Bastian Schmack

Role of Heart Rate Reduction in the Prevention of Experimental Heart Failure: Comparison Between If-Channel Blockade and β-Receptor Blockade

To investigate whether heart rate reduction via If-channel blockade and &bgr;-receptor blockade prevents left ventricular (LV) dysfunction, we studied ivabradine and metoprolol in angiotensin II–induced heart failure. Cardiac dysfunction in C57BL/6J mice was induced by implantation of osmotic pumps for continuous subcutaneous dosing of angiotensin II (1.8 mg/kg per day SC) over a period of 3 weeks. Ivabradine (10 mg/kg per day) and metoprolol (90 mg/kg per day), which resulted in similar heart rate reduction, or placebo treatments were simultaneously started with infusion of angiotensin II. After 3 weeks, LV function was estimated by conductance catheter technique, cardiac remodeling assessed by estimation of cardiac hypertrophy, fibrosis, and inflammatory stress response by immunohistochemistry or PCR, respectively. Compared with controls, angiotensin II infusion resulted in hypertension in impaired systolic (LV contractility, stroke volume, end systolic elastance, afterload, index of arterial-ventricular coupling, and cardiac output; P<0.05) and diastolic (LV relaxation, LV end diastolic pressure, &tgr;, and stiffness constant &bgr;; P<0.05) LV function. This was associated with a significant increase in cardiac hypertrophy and fibrosis. Increased cardiac stress was also indicated by an increase in cardiac inflammation and apoptosis. Both ivabradine and metoprolol led to a similar reduction in heart rate. Metoprolol also reduced systolic blood pressure. Ivabradine led to a significant improvement in systolic and diastolic LV function (P<0.05). This was associated with less cardiac hypertrophy, fibrosis, inflammation, and cardiac apoptosis (P<0.05). Metoprolol treatment did not prevent the reduction in cardiac function and adverse remodeling, despite a reduction of the inflammatory stress response. Behind heart rate reduction, additional beneficial cardiac effects contribute to heart failure prevention with If-channel inhibition.

Constrictive pericarditis: risks, aetiologies and outcomes after total pericardiectomy: 24 years of experience

OBJECTIVES Constrictive pericarditis is the result of a spectrum of primary cardiac and non-cardiac conditions. Few data exist on the preoperative risk specific to survival after pericardiectomy. This study was designed to compare the association of aetiology of constrictive pericarditis and other clinical variables, with long-term survival after total pericardiectomy. METHODS A total of 89 patients were studied, who underwent pericardiectomy for constrictive pericarditis at a single surgical centre between 1988 and 2012. Constrictive pericarditis was confirmed by the surgical report. Demographic, pre-, intra- and postoperative data and long-term outcome were investigated. Survival was assessed by the Kaplan-Meier method. RESULTS Aetiology of constrictive pericarditis was idiopathic in 49 patients (55%), prior cardiac surgery in 21 patients (23.6%), tuberculosis in 5 patients (5.6%), radiation treatment in 5 (5.6%), uraemia in 4 (4.5%), inflammation in 3 (3.5%) myocardial infarction in 2 (2.2%), and perioperative mortality was 7%. Seventy-five percent of patients were in New York Heart Association (NYHA) class III-IV, which status significantly improved in long-term survivors (95% in NYHA I-II). Idiopathic constrictive pericarditis had the best prognosis (5-year Kaplan-Meier survival: 81%) followed by post-surgical (50%) and post-radiation pericarditis (no survivors after 5 years). Tuberculosis, myocardial infarction and uraemia have survival rates comparable with idiopathic aetiology. In addition, preoperative NYHA class IV was associated with significantly lower long-term survival. CONCLUSIONS Long-term survival after pericardiectomy for constrictive pericarditis is related to underlying aetiology and overall clinical condition. The relatively good survival with idiopathic constrictive pericarditis emphasizes the safety of pericardiectomy in this subgroup.

