bims-hafaim Biomed News
on Heart failure metabolism
Issue of 2022–09–04
fourteen papers selected by
Kyle McCommis, Saint Louis University
  1. Myocardial disturbances of intermediary metabolism in Barth syndrome.
  2. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials.
  3. Disruption of mitochondria-sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure.
  4. Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER.
  5. Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction.
  6. Dapagliflozin and New York Heart Association functional class in heart failure with mildly reduced or preserved ejection fraction: the DELIVER trial.
  7. The Role of SGLT2 Inhibitor Ipragliflozin on Cardiac Hypertrophy and microRNA Expression Profiles in a Non-diabetic Rat Model of Cardiomyopathy.
  8. Dapagliflozin, atrial fibrillation, and heart failure with mildly reduced or preserved ejection fraction in DELIVER.
  9. Sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials.
  10. Estimated Event-Free Survival Benefits with Dapagliflozin in HF with Mildly Reduced or Preserved Ejection Fraction.
  11. L-2-Hydroxyglutarate Protects Against Cardiac Injury via Metabolic Remodeling.
  12. Analysis of metabolic disturbances attributable to sepsis-induced myocardial dysfunction using metabolomics and transcriptomics techniques.
  13. CoQ10 Improves Myocardial Damage in Doxorubicin-Induced Heart Failure in C57BL/6 Mice.
  14. Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac Low-Density Lipoprotein Receptor Expression.
  1. Front Cardiovasc Med. 2022 ;9 981972
    Myocardial disturbances of intermediary metabolism in Barth syndrome.
    Amanda A Greenwell, Seyed Amirhossein Tabatabaei Dakhili, John R Ussher.
      Barth Syndrome (BTHS) is a rare X-linked mitochondrial disorder due to mutations in the gene TAFAZZIN, which leads to immature cardiolipin (CL) remodeling and is characterized by the development of cardiomyopathy. The immature CL remodeling in BTHS results in electron transport chain respiratory defects and destabilization of supercomplexes, thereby impairing ATP production. Thus, BTHS-related cardiomyopathy appears to share metabolic characteristics of the failing heart being an "engine out of fuel." As CL associates with numerous mitochondrial enzymes involved in ATP production, BTHS is also characterized by several defects in intermediary energy metabolism. Herein we will describe the primary disturbances in intermediary energy metabolism relating to the heart's major fuel sources, fatty acids, carbohydrates, ketones, and amino acids. In addition, we will interrogate whether these disturbances represent potential metabolic targets for alleviating BTHS-related cardiomyopathy.
    Keywords:  Barth syndrome (BTHS); cardiac energetics; cardiomyopathy; fatty acid oxidation; glucose oxidation; ketone oxidation
    DOI:  https://doi.org/10.3389/fcvm.2022.981972
  2. Lancet. 2022 Aug 26. pii: S0140-6736(22)01429-5. [Epub ahead of print]
    SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials.
    Muthiah Vaduganathan, Kieran F Docherty, Brian L Claggett, Pardeep S Jhund, Rudolf A de Boer, Adrian F Hernandez, Silvio E Inzucchi, Mikhail N Kosiborod, Carolyn S P Lam, Felipe Martinez, Sanjiv J Shah, Akshay S Desai, John J V McMurray, Scott D Solomon.
       BACKGROUND: SGLT2 inhibitors are strongly recommended in guidelines to treat patients with heart failure with reduced ejection fraction, but their clinical benefits at higher ejection fractions are less well established. Two large-scale trials, DELIVER and EMPEROR-Preserved, in heart failure with mildly reduced or preserved ejection fraction have been done, providing power to examine therapeutic effects on cardiovascular mortality and in patient subgroups when combined with the earlier trials in reduced ejection fraction.
    METHODS: We did a prespecified meta-analysis of DELIVER and EMPEROR-Preserved, and subsequently included trials that enrolled patients with reduced ejection fraction (DAPA-HF and EMPEROR-Reduced) and those admitted to hospital with worsening heart failure, irrespective of ejection fraction (SOLOIST-WHF). Using trial-level data with harmonised endpoint definitions, we did a fixed-effects meta-analysis to estimate the effect of SGLT2 inhibitors on various clinical endpoints in heart failure The primary endpoint for this meta-analysis was time from randomisation to the occurrence of the composite of cardiovascular death or hospitalisation for heart failure. We assessed heterogeneity in treatment effects for the primary endpoint across subgroups of interest. This study is registered with PROSPERO, CRD42022327527.
