Decoding Patient Heterogeneity Influencing Radiation-Induced Brain Necrosis.

PURPOSE: In radiotherapy (RT) for brain tumors, patient heterogeneity masks treatment effects, complicating the prediction and mitigation of radiation-induced brain necrosis. Therefore, understanding this heterogeneity is essential for improving outcome assessments and reducing toxicity. EXPERIMENTAL DESIGN: We developed a clinically practical pipeline to clarify the relationship between dosimetric features and outcomes by identifying key variables. We processed data from a cohort of 130 patients treated with proton therapy for brain and head and neck tumors, utilizing an expert-augmented Bayesian network to understand variable interdependencies and assess structural dependencies. Critical evaluation involved a 3-level grading system for each network connection and a Markov blanket analysis to identify variables directly impacting necrosis risk. Statistical assessments included log-likelihood ratio (LLR), integrated discrimination index (IDI), net reclassification index (NRI), and receiver operating characteristic (ROC). RESULTS: The analysis highlighted tumor location and proximity to critical structures like white matter and ventricles as major determinants of necrosis risk. The majority of network connections were clinically supported, with quantitative measures confirming the significance of these variables in patient stratification (LLR=12.17, p=0.016; IDI=0.15; NRI=0.74). The ROC curve area was 0.66, emphasizing the discriminative value of non-dosimetric variables. CONCLUSIONS: Key patient variables critical to understanding brain necrosis post-RT were identified, aiding the study of dosimetric impacts and providing treatment confounders and moderators. This pipeline aims to enhance outcome assessments by revealing at-risk patients, offering a versatile tool for broader applications in RT to improve treatment personalization in different disease sites.

Society for Cardiovascular Magnetic Resonance 2023 Cases of SCMR Case Series.

"Cases of SCMR" is a case series on the SCMR website (https://www.scmr.org) for the purpose of education. The cases reflect the clinical presentation, and the use of cardiovascular magnetic resonance (CMR) in the diagnosis and management of cardiovascular disease. The 2023 digital collection of cases are presented in this manuscript.

Door-to-Balloon Time in ST-Elevation Myocardial Infarction (STEMI) Patients Undergoing Primary Angioplasty in Myocardial Infarction (PAMI): An Observational Study From a Tertiary Care Centre.

Background ST-elevation myocardial infarction (STEMI) requires swift intervention, with primary percutaneous coronary intervention (PCI) being essential to limit myocardial damage. The key factor affecting PCI effectiveness is the door-to-balloon (DTB) time. This observational study evaluated DTB times in STEMI patients at a tertiary care center who underwent primary angioplasty, examining adherence to benchmarks and identifying factors contributing to delays. Methodology This prospective observational study was conducted from March 2017 to August 2018 at Fortis Hospital Mulund, Mumbai, India. It included 171 STEMI patients aged 18 and older who underwent primary angioplasty. Patients with non-ST elevation myocardial infarction (NSTEMI), those who received thrombolysis, or had medical contraindications to primary angioplasty were excluded. Data on key time intervals were collected via direct observation and then analyzed using SPSS for Windows, Version 15 (Released 2006; SPSS Inc., Chicago, United States). Qualitative data were summarized using frequency and percentages, whereas quantitative data were presented as mean (±SD). T-test was applied to compare the mean duration between the two groups, i.e., DTB time ≤90 minutes and DTB time >90 minutes, and a p-value <0.05 was considered statistically significant. Results The participants had a mean age of 56.5 (±13.1) years and were predominantly male (78.4%). The mean DTB time was 70.21 (±29.16) minutes, with 79.5% achieving ≤90 minutes. Patient-related delays (48.6%) were mainly due to consent issues (31.4%), which was the most predominant cause. Hospital-related delays (51.4%) included catheterization laboratory occupancy (14.3%) and diagnostic delays (14.3%). Patients with DTB times >90 minutes had significantly longer durations in all procedural steps except door-to-ECG time. Conclusion This study underscores the complex challenges in achieving timely DTB times for STEMI patients undergoing primary angioplasty. Overcoming these barriers through targeted interventions is essential for optimizing management and enhancing outcomes. Insights into delay factors inform evidence-based strategies to improve the timeliness and effectiveness of STEMI care delivery.

Expanding the spectrum on brain-heart interactions in cerebellopontine angle surgeries.

