Aspects of cyclosporine A toxicity in the development of coronary artery disease in transplant recipients.
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Biomedical subjects
Publications and source records attributed to R Hetzer.
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OBJECTIVE: Cryopreserved homograft valves have been used for acute infective aortic root endocarditis with great success but it is compounded by its availability in all sizes. The long-term clinical results of geometric mismatched homografts are not well defined and addressed. METHODS: Over a 15-year period (April 1986-June 2001), 816 patients presented with active infective endocarditis. One hundred and eighty-two of the patients aged between 9 and 78 years (mean: 51.0 +/- 1.13 years) consisting of 142 males and 40 females received homograft aortic valves. One hundred and ten patients were in NYHA functional class III and 72 in class IV and in cardiogenic shock. Of the patients, 2.7% suffered from septic embolism. One hundred and twenty-four (68.1%) patients presented with periannular abscesses and 58 (31.9%) with no abscess while 107 native valve (NVE) and 75 prosthetic valve (PVE) endocarditis were diagnosed preoperatively by transesophageal echocardiography (TEE) and confirmed intraoperatively. Freehand subcoronary implantation (FSCI) was used in 106 patients and root replacement in 76 patients. RESULTS: The operative death was 8.5% and for patients in NYHA functional class IV and in cardiogenic shock was 14.5%. Late mortality rate was 7.9%. Patient survival after discharge from hospital at 1 year was 97% and at 10 years was 91%, respectively. Thirty-one (22.1%) patients underwent reoperation after 1.7 years (mean) with two deaths (6.4%). Early (< or = 60 days) and late reinfection rate was 2.7 and 3.6%, respectively. Freedom from reoperation for matched and undersized homografts at 10-13 years was 85 and 55%, respectively. The univariate model identified undersized homograft (P=0.002), FSCI (P=0.09) and reinfection (P=0.0001) as independent risk factors for developing early and late valve dysfunction resulting in reoperation and homograft explant. CONCLUSION: Early aggressive valve replacement with homograft for active infective aortic root endocarditis with periannular abscesses is more successful than delayed last resort surgery. Homografts exhibit excellent clinical performance and durability with a low rate of reinfection, if properly inserted. Undersized homograft is an incremental risk factor for early and late reoperation.
AIMS: Secondary involvement of the mitral valve is well documented in primary aortic valve endocarditis. A poorly considered, but probably important causative mechanism, involving both left-sided valves, is 'mitral kissing vegetation'. This results from large aortic vegetations prolapsing into the left ventricular outflow tract and making contact with the ventricular aspect of the anterior mitral leaflet thus causing secondary infection. METHODS AND RESULTS: In 192 consecutive patients with aortic valve endocarditis, two to 18 (7.6+/-2.6) serial transoesophageal echocardiographic examinations were analysed per patient to demonstrate the development of mitral kissing vegetation on initially competent, morphologically normal mitral leaflets. In 19 patients (9.9%) with aortic valve endocarditis, mitral kissing vegetation was diagnosed within 11.6+/-9.0 (range 1-31) days following primary transoesophageal echocardiography. In all patients with mitral kissing vegetation, vegetations attached to aortic cusps were >6 mm. On hospital admission, patients with aortic valve endocarditis plus mitral kissing vegetation presented more often with a positive sepsis score, embolic events, renal failure and had larger aortic valve vegetations (9.9+/-3.3 vs 5.7+/-2.3 mm). Prognosis of aortic valve endocarditis plus mitral kissing vegetation was unfavourable (P<0.005) when compared to patients with aortic valve endocarditis alone. CONCLUSION: In aortic valve endocarditis early echocardiographic detection of mitral kissing vegetation and timely surgery may preserve the mitral valve apparatus, and favourably influence the long-term prognosis.
