The effects of donor-specific antibody characteristics on cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) causes late graft dysfunction and post-transplant mortality. Currently, the effects of different donor-specific antibodies (DSA) on the severity of CAV remain unclear. METHOD: We evaluated 526 adult heart transplant recipients at a single center between January 2010 and August 2015. Subjects were divided into those with DSA (n = 142) and those without DSA (n = 384, control). The DSA group was stratified into persistent DSA (n = 34), transient DSA (n = 105), 1:8 dilution DSA (n = 45), complement-binding (C1q) DSA (n = 36), Class I DSA (n = 37), and Class II DSA (n = 105). The primary outcome was the incidence of moderate-to-severe CAV (CAV 2/3) at 5-year follow-up. RESULTS: Subjects with persistent DSA, 1:8 dilution DSA, and C1q DSA had higher incidence of CAV 2/3 compared the control group (17.6%, 13.3%, and 16.7% vs. 3.1%, respectively; P≤ .001). The incidence of CAV 2/3 between subjects with transient DSA and the control group was similar (2.8% vs. 3.1%; P = .888). Subjects with Class II DSA also had higher incidence of CAV 2/3 (7.6% vs. 3.1%; P = .039). CONCLUSION: DSA that are persistent, 1:8 dilution positive, C1q positive, and Class II are associated with more severe grades of CAV. These DSA characteristics may prognosticate disease and warrant consideration for treatment.

Hypothermia promotes mitochondrial elongation In cardiac cells via inhibition of Drp1.

Hypothermia is a valuable clinical tool in mitigating against the consequences of ischemia in surgery, stroke, cardiac arrest and organ preservation. Protection is afforded principally by a reduction of metabolism, manifesting as reduced rates of oxygen uptake, preservation of ATP levels, and a curtailing of ischemic calcium overload. The effects of non-ischemic hypothermic stress are relatively unknown. We sought to investigate the effects of clinically mild-to-severe hypothermia on mitochondrial morphology, oxygen consumption and protein expression in normoxic hearts and cardiac cells. Normoxic perfusion of rat hearts at 28-32 °C was associated with inhibition of mitochondrial fission, evidenced by a reduced abundance of the active phosphorylated form of the fission receptor Drp1 (pDrp1S616). Abundance of the same residue was reduced in H9c2 cells subjected to hypothermic culture (25-32 °C), in addition to a reduced abundance of the Drp1 receptor MFF. Hypothermia-treated H9c2 cardiomyocytes exhibited elongated mitochondria and depressed rates of mitochondrial-associated oxygen consumption, which persisted upon rewarming. Hypothermia also promoted a reduction in mRNA expression of the capsaicin receptor TRPV1 in H9c2 cells. When normothermic H9c2 cells were transfected with TRPV1 siRNA we observed reduced pDrp1S616 and MFF abundance, elongated mitochondria, and reduced rates of mitochondrial-associated oxygen consumption, mimicking the effects of hypothermic culture. In conclusion hypothermia promoted elongation of cardiac mitochondria via reduced pDrp1S616 abundance which was also associated with suppression of cellular oxygen consumption. Silencing of TRPV1 in H9c2 cardiomyocytes reproduced the morphological and respirometric phenotype of hypothermia. This report demonstrates a novel mechanism of cold-induced inhibition of mitochondrial fission.

Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). The International Society for Heart and Lung Transplantation (ISHLT) subdivides PGD into 3 grades of increasing severity. Most studies have assessed risk factors for PGD without distinguishing between PGD severity grade. We sought to identify recipient, donor and surgical risk factors specifically associated with mild/moderate or severe PGD. METHODS: We identified 734 heart transplant recipients at our institution transplanted between January 1, 2012 and December 31, 2018. PGD was defined according to modified ISHLT criteria. Recipient, donor and surgical variables were analyzed by multinomial logistic regression with mild/moderate or severe PGD as the response. Variables significant in single variable modeling were subject to multivariable analysis via penalized logistic regression. RESULTS: PGD occurred in 24% of the cohort (n = 178) of whom 6% (n = 44) had severe PGD. One-year survival was reduced in recipients with severe PGD but not in those with mild or moderate PGD. Multivariable analysis identified 3 recipient factors: prior cardiac surgery, recipient treatment with ACEI/ARB/ARNI plus MRA, recipient treatment with amiodarone plus beta-blocker, and 3 surgical factors: longer ischemic time, more red blood cell transfusions, and more platelet transfusions, that were associated with severe PGD. We developed a clinical risk score, ABCE, which provided acceptable discrimination and calibration for severe PGD. CONCLUSIONS: Risk factors for mild/moderate PGD were largely distinct from those for severe PGD, suggesting a differing pathophysiology involving several biological pathways. Further research into mechanisms underlying the development of PGD is urgently needed.

