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Background Calcineurin-inhibitor-(CNI)-induced renal failure is one major cause of morbidity in cardiac transplantation (HTx). In this prospective, randomized, multicenter trial, the impact of immunosuppressive conversion toward CNI-free (mycophenolate mofetil [MMF] and sirolimus) or a CNI-reduced immunosuppressive regimen on renal function, efficacy, and safety was evaluated. Methods Since 2004, 63 HTx-patients (0.5-18.4 years after HTx) with CNI-based immunosuppression and reduced creatinine clearance less than 60 mL/min (39+/-15 mL/min) were included in this trial. Patients in the CNI-free-Group (group 1) were converted to sirolimus that was started with 2 mg/day until target trough levels (8-14 ng/mL) were achieved. Subsequently, CNIs were withdrawn. In CNI-reduction-Group (group 2), CNI target trough levels were reduced by 40%. In both groups MMF was continued and trough level adjusted (1.5-4 microg/mL). Results Patients demographics and survival (mean follow-up time: 16.7+/-9 months) was equal (100%). Renal function improved significantly after complete CNI withdrawal while remaining unchanged with CNI-reduction (Creatinine clearance after 12 months: 53+/-24 mg/dL [group 1] vs. 38+/-20 mg/dL [group 2], P=0.01). End-stage renal failure (hemodialysis) was avoided by CNI-withdrawal and occurred only after CNI reduction (n=6; P=0.01). Acute rejection episodes were more common in group 2 (4 vs. 2). Graft function remained stable (echocardiography) within both groups. Adverse events were more common in group 1 (65%) than in group 2 (n=40%) and were responsible for discontinuation in 4 and 0 cases, respectively. Conclusions Conversion toward a CNI-free immunosuppression (Mycophenolate, sirolimus) is superior to CNI-reduced immunosuppression in improving renal failure in late HTx-recipients. However, this benefit is relativized by the increased incidence and severity of sirolimus/MMF-associated side effects.

Risk stratification in patients with congestive heart failure (CHF) is an obligatory part of the heart transplantation (HTx) selection process. New medical therapies and the predictive value of hemodynamic changes over time have not been adequately taken into account in previous stratification models. In this study we assessed the prognostic value of 55 variables at baseline and 9 variables representing changes of hemodynamic parameters over time.A total of 178 patients with CHF were examined on 3.4 +/- 2.6 occasions (mean follow-up 19 +/- 19 months). Using the Cox proportional hazards model, univariate and multivariate relative risks (RRs) with 95% confidence intervals (CI) were determined for predicting event-free survival. A prognostic score (Munich score) was derived from the multivariate Cox model and three risk groups were derived.During follow-up, 23 patients (13%) died and 63 (35%) underwent HTx. The univariate analysis yielded 21 statistically significant (p0.05) predictors of event-free survival. However, only four baseline variables (etiology of ischemic cardiomyopathy, systolic blood pressure, left ventricular [LV] end-diastolic diameter, maximal workload) and the change over 12 months in fractional shortening remained statistically significant (p0.05) in the multivariate Cox model and were used for the prognostic score. Within 12 months, no event occurred in the low-risk group, 8.1% in the intermediate, and 30.1% in the high-risk group.The incorporation of changes over time in hemodynamic parameters allowed for an improved baseline risk stratification model for the HTx selection process, especially in the era of new medical therapies such as beta-blocker therapy. All significant variables of the Munich score can be obtained in routinely performed non-invasive tests.

Endothelial dysfunction precedes hypertension and atherosclerosis and predicts cardiac allograft vasculopathy and death in heart transplant recipients. Endothelial overproduction of reactive oxygen species, such as superoxide anions produced by NAD(P)H oxidase, induces endothelial dysfunction. Because immunosuppressive drugs have been associated with increased reactive oxygen species production and endothelial dysfunction, we sought to elucidate the underlying mechanisms. Reactive oxygen species, release of superoxide anions, and NAD(P)H oxidase activity were studied in human umbilical vein endothelial cells and in polymorphonuclear neutrophils. Gp91ds- tat was used to specifically block NAD(P)H oxidase. Transcriptional activation of different subunits of NAD(P)H oxidase was assessed by real-time RT-PCR. Rac1 subunit translocation and activation were studied by membrane fractionation and pull-down assays. Calcineurin inhibitors significantly increased endothelial superoxide anions production because of NAD(P)H oxidase, whereas mycophenolate acid (MPA) blocked it. MPA also attenuated the respiratory burst induced by neutrophil NAD(P)H oxidase. Because transcriptional activation of NAD(P)H oxidase was not affected, but addition of guanosine restored endothelial superoxide anions formation after MPA treatment, we speculate that the inhibitory effect of MPA was mediated by depletion of cellular guanosine triphosphate content. This prevented activation of Rac1 and, thus, of endothelial NAD(P)H oxidase. Because all heart transplant recipients are at risk for cardiac allograft vasculopathy development, these differential effects of immunosuppressants on endothelial oxidative stress should be considered in the choice of immunosuppressive drugs.

