Abstract
Heart failure with preserved ejection fraction (HFpEF) and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasingly prevalent, interrelated conditions driven by the global rise in obesity and metabolic syndrome. Once viewed in isolation, HFpEF and MASLD are now recognized as organ-specific manifestations of shared systemic metabolic dysfunction. Evidence from the past decade highlights not only overlapping risk factors but also a dynamic, bidirectional inter-organ crosstalk between the liver and the heart that shapes their natural history. In this Review, we explore the epidemiological and mechanistic basis of the MASLD–HFpEF connection, focusing on shared metabolic drivers such as lipotoxicity, meta-inflammation and oxidative stress. We also discuss emerging liver-derived mediators, including hepatokines, metabolites and extracellular vesicles, that influence cardiac structure and function. Finally, we highlight diagnostic and therapeutic strategies relevant to both conditions and propose a multiorgan framework to improve their clinical recognition and management. Understanding the liver–heart axis is key to rethinking cardiometabolic disease beyond organ silos and towards more integrated, mechanism-based approaches.
Key points
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Cardiometabolic heart failure with preserved ejection fraction (HFpEF) and metabolic dysfunction-associated steatotic liver disease (MASLD) are manifestations, with unique features, of a shared systemic metabolic disorder, namely the metabolic syndrome, affecting the heart and liver, respectively.
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Both cardiometabolic HFpEF and MASLD have been recognized as multiorgan metabolic diseases, aligning with growing evidence linking their epidemiological and pathogenic features.
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Beyond a shared metabolic framework, cardiometabolic HFpEF and MASLD influence each other through direct liver–heart crosstalk, but our understanding of this relationship is still in its early stages.
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Recognizing the overlap between the clinical presentation of HFpEF and MASLD offers an opportunity for a unified diagnostic approach, improving clinical assessment and aiding in the stratification of patients at risk of these conditions.
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A shared therapeutic approach for HFpEF and MASLD, targeting common features of metabolic disease, is extremely relevant given the limited disease-specific treatments and lack of substantial outcome improvements so far.
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References
Bozkurt, B. et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur. J. Heart Fail. 23, 352–380 (2021).
Savarese, G., Stolfo, D., Sinagra, G. & Lund, L. H. Heart failure with mid-range or mildly reduced ejection fraction. Nat. Rev. Cardiol. 19, 100–116 (2022).
Hamo, C. E. et al. Heart failure with preserved ejection fraction. Nat. Rev. Dis. Primers 10, 55 (2024).
Lupon, J. et al. Heart failure with preserved ejection fraction infrequently evolves toward a reduced phenotype in long-term survivors. Circ. Heart Fail. 12, e005652 (2019).
Bozkurt, B. et al. HF STATS 2024: heart failure epidemiology and outcomes statistics an updated 2024 report from the Heart Failure Society of America. J. Card. Fail. 31, 66–116 (2025).
Peters, A. E. et al. Phenomapping in heart failure with preserved ejection fraction: insights, limitations, and future directions. Cardiovasc. Res. 118, 3403–3415 (2023).
Cohen, J. B. et al. Clinical phenogroups in heart failure with preserved ejection fraction: detailed phenotypes, prognosis, and response to spironolactone. JACC Heart Fail. 8, 172–184 (2020).
Savji, N. et al. The association of obesity and cardiometabolic traits with incident HFpEF and HFrEF. JACC Heart Fail. 6, 701–709 (2018).
Rinella, M. E. et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J. Hepatol. 79, 1542–1556 (2023).
Rinella, M. E. et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 77, 1797–1835 (2023).
Day, C. P. & James, O. F. Steatohepatitis: a tale of two “hits”? Gastroenterology 114, 842–845 (1998).
Loomba, R., Friedman, S. L. & Shulman, G. I. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 184, 2537–2564 (2021).
Buzzetti, E., Pinzani, M. & Tsochatzis, E. A. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65, 1038–1048 (2016).
Chalasani, N. et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55, 2005–2023 (2012).
Hsu, C. L. & Loomba, R. From NAFLD to MASLD: implications of the new nomenclature for preclinical and clinical research. Nat. Metab. 6, 600–602 (2024).
Younossi, Z. M. et al. Clinical profiles and mortality rates are similar for metabolic dysfunction-associated steatotic liver disease and non-alcoholic fatty liver disease. J. Hepatol. 80, 694–701 (2024).
Platek, A. E. & Szymanska, A. Metabolic dysfunction-associated steatotic liver disease as a cardiovascular risk factor. Clin. Exp. Hepatol. 9, 187–192 (2023).
Hashida, R., Nakano, D., Kawaguchi, M., Younossi, Z. M. & Kawaguchi, T. Changing from NAFLD to MASLD: the implications for health-related quality of life data. J. Hepatol. 80, e249–e251 (2024).
Song, R., Li, Z., Zhang, Y., Tan, J. & Chen, Z. Comparison of NAFLD, MAFLD and MASLD characteristics and mortality outcomes in United States adults. Liver Int. 44, 1051–1060 (2024).
Le, P. et al. Disease state transition probabilities across the spectrum of NAFLD: a systematic review and meta-analysis of paired biopsy or imaging studies. Clin. Gastroenterol. Hepatol. 21, 1154–1168 (2023).
Iturbe-Rey, S. et al. Lipotoxicity-driven metabolic dysfunction-associated steatotic liver disease (MASLD). Atherosclerosis 400, 119053 (2025).
Lembo, E. et al. Prevalence and predictors of non-alcoholic steatohepatitis in subjects with morbid obesity and with or without type 2 diabetes. Diabetes Metab. 48, 101363 (2022).
Younossi, Z. M. et al. Global epidemiology of nonalcoholic fatty liver disease — meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73–84 (2016).
Singh, S. et al. Fibrosis progression in nonalcoholic fatty liver vs nonalcoholic steatohepatitis: a systematic review and meta-analysis of paired-biopsy studies. Clin. Gastroenterol. Hepatol. 13, 643–654 (2015).
Owan, T. E. et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N. Engl. J. Med. 355, 251–259 (2006).
Savarese, G. et al. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc. Res. 118, 3272–3287 (2023).
Haass, M. et al. Body mass index and adverse cardiovascular outcomes in heart failure patients with preserved ejection fraction: results from the Irbesartan in heart failure with preserved ejection fraction (I-PRESERVE) trial. Circ. Heart Fail. 4, 324–331 (2011).
Tromp, J. et al. Global differences in heart failure with preserved ejection fraction: the PARAGON-HF trial. Circ. Heart Fail. 14, e007901 (2021).
Younossi, Z. M. et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 77, 1335–1347 (2023).
Younossi, Z. M. et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J. Hepatol. 71, 793–801 (2019).
Stefan, N. & Cusi, K. A global view of the interplay between non-alcoholic fatty liver disease and diabetes. Lancet Diabetes Endocrinol. 10, 284–296 (2022).
Quek, J. et al. Global prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in the overweight and obese population: a systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 8, 20–30 (2023).
Yki-Jarvinen, H. Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. Lancet Diabetes Endocrinol. 2, 901–910 (2014).
Mantovani, A. et al. Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: an updated systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 6, 903–913 (2021).
Hagstrom, H. et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J. Hepatol. 67, 1265–1273 (2017).
Plunkett, R. D. et al. Trends and demographic disparities in heart failure mortality rates in non-alcoholic fatty liver disease: a population-based retrospective study in the United States from 1999 to 2020. Am. J. Cardiovasc. Dis. 15, 166–174 (2025).
Han, E. et al. Association of temporal MASLD with type 2 diabetes, cardiovascular disease and mortality. Cardiovasc. Diabetol. 24, 289 (2025).
Chung, G. E. et al. Metabolic dysfunction-associated steatotic liver disease increases cardiovascular disease risk in young adults. Sci. Rep. 15, 5777 (2025).
Inciardi, R. M., Mantovani, A. & Targher, G. Non-Alcoholic fatty liver disease as an emerging risk factor for heart failure. Curr. Heart Fail. Rep. 20, 308–319 (2023).
Mantovani, A. et al. Non-alcoholic fatty liver disease and risk of new-onset heart failure: an updated meta-analysis of about 11 million individuals. Gut https://doi.org/10.1136/gutjnl-2022-327672 (2022).
Takahashi, T. et al. The impact of non-alcoholic fatty liver disease fibrosis score on cardiac prognosis in patients with chronic heart failure. Heart Vessel. 33, 733–739 (2018).
Fudim, M. et al. Nonalcoholic fatty liver disease and risk of heart failure among medicare beneficiaries. J. Am. Heart Assoc. 10, e021654 (2021).
Chang, K. C. et al. Metabolic dysfunction-associated steatotic liver disease is associated with increased risks of heart failure. Eur. J. Heart Fail. 27, 512–520 (2025).
Wijarnpreecha, K. et al. Association between diastolic cardiac dysfunction and nonalcoholic fatty liver disease: a systematic review and meta-analysis. Dig. Liver Dis. 50, 1166–1175 (2018).
Goliopoulou, A. et al. Non-alcoholic fatty liver disease and echocardiographic parameters of left ventricular diastolic Function: a systematic review and meta-analysis. Int. J. Mol. Sci. 24, 14292 (2023).
Wang, S., Zhang, X., Zhang, Q., Zhang, B. & Zhao, L. Is non-alcoholic fatty liver disease a sign of left ventricular diastolic dysfunction in patients with type 2 diabetes mellitus? A systematic review and meta-analysis. BMJ Open Diabetes Res. Care 11, e003198 (2023).
Miller, A., McNamara, J., Hummel, S. L., Konerman, M. C. & Tincopa, M. A. Prevalence and staging of non-alcoholic fatty liver disease among patients with heart failure with preserved ejection fraction. Sci. Rep. 10, 12440 (2020).
Peters, A. E. et al. Association of liver fibrosis risk scores with clinical outcomes in patients with heart failure with preserved ejection fraction: findings from TOPCAT. ESC Heart Fail. 8, 842–848 (2021).
Konerman, M. A., McNamara, J., Hummel, S. L. & Konerman, M. C. Prevalence of and characteristics associated with non-alcoholic fatty liver disease among patients with heart failure with preserved ejection fraction. J. Card. Fail. 24, S51–S51 (2018).