Lesions at the cerebellopontine angle (CP angle) are associated with various brain-heart interactions, which can include those from stimulation of the fifth cranial nerve along the scalp incision in a retrosigmoid suboccipital surgical approach. A 27-year-old male patient with recently diagnosed hypertension (on calcium channel blocker) underwent left CP angle lesion decompression. Transient episodes of bradycardia, hypotension, and bradypnea were observed from the skin incision onward, exacerbated during tumor manipulation. Most episodes subsided with cessation of the surgical stimulus while some required intervention. Postoperatively, blood pressure decreased below the pre-operative levels. Thus, trigeminocardiac reflex can occur as early as the skin incision even in a retrosigmoid approach due to stimulation of the mandibular division, when specific risk factors exist. Such episodes may serve as early warning signs for subsequent intraoperative occurrences. Brainstem compression can be a possible etiology of hypertension in young patients. It underscores the importance of considering brain-heart interactions in surgical interventions involving the CP angle.

Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival.

The first-generation Molecular Microscope (MMDx) system for heart transplant endomyocardial biopsies used expression of rejection-associated transcripts (RATs) to diagnose not only T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR) but also acute injury. However, the ideal system should detect rejection without being influenced by injury, to permit analysis of the relationship between rejection and parenchymal injury. To achieve this, we developed a new rejection classification in an expanded cohort of 3230 biopsies: 1641 from INTERHEART (ClinicalTrials.gov NCT02670408), plus 1589 service biopsies added to improve the power of the machine learning algorithms. The new system used 6 rejection classifiers instead of RATs and generated 7 rejection archetypes: No rejection, 48%; Minor, 24%; TCMR1, 2.3%; TCMR2, 2.7%; TCMR/mixed, 2.7%; early-stage ABMR, 3.9%; and fully developed ABMR, 16%. Using rejection classifiers eliminated cross-reactions with acute injury, permitting separate assessment of rejection and injury. TCMR was associated with severe-recent injury and late atrophy-fibrosis and rarely had normal parenchyma. ABMR was better tolerated, seldom producing severe injury, but in later biopsies was often associated with atrophy-fibrosis, indicating long-term risk. Graft survival and left ventricular ejection fraction were reduced not only in hearts with TCMR but also in hearts with severe-recent injury and atrophy-fibrosis, even without rejection.

Racial Differences in Donor-Derived Cell-Free DNA and Mitochondrial DNA After Heart Transplantation, on Behalf of the GRAfT Investigators.

BACKGROUND: Black heart transplant patients are at higher risk of acute rejection (AR) and death than White patients. We hypothesized that this risk may be associated with higher levels of donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA. METHODS: The Genomic Research Alliance for Transplantation is a multicenter, prospective, longitudinal cohort study. Sequencing was used to quantitate dd-cfDNA and polymerase chain reaction to quantitate cell-free mitochondrial DNA in plasma. AR was defined as ≥2R cellular rejection or ≥1 antibody-mediated rejection. The primary composite outcome was AR, graft dysfunction (left ventricular ejection fraction <50% and decrease by ≥10%), or death. RESULTS: We included 148 patients (65 Black patients and 83 White patients), median age was 56 years and 30% female sex. The incidence of AR was higher in Black patients compared with White patients (43% versus 19%; P=0.002). Antibody-mediated rejection occurred predominantly in Black patients with a prevalence of 20% versus 2% (P<0.001). After transplant, Black patients had higher levels of dd-cfDNA, 0.09% (interquartile range, 0.001-0.30) compared with White patients, 0.05% (interquartile range, 0.001-0.23; P=0.003). Beyond 6 months, Black patients showed a persistent rise in dd-cfDNA with higher levels compared with White patients. Cell-free mitochondrial DNA was higher in Black patients (185 788 copies/mL; interquartile range, 101 252-422 133) compared with White patients (133 841 copies/mL; interquartile range, 75 346-337 990; P<0.001). The primary composite outcome occurred in 43% and 55% of Black patients at 1 and 2 years, compared with 23% and 27% in White patients, P<0.001. In a multivariable model, Black patient race (hazard ratio, 2.61 [95% CI, 1.35-5.04]; P=0.004) and %dd-cfDNA (hazard ratio, 1.15 [95% CI, 1.03-1.28]; P=0.010) were associated with the primary composite outcome. CONCLUSIONS: Elevated dd-cfDNA and cell-free mitochondrial DNA after heart transplant may mechanistically be implicated in the higher incidence of AR and worse clinical outcomes in Black transplant recipients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.

