Clinical heart transplantation with extended preservation time (>5 hours): experience with University of Wisconsin solution.

BACKGROUND: Use of University of Wisconsin solution has been suggested for extended organ preservation >4 hours in experimental cardiac transplantation, but few data have been reported from clinical use. This study investigated the impact of preservation with UW solution after prolonged ischemic times on myocardial damage and outcomes after heart transplantation. MATERIALS AND METHODS: Between 1994 and 2006, 34 orthotopic heart transplantations were performed at our institution with cold ischemic times of >or=300 minutes (mean, 325.1 +/- 21.3). Donor organs were perfused with and stored in 1000 mL of University of Wisconsin solution. No significant differences were observed with regard to age, gender, diagnosis, donor inotropic support, and donor-recipient weight ratio when compared with recipients undergoing an ischemic time <300 minutes. RESULTS: After a mean follow-up of 47.6 months (range, 1 day to 147.1 months), Kaplan-Meier survival analysis revealed survivals of 91.0% at 3 months, and 82.9% for the entire observation period. The time required to wean from bypass (mean, 78.1 minutes) was equal when compared with that of recipients experiencing grafts undergoing an ischemic time of <300 minutes, but there was a significantly greater average need for inotropic support over the first 48 posttransplant hours. Neither hospital stay in the ICU (mean, 13.0 days; range, 1-55 days) nor the incidence of acute graft failure or survival was different. CONCLUSION: We conclude that heart preservation with UW limited ischemic damage from prolonged storage and improved myocardial function in the early posttransplant period, thus allowing transplantation of organs with ischemic times >300 minutes.

Biliary diseases in heart transplanted patients: a comparison between cyclosporine A versus tacrolimus-based immunosuppression.

A cyclosporine (CsA)-based immunosuppression is associated with an increased incidence of cholelithiasis after heart transplantation. It is not known if tacrolimus (Tac) has comparable biliary side effects in humans. We evaluated the incidence of gallbladder sludge and cholelithiasis under Tac-based immunosuppression by ultrasound examinations in 31 cardiac transplants (25 male, 6 female, mean age: 59 ' 11 years). Data were compared to 57 patients (47 male, 10 female, mean age: 58 ' 11 years) who received CsA-based immunosuppression. 6 patients receiving Tac and 6 patients receiving CsA had already gallstones prior to transplantation so that finally 25 patients of the Tac group and 51 patients of the CsA group could be evaluated. In the Tac group the incidence of biliary sludge was 4% (1 of 25), of gallstones 28% (7 of 25). In comparison, patients receiving CsA developed biliary sludge in also 4% (2 of 51) and gallstones in 25% (13 of 51). Nine of 42 males in the CsA group (21%) and eight of 20 males in the Tac group (40%) developed either gallstones or sludge (n.s). Six of nine females in the CsA group (67%), but none of five females in the Tac group (0%) developed either gallstones or sludge (p = 0.01). In summary, the incidence of biliary disease in patients with Tac is comparable with CsA-based immunosuppression. We recommend regular sonographical examinations to detect biliary diseases as early as possible. In cases of clinically, laboratory and sonographical signs of cholecystitis cholecystectomy is indicated. It seems that towards lithogenicity female patients benefit more from a Tac-based treatment because the occurrence of gallstones is rare.

Human herpesvirus 6 in bronchalveolar lavage fluid after lung transplantation: a risk factor for bronchiolitis obliterans syndrome?

Bronchiolitis obliterans syndrome (BOS) is the limiting factor to long-term survival after lung transplantation. Previous studies suggested respiratory viral tract infections are associated with the development of BOS. To identify the impact of virus detection in bronchoalveolar lavage (BAL) fluid, we analyzed BAL samples from 87 consecutive lung transplant recipients for human herpesvirus (HHV)-6, Epstein-Barr virus, Herpes simplex virus 1/2, Cytomegalovirus, respiratory syncytical virus and adenovirus by PCR. Acute rejection, BOS and death were recorded for a mean follow-up time of 3.27 +/- 0.47 years. Results of PCR analysis and other potential risk factors were entered into a Cox regression analysis of BOS predictors and death. Only acute rejection was a distinct risk factor for BOS of all stages, death and death from BOS. HHV-6 was detected in 20 patients. Univariate and multivariate analysis revealed that HHV-6 was associated with an increased risk to develop BOS > orb = stage 1 and death, separate from the risk attributable to acute rejection. Identification of HHV-6 DNA in BAL fluid is a potential risk factor for BOS. Our results warrant further studies to elucidate a possible causal link between HHV-6 and BOS.

