bims-hafaim 2021-03-14 papers

bims-hafaim

Biomed News

on Heart Failure Metabolism

Issue of 2021‒03‒14
eleven papers selected by
Kyle McCommis
Saint Louis University

Metabolic alterations in a rat model of Takotsubo syndrome.
Long-Term Dipeptidyl Peptidase 4 Inhibition Worsens Hypertension and Renal and Cardiac Abnormalities in Obese Spontaneously Hypertensive Heart Failure Rats.
Nicotinamide mononucleotide attenuates isoproterenol-induced cardiac fibrosis by regulating oxidative stress and Smad3 acetylation.
Allyl Methyl Sulfide Preserved Pressure Overload-Induced Heart Failure Via Modulation of Mitochondrial Function.
Identifying functional metabolic shifts in heart failure with the integration of omics data and a heart-specific, genome-scale model.
Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes.
mtDNA Heteroplasmy at the Core of Aging-Associated Heart Failure. An Integrative View of OXPHOS and Mitochondrial Life Cycle in Cardiac Mitochondrial Physiology.
Ketone Therapy for Heart Failure: Current Evidence for Clinical Use.
The effects of UCP2 on autophagy through the AMPK signaling pathway in septic cardiomyopathy and the underlying mechanism.
SGLT2 inhibitors break the vicious circle between heart failure and insulin resistance: targeting energy metabolism.
Understanding HFpEF With Obesity: Will Pigs Come to the Rescue?

Cardiovasc Res. 2021 Mar 12. pii: cvab081. [Epub ahead of print]

Metabolic alterations in a rat model of Takotsubo syndrome.

Nadine Godsman, Michael Kohlhaas, Alexander Nickel, Lesley Cheyne, Marco Mingarelli, Lutz Schweiger, Claire Hepburn, Chantal Munts, Andy Welch, Mirela Delibegovic, Marc Van Bilsen, Christoph Maack, Dana K Dawson.

  AIMS: Cardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies.METHODS AND RESULTS: An isoprenaline-injection female rat model (versus sham) was studied at day-3; recovery assessed at day-7. Substrate uptake, metabolism, inflammation and remodelling were investigated by 18F-FDG-PET, metabolomics, qPCR and WB. Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates).Cardiac 18F-FDG metabolic rate was increased in takotsubo (p = 0.006), as were expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all p < 0.05), with concomitant accumulation of glucose- and fructose-6-phosphates (p > 0.0001). Both lactate and pyruvate were lower (p < 0.05) despite increases in LDH-RNA and PDH (p < 0.05 both). β-oxidation enzymes CPT1b-RNA and 3KAT were increased (p < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (p = 0.01) with decreased fatty acids and acyl-carnitines levels (p = 0.0001-0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (p < 0.05) as was cellular ATP reporter dihydroorotate (p = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on day-3 (p < 0.0001), inducing oxidation of NAD(P)H and FAD (p = 0.03) but resolved by day-7. There were no differences in mitochondrial respiratory function, sarcomere shortening or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated - increased CD68-RNA, collagen RNA/protein and skeletal actin RNA (all p < 0.05).
CONCLUSION: Dys-regulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterises takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation and upregulation of remodelling pathways, with preservation of sarcomeric and mitochondrial integrity.
TRANSLATIONAL PERSPECTIVE: The simultaneous dysregulation in the glycolytic and beta-oxidation pathways which underlies the energetic deficit of the takotsubo heart supports further testing of currently available metabolic modulators as possible candidates for successful therapy, as well as targeting the inflammatory and remodelling pathways.

Keywords:  energetics; heart failure; inflammation; metabolism; remodelling; takotsubo

DOI:  https://doi.org/10.1093/cvr/cvab081
J Am Heart Assoc. 2021 Mar 08. e020088

Long-Term Dipeptidyl Peptidase 4 Inhibition Worsens Hypertension and Renal and Cardiac Abnormalities in Obese Spontaneously Hypertensive Heart Failure Rats.

Edwin K Jackson, Zaichuan Mi, Delbert G Gillespie, Dongmei Cheng, Stevan P Tofovic.

