bims-hafaim 2021-10-10 papers

bims-hafaim

Biomed News

on Heart failure metabolism

Issue of 2021‒10‒10
thirteen papers selected by
Kyle McCommis
Saint Louis University

Trimetazidine Attenuates Heart Failure by Improving Myocardial Metabolism via AMPK.
Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart.
PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes.
Sodium-glucose cotransporter 2 inhibitors in patients with heart failure: a systematic review and meta-analysis of randomized trials.
Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload.
SIRT5-Related Desuccinylation Modification Contributes to Quercetin-Induced Protection against Heart Failure and High-Glucose-Prompted Cardiomyocytes Injured through Regulation of Mitochondrial Quality Surveillance.
Cardiomyocyte-specific miR-100 overexpression preserves heart function under pressure overload in mice and diminishes fatty acid uptake as well as ROS production by direct suppression of Nox4 and CD36.
Epigallocatechin gallate (EGCG) attenuates myocardial hypertrophy and fibrosis induced by transverse aortic constriction via inhibiting the Akt/mTOR pathway.
Creatine deficiency and heart failure.
S-Propargyl-Cysteine Attenuates Diabetic Cardiomyopathy in db/db Mice Through Activation of Cardiac Insulin Receptor Signaling.
Sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.
SGLT2 inhibitors and cardiac remodelling: a systematic review and meta-analysis of randomized cardiac magnetic resonance imaging trials.
Empagliflozin Treatment is Associated With Improvements in Cardiac Energetics and Function and Reductions in Myocardial Cellular Volume in Patients With Type 2 Diabetes.

Front Pharmacol. 2021 ;12 707399

Trimetazidine Attenuates Heart Failure by Improving Myocardial Metabolism via AMPK.

Hongyang Shu, Weijian Hang, Yizhong Peng, Jiali Nie, Lujin Wu, Wenjun Zhang, Dao Wen Wang, Ning Zhou.

  Energic deficiency of cardiomyocytes is a dominant cause of heart failure. An antianginal agent, trimetazidine improves the myocardial energetic supply. We presumed that trimetazidine protects the cardiomyocytes from the pressure overload-induced heart failure through improving the myocardial metabolism. C57BL/6 mice were subjected to transverse aortic constriction (TAC). After 4 weeks of TAC, heart failure was observed in mice manifested by an increased left ventricular (LV) chamber dimension, an impaired LV ejection fraction evaluated by echocardiography analysis, which were significantly restrained by the treatment of trimetazidine. Trimetazidine restored the mitochondrial morphology and function tested by cardiac transmission electron microscope and mitochondrial dynamic proteins analysis. Positron emission tomography showed that trimetazidine significantly elevated the glucose uptake in TAC mouse heart. Trimetazidine restrained the impairments of the insulin signaling in TAC mice and promoted the translocation of glucose transporter type IV (GLUT4) from the storage vesicle to membrane. However, these cardioprotective effects of trimetazidine in TAC mice were notably abolished by compound C (C.C), a specific AMPK inhibitor. The enlargement of neonatal rat cardiomyocyte induced by mechanical stretch, together with the increased expression of hypertrophy-associated proteins, mitochondria deformation and dysfunction were significantly ameliorated by trimetazidine. Trimetazidine enhanced the isolated cardiomyocyte glucose uptake in vitro. These benefits brought by trimetazidine were also removed with the presence of C.C. In conclusion, trimetazidine attenuated pressure overload-induced heart failure through improving myocardial mitochondrial function and glucose uptake via AMPK.

Keywords:  AMPK; heart failure; myocardial metabolism; pressure overload; trimetazidine

DOI:  https://doi.org/10.3389/fphar.2021.707399
ESC Heart Fail. 2021 Oct 06.

Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart.

Shingo Takahara, Shubham Soni, Kiran Phaterpekar, Ty T Kim, Zaid H Maayah, Jody L Levasseur, Heidi L Silver, Darren H Freed, Mourad Ferdaoussi, Jason R B Dyck.

