Matthias Loebe

The 2013 International Society for Heart and Lung Transplantation Guidelines for mechanical circulatory support: Executive summary

Institutional Affiliations Co-chairs Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, Georgia Institute of Technology and Morehouse School of Medicine; Pamboukian SV: University of Alabama at Birmingham, Birmingham, Alabama; Teuteberg JJ: University of Pittsburgh, Pittsburgh, Pennsylvania Task force chairs Birks E: University of Louisville, Louisville, Kentucky; Lietz K: Loyola University, Chicago, Maywood, Illinois; Moore SA: Massachusetts General Hospital, Boston, Massachusetts; Morgan JA: Henry Ford Hospital, Detroit, Michigan Contributing writers Arabia F: Mayo Clinic Arizona, Phoenix, Arizona; Bauman ME: University of Alberta, Alberta, Canada; Buchholz HW: University of Alberta, Stollery Children’s Hospital and Mazankowski Alberta Heart Institute, Edmonton, Alberta, Canada; Deng M: University of California at Los Angeles, Los Angeles, California; Dickstein ML: Columbia University, New York, New York; El-Banayosy A: Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania; Elliot T: Inova Fairfax, Falls Church, Virginia; Goldstein DJ: Montefiore Medical Center, New York, New York; Grady KL: Northwestern University, Chicago, Illinois; Jones K: Alfred Hospital, Melbourne, Australia; Hryniewicz K: Minneapolis Heart Institute, Minneapolis, Minnesota; John R: University of Minnesota, Minneapolis, Minnesota; Kaan A: St. Paul’s Hospital, Vancouver, British Columbia, Canada; Kusne S: Mayo Clinic Arizona, Phoenix, Arizona; Loebe M: Methodist Hospital, Houston, Texas; Massicotte P: University of Alberta, Stollery Children’s Hospital, Edmonton, Alberta, Canada; Moazami N: Minneapolis Heart Institute, Minneapolis, Minnesota; Mohacsi P: University Hospital, Bern, Switzerland; Mooney M: Sentara Norfolk, Virginia Beach, Virginia; Nelson T: Mayo Clinic Arizona, Phoenix, Arizona; Pagani F: University of Michigan, Ann Arbor, Michigan; Perry W: Integris Baptist Health Care, Oklahoma City, Oklahoma; Potapov EV: Deutsches Herzzentrum Berlin, Berlin, Germany; Rame JE: University of Pennsylvania, Philadelphia, Pennsylvania; Russell SD: Johns Hopkins, Baltimore, Maryland; Sorensen EN: University of Maryland, Baltimore, Maryland; Sun B: Minneapolis Heart Institute, Minneapolis, Minnesota; Strueber M: Hannover Medical School, Hanover, Germany Independent reviewers Mangi AA: Yale University School of Medicine, New Haven, Connecticut; Petty MG: University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota; Rogers J: Duke University Medical Center, Durham, North Carolina

Mechanical Circulatory Support for Advanced Heart Failure

Background—Use of wearable left ventricular assist systems (LVAS) in the treatment of advanced heart failure has steadily increased since 1993, when these devices became generally available in Europe. The aim of this study was to identify in an unselected cohort of LVAS recipients those aspects of patient selection that have an impact on postimplant survival. Methods and Results—Data were obtained from the Novacor European Registry. Between 1993 and 1999, 464 patients were implanted with the Novacor LVAS. The majority had idiopathic (60%) or ischemic (27%) cardiomyopathy; the median age at implant was 49 (16 to 75) years. The median support time was 100 days (4.1 years maximum). Forty-nine percent of the recipients were discharged from the hospital on LVAS; they spent 75% of their time out of the hospital. For a subset of 366 recipients, for whom a complete set of data was available, multivariate analysis revealed that the following preimplant conditions were independent risk factors for survival after LV...

