bims-hafaim 2021-11-28 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021–11–28
eight papers selected by
Kyle McCommis, Saint Louis University

Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to N-Terminal Pro-B-Type Natriuretic Peptide: Insights From the DAPA-HF Trial.
The Contribution of Cardiac Fatty Acid Oxidation to Diabetic Cardiomyopathy Severity.
Long-chain fatty acid oxidation and respiratory complex I deficiencies distinguish Barth Syndrome from idiopathic pediatric cardiomyopathy.
Relevance of mitochondrial dysfunction in heart disease associated with insulin resistance conditions.
Multi-omics of a pre-clinical model of diabetic cardiomyopathy reveals increased fatty acid supply impacts mitochondrial metabolic selectivity.
Depletion of cardiac cardiolipin synthase alters systolic and diastolic function.
Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts.
EMPEROR-Preserved: SGLT2 inhibitors breakthrough in the management of heart failure with preserved ejection fraction.

Circ Heart Fail. 2021 Nov 22. CIRCHEARTFAILURE121008837

Efficacy and Safety of Dapagliflozin in Heart Failure With Reduced Ejection Fraction According to N-Terminal Pro-B-Type Natriuretic Peptide: Insights From the DAPA-HF Trial.

Jawad H Butt, Carly Adamson, Kieran F Docherty, Rudolf A de Boer, Mark C Petrie, Silvio E Inzucchi, Mikhail N Kosiborod, Anna Maria Langkilde, Daniel Lindholm, Felipe A Martinez, Olof Bengtsson, Morten Schou, Eileen O'Meara, Piotr Ponikowski, Marc S Sabatine, Mikaela Sjöstrand, Scott D Solomon, Pardeep S Jhund, John J V McMurray, Lars Køber.

   BACKGROUND: Effective therapies for HFrEF usually reduce NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and it is important to establish whether new treatments are effective across the range of NT-proBNP.
METHODS: We evaluated both these questions in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial. Patients in New York Heart Association functional class II to IV with a left ventricular ejection fraction ≤40% and a NT-proBNP level ≥600 pg/mL (≥600 ng/L; ≥400 pg/mL if hospitalized for HF within the previous 12 months or ≥900 pg/mL if atrial fibrillation/flutter) were eligible. The primary outcome was the composite of an episode of worsening HF or cardiovascular death.
RESULTS: Of the 4744 randomized patients, 4742 had an available baseline NT-proBNP measurement (median, 1437 pg/mL [interquartile range, 857-2650 pg/mL]). Compared with placebo, treatment with dapagliflozin significantly reduced NT-proBNP from baseline to 8 months (absolute least-squares mean reduction, -303 pg/mL [95% CI, -457 to -150 pg/mL]; geometric mean ratio, 0.92 [95% CI, 0.88-0.96]). Dapagliflozin reduced the risk of worsening HF or cardiovascular death, irrespective of baseline NT-proBNP quartile; the hazard ratio for dapagliflozin versus placebo, from lowest to highest quartile was 0.43 (95% CI, 0.27-0.67), 0.77 (0.56-1.04), 0.78 (0.60-1.01), and 0.78 (0.64-0.95); P for interaction=0.09. Consistent benefits were observed for all-cause mortality. Compared with placebo, dapagliflozin increased the proportion of patients with a meaningful improvement (≥5 points) in Kansas City Cardiomyopathy Questionnaire total symptom score (P for interaction=0.99) and decreased the proportion with a deterioration ≥5 points (P for interaction=0.87) across baseline NT-proBNP quartiles.
CONCLUSIONS: In patients with HFrEF, dapagliflozin reduced NT-proBNP by 300 pg/mL after 8 months of treatment compared with placebo. In addition, dapagliflozin reduced the risk of worsening HF and death, and improved symptoms, across the spectrum of baseline NT-proBNP levels included in DAPA-HF.
REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Keywords:  clinical trials; heart failure with reduced ejection fraction; natriuretic peptides; sodium-glucose cotransporter 2 inhibitors

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.121.008837
Cells. 2021 Nov 21. pii: 3259. [Epub ahead of print]10(11):

The Contribution of Cardiac Fatty Acid Oxidation to Diabetic Cardiomyopathy Severity.

Qutuba G Karwi, Qiuyu Sun, Gary D Lopaschuk.

