Clinical and molecular characteristics of comorbid patients with chronic heart failure with preserved left ventricular ejection fraction in the context of medical rehabilitation

The aim of the study: to evaluate clinical, functional, molecular and genetic indicators and to develop prognostic markers of chronic heart failure with preserved left ventricular ejection fraction (CHFpEF) in comorbid patients in the context of medical rehabilitation. Material and methods. The study was conducted on the basis of the State Budgetary Healthcare Institution of the Novosibirsk Region “NOKGVV № 3” and the State Budgetary Healthcare Institution of the Novosibirsk Region “City Clinical Hospital № 1” of Novosibirsk (the period from December 1, 2022 to December 1, 2023) with the participation of 260 patients with myocardial infarction and CHFpEF. The main group (n = 132) underwent a one-year course of medical rehabilitation (MR); the comparison group (n = 128) refused MR. At the start and after 12 months, a comprehensive examination was performed (general clinical diagnostics, including NT-proBNP, 6-minute walk test, EQ-5D questionnaire), genetic testing – rs632793 of the NPPB gene, rs5065 of the NPPA gene), with subsequent observation of the groups until December 1, 2024 with an assessment of “soft” and “hard” endpoints. Results. An association was found between the G/G rs5065 genotype of the NPPA gene and the development of recurrent myocardial infarction (OR 5.139, 95 % CI 1.593–16.583, p = 0.003), GG rs5065 genotype (OR 3.357; 95 % CI 1.025–10.999; p = 0.035) and allele G (OR 1.805; 95 % CI 1.159–2.813; p = 0.009), CKD stages 3a–4 (OR = 2.813; 95 % CI 1.259–6.281; p = 0.010) and stage I–III obesity (OR = 3.023; 95 % CI 1.340–6.817; p = 0.006) with an unfavorable 1-year outcome. MR significantly increased the left ventricular ejection fraction (LVEF), functional status, and quality of life. Refusal of MR was associated with an increased frequency of hospitalizations for CHF decompensation (OR 4.762, 95 % CI 2.788–8.132, p < 0.001), the risk of a combined endpoint (OR 8.667, 95 % CI 4.888–15.366, p < 0.001), and mortality (OR 8.628, 95 % CI 1.931–38.545, p < 0.001). The probability of LVEF reduction was determined by a mathematical model that included: Nt-proBNP, hemoglobin, TSH, HDL-C, rs5065 of the NPPA gene, ESV, left atrial volume, CKD, and the fact of MR. Conclusions. The GG genotype of rs5065 of the NPPA gene, CKD stages 3a–4, and obesity are predictors of an unfavorable outcome in CHFpEF. MR reduces mortality and improves the functional status of patients.

1. Boytsov S.A., Drapkina O.M., Shlyakhto E.V., Konradi A.O., Balanova Yu.A., Zhernakova Yu.V., Metelskaya V.A., Oshchepkova E.V., Rotar O.P., Shalnova S.A. Epidemiology of Cardiovascular Diseases and their Risk Factors in Regions of Russian Federation (ESSERF) study. Ten years later. Cardiovasc. Ther. and Prevention, 2021; 20 (5): 3007. (In Russ.). doi: 10.15829/1728-8800-2021-3007

2. Polyakov D.S., Fomin I.V., Belenkov Yu.N., Mareev V.Yu., Ageev F.T., Artemyeva E.G., Badin Yu.V., Bakulina E.V., Vinogradova N.G., Galyavich A.S., Ionova T.S., Kamalov G.M., Kechedzhieva S.G., Koziolova N.A., Malenkova V.Yu., Malchikova S.V., Mareev Yu.V., Smirnova E.A., Tarlovskaya E.I., Shcherbinina E.V., Yakushin S.S. Chronic heart failure in the Russian Federation: what has changed over 20 years of follow-up? Results of the EPOCH-CHF study. Kardiology, 2021; 61 (4): 4–14. (In Russ.). doi: 10.18087/cardio.2021.4.n1628