Angiotensin II–Induced Leukocyte Adhesion on Human Coronary Endothelial Cells Is Mediated by E-Selectin

Clinical data suggest a link between the activation of the renin-angiotensin system and cardiovascular ischemic events. Leukocyte accumulation in the vessel wall is a hallmark of early atherosclerosis and plaque progression. E-Selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) are adhesion molecules participating in mediating interactions between leukocytes and endothelial cells and have been found to be expressed in athero-sclerotic plaques. We investigated whether angiotensin II, the effector of the renin-angiotensin system, influences the endothelial expression of E-selectin, VCAM-1, and ICAM-1. In coronary endothelial cells derived from explanted human hearts, angiotensin II (10(-11) to 10(-5) mol/L) induced a concentration-dependent increase in E-selectin expression. The effect was measured by cell ELISA and duplex reverse-transcription polymerase chain reaction (RT-PCR) and reached its maximum at 10(-7) mol/L. Angiotensin II induced only a small increase in E-selectin expression in cardiac microvascular endothelial cells. VCAM-1 and ICAM-1 were not affected by angiotensin II stimulation. In addition, the effect of angiotensin II-induced E-selectin expression on leukocyte adhesion was quantified under flow conditions. Angiotensin II (10(-7) mol/L) increased leukocyte adhesion significantly to 67% of the maximal effect by tumor necrosis factor-alpha at a wall shear stress of 2 dyne/cm2. This adhesion was found to be E-selectin dependent, as demonstrated by blocking antibodies. The AT1-receptor antagonist DUP 753 significantly reduced E-selectin-dependent adhesion, whereas the AT2-receptor antagonist PD 123177 had no inhibitory effect. In addition, only AT1-receptor, but not AT2-receptor, mRNA could be detected by RT-PCR in coronary endothelial cells. Therefore, it is suggested that AT1 receptors mediate the effects of angiotensin II on E-selectin expression and leukocyte adhesion on coronary endothelial cells.

Application of stereolithography for scaffold fabrication for tissue engineered heart valves.

A crucial factor in tissue engineering of heart valves is the functional and physiologic scaffold design. In our current experiment, we describe a new fabrication technique for heart valve scaffolds, derived from x-ray computed tomography data linked to the rapid prototyping technique of stereolithography. To recreate the complex anatomic structure of a human pulmonary and aortic homograft, we have used stereolithographic models derived from x-ray computed tomography and specific software (CP, Aachen, Germany). These stereolithographic models were used to generate biocompatible and biodegradable heart valve scaffolds by a thermal processing technique. The scaffold forming polymer was a thermoplastic elastomer, a poly-4-hydroxybutyrate (P4HB) and a polyhydroxyoctanoate (PHOH) (Tepha, Inc., Cambridge, MA). We fabricated one human aortic root scaffold and one pulmonary heart valve scaffold. Analysis of the heart valve included functional testing in a pulsatile bioreactor under subphysiological and supraphysiological flow and pressure conditions. Using stereolithography, we were able to fabricate plastic models with accurate anatomy of a human valvular homograft. Moreover, we fabricated heart valve scaffolds with a physiologic valve design, which included the sinus of Valsalva, and that resembled our reconstructed aortic root and pulmonary valve. One advantage of P4HB and PHOH was the ability to mold a complete trileaflet heart valve scaffold from a stereolithographic model without the need for suturing. The heart valves were tested in a pulsatile bioreactor, and it was noted that the leaflets opened and closed synchronously under subphysiological and supraphysiological flow conditions. Our preliminary results suggest that the reproduction of complex anatomic structures by rapid prototyping techniques may be useful to fabricate custom made polymeric scaffolds for the tissue engineering of heart valves.

Experience with over 1000 Implanted Ventricular Assist Devices

Abstract  Purpose: The use of ventricular assist devices (VADs) in patients with chronic end‐stage or acute heart failure has led to improved survival. We present our experience since 1987. Subjects and Methods: Between July 1987 and December 2006, 1026 VADs were implanted in 970 patients. Most of them were men (81.9%). The indications were: cardiomyopathy (n = 708), postcardiotomy heart failure (n = 173), acute myocardial infarction (n = 36), acute graft failure (n = 45), a VAD problem (n = 6), and others (n = 2). Mean age was 46.1 (range 3 days to 78) years. In 50.5% of the patients the VAD implanted was left ventricular, in 47.9% biventricular, and in 1.5% right ventricular. There were 14 different types of VAD. A total artificial heart was implanted in 14 patients. Results: Survival analysis showed higher early mortality (p < 0.05) in the postcardiotomy group (50.9%) than in patients with preoperative profound cardiogenic shock (31.1%) and patients with preoperative end‐stage heart failure without severe shock (28.9%). A total of 270 patients were successfully bridged to heart transplantation (HTx). There were no significant differences in long‐term survival after HTx among patients with and without previous VAD. In 76 patients the device could be explanted after myocardial recovery. In 72 patients the aim of implantation was permanent support. During the study period 114 patients were discharged home. Currently, 54 patients are on a device. Conclusions: VAD implantation may lead to recovery from secondary organ failure. Patients should be considered for VAD implantation before profound, possibly irreversible, cardiogenic shock occurs. In patients with postcardiotomy heart failure, a more efficient algorithm should be developed to improve survival. With increased experience, more VAD patients can participate in out‐patient programs.

