Philipp Seppelt

Predictive Risk Factors for Patients With Cirrhosis Undergoing Heart Surgery

BACKGROUND Empiric experiences suggest higher mortality and complication risk for patients with cirrhosis of the liver after cardiac surgery. However, cirrhosis is not considered a risk factor in either the EuroSCORE or The Society of Thoracic Surgeons score. We report a large single-center experience of patients with cirrhosis undergoing cardiac surgery with extracorporeal circulation and aimed to evaluate the severity of cirrhosis as a predictor of outcome. METHODS During 2001 and 2011, we operated on 109 consecutive patients (average age, 64 years; 82 male) diagnosed for cirrhosis with cardiopulmonary bypass for different indications. Thirty-day mortality and long-term mortality were set as primary study end points. RESULTS Thirty-day mortality was 26%, and 5-year survival was 19%. Patients categorized as Child-Turcotte-Pugh (CHILD) C (n=6; 67% 30-day survival; 0% 5-year survival) and B (n=30; 60%; 5%) had worse 30-day and 5-year survival compared with patients categorized as CHILD A (n=73; 80%; 25%). For 30-day mortality, preoperative EuroSCORE (p=0.015), model for end-stage liver disease (MELD) score (p=0.006), albumin (p=0.023), total protein (p=0.01), and myocardial infarction (p=0.049) revealed significant differences between survivors and nonsurvivors. Multivariate logistic regression identified only MELD score (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.03 to 1.23; p=0.011) and total protein (OR, 0.97; 95% CI, 0.95 to 1; p=0.049) were connected with increased 30-day mortality. Cox regression analysis revealed EuroSCORE (OR, 1.02; 95% CI, 1.01 to 1.03; p<0.0001) and MELD (OR, 1.06; 95% CI, 1.01 to 1.12; p=0.016) predicting the overall mortality. Receiver operating characteristic analysis indicated significant predictive power of MELD (p=0.001) and EuroSCORE (p=0.027) for 30-day mortality. CONCLUSIONS Patients with cirrhosis undergoing heart surgery with extracorporeal circulation have a poor prognosis. Several preoperative factors are related to outcome. EuroSCORE and MELD score may help to evaluate operation risk and indication.

Gender-specific differences in outcome of ascending aortic aneurysm surgery.

Objectives Gender specific differences receive increasing attention and are known to affect the outcome of cardiovascular diseases. We investigated possible risk-factors for gender-specific differences in ascending aortic aneurysm surgery. Methods 548 consecutive patients (male: n = 390, age: 58.3±14.4 years; female: n = 158, age: 65.3±12.9 years) with aneurysms of the ascending aorta eligible for cardiac surgery were retrospectively analyzed. Results Women were significantly older when operation was indicated (p<0.001) and presented with significantly more hypertension (p=0.04) and chronic obstructive pulmonary disease (COPD; p = 0.017), whereas men had significantly more previous cardiac operations (p = 0.016). Normalized aortic diameters (diameter / body surface area) were significantly larger in women (3.10±0.6 cm) vs. (2.75±0,5 cm, p≤0.001) in men, without differences in absolute values (5.74±1.04 cm vs. 5.86±1.34 cm). The aortic arch was significantly more involved in aneurysm formation in women (p = 0.04). Follow-up was available in 93% of the patients with a mean follow-up time of 3.9±3.9 (0-17.8) years. 30-day mortality was 3.5% in men (n=12) and 7.9% in women (n=11; p = 0.058). Univariate regression analysis shows gender specific risk factors for 30-day mortality in men to be age: p = 0.028; myocardial infarction: p = 0.0.24 and in women diameter of the ascending aorta: p=0.014; renal insufficiency: p=0.007. Long-term survival was significantly reduced in women (log-rank p = 0.0052). Conclusions The outcome after surgery for ascending aortic aneurysm is less favourable in women with significantly reduced long-term survival and a trend to increased 30-day mortality in this cohort. Larger normalized aortic diameters, higher incidence of involvement of the aortic arch and differences in comorbidities may contribute to gender differences. Women undergo surgery at higher age and more progressed state of aortic disease. Therefore, gender-specific guidelines for ascending replacement may be useful to improve outcome in women.

Aortic mispuncture during routine catheterization requires emergency cardiac operation.

