Effects of ketone body 3-hydroxybutyrate on cardiac and mitochondrial function during donation after circulatory death heart transplantation.

Normothermic regional perfusion (NRP) allows assessment of therapeutic interventions prior to donation after circulatory death transplantation. Sodium-3-hydroxybutyrate (3-OHB) increases cardiac output in heart failure patients and diminishes ischemia-reperfusion injury, presumably by improving mitochondrial metabolism. We investigated effects of 3-OHB on cardiac and mitochondrial function in transplanted hearts and in cardiac organoids. Donor pigs (n = 14) underwent circulatory death followed by NRP. Following static cold storage, hearts were transplanted into recipient pigs. 3-OHB or Ringer's acetate infusions were initiated during NRP and after transplantation. We evaluated hemodynamics and mitochondrial function. 3-OHB mediated effects on contractility, relaxation, calcium, and conduction were tested in cardiac organoids from human pluripotent stem cells. Following NRP, 3-OHB increased cardiac output (P < 0.0001) by increasing stroke volume (P = 0.006), dP/dt (P = 0.02) and reducing arterial elastance (P = 0.02). Following transplantation, infusion of 3-OHB maintained mitochondrial respiration (P = 0.009) but caused inotropy-resistant vasoplegia that prevented weaning. In cardiac organoids, 3-OHB increased contraction amplitude (P = 0.002) and shortened contraction duration (P = 0.013) without affecting calcium handling or conduction velocity. 3-OHB had beneficial cardiac effects and may have a potential to secure cardiac function during heart transplantation. Further studies are needed to optimize administration practice in donors and recipients and to validate the effect on mitochondrial function.

Ex-situ oxygenated hypothermic machine perfusion in donation after circulatory death heart transplantation following either direct procurement or in-situ normothermic regional perfusion.

BACKGROUND: Heart transplantation in donation after circulatory death (DCD) relies on warm perfusion using either in situ normothermic regional perfusion (NRP) or ex situ normothermic machine perfusion. In this study, we explore an alternative: oxygenated hypothermic machine perfusion (HMP) using a novel clinically applicable perfusion system, which is compared to NRP with static cold storage (SCS). METHODS: In a porcine model, a DCD setting was simulated, followed by either (1) NRP and SCS (2) NRP and HMP with the XVIVO Heart preservation system or (3) direct procurement (DPP) and HMP. After preservation, heart transplantation (HTX) was performed. After weaning from cardiopulmonary bypass (CPB), biventricular function was assessed by admittance and Swan-Ganz catheters. RESULTS: Only transplanted hearts in the HMP groups showed significantly increased biventricular contractility (end-systole elastance) 2 hour post-CPB (left ventricle absolute change: NRP HMP: +1.8 ± 0.56, p = 0.047, DPP HMP: +1.5 ± 0.43, p = 0.045 and NRP SCS: +0.97 ± 0.47 mmHg/ml, p = 0.21; right ventricle absolute change: NRP HMP: +0.50 ± 0.12, p = 0.025, DPP HMP: +0.82 ± 0.23, p = 0.039 and NRP SCS: +0.28 ± 0.26, p = 0.52) while receiving significantly less dobutamine to maintain a cardiac output >4l/min compared to SCS. Diastolic function was preserved in all groups. Post-HTX, both HMP groups showed significantly less increments in plasma troponin T compared to SCS. CONCLUSION: In DCD HTX, increased biventricular contractility post-HTX was only observed in hearts preserved with HMP. In addition, the need for inotropic support and signs of myocardial damage were lower in the HMP groups. DCD HTX can be successfully performed using DPP followed by preservation with HMP in a preclinical setting.

Clamping of the Aortic Arch Vessels During Normothermic Regional Perfusion Does Not Negatively Affect Donor Cardiac Function in Donation After Circulatory Death.

