Incidence, Risk Factors, and Outcomes of Stroke Following Cardiac Transplantation.

Background and Purpose: Less is known about the risk factors and outcomes associated with stroke in the current era of increasing heart transplantation (HT) being performed in older patients. The impact of immunosuppression on risk of stroke has not yet been previously studied. We aimed to determine the incidence, risk factors and outcomes of stroke after HT. Methods: We retrospectively analyzed the incidence of ischemic and hemorrhagic strokes and associated outcomes in all consecutive HT recipients transplanted between 1994 and 2016 at a single institution. Results: Of 529 patients who underwent HT, 57 (10.7%) developed stroke, 8.1% had an ischemic events and (2.6%) had a hemorrhagic stroke. Age at HT (adjusted hazard ratio [HR] 1.33; P=0.03) and diabetes (HR, 2.60; P=0.02) were associated with increased risk of ischemic events. Patients with stroke (any type) were more likely to have worse kidney function (HR, 1.81; P=0.02) whereas patients with ischemic events were more likely to undergo combined organ transplantation (HR, 2.01; P=0.05). Cytomegalovirus infection was found to be associated with increased risk of any stroke (HR, 2.09; P=0.02).Conversion from calcineurin inhibitor to sirolimus-based immunosuppression was not found to be associated with a significant change in stroke risk (HR, 1.39; P=0. 45) compared with calcineurin inhibitor maintenance therapy. Stroke of any type and ischemic events were independently associated with increased risk of death (HR, 1.90; P=0.001 and HR, 2.14; P<0.001, respectively). Conclusions: Stroke after HT is associated with increased mortality. Older age at HT, diabetes, renal dysfunction, and CMV infection were associated with greater risk of stroke.

Effects of mTOR inhibitor-related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients.

We have previously described the use of sirolimus (SRL) as primary immunosuppression following heart transplantation (HT). The advantages of this approach include attenuation of cardiac allograft vasculopathy (CAV), improvement in glomerular filtration rate (GFR), and reduced malignancy. However, in some patients SRL may cause significant proteinuria. We sought to investigate the prognostic value of proteinuria after conversion to SRL. CAV progression and adverse clinical events were studied. CAV progression was assessed by measuring the Δ change in plaque volume (PV) and plaque index (PI) per year using coronary intravascular ultrasound. Proteinuria was defined as Δ urine protein ≥300 mg/24 h at 1 year after conversion to SRL. Overall, 137 patients were analyzed (26% with proteinuria). Patients with proteinuria had significantly lower GFR (P = .005) but similar GFR during follow-up. Delta PV (P < .001) and Δ PI (P = .001) were significantly higher among patients with proteinuria after adjustment for baseline characteristics. Multivariate Cox regression analysis showed higher all-cause mortality (hazard ratio 3.8; P = .01) with proteinuria but similar risk of CAV-related events (P = .61). Our results indicate that proteinuria is a marker of baseline renal dysfunction, and that HT recipients who develop proteinuria after conversion to SRL have less attenuation of CAV progression and higher mortality risk.

Association of Aspirin Treatment With Cardiac Allograft Vasculopathy Progression and Adverse Outcomes After Heart Transplantation.

BACKGROUND: Enhanced platelet reactivity may play a role in cardiac allograft vasculopathy (CAV) progression. The use of antiplatelet agents after heart transplantation (HT) has been inconsistent and although aspirin (ASA) is often a part of the medication regimen after HT, limited evidence is available on its benefit. METHODS AND RESULTS: CAV progression was assessed by measuring the difference in plaque volume and plaque index between the last follow-up and the baseline coronary intravascular ultrasound examination. Overall, 529 HT recipients were retrospectively analyzed (337 had ≥2 intravascular ultrasound studies). The progression in plaque volume (P = .007) and plaque index (P = .002) was significantly attenuated among patients treated with early ASA (within the first year after HT). Over a 6.7-year follow-up, all-cause mortality was lower with early ASA compared with late or no ASA use (P < .001). No cardiac deaths were observed in the early ASA group, and the risk of CAV-related graft dysfunction was significantly lower in this group (P = .03). However, the composite of all CAV-related events (cardiac death, CAV-related graft dysfunction, or coronary angioplasty) was not significantly different between the groups (P = .16). CONCLUSIONS: Early ASA use after HT may delay CAV progression and decrease mortality and CAV-related graft dysfunction, but does not seem to affect overall CAV-associated events.

