The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation.

Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues. ADAR2 was required in the endothelium for the expression of the IL-6 receptor subunit, IL-6 signal transducer (IL6ST; gp130), and subsequently, for IL-6 trans-signaling responses. ADAR2-induced adenosine-to-inosine RNA editing suppressed the Drosha-dependent primary microRNA processing, thereby overwriting the default endothelial transcriptional program to safeguard gp130 expression. This work demonstrates a role for ADAR2 epitranscriptional activity as a checkpoint in IL-6 trans-signaling and immune cell trafficking to sites of tissue injury.

Distinct Transcriptomic and Proteomic Profile Specifies Patients Who Have Heart Failure With Potential of Myocardial Recovery on Mechanical Unloading and Circulatory Support.

BACKGROUND: Extensive evidence from single-center studies indicates that a subset of patients with chronic advanced heart failure (HF) undergoing left ventricular assist device (LVAD) support show significantly improved heart function and reverse structural remodeling (ie, termed "responders"). Furthermore, we recently published a multicenter prospective study, RESTAGE-HF (Remission from Stage D Heart Failure), demonstrating that LVAD support combined with standard HF medications induced remarkable cardiac structural and functional improvement, leading to high rates of LVAD weaning and excellent long-term outcomes. This intriguing phenomenon provides great translational and clinical promise, although the underlying molecular mechanisms driving this recovery are largely unknown. METHODS: To identify changes in signaling pathways operative in the normal and failing human heart and to molecularly characterize patients who respond favorably to LVAD unloading, we performed global RNA sequencing and phosphopeptide profiling of left ventricular tissue from 93 patients with HF undergoing LVAD implantation (25 responders and 68 nonresponders) and 12 nonfailing donor hearts. Patients were prospectively monitored through echocardiography to characterize their myocardial structure and function and identify responders and nonresponders. RESULTS: These analyses identified 1341 transcripts and 288 phosphopeptides that are differentially regulated in cardiac tissue from nonfailing control samples and patients with HF. In addition, these unbiased molecular profiles identified a unique signature of 29 transcripts and 93 phosphopeptides in patients with HF that distinguished responders after LVAD unloading. Further analyses of these macromolecules highlighted differential regulation in 2 key pathways: cell cycle regulation and extracellular matrix/focal adhesions. CONCLUSIONS: This is the first study to characterize changes in the nonfailing and failing human heart by integrating multiple -omics platforms to identify molecular indices defining patients capable of myocardial recovery. These findings may guide patient selection for advanced HF therapies and identify new HF therapeutic targets.

Bridge-to-transplant temporary mechanical circulatory support and risk of allosensitization.

INTRODUCTION: Since the 2018 change in the US adult heart allocation policy, more patients are bridged-to-transplant on temporary mechanical circulatory support (tMCS). Previous studies indicate that durable left ventricular assist devices (LVAD) may lead to allosensitization. The goal of this study was to assess whether tMCS implantation is associated with changes in sensitization. METHODS: We included patients evaluated for heart transplants between 2015 and 2022 who had alloantibody measured before and after MCS implantation. Allosensitization was defined as development of new alloantibodies after tMCS implant. RESULTS: A total of 41 patients received tMCS before transplant. Nine (22.0%) patients developed alloantibodies following tMCS implantation: 3 (12.0%) in the intra-aortic balloon pump group (n = 25), 2 (28.6%) in the microaxial percutaneous LVAD group (n = 7), and 4 (44.4%) in the veno-arterial extra-corporeal membrane oxygenation group (n = 9)-p = .039. Sensitized patients were younger (44.7 ± 11.6 years vs. 54.3 ± 12.5 years, p = .044), were more likely to be sensitized at baseline - 3 of 9 (33.3%) compared to 2 out of 32 (6.3%) (p = .028) and received more transfusions with red blood cells (6 (66.6%) vs. 8 (25%), p = .02) and platelets (6 (66.6%) vs. 5 (15.6%), p = .002). There was no significant difference in tMCS median duration of support (4 [3,15] days vs. 8.5 [5,14.5] days, p = .57). Importantly, out of the 11 patients who received a durable LVAD after tMCS, 5 (45.5%) became sensitized, compared to 4 out of 30 patients (13.3%) who only had tMCS-p = .028. CONCLUSIONS: Our findings suggest that patients bridged-to-transplant with tMCS, without significant blood product transfusions and a subsequent durable LVAD implant, have a low risk of allosensitization. Further studies are needed to confirm our findings and determine whether risk of sensitization varies by type of tMCS and duration of support.