Heart Transplantation for Giant Cell Myocarditis: A Case Series.

BACKGROUND: Giant cell myocarditis (GCM) has a poor prognosis without heart transplant, but post-transplant survival is unknown. PURPOSE: To describe the post-transplant survival of patients with GCM at a large transplant center. METHODS: Seven patients underwent heart transplant for histologically confirmed GCM of the explanted heart. The median age was 59 years, and 43% (3 of 7) were female. All patients had cardiogenic shock, multiorgan failure, elevated troponin, and recurrent ventricular tachycardia, and some required mechanical circulatory support. All patients received rabbit antithymocyte globulin (rATG) in the perioperative period at a dose of 1.5 mg/kg daily for 1 to 5 days and 4 received intravenous immunoglobulin 1 g/kg daily for 2 days after rATG. All patients had early initiation of tacrolimus by first to third postoperative day depending on renal function, early mycophenolate, and high dose steroid. All were maintained using tacrolimus, mycophenolate, and prednisone. RESULTS: One patient had asymptomatic recurrence of GCM at 3 months, managed by up-titration of tacrolimus, and had asymptomatic 2R cellular rejection at 4 months, managed with steroid bolus. No patient had high-grade rejection. One patient died at 267 days, possibly of GCM. Six of 7 (86%) remain alive at a median of 842 days (2.3 years) post transplant. CONCLUSIONS: Patients with GCM have excellent post-transplant survival with use of rATG and triple drug immunosuppressive therapy; however, some patients remain at risk for GCM recurrence after transplant, which may respond to augmented immunosuppression.

Successful Treatment of Severe COVID-19 Pneumonia With Clazakizumab in a Heart Transplant Recipient: A Case Report.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by an overwhelming cytokine response. Various treatment strategies have been attempted. METHODS AND RESULTS: A 61-year-old man with heart transplantation in 2017 presented with fever, cough, and dyspnea, and was confirmed positive for coronavirus disease 2019 (COVID-19). Laboratory tests showed significant elevations in C-reactive protein and interleukin-6 (IL-6). Echocardiogram showed left ventricular ejection fraction 58% (with ejection fraction 57% 6 months prior). Given the lack of clear management guidelines, the patient was initially managed symptomatically. However, the patient subsequently had a rapid respiratory deterioration with worsening inflammatory markers on day 5 of admission. Tocilizumab (anti-IL-6R) was in low supply in the hospital. The patient was offered clazakizumab (anti-IL-6) for compassionate use. Patient received 25 mg intravenously × 1 dose. Within 24 hours, he showed significant improvement in symptoms, oxygen requirements, radiological findings, and inflammatory markers. There was a transient leukopenia that improved in 4 days. He was discharged home on day 11, with negative nasopharyngeal SARS-CoV-2 PCR as an outpatient on day 35, development of positive serum COVID-19 IgG antibody, and he continued to do well on day 60, with no heart-related symptoms. CONCLUSION: Clazakizumab is a monoclonal antibody against human IL-6, which may be helpful in inhibiting the cytokine response to SARS-CoV-2 in COVID-19. Although not yet FDA approved, it is being investigated for treatment of renal antibody-mediated rejection. Clinical trials of clazakizumab for treatment of COVID-19 are underway worldwide.

Platelet Mapping by Thromboelastography and Whole Blood Aggregometry in Adult Patients Supported by Mechanical Circulatory Support Device on Aspirin Therapy.

