Search

The novel total left anterior descending devascularization (TLD) approach in a canine ischemic heart failure model limits collateral flow in the ischemic zone and provides excellent early survival and repeatable development of chronic ischemic heart failure in the canine heart. This work provides a consistent large animal model for investigating heart failure mechanisms and testing novel therapeutics.

Intra-aortic balloon pump (IABP) utilization has significantly outpaced other Status 2 eligibility criteria for heart transplant. The risk of waitlist mortality of IABP-supported patients relative to other Status 2 listed patients has not been described.We performed a retrospective analysis of all adult patients listed Status 2 for heart transplantation under the current U.S. allocation policy, using data from the United Network for Organ Sharing. Patients listed status 1 and status 3 for high-dose inotropes were included for reference. Mortality and waitlist decompensation were modeled as a function of time-varying status in cause-specific Cox survival models.We identified 3638 Status 2 listings, of whom 1676 (46%) were Status 2 due to IABP. Relative to patients supported with IABP, status 2 patients with ventricular tachycardia/fibrillation [VT/VF] (HR 4.0, p.001), right-or-biventricular assist device configurations (HR 2.3, p = .002), or temporary surgical left ventricular assist devices [LVAD] (HR 2.6, p = .003) had greater risk of waitlist mortality and decompensation. Other Status 2 subgroups had mortality comparable to IABP Status 2. Risk of waitlist mortality and decompensation for IABP Status 2 was similar to Status 3 patients listed for high-dose inotropes (HR 1.2, p = .27) and lower than Status 1 patients (HR 0.7, p = .002).Waitlist mortality varies significantly by Status 2 eligibility criteria and is highest among patients listed for VT/VF, right-or-biVAD configurations, or temporary surgical LVADs. IABP-supported patients were among those with the lowest Status 2 waitlist mortality risk and comparable to Status 3 inotrope-supported patients.

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.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; P0.001). 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.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.

The COVID -19 pandemic presents a high mortality rate amongst patients who develop severe acute respiratory distress syndrome (ARDS). The purpose of this study was to evaluate the outcomes of venovenous ECMO in COVID-19-related ARDS and identify the patients that benefit the most from this procedure.Adult COVID-19 patients with severe ARDS requiring VV-ECMO support at four academic insititutions between March and October 2020 were included. Data were collected through retrospective chart reviews. Bivariate and multivariable analysis were performed with the primary outcome of in-hospital mortality.Fifty-one consecutive patients underwent VV-ECMO with a mean age of 50.4 years; 64.7% were male. Survival to hospital discharge was 62.8%. Median ICU and hospitalization duration were 27.4 (IQR:17-37) and 34.5 days (IQR:23-43), respectively. Survivors and non-survivors had a median ECMO cannulation time of 11 days (IQR 8-18) and 17 days (IQR: 12-25). The average post decannulation length of stay was 17.5 days (IQR: 12.4-25) for survivors and 0 days for non-survivors (IQR 0-6 days). Only one non-survivor was able to be decannulated. Clinical characteristics associated with mortality between non-surviors and survivors included increasing age (p=0.0048), hemorrhagic stroke (p=0.0014), and post operative dialysis (p=0.0013)were associated with mortality in a bivariate model and retained statistical significance in a multivariable model.This multicenter study confirms the effectiveness of VV-ECMO in selected critically ill patients with COVID-19-related severe ARDS. The survival of these patients is comparable to non-COVID-19-related ARDS.

The right ventricle (RV) and pulmonary arterial (PA) tree are inextricably linked, continually transferring energy back and forth in a process known as RV-PA coupling. Healthy organisms maintain this relationship in optimal balance by modulating RV contractility, pulmonary vascular resistance, and compliance to sustain RV-PA coupling through life's many physiologic challenges. Early in states of adaptation to cardiovascular disease-for example, in diastolic heart failure-RV-PA coupling is maintained via a multitude of cellular and mechanical transformations. However, with disease progression, these compensatory mechanisms fail and become maladaptive, leading to the often-fatal state of "uncoupling." Noninvasive imaging modalities, including echocardiography, magnetic resonance imaging, and computed tomography, allow us deeper insight into the state of coupling for an individual patient, providing for prognostication and potential intervention before uncoupling occurs. In this review, we discuss the physiologic foundations of RV-PA coupling, elaborate on the imaging techniques to qualify and quantify it, and correlate these fundamental principles with clinical scenarios in health and disease. © 2022 American Physiological Society. Compr Physiol 12: 1-26, 2022.

