Postconditioning of the lungs with inhaled carbon monoxide after cardiopulmonary bypass in pigs.

BACKGROUND: Administration of inhaled carbon monoxide before organ ischemic injury exerts protective effects in animal models. Because there are no data showing that this also works after an ischemic insult, our objective in this study was to investigate whether inhaled carbon monoxide attenuates cardiopulmonary bypass (CPB)-induced lung injury in a pig model. METHODS: Animals were randomized to a SHAM group (n = 5), a SHAM group plus inhaled carbon monoxide (n = 5), standard CPB (n = 10), and to CPB plus inhaled carbon monoxide (n = 10). Carbon monoxide (250 ppm) was given for 1 hour after termination of CPB. Lung biopsies were obtained before CPB, immediately after separation from CPB, and for 5 hours after termination of CPB to determine expression of pulmonary heat shock proteins 70 and 90, cytokines, alveolar macrophage infiltration, and fluorogenic caspase-3 activity. RESULTS: At 5 hours after CPB, administration of inhaled carbon monoxide was associated with reduced pulmonary expression of the inflammatory cytokines tumor necrosis factor (CPB + CO 521 ± 77 vs CPB 821 ± 97 pg · mL(-1), P < 0.001) and interleukin-6 (304 ± 81 vs 860 ± 153 pg · mL(-1), P < 0.001), increased pulmonary expression of the cytoprotective heat shock protein 70 (CPB + CO 79 ± 14 vs CPB 36 ± 9 ng · mL(-1), P < 0.001) and the antiinflammatory cytokine interleukin-10 (CPB + CO 278 ± 40 vs CPB 63 ± 20 pg · mL(-1), P < 0.001), and with reduced pulmonary apoptotic protein caspase-3 activity (CPB + CO 0.73 ± 0.11 vs CPB 0.99 ± 0.1 RFU, P < 0.05). Carbon monoxide administration was associated with reduced histological evidence of lung injury and alveolar macrophage infiltration (78 ± 39 vs 145 ± 34 counts per field of vision, P < 0.001). CONCLUSIONS: These results suggest that administration of low concentrations of carbon monoxide after CPB ("postconditioning") protects the lung from CPB-related lung injury.

Thoracic endovascular stent grafting inhibits aortic growth: an experimental study.

OBJECTIVE: Dilatation of the aorta at the landing zone site may be exaggerated by the radial force of stent grafts potentially limiting long-term results of endovascular therapy. We evaluated growth patterns and morphology of the thoracic aorta in young piglets after thoracic stent-graft placement. METHODS: Eight domestic piglets (37+/-2 kg) had an endovascular stent graft placed in the proximal descending thoracic aorta using retroperitoneal access. At implantation, the stent was oversized by 10%. Aortic size was documented after thoracotomy by intraoperative measurement and angiography. Subsequently the piglets were grown to adult size (181+/-42 kg). At explantation 6-15 months later, CT scan and surgical evaluation for endoleaks, defined as perigraft flow, was performed. Histopathological assessment of the explanted aorta was performed in stented and non-stented segments and compared to five normal porcine aortas. RESULTS: No endoleak (perigraft flow) or stent migration occurred even in 230kg pigs. The stent grafts expanded to full size, but there was no further growth in the stented area. The aortic diameter increased significantly by 32+/-9% 1cm proximal to the stents (p=0.0012) and by 45+/-13% 1cm distal to the stents (p=0.0033). The stented area grew less than the proximal (p=0.0011) and distal aorta (p<0.0001). In all pigs, the distal aorta was larger than the proximal overstented segment. Histology of the stented aorta showed significant thickening of the intima (p=0.018) and media (p=0.006) with neointimal formation and segmental fibrosis of the inner 1/3 of the media with loss of smooth muscle cells and compression of the elastic fibers but normal architecture in the outer 2/3 of the media. CONCLUSIONS: Endovascular stent grafting may inhibit growth of the nonatherosclerotic normal aorta and lead to intimal hyperplasia and focal fibrosis in the inner media part adjacent to the stent. Stent-graft interaction with aortic tissue over time is important and should receive more detailed evaluation. Testing this interaction in an animal model of nonatherosclerotic dilative aortic disease could be of great interest.