Canada, J. M. et al. Relation of hepatic fibrosis in nonalcoholic fatty liver disease to left ventricular diastolic function and exercise tolerance. Am. J. Cardiol. 123, 466–473 (2019).
Yoshihisa, A. et al. Liver fibrosis score predicts mortality in heart failure patients with preserved ejection fraction. ESC Heart Fail. 5, 262–270 (2018).
VanWagner, L. B. et al. Longitudinal association of non-alcoholic fatty liver disease with changes in myocardial structure and function: The CARDIA study. J. Am. Heart Assoc. 9, e014279 (2020).
Chiu, L. S. et al. The association of non-alcoholic fatty liver disease and cardiac structure and function — Framingham Heart Study. Liver Int. 40, 2445–2454 (2020).
DiStefano, J. K. & Gerhard, G. S. NAFLD in normal weight individuals. Diabetol. Metab. Syndr. 14, 45 (2022).
Cong, F., Zhu, L., Deng, L., Xue, Q. & Wang, J. Correlation between nonalcoholic fatty liver disease and left ventricular diastolic dysfunction in non-obese adults: a cross-sectional study. BMC Gastroenterol. 23, 90 (2023).
Peng, D. et al. Association of metabolic dysfunction-associated fatty liver disease with left ventricular diastolic function and cardiac morphology. Front. Endocrinol. 13, 935390 (2022).
Tao, M. et al. Visceral adipose tissue and risk of nonalcoholic fatty liver disease: a Mendelian randomization study. Clin. Endocrinol. 99, 370–377 (2023).
Sorimachi, H. et al. Pathophysiologic importance of visceral adipose tissue in women with heart failure and preserved ejection fraction. Eur. Heart J. 42, 1595–1605 (2021).
Fuster, J. J., Ouchi, N., Gokce, N. & Walsh, K. Obesity-Induced changes in adipose tissue microenvironment and their impact on cardiovascular disease. Circ. Res. 118, 1786–1807 (2016).
Kolb, H. Obese visceral fat tissue inflammation: from protective to detrimental? BMC Med. 20, 494 (2022).
Wu, D. et al. Characterization of regulatory T cells in obese omental adipose tissue in humans. Eur. J. Immunol. 49, 336–347 (2019).
Fujisaka, S. et al. M2 macrophages in metabolism. Diabetol. Int. 7, 342–351 (2016).
Murano, I. et al. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J. Lipid Res. 49, 1562–1568 (2008).
Pasarica, M. et al. Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58, 718–725 (2009).
Gliniak, C. M., Pedersen, L. & Scherer, P. E. Adipose tissue fibrosis: the unwanted houseguest invited by obesity. J. Endocrinol. 259, e230180 (2023).
Kusminski, C. M. & Scherer, P. E. Mitochondrial dysfunction in white adipose tissue. Trends Endocrinol. Metab. 23, 435–443 (2012).
Pafili, K. et al. Mitochondrial respiration is decreased in visceral but not subcutaneous adipose tissue in obese individuals with fatty liver disease. J. Hepatol. 77, 1504–1514 (2022).
Kirichenko, T. V. et al. The role of adipokines in inflammatory mechanisms of obesity. Int. J. Mol. Sci. 23, 14982 (2022).
Rochlani, Y., Pothineni, N. V., Kovelamudi, S. & Mehta, J. L. Metabolic syndrome: pathophysiology, management, and modulation by natural compounds. Ther. Adv. Cardiovasc. Dis. 11, 215–225 (2017).
Iacobellis, G. Epicardial adipose tissue in contemporary cardiology. Nat. Rev. Cardiol. 19, 593–606 (2022).
Petta, S. et al. Epicardial fat, cardiac geometry and cardiac function in patients with non-alcoholic fatty liver disease: association with the severity of liver disease. J. Hepatol. 62, 928–933 (2015).
Inciardi, R. M. & Chandra, A. Epicardial adipose tissue in heart failure: risk factor or mediator? Eur. J. Heart Fail. 24, 1357–1358 (2022).
Kenchaiah, S. et al. Pericardial fat and the risk of heart failure. J. Am. Coll. Cardiol. 77, 2638–2652 (2021).
Liu, B. et al. Association of epicardial adipose tissue with non-alcoholic fatty liver disease: a meta-analysis. Hepatol. Int. 13, 757–765 (2019).
Bale, L. K., West, S. A. & Conover, C. A. Characterization of mouse pericardial fat: regulation by PAPP-A. Growth Horm. IGF Res. 42-43, 1–7 (2018).
Capone, F., Vettor, R. & Schiattarella, G. G. Cardiometabolic HFpEF: NASH of the Heart. Circulation 147, 451–453 (2023).
McGavock, J. M. et al. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 116, 1170–1175 (2007).
Kankaanpaa, M. et al. Myocardial triglyceride content and epicardial fat mass in human obesity: relationship to left ventricular function and serum free fatty acid levels. J. Clin. Endocrinol. Metab. 91, 4689–4695 (2006).
Daneii, P. et al. Lipids and diastolic dysfunction: recent evidence and findings. Nutr. Metab. Cardiovasc. Dis. 32, 1343–1352 (2022).
Schiattarella, G. G. et al. Nitrosative stress drives heart failure with preserved ejection fraction. Nature 568, 351–356 (2019).
Schiattarella, G. G. et al. Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction. Nat. Commun. 12, 1684 (2021).
Williams, M. et al. Mouse model of heart failure with preserved ejection fraction driven by hyperlipidemia and enhanced cardiac low-density lipoprotein receptor expression. J. Am. Heart Assoc. 11, e027216 (2022).
Wu, C. K. et al. Myocardial adipose deposition and the development of heart failure with preserved ejection fraction. Eur. J. Heart Fail. 22, 445–454 (2020).
Mahmod, M. et al. The interplay between metabolic alterations, diastolic strain rate and exercise capacity in mild heart failure with preserved ejection fraction: a cardiovascular magnetic resonance study. J. Cardiovasc. Magn. Reson. 20, 88 (2018).
Rayner, J. J. et al. The relative contribution of metabolic and structural abnormalities to diastolic dysfunction in obesity. Int. J. Obes. 42, 441–447 (2018).
Hammer, S. et al. Progressive caloric restriction induces dose-dependent changes in myocardial triglyceride content and diastolic function in healthy men. J. Clin. Endocrinol. Metab. 93, 497–503 (2008).
Bianco, C. et al. Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores. J. Hepatol. 74, 775–782 (2021).
Romeo, S., Sanyal, A. & Valenti, L. Leveraging human genetics to identify potential new treatments for fatty liver disease. Cell Metab. 31, 35–45 (2020).
Lipke, K., Kubis-Kubiak, A. & Piwowar, A. Molecular mechanism of lipotoxicity as an interesting aspect in the development of pathological states-current view of knowledge. Cells 11, 844 (2022).
Ahmed, A., Cule, M., Bell, J. D., Sattar, N. & Yaghootkar, H. Differing genetic variants associated with liver fat and their contrasting relationships with cardiovascular diseases and cancer. J. Hepatol. 81, 921–929 (2024).
Koliaki, C. et al. Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Cell Metab. 21, 739–746 (2015).
Peng, K. Y. et al. Mitochondrial dysfunction-related lipid changes occur in nonalcoholic fatty liver disease progression. J. Lipid Res. 59, 1977–1986 (2018).
Li, M. et al. Trends in insulin resistance: insights into mechanisms and therapeutic strategy. Signal. Transduct. Target. Ther. 7, 216 (2022).
Alshehade, S. et al. The role of protein kinases as key drivers of metabolic dysfunction-associated fatty liver disease progression: new insights and future directions. Life Sci. 305, 120732 (2022).
Jaishy, B. et al. Lipid-induced NOX2 activation inhibits autophagic flux by impairing lysosomal enzyme activity. J. Lipid Res. 56, 546–561 (2015).
Joseph, L. C. et al. Inhibition of NAPDH oxidase 2 (NOX2) prevents oxidative stress and mitochondrial abnormalities caused by saturated fat in cardiomyocytes. PLoS One 11, e0145750 (2016).
Han, J. & Kaufman, R. J. The role of ER stress in lipid metabolism and lipotoxicity. J. Lipid Res. 57, 1329–1338 (2016).
Lebeaupin, C. et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. J. Hepatol. 69, 927–947 (2018).
Leggat, J., Bidault, G. & Vidal-Puig, A. Lipotoxicity: a driver of heart failure with preserved ejection fraction? Clin. Sci. 135, 2265–2283 (2021).
Geng, Y., Faber, K. N., de Meijer, V. E., Blokzijl, H. & Moshage, H. How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease? Hepatol. Int. 15, 21–35 (2021).
Incalza, M. A. et al. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vasc. Pharmacol. 100, 1–19 (2018).
Zhang, Q. J. et al. Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex. Diabetes 61, 1848–1859 (2012).
Rada, P., Gonzalez-Rodriguez, A., Garcia-Monzon, C. & Valverde, A. M. Understanding lipotoxicity in NAFLD pathogenesis: is CD36 a key driver? Cell Death Dis. 11, 802 (2020).
Peiseler, M. et al. Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease — novel insights into cellular communication circuits. J. Hepatol. 77, 1136–1160 (2022).
Huby, T. & Gautier, E. L. Immune cell-mediated features of non-alcoholic steatohepatitis. Nat. Rev. Immunol. 22, 429–443 (2022).
Hanna, A. & Frangogiannis, N. G. Inflammatory cytokines and chemokines as therapeutic targets in heart failure. Cardiovasc. Drugs Ther. 34, 849–863 (2020).
Li, N. et al. The Th17/Treg imbalance exists in patients with heart failure with normal ejection fraction and heart failure with reduced ejection fraction. Clin. Chim. Acta 411, 1963–1968 (2010).
Hahn, V. S. et al. Myocardial gene expression signatures in human heart failure with preserved ejection fraction. Circulation 143, 120–134 (2021).
Hahn, V. S. et al. Endomyocardial biopsy characterization of heart failure with preserved ejection fraction and prevalence of cardiac amyloidosis. JACC Heart Fail. 8, 712–724 (2020).
Ye, B. et al. Left ventricular gene expression in heart failure with preserved ejection fraction-profibrotic and proinflammatory pathways and genes. Circ. Heart Fail. 16, e010395 (2023).
Smolgovsky, S. et al. Impaired T cell IRE1α/XBP1 signaling directs inflammation in experimental heart failure with preserved ejection fraction. J. Clin. Invest. 133, e171874 (2023).