  Diabetes is a major risk factor for the development of cardiovascular disease via contributing and/or triggering significant cellular signaling and metabolic and structural alterations at the level of the heart and the whole body. The main cause of mortality and morbidity in diabetic patients is cardiovascular disease including diabetic cardiomyopathy. Therefore, understanding how diabetes increases the incidence of diabetic cardiomyopathy and how it mediates the major perturbations in cell signaling and energy metabolism should help in the development of therapeutics to prevent these perturbations. One of the significant metabolic alterations in diabetes is a marked increase in cardiac fatty acid oxidation rates and the domination of fatty acids as the major energy source in the heart. This increased reliance of the heart on fatty acids in the diabetic has a negative impact on cardiac function and structure through a number of mechanisms. It also has a detrimental effect on cardiac efficiency and worsens the energy status in diabetes, mainly through inhibiting cardiac glucose oxidation. Furthermore, accelerated cardiac fatty acid oxidation rates in diabetes also make the heart more vulnerable to ischemic injury. In this review, we discuss how cardiac energy metabolism is altered in diabetic cardiomyopathy and the impact of cardiac insulin resistance on the contribution of glucose and fatty acid to overall cardiac ATP production and cardiac efficiency. Furthermore, how diabetes influences the susceptibility of the myocardium to ischemia/reperfusion injury and the role of the changes in glucose and fatty acid oxidation in mediating these effects are also discussed.

Keywords:  cardiac insulin resistance; diabetic cardiomyopathy; fatty acid oxidation; glucose oxidation; ischemia/reperfusion; lipotoxicity

DOI:  https://doi.org/10.3390/cells10113259
J Inherit Metab Dis. 2021 Nov 25.

Long-chain fatty acid oxidation and respiratory complex I deficiencies distinguish Barth Syndrome from idiopathic pediatric cardiomyopathy.

Kathryn C Chatfield, Genevieve C Sparagna, Kalyn S Specht, Luke A Whitcomb, Asma K Omar, Shelley D Miyamoto, Lisa M Wolfe, Adam J Chicco.

Barth syndrome (BTHS) is an X-linked disorder that results from mutations in the TAFAZZIN gene, which encodes a phospholipid transacylase responsible for generating the mature form of cardiolipin in inner mitochondrial membranes. BTHS patients develop early-onset cardiomyopathy and a derangement of intermediary metabolism consistent with mitochondrial disease, but the precise alterations in cardiac metabolism that distinguish BTHS from idiopathic forms of cardiomyopathy are unknown. We performed the first metabolic analysis of myocardial tissue from BTHS cardiomyopathy patients compared to age- and sex-matched patients with idiopathic dilated cardiomyopathy (DCM) and non-failing (NF) controls. Results corroborate previous evidence for deficiencies in cardiolipin content and its linoleoyl enrichment as defining features of BTHS cardiomyopathy, and reveal a dramatic accumulation of hydrolyzed (monolyso-) cardiolipin molecular species. Respiratory chain protein deficiencies were observed in both BTHS and DCM, but a selective depletion of Complex I was seen only in BTHS after controlling for an apparent loss of mitochondrial density in cardiomyopathic hearts. Distinct shifts in the expression of long-chain fatty acid oxidation enzymes and the tissue acyl-CoA profile of BTHS hearts suggest a specific block in mitochondrial fatty acid oxidation upstream of the conventional matrix beta-oxidation cycle, which may be compensated for by a greater reliance upon peroxisomal fatty acid oxidation and the catabolism of ketones, amino acids and pyruvate to meet cardiac energy demands. These results provide a comprehensive foundation for exploring novel therapeutic strategies that target the adaptive and maladaptive metabolic features of BTHS cardiomyopathy. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/jimd.12459
Pflugers Arch. 2021 Nov 22.

Relevance of mitochondrial dysfunction in heart disease associated with insulin resistance conditions.

Natalia de Las Heras, Vicente Lahera.

  Insulin resistance plays a key role in the development and progression of obesity, diabetes, and their complications. Moreover, insulin resistance is considered the principal link between metabolic diseases and cardiovascular diseases. Heart disease associated with insulin resistance is one of the most important consequences of both obesity and diabetes, and it is characterized by impaired cardiac energetics, diastolic dysfunction, and finally heart failure. Mitochondrion plays a key role in cell energy homeostasis and is the main source of reactive oxygen species. Obesity and diabetes are associated with alterations in mitochondrial function and dynamics. Mitochondrial dysfunction is characterized by changes in mitochondrial respiratory chain with reduced ATP production and elevated reactive oxygen species production. These mitochondrial alterations together with inflammation contribute to the development and progression of heart disease under insulin resistance conditions. Finally, numerous miRNAs participate in the regulation of energy substrate metabolism, reactive oxygen species production, and apoptotic pathways within the mitochondria. This notion supports the relevance of interactions between miRNAs and mitochondrial dysfunction in the pathophysiology of metabolic heart disease.