  AIMS: Recent evidence has demonstrated that ketone bodies, particularly β-hydroxybutyrate (BHB), are beneficial to the failing heart due to their potential as an alternative energy substrate as well as their anti-inflammatory and anti-oxidative properties. Exogenous supplementation of ketones also helps prevent heart failure (HF) development in rodent models, but whether ketones can be used to treat HF remains unexplored. Herein, we investigated whether chronic supplementation of ketones is beneficial for the heart in a mouse model of established HF.METHODS AND RESULTS: To elevate circulating ketone levels, we utilized (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate [ketone ester (KE)]. C57Bl/6N male mice were subjected to transverse aortic constriction (TAC) surgery. After developing HF, mice were treated with either 20% KE or vehicle via drinking water for 2 weeks. In another cohort, mice 3-4 weeks post-TAC received acute intravenous infusions of BHB or saline for 1 h and their cardiac function was measured. 20% KE significantly elevated blood BHB in mice (P < 0.01) without inducing ketoacidosis or altering other metabolic parameters. Mice with overt HF (30-45% ejection fraction) treated with 20% KE displayed significantly elevated circulating ketone levels compared with vehicle-treated mice (P < 0.05). The significant cardiac dysfunction in mice with HF continued to worsen after 2 weeks of vehicle treatment, whereas this decline was absent in KE-treated mice (mean difference 4.7% ejection fraction; P < 0.01). KE treatment also alleviated TAC-induced cardiomyocyte hypertrophy (P < 0.05) and reduced the TAC-induced elevated cardiac periostin (P < 0.05), a marker of activated fibroblasts. Cardiac fibrosis was also significantly reduced with KE treatment in TAC mice (P < 0.01). In another cohort, acute BHB infusion significantly increased the cardiac output of mice with HF (P < 0.05), providing further support that ketone therapy can be used to treat HF.
CONCLUSIONS: We show that chronic treatment of exogenous ketones is of benefit to the failing heart and that chronic ketone elevation may be a therapeutic option for HF. Further investigations to elucidate the underlying mechanism(s) are warranted.

Keywords:  Heart failure; Ketone ester; β-Hydroxybutyrate

DOI:  https://doi.org/10.1002/ehf2.13634
Cell Rep. 2021 Oct 05. pii: S2211-1247(21)01221-3. [Epub ahead of print]37(1): 109767

PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes.

Aude Angelini, Pradip K Saha, Antrix Jain, Sung Yun Jung, Randall L Mynatt, Xinchun Pi, Liang Xie.

  Cardiac metabolism is a high-oxygen-consuming process, showing a preference for long-chain fatty acid (LCFA) as the fuel source under physiological conditions. However, a metabolic switch (favoring glucose instead of LCFA) is commonly reported in ischemic or late-stage failing hearts. The mechanism regulating this metabolic switch remains poorly understood. Here, we report that loss of PHD2/3, the cellular oxygen sensors, blocks LCFA mitochondria uptake and β-oxidation in cardiomyocytes. In high-fat-fed mice, PHD2/3 deficiency improves glucose metabolism but exacerbates the cardiac defects. Mechanistically, we find that PHD2/3 bind to CPT1B, a key enzyme of mitochondrial LCFA uptake, promoting CPT1B-P295 hydroxylation. Further, we show that CPT1B-P295 hydroxylation is indispensable for its interaction with VDAC1 and LCFA β-oxidation. Finally, we demonstrate that a CPT1B-P295A mutant constitutively binds to VDAC1 and rescues LCFA metabolism in PHD2/3-deficient cardiomyocytes. Together, our data identify an oxygen-sensitive regulatory axis involved in cardiac metabolism.

Keywords:  cardiac metabolism switch; cardiomyocyte; carnitine O-palmitoyltransferase 1b; heart failure; hypoxia; long-chain fatty acid; myocardial infarction; prolyl hydroxylase domain protein; voltage-dependent anion channel

DOI:  https://doi.org/10.1016/j.celrep.2021.109767
Eur Heart J Qual Care Clin Outcomes. 2021 Oct 07. pii: qcab072. [Epub ahead of print]

Sodium-glucose cotransporter 2 inhibitors in patients with heart failure: a systematic review and meta-analysis of randomized trials.

Yousif Ahmad, Mahesh V Madhavan, Gregg W Stone, Darrel Francis, Raj Makkar, Deepak L Bhatt, James P Howard.