  Background The long-term effects of dipeptidyl peptidase 4 (DPP4) inhibitors on blood pressure and cardiovascular and renal health remain controversial. Herein, we investigated the extended (>182 days) effects of DPP4 inhibition in a model of spontaneous hypertension, heart failure, diabetes mellitus, obesity and hyperlipidemia. Methods and Results Adult obese spontaneously hypertensive heart failure rats (SHHF) were implanted with radio transmitters for measurement of arterial blood pressures. Two weeks later, SHHF were randomized to receive either a DPP4 inhibitor (sitagliptin, 80 mg/kg per day in drinking water) or placebo. At the end of the radiotelemetry measurements, renal and cardiac function and histology, as well as other relevant biochemical parameters, were assessed. For the first 25 days, mean arterial blood pressures were similar in sitagliptin-treated versus control SHHF; afterwards, mean arterial blood pressures increased more in sitagliptin-treated SHHF (P<0.000001). The time-averaged mean arterial blood pressures from day 26 through 182 were 7.2 mm Hg higher in sitagliptin-treated SHHF. Similar changes were observed for systolic (8.6 mm Hg) and diastolic (6.1 mm Hg) blood pressures, and sitagliptin augmented hypertension throughout the light-dark cycle. Long-term sitagliptin treatment also increased kidney weights, renal vascular resistances, the excretion of kidney injury molecule-1 (indicates injury to proximal tubules), renal interstitial fibrosis, glomerulosclerosis, renal vascular hypertrophy, left ventricular dysfunction, right ventricular degeneration, and the ratios of collagen IV/collagen III and collagen IV/laminin in the right ventricle. Conclusions These findings indicate that, in some genetic backgrounds, long-term DPP4 inhibitor treatment is harmful and identify an animal model to study mechanisms of, and test ways to prevent, DPP4 inhibitor-induced pathological conditions.

Keywords:  dipeptidyl peptidase 4 inhibitors; heart damage; hypertension; kidney damage; spontaneously hypertensive heart failure rats

DOI:  https://doi.org/10.1161/JAHA.120.020088
Life Sci. 2021 Mar 03. pii: S0024-3205(21)00284-8. [Epub ahead of print] 119299

Nicotinamide mononucleotide attenuates isoproterenol-induced cardiac fibrosis by regulating oxidative stress and Smad3 acetylation.

KeKe Wu, Biao Li, Qiuzhen Lin, Wanghan Xu, Wanyun Zuo, Jiayi Li, Liu Na, Tao Tu, Baojian Zhang, Yichao Xiao, Qiming Liu.

  AIMS: Cardiac fibrosis is a pathological hallmark of progressive heart diseases currently lacking effective treatment. Nicotinamide mononucleotide (NMN), a member of the vitamin B3 family, is a defined biosynthetic precursor of nicotinamide adenine dinucleotide (NAD+). Its beneficial effects on cardiac diseases are known, but its effects on cardiac fibrosis and the underlying mechanism remain unclear. We aimed to elucidate the protective effect of NMN against cardiac fibrosis and its underlying mechanisms of action.MATERIALS AND METHODS: Cardiac fibrosis was induced by isoproterenol (ISO) in mice. NMN was administered by intraperitoneal injection. In vitro, cardiac fibroblasts (CFs) were stimulated by transforming growth factor-beta (TGF-β) with or without NMN and sirtinol, a SIRT1 inhibitor. Levels of cardiac fibrosis, NAD+/SIRT1 alteration, oxidative stress, and Smad3 acetylation were evaluated by real-time polymerase chain reaction, western blots, immunohistochemistry staining, immunoprecipitation, and assay kits.
KEY FINDINGS: ISO treatment induced cardiac dysfunction, fibrosis, and hypertrophy in vivo, whereas NMN alleviated these changes. Additionally, NMN suppressed CFs activation stimulated by TGF-β in vitro. Mechanistically, NMN restored the NAD+/SIRT1 axis and inhibited the oxidative stress and Smad3 acetylation induced by ISO or TGF-β. However, the protective effects of NMN were partly antagonized by sirtinol in vitro.
SIGNIFICANCE: NMN could attenuate cardiac fibrosis in vivo and fibroblast activation in vitro by suppressing oxidative stress and Smad3 acetylation in a NAD+/SIRT1-dependent manner.