The Efficacy and Safety of High Dose (10 mg) of Desloratadine (Dazit® 10) in the Treatment of Chronic Spontaneous Urticaria in India: A Phase III, Multicentric, Open-Label, Single-Arm Study.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a debilitating affliction that affects diverse quality of life (QoL) parameters such as sleep, self-esteem, and daily activities. Second-generation antihistamines, such as desloratadine, are more effective and safer in managing CSU. Desloratadine is a nonsedating, potent, and highly selective H1 receptor antagonist. At its daily dose of 5 mg, almost half of CSU patients do not show symptomatic improvement. European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum (EDF) (EuroGuiDerm)/Asia Pacific Association of Allergy, Asthma and Clinical Immunology (APAAACI) guidelines recommend increasing the dosage to up to four times in such nonresponsive patients. However, there is insufficient clinical evidence in Indian settings. METHOD: We evaluated the efficacy and safety of 10 mg desloratadine (OD) in 256 nonresponsive patients with moderate to severe CSU. The primary outcome was the change in Urticaria Activity Score (UAS7) from baseline to four weeks. Additionally, change in Chronic Urticaria Quality of Life (CU-Q2oL) scores during the course of treatment was also evaluated. RESULT: The mean UAS7 scores showed a significant reduction from 31.9 ± 4.8 at baseline to 18.2 ± 8.1 at the end of the study (p < 0.0001). The use of a higher dose of desloratadine also decreased the CU-Q2oL scores significantly from 59.8 ± 14.7 at baseline to 35.4 ± 10 at four weeks (p < 0.0001). The incidence of adverse events (AEs) possibly linked to the drug was low (1.6%), and no serious adverse events were reported. CONCLUSION: Results indicated improvements in the disease severity as well as its positive impact on participants' QoL. This study confirms the efficacy and safety of daily use of a twofold dose of desloratadine in nonresponsive moderate to severe CSU patients.

Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. METHODS: In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. RESULTS: A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. CONCLUSIONS: In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Molecular states associated with dysfunction and graft loss in heart transplants.

BACKGROUND: We explored the changes in gene expression correlating with dysfunction and graft failure in endomyocardial biopsies. METHODS: Genome-wide microarrays (19,462 genes) were used to define mRNA changes correlating with dysfunction (left ventricular ejection fraction [LVEF] ≤ 55) and risk of graft loss within 3 years postbiopsy. LVEF data was available for 1,013 biopsies and survival data for 779 patients (74 losses). Molecular classifiers were built for predicting dysfunction (LVEF ≤ 55) and postbiopsy 3-year survival. RESULTS: Dysfunction is correlated with dedifferentiation-decreased expression of normal heart transcripts, for example, solute carriers, along with increased expression of inflammation genes. Many genes with reduced expression in dysfunction were matrix genes such as fibulin 1 and decorin. Gene ontology (GO) categories suggested matrix remodeling and inflammation, not rejection. Genes associated with the risk of failure postbiopsy overlapped dysfunction genes but also included genes affecting microcirculation, for example, arginase 2, which reduces NO production, and endothelin 1. GO terms also reflected increased glycolysis and response to hypoxia, but decreased VEGF and angiogenesis pathways. T cell-mediated rejection was associated with reduced survival and antibody-mediated rejection with relatively good survival, but the main determinants of survival were features of parenchymal injury. Both dysfunction and graft loss were correlated with increased biopsy expression of BNP (gene NPPB). Survival probability classifiers divided hearts into risk quintiles, with actuarial 3-year postbiopsy survival >95% for the highest versus 50% for the lowest. CONCLUSIONS: Dysfunction in transplanted hearts reflects dedifferentiation, decreased matrix genes, injury, and inflammation. The risk of short-term loss includes these changes but is also associated with microcirculation abnormalities, glycolysis, and response to hypoxia.

Physiological effects of ivabradine in heart failure and beyond.

Ivabradine is a pharmacologic agent that inhibits the funny current responsible for determining heart rate in the sinoatrial node. Ivabradine's clinical potential has been investigated in the context of heart failure since it is associated with reduced myocardial oxygen demand, enhanced diastolic filling, stroke volume, and coronary perfusion time; however, it is yet to demonstrate definitive mortality benefit. Alternative effects of ivabradine include modulation of the renin-angiotensin-aldosterone system, sympathetic activation, and endothelial function. Here, we review key clinical trials informing the clinical use of ivabradine and explore opportunities for leveraging its potential pleiotropic effects in other diseases, including treatment of hyperadrenergic states and mitigating complications of COVID-19 infection.

Thoracic Aortic Injuries Following Intra-Aortic Balloon Pump Placement: A Retrospective Case Series.