  AIMS: Sodium-glucose cotransporter 2 (SGLT-2 inhibitors) have now been evaluated for the treatment of heart failure in several placebo-controlled randomized controlled trials (RCTs) across various ejection fraction ranges, but these trials were powered for composite outcomes rather than individual clinical endpoints. We therefore performed a meta-analysis to assess their safety and efficacy on all-cause mortality, cardiovascular mortality and heart failure hospitalizations.METHODS AND RESULTS: We performed a prospectively registered random-effects meta-analysis of all RCTs comparing SGLT-2 inhibitors to placebo in patients with heart failure. The prespecified primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular mortality, heart failure hospitalizations and the composite of cardiovascular mortality and heart failure. Four trials with 15,684 patients were eligible. The SGLT-2 inhibitor tested was empagliflozin in two trials, dapagliflozin in one trial and sotagliflozin in one trial. The weighted mean-follow up was 20.1 months. The hazard ratio (HR) for all-cause mortality was 0.91, 95% confidence interval (CI) 0.82 to 1.01, P = 0.071. There was a 14% reduction in cardiovascular mortality (HR 0.86, 95% CI 0.76 to 0.96, P = 0.018), and a 31% reduction in heart failure hospitalization (HR 0.69, 95% CI 0.61 to 0.77, P < 0.001).
CONCLUSIONS: SGLT-2 inhibitors significantly reduced cardiovascular mortality and heart failure hospitalizations in patients with heart failure. The effect appears consistent across three drugs studied in four trials. SGLT-2 inhibitors should become standard care for patients with heart failure.

Keywords:  Clinical trials; Heart failure; Meta-analysis

DOI:  https://doi.org/10.1093/ehjqcco/qcab072
Front Physiol. 2021 ;12 738594

Sotagliflozin, a Dual SGLT1/2 Inhibitor, Improves Cardiac Outcomes in a Normoglycemic Mouse Model of Cardiac Pressure Overload.

Sophia L Young, Lydia Ryan, Thomas P Mullins, Melanie Flint, Sarah E Steane, Sarah L Walton, Helle Bielefeldt-Ohmann, David A Carter, Melissa E Reichelt, Linda A Gallo.

  Selective SGLT2 inhibition reduces the risk of worsening heart failure and cardiovascular death in patients with existing heart failure, irrespective of diabetic status. We aimed to investigate the effects of dual SGLT1/2 inhibition, using sotagliflozin, on cardiac outcomes in normal diet (ND) and high fat diet (HFD) mice with cardiac pressure overload. Five-week-old male C57BL/6J mice were randomized to receive a HFD (60% of calories from fat) or remain on ND for 12 weeks. One week later, transverse aortic constriction (TAC) was employed to induce cardiac pressure-overload (50% increase in right:left carotid pressure versus sham surgery), resulting in left ventricular hypertrophic remodeling and cardiac fibrosis, albeit preserved ejection fraction. At 4 weeks post-TAC, mice were treated for 7 weeks by oral gavage once daily with sotagliflozin (10 mg/kg body weight) or vehicle (0.1% tween 80). In ND mice, treatment with sotagliflozin attenuated cardiac hypertrophy and histological markers of cardiac fibrosis induced by TAC. These benefits were associated with profound diuresis and glucosuria, without shifts toward whole-body fatty acid utilization, increased circulating ketones, nor increased cardiac ketolysis. In HFD mice, sotagliflozin reduced the mildly elevated glucose and insulin levels but did not attenuate cardiac injury induced by TAC. HFD mice had vacuolation of proximal tubular cells, associated with less profound sotagliflozin-induced diuresis and glucosuria, which suggests dampened drug action. We demonstrate the utility of dual SGLT1/2 inhibition in treating cardiac injury induced by pressure overload in normoglycemic mice. Its efficacy in high fat-fed mice with mild hyperglycemia and compromised renal morphology requires further study.

Keywords:  cardiac hypertrophy; cardiovasclar disease; energy expenditure; energy intake; heart failure; high fat diet; hyperglycemia; proximal tubular cell damage

DOI:  https://doi.org/10.3389/fphys.2021.738594
Oxid Med Cell Longev. 2021 ;2021 5876841

SIRT5-Related Desuccinylation Modification Contributes to Quercetin-Induced Protection against Heart Failure and High-Glucose-Prompted Cardiomyocytes Injured through Regulation of Mitochondrial Quality Surveillance.

Xing Chang, Tian Zhang, Junyan Wang, Yan Liu, Peizheng Yan, Qingyan Meng, Yongtian Yin, Shiyuan Wang.