    FINDINGS: Among 12 251 participants from DELIVER and EMPEROR-Preserved, SGLT2 inhibitors reduced composite cardiovascular death or first hospitalisation for heart failure (hazard ratio 0·80 [95% CI 0·73-0·87]) with consistent reductions in both components: cardiovascular death (0·88 [0·77-1·00]) and first hospitalisation for heart failure (0·74 [0·67-0·83]). In the broader context of the five trials of 21 947 participants, SGLT2 inhibitors reduced the risk of composite cardiovascular death or hospitalisation for heart failure (0·77 [0·72-0·82]), cardiovascular death (0·87 [0·79-0·95]), first hospitalisation for heart failure (0·72 [0·67-0·78]), and all-cause mortality (0·92 [0·86-0·99]). These treatment effects for each of the studied endpoints were consistently observed in both the trials of heart failure with mildly reduced or preserved ejection fraction and across all five trials. Treatment effects on the primary endpoint were generally consistent across the 14 subgroups examined, including ejection fraction.
    INTERPRETATION: SGLT2 inhibitors reduced the risk of cardiovascular death and hospitalisations for heart failure in a broad range of patients with heart failure, supporting their role as a foundational therapy for heart failure, irrespective of ejection fraction or care setting.
    FUNDING: None.
    DOI:  https://doi.org/10.1016/S0140-6736(22)01429-5
  3. Proc Natl Acad Sci U S A. 2022 Sep 06. 119(36): e2206708119
    Disruption of mitochondria-sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure.
    Lu Ren, Raghavender R Gopireddy, Guy Perkins, Hao Zhang, Valeriy Timofeyev, Yankun Lyu, Daphne A Diloretto, Pauline Trinh, Padmini Sirish, James L Overton, Wilson Xu, Nathan Grainger, Yang K Xiang, Elena N Dedkova, Xiao-Dong Zhang, Ebenezer N Yamoah, Manuel F Navedo, Phung N Thai, Nipavan Chiamvimonvat.
      The sinoatrial node (SAN), the leading pacemaker region, generates electrical impulses that propagate throughout the heart. SAN dysfunction with bradyarrhythmia is well documented in heart failure (HF). However, the underlying mechanisms are not completely understood. Mitochondria are critical to cellular processes that determine the life or death of the cell. The release of Ca2+ from the ryanodine receptors 2 (RyR2) on the sarcoplasmic reticulum (SR) at mitochondria-SR microdomains serves as the critical communication to match energy production to meet metabolic demands. Therefore, we tested the hypothesis that alterations in the mitochondria-SR connectomics contribute to SAN dysfunction in HF. We took advantage of a mouse model of chronic pressure overload-induced HF by transverse aortic constriction (TAC) and a SAN-specific CRISPR-Cas9-mediated knockdown of mitofusin-2 (Mfn2), the mitochondria-SR tethering GTPase protein. TAC mice exhibited impaired cardiac function with HF, cardiac fibrosis, and profound SAN dysfunction. Ultrastructural imaging using electron microscope (EM) tomography revealed abnormal mitochondrial structure with increased mitochondria-SR distance. The expression of Mfn2 was significantly down-regulated and showed reduced colocalization with RyR2 in HF SAN cells. Indeed, SAN-specific Mfn2 knockdown led to alterations in the mitochondria-SR microdomains and SAN dysfunction. Finally, disruptions in the mitochondria-SR microdomains resulted in abnormal mitochondrial Ca2+ handling, alterations in localized protein kinase A (PKA) activity, and impaired mitochondrial function in HF SAN cells. The current study provides insights into the role of mitochondria-SR microdomains in SAN automaticity and possible therapeutic targets for SAN dysfunction in HF patients.
    Keywords:  bradycardia; heart failure; mitochondria; sinoatrial node; sinoatrial node dysfunction
    DOI:  https://doi.org/10.1073/pnas.2206708119
  4. Nat Med. 2022 Aug 27.
    Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER.
    Pardeep S Jhund, Toru Kondo, Jawad H Butt, Kieran F Docherty, Brian L Claggett, Akshay S Desai, Muthiah Vaduganathan, Samvel B Gasparyan, Olof Bengtsson, Daniel Lindholm, Magnus Petersson, Anna Maria Langkilde, Rudolf A de Boer, David DeMets, Adrian F Hernandez, Silvio E Inzucchi, Mikhail N Kosiborod, Lars Køber, Carolyn S P Lam, Felipe A Martinez, Marc S Sabatine, Sanjiv J Shah, Scott D Solomon, John J V McMurray.