Schiattarella, G. G. et al. Immunometabolic mechanisms of heart failure with preserved ejection fraction. Nat. Cardiovasc. Res. 1, 211–222 (2022).
Schiattarella, G. G., Rodolico, D. & Hill, J. A. Metabolic inflammation in heart failure with preserved ejection fraction. Cardiovasc. Res. 117, 423–434 (2021).
Hammoutene, A. & Rautou, P. E. Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. J. Hepatol. 70, 1278–1291 (2019).
Kim, S. Y. et al. Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex. Nat. Commun. 8, 2247 (2017).
Peleman, C., Francque, S. & Berghe, T. V. Emerging role of ferroptosis in metabolic dysfunction-associated steatotic liver disease: revisiting hepatic lipid peroxidation. EBioMedicine 102, 105088 (2024).
Fonseka, O. et al. XBP1s-EDEM2 prevents the onset and development of HFpEF by ameliorating cardiac lipotoxicity. Circulation 151, 1583–1605 (2025).
Xiong, Y. et al. Inhibition of ferroptosis reverses heart failure with preserved ejection fraction in mice. J. Transl. Med. 22, 199 (2024).
Delalat, S. et al. Dysregulated inflammation, oxidative stress, and protein quality control in diabetic HFpEF: unraveling mechanisms and therapeutic targets. Cardiovasc. Diabetol. 24, 211 (2025).
Schnabl, B., Damman, C. J. & Carr, R. M. Metabolic dysfunction-associated steatotic liver disease and the gut microbiome: pathogenic insights and therapeutic innovations. J. Clin. Invest. 135, e186423 (2025).
Snelson, M. et al. Gut-heart axis: the role of gut microbiota and metabolites in heart failure. Circ. Res. 136, 1382–1406 (2025).
Guivala, S. J. et al. Interactions between the gut microbiome, associated metabolites and the manifestation and progression of heart failure with preserved ejection fraction in ZSF1 rats. Cardiovasc. Diabetol. 23, 299 (2024).
Dong, Z., Zheng, S., Shen, Z., Luo, Y. & Hai, X. Trimethylamine N-oxide is associated with heart failure risk in patients with preserved ejection fraction. Lab. Med. 52, 346–351 (2021).
Bradley, S. E. et al. The effect of exercise on the splanchnic blood flow and splanchnic blood volume in normal man. Clin. Sci. 15, 457–463 (1956).
Hirooka, M. et al. Nonalcoholic fatty liver disease: portal hypertension due to outflow block in patients without cirrhosis. Radiology 274, 597–604 (2015).
Fudim, M., Sobotka, P. A. & Dunlap, M. E. Extracardiac abnormalities of preload reserve: mechanisms underlying exercise limitation in heart failure with preserved ejection fraction, autonomic dysfunction, and liver disease. Circ. Heart Fail. 14, e007308 (2021).
Ahlers, C. G., Patel, P., Parikh, K. & Fudim, M. Use of invasive cardiopulmonary exercise testing to diagnose preload reserve failure in patients with liver disease. ESC Heart Fail. 11, 587–593 (2024).
Matyas, C., Hasko, G., Liaudet, L., Trojnar, E. & Pacher, P. Interplay of cardiovascular mediators, oxidative stress and inflammation in liver disease and its complications. Nat. Rev. Cardiol. 18, 117–135 (2021).
Turco, L. et al. Cardiopulmonary hemodynamics and C-reactive protein as prognostic indicators in compensated and decompensated cirrhosis. J. Hepatol. 68, 949–958 (2018).
Razpotnik, M. et al. The prevalence of cirrhotic cardiomyopathy according to different diagnostic criteria. Liver Int. 41, 1058–1069 (2021).
Stundiene, I. et al. Liver cirrhosis and left ventricle diastolic dysfunction: systematic review. World J. Gastroenterol. 25, 4779–4795 (2019).
Glenn, T. K., Honar, H., Liu, H., ter Keurs, H. E. & Lee, S. S. Role of cardiac myofilament proteins titin and collagen in the pathogenesis of diastolic dysfunction in cirrhotic rats. J. Hepatol. 55, 1249–1255 (2011).
Jamialahmadi, O., Tavaglione, F., Rawshani, A., Ljungman, C. & Romeo, S. Fatty liver disease, heart rate and cardiac remodelling: evidence from the UK Biobank. Liver Int. 43, 1247–1255 (2023).
Xanthopoulos, A., Starling, R. C., Kitai, T. & Triposkiadis, F. Heart failure and liver disease: cardiohepatic interactions. JACC Heart Fail. 7, 87–97 (2019).
Shi, Y. et al. Metabolic syndrome nonalcoholic steatohepatitis male mouse with adeno-associated viral renin as a novel model for heart failure with preserved ejection fraction. J. Am. Heart Assoc. 13, e035894 (2024).
Kotronen, A. et al. Increased coagulation factor VIII, IX, XI and XII activities in non-alcoholic fatty liver disease. Liver Int. 31, 176–183 (2011).
Degertekin, B., Ozenirler, S., Elbeg, S. & Akyol, G. The serum endothelin-1 level in steatosis and NASH, and its relation with severity of liver fibrosis. Dig. Dis. Sci. 52, 2622–2628 (2007).
Targher, G., Corey, K. E. & Byrne, C. D. NAFLD, and cardiovascular and cardiac diseases: factors influencing risk, prediction and treatment. Diabetes Metab. 47, 101215 (2021).
Wang, Y., Zeng, Y., Lin, C. & Chen, Z. Hypertension and non-alcoholic fatty liver disease proven by transient elastography. Hepatol. Res. 46, 1304–1310 (2016).
Zhou, X. D. et al. Effect of hypertension on long-term adverse clinical outcomes and liver fibrosis progression in MASLD. J. Hepatol. https://doi.org/10.1016/j.jhep.2025.08.017 (2025).
Lonardo, A., Nascimbeni, F., Mantovani, A. & Targher, G. Hypertension, diabetes, atherosclerosis and NASH: cause or consequence? J. Hepatol. 68, 335–352 (2018).
Jeong, J. et al. Association of metabolic dysfunction-associated steatotic liver disease and steatosis-associated fibrosis estimator with subclinical coronary atherosclerosis: observation cohort study. Sci. Rep. 15, 24953 (2025).
Anstee, Q. M., Mantovani, A., Tilg, H. & Targher, G. Risk of cardiomyopathy and cardiac arrhythmias in patients with nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 15, 425–439 (2018).
Stahl, E. P. et al. Nonalcoholic fatty liver disease and the heart: JACC state-of-the-art review. J. Am. Coll. Cardiol. 73, 948–963 (2019).
Mantovani, A. et al. Risk of heart failure in patients with nonalcoholic fatty liver disease: JACC review topic of the week. J. Am. Coll. Cardiol. 79, 180–191 (2022).
Itier, R. et al. Non-alcoholic fatty liver disease and heart failure with preserved ejection fraction: from pathophysiology to practical issues. ESC Heart Fail. 8, 789–798 (2021).
Badmus, O. O., Hinds, T. D. Jr. & Stec, D. E. Mechanisms linking metabolic-associated fatty liver disease (MAFLD) to cardiovascular disease. Curr. Hypertens. Rep. 25, 151–162 (2023).
Zhou, J., Bai, L., Zhang, X. J., Li, H. & Cai, J. Nonalcoholic fatty liver disease and cardiac remodeling risk: pathophysiological mechanisms and clinical implications. Hepatology 74, 2839–2847 (2021).
Byrne, C. D. & Targher, G. Non-alcoholic fatty liver disease-related risk of cardiovascular disease and other cardiac complications. Diabetes Obes. Metab. 24, 28–43 (2022).
Perseghin, G. et al. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Hepatology 47, 51–58 (2008).
Bugianesi, E. & Gastaldelli, A. Hepatic and cardiac steatosis: are they coupled? Heart Fail. Clin. 8, 663–670 (2012).
Badmus, O. O. et al. Loss of hepatic PPARα in mice causes hypertension and cardiovascular disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 325, R81–R95 (2023).
Badmus, O. O. et al. Cardiac lipotoxicity and fibrosis underlie impaired contractility in a mouse model of metabolic dysfunction-associated steatotic liver disease. FASEB Bioadv. 6, 131–142 (2024).
Kucsera, D. et al. NASH triggers cardiometabolic HFpEF in aging mice. Geroscience 46, 4517–4531 (2024).
Kucsera, D. et al. IL-1β neutralization prevents diastolic dysfunction development, but lacks hepatoprotective effect in an aged mouse model of NASH. Sci. Rep. 13, 356 (2023).
Heeren, J. & Scheja, L. Metabolic-associated fatty liver disease and lipoprotein metabolism. Mol. Metab. 50, 101238 (2021).
Capone, F. et al. Cardiac metabolism in HFpEF: from fuel to signalling. Cardiovascular Res. 118, 3556–3575 (2023).
Schulze, P. C., Drosatos, K. & Goldberg, I. J. Lipid use and misuse by the heart. Circ. Res. 118, 1736–1751 (2016).
Tang, K. et al. Association between non-alcoholic fatty liver disease and myocardial glucose uptake measured by 18F-fluorodeoxyglucose positron emission tomography. J. Nucl. Cardiol. 27, 1679–1688 (2020).
Lautamaki, R. et al. Liver steatosis coexists with myocardial insulin resistance and coronary dysfunction in patients with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 291, E282–E290 (2006).
Karwi, Q. G. et al. Weight loss enhances cardiac energy metabolism and function in heart failure associated with obesity. Diabetes Obes. Metab. 21, 1944–1955 (2019).
Jelenik, T. et al. Insulin resistance and vulnerability to cardiac ischemia. Diabetes 67, 2695–2702 (2018).
Viglino, C., Khoramdin, B., Praplan, G. & Montessuit, C. Pleiotropic effects of chronic phorbol ester treatment to improve glucose transport in insulin-resistant cardiomyocytes. J. Cell Biochem. 118, 4716–4727 (2017).
Jia, G., DeMarco, V. G. & Sowers, J. R. Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat. Rev. Endocrinol. 12, 144–153 (2016).
Tran, D. H. & Wang, Z. V. Glucose metabolism in cardiac hypertrophy and heart failure. J. Am. Heart Assoc. 8, e012673 (2019).