Elevated pulmonary vascular resistance (PVR) is relevant to prognosis of congestive heart failure and heart transplantation. Proof of reversibility by pharmacologic testing in potential transplantation candidates is important because it indicates a reduced probability of right ventricular failure or death in the early post-transplant period. This study aimed to clarify the possible extent of acute reversibility of elevated PVR in a large, consecutive cohort of heart transplant candidates.This study included 208 consecutive patients (age 52 +/- 10 years, 89% men and 11% women, ejection fraction 21 +/- 9%, Vo2max 12.6 +/- 4.2 ml/kg/min) being evaluated for heart transplantation in 7 transplant centers in Germany and Switzerland. Testing was performed with increasing intravenous doses of prostaglandin E1 (PGE1; average maximum dose 173 +/- 115 ng/kg/min for at least 10 minutes) in 92 patients exhibiting a baseline PVR of2.5 Wood units (WU) and/or a transpulmonary gradient (TPG) of12 mm Hg.PGE1 testing lowered PVR from 4.1 +/- 2.0 to 2.1 +/- 1.1 WU (p0.01), increased cardiac output from 3.8 +/- 1.0 to 5.0 +/- 1.5 liters/min (p0.01), and decreased TPG from 14 +/- 4 to 10 +/- 3 mm Hg (p0.01), mean pulmonary artery pressure (PAM) from 39 +/- 9 to 29 +/- 9 mm Hg (p0.01) and mean pulmonary capillary wedge pressure (PCWP) from 24 +/- 7 to 19 +/- 9 mm Hg (p0.01). Mean aortic pressure (MAP) decreased to 85% and systemic vascular resistance (SVR) to 65% of baseline values (p0.01). Symptomatic systemic hypotension was not observed. For the whole population the percentage of patients with PVR2.5 WU was reduced from 44.2% to 10.5% with PGE1. PVR decreased in each patient; only 2 patients (1%) remained ineligible for listing because of a final PVR of4.0 WU. TPG, ejection fraction and male gender were independent predictors of reversibility of PVR.Elevated PVR in heart transplant candidates is highly reversible and can be normalized during acute pharmacologic testing with PGE1.

Background The long-term outcome after heart transplantation (HTx) is essentially influenced by the occurrence and extent of cardiac allograft vasculopathy (CAV). Single photon emission computed tomography-myocardial perfusion imaging (SPECT-MPI) has been shown to be a useful and cost-effective non-invasive method in patients with known or suspected coronary artery disease, but its role in detecting CAV remains unclear. Aim To evaluate the accuracy and predictive value of dobutamine MPI in patients after HTx during a 12-month follow-up. Methods Seventy-seven patients (60 males, 17 females) underwent a total of 216 dobutamine MPI examinations over a period of 5 years. Examinations were obtained an average of 89 ′ 42 months after orthotopic HTx according to a 1 -day protocol using 9 9 m Tc-methoxyisobutylisonitrile ( 9 9 m Tc-MIBI) with and without attenuation correction. For the present study, findings from 77 MPI examinations (one MPI examination per patient) were analysed visually and semiquantitatively using a 20-segment model. Summed stress scores (SSS) and summed rest scores (SRS) were calculated and receiver operating characteristic (ROC) analysis was performed to detect optimum threshold values. Patients were followed up for 12 months and cardiac events were registered. Results Cardiac events were observed in 10 of the 77 patients. Good interobserver agreement was found for global visual and SRS-/SSS-based analysis (κ=0.74 and 0.66, respectively). SSS was superior to SRS in the detection of cardiac events. ROC analysis showed an optimized SSS threshold value of three. For predicting a cardiac event during the 12-month follow-up, global visual and semiquantitative analysis reached sensitivities of 90% and 90%, specificities of 72% and 88%, accuracies of 74% and 87%, positive predictive values of 32% and 53% and negative predictive values of 98% and 98%, respectively. The sensitivity, specificity, accuracy and positive and negative predictive values for MPI to detect clinically relevant coronary artery stenoses ( ≥ 50%) at conventional coronary angiography were 83%, 87%, 86%, 56% and 96%, respectively. Conclusions Non-invasive dobutamine MPI reliably identifies patients at risk for subsequent cardiac events in cases of CAV, with a high negative predictive value of 98% and an accuracy of 87%.

Fractional flow reserve (FFR) is a new but well established parameter for the hemodynamic evaluation of coronary stenoses. A FFR below 0.75 was validated as functionally significant in coronary one or two vessel disease. This study was designed to prospectively define the best FFR cut off value (BCV) in patients with multivessel disease using two noninvasive tests, myocardial perfusion scintigraphy (SPECT) and contrast-enhanced dobutamine stress echocardiography (DSE) as reference methods.47 symptomatic patients (29 male, mean age 64+/-10 yrs) with angiographically intermediate coronary lesions (50-75% diameter stenosis) entered the study. DSE (5-40 microg/min/kg dobutamine) was performed after intravenous injection of a second generation transpulmonary contrast agent. SPECT (Tc-99m-MIBI) was done at peak stress. All tests (DSE, SPECT and FFR) were performed within 4 weeks.SPECT yielded positive results in 15 and DSE in 16 patients, respectively. Mean FFR measured in the target lesion (RCA n=10; LAD n=22, RCX n=15) was 0.80+/-0.13. FFR was0.75 in 15 patients. By performing a ROC analysis the BCV (highest sum of sensitivity and specificity) was found at 0.75. At this cut off value using both non-invasive tests as reference method, sensitivity and specificity were 83 and 77%.In patients with multivessel disease, a FFR0.75 identifies a hemodynamically relevant lesion as compared to DSE and SPECT. This study underlines that FFR criteria are also applicable in patients with complex coronary artery disease.