      Whether the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk of a range of morbidity and mortality outcomes in patients with heart failure regardless of ejection fraction is unknown. A patient-level pooled meta-analysis of two trials testing dapagliflozin in participants with heart failure and different ranges of left ventricular ejection fraction (≤40% and >40%) was pre-specified to examine the effect of treatment on endpoints that neither trial, individually, was powered for and to test the consistency of the effect of dapagliflozin across the range of ejection fractions. The pre-specified endpoints were: death from cardiovascular causes; death from any cause; total hospital admissions for heart failure; and the composite of death from cardiovascular causes, myocardial infarction or stroke (major adverse cardiovascular events (MACEs)). A total of 11,007 participants with a mean ejection fraction of 44% (s.d. 14%) were included. Dapagliflozin reduced the risk of death from cardiovascular causes (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76-0.97; P = 0.01), death from any cause (HR 0.90, 95% CI 0.82-0.99; P = 0.03), total hospital admissions for heart failure (rate ratio 0.71, 95% CI 0.65-0.78; P < 0.001) and MACEs (HR 0.90, 95% CI 0.81-1.00; P = 0.045). There was no evidence that the effect of dapagliflozin differed by ejection fraction. In a patient-level pooled meta-analysis covering the full range of ejection fractions in patients with heart failure, dapagliflozin reduced the risk of death from cardiovascular causes and hospital admissions for heart failure (PROSPERO: CRD42022346524).
    DOI:  https://doi.org/10.1038/s41591-022-01971-4
  5. J Am Coll Cardiol. 2022 Aug 26. pii: S0735-1097(22)05673-X. [Epub ahead of print]
    Dapagliflozin in Patients Recently Hospitalized With Heart Failure and Mildly Reduced or Preserved Ejection Fraction.
    Jonathan W Cunningham, Muthiah Vaduganathan, Brian L Claggett, Ian J Kulac, Akshay S Desai, Pardeep S Jhund, Rudolf A de Boer, David DeMets, Adrian F Hernandez, Silvio E Inzucchi, Mikhail N Kosiborod, Carolyn S P Lam, Felipe Martinez, Sanjiv J Shah, Martina M McGrath, Eileen O'Meara, Ulrica Wilderäng, Daniel Lindholm, Magnus Petersson, Anna Maria Langkilde, John J V McMurray, Scott D Solomon.
       BACKGROUND: Patients recently hospitalized for heart failure (HF) are at high risk for rehospitalization and death.
    OBJECTIVES: The purpose of this study was to investigate clinical outcomes and response to dapagliflozin in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF) who were enrolled during or following hospitalization.
    METHODS: The DELIVER (Dapagliflozin Evaluation to Improve the LIVES of Patients With PReserved Ejection Fraction Heart Failure) trial randomized patients with HF and LVEF >40% to dapagliflozin or placebo. DELIVER permitted randomization during or shortly after hospitalization for HF in clinically stable patients off intravenous HF therapies. This prespecified analysis investigated whether recent HF hospitalization modified risk of clinical events or response to dapagliflozin. The primary outcome was worsening HF event or cardiovascular death.
    RESULTS: Of 6,263 patients in DELIVER, 654 (10.4%) were randomized during HF hospitalization or within 30 days of discharge. Recent HF hospitalization was associated with greater risk of the primary outcome after multivariable adjustment (HR: 1.88; 95% CI: 1.60-2.21; P < 0.001). Dapagliflozin reduced the primary outcome by 22% in recently hospitalized patients (HR: 0.78; 95% CI: 0.60-1.03) and 18% in patients without recent hospitalization (HR: 0.82; 95% CI: 0.72-0.94; Pinteraction = 0.71). Rates of adverse events, including volume depletion, diabetic ketoacidosis, or renal events, were similar with dapagliflozin and placebo in recently hospitalized patients.
    CONCLUSIONS: Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization. Starting dapagliflozin during or shortly after HF hospitalization in patients with mildly reduced or preserved LVEF appears safe and effective. (Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).
    Keywords:  heart failure; hospitalization; preserved ejection fraction; sodium-glucose co-transporter-2 inhibitor
    DOI:  https://doi.org/10.1016/j.jacc.2022.07.021
  6. Eur J Heart Fail. 2022 Aug 11.
    Dapagliflozin and New York Heart Association functional class in heart failure with mildly reduced or preserved ejection fraction: the DELIVER trial.
    John W Ostrominski, Muthiah Vaduganathan, Brian L Claggett, Rudolf A de Boer, Akshay S Desai, Dan Dobreanu, Adrian F Hernandez, Silvio E Inzucchi, Pardeep S Jhund, Mikhail Kosiborod, Carolyn S P Lam, Anna M Langkilde, Daniel Lindholm, Felipe A Martinez, Eileen O'Meara, Magnus Petersson, Sanjiv J Shah, Jorge Thierer, John J V McMurray, Scott D Solomon.