Patients on mechanical circulatory support (MCS) devices are placed on aspirin and may require platelet function testing (PFT) to monitor the adequacy of therapy. Routine laboratory PFT is performed using whole blood aggregation (WBA) which typically has a long turnaround time (4-5 hours) and may not be readily available. By contrast, platelet mapping by thromboelastography (TPM) can provide results within 45 minutes. The objective of this study was to compare the results of TPM with WBA. We compared platelet mapping maximal amplitude (MA) by TPM with that of arachidonic acid (AA) to WBA with AA by impedance. We analyzed paired samples where both TPM and WBA were available. Of 45 paired samples, 34 were from 29 MCS patients and 11 were from non-MCS patients. When applying institutional interpretation guidelines with an MAActivator cutoff of ≤40 mm, WBAAA vs TPM MAAA in non-MCS and MCS patients correlated well with an accuracy of 100 and 94.4%, respectively. MAActivator >40 had poor correlation with an accuracy of 37.5%. Irrespective of MAActivator value, TPM AA inhibition expressed in percent of inhibition had poor accuracy. When used with proper guidelines for interpretation, specifically when MAActivator ≤ 40 mm, TPM is a suitable and reliable test to use for MCS patients on aspirin.

Combined Heart and Kidney Transplantation: Clinical Experience in 100 Consecutive Patients.

Background Combined heart and kidney transplantation ( HKT x) is performed in patients with severe heart failure and advanced renal insufficiency. We analyzed the long-term survival after HKT x, the influence of age and dialysis status, the rates of cardiac rejection, and the influence of sensitization. Methods and Results From June 1992 to December 2016, we performed 100 HKT x procedures. We compared older (≥60 years, n=53) with younger (<60 years, n=47) recipients, and recipients on preoperative dialysis (n=49) and not on dialysis (n=51). We analyzed actuarial freedom from any cardiac rejection, acute cellular rejection, and antibody-mediated rejection, and survival rates by sensitized status with panel-reactive antibody levels <10%, 10% to 50%, and >50%, and compared these survival rates with those from the United Network for Organ Sharing database. There was no difference in 15-year survival between the 2 age groups (35±12.4% and 49±17.3%, ≥60 versus <60 years; P=0.45). There was no difference in 15-year survival between the dialysis and nondialysis groups (44±13.4% and 37±15.2%, P=0.95). Actuarial freedom from any cardiac rejection ( acute cellular rejection >0 or antibody-mediated rejection >0) was 92±2.8% and 84±3.8%, acute cellular rejection (≥2R/3A) 98±1.5% and 94±2.5%, and antibody-mediated rejection (≥1) 96±2.1% and 93±2.6% at 30 days and 1 year after HKT x. There was no difference in the 5-year survival among recipients by sensitization status with panel-reactive antibody levels <10%, 10% to 50%, and >50% (82±5.9%, 83±10.8%, and 92±8.0%; P=0.55). There was no difference in 15-year survival after HKT x between the United Network for Organ Sharing database and our center (38±3.2% and 40±10.1%, respectively; P=0.45). Conclusions HKT x is safe to perform in patients 60 years and older or younger than 60 years and with or without dialysis dependence, with excellent outcomes. The degree of panel-reactive antibody sensitization did not appear to affect survival after HKT x.

Predicted heart mass is the optimal metric for size match in heart transplantation.

BACKGROUND: Donor-recipient size match is traditionally assessed by body weight. We assessed the ability of 5 size match metrics-predicted heart mass (PHM), weight, height, body mass index (BMI) and body surface area (BSA)-to predict 1-year mortality after heart transplant and to assess the effect of size match on donor heart turn down for size. METHODS: The study cohort comprised 19,168 adult heart transplant recipients in the United Network for Organ Sharing registry between 2007 and 2016. Each size match metric was divided into 7 equally sized groups using the donor-recipient ratio for each metric. Single and multivariable Cox proportional hazard models for mortality 1 year after transplant were constructed. RESULTS: Recipients in the severely (donor-recipient PHM ratio 0.54-0.86) undersized group for PHM experienced increased mortality, with a hazard ratio of 1.34 (95% confidence interval, 1.13-1.59; p < 0.001). There was no increased risk of death at 1 year if donors were undersized for weight, height, BMI, or BSA. We found that 32% of heart offers turned down for donor size would be acceptable using a PHM threshold of 0.86 or greater and that 14% of offers accepted (most of which are female donor to male recipient) were below this threshold. CONCLUSIONS: PHM is the optimal donor-recipient size match metric for prediction of mortality after heart transplant. Many offers turned down for donor size were above the threshold for adequacy of size match by PHM identified, and thus, the use of PHM could improve donor heart utilization and post-transplant survival.