After the introduction of mechanical circulatory support (MCS) for treatment of patients with severe cardiogenic shock, the survival rate of these patients increased significantly. Temporary MCS may be applied over a period of several days up to months prior to heart transplantation (HTx). Oral surgical management of patients with MCS is seriously complicated by a combination of anticoagulant and antiaggregant medication. Moreover, contact of blood with artificial surfaces, i.e. polyurethane and silicone, may increase the risk of thromboembolic events and infections. A total of 32 patients with MCS (29 men and three women with a median age 48 years [range 27-60 years]) were examined for odontogenic foci, treatment needs and local and cardiovascular complications after oral surgical intervention. In 27 patients (84%) at least one potential focus was diagnosed. Following tooth extraction 4 out of 6 patients presented with local haemorrhage (n=3) and thromboembolic events (n=2). Generally MCS has to be considered a relative contraindication for elective oral surgical interventions.
BACKGROUND: Continuous antegrade blood cardioplegia (CABCP) is used at different temperatures. We investigated the consequences of CABCP at 6 degrees C (COLD) vs. 28 degrees C (TEPID). METHODS: Anesthetized open-chest pigs (25 +/- 2 kg) were placed on cardiopulmonary bypass (CPB). The hearts were arrested for 30 min by 6 degrees C cold or 28 degrees C tepid CABCP (n = 8 each). After an initial 3 min antegrade application of high potassium (20 mEq) cold (6 degrees C) blood cardioplegia, the hearts were arrested for a subsequent 27 min by normokalemic blood delivered antegrade at either 6 degrees C or 28 degrees C. After this, the hearts underwent perfusion with warm systemic blood for an additional 30 min on CPB. Biochemical cardiac data (MVO2 [ml/min/100 g], release of creatine kinase [CK U/min/100 g] and lactate [mg/min/100 g]) were measured during CPB. Total tissue water content (%) and left ventricular stroke work index (SWI g x m/kg) were determined 30 min after discontinuation of CPB and compared to pre-CPB controls. RESULTS: Cold CABCP kept all hearts continuously arrested. The COLD hearts showed no biochemical or functional disturbance. The TEPID hearts intermittently fibrillated and required additional high potassium BCP shots. The TEPID hearts showed a marked CK leakage (2.6 +/- 0.4 vs. 0.7 +/- 0.4), lactate production (4.0 +/- 1.6 vs. extraction from the COLD group) despite the non-ischemic protocol, an impaired initial oxygen consumption (4.2 +/- 1.3 vs. 7.1 +/- 1.6) at the end of cardiac arrest, the formation of myocardial edema (79.5 +/- 1.0 vs. 77.0 +/- 0.8), and a depressed recovery of SWI (0.69 +/- 0.15 degrees vs. 1.41 +/- 0.13). *p < 0.05 for comparison of TEPID vs. COLD hearts using Student's t-test for unpaired data; degrees p < 0.05 for intergroup-comparison of TEPID vs. COLD vs. controls using ANOVA adjusted for repeated measures. CONCLUSIONS: Uninterrupted cardioplegia can be safely performed with cold normokalemic CABCP. In contrast, tepid normokalemic CABCP leads to fibrillation, jeopardizes the heart, and should be avoided.UND
BACKGROUND: This study was undertaken to investigate the physiological effects of cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) on cerebral oxygen metabolism estimated by near-infrared spectroscopy (NIRS). METHODS: Ten newborn piglets (2.1 to 2.6 kg) were monitored with right frontal NIRS; the right jugular bulb was cannulated for intermittent sampling of jugular venous blood. All animals underwent CPB, cooling to a core temperature below 15 degrees C, 60 minutes of DHCA followed by subsequent reperfusion and rewarming. Continuously recorded NIRS data and intermittent jugular venous blood values were compared. RESULTS: NIRS performance was examined over the jugular venous oxygen saturation (SjvO2) range of 40 to 98 %, a linear correlation was found between SjvO2 and NIRS-derived regional cerebral oxygen saturation (rSO2) (r = 0.91, p < 0.001). A correlation was observed between the cellular oxidation NIRS-parameter cytochrome oxidase aa3 (CytOx) slope during the DHCA period in relation to rectal and nasopharyngeal temperature immediately before the onset of DHCA (r = 0.75 and 0.85, p < 0.001). CONCLUSIONS: This study suggests that NIRS-measured hemoglobin oxygenation parameters may reflect functional changes in cerebral hemodynamics and brain tissue oxygenation, while CytOx values represent related effects on intracellular oxidative metabolism.