Thoracic aortic injuries from intra-aortic balloon pump (IABP) are rare, and no publications exist in the context of patients awaiting heart transplantation. We present a single-institution case series involving five patients out of 107 who sustained thoracic aortic injuries following IABP placement awaiting heart transplantation. The goal of this study is to describe the characteristics of patients, presenting symptoms, treatment and the impact of these injuries on their suitability for transplantation. DESIGN: Retrospective, single-institution study through chart review of five patients with known thoracic aortic injuries following IABP placement awaiting heart transplant. SETTING: Tertiary care academic teaching hospital with all patients requiring cardiac ICU admission. PATIENTS: All five patients were diagnosed with advanced heart failure awaiting heart transplantation. INTERVENTIONS: Each patient had an IABP placed while awaiting transplant. MEASUREMENTS AND MAIN RESULTS: Five patients (4.6%) out of a total of 107 supported with IABP awaiting heart transplantation were identified with thoracic aortic injury. Three underwent transplantation and subsequently received thoracic endovascular aortic repair, and they are doing well with a mean follow-up of 6 months. One patient died acutely and the other did not require intervention. CONCLUSIONS: IABP-related aortic injuries may be more common in patients awaiting transplantation and that endovascular therapy is a suitable treatment modality with no immediate impact on transplantation outcomes. Pooled data from multiple centers may help identify patients risk profile to potentially design an algorithm that can more quickly identify these injuries.

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.

Gamma Knife Radiosurgery in Partially Embolised Arteriovenous Malformations: Management Dilemmas and Outcomes.

Introduction: The role of Gamma Knife radiosurgery (GKRS) in partially embolized arteriovenous malformations (AVMs) has always remained a subject of debate. The aim of this study was to evaluate the efficacy of GKRS in partially embolized AVMs and to analyze factor that influence its obliteration. Methods: This was a retrospective study from a single institute performed over a period of 12 years (2005-2017). It included all patients who underwent GKRS for partially embolized AVMs. Demographic characteristics, treatment profiles, and clinical and radiological data were obtained during treatment and follow-up. Obliteration rates and factors affecting the same were sought and analyzed. Results: A total of 46 patients with a mean age of 30 years (range: 9-60 years) were included in the study. Follow-up imaging was available for 35 patients either by digital subtraction angiography (DSA) or magnetic resonance imaging (MRI). We found complete AVM obliteration in 21 patients (60%): one had near total obliteration (>90% obliteration), 12 had subtotal obliteration (<90%), and one had no change in the volume following GKRS. Following embolization alone, an average of 67% of the AVM volume was obliterated which resulted in an average 79% final obliteration rate after Gamma Knife radiosurgery. Mean duration to complete obliteration was found to be 3.45 years (range: 1-10 years). There was a significant difference (P = 0.04) in the mean interval between embolization and GKRS among cases with complete obliteration (12 months) and those with incomplete obliteration (36 months). There was no significant difference (P = 0.49) in the average obliteration rate between the ARUBA-eligible unruptured AVMs (79.22%) and ruptured AVMs (79.04%). Bleeding after GKRS during the latency period had a negative impact on obliteration (P = 0.05). Other factors like age, sex, Spetzler-Martin (SM)-grade, Pollock Flickinger score (PF-score), nidus volume, radiation dose, or presentation before embolization had no significant influence on obliteration. Three patients had permanent neurological deficits after embolization and none after radiosurgery. Six out of nine patients (66%) presenting with seizures were seizure-free after the treatment. Hemorrhage was noted in three patients following combined treatment and were managed non-surgically. Conclusion: Obliteration rates in partially embolized AVM after Gamma Knife are inferior when compared to Gamma Knife alone; moreover with volume staging and/or dose staging being increasingly plausible due to the new ICON machine, embolization may be completely replaced. However we have shown that in complicated and carefully chosen AVMs, embolization followed by GKRS is a valid modality of management. This study represents a real-world picture of individualized AVM treatment depending on patient choices and resources available.

Analgesia Nociception Index (ANI) as a monitor of peri-operative nociception-antinociception balance in paediatric craniotomies: a prospective observational study.

INTRODUCTION: Analgesia Nociception Index (ANI) as a monitor of peri-operative nociception-anti-nociception balance has not been studied in paediatric neurosurgery. The objectives were to study the correlation between ANI (Mdoloris Education system) and revised FLACC (r-FLACC) score for the prediction of acute postoperative pain in paediatric population undergoing elective craniotomies and to compare the changes in ANI values with heart rate (HR), mean arterial pressure (MAP) and surgical plethysmographic index (SPI) during various time points of intraoperative noxious stimulation and before and after opioid administration. METHODS: This prospective observational pilot study included 14 patients between 2 and 12 years of age undergoing elective craniotomies. HR, MAP, SPI, ANI instantaneous (ANIi) and ANI mean (ANIm) values were recorded intraoperatively and before and after opioid administration. Postoperatively HR, MAP, ANIi and ANIm, and pain scores (r-FLACC scale) were recorded. RESULTS: There was a statistically significant negative correlation between ANIi and ANIm with r-FLACC during the time course of PACU stay (r = - 0.89, p < 0.001 and r = - 0.88 and p < 0.001 respectively). Intraoperatively, in patients with ANIi values < 50, with additional fentanyl administration, there was an increasing trend in values beyond 50, which was statistically significant (p < 0.05) at 3, 4, 5 and 10 min. The trend in changes of SPI after opioid administration was not found to be significant for patients irrespective of the baseline SPI values. CONCLUSION: The ANI is a reliable tool for objective assessment of acute postoperative pain as assessed by r-FLACC in children undergoing craniotomies for intracranial lesions. It may be used as a guide to nociception-antinociception balance during the peri-operative period in this population.