Mittendorfer, B., Yoshino, M., Patterson, B. W. & Klein, S. VLDL triglyceride kinetics in lean, overweight, and obese men and women. J. Clin. Endocrinol. Metab. 101, 4151–4160 (2016).
Fabbrini, E. et al. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134, 424–431 (2008).
Puchalska, P. & Crawford, P. A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25, 262–284 (2017).
Horton, J. L. et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight 4, e124079 (2019).
Aubert, G. et al. The failing heart relies on ketone bodies as a fuel. Circulation 133, 698–705 (2016).
Bedi, K. C. Jr. et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation 133, 706–716 (2016).
Mey, J. T. et al. β-Hydroxybutyrate is reduced in humans with obesity-related NAFLD and displays a dose-dependent effect on skeletal muscle mitochondrial respiration in vitro. Am. J. Physiol. Endocrinol. Metab. 319, E187–E195 (2020).
Moore, M. P. et al. Relationship between serum β-hydroxybutyrate and hepatic fatty acid oxidation in individuals with obesity and NAFLD. Am. J. Physiol. Endocrinol. Metab. 326, E493–E502 (2024).
Fletcher, J. A. et al. Impaired ketogenesis and increased acetyl-CoA oxidation promote hyperglycemia in human fatty liver. JCI Insight 5, e127737 (2019).
Deng, Y. et al. Targeting mitochondria-inflammation circuit by β-hydroxybutyrate mitigates HFpEF. Circ. Res. 128, 232–245 (2021).
Youm, Y. H. et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263–269 (2015).
Burrage, M. K. et al. Energetic basis for exercise-induced pulmonary congestion in heart failure with preserved ejection fraction. Circulation 144, 1664–1678 (2021).
Shi, X. et al. Circulating branch chain amino acids and improvement in liver fat content in response to exercise interventions in NAFLD. Sci. Rep. 11, 13415 (2021).
McGarrah, R. W. et al. Dietary branched-chain amino acid restriction alters fuel selection and reduces triglyceride stores in hearts of Zucker fatty rats. Am. J. Physiol. Endocrinol. Metab. 318, E216–E223 (2020).
Montgomery, M. K., De Nardo, W. & Watt, M. J. Impact of lipotoxicity on tissue “cross talk” and metabolic regulation. Physiology 34, 134–149 (2019).
Meex, R. C. et al. Fetuin B Is a secreted hepatocyte factor linking steatosis to impaired glucose metabolism. Cell Metab. 22, 1078–1089 (2015).
Montgomery, M. K. et al. Deep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control. Nat. Commun. 13, 1259 (2022).
Stefan, N., Schick, F., Birkenfeld, A. L., Haring, H. U. & White, M. F. The role of hepatokines in NAFLD. Cell Metab. 35, 236–252 (2023).
Liu, S. et al. Systematic review and meta-analysis of circulating fetuin-A levels in nonalcoholic fatty liver disease. J. Clin. Transl. Hepatol. 9, 3–14 (2021).
Pal, D. et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 18, 1279–1285 (2012).
Al Ali, L. et al. Fetuin-A and its genetic association with cardiometabolic disease. Sci. Rep. 13, 21469 (2023).
Pan, X. et al. Fetuin-A in Metabolic syndrome: a systematic review and meta-analysis. PLoS One 15, e0229776 (2020).
Itoh, N., Nakayama, Y. & Konishi, M. Roles of FGFs as paracrine or endocrine signals in liver development, health, and disease. Front. Cell Dev. Biol. 4, 30 (2016).
Itoh, N. & Ohta, H. Pathophysiological roles of FGF signaling in the heart. Front. Physiol. 4, 247 (2013).
Badman, M. K. et al. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 5, 426–437 (2007).
Ong, K. L. et al. Association of elevated circulating fibroblast growth factor 21 levels with prevalent and incident metabolic syndrome: the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 281, 200–206 (2019).
He, L. et al. Diagnostic value of CK-18, FGF-21, and related biomarker panel in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Biomed. Res. Int. 2017, 9729107 (2017).
Falamarzi, K. et al. The role of FGF21 and its analogs on liver associated diseases. Front. Med. 9, 967375 (2022).
Harrison, S. A., Rolph, T., Knot, M. & Dubourg, J. FGF21 agonists: an emerging therapeutic for metabolic dysfunction-associated steatohepatitis and beyond. J. Hepatol. https://doi.org/10.1016/j.jhep.2024.04.034 (2024).
Geng, L., Lam, K. S. L. & Xu, A. The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nat. Rev. Endocrinol. 16, 654–667 (2020).
Yano, K. et al. Hepatocyte-specific fibroblast growth factor 21 overexpression ameliorates high-fat diet-induced obesity and liver steatosis in mice. Lab. Invest. 102, 281–289 (2022).
Jimenez, V. et al. Reversion of metabolic dysfunction-associated steatohepatitis by skeletal muscle-directed FGF21 gene therapy. Mol. Ther. 32, 4285–4302 (2024).
Hui, Q., Jin, Z., Li, X., Liu, C. & Wang, X. FGF family: from drug development to clinical application. Int. J. Mol. Sci. 19, 1875 (2018).
Planavila, A. et al. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat. Commun. 4, 2019 (2013).
Planavila, A., Redondo-Angulo, I. & Villarroya, F. FGF21 and cardiac physiopathology. Front. Endocrinol. 6, 133 (2015).
Yang, H. et al. Fibroblast growth factor-21 prevents diabetic cardiomyopathy via AMPK-mediated antioxidation and lipid-lowering effects in the heart. Cell Death Dis. 9, 227 (2018).
Yan, X. et al. FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation. J. Cell Mol. Med. 19, 1557–1568 (2015).
Jin, L. et al. FGF21-sirtuin 3 axis confers the protective effects of exercise against diabetic cardiomyopathy by governing mitochondrial integrity. Circulation 146, 1537–1557 (2022).
Sun, J. Y. et al. An IL-6/STAT3/MR/FGF21 axis mediates heart-liver cross-talk after myocardial infarction. Sci. Adv. 9, eade4110 (2023).
Yanucil, C. et al. FGF21-FGFR4 signaling in cardiac myocytes promotes concentric cardiac hypertrophy in mouse models of diabetes. Sci. Rep. 12, 7326 (2022).
Di Lisa, F. & Itoh, N. Cardiac Fgf21 synthesis and release: an autocrine loop for boosting up antioxidant defenses in failing hearts. Cardiovasc. Res. 106, 1–3 (2015).
Chou, R. H. et al. Circulating fibroblast growth factor 21 is associated with diastolic dysfunction in heart failure patients with preserved ejection fraction. Sci. Rep. 6, 33953 (2016).
Yan, B., Ma, S., Yan, C. & Han, Y. Fibroblast growth factor 21 and prognosis of patients with cardiovascular disease: a meta-analysis. Front. Endocrinol. 14, 1108234 (2023).
So, W. Y. et al. High glucose represses β-klotho expression and impairs fibroblast growth factor 21 action in mouse pancreatic islets: involvement of peroxisome proliferator-activated receptor γ signaling. Diabetes 62, 3751–3759 (2013).
Fisher, F. M. et al. Obesity is a fibroblast growth factor 21 (FGF21)-resistant state. Diabetes 59, 2781–2789 (2010).
Geng, L. et al. Exercise alleviates obesity-induced metabolic dysfunction via enhancing FGF21 sensitivity in adipose tissues. Cell Rep. 26, 2738–2752.e4 (2019).
Liu, X., Shao, Y., Han, L., Zhang, R. & Chen, J. Emerging evidence linking the liver to the cardiovascular system: liver-derived secretory factors. J. Clin. Transl. Hepatol. 11, 1246–1255 (2023).
Jung, T. W., Yoo, H. J. & Choi, K. M. Implication of hepatokines in metabolic disorders and cardiovascular diseases. BBA Clin. 5, 108–113 (2016).
Jasaszwili, M., Billert, M., Strowski, M. Z., Nowak, K. W. & Skrzypski, M. Adropin as a fat-burning hormone with multiple functions-review of a decade of research. Molecules 25, 549 (2020).
Kutlu, O. et al. Serum adropin levels are reduced in adult patients with nonalcoholic fatty liver disease. Med. Princ. Pract. 28, 463–469 (2019).
Altamimi, T. R. et al. Adropin regulates cardiac energy metabolism and improves cardiac function and efficiency. Metabolism 98, 37–48 (2019).
Thapa, D. et al. Adropin treatment restores cardiac glucose oxidation in pre-diabetic obese mice. J. Mol. Cell Cardiol. 129, 174–178 (2019).
Thapa, D. et al. Adropin regulates pyruvate dehydrogenase in cardiac cells via a novel GPCR-MAPK-PDK4 signaling pathway. Redox Biol. 18, 25–32 (2018).
Liu, M. et al. Adropin alleviates myocardial fibrosis in diabetic cardiomyopathy rats: a preliminary study. Front. Cardiovasc. Med. 8, 688586 (2021).
Cao, Y. et al. Liver-heart cross-talk mediated by coagulation factor XI protects against heart failure. Science 377, 1399–1406 (2022).
Strocchi, S. et al. Systems biology approach uncovers candidates for liver-heart interorgan crosstalk in HFpEF. Circ. Res. 135, 873–876 (2024).
Raposo, G. & Stoorvogel, W. Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 200, 373–383 (2013).
Huang-Doran, I., Zhang, C. Y. & Vidal-Puig, A. Extracellular vesicles: novel mediators of cell communication in metabolic disease. Trends Endocrinol. Metab. 28, 3–18 (2017).
Wang, W. et al. The crosstalk: exosomes and lipid metabolism. Cell Commun. Signal. 18, 119 (2020).
Li, W. & Yu, L. Role and therapeutic perspectives of extracellular vesicles derived from liver and adipose tissue in metabolic dysfunction-associated steatotic liver disease. Artif. Cell Nanomed. Biotechnol. 52, 355–369 (2024).
Gonzalez-Blanco, C. et al. The role of extracellular vesicles in metabolic diseases. Biomedicines 12, 992 (2024).
Zhang, J. et al. Lipid-induced DRAM recruits STOM to lysosomes and induces LMP to promote exosome release from hepatocytes in NAFLD. Sci. Adv. 7, eabh1541 (2021).