BACKGROUND: The hemodynamic effects of aortic arch vessel (AAV) clamping during normothermic regional perfusion (NRP) in donation after circulatory death is unknown. We investigated effects of AAV clamping during NRP compared with no clamping in a porcine model. METHODS: In 16 pigs, hemodynamic parameters were recorded including biventricular pressure-volume measurements and invasive blood pressure. Additionally, blood gas parameters and inflammatory cytokines were used to assess the effect of AAV clamping. The animals were centrally cannulated for NRP, and baseline measurements were obtained before hypoxic circulatory arrest was induced by halting mechanical ventilation. During an 8-min asystole period, the animals were randomized to clamp (n = 8) or no-clamp (n = 8) of the AAV before commencement of NRP. During NRP, circulation was supported with norepinephrine (NE) and dobutamine. After 30 min of NRP, animals were weaned and observed for 180 min post-NRP. RESULTS: All hearts were successfully reanimated and weaned from NRP. The nonclamp groups received significantly more NE to maintain a mean arterial pressure >60 mm Hg during and after NRP compared with the clamp group. There were no between group differences in blood pressure or cardiac output. Pressure-volume measurements demonstrated preserved cardiac function' including ejection fraction and diastolic and systolic function. No between group differences in inflammatory markers were observed. CONCLUSIONS: AAV clamping did not negatively affect donor cardiac function or inflammation after circulatory death and NRP. Significantly less NE was used to support in the clamp group than in the nonclamp group.

Balloon pulmonary angioplasty for patients with chronic thromboembolic pulmonary hypertension previously operated by pulmonary endarterectomy.

Balloon pulmonary angioplasty improved hemodynamics, walking distance, and World Health Organization functional class in patients with chronic thromboembolic pulmonary hypertension not eligible for pulmonary endarterectomy (Non-PEA) and patients with persistent pulmonary hypertension after PEA (PEA). More mild complications were observed in PEA- compared to Non-PEA.

Association of residual pulmonary hypertension with survival after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

This study investigated whether residual pulmonary hypertension (PH), defined as early postoperative mean pulmonary artery pressure (mPAP) of ≥30 mmHg, after undergoing pulmonary endarterectomy (PEA) for chronic thromboembolic pulmonary hypertension (CTEPH) was associated with long-term survival. All patients who underwent PEA for CTEPH at two Scandinavian centers were included in this study. Baseline characteristics and vital statuses were obtained from patient charts and national health-data registers. The patients were then categorized based on residual PH measured via right heart catheterization within 48 h after undergoing PEA. Crude and weighted flexible parametric survival models were used to estimate the association between residual PH and all-cause mortality and to quantify absolute survival differences. From 1992 to 2020, 444 patients underwent surgery. We excluded 6 patients who died on the day of surgery and 12 patients whose early postoperative pulmonary hemodynamic data was unavailable. Of the total study population (n = 426), 174 (41%) and 252 (59%) patients had an early postoperative mPAP <30 and ≥30 mmHg, respectively. After weighting, there was a significant association between residual PH and all-cause mortality (hazard ratio: 2.49; 95% confidence interval [CI]: 1.60-3.87), and the absolute survival difference between the groups at 10 and 20 years was -22% (95% CI: -32% to -12%) and-32% (95% CI: -47% to -18%), respectively. A strong and clinically relevant association of residual PH with long-term survival after PEA for CTEPH was found. After accounting for differences in baseline characteristics, the absolute survival difference at long-term follow-up was clinically meaningful and imply careful surveillance to improve clinical outcomes in these patients. Early postoperative right heart catheter measurements of mPAP seem to be helpful for prognostication following PEA for CTEPH.

Sex and survival following pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension: a Scandinavian observational cohort study.

Studies have suggested sex-related survival differences in chronic thromboembolic pulmonary hypertension (CTEPH). Whether long-term prognosis differs between men and women following pulmonary endarterectomy for CTEPH remains unclear. We investigated sex-specific survival after pulmonary endarterectomy for CTEPH. We included all patients who underwent pulmonary endarterectomy for CTEPH at two Scandinavian centers and obtained baseline characteristics and vital statuses from patient charts and national health-data registers. Propensity scores and weighting were used to account for baseline differences. Flexible parametric survival models were employed to estimate the association between sex and all-cause mortality and the absolute survival differences. The expected survival in an age-, sex-, and year of surgery matched general population was obtained from the Human Mortality Database, and the relative survival was used to estimate cause-specific mortality. A total of 444 patients were included, comprising 260 (59%) men and 184 (41%) women. Unadjusted 30-day mortality was 4.2% in men versus 9.8% in women (p = 0.020). In weighted analyses, long-term survival did not differ significantly in women compared with men (hazard ratio: 1.36; 95% confidence interval: 0.89-2.06). Relative survival at 15 years conditional on 30-day survival was 94% (79%-107%) in men versus 75% (59%-88%) in women. In patients who underwent pulmonary endarterectomy for CTEPH, early mortality was higher in women compared with men. After adjustment for differences in baseline characteristics, female sex was not associated with long-term survival. However, relative survival analyses suggested that the observed survival in men was close to the expected survival in the matched general population, whereas survival in women deviated notably from the matched general population.