Myocardial fibrosis represents the primary pathological change associated with diabetic cardiomyopathy and heart failure, and it leads to decreased myocardial compliance with impaired cardiac diastolic and systolic function. Quercetin, an active ingredient in various medicinal plants, exerts therapeutic effects against cardiovascular diseases. Here, we investigate whether SIRT5- and IDH2-related desuccinylation is involved in the underlying mechanism of myocardial fibrosis in heart failure while exploring related therapeutic drugs for mitochondrial quality surveillance. Mouse models of myocardial fibrosis and heart failure, established by transverse aortic constriction (TAC), were administered with quercetin (50 mg/kg) daily for 4 weeks. HL-1 cells were pretreated with quercetin and treated with high glucose (30 mM) in vitro. Cardiac function, western blotting, quantitative PCR, enzyme-linked immunosorbent assay, and immunofluorescence analysis were employed to analyze mitochondrial quality surveillance, oxidative stress, and inflammatory response in myocardial cells, whereas IDH2 succinylation levels were detected using immunoprecipitation. Myocardial fibrosis and heart failure incidence increased after TAC, with abnormal cardiac ejection function. Following high-glucose treatment, HL-1 cell activity was inhibited, causing excess production of reactive oxygen species and inhibition of mitochondrial respiratory complex I/III activity and mitochondrial antioxidant enzyme activity, as well as increased oxidative stress and inflammatory response, imbalanced mitochondrial quality surveillance and homeostasis, and increased apoptosis. Quercetin inhibited myocardial fibrosis and improved cardiac function by increasing mitochondrial energy metabolism and regulating mitochondrial fusion/fission and mitochondrial biosynthesis while inhibiting the inflammatory response and oxidative stress injury. Additionally, TAC inhibited SIRT5 expression at the mitochondrial level and increased IDH2 succinylation. However, quercetin promoted the desuccinylation of IDH2 by increasing SIRT5 expression. Moreover, treatment with si-SIRT5 abolished the protective effect of quercetin on cell viability. Hence, quercetin may promote the desuccinylation of IDH2 through SIRT5, maintain mitochondrial homeostasis, protect mouse cardiomyocytes under inflammatory conditions, and improve myocardial fibrosis, thereby reducing the incidence of heart failure.

DOI: https://doi.org/10.1155/2021/5876841
FASEB J. 2021 Nov;35(11): e21956

Cardiomyocyte-specific miR-100 overexpression preserves heart function under pressure overload in mice and diminishes fatty acid uptake as well as ROS production by direct suppression of Nox4 and CD36.

Christian Smolka, Delia Schlösser, Christoph Koentges, Aleksandre Tarkhnishvili, Oliver Gorka, Dietmar Pfeifer, Xavier Bemtgen, Alexander Asmussen, Olaf Groß, Philipp Diehl, Martin Moser, Christoph Bode, Heiko Bugger, Sebastian Grundmann, Franziska Pankratz.

  MicroRNAs are key regulators of the cardiac response to injury. MiR-100 has recently been suggested to be involved in different forms of heart failure, but functional studies are lacking. In the present study, we examined the impact of transgenic miR-100 overexpression on cardiac structure and function during physiological aging and pathological pressure-overload-induced heart failure in mice after transverse aortic constriction surgery. MiR-100 was moderately upregulated after induction of pressure overload in mice. While in our transgenic model the cardiomyocyte-specific overexpression of miR-100 did not result in an obvious cardiac phenotype in unchallenged mice, the transgenic mouse strain exhibited less left ventricular dilatation and a higher ejection fraction than wildtype animals, demonstrating an attenuation of maladaptive cardiac remodeling by miR-100. Cardiac transcriptome analysis identified a repression of several regulatory genes related to cardiac metabolism, lipid peroxidation, and production of reactive oxygen species (ROS) by miR-100 overexpression, possibly mediating the observed functional effects. While the modulation of ROS-production seemed to be indirectly affected by miR-100 via Alox5-and Nox4-downregulation, we demonstrated that miR-100 induced a direct repression of the scavenger protein CD36 in murine hearts resulting in a decreased uptake of long-chain fatty acids and an alteration of mitochondrial respiratory function with an enhanced glycolytic state. In summary, we identified miR-100 as a modulator of cardiac metabolism and ROS production without an apparent cardiac phenotype at baseline but a protective effect under conditions of pressure-overload-induced cardiac stress, providing new insight into the mechanisms of heart failure.

