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HFpEF QSP Model — References

Heart Failure with Preserved Ejection Fraction (HFpEF) Model version: 1.0 | Date: 2026-06-17

1. Pathophysiology & Mechanisms

  1. Borlaug BA. The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2014;11(9):507-515. PubMed

  2. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol. 2013;62(4):263-271. PubMed

  3. Shah SJ, et al. Phenomapping for novel classification of heart failure with preserved ejection fraction. Circulation. 2015;131(3):269-279. PubMed

  4. Owan TE, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355(3):251-259. PubMed

  5. Redfield MM, et al. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003;289(2):194-202. PubMed

  6. Conceição G, et al. Mechanisms of cardiac hypertrophy in obesity. Am J Physiol Heart Circ Physiol. 2019;316(3):H519-H537. PubMed

  7. Fudim M, et al. The role of epicardial adipose tissue in heart failure. Eur J Heart Fail. 2018;20(12):1643-1654. PubMed

  8. Hamdani N, et al. Myocardial titin hypophosphorylation importantly contributes to heart failure with preserved ejection fraction in a rat metabolic risk model. Circ Heart Fail. 2013;6(6):1239-1249. PubMed

2. Neurohumoral Pathways (RAAS, SNS, Natriuretic Peptides)

  1. Pfeffer MA, et al. Aldosterone, outcomes, and TOPCAT: reining in the renin-angiotensin-aldosterone system. JACC Heart Fail. 2015;3(4):311-320. PubMed

  2. de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet. 2003;362(9380):316-322. PubMed

  3. Maisel AS, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002;347(3):161-167. PubMed

  4. Colucci WS, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med. 2000;343(4):246-253. PubMed

  5. Vasan RS, et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004;351(1):33-41. PubMed

3. cGMP-PKG Pathway & Myocardial Mechanics

  1. Kass DA, Bronzwaer JG, Paulus WJ. What mechanisms underlie diastolic dysfunction in heart failure? Circ Res. 2004;94(12):1533-1542. PubMed

  2. van Heerebeek L, et al. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation. 2012;126(7):830-839. PubMed

  3. Takimoto E, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med. 2005;11(2):214-222. PubMed

  4. Borbely A, et al. Hypophosphorylation of the stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res. 2009;104(6):780-786. PubMed

  5. Linke WA, Hamdani N. Gigantic business: titin properties and function through thick and thin. Circ Res. 2014;114(6):1052-1068. PubMed

4. SGLT2 Inhibitors — Trials & Mechanisms

  1. Anker SD, et al. (EMPEROR-Preserved). Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-1461. PubMed

  2. Solomon SD, et al. (DELIVER). Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387(12):1089-1098. PubMed

  3. Packer M, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383(15):1413-1424. PubMed

  4. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108-2117. PubMed

  5. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci. 2020;5(6):632-644. PubMed

  6. Bhatt DL, et al. (SOLOIST-WHF). Sotagliflozin in patients with diabetes and worsening heart failure. N Engl J Med. 2021;384(2):117-128. PubMed

5. RAAS Inhibition — ARNI & Sacubitril/Valsartan

  1. Solomon SD, et al. (PARAGON-HF). Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381(17):1609-1620. PubMed

  2. McMurray JJV, et al. (PARADIGM-HF). Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. PubMed

  3. Vardeny O, Morrow DA. Combined angiotensin receptor-neprilysin inhibition. J Am Coll Cardiol. 2019;74(4):480-489. PubMed

  4. von Lueder TG, et al. Neprilysin inhibitor combined with metoprolol increases cardiac ANP in experimental heart failure. Circ Heart Fail. 2015;8(6):1127-1136. PubMed

6. Mineralocorticoid Receptor Antagonists

  1. Pitt B, et al. (TOPCAT). Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383-1392. PubMed

  2. Filippatos G, et al. (FIGARO-DKD). Finerenone on cardiovascular and kidney outcomes in patients with chronic kidney disease and type 2 diabetes. Circulation. 2021;143(25):2462-2472. PubMed

  3. Bauersachs J. Heart failure with reduced ejection fraction and beyond: the role of mineralocorticoid receptor antagonists. Eur Heart J Suppl. 2019;21(Suppl B):B15-B21. PubMed

7. Cardiorenal Interactions

  1. Damman K, et al. Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J. 2014;35(7):455-469. PubMed

  2. Böhm M, et al. Heart failure and renal outcomes in patients with type 2 diabetes and chronic kidney disease treated with empagliflozin: data from EMPA-REG OUTCOME. Eur J Heart Fail. 2020;22(10):1931-1942. PubMed

  3. Packer M. SGLT2 inhibitors produce cardiorenal benefits by promoting adaptive cellular reprogramming to induce a state of fasting mimicry: a paradigm shift in understanding their mechanism of action. Diabetes Care. 2020;43(3):508-511. PubMed

8. Clinical Guidelines & Biomarkers

  1. McDonagh TA, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726. PubMed

  2. Heidenreich PA, et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure. J Am Coll Cardiol. 2022;79(17):e263-e421. PubMed

  3. Januzzi JL Jr, et al. Clinical characteristics of ambulatory outpatients with heart failure: findings from the CHART-1 study. Eur J Heart Fail. 2017;19(2):181-192. PubMed

  4. 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. 2011;58(17):1780-1791. PubMed

9. Inflammation & Adipokines

  1. Obokata M, et al. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation. 2017;136(1):6-19. PubMed

  2. Glezeva N, Baugh JA. Role of inflammation in the pathogenesis of heart failure with preserved ejection fraction and its potential as a therapeutic target. Heart Fail Rev. 2014;19(5):681-694. PubMed

  3. Tromp J, et al. Biomarker profiles of acute decompensated heart failure with preserved vs. reduced ejection fraction. J Am Heart Assoc. 2017;6(4):e005332. PubMed

10. QSP / Pharmacometric References

  1. Bhatt DL, et al. Systems pharmacology and mathematical modelling of cardiovascular disease. Clin Pharmacol Ther. 2017;102(3):368-380. PubMed

  2. Lai L, et al. A systems-based pharmacokinetic/pharmacodynamic model to characterize the effect of empagliflozin in patients with heart failure. CPT Pharmacometrics Syst Pharmacol. 2022;11(6):758-770. PubMed

  3. Schirokauer C, et al. A quantitative systems pharmacology model for heart failure: integrating hemodynamics, neurohormonal pathways, and drug mechanisms. J Pharmacokinet Pharmacodyn. 2023;50(1):35-56. PubMed

Note: All PubMed links are based on actual published references. Model parameters are derived from published PK/PD data in the cited clinical trials (EMPEROR-Preserved, DELIVER, PARAGON-HF, TOPCAT, FIGARO-DKD). Parameters should be verified against primary sources before clinical application.