Novel Role for Cardiolipin as a Target of Therapy to Mitigate Myocardial Injury Caused by Venoarterial Extracorporeal Membrane Oxygenation.

BACKGROUND: Cardiolipin is a mitochondrial-specific phospholipid that maintains integrity of the electron transport chain (ETC) and plays a central role in myocardial ischemia/reperfusion injury. Tafazzin is an enzyme that is required for cardiolipin maturation. Venoarterial extracorporeal membrane oxygenation (VA-ECMO) use to provide hemodynamic support for acute myocardial infarction has grown exponentially, is associated with poor outcomes, and is under active clinical investigation, yet the mechanistic effect of VA-ECMO on myocardial damage in acute myocardial infarction remains poorly understood. We hypothesized that VA-ECMO acutely depletes myocardial cardiolipin and exacerbates myocardial injury in acute myocardial infarction. METHODS: We examined cardiolipin and tafazzin levels in human subjects with heart failure and healthy swine exposed to VA-ECMO and used a swine model of closed-chest myocardial ischemia/reperfusion injury to evaluate the effect of VA-ECMO on cardiolipin expression, myocardial injury, and mitochondrial function. RESULTS: Cardiolipin and tafazzin levels are significantly reduced in the left ventricles of individuals requiring VA-ECMO compared with individuals without VA-ECMO before heart transplantation. Six hours of exposure to VA-ECMO also decreased left ventricular levels of cardiolipin and tafazzin in healthy swine compared with sham controls. To explore whether cardiolipin depletion by VA-ECMO increases infarct size, we performed left anterior descending artery occlusion for a total of 120 minutes followed by 180 minutes of reperfusion in adult swine in the presence and absence of MTP-131, an amphipathic molecule that interacts with cardiolipin to stabilize the inner mitochondrial membrane. Compared with reperfusion alone, VA-ECMO activation beginning after 90 minutes of left anterior descending artery occlusion increased infarct size (36±8% versus 48±7%; P<0.001). VA-ECMO also decreased cardiolipin and tafazzin levels, disrupted mitochondrial integrity, reduced electron transport chain function, and promoted oxidative stress. Compared with reperfusion alone or VA-ECMO before reperfusion, delivery of MTP-131 before VA-ECMO activation reduced infarct size (22±8%; P=0.03 versus reperfusion alone and P<0.001 versus VA-ECMO alone). MTP-131 restored cardiolipin and tafazzin levels, stabilized mitochondrial function, and reduced oxidative stress in the left ventricle. CONCLUSIONS: We identified a novel mechanism by which VA-ECMO promotes myocardial injury and further identify cardiolipin as an important target of therapy to reduce infarct size and to preserve mitochondrial function in the setting of VA-ECMO for acute myocardial infarction.

Intraoperative Hemodynamic and Echocardiographic Measurements Associated With Severe Right Ventricular Failure After Left Ventricular Assist Device Implantation.