Keywords:  Heart disease; Inflammation; Metabolic diseases; MicroRNAs; Mitochondrial dysfunction; Oxidative stress

DOI:  https://doi.org/10.1007/s00424-021-02638-8
J Mol Cell Cardiol. 2021 Nov 23. pii: S0022-2828(21)00224-8. [Epub ahead of print]

Multi-omics of a pre-clinical model of diabetic cardiomyopathy reveals increased fatty acid supply impacts mitochondrial metabolic selectivity.

Desmond K Li, Lauren E Smith, Alexander W Rookyard, Shivanjali J Lingam, Yen C Koay, Holly P McEwen, Stephen Twigg, Anthony S Don, John F O'Sullivan, Stuart J Cordwell, Melanie Y White.

  The incidence of type 2 diabetes (T2D) is increasing globally, with long-term implications for human health and longevity. Heart disease is the leading cause of death in T2D patients, who display an elevated risk of an acute cardiovascular event and worse outcomes following such an insult. The underlying mechanisms that predispose the diabetic heart to this poor prognosis remain to be defined. This study developed a pre-clinical model (Rattus norvegicus) that complemented caloric excess from a high-fat diet (HFD) and pancreatic β-cell dysfunction from streptozotocin (STZ) to produce hyperglycaemia, peripheral insulin resistance, hyperlipidaemia and elevated fat mass to mimic the clinical features of T2D. Ex vivo cardiac function was assessed using Langendorff perfusion with systolic and diastolic contractile depression observed in T2D hearts. Cohorts representing untreated, individual HFD- or STZ-treatments and the combined HFD + STZ approach were used to generate ventricular samples (n = 9 per cohort) for sequential and integrated analysis of the proteome, lipidome and metabolome by liquid chromatography-tandem mass spectrometry. This study found that in T2D hearts, HFD treatment primed the metabolome, while STZ treatment was the major driver for changes in the proteome. Both treatments equally impacted the lipidome. Our data suggest that increases in β-oxidation and early TCA cycle intermediates promoted rerouting via 2-oxaloacetate to glutamate, γ-aminobutyric acid and glutathione. Furthermore, we suggest that the T2D heart activates networks to redistribute excess acetyl-CoA towards ketogenesis and incomplete β-oxidation through the formation of short-chain acylcarnitine species. Multi-omics provided a global and comprehensive molecular view of the diabetic heart, which distributes substrates and products from excess β-oxidation, reduces metabolic flexibility and impairs capacity to restore high energy reservoirs needed to respond to and prevent subsequent acute cardiovascular events.

Keywords:  Fatty acid β-oxidation; LC-MS/MS; Lipidomics; Metabolomics; Proteomics; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.yjmcc.2021.11.009
iScience. 2021 Nov 19. 24(11): 103314

Depletion of cardiac cardiolipin synthase alters systolic and diastolic function.

Elia Smeir, Sarah Leberer, Annelie Blumrich, Georg Vogler, Anastasia Vasiliades, Sandra Dresen, Carsten Jaeger, Yoann Gloaguen, Christian Klose, Dieter Beule, P Christian Schulze, Rolf Bodmer, Anna Foryst-Ludwig, Ulrich Kintscher.

  Cardiolipin (CL) is a major cardiac mitochondrial phospholipid maintaining regular mitochondrial morphology and function in cardiomyocytes. Cardiac CL production includes its biosynthesis and a CL remodeling process. Here we studied the impact of CL biosynthesis and the enzyme cardiolipin synthase (CLS) on cardiac function. CLS and cardiac CL species were significantly downregulated in cardiomyocytes following catecholamine-induced cardiac damage in mice, accompanied by increased oxygen consumption rates, signs of oxidative stress, and mitochondrial uncoupling. RNAi-mediated cardiomyocyte-specific knockdown of CLS in Drosophila melanogaster resulted in marked cardiac dilatation, severe impairment of systolic performance, and slower diastolic filling velocity assessed by fluorescence-based heart imaging. Finally, we showed that CL72:8 is significantly decreased in cardiac samples from patients with heart failure with reduced ejection fraction (HFrEF). In summary, we identified CLS as a regulator of cardiac function. Considering the cardiac depletion of CL species in HFrEF, pharmacological targeting of CLS may be a promising therapeutic approach.