Long-term changes of exercise hemodynamics and physical capacity in chronic thromboembolic pulmonary hypertension after pulmonary thromboendarterectomy.

BACKGROUND: A substantial number of chronic thromboembolic pulmonary hypertension (CTEPH) patients experience dyspnea on exertion and limited exercise capacity despite surgically successful pulmonary endarterectomy (PEA). We sought to prospectively evaluate resting and peak exercise hemodynamics before, 3 and 12 months after PEA in consecutive CTEPH-patients and correlate it to physical functional capacity. METHODS AND RESULTS: Twenty consecutive CTEPH-patients were examined. Twelve months after PEA, 75% of patients with severely increased pre-PEA mean pulmonary arterial pressure (mPAP) at rest had normal or mildly increased mPAP. However, mPAP reduction was less pronounced during exercise where only 45% had normal or mildly increased mPAP at 12 months. Hemodynamic changes during exercise were tested using the pressure-flow relationship (i.e. mPAP/cardiac output (CO) slope). The average mPAP/CO slope was 7.5 ± 4.2 mm Hg/L/min preoperatively and 3.9 ± 3.0 mm Hg/L/min at 12 months (p < .005). CO reserve (CO increase from rest to peak exercise) was increased (5.7 ± 2.9 L/min) 12 months after PEA compared with pre-PEA (2.5 ± 1.8 L/min), p < .0001. However, 12 months after PEA, the CO reserve was only 49% of that of healthy controls, p < .0001. Changes in cardiac output (∆CO), calculated as the difference between CO before PEA and 12 months later, were significantly correlated with six-minute-walk-test and peak oxygen uptake (VO2), both at rest and peak exercise. CONCLUSION: Invasive exercise hemodynamic examination in CTEPH-patients demonstrates that after otherwise successful PEA surgery, >50% of patients have a significant increase in exercise mPAP, and the CO reserve remains compromised 12 months after PEA. Improvement in physical capacity is correlated with ∆CO.

Long-term changes of resting and exercise right ventricular systolic performance in patients with chronic thromboembolic pulmonary hypertension following pulmonary thromboendarterectomy - A two-dimensional and three-dimensional echocardiographic study.

AIMS: To characterize right ventricular (RV) geometry and function in chronic thromboembolic pulmonary hypertension (CTEPH) patients at rest and during exercise before pulmonary thromboendarterectomy (PEA), and at 3 and 12 months after PEA using two-dimensional and three-dimensional echocardiography with reference to clinical performance and exercise capacity. METHODS AND RESULTS: Forty subjects (20 CTEPH patients and 20 controls) were enrolled between December 2014 and January 2017. Three-dimensional echocardiography demonstrated a significant reduction and normalization of end-diastolic and end-systolic RV volumes in CTEPH patients 12 months after PEA. RV systolic function improved after PEA; however, tricuspid annular plane systolic excursion (TAPSE) (baseline 18 ± 6 mm vs 15 ± 3 mm at 12 months after PEA, P < .05) and tricuspid lateral annular systolic velocity (RV-S') (baseline -8.3 ± 2.1 cm/s vs -7.2 ± 1.3 cm/s at 12 months after PEA, P < .05) declined significantly after PEA. Tricuspid regurgitation gradient was 64 ± 21 mm Hg at baseline, 40 ± 14 mm Hg at 3 months, and 30 ± 13 at 12 months, P < .00001. RV free-wall longitudinal strain at peak exercise was significantly increased from baseline (-10.6 ± 5.5%) to 12 months of follow-up (-15.8 ± 5.2%), P < .005. Physical exercise capacity, measured as peak oxygen uptake, was significantly increased and correlated directly with improvement of resting and exercise-induced RV-EF. CONCLUSION: Improvement of RV geometry and systolic function, along with the reduction of systolic pulmonary pressure, can be expected following PEA in CTEPH patients during long-term follow-up. Improvement of RV myocardial contractility after PEA was only revealed at peak exercise over time. Importantly, physical exercise capacity was significantly increased and was found to be directly correlated with improvement of resting and exercise-induced RV-EF.

Large Solid Right Atrial Thrombus Treated by AngioVac Catheter-Based Suction Thrombectomy.