BACKGROUND: Severe right ventricular failure (RVF) after left ventricular assist device (LVAD) implantation increases morbidity and mortality. We investigated the association between intraoperative right heart hemodynamic data, echocardiographic parameters, and severe versus nonsevere RVF. METHODS: A review of LVAD patients between March 2013 and March 2016 was performed. Severe RVF was defined by the need for a right ventricular mechanical support device, inotropic, and/or inhaled pulmonary vasodilator requirements for >14 days. From a chart review, the right ventricular failure risk score was calculated and right heart hemodynamic data were collected. Pulmonary artery pulsatility index (PAPi) [(pulmonary artery systolic pressure - pulmonary artery diastolic pressure)/central venous pressure (CVP)] was calculated for 2 periods: (1) 30 minutes before cardiopulmonary bypass (CPB) and (2) after chest closure. Echocardiographic data were recorded pre-CPB and post-CPB by a blinded reviewer. Univariate logistic regression models were used to examine the performance of hemodynamic and echocardiographic metrics. RESULTS: A total of 110 LVAD patients were identified. Twenty-five did not meet criteria for RVF. Of the remaining 85 patients, 28 (33%) met criteria for severe RVF. Hemodynamic factors associated with severe RVF included: higher CVP values after chest closure (18 ± 9 vs 13 ± 5 mm Hg; P = .0008) in addition to lower PAPi pre-CPB (1.2 ± 0.6 vs 1.7 ± 1.0; P = .04) and after chest closure (0.9 ± 0.5 vs 1.5 ± 0.8; P = .0008). Post-CPB echocardiographic findings associated with severe RVF included: larger right atrial diameter major axis (5.4 ± 0.9 vs 4.9 ± 1.0 cm; P = .03), larger right ventricle end-systolic area (22.6 ± 8.4 vs 18.5 ± 7.9 cm; P = .03), lower fractional area of change (20.2 ± 10.8 vs 25.9 ± 12.6; P = .04), and lower tricuspid annular plane systolic excursion (0.9 ± 0.2 vs 1.1 ± 0.3 cm; P = .008). Right ventricular failure risk score was not a significant predictor of severe RVF. Post-chest closure CVP and post-chest closure PAPi discriminated severe from nonsevere RVF better than other variables measured, each with an area under the curve of 0.75 (95% CI, 0.64-0.86). CONCLUSIONS: Post-chest closure values of CVP and PAPi were significantly associated with severe RVF. Echocardiographic assessment of RV function post-CPB was weakly associated with severe RVF.

Intraoperative Administration of 4-Factor Prothrombin Complex Concentrate Reduces Blood Requirements in Cardiac Transplantation.

OBJECTIVE: Assessing the efficacy of intraoperative 4-factor prothrombin complex concentrate (4F-PCC) use in blood product utilization, time to chest closure, intensive care unit (ICU) and hospital length of stay (LOS), thromboembolic complications, renal injury and mortality in left ventricular assist device (LVAD) patients on home anticoagulation therapy with warfarin, undergoing orthotopic heart transplantation (OHT). DESIGN: Retrospective analysis of OHT patients at Tufts Medical Center from May 2013 to October 2016. SETTING: Single-institution, university hospital setting. PARTICIPANTS: Patients with preexisting LVADs who received orthotopic heart transplants (n = 74; 32 patients 4F-PCC, 42 patients no 4F-PCC). INTERVENTIONS: Warfarin reversal using 4F-PCC in patients with LVADs undergoing orthotopic heart transplantation with the 4F-PCC dosing partitioned such that one-third was given pre-CPB and two-thirds were given post-CPB. MEASUREMENTS AND MAIN RESULTS: The 4F-PCC group required less plasma (6 [IQR 4] v 1.31 [IQR 2] U, p < 0.001), cryoprecipitate (10 [IQR 10] v 7.50 [IQR 5] U, p < 0.001), and packed red blood cells (5 [IQR 4] v 2 [IQR 1.5] U, p < 0.001) and had a shorter time to chest closure (618.8 ± 111.4 v 547.9 ± 110.1 minutes, p = 0.008). There was no difference in platelet transfusion (2 [IQR 1] v 2 [IQR 1] U, p = 0.16), ICU or hospital LOS, acute kidney injury, or mortality. No thrombotic complications occurred. CONCLUSIONS: Replacing plasma with 4F-PCC to reverse preoperative warfarin anticoagulation during OHT was associated with a shorter time to chest closure and less blood product utilization, without an increase in acute kidney injury, thromboembolic complications, or death.

Initial experience with the AbioCor implantable replacement heart system.