A bridge-to-bridge approach to heart transplantation using extracorporeal membrane oxygenation and total artificial heart.

BACKGROUND: This study aims to describe the outcomes after heart transplantation using a bridge-to-bridge strategy with a sequence of extracorporeal membrane oxygenation (ECMO) support followed by temporary total artificial heart implantation (TAH-t). METHODS: A retrospective, multicenter analysis of 54 patients who underwent TAH-t implantation following an ECMO for cardiogenic shock was performed (ECMO-TAH-t group). A control group of 163 patients who underwent TAH-t implantation as a direct bridge to transplantation (TAH-t group) was used to assess this strategy's impact on outcomes. RESULTS: Fifty-four patients, averaging 47 ± 13 year old, underwent implantation of a TAH-t after 5.3 ± 3.4 days of ECMO perfusion for cardiogenic shock. In the ECMO-TAH-t group, 20 patients (20/54%; 37%) died after TAH-t implantation and 57 patients (57/163%; 35%) died in the TAH-t group (Gray test; P = .49). The top 3 causes of death of patients on TAH-t support were multisystem organ failure (40%), sepsis (20%), and neurologic events (20%). Overall, 32 patients (32/54%; 59%) underwent heart transplantation in the ECMO-TAH-t group compared with 106 patients (106/163%, 65%) in the TAH-t group (P = .44). No significant difference in survival was observed at 6 months, 1 year, and 3 years after heart transplant (ECMO-TAH-t group: 94%, 87%, and 80% vs 87%, 83%, and 76% in the TAH-t group, respectively). Deterioration of liver function (bilirubin, aspartate transaminase, and alanine aminotransferase levels on TAH-t) was associated with increased mortality before heart transplant in both groups. CONCLUSIONS: Sequential bridging from ECMO to TAH-t followed by heart transplantation is a viable option for a group of highly selected patients.

Assessing the Relationship Between Molecular Rejection and Parenchymal Injury in Heart Transplant Biopsies.

BACKGROUND: The INTERHEART study (ClinicalTrials.gov #NCT02670408) used genome-wide microarrays to detect rejection in endomyocardial biopsies; however, many heart transplants with no rejection have late dysfunction and impaired survival. We used the microarray measurements to develop a molecular classification of parenchymal injury. METHODS: In 1320 endomyocardial biopsies from 645 patients previously studied for rejection-associated transcripts, we measured the expression of 10 injury-induced transcript sets: 5 induced by recent injury; 2 reflecting macrophage infiltration; 2 normal heart transcript sets; and immunoglobulin transcripts, which correlate with time. We used archetypal clustering to assign injury groups. RESULTS: Injury transcript sets correlated with impaired function. Archetypal clustering based on the expression of injury transcript sets assigned each biopsy to 1 of 5 injury groups: 87 Severe-injury, 221 Late-injury, and 3 with lesser degrees of injury, 376 No-injury, 526 Mild-injury, and 110 Moderate-injury. Severe-injury had extensive loss of normal transcripts (dedifferentiation) and increase in macrophage and injury-induced transcripts. Late-injury was characterized by high immunoglobulin transcript expression. In Severe- and Late-injury, function was depressed, and short-term graft failure was increased, even in hearts with no rejection. T cell-mediated rejection almost always had parenchymal injury, and 85% had Severe- or Late-injury. In contrast, early antibody-mediated rejection (AMR) had little injury, but late AMR often had the Late-injury state. CONCLUSIONS: Characterizing heart transplants for their injury state provides new understanding of dysfunction and outcomes and demonstrates the differential impact of T cell-mediated rejection versus AMR on the parenchyma. Slow deterioration from AMR emerges as a major contributor to late dysfunction.

Circulating microRNAs in cellular and antibody-mediated heart transplant rejection.

BACKGROUND: Noninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection. METHODS: The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use. RESULTS: The GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively. CONCLUSIONS: We identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR.