Sympathetic reinnervation, exercise performance and effects of beta-adrenergic blockade in cardiac transplant recipients.

AIMS: To evaluate effects of beta-adrenergic receptor blockade on allograft performance, and to correlate these effects with sympathetic reinnervation. METHODS AND RESULTS: Myocardial catecholamine storage capacity was determined in 12 non-rejecting transplant recipients using PET and C-11 adrenaline (epinephrine). Haemodynamics and left ventricular function were measured using radionuclide angiography at rest and during symptom-limited exercise before and after non-selective beta-blockade (propranolol iv). Exercise time and stress-induced increases of heart rate and LVEF before beta-blockade were significantly higher in reinnervated compared to denervated recipients. While resting LVEF remained unchanged, heart rate and blood pressure were generally reduced by beta-blockade, which was well tolerated by all patients. Exercise time and increases of heart rate and LVEF were more attenuated in reinnervated recipients. Differences of chronotropic and inotropic response to exercise between groups were no longer present following beta-blockade. Correlations between myocardial adrenaline retention, peak heart rate and increase of global, as well as regional ejection fraction during exercise were observed before, but not during beta-blockade. CONCLUSION: Acute, non-selective beta-blockade is well tolerated by transplant recipients, but significantly attenuates beneficial functional effects of sympathetic reinnervation on exercise performance. The data suggest that reappearance of sympathetic nerve terminals is associated with reestablishment of intact pre-/postsynaptic interaction.     

LMNA mutations in cardiac transplant recipients

Lamin A and C are components of the nuclear envelope, located at the nucleoplasmatic surface of the inner nuclear membrane within cells. Recently, mutations within LMNA encoding lamin A/C have been associated with various disease entities including cardiomyopathy. We screened heart transplant recipients suffering from dilated cardiomyopathy (DCM) with a positive family history of LMNA mutations. Four index patients and one relative belonging to four unrelated families carrying LMNA mutations were identified. The mutations p.Q355X and p.S22L have not been reported before, whereas p.R190W has already been reported in other studied DCM cohorts. In the patients of the present study, the mean age at manifestation of heart disease was 37.6 years (range 30-45 years), with progression to end-stage heart failure requiring transplantation at a mean age of 45.8 years (range 35-54 years). Three patients presented initially with atrial fibrillation. These data confirm the involvement of LMNA mutations in patients with DCM and extend the mutational spectrum of LMNA. The p.R190W mutation has been reported in different populations and may therefore be useful for analyzing the impact of a specific LMNA mutation on the phenotype of muscle disease.     

Pulmonary complications in cardiac transplant recipients

BACKGROUND: The incidence of pulmonary complications in heart transplant recipients has not been extensively studied. We report pulmonary complications in 159 consecutive adult orthotopic heart transplantations (OHTs) performed in 157 patients. Materials and methods: Retrospective review of medical records. RESULTS: Forty-seven of 159 recipients (29.9%) had 81 pulmonary complications. Pneumonia was the most common (n = 27), followed by bronchitis (n = 15), pleural effusion (n = 10), pneumothorax (n = 7), prolonged respiratory failure requiring tracheotomy (n = 7), and obstructive sleep apnea syndrome (n = 6). All patients with late-onset (> 6 months after transplantation) community-acquired bacterial pneumonia presented with fever, cough, and a new lobar consolidation on the chest radiograph, and responded promptly to empiric antibiotics without undergoing an invasive diagnostic procedure. In contrast, early-onset nosocomial bacterial pneumonias carried a 33.3% mortality rate. A positive tuberculin skin test result was associated with a significantly higher rate of pulmonary complications (62.5% vs 26.8%, p = 0.007). Lung cancer and posttransplant lymphoproliferative disorder (PTLD) developed exclusively in 6 of the 61 patients (8.1%) who received induction immunosuppression with murine monoclonal antibody (OKT3). CONCLUSION: Pulmonary complications are common following heart transplantation, occurring in 29.9% of recipients, and are attributed to pneumonia of primarily bacterial origin in one half of cases. Late-onset community-acquired pneumonia carried an excellent prognosis following empiric antibiotic therapy, suggesting that in the appropriate clinical setting invasive diagnostic procedures are unnecessary. Analogous to reports in other solid-organ transplant recipients, induction therapy with OKT3 was associated with an increased incidence of lung cancer and PTLD. Overall, the development of pulmonary complications after OHT has prognostic significance given the higher mortality in this subset of patients.     

