Thorsten Wahlers

Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis

Oxidation products of low-density lipoproteins have been suggested to promote inflammation during atherogenesis, and reticulocyte-type 15-lipoxygenase has been implicated to mediate this oxidation. In addition, the 5-lipoxygenase cascade leads to formation of leukotrienes, which exhibit strong proinflammatory activities in cardiovascular tissues. Here, we studied both lipoxygenase pathways in human atherosclerosis. The 5-lipoxygenase pathway was abundantly expressed in arterial walls of patients afflicted with various lesion stages of atherosclerosis of the aorta and of coronary and carotid arteries. 5-lipoxygenase localized to macrophages, dendritic cells, foam cells, mast cells, and neutrophilic granulocytes, and the number of 5-lipoxygenase expressing cells markedly increased in advanced lesions. By contrast, reticulocyte-type 15-lipoxygenase was expressed at levels that were several orders of magnitude lower than 5-lipoxygenase in both normal and diseased arteries, and its expression could not be related to lesion pathology. Our data support a model of atherogenesis in which 5-lipoxygenase cascade-dependent inflammatory circuits consisting of several leukocyte lineages and arterial wall cells evolve within the blood vessel wall during critical stages of lesion development. They raise the possibility that antileukotriene drugs may be an effective treatment regimen in late-stage disease.

Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30 000 patients

AIMS To determine the strength of evidence for preoperative statin use for prevention of adverse postoperative outcomes in patients undergoing cardiac surgery. METHODS AND RESULTS After literature search in major databases, 19 studies were identified [three RCT (randomized prospective clinical trials), 16 observational] that reported outcomes of 31 725 cardiac surgery patients with (n = 17 201; 54%) or without (n = 14 524; 46%) preoperative statin therapy. Outcomes that were analysed included early all-cause mortality (30-day mortality), myocardial infarction (MI), atrial fibrillation (AF), stroke and renal failure. Odds ratio (OR) with 95% confidence intervals (95%CI) were reported using fixed or random effect models and publication bias was assessed. Preoperative statin therapy resulted in a 1.5% absolute risk reduction (2.2 vs. 3.7%; P < 0.0001) and 43% odds reduction for early all-cause mortality (OR 0.57; 95%CI: 0.49-0.67). A significant reduction (P < 0.01) in statin pretreated patients was also observed for AF (24.9 vs. 29.3%; OR 0.67, 95%CI: 0.51-0.88), stroke (2.1 vs. 2.9%, OR 0.74, 95%CI: 0.60-0.91), but not for MI (OR 1.11; 95%CI: 0.93-1.33) or renal failure (OR 0.78, 95%CI: 0.46-1.31). Funnel plot and Eggers regression analysis (P = 0.60) excluded relevant publication bias. CONCLUSION Our meta-analysis provides evidence that preoperative statin therapy exerts substantial clinical benefit on early postoperative adverse outcomes in cardiac surgery patients, but underscores the need for RCT trials.

Regulation of the Human Cardiac Mitochondrial Ca2+ Uptake by 2 Different Voltage-Gated Ca2+ Channels

Background— Impairment of intracellular Ca2+ homeostasis and mitochondrial function has been implicated in the development of cardiomyopathy. Mitochondrial Ca2+ uptake is thought to be mediated by the Ca2+ uniporter (MCU) and a thus far speculative non-MCU pathway. However, the identity and properties of these pathways are a matter of intense debate, and possible functional alterations in diseased states have remained elusive. Methods and Results— By patch clamping the inner membrane of mitochondria from nonfailing and failing human hearts, we have identified 2 previously unknown Ca2+-selective channels, referred to as mCa1 and mCa2. Both channels are voltage dependent but differ significantly in gating parameters. Compared with mCa2 channels, mCa1 channels exhibit a higher single-channel amplitude, shorter openings, a lower open probability, and 3 to 5 subconductance states. Similar to the MCU, mCa1 is inhibited by 200 nmol/L ruthenium 360, whereas mCa2 is insensitive to 200 nmol/L ruthenium 360 and reduced only by very high concentrations (10 &mgr;mol/L). Both mitochondrial Ca2+ channels are unaffected by blockers of other possibly Ca2+-conducting mitochondrial pores but were activated by spermine (1 mmol/L). Notably, activity of mCa1 and mCa2 channels is decreased in failing compared with nonfailing heart conditions, making them less effective for Ca2+ uptake and likely Ca2+-induced metabolism. Conclusions— Thus, we conclude that the human mitochondrial Ca2+ uptake is mediated by these 2 distinct Ca2+ channels, which are functionally impaired in heart failure. Current properties reveal that the mCa1 channel underlies the human MCU and that the mCa2 channel is responsible for the ruthenium red–insensitive/low-sensitivity non-MCU–type mitochondrial Ca2+ uptake.