Keywords:  CD36; cardiac metabolism; fatty acid; miRNA-100; pressure-overload-induced heart failure

DOI:  https://doi.org/10.1096/fj.202100829RR
Pharm Biol. 2021 Dec;59(1): 1305-1313

Epigallocatechin gallate (EGCG) attenuates myocardial hypertrophy and fibrosis induced by transverse aortic constriction via inhibiting the Akt/mTOR pathway.

Yue Cui, Yongqiang Wang, Gang Liu.

  CONTEXT: Epigallocatechin gallate (EGCG) is the most abundant catechin from tea. Previous studies have indicated EGCG has a cardioprotective effect.OBJECTIVE: This manuscript mainly explores the role of EGCG in pressure-overload cardiac hypertrophy and its mechanism related to the Akt/mTOR pathway.
METHODS AND METHODS: Transverse aortic constriction (TAC) was utilized to establish the cardiac hypertrophy mice model. C57BL/6 mice were assigned into 6 groups. Starting from the first day after surgery, mice received different doses of EGCG (20, 40, 80 mg/kg) or vehicle orally for four weeks. Heart weight to body weight (HW/BW) ratio and heart weight to tibia length (HW/TL) ratio as well as hematoxylin-eosin staining were utilized to evaluate cardiac hypertrophy. Masson's trichrome and Sirius red staining were used to depict cardiac fibrosis. The expressions of fibrosis and hypertrophy-related markers and Akt/mTOR pathway were quantified by western blot and qRT-PCR.
RESULTS: EGCG significantly attenuated cardiac function shown by decreased HW/BW (TAC, 6.82 ± 0.44 vs. 20 mg/kg EGCG, 5.53 ± 0.45; 40 mg/kg EGCG, 4.79 ± 0.32; 80 mg/kg EGCG, 4.81 ± 0.38) and HW/TL (TAC, 11.94 ± 0.69 vs. 20 mg/kg EGCG, 11.44 ± 0.49; 40 mg/kg EGCG, 8.83 ± 0.58; 80 mg/kg EGCG, 8.98 ± 0.63) ratios as well as alleviated cardiac histology. After treatment, hemodynamics was improved, cardiac fibrosis was attenuated. The activated Akt/mTOR pathway was inhibited by EGCG.
DISCUSSION AND CONCLUSIONS: EGCG plays a protective role in the TAC model by regulating the Akt/mTOR pathway, which provides a theoretical basis for its clinical treatment.

Keywords:  Akt/mTOR; Cardiac hypertrophy; epigallocatechin gallate (EGCG)

DOI:  https://doi.org/10.1080/13880209.2021.1972124
Heart Fail Rev. 2021 Oct 07.

Creatine deficiency and heart failure.

Annamaria Del Franco, Giuseppe Ambrosio, Laura Baroncelli, Tommaso Pizzorusso, Andrea Barison, Iacopo Olivotto, Fabio A Recchia, Carlo M Lombardi, Marco Metra, Yu F Ferrari Chen, Claudio Passino, Michele Emdin, Giuseppe Vergaro.

  Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart failure aetiologies. The energy-depletion hypothesis was pursued by several researchers, and is still a topic of considerable interest. Unlike most organs, in the heart, the creatine kinase system represents a major component of the metabolic machinery, as it functions as an energy shuttle between mitochondria and cytosol. In heart failure, the decrease in creatine level anticipates the reduction in adenosine triphosphate, and the degree of myocardial phosphocreatine/adenosine triphosphate ratio reduction correlates with disease severity, contractile dysfunction, and myocardial structural remodelling. However, it remains to be elucidated whether an impairment of phosphocreatine buffer activity contributes to the pathophysiology of heart failure and whether correcting this energy deficit might prove beneficial. The effects of creatine deficiency and the potential utility of creatine supplementation have been investigated in experimental and clinical models, showing controversial findings. The goal of this article is to provide a comprehensive overview on the role of creatine in cardiac energy metabolism, the assessment and clinical value of creatine deficiency in heart failure, and the possible options for the specific metabolic therapy.

