M. Weyand

First successful implantation of a biodegradable metal stent into the left pulmonary artery of a preterm baby

Stent implantation in the youngest patients with a congenital heart disease implicates limitations concerning further vessel growth, the need of staged redilation, and later surgical removal. The search to overcome these restrictions led to open stent designs, with a wide adaptability to the vessel growth and recently to the development of bioabsorbable stent materials. A preterm baby born at 26 weeks of gestation was referred to our clinic following inadvertent ligation of the left pulmonary artery. Despite efficient debanding, the left lung perfusion was absent. Implantation of a biodegradable 3 mm magnesium stent was performed in a hybrid procedure when the baby weighed 1.7 kg. Reperfusion of the left lung was established and persisted throughout the 4‐month follow‐up period during which the gradual degradation process of the stent completed. Additional interventions, should they become necessary, seem not to be limited. Despite the small size of the baby, the degradation process was clinically well tolerated. The mechanical and degradation characteristics of the magnesium stent proved to be adequate to secure reperfusion of the previously occluded left pulmonary artery. Bioabsorbable stents with different diameters may help develop new strategies in the therapy of vessel stenosis in pediatric patients.

Systematic assessment of atypical deletions reveals genotype–phenotype correlation in 22q11.2

Introduction: Clinical variability associated with the common 22q11.2 microdeletion is well known, and has led to a broad application of FISH diagnostics with probes for loci TUPLE1 or D22S75 (N25), although, rarely reported atypical deletions associated with the same phenotypic spectrum would not be discovered by these probes. As most types of 22q11.2 deletions occur between low copy repeats within the region (LCR22), we assumed that atypical deletions should be more common than has been reported. To address this question and the possibility of a deletion size related genotype-phenotype correlation, we systematically assessed the frequency of typical and atypical 22q11.2 deletions in a large cohort of patients. Methods: We used a set of 10 fluorescent in situ hybridisation (FISH) DNA probes, capable of detecting all reported and hypothetical deletions between the LCR22, and analysed 350 patients. Deletion sizes in atypical deletions were established by use of further FISH probes. Frequency of certain atypical deletions was analysed in controls by FISH and quantitative PCR. Results: Patients with conotruncal heart defects (ctCHD) and with typical VCFS phenotype showed the common 3 Mb or nested 1.5 Mb deletions (in 18.5% and 78.6%, respectively), but no atypical deletion, while 5% (3/63) of patients with a mildly suggestive, atypical phenotype showed atypical distal deletions, which were not detected in patients with mental retardation of unknown origin or in healthy controls. Discussion: These statistically significant differences demonstrate that atypical distal 22q11.2 deletions are very uncommon in patients with ctCHDs, while atypical congenital heart defects and mild dysmorphism are recognisable feature of atypical distal deletions. Further phenotype-genotype analysis disclosed association of significant developmental delay with the distal part of the common deletion region, and choanal atresia and atypical CHDs with the adjacent distal deletion region.

Comparison of Dual Source Computed Tomography Versus Intravascular Ultrasound for Evaluation of Coronary Arteries at Least One Year After Cardiac Transplantation

This study evaluated the ability of dual-source computed tomography (DSCT) to detect coronary allograft vasculopathy (CAV) in heart transplant recipients using intravascular ultrasound (IVUS) as the standard of reference. Thirty patients with heart transplants (81% men, mean age 40 years) underwent DSCT (330-ms gantry rotation, 2 x 64 x 0.6-mm collimation, 60- to 80-ml contrast agent, no additional beta blockers) before invasive coronary angiography including IVUS of 1 vessel. Detection of CAV by DSCT was qualitatively defined as the presence of any coronary plaque. Mean heart rate during dual-source computed tomographic scanning was 80 +/- 14 beats/min. Four hundred fifty-nine segments with a vessel caliber >or=1.5 mm according to quantitative coronary angiography were evaluated in 30 patients. Of these, 96% were considered to have excellent or good image quality. IVUS detected CAV in 17 of 30 patients (57%) and in 41 of 110 coronary segments (37%). Compared to IVUS, sensitivity, specificity, positive and negative predictive values for the detection of CAV by DSCT were 85%, 84%, 76%, and 91%, respectively. In conclusion, DSCT permits the investigation of transplant recipients concerning the presence of CAV with good image quality and high diagnostic accuracy.