SMYD1a protects the heart from ischemic injury by regulating OPA1-mediated cristae remodeling and supercomplex formation.

SMYD1, a striated muscle-specific lysine methyltransferase, was originally shown to play a key role in embryonic cardiac development but more recently we demonstrated that loss of Smyd1 in the murine adult heart leads to cardiac hypertrophy and failure. However, the effects of SMYD1 overexpression in the heart and its molecular function in the cardiomyocyte in response to ischemic stress are unknown. In this study, we show that inducible, cardiomyocyte-specific overexpression of SMYD1a in mice protects the heart from ischemic injury as seen by a > 50% reduction in infarct size and decreased myocyte cell death. We also demonstrate that attenuated pathological remodeling is a result of enhanced mitochondrial respiration efficiency, which is driven by increased mitochondrial cristae formation and stabilization of respiratory chain supercomplexes within the cristae. These morphological changes occur concomitant with increased OPA1 expression, a known driver of cristae morphology and supercomplex formation. Together, these analyses identify OPA1 as a novel downstream target of SMYD1a whereby cardiomyocytes upregulate energy efficiency to dynamically adapt to the energy demands of the cell. In addition, these findings highlight a new epigenetic mechanism by which SMYD1a regulates mitochondrial energetics and functions to protect the heart from ischemic injury.

Interrupted Time Series Analysis of Donor Heart Use Before and After the 2018 UNOS Heart Allocation Policy Change.

BACKGROUND: Donor heart scarcity remains the fundamental barrier to increased transplant access. We examined whether 2018 United Network for Organ Sharing (UNOS) policy changes have had an impact on donor heart acceptance rates. METHODS AND RESULTS: We performed an interrupted time series analysis in UNOS to evaluate for abrupt changes in donor heart-acceptance rates associated with the new policy. All adult donor offers were evaluated between 2015 and 2021 (n = 66,654 donors). Donor volumes and transplants increased during this period, but the donor acceptance rate declined significantly from 31% in quarter 3 of 2018 to 26% acceptance in quarter 3 of 2021 (slope change -0.4% per quarter; P < 0.001). We identified 2 trends associated with this decline: (1) a growing number of donors with high-risk features, and (2) decreased acceptance of donors with certain high-risk features in the new allocation system. CONCLUSIONS: Heart transplant volumes have increased in recent years as a result of increased donor volumes, but donor heart acceptance rates began decreasing under the current allocation system. Changes in the donor pool and acceptance patterns for certain donor-risk features may explain this shift and warrant further evaluation to maximize donor heart use.

Ryanodine Receptor Staining Identifies Viable Cardiomyocytes in Human and Rabbit Cardiac Tissue Slices.

In terms of preserving multicellularity and myocardial function in vitro, the cultivation of beating myocardial slices is an emerging technique in basic and translational cardiac research. It can be used, for example, for drug screening or to study pathomechanisms. Here, we describe staining for viable cardiomyocytes based on the immunofluorescence of ryanodine receptors (RyRs) in human and rabbit myocardial slices. Biomimetic chambers were used for culture and measurements of contractile force. Fixable fluorophore-conjugated dextran, entering cells with a permeable membrane, was used for death staining. RyRs, nuclei and the extracellular matrix, including the t-system, were additionally stained and analyzed by confocal microscopy and image processing. We found the mutual exclusion of the RyR and dextran signals in cultivated slices. T-System density and nucleus size were reduced in RyR-negative/dextran-positive myocytes. The fraction of RyR-positive myocytes and pixels correlated with the contractile force. In RyR-positive/dextran-positive myocytes, we found irregular RyR clusters and SERCA distribution patterns, confirmed by an altered power spectrum. We conclude that RyR immunofluorescence indicates viable cardiomyocytes in vibratome-cut myocardial slices, facilitating the detection and differential structural analysis of living vs. dead or dying myocytes. We suggest the loss of sarcoplasmic reticulum integrity as an early event during cardiomyocyte death.