Combining Stem Cell Therapy for Advanced Heart Failure and Ventricular Assist Devices: A Review.

The use of stem cell therapy in combination with a left ventricular assist device (LVAD) for patients with advanced heart failure (HF) is an attractive concept with the potential to alter the natural history of HF. Cell therapy trials for HF have demonstrated excellent safety and encouraging results, but current rates of myocardial recovery after LVAD implantation are limited. Early trials combining these 2 therapies to increase the likelihood of recovery and to potentially obviate the need for subsequent transplantation appear promising. Additionally, the application of cell therapy to patients undergoing LVAD implantation as a bridge to cardiac transplantation creates an opportunity to examine cardiac tissue before and after treatment and to study the mechanism of benefit. Despite the promise, there is a paucity of data for the combination of stem cell therapy with LVAD insertion in patients with HF. Of 11 case series or clinical trials, the largest enrolled 30 patients. We highlight clinical trials using stem cell therapy for end-stage HF most relevant to an LVAD patient population and comprehensively review the preclinical and clinical studies of combined stem cell therapy and long-term mechanical circulatory support. Based on the available clinical trials, the combination of stem cell therapy and LVAD support is a promising approach but requires further clinical refinement, with additional clinical data and larger numbers of patients required to support its clinical application.

Left Ventricular Reconstruction for Postinfarction Left Ventricular Aneurysm: Review of Surgical Techniques.

Different surgical techniques, each with its own advantages and disadvantages, have been used to reverse adverse left ventricular remodeling due to postinfarction left ventricular aneurysm. The most appropriate surgical technique depends on the location and size of the aneurysm and the scarred tissue, the patient's preoperative characteristics, and surgeon preference. This review covers the reconstructive surgical techniques for postinfarction left ventricular aneurysm.

Role of Thromboelastography Platelet Mapping and International Normalized Ratio in Defining "Normocoagulability" During Anticoagulation for Mechanical Circulatory Support Devices: A Pilot Retrospective Study.

Thromboembolic (TE) events and hemorrhagic complications continue to remain as frequent adverse events and causes of death after mechanical circulatory support device (MCSD) implantation. To counterbalance this postimplant multifactorial hypercoagulable state, antithrombotic therapy given postimplant must be individually tailored to keep patient adequately anticoagulated yet normocoagulable. Prior studies describing different anticoagulation protocols do not define normocoagulability for patients on MCSDs. We evaluated the role of thromboelastography platelet mapping (TEG PM) in defining "normocoagulability" for MCS patients on anticoagulant (warfarin) and antiplatelet agents. Ninety-eight MCSD patients who underwent TEG PM assay at our institution from 2012 to 2014 were included for retrospective analysis. Eleven (11.2%) subjects developed at least one TE event during the study period. Of the 13 TE events, 8 occurred in patients with total artificial heart (TAH). TEG parameters closest to the event or when patient was clinically adequately anticoagulated and corresponding international normalized ratio (INR) were measured. Thromboelastography coagulation index (CI) appears to be the single most statistically significant parameter that can be used to designate a patient as normocoagulable. Based on our results, patients with HeartMate II (HM II) and Heart Ware (HW) devices should be maintained at a CI value of less than or equal to 1.5 whereas patients with TAH devices should be maintained at a CI less than or equal to 1.2. The CI should be correlated with the degree of Vitamin K-dependent coagulation factor inhibition that is achieved using device-specific goal INR ranges. A recent modification, TEG PM assesses the effects of antiplatelet drug. Maximal amplitude arachidonic acid (MA-AA) < 50 and maximal amplitude adenosine diphosphate (MA-ADP) < 50 are desired for normocoagulable state.

Pathology of Chronic Chagas Cardiomyopathy in the United States: A Detailed Review of 13 Cardiectomy Cases.

