Multicenter study of universal prophylaxis versus pre-emptive therapy for patients at intermediate risk (R+) for CMV following heart transplantation.

INTRODUCTION: Heart transplant (HT) recipients with prior exposure to cytomegalovirus (CMV R+) are considered intermediate risk for CMV-related complications. Consensus guidelines allow for either universal prophylaxis (UP) or preemptive therapy (PET) (serial CMV testing) approaches to CMV prevention in such patients. Whether an optimal approach to mitigate CMV related risks exists in this setting remains uncertain. We therefore assessed the utility of PET as compared to UP in CMV R+ HT recipients. METHODS: Retrospective analysis of all CMV R+ HT recipients from 6 U.S. centers between 2010 and 2018 was performed. The primary outcome was the development of CMV DNAemia or end-organ disease resulting in the initiation/escalation of anti-CMV therapy. The secondary outcome was CMV-related hospitalization. Additional outcomes included incidence of acute cellular rejection (ACR) ≥ grade 2R, death, cardiac allograft vasculopathy (CAV), and leukopenia. RESULTS: Of 563 CMV R+ HT recipients, 344 (61.1%) received UP. PET was associated with increased risk for the primary (adjusted HR 3.95, 95% CI: 2.65-5.88, p < .001) and secondary (adjusted HR 3.19, 95% CI: 1.47-6.94, p = .004) outcomes, and with increased ACR ≥ grade 2R (PET 59.4% vs. UP 34.4%, p < .001). Incidence of detectable CAV was similar at 1 year (PET 8.2% vs. UP 9.5%, p = .698). UP was associated with increased incidence of leukopenia within 6 months post-HT (PET 34.7% vs. UP 43.6%, p = .036). CONCLUSION: The use of a PET CMV prophylaxis strategy in intermediate risk HT recipients associated with increased risk of CMV infection and CMV-related hospitalization, and may associate with worse post-HT graft outcomes.

Porcine Model of the Arterial Switch Operation: Implications for Unique Strategies in the Management of Hypoplastic Left Ventricles.

There are no reports on the performance of the arterial switch operation (ASO) in a normal heart with normally related great vessels. The objective of this study was to determine whether the ASO could be performed in a healthy animal model. Cardiopulmonary bypass (CPB) and coronary translocation techniques were used to perform ASO in neonatal piglets or a staged ASO with prior main pulmonary artery (PA) banding. Primary ASO was performed in four neonatal piglets. Coronary translocation was effective with angiograms confirming patency. Piglets could not be weaned from CPB due to right ventricle (RV) dysfunction. To improve RV function for the ASO, nine piglets had PA banding. All survived the procedure. Post-banding RV pressure increased from a mean of 20.3 ± 2.2 mmHg to 36.5 ± 7.3 mmHg (p = 0.007). At 58 ± 1 days post-banding, piglets underwent cardiac MRIs revealing RV hypertrophy, and RV pressure overload with mildly reduced RV function. Catheterization confirmed RV systolic pressures of 84.0 ± 6.7 mmHg with LV systolic pressure 83.3 ± 6.7 mmHg (p = 0.43). The remaining five PA banded piglets underwent ASO at 51 ± 0 days post-banding. Three of five were weaned from bypass with patent coronary arteries and adequate RV function. We were able to successfully perform an arterial switch with documented patent coronary arteries on standard anatomy great vessels in a healthy animal model. To our knowledge this is the first time this procedure has been successfully performed. The model may have implications for studying the failing systemic RV, and may support a novel approach for management of borderline, pulsatile left ventricles.

A Novel Model Incorporating Pectoralis Muscle Measures to Predict Mortality After Ventricular Assist Device Implantation.