Computational fluid dynamics in patients with continuous-flow left ventricular assist device support show hemodynamic alterations in the ascending aorta

OBJECTIVE Increased use of continuous-flow left ventricular assist devices for long-term mechanical support necessitates a better understanding of hemodynamic changes in the native heart and the ascending aorta. By using patient-specific computational models, correlations of potentially adverse hemodynamic conditions with the orientation of the left ventricular assist device outflow graft and their relationship with aortic insufficiency and ischemic events were investigated. METHODS Computed hemodynamic parameters, including wall shear stress, pressure in the ascending aorta, and dissipation of turbulent energy, were correlated with the orientation of the left ventricular assist device graft outflow in 5 patients (4 with the HeartMate II device [Thoratec Corp, Pleasanton, Calif] and 1 with the HeartWare Ventricular Assist Device [HeartWare Inc, Framingham, Mass]; 3 patients experienced moderate aortic insufficiency, and 2 patients experienced ischemic events). Hemodynamic conditions for aortic insufficiency and ischemic events were differentiated by linear discriminant analysis. RESULTS Positive correlations between left ventricular assist device outflow graft orientation and wall shear stress, pressure, and turbulent energy dissipation in the ascending aorta were found (R(2) > 0.68). Linear discriminant analysis indicated a relationship of the velocity magnitude of retrograde flow toward the aortic root with aortic insufficiency and of the turbulent energy and wall shear stress with ischemic events. CONCLUSIONS Computational fluid dynamic simulations using clinical image data indicate altered hemodynamic conditions after left ventricular assist device implantation. Consequently, the left ventricular assist device outflow graft should be placed so the jet of blood is aimed toward the lumen of the aortic arch to avoid turbulences that will increase wall shear stress and retrograde pressure of the aortic root. Further investigations are warranted to confirm these findings in a larger patient cohort.

Influence of LVAD cannula outflow tract location on hemodynamics in the ascending aorta: a patient-specific computational fluid dynamics approach.

To develop a better understanding of the hemodynamic alterations in the ascending aorta, induced by variation of the cannula outflow position of the left ventricular assist device (LVAD) device based on patient-specific geometries, transient computational fluid dynamics (CFD) simulations using the realizable k-&egr;turbulent model were conducted for two of the most common LVAD outflow geometries. Thoracic aortic flow patterns, pressures, wall shear stresses (WSSs), turbulent dissipation, and energy were quantified in the ascending aorta at the location of the cannula outflow. Streamlines for the lateral geometry showed a large region of disturbed flow surrounding the LVAD outflow with an impingement zone at the contralateral wall exhibiting increased WSSs and pressures. Flow disturbance was reduced for the anterior geometries with clearly reduced pressures and WSSs. Turbulent dissipation was higher for the lateral geometry and turbulent energy was lower. Variation in the position of the cannula outflow clearly affects hemodynamics in the ascending aorta favoring an anterior geometry for a more ordered flow pattern. The new patient-specific approach used in this study for LVAD patients emphasizes the potential use of CFD as a truly translational technique.

Comparison of hemodynamics in the ascending aorta between pulsatile and continuous flow left ventricular assist devices using computational fluid dynamics based on computed tomography images.

This study aims to investigate differences in hemodynamic conditions in the thoracic aorta for pulsatile and continuous-flow left ventricular assist devices (LVADs) using computational fluid dynamics (CFD). Patient-specific models were reconstructed from three patients with continuous-flow LVAD (HeartMate II, Thoratec Corporation) and three patients with biventricular assist devices (Excor, Berlin Heart) where only the aortic part was included in the simulations. CFD simulations were performed with constant inflow for the continuous-flow LVADs and time-varying inflow for the pulsatile devices. Differences in flow patterns, wall shear stress (WSS), and dynamic pressure in the ascending aorta were compared for both cases. Retrograde flow patterns were observed in all cases proximal to the location of the outflow cannula anastomosis site. On average, dynamic pressures derived from the retrograde flow velocities were higher in the continuous-flow group with large variations dependent on the angle of the cannula anastomosis relative to the ascending aorta (continuous group: 0.14 ± 0.2 mm Hg, pulsatile group: 0.013 ± 0.008 mm Hg). Elevated WSS contralaterally to the anastomosis site was observed in three of the six models with higher values for the continuous cases. Lower WSS and reduced pressure in the ascending aorta, both favorable hemodynamic conditions, were found in pulsatile versus continuous-flow LVADs by means of CFD. These findings indicate, along with clinical observations reported by others, the superior performance of pulsatile LVADs.