Keywords:  Cardiac energy metabolism; Creatine; Creatine deficiency; Heart failure

DOI:  https://doi.org/10.1007/s10741-021-10173-y
Front Cardiovasc Med. 2021 ;8 737191

S-Propargyl-Cysteine Attenuates Diabetic Cardiomyopathy in db/db Mice Through Activation of Cardiac Insulin Receptor Signaling.

Ye Li, Kui-Fang Xie, Ya-Hong Chang, Cheng Wang, Ying Chen, Ming-Jie Wang, Yi-Chun Zhu.

  Background: Endogenous hydrogen sulfide (H2S) is emerging as a key signal molecule in the development of diabetic cardiomyopathy. The aim of this study was to explore the effect and underlying mechanism of S-propargyl-cysteine (SPRC), a novel modulator of endogenous H2S, on diabetic cardiomyopathy in db/db diabetic mice. Methods and Results: Vehicle or SPRC were orally administered to 8-month-old male db/db mice and their wild type littermate for 12 weeks. SPRC treatment ameliorated myocardial hypertrophy, fibrosis, and cardiac systolic dysfunction assessed by histopathological examinations and echocardiography. The functional improvement by SPRC was accompanied by a reduction in myocardial lipid accumulation and ameliorated plasma lipid profiles. SPRC treatment improved glucose tolerance in db/db mice, with fasting blood glucose and peripheral insulin resistance remaining unchanged. Furthermore, insulin receptor signaling involving the phosphorylation of protein kinase B (Akt/PKB) and glycogen synthase kinase 3β (GSK3β) were elevated and activated by SPRC treatment. Primary neonatal mice cardiomyocytes were cultured to explore the mechanisms of SPRC on diabetic cardiomyopathy in vitro. Consistent with the results in vivo, SPRC not only up-regulated insulin receptor signaling pathway in cardiomyocytes in dose-dependent manner in the basal state, but also relieved the suppression of insulin receptor signaling induced by high concentrations of glucose and insulin. Furthermore, SPRC also enhanced the expression of glucose transporter 4 (GLUT4) and 3H glucose uptake in cardiomyocytes. Conclusions: In this study, we found a novel beneficial effect of SPRC on diabetic cardiomyopathy, which was associated with activation of insulin receptor signaling. SPRC may be a promising medication for diabetic cardiomyopathy in type 2 diabetes mellitus patients.

Keywords:  S-propargyl-cysteine; diabetic cardiomyopathy; glucose uptake; hydrogen sulfide; insulin receptor signaling

DOI:  https://doi.org/10.3389/fcvm.2021.737191
Br J Clin Pharmacol. 2021 Oct 07.

Sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.

Hani Essa, Lauren Walker, Rajiv Sankaranarayanan.

  Heart failure (HF) with reduced ejection fraction (HFrEF) is a global cause of morbidity and mortality with over 60 million estimated cases worldwide. The burden of HF care is expected to increase with an ageing population as evidenced by the fact that 80% of HF-related hospitalizations occur in those aged above 65. Given the significant morbidity and mortality associated with HFrEF, there is a need for new prognostic therapies that have an impact on morbidity and mortality. In February of 2021, the National institute for Health and Care Excellence (NICE) released new guidance on the utility of Dapagliflozin for the management of heart failure with reduced ejection fraction (HFrEF). NICE advocated that dapagliflozin is a viable treatment option in symptomatic HFrEF patients on optimal medical management. The current list price of dapagliflozin is around £36.59 per 28-tablet pack with an estimated annual cost of £476.98 equating to £6939 per quality-adjusted life year. The guidance was mainly based on evidence produced from the 2019 DAPA-HF trial. This demonstrated that in HFrEF population, the use of dapagliflozin led to a significant reduction in worsening HF events, cardiovascular, and all-cause death. In this article, we summarize the evidence base for sodium-glucose co-transporter-2 inhibitors in the non-diabetic heart failure patient.

Keywords:  New York Heart Association; heart failure with mid-range ejection fraction; heart failure with preserved ejection fraction; heart failure with reduced ejection fraction; left ventricular ejection fraction; sodium-glucose co-transporter-2 inhibitors

DOI:  https://doi.org/10.1111/bcp.15085
ESC Heart Fail. 2021 Oct 08.

SGLT2 inhibitors and cardiac remodelling: a systematic review and meta-analysis of randomized cardiac magnetic resonance imaging trials.