BACKGROUND: Four risk-stratification scores (RSSs - Euro, French, CCS/Higgins, Parsonnet) were tested as predictors of mortality in coronary artery bypass grafting (CABG) surgery. METHODS: From March to April 2000, the perioperative courses of 245 consecutive CABG patients were compared to the predictions according to the RSSs. Sensitivity and specificity were determined with receiver operating characteristics (ROC) curves. RESULTS: CCS/Higgins uses the most easily acquired patient data, and rates emergency conditions as high-risk. Euro focuses on advanced age and septal rupture. French uses the smallest number of patient parameters and rates rare critical situations as high-risk. Parsonnet is partially based on the physician's subjective assessment of a "catastrophic state," making the scoring arbitrary. All RSSs gave similar (not significant) areas under the ROC curves regarding mortality (Euro 0.826 +/- 0.080, French 0.783 +/- 0.094, CCS/Higgins 0.820 +/- 0.060, Parsonnet 0.831 +/- 0.042). Predicted risk levels for the 11 patients who died differed between the RSSs--Higgins placed these patients in 3 of 5 risk levels with ascending distribution. The other RSSs placed these patients in the highest risk level except for one and two patients, respectively, who were placed in the lowest Euro and French risk level. Euro and Parsonnet placed about half of all patients with non-lethal outcome in the highest risk level. CONCLUSIONS: All RSSs satisfactorily estimated the group risk for mortality. No RSS expressed sufficient validity to predict individuals with lethal outcome. In clinical use, CCS/Higgins proved the most practicable.
BACKGROUND AND OBJECTIVE: Endomyocardial biopsy is the gold standard for monitoring rejection in cardiac recipients. The death rate due to rejection with this invasive method is 5-6 % in the first postoperative year. The aim of this retrospective data analysis from cardiac recipients was to prove the diagnostic reliability of a non-invasive electrophysiological method for rejection monitoring. PATIENTS AND METHODS: We daily analyzed the QRS-complex amplitude of the intramyocardial electrogram, which we received over a period from one year via a pacemaker with a telemetric capability. The diagnostic guideline for a suspected rejection was the reduction of the QRS-complex amplitude by more than 8 %. Out of 734 patients 558 were included in the study. Biopsy was only performed when the non-invasive rejection monitoring data (QRS-complex amplitude plus echocardiography) showed a discrepancy for rejection. RESULTS: None of the patients died due to rejection, 273 at least once underwent a biopsy, and 285 never had a biopsy. The method reached a sensitivity of 0.9777, a specificity of 0.9634, a negative predictive value of 0.9850, and a positive predictive value of 0.9459. CONCLUSION: Daily electrophysiological non-invasive monitoring of rejection seems to be superior to endomyocardial biopsy. Death of patients due to rejection can be minimised. The number of necessary biopsies can be drastically reduced when compared to the usual number performed.
BACKGROUND: To date, donor-specific markers to predict outcome after heart transplantation (HTx) are unknown. Increased procalcitonin (PCT) levels have been found in infectious inflammation with systemic reactions and/or poor organ perfusion but have not been studied in heart donors. We evaluated PCT as a predictor of early graft failure-related mortality after HTx. METHODS AND RESULTS: PCT and C-reactive protein (CRP) serum concentrations were measured in samples collected immediately before pericardium opening from 81 consecutive brain-dead multiple-organ donors. Donors for high-urgency-status recipients (n=2) were excluded from analysis. The remaining donors were retrospectively divided into 2 groups: donors for recipients who died within 30 days after HTx, after an early graft failure (group II, n=8), and all other donors (group I, n=71). No differences in donor and recipient demographic characteristics were found between groups. Areas under the receiver operating characteristic curves for graft failure-related mortality were 0.71 for PCT and 0.64 for CRP. A PCT value >2 ng/mL as a predictor of graft failure-related mortality had a specificity of 95.8% and sensitivity of 50.0%. The odds ratio for graft failure-related mortality for recipients of hearts from donors with PCT levels >2 ng/mL was 22.7 (unadjusted, 95% CI 3.7 to 137.8, P=0.0007) and 43.8 (after adjustment for prespecified potential confounders, 95% CI 1.4 to 1361.0, P=0.031). CONCLUSIONS: A PCT level >2 ng/mL in a cardiac donor at the time of explantation appears to predict early graft failure-related mortality.