[Effect of immunosuppression-induced hypogonadism on bone metabolism after heart transplantation]. / Einfluss des Immunsuppressiva-induzierten Hypogonadismus auf den Knochenmetabolismus nach Herztransplantation.

BACKGROUND AND OBJECTIVE: Accelerated bone loss is a well recognized complication after cardiac transplantation (HTx). The role of an immunosuppressive-induced hypogonadism, a well-known cause of osteoporosis in men and its prevention are less defined after HTx. The aim of this study was first, to evaluate the incidence of hypogonadism after HTx and its influence on bone mineral metabolism and second, to assess the effect of a testosterone replacement therapy in hypogonadal transplants. PATIENTS AND METHODS: Due to hormonal status, 88 male cardiac transplants were randomised to a normogonadal or hypogonadal group. At baseline as well as after 1 and 2 years bone mineral density (BMD g/cm (2), T-score) was measured at the lumbar spine with DEXA. All patients received a basic therapy of calcium and vitamin D. The hypogonadal patients received additional testosterone. RESULTS: 21 patients (24 %) showed an age-independent hypogonadism. Hypogonadal transplants showed a significant lower BMD (p < 0.001) (BMD = 0.8070 g/cm (2), T-value = -2.6514) than normogonadal patients (BMD = 0.9882 g/cm (2), T-value = -1.0568). Despite testosterone replacement hypogonadal patients showed no significant additional increase in BMD over 1 - 2 years compared with the normogonadal. CONCLUSION: Male cardiac transplants in all age groups show an high prevalence of hypogonadism (approximately 25 %) which contributes to a significant bone loss. An additional testosterone substitution did not significantly increase BMD.

[Leiomyosarcoma of the heart--interdisciplinary therapeutic approach of systemic chemotherapy and subsequent heart transplantation]. / Leiomyosarkom des Herzen--interdisziplinärer Therapieansatz mit systemischer Chemotherapie und anschliessender Herztransplantation.

HISTORY AND ADMISSION FINDINGS: A 35-year-old man reported progressive exercise dyspnea, decreased exercise tolerance and weight loss of 10 kg in 2 months. Imaging tests demonstrated a tumor of maximally 7 cm diameter in the region of the left atrium. Histologically it was a poorly differentiated leiomyosarcoma G 3, which could not be completely resected (R 2 resection). SUBSEQUENT INVESTIGATION: Six weeks after surgical resection a rapidly growing tumor, maximally 7.5 cm in diameter, was visualized at the right lateral region of the left atrium. It filled it almost completely and extended via the right upper pulmonary vein to the right hilus. TREATMENT AND COURSE: As part of a multimodal therapeutic approach he was given 6 cycles of chemotherapy (doxorubicin and ifosfamide), bringing about significant reduction of the tumor size. The tumor was then completely resected, followed by an orthotopic heart transplantation with right pneumonectomy. The resected surgical specimen indicated complete remission, no vital tumor cells being demonstrated. No tumor recurrence or distal metastasis was seen during a follow-up period of 36 months. The patient died from right heart failure with advanced pulmonary hypertension 45 months after the diagnosis had first been made, 37 months after the cardiac transplantation.

The new German allocation system for donated thoracic organs causes longer ischemia and increased costs.

