Cardiac signaling molecules and plasma biomarkers after cardiac transplantation: impact of tacrolimus versus cyclosporine.

BACKGROUND: We investigated cardiac proinflammatory, mitogenic, and apoptotic signaling events, and plasma biomarkers of inflammation and oxidative stress in de novo adult cardiac transplant (CTX) patients receiving tacrolimus (TAC) or cyclosporine A (CsA). METHODS: One hundred CTX recipients were randomized 1:1 to TAC/CsA in a prospective, randomized open-label multicenter study. Biomarkers of inflammation, immunity, oxidative stress, and cardiac signaling underlying growth and inflammation (extracellular signal-related kinase 1/2, p38 mitogen-activated protein kinase, mitogen-activated protein kinase kinases [MEK] 1/2 and 3/6, c-Src), and apoptosis and survival (c-Jun NH2-terminal kinases [JNK], Bax/Bcl2, Akt) were assessed at 2, 4, 12, 26, and 52 weeks post-CTX. Plasma from healthy controls (n = 30) and tissue from explanted non-failing hearts (n = 6) were used as controls. RESULTS: Biomarkers of inflammation/immunity (interleukin -6 and -18, soluble intercellular adhesion molecule, E-selectin, monocyte chemoattractant protein-1, osteopontin, fibrinogen, N-terminal prohormone brain natriuretic peptide, high-sensitive C-reactive protein) and oxidative stress (thiobarbituric acid reactive substances, nitrotyrosine) were increased, and antioxidant capacity was (glutathione/glutathione disulfide) decreased in patients vs healthy controls (p < 0.05). Phosphorylation of mitogen-activated protein kinases and Akt was increased, and Bax/Bcl was decreased in transplanted vs non-transplanted hearts. Except for plasma fibrinogen, which was lower in TAC vs. CsA, (p = 0.01), there were no significant differences in parameters studied between TAC vs CsA immunoprophylaxis. CONCLUSIONS: De novo CTX recipients exhibit significant sub-clinical inflammation and oxidative stress that persists 12 months after transplantation. Associated with this is activation of myocardial growth and inflammatory signaling and decreased apoptosis. Our findings suggest that CTX is an inflammatory condition associated with oxidative stress and myocardial growth regardless of CsA or TAC immunoprophylaxis and independently of rejection status.

Cardiac phenotype and clinical outcome of familial amyloid polyneuropathy associated with transthyretin alanine 60 variant.

AIMS: Familial amyloid polyneuropathy (FAP) is a dominantly inherited multi-system disease associated with transthyretin (TTR) mutations. Previous series have predominantly described patients with the TTR variant Val30Met (V30M), which is the most prevalent cause of FAP worldwide. Here, we report the dominant cardiac phenotype and outcome of FAP associated with TTR Thr60Ala (T60A), the most common UK variant. METHODS AND RESULTS: Sixty consecutive patients with FAP associated with TTR T60A (FAP T60A) were prospectively evaluated in two centres between 1992 and 2009. Median (range) age of symptom development was 63 (45-78) years. A family history of amyloidosis was present in only 37%. Autonomic and peripheral neuropathy were present in 44 and 32 patients, respectively, at diagnosis. Cardiac involvement was evident on echocardiography at diagnosis in 56 patients, but was associated with reduced QRS voltages on electrocardiography in only 16% evaluable cases. Seventeen patients received implantable anti-arrhythmic devices. Median survival was 6.6 years following onset of symptoms and 3.4 years from diagnosis, and correlated with serum N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration and certain echocardiographic parameters at the latter. Orthotopic liver transplantation (OLT), performed to eliminate the predominant hepatic source of variant TTR T60A protein, was performed in eight patients including one who received a concomitant cardiac transplant. Cardiac amyloidosis progressed in all lone OLT recipients, of whom four died within 5 years. CONCLUSION: Cardiac amyloidosis is almost always present at diagnosis in FAP T60A, and is a major determinant of its poor prognosis. Outcome of liver transplantation in FAP T60A has been discouraging.

Increased morbidity in diabetic cardiac transplant recipients.