Background: Our current understanding of right heart failure (RHF) post-left ventricular assist device (LVAD) is lacking. Recently, a new Interagency Registry for Mechanically Assisted Circulatory Support definition of RHF was introduced. Based on this definition, we investigated natural history, risk factors, and outcomes of post-LVAD RHF. Methods: Patients implanted with continuous flow LVAD between June 2, 2014, and June 30, 2016 and registered in the Interagency Registry for Mechanically Assisted Circulatory Support/Society of Thoracic Surgeons Database were included. RHF incidence and predictors, and survival after RHF were assessed. The manifestations of RHF which were separately analyzed were elevated central venous pressure, peripheral edema, ascites, and use of inotropes. Results: Among 5537 LVAD recipients (mean 57±13 years, 49% destination therapy, support 18.9 months) prevalence of 1-month RHF was 24%. Of these, RHF persisted at 12 months in 5.3%. In contrast, de novo RHF, first identified at 3 months, occurred in 5.1% and persisted at 12 months in 17% of these, and at 6 months occurred in 4.8% and persisted at 12 months in 25%. Higher preimplant blood urea nitrogen (ORs,1.03–1.09 per 5 mg/dL increase; P P P =0.004); and centrifugal versus axial LVAD (ORs,1.15–1.78; P =0.001) represented risk factors for RHC incidence at 3 months. Patients with persistent RHF at 3 months had the lowest 2-year survival (57%) while patients with de novo RHF or RHF which resolved by 3 months had more favorable survival outcomes (75% and 78% at 2 years, respectively; P Conclusions: RHF at 1 or 3 months post-LVAD was a common and frequently transient condition, which, if resolved, was associated with relatively favorable prognosis. Conversely, de novo, late RHF post-LVAD (>6 months) was more frequently a persistent disorder and associated with increased mortality. The 1-, 3-, and 6-month time points may be used for RHF assessment and risk stratification in LVAD recipients.

RESEARCH QUESTION: Given the relative independence of ventilator settings from gas exchange and plasticity of blood gas values during extracorporeal cardiopulmonary resuscitation (ECPR), do mechanical ventilation parameters and blood gas values influence survival? METHODS: Observational cohort study of 7,488 adult patients with ECPR from the Extracorporeal Life Support Organization (ELSO) Registry. We performed case-mix adjustment for severity of illness and patient type using generalized estimating equation logistic regression to determine factors associated with hospital survival accounting for clustering by center, standardizing variables by 1 standard deviation (SD) of their values. We examined non-linear relationships between ventilatory and blood gas values with hospital survival. RESULTS: Hospital survival was decreased with higher PaO(2) on ECMO (OR 0.69, per 1SD increase [95% CI 0.64, 0.74]; p 20cmH(2)0 (OR 0.69, per 1SD [0.64, 0.75]; p

Background: Extrinsic control of cardiomyocyte metabolism is poorly understood in heart failure (HF). FGF21 (Fibroblast growth factor 21), a hormonal regulator of metabolism produced mainly in the liver and adipose tissue, is a prime candidate for such signaling. Methods: To investigate this further, we examined blood and tissue obtained from human subjects with end-stage HF with reduced ejection fraction at the time of left ventricular assist device implantation and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters. Results: Circulating FGF21 levels were substantially elevated in HF with reduced ejection fraction, compared with healthy subjects (HF with reduced ejection fraction: 834.4 [95% CI, 628.4–1040.3] pg/mL, n=40; controls: 146.0 [86.3–205.7] pg/mL, n=20, P =1.9×10 −5 ). There was clear FGF21 staining in diseased cardiomyocytes, and circulating FGF21 levels negatively correlated with the expression of cardiac genes involved in ketone metabolism, consistent with cardiac FGF21 signaling. FGF21 gene expression was very low in failing and nonfailing hearts, suggesting extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP (B-type natriuretic peptide) and total bilirubin, markers of chronic cardiac and hepatic congestion. Conclusions: Circulating FGF21 levels are elevated in HF with reduced ejection fraction and appear to bind to the heart. The liver is likely the main extracardiac source. This supports a model of hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardiohepatic signaling circuit in human HF.