Keywords:  Acetylation; Cardiac fibrosis; Nicotinamide mononucleotide; Oxidative stress; Smad signaling

DOI:  https://doi.org/10.1016/j.lfs.2021.119299
Biomed Pharmacother. 2021 Mar 05. pii: S0753-3322(21)00101-3. [Epub ahead of print]138 111316

Allyl Methyl Sulfide Preserved Pressure Overload-Induced Heart Failure Via Modulation of Mitochondrial Function.

Soheb Anwar Mohammed, Bugga Paramesha, Himanshu Meghwani, Maramreddy Prasanna Kumar Reddy, Sudheer Kumar Arava, Sanjay Kumar Banerjee.

  BACKGROUND: Cardiovascular diseases are the leading cause of death globally, and they are causing enormous socio-economic burden to the developed and developing countries. Allyl Methyl Sulfide (AMS) is a novel cardioprotective metabolite identified in the serum of rats after raw garlic administration. The present study explored the cardioprotective effect of AMS on thoracic aortic constriction (TAC)-induced cardiac hypertrophy and heart failure model in rats.METHODS: Thoracic aortic constriction (TAC) by titanium ligating clips resulted in the development of pressure overload-induced cardiac hypertrophy and heart failure model. Four weeks prior to TAC and for 8 weeks after TAC, Sprague Dawley (SD) rats were administered with AMS (25 and 50 mg/kg/day) or Enalapril (10 mg/kg/day).
RESULTS: We have observed AMS (25 and 50 mg/kg/day) intervention significantly improved structural and functional parameters of the heart. mRNA expression of fetal genes i.e., atrial natriuretic peptide (ANP), alpha skeletal actin (α-SA) and beta myosin heavy chain (β-MHC) were reduced in AMS treated TAC hearts along with decrease in perivascular and interstitial fibrosis. AMS attenuated lipid peroxidation and improved protein expression of endogenous antioxidant enzymes i.e., catalase and manganese superoxide dismutase (MnSOD) along with electron transport chain (ETC) complex activity. AMS increased mitochondrial fusion proteins i.e., mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy protein (OPA1), and reduced fission protein i.e., dynamin-related protein 1 (DRP1). Preliminary study suggests that AMS intervention upregulated genes involved in mitochondrial bioenergetics in normal rats. Further, in-vitro studies suggest that AMS reduced mitochondrial reactive oxygen species (ROS), preserved mitochondrial membrane potential and oxygen consumption rate (OCR) in isoproterenol-treated cardiomyoblast.
CONCLUSION: This study demonstrated that AMS protected cardiac remodelling, LV dysfunction and fibrosis in pressure overload-induced cardiac hypertrophy and heart failure model by improving endogenous antioxidants and mitochondrial function.

Keywords:  Allyl Methyl Sulfide; Heart failure; Metabolite; Mitochondrial dynamics; Thoracic aortic constriction

DOI:  https://doi.org/10.1016/j.biopha.2021.111316
Cell Rep. 2021 Mar 09. pii: S2211-1247(21)00150-9. [Epub ahead of print]34(10): 108836

Identifying functional metabolic shifts in heart failure with the integration of omics data and a heart-specific, genome-scale model.

Bonnie V Dougherty, Kristopher D Rawls, Glynis L Kolling, Kalyan C Vinnakota, Anders Wallqvist, Jason A Papin.

  In diseased states, the heart can shift to use different carbon substrates, measured through changes in uptake of metabolites by imaging methods or blood metabolomics. However, it is not known whether these measured changes are a result of transcriptional changes or external factors. Here, we explore transcriptional changes in late-stage heart failure using publicly available data integrated with a model of heart metabolism. First, we present a heart-specific genome-scale metabolic network reconstruction (GENRE), iCardio. Next, we demonstrate the utility of iCardio in interpreting heart failure gene expression data by identifying tasks inferred from differential expression (TIDEs), which represent metabolic functions associated with changes in gene expression. We identify decreased gene expression for nitric oxide (NO) and N-acetylneuraminic acid (Neu5Ac) synthesis as common metabolic markers of heart failure. The methods presented here for constructing a tissue-specific model and identifying TIDEs can be extended to multiple tissues and diseases of interest.

