Donor Heart Preservation at 10°C After Thoracoabdominal Normothermic Regional Perfusion Lowers Rates of Severe Primary Graft Dysfunction and Improves Recipient Transplant Outcomes.

This study compares a novel static cold storage (SCS) method using 10°C preservation to conventional ice following thoracoabdominal normothermic regional perfusion (TA-NRP) in donation after circulatory death (DCD) heart transplantation. We retrospectively analyzed adult recipients at a single center from October 2020 to October 2024, excluding congenital and multi-organ transplants. A total of 147 recipients met inclusion criteria (Ice = 96; 10°C = 51).

Antibody-independent microvascular inflammation impacts long-term risk in heart transplantation.

Background: Microvascular inflammation (MVI) following heart transplantation can occur with or without circulating anti-HLA donor-specific antibodies (DSAs). We sought to characterize the relationship between MVI, with or without accompanying DSA, and post-transplant outcomes.

Methods: We analyzed 8,305 endomyocardial biopsies (EMB) from 832 adult and pediatric HT recipients between July 1, 2013 and October 31, 2023.

Integrated multiomics of pressure overload in the human heart prioritizes targets relevant to heart failure.

Pressure overload initiates a series of alterations in the human heart that predate macroscopic organ-level remodeling and downstream heart failure. We study aortic stenosis through integrated proteomic, tissue transcriptomic, and genetic methods to prioritize targets causal in human heart failure. First, we identify the circulating proteome of cardiac remodeling in aortic stenosis, specifying known and previously-unknown mediators of fibrosis, hypertrophy, and oxidative stress, several associated with interstitial fibrosis in a separate cohort (N = 145).

10-minute Asystolic Warm Ischemic Time (AWIT) Predicts Mortality and Severe Primary Graft Dysfunction in Donation After Circulatory Death Hearts Recovered With Thoracoabdominal Normothermic Regional Perfusion.

Objectives: Donor warm ischemic time (WIT) during donation after circulatory death (DCD) has been linked to adverse outcomes in non-cardiac transplants, but its impact on heart transplant recipients remains unclear. This study evaluated the association between prolonged WIT and outcomes in adult recipients of thoracoabdominal normothermic regional perfusion (NRP)-recovered cardiac allografts.

Methods: We retrospectively reviewed adult heart transplant recipients who received NRP-recovered DCD allografts at a single center between October 2020 and February 2025.

The extracellular vesicle transcriptome provides tissue-specific functional genomic annotation relevant to disease susceptibility in obesity.

We characterized circulating extracellular vesicles (EVs) in obese and lean humans, identifying transcriptional cargo differentially expressed in obesity (277 unique genes; false discovery rate < 10%). Since circulating EVs may have broad origin, we compared this obesity EV transcriptome with expression from human visceral-adipose-tissue-derived EVs from freshly collected and cultured biopsies from the same obese individuals, observing high concordance. Using a comprehensive set of adipose-specific epigenomic and chromatin conformation assays, we found that the differentially expressed transcripts from the EVs were those regulated in adipose by body mass index-associated SNPs (p < 5 × 108) from a large-scale genome-wide association study (GWAS).

Multi-omics of human obesity and related multi-system diseases.

Context: Efforts to characterize the shared molecular risk factors that contribute to obesity and the downstream disease sequelae it triggers have been limited.

Objective: We aimed to identify functional genes with evidence for both causal and consequential effects on obesity related traits and their downstream sequalae using integrated genomic and proteomic data.

Methods: We investigated the association of obesity related traits with 2,912 plasma proteins in 259 individuals from the Cameron County Hispanic Cohort (CCHC) with validation of results in ∼45,000 participants from UK Biobank (UKBB).

Two hundred cases of cardiac donation after circulatory death utilizing normothermic regional perfusion: The 4-year Vanderbilt experience.

Objectives: Studies evaluating normothermic regional perfusion (NRP) for donation after circulatory death (DCD) heart recovery involve low volume centers or multi-center studies with wide variation in practice/technique. We sought to provide a single high-volume center's experience encompassing our program's evolution of NRP over time.

Methods: Adult DCD heart transplant patients who received cardiac allografts recovered using only thoracoabdominal NRP were retrospectively reviewed from October 2020 to November 2024.