Amniotic products are potent immunomodulators used clinically to repair tissue injury. Little information exists regarding the potential of cell-free human amniotic fluid (hAF) to treat cardiovascular disease. Herein, we sought to determine the influence and efficacy of acellular hAF on myocardial ischemia-reperfusion injury. Processed hAF was obtained from volunteer donors at the time of elective caesarean section and manufactured using proprietary methods. Left anterior descending coronary artery ligation was performed on rats for 60 min. Thirty minutes after release and reperfusion, either saline or hAF was injected intramyocardially. Serial echocardiography revealed that compared with saline-injected rats, hAF animals maintained their ejection fraction and did not adversely remodel through the 4-wk period. This preserved ventricular function correlated with decreased infarct size, less fibrosis, and reduced expression of cytokines and infiltrating inflammatory cells. Comparative arrays of different donor hAF lots confirmed the presence of a wide array of immunomodulatory and host-defense proteins. The observed functional cardioprotection was furthermore evident when given intravenously and across multiple hAF donors. In conclusion, our data demonstrate, for the first time, the cardioprotective effect of acellular hAF on myocardial injury. These observations spanned across diverse donors and likely result from the mixture of a plethora of naturally produced cytokines, chemokines, and immune-modulating proteins rather than a single, defined mechanistic culprit. The ubiquitous availability of hAF as a cell-free solution further suggests its potential for widespread adoption as a therapy for myocardial ischemia-reperfusion injury.

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.

Heart failure remains among the most common and morbid health conditions. The Heart Failure Strategically Focused Research Network (HF SFRN) was funded by the American Heart Association to facilitate collaborative, high‐impact research in the field of heart failure across the domains of basic, clinical, and population research. The Network was also charged with developing training opportunities for young investigators. Four centers were funded in 2016: Duke University, University of Colorado, University of Utah, and Massachusetts General Hospital‐University of Massachusetts. This report summarizes the aims of each center and major research accomplishments, as well as training outcomes from the HF SFRN.

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, 13 C-labeled ketone (D3-hydroxybutyrate) or the 4 carbon, 13 C-labeled SCFA butyrate in the presence of glucose and the LCFA palmitate. Oxidation of ketone and SCFA was compared by in vitro 13 C 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 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.

A growing proportion of transplant donors and recipients have a history of COVID-19 infection. This study sought to characterize clinical practice after recipient or donor COVID-19 infection.An online survey was distributed to heart transplant clinicians through a professional society message board and social media. Responses were collected between September 29 and November 5, 2021.There were 222 health care professionals (68% transplant cardiologists, 22% transplant surgeons, 10% other) across diverse geographic regions who completed the survey. While there was significant variation in donor acceptance, as it relates to past and current COVID-19 infection, the respondents were fairly cautious: 28% would not typically accept a donor with a history of COVID-19 regardless of the infection course and 80% would not accept donors who had evidence of myocardial dysfunction during past COVID-19 infection, or who died of COVID-19 or its complications. The timing of candidate reactivation on the waiting list after COVID-19 infection also varied and often diverged from scenarios addressed by social guidelines. Eighty-one percent of the respondents felt COVID-19 vaccine should be mandatory before transplant, but this rate varied by geographic region.Our results reflect evolving experience of the heart transplant field at a time of lack of high-quality evidence. In the absence of longer-term outcome data for donors and transplant candidates with history of COVID-19 infection, clinicians remain cautious; however, this approach will likely need to be refined as an increasing proportion of the population will continue to be infected with COVID-19.

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.

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 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.

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.

Postoperative atrial fibrillation (POAF) after cardiac surgery remains a highly prevalent and costly condition that negatively impacts patient quality of life and survival. Numerous retrospective studies, meta-analysis, and review papers have been reported identifying POAF risk based on patients' risk factors and clinical biomarkers. In this narrative review, the authors report significant variations among selected pre- and perioperative biomarkers used to predict POAF incidence in patients without a history of atrial fibrillation (AF). POAF prediction based on B-type natriuretic peptide, N-terminal pro B-type natriuretic peptide, C-reactive protein, interleukin-6, creatinine, and plasminogen activator inhibitor-1 differs significantly among different studies, thereby limiting their clinical utility to predict POAF risk with high accuracy. Conversely, soluble vascular endothelial cells adhesion molecule-1, soluble CD40 ligand, Galectin-3, and aldosterone show promise for better POAF prediction. However, the current datasets for these selected biomarkers are not of sufficient size to validate the broad clinical application specifically for patients with no prior history of AF.

Reoperative aortic root replacement, following prior biologic or mechanical valved conduit aortic root prosthesis, presents a technical challenge. The rapid-deployment aortic valve prosthesis is an approved alternative to traditional bioprosthetic aortic valve replacement. We present three clinical cases in which rapid-deployment aortic valve prostheses were utilized in lieu of reoperative full aortic root replacement. All three patients recovered uneventfully. The rapid-deployment valve insertion in a prior surgical aortic root prosthesis is a safe option to avoid reoperative full aortic root replacement.