Keywords:  GENRE; N-acetylneuraminic acid; heart failure; heart metabolism; metabolic network; nitric oxide; transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2021.108836
Cardiovasc Res. 2021 Mar 10. pii: cvab077. [Epub ahead of print]

Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes.

Chrishan J A Ramachandra, Myu Mai Ja Kp, Jasper Chua, Sauri Hernandez-Resendiz, Elisa A Liehn, Li-Ming Gan, Erik Michaëlsson, Malin K B Jonsson, Katarina Ryden-Markinhuhta, Ratan V Bhat, Regina Fritsche-Danielson, Ying-Hsi Lin, Sakthivel Sadayappan, Hak Chiaw Tang, Philip Wong, Winston Shim, Derek J Hausenloy.

  AIMS: Hypertrophic cardiomyopathy (HCM) is characterised by cardiomyocyte hypertrophy and disarray, and myocardial stiffness due to interstitial fibrosis, which result in impaired left ventricular filling and diastolic dysfunction. The latter manifests as exercise intolerance, angina, and dyspnoea. There is currently no specific treatment for improving diastolic function in HCM. Here, we investigated whether myeloperoxidase (MPO) is expressed in cardiomyocytes and provides a novel therapeutic target for alleviating diastolic dysfunction in HCM.METHODS AND RESULTS: Human cardiomyocytes derived from control induced pluripotent stem cells (iPSC-CMs) were shown to express MPO, with MPO levels being increased in iPSC-CMs generated from two HCM patients harbouring sarcomeric mutations in the MYBPC3 and MYH7 genes. The presence of cardiomyocyte MPO was associated with higher chlorination and peroxidation activity, increased levels of 3-chlorotyrosine-modified cardiac myosin binding protein-C (MYBPC3), attenuated phosphorylation of MYBPC3 at Ser-282, perturbed calcium signalling, and impaired cardiomyocyte relaxation. Interestingly, treatment with the MPO inhibitor, AZD5904, reduced 3-chlorotyrosine-modified MYBPC3 levels, restored MYBPC3 phosphorylation, and alleviated the calcium signalling and relaxation defects. Finally, we found that MPO protein was expressed in healthy adult murine and human cardiomyocytes, and MPO levels were increased in diseased hearts with left ventricular hypertrophy.
CONCLUSION: This study demonstrates that MPO inhibition alleviates the relaxation defect in hypertrophic iPSC-CMs through MYBPC3 phosphorylation. These findings highlight cardiomyocyte MPO as a novel therapeutic target for improving myocardial relaxation associated with HCM, a treatment strategy which can be readily investigated in the clinical setting, given that MPO inhibitors are already available for clinical testing.
TRANSLATIONAL PERSPECTIVE: There are currently no specific therapies for improving diastolic function in patients with HCM. We show for the first time that myeloperoxidase (MPO) is present in and is up-regulated in cardiomyocytes derived from human iPSCs obtained from HCM patients, where it impairs cardiomyocyte relaxation by reducing phosphorylation of cardiac MYBPC3. Treatment with the MPO inhibitor, AZD5904, restored MYBPC3 phosphorylation and alleviated the relaxation defect, demonstrating cardiomyocyte MPO to be a novel therapeutic target for improving diastolic function in HCM, a treatment strategy which can be evaluated in HCM patients given that MPO inhibitors are already available for clinical testing.

Keywords:  Myeloperoxidase; cardiac myosin binding protein-C (MYBPC3); diastolic dysfunction; human induced pluripotent stem cells (hiPSCs); hypertrophic cardiomyopathy (HCM); oxidative stress

DOI:  https://doi.org/10.1093/cvr/cvab077
Front Cell Dev Biol. 2021 ;9 625020

mtDNA Heteroplasmy at the Core of Aging-Associated Heart Failure. An Integrative View of OXPHOS and Mitochondrial Life Cycle in Cardiac Mitochondrial Physiology.