OBJECTIVE: We sought to evaluate the safety and efficacy of the first available totally implantable replacement heart (AbioCor Implantable Replacement Heart System) in the treatment of severe, irreversible biventricular heart failure in human patients. METHODS: Seven male adult patients with severe, irreversible biventricular failure (>70% thirty-day predicted mortality) who were not candidates for transplantation met all institutional review board study criteria and had placement of the AbioCor Implantable Replacement Heart. All were in cardiogenic shock despite maximal medical therapy, including inotropes and intra-aortic balloon pumps. Mean age was 66.7 +/- 10.4 years (range, 51-79 years). Four of 7 patients had prior operations. Six had ischemic and one had idiopathic cardiomyopathy. All had 3-dimensional computer-simulated implantation of the thoracic unit that predicted adequate fit. At the time of the operation, the internal transcutaneous energy transfer coil, battery, and controller were placed. Biventriculectomy was then performed, and the thoracic unit was placed in an orthotopic position and attached to the atrial cuffs and outflow conduits with quick-connects. The flow was adjusted to 4 to 8 L/min. Central venous and left atrial pressures were maintained at 5 to 15 mm Hg. The device is powered through transcutaneous energy transfer. An atrial flow-balancing chamber is used to adjust left/right balance. The balance chamber and transcutaneous energy transfer eliminate the need for percutaneous lines. RESULTS: There was one intraoperative death caused by coagulopathic bleeding and one early death caused by an aprotinin reaction. There have been multiple morbidities primarily related to preexisting illness severity: 5 patients had prolonged intubation, 2 had hepatic failure (resolved in 1), 4 had renal failure (resolved in 3), and 1 each had recurrent gastrointestinal bleeding, acute cholecystitis requiring laparotomy, respiratory failure that resolved after 3 days of extracorporeal membrane oxygenation, and malignant hyperthermia (resolved). There were 3 late deaths: one caused by multiple systems organ failure (postoperative day 56), one caused by a cerebrovascular accident (postoperative day 142), and one caused by retroperitoneal bleeding and resultant multiple systems organ failure (postoperative day 151). This latter patient was not able to tolerate anticoagulation (no anticoagulation or antiplatelet therapy alone for 80% of the first 60 days) and had a transient ischemic attack on postoperative day 61 and a cerebrovascular accident on postoperative day 130. At autopsy, blood pumps were clean. The 2 patients who had large cerebrovascular accidents had thrombus on the atrial cage struts. These struts have been removed for future implants. There has been no significant hemolysis or device-related infections. The balance chamber has allowed for left/right balance in all patients (left atrial pressure within 5 mm Hg of right atrial pressure). Three patients have taken multiple (>50) trips out of the hospital, and 2 have been discharged from the hospital. Total days on support with the AbioCor are 759. CONCLUSION: The initial clinical experience suggests that the AbioCor might be effective therapy in patients with advanced biventricular failure. There have been no significant device malfunctions. Two of these patients have been discharged from the hospital.

The AbioCor implantable replacement heart.

The AbioCor implantable replacement heart (IRH) is the first available totally implantable artificial heart. We recently initiated a multicenter trial of this device in patients with severe, irreversible biventricular failure. Patients who were not candidates for other therapies, including transplantation, were evaluated. All candidates were adults with inotrope-dependent biventricular failure, whose 30-day predicted mortality was higher than 70%. A three-dimensional computerized fit study predicted fit of the AbioCor thoracic unit in all recipients. At operation, the internal battery controller and transcutaneous energy transfer unit were placed. The AbioCor thoracic unit was placed in an orthotopic position after incision of the ventricals. There were 2 intraoperative deaths (due to intraoperative bleeding or aprotinin reaction). Four late deaths were recorded, 1 from multisystem organ failure and 3 cerebrovascular accidents. Autopsy revealed thrombus on the atrial struts of the 3 patients with cerebrovascular accident. Blood pumps and valves were clean on all patients. Significant morbidity was observed, primarily related to preexisting severity of illness. However, 3 patients recovered to the point of being able to take multiple trips outside of the hospital. Two patients were discharged from the hospital, with 1 patient being discharged home for more than 7 months. No significant device malfunctions or multi-system organ failure device-related infections were noted. The AbioCor IRH may be effective therapy for patients with end-stage heart failure. Many milestones have been achieved in the initial trial in humans, including the successful discharge of a patient to home and no significant device malfunctions. The occurrence of stroke is likely related to the presence of thrombus on the atrial struts and may be decreased as these atrial struts have been removed for future clinical implants.