Heart failure (HF) is a leading cause of morbidity and mortality in the United States and worldwide. As a multifactorial syndrome with unpredictable clinical outcomes, identifying the common molecular underpinnings that drive HF pathogenesis remains a major focus of investigation. Disruption of cardiac gene expression has been shown to mediate a common final cascade of pathological hallmarks wherein the heart reactivates numerous developmental pathways. Although the central regulatory mechanisms that drive this cardiac transcriptional reprogramming remain unknown, epigenetic contributions are likely. In the current study, we examined whether the epigenome, specifically DNA methylation, is reprogrammed in HF to potentiate a pathological shift in cardiac gene expression. To accomplish this, we used paired-end whole genome bisulfite sequencing and next-generation RNA sequencing of left ventricle tissue obtained from seven patients with end-stage HF and three nonfailing donor hearts. We found that differential methylation was localized to promoter-associated cytosine-phosphate-guanine islands, which are established regulatory regions of downstream genes. Hypermethylated promoters were associated with genes involved in oxidative metabolism, whereas promoter hypomethylation enriched glycolytic pathways. Overexpression of plasmid-derived DNA methyltransferase 3A in vitro was sufficient to lower the expression of numerous oxidative metabolic genes in H9c2 rat cardiomyoblasts, further supporting the importance of epigenetic factors in the regulation of cardiac metabolism. Last, we identified binding-site competition via hypermethylation of the nuclear respiratory factor 1 (NRF1) motif, an established upstream regulator of mitochondrial biogenesis. These preliminary observations are the first to uncover an etiology-independent shift in cardiac DNA methylation that corresponds with altered metabolic gene expression in HF. NEW & NOTEWORTHY The failing heart undergoes profound metabolic changes because of alterations in cardiac gene expression, reactivating glycolytic genes and suppressing oxidative metabolic genes. In the current study, we discover that alterations to cardiac DNA methylation encode this fetal-like metabolic gene reprogramming. We also identify novel epigenetic interference of nuclear respiratory factor 1 via hypermethylation of its downstream promoter targets, further supporting a novel contribution of DNA methylation in the metabolic remodeling of heart failure.

Left ventricular assist-device (LVAD) implantation is a life-saving therapy for patients with advanced heart failure (HF). With chronic unloading and circulatory support, LVAD-supported hearts often show significant reverse remodeling at the structural, cellular and molecular level. However, translation of these changes into meaningful cardiac recovery allowing LVAD explant is lagging. Part of the reason for this discrepancy is lack of anticipation and hence promotion and evaluation for recovery post LVAD implant. There is additional uncertainty about the long-term course of HF following LVAD explant. In selected patients, however, guided by the etiology of HF, duration of disease and other clinical factors, significant functional improvement and LVAD explantation with long-term freedom from recurrent HF events has been demonstrated to be feasible in a reproducible manner. The identified predictors of myocardial recovery suggest that the elective therapeutic use of potentially less invasive VADs for reversal of HF earlier in the disease process is a future goal that warrants further investigation. Hence, it is prudent to develop and implement tools to predict HF reversibility prior to LVAD implant, optimize unloading-promoted recovery with guideline directed medical therapy and monitor for myocardial improvement. This review article summarizes the clinical aspects of myocardial recovery and together with its companion review article focused on the biological aspects of recovery, they aim to provide a useful framework for clinicians and investigators.

Introduction: Accurate assessment of the risk of adverse outcomes can assist in the management of patients with heart failure (HF). Hypothesis: Health-related quality of life (HRQoL) can improve prediction of HF outcomes beyond that of the more traditional clinical disease characteristics. Methods: We included consecutive patients with HF with reduced ejection fraction (HFrEF) who were seen in the HF clinic and completed patient reported outcome assessment (PROs) as part of routine care. Elastic net and gradient boosting regression analysis were used to build predictive models for HF hospitalization, heart transplant, left ventricular assist device implantation or death (composite outcome), including a range of clinical variables and PRO results as covariates. Results: There were 1,165 patients with HFrEF (mean age 60.5±16.2, 65% male) with median follow-up time of 490 days. Addition of PROs to more traditional risk factors improved model performance, as analyzed by C-statistics. The gradient boosting regression was chosen as the final model based on superior prediction performance - c-statistic 0.733 and favorable stratification of patient risk - Figure 1A . The Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ) and PROMIS dimensions of Satisfaction with social roles and activities and Physical function were covariates with high variable importance measure in the model. The predictive value of PROs was also confirmed by determining freedom from the composite endpoint in the 20th, 50th and 80th percentiles of PRO strata, while assigning the remaining clinical variables a median value ( Figure 1B ). In this analysis, PROs discriminated outcomes independent of other clinical characteristics. Conclusions: HRQoL appears to significantly modify outcome in HFrEF. Routine assessment of PROs could help to more accurately assess risk of adverse outcomes and personalize informed treatment decisions.