Coronary angioplasty in cardiac transplant recipients

Accelerated coronary artery disease following cardiac transplantationremains an important obstacle to long-term survival and thecorrect management strategy remains unclear. This observational,prospective study was designed to examine the feasibility ofusing percutaneous transluminal coronary angioplasty (PTCA)in the treatment of post-transplant coronary disease. Thirteen consecutive patients were selected from the total populationof 276 transplant recipients who underwent routine coronaryangiography between 1987 and 1990. Selection of patients wason angiographic criteria alone and PTCA was performed to allaccessible stenoses with more than 80% luminal narrowing. PTCAwas performed using standard angioplasty equipment and procedureas considered appropriate for the individual lesion. A successfulPTCA was defined as more than 30% reduction in luminal narrowingand a residual narrowing of less than 50%. Restenosis was definedas a loss of 50% or more of the gain achieved at the time ofsuccessful PTCA or more than a 30% increase in narrowing atthe site of stenosis. A total of 31 lesions were dilated inthis group and a successful result was achieved in 29 of these(93%) and in 12 of the 13 patients. The one patient with failedPTCA underwent later successful coronary artery bypass graftingto complete revascularization. Four of the 13 patients havehad two angioplasty procedures, two for restenosis and two fordisease progression in other sites. One patient died 15 monthsafter the initial PTCA and remaining 12 were asymptomatic withgood exercise tolerance and ventricular function at a mean of19 months (range 1–39 months) following first PTCA. Thus, PTCA can be considered a feasible form of treatment forsignificant single and multiple vessel disease in selected cardiactransplant recipients. Further study is required to assess theeffect of this early intervention on long-term mortality.     

Increasing pericardial effusion in cardiac transplant recipients

Although pericardial effusion after cardiac surgery is frequent and usually benign, its etiology and prognosis after cardiac transplantation are unknown. During 1 year (1985-1986), 12 of our current transplant population (total, 189) developed moderate or large pericardial effusions confirmed by two-dimensional echocardiography. These effusions occurred within 1 month of transplantation in 10 patients and at 3 months and 4.5 years in the other two. Pericardiocentesis was performed because of clinical evidence of increasing effusions in eight patients, with demonstrable hemodynamic compromise secondary to tamponade in five. Pericardial fluid was sterile in all but one. Endomyocardial biopsy at the time of increasing effusion revealed moderate acute rejection in five patients, mild rejection in three, and no rejection in four. All three patients with mild rejection had moderate acute rejection on subsequent biopsy performed within 7 days. In two of the four with no rejection, repeat biopsy within 5 days showed moderate acute rejection; in a third, moderate rejection was present on biopsy performed 14 days later. Legionella dumoffii was isolated from the pericardial fluid of the fourth patient, whose subsequent biopsies never showed rejection. Three of the 12 patients developed progressive ventricular dysfunction sufficiently severe to require retransplantation. One patient died suddenly 12 months after transplantation, and autopsy examination revealed severe coronary artery disease. Two died of sepsis within 3 months of transplantation. Intense inflammatory infiltrates and thickening of the pericardium and epicardium were characteristically present in explanted and autopsy hearts.(ABSTRACT TRUNCATED AT 250 WORDS)     

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 χ² 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.     

Prevention of osteoporosis in cardiac transplant recipients

Osteoporosis is a leading cause of pretransplant and posttransplant morbidity. The need for early detection by measuring bone mineral density, even before transplant, must be emphasized. Preventive measures are not comparable. The use of calcium and vitamin D supplements, although recommended, is inadequate for the prevention of bone loss and complications such as vertebral fractures. Bisphosphonates have been shown to attenuate the bone loss and reduce fractures associated with steroid-induced osteoporosis. Small studies in transplant recipients suggest similar results. Other preventive measures such as hormone replacement therapy are also helpful. There are limited data on the administration of nasal calcitonin in transplant recipients.     