We present the successful treatment of a large solid right atrial thrombus by the catheter-based suction embolectomy system AngioVac® (AngioDynamics, NY, USA). A previously healthy 60-year-old male was referred with acute pulmonary embolism, a large deep vein thrombus and a large right atrial thrombus. After one week of anticoagulation, the size of the atrial thrombus was unaltered, and the patient was treated by catheter-directed embolectomy using the AngioVac system. The solid thrombus occluded the catheter during the procedure. With the vacuum maintained, the occluded catheter was removed from the patient and the thrombus mass was removed. The remaining atrial thrombus was successfully removed by suction after the reinsertion of the catheter. The patient recovered well and was discharged 7 days after the procedure. The therapy was safe and minimally invasive.

Results from more than 20 years of surgical pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension in Denmark.

OBJECTIVES: Chronic thromboembolic pulmonary hypertension is a fatal disease if left untreated, and pulmonary endarterectomy (PEA) is the potentially curable treatment of choice. We aimed to estimate the current in-hospital mortality rate, complication rate and long-term survival for patients with chronic thromboembolic pulmonary hypertension undergoing PEA in Denmark. METHODS: All chronic thromboembolic pulmonary hypertension patients who underwent PEA in the period 1994 till 2016 were consecutively enrolled in our single-centre study. All patients were followed from PEA until death or end of study. Kaplan-Meier survival analysis was used to estimate the 3-, 5- and 10-year survival rates with 95% confidence interval (CI). RESULTS: In total, 239 patients were operated in the study period. A significant reduction in mean pulmonary arterial pressure from 48 mmHg to 33 mmHg, and pulmonary vascular resistance from 800 dynes s cm-5 to 289 dynes s cm-5, was observed during the first postoperative day after PEA. Overall, in-hospital mortality rate was 8.4%. A significantly lower mortality rate in the late decade (2005-2016) compared with the early decade (1994-2004) was observed (4.3% vs 22.6%, P < 0.001). In-hospital mortality during the last 5 years (n = 80) was 2.5%. Three-, 5- and 10-year survival rates were 84% (CI: 77.8-88), 77% (CI: 70.7-82.7) and 62% (CI: 53-69.1), respectively. The majority of patients improved in World Health Organization functional class from III/IV to I/II and significantly increased their 6-min walking distance. CONCLUSIONS: PEA in Denmark is associated with a low in-hospital mortality rate and significant improvements in both haemodynamics and exercise capacity. Long-term survival is excellent and similar to high-volume international centres.

Left ventricular global longitudinal strain predicts major adverse cardiac events and all-cause mortality in heart transplant patients.

BACKGROUND: Left ventricular global longitudinal strain (LVGLS) is a robust longitudinal myocardial deformation marker that is strongly affected by cardiac allograft vasculopathy (CAV), microvascular dysfunction, and acute cellular rejection (ACR). We evaluated graft deformation for risk stratification in long-term heart transplant (HTx) patients. METHODS: The study included 196 patients who underwent HTx between 2011 and 2013. Patients underwent comprehensive echocardiography and coronary angiography. Previous rejection burden was assessed, and ACR grades were calculated. Patients were prospectively followed until February 24, 2016. Major adverse cardiac events (MACE), including coronary event, heart failure, treated rejection, and cardiovascular death, and all-cause mortality were recorded. RESULTS: During follow-up, 57 patients experienced MACE. Median follow-up was 1,035 (interquartile range [IQR] 856-1,124) days. Median time to first event was 534 (IQR 276-763) days. LVGLS was a strong predictor of MACE (hazard ratio [HR] 4.9, 95% confidence interval [CI] 2.7-8.9, p < 0.0001) in patients with and without CAV. LVGLS was a strong predictor of all-cause mortality (HR 4.9, 95% CI 2.2-10.8, p < 0.0001). Left ventricular ejection fraction (LVEF) also predicted MACE, but only in patients with CAV. No relationship between LVEF and all-cause mortality was seen. We obtained a strong MACE (HR 6.3, 95% CI 2.8-14.1, p < 0.0001) and all-cause mortality (HR 6.6, 95% CI 2.3-19.2, p < 0.0001) predictive model by combining LVGLS and restrictive left ventricular filling pattern (LVFP), which remained strong after adjustment for CAV, ACR score, hemoglobin, creatinine, and time since transplantation. CONCLUSIONS: Measurement of LVGLS strongly predicts MACE and mortality in long-term HTx patients. Predictive ability was seen in patients with and without CAV. A combined model of left ventricular systolic deformation by LVGLS and diastolic graft performance by LVFP was a stronger model for prediction of MACE and all-cause mortality.

[Diagnosis and treatment of chronic thromboembolic pulmonary hypertension in Denmark].