Platelet Secretion Defects and Acquired von Willebrand Syndrome in Patients With Ventricular Assist Devices.

BACKGROUND: The number of implanted ventricular assist devices (VADs) has increased significantly recently. Bleeding, the most frequent complication, cannot be solely attributed to anticoagulation therapy. Acquired von Willebrand syndrome (AVWS) caused by increased shear stress is frequent in VAD patients and can increase the bleeding risk. The HeartMate III (HM III) is a novel left VAD featuring potential improvements over the HeartMate II. METHODS AND RESULTS: In this study, we investigated the prevalence and onset of AVWS in 198 VAD patients. To our knowledge, this is the largest cohort of VAD patients whose longitudinal data on AVWS have been collected. We also analyzed whether AVWS is less severe in HM III patients than in HeartMate II patients. Because platelet dysfunction can raise the bleeding risk, we investigated platelet function in a subset of patients. In total, 198 VAD patients and 60 patients with heart transplants as controls were included in this study. The ratio of von Willebrand factor collagen binding capacity to von Willebrand factor:antigen, multimer analyses, and platelet function (especially secretion of α- and δ-granules) were investigated. All 198 VAD patients developed AVWS. As soon as the VAD was explanted, the AVWS disappeared within hours. AVWS was less severe in the HM III patients than in the HeartMate II patients. The HM III patients had fewer bleeding symptoms. In addition, VAD patients exhibited a platelet α- and δ-granule secretion defect. CONCLUSIONS: AVWS develops in VAD patients and may increase the bleeding risk. The HM III device causes less severe AVWS. Platelet secretion defects should be investigated in VAD patients because they also raise the bleeding risk. CLINICAL TRIAL REGISTRATION: https://www.drks.de/drks_web. Unique identifier: DRKS00000649.

Acquired Von Willebrand syndrome in patients on long-term support with HeartMate II.

Objectives: Impaired binding of Von Willebrand factor (VWF) to platelets and to collagen due to acquired Von Willebrand syndrome (AVWS) is associated with support from a ventricular assist device (VAD) and can contribute to bleeding tendencies in patients with VADs. The onset of AVWS has been shown to occur immediately after VAD implantation. Our aim was to determine long-term data on AVWS in VAD patients. Methods: We analysed 278 data sets of 74 patients on HeartMate II (HMII) support for 3-80 months after implantation (11.2 ± 12.1, median 6.3 months.). Ristocetin cofactor activity (VWF:RCo), collagen binding capacity (VWF:CB), VWF antigen (VWF:Ag) and the ratios of VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag were determined. Further, the presence of high molecular weight (HMW) multimers of VWF was investigated. Results: Abnormally low values of VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag were found in 69% and 97% of blood samples, respectively. Only ten of 181 multimer analyses showed a normal pattern, and HMW multimers were present in both specimens in only one of the 74 patients. No significant changes in these parameters were observed over time. The VWF:CB/VWF:Ag ratio correlated with the multimer patterns, whereas the VWF:RCo/VWF:Ag ratio seemed to be less sensitive for AVWS. Conclusions: Our data indicate that AVWS is a typical phenomenon in patients with VAD support and that there are no time-dependent changes in these parameters apparent in most patients on long-term support with HMII.

Proteomics highlights decrease of matricellular proteins in left ventricular assist device therapy†.