OBJECTIVE: Allocation criteria changed in 2000 as a result of Germany's new transplantation law. Before, thoracic organs were primarily allocated electively within the donor region (according to urgency and waiting time). Afterwards, all patients in Germany eligible for heart transplants were registered in a national waiting list. With the exception of high-urgency patients that are approved by an audit committee, waiting time has become the major criteria for allocation. In this study, we investigated the impact of the new allocation system on economic aspects as on clinical results. METHODS: One year in the new allocation system (NA) was compared to the previous year in the old allocation system (OA) regarding explantation/transportation distance, costs, ischemia time and clinical outcome. All explantations performed by our institution within Germany were evaluated. RESULTS: The number of transplantations and the spectrum was similar between the two time periods (NA vs. OA: 61 vs. 57 overall). Eighty-two percent of these explanted organs were transplanted within the donor region in the OA time period, but only 37 % in the NA period. This resulted in higher transportation distances (NA: 441 +/- 177 km vs. OA: 179 +/- 118 km), higher transportation cost (NA: EUR 4,472 +/- 2,858 per explantation vs. OA: EUR 1,858 +/- 2,293 explantation, p = 0.001), and therefore longer ischemia times in the NA period (NA: 264 +/- 56 min: OA: 208 + 61 min, p = 0.001). Perioperative results and survival after a mean clinical follow-up of 21 +/- 8 (OA) and 11 +/- 5 (NA) months were comparable (86 % vs. 87 % (p = 0.93). CONCLUSION: Transportation distance, costs for explantation and ischemia time increased significantly with the NA period. While the clinical short-term outcome proved to be comparable, we cannot yet judge the long-term impact of the prolonged ischemia time on the development of chronic rejection.

Intensive care after minimally invasive and conventional coronary surgery: a prospective comparison.

OBJECTIVE: The purpose of this study was to compare the intensive care course of patients after minimally invasive coronary surgery to conventional coronary artery bypass grafting. DESIGN: Prospective observational study. SETTING: Intensive care unit of a university hospital. PATIENTS AND PARTICIPANTS: One hundred and five patients with two-vessel disease consecutively scheduled for elective coronary bypass surgery were enrolled. INTERVENTIONS: Two techniques of revascularization were performed: the Octopus procedure via median sternotomy without cardiopulmonary bypass (n = 52) and conventional coronary artery bypass grafting CABG (n = 53). MEASUREMENTS AND RESULTS: Three major categories describing the patients' postoperative course were defined: (1) clinical and laboratory findings, i.e., transfusion rate, catecholamine support, duration of ventilation, Simplified Acute Physiology Score II (SAPS II), serum levels of cardiac enzymes and lactic acid; (2) postoperative complications, i.e., incidence of myocardial infarction (MI), atrial fibrillation (AF), and neurological deficits; (3) this category was defined as "the extent of care" as represented by the Therapeutic Intervention Scoring System (TISS), and the length of stay in the ICU and in the hospital. In the Octopus group significantly lower figures were noted for duration of ventilation [6.1(5.5/9.5) vs 10.2(8.2/11.8) h], cardiac enzymes (CK-MB-Mass [5.1(2.0/8.3) vs 31.3(21.4/39.3) ng/ml], and lactic acid [2.0(1.5/3.3) vs 3.2(2.2/6.5) mmol/l]), incidence of AF (2/52 vs 9/53), and neurological deficits (0/52 vs 4/53), TISS score [72(44/83) vs 84(73/93)], LOS in the ICU [2(1/2) vs 2(2/2) days], and in the hospital [6(5/9) vs 9(8/12) days]. Catecholamine support, SAPS II scores, and incidence of MI of each group did not differ significantly. CONCLUSIONS: Off-pump coronary surgery via the Octopus technique was superior to conventional CABG regarding the course of patients in the early postoperative period. This implies benefits for the patients and the entire healthcare system.

Vagal reinnervation in the long term after orthotopic heart transplantation.