Normothermic regional perfusion in donation after circulatory death compared with brain dead donors: Single-center cardiac allograft outcomes.

Objective: We sought to provide a single-center analysis of our normothermic regional perfusion (NRP)-recovered donation after circulatory death (DCD) heart transplant outcomes compared with a historical control group of donors of donation after brain death (DBD). We hypothesized that postoperative short-term outcomes and long-term survival trends are comparable in DCD-NRP and DBD cardiac allografts.

Methods: All adult heart-only transplants performed at our institution between January 2020 and June 2024 were retrospectively reviewed.

Molecular architecture of human atherosclerosis revealed through integrative human genetics.

Current genetic discovery methods are largely restricted to profiling circulating molecules or genetic architecture, limited in use of tissue-based molecular genetics to identify pathogenic and therapeutic targets. Here, we leverage a multi-level genetic discovery platform integrating population-level proteomics with functional genomic analyses based on human coronary artery tissue to reveal determinants of coronary disease susceptibility. Using aptamer-based proteomics (~7,000 aptamers) across ~3,000 individuals, we first identified the circulating proteome of prevalent and incident coronary artery calcium (CAC), a sensitive marker of subclinical coronary artery disease (CAD), with causal implication in calcified plaque formation or disease phenotypes via parallel genetic approaches (Mendelian randomization, MR) and proteome-wide association (PWAS).

Dynamic responses to rejection in the transplanted human heart revealed through spatial transcriptomics.

Allograft rejection following solid-organ transplantation is a major cause of graft dysfunction and mortality. Current approaches to diagnosis rely on histology, which exhibits wide diagnostic variability and lacks access to molecular phenotypes that may stratify therapeutic response. Here, we leverage image-based spatial transcriptomics at sub-cellular resolution in longitudinal human cardiac biopsies to characterize transcriptional heterogeneity in 62 adult and pediatric heart transplant (HT) recipients during and following histologically-diagnosed rejection.

Patient-specific Predictors of Haemolysis with Percutaneous Ventricular Assist Devices.

Introduction: Percutaneous ventricular assist devices (pVADs) are increasingly used in cardiogenic shock but are associated with complications including haemolysis. The aim of this study was to investigate patient characteristics associated with haemolysis in cardiogenic shock patient population.

Methods: Consecutive patients were identified using Current Procedural Terminology (CPT) codes for pVAD insertion.

The Safety and Late Hemodynamics of Donor Cardiac Undersizing in Heart Transplantation.

Background: Predicted heart mass (PHM) ratio has become the standard donor-recipient size matching method in heart transplantation. Although use of small PHM ratio hearts is associated with increased 1-year mortality, the underlying mechanisms and time horizon of mortality remain uncertain.

Methods: A single-institution analysis of 334 isolated heart transplant recipients (January 2019-July 2022) was performed.

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.

Hepatic steatosis is a central phenotype in multi-system metabolic dysfunction and is increasing in parallel with the obesity pandemic. We use a translational approach integrating clinical phenotyping and outcomes, circulating proteomics, and tissue transcriptomics to identify dynamic, functional biomarkers of hepatic steatosis. Using multi-modality imaging and broad proteomic profiling, we identify proteins implicated in the progression of hepatic steatosis that are largely encoded by genes enriched at the transcriptional level in the human liver.

The extracellular vesicle transcriptome provides tissue-specific functional genomic annotation relevant to disease susceptibility in obesity.

We characterized circulating extracellular vesicles (EVs) in obese and lean humans, identifying transcriptional cargo differentially expressed in obesity. Since circulating EVs may have broad origin, we compared this obesity EV transcriptome to expression from human visceral adipose tissue derived EVs from freshly collected and cultured biopsies from the same obese individuals. Using a comprehensive set of adipose-specific epigenomic and chromatin conformation assays, we found that the differentially expressed transcripts from the EVs were those regulated in adipose by BMI-associated SNPs from a large-scale GWAS.

Cardiomyocyte-derived circulating extracellular vesicles allow a non-invasive liquid biopsy of myocardium in health and disease.

The ability to track disease without tissue biopsy in patients is a major goal in biology and medicine. Here, we identify and characterize cardiomyocyte-derived extracellular vesicles in circulation (EVs; "cardiovesicles") through comprehensive studies of induced pluripotent stem cell-derived cardiomyocytes, genetic mouse models, and state-of-the-art mass spectrometry and low-input transcriptomics. These studies identified two markers (, ) enriched on cardiovesicles for biotinylated antibody-based immunocapture.