Outcomes of Patients With Familial Transthyretin Amyloidosis After Liver Transplantation.

BACKGROUND: Familial transthyretin amyloidosis is a disease caused by misfolded transthyretin aggregates that can impair multiple organ systems. Liver transplantation is the first-line treatment for familial transthyretin amyloidosis. RESEARCH QUESTION: Our objective is to study outcomes and survival among patients with familial transthyretin amyloidosis after transplantation. DESIGN: All patients undergoing orthotopic liver transplant for familial transthyretin amyloidosis at Mayo Clinic between 1997 and 2012 were reviewed. Baseline clinical characteristics, organs transplanted, and posttransplant clinical course were assessed. RESULTS: Of the 40 patients, 7 patients had the V30M mutation and 33 had other mutations. Nineteen patients received liver only, 19 liver and heart, and 2 combined liver, heart, and kidney transplants. The 5-year overall survival was 85% for those receiving multiple organ transplant and 52% for those receiving liver transplant only ( P = .057). There was no difference in overall survival based on mutation (V30M vs other mutations), but survival was confounded by varied disease involvement and organs transplanted. Those who had early death (≤24 months from liver transplant) had a higher incidence of baseline peripheral neuropathy, autonomic neuropathy, lower modified BMI, and higher alkaline phosphatase. DISCUSSION: Outcomes of orthotopic liver transplant in familial transthyretin amyloidosis are variable due to heterogeneity in mutations and patient status at the time of transplant. Familial transthyretin amyloidosis can progress, despite liver transplantation. Patients receiving combined liver, heart/kidney transplant demonstrated improved survival compared to liver transplant alone.

Current indications, strategies, and outcomes with cardiac transplantation for cardiac amyloidosis and sarcoidosis.

PURPOSE OF REVIEW: We describe the general strategies for the management of cardiac amyloidosis with particular focus on the use of cardiac transplantation for amyloid cardiomyopathy. Within this article, we highlight recent data regarding the use of combined heart transplant-chemotherapy, use of cardiac transplant in mutant amyloid disease, and underutilization of cardiac transplantation in sarcoidosis. RECENT FINDINGS: Several center experiences have been recently published, describing management strategies in AL amyloid, with focus on timing of chemotherapy as it relates to transplant, and in mutant amyloid in particular. SUMMARY: Outcomes after heart transplantation are typically worse than in patients undergoing heart transplantation for nonamyloid disease. Staged heart transplantation followed by autologous stem cell transplant therapy appears to provide the best long-term outcome for AL amyloid in highly selected patients. Mutant transthyretin amyloidosis is a disorder related to production of abnormal transthyretin protein in the liver. Combined heart/liver transplant has been utilized to treat both the production of the abnormal transthyretin protein and manage the cardiac dysfunction in highly selected patients, with favorable outcomes. Wild-type transthyretin amyloidosis occurs predominantly in older men. Cardiac transplantation can be utilized for highly selected patients. Sarcoidosis with cardiac involvement, unresponsive to immunosuppressive therapy, may be treated successfully with cardiac transplantation.

Red-shifted emission from 1,2-dioxetane-based chemiluminescent reactions.