Short-Chain Fatty Acids Outpace Ketone Oxidation in the Failing Heart.

BACKGROUND: The failing heart is energy starved with impaired oxidation of long-chain fatty acids (LCFAs) at the level of reduced CPT1 (carnitine palmitoyltransferase 1) activity at the outer mitochondrial membrane. Recent work shows elevated ketone oxidation in failing hearts as an alternate carbon source for oxidative ATP generation. We hypothesized that another short-chain carbon source, short-chain fatty acids (SCFAs) that bypass carnitine palmitoyltransferase 1, could similarly support energy production in failing hearts. METHODS: Cardiac hypertrophy and dysfunction were induced in rats by transverse-aortic constriction (TAC). Fourteen weeks after TAC or sham operation, isolated hearts were perfused with either the 4 carbon, 13C-labeled ketone (D3-hydroxybutyrate) or the 4 carbon, 13C-labeled SCFA butyrate in the presence of glucose and the LCFA palmitate. Oxidation of ketone and SCFA was compared by in vitro 13C nuclear magnetic resonance spectroscopy, as was the capacity for short-chain carbon sources to compensate for impaired LCFA oxidation in the hypertrophic heart. Adaptive changes in enzyme expression and content for the distinct pathways of ketone and SCFA oxidation were examined in both failing rat and human hearts. RESULTS: TAC produced pathological hypertrophy and increased the fractional contributions of ketone to acetyl coenzyme-A production in the tricarboxylic acid cycle (0.60±0.02 sham ketone versus 0.70±0.02 TAC ketone; P<0.05). However, butyrate oxidation in failing hearts was 15% greater (0.803±0.020 TAC SCFA) than ketone oxidation. SCFA was also more readily oxidized than ketone in sham hearts by 15% (0.693±0.020 sham SCFA). Despite greater SFCA oxidation, TAC did not change short-chain acyl coenzyme-A dehydrogenase content. However, failing hearts of humans and the rat model both contain significant increases in acyl coenzyme-A synthetase medium-chain 3 enzyme gene expression and protein content. The increased oxidation of SCFA and ketones occurred at the expense of LCFA oxidation, with LCFA contributing less to acetyl coenzyme-A production in failing hearts perfused with SCFA (0.190±0.012 TAC SCFA versus 0.3163±0.0360 TAC ketone). CONCLUSIONS: SCFAs are more readily oxidized than ketones in failing hearts, despite both bypassing reduced CPT1 activity and represent an unexplored carbon source for energy production in failing hearts.

Cardiomyocyte Krüppel-Like Factor 5 Promotes De Novo Ceramide Biosynthesis and Contributes to Eccentric Remodeling in Ischemic Cardiomyopathy.

