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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 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.

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: The HeartMate 3 (HM 3; Abbott) left ventricular assist device (LVAD) has improved hemocompatibility-related adverse outcomes. In sporadic cases, external compression of the outflow graft causing obstruction (eOGO) can result from substance accumulation between the outflow graft and its bend relief. We sought to evaluate the prevalence, course, and clinical implications of eOGO in an international study. Methods: A multicenter retrospective analysis of HM 3 LVADs implanted between November 2014 and April 2021 (n = 2108) was conducted across 17 cardiac centers in 8 countries. We defined eOGO as obstruction >25% in the cross-sectional area in imaging (percutaneous angiography, computed tomography, or intravascular ultrasound). The prevalence and annual incidence were calculated. Serious adverse events and outcomes (death, transplantation, or device exchange) were analyzed for eOGO cases. Results: Of 2108 patients, 62 were diagnosed with eOGO at a median LVAD support duration of 953 (interquartile range, 600-1267) days. The prevalence of eOGO was 3.0% and the incidence at 1, 2, 3, 4, and 5 years of support was 0.6%, 2.8%, 4.0%, 5.2%, and 9.1%, respectively. Of 62 patients, 9 were observed, 27 underwent surgical revision, 15 underwent percutaneous stent implantation, 8 received a heart transplant, and 2 died before intervention. One patient underwent surgical revision and later stent implantation. The mortality with therapeutic intervention was 9/53 (17.0%). Conclusions: Although uncommon, HM 3 LVAD-supported patients might develop eOGO with an increasing incidence after 1 year of support. Although engineering efforts to reduce this complication are under way, clinicians must maintain a focus on early detection and remain vigilant.

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.