BACKGROUNDIn chronic heart failure (HF) patients supported with continuous-flow left ventricular assist device (CF-LVAD), we aimed to assess the clinical association of baseline QRS duration (QRSd) with post-LVAD cardiac recovery, and its correlation with pre- to post-LVAD change in left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDD).METHODSChronic HF patients (n=402) undergoing CF-LVAD implantation were prospectively enrolled, at one of the centers comprising the U.T.A.H. (Utah Transplant Affiliated Hospitals) consortium. After excluding patients with acute HF etiologies, hypertrophic or infiltrative cardiomyopathy, and/or inadequate post-LVAD follow up (RESULTSThirty-five patients (11%) achieved ‘R’ criteria, and exhibited a 15% shorter QRSd compared to ‘NR’ (123±37 ms vs 145±36 ms; pCONCLUSIONChronic advanced HF patients with a shorter baseline QRSd exhibit an increased potential for cardiac recovery after LVAD support.

The 2018 U.S. heart allocation system offers an accelerated pathway for heart transplantation to the most urgent patients.This study sought to determine whether the new allocation system resulted in lower likelihood of candidate recovery.Adult patients waitlisted for heart transplantation with temporary mechanical circulatory support at the time of initial listing between 2010 and 2020 in the United Network for Organ Sharing registry were included. Competing events of heart transplantation, waitlist death or delisting for deteriorating condition, and delisting for improved condition (candidate recovery) were analyzed in the new vs old heart allocation system.A total of 688 patients were waitlisted with venoarterial extracorporeal membrane oxygenation or a surgical nondischargeable biventricular assist device (status 1 or old 1A). Overall, 2,237 patients were waitlisted with an intra-aortic balloon pump, a percutaneous left ventricular assist device (LVAD), or a surgical nondischargeable LVAD (status 2 or old 1A). Patients waitlisted with venoarterial extracorporeal membrane oxygenation or a nondischargeable biventricular assist device had significantly shorter median waitlist times (5 vs 31 days), higher incidence for cardiac transplantation (81.5% vs 43.0%), and lower incidence of candidate recovery (1.5% vs 7.9%) in the new vs old heart allocation system (all P 0.05). Patients waitlisted with an intra-aortic balloon pump or percutaneous or a nondischargeable LVAD also had significantly shorter median waitlist times (8 vs 35 days), higher incidence of transplantation (88.9% vs 64.9%), and lower incidence of candidate recovery (0.2% vs 1.6%) in the new vs old heart allocation system (all P 0.05).Current practice of the new allocation system may not offer select temporary mechanical circulatory support patients the opportunity and adequate time to recover to the point of waitlist removal. Further research will determine which patients would benefit from urgent transplantation vs recovery strategy.

BackgroundExtrinsic control of cardiac contractility and ultrastructure via neurohormonal signaling is well established, but how other organs regulate cardiomyocyte metabolism is less well understood. Fibroblast growth factor-21 (FGF21) a hormonal regulator of metabolism mainly produced in the liver and adipose tissue, is a prime candidate for such signaling.MethodsTo investigate this further, we examined blood and tissue obtained from human subjects with heart failure with reduced ejection fraction (HFrEF) at the time of left ventricular assist device (LVAD) implantation, and correlated serum FGF21 levels with cardiac gene expression, immunohistochemistry, and clinical parameters.ResultsCirculating FGF21 levels were substantially elevated in HFrEF, compared to healthy subjects (HFrEF: 834.4 ± 101.8 pg/mL, n = 40; controls: 145.9 ± 28.6 pg/mL, n = 20, p = 5.5 × 10−8). There was clear FGF21 staining in diseased cardiomyocytes, and circulating FGF21 levels negatively correlated with the expression of cardiac genes involved in ketone metabolism, consistent with cardiac FGF21 signaling. FGF21 gene expression was low in failing and non-failing hearts, suggesting at least partial extracardiac production of the circulating hormone. Circulating FGF21 levels were correlated with BNP and total bilirubin, markers of chronic cardiac and hepatic congestion.ConclusionsCirculating FGF21 levels are elevated in HFrEF. The liver is likely the main extracardiac source, and congestive hepatopathy, common in HFrEF, was likely the proximate signal leading to FGF21 elevations. This supports a model of venous congestion from cardiomyopathy driving hepatic FGF21 communication to diseased cardiomyocytes, defining a potential cardio-hepatic signaling circuit in human heart failure.