To determine the prognostic value of fractional flow reserve (FFR) measurements after coronary stent implantation including multiple clinical and angiographic parameters collected in one centre.119 consecutive patients were enrolled who had a stent implanted with the use of a pressure wire as a guidewire. Patients were followed up for at least six months. Any death, myocardial infarction, and target vessel revascularisation were considered major adverse cardiac events (MACE). Multivariate logistic regression was used to determine adjusted odds ratios (OR) and 95% confidence intervals (CI) for FFR and covariates.Complete follow up data were available for all 119 patients. Pre-interventional FFR increased from 0.65 (0.15) to 0.94 (0.06) (p0.0001) after stent implantation. Eighteen MACE (15%) occurred during follow up including 15 (12.6%) target vessel revascularisations. Final FFR was significantly higher in patients without than in patients with an event (0.95 (0.05) v 0.88 (0.08), p = 0.001). In the multivariate logistic regression analysis, only final FFR0.95 (OR 6.22, 95% CI 1.79 to 21.62, p = 0.004) and reduced left ventricular function (OR 0.95, 95% CI 092 to 0.99, p = 0.021) remained as significant independent predictors for MACE.These results including multiple parameters underline that FFR after coronary stenting is a strong and independent predictor for subsequent cardiac events after six months' follow up.

Achievement of maximal hyperemia of the coronary microcirculation is a prerequisite for the measurement of fractional flow reserve (FFR). Intravenous adenosine is considered the standard method, but its use in the catheterization laboratory is time consuming and expensive compared with intracoronary adenosine. Therefore, this study compared different high, intracoronary doses of adenosine for the potential to achieve a maximal hyperemia equivalent to the standard intravenous route.FFR was assessed in 50 patients with 50 intermediate lesions during cardiac catheterization. FFR was calculated as the ratio of the distal coronary pressure to the aortic pressure at hyperemia. Different incremental doses of intracoronary adenosine (60, 90, 120, and 150 microg as boli) and a standard intravenous infusion of 140 microg/kg/min were administered in a randomized fashion.Different incremental doses of intracoronary adenosine were well tolerated, with fewer systemic adverse effects than intravenous adenosine. At baseline, there were no significant differences for mean aortic and distal coronary pressure or heart rate in the different adenosine doses and routes. FFR decreased with increasing adenosine doses, with the lowest values observed with the 150-microg intracoronary bolus and 140-microg/kg/min dose of intravenous adenosine. All intracoronary doses, except the 150-microg bolus, resulted in mean FFR values that were significantly (P.05) higher than FFR after the administration intravenous adenosine. Furthermore, 5 patients (10%) with a FFR value0.75 and 3 subjects (6%) with a FFR value0.80 who received a 60-microg intracoronary bolus reached a value below the cutoff point of 0.75 with the intravenous administration.This study suggests a dose-response relationship on hyperemia for intracoronary adenosine doses60 microg. The administration of very high intracoronary adenosine boli is safe and associated with fewer systemic adverse effects than standard intravenous adenosine. However, intravenous adenosine administration with 140 microg/kg/min produced a more pronounced hyperemia than intracoronary adenosine in most patients and should be the preferred mode of application for the assessment of FFR.

Background The aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage. Methods Sixty patients (TAC, n = 30; CsA, n = 30) undergoing heart transplantation were randomized into a prospective, open-label, controlled trial. Immunosuppression consisted of TAC or CsA in combination with MMF and corticosteroids. Target blood trough levels of TAC, CsA, and mycophenolic acid (MPA) were in the range of 10 to 15 ng/mL, 100 to 300 ng/mL, and 1.5 to 4.0 microg/mL, respectively. Acute rejection episodes (ARE); survival data; and adverse events with a special emphasis on infections, diabetes, hypertension, hypercholesterolemia, and the development of graft vessel disease (GVD) were recorded. Results Baseline characteristics were well balanced. All patients were successfully withdrawn from corticosteroids within 6 months of transplant. Freedom from acute rejection was significantly higher (P = 0.0001) and the incidence of ARE per 100 patient days significantly lower in the TAC-MMF group than in the CsA-MMF group (0.03 vs. 0.15; P = 0.00007). Overall patient survival during follow-up was similar (93% vs. 90%). To achieve the targeted MPA blood levels, a significantly lower dose of MMF was required for TAC versus CsA patients. After a follow-up time of 2 years, the mean GVD score was 1.85 +/- 3.18 in the TAC-MMF group and 3.95 +/- 4.8 in the CsA-MMF group (P = 0.08). Conclusions At the selected doses and target levels for TAC and CsA used in this study, trough level adjusted MMF was more efficacious in combination with TAC for prevention of ARE. Furthermore, CsA patients need significantly more MMF to achieve similar MPA levels.