Commercial chemiluminescent reagents emit across a broad portion of the electromagnetic spectrum (400-500 nm). A challenge to the use of chemiluminescence to monitor biological processes is the presence of interfering substances in the biological optical window. In the present study, longer wavelength emitting fluorophores (the organic dyes Alexa 568 and Alexa 647), and a semiconductor nanoparticle (QDOT800) were used to red-shift the emission from commercially available 1,2-dioxetane-based chemiluminescent substrate reactions. By adding non-conjugated fluorescent emitters into chemiluminescent reaction mixtures, an emission peak occurred at the predicted wavelength of the fluorescent emitter. The excitation and emission from QDOT800 was preserved in the presence of a 100 µm-thick glass barrier separating it from the chemiluminescent reaction components. The maximum tissue phantom penetration by QDOT800 emission was 8.5 mm; in comparison, the native chemiluminescent emission at 500 nm was unable to penetrate the thinnest tissue phantom of 2.5 mm. The described method for red-shifted emissions from chemiluminescent reactions does not require direct interaction between the chemiluminescent reaction and the fluorescent emitters. This suggests that the mechanism of chemiluminescent excitation of fluorophores and QDOT800 is not exclusive to chemiluminescence resonance energy transfer or sensitized chemiluminescence, but rather by broad energization from the native chemiluminescent emission.

Sirolimus as primary immunosuppression attenuates allograft vasculopathy with improved late survival and decreased cardiac events after cardiac transplantation.

BACKGROUND: We retrospectively analyzed the potential of sirolimus as a primary immunosuppressant in the long-term attenuation of cardiac allograft vasculopathy progression and the effects on cardiac-related morbidity and mortality. METHODS AND RESULTS: Forty-five cardiac transplant recipients were converted to sirolimus 1.2 years (0.2, 4.0) after transplantation with complete calcineurin inhibitor withdrawal. Fifty-eight control subjects 2.0 years (0.2, 6.5 years) from transplantation were maintained on calcineurin inhibitors. Age, sex, ejection fraction, and time from transplantation to baseline intravascular ultrasound study were not different (P>0.2 for all) between the groups; neither were secondary immunosuppressants and use of steroids. Three-dimensional intravascular ultrasound studies were performed at baseline and 3.1 years (1.3, 4.6 years) later. Plaque index progression (plaque volume/vessel volume) was attenuated in the sirolimus group (0.7±10.5% versus 9.3±10.8%; P=0.0003) owing to reduced plaque volume in patients converted to sirolimus early (<2 years) after transplantation (P=0.05) and improved positive vascular remodeling (P=0.01) in patients analyzed late (>2 years) after transplantation. Outcome analysis in 160 consecutive patients maintained on 1 therapy was performed regardless of performance of intravascular ultrasound examinations. Five-year survival was improved with sirolimus (97.4±1.8% versus 81.8±4.9%; P=0.006), as was freedom from cardiac-related events (93.6±3.2% versus 76.9±5.5%; P=0.002). CONCLUSIONS: Substituting calcineurin inhibitor with sirolimus as primary immunosuppressant attenuates long-term cardiac allograft vasculopathy progression and may improve long-term allograft survival owing to favorable coronary remodeling. Because of the lack of randomization and retrospective nature of our analysis, the differences in outcome should be interpreted cautiously, and prospective clinical trials are required.

TPMT genetic variants are associated with increased rejection with azathioprine use in heart transplantation.