BACKGROUND: We have previously demonstrated that pectoralis muscle mass and tissue attenuation obtained on preoperative CT scans were powerful predictors of mortality after left ventricular assist device implantation. In this analysis, we confirm our findings in a separate left ventricular assist device implantation cohort, and we present a novel, user-friendly mortality-prediction model incorporating these measures. METHODS AND RESULTS: Patients with chest CTs performed ≤ 3 months prior to left ventricular assist device implantation at University of Minnesota (n = 143) and Houston Methodist Hospital (n = 133) were identified. Unilateral pectoralis muscle mass indexed to body surface area (PMI) and attenuation (approximated by mean Hounsfield units) (PHUm) were measured on preoperative chest CT scans. To develop a prediction model incorporating pectoralis muscle measures, we implemented a cross-validated model-selection approach using Cox proportional hazards regression models. The final model included PHUm, PMI, African American race, creatinine, total bilirubin, body mass index, bridge to transplant, and presence or absence of contrast. Receiver-operating characteristic curves for 30-, 90- and 365-day survival were generated. The area under the curve for the model at 30, 90 and 365 days was 0.78, 0.76 and 0.76, respectively. CONCLUSIONS: The Minnesota Pectoralis Risk Score had favorable discrimination in this multicenter dataset. These skeletal-muscle measures appear to add important information to preoperative risk assessment.

Safety and prognostic value of regadenoson stress cardiovascular magnetic resonance imaging in heart transplant recipients.

BACKGROUND: There is a critical need for non-invasive methods to detect coronary allograft vasculopathy and to risk stratify heart transplant recipients. Vasodilator stress testing using cardiovascular magnetic resonance imaging (CMR) is a promising technique for this purpose. We aimed to evaluate the safety and the prognostic value of regadenoson stress CMR in heart transplant recipients. METHODS: To evaluate the safety, we assessed adverse effects in a retrospective matched cohort study of consecutive heart transplant recipients who underwent regadenoson stress CMR matched in a 2:1 ratio to age- and gender-matched non-heart transplant patients. To evaluate the prognostic value, we compared the outcomes of patients with abnormal vs. normal regadenoson stress CMRs using a composite endpoint of myocardial infarction, percutaneous intervention, cardiac hospitalization, retransplantation or death. RESULTS: For the safety analysis, 234 regadenoson stress CMR studies were included - 78 performed in 57 heart transplant recipients and 156 performed in non-heart transplant patients. Those in heart transplant recipients were performed at a median of 2.74 years after transplantation. Thirty-four (44%) CMR studies were performed in the first two years after heart transplantation. There were no differences in the rates of adverse effects between heart transplant recipients and non-heart transplant patients. To study the prognostic value of regadenoson stress CMRs, 20 heart transplant recipients with abnormal regadenoson stress CMRs were compared to 37 with normal regadenoson stress CMRs. An abnormal regadenoson stress CMR was associated with a significantly higher incidence of the composite endpoint compared with a normal regadenoson stress CMR (3-year cumulative incidence estimates of 32.1% vs. 12.7%, p = 0.034). CONCLUSIONS: Regadenoson stress CMR is safe and well tolerated in heart transplant recipients, with no incidence of sinus node dysfunction or high-degree atrioventricular block, including in the first two years after heart transplantation. An abnormal regadenoson stress CMR identifies heart transplant recipients at a higher risk for major adverse cardiovascular events.

Bosma arhinia microphthalmia syndrome: Clinical report and review of the literature.

Bosma arhinia microphthalmia syndrome (Bosma syndrome)(OMIM 603457) is a congenital condition characterized by microphthalmia with coloboma, arhinia and endocrine findings in the setting of normal intelligence and brain structure. This condition is quite rare with fewer than 50 case reports and series. Although pathogenesis is presumed to be genetic, the cause remains unknown. We report an individual with Bosma syndrome who had bilateral colobomatous microphthalmia, arhinia, high arched palate, mild ear malformations, and hypogonadotropic hypogonadism requiring growth hormone treatment in childhood, and normal intelligence. Clinical evaluation was significant for a geometrically abnormal aorta with effacement of the sinotubular ridge, a finding not previously reported in this condition. An MRI revealed absent olfactory bulbs. Suggested criteria for diagnosis of Bosma should include arhinia, hypoplastic maxilla, normal cognition, and hypogonadotropic hypogonadism in males.