It is not know if hospital-level extracorporeal cardiopulmonary resuscitation (ECPR) case volume, or postcannulation clinical management associate with survival outcomes.To describe variation in postresuscitation management practices, and annual hospital-level case volume, for patients who receive ECPR and to determine associations between these management practices and hospital survival.Observational cohort study using case-mix adjusted survival analysis.Adult patients greater than or equal to 18 years old who received ECPR from the Extracorporeal Life Support Organization Registry from 2008 to 2019.Generalized estimating equation logistic regression was used to determine factors associated with hospital survival, accounting for clustering by center. Factors analyzed included specific clinical management interventions after starting extracorporeal membrane oxygenation (ECMO) including coronary angiography, mechanical unloading of the left ventricle on ECMO (with additional placement of a peripheral ventricular assist device, intra-aortic balloon pump, or surgical vent), placement of an arterial perfusion catheter distal to the arterial return cannula (to mitigate leg ischemia); potentially modifiable on-ECMO hemodynamics (arterial pulsatility, mean arterial pressure, ECMO flow); plus hospital-level annual case volume for adult ECPR.Case-mix adjusted patient-level management practices varied widely across individual hospitals. We analyzed 7,488 adults (29% survival); median age 55 (interquartile range, 44-64), 68% of whom were male. Adjusted hospital survival on ECMO was associated with mechanical unloading of the left ventricle (odds ratio [OR], 1.3; 95% CI, 1.08-1.55;Modifiable ECMO management strategies and annual case volume vary across hospitals, appear to be associated with survival and should be the focus of future research to test if these hypothesis-generating associations are causal in nature.

The aim of this study was to develop and validate a score to accurately predict the probability of death for adult extracorporeal cardiopulmonary resuscitation (ECPR).ECPR is being increasingly used to treat refractory in-hospital cardiac arrest (IHCA), but survival varies from 20% to 40%.Adult patients with extracorporeal membrane oxygenation for IHCA (ECPR) were identified from the American Heart Association GWTG-R (Get With the Guidelines-Resuscitation) registry. A multivariate survival prediction model and score were developed to predict hospital death. Findings were externally validated in a separate cohort of patients from the Extracorporeal Life Support Organization registry who underwent ECPR for IHCA.A total of 1,075 patients treated with ECPR were included. Twenty-eight percent survived to discharge in both the derivation and validation cohorts. A total of 6 variables were associated with in-hospital death: age, time of day, initial rhythm, history of renal insufficiency, patient type (cardiac vs noncardiac and medical vs surgical), and duration of the cardiac arrest event, which were combined into the RESCUE-IHCA (Resuscitation Using ECPR During IHCA) score. The model had good discrimination (area under the curve: 0.719; 95% CI: 0.680-0.757) and acceptable calibration (Hosmer and Lemeshow goodness of fit P = 0.079). Discrimination was fair in the external validation cohort (area under the curve: 0.676; 95% CI: 0.606-0.746) with good calibration (P = 0.66), demonstrating the model's ability to predict in-hospital death across a wide range of probabilities.The RESCUE-IHCA score can be used by clinicians in real time to predict in-hospital death among patients with IHCA who are treated with ECPR.

Background: Variable definitions and an incomplete understanding of the gradient of reverse cardiac remodeling following continuous flow left ventricular assist device (LVAD) implantation has limited the field of myocardial plasticity. We evaluated the continuum of LV remodeling by serial echocardiographic imaging to define 3 stages of reverse cardiac remodeling following LVAD. Methods: The study enrolled consecutive LVAD patients across 4 study sites. A blinded echocardiographer evaluated the degree of structural (LV internal dimension at end-diastole [LVIDd]) and functional (LV ejection fraction [LVEF]) change after LVAD. Patients experiencing an improvement in LVEF ≥40% and LVIDd ≤6.0 cm were termed responders, absolute change in LVEF of ≥5% and LVEF Results: Among 358 LVAD patients, 34 (10%) were responders, 112 (31%) partial responders, and the remaining 212 (59%) were nonresponders. The use of guideline-directed medical therapy for heart failure was higher in partial responders and responders. Structural changes (LVIDd) followed a different pattern with significant improvements even in patients who had minimal LVEF improvement. With mechanical unloading, the median reduction in LVIDd was −0.6 cm (interquartile range [IQR], −1.1 to −0.1 cm; nonresponders), −1.1 cm (IQR, −1.8 to −0.4 cm; partial responders), and −1.9 cm (IQR, −2.9 to −1.1 cm; responders). Similarly, the median change in LVEF was −2% (IQR, −6% to 1%), 9% (IQR, 6%–14%), and 27% (IQR, 23%–33%), respectively. Conclusions: Reverse cardiac remodeling associated with durable LVAD support is not an all-or-none phenomenon and manifests in a continuous spectrum. Defining 3 stages across this continuum can inform clinical management, facilitate the field of myocardial plasticity, and improve the design of future investigations.