DSE and SPECT are two well-established methods to non-invasively investigate the functional significance of coronary artery stenoses in patients with coronary artery disease. The measurement of Fractional Flow Reserve has emerged a new invasive reference standard for lesion specific quantification of coronary artery stenoses. The objective of our prospective study was to compare sensitivity and specificity of Dobutamine Stress Echocardiography (DSE) and Single Photon Emission Computer tomography (SPECT) with the pressure derived Fractional Flow Reserve (FFR) for the identification of hemodynamic relevant coronary lesions in patients with predominately coronary multivessel disease and angiographically intermediate stenoses.Inclusion criteria were a coronary lesion of 50-75% diameter stenosis by visual assessment in patients with known or suspected CAD. SPECT, DSE and FFR testing was performed within one week of coronary angiography.The study comprised 48 consecutive symptomatic patients. In 41 cases, a coronary multivessel disease was present. Mean FFR was 0.80 +/- 0.13 (0.41-1.0). Overall sensitivity of DSE and SPECT was 67% and 69% whereas specificity reached 77% and 87%. However, sensitivity was significantly reduced if the target lesion was located distally. DSE showed poor results if the lesions were located in the circumflex artery or if a history of prior myocardial infarctions was present.DSE and SPECT are both useful methods for the non-invasive assessment of coronary artery disease. DSE showed reasonable combination of sensitivity and specificity even in patients with multivessel disease. Although use of noninvasive stress tests is only limited in patients with prior myocardial infarctions and invasive stress testing should be preferred in these patients.

Elective transcatheter closure of congenital septal defects has emerged as a valuable method, but the clinical experience on occlusion of ventricular septal rupture after myocardial infarction is very limited. We report a case of fatal outcome in a patient with inferior myocardial infarction and cardiogenic shock despite technically successful transcatheter closure of a large complex ventricular septal defect.

Fractional flow reserve (FFR) is a measure of coronary stenosis severity that is based on pressure measurements obtained at maximal hyperemia. Therefore, achievement of maximal vasodilatation of the coronary microcirculation is a prerequisite for the measurement of FFR. The study was designed to address the hypothesis that intracoronary adenosine yields more complete vasodilatation of the coronary microcirculation when high doses are used, resulting in a more accurate FFR measurement.Thirty-six patients with 43 moderate lesions underwent determination of FFR during cardiac catheterization. FFR was calculated in all lesions as the ratio of the distal coronary pressure to the aortic pressure at hyperemia. Different incremental doses of intracoronary adenosine (16, 24, 32 and 40 microg for both coronary arteries) were administered in a randomized fashion.No adverse events occurred with any intracoronary adenosine bolus. At baseline there were no significant differences for mean aortic and distal coronary pressure, heart rate as well as FFR values between the different doses. FFR was not significantly altered from the different incremental adenosine doses. However, in 27 (63%) out of 43 lesions there was a further reduction of FFR up to 0.23 when a dose16 microg was injected.This study suggests that doses of adenosine up to 40 microg are safe and can be used to achieve a more pronounced vasodilatation in individual patients compared to the standard doses. This may have therapeutic impact with FFR values near cut-off points in patients undergoing diagnostic coronary angiography as well as in patients in whom FFR is used to assess the outcome of interventions.

BACKGROUND Tacrolimus (FK506) is a new immunosuppressive drug in organ transplantation that has demonstrated experimentally to be more deleterious on bone mineral metabolism than cyclosporine. The purpose of this clinical study was to evaluate the effects of a tacrolimus-based immunosuppression on the skeleton and to investigate in a prospective, longitudinal, randomized, double-blind, study the effect of 0.25 microg calcitriol (1,25-dihydroxyvitamin D3) versus placebo in the prevention of bone loss and fracture rate after heart transplantion (HTx). METHODS A total of 53 patients (5 female, 48 male, mean age: 53+/-11 years) were randomized to the study medication. Basic therapy included calcium and sex hormone replacement in hypogonadism. Bone mineral density of the lumbar spine (LS) and femoral neck (FN) were performed at baseline, after 12 and 24 months. Biochemical indexes of mineral metabolism were measured every 3 months. RESULTS Overall bone mineral density (BMD) was significantly decreased after HTx (T-score-LS: 89+/-13%; FN: 88+/-14%). LS-BMD (% change in g/cm2) increased significantly within the study period in the calcitriol group (12 months: 7.1+/-8.1%, P

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

Background Previous studies showed that moderate and severe acute cardiac rejection (AR) but not mild AR is associated with significant myocardial acoustic changes. This study examines whether serial measurements of end-diastolic two-dimensional integrated backscatter (2D-IB) enhance the diagnostic potential of ultrasonic tissue analysis in AR. Methods and Results Serial endomyocardial biopsies, conventional echocardiograms, and parasternal long-axis radiofrequency signals for determination of posterior wall and septal 2D-IB were performed in 52 transplant patients. Histology showed no AR in 155 biopsy samples, AR grade 1A in 25, AR grade 1B/2 in 27, and AR grade 3A/3B in 13. Whereas no significant 2D-IB changes occurred between AR-free studies and during AR grade 1A, posterior wall and septal 2D-IB increased during AR grade 1B/2 from −47.80±4.36 to −42.97±5.11 dB and from −36.72±7.45 to −32.52±7.98 dB ( P P P P P P r =.41 and r =.39, both P r =.35, P Conclusions Increases in end-diastolic posterior wall and septal 2D-IB in serial studies permit reliable identification not only of moderate and severe AR but also of mild AR. Because 2D-IB increases significantly more in AR with myocyte damage than without such damage, an estimate of AR severity appears feasible. Significant myocardial acoustic changes during AR may occur independently of changes in contractile performance.