ATP-binding cassette transporter Abcg2 lineage contributes to the cardiac vasculature after oxidative stress.

Due to their specialized location, stem and progenitor cells are often exposed to oxidative stress. Although ATP-binding cassette transporter subfamily G member 2 (Abcg2)-expressing cells have been implicated in cardiac protective mechanisms involving oxidative stress, there remains a lack of understanding regarding the behavior of cardiac Abcg2-expressing cells when exposed to ROS. The aim of the present study was to characterize the response of the cardiac Abcg2 lineage to oxidative stress. In vitro analysis demonstrated that the antioxidant program regulated by Abcg2 is dependent on a functional transporter. Delivery of paraquat dichloride (PQ), a systemic oxidative stress-inducing agent, to mice confirmed that Abcg2 provides a survival benefit. When exposed to PQ, reporter mice showed an increase in the Abcg2 lineage. Transcriptional and immunohistochemical analysis of Abcg2 lineage-positive cells revealed an enhanced vascular commitment after stress. Finally, preconditioning with PQ demonstrated a reduction in scar size and an increase in angiogenesis after permanent left coronary artery ligation. In conclusion, the data suggest that Abcg2 plays a cytoprotective role in response to in vivo oxidative stress. The contribution of the Abcg2 lineage to the vasculature in the heart is increased after PQ delivery.

Cardiomyopathies in Women.

Heart failure affects over 2.6 million people in the United States. While women have better overall survival rates, they also suffer from higher morbidity as shown by higher rates of hospitalization and worse quality of life. Several anatomical differences in women's hearts affect both systolic and diastolic cardiac physiology. Despite these findings, women are significantly underrepresented in clinical trials, necessitating extrapolation of data from males. Because women have sex-specific etiologies of heart failure and unique manifestations in genetic-related cardiomyopathies, meaningful sex-related differences affect heart failure outcomes as well as access to and outcomes in advanced heart failure therapies in women. This review explores these gender-specific differences and potential solutions to balance care between women and men.

Survival After Simultaneous Heart-kidney Transplant in Recipients With a Durable LVAD and Chronic Kidney Disease: Effect of the 2018 Heart Allocation Policy Change.

BACKGROUND: Heart transplantation remains the most definitive therapy for qualified candidates with end-stage heart failure. Concomitant kidney disease is common in this population prompting an increase in simultaneous heart-kidney (SHK) transplantation in recent years. The goal of our study was to explore the effects of the 2018 heart allocation policy (HAP) change on candidate listing characteristics and compare survival rates at 1 y in patients that were supported with a left ventricular assist device (LVAD) pretransplant and underwent SHK or heart alone transplant (HAT). METHODS: We used data from the Scientific Registry of Transplant Recipients and identified all adults who underwent primary SHK or HAT between January 2010 and March 2022. Recipients supported with a durable LVAD and estimated glomerular filtration rate <60 mL/min/1.73 m 2 were selected (n = 309 SHK; 217 pre- and 92 post-HAP and n = 3,324 HAT; 2738 pre- and 586 post-HAP). RESULTS: Difference in survival at 1 y did not reach statistical significance. Comparing the 1-y survival of SHK and HAT recipients who were bridged with LVAD pre-HAP, we found no significant difference ( P = 0.694). Adjusting for the same covariates in a multivariable model did not affect the results (SHK versus HAT hazard ratio 0.84 [0.51, 1.37]; P = 0.48). In contrast, SHK recipients supported with an LVAD who were listed and transplanted post-HAP change had significantly lower 1-y survival, when compared with HAT ( P = 0.037). CONCLUSIONS: Our findings suggest that the HAP change had a potentially negative impact on the survival of select patients undergoing SHK transplant. Further research is warranted in this area.

Multi-omic and multispecies analysis of right ventricular dysfunction.