Decreased plasma concentration of brain natriuretic peptide as a potential indicator of cardiac recovery in patients supported by mechanical circulatory assist systems

OBJECTIVES We sought to investigate the relationship between the plasma concentration of brain natriuretic peptide (BNP), echocardiographic findings and the clinical outcome of patients supported with ventricular assist devices (VADs) to determine the role of BNP as a predictor for cardiac recovery. BACKGROUND Ventricular unloading in patients with end-stage heart failure supported by VADs may lead to myocardial recovery. The BNP is produced in the myocardium in response to chronic volume overload, but the effects on it of ventricular unloading by VADs are largely unknown. METHODS Twenty-one patients diagnosed with nonischemic cardiomyopathy and supported by VADs were evaluated for echocardiographic data and blood chemistry including BNP. They were divided into patients who died while on mechanical support (group I; n = 9), patients who were transplanted (group II; n = 8) and patients who were successfully weaned off the system and did not require transplantation (group III; n = 4). RESULTS Brain natriuretic peptide plasma concentrations decreased significantly after initiation of mechanical circulatory support (p = 0.017). Furthermore, the changes in BNP plasma concentrations showed a faster decrease to normal levels within the first week after implantation of the VAD in patients who were weaned off the system (group III) compared to patients in group I and group II. CONCLUSIONS This study shows that ventricular unloading with VADs decreases BNP plasma concentrations in patients who suffer from end-stage heart failure. Furthermore, we hypothesize that an early decrease of BNP plasma concentration may be indicative of recovery of ventricular function during mechanical circulatory support.

Blockade of IL-6 Trans Signaling Attenuates Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2–3 y of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of IL-6 results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6Rα, or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sIL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sIL-6Rα. In vivo neutralization of sIL-6Rα attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin, and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Taken together, these findings demonstrate that the production of sIL-6Rα from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.

Inflammatory response after implantation of a left ventricular assist device: comparison between the axial flow MicroMed DeBakey VAD and the pulsatile Novacor device.

The implantation of a ventricular assist device (VAD) is associated with a stimulation of the inflammatory system. We compared changes in the inflammatory response after implantation of a pulsatile Novacor left (L) VAD and the axial flow MicroMed DeBakey VAD. Six consecutive patients after implantation of a Novacor LVAD (NC) and six patients after implantation of a MicroMed DeBakey VAD (MD) were included in the investigation. Patients received LVADs for medically non treatable end-stage heart failure. Tumor necrosis factor alpha (TNF), C3a, C5a, interleukin 6 (IL-6), and neutrophil elastase were measured twice a week over a period of 3 months after implantation of the device. All tests were performed with an enzyme-linked immunosorbent assay. There was no significant difference in the clinical course of the two groups. All inflammatory parameters were elevated in both groups during the entire period of the investigation. There was no difference in TNF, polynuclear leukocyte elastase, or C3a levels between the two groups; however, IL-6 (NC: 23.6 ± 37.6 pg/ml vs. MD: 63 ± 114 pg/ml, p < 0.001) and C5a (NC: 708 ± 352 &mgr;g/L vs. MD: 1,745 ± 1,305 &mgr;g/L, p < 0.001) were increased significantly more in patients following implantation of the axial flow MicroMed DeBakey VAD. Compared with the pulsatile Novacor device, the implantation of the axial flow MicroMed DeBakey LVAD seems to be associated with an increased stimulation of one part of the inflammatory system. Further investigations are necessary for evaluation of the pathophysiologic mechanism and clinical implications of these findings.