A method to determine suitable fluoroscopic projections for transcatheter aortic valve implantation by computed tomography.

BACKGROUND In transcatheter aortic valve implantation (TAVI), optimal selection of fluoroscopic projections that permit orthogonal visualization of the aortic valve plane is important but may be difficult to achieve. OBJECTIVE We developed and validated a simple method to predict suitable fluoroscopic projections on the basis of cardiac CT datasets. METHODS In 75 consecutive patients that underwent TAVI, angulations in which a 35-mm thick maximum intensity projection would render all aortic valve calcium into 1 plane were determined by manual interaction with contrast-enhanced dual-source CT datasets. TAVI operators used the predicted angulation for the first aortic angiogram and performed additional aortic angiograms if no satisfactory view of the aortic valve plane was obtained. Predicted angulations were compared with the angulation used for valve implantation. Radiation exposure and contrast use was compared between patients with accurate prediction of fluoroscopic angulations by CT and patients in whom CT failed to predict a suitable view. RESULTS The mean difference between the predicted angulation according to CT and the angulation used for implantation was 3 ± 6 degrees. CT predicted a suitable angulation (<5-degree deviation) in 63 of 75 cases (84%). The mean number of aortic angiograms acquired in patients with correct prediction (1.02 ± 0.1) was significantly lower than in patients with incorrect prediction of the implantation angle by CT (3.0 ± 1.7; P < 0.001). Contrast agent required for the entire TAVI procedure was lower in patients with correct prediction (72 ± 36 mL vs 106 ± 39 mL; P = 0.001). CONCLUSION CT permits prediction of suitable angulations for TAVI in most cases.

Comparison of Plasma and Urine Biomarker Performance in Acute Kidney Injury

Background New renal biomarkers measured in urine promise to increase specificity for risk stratification and early diagnosis of acute kidney injury (AKI) but concomitantly may be altered by urine concentration effects and chronic renal insufficiency. This study therefore directly compared the performance of AKI biomarkers in urine and plasma. Methods This single-center, prospective cohort study included 110 unselected adults undergoing cardiac surgery with cardiopulmonary bypass between 2009 and 2010. Plasma and/or urine concentrations of creatinine, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), liver fatty acid-binding protein (L-FABP), kidney injury molecule 1 (KIM1), and albumin as well as 15 additional biomarkers in plasma and urine were measured during the perioperative period. The primary outcome was AKI defined by AKIN serum creatinine criteria within 72 hours after surgery. Results Biomarkers in plasma showed markedly better discriminative performance for preoperative risk stratification and early postoperative (within 24h after surgery) detection of AKI than urine biomarkers. Discriminative power of urine biomarkers improved when concentrations were normalized to urinary creatinine, but urine biomarkers had still lower AUC values than plasma biomarkers. Best diagnostic performance 4h after surgery had plasma NGAL (AUC 0.83), cystatin C (0.76), MIG (0.74), and L-FAPB (0.73). Combinations of multiple biomarkers did not improve their diagnostic power. Preoperative clinical scoring systems (EuroSCORE and Cleveland Clinic Foundation Score) predicted the risk for AKI (AUC 0.76 and 0.71) and were not inferior to biomarkers. Preexisting chronic kidney disease limited the diagnostic performance of both plasma and urine biomarkers. Conclusions In our cohort plasma biomarkers had higher discriminative power for risk stratification and early diagnosis of AKI than urine biomarkers. For preoperative risk stratification of AKI clinical models showed similar discriminative performance to biomarkers. The discriminative performance of both plasma and urine biomarkers was reduced by preexisting chronic kidney disease.