BACKGROUND: Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. METHODS: Transcriptomics and proteomics analyses defined the pathways associated with cardiac magnetic resonance imaging (MRI)-derived values of RV hypertrophy, dilation, and dysfunction in control and pulmonary artery banded (PAB) pigs. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare molecular responses across species. RESULTS: PAB pigs displayed significant right ventricle/ventricular (RV) hypertrophy, dilation, and dysfunction as quantified by cardiac magnetic resonance imaging. Transcriptomic and proteomic analyses identified pathways associated with RV dysfunction and remodeling in PAB pigs. Surprisingly, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across the 3 species. FAO and ETC proteins and transcripts were mostly downregulated in rats but were predominately upregulated in PAB pigs, which more closely matched the human response. All species exhibited similar dysregulation of the dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy pathways. CONCLUSIONS: The porcine metabolic molecular signature was more similar to human RVF than rodents. These data suggest there may be divergent molecular responses of RVF across species, and pigs may more accurately recapitulate metabolic aspects of human RVF.

Etv2 rescues Flk1 mutant embryoid bodies.

Independent mouse knockouts of Etv2 and Flk1 are embryonic lethal and lack hematopoietic and endothelial lineages. We previously reported that Flk1 activates Etv2 in the initiation of hematopoiesis and vasculogenesis. However, Flk1 and its ligand VEGF are expressed throughout development, from E7.0 to adulthood, whereas Etv2 is expressed only transiently during embryogenesis. These observations suggest a complex regulatory interaction between Flk1 and Etv2. To further examine the Flk1 and Etv2 regulatory interaction, we transduced Etv2 and Flk1 mutant ES cells with viral integrants that inducibly overexpress Flk1 or Etv2. We demonstrated that forced expression of Etv2 rescued the hematopoietic and endothelial potential of differentiating Flk1 and Etv2 mutant cells. We further discovered that forced expression of Flk1 can rescue that of the Flk1, but not Etv2 mutant cells. Therefore, we conclude that the requirement for Flk1 can be bypassed by expressing Etv2, supporting the notion that disruption of Etv2 expression is responsible for the early phenotypes of the Etv2 and Flk1 mutant embryos.

Sudden Onset Iron Overload Cardiomyopathy After Liver Transplantation.

Iron overload cardiomyopathy has been described in patients who develop acute heart failure after liver transplantation but few reports of this are available. We present a case of a patient with end-stage liver disease who underwent a deceased donor liver transplantation and developed acute onset systolic heart failure with reduced left ventricular ejection fraction. A cardiac magnetic resonance image demonstrated late gadolinium enhancement with diffuse enhancement globally and T1 mapping with severely decreased pre-contrast T1 values suggesting iron overload cardiomyopathy. The patient was treated with iron chelating therapy as well as heart failure guideline-directed medical therapy with subsequent improvement in cardiac function on follow-up magnetic resonance images. Despite our patient's diagnosis of iron overload cardiomyopathy, her iron studies showed normal serum iron and ferritin levels and no evidence of hepatic iron deposition in the transplanted liver.

Temporary Mechanical Circulatory Support Use and Clinical Outcomes of Simultaneous Heart/Kidney Transplant Recipients in the Pre- and Post-heart Allocation Policy Change Eras.