Transseptal puncture for left heart catheter or left atrial appendage occlusion is a highly standardized routine intervention in interventional cardiology. However, mispuncture is rare but can be life threatening at worst. Here, we report the case of a combined mispuncture of the right atrium and the ascending aorta resulting in a pericardial effusion with a hemodynamic effective tamponade requiring urgent cardiac operation for successful life saving.

Loss of Endothelial Barrier in Marfan Mice (mgR/mgR) Results in Severe Inflammation after Adenoviral Gene Therapy

Objectives Marfan syndrome is an autosomal dominant inherited disorder of connective tissue. The vascular complications of Marfan syndrome have the biggest impact on life expectancy. The aorta of Marfan patients reveals degradation of elastin layers caused by increased proteolytic activity of matrix metalloproteinases (MMPs). In this study we performed adenoviral gene transfer of human tissue inhibitor of matrix metalloproteinases-1 (hTIMP-1) in aortic grafts of fibrillin-1 deficient Marfan mice (mgR/mgR) in order to reduce elastolysis. Methods We performed heterotopic infrarenal transplantation of the thoracic aorta in female mice (n = 7 per group). Before implantation, mgR/mgR and wild-type aortas (WT, C57BL/6) were transduced ex vivo with an adenoviral vector coding for human TIMP-1 (Ad.hTIMP-1) or β-galactosidase (Ad.β-Gal). As control mgR/mgR and wild-type aortas received no gene therapy. Thirty days after surgery, overexpression of the transgene was assessed by immunohistochemistry (IHC) and collagen in situ zymography. Histologic staining was performed to investigate inflammation, the neointimal index (NI), and elastin breaks. Endothelial barrier function of native not virus-exposed aortas was evaluated by perfusion of fluorescent albumin and examinations of virus-exposed tissue were performed by transmission electron microscopy (TEM). Results IHC and ISZ revealed sufficient expression of the transgene. Severe cellular inflammation and intima hyperplasia were seen only in adenovirus treated mgR/mgR aortas (Ad.β-Gal, Ad.hTIMP-1 NI: 0.23; 0.43), but not in native and Ad.hTIMP-1 treated WT (NI: 0.01; 0.00). Compared to native mgR/mgR and Ad.hTIMP-1 treated WT aorta, the NI is highly significant greater in Ad.hTIMP-1 transduced mgR/mgR aorta (p = 0.001; p = 0.001). As expected, untreated Marfan grafts showed significant more elastolysis compared to WT (p = 0.001). However, elastolysis in Marfan aortas was not reduced by adenoviral overexpression of hTIMP-1 (compared to untreated Marfan aorta: Ad.hTIMP-1 p = 0.902; control Ad.β-Gal. p = 0.165). The virus-untreated and not transplanted mgR/mgR aorta revealed a significant increase of albumin diffusion through the endothelial barrier (p = 0.037). TEM analysis of adenovirus-exposed mgR/mgR aortas displayed disruption of the basement membrane and basolateral space. Conclusions Murine Marfan aortic grafts developed severe inflammation after adenoviral contact. We demonstrated that fibrillin-1 deficiency is associated with relevant dysfunction of the endothelial barrier that enables adenovirus to induce vessel-harming inflammation. Endothelial dysfunction may play a pivotal role in the development of the vascular phenotype of Marfan syndrome.