Acute myocardial infarction in cardiac transplant recipients

To characterize the clinical and pathologic features of acute myocardial infarction (AMI) in cardiac transplant recipients, 22 Stanford patients who had 25 documented infarcts at a mean of 3.86 years after transplantation were reviewed. Symptoms included chest pain (2), arm pain (3), weakness (16), dyspnea (11) and palpitations (8). Three episodes were clinically silent, detected only as new electrocardiographic changes during routine follow-up. Of 18 patients hospitalized with symptoms, only 7 had electrocardiographic changes of typical Q-wave AMI; 5 had nonspecific ST-segment changes and 2 had no documented changes. Two had old Q waves. Twelve of the 18 were misdiagnosed at admission as having infection or congestive heart failure. Serial creatine phosphokinase levels were obtained in 13 patients, and values were elevated in 8. Six of 25 AMI episodes were associated with development of congestive heart failure and 4 others led to development of cardiogenic shock. Seven patients died during the acute phase of infarction, 12 were retransplanted from 2 days to 6 months after infarct and 1 died suddenly after discharge. Two healed myocardial infarctions of unknown duration were found at autopsy or on explantation in patients not clinically suspected of having an AMI. All infarcts occurred in patients known to have angiographic evidence of transplant coronary artery disease, based on annual coronary arteriography. At autopsy or explantation all hearts were found to have characteristic diffuse concentric coronary artery narrowing, and 4 (18%) had an unusual pattern of multiple foci of nontransmural AMI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of hyperlipidemia in cardiac transplant recipients

Of the 60,000 patients receiving heart transplants between 1982 and 2001, approximately 12,000 are currently alive. The high incidence of hyperlipidemia and coronary disease (also known as accelerated graft atherosclerosis, or AGA) in these patients warrants early prophylaxis soon after transplantation with 3-hydroxy-3-methylglutaryl (HMG) Co-A reductase inhibitors (statins). Immunosuppressive agents such as prednisone, cyclosporine, mycophenylate mofetil, and sirolimus are associated with hyperlipidemia. Statins, in addition to lowering cholesterol levels, also benefit cardiac transplant recipients via effects on the immune system and endothelial function. Recent data have demonstrated that statins decrease AGA and mortality rates. Furthermore, greater benefits are seen when statins are started early. The 2 statins shown to decrease mortality in patients after cardiac transplantation are pravastatin and simvastatin, which differ in their metabolism (pravastatin is the only statin with non-cytochrome metabolism) and lipophilicity (pravastatin is less lipophilic). Although the benefit of simvastatin has been shown to extend to 8 years after transplantation, increased adverse effects in other studies with higher doses of simvastatin have resulted in new prescribing recommendations, which state that the dose of simvastatin should probably not exceed 10 mg with cyclosporine or gemfibrozil and 20 mg with amiodarone or verapamil. The evidence for potential benefits, interactions, and adverse effects of other potential lipid-lowering drugs for this patient population, such as fibrates, niacin, fish oil, cholestyramine, and ezetimibe, are also discussed. A summary algorithm is proposed, including approaches to patients with statin-associated musculoskeletal symptoms and patients with inadequate results after initial statin therapy.     

Lovastatin therapy for hypercholesterolemia in cardiac transplant recipients

Hypercholesterolemia (type II hyperlipidemia) after cardiac transplantation is common and may play a role in the accelerated rate of coronary atherosclerosis seen following the procedure. However, conventional cholesterol-lowering drugs are either ineffective or contraindicated for use in transplant recipients. The presence of type II hyperlipidemia was identified in 11 cardiac transplant recipients during a mean follow-up period of 15 months (range 3 to 41) after transplantation. Lovastatin, at an initial dosage of 20 mg/day, was administered for a period of 1 year. The maximal dosage of lovastatin was 60 mg/day. All patients received maintenance dosages of immunosuppressive agents, including cyclosporine-A, prednisone and, in some instances, azathioprine. Lipid profiles, hepatic transaminases, serum creatinine, creatine kinase and cyclosporine-A serum trough levels were measured quarterly. Total cholesterol decreased by 27% (354 +/- 50 vs 258 +/- 36 mg/dl, p less than 0.01) after 3 months and remained stable thereafter. Similarly, low density lipoprotein cholesterol decreased by 34% (221 +/- 51 vs 146 +/- 40 mg/dl, p less than 0.01) after 3 months and remained constant. Triglycerides, high density lipoprotein, hepatic transaminases, creatinine, creatine kinase and trough cyclosporine-A levels remained stable during the 1-year follow-up period. Lovastatin was uniformly well tolerated in this study group. When given in modest dosages, lovastatin appears to be a safe, effective and well-tolerated therapy for hypercholesterolemia in cardiac transplant recipients.     