BACKGROUND: Sympathetic reinnervation after orthotopic heart transplantation (HTx) has become an accepted phenomenon, particularly in long-term transplanted patients. Parasympathetic reinnervation, however, still remains questionable. METHODS: In 38 HTx recipients, mean age of 51.6 +/- 9.7 years (range, 29 to 70 years), with a time span after HTx of 4.6 +/- 2.8 years (0.5 to 10.5 years), we stimulated carotid baroreceptors using periodic neck suction at low (0.1 Hz) and high (0.2 Hz) frequencies to test sympathetic and vagal responses, respectively. Respiratory rate was fixed at 0.25 Hz. We simultaneously recorded surface electrocardiogram, finger blood pressure, respiration and neck pressure signals while patients rested in the supine position. Time series of RR intervals, respiration, and neck and blood pressures were generated and subjected to spectral analysis. RESULTS: All patients demonstrated a 0.25-Hz peak in RR-interval spectrum, caused by non-autonomic respiratory sinus arrhythmia. Thirteen patients (5. 2 +/- 3.5 years after HTx; range, 0.9 to 10.2 years) showed a baroreflex-induced sharp peak at 0.1 Hz in RR-interval power spectrum during 0.1-Hz neck suction, indicating sympathetic reinnervation. However at 0.2-Hz neck suction, 4 of the 13 sympathetically reinnervated patients displayed a baroreflex-induced 0.2-Hz peak, which could be suppressed with atropine administration-strong evidence for vagal reinnervation. CONCLUSIONS: Non-invasive carotid baroreflex stimulation is an appropriate tool to prove restoration of autonomic control after orthotopic HTx. Sympathetic reinnervation parallels parasympathetic reinnervation in long-term transplanted patients.

Sympathetic reinnervation of sinus node and left ventricle after heart transplantation in humans: regional differences assessed by heart rate variability and positron emission tomography.

BACKGROUND: Orthotopic heart transplantation (HTx) results in complete cardiac denervation. Reestablished partial sympathetic nerve function has been found in patients some years after HTx. However, the atrial and ventricular regional patterns of reinnervation have not been established. METHODS: Two parallel methods were used to evaluate the regional restoration of sympathetic nerves in the myocardium. Patients were investigated with respect to ventricular reinnervation (VI) using positron emission tomography (PET) and the norepinephrine analogue C-11-hydroxyephedrine (HED). Tracer uptake was quantified using dynamic imaging protocols, yielding regional HED retention fraction. A regional value above 7%/minute ( +/- 2.5 SD above the mean value of denervated hearts) was considered evidence of sympathetic reinnervation. Spectral analysis of heart rate variability (HRV) served as a quantitative marker for reinnervation at the sinus node (SI). Spectra of HRV during positive head-up tilt were calculated. The low frequency (LF) power spectral density (0.05 to 0.18 Hz) was evaluated. RESULTS: After HTx (4. 6 +/- 3.9 years; range, 0.2 to 13.6 years), 38 patients (aged 50.9 +/- 7.6 years; range, 37 to 65 years) were investigated by PET imaging and HRV. Twenty-two patients with a mean HED retention of 10. 7 +/- 2.6%/minute were classified as left ventricular reinnervated. Sixteen patients with a mean HED retention of 4.8 +/- 0.8%/minute did not reach the threshold. The time difference after HTx was significant for these 2 groups, 5.3 +/- 3.0 years vs 3.8 +/- 4.7 years ( p < 0.05 ). The LF power spectral density of the ventricular reinnervated patients was 5.9 +/- 8.6 ms(2), and 1.8 +/- 4.4 ms(2) (p <0.005 ) for those not reinnervated. Low frequency showed small values and narrow distribution for the patients not reinnervated, assuming sinus node denervation, and showed extended distribution for the reinnervated, suggesting a heterogeneous reinnervation pattern. CONCLUSIONS: Two non-invasive parallel methods were used to investigate regional reestablishment of cardiac nerves in the myocardium in HTx patients. Left VI assessed by PET imaging and SI by HRV was congruent in 60% of HTx patients. Lack of SI paralleled absence of VI. Our results suggest that partial VI occurs prior to SI.

Incomplete sympathic reinnervation of the orthotopically transplanted human heart: observation up to 13 years after heart transplantation.