Alvaro A Elorza, Juan Pablo Soffia.

  The most common aging-associated diseases are cardiovascular diseases which affect 40% of elderly people. Elderly people are prone to suffer aging-associated diseases which are not only related to health and medical cost but also to labor, household productivity and mortality cost. Aging is becoming a world problem and it is estimated that 21.8% of global population will be older than 65 years old in 2050; and for the first time in human history, there will be more elderly people than children. It is well accepted that the origin of aging-associated cardiovascular diseases is mitochondrial dysfunction. Mitochondria have their own genome (mtDNA) that is circular, double-stranded, and 16,569 bp long in humans. There are between 500 to 6000 mtDNA copies per cell which are tissue-specific. As a by-product of ATP production, reactive oxygen species (ROS) are generated which damage proteins, lipids, and mtDNA. ROS-mutated mtDNA co-existing with wild type mtDNA is called mtDNA heteroplasmy. The progressive increase in mtDNA heteroplasmy causes progressive mitochondrial dysfunction leading to a loss in their bioenergetic capacity, disruption in the balance of mitochondrial fusion and fission events (mitochondrial dynamics, MtDy) and decreased mitophagy. This failure in mitochondrial physiology leads to the accumulation of depolarized and ROS-generating mitochondria. Thus, besides attenuated ATP production, dysfunctional mitochondria interfere with proper cellular metabolism and signaling pathways in cardiac cells, contributing to the development of aging-associated cardiovascular diseases. In this context, there is a growing interest to enhance mitochondrial function by decreasing mtDNA heteroplasmy. Reduction in mtDNA heteroplasmy is associated with increased mitophagy, proper MtDy balance and mitochondrial biogenesis; and those processes can delay the onset or progression of cardiovascular diseases. This has led to the development of mitochondrial therapies based on the application of nutritional, pharmacological and genetic treatments. Those seeking to have a positive impact on mtDNA integrity, mitochondrial biogenesis, dynamics and mitophagy in old and sick hearts. This review covers the current knowledge of mitochondrial physiopathology in aging, how disruption of OXPHOS or mitochondrial life cycle alter mtDNA and cardiac cell function; and novel mitochondrial therapies to protect and rescue our heart from cardiovascular diseases.

Keywords:  OXPHOS; ROS; aging; biogenesis; cardiac; heart failure; mitophagy; mtDNA heteroplasmy

DOI:  https://doi.org/10.3389/fcell.2021.625020
Cardiovasc Res. 2021 Mar 10. pii: cvab068. [Epub ahead of print]

Ketone Therapy for Heart Failure: Current Evidence for Clinical Use.

Shingo Takahara, Shubham Soni, Zaid H Maayah, Mourad Ferdaoussi, Jason R B Dyck.

  During conditions that result in depleted circulating glucose levels, ketone bodies synthesized in the liver are necessary fuel substrates for the brain. In other organs such as the heart, the reliance on ketones for generating energy is less life threatening as the heart can utilize alternative fuel sources such as fatty acids. However, during pathophysiological conditions such as heart failure, cardiac defects in metabolic processes that normally allow for sufficient energy production from fatty acids and carbohydrates contribute to a decline in contractile function. As such, it has been proposed that the failing heart relies more on ketone bodies as an energy source than previously appreciated. Furthermore, it has been suggested that ketone bodies may function as signaling molecules that can suppress systemic and cardiac inflammation. Thus, it is possible that intentionally elevating circulating ketones may be beneficial as an adjunct treatment for heart failure. Although many approaches can be used for 'ketone therapy', each of these has their own advantages and disadvantages in the treatment of heart failure. Thus, we summarize current preclinical and clinical studies involving various types of ketone therapy in cardiac disease and discuss the advantages and disadvantages of each modality as possible treatments for heart failure.

Keywords:  heart failure; inflammation; ketone; metabolism; oxidative stress

DOI:  https://doi.org/10.1093/cvr/cvab068
Ann Transl Med. 2021 Feb;9(3): 259

The effects of UCP2 on autophagy through the AMPK signaling pathway in septic cardiomyopathy and the underlying mechanism.