BACKGROUND: We previously showed that cardiomyocyte Krϋppel-like factor (KLF) 5 regulates cardiac fatty acid oxidation. As heart failure has been associated with altered fatty acid oxidation, we investigated the role of cardiomyocyte KLF5 in lipid metabolism and pathophysiology of ischemic heart failure. METHODS: Using real-time polymerase chain reaction and Western blot, we investigated the KLF5 expression changes in a myocardial infarction (MI) mouse model and heart tissue from patients with ischemic heart failure. Using 2D echocardiography, we evaluated the effect of KLF5 inhibition after MI using pharmacological KLF5 inhibitor ML264 and mice with cardiomyocyte-specific KLF5 deletion (αMHC [α-myosin heavy chain]-KLF5-/-). We identified the involvement of KLF5 in regulating lipid metabolism and ceramide accumulation after MI using liquid chromatography-tandem mass spectrometry, and Western blot and real-time polymerase chain reaction analysis of ceramide metabolism-related genes. We lastly evaluated the effect of cardiomyocyte-specific KLF5 overexpression (αMHC-rtTA [reverse tetracycline-controlled transactivator]-KLF5) on cardiac function and ceramide metabolism, and rescued the phenotype using myriocin to inhibit ceramide biosynthesis. RESULTS: KLF5 mRNA and protein levels were higher in human ischemic heart failure samples and in rodent models at 24 hours, 2 weeks, and 4 weeks post-permanent left coronary artery ligation. αMHC-KLF5-/- mice and mice treated with ML264 had higher ejection fraction and lower ventricular volume and heart weight after MI. Lipidomic analysis showed that αMHC-KLF5-/- mice with MI had lower myocardial ceramide levels compared with littermate control mice with MI, although basal ceramide content of αMHC-KLF5-/- mice was not different in control mice. KLF5 ablation suppressed the expression of SPTLC1 and SPTLC2 (serine palmitoyltransferase [SPT] long-chain base subunit ()1 2, respectively), which regulate de novo ceramide biosynthesis. We confirmed our previous findings that myocardial SPTLC1 and SPTLC2 levels are increased in heart failure patients. Consistently, αMHC-rtTA-KLF5 mice showed increased SPTLC1 and SPTLC2 expression, higher myocardial ceramide levels, and systolic dysfunction beginning 2 weeks after KLF5 induction. Treatment of αMHC-rtTA-KLF5 mice with myriocin that inhibits SPT, suppressed myocardial ceramide levels and alleviated systolic dysfunction. CONCLUSIONS: KLF5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of KLF5 in mice with MI prevents ceramide accumulation, alleviates eccentric remodeling, and increases ejection fraction. Thus, KLF5 emerges as a novel therapeutic target for the treatment of ischemic heart failure.

Initial Derivation of a Predictive Model for Left Ventricular Longitudinal Strain (LS) in Early Sepsis.

Septic shock is a common deadly disease often associated with cardiovascular dysfunction. Left ventricular longitudinal strain (LV LS) has been proposed as a sensitive marker to measure cardiovascular function; however, it is not available universally in standard clinical echocardiograms. We sought to derive a predictive model for LV LS, using machine learning techniques with the hope that we may uncover surrogates for LV LS. We found that left ventricular ejection fraction, tricuspid annular plane systolic excursion, sepsis source, height, mitral valve Tei index, LV systolic dimension, aortic valve ejection time, and peak acceleration rate were all predictive of LV LS in this initial exploratory model. Future modeling work may uncover combinations of these variables which may be powerful surrogates for LV LS and cardiovascular function.

Intermittent fasting and changes in Galectin-3: A secondary analysis of a randomized controlled trial of disease-free subjects.

BACKGROUND AND AIMS: Intermittent fasting reduces risk of interrelated cardiometabolic diseases, including type 2 diabetes and heart failure (HF). Previously, we reported that intermittent fasting reduced homeostasis model assessment of insulin resistance (HOMA-IR) and Metabolic Syndrome Score (MSS) in the WONDERFUL Trial. Galectin-3 may act to reduce insulin resistance. This post hoc evaluation assessed whether intermittent fasting increased galectin-3. METHODS AND RESULTS: The WONDERFUL Trial enrolled adults ages 21-70 years with ≥1 metabolic syndrome features or type 2 diabetes who were not taking anti-diabetic medication, were free of statins, and had elevated LDL-C. Subjects were randomized to water-only 24-h intermittent fasting conducted twice-per-week for 4 weeks and once-per-week for 22 weeks or to a parallel control arm with ad libitum energy intake. The study evaluated 26-week change scores of galectin-3 and other biomarkers. Overall, n = 67 subjects (intermittent fasting: n = 36; control: n = 31) completed the trial and had galectin-3 results. At 26-weeks, the galectin-3 change score was increased by intermittent fasting (median: 0.793 ng/mL, IQR: -0.538, 2.245) versus control (median: -0.332 ng/mL, IQR: -0.992, 0.776; p = 0.021). Galectin-3 changes correlated inversely with 26-week change scores of HOMA-IR (r = -0.288, p = 0.018) and MSS (r = -0.238, p = 0.052). Other HF biomarkers were unchanged by fasting. CONCLUSION: A 24-h water-only intermittent fasting regimen increased galectin-3. The fasting-triggered galectin-3 elevation was inversely correlated with declines in HOMA-IR and MSS. This may be an evolutionary adaptive survival response that protects human health by modifying disease risks, including by reducing inflammation and insulin resistance. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02770313 (registered on May 12, 2016; first subject enrolled: November 30, 2016; final subject's 26-week study visit: February 19, 2020).

Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Devices (RESTAGE-HF [Remission from Stage D Heart Failure]): Medium-Term and Primary End Point Results.

BACKGROUND: Left ventricular assist device (LVAD) unloading and hemodynamic support in patients with advanced chronic heart failure can result in significant improvement in cardiac function allowing LVAD removal; however, the rate of this is generally considered to be low. This prospective multicenter nonrandomized study (RESTAGE-HF [Remission from Stage D Heart Failure]) investigated whether a protocol of optimized LVAD mechanical unloading, combined with standardized specific pharmacological therapy to induce reverse remodeling and regular testing of underlying myocardial function, could produce a higher incidence of LVAD explantation. METHODS: Forty patients with chronic advanced heart failure from nonischemic cardiomyopathy receiving the Heartmate II LVAD were enrolled from 6 centers. LVAD speed was optimized with an aggressive pharmacological regimen, and regular echocardiograms were performed at reduced LVAD speed (6000 rpm, no net flow) to test underlying myocardial function. The primary end point was the proportion of patients with sufficient improvement of myocardial function to reach criteria for explantation within 18 months with sustained remission from heart failure (freedom from transplant/ventricular assist device/death) at 12 months. RESULTS: Before LVAD, age was 35.1±10.8 years, 67.5% were men, heart failure mean duration was 20.8±20.6 months, 95% required inotropic and 20% temporary mechanical support, left ventricular ejection fraction was 14.5±5.3%, end-diastolic diameter was 7.33±0.89 cm, end-systolic diameter was 6.74±0.88 cm, pulmonary artery saturations were 46.7±9.2%, and pulmonary capillary wedge pressure was 26.2±7.6 mm Hg. Four enrolled patients did not undergo the protocol because of medical complications unrelated to the study procedures. Overall, 40% of all enrolled (16/40) patients achieved the primary end point, P<0.0001, with 50% (18/36) of patients receiving the protocol being explanted within 18 months (pre-explant left ventricular ejection fraction, 57±8%; end-diastolic diameter, 4.81±0.58 cm; end-systolic diameter, 3.53±0.51 cm; pulmonary capillary wedge pressure, 8.1±3.1 mm Hg; pulmonary artery saturations 63.6±6.8% at 6000 rpm). Overall, 19 patients were explanted (19/36, 52.3% of those receiving the protocol). The 15 ongoing explanted patients are now 2.26±0.97 years after explant. After explantation survival free from LVAD or transplantation was 90% at 1-year and 77% at 2 and 3 years. CONCLUSIONS: In this multicenter prospective study, this strategy of LVAD support combined with a standardized pharmacological and cardiac function monitoring protocol resulted in a high rate of LVAD explantation and was feasible and reproducible with explants occurring in all 6 participating sites. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01774656.

The Role of Nonglycolytic Glucose Metabolism in Myocardial Recovery Upon Mechanical Unloading and Circulatory Support in Chronic Heart Failure.