This study investigates the comparative sensitivity of video and radiofrequency imaging to detect changes of the myocardial acoustic properties after intravenous Albunex. Thirty-six patients received Albunex, 0.08 and 0.22 ml/kg intravenously, during transesophageal imaging of the ventricular short axis. Analysis of video images was performed in all patients and of radiofrequency data in 20 patients. Although myocardial videointensity remained unchanged, 57% of the myocardial backscatter plots demonstrated significant contrast enhancement. The study demonstrates that intravenous Albunex is capable of myocardial contrast enhancement and proves the diagnostic superiority of radiofrequency compared with video imaging. Ultrasonic radiofrequency imaging may provide a technical basis for future noninvasive assessment of myocardial perfusion.

Background: Cross-sectional studies have shown that more than 50% of patients with congestive heart failure (CHF) have decreased bone mineral density (BMD). There is limited knowledge about the longitudinal changes of BMD and how to treat bone loss in patients with CHF. Methods: The present study was a prospective, longitudinal trial in which 33 male patients with CHF (ejection fraction (EF): 30±11%) were assigned to 1000 mg calcium supplementation or no supplementation. BMD was measured at the lumbar spine (LS) and the femoral neck (FN) by dual-energy X-ray absorptiometry at baseline and after 12 months. Results: Osteopenia (LS 33% and FN 36%) and osteoporosis (LS 15% and FN 6%) were frequently seen in these patients; 70% showed impaired renal function, 42% secondary hyperparathyroidism, and 33% hypogonadism. Bone resorption markers were strongly elevated and correlated negatively with the EF. Patients without calcium supplementation revealed a reduction of BMD (LS 1.7% and FN 1.9%) within 12 months. The fracture incidence was 6%. Patients with calcium supplementation also demonstrated a 6% fracture incidence and a decrease in BMD (LS 1.2% and FN 1.6%), which was not significantly different from the untreated group. Loss of BMD at FN was only seen in patients with impaired renal function. Conclusions: Patients with CHF demonstrate a progressive decrease in BMD when compared with age-matched healthy individuals. Increased bone resorption due to renal insufficiency with consecutive secondary hyperparathyroidism is a main reason for BMD loss in CHF. Calcium supplementation alone cannot sufficiently prevent the decrease in BMD.

Pressure derived myocardial FFR, a functional index of epicardial stenosis has been proposed for the assessment of optimal stent deployment. The following study evaluated the potential of serial fractional flow reserve (FFR) measurements in comparison to the 'gold standard' intravascular ultrasound (IVUS) for optimal stent deployment and its long-term outcome.35 patients with a single de novo lesion underwent PTCA followed by stent implantation with an initial inflation pressure of 12 atm. If optimal stent expansion using IVUS-criteria were not fulfilled, re-dilatation at 16 atm as well as additional inflations with larger balloon sizes were performed to reach the procedural end-point. IVUS and FFR were performed after each dilatation (n = 136). Angiography was repeated after 6 months.In 30 pts who fulfilled IVUS criteria, mean lumen area (2.9+/-1.3 mm2) increased after PTCA and stent implantation to 10.0+/-3.0 mm2. In six pts, optimum stent deployment according to a value of FFR0.94 was not reached. Four of six pts reached the IVUS criteria at 12 atm and two pts at 16 atm, respectively. Positive and negative predictive values of FFR were 26 and 64%. Three of the 30 pts (10%) revealed a restenosis at three months follow-up. One of these restenosis was seen in a patient with a post-procedural FFR0.94.FFR was not valid to predict optimal stent expansion according to IVUS criteria but could delineate under-expanded stents despite a reasonable angiographic appearance. Morphologic (IVUS) and functional criteria (FFR) for optimal stent deployment revealed a comparably low restenosis rate.

Publisher Summary This chapter reviews the effect of sex-steroid deficiency on skeletal and its therapy before and after cardiac transplantation. Hypogonadism is a clinical condition characterized by low serum levels of gonadal hormones. It is frequently associated with cardiac transplantation and may play a role in the multifactorial pathogenesis of immunosuppression-induced bone loss. It, in either sex stimulates the production of osteoblasts and osteoclasts, resulting in an increase in bone turnover with an imbalance between bone formation and resorption. These changes are mediated by up-regulating the production and action of cytokines, including IL-6. The loss of gonadal function may increase the sensitivity of mechanisms regulating osteoclast function and activity to IL-6 and IL-1. Sex-steroid deficiency also causes osteoblast apoptosis and, in addition, anti-apoptotic effects on osteoclasts, resulting in a shortening of the lifespan of the osteoblast and an extension of the working lifespan of the osteoclast. The latter is likely to be responsible for the deeper resorption cavities and hence, the trabecular perforation can be seen in the case of estrogen deficiency. The chapter also deals with the influence of hormone replacement therapy on the rate of bone loss after organ transplantation.

Cocaine use is a major problem worldwide and there are numerous reports about cocaine-associated myocardial infarction. Nevertheless minimal data are available from randomised clinical trials to suggest evidence-based approaches to the management of cocaine-associated myocardial ischemia. Moreover, most reports have been limited to conservative management of cocaine-associated myocardial infarction. We report a case of a young male cocaine user with acute myocardial infarction, undergoing diagnostic coronary angiography and intravascular ultrasound revealing severe atherosclerosis, followed by successful stent implantation.