       AIMS: This pre-specified analysis of the DELIVER trial examined whether clinical benefits of dapagliflozin in heart failure (HF) with left ventricular ejection fraction (LVEF) >40% varied by baseline New York Heart Association (NYHA) class and examined the treatment effects on NYHA class over time.
    METHODS AND RESULTS: Treatment effects of dapagliflozin by baseline NYHA class II (n = 4713) versus III/IV (n = 1549) were examined on the primary endpoint (cardiovascular death or worsening HF event) and key secondary endpoints. Effects of dapagliflozin on change in NYHA class at 4, 16, and 32 weeks were also evaluated. Higher baseline NYHA class was associated with older age, female sex, greater comorbidity burden, lower LVEF, and higher natriuretic peptide levels. Participants with baseline NYHA class III/IV, as compared with II, were independently more likely to experience the primary endpoint (adjusted hazard ratio [HR] 1.16 [95% confidence interval, 1.02-1.33]) and all-cause death (adjusted HR 1.22 [1.06-1.40]). Dapagliflozin consistently reduced the risk of the primary endpoint compared with placebo, irrespective of baseline NYHA class (HR 0.81 [0.70-0.94] for NYHA class II vs. HR 0.80 [0.65-0.98] for NYHA class III/IV; pinteraction  = 0.921). Participants with NYHA class III/IV had greater improvement in Kansas City Cardiomyopathy Questionnaire total symptom scores between baseline and 32 weeks (+4.8 [2.5-7.1]) versus NYHA class II (+1.8 [0.7-2.9]; pinteraction  = 0.011). Dapagliflozin was associated with higher odds of any improvement in NYHA class (odds ratio [OR] 1.32 [1.16-1.51]), as well as improvement to NYHA class I (OR 1.43 [1.17-1.75]), versus placebo at 32 weeks, with benefits seen as early as 4 weeks.
    CONCLUSIONS: Among symptomatic patients with HF and LVEF >40%, treatment with dapagliflozin provided clinical benefit irrespective of baseline NYHA class and was associated with early and sustained improvements in NYHA class over time.
    Keywords:  Dapagliflozin; Functional status; Heart failure with preserved ejection fraction; New York Heart Association classification
    DOI:  https://doi.org/10.1002/ejhf.2652
  7. Biol Pharm Bull. 2022 ;45(9): 1321-1331
    The Role of SGLT2 Inhibitor Ipragliflozin on Cardiac Hypertrophy and microRNA Expression Profiles in a Non-diabetic Rat Model of Cardiomyopathy.
    Toshiyuki Takasu.
      Evidence from clinical trials suggests that the cardioprotective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors may arise through non-glycemic control-related mechanisms. Further, the cardiovascular advantages of SGLT2 inhibitors are likely present among non-diabetic patients with known cardiovascular diseases (CVDs). Here, we studied the impact of ipragliflozin, a selective SGLT2 inhibitor, on cardiac histopathology and microRNA (miRNA) expression profiles in a non-diabetic rat model of cardiomyopathy. Ipragliflozin was added to chow (0.01% (w/w)) and given to male DahlS.Z-Leprfa/Leprfa (DS/obese) rats for 6 weeks. Similarly aged male DahlS.Z-Lepr+/Lepr+ (DS/lean) rats were treated as controls. Measurements of systolic blood pressure (SBP) and heart rate (HR) were taken every other week. Following ipragliflozin treatment for 6 weeks, we conducted echocardiography, histopathological examination, and miRNA expression analysis (microarray). The impact of ipragliflozin on blood parameters was additionally examined. In DS/obese rats, ipragliflozin reduced SBP without affecting HR, reduced interventricular septal thickness in echocardiography and left ventricular (LV) organ weight, and improved hypertrophy of cardiomyocytes according to histopathological experiments. Further, ipragliflozin reduced plasma inflammatory cytokine levels in DS/obese rats. Additionally, ipragliflozin treatment altered the expression profile of miRNAs related to cardiac hypertrophy and heart failure in the LV compared to DS/obese control rats. Ipragliflozin prevented LV hypertrophy and altered related miRNA expression profiles in non-diabetic DS/obese rats. These findings suggest that miRNAs may play a partial role in regulating the structure of the heart and that SGLT2 inhibitors may exert cardio-protective effects by changing miRNA expression profiles in non-diabetic patients with CVDs.