BACKGROUND: Significant improvements in myocardial structure and function have been reported in some patients with advanced heart failure (termed responders [R]) following left ventricular assist device (LVAD)-induced mechanical unloading. This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Specifically, our previous work demonstrated a post-LVAD dissociation of glycolysis and oxidative-phosphorylation characterized by induction of glycolysis without subsequent increase in pyruvate oxidation through the tricarboxylic acid cycle. The underlying mechanisms responsible for this dissociation are not well understood. We hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, such as the pentose-phosphate pathway and 1-carbon metabolism, which may mediate myocardial recovery in R. METHODS: We prospectively obtained paired left ventricular apical myocardial tissue from nonfailing donor hearts as well as R and nonresponders at LVAD implantation (pre-LVAD) and transplantation (post-LVAD). We conducted protein expression and metabolite profiling and evaluated mitochondrial structure using electron microscopy. RESULTS: Western blot analysis shows significant increase in rate-limiting enzymes of pentose-phosphate pathway and 1-carbon metabolism in post-LVAD R (post-R) as compared with post-LVAD nonresponders (post-NR). The metabolite levels of these enzyme substrates, such as sedoheptulose-6-phosphate (pentose phosphate pathway) and serine and glycine (1-carbon metabolism) were also decreased in Post-R. Furthermore, post-R had significantly higher reduced nicotinamide adenine dinucleotide phosphate levels, reduced reactive oxygen species levels, improved mitochondrial density, and enhanced glycosylation of the extracellular matrix protein, α-dystroglycan, all consistent with enhanced pentose-phosphate pathway and 1-carbon metabolism that correlated with the observed myocardial recovery. CONCLUSIONS: The recovering heart appears to direct glycolytic metabolites into pentose-phosphate pathway and 1-carbon metabolism, which could contribute to cardioprotection by generating reduced nicotinamide adenine dinucleotide phosphate to enhance biosynthesis and by reducing oxidative stress. These findings provide further insights into mechanisms responsible for the beneficial effect of glycolysis induction during the recovery of failing human hearts after mechanical unloading.

Vascular function in continuous-flow left ventricular assist device recipients: effect of a single pulsatility treatment session.

Vascular function is further attenuated in patients with chronic heart failure implanted with a continuous-flow left ventricular assist device (LVAD), likely due to decreased arterial pulsatility, and this may contribute to LVAD-associated cardiovascular complications. However, the impact of increasing pulsatility on vascular function in this population is unknown. Therefore, 15 LVAD recipients and 15 well-matched controls underwent a 45-min, unilateral, arm pulsatility treatment, evoked by intermittent cuff inflation/deflation (2-s duty cycle), distal to the elbow. Vascular function was assessed by percent brachial artery flow-mediated dilation (%FMD) and reactive hyperemia (RH) (Doppler ultrasound). Pretreatment, %FMD (LVAD: 4.0 ± 1.7; controls: 4.2 ± 1.4%) and RH (LVAD: 340 ± 101; controls: 308 ± 94 mL) were not different between LVAD recipients and controls; however, %FMD/shear rate was attenuated (LVAD: 0.10 ± 0.04; controls: 0.17 ± 0.06%/s-1, P < 0.05). The LVAD recipients exhibited a significantly attenuated pulsatility index (PI) compared with controls prior to treatment (LVAD: 2 ± 2; controls: 15 ± 7 AU, P < 0.05); however, during the treatment, PI was no longer different (LVAD: 37 ± 38; controls: 36 ± 14 AU). Although time to peak dilation and RH were not altered by the pulsatility treatment, %FMD (LVAD: 7.0 ± 1.8; controls: 7.4 ± 2.6%) and %FMD/shear rate (LVAD: 0.19 ± 0.07; controls: 0.33 ± 0.15%/s-1) increased significantly in both groups, with, importantly, %FMD/shear rate in the LVAD recipients being restored to that of the controls pretreatment. This study documents that a localized pulsatility treatment in LVAD recipients and controls can recover local vascular function, an important precursor to the development of approaches to increase systemic pulsatility and reduce systemic vascular complications in LVAD recipients.

Predicting mortality in cardiogenic shock secondary to ACS requiring short-term mechanical circulatory support: The ACS-MCS score.

