be an efficacious therapeutic tool to effect regression of established cardiac hypertrophy.

Topics: Cardiomyopathy, Hypertrophic; Female; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Sirolimus; Tacrolimus; Ultrasonography

Hypertrophic obstructive cardiomyopathy (HOCM) is an unusual but serious side-effect of tacrolimus (TAC) based immunosuppression primarily affecting pediatric patients after solid organ transplant. TAC-induced HOCM has already been described in patients after liver, bowel and heart transplant shortly after the procedure. Herein, we present the first case report of TAC-induced HOCM in a young renal transplant recipient 5 yr after renal transplant. The condition was diagnosed by ECHO and EKG and successfully treated by discontinuation of TAC followed by conversion to cyclosporine (CsA).

Topics: Adolescent; Cardiomyopathy, Hypertrophic; Child; Cyclosporine; Echocardiography; Electrocardiography; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Tacrolimus; Time Factors

This study was carried out to compare echocardiographic findings of children taking tacrolimus and cyclosporin A (CsA) after orthotopic liver transplantation (OLT). Echocardiograms of 19 children were reviewed during hospitalizations after OLT, and echocardiograms were performed on 23 children who returned to the clinic for a routine follow-up visit after OLT. Measurements were made of the left ventricle (LV) end-diastolic dimension, and of the thickness of the LV free wall (LVFW) and the inter-ventricular septum (IVS). From these measurements, the LV mass was calculated. LV outflow gradient was measured by using Doppler interrogation. Comparisons were made between patients on CsA and patients on tacrolimus. Children with hypertrophic cardiomyopathy (HCM) were identified. Two patients from the in-patient tacrolimus group were found to have HCM. These two patients had asymmetric septal hypertrophy with dynamic LV outflow obstruction and were successfully treated with propranolol, with or without discontinuing tacrolimus. In the out-patient studies, there was no difference in LVFW and IVS thickness, or LV mass index, between children on CsA and children on tacrolimus. Hence, tacrolimus is associated with the development of HCM in children. The effect of tacrolimus on HCM development may be acute and temporary. More data are needed to determine the incidence of HCM in children on tacrolimus therapy and to establish guidelines for clinicians who follow-up these children.

Topics: Adolescent; Cardiomyopathy, Hypertrophic; Child; Child, Preschool; Cyclosporine; Female; Graft Rejection; Heart Ventricles; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Transplantation; Male; Tacrolimus; Ultrasonography; Ventricular Function, Left

Topics: Adenoviridae; Animals; Calcineurin; Calcineurin Inhibitors; Cardiomyopathy, Hypertrophic; Carrier Proteins; Cyclosporine; Disease Models, Animal; DNA-Binding Proteins; Gene Dosage; Gene Expression; Genes, Dominant; Intracellular Signaling Peptides and Proteins; Mice; Mice, Transgenic; Muscle Proteins; Mutation; Peptides; Signal Transduction; Tacrolimus

Hypertrophic cardiomyopathy (HCM) has been reported in pediatric transplant patients receiving tacrolimus. It is unclear whether tacrolimus is associated with HCM in adult transplant recipients.. To determine the prevalence of HCM in noncardlac adult transplant patients receiving tacrolimus.. A retrospective analysis of nonheart transplant recipients who received tacrolimus at our institution from January 1982 to April 1996 was conducted. Patients with left-ventricular hypertrophy (LVH) defined as a posterior or septal wall thickness > or = 1.3 cm by echocardiography (ECHO) were independently evaluated.. There were 3609 patients who met entry criteria including 2257 liver, 1333 kidney, and 19 other organ transplants. Of the 502 patients who had undergone ECHOs after transplantation, 171 had LVH. The etiology of LVH was categorized as valvular disease (36%), hypertensive disease (29%), ischemic heart disease (17%), or multifactonal (15%). There were six patients in whom, after detailed chart review, no underlying cause of LVH was evident. Five of these patients had HCM, representing an overall prevalence of 0.1% in the entire group of tacrolimus-treated patients, and 1% in patients referred for ECHO.. The prevalence of HCM in our tacrolimus-treated adult transplant population is similar to that reported in general population studies. These data suggest that tacrolimus is not a risk factor for HCM in adult transplant recipients.

Topics: Adult; Cardiomyopathy, Hypertrophic; Echocardiography; Female; Graft Rejection; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Postoperative Complications; Prevalence; Retrospective Studies; Tacrolimus

Hypertrophic obstructive cardiomyopathy (HOCM) associated with the use of tacrolimus is a rare complication of liver and intestinal transplantation seen almost exclusively among pediatric patients. Reduction of tacrolimus dosage or conversion to cyclosporin A (CsA) has been used as an effective treatment in reviewed cases. We present three pediatric transplant recipients who developed hypertrophic obstructive cardiomyopathy while under tacrolimus immunosuppression and were treated with conversion to sirolimus (Rapamycin). The patients (ages 6 yr, 12 yr and 11 months) were transplant recipients (liver, n = 2; liver and intestine, n = 1) who developed significant cardiomyopathy 15 and 96 months post-transplant. One patient died of post-transplant lymphoproliferative disorder 21 days after starting sirolimus. One patient had received two liver transplants and had been on CsA for 12 yr before conversion to tacrolimus at 60 months post-transplant for acute and chronic rejection. The surviving patients were receiving mycophenolate mofetil, tacrolimus and steroids at the time of diagnosis. Dose reduction of tacrolimus and treatment with beta blockers failed to alleviate the hemodynamic changes. The patients were converted to sirolimus 1.6, 37 and 148 months post-transplant and maintained a whole-blood trough level of 15-20 ng/mL 21 days after starting sirolimus. Repeat echocardiograms in the surviving patients showed improvement in cardiomyopathy. One patient had one rejection episode (intestinal biopsy, mild acute cellular rejection) after starting sirolimus that responded to a transient increase in steroids. The early demise of the third patient after sirolimus conversion prevented an adequate assessment of cardiomyopathy. Conversion to sirolimus was associated with a reduction in the cardiomyopathy of the two surviving patients while still providing effective immunosuppression. To our knowledge this observation has not been previously reported.