    Keywords:  cardio-protective effect; ipragliflozin L-proline; microRNA; sodium-dependent glucose cotransporter 2
    DOI:  https://doi.org/10.1248/bpb.b22-00289
  8. J Am Coll Cardiol. 2022 Aug 13. pii: S0735-1097(22)06529-9. [Epub ahead of print]
    Dapagliflozin, atrial fibrillation, and heart failure with mildly reduced or preserved ejection fraction in DELIVER.
    Jawad H Butt, Toru Kondo, Pardeep S Jhund, Josep Comin-Colet, Rudolf A de Boer, Akshai S Desai, Adrian F Hernandez, Silvio E Inzucchi, Stefan P Janssens, Mikhail N Kosiborod, Carolyn S P Lam, Anna Maria Langkilde, Daniel Lindholm, Felipe Martinez, Magnus Petersson, Sanjiv J Shah, Jorge Thierer, Muthiah Vaduganathan, Subodh Verma, Ulrica Wilderäng, Brian C Claggett, Scott D Solomon, John Jv McMurray.
       BACKGROUND: Atrial fibrillation (AF) is common in heart failure (HF), is associated with worse outcomes, compared to sinus rhythm, and may modify the effects of therapy.
    OBJECTIVES: We examined the effects of dapagliflozin according to the presence or not of AF in the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure trial (DELIVER).
    METHODS: A total of 6,263 patients with HF with NYHA functional class II-IV, LVEF >40%, evidence of structural heart disease, and elevated NT-proBNP levels were randomized to dapagliflozin or placebo. Clinical outcomes, and the effect of dapagliflozin, according to AF status, were examined. The primary outcome was a composite of cardiovascular death or a worsening HF.
    RESULTS: Of the 6,261 patients with data on baseline AF, 43.3% had no AF, 18.0% paroxysmal AF, and 38.7% persistent/permanent AF. The risk of the primary endpoint was higher in patients with AF, especially paroxysmal AF, driven by a higher rate of HF hospitalization: no AF, HF hospitalization rate per 100 person-years (95% CI), 4.5 (4.0-5.1); paroxysmal AF 7.5 (6.4-8.7); persistent/permanent AF 6.4 (5.7-7.1) (P<0.001). The benefit of dapagliflozin on the primary outcome was consistent across AF types: no AF, HR (95% CI) 0.89 (0.74-1.08); paroxysmal AF, 0.75 (0.58-0.97); persistent AF, 0.79 (0.66-0.95) [Pinteraction=0.49]. Consistent effects were observed for HF hospitalization, cardiovascular death, all-cause mortality, and improvement in the KCCQ-TSS.
    CONCLUSIONS: In DELIVER, the beneficial effects of dapagliflozin, compared with placebo, on clinical events and symptoms were consistent, irrespective of type of AF at baseline.
    Keywords:  Heart failure; atrial fibrillation; clinical trial; outcomes
    DOI:  https://doi.org/10.1016/j.jacc.2022.08.718
  9. Int J Cardiol Heart Vasc. 2022 Oct;42 101103
    Sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction: A meta-analysis of randomized controlled trials.
    Hidekatsu Fukuta, Hiromi Hagiwara, Takeshi Kamiya.
       Background: Nearly half of patients with heart failure (HF) have preserved ejection fraction (EF) and the mortality and morbidity of patients with HF with preserved EF (HFpEF) are high. Patients with HFpEF are often elderly and their primary chronic symptom is severe exercise intolerance that results in a reduced quality of life. Thus, improvement of exercise capacity and quality of life presents another important clinical outcome in HFpEF patients. Recent randomized controlled trials (RCTs) and meta-analyses of RCTs reported that sodium-glucose cotransporter 2 (SGLT-2) inhibitors improved cardiovascular (CV) outcomes in patients with HF with reduced EF. Although the effects of SGLT-2 inhibitors in HFpEF patients have been examined in multiple RCTs, results are inconsistent due partly to limited power. We aimed to conduct a meta-analysis of RCTs on the effects of SGLT-2 inhibitors in HFpEF patients.
    Methods and Results: The search of electronic databases identified 11 RCTs including 10,845 patients. In pooled analyses, SGLT-2 inhibitors reduced the risk of a composite of hospitalization for HF and CV death (hazard ratio [95 % CI] = 0.78 [0.70, 0.87], Pfix < 0.001). SGLT-2 inhibitors significantly increased 6-minute walk distance (weighted mean difference [95 % CI] = 18.0 [6.8, 29.3] m; Pfix = 0.002) and the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (weighted mean difference [95 % CI] = 2.57 [0.19, 4.96] points; Prandom = 0.035) and reduced plasma NT-pro B-type natriuretic peptide levels (weighted mean difference [95 % CI] = -60.16 [-82.99, -37.33] pg/ml; Pfix < 0.001) compared with control.