Background The high incidence of gastrointestinal bleeding (GIB) in patients with ventricular assist devices (VAD) is well known, but there is limited evidence to support the use of proton pump inhibitors (PPIs) or histamine receptor antagonists (H2RA) for preventing GIB in patients with VAD. Materials and methods The surgical ICU and VAD databases within a large regional academic cardiac mechanical support and transplant center were queried for patients who underwent VAD implantation between 2010 and 2014. An observational cohort study was conducted to identify which acid suppressing drug regimen was associated with the fewest number of GIB events within 30 d after VAD implantation: PPI, H2RA, or neither. Secondary outcomes included timing, etiology, and location of GIB. Multivariable logistic regression was used to compare treatment cohorts to GIB. Odds ratios, 95% confidence intervals, and P-values were reported from the model. Results One hundred thirty-eight patients were included for final analysis, 19 of which had a GIB within 30 days of VAD implantation. Both H2RA and PPI use were associated with reduced GIB compared with the cohort with no acid suppressive therapy. In the multivariate analysis, the PPI cohort showed a statistically significant reduction in GIB (Odds ratio 0.18 [95% confidence interval 0.04-0.79] P = 0.026). Conclusions Using PPI postoperatively in patients with new VAD was associated with a reduced incidence of GIB. Given that GIB is a known complication after VAD placement, clinicians should consider the use of acid suppressive therapy for primary prevention.

To determine whether intraoperative measures of right ventricular (RV) function using transesophageal echocardiography are associated with subsequent RV failure after left ventricular assist device (LVAD) implantation.Retrospective, nonrandomized, observational study.Single tertiary-level, university-affiliated hospital.The study comprised 100 patients with systolic heart failure undergoing elective LVAD implantation.Transesophageal echocardiographic images before and after cardiopulmonary bypass were analyzed to quantify RV function using tricuspid annular plane systolic excursion (TAPSE), tricuspid annular systolic velocity (S'), fractional area change (FAC), RV global longitudinal strain, and RV free wall strain. A chart review was performed to determine which patients subsequently developed RV failure (right ventricular assist device placement or prolonged inotrope requirement ≥14 days).Nineteen patients (19%) subsequently developed RV failure. Postbypass FAC was the only measure of RV function that distinguished between the RV failure and non-RV failure groups (21.2% v 26.5%; p = 0.04). The sensitivity, specificity, and area under the curve of an abnormal RV FAC (35%) for RV failure after LVAD implantation were 84%, 20%, and 0.52, respectively. No other intraoperative measure of RV function was associated with subsequent RV failure. RV failure increased ventilator time, intensive care unit and hospital length of stay, and mortality.Intraoperative measures of RV function such as tricuspid annular plane systolic excursion, tricuspid annular systolic velocity, and RV strain were not associated with RV failure after LVAD implantation. Decreased postbypass FAC was significantly associated with RV failure but showed poor discrimination.

Recent clinical trials have suggested that blockade of interleukin-1 (IL-1) can have a favorable impact on patients with myocardial infarction and heart failure. However, the mechanism of antagonism of this specific cytokine in mediating cardiac disease remains unclear. Hence, we sought to determine the influence of IL-1 blockade on acute hypertensive remodeling.Transverse aortic constriction was performed in C57BL mice with or without intraperitoneal administration of interleukin 1 receptor antagonism (IL-1Ra). Function, structure, and molecular diagnostics were subsequently performed and analyzed.Six weeks after transverse aortic constriction, a progressive decline of ejection fraction and increases in left ventricle mass and dimensions were effectively mitigated with IL-1Ra. Transverse aortic constriction resulted in an expected profile of hypertrophic markers including myosin heavy chain, atrial natriuretic peptide, and skeletal muscle actin, which were all significantly lower in IL-1Ra treated mice. Although trichrome staining 2 weeks after transverse aortic constriction demonstrated similar levels of fibrosis, IL-1ra-reduced expression of collagen-1, tissue inhibitor of metallopeptidase 1, and periostin. Investigating the angiogenic response to pressure overload, similar levels of vascular endothelial growth factor were observed, but IL-1Ra was associated with more stromal cell-derived factor-1. Immune cell infiltration (macrophages and lymphocytes) was also decreased in IL-1Ra treated mice. Similarly, cytokine concentrations of IL-1, IL-18, and IL-6 were all reduced in IL-1Ra-treated animals.Interleukin-1Ra prevents the progression toward heart failure associated with acute pressure overload. This functional response was associated with reductions in mediators of fibrosis, cellular infiltration, and cytokine production. These results provide mechanistic insight into recent clinical trials and could springboard future investigations in patients with pressure-overload-based cardiomyopathies.