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important differential diagnosis in patients with unexplained dyspnoea. CTEPH is under-recognized and carries a poor prognosis without treatment. Surgical pulmonary endarterectomy is the preferred treatment for the majority of patients. Advances in surgical and anaesthetic techniques and post-operative intensive treatment have reduced perioperative morbidity and mortality. Pulmonary endarterectomy results in major improvement of haemodynamics and clinical status and offers excellent long-term survival. It is most often a curative treatment. The surgical treatment of CTEPH in Denmark is centralized at Aarhus University Hospital. Pulmonary vasodilators and pulmonary balloon angioplasty are supplementary treatment options in this patient group.

[A combination of cardiac arrest and cerebral haemorrhage treated with extracorporeal membrane oxygenation].

A 46-year-old, healthy woman with sudden hemiplegia and nausea suffered cardiac arrest during transport to the hospital. This was treated en route with LUCAS-2. A computed tomography ruled out cerebral haemorrhage, and an electricardiogramme showed inferior myocardial infarction. During percutaneous intervention the patient had another cardiac arrest. Despite revascularization she was very unstable and received more than 20 cardioversions of ventricular fibrillation. In the catheterization laboratory, the patient was connected to a heart lung machine (extracorporeal membrane oxygenation) while treated with LUCAS-2. After two months of hospitalization, the patient was able to walk and had minor cognitive impairment.

Twenty years' experience at the Heart Transplant Center, Aarhus University Hospital, Skejby, Denmark.

OBJECTIVES: The Heart Transplantation Center, Aarhus University Hospital, Skejby, now has 20 years' experience with heart transplantation (HTX). This study aims to evaluate long-term outcome after HTX including incidences of cancer and severe renal dysfunction. DESIGN: Outcomes were reviewed using the transplant database of our department, the Scandiatransplant database, hospital medical records, and national database of biopsies. RESULTS: From December 31, 1992 to February 27, 2013, a total of 258 patients underwent index HTX. Survival for the whole patient cohort at 1 month and 1 year was 95% and 88%. Long-term survival estimates of 5, 10, 15, and 20 years were 80%, 70%, 55%, and 40%, respectively. Median survival time was 15.6 years. Significant improvement in survival was observed from the 1992-1998 vs. 1999-2005 era and the 1992-1998 vs. the 2006-2012 era. Three patients (1%) underwent renal transplantation, and 29 patients (11%) developed severe renal dysfunction requiring dialysis. Sixty-four (25%) patients developed cancer, with skin cancer being most common. CONCLUSION: HTX is an excellent treatment for selected patients with end-stage heart failure. The prognosis has improved in the latest transplantation eras. With balanced immunosuppressive treatment, severe renal dysfunction and cancer can be limited to an acceptable level.

Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry.

OBJECTIVE: Pulmonary endarterectomy is a curative surgical treatment option for the majority of patients with chronic thromboembolic pulmonary hypertension. The current surgical management and postoperative outcome of patients enrolled in an international registry on chronic thromboembolic pulmonary hypertension were investigated. METHODS: The registry included newly diagnosed (≤6 months) consecutive patients with chronic thromboembolic pulmonary hypertension from February 2007 to January 2009. RESULTS: A total of 679 patients were registered from 1 Canadian and 26 European centers, of whom 386 (56.8%) underwent surgery. The median age of patients undergoing surgery was 60 years, and 54.1% were male. Previous pulmonary embolism was confirmed for 79.8% of patients. Perioperative complications occurred in 189 patients (49.2%): infection (18.8%), persistent pulmonary hypertension (16.7%), neurologic (11.2%) or bleeding (10.2%) complications, pulmonary reperfusion edema (9.6%), pericardial effusion (8.3%), need for extracorporeal membrane oxygenation (3.1%), and in-hospital mortality due to perioperative complications (4.7%). Documented 1-year mortality was 7%. Preoperative exercise capacity was predictive of 1-year mortality. Postoperative pulmonary vascular resistance predicted in-hospital and 1-year mortality. In patients evaluated within 1 year after surgery, the median pulmonary vascular resistance had decreased from 698 to 235 dyn x s x cm(-5) (95% confidence limit, 640-874 and 211-255, respectively, n = 70) and the median 6-minute walk distance had increased from 362 to 459 m (95% confidence limit, 340-399 and 440-473, respectively, n = 168). New York Heart Association functional class improved with most patients progressing from class III/IV to class I/II. CONCLUSIONS: Pulmonary endarterectomy is associated with a low in-hospital mortality rate and improvements in hemodynamics and exercise capacity.