Jia-Yu Mao, Long-Xiang Su, Dong-Kai Li, Hong-Min Zhang, Xiao-Ting Wang, Da-Wei Liu.

  Background: Mitochondrial dysfunction plays an important role in the development of septic cardiomyopathy. This study aimed to reveal the protective role of uncoupling protein 2 (UCP2) in mitochondria through AMP-activated protein kinase (AMPK) on autophagy during septic cardiomyopathy.Methods: UCP2 knockout mice via a cecal ligation and puncture (CLP) model and the H9C2 cardiomyocyte cell line in response to lipopolysaccharide (LPS) in vitro were used to study the effect. The myocardial morphological alterations, indicators of mitochondrial injury and levels of autophagy-associated proteins (pAMPK, pmTOR, pULK1, pTSC2, Beclin-1, and LC3-I/II) were assessed. In addition, the mechanism of the interaction between UCP2 and AMPK was further studied through gain- and loss-of-function studies.
Results: Compared with the wild-type mice, the UCP2 knockout mice exhibited more severe cardiomyocyte injury after CLP, and the AMPK agonist AICAR protected against such injury. Consistent with this result, silencing UCP2 augmented the LPS-induced pathological damage and mitochondrial injury in the H9C2 cells, limited the upregulation of autophagy proteins and reduced AMPK phosphorylation. AICAR protected the cells from morphological changes and mitochondrial membrane potential loss and promoted autophagy. The silencing and overexpression of UCP2 led to correlated changes in the AMPK upstream kinases pLKB1 and CAMKK2.
Conclusions: UCP2 exerts cardioprotective effects on mitochondrial dysfunction during sepsis via the action of AMPK on autophagy.

Keywords:  AMPK; Septic cardiomyopathy; autophagy; uncoupling protein 2 (UCP2)

DOI:  https://doi.org/10.21037/atm-20-4819
Heart Fail Rev. 2021 Mar 12.

SGLT2 inhibitors break the vicious circle between heart failure and insulin resistance: targeting energy metabolism.

Xiaodan Wang, Jingyu Ni, Rui Guo, Lan Li, Jing Su, Feng He, Guanwei Fan.

  Heart failure (HF) often coexists with insulin resistance (IR), and the incidence of HF in type 2 diabetes mellitus (T2DM) patients is significantly higher. The reciprocal relationship between HF and IR has long been recognized, and the integration complicates the therapy of both. A number of mechanisms ascribe to the progression of cardiac IR, in which the main factors are the shift of myocardial substrate metabolism. Studies have found that SGLT2 inhibitors, an anti-diabetic drug, can improve the cardiac prognosis of patients with T2DM, which may be at least partially due to the relief of cardiac IR. Basic and clinical studies have revealed the important role of cardiac IR in the pathogenesis and progression of HF, and studies suggest that energy metabolism plays an important role in the pathogenesis of cardiac IR and HF. SGLT2 inhibitors mediated cardiovascular benefits through various mechanisms such as improving substrate utilization and improving myocardial energy. The regulation of SGLT2 inhibitors on cardiac energy status including carbohydrates, fatty acids (FA), amino acids and ketones, ATP transfer to the cytoplasm, and mitochondrial functional status have received extensive attention in HF, but its specific mechanism of action is still unclear. Therefore, this article reviews the relationship between IR and HF from the perspective of energy metabolism; subsequently, targeting energy metabolism discusses the pivotal role of SGLT2 inhibitors in improving cardiac IR and HF based on basic and clinical research evidences, and sought to clarify the molecular mechanism involved. (Fig. 1).

Keywords:  Energy metabolism; Heart failure; Insulin resistance; SGLT2 inhibitors

DOI:  https://doi.org/10.1007/s10741-021-10096-8
JACC Basic Transl Sci. 2021 Feb;6(2): 171-173

Understanding HFpEF With Obesity: Will Pigs Come to the Rescue?

David A Kass.



Keywords:  animal models; diastolic heart failure; ejection fraction; heart failure; metabolic syndrome; obesity

DOI:  https://doi.org/10.1016/j.jacbts.2020.12.010