Kornek, M. et al. Circulating microparticles as disease-specific biomarkers of severity of inflammation in patients with hepatitis C or nonalcoholic steatohepatitis. Gastroenterology 143, 448–458 (2012).
Jiang, F. et al. Hepatocyte-derived extracellular vesicles promote endothelial inflammation and atherogenesis via microRNA-1. J. Hepatol. 72, 156–166 (2020).
Hirsova, P. et al. Lipid-induced signaling causes release of inflammatory extracellular vesicles from hepatocytes. Gastroenterology 150, 956–967 (2016).
Zuo, R. et al. Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7. J. Nanobiotechnol. 19, 396 (2021).
de Abreu, R. C. et al. Native and bioengineered extracellular vesicles for cardiovascular therapeutics. Nat. Rev. Cardiol. 17, 685–697 (2020).
Povero, D. et al. Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease. PLoS One 9, e113651 (2014).
Povero, D. et al. Characterization and proteome of circulating extracellular vesicles as potential biomarkers for NASH. Hepatol. Commun. 4, 1263–1278 (2020).
Paluschinski, M. et al. Extracellular vesicles as markers of liver function: optimized workflow for biomarker identification in liver disease. Int. J. Mol. Sci. 24, 9631 (2023).
Newman, L. A. et al. Selective isolation of liver-derived extracellular vesicles redefines performance of miRNA biomarkers for non-alcoholic fatty liver disease. Biomedicines 10, 195 (2022).
Garcia-Martinez, I. et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J. Clin. Invest. 126, 859–864 (2016).
Bandiera, S., Pfeffer, S., Baumert, T. F. & Zeisel, M. B. miR-122-a key factor and therapeutic target in liver disease. J. Hepatol. 62, 448–457 (2015).
Esau, C. et al. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 3, 87–98 (2006).
Cermelli, S., Ruggieri, A., Marrero, J. A., Ioannou, G. N. & Beretta, L. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One 6, e23937 (2011).
Corsten, M. F. et al. Circulating microRNA-208b and microRNA-499 reflect myocardial damage in cardiovascular disease. Circ. Cardiovasc. Genet. 3, 499–506 (2010).
Stojkovic, S. et al. Liver-specific microRNA-122 as prognostic biomarker in patients with chronic systolic heart failure. Int. J. Cardiol. 303, 80–85 (2020).
Cakmak, H. A. et al. The prognostic value of circulating microRNAs in heart failure: preliminary results from a genome-wide expression study. J. Cardiovasc. Med. 16, 431–437 (2015).
Liu, Y., Song, J. W., Lin, J. Y., Miao, R. & Zhong, J. C. Roles of microRNA-122 in cardiovascular fibrosis and related diseases. Cardiovasc. Toxicol. 20, 463–473 (2020).
Wang, Y., Jin, P., Liu, J. & Xie, X. Exosomal microRNA-122 mediates obesity-related cardiomyopathy through suppressing mitochondrial ADP-ribosylation factor-like 2. Clin. Sci. 133, 1871–1881 (2019).
Royo, F. et al. Hepatocyte-secreted extracellular vesicles modify blood metabolome and endothelial function by an arginase-dependent mechanism. Sci. Rep. 7, 42798 (2017).
European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J. Hepatol. 81, 492–542 (2024).
McDonagh, T. A. et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 42, 3599–3726 (2021).
Heidenreich, P. A. et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 145, e895–e1032 (2022).
Hernaez, R. et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology 54, 1082–1090 (2011).
Bril, F. et al. Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients. Liver Int. 35, 2139–2146 (2015).
Siddiqui, M. S. et al. Vibration-controlled transient elastography to assess fibrosis and steatosis in patients with nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 17, 156–163.e2 (2019).
Castera, L. et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 51, 828–835 (2010).
Pieske, B. et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur. Heart J. 40, 3297–3317 (2019).
Obokata, M. et al. Direct comparison of cardiac magnetic resonance feature tracking and 2D/3D echocardiography speckle tracking for evaluation of global left ventricular strain. Eur. Heart J. Cardiovasc. Imaging 17, 525–532 (2016).
Chamsi-Pasha, M. A., Zhan, Y., Debs, D. & Shah, D. J. CMR in the evaluation of diastolic dysfunction and phenotyping of HFpEF: current role and future perspectives. JACC Cardiovasc. Imaging 13, 283–296 (2020).
Rider, O. J. et al. Myocardial tissue phase mapping reveals impaired myocardial tissue velocities in obesity. Int. J. Cardiovasc. Imaging 31, 339–347 (2015).
Ito, H. et al. Cardiovascular magnetic resonance feature tracking for characterization of patients with heart failure with preserved ejection fraction: correlation of global longitudinal strain with invasive diastolic functional indices. J. Cardiovasc. Magn. Reson. 22, 42 (2020).
Bakermans, A. J. et al. Quantification of myocardial creatine and triglyceride content in the human heart: precision and accuracy of in vivo proton magnetic resonance spectroscopy. J. Magn. Reson. Imaging 54, 411–420 (2021).
Ellims, A. H. et al. Diffuse myocardial fibrosis evaluated by post-contrast T1 mapping correlates with left ventricular stiffness. J. Am. Coll. Cardiol. 63, 1112–1118 (2014).
Schelbert, E. B. et al. Temporal relation between myocardial fibrosis and heart failure with preserved ejection fraction: association with baseline disease severity and subsequent outcome. JAMA Cardiol. 2, 995–1006 (2017).
Rider, O. J. et al. Noninvasive in vivo assessment of cardiac metabolism in the healthy and diabetic human heart using hyperpolarized 13C MRI. Circ. Res. 126, 725–736 (2020).
Pradella, M. et al. A comprehensive evaluation of the left atrium using cardiovascular magnetic resonance. J. Cardiovasc. Magn. Reson. 27, 101852 (2025).
Gu, J. et al. Diagnostic value of MRI-PDFF for hepatic steatosis in patients with non-alcoholic fatty liver disease: a meta-analysis. Eur. Radiol. 29, 3564–3573 (2019).
Pavlides, M. et al. Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity. Liver Int. 37, 1065–1073 (2017).
McCracken, C. et al. Multi-organ imaging demonstrates the heart-brain-liver axis in UK Biobank participants. Nat. Commun. 13, 7839 (2022).
Roca-Fernandez, A. et al. Liver disease is a significant risk factor for cardiovascular outcomes — a UK Biobank study. J. Hepatol. 79, 1085–1095 (2023).
Loomba, R. et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N. Engl. J. Med. 391, 299–310 (2024).
Reddy, Y. N. V. et al. Characterization of the obese phenotype of heart failure with preserved ejection fraction: a RELAX Trial Ancillary Study. Mayo Clin. Proc. 94, 1199–1209 (2019).
He, J. et al. Clinical features, myocardial strain and tissue characteristics of heart failure with preserved ejection fraction in patients with obesity: a prospective cohort study. EClinicalMedicine 55, 101723 (2023).
Reddy, Y. N. V. et al. Evidence-based application of natriuretic peptides in the evaluation of chronic heart failure with preserved ejection fraction in the ambulatory outpatient setting. Circulation 151, 976–989 (2025).
Verbrugge, F. H. et al. Heart failure with preserved ejection fraction in patients with normal natriuretic peptide levels is associated with increased morbidity and mortality. Eur. Heart J. 43, 1941–1951 (2022).
Baccouche, B. M. & Rhodenhiser, E. Galectin-3 and HFpEF: clarifying an emerging relationship. Curr. Cardiol. Rev. 19, 19–26 (2023).
Rabkin, S. W. & Tang, J. K. K. The utility of growth differentiation factor-15, galectin-3, and sST2 as biomarkers for the diagnosis of heart failure with preserved ejection fraction and compared to heart failure with reduced ejection fraction: a systematic review. Heart Fail. Rev. 26, 799–812 (2021).
Duprez, D. A. et al. Predictive value of collagen biomarkers for heart failure with and without preserved ejection fraction: MESA (Multi-Ethnic Study of Atherosclerosis). J. Am. Heart Assoc. 7, e007885 (2018).
Krebber, M. M. et al. Matrix metalloproteinases and tissue inhibitors of metalloproteinases in extracellular matrix remodeling during left ventricular diastolic dysfunction and heart failure with preserved ejection fraction: a systematic review and meta-analysis. Int. J. Mol. Sci. 21, 6742 (2020).
Guo, S. et al. The value of IGF-1 and IGFBP-1 in patients with heart failure with reduced, mid-range, and preserved ejection fraction. Front. Cardiovasc. Med. 8, 772105 (2021).
Bracun, V. et al. Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence. ESC Heart Fail. 9, 4167–4176 (2022).
Chirinos, J. A. et al. Endotrophin, a collagen VI formation-derived peptide, in heart failure. NEJM Evid. 1, evidoa2200091 (2022).
Ianos, R. D. et al. Diagnostic performance of serum biomarkers fibroblast growth factor 21, galectin-3 and copeptin for heart failure with preserved ejection fraction in a sample of patients with type 2 diabetes mellitus. Diagnostics 11, 1577 (2021).
Roy, C. et al. Fibroblast growth factor 23: a biomarker of fibrosis and prognosis in heart failure with preserved ejection fraction. ESC Heart Fail. 7, 2494–2507 (2020).
Kresoja, K. P. et al. Proteomics to improve phenotyping in obese patients with heart failure with preserved ejection fraction. Eur. J. Heart Fail. 23, 1633–1644 (2021).
Bevan, G. H., Jenkins, T., Josephson, R., Rajagopalan, S. & Al-Kindi, S. G. Endothelin-1 and peak oxygen consumption in patients with heart failure with preserved ejection fraction. Heart Lung 50, 442–446 (2021).
Chowdhury, M. A. et al. Endothelin 1 is associated with heart failure hospitalization and long-term mortality in patients with heart failure with preserved ejection fraction and pulmonary hypertension. Cardiology 143, 124–133 (2019).
Reddy, Y. N. V., Carter, R. E., Obokata, M., Redfield, M. M. & Borlaug, B. A. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 138, 861–870 (2018).
Reddy, Y. N. V. et al. An evidence-based screening tool for heart failure with preserved ejection fraction: the HFpEF-ABA score. Nat. Med. 30, 2258–2264 (2024).
Crudele, L. et al. Fatty Liver Index (FLI) is the best score to predict MASLD with 50% lower cut-off value in women than in men. Biol. Sex. Differ. 15, 43 (2024).