Keywords:  Animal physiology; Lipidomics; Molecular biology; Molecular physiology

DOI:  https://doi.org/10.1016/j.isci.2021.103314
Metabolism. 2021 Nov 18. pii: S0026-0495(21)00236-5. [Epub ahead of print]127 154936

Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts.

Raffaele Marfella, Nunzia D'Onofrio, Maria Consiglia Trotta, Celestino Sardu, Lucia Scisciola, Cristiano Amarelli, Maria Luisa Balestrieri, Vincenzo Grimaldi, Gelsomina Mansueto, Salvatore Esposito, Michele D'Amico, Paolo Golino, Giuseppe Signoriello, Marisa De Feo, Ciro Maiello, Claudio Napoli, Giuseppe Paolisso.

   BACKGROUND: The pathogenesis of experimental diabetic cardiomyopathy may involve the activator protein 1 (AP-1) member, JunD. Using non-diabetic heart transplant (HTX) in recipients with diabetes, we examined the effects of the diabetic milieu (hyperglycemia and insulin resistance) on cardiac JunD expression over 12 months. Because sodium/glucose cotransporter-2 inhibitors (SGLT2i) significantly reverse high glucose-induced AP-1 binding in the proximal tubular cell, we investigated JunD expression in a subgroup of type 2 diabetic recipients receiving SGLT2i treatment.
METHODS: We evaluated 77 first HTX recipients (40 and 37 patients with and without diabetes, respectively). Among the recipients with diabetes, 17 (45.9%) were receiving SGLT2i treatment. HTX recipients underwent standard clinical evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsy). In the biopsy samples, we evaluated JunD, insulin receptor substrates 1 and 2 (IRS1 and IRS2), peroxisome proliferator-activated receptor-γ (PPAR-γ), and ceramide levels using real-time polymerase chain reaction and immunofluorescence. The biopsy evaluations in this study were performed at 1-4 weeks (basal), 5-12 weeks (intermediate), and up to 48 weeks (final, end of 12-month follow-up) after HTX.
RESULTS: There was a significant early and progressive increase in the cardiac expression of JunD/PPAR-γ and ceramide levels, along with a significant decrease in IRS1 and IRS2 in recipients with diabetes but not in those without diabetes. These molecular changes were blunted in patients with diabetes receiving SGLT2i treatment.
CONCLUSION: Early pathogenesis in human diabetic cardiomyopathy is associated with JunD/PPAR-γ overexpression and lipid accumulation following HTX in recipients with diabetes. Remarkably, this phenomenon was reduced by concomitant therapy with SGLT2i, which acted directly on diabetic hearts.

Keywords:  Diabetic cardiomyopathy; JunD; SGLT2i

DOI:  https://doi.org/10.1016/j.metabol.2021.154936
Glob Cardiol Sci Pract. 2021 Oct 30. 2021(3): e202117

EMPEROR-Preserved: SGLT2 inhibitors breakthrough in the management of heart failure with preserved ejection fraction.

Kerolos Wagdy, Sherif Nagy.

Background: Heart failure with preserved ejection fraction (HFpEF) is a complex disease which accounts for more than half of all HF hospital admissions with high prevalence and lack of effective evidence-based management. Sodium-glucose cotransporter 2 (SGLT2) inhibitor is a new antidiabetic drug that recently gained a new role in the management of heart failure with reduced ejection fraction but its role in HFpEF had yet to be studied. Study and results: EMPEROR-Preserved trial set out to evaluate the effects of SGLT2 inhibition with empagliflozin on major heart failure outcomes in patients with HFpEF. The patients were randomized in a 1:1 fashion into two groups; to receive either empagliflozin 10 mg per day (n = 2, 997) or placebo (n = 2, 991) in addition to usual therapy. Empagliflozin led to a 21% risk reduction of the composite of cardiovascular death or hospitalization for heart failure, which was mainly related to a 29% lower risk of hospitalization for heart failure rather than effect on cardiovascular death empagliflozin. The effects SGLT2 inhibitors were consistent in all patients. What we have learnt: The EMPEROR-Preserved trial is the first randomized controlled trial testing the efficacy and safety of SGLT2 inhibitor (empagliflozin) in patients with HFpEF. The trial proves that SGLT2 inhibitors (empagliflozin) can significantly reduce HF hospitalization with neutral effect on cardiovascular (CV) death.

DOI: https://doi.org/10.21542/gcsp.2021.17