OBJECTIVES: Azathioprine (AZA) is an important immunosuppressant drug used in heart transplantation (HTX). Consensus guidelines recommend that patients with thiopurine S-methyltransferase (TPMT) genetic variants be started on lower AZA dose because of higher active metabolite levels and risk of adverse events. However, in-vitro lymphocyte proliferation assays performed in participants with inactive TPMT alleles have suggested that AZA use may result in decreased immunosuppressant efficacy as compared with wild-type (WT) individuals. The objective of this study was therefore to determine the effect of TPMT genetic variation on AZA efficacy or prevention of rejection in HTX recipients treated with AZA. PARTICIPANTS AND METHODS: We genotyped 93 HTX recipients treated with AZA and measured erythrocyte TPMT enzyme activity. Acute rejection was monitored by routine endomyocardial biopsies. RESULTS: There were 83 WT and 10 heterozygote (HZ) HTX recipients. TPMT activity level was lower in HZ compared with WT (13.1±2.8 vs. 21±4.5 U/ml red blood cell, P<0.001). Despite similar AZA dose, HZ developed severe rejection earlier (P<0.001), and the total rejection score was higher (P=0.02) than WT. AZA was discontinued more frequently in HZ (P=0.01) because of rejection. The incidence of leukopenia was similar between the groups (40 vs. 43%, P=1.0). CONCLUSION: HTX recipients with TPMT genetic variant alleles who are treated with AZA develop acute rejection earlier, more frequently, and of greater severity. These patients, despite having lower TPMT enzymatic activity, should be monitored carefully for possible increased risk of acute rejection.

Decreased postoperative atrial fibrillation following cardiac transplantation: the significance of autonomic denervation.

BACKGROUND: Endocardial ablation approaches targeting the retroatrial cardiac ganglia to treat atrial fibrillation (AF) have been proposed. However, the potential value using this approach is unknown. Disruption of the autonomic inputs with orthotropic heart transplant (OHT) provides a unique opportunity to study the effects of autonomic innervation on AF genesis and maintenance. We hypothesized that due to denervation, the risk of postoperative AF would be lower following OHT compared to surgical maze even though both groups get isolation of the pulmonary veins. METHODS AND RESULTS: We reviewed 155 OHTs (mean age 52 ± 11 years, 72% males) and used 1:1 age-, sex-, and date-of-surgery-matched two control groups from patients undergoing surgical maze or only coronary artery bypass grafting (CABG). Using conditional logistic regression we compared the odds of AF within 2 weeks following OHT versus controls. Postoperative AF occurred in 10/155 (6.5%) OHT patients. The conditional odds of postoperative AF were lower for OHT as compared to controls (vs maze: odds ratio [OR] 0.27 [95% confidence interval (CI) 0.13-0.57], vs CABG: OR 0.38 [0.17-0.81], P = 0.003; and on additional adjustment for left atrial enlargement, vs maze: OR 0.28 [0.13-0.60], vs CABG: OR 0.14 [0.04-0.47], P = 0.0009). CONCLUSIONS: Risk of postoperative AF is significantly lower with OHT as in comparison to surgical maze. As both surgeries entail isolation of the pulmonary veins but only OHT causes disruption of autonomic innervation, this observation supports a mechanistic role of autonomic nervous system in AF. The benefit of targeting the cardiac autonomic system to treat AF needs further investigation.

Optimizing Referral Timing of Patients With Fontan Circulatory Failure for Heart Transplant.

BACKGROUND: There are no criteria guiding the timing of heart transplant referral for Fontan patients, nor are there any characteristics of those deferred or declined listing reported. This study examines comprehensive transplant evaluations for Fontan patients of all ages, listing decisions, and outcomes to inform referral practices. METHODS: Retrospective review of 63 Fontan patients formally assessed by the advanced heart failure service and presented at Mayo Clinic transplant selection committee meetings (TSM) January 2006 to April 2021. The study is compliant with the Helsinki Congress and Declaration of Istanbul and included no prisoners. Statistical analysis was performed with Wilcoxon Rank Sum and Fisher's Exact tests. RESULTS: Median age at TSM was 26 years (17.5, 36.5). Most were approved (38/63 [60%]); 9 of 63 (14%) were deferred and 16 of 63 (25%) were declined. Approved patients more commonly were <18 years old at TSM (15/38 [40%] vs 1/25 [4%], P = .002) compared with those deferred/declined. Complications of Fontan circulatory failure were less common in approved vs deferred/declined patients: ascites (15/38 [40%] vs 17/25 [68%], P = .039), cirrhosis (16/38 [42%] vs 19/25 [76%], P = .01), and renal insufficiency (6/38 [16%] vs 11/25 [44%], P = .02). Ejection fraction and atrioventricular valve regurgitation did not differ between groups. Pulmonary artery wedge pressure was overall high normal (12 mm Hg [9,16]) but higher in deferred/declined vs approved patients, 14.5 (11, 19) vs 10 (8, 13.5) mm Hg, P = .015. Overall survival was significantly lower in deferred/declined patients (P = .0018). CONCLUSION: Fontan patient referral for heart transplant at younger age and before the onset of end-organ complications is associated with increased approval for transplant listing.