Noninvasive Control of Adequate Cerebral Oxygenation During Low‐Flow Antegrade Selective Cerebral Perfusion on Adults and Infants in the Aortic Arch Surgery

Abstract  Real‐time readings of the regional oxygen saturation (rSO2) using near‐infrared spectroscopy (NIRS) during the aortic arch surgery can provide an early detection of perfusion or oxygenation abnormalities. Background: Aortic arch repair techniques using low‐flow antegrade selective cerebral perfusion have been standardized to a certain degree. However, some of the often‐stated beneficial effects have never been proven. Especially, the existence of an adequate continuous flow in both cerebral hemispheres during the surgical procedure still remains unclear as the monitoring of an effective perfusion remains a nonstandardized technique. Methods: Seventeen patients underwent surgical reconstruction of the aortic arch due to aortic aneurysm surgery (adult group n = 8 patients) or of the hypoplastic aortic arch due to hypoplastic left heart syndrome (HLHS) or aortic coarctation (infant group n = 9 patients) under general anesthesia and mild hypothermia (adult group 28 °C; infant group 25 °C). Mean weights were 92.75 ± 14.00 kg and 4.29 ± 1.32 kg, and mean ages were 58.25 ± 10.19 years and 55.67 ± 51.11 days in the adult group and the infant group, respectively. The cerebral O2 saturation measurement was performed by continuous plotting of the somatic reflectance oximetry of the frontal regional tissue on both cerebral hemispheres (rSO2, INVOS®; Somanetics Corporation, Troy, MI, USA). Results: During low‐flow antegrade perfusion via innominate artery, continuous plots with similar values of O2 saturation (rSO2) in both cerebral hemispheres were observed, whereas a decrease in the rSO2 values below the desaturation threshold correlated with a displacement or an incorrect positioning of the arterial cannula in the right subclavian artery. Conclusions: Continuous monitorization of the cerebral O2 saturation during aortic arch surgery in adults and infants is a feasible technique to control an adequate cannula positioning and to optimize clinical outcomes avoiding neurological complications related to cerebral malperfusion.

Inhibition of aldehyde dehydrogenase type 2 attenuates vasodilatory action of nitroglycerin in human veins

Recent studies suggest that the mitochondrial aldehyde dehydrogenase (ALDH)2 is involved in vascular bioactivation of nitroglycerin (GTN). However, neither expression of ALDH2 nor its functional role in GTN bioactivation has been reported for the main drug target in humans, namely capacitance vessels. We investigated whether ALDH2 is expressed in human veins and whether inhibition of the enzyme attenuates nitroglycerin effects in these vessels. We determined expression of ALDH2 and dehydrogenase activity in human veins by reverse transcriptase‐polymerase chain reaction, Western blotting, and immunofluorescence microscopy. In vitro contraction experiments were performed in the presence or absence of the ALDH inhibitors chloral hydrate, cyanamide, and ethoxycyclopropanol. Concentration response curves were determined for the α‐agonist phenylephrine, nitroglycerin, and the direct NO donor diethylamine NONOate (DEA‐NONOate). ALDH2 expression was largely confined to smooth muscle cells as determined by confocal immunofluorescence microscopy. Contractile responses to phenylephrine were unaffected by all ALDH inhibitors tested. In clear contrast, the ALDH inhibitors significantly reduced the potency of nitroglycerin by approximately 1 order of magnitude (T<0.01). Neither of the inhibitors affected the potency of the direct NO donor DEA‐NONOate, which ruled out nonspecific effects on the NO signaling cascade. In human capacitance vessels, ALDH2 is a key enzyme in the biotransformation of the frequently used antianginal drug nitroglycerin.—Huellner, M. W., Schrepfer, S., Weyand, M., Weiner, H., Wimplinger, I., Eschenhagen, T., Rau, T. Inhibition of aldehyde dehydrogenase type 2 attenuates vasodilatory action of nitroglycerin in human veins. FASEB J. 22, 2561–2568 (2008)

Combination of clopidogrel and everolimus dramatically reduced the development of transplant arteriosclerosis in murine aortic allografts