Background The extent of myocardial salvage after primary percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction (AMI) is variable and can not be predicted on the basis of vessel patency. The aim of this study was to evaluate the tissue salvage and the microvascular integrity after successful intervention in AMI by coronary blood flow velocity and sestamibi perfusion imaging. Methods Twenty-two patients (17 m, 5 f; mean age 57 ± 14 yrs.) undergoing primary PTCA and stent implantation for AMI were studied. 99mTc Sestamibi was injected intravenously before intervention and single photon emission computed tomography (SPECT) was performed immediately after successful reperfusion to determine the area at risk before PTCA due to the minimal 99mTc Sestamibi redistribution. Sestamibi SPECT was repeated 3 days and 6 months after AMI. Area at risk (%) was determined automatically by myocardial perfusion tomography (PERFIT) with the use of a multistage, 3D iterative inter-subject registration of patient images to normal templates (2SD) and myocardial salvage was calculated. Coronary flow velocity was measured using a Doppler-tipped guidewire in the infarct-related artery after successful completion of primary PTCA and in an angiographically normal reference vessel. Absolute coronary flow reserve (CFR) and relative CFR (rCFR) were calculated using hyperemic to basal average peak velocity. Results Despite successful reperfusion of the target vessel (TIMI grade III flow) CFR and rCFR remained impaired (1.8 ± 0.9 and 0.77 ± 0.21). Area at risk decreased significantly from 21 ± 9% to 9 ± 10% (p < 0.05) corresponding to 11 ± 8 % myocardial salvage. Acute CFR and rCFR showed no correlation with the area at risk before and after primary PTCA. The increase of CFR within 6 months correlated with the myocardial salvage (p < 0.05). Conclusions Despite successful primary PTCA in AMI, CFR and rCFR often remain impaired because of a significant loss of microvascular integrity. The long-term success of primary PTCA can be assessed by myocardial salvage and the change of CFR which might be a useful parameter for additional reperfusion strategies such as glycoprotein IIb/IIIA receptor inhibition.

A new interface for high resolution online digitization of unprocessed radiofrequency signals was developed. Preliminary clinical data suggest that, based on measurements of end-diastolic integrated ultrasonic backscatter, this new device permits the noninvasive recognition and monitoring of acute cardiac allograft rejection in transplant patients. >

The aim of the study was to evaluate whether cyclic variation of integrated backscatter (CVIB) measurements allow discrimination between normal and acutely ischemic myocardium as well as infarcted areas. Second, whether this parameter permits an early assessment of the success of revascularization procedures (accelerated rtPA-thrombolysis or acute PTCA). CVIB was measured frame by frame within normal and injured myocardium in 14 patients with acute myocardial infarction. CVIB rapidly detected infarcted zones and allowed early noninvasive assessment of the success of revascularization procedures in all patients.

The aim of the study was to evaluate whether myocardial structural changes during acute rejections (AR) after heterotopic heart transplantation would alter the spatial distribution of myocardial echo amplitudes, assessed by echocardiographic texture analysis using Cooccurrence- and Run Length Matrix. Results showed that only severe AR are associated with significant changes of texture analysis parameters. Thus, texture analysis is not suitable to improve the sensitivity of AR diagnosis.

Coronary flow velocity reserve (CFVR) (maximum/baseline flow velocity, 16 microg adenosine) was compared with dobutamine stress echocardiography (DSE) (5 to 40 microg/kg/min) to assess the progression of angiographically silent cardiac allograft vasculopathy (CAV). As a reference for the morphologic assessment of CAV, serial intracoronary ultrasound (ICUS) measurements were performed. An increase in CFVR could be observed in all transplant patients despite morphologic or functional progression of CAV or non-progressive CAV as assessed by ICUS or DSE. Thus, serial intracoronary Doppler flow analysis is not useful to predict morphologic or functional progression of CAV.

Tacrolimus (FK506) is a new immunosuppressive drug in organ transplantation that has demonstrated experimentally to be more deleterious on bone mineral metabolism than cyclosporine. The purpose of this clinical study was to evaluate the effects of a tacrolimus-based immunosuppression on the skeleton and to investigate in a prospective, longitudinal, randomized, double-blind, study the effect of 0.25 microg calcitriol (1,25-dihydroxyvitamin D3) versus placebo in the prevention of bone loss and fracture rate after heart transplantion (HTx).A total of 53 patients (5 female, 48 male, mean age: 53+/-11 years) were randomized to the study medication. Basic therapy included calcium and sex hormone replacement in hypogonadism. Bone mineral density of the lumbar spine (LS) and femoral neck (FN) were performed at baseline, after 12 and 24 months. Biochemical indexes of mineral metabolism were measured every 3 months.Overall bone mineral density (BMD) was significantly decreased after HTx (T-score-LS: 89+/-13%; FN: 88+/-14%). LS-BMD (% change in g/cm2) increased significantly within the study period in the calcitriol group (12 months: 7.1+/-8.1%, P0.01; 24 months: 14.0+/-10.1%, P0.01) and showed a positive trend in the placebo group (12 months: 4.5+/-9.3%, NS; 24 months: 6.2+/-8.0%, NS). FN-BMD in the calcitriol group was stable (12 months: -2.1+/-4.2%; NS; 24 months: -0.9+/-3.2%, NS). FN-BMD in the placebo group decreased significantly within the first 12 month follow-up period (-7.3+/-5.4; P0.05) and stabilized within 2 years (-8.0+/-4.1%; P0.05). Fracture incidence was low during the study interval (first year: 5.0%, second year: 0%). Bone resorption markers decreased significantly during calcitriol therapy.High dose tacrolimus-based immunosuppressive regimen is associated with a rapid bone loss early after cardiac transplantation. Beyond the first 6 months after HTx, calcium, vitamin D, and hormone supplementation in hypogonadism lead sufficiently to bone mineral recovery. Besides immunosuppression, both concomitant hypogonadism and secondary hyperparathyroidism play a major role for the bone loss and should be therefore monitored and treated adequately. Low dose calcitriol should be substituted for at least 2 years as additional antiresorptive therapy.