OBJECTIVE: Heart transplantation (HTx) is associated with autonomic denervation of the donor heart. Sympathetic reinnervation (RI) as defined by the presence of functional nerve terminals occurs only if sympathetic ganglia outside the heart are connected with nerve terminals in the transplanted heart. The purpose of this study was to define the incidence and functional consequences of RI over time after HTx. The activity and distribution of norepinephrine (NE) uptake sites were assessed by positron emission tomography (PET) imaging. Symptom limited exercise testing was performed by bicycle-ergometer. METHODS: Forty-seven patients (m:f=42:5, 47.6+/-8. 2 years, age range 27-65 years) were investigated between 2 months and 13.6 years after HTx using PET and the NE analogue C-11-hydroxyephedrine (HED). Tracer uptake was quantified using dynamic imaging protocols yielding regional HED retention fraction. A regional value above 7%/min (+/-2.5 SD above the mean value of denervated hearts) was considered evidence for RI. The functional significance of RI was investigated in 34 patients (m:f=30:4, 49. 3+/-8.4 age range 27-62 years) by symptom limited exercise testing. Cardiac catheterization was performed at the time of PET imaging. RESULTS: RI could not be assessed in the first year after HTx, in 11% in the second year and in 80% of the patients from the third year on. Retention values plateaued then. In all time intervals, beyond the third year, not reinnervated patients were found. RI remained incomplete and was always restricted to the anterior wall of the left ventricle. Extent of retention of the left ventricle revealed a large individual range up to 66%, averaging of 20%. Recipient age at the time of HTx, reinnervated patients were 5.5 years younger than not reinnervated ones, proved as the only significant influencing factor for RI (P<0.05). Dividing patients into scintigraphically reinnervated (n=20) and not reinnervated (n=14), reinnervated patients displayed during exercise a higher maximal heart rate (137+/-14 vs. 123+/-20/min, P<0.05), heart rate increase (40+/-15 vs. 28+/-13/min, P<0.05), max. oxygen consumption (1674+/-424 vs. 1279+/-308 ml/min, P<0.01) and anaerobic threshold (887+/-170 vs. 717+/-183 mlO(2)/min, P<0.01) than not reinnervated ones. A correlation between transplant vasculopathy and RI could not be demonstrated. CONCLUSION: ++: RI assessed by PET and the NE analogue HED is time dependent, incomplete, displays a typical pattern and demonstrates a broad individual spread. Furthermore, RI enhances functional parameters of exercise testing.

Predictors of reduced coronary flow reserve in heart transplant recipients without angiographically significant coronary artery disease.

BACKGROUND: Determination of coronary flow reserve (CFR) is increasingly used to assess the functional significance of cardiac allograft vasculopathy. Although the relation between CFR and angiographically defined vasculopathy has been studied extensively, little is known about other factors determining CFR in heart transplant recipients without significant lesions by coronary angiography. METHODS: Sixty consecutive patients were studied 0.5 to 148 months after heart transplantation with intracoronary Doppler and intravascular ultrasound. An endothelium-independent CFR< or =2.5 was defined as abnormal. Stepwise logistic regression analysis was used to identify factors (demographic data of donor and recipient, lipid profile, epicardial vessel morphology by intravascular ultrasound, left ventricular hypertrophy, acute rejection episodes, and hemodynamics) potentially associated with a reduced CFR. RESULTS: Only the presence of left ventricular hypertrophy (48% vs. 14%, P=0.007 and P=0.023, bivariate and multivariate analysis, respectively) and higher donor ages (41+/-12 vs. 29+/-11 years, P=0.002 and P=0.013, bivariate and multivariate analysis, respectively) showed an independent association with an abnormal flow reserve. CFR in patients with left ventricular hypertrophy was reduced due to higher baseline flow velocities (27+/-11 vs. 20+/-6 cm/sec, P=0.004). Furthermore, resting flow velocity increased as a function of donor age (r=0.264, P=0.047), while hyperemic flow velocity was not different. Other patient characteristics and hemodynamics did not affect CFR. CONCLUSION: The presence of left ventricular hypertrophy and higher donor ages independently contribute to a reduced CFR in patients after heart transplantation. This reduction in CFR is due to elevated baseline flow velocities rather than to a change in hyperemic flow velocities. These findings should be taken into account for the interpretation of reduced CFR values obtained by intracoronary Doppler in heart transplant recipients without angiographically overt coronary lesions.

Functional significance of cardiac reinnervation in heart transplant recipients.