Objective Vertical transmission from SARS CoV-2-infected women is uncommon and coronavirus has not been detected in amniotic fluid. Human amniotic products have a broad immune-mediating profile. Observing that many COVID-19 patients have a profound inflammatory response to the virus, we sought to determine the influence of human amniotic fluid (hAF) on hospitalized patients with COVID-19. Results A 10-patient case series was IRB-approved to study the impact of hAF on hospitalized patients with documented COVID-19. Nine of the 10 patients survived to discharge, with one patient succumbing to the disease when enrolled on maximal ventilatory support and severe hypoxia. The study design was altered by the IRB such that the last 6 patients received higher dose of intravenous hAF. In this latter group, patients that had observed reductions in C-reactive protein were associated with improved clinical outcomes. No hAF-related adverse events were noted. Acknowledging some of the inherent limitations of this case series, these results inform and catalyze a larger scaled randomized prospective trial to further investigate hAF as a therapy for COVID-19. Trial Registration ClinicalTrials.gov: NCT04319731; March 23, 2020

While left ventricular assist devices (LVAD) successfully unload the failing ventricle, most hearts do not regain sufficient function to allow for device explantation. Herein, we report a pilot series of LVAD patients treated with interleukin-1 receptor antagonism as a biologic adjuvant that safely and effectively treated inflammation so as to create a milieu whereby the heart could functionally improve. This pilot study sets the stage for a more rigorous, controlled trial of interleukin-1 receptor antagonism in treating heart failure and promoting myocardial recovery in patients supported by LVADs.

National and institutional quality initiatives provide benchmarks for evaluating the effectiveness of medical care. However, the dramatic growth in the number and type of medical and organizational quality-improvement standards creates a challenge to identify and understand those that most accurately determine quality in cardiac surgery. It is important that surgeons have knowledge and insight into valid, useful indicators for comparison and improvement. We therefore reviewed the medical literature and have identified improvement initiatives focused on cardiac surgery. We discuss the benefits and drawbacks of existing methodologies, such as comprehensive regional and national databases that aid self-evaluation and feedback, volume-based standards as structural indicators, process measurements arising from evidence-based research, and risk-adjusted outcomes. In addition, we discuss the potential of newer methods, such as patient-reported outcomes and composite measurements that combine data from multiple sources.

Introduction: Left ventricular assist device (LVAD) therapy aims to improve LV reverse remodeling, but still >50% of chronic heart failure (CHF) patients show ‘no’ recovery. The current clinical paradigm to assess post-LVAD myocardial recovery relies on ventricular rotational and deformational mechanics. Investigating the role of a pre-LVAD QRS as a potential indicator for post-LVAD LV recovery in CHF patients may help clinicians develop optimal care plans for LVAD patients. Hypothesis: Pre-LVAD short QRS has potential value to be useful as an independent predictor for early myocardial recovery following LVAD implantation. Methods: Chronic and dilated cardiomyopathy patients (n=315) undergoing LVAD implantation were retrospectively studied. Acute HF etiology and post-LVAD follow up (6 cm. From 315 LVAD patients, 39 fulfilled the criteria of myocardial recovery as ‘R’. Results: Based on univariate logistic regression, pre-LVAD QRS duration is found to be a predictor of myocardial recovery following LVAD implantation (OR:0.986, 95% CI:0.976-0.996, p=0.005) in LVAD patients. QRS duration is 14.5% longer in the ‘NR’ group as compared with the ‘R’ group (145±36 ms vs 124±37 ms). In multivariate logistic regression, after adjusting for previous thoracotomy, beta-blockers, and a previously evaluated composite score (UCARS) including age, HF duration, and LVEDD, pre-LVAD QRS remains a significant predictor of ‘R’ status (OR:0.983, 95% CL:0.973-0.994, p=0.003). The model shows an accuracy of 0.74 with a p-value of Conclusions: Pre-LVAD short QRS interval is associated with post-LVAD LV reverse remodeling in the ‘R’ group, and thus could be of use in a clinical setting for predicting post-LVAD early myocardial recovery.