A high restenosis rate often follows treatment of coronary stenoses in cardiac allograft vasculopathy. We report successful coronary brachytherapy of a second in-stent restenosis in a patient after heart transplantation.

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.

HE MACROLIDE lactone tacrolimus (FK506) is a new immunosuppressive drug that has demonstrated to be 10 to 100 times more potent than cyclosporine A. After forming a complex with the immunophilin FK506binding protein, the complex acts in a similar fashion to the cyclosporine-immunophilin complex, resulting in an inhibition of calcineurin, a calcium-dependent serine/threonine protein phosphatase. This inhibition prevents the assembly of the functional transcription of interleukin 2. Although tacrolimus has reputedly less severe side effects, recent experimental studies have demonstrated an increase of bone formation and bone resorption, accompanied by a significant reduction in percent trabecular area. 1 The present study was undertaken to assess the effects of tacrolimus-based immunosuppression on bone mineral metabolism after orthotopic heart transplantation.

Conventional active stress tests for the evaluation of coronary artery disease are not feasible for patients in whom a significant blood pressure increase during a stress procedure should be avoided, for example, those with a coexisting aortic aneurysm. Transesophageal echocardiography (TEE) with simultaneous atrial pacing is a new, highly specific, and sensitive stress technique for the detection of coronary artery disease. Furthermore, TEE can be performed safely with only mild blood pressure increases. Therefore in the present case report of a 70-year-old male, application of combined TEE and atrial pacing was used successfully to exclude the hemodynamic significance of a circumflex artery stenosis and avoided a significant blood pressure increase before surgical correction of an abdominal aortic aneurysm.

Echocardiographic tissue characterization is a promising, relatively new application of ultrasound in cardiology. It is based on the assumptions that a relationship exists between the acoustic properties and the morphology of the myocardial tissue, and that pathologic and physiologic processes within the heart muscle lead to reproducible changes in these acoustic properties, which are amenable to quantitation. Much information has been accumulated from animal and in vitro studies using quantitative analysis of transmitted ultrasound. Clinical research in this field has mostly been based on the evaluation of myocardial backscatter, that is of the scattered low intensity echoes originating from reflectors within the tissue, which are small compared with the wavelength of the ultrasonic beam. Echocardiographic tissue characterization aims primarily at the discrimination between normal and diseased myocardium; its ultimate goal, however, is the noninvasive identification of the site, extent, and specific nature of different acute and chronic diseases of the heart muscle.

Toxoplasmosis may cause serious problems after organ transplantation. For treatment of active infection, pyrimethamine combined with a sulfonamide is recommended. During oral sulfadiazine therapy, a significant decrease in cyclosporine concentrations was observed in three heart transplant recipients. This interaction has not been reported previously.

Transesophageal echocardiography (TEE) is accepted as the procedure of choice for the diagnosis of intracardiac sources of systemic embolism. A case report is presented on a 74-year-old patient with atrial fibrillation referred for TEE evaluation after an acute embolic event. During TEE, atrial fibrillation converted to sinus rhythm. Although TEE is a very safe method, which is performed in increasing numbers of patients, this is the first reported case of conversion of atrial fibrillation to sinus rhythm during the procedure. We suggest that no restriction should be imposed on the use of TEE in patients with atrial fibrillation, as the small risk associated with conversion of atrial fibrillation is outweighed by the potential diagnostic benefits.

The effects of graded supine ergometry on blood pressure, heart rate, and plasma hormones were studied in 14 hypertensive heart transplant recipients before and after 2 weeks and 6 months of enlapril (20 mg/day) plus furosemide (20–80 mg/day) alone or combined with verapamil (120–360 mg/day). Each time, measurements were obtained at rest and at 25 and 50 W exercise. Anti-hypertensive therapy normalized blood pressure, while heart rate and the blood pressure response to exercise remained unaltered. Pretreatment resting plasma renin activity and catecholamine levels were normal, while atrial natriuretic factor and cyclic guanosine monophosphate concentrations were elevated. All hormones increased significantly with exercise. During treatment, plasma renin activity increased and atrial natriuretic factor and cyclic guanosine monosphosphate levels decreased significantly, with a blunted exercise response; concentration of catecholamines increased significantly, with augmented exercise response. Thus, the chosen regimen allowed effective, lasting BP control in hypertensive transplant patients but was associated with significant changes in plasma hormones. Whereas the rise in plasma renin activity may be attributed to converting enzyme inhibition, the decreases in atrial natriuretic factor and cyclic guanosine monophosphate and increases in catecholamine levels seem to indicate marked changes in resting and particularly exercise hemodynamics during antihypertensive therapy.