OBJECTIVES: The pathologic features of chronic Chagas cardiomyopathy may not be widely appreciated in the United States. We sought to describe the gross, microscopic, immunohistochemical, and molecular pathology features useful to diagnose chronic Chagas cardiomyopathy. METHODS: The features from a case series of cardiectomy specimens of patients undergoing heart transplantation (12 patients) or mechanical circulatory support device implantation (one patient) for chronic Chagas cardiomyopathy at three institutions in the United States are reported and analyzed. RESULTS: Gross findings included enlarged and dilated ventricles (100% of cases), mural thrombi (54%), epicardial plaques (42%), and left ventricular aneurysm (36%). Microscopic evaluation revealed myocarditis (100% of cases) characterized by mononuclear cell infiltration, fibrosis (100%), nonnecrotizing granulomas (62%), and giant cells (38%). Two specimens (15%) showed rare intracellular amastigotes. Immunohistochemical assays for Trypanosoma cruzi organisms were negative in all cardiectomy specimens, whereas tissue polymerase chain reaction was positive in six (54%) of 11 cases. CONCLUSIONS: The gross and microscopic features of chronic Chagas cardiomyopathy in the United States appear similar to those reported in endemic countries. Importantly, tissue polymerase chain reaction may be useful to confirm the diagnosis.

Combined Lung-Kidney Transplantation: An Analysis of the UNOS/OPTN Database.

Poor outcomes after thoracic transplantation with concurrent renal dysfunction are well described: without transplantation or with thoracic-only transplantation, patients face unacceptably high mortality. Outcomes after combined lung-kidney transplantation (LKT) remain largely uninvestigated. The United Network for Organ Sharing/Organ Procurement and Transplantation Network database was queried to identify all LKTs, lung transplantations (LTs), and kidney transplantations (KTs) performed in the United States from 1995 to 2013. Survival was calculated using the Kaplan-Meier method and compared using log-rank tests or Cox regression models. Thirty-one LKTs were performed. Mean recipient age was 45.4 ± 13.5 years; 48.3 per cent were male. Retransplantation for graft failure was the leading indication for LT (n = 13) and the most common renal indication was calcineurin inhibitor nephrotoxicity (n = 11). Mean lung allocation score was 46.6 ± 14.4, mean creatinine was 3.7 ± 2.8 g/dL, and glomerular filtration rate was 23.1 (interquartile range 11.9, 38.3) mL/min/1.7 m(2), and 11 (35.5%) were dialysis dependent. Patient survival after LKT was 92.9 per cent, 71.0 per cent, and 71.0 per cent at one month, six months, and one year, with a median survival of 95.2 months. One- and five-year survival after LKT, 71.0 per cent and 59.9 per cent, were similar to LT (n = 23,913), 81.7 per cent and 51.4 per cent (P = 0.061 and 0.55), and inferior to KT (n = 175,269), 94.9 per cent and 82.8 per cent (P < 0.0001), respectively. Patient survival after LKT was similar to isolated LT, and these results suggest that LKT is a feasible therapeutic option for LT candidates with significant renal dysfunction.

Prevalence of Warfarin Genotype Polymorphisms in Patients with Mechanical Circulatory Support.

Polymorphisms for VKORC1 and CYP2C9 are associated with increased warfarin sensitivity. The prevalence of these polymorphisms in patients with mechanical circulatory support (MCS) is unknown. Polymorphisms for VKORC1 and CYP2C9 were determined in 65 patients undergoing MCS surgery. Postoperative warfarin dose, international normalized ratio (INR), and bleeding events were measured until discharge, 6 months, or composite end point (in-hospital MCS recovery, heart transplant, or death). A total of 67.7% (44/65) had at least one polymorphism: VKORC1 (44.6%), CYP2C9*2 (7.7%), CYP2C9*3 (4.6%), CYP2C9*2 and VKORC1 (3.1%), or CYP2C9*3 and VKORC1 (7.7%). At discharge or before composite end point, patients with any polymorphism received a lower mean warfarin dosage than patients having no polymorphism (3.21 ± 1.47 vs. 5.57 ± 3.72 mg, p = 0.015) and achieved a similar mean INR (2.20 ± 0.67 vs. 2.19 ± 0.69, p = 0.96). There was no significant difference in bleeding rates within 6 months or before composite end point (6.13 vs. 8.02 events/patient-year, p = 0.13). One or more polymorphisms for VKORC1 or CYP2C9 (associated with warfarin sensitivity) were found in 67.7% of MCS patients. By using a warfarin genotype-guided approach, MCS patients with polymorphisms received a lower warfarin dosage to achieve a similar INR, with similar bleeding rates, in comparison with no polymorphisms. A warfarin genotype-guided approach avoided excessive anticoagulation and its attendant bleeding risks.