Our group has shown that platelet inhibition with clopidogrel, an antagonist of the P2Y12 adenosine diphosphate receptor on platelets, reduced the formation of transplant arteriosclerosis. The aim of this study was to investigate whether a combination of cyclosporin or everolimus with clopidogrel has a beneficial effect on the development of transplant arteriosclerosis. Fully MHC mismatched C57Bl/6 (H2b) donor aortas were transplanted into CBA.J (H2k) recipients and mice received either clopidogrel alone (1 mg/kg/day) or in combination with cyclosporin (2 mg/kg/day) or everolimus (0.05 mg/kg/day). Grafts were analysed by histology and morphometry on day 30 after transplantation. In mice treated with clopidogrel alone, transplant arteriosclerosis was significantly reduced [intima proliferation 56 ± 11% vs. 81 ± 7% (control)/n = 7]. Daily application of everolimus reduced the development of transplant arteriosclerosis compared with untreated controls [intima proliferation of 29 ± 9% vs. 81 ± 7% (control)/n = 7]. Strikingly, combination of clopidogrel and everolimus almost abolished the formation of transplant arteriosclerosis [intima proliferation: 11 ± 8% vs. 81 ± 7% (control)/n = 7]. By contrast, combination of cyclosporin and clopidogrel compared with clopidogrel alone showed no additive effect. These results demonstrate that combination of platelet‐ and mammalian target of Rapamycin‐inhibition can dramatically reduce the development of transplant arteriosclerosis.

Inhibition of TNF‐α reduces transplant arteriosclerosis in a murine aortic transplant model

Experimental and clinical data provide evidence that TNF‐α contributes to acute and chronic allograft rejection. In this study, we explored the effect of TNF‐α blockade using the chimeric monoclonal antibody infliximab on the development of transplant arterisoclerosis in a fully mismatched aortic allograft model. Post‐transplant treatment of CBA (H2k) recipients with 250 μg infliximab (cumulative dose 1.25 mg) reduced luminal occlusion of C57Bl/6 (H2b) aortic grafts on day 30 from 77 ± 5% in untreated controls to 52 ± 6%. Increasing the dose of anti‐TNF‐α antibody had no further beneficial effect. Treatment with human control immunoglobulin had no effect on intima proliferation. Under TNF‐α blockade, ICAM‐1 and PDGF mRNA expression within the grafts was strongly reduced, whereas iNOS expression was enhanced. The data show that TNF‐α blockade using infliximab can reduce the development of transplant arteriosclerosis in fully mismatched murine aortic grafts.

Atherosclerotic inflammation triggers osteogenic bone transformation in calcified and stenotic human aortic valves: Still a matter of debate

Sclerotic calcification of the aortic valve is a common disease in advanced age. However, pathophysiologic processes leading to valve calcifications are poorly understood. Transformation of atherosclerotic triggers to osteogenic differentiation is controversially discussed and is thought as a trigger of bone transformation in end stage disease. This study focuses on the transcriptional gene-profiling of severe calcified stenotic human aortic valves to clarify the molecular basis of the pathophysiological process. We collected severely calcified and stenotic human aortic valves (CSAV) with (CSAV+, n=10) and without (CSAV-, n=10) at least 4 weeks of statin pre-treatment prior to valve replacement and investigated transcriptional steady-state gene-profiling by using micro array technique and GAPDH-adjusted PCR for confirmation. Results were compared with findings in non-sclerotic aortic valves: C (n=6). Various parameters of inflammation were significantly up regulated as compared to C: eotaxin3, monokine induced by gamma-interferon, vascular adhesion protein-1 (VAP-1), peroxisome proliferative activated receptor-alpha or transforming growth factor beta 1 (TGF beta 1). Except for TGF beta 1 and VAP-1, statin pre-treatment neutralized altered gene expression. Genes of osteogenic bone transformation (tenascin C, bone sialoprotein, Cbfa1, Osteocalcin, Beta-catenin, Sox- and Cyclin-genes) were found unaltered in their expression in both, CSAV- or CSAV+ in comparison to C. This study shows continuing atherosclerotic inflammation on CSAV. Additionally, no evidence of initiated osteoblastic differentiation process was found. Pre-treatment of patients with statins partially neutralized the gene pattern of inflammation on the aortic valves. This suggests that there are potent benefits of statins on early development of inflammation on calcified aortic valves.