OBJECTIVES: We investigated the impact of mechanical unloading with a left ventricular assist device (LVAD) on the myocardial proteome. METHODS: We collected 11 patient-matched samples of myocardial left ventricular tissue of patients with non-ischaemic dilate cardiomyopathy, harvested at time of LVAD implant ('pre-LVAD') and heart transplant ('post-LVAD'). Samples were studied by quantitative proteomics. Further we performed histological assessment of deposited collagens and immune infiltration in both pre- and post-LVAD samples. RESULTS: A core set of >1700 proteins was identified and quantified at a false discovery rate <1%. The previously established decrease post-LVAD of alpha-1-antichymotrypsin was corroborated. We noted a post-LVAD decrease of matricellular proteins and proteoglycans such as periostin and versican. Also, proteins of the complement system and precursors of cardiac peptide hormones were decreased post-LVAD. An increase post-LVAD was evident for individual proteins linked to the innate immune response, proteins involved in diverse metabolic pathways, and proteins involved in protein synthesis. Histological analysis did not reveal significant alterations post-LVAD of deposited collagens or immune infiltration. The proteomic data further highlighted a pronounced inter-patient heterogeneity with regards to the impact of LVAD therapy on the left ventricular myocardial proteome. Finally, the proteomic data showed differential proteolytic processing in response to LVAD therapy. CONCLUSIONS: Our findings underline a strong impact of LVAD therapy on the left ventricular myocardial proteome. Together with previous studies, protein markers of LVAD therapy such as alpha-1-antichymotrypsin are becoming apparent. Further, matricellular proteins are emerging as important components in response to LVAD therapy.

Genetic variations of phenprocoumon metabolism in patients with ventricular assist devices.

OBJECTIVES: Anticoagulation in patients with ventricular assist device (VAD) support is crucial and to date, no alternative to vitamin K antagonists (VKAs) can be safely used. Genetic variances of cytochrome p450 2C9 (CYP2C9) and vitamin K epoxide reductase (VKORC) have been recently connected with variation of VKA maintenance as well as loading doses. In this retrospective study, we assessed the incidence of genetic variations and the influence of different genotypes of CYP2C9 and VKORC1 in VAD patients. METHODS: A total of 161 patients received a VAD implant in our institution between January 2006 and July 2014. Of these, 63 consented to genetic analysis and completed an interview with standardized questions on phenprocoumon (PC) dosage, international normalized ratio and anticoagulation-related complications. Determination of VKORC (-1639 G > A; -1173 C > T) and of CYP2C9 (*2, 430 C > T; *3, 1075 A > C) polymorphisms was performed by polymerase chain reaction and restriction analysis. RESULTS: The most common VKORC-1639 allele combination was wild-type GG (41%) followed by GA (32%) and AA (27%). Patients with VKORC1 polymorphisms AA and GA needed less PC in the maintenance phase of anticoagulation (P < 0.001) compared with wild-type GG patients. In contrast, CYP2C9 polymorphisms showed no effect on PC doses. Similar findings were observed in the initiation phase of PC therapy. High complications rates under PC therapy were observed particularly at the beginning. CONCLUSIONS: VKORC polymorphism affects PC dosage in the initiation as well as the maintenance phase. High rates of bleeding complications and thromboembolic events were found at the beginning of PC therapy in VAD patients. Therefore, a genotype-guided dosage algorithm might be useful in VAD patients.

Mechanical heart valve recipients: anticoagulation in patients with genetic variations of phenprocoumon metabolism.

OBJECTIVES: Oral anticoagulation in mechanical heart valve recipients remains crucial, and vitamin K antagonists (VKA) are still the gold standard. Polymorphisms of vitamin K epoxide oxidase reductase (VKORC) and cytochrome p450 (CYP2C9) were recently found to influence VKA metabolism. We retrospectively investigated the prevalence of these genotypes and associated anticoagulation-related complications in our patients. METHODS: Between August 1998 and August 2008, 563 patients received mechanical heart valve replacement in our institution. Of these, 179 completed a questionnaire on anticoagulation-related complications and consented to genetic analysis. We analysed polymorphisms of VKORC (-1639 G>A; 1173 C>T) and of CYP2C9 (*2, 144 C>T; *3, 359 A>C) by PCR and restriction analysis. RESULTS: For VKORC-1639/1173 alleles, there were 62 (35%) patients with the combination GG/CC, 91 (51%) with GA/CT, 25 (14%) with AA/TT and 1 (1%) with AA/CT. Phenprocoumon (PC) dosage was related to VKORC polymorphism (P < 0.001) with lower doses required for AA/TT patients. Overall, there were 27 severe bleedings and 11 thromboembolic events. For GG/CC, the incidence of major bleeding events and thromboembolic events was 13 and 6%, respectively, and for AA/TT, it was 27 and 12%, respectively. Variation in international normalized ratio (INR) >1.5 was associated with severe bleeding complications (P = 0.025) and GA/CT patients were predisposed to INR variations >1.5 (P = 0.028). No influence of CYP2C9 polymorphism on PC dosage and anticoagulation-related complications was found. CONCLUSIONS: VKORC polymorphism affects PC dosage and anticoagulation-related complication rates in mechanical heart valve recipients. Genotyping may help to identify patients at particular risk of anticoagulation-related complications.