Bioartificial Heart: A Human-Sized Porcine Model – The Way Ahead

Background A bioartificial heart is a theoretical alternative to transplantation or mechanical left ventricular support. Native hearts decellularized with preserved architecture and vasculature may provide an acellular tissue platform for organ regeneration. We sought to develop a tissue-engineered whole-heart neoscaffold in human-sized porcine hearts. Methods We decellularized porcine hearts (n = 10) by coronary perfusion with ionic detergents in a modified Langendorff circuit. We confirmed decellularization by histology, transmission electron microscopy and fluorescence microscopy, quantified residual DNA by spectrophotometry, and evaluated biomechanical stability with ex-vivo left-ventricular pressure/volume studies, all compared to controls. We then mounted the decellularized porcine hearts in a bioreactor and reseeded them with murine neonatal cardiac cells and human umbilical cord derived endothelial cells (HUVEC) under simulated physiological conditions. Results Decellularized hearts lacked intracellular components but retained specific collagen fibers, proteoglycan, elastin and mechanical integrity; quantitative DNA analysis demonstrated a significant reduction of DNA compared to controls (82.6±3.2 ng DNA/mg tissue vs. 473.2±13.4 ng DNA/mg tissue, p<0.05). Recellularized porcine whole-heart neoscaffolds demonstrated re-endothelialization of coronary vasculature and measurable intrinsic myocardial electrical activity at 10 days, with perfused organ culture maintained for up to 3 weeks. Conclusions Human-sized decellularized porcine hearts provide a promising tissue-engineering platform that may lead to future clinical strategies in the treatment of heart failure.

Perfusion-Decellularization of Porcine Lung and Trachea for Respiratory Bioengineering

Decellularization of native organs may provide an acellular tissue platform for organ regeneration. However, decellularization involves a trade-off between removal of immunogenic cellular elements and preservation of biomechanical integrity. We sought to develop a bioartificial scaffold for respiratory tissue engineering by decellularization of porcine lungs and trachea while preserving organ architecture and vasculature. Lung-trachea preparations from 25 German Landrace pigs were perfused in a modified Langendorff circuit and decellularized by an SDC (sodium deoxycholate)-based perfusion protocol. Decellularization was evaluated by histology and fluorescence microscopy, and residual DNA quantified spectrophotometrically and compared with controls. Airway compliance was evaluated by endotracheal intubation and mechanical ventilation to simulate physiological breathing-induced stretch. Structural integrity was evaluated by bronchoscopy and biomechanical stress/strain analysis by measuring passive tensile strength, all compared with controls. Decellularized lungs and trachea lacked intracellular components but retained specific collagen fibers and elastin. Quantitative DNA analysis demonstrated a significant reduction of DNA compared with controls (32.8 ± 12.4 μg DNA/mg tissue vs. 179.7 ± 35.8 μg DNA/mg tissue, P < 0.05). Lungs and trachea decellularized by our perfusion protocol demonstrated increased airway compliance but preserved biomechanical integrity as compared with native tissue. Whole porcine lungs-tracheae can be successfully decellularized to create an acellular scaffold that preserves extracellular matrix and retains structral integrity and three-dimensional architecture to provide a bioartifical platform for respiratory tissue engineering.