Seligman's theory of attributional style: optimism, pessimism, and quality of life after heart transplant.

CONTEXT: Posttransplant quality of life can be significantly affected by personality characteristics identified before transplant. OBJECTIVE: Although overall quality of life in heart transplant patients improves after transplant, many studies reveal poorer mental health outcomes after transplant. We aimed to determine whether transplant recipients with an optimistic explanatory style had improved quality of life, fewer depressive symptoms, and increased survival. DESIGN: We reviewed 68 patients who had completed a Minnesota Multiphasic Personality Inventory a mean of 2 years before transplant and examined associations between scores on the Optimism-Pessimism scale, survival rates, and results from the Health Status Questionnaire nearly 4 years after transplant. RESULTS: Optimism was significantly associated with higher quality of life even after age (at the time of transplant), sex, depression score before transplant, time from the personality inventory to transplant, and time from transplant to the Health Status Questionnaire were controlled for. Furthermore, a pessimistic explanatory style was significantly associated with self-reported depressive symptoms, even after depression before transplant was adjusted for. Neither optimism nor pessimism was associated with length of survival. CONCLUSIONS: Pretransplant patients with a pessimistic explanatory style reported depressive symptoms nearly 5 years later. Furthermore, over the same time span, patients with an optimistic explanatory style described a significantly higher quality of life than the pessimists described.

Sirolimus-Based Immunosuppression Is Associated with Decreased Incidence of Post-Transplant Lymphoproliferative Disorder after Heart Transplantation: A Double-Center Study.

Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein-Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8-26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04-0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03-0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.

Autologous Umbilical Cord Blood-Derived Mononuclear Cell Therapy Promotes Cardiac Proliferation and Adaptation in a Porcine Model of Right Ventricle Pressure Overload.

Congenital heart diseases, including single ventricle circulations, are clinically challenging due to chronic pressure overload and the inability of the myocardium to compensate for lifelong physiological demands. To determine the clinical relevance of autologous umbilical cord blood-derived mononuclear cells (UCB-MNCs) as a therapy to augment cardiac adaptation following surgical management of congenital heart disease, a validated model system of right ventricular pressure overload due to pulmonary artery banding (PAB) in juvenile pigs has been employed. PAB in a juvenile porcine model and intramyocardial delivery of UCB-MNCs was evaluated in three distinct 12-week studies utilizing serial cardiac imaging and end-of-study pathology evaluations. PAB reproducibly induced pressure overload leading to chronic right ventricular remodeling including significant myocardial fibrosis and elevation of heart failure biomarkers. High-dose UCB-MNCs (3 million/kg) delivered into the right ventricular myocardium did not cause any detectable safety issues in the context of arrhythmias or abnormal cardiac physiology. In addition, this high-dose treatment compared with placebo controls demonstrated that UCB-MNCs promoted a significant increase in Ki-67-positive cardiomyocytes coupled with an increase in the number of CD31+ endothelium. Furthermore, the incorporation of BrdU-labeled cells within the myocardium confirmed the biological potency of the high-dose UCB-MNC treatment. Finally, the cell-based treatment augmented the physiological adaptation compared with controls with a trend toward increased right ventricular mass within the 12 weeks of the follow-up period. Despite these adaptations, functional changes as measured by echocardiography and magnetic resonance imaging did not demonstrate differences between cohorts in this surgical model system. Therefore, this randomized, double-blinded, placebo-controlled pre-clinical trial establishes the safety of UCB-MNCs delivered via intramyocardial injections in a dysfunctional right ventricle and validates the induction of cardiac proliferation and angiogenesis as transient paracrine mechanisms that may be important to optimize long-term outcomes for surgically repaired congenital heart diseases.