OBJECTIVE: To identify predictors of 30-day all-cause mortality for patients with cardiogenic shock secondary to acute coronary syndrome (ACS-CS) who require short-term mechanical circulatory support (ST-MCS). BACKGROUND: ACS-CS mortality is high. ST-MCS is an attractive treatment option for hemodynamic support and stabilization of deteriorating patients. Mortality prediction modeling for ACS-CS patients requiring ST-MCS has not been well-defined. METHODS: The Utah Cardiac Recovery (UCAR) Shock database was used to identify patients admitted with ACS-CS requiring ST-MCS devices between May 2008 and August 2018. Pre-ST-MCS clinical, laboratory, echocardiographic, and angiographic data were collected. The primary endpoint was 30-day all-cause mortality. A weighted score comprising of pre-ST-MCS variables independently associated with 30-day all-cause mortality was derived and internally validated. RESULTS: A total of 159 patients (mean age, 61 years; 78% male) were included. Thirty-day all-cause mortality was 49%. Multivariable analysis resulted in four independent predictors of 30-day all-cause mortality: age, lactate, SCAI CS classification, and acute kidney injury. The model had good calibration and discrimination (area under the receiver operating characteristics curve 0.80). A predictive score (ranging 0-4) comprised of age ≥ 60 years, pre-ST-MCS lactate ≥2.5 mmol/L, AKI at time of ST-MCS implementation, and SCAI CS stage E effectively risk stratified our patient population. CONCLUSION: The ACS-MCS score is a simple and practical predictive score to risk-stratify CS secondary to ACS patients based on their mortality risk. Effective mortality risk assessment for ACS-CS patients could have implications on patient selection for available therapeutic strategy options.

State-of-the-art machine learning algorithms for the prediction of outcomes after contemporary heart transplantation: Results from the UNOS database.

PURPOSE: We sought to develop and validate machine learning (ML) models to increase the predictive accuracy of mortality after heart transplantation (HT). METHODS AND RESULTS: We included adult HT recipients from the United Network for Organ Sharing (UNOS) database between 2010 and 2018 using solely pre-transplant variables. The study cohort comprised 18 625 patients (53 ± 13 years, 73% males) and was randomly split into a derivation and a validation cohort with a 3:1 ratio. At 1-year after HT, there were 2334 (12.5%) deaths. Out of a total of 134 pre-transplant variables, 39 were selected as highly predictive of 1-year mortality via feature selection algorithm and were used to train five ML models. AUC for the prediction of 1-year survival was .689, .642, .649, .637, .526 for the Adaboost, Logistic Regression, Decision Tree, Support Vector Machine, and K-nearest neighbor models, respectively, whereas the Index for Mortality Prediction after Cardiac Transplantation (IMPACT) score had an AUC of .569. Local interpretable model-agnostic explanations (LIME) analysis was used in the best performing model to identify the relative impact of key predictors. ML models for 3- and 5-year survival as well as acute rejection were also developed in a secondary analysis and yielded AUCs of .629, .609, and .610 using 27, 31, and 91 selected variables respectively. CONCLUSION: Machine learning models showed good predictive accuracy of outcomes after heart transplantation.

Chronic antioxidant administration restores macrovascular function in patients with heart failure with reduced ejection fraction.