Lee, J. H. et al. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig. Liver Dis. 42, 503–508 (2010).
Kotronen, A. et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology 137, 865–872 (2009).
Kwok, R. et al. Systematic review with meta-analysis: non-invasive assessment of non-alcoholic fatty liver disease-the role of transient elastography and plasma cytokeratin-18 fragments. Aliment. Pharmacol. Ther. 39, 254–269 (2014).
Grigorescu, M. et al. A novel pathophysiological-based panel of biomarkers for the diagnosis of nonalcoholic steatohepatitis. J. Physiol. Pharmacol. 63, 347–353 (2012).
Hui, J. M. et al. Beyond insulin resistance in NASH: TNF-alpha or adiponectin? Hepatology 40, 46–54 (2004).
Shen, J. et al. Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers. J. Hepatol. 56, 1363–1370 (2012).
Vallet-Pichard, A. et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Hepatology 46, 32–36 (2007).
Wai, C. T. et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 38, 518–526 (2003).
Angulo, P. et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 45, 846–854 (2007).
Tavaglione, F. et al. Development and validation of a score for fibrotic nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. 21, 1523–1532.e1 (2023).
Raverdy, V. et al. Performance of non-invasive tests for liver fibrosis resolution after bariatric surgery. Metabolism 153, 155790 (2024).
Serra-Burriel, M. et al. Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study. Lancet 402, 988–996 (2023).
Lichtinghagen, R. et al. The Enhanced Liver Fibrosis (ELF) score: normal values, influence factors and proposed cut-off values. J. Hepatol. 59, 236–242 (2013).
Noureddin, M. et al. MRI-based (MAST) score accurately identifies patients with NASH and significant fibrosis. J. Hepatol. 76, 781–787 (2022).
Newsome, P. N. et al. FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study. Lancet Gastroenterol. Hepatol. 5, 362–373 (2020).
Ajmera, V. et al. Liver stiffness on magnetic resonance elastography and the MEFIB Index and liver-related outcomes in nonalcoholic fatty liver disease: a systematic review and meta-analysis of individual participants. Gastroenterology 163, 1079–1089 e1075 (2022).
Vest, A. R. et al. Nutrition, obesity, and cachexia in patients with heart failure: a consensus statement from the Heart Failure Society of America Scientific Statements Committee. J. Card. Fail. 25, 380–400 (2019).
Tamaki, N. et al. Clinical utility of 30% relative decline in MRI-PDFF in predicting fibrosis regression in non-alcoholic fatty liver disease. Gut 71, 983–990 (2022).
Yki-Jarvinen, H., Luukkonen, P. K., Hodson, L. & Moore, J. B. Dietary carbohydrates and fats in nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 18, 770–786 (2021).
Hansen, C. D. et al. Effect of calorie-unrestricted low-carbohydrate, high-fat diet versus high-carbohydrate, low-fat diet on type 2 diabetes and nonalcoholic fatty liver disease: a randomized controlled trial. Ann. Intern. Med. 176, 10–21 (2023).
Kitzman, D. W. et al. Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 315, 36–46 (2016).
Kawaguchi, T. et al. Effects of Mediterranean diet in patients with nonalcoholic fatty liver disease: a systematic review, meta-analysis, and meta-regression analysis of randomized controlled trials. Semin. Liver Dis. 41, 225–234 (2021).
Yaskolka Meir, A. et al. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial. Gut 70, 2085–2095 (2021).
Hassani Zadeh, S., Mansoori, A. & Hosseinzadeh, M. Relationship between dietary patterns and non-alcoholic fatty liver disease: a systematic review and meta-analysis. J. Gastroenterol. Hepatol. 36, 1470–1478 (2021).
Gepner, Y. et al. The beneficial effects of Mediterranean diet over low-fat diet may be mediated by decreasing hepatic fat content. J. Hepatol. 71, 379–388 (2019).
Fito, M. et al. Effect of the Mediterranean diet on heart failure biomarkers: a randomized sample from the PREDIMED trial. Eur. J. Heart Fail. 16, 543–550 (2014).
Kouvari, M. et al. Mediterranean diet and prognosis of first-diagnosed acute coronary syndrome patients according to heart failure phenotype: Hellenic Heart Failure Study. Eur. J. Clin. Nutr. https://doi.org/10.1038/ejcn.2017.122 (2017).
Nordmann, A. J. et al. Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials. Arch. Intern. Med. 166, 285–293 (2006).
Ezpeleta, M. et al. Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: a randomized controlled trial. Cell Metab. 35, 56–70.e3 (2023).
Wei, X. et al. Effects of time-restricted eating on nonalcoholic fatty liver disease: the TREATY-FLD randomized clinical trial. JAMA Netw. Open 6, e233513 (2023).
Holmer, M. et al. Treatment of NAFLD with intermittent calorie restriction or low-carb high-fat diet — a randomised controlled trial. JHEP Rep. 3, 100256 (2021).
Joseph, J. et al. Genetic architecture of heart failure with preserved versus reduced ejection fraction. Nat. Commun. 13, 7753 (2022).
Crosby, L. et al. Ketogenic diets and chronic disease: weighing the benefits against the risks. Front. Nutr. 8, 702802 (2021).
Kim, D., Vazquez-Montesino, L. M., Li, A. A., Cholankeril, G. & Ahmed, A. Inadequate physical activity and sedentary behavior are independent predictors of nonalcoholic fatty liver disease. Hepatology 72, 1556–1568 (2020).
Stine, J. G. et al. American College of Sports Medicine (ACSM) International Multidisciplinary Roundtable report on physical activity and nonalcoholic fatty liver disease. Hepatol. Commun. 7, e0108 (2023).
Pandey, A. et al. Relationship between physical activity, body mass index, and risk of heart failure. J. Am. Coll. Cardiol. 69, 1129–1142 (2017).
Vacca, A. et al. Lifestyle interventions in cardiometabolic HFpEF: dietary and exercise modalities. Heart Fail. Rev. https://doi.org/10.1007/s10741-024-10439-1 (2024).
Edelmann, F. et al. Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J. Am. Coll. Cardiol. 58, 1780–1791 (2011).
Donelli da Silveira, A. et al. High-intensity interval training is effective and superior to moderate continuous training in patients with heart failure with preserved ejection fraction: a randomized clinical trial. Eur. J. Prev. Cardiol. 27, 1733–1743 (2020).
Sachdev, V. et al. Supervised exercise training for chronic heart failure with preserved ejection fraction: a scientific statement from the American Heart Association and American College of Cardiology. Circulation 147, e699–e715 (2023).
Walters, G. W. M. et al. The effectiveness of lifestyle interventions in heart failure with preserved ejection fraction: a systematic review and network meta-analysis. J. Card. Fail. 30, 994–1009 (2024).
Baker, C. J. et al. Effect of exercise on hepatic steatosis: are benefits seen without dietary intervention? A systematic review and meta-analysis. J. Diabetes 13, 63–77 (2021).
Sabag, A. et al. The effect of high-intensity interval training vs moderate-intensity continuous training on liver fat: a systematic review and meta-analysis. J. Clin. Endocrinol. Metab. 107, 862–881 (2022).
Di Lorenzo, N. et al. Clinical practice guidelines of the European Association for Endoscopic Surgery (EAES) on bariatric surgery: update 2020 endorsed by IFSO-EC, EASO and ESPCOP. Surg. Endosc. 34, 2332–2358 (2020).
Panunzi, S. et al. Determinants of diabetes remission and glycemic control after bariatric surgery. Diabetes Care 39, 166–174 (2016).
Aminian, A. et al. Association of bariatric surgery with major adverse liver and cardiovascular outcomes in patients with biopsy-proven nonalcoholic steatohepatitis. JAMA 326, 2031–2042 (2021).
Fakhry, T. K. et al. Bariatric surgery improves nonalcoholic fatty liver disease: a contemporary systematic review and meta-analysis. Surg. Obes. Relat. Dis. 15, 502–511 (2019).
Zhou, H. et al. Bariatric surgery improves nonalcoholic fatty liver disease: systematic review and meta-analysis. Obes. Surg. 32, 1872–1883 (2022).
Lassailly, G. et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology 159, 1290–1301.e5 (2020).
Verrastro, O. et al. Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial. Lancet 401, 1786–1797 (2023).
Miranda, W. R. et al. Impact of bariatric surgery on quality of life, functional capacity, and symptoms in patients with heart failure. Obes. Surg. 23, 1011–1015 (2013).
Shimada, Y. J., Tsugawa, Y., Brown, D. F. M. & Hasegawa, K. Bariatric surgery and emergency department visits and hospitalizations for heart failure exacerbation: population-based, self-controlled series. J. Am. Coll. Cardiol. 67, 895–903 (2016).
Mikhalkova, D. et al. Bariatric surgery-induced cardiac and lipidomic changes in obesity-related heart failure with preserved ejection fraction. Obesity 26, 284–290 (2018).
Mentias, A. et al. Trends and outcomes associated with bariatric surgery and pharmacotherapies with weight loss effects among patients with heart failure and obesity. Circ. Heart Fail. 17, e010453 (2024).
Bonora, B. M., Avogaro, A. & Fadini, G. P. Extraglycemic effects of SGLT2 inhibitors: a review of the evidence. Diabetes Metab. Syndr. Obes. 13, 161–174 (2020).
Ridderstrale, M. et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2, 691–700 (2014).
Kolijn, D. et al. Empagliflozin improves endothelial and cardiomyocyte function in human heart failure with preserved ejection fraction via reduced pro-inflammatory-oxidative pathways and protein kinase Gα oxidation. Cardiovasc. Res. 117, 495–507 (2021).
Sun, X. et al. Empagliflozin ameliorates obesity-related cardiac dysfunction by regulating sestrin2-mediated AMPK-mTOR signaling and redox homeostasis in high-fat diet-induced obese mice. Diabetes 69, 1292–1305 (2020).
Li, C. et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc. Diabetol. 18, 15 (2019).
Lee, H. C. et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc. Diabetol. 18, 45 (2019).
Billing, A. M. et al. Metabolic communication by SGLT2 inhibition. Circulation 149, 860–884 (2024).