BACKGROUND: The use of temporary mechanical circulatory support (tMCS) devices (intra-aortic balloon pump; Impella 2.5, CP, 5.0; venoarterial extracorporeal membrane oxygenation) increased significantly across the United States for heart transplant candidates after the allocation policy change. Whether this practice change also affected simultaneous heart-kidney (SHK) candidates and recipient survival is understudied. METHODS: We used the Scientific Registry of Transplant Recipients database to identify adult SHK recipients between January 2010 and March 2022. The population was stratified into pre- and post-heart allocation change cohorts. Kaplan-Meier curves were generated to compare 1-y survival rates. A Cox proportional hazards model was used to investigate the effect of allocation period on patient survival. Recipient outcomes bridged with eligible tMCS devices were compared in the post-heart allocation era. In a separate analysis, SHK waitlist mortality was evaluated between the allocation eras. RESULTS: A total of 1548 SHK recipients were identified, and 1102 were included in the final cohort (534 pre-allocation and 568 post-allocation change). tMCS utilization increased from 17.9% to 51.6% after the allocation change, with venoarterial extracorporeal membrane oxygenation use rising most significantly. However, 1-y post-SHK survival remained unchanged in the full cohort (log-rank P = 0.154) and those supported with any of the eligible tMCS devices. In a separate analysis (using a larger cohort of all SHK listings), SHK waitlist mortality at 1 y was significantly lower in the current allocation era ( P = 0.002). CONCLUSIONS: Despite the remarkable increase in tMCS use in SHK candidates after the heart allocation change, 1 y posttransplant survival remained unchanged. Further studies with larger cohorts and longer follow-ups are needed to confirm these findings.

Outcomes of Patients Referred for Cardiac Rehabilitation After Left Ventricular Assist Device Implantation.

A single-center continuous-flow left ventricular assist device (LVAD) cohort (n = 503) was reviewed for patients with information on cardiac rehabilitation (CR) participation (n = 273) over a 13-year period. The analysis was then limited LVAD recipients who fit into three main CR categories: those who graduated CR (n = 138), those who were able to but declined participation (n = 61), and those who were too sick to complete or start CR (n = 28). To assess the association between CR categories and mortality and hospitalizations on LVAD support, multivariate cox regression and negative binomial regression analyses were performed, respectively. Among those who started CR and had the opportunity to finish (enough follow-up time, insurance coverage), 79% graduated. Those who graduated CR had a 96% survival at 1 year (95% confidence interval [CI], 91-98). Compared with the graduated group, those in the too sick group had an increased hazards rate of mortality (hazard ratio, 2.85; 95% CI, 1.49-5.44; p < 0.01) and an increase in the incidence rate of hospitalizations (incidence rate ratio, 1.74; 95% CI, 1.14-2.66, p = 0.01). This study is the largest to date to report outcomes of LVAD recipients referred for CR. The lower readmission rates and high survival in the group that graduated CR provides further evidence for the safety of CR in LVAD recipients.

Initial hospital length of stay and long-term survival of patients successfully resuscitated using extracorporeal cardiopulmonary resuscitation for refractory out-of-hospital cardiac arrest.

AIMS: The long-term outcomes of patients treated with extracorporeal cardiopulmonary resuscitation (ECPR) for refractory ventricular tachycardia/ventricular fibrillation (VT/VF) out-of-hospital cardiac arrest (OHCA) remain poorly defined. The purpose of this study was to describe the hospital length of stay and long-term survival of patients who were successfully rescued with ECPR after refractory VT/VF OHCA. METHODS AND RESULTS: In this retrospective cohort study, the length of index admission and long-term survival of patients treated with ECPR after OHCA at a single centre were evaluated. In a sensitivity analysis, survival of patients managed with left ventricular assist device (LVAD) implantation or heart transplantation during the same period was also evaluated. Between 1 January 2016 and 12 January 2020, 193 patients were transferred for ECPR considerations and 160 underwent peripheral veno-arterial extracorporeal membrane oxygenation cannulation. Of these, 54 (33.7%) survived the index admission. These survivors required a median 16 days of intensive care and 24 days total hospital stay. The median follow-up time of the survivors was 1216 (683, 1461) days. Of all, 79.6 and 72.2% were alive at 1 and 4 years, respectively. Most deaths within the first year occurred among the patients requiring discharge to a long-term acute care facility. Overall survival rates at 4 years were similar in the ECPR and LVAD cohorts (P = 0.30) but were significantly higher for transplant recipients (P < 0.001). CONCLUSION: This data suggest that the lengthy index hospitalization required to manage OHCA patients with ECPR is rewarded by excellent long-term clinical outcomes in an expert ECPR programme.