Current management of cardiac transplant recipients.

Changes in the management of cardiac transplant recipients over the past 10 years have resulted in a substantial improvement in the outlook for survival. Imuran and prednisone remain the primary immunosuppressive agents, but rabbit antihuman thymocyte globulin is used initially and reinstituted during rejection. Endomyocardial biopsy has allowed more precise diagnosis and management of rejection, and more recently immunological monitoring has been introduced to provide more frequent assessment of the host immune response. Infection is the major cause of death, and its diagnosis and treatment is managed aggressively. Current survival figures justify the use of cardiac transplantation, by an experienced team, when other measures have been exhausted.     

Current management of cardiac transplant recipients.

Changes in the management of cardiac transplant recipients over the past 10 years have resulted in a substantial improvement in the outlook for survival. Imuran and prednisone remain the primary immunosuppressive agents, but rabbit antihuman thymocyte globulin is used initially and reinstituted during rejection. Endomyocardial biopsy has allowed more precise diagnosis and management of rejection, and more recently immunological monitoring has been introduced to provide more frequent assessment of the host immune response. Infection is the major cause of death, and its diagnosis and treatment is managed aggressively. Current survival figures justify the use of cardiac transplantation, by an experienced team, when other measures have been exhausted.     

Heart rate and late mortality in cardiac transplant recipients

There are currently 104 patients at this centre who have survivedat least 3 months after orthotopic cardiac transplantation.Seven of these long-term survivors have subsequently died andin three cases death was sudden and unexpected. All three ofthese patients had been noted to have inappropriately high restingheart rates (>130 b.min^–1) The rhythm was sinus tachycardia,supraventricular tachycardia or both intermittently. The heart rates of all 104 long-term survivors were recordedfrom ECGs taken at routine follow-up visits every 3 months forone year and annually thereafter. The overall mean heart ratewas 100±13.2 b.min^–1. Four patients, including the three identified above, had meanheart rates greater than the 95th centile. The mortality ratein this group is 75%. Four deaths have occurred in the remaining100 patients (P <0.001). In our series, an inappropriately high resting heart rate dueto sinus tachycardia or supraventricular tachycardia in long-termsurvivors of cardiac transplantation, is an adverse prognosticsign.     

Vascular effects of sildenafil in hypertensive cardiac transplant recipients

BACKGROUND: Sildenafil is commonly used in the treatment of erectile dysfunction in hypertensive male cardiac transplant recipients (CTR); however, little is known about the vascular effects of sildenafil in these patients. METHODS: Central and peripheral arterial blood pressure (BP), heart rate, and brachial artery reactivity were determined in 15 hypertensive male CTR before and after oral sildenafil (50 mg) administration. RESULTS: Sildenafil improved brachial and aortic systolic BP, pulse pressure, aortic augmentation index, left ventricular tension time index, travel time of the reflected aortic pressure wave, and brachial artery reactivity (P <.01 for each comparison). No patient became hypotensive with sildenafil despite continuation of usual antihypertensive medications. CONCLUSIONS: Sildenafil (50 mg) is well tolerated in hypertensive CTR and improves BP, aortic augmentation index, and endothelial function. By decreasing the amplitude of the reflected pressure wave and delaying its return to the heart, sildenafil reduces left ventricular afterload and systolic stress.     

Maxepa versus bezafibrate in hyperlipidemic cardiac transplant recipients.

Accelerated coronary artery disease is the most serious obstacle to long-term survival in cardiac transplant recipients. Lipid abnormalities are found frequently in these patients, and there is growing evidence that even minimally increased levels of cholesterol and triglycerides contribute to the development of accelerated coronary artery disease. However, the optimal lipid-lowering therapy after cardiac transplantation has not been defined. In an open, randomized study, the efficacy and safety of bezafibrate (400 mg/day) and fish oil (Maxepa) (10 g/day) for 3 months were compared in 87 cardiac transplant recipients with serum total cholesterol > 6.5 or triglycerides > 2.8 mmol/liter, or both. After 1 month, bezafibrate reduced total cholesterol by 13%, low-density lipoprotein cholesterol by 20% and apolipoprotein B by 13%. It also increased apolipoprotein A1 and high-density lipoprotein cholesterol by 12 and 20%, respectively, and significantly reduced fibrinogen at 3 months. Maxepa had no significant effect on these variables, but was as effective as bezafibrate in reducing triglycerides (36 and 31%, respectively). Both drugs increased lipoprotein (a) to a similar extent, and bezafibrate significantly increased serum creatinine. These results suggest that bezafibrate has better lipid-, apolipoprotein- and hemostatic modifying properties than does Maxepa, but its potentially adverse effect on renal function needs further investigation.     

Physical activity patterns and exercise performance in cardiac transplant recipients

BACKGROUND: Cardiac transplantation (CTX) improves exercise tolerance, but CTX recipients still achieve only 50% to 70% of normal values for exercise capacity. Among the factors suggested to explain the reduced exercise tolerance in CTX recipients is deconditioning. Little is known about the relation between physical activity patterns and exercise test responses in CTX patients. METHODS: Forty-seven CTX patients (mean age 47 +/- 12 years; mean 4.8 +/- 3.0 years after CTX) underwent maximal exercise testing and assessment of current and past physical activity patterns using a questionnaire. Energy expenditure from recreational and occupational activities over the last year and for adulthood were expressed in kcal/week and correlated with peak oxygen consumption (VO(2)), VO(2) at the ventilatory threshold, and the percentage of age-predicted peak VO(2) achieved. RESULTS: The patients reported expending a mean of approximately 1100 kcal/week in recreational activity, suggesting a moderate level of physical activity is maintained after CTX. The mean peak VO(2) achieved for the group was 17.2 +/- 5.2 mL/kg/min, corresponding to 59% +/- 14% of age-predicted exercise capacity. Significant but modest associations were observed between recreational energy expenditure during the last year and percentage of age-predicted peak VO(2) achieved (r = 0.34, P <.01), and VO(2) at the ventilatory threshold (r = 0.45, P <.01). Energy expenditure from blocks walked and stairs climbed per week was modestly associated with peak VO(2) (r = 0.36, P <.05), percentage of predicted peak VO(2) achieved (r = 0.39, P <.01), and VO(2) at the ventilatory threshold (r = 0.42, P <.01). Exercise capacity was poorly related to occupational and recreational activities when expressed as average weekly energy expended throughout adulthood. CONCLUSION: Post-CTX patients maintain a moderately active lifestyle. Measures of exercise tolerance generally are related to recent daily recreational activities in CTX patients, but these associations are modest. The many physiologic factors unique to CTX recipients likely play a more important role than deconditioning in determining exercise tolerance in these patients.     

Altered sympathoadrenal response to dynamic exercise in cardiac transplant recipients

The cardiac denervation produced by heart transplantation modifies the physiological response to exercise. The cardiorespiratory and sympathoadrenal response of seven "healthy" orthotopic heart transplant recipients was compared to seven age matched normal subjects during progressive dynamic exercise. The initial venous noradrenaline concentration tended to be higher in the transplant group, at 3.6 (SEM 0.6) v 2.9(0.2) nmol-litre-1 (NS). Noradrenaline concentrations were significantly higher in the transplant group during exercise (p less than 0.05, by analysis of variance). The transplant recipients reached a lower maximum workload than the normal subjects, at 102(8) v 170(10) watts (p less than 0.01) and the peak noradrenaline concentrations were similar in the two groups. The fall in noradrenaline concentrations after exercise was similar in the two groups. This showed that noradrenaline clearance was normal in the transplant recipients and the higher noradrenaline level reflected increased sympathetic activity. Despite the normal peak noradrenaline concentration, the transplant recipients achieved lower maximum heart rates than the normal subjects, at 142(3) v 181(5) beats min-1 (p less than 0.01). Adrenaline concentrations were similar in the two groups during submaximal exercise and tended to be lower in the transplant recipients at maximal exercise. The increased sympathetic activity may be a response to altered cardiac performance because of efferent cardiac denervation or to loss of tonic inhibition of sympathetic activity by cardiac receptors due to afferent denervation. Both circulating noradrenaline and adrenaline appear to play a significant role in the heart rate response to exercise after cardiac transplantation.