Ex vivo lung perfusion - state of the art in lung donor pool expansion.

Lung transplantation remains the gold standard for patients with end-stage lung disease. Nevertheless, the number of suitable donor lungs for the increasing number of patients on the waiting list necessitates alternative tools to expand the lung donor pool. Modern preservation and lung assessment techniques could contribute to improved function in previously rejected lungs. Ex vivo lung perfusion (EVLP) already demonstrated its value in identification of transplantable grafts from the higher risk donor pool. Moreover, lungs from EVLP did not show significantly different postoperative results compared to standard criteria lungs. This could be explained by the reduction of the ischemia-reperfusion injury through EVLP application. The aim of this article is to review technical characteristics and the growing clinical EVLP experience with special attention to EVLP application for donation after cardiac death (DCD) lungs.

Analysis of malignancies in patients after heart transplantation with subsequent immunosuppressive therapy

Objective The aim of this study was to analyze the distribution of malignancies in patients after heart transplantation (HTX) and to evaluate the risk factors including immunosuppressive therapy with regard to the development of malignancies and survival. Special emphasis was placed on the effects of a mammalian target of rapamycin (mTOR) containing immunosuppressive regimen. Methods A total of 381 patients (age ≥18 years) receiving HTX were included in the present analysis. All patients were followed-up at the University of Heidelberg Heart Center, Heidelberg, Germany. Data were retrieved from the Heidelberg Registry for Heart Transplantation being collected between 1989 and 2014. According to center standard, all patients received induction therapy with anti-thymocyte globulin guided by T-cell monitoring since 1994. The initial immunosuppressive regimen consisting of cyclosporine A (CsA) and azathioprine (AZA) was replaced by CsA and mycophenolate mofetil (MMF) in 2001 and by tacrolimus (TAC) and MMF in 2006. Additionally, mTOR inhibitors (everolimus/sirolimus) were applied since 2003. Results Mean recipient age at HTX was 51.2±10.5 years and the mean follow-up period after HTX was 9.7±5.9 years. During follow-up, 130 patients developed a neoplasm (34.1% of total). Subgroup analysis revealed 58 patients with cutaneous malignancy only (15.2%), 56 patients with noncutaneous malignancy only (14.7%), and 16 patients with both cutaneous and noncutaneous malignancy (4.2%). Statistically significant risk factors associated with an increased risk of malignancy after HTX were older age (P<0.0001), male recipients (P=0.0008), dyslipidemia (P=0.0263), diabetes mellitus (P=0.0003), renal insufficiency (P=0.0247), and >1 treated rejection episode (TRE) in the first year after HTX (P=0.0091). Administration of CsA (P=0.0195), AZA (P=0.0008), or steroids (P=0.0018) for >1 year after HTX was associated with increased development of malignancy, whereas administration of MMF (P<0.0001) or mTOR inhibitors (P<0.0001) was associated with a lower risk for development of malignancy. Additionally, 5-year follow-up of cutaneous malignancy recurrence (P=0.0065) and noncutaneous malignancy mortality (P=0.0011) was significantly lower in patients receiving an mTOR inhibitor containing therapy after the development of a malignancy. Conclusion This study highlights the complexity of risk factors including immunosuppression with regard to the development of malignancies after HTX. mTOR-inhibitor-based immunosuppression is associated with a better outcome after HTX, particularly in cases with noncutaneous malignancy.

Utilization of the Organ Care System – A Game-Changer in Combating Donor Organ Shortage

For patients with end-stage heart failure, cardiac transplantation persists to be the gold standard. Nevertheless, the availability of organs remains a main constraint to the treatment. Through mounting usage of ex vivo heart perfusion an increase in organ availability was achieved by reconditioning of organs formerly not regarded as appropriate for transplantation. We propose the future standard application of this state-of-the-art technology to improve the pool of donor organs by evaluating hearts outside standard acceptability criteria.