    Conclusion: The present meta-analysis suggests that SGLT-2 inhibitors may be beneficial for HFpEF patients, especially in diabetic patients.
    Keywords:  Heart failure; Meta-analysis; Preserved ejection fraction; Sodium–glucose cotransporter 2 inhibitors
    DOI:  https://doi.org/10.1016/j.ijcha.2022.101103
  10. J Am Coll Cardiol. 2022 Aug 24. pii: S0735-1097(22)06611-6. [Epub ahead of print]
    Estimated Event-Free Survival Benefits with Dapagliflozin in HF with Mildly Reduced or Preserved Ejection Fraction.
    Muthiah Vaduganathan, Brian L Claggett, Pardeep Jhund, Rudolf A de Boer, Adrian F Hernandez, Silvio E Inzucchi, Mikhail N Kosiborod, Carolyn S P Lam, Felipe Martinez, Sanjiv J Shah, Akshay S Desai, Daniel Lindholm, Magnus Petersson, Anna Maria Langkilde, John J V McMurray, Scott D Solomon.
       BACKGROUND: Recent guidelines support consideration of sodium glucose co-transporter(SGLT)-2 inhibitors in the long-term management of heart failure (HF) with mildly reduced or preserved ejection fraction. Patients and clinicians may be interested in the expected lifetime benefits of SGLT-2 inhibitors.
    OBJECTIVES: To estimate event-free survival gains from long-term use of dapagliflozin in patients with HF with mildly reduced or preserved ejection fraction overall and in clinically relevant subgroups.
    METHODS: In this pre-specified analysis of DELIVER, we applied validated nonparametric age-based methods to extrapolate potential gains in survival free from the primary endpoint (cardiovascular death or worsening HF event) from long-term use of dapagliflozin. Eligible participants had symptomatic HF, LVEF>40%, elevated natriuretic peptide levels, and structural heart disease. For every year between age 55 and 85, we estimated event-free survival using age at randomization rather than time from randomization as the time horizon. Residual lifespan free from primary endpoint was estimated based on area under the survival curve in each arm.
    RESULTS: Among 6,263 participants, mean survival free from the primary endpoint for a 65-year-old participant was 12.1 (95%CI 11.0 to 13.2) years with dapagliflozin and 9.7 (95%CI 8.8 to 10.7) years with placebo, representing a 2.3 (95%CI 0.9 to 3.8) year event-free survival gain(P=0.002). Treatment gains in survival free from the primary endpoint ranged from 2.0 (95%CI -0.6 to 4.6) years in a 55-year-old to 1.2 (95%CI -0.1 to 2.4) years in a 75-year-old. Mean event-free survival was greater with dapagliflozin than with placebo across all 14 subgroups.
    CONCLUSIONS: Treatment with dapagliflozin is projected to extend event-free survival by up to 2-2.5 years among middle age and older individuals with HF with mildly reduced, preserved, or improved ejection fraction.
    Keywords:  SGLT-2 inhibitors; heart failure with improved ejection fraction; heart failure with mildly reduced ejection fraction; heart failure with preserved ejection fraction; implementation science; modeling
    DOI:  https://doi.org/10.1016/j.jacc.2022.08.745
  11. Circ Res. 2022 Aug 31. 101161CIRCRESAHA122321227
    L-2-Hydroxyglutarate Protects Against Cardiac Injury via Metabolic Remodeling.
    Huamei He, Ryan M Mulhern, William M Oldham, Wusheng Xiao, Yi-Dong Lin, Ronglih Liao, Joseph Loscalzo.
       BACKGROUND: L-2-hydroxyglutarate (L2HG) couples mitochondrial and cytoplasmic energy metabolism to support cellular redox homeostasis. Under oxygen-limiting conditions, mammalian cells generate L2HG to counteract the adverse effects of reductive stress induced by hypoxia. Very little is known, however, about whether and how L2HG provides tissue protection from redox stress during low-flow ischemia (LFI) and ischemia-reperfusion injury. We examined the cardioprotective effects of L2HG accumulation against LFI and ischemia-reperfusion injury and its underlying mechanism using genetic mouse models.