BACKGROUND: Diabetes currently affects more than 7% of the Canadian population, and heart failure is a well-documented complication of diabetes. The medical management of heart failure is often limited by disease progression, and cardiac transplantation is a key therapeutic option in end-stage disease. However, both American and Canadian guidelines continue to list diabetes as a relative contraindication to cardiac transplantation. OBJECTIVE: To determine the effect of preoperative diabetes on morbidity and mortality in patients undergoing cardiac transplantation. METHODS: A retrospective analysis of 136 adult patients undergoing cardiac transplantation at the London Health Sciences Centre (London, Ontario) between February 1995 and November 2003 was performed. Preoperatively, 14% of patients were diabetic. Unpaired Student's t tests and x(2) tests were used to compare outcomes between diabetic and nondiabetic cardiac transplant recipients. RESULTS: Diabetic and nondiabetic cardiac transplant recipients were similar in age, sex, body mass index and ischemic time. Preoperatively, diabetic recipients had a higher mean serum glucose and an increased incidence of ischemic cardiomyopathy. At three years postcardiac transplantation, diabetic recipients were found to have increased rates of transplant coronary artery disease, as well as decreased cardiac function. However, diabetic and nondiabetic patients showed no differences in rates of clinically significant infection or rejection in the first three postoperative months. Furthermore, survival rates were similar between these two groups. CONCLUSION: Diabetes is not a contraindication to cardiac transplantation, but increased vigilance is warranted in this population to minimize postoperative morbidity.

Angiographic, pathologic, and clinical relationships in coronary artery disease in cardiac allografts.

BACKGROUND: To date, the etiologic factors involved in the development of allograft coronary disease remain speculative and the treatment uncertain. The purpose of this study was to review the relationship of clinical, angiographic, and pathologic features of cardiac allograft vascular disease in a large population of heart transplant recipients followed for up to 15 years. METHODS: From 1981 to 1996, 789 angiograms from 255 cardiac allografts were reviewed to determine the prevalence and severity of coronary artery disease. Demographic, clinical, and laboratory variables were analyzed to identify factors associated with the presence of angiographic coronary artery disease. In addition, pathologic examination was performed on many of the lost grafts. RESULTS: Unsuspected severe donor coronary artery disease may be responsible for up to 10% of early graft failures. Angiographic coronary artery disease prevalence increased by approximately 10% with every 2-year interval after transplantation. Angiographic coronary artery disease consisted most often of minor luminal irregularities. Severe disease occurred in 12% of patients. At 1 year, the most significant factors associated with the presence of coronary artery disease were older donor age and the number of rejection episodes. Immunologic factors as well as traditional coronary risk factors such as hypercholesterolemia and hyperglycemia may play an important role in the genesis and progression of later-developing abnormalities. CONCLUSIONS: Cardiac allograft coronary artery disease is a major limiting factor to the long-term success of cardiac transplantation. Immune processes, as well as traditional coronary artery disease risk factors, appear to play a role in the development of this disease.

Validation of a three-dimensional intravascular ultrasound imaging technique to assess atherosclerotic burden: potential for improved assessment of cardiac allograft coronary artery disease.

BACKGROUND: Serial analysis of intracoronary ultrasound images is limited by difficulty with spatial registration and inability to assess the full extent of vascular disease. Three-dimensional (3D) imaging of coronary arteries can potentially overcome these limitations. OBJECTIVES: To assess the feasibility of using a PC-based 3D rendering technique to assess atherosclerotic burden. METHODS: To define the accuracy of 3D intravascular ultrasound (IVUS) measurements in vitro, six porcine iliac arteries and nine human cadaveric iliac arteries were pressure fixed and imaged with a commercial IVUS system. 3D datasets of the arteries were constructed, and measurements were correlated with histomorphometry. In vivo studies of 53 arterial segments (19 right coronary, 26 anterior descending and eight circumflex) were scanned in 18 patients, one month to nine years post-transplantation and correlated to corresponding angiographic images for the presence of atherosclerosis. RESULTS: Porcine artery length and volume measurements by IVUS showed a high degree of correlation with histomorphometry measurements (r=0.99, P<0.0003 and r=0.99, P<0.0001, respectively). Human arterial length, total artery volume and lumen volume measurements were similarly correlated (r=0.99, P<0.0001, r=0.99, P<0.0001 and r=0.98, P<0.0001, respectively). For plaque volume, r=0.84, P<0.05. In vivo 3D IVUS scans demonstrated atherosclerotic lesions in nine of 18 patients, compared with five detected by angiography alone. CONCLUSIONS: 3D IVUS imaging allows rapid and accurate measurement of arterial length, volume and plaque dimensions in addition to lumenal area and can demonstrate the full extent of atherosclerotic pathology. Because of its superior reproducibility, this technique may be used to assess the progression of coronary artery disease and allow for more accurate evaluation of interventions aimed at preventing or retarding coronary artery disease.