Thoratec paracorporeal biventricular assist device therapy: the Freiburg experience.

OBJECTIVE: The treatment of severe biventricular (BV) contractile failure using mechanical circulatory support is challenging. We analyzed our center's results following implantation of a biventricular assist device (BVAD). METHODS: We implanted 39 BVADs between September 2001 and January 2009. All patients were qualified candidates for heart transplantation, without an organ available at time of BVAD implantation. Fifteen patients without a history of chronic cardiomyopathy suffered from acute BV failure (group 1), whereas the other 24 suffered from severe chronic cardiomyopathy (group 2). The indication for BVAD implantation was determined in reference to echocardiography, the degree of end-organ damage, and whether the patient qualified for a heart transplant or was a candidate for bridge to recovery. RESULTS: Both groups were similar regarding their preoperative hemodynamics, intraoperative and early postoperative findings, and adverse events. Patients in group 1 were younger (mean age 37±17 years) than those in group 2 (51±12 years). Mean duration of support in group 1 was 137±109 days, and 65±61 days in group 2. In group 1, 33% (5/15) were weaned off the device and 53% (8/15) underwent heart transplantation, whereas 8/24 patients (42%) in the chronic group were transplanted. Group 1's mortality on the device was lower than that of group 2 (13% vs 67%). Furthermore, 11 patients of group 1 survived for 1 year compared with four in group 2 (73% vs 17%). CONCLUSION: Implantation of a BVAD in patients with chronic heart failure and acute decompensation is associated with a high mortality and morbidity rate. By contrast, BVAD implantation can achieve excellent results in patients with acute BV failure without a history of chronic cardiomyopathy, even if they are in cardiogenic shock upon admission.

Biventricular cannulation is superior regarding hemodynamics and organ recovery in patients on biventricular assist device support.

BACKGROUND: Adequate pump flow is a prerequisite for recovery of end-organ failure and outcome in patients treated with a biventricular assist device (BiVAD). We hypothesized that hemodynamics and organ recovery would improve after biventricular, apical cannulation compared with right atrial cannulation. METHODS: Between 2003 and 2009, we treated 31 patients (21 men, 10 women; mean age, of 43 ± 15 years) with a paracorporeal BiVAD (Thoratec BVAD, Pleasanton, CA). In 15 of 31 patients, the inflow cannula of the right VAD (RVAD) was positioned inside the right ventricle (RV) through the RV apex (biapical) instead of the right atrium (conventional). We analyzed pump flow, driving pressure, and vacuum of the Thoratec driving console and recovery of kidney (creatinine, blood urea nitrogen) and liver function (bilirubin). RESULTS: Mean duration of BiVAD support was 84 ± 72 days. BiVAD weaning was successful in 4 of 31 patients (13%), 12 underwent cardiac transplantation (39%), and 15 (48%) died. We observed significantly higher pump flow of the LVAD and RVAD in patients after biapical cannulation compared with those with conventional cannulation (LVAD, 5.6 ± 0.4 vs 5.1 ± 0.3 liters/min, p = 0.002; and RVAD: 4.9 ± 0.3 vs 4.2 ± 0.3 liters/min, p < 0.001). This superior circulatory support correlated with faster recovery of kidney function. CONCLUSION: Cardiac support with a BiVAD is hemodynamically more effective after biventricular apical cannulation compared with conventional right atrial cannulation. Consequently, higher pump flow results in better end-organ recovery using biapical cannulation.

Successful resuscitation after prolonged periods of cardiac arrest: a new field in cardiac surgery.