BACKGROUND: Invasive screenings at predefined time intervals for acute rejection and transplant coronary artery disease (TxCAD) are standard procedures. However, cardiac biopsies and catheterizations are distressing and risky for the patients and are also costly. We assessed the reliability of pulsed-wave tissue Doppler imaging (PW-TDI) for the timing of invasive examinations in heart recipients in an attempt to avoid unnecessary endomyocardial biopsies (EMBs) and catheterizations. METHODS AND RESULTS: PW-TDI obtained at the basal left ventricular posterior wall before 408 EMBs and 293 catheterizations was tested for its diagnostic value regarding rejection and TxCAD with the use of International Society of Heart and Lung Transplantation biopsy grading, coronary angiography, and intravascular ultrasound as standards. Early diastolic peak wall motion velocity and relaxation time showed high sensitivities for clinically relevant rejection diagnosis (90.0% and 93.3%, respectively). The negative and positive predictive values for rejection of diastolic parameter changes appeared high enough (up to 96% and 92%, respectively) to allow a reliable noninvasive PW-TDI monitoring with efficiently timed, instead of routinely scheduled, EMBs. At definite cutoff values for systolic parameters, the probability for TxCAD reached 92% to 97%. The Fisher classification functions allowed TxCAD exclusion with 80% probability. CONCLUSIONS: Without diastolic parameter changes, acute rejection can be practically excluded, and serial PW-TDI can save patients from routine EMBs. The high specificity and negative predictive value for TxCAD of reduced systolic peak velocities and extended systolic time allow optimized timed catheterizations. Peak systolic velocity and systolic time allow diagnostic classifications that enable patients without known TxCAD but with high risk for catheterization to be spared routine angiographies.
BACKGROUND: The coxsackievirus and adenovirus receptor (CAR) was identified as a common cellular receptor for both viruses, but its biological and pathogenic relevance is uncertain. Knowledge of CAR localization in the human cardiovascular system is limited but important with respect to CAR-dependent viral infections and gene transfer using CAR-dependent viral vectors. METHODS AND RESULTS: Explanted failing hearts from 13 patients (8 with dilated cardiomyopathy [DCM] and 5 with other heart diseases [non-DCM]) and normal donor hearts (n=7) were investigated for the expression levels and subcellular localization of CAR and the adenovirus coreceptors alpha(v)beta(3) and alpha(v)beta(5) integrins. CAR immunoreactivity was very low in normal and non-DCM hearts, whereas strong CAR signals occurred at the intercalated discs and sarcolemma in 5 of the 8 DCM hearts (62.5%); these strong signals colocalized with both integrins. In all hearts, CAR was detectable in subendothelial layers of the vessel wall, but not on the luminal endothelial surface, and on interstitial cells. Human CAR (hCAR) expressed in rat cardiomyocytes was targeted to cell-cell contacts, which resembled CAR localization in DCM hearts and resulted in 15-fold increased adenovirus uptake. CONCLUSIONS: Low hCAR abundance may render normal human myocardium resistant to CAR-dependent viruses, whereas re-expression of hCAR, such as that observed in DCM, may be a key determinant of cardiac susceptibility to viral infections. Asymmetric expression of hCAR in the vessel wall may be an important determinant of adenovirus tropism in humans. hCAR subcellular localization in human myocardium and hCAR targeting to cell-cell contacts in cardiomyocyte cultures suggest that hCAR may play a role in cell-cell contact formation.