Statins for prevention of atrial fibrillation after cardiac surgery: a systematic literature review

OBJECTIVE To determine the strength of evidence of preoperative statin therapy for prevention of atrial fibrillation after cardiac surgery. METHODS A meta-analysis was performed of randomized controlled trials and observational trials reporting the impact of preoperative statin therapy on the incidence of any type and new-onset atrial fibrillation after cardiac surgery. Unadjusted and adjusted treatment effects (odds ratio, 95% confidence intervals) were pooled using a random-effects model, and publication bias was assessed. RESULTS Thirteen studies were identified (3 randomized controlled trials, 10 observational trials) that reported the incidence of postoperative atrial fibrillation in 17,643 patients having cardiac surgery with (n = 10,304; 58%) or without (n = 7339; 42%) preoperative statin use. New-onset atrial fibrillation was reported in a total of 7855 patients. Postoperative incidence rates for any or new-onset atrial fibrillation were 24.6% and 29.9%, respectively. Preoperative statin use resulted in a 22% and 34% unadjusted odds reduction for any atrial fibrillation (odds ratio, 0.78; 95% confidence interval, 0.67-0.90) or new-onset atrial fibrillation (odds ratio, 0.66; 95% confidence interval, 0.51-0.84) after surgery (P < .001). Relevant publication bias and an unequal distribution of confounding variables favoring patients treated with statins were identified. Nevertheless, the beneficial actions of statins on atrial fibrillation persisted after pooled analysis of risk-adjusted treatment effects from randomized controlled trials and observational trials (any atrial fibrillation-odds ratio, 0.64; 95% confidence interval, 0.48-0.87; new-onset atrial fibrillation-odds ratio, 0.66; 95% confidence intervals, 0.48-0.89; P < .01). CONCLUSION Our meta-analysis provides evidence that preoperative statin therapy is associated with a reduction in the incidence of atrial fibrillation after cardiac surgery.

Marginal donor grafts in heart transplantation: lessons learned from 25 years of experience

Heart transplantation represents an established procedure in end‐stage heart failure patients and results in satisfying long‐term results. However, this surgical therapy is continuously limited by severe and progredient donor organ shortage in the last years. Therefore, adequate and optimal utilization of all suitable donor organs is mandatory to increase graft availability. Evidence exists that certain ‘standard’ donor criteria can be significantly liberalized to increase the available donor pool by accepting ‘Marginal Donors’ who would, under conventional transplant guidelines, be declined as potential organ donors. The aim of this study was to review the available literature with regard to definitions and experiences with ‘marginal’ donor hearts and to discuss critically the controversies of numerous entities of donor criteria, which might be successfully liberalized. This review is thought to give an up‐to‐date overview of a modern concept of cardiac allograft acceptance based on a 25‐year experience with heart transplantation.

Inhibition of atrial fibrillation by pulmonary vein isolation and auricular resection : experimental study in a sheep model

OBJECTIVE The MAZE procedure has proven effective for surgically treating atrial fibrillation, but its acceptance has been limited due to the complex dissection pattern. A new simplified operative technique, that comprises two important components of the MAZE procedure, has been evaluated in an established animal model of induced sustained atrial fibrillation. METHODS In eight sheep, median sternotomy was performed for cardiopulmonary bypass via femoral and bicaval cannuiation. Bipolar atrial and ventricular electrodes (16) were applied for computerized EKG-sampling. Atrial fibrillation was induced during continuous theophylline infusion (0.5 mg/kg/min) by repetitive (10x) biatrial stimulation. Atrial response was monitored and mapped. The operative procedure was accomplished in induced ventricular fibrillation: Right and left atrial appendices were resected and a circumferential transmural incision around all pulmonary veins was performed and closed. After defibrillation, the atria were stimulated again using the above protocol and EKGs were sampled. RESULTS Sustained atrial fibrillation was inducible in all animals (80 stimulation episodes, median duration 31 s, 6 incessant episodes) prior to dissection. Post resection of the atrial appendices and pulmonary vein isolation, atrial fibrillation was not inducible in any of the eight animals (80 stimulation episodes). A significant interatrial (104 +/- 13 ms) and atrioventricular (208 +/- 19 ms) conduction delay was observed post dissection. CONCLUSION We conclude that the described procedure is effective for the inhibition of sustained atrial fibrillation in morphologically unaltered atria. The operative approach involves less dissection than the MAZE procedure, which could facilitate its use in concomitant mitral procedures. The clinical significance of the observed AV-Delay has to be evaluated.