Regenerative medicine: a reality of stem cell technology.

Regenerative medicine aims to restore homeostasis through a broad spectrum of strategies ranging from transplantation of donor organs to augmentation of innate healing processes. Its first clinical application emerged five decades ago when bone marrow-derived stem cells were used to replace defective progenitor cells. Since then, a variety of technological advances have expanded its scope. Most recently, the advent of natural or bioengineered stem cell products for tissue repair has inspired hope that the toughest obstacles in transplant medicine--the shortage of organs and organ rejection--might be overcome.This article describes the evolution of regenerative medicine and some of the ways it is being used in research and clinical practice.

Hand transplantation.

The first successful hand transplant was performed in 1998, opening up a new possibility for patients who have suffered mutilating hand injuries. Since then, more than 60 such procedures have been performed throughout the world. This article describes the evolution of hand transplantation, outcomes of patients listed in the International Registry of Hand and Composite Tissue Transplantation, and ethical issues involved in hand transplantation. It also describes the hand transplantation program at Mayo Clinic, which was established in 2010.

Heart-After-Liver Transplantation Attenuates Rejection of Cardiac Allografts in Sensitized Patients.

BACKGROUND: In patients undergoing heart transplantation, significant allosensitization limits access to organs, resulting in longer wait times and high waitlist mortality. Current desensitization strategies are limited in enabling successful transplantation. OBJECTIVES: The purpose of this study was to describe the cumulative experience of combined heart-liver transplantation using a novel heart-after-liver transplant (HALT) protocol resulting in profound immunologic protection. METHODS: Reported are the results of a clinical protocol that was instituted to transplant highly sensitized patients requiring combined heart and liver transplantation at a single institution. Patients were dual-organ listed with perceived elevated risk of rejection or markedly prolonged waitlist time due to high levels of allo-antibodies. Detailed immunological data and long-term patient and graft outcomes were obtained. RESULTS: A total of 7 patients (age 43 ± 7 years, 86% women) with high allosensitization (median calculated panel reactive antibody = 77%) underwent HALT. All had significant, unacceptable donor specific antibodies (DSA) (>4,000 mean fluorescence antibody). Prospective pre-operative flow cytometric T-cell crossmatch was positive in all, and B-cell crossmatch was positive in 5 of 7. After HALT, retrospective crossmatch (B- and T-cell) became negative in all. DSA fell dramatically; at last follow-up, all pre-formed or de novo DSA levels were insignificant at <2,000 mean fluorescence antibody. No patients experienced >1R rejection over a median follow-up of 48 months (interquartile range: 25 to 68 months). There was 1 death due to metastatic cancer and no significant graft dysfunction. CONCLUSIONS: A heart-after-liver transplantation protocol enables successful transplantation via near-elimination of DSA and is effective in preventing adverse immunological outcomes in highly sensitized patients listed for combined heart-liver transplantation.

Sirolimus as primary immunosuppression is associated with improved coronary vasomotor function compared with calcineurin inhibitors in stable cardiac transplant recipients.