Prevalence of hypertension in the Gambia and Sierra Leone, western Africa: a cross-sectional study.

BACKGROUND: Hypertension (HTN) is one of the causes of cardiovascular disease (CVD) in Africa, and may be associated with lower socio-economic status (SES). The prevalence of HTN is not well established in the Gambia or in Sierra Leone. METHODS: A cross-sectional, population-based study of adults was conducted in the Gambia in 2000 and in Sierra Leone from 2001 to 2003 and in 2009. The study was conducted as part of the annual visit to countries in western Africa sponsored by a medical delegation from California. People from the Gambia and Sierra Leone were examined by the medical delegation and blood pressures were measured. RESULTS: A total of 2 615 adults were examined: 1 400 females and 1 215 males. The mean systolic blood pressure (SBP) of the females was 134.3 ± 29.7 mmHg, mean diastolic blood pressure (DBP) was 84.5 ± 17.5 mmHg, and 46.2% were hypertensive. The mean SBP of the males was 132.8 ± 28.5 mmHg, mean DBP was 82.8 ± 16.2 mmHg, and 43.2% were hypertensive. Overall prevalence of HTN in the subjects was 44.8%. Mean SBP, mean DBP and HTN prevalence increased with age decade, both in males and females. In addition, after age adjustment (known age), females had higher mean SBP (p = 0.042), mean DBP (p = 0.001) and rate of occurrence of HTN (p = 0.016) when compared with males. CONCLUSIONS: Prevalence rates of HTN in the Gambia and Sierra Leone were higher than 40% in males and females, and may be a major contributor to CVD in both countries. Due to the association of HTN with low SES, improvements in educational, public health, economic, non-governmental and governmental efforts in the Gambia and Sierra Leone may lead to a lower prevalence of HTN. The cause of the higher prevalence in women may be due to post-menopausal hormonal changes.

Human cardiosphere-derived cells from advanced heart failure patients exhibit augmented functional potency in myocardial repair.

OBJECTIVES: This study sought to compare the regenerative potency of cells derived from healthy and diseased human hearts. BACKGROUND: Results from pre-clinical studies and the CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial support the notion that cardiosphere-derived cells (CDCs) from normal and recently infarcted hearts are capable of regenerating healthy heart tissue after myocardial infarction (MI). It is unknown whether CDCs derived from advanced heart failure (HF) patients retain the same regenerative potency. METHODS: In a mouse model of acute MI, we compared the regenerative potential and functional benefits of CDCs derived from 3 groups: 1) non-failing (NF) donor: healthy donor hearts post-transplantation; 2) MI: patients who had an MI 9 to 35 days before biopsy; and 3) HF: advanced cardiomyopathy tissue explanted at cardiac transplantation. RESULTS: Cell growth and phenotype were identical in all 3 groups. Injection of HF CDCs led to the greatest therapeutic benefit in mice, with the highest left ventricular ejection fraction, thickest infarct wall, most viable tissue, and least scar 3 weeks after treatment. In vitro assays revealed that HF CDCs secreted higher levels of stromal cell-derived factor (SDF)-1, which may contribute to the cells' augmented resistance to oxidative stress, enhanced angiogenesis, and improved myocyte survival. Histological analysis indicated that HF CDCs engrafted better, recruited more endogenous stem cells, and induced greater angiogenesis and cardiomyocyte cell-cycle re-entry. CDC-secreted SDF-1 levels correlated with decreases in scar mass over time in CADUCEUS patients treated with autologous CDCs. CONCLUSIONS: CDCs from advanced HF patients exhibit augmented potency in ameliorating ventricular dysfunction post-MI, possibly through SDF-1­mediated mechanisms.