Lin, X. F. et al. SGLT2 inhibitors ameliorate NAFLD in mice via downregulating PFKFB3, suppressing glycolysis and modulating macrophage polarization. Acta Pharmacol. Sin. 45, 2579–2597 (2024).
Radlinger, B. et al. Empagliflozin protects mice against diet-induced obesity, insulin resistance and hepatic steatosis. Diabetologia 66, 754–767 (2023).
Suga, T. et al. Ipragliflozin-induced improvement of liver steatosis in obese mice may involve sirtuin signaling. World J. Hepatol. 12, 350–362 (2020).
Liu, W. et al. SGLT2 inhibitor promotes ketogenesis to improve MASH by suppressing CD8+ T cell activation. Cell Metab. 36, 2245–2261.e6 (2024).
Gohari, S. et al. The effect of sodium-glucose co-transporter-2 (SGLT2) inhibitors on blood interleukin-6 concentration: a systematic review and meta-analysis of randomized controlled trials. BMC Endocr. Disord. 23, 257 (2023).
Theofilis, P. et al. The impact of SGLT2 inhibitors on inflammation: a systematic review and meta-analysis of studies in rodents. Int. Immunopharmacol. 111, 109080 (2022).
Quagliariello, V. et al. The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin. Cardiovasc. Diabetol. 20, 150 (2021).
Wu, P. et al. Systematic review and meta-analysis of randomized controlled trials on the effect of SGLT2 inhibitor on blood leptin and adiponectin level in patients with type 2 diabetes. Horm. Metab. Res. 51, 487–494 (2019).
Ye, T. et al. Empagliflozin attenuates obesity-related kidney dysfunction and NLRP3 inflammasome activity through the HO-1-adiponectin axis. Front. Endocrinol. 13, 907984 (2022).
Petrescu, A. D. et al. Leptin enhances hepatic fibrosis and inflammation in a mouse model of cholestasis. Am. J. Pathol. 192, 484–502 (2022).
Mao, Y., Zhao, K., Li, P. & Sheng, Y. The emerging role of leptin in obesity-associated cardiac fibrosis: evidence and mechanism. Mol. Cell Biochem. 478, 991–1011 (2023).
Whitehead, J. P., Richards, A. A., Hickman, I. J., Macdonald, G. A. & Prins, J. B. Adiponectin — a key adipokine in the metabolic syndrome. Diabetes Obes. Metab. 8, 264–280 (2006).
McDonagh, T. A. et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 44, 3627–3639 (2023).
Taheri, H. et al. Effect of empagliflozin on liver steatosis and fibrosis in patients with non-alcoholic fatty liver disease without diabetes: a randomized, double-blind, placebo-controlled trial. Adv. Ther. 37, 4697–4708 (2020).
Latva-Rasku, A. et al. The SGLT2 inhibitor dapagliflozin reduces liver fat but does not affect tissue insulin sensitivity: a randomized, double-blind, placebo-controlled study with 8-week treatment in type 2 diabetes patients. Diabetes Care 42, 931–937 (2019).
Harrison, S. A. et al. Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study. Nat. Med. 28, 1432–1438 (2022).
Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989–1002 (2021).
Jastreboff, A. M. et al. Tirzepatide once weekly for the treatment of obesity. N. Engl. J. Med. 387, 205–216 (2022).
Jastreboff, A. M. et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N. Engl. J. Med. 389, 514–526 (2023).
Zheng, Z. et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal. Transduct. Target. Ther. 9, 234 (2024).
Baggio, L. L. et al. GLP-1 receptor expression within the human heart. Endocrinology 159, 1570–1584 (2018).
Ban, K. et al. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 117, 2340–2350 (2008).
Wei, R. et al. Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner. Am. J. Physiol. Endocrinol. Metab. 310, E947–E957 (2016).
Kushima, H. et al. The role of endothelial nitric oxide in the anti-restenotic effects of liraglutide in a mouse model of restenosis. Cardiovasc. Diabetol. 16, 122 (2017).
Chai, W. et al. Glucagon-like peptide 1 recruits microvasculature and increases glucose use in muscle via a nitric oxide-dependent mechanism. Diabetes 61, 888–896 (2012).
Kim, M. et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat. Med. 19, 567–575 (2013).
Helmstadter, J. et al. Endothelial GLP-1 (glucagon-like peptide-1) receptor mediates cardiovascular protection by liraglutide in mice with experimental arterial hypertension. Arterioscler. Thromb. Vasc. Biol. 40, 145–158 (2020).
Rakipovski, G. et al. The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE-/- and LDLr-/- mice by a mechanism that includes inflammatory pathways. JACC Basic Transl. Sci. 3, 844–857 (2018).
Liu, Q., Zhu, J., Kong, B., Shuai, W. & Huang, H. Tirzepatide attenuates lipopolysaccharide-induced left ventricular remodeling and dysfunction by inhibiting the TLR4/NF-kB/NLRP3 pathway. Int. Immunopharmacol. 120, 110311 (2023).
Capone, F., Nambiar, N. & Schiattarella, G. G. Beyond weight loss: the emerging role of incretin-based treatments in cardiometabolic HFpEF. Curr. Opin. Cardiol. 39, 148–153 (2024).
Withaar, C. et al. The cardioprotective effects of semaglutide exceed those of dietary weight loss in mice with HFpEF. JACC Basic Transl. Sci. 8, 1298–1314 (2023).
Alharbi, S. H. Anti-inflammatory role of glucagon-like peptide 1 receptor agonists and its clinical implications. Ther. Adv. Endocrinol. Metab. 15, 20420188231222367 (2024).
Liu, J. et al. Liver-derived fibroblast growth factor 21 mediates effects of glucagon-like peptide-1 in attenuating hepatic glucose output. EBioMedicine 41, 73–84 (2019).
Deanfield, J. et al. Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial. Lancet 404, 773–786 (2024).
Kosiborod, M. N. et al. Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: a pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials. Lancet 404, 949–961 (2024).
Aronne, L. J. et al. Tirzepatide as compared with semaglutide for the treatment of obesity. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2416394 (2025).
Zile, M. R. et al. Effects of tirzepatide on the clinical trajectory of patients with heart failure, a preserved ejection fraction, and obesity. Circulation https://doi.org/10.1161/CIRCULATIONAHA.124.072679 (2024).
Packer, M. et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2410027 (2024).
Kramer, C. M. et al. Tirzepatide reduces LV mass and paracardiac adipose tissue in obesity-related heart failure: SUMMIT CMR substudy. J. Am. Coll. Cardiol. 85, 699–706 (2025).
Petrie, M. C. et al. Semaglutide and NT-proBNP in obesity-related HFpEF: insights from the STEP-HFpEF Program. J. Am. Coll. Cardiol. 84, 27–40 (2024).
McGlone, E. R. et al. Chronic treatment with glucagon-like peptide-1 and glucagon receptor co-agonist causes weight loss-independent improvements in hepatic steatosis in mice with diet-induced obesity. Biomed. Pharmacother. 176, 116888 (2024).
Xu, F. et al. SIRT1 mediates the effect of GLP-1 receptor agonist exenatide on ameliorating hepatic steatosis. Diabetes 63, 3637–3646 (2014).
Gao, Z. et al. β-Catenin mediates the effect of GLP-1 receptor agonist on ameliorating hepatic steatosis induced by high fructose diet. Eur. J. Histochem. 64, 3160 (2020).
Newsome, P. N. et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N. Engl. J. Med. 384, 1113–1124 (2021).
Sanyal, A. J. et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2413258 (2025).
Gastaldelli, A. et al. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. 10, 393–406 (2022).
Sanyal, A. J. et al. A phase 2 randomized trial of survodutide in MASH and fibrosis. N. Engl. J. Med. 391, 311–319 (2024).
Nahra, R. et al. Effects of cotadutide on metabolic and hepatic parameters in adults with overweight or obesity and type 2 diabetes: a 54-week randomized phase 2b study. Diabetes Care 44, 1433–1442 (2021).
Romero-Gomez, M. et al. A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease. J. Hepatol. 79, 888–897 (2023).
Harrison, S. A. et al. Effect of pemvidutide, a GLP-1/glucagon dual receptor agonist, on MASLD: a randomized, double-blind, placebo-controlled study. J. Hepatol. https://doi.org/10.1016/j.jhep.2024.07.006 (2024).
Mantovani, A. et al. Glucagon-like peptide-1 receptor agonists improve MASH and liver fibrosis: a meta-analysis of randomised controlled trials. Liver Int. 45, e70256 (2025).
Wester, A., Shang, Y., Toresson Grip, E., Matthews, A. A. & Hagstrom, H. Glucagon-like peptide-1 receptor agonists and risk of major adverse liver outcomes in patients with chronic liver disease and type 2 diabetes. Gut 73, 835–843 (2024).
Kanwal, F. et al. GLP-1 receptor agonists and risk for cirrhosis and related complications in patients with metabolic dysfunction-associated steatotic liver disease. JAMA Intern. Med. 184, 1314–1323 (2024).
Havranek, B., Loh, R., Torre, B., Redfield, R. & Halegoua-DeMarzio, D. Glucagon-like peptide-1 receptor agonists improve metabolic dysfunction-associated steatotic liver disease outcomes. Sci. Rep. 15, 4947 (2025).
Solomon, S. D. et al. Finerenone in heart failure with mildly reduced or preserved ejection fraction. N. Engl. J. Med. https://doi.org/10.1056/NEJMoa2407107 (2024).
Tuck, M. L., Sowers, J., Dornfeld, L., Kledzik, G. & Maxwell, M. The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N. Engl. J. Med. 304, 930–933 (1981).
Briones, A. M. et al. Adipocytes produce aldosterone through calcineurin-dependent signaling pathways: implications in diabetes mellitus-associated obesity and vascular dysfunction. Hypertension 59, 1069–1078 (2012).
Butt, J. H. et al. Finerenone, obesity, and heart failure with mildly reduced/preserved ejection fraction: prespecified analysis of FINEARTS-HF. J. Am. Coll. Cardiol. 85, 140–155 (2025).
Habibi, J. et al. Targeting mineralocorticoid receptors in diet-induced hepatic steatosis and insulin resistance. Am. J. Physiol. Regul. Integr. Comp. Physiol. 322, R253–R262 (2022).
Wada, T. et al. Eplerenone ameliorates the phenotypes of metabolic syndrome with NASH in liver-specific SREBP-1c Tg mice fed high-fat and high-fructose diet. Am. J. Physiol. Endocrinol. Metab. 305, E1415–E1425 (2013).