A Multi-omic and Multi-Species Analysis of Right Ventricular Failure.

Right ventricular failure (RVF) is a leading cause of morbidity and mortality in multiple cardiovascular diseases, but there are no approved treatments for RVF as therapeutic targets are not clearly defined. Contemporary transcriptomic/proteomic evaluations of RVF are predominately conducted in small animal studies, and data from large animal models are sparse. Moreover, a comparison of the molecular mediators of RVF across species is lacking. Here, we used transcriptomics and proteomics analyses to define the molecular pathways associated with cardiac MRI-derived values of RV hypertrophy, dilation, and dysfunction in pulmonary artery banded (PAB) piglets. Publicly available data from rat monocrotaline-induced RVF and pulmonary arterial hypertension patients with preserved or impaired RV function were used to compare the three species. Transcriptomic and proteomic analyses identified multiple pathways that were associated with RV dysfunction and remodeling in PAB pigs. Surprisingly, disruptions in fatty acid oxidation (FAO) and electron transport chain (ETC) proteins were different across the three species. FAO and ETC proteins and transcripts were mostly downregulated in rats, but were predominately upregulated in PAB pigs, which more closely matched the human data. Thus, the pig PAB metabolic molecular signature was more similar to human RVF than rodents. These data suggest there may be divergent molecular responses of RVF across species, and that pigs more accurately recapitulate the metabolic aspects of human RVF.

Nkx2-5 transactivates the Ets-related protein 71 gene and specifies an endothelial/endocardial fate in the developing embryo.

Recent studies support the existence of a common progenitor for the cardiac and endothelial cell lineages, but the underlying transcriptional networks responsible for specification of these cell fates remain unclear. Here we demonstrated that Ets-related protein 71 (Etsrp71), a newly discovered ETS family transcription factor, was a novel downstream target of the homeodomain protein, Nkx2-5. Using genetic mouse models and molecular biological techniques, we demonstrated that Nkx2-5 binds to an evolutionarily conserved Nkx2-5 response element in the Etsrp71 promoter and induces the Etsrp71 gene expression in vitro and in vivo. Etsrp71 was transiently expressed in the endocardium/endothelium of the developing embryo (E7.75-E9.5) and was extinguished during the latter stages of development. Using a gene disruption strategy, we found that Etsrp71 mutant embryos lacked endocardial/endothelial lineages and were nonviable. Moreover, using transgenic technologies and transcriptional and chromatin immunoprecipitation (ChIP) assays, we further established that Tie2 is a direct downstream target of Etsrp71. Collectively, our results uncover a novel functional role for Nkx2-5 and define a transcriptional network that specifies an endocardial/endothelial fate in the developing heart and embryo.

Axillary or Subclavian Impella 5.0 Support in Cardiogenic Shock: A Systematic Review and Meta-analysis.

data around survival and adverse events of cardiogenic shock (CS) patients supported with axillary or subclavian artery 5.0 Impella are presently unavailable. We performed a systematic search of studies reporting the outcomes of axillary or subclavian access 5.0 Impella for refractory CS in PubMed, EMBASE, and the Cochrane Library. The primary outcome was 30-day survival. Secondary outcomes included survival to next therapy and adverse events on support. Proportional meta-analysis was used to pool across studies. Of the 795 potential studies identified, 13 studies were included in the meta-analysis (n = 256 patients). The average age of patients across studies was 56 ± 5 years. Thirty-day survival for the overall cohort was 66% (95% CI: 59-73). Survival to the next therapy was 68% (95% CI: 60-76). The occurrence of adverse events over an average of 13 (95% CI: 12-14) days of support was the following: stroke 5.9%, hemolysis 27%, pump thrombosis 4.4%, limb ischemia 0.1%, major bleeding 5.4%, device malfunction 10.6%, exchange 6.6%, and infection 14%. In this systematic review and meta-analysis, we report survival and adverse event rates of axillary or subclavian access 5.0 Impella for CS. Such summary data can inform clinician decision-making.