Anticoagulation during Cardiopulmonary Bypass in Patients with Heparin-induced Thrombocytopenia Type II and Renal Impairment Using Heparin and the Platelet Glycoprotein IIb-IIIa Antagonist Tirofiban

BackgroundPatients with heparin-induced thrombocytopenia type II require an alternative to standard heparin anticoagulation. However, in patients with renal impairment, anticoagulation during cardiopulmonary bypass with agents such as danaparoid sodium or r-hirudin are associated with hemorrhage. Anticoagulation with unfractionated heparins combined with prostacyclin, a potent platelet aggregation inhibitor, is associated with severe hypotension. The authors investigated a new concept using unfractionated heparins after platelet inhibition with the short-acting platelet glycoprotein IIb–IIIa antagonist tirofiban. MethodsTen patients with heparin-induced thrombocytopenia type II and renal impairment were enrolled in the investigation. All had heparin-induced thrombocytopenia type II antibodies present as proved by the heparin-induced platelet aggregation assay, the heparin–platelet factor 4 enzyme-linked immunosorbent assay, or both. In all patients, preoperative anticoagulation to an activated partial thromboplastin time of 40–60 s was performed with r-hirudin. Anticoagulation during cardiopulmonary bypass was achieved with a bolus of 400 IU/kg unfractionated heparins after a bolus of tirofiban 10 &mgr;g/kg followed by an infusion of tirofiban at a rate of 0.15 &mgr;g · kg−1 · min−1 until 1 h before conclusion of cardiopulmonary bypass. Additional unfractionated heparins were only administered if activated clotting time decreased below 480 s. Coagulation was monitored by a abciximab-modified TEG® and the adenosine diphosphate–stimulated (20 &mgr;m) platelet aggregometry. D-dimer concentrations, as a marker of venous thromboembolism, were measured before and 12, 24, and 48 h after surgery. Postoperative antithrombotic therapy was started immediately with r-hirudin to anticoagulation to an activated partial thromboplastin time of 40–60 s. ResultsThe postoperative blood loss ranged from 110 to 520 ml. No patient needed reexploration. In no patient was there clinical evidence of thrombosis or embolism in the postoperative period or of a critical increase of the D-dimer concentrations, suggesting venous thromboembolism. Transfusion of platelets was necessary in only two patients. ConclusionsThe protocol is easy to perform and no increased postoperative bleeding and no thromboembolic complications occurred. The combination of unfractionated heparins and tirofiban may be an alternative to other anticoagulation strategies in patients with heparin-induced thrombocytopenia.

Degree of cardiac fibrosis and hypertrophy at time of implantation predicts myocardial improvement during left ventricular assist device support

BACKGROUND There have been increasing reports of cardiac improvement in heart failure patients supported by left ventricular assist devices (LVADs i.e.), including a number of patients who have tolerated removal of the device without the benefit of cardiac transplant. In the current study, we retrospectively investigated echocardiographic and histologic changes in patients supported by LVADs (n = 18). The goal of our study was to determine if the degree of cardiac fibrosis and myocyte size in pre-implant biopsies could predict myocardial improvement as assessed by improvements in ejection fraction (EF) during LVAD support. METHODS We determined total collagen content in myocardial biopsy specimens by a semi-quantitative analysis of positive Picro-Sirius Red-stained areas and myocyte size measurements by computerized edge detection software. RESULTS During LVAD support, 9 of the 18 patients (Group A) were distinguished by significant improvement in ejection fraction (pre <20% vs unloaded 34 +/- 5%). In addition, Group A patients had significantly less fibrosis and smaller myocytes than their Group B counterparts, whose EF did not improve. There was an inverse correlation between pre-implant biopsy collagen levels and myocyte size with increases in EF during LVAD unloading. CONCLUSIONS We found that the patients who demonstrated the greatest improvements in EF during support had less fibrosis and smaller myocytes at the time of device implantation. We propose that tissue profiling a patients pre-implant biopsy for fibrosis and myocyte size may allow stratification in Stage IV heart failure and may predict myocardial improvement during LVAD support.