Perakakis, N. et al. Efficacy of finerenone in patients with type 2 diabetes, chronic kidney disease and altered markers of liver steatosis and fibrosis: a FIDELITY subgroup analysis. Diabetes Obes. Metab. 26, 191–200 (2024).
Harrison, S. A. et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N. Engl. J. Med. 390, 497–509 (2024).
Harrison, S. A. et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nat. Med. 29, 2919–2928 (2023).
Wong, S. K., Chin, K. Y., Suhaimi, F. H., Ahmad, F. & Ima-Nirwana, S. Vitamin E as a potential interventional treatment for metabolic syndrome: evidence from animal and human studies. Front. Pharmacol. 8, 444 (2017).
Sato, K. et al. Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta-analysis of randomized controlled trials. Nutrition 31, 923–930 (2015).
Xu, R., Tao, A., Zhang, S., Deng, Y. & Chen, G. Association between vitamin E and non-alcoholic steatohepatitis: a meta-analysis. Int. J. Clin. Exp. Med. 8, 3924–3934 (2015).
Chae, C. U., Albert, C. M., Moorthy, M. V., Lee, I. M. & Buring, J. E. Vitamin E supplementation and the risk of heart failure in women. Circ. Heart Fail. 5, 176–182 (2012).
Ratchford, S. M. et al. Impact of acute antioxidant administration on inflammation and vascular function in heart failure with preserved ejection fraction. Am. J. Physiol. Regul. Integr. Comp. Physiol. 317, R607–R614 (2019).
Belfort, R. et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med. 355, 2297–2307 (2006).
Cusi, K. et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann. Intern. Med. 165, 305–315 (2016).
Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1675–1685 (2010).
Francque, S. M. et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N. Engl. J. Med. 385, 1547–1558 (2021).
Das Pradhan, A. et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N. Engl. J. Med. 387, 1923–1934 (2022).
Ayada, I. et al. Dissecting the multifaceted impact of statin use on fatty liver disease: a multidimensional study. EBioMedicine 87, 104392 (2023).
Shen, S. et al. Colchicine alleviates inflammation and improves diastolic dysfunction in heart failure rats with preserved ejection fraction. Eur. J. Pharmacol. 929, 175126 (2022).
Shchendrygina, A. et al. Colchicine in patients with heart failure and preserved left ventricular ejection fraction: rationale and design of a prospective, randomised, open-label, crossover clinical trial. Open Heart 10, e002360 (2023).
Van Tassell, B. W. et al. IL-1 blockade in patients with heart failure with preserved ejection fraction. Circ. Heart Fail. 11, e005036 (2018).
Ridker, P. M. et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 397, 2060–2069 (2021).
Gargani, L. et al. Lung ultrasound in acute and chronic heart failure: a clinical consensus statement of the European Association of Cardiovascular Imaging (EACVI). Eur. Heart J. Cardiovasc. Imaging 24, 1569–1582 (2023).
Kagami, K. et al. Incremental diagnostic value of post-exercise lung congestion in heart failure with preserved ejection fraction. Eur. Heart J. Cardiovasc. Imaging 24, 553–561 (2023).
Simonovic, D. et al. Exercise-induced B-lines in heart failure with preserved ejection fraction occur along with diastolic function worsening. ESC Heart Fail. 8, 5068–5080 (2021).
Rush, C. J. et al. Prevalence of coronary artery disease and coronary microvascular dysfunction in patients with heart failure with preserved ejection fraction. JAMA Cardiol. 6, 1130–1143 (2021).
Mahajan, R. et al. Cardiovascular magnetic resonance of total and atrial pericardial adipose tissue: a validation study and development of a 3 dimensional pericardial adipose tissue model. J. Cardiovasc. Magn. Reson. 15, 73 (2013).
Wang, K., Bao, J., Wang, M., Yu, Y. & Wang, M. Prospective comparative diagnostic performance of quantitative ultrasound parameters for the measurement of hepatic steatosis in a biopsy-proven MASLD cohort. Br. J. Radiol. https://doi.org/10.1093/bjr/tqae212 (2024).
Bae, J. S. et al. Assessment of hepatic steatosis by using attenuation imaging: a quantitative, easy-to-perform ultrasound technique. Eur. Radiol. 29, 6499–6507 (2019).
Malandris, K. et al. Accuracy of controlled attenuation parameter for liver steatosis in patients at risk for metabolic dysfunction-associated steatotic liver disease using magnetic resonance imaging: a systematic review and meta-analysis. Ann. Gastroenterol. 37, 579–587 (2024).
Cao, Y. T. et al. Accuracy of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) for assessing steatosis and fibrosis in non-alcoholic fatty liver disease: a systematic review and meta-analysis. EClinicalMedicine 51, 101547 (2022).
Borlaug, B. A., Nishimura, R. A., Sorajja, P., Lam, C. S. & Redfield, M. M. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ. Heart Fail. 3, 588–595 (2010).
Eisman, A. S. et al. Pulmonary capillary wedge pressure patterns during exercise predict exercise capacity and incident heart failure. Circ. Heart Fail. 11, e004750 (2018).
Simon, T. G., Roelstraete, B., Khalili, H., Hagstrom, H. & Ludvigsson, J. F. Mortality in biopsy-confirmed nonalcoholic fatty liver disease: results from a nationwide cohort. Gut 70, 1375–1382 (2021).
Siddiqui, M. S. et al. Diagnostic accuracy of noninvasive fibrosis models to detect change in fibrosis stage. Clin. Gastroenterol. Hepatol. 17, 1877–1885.e5 (2019).
Kouvari, M. et al. Liver biopsy-based validation, confirmation and comparison of the diagnostic performance of established and novel non-invasive steatotic liver disease indexes: results from a large multi-center study. Metabolism 147, 155666 (2023).
Ramirez, M. F. et al. Obesity-Related biomarkers are associated with exercise intolerance and HFpEF. Circ. Heart Fail. 16, e010618 (2023).
Mendez, A. B., Azancot, M. A., Olivella, A. & Soler, M. J. New aspects in cardiorenal syndrome and HFpEF. Clin. Kidney J. 15, 1807–1815 (2022).
Wong, C. N., Gui, X. Y. & Rabkin, S. W. Myeloperoxidase, carnitine, and derivatives of reactive oxidative metabolites in heart failure with preserved versus reduced ejection fraction: a meta-analysis. Int. J. Cardiol. 399, 131657 (2024).
Daniels, S. J. et al. ADAPT: an algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis. Hepatology 69, 1075–1086 (2019).
Feng, G. et al. Machine learning algorithm outperforms fibrosis markers in predicting significant fibrosis in biopsy-confirmed NAFLD. J. Hepatobiliary Pancreat. Sci. 28, 593–603 (2021).
Carlsson, B. et al. Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 51, 1305–1320 (2020).
Eslam, M., Valenti, L. & Romeo, S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J. Hepatol. 68, 268–279 (2018).
Pirazzi, C. et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J. Hepatol. 57, 1276–1282 (2012).
Jamialahmadi, O. et al. Partitioned polygenic risk scores identify distinct types of metabolic dysfunction-associated 2 steatotic liver disease. Nat. Med. 30, 3614–3623 (2024).
Schrader, L. A., Ronnekleiv-Kelly, S. M., Hogenesch, J. B., Bradfield, C. A. & Malecki, K. M. Circadian disruption, clock genes, and metabolic health. J. Clin. Invest. 134, e170998 (2024).
Che, Y. et al. Chronic circadian rhythm disorder induces heart failure with preserved ejection fraction-like phenotype through the Clock-sGC-cGMP-PKG1 signaling pathway. Sci. Rep. 14, 10777 (2024).
Padilla, J. et al. Circadian dysfunction induces NAFLD-related human liver cancer in a mouse model. J. Hepatol. 80, 282–292 (2024).
Acknowledgements
G.G.S. is supported by the following grants: DZHK (German Centre for Cardiovascular Research, 81 × 3100210 and 81 × 2100282), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, SFB-1470–A02), the European Research Council (ERC, StG 101078307) and HI-TAC (Helmholtz Institute for Translational AngioCardiScience). A.J.L. is supported by NIH grants HL170326, NIH DK136405 and NIH DK117850. B.R. is funded by a Wellcome Career Development Award fellowship (302210/Z/23/Z). M.F. is supported by the NIH, Alleviant, Gradient, Reprieve, Sardocor, NIH and Doris Duke. M.V. is supported by the Heisenberg Program of the German Research Foundation (DFG).
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F.C., S.P.H., S.S. and G.G.S. researched data for article. F.C., S.P.H. and G.G.S. wrote the manuscript. F.C., S.P.H., L.L., S.R. and G.G.S. provided substantial contribution to discussion of content. F.C., C.L., A.J.L., M.P., D.M.M., O.J.R., B.R., M.F., S.R., Y.W., M.V., S.H.S. and G.G.S. reviewed and/or edited the manuscript before submission.
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G.G.S. reports consultancy service and/or has interest in Boehringer Ingelheim, Pfizer, NovoNordisk, e-Therapeutics and Sanofi. M.F. is a consultant and/or has ownership interest in Abbott, Acorai, Ajax, Alio Health, Alleviant, Artha, Astellas, Audicor, AxonTherapies, Bodyguide, Bodyport, Boston Scientific, Broadview, Cadence, Cardiosense, Cardioflow, Clinical Accelerator, CVRx, Daxor, Edwards LifeSciences, Echosens, EKO, Endotronix, Feldschuh Foundation, Fire1, FutureCardia, Gradient, Hatteras, HemodynamiQ, Impulse Dynamics, ISHI, Lumina Health, Medtronic, NovoNordisk, NucleusRx, Omega, Orchestra, Parasym, Pharmacosmos, Presidio, Procyreon, Proton Intelligence, Puzzle, ReCor, Scirent, SCPharma, Shifamed, Splendo, Summacor, SyMap, Terumo, Vascular Dynamics, Vironix, Viscardia and Zoll.
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Capone, F., Häseli, S.P., Liu, L. et al. HFpEF and MASLD: converging mechanisms and clinical implications. Nat Rev Cardiol (2026). https://doi.org/10.1038/s41569-026-01257-z
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DOI: https://doi.org/10.1038/s41569-026-01257-z