Topics: Acute Disease; Cardiomyopathy, Hypertrophic; Child; Chronic Disease; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Intestine, Small; Liver Transplantation; Sirolimus; Tacrolimus

Dominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (alphaMHC(403/+)), when treated with calcineurin inhibitors or a K(+)-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca(2+) concentrations in wild-type cardiac myocytes; alphaMHC(403/+) myocytes failed to respond. Pretreatment with a Ca(2+)-channel antagonist abrogated diastolic Ca(2+) changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated alphaMHC(403/+) mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca(2+) responses that initiate a hypertrophic response. These data define an important Ca(2+)-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.

Topics: Animals; Calcineurin Inhibitors; Calcium; Cardiomyopathy, Hypertrophic; Cyclosporine; Echocardiography; Enzyme Inhibitors; Heart Ventricles; Mice; Minoxidil; Mutation; Myosin Heavy Chains; Sarcomeres; Survival Analysis; Tacrolimus

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Calcium Signaling; Cardiomyopathy, Hypertrophic; Cyclosporine; Disease Models, Animal; Humans; Mice; Mice, Knockout; Molecular Motor Proteins; Muscles; Mutation; Myosin Heavy Chains; Tacrolimus

Topics: Adult; Cardiomyopathy, Hypertrophic; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Tacrolimus

Hypertrophic cardiomyopathy (HCM) is an inherited form of heart disease that affects 1 in 500 individuals. Here it is shown that calcineurin, a calcium-regulated phosphatase, plays a critical role in the pathogenesis of HCM. Administration of the calcineurin inhibitors cyclosporin and FK506 prevented disease in mice that were genetically predisposed to develop HCM as a result of aberrant expression of tropomodulin, myosin light chain-2, or fetal beta-tropomyosin in the heart. Cyclosporin had a similar effect in a rat model of pressure-overload hypertrophy. These results suggest that calcineurin inhibitors merit investigation as potential therapeutics for certain forms of human heart disease.

Topics: Animals; Calcineurin; Calcineurin Inhibitors; Calcium; Cardiac Myosins; Cardiomegaly; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Carrier Proteins; Cyclosporine; Female; Mice; Mice, Transgenic; Microfilament Proteins; Models, Cardiovascular; Myocardium; Myosin Light Chains; Rats; Signal Transduction; Tacrolimus; Tropomodulin; Tropomyosin

We recently reported partially to wholly reversible hypertrophic cardiomyopathy, including severe hypertrophic obstructive cardiomyopathy, as a side effect in pediatric transplant recipients receiving tacrolimus immunosuppression. This seemed to be dose related. We describe a pediatric patient receiving tacrolimus who died 3 weeks after liver/bowel transplantation. Postmortem findings revealed arteritis of cardiac arteries and extensive calcification of cardiac tissue suggesting a possible mechanism of tacrolimus cardiac toxicity. This is consistent with recent reports of tacrolimus increasing calcium release into the sarcoplasmic reticulum of cardiac and striated muscle.

Topics: Arteritis; Calcium; Cardiomyopathy, Hypertrophic; Carrier Proteins; Child, Preschool; Humans; Immunosuppressive Agents; Intestine, Small; Liver Transplantation; Male; Sarcoplasmic Reticulum; Tacrolimus; Transplantation, Homologous

Topics: Administration, Oral; Cardiomyopathy, Hypertrophic; Cyclosporine; Echocardiography; Edema; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Tacrolimus

Reported side-effects of tacrolimus, a potent immunosuppressive agent, have not included cardiotoxicity. We describe 5 consecutive paediatric transplant recipients (3 small bowel with or without liver and 2 liver) who received tacrolimus. 2 developed congestive heart failure and hypertrophic obstructive cardiomyopathy which resolved after changing to cyclosporin. In the other 3 patients the cardiomyopathy regressed or improved with a lower dose of tacrolimus or after stopping the drug.

Topics: Blood Pressure; Cardiomyopathy, Hypertrophic; Child, Preschool; Colon; Echocardiography; Female; Heart Failure; Humans; Infant; Liver Transplantation; Male; Postoperative Complications; Tacrolimus

Topics: Bronchopulmonary Dysplasia; Cardiomyopathy, Hypertrophic; Child, Preschool; Dexamethasone; Humans; Infant; Infant, Newborn; Infant, Premature; Tacrolimus

Topics: Adult; Anemia, Aplastic; Bone Marrow Transplantation; Cardiomyopathy, Hypertrophic; Humans; Immunosuppressive Agents; Male; Tacrolimus

Topics: Bronchiolitis, Viral; Cardiomyopathy, Hypertrophic; Child, Preschool; Diarrhea; Female; Humans; Immunosuppressive Agents; Intestine, Small; Parenteral Nutrition; Respiratory Syncytial Virus Infections; Selenium; Tacrolimus