BACKGROUND: Cardiac troponin I and T (cTnI and cTnT) are sensitive and specific markers of myocardial damage. We evaluated them for the selection of heart donors and as predictors of early graft failure after heart transplantation. METHODS: cTnI, cTnT, myoglobin, and creatine kinase (CK) levels and its isoenzyme MB (CKMB) activity and mass were measured in serum samples immediately before opening the pericardium from 126 consecutive brain-dead multi-organ donors over 10 years of age inspected by our harvesting team. Donors with serum creatinine >2.0 mg/dL (n=6) were excluded from the analysis. Donors for high-urgency status recipients (n=2) were also excluded. The remaining donors were retrospectively divided into three groups: group I (n=68), grafts with good function; group II (n=11), grafts with impaired function; and group III (n=39), grafts not accepted for transplantation. RESULTS: No differences in donor and recipient characteristics were found among the groups. The mean values of cTnI (0.36+/-0.88 microg/L, 4.45+/-3.28 microg/L, and 3.02+/-7.88 micog/L, respectively) and cTnT (0.016+/-0.029 microg/L, 0.134+/-0.114 microg/L, and 0.123+/-0.245 microg/L, respectively) were lower in group I when compared with groups II or III (cTnI: P<0.0001, P=0.018; cTnT: P<0.0001, P=0.012). The cTnI value was higher in group II compared with group III (P=0.023). The cTnT values were similar in groups II and III. A cTnI value >1.6 microg/L as a predictor of early graft failure had a specificity of 94%, and a cTnT value of >0.1 microg/L had a specificity of 99%. The odds ratio for the development of acute graft failure after heart transplantation was 42.7 for donors with cTnI >1.6 microg/L and 56.9 for donors with cTnT >0.1 microg/L. No differences of myoglobin, CKMB activity, or CKMB/CK ratio were found among the groups. CONCLUSIONS: Significantly higher cTnI and cTnT values were found in peripheral blood at the time of explantation in donors of hearts with subsequently impaired graft function and in not accepted donors. cTnI and cTnT are useful as additional parameters for heart donor selection.
Naturally occurring antisense RNA has the potential to form a duplex with its complementary sense mRNA, thereby regulating protein expression. Previously, we demonstrated considerable amounts of endogenous antisense RNA for both alpha- and beta-myosin heavy chain (MHC) in rat heart suggesting a role in posttranscriptional MHC-regulation (Luther et al. [1997] J Mol Cell Cardiol 29(1):27-35). To evaluate whether antisense RNA is also involved in MHC regulation in human heart we analyzed ventricular myocardium transcripts in nonfailing hearts (n=3) and hearts from patients undergoing heart transplantation (n=5). Investigation of RNA by reverse transcription polymerase chain reaction (RT-PCR) detected an antisense RNA transcript for beta-MHC but none for alpha-MHC. Northern blot analysis of normal and failing hearts detected sense mRNA for beta-MHC, but not alpha-MHC suggesting no functionally relevant levels of alpha-MHC mRNA exist in the human ventricle. The results describe-for the first time-the existence of endogenous polyadenylated MHC antisense transcripts in the human heart. The potential effect of attenuating translation was shown in an in vitro translation assay using a synthetic antisense-oligonucleotide derived from the sequence of the naturally occurring antisense RNA.
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To date, one approach to tissue engineering has been to develop in vitro conditions to ultimately fabricate functional cardiovascular structures prior to final implantation. In our current experiment, we developed a new pulsatile flow system that provides biochemical and biomechanical signals to regulate autologous patch-tissue development in vitro. The newly developed patch bioreactor is made of Plexiglas and is completely transparent (Mediport Kardiotechnik, Berlin). The bioreactor is connected to an air-driven respirator pump, and the cell culture medium continuously circulates through a closed-loop system. We thus developed a closed-loop, perfused bioreactor for long-term patch-tissue conditioning, which combines continuous, pulsatile perfusion and mechanical stimulation by periodically stretching the tissue-engineered patch constructs. By adjusting the stroke volume, the stroke rate, and the inspiration/expiration time of the ventilator, it allows various pulsatile flows and different levels of pressure. The whole system is a highly isolated cell culture setting, which provides a high level of sterility, gas supply, and fits into a standard humidified incubator. The bioreactor can be sterilized by ethylene oxide and assembled with a standard screwdriver. Our newly developed bioreactor provides optimal biomechanical and biodynamical stimuli for controlled tissue development and in vitro conditioning of an autologous tissue-engineered patch.