Nitish K Dhingra, Nikhil Mistry, Pankaj Puar, Raj Verma, Stefan Anker, C David Mazer, Subodh Verma.

  AIMS: Recent large randomized controlled trials (RCTs) have demonstrated efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in both preventing and treating heart failure (HF). SGLT2i-induced reversal of left ventricular remodelling has been proposed as a mechanism contributing to this effect.METHODS AND RESULTS: We performed a systematic review and meta-analysis of RCTs to compare SGLT2i versus placebo (treatment duration >3 months) on cardiac remodelling parameters as measured by cardiac magnetic resonance imaging (cMRI) in patients with HF and/or diabetes. The PubMed and ClinicalTrials.gov databases were searched until 15 June 2021. Our primary outcome was change in absolute left ventricular mass (LVM) from baseline to study endpoint. Secondary outcomes included changes in LVM indexed to body surface area, left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF) from baseline to study endpoint. The Cochrane Collaboration's tool was used to assess risk of bias. Five studies representing 408 patients were included. SGLT2i was associated with greater LVM regression compared to placebo (MD, -5.76 g; 95% CI, -10.87 g to -0.64 g, I2 = 73%; overall effect, P < 0.03; four RCTs). Statistical subgroup differences were not observed in our sensitivity analysis focusing on HF with reduced ejection fraction (P = 0.37) and were observed in our sensitivity analysis focusing on diabetes (P < 0.001). SGLT2i was not associated with statistical changes in LV mass indexed to body surface area (I2 = 75%; P = 0.16; five RCTs), LVESV (I2 = 87%; P = 0.07; five RCTs), LVEDV (I2 = 81%; P = 0.20; five RCTs), nor LVEF (I2 = 85%; P = 0.19; five RCTs) versus placebo. Sixty per cent of RCTs had low risk of bias.
CONCLUSIONS: Sodium-glucose cotransporter-2 inhibitors treatment was associated with a reduction in left ventricular mass as assessed by cMRI.

Keywords:  Cardiac magnetic resonance imaging; Cardiac remodelling; Diabetes; HFrEF; SGLT2i

DOI:  https://doi.org/10.1002/ehf2.13645
Diabetes. 2021 Oct 05. pii: db210270. [Epub ahead of print]

Empagliflozin Treatment is Associated With Improvements in Cardiac Energetics and Function and Reductions in Myocardial Cellular Volume in Patients With Type 2 Diabetes.

Sharmaine Thirunavukarasu, Nicholas Jex, Amrit Chowdhary, Imtiaz Ul Hassan, Sam Straw, T P Craven Craven, M Gorecka, David Broadbent, Peter Swoboda, Klaus K Witte, Richard M Cubbon, Hui Xue, Peter Kellman, John P Greenwood, Sven Plein, Eylem Levelt.

Sodium-glucose-cotransporter-2 (SGLT2) inhibitors reduce the risk of major adverse CV events and hospitalization for heart failure in type 2 diabetes (T2D) patients. Utilising cardiovascular magnetic resonance imaging (CMR) and 31phosphorus magnetic resonance spectroscopy(31P-MRS) in a longitudinal cohort study, we aimed to investigate the effects of the selective SGLT2i empagliflozin on myocardial energetics, cellular volume, function and perfusion. Eighteen T2D patients underwent CMR and 31P-MRS scans before and after twelve-week empagliflozin treatment. Plasma N-terminal pro hormone B-type natriuretic peptide (NT-proBNP) levels were measured. Ten volunteers with normal glycaemic control underwent an identical scan protocol on a single visit. Empagliflozin treatment was associated with led to significant improvements in PCr/ATP ratio (1.52 to 1.76, p=0.009). This was accompanied by a 7% absolute improvement increase in the mean LVEF (p=0.001), 3% absolute improvement increase in the mean global longitudinal strain (p=0.01), 8 ml/m2 absolute reduction in the mean myocardial cell volume (p=0.04) and 61% relative reduction in the mean NTproBNP (p=0.05) from baseline measurements. No significant change in myocardial blood flow or diastolic strain was detected. Empagliflozin thus ameliorates the 'cardiac energy-deficient' state, regresses adverse myocardial cellular remodelling, and improves cardiac function, offering therapeutic opportunities to prevent or modulate heart failure in T2D.

DOI: https://doi.org/10.2337/db21-0270