There is little awareness of the limitations of flow detection with the commercially available color Doppler flow mapping system. The influence of flow velocity, ultrasound attenuation, and penetration depth on flow detection in color Doppler (Toshiba SSH 65A) were therefore studied in vitro and compared with conventional Doppler. The flow model had physiological flow volumes and laminar flow with parabolic velocity profile in a horizontal tube of Lucite with less than 3 degrees of coincidence. Conventional Doppler flow velocity measurements correlated highly with laser Doppler anemometry results (r = 0.99, SEE = 3 cm/sec). Signal strength of color Doppler and pulsed Doppler was semi-quantitatively graded using a scale from 0 to 5. Scale 1 (sparse signals) was useless for any assessment in color Doppler but just allowed velocity measurement in pulsed Doppler. Using 19-dB attenuation, flow velocities greater than 100 cm/sec had good scores with moderate gain, 60-100 cm/sec needed increasing gain, and velocities less than 40 cm/sec were not detectable with color Doppler but readily so with pulsed Doppler. With increasing attenuation (1-29 dB) and also with increasing penetration depth, flow detection was reduced significantly (P less than 0.001) more in color Doppler than in the pulsed technique (P less than 0.01). In conclusion, low flow velocities, high attenuation, and greater than 8 cm penetration depth may hamper flow detection in color Doppler and, thus, diagnostic accuracy. Conventional Doppler with its superior accuracy and sensitivity should therefore consolidate diagnostic ultrasound assessment.

Flow detection by color Doppler is impaired by low velocity of flow and increasing attenuation and depth of ultrasound penetration. The effects of increased echogenicity on flow detection (Toshiba SSH 65A) were thus studied in a flow model, which yielded similar strengths of Doppler signals as seen in the clinical routine, by adding microbubble solutions to the blood analog fluid (45% aqueous glycerin) and comparing signal strength (score 0-5) prior to and after contrast. The flow within the plexiglass tube with less than 3 degrees angle of coincidence for Doppler interrogation was laminar with a parabolic velocity profile at physiological velocities and pressures. In comparison with various contrast agents at a flow velocity of 18 cm/sec and 19 dB attenuation, flow was not detectable in control color Doppler, after 4 mL of the blood analog fluid, and after 4 mL of an agitated saline solution 9 mg/mL, but visible after 4 mL of Echovist, a polysaccharide solution with reproducible bubble size and concentration and after 4 mL of an agitated polygelatin solution. Increasing concentration of Echovist (50-400 mg/mL) improved flow detection. Echovist 200 mg/mL enhanced the score by 1.1 + -0.6 for velocities 5-20 cm/sec (P less than 0.01), by 1.6 + -0.8 for 40-100 cm/sec (P less than 0.001), and by 1.1 + -0.6 for velocities greater than 150 cm/sec (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Echokardiographische Diagnostik basierte traditionell auf einer Analyse kardialer Morphologie und Funktion anhand der flachigen Echos hoher Intensitat, die an den glatten Oberflachen der Herzklappen, der Gefase und des Endo- und Epi-kards entstehen. Die aus dem Myokard stammenden Streuechos niedriger Signalstarke, die an im Verhaltnis zur Wellenlange des Ultraschalls kleinen Strukturelementen des Herzmuskels entstehen und sich zwischen den endo- und epikardialen Reflexionen abbilden, blieben lange Zeit entweder vollig unberucksichtigt oder wurden nur qualitativ in die Beurteilung des echokardiographischen Befundes mit einbezogen. Dabei fielen jedoch bei verschiedenen Erkrankungen des Herzmuskels wie der Amyloidose, der hypertrophen Kardiomyopathie und dem Myokardinfarkt bereits visuell eine veranderte Intensitat und Struktur der myokardialen Echos auf [5, 12, 22, 24].

TEE, which was for the first time used for evaluation of transplant patients in this study, yielded important information on the morphology and function of the transplanted heart, which cannot be obtained by TTE. The TEE findings indicate the need for antiplatelet therapy in patients with SEC and provide a potential clue to the pathogenesis of the AV valve incompetence.

ACUTE rejection (AR) following heart transplantation (HTX) is characterized histologically by patchy or diffuse cellular infiltrates, interstitial oedema, and, if AR is more severe, by myocyte necrosis and hemorrhage. Main criterion for the usefulness of any diagnostic tool is its capability to rapidly and reliably detect AR at the latest stage when intensified immunosuppression is required. For many years, histology from endomyocardial biopsies (EMB) has remained the gold standard; no other method has been shown to consistently fulfill this requirement. All attempts to diagnose AR noninvasively by ultrasound aim at identification of its morphologic and functional consequences. Several approaches have been employed: Conventional M-mode and two-dimensional echocardiography (2D-E), pulsed Doppler (D) E and E-based tissue analysis, using either videodensitometry or 2D integrated backscatter (IB) measurements based on unprocessed radiofrequency (RF) data. More recently, Doppler Tissue Imaging (DTI) has been proposed as a diagnostic tool. This article reviews the published literature on AR diagnosis based on cardiac ultrasound and discusses practical usefulness and limitations of the various techniques.