    METHODS AND RESULTS: L2HG accumulation was induced by homozygous (L2HGDH [L-2-hydroxyglutarate dehydrogenase]-/-) or heterozygous (L2HGDH+/-) deletion of the L2HGDH gene in mice. Hearts isolated from these mice and their wild-type littermates (L2HGDH+/+) were subjected to baseline perfusion or 90-minute LFI or 30-minute no-flow ischemia followed by 60- or 120-minute reperfusion. Using [13C]- and [31P]-NMR spectroscopy, high-performance liquid chromatography, real-time quantitative real-time polymerase chain reaction, ELISA, triphenyltetrazolium staining, colorimetric/fluorometric spectroscopy, and echocardiography, we found that L2HGDH deletion induces L2HG accumulation at baseline and under stress conditions with significant functional consequences. In response to LFI or ischemia-reperfusion, L2HG accumulation shifts glucose flux from glycolysis towards the pentose phosphate pathway. These key metabolic changes were accompanied by enhanced cellular reducing potential, increased elimination of reactive oxygen species, attenuated oxidative injury and myocardial infarction, preserved cellular energy state, and improved cardiac function in both L2HGDH-/- and L2HGDH+/- hearts compared with L2HGDH+/+ hearts under ischemic stress conditions.
    CONCLUSION: L2HGDH deletion-induced L2HG accumulation protects against myocardial injury during LFI and ischemia-reperfusion through a metabolic shift of glucose flux from glycolysis towards the pentose phosphate pathway. L2HG offers a novel mechanism for eliminating reactive oxygen species from myocardial tissue, mitigating redox stress, reducing myocardial infarct size, and preserving high-energy phosphates and cardiac function. Targeting L2HG levels through L2HGDH activity may serve as a new therapeutic strategy for cardiovascular diseases related to oxidative injury.
    Keywords:  glycolysis; ischemia; pentose phosphate pathway; reactive oxygen species; reperfusion
    DOI:  https://doi.org/10.1161/CIRCRESAHA.122.321227
  12. Front Mol Biosci. 2022 ;9 967397
    Analysis of metabolic disturbances attributable to sepsis-induced myocardial dysfunction using metabolomics and transcriptomics techniques.
    Xiaonan Jia, Yahui Peng, Xiaohui Ma, Xiaowei Liu, Kaijiang Yu, Changsong Wang.
      Background: Sepsis-induced myocardial dysfunction (SIMD) is the most common and severe sepsis-related organ dysfunction. We aimed to investigate the metabolic changes occurring in the hearts of patients suffering from SIMD. Methods: An animal SIMD model was constructed by injecting lipopolysaccharide (LPS) into mice intraperitoneally. Metabolites and transcripts present in the cardiac tissues of mice in the experimental and control groups were extracted, and the samples were studied following the untargeted metabolomics-transcriptomics high-throughput sequencing method. SIMD-related metabolites were screened following univariate and multi-dimensional analyses methods. Additionally, differential analysis of gene expression was performed using the DESeq package. Finally, metabolites and their associated transcripts were mapped to the relevant metabolic pathways after extracting transcripts corresponding to relevant enzymes. The process was conducted based on the metabolite information present in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results: One hundred and eighteen significant differentially expressed metabolites (DEMs) (58 under the cationic mode and 60 under the anionic mode) were identified by studying the SIMD and control groups. Additionally, 3,081 significantly differentially expressed genes (DEGs) (1,364 were down-regulated and 1717 were up-regulated DEGs) were identified in the transcriptomes. The comparison was made between the two groups. The metabolomics-transcriptomics combination analysis of metabolites and their associated transcripts helped identify five metabolites (d-mannose, d-glucosamine 6-phosphate, maltose, alpha-linolenic acid, and adenosine 5'-diphosphate). Moreover, irregular and unusual events were observed during the processes of mannose metabolism, amino sugar metabolism, starch metabolism, unsaturated fatty acid biosynthesis, platelet activation, and purine metabolism. The AMP-activated protein kinase (AMPK) signaling pathways were also accompanied by aberrant events. Conclusion: Severe metabolic disturbances occur in the cardiac tissues of model mice with SIMD. This can potentially help in developing the SIMD treatment methods.
    Keywords:  SIMD; metabolic; myocardial dysfunction; sepsis; transcriptomics
    DOI:  https://doi.org/10.3389/fmolb.2022.967397
  13. Front Biosci (Landmark Ed). 2022 Aug 15. 27(8): 244
    CoQ10 Improves Myocardial Damage in Doxorubicin-Induced Heart Failure in C57BL/6 Mice.
    Zuowei Pei, Liang Ma, Yawen Li, Jin Yang, Qin Yang, Wei Yao, Shijun Li.