Die Maus als Modell für die Grundlagenforschung bei Marfan-Syndrom

ZusammenfassungDas Marfan-Syndrom ist mit einer Inzidenz von 2–3 Patienten auf 10.000 Geburten eine seltene hereditäre, systemische Bindegewebsstörung. Marfan-Patienten sind durch die Ausbildung von Aneurysmen der Aorta und durch spontane Aortendissektionen gefährdet. Das primäre Ziel bei der Therapie ist die Prävention von lebensbedrohlichen kardiovaskulären Ereignissen. Die Pathogenese der Aortenerkrankung ist nicht abschließend geklärt. Für die Entwicklung neuer Therapieansätze ist eine detaillierte Erforschung der Pathophysiologie vor allem auf molekularer Ebene notwendig. Aus ethischen Überlegungen ist für die Entwicklung experimenteller Therapieansätze ein präklinisches Modell sinnvoll. Hauptanspruch an das Modell ist die Imitation der humanen Pathologie für eine möglichst genaue Translation von Modell zu Mensch. Der vorliegende Beitrag stellt ein Mausmodell des Marfan-Syndroms vor. Die mgR/mgR-Maus zeigt auf makroskopischer und mikroskopischer Ebene phänotypische Manifestationen des Marfan-Syndroms. Damit ermöglicht die mgR/mgR-Maus ein besseres Verständnis der Pathophysiologie und die Entwicklung neuer Therapieansätze zur Behandlung der kardiovaskulären Manifestationen des Marfan-Syndroms.AbstractMarfan syndrome is a rare hereditary systemic connective tissue disease with a prevalence of 2–3 in 10,000 births. Aneurysm formation and aortic dissection still remain the most life-threatening complications in Marfan syndrome but the pathogenesis of the aortic disease is poorly understood. The primary goal of treatment is the prevention of life-threatening cardiovascular events. Further investigations on the molecular mechanisms of aortic disease are crucial for the development of new treatment-strategies. Experimental therapies should be established in a preclinical model which needs to mimic the human pathology of Marfan syndrome for a valuable translation from model to human. This report provides information on a murine model of Marfan syndrome. The mgR/mgR mouse presents with phenotypic manifestations of Marfan syndrome at the macroscopic and microscopic levels. Further investigations on mgR/mgR mice could reveal new insights into the molecular understanding of aortic disease and could offer targets to improve treatment of the life-threatening cardiovascular manifestations of Marfan syndrome.

Extracorporeal life support with left ventricular decompression—improved survival in severe cardiogenic shock: results from a retrospective study

Objective Extracorporeal life support (ECLS) is a life-saving procedure used in the treatment of severe cardiogenic shock. Within this retrospective single centre study, we examined our experience in this critically ill patient cohort to assess outcomes and clinical parameters by comparison of ECLS with or without selective left ventricular decompression. Methods Between 2004 and 2014 we evaluated 48 adult patients with INTERMACS level 1 heart failure (age 49.7 ± 19.5 years), who received either central ECLS with (n = 20, 41.7%) or ECLS without (n = 28, 58.3%, including 10 peripheral ECLS) integrated left ventricular vent in our retrospective single centre trial. Results Follow up was 100% with a mean of 0.83 ± 1.85 years. Bridge to ventricular assist device was feasible in 29.2% (n = 14), bridge to transplant in 10.4% (n = 5) and bridge to recovery in 8.3% (n = 4). Overall 30-day survival was 37.5%, 6-month survival 27.1% and 1-year survival 25.0%. ECLS support with left ventricular decompression showed favourable 30-day survival compared to ECLS without left ventricular decompression (p = 0.034). Thirty-day as well as long-term survival did not differ between the subgroups (central ECLS with vent, ECLS without vent and peripheral ECLS without vent). Multivariate logistic regression adjusted for age and gender revealed ECLS without vent as independent factor influencing 30-day survival. Conclusion ECLS is an established therapy for patients in severe cardiogenic shock. Independent of the ECLS approach, 30-day mortality is still high but with superior 30-day survival for patients with ECLS and left ventricular venting. Moreover, by unloading the ventricle, left ventricular decompression may provide an important time window for recovery or further treatment, such as bridge to bridge or bridge to transplant.

AP-1 Oligodeoxynucleotides Reduce Aortic Elastolysis in a Murine Model of Marfan Syndrome

Marfan syndrome is characterized by high expression of matrix metalloproteinases (MMPs) in aortic smooth muscle cells (AoSMCs) associated with medial elastolysis and aortic root aneurysm. We aimed to reduce aortic elastolysis through decrease of MMP expression with decoy oligodeoxynucleotides (dODNs) neutralizing the transcription factor activating factor-1 (AP-1). AP-1 abundance in nuclear extracts as well as MMP-2 and MMP-9 expression were significantly increased in isolated mAoSMC of mgR/mgR Marfan mice compared to wild-type cells. Exposure to AP-1 neutralizing dODNs resulted in a significant reduction of basal and interleukin-1β-stimulated MMP expression and activity in mAoSMCs. Moreover, increased migration and formation of superoxide radical anions was substantially decreased in mAoSMCs by AP-1 dODN treatment. Aortic grafts from donor Marfan mice were treated with AP-1- dODN ex vivo and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Pretreatment of aortic grafts with AP-1 dODN led to reduced elastolysis, macrophage infiltration, and MMP activity. Permeability of the endothelial monolayer was increased for dODN in mgR/mgR aortae with observed loss of tight junction proteins ZO-1 and occludin, enabling dODN to reach the tunica media. Targeting AP-1 activity offers a new potential strategy to treat the vascular phenotype associated with Marfan syndrome.