Transapical aortic valve implantation with a self-expanding anatomically oriented valve

AIMS The Medtronic Engager™ aortic valve bioprosthesis is a self-expanding valve with support arms facilitating anatomically correct positioning and axial fixation. Valve leaflets, made of bovine pericardium, are mounted on a Nitinol frame. Here, we report the first in man study with this new implant (Trial Identifier NCT00677638). METHODS AND RESULTS Thirty patients (mean age 83.4 ± 3.8 years; 83% female) with tricuspid aortic valve stenosis were included in the study. Mean logistic EuroSCORE was 23.4 ± 11.9. Mean aortic annulus diameter was 21.8 ± 1.4 mm. For this study, the Engager was available in only one size (23 mm), to fit aortic annuli of 19-23 mm. Standard transapical valve implantation was performed using pre-dilation of the aortic valve and rapid ventricular pacing during balloon valvuloplasty and most valve deployments. Accurate valve placement was achieved in 29/30 cases (97%). Post-implant peak-to-peak gradient was 13.3 ± 9.3 mmHg. In 80% of the patients, no more than grade I paravalvular leakage was observed, in 13% grades I-II and in 3% grade II. Three patients (10%) required permanent pacemaker implantation for higher-degree or complete atrioventricular block. Four dissections (13%) occurred during positioning of the valve and were treated surgically in three cases. Thirty-day and in-hospital mortality were 20% and 23%, respectively, and 6-month survival was 56.7%. No structural failure occurred for up to 1 year. CONCLUSION This series established the feasibility of implanting a novel self-expanding transapical aortic valve prosthesis predictably into an anatomically correct position. Observed complications led to complete redesign of the delivery system for upcoming clinical studies with the goal of establishing safety and performance.

Chronic thromboembolic pulmonary hypertension (CTEPH): Updated Recommendations of the Cologne Consensus Conference 2011 ✩

In the 2009 European Guidelines on the diagnosis and treatment of pulmonary hypertension (PH), one section covers aspects of pathophysiology, diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The practical implementation of the guidelines for this disease is of crucial importance, because CTEPH is a subset of PH which can potentially be cured by pulmonary endarterectomy (PEA). Nowadays, CTEPH is commonly underdiagnosed and not properly managed. Any patient with unexplained PH should be evaluated for the presence of CTEPH, and a ventilation/perfusion (V/Q) lung scan is recommended as screening method of choice. If the V/Q scan or CT angiography reveals signs of CTEPH, the patient should be referred to a specialized center with expertise in the medical and surgical management of this disease. Every case has to be reviewed by an experienced PEA surgeon for the assessment of operability. In this updated recommendation, important contents of the European guidelines were commented, and more recent information regarding diagnosis and treatment was added.

Extraanatomic thoracic aortic bypass grafts : Indications, techniques, and results

OBJECTIVE Even in the age of extensive aortic replacement special circumstances may warrant the insertion of extraanatomic thoracic aortic bypass grafts. Our experience with 17 patients is analyzed. METHODS Between 1988 and 1994, ten female and seven male patients (mean age 37.5 years, range 9-69 years) were treated for the following indications: (1) complex CoA (n = 5); (2) reoperation for CoA (n = 6); (3) extensive aortic occlusive disease (n = 4); and (4) complicated aneurysm (n = 2). Routing of the grafts was: ascending-descending aorta (8); ascending-abdominal aorta (4); left subdavian artery- descending aorta (2); descending-descending aorta (2); and descending-abdominal aorta (1). Eight procedures were reoperations. In four patients concomitant cardiac operations were performed: one aortic valve replacement, one patch plasty of the LCA, and two composite graft replacements of aortic valve and ascending aorta, one of them with CABG. RESULTS Three early deaths occurred. two after emergency operation in thoracic aneurysm under dire conditions (one perforation, one infection), one after ascending-abdominal aortic grafting with multiple branch revascularization. The underlying pathology was relieved successfully in all 14 survivors. In the two patients with concomitant aortic valve and isthmic stenosis, critical anterior motion of the mitral valve, presumably because of the massive afterload reduction of the left ventricle, complicated the perioperative course. One patient was reoperated because of aneurysm 4 years after descending-descending aortic grafting for complex CoA with poststenotic dilatation. CONCLUSIONS In complex aortic coarctation or hypoplasia extraanatomic bypass grafts are expedient and effective procedures, especially for reoperation. Their use in the treatment of aneurysmal lesions remains an exception.

Mechanism of luminal narrowing in cardiac allograft vasculopathy : Inadequate vascular remodeling rather than intimal hyperplasia is the major predictor of coronary artery stenosis

BACKGROUND Despite increasing knowledge about degree and distribution pattern of intimal hyperplasia in cardiac allograft vasculopathy, coronary artery remodeling is only poorly understood in this disease. METHODS To evaluate vascular geometry, intravascular ultrasound was used to characterize 57 advanced lesions in 35 consecutive transplant recipients. Lumen, plaque, and vessel area in these target lesions were compared with proximal and distal reference sites. RESULTS AND CONCLUSIONS Vascular remodeling by compensatory local vessel enlargement (positive remodeling) and circumscript vascular constriction (negative remodeling) could be demonstrated. Plaque area in stenotic lesions was significantly increased compared with the mean reference site (5.6+/-3.0 mm2 versus 2.8+/-1.5 mm2, p < 0.001); however, inadequate compensatory enlargement rather than intimal hyperplasia was shown to be the most important predictor of luminal obstruction (r = 0.77, p < 0.001).