       BACKGROUND: Cardiovascular disease is associated with high morbidity and mortality. Doxorubicin (DOX) is an effective adjunct to cancer chemotherapy but leads to cardiovascular-related side effects. Because coenzyme Q10 (CoQ10) has been shown to protect against cardiac damage, this study was conducted to investigate the protective effects of CoQ10 against cardiac damage in mice.
    METHODS: We randomly divided six-week-old male C57BL/6 mice into four groups: control (n = 7), CoQ10 (n = 7), heart failure (HF) (n = 7), and HF+CoQ10 (n = 6) groups. HF group was induced via intraperitoneal injections with DOX (5 mg/kg) once weekly for 4 weeks. CoQ10 was solube in corn oil. The mice of CoQ10 and HF+CoQ10 group were given CoQ10 (100 mg/kg) once a day for 8 weeks. All mice were subjected to different treatment regimens for eight weeks. Metabolic characteristics, cardiac damage, oxidative stress markers (SIRT1, SIRT3, eNOS, TE, P53, SIRT5, CAT, HO-1, and SOD), energy metabolism markers (PARP-1 and PPAR-γ), myocardial fibrosis markers (Smad3 and TGF-β), and apoptosis markers (BAK, BCL-XL, and caspase-8) were analyzed at eight weeks after the different treatments.
    RESULTS: CoQ10 reduced the levels of molecules related to cardiac damage, oxidative stress, energy metabolism, and myocardial fibrosis in mice with doxorubicin-induced HF. CoQ10 also exerted anti-apoptotic effects in HF mice.
    CONCLUSIONS: CoQ10 may be useful for preventing cardiac damage in DOX-induced HF.
    Keywords:  cardiac damage; coenzyme Q10; doxorubicin; heart failure
    DOI:  https://doi.org/10.31083/j.fbl2708244
  14. J Am Heart Assoc. 2022 Sep 03. e027216
    Mouse Model of Heart Failure With Preserved Ejection Fraction Driven by Hyperlipidemia and Enhanced Cardiac Low-Density Lipoprotein Receptor Expression.
    Monique Williams, Jose Manuel Condor Capcha, Camila Iansen Irion, Grace Seo, Guerline Lambert, Ali Kamiar, Keyan Yousefi, Rosemeire Kanashiro-Takeuchi, Lauro Takeuchi, Ali G Saad, Armando Mendez, Keith A Webster, Jeffrey J Goldberger, Joshua M Hare, Lina A Shehadeh.
      Background The pathways of diastolic dysfunction and heart failure with preserved ejection fraction driven by lipotoxicity with metabolic syndrome are incompletely understood. Thus, there is an urgent need for animal models that accurately mimic the metabolic and cardiovascular phenotypes of this phenogroup for mechanistic studies. Methods and Results Hyperlipidemia was induced in WT-129 mice by 4 weeks of biweekly poloxamer-407 intraperitoneal injections with or without a single intravenous injection of adeno-associatedvirus 9-cardiac troponin T-low-density lipoprotein receptor (n=31), or single intravenous injection with adeno-associatedvirus 9-cardiac troponin T-low-density lipoprotein receptor alone (n=10). Treatment groups were compared with untreated or placebo controls (n=37). Echocardiography, blood pressure, whole-body plethysmography, ECG telemetry, activity wheel monitoring, and biochemical and histological changes were assessed at 4 to 8 weeks. At 4 weeks, double treatment conferred diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Blood pressure and whole-body plethysmography results were normal, but respiration decreased at 8 weeks (P<0.01). ECG and activity wheel monitoring, respectively, indicated heart block and decreased exercise activity (P<0.001). Double treatment promoted elevated myocardial lipids including total cholesterol, fibrosis, increased wet/dry lung (P<0.001) and heart weight/body weight (P<0.05). Xanthelasma, ascites, and cardiac ischemia were evident in double and single (p407) groups. Sudden death occurred between 6 and 12 weeks in double and single (p407) treatment groups. Conclusions We present a novel model of heart failure with preserved ejection fraction driven by dyslipidemia where mice acquire diastolic dysfunction, arrhythmia, cardiac hypertrophy, fibrosis, pulmonary congestion, exercise intolerance, and preserved ejection fraction in the absence of obesity, hypertension, kidney disease, or diabetes. The model can be applied to dissect pathways of metabolic syndrome that drive diastolic dysfunction in this lipotoxicity-mediated heart failure with preserved ejection fraction phenogroup mimic.
    Keywords:  heart failure; hyperlipidemias; mice; stroke volume
    DOI:  https://doi.org/10.1161/JAHA.122.027216
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