OBJECTIVE: Cardiopulmonary resuscitation is associated with high mortality and poor neurological recovery. Cardiopulmonary resuscitation can cause ischemia-reperfusion injury of the whole body and brain. We assessed the hypothesis that controlled reperfusion of the whole body with cardiopulmonary bypass would limit reperfusion injury after 15 minutes of normothermic cardiac arrest with better survival and neurological recovery. METHODS: Eleven pigs were exposed to normothermic ischemia for 15 minutes by inducing ventricular fibrillation, followed by cardiopulmonary resuscitation (control group, n = 4) or 60 minutes of cardiopulmonary bypass (treatment group, n = 7). Conditions of reperfusion and the reperfusate were controlled with cardiopulmonary bypass. Animals were observed for up to 7 days, and neurological assessment (Neurological Deficit Score: 0, normal; 500, brain death), magnetic resonance imaging, and brain histology were performed. RESULTS: All animals in the control group died after 20 minutes of cardiopulmonary resuscitation (n = 4). All (n = 7) survived in the treatment group. Clinically apparent neurological recovery occurred within 24 hours; 1 fully conscious pig could not walk. The Neurological Deficit Score was 98 +/- 31 in all animals (n = 7) after 24 hours and decreased to 0 after 48 hours in 4 of 5 eligible animals; 1 animal had a Neurological Deficit Score of 110 after 3 days. Brain histology revealed hypoxic and apoptotic neurons with an inconclusive correlation regarding neurological recovery. CONCLUSION: Clinically apparent neurological recovery after a period of 15 minutes of cardiac arrest occurred with cardiopulmonary bypass instead of cardiopulmonary resuscitation for reperfusing the whole body. This approach contrasts with cardiopulmonary resuscitation, in which resuscitation has been reported as successful after only 3 to 5 minutes of cardiac arrest. Cardiopulmonary bypass might be a key to improve survival and neurological recovery after cardiac arrest.

Endovascular treatment for thoracoabdominal aneurysms: outcomes and results.

OBJECTIVE: Endovascular treatment of thoracoabdominal aortic aneurysms (TAAA) in combination with selective open surgical revascularization may be an alternative to conventional surgical repair. We analyzed our patient outcomes after elective and emergent endovascular TAAA repair. METHODS: Mortality and outcome data from 21 consecutive patients treated with endovascular TAAA repair between 2000 and 2006 were reviewed. An integrated neuroprotective approach was used on all patients. Mortality risk estimates for open surgery (OS) were calculated using the published risk assessment models and compared to our outcomes. RESULTS: Of the 21 patients, 9 had acute presentation: acute pain (9), rupture (6), and malperfusion (1). The celiac axis was overstented in 15. Nine hybrid open surgical procedures were performed: visceral/renal arteries (5), infrarenal aorta (3) and complete arch revascularization (1). Eleven patients had previous aortic surgery. Thirty-day mortality rate was 4.8% (1/21, predicted OS value 8.3%), 1-, 2- and 3-year survival was 80%. One hospital death occurred due to ischemic colitis after inferior mesenteric artery overstenting. No patient with acute presentation died during the initial hospital admission. There was no paraplegia (predicted OS rate 11.46%) and one event of delayed temporary paraparesis 3 weeks after hospital discharge corrected with raising the blood pressure. Other neurologic complications included one minor left pontine stroke with complete resolution, postoperative confusion (1) and saphenous nerve injury (1). No new late endoleaks occurred after initial complete aneurysm exclusion. Five patients underwent early (<30 days) and four patients underwent late endovascular reinterventions for persistent endoleak. An additional reintervention included percutaneous stenting of a superior mesenteric artery stenosis. Actual freedom from late reintervention was 81%, and 76% at 1-, 2 and 3-year follow-up. Late major adverse events included one stent infection leading to multi-organ failure and death. CONCLUSIONS: Endovascular treatment of thoracoabdominal aneurysms with selective visceral and renal revascularization is associated with low mortality and can only be effectively performed by a surgeon. High-risk patients and those with acute presentation appear to benefit most from this therapy. Early results up to three years of this therapy are encouraging, but further follow up to validate long-term results is required.