BACKGROUND: There is accumulating evidence of structural sympathetic reinnervation after human cardiac transplantation. However, the functional significance of reinnervation in terms of exercise capacity has not been established as yet; we therefore investigated the influence of reinnervation on cardiopulmonary exercise testing. METHODS: After orthotopic heart transplantation 35 patients (mean age, 49.1 +/- 8.4 years) underwent positron emission tomography with scintigraphically measured uptake of C11-hydroxyephedrine (HED), lung function testing, and cardiopulmonary exercise testing. Two groups were defined based on scintigraphic findings, indicating a denervated group (n = 15) with a HED uptake of 5.45%/min and a reinnervated group (n = 20) with a HED uptake of 10.59%/min. RESULTS: The two study groups did not show significant differences with regard to anthropometric data, number of rejection episodes, preoperative hemodynamics, and postoperative lung function data. The reinnervated group had a significant longer time interval from transplantation (1625 +/- 1069 versus 800 +/- 1316 days, p < .05). In transplant recipients with reinnervation, heart rate at maximum exercise (137 +/- 15 versus 120 +/- 20 beats/min, p = .012), peak oxygen uptake (21.0 +/- 4 versus 16.1 +/- 5 mL/min/kg, p = .006), peak oxygen pulse (12.4 +/- 2.9 versus 10.2 +/- 2.7 mL/min/beat, p = .031), and anaerobic threshold (11.2 +/- 1.8 versus 9.5 +/- 2.1 mL/min, p = .046) were significantly increased in comparison to denervated transplant recipients. Additionally, a decreased functional dead space ventilation (0.24 +/- 0.05 versus 0.30 +/- 0.05, p = .004) was observed in the reinnervated group. CONCLUSIONS: Our study results support the hypothesis that partial sympathetic reinnervation after cardiac transplantation is of functional significance. Sympathetic reinnervation enables an increased peak oxygen uptake. This is most probably due to partial restoration of the chronotropic and inotropic competence of the heart as well as an improved oxygen delivery to the exercising muscles and a reduced ventilation-perfusion mismatching.

Detection of humoral rejection in human cardiac allografts by assessing the capillary deposition of complement fragment C4d in endomyocardial biopsies.

BACKGROUND: There are no well-established diagnostic criteria to detect humoral rejection in organ transplantation. The value of commonly used markers in immunohistochemistry, such as C1q, C3c, IgG, IgM and fibrinogen, is questioned by some groups. Complement fragment C4d is a more stable marker of complement activation as it is covalently bound to graft capillaries. C4d has been shown to identify clinically relevant, but otherwise undetectable humoral anti-graft reactions in human kidney transplants. METHODS: Immunohistochemical techniques were used to evaluate 155 endomyocardial biopsies from 56 heart transplant recipients less than 3 months post transplantation for the presence of capillary C4d staining. In a subset of patients, C4d staining was compared with C1q, C3c, IgM and fibrin staining and was correlated with clinical outcome. RESULTS: Within 3 months 9 of 56 patients died. Five of these nonsurvivors had prominent C4d staining (p < .05), whereas C1q, C3c and IgM showed no correlation with clinical outcome. Presence of fibrin correlated with clinical outcome and C4d staining (p < .05). CONCLUSIONS: The capillary deposition of complement split product C4d in human endomyocardial biopsies was significantly associated with graft loss. Determination of fibrin deposition may yield additional information to establish a diagnosis of humoral rejection. The immunohistochemical assessment of capillary deposition of C4d and fibrin appears to be an appropriate tool for the identification of patients, who may require additional or alternative immunosuppressive therapy targeted against the humoral immune system.

Prevention of osteoporosis after cardiac transplantation: a prospective, longitudinal, randomized, double-blind trial with calcitriol.