AIMS: The aim of this study was to evaluate coronary vasomotor function in cardiac transplant recipients maintained on sirolimus (SRL)- or cyclosporin (CyA)-based immunosuppression. METHODS AND RESULTS: Endothelium-independent response to intracoronary nitroglycerin and adenosine and endothelium-dependent response to intracoronary acetylcholine (Ach) were assessed in 15 SRL- and 21 CyA- treated subjects with angiographically normal coronary arteries. Baseline mean blood pressure was lower in the SRL group (85.6 +/- 10.3 vs. 105.2 +/- 8.7 mmHg, P = 0.002). There was no difference between the groups in coronary flow reserve after adenosine administration in multivariable analysis (P = 0.34). Nitroglycerin administration resulted in increase in coronary artery diameter in the SRL compared with the CyA groups (2.79 +/- 0.54 vs. 2.57 +/- 0.61, P = 0.0036). In 13 SRL-treated subjects without evidence of cardiac allograft vasculopathy (CAV), Ach administration resulted in less epicardial vasoconstriction compared with CyA-treated subjects (2.7 +/- 17.7 vs. -15.6 +/- 17.2%, P = 0.005). Two SRL-treated subjects with three-dimensional intravascular ultrasound evidence of CAV developed coronary spasm in response to Ach 10(-4). Microvascular endothelial function did not differ between the groups. CONCLUSION: Sirolimus immunosuppression is associated with less pronounced coronary epicardial endothelial dysfunction compared with CyA immunosuppression. Improvement of coronary vasomotor function with SRL may be an important mechanism for the prevention of CAV.

Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs.

Ribonucleoprotein (RNP) granules are biomolecular condensates-liquid-liquid phase-separated droplets that organize and manage messenger RNA metabolism, cell signaling, biopolymer assembly, biochemical reactions and stress granule responses to cellular adversity. Dysregulated RNP granules drive neuromuscular degenerative disease but have not previously been linked to heart failure. By exploring the molecular basis of congenital dilated cardiomyopathy (DCM) in genome-edited pigs homozygous for an RBM20 allele encoding the pathogenic R636S variant of human RNA-binding motif protein-20 (RBM20), we discovered that RNP granules accumulated abnormally in the sarcoplasm, and we confirmed this finding in myocardium and reprogrammed cardiomyocytes from patients with DCM carrying the R636S allele. Dysregulated sarcoplasmic RBM20 RNP granules displayed liquid-like material properties, docked at precisely spaced intervals along cytoskeletal elements, promoted phase partitioning of cardiac biomolecules and fused with stress granules. Our results link dysregulated RNP granules to myocardial cellular pathobiology and heart failure in gene-edited pigs and patients with DCM caused by RBM20 mutation.

Diastolic Pulmonary Gradient as a Predictor of Right Ventricular Failure After Left Ventricular Assist Device Implantation.

Background Diastolic pulmonary gradient (DPG) was proposed as a better marker of pulmonary vascular remodeling compared with pulmonary vascular resistance (PVR) and transpulmonary gradient (TPG). The prognostic significance of DPG in patients requiring a left ventricular assist device (LVAD) remains unclear. We sought to investigate whether pre-LVAD DPG is a predictor of survival or right ventricular (RV) failure post-LVAD. Methods and Results We retrospectively reviewed 268 patients who underwent right heart catheterization before LVAD implantation from 2007 to 2017 and had pulmonary hypertension because of left heart disease. Patients were dichotomized using DPG ≥7 mm Hg, PVR ≥3 mm Hg, or TPG ≥12 mm Hg. The associations between these parameters and all-cause mortality or RV failure post LVAD were assessed with Cox proportional hazards regression and Kaplan-Meier analyses. After a mean follow-up time of 35 months, elevated DPG was associated with increased risk of RV failure (hazard ratio [HR]: 3.30; P=0.004, for DPG ≥7 versus DPG <7), whereas elevated PVR (HR 1.85, P=0.13 for PVR ≥3 versus PVR <3) or TPG (HR 1.47, P=0.35, for TPG ≥12 versus TPG <12) were not associated with the development of RV failure. Elevated DPG was not associated with mortality risk (HR 1.16, P=0.54, for DPG ≥7 versus DPG <7), whereas elevated PVR, but not TPG, was associated with higher mortality risk (HR 1.55; P=0.026, for PVR ≥3 versus PVR <3). Conclusions Among patients with pulmonary hypertension because of left heart disease requiring LVAD support, elevated DPG was associated with RV failure but not survival, while elevated PVR predicted mortality post LVAD implantation.