NEW FINDINGS: What is the central question of this study? We aimed to examine oxidative stress, antioxidant capacity and macro- and microvascular function in response to 30 days of oral antioxidant administration in patients with heart failure with reduced ejection fraction. What is the main finding and its importance? We observed an approximately twofold improvement in macrovascular function, assessed via brachial artery flow-mediated dilatation, and a reduction in oxidative stress after antioxidant administration in patients with heart failure with reduced ejection fraction. The improvement in macrovascular function was reversed 1 week after treatment cessation. These findings have identified the potential of oral antioxidant administration to optimize macrovascular health in this patient group. ABSTRACT: Heart failure with reduced ejection fraction (HFrEF) is characterized by macrovascular dysfunction and elevated oxidative stress that may be mitigated by antioxidant (AOx) administration. In this prospective study, we assessed flow-mediated dilatation (FMD) and reactive hyperaemia responses in 14 healthy, older control participants and 14 patients with HFrEF, followed by 30 days of oral AOx administration (1 g vitamin C, 600 I.U. vitamin E and 0.6 g α-lipoic acid) in the patient group. Blood biomarkers of oxidative stress (malondialdehyde) and AOx capacity (ferric reducing ability of plasma) were also assessed. Patients with HFrEF had a lower %FMD (2.63 ± 1.57%) than control participants (5.62 ± 2.60%), and AOx administration improved %FMD in patients with HFrEF (30 days, 4.90 ± 2.38%), effectively restoring macrovascular function to that of control participants. In a subset of patients, we observed a progressive improvement in %FMD across the treatment period (2.62 ± 1.62, 4.23 ± 2.69, 4.33 ± 2.24 and 4.97 ± 2.56% at days 0, 10, 20 and 30, respectively, n = 12) that was abolished 7 days after treatment cessation (2.99 ± 1.78%, n = 9). No difference in reactive hyperaemia was evident between groups or as a consequence of the AOx treatment. Ferric reducing ability of plasma levels increased (from 6.08 ± 2.80 to 6.70 ± 1.59 mm, day 0 versus 30) and malondialdehyde levels decreased (from 6.81 ± 2.80 to 6.22 ± 2.84 µm, day 0 versus 30) after treatment. These findings demonstrate the efficacy of chronic AOx administration in attenuating oxidative stress, improving AOx capacity and restoring macrovascular function in patients with HFrEF.

Longitudinal assessment of the platelet transcriptome in advanced heart failure patients following mechanical unloading.

Patients with heart failure (HF) and left ventricular assist devices (LVAD) have dysregulated thrombo-inflammatory responses, mediated in part by platelets. While studies of platelet activation have been undertaken in HF, changes in the platelet transcriptome in HF patients following mechanical unloading with an LVAD have not been investigated. We prospectively enrolled and longitudinally followed advanced HF patients (n = 32) for a mean of 57 months post-LVAD implantation. For comparison, healthy donors were also enrolled (n = 20). Platelets were hyperactive in HF, as evidenced by significantly increased formation of circulating platelet-monocyte aggregate formation. Platelet transcriptome interrogation by next-generation RNA-sequencing identified that the expression of numerous genes (n = 588) was significantly (FDR < 0.05) altered in HF patients prior to LVAD implantation. Differentially expressed genes were predicted to have roles in angiogenesis, immune and inflammatory responses, apoptosis, and cardiac muscle contraction. 90 days following LVAD implantation, the majority (80%) of differentially expressed genes in HF patients normalized, as compared to the platelet transcriptomes of healthy donors. In conclusion, advanced HF is associated with marked alterations in the platelet transcriptome. While LVAD implantation to off load the failing heart results in resolution in the majority of differentially expressed genes, a subset of the platelet transcriptome remains persistently altered.

Outcomes of Asian-Americans Implanted With Left Ventricular Assist Devices: An Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Analysis.

BACKGROUND: Studies have indicated differences between Asians and Whites in their propensity for stroke, coronary artery disease, heart failure, bleeding and thrombosis. We investigated whether Asian-Americans on durable left ventricular assist devices (LVADs) exhibit differential morbidity and mortality when compared to Whites. METHODS: We analysed prospectively collected data from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database to compare the outcomes after LVAD implantation of Asians versus Whites. RESULTS: In total, 7,018 patients were included, 130 were identified as Asian-Americans. Asian-Americans were younger, had lower body mass index, higher serum bilirubin and lower albumin levels. In a multivariable regression model, there was no difference in survival between the two groups. Asian-Americans had lower incidence of device malfunction and after adjusting for multiple factors this remained lower. The adjusted risk of a major safety composite outcome, including major bleeding, major infection, stroke and device malfunction, revealed no difference between the two groups. CONCLUSIONS: Although prior studies have reported worse cardiac surgery outcomes in Asians, in this INTERMACS analysis Asian-Americans appear to have similar survival and risk of adverse events as their White counterparts. The incidence of device malfunction was lower in the Asian-Americans, both in a univariate model and after adjusting for multiple clinical factors. Future, larger studies of Asian-Americans with end-stage heart failure and LVAD support are warranted to confirm these results.