Single-cell RNA-sequencing identifies unique cell-specific gene expression profiles in high-grade cardiac allograft vasculopathy.

Background: Cardiac allograft vasculopathy (CAV), a diffuse thickening of the intima of the coronary arteries and microvasculature, is the leading cause of late graft failure and mortality after heart transplantation (HT). Diagnosis involves invasive coronary angiography, which carries substantial risk, and minimally-invasive approaches to CAV diagnosis are urgently needed. Using single-cell RNA-sequencing in peripheral blood mononuclear cells (PBMCs), we sought to identify cell-specific gene expression profiles in CAV.

Capillary blood self-collection for high-throughput proteomics.

In this study, we sought to compare protein concentrations obtained from a high-throughput proteomics platform (Olink) on samples collected using capillary blood self-collection (with the Tasso+ device) versus standard venipuncture (control). Blood collection was performed on 20 volunteers, including one sample obtained via venipuncture and two via capillary blood using the Tasso+ device. Tasso+ samples were stored at 2°C-8°C for 24-hs (Tasso-24) or 48-h (Tasso-48) prior to processing to simulate shipping times from a study participant's home.

Differences in Cardiometabolic Proteins in Pregnancy Prioritize Relevant Targets of Preeclampsia.

Background: Preeclampsia is a hypertensive disorder of pregnancy characterized by widespread vascular inflammation. It occurs frequently in pregnancy, often without known risk factors, and has high rates of maternal and fetal morbidity and mortality. Identification of biomarkers that predict preeclampsia and its cardiovascular sequelae before clinical onset, or even before pregnancy, is a critical unmet need for the prevention of adverse pregnancy outcomes.

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.

Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing in parallel with an obesity pandemic, calling for novel strategies for prevention and treatment. We defined a circulating proteome of human MASLD across ≈7000 proteins in ≈5000 individuals from diverse, at-risk populations across the metabolic health spectrum, demonstrating reproducible diagnostic performance and specifying both known and novel metabolic pathways relevant to MASLD (central carbon and amino acid metabolism, hepatocyte regeneration, inflammation, fibrosis, insulin sensitivity). A parsimonious proteomic signature of MASLD was associated with a protection from MASLD and its related multi-system metabolic consequences in >26000 free-living individuals, with an additive effect to polygenic risk.

Proteomic Biomarkers of Quantitative Interstitial Abnormalities in COPDGene and CARDIA Lung Study.

Quantitative interstitial abnormalities (QIAs) are early measures of lung injury automatically detected on chest computed tomography scans. QIAs are associated with impaired respiratory health and share features with advanced lung diseases, but their biological underpinnings are not well understood. To identify novel protein biomarkers of QIAs using high-throughput plasma proteomic panels within two multicenter cohorts.

Early Assessment of Cardiac Allograft Vasculopathy Risk Among Recipients of Hepatitis C Virus-infected Donors in the Current Era.

Background: Transplantation of hearts from hepatitis C virus (HCV)-positive donors has increased substantially in recent years following development of highly effective direct-acting antiviral therapies for treatment and cure of HCV. Although historical data from the pre-direct-acting antiviral era demonstrated an association between HCV-positive donors and accelerated cardiac allograft vasculopathy (CAV) in recipients, the relationship between the use of HCV nucleic acid test-positive (NAT+) donors and the development of CAV in the direct-acting antiviral era remains unclear.

Methods And Results: We performed a retrospective, single-center observational study comparing coronary angiographic CAV outcomes during the first year after transplant in 84 heart transplant recipients of HCV NAT+ donors and 231 recipients of HCV NAT- donors.

Outcomes of Heart Transplant Donation After Circulatory Death.

Background: Heart transplantation using donation after circulatory death (DCD) allografts is increasingly common, expanding the donor pool and reducing transplant wait times. However, data remain limited on clinical outcomes.

Objectives: We sought to compare 6-month and 1-year clinical outcomes between recipients of DCD hearts, most of them recovered with the use of normothermic regional perfusion (NRP), and recipients of donation after brain death (DBD) hearts.