BACKGROUND: Accelerated bone loss is a well-recognized complication after cardiac transplantation (HTx) due to immunosuppressive therapy. The purpose of this prospective, longitudinal, randomized, placebo-controlled, double-blind study was to investigate the effect of calcitriol (1,25-dihydroxyvitamin D3) in the prevention of bone loss and fracture rate after HTx. METHODS: Basic therapy included 1000 mg of calcium daily and sex hormone replacement in hypogonadal patients. A total of 132 patients (111 male, 21 female; mean age: 51+/-10 years; 35+/-25 months after HTx) were randomized to 0.25 microg of calcitriol or placebo. Bone mineral density (BMD, g/cm2; T score, %) of the lumbar spine and x-rays for the assessment of vertebral fractures were performed at baseline and after 12, 24, and 36 months. Biochemical indexes of mineral metabolism were measured every 3 months. RESULTS: Overall BMD was significantly decreased after HTx (T score 87+/-13%). BMD increased continuously within the study period in the calcitriol group (1 year: 2.2+/-4.8%; 2 years: 3.9+/-5.4%; 3 years: 5.7+/-4.4%) as well as in the placebo group (1 year: 1.8+/-4.9%; 2 years: 3.7+/-6.5%; 3 years: 6.1+/-7.8%) without statistical difference between the groups. Fracture incidence was low during the study interval (1 year: 2.0%; 2 years: 3.4%; 3 years: 0%). Hypogonadism (20%) was associated with a lower BMD (78+/-12% vs. 88+/-12%; P<0.01) and a higher increase (35%) after hormone replacement in comparison to normogonadal patients. Increased intact parathyroid hormone and bone resorption markers decreased significantly during therapy. CONCLUSIONS: Calcium supplementation and sex hormone replacement in hypogonadism proved a sufficient long-term prevention therapy to improve decreased BMD and to prevent fractures after HTx. Besides immunosuppression, both concomitant hypogonadism and secondary hyperparathyroidism play a major role in the long-term bone loss and should therefore be monitored and treated adequately. Low-dose calcitriol demonstrated no significant extra benefit regarding BMD and fracture rate in the long-term period after HTx.

Lung function and cardiopulmonary exercise performance after heart transplantation: influence of cardiac allograft vasculopathy.

STUDY OBJECTIVE: The reduced exercise capacity observed in most patients after heart transplantation may be due to treatment with immunosuppressive drugs, deconditioning, cardiac denervation, and graft rejection. Cardiac allograft vasculopathy (CAV) is presently the major factor limiting long-term survival after transplantation. Little information is available with regard to the relationship between CAV and functional impairment in these patients. DESIGN: Prospective. SETTING: A university hospital and a large transplant center. PATIENTS: About 37+/-5 months (range, 2 to 137 months) after orthotopic heart transplantation, 120 patients underwent lung function testing, cardiopulmonary exercise testing, and right and left heart catheterization. Significant CAV was defined as a stenosis > or =70% or severe diffuse obliteration in any of the three main vessels. Group I (n = 28) had a significant CAV; group II (n = 92), without a remarkable CAV, was the control group. MEASUREMENTS AND RESULTS: Overall, the maximum heart rate was 86+/-2% of what was predicted, and the peak oxygen consumption was 18.8+/-0.7 mL/kg/min (64% of that predicted). Groups I and II did not show significant differences with regard to anthropometric data, hemodynamic measurements, or number of rejection episodes. Group I exhibited significant differences in maximum heart rate (120+/-5 vs. 134+/-3 beats/min; p<0.01), work capacity (47+/-5% vs. 59+/-3%; p<0.05), peak oxygen uptake (16+/-1 vs. 20+/-1 mL/min/kg; p<0.01), and functional dead space ventilation (31+/-2 vs. 26+/-1; p<0.01). Pretransplant status, etiology of heart failure, ischemic time, and the number of rejection episodes did not correlate with any exercise parameter. CONCLUSIONS: Following heart transplantation, patients with significant CAV show a diminished exercise capacity, a reduced oxygen uptake, and a ventilation-perfusion mismatch. Thus, CAV may be a major factor limiting exercise capacity in heart-transplant patients.

Diagnostic and prognostic value of serial dobutamine stress echocardiography for noninvasive assessment of cardiac allograft vasculopathy: a comparison with coronary angiography and intravascular ultrasound.

BACKGROUND: Routine methods for surveillance of cardiac allograft vasculopathy (CAV) are coronary angiography and intravascular ultrasound (IVUS). This study analyzed the diagnostic and prognostic value of dobutamine stress echocardiography (DSE) for noninvasive assessment of CAV. METHODS AND RESULTS: In 109 heart transplant recipients, 333 DSEs were compared with 285 coronary angiograms and 199 IVUS analyses. Studies were repeated after 1, 2, 3, 4, and >/=5 years in 88, 74, 37, 18, and 7 patients, respectively. Resting 2D echocardiography detected CAV defined by IVUS and angiography with a sensitivity of 57% (specificity 88%). DSE increased the sensitivity to 72% (P=0.002). M-mode analysis increased the sensitivity of 2D rest and stress analysis (P=0.001, 0.004). Cardiac events occurred after 1.9% of normal stress tests by 2D analysis (combined 2D and M-mode: 0%), compared with 6.3% (3.8%) of normal resting studies. Worsening of serial DSE indicated an increased risk of events compared with no deterioration (relative risk 7.26, P=0.0014). Serial deterioration detected by stress only was associated with a higher risk of events than changes evident from resting studies (relative risk 3.06, P=0.0374). CONCLUSIONS: DSE identifies patients at risk for events and facilitates monitoring of CAV. A normal DSE predicts an uneventful clinical course and justifies postponement of invasive studies. The prognostic value of DSE is comparable to that of IVUS and angiography.

Coronary risk factor management for the prevention and treatment of graft vessel disease in heart transplant patients.

There is increasing evidence that atherogenic risk factors largely contribute to the pathogenesis of graft vessel disease (GVD) after heart transplantation. Initial endothelial damage of the transplant heart derives from reperfusion ischemia during operation, repeated infections, and rejection episodes. Immunosuppressive medication considerably increases low density lipoprotein (LDL) cholesterol, lipoprotein(a), and fibrinogen blood levels, which in turn further damage the endothelium of the graft coronaries. Probably, this interplay of immunological and atherogenic factors accounts for the rapid development of GVD and its poor prognosis. The rapidity of the disease process makes it necessary to eliminate important risk factors as early and as efficiently as possible. Therefore, we studied whether heart transplant patients could benefit from a combined treatment of statins and apheresis heparin extracorporeal LDL/fibrinogen precipitation (HELP), which has already been shown to be beneficial for the treatment of advanced coronary artery disease. Such a combined treatment allows simultaneous and drastic reduction of LDL, lipoprotein(a), and fibrinogen blood levels and significantly prevented GVD. Moreover, it did not affect the prevention of rejections and infections, respectively.

Functional and morphological findings in heart transplant recipients with a normal coronary angiogram: an analysis by dobutamine stress echocardiography, intracoronary Doppler and intravascular ultrasound.

BACKGROUND: Coronary angiography is still the routine screening method for cardiac allograft vasculopathy in most transplant centers. This study was designed to analyze functional and morphologic changes in heart transplant recipients with normal angiographic findings. METHODS: Dobutamine stress echocardiography and intracoronary ultrasound were obtained in 56 patients with a normal coronary angiogram 41+/-31 months after heart transplantation. Intracoronary Doppler flow velocity measurements before and after intracoronary adenosine administration were performed in 34 of 56 patients. Any regional wall motion abnormalities detected by stress echocardiography were regarded as abnormal. By quantitative intracoronary ultrasound analysis using a 6-grade scale, a mean grade of all coronary segments >3.0 was defined as significant intimal hyperplasia. RESULTS: Only 17 patients (30%) showed both a normal dobutamine stress echocardiogram and absence of significant intimal hyperplasia by intravascularultrasound. Abnormal findings were observed in 39 patients (70%): both by dobutamine stress echocardiography and intravascular ultrasound in 22 patients, by intravascular ultrasound alone in 11 patients, and by dobutamine stress echocardiography alone in 6 patients. Coronary flow velocity reserve did not discriminate between patients with normal or abnormal intravascular ultrasound or dobutamine stress echocardiographic findings. CONCLUSIONS: Only a minority of heart transplant patients with a normal coronary angiogram is free of pathological changes, when assessed by intravascular ultrasound and dobutamine stress echocardiography. Coronary flow velocity reserve does not seem useful to further characterize these patients.