3. Shlyakhto E.V., Belenkov Yu.N., Boytsov S.A., Villevalde S.V., Galyavich A.S., Glezer M.G., Zvartau N.Z., Kobalava Zh.D., Lopatin Yu.M., Mareev V.Yu., Tereshchenko S.N., Fomin I.V., Barbarash O.L., Vinogradova N.G., Duplyakov D.V., Zhirov I.V., Kosmacheva E.D., Nevzorova V.A., Reitblat O.M., Solovieva A.E., Zorina E.A. Interim analysis of a prospective observational multicenter registry study of patients with chronic heart failure in the Russian Federation “PRIORITET-CHF”: initial characteristics and treatment of the first included patients. Russian Journal of Cardiology, 2023; 28 (10): 5593. (In Russ.). doi: 10.15829/1560-4071-2023-5593

4. Ageev A.A., Kozhevnikova M.V., Tyurina D.A., Korobkova E.O., Kondratieva T.B., Shestakova K.M., Moskaleva N.E., Markin P.A., Khabarova N.V., Appolonova S.A., Belenkov Yu.N. Predictors of left ventricular remodeling in chronic heart failure of ischemic etiology. Cardiology, 2024; 64 (11): 106–116. (In Russ.). doi: 10.18087/cardio.2024.11.n2794

5. Panarina A.Ya., Lifshits G.I. Association of genetic polymorphisms of brain natriuretic peptide with cardiovascular diseases. Russian Journal of Cardiology, 2024; 29 (10): 5906. (In Russ.). doi: 10.15829/1560-4071-2024-5906

6. Yang Y., Zmuda J.M., Wojczynski M.K., Thyagarajan B., Christensen K., Cvejkus R.K., Kuipers A.L.. Genetic association analysis of the cardiovascular biomarker: N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP). PLoS One, 2021; 16 (3): e0248726. doi: 10.1371/journal.pone.0248726

7. Figueiral M., Paldino A., Fazzini L., Pereira N.L. Genetic biomarkers in heart failure: from gene panels to polygenic risk scores. Curr. Heart Fail. Rep., 2024; 21 (6): 554–569. doi: 10.1007/s11897-024-00687-5

8. Arvanitis M., Tampakakis E., Zhang Y., Wang W., Auton A.; 23 and Me Research Team; Dutta D., Glavaris S., Keramati A., Chatterjee N., Chi N.C., Ren B., Post W.S., Battle A. Genome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure. Nat. Commun., 2020; 11 (1): 1122. doi: 10.1038/s41467-020-14843-7

9. Molloy C., Long L., Mordi I.R., Bridges C., Sagar V.A., Davies E.J., Coats A.J., Dalal H., Rees K., Singh S.J., Taylor R.S. Exercise-based cardiac rehabilitation for adults with heart failure. Cochrane Database Syst. Rev., 2024; 3 (3): CD003331. doi: 10.1002/14651858.CD003331.pub6

10. Ciuca-Pană M.A., Boulmpou A., Ileri C., Manzi G., Golino M., Ostojic M., Galimzhanov A., Busnatu S., Mega S., Perone F. Chronic heart failure and coronary artery disease: pharmacological treatment and cardiac rehabilitation. Medicina, 2025; 61: 211. doi: 10.3390/medicina61020211

11. Semaev S.E., Shcherbakova L.V., Orlov P.S., Ivanoshchuk D.E., Malyutina S.K., Gafarov V.V., Voevoda M.I., Ragino Yu.I., Shakhtshneider E.V. Association of variants of the APOE, CETP genes and the chromosomal region 9P21.3 with coronary heart disease, myocardial infarction and acute heart failure. Atherosclerosis, 2024; 20 (2): 121–135. (In Russ.). doi: 10.52727/2078-256X-2024-20-2-121-135

12. Russian Society of Cardiology. Clinical guidelines. Chronic heart failure. 2020. Russian Journal of Cardiology, 2020; 25 (11): 4083. (In Russ.). doi: 10.15829/1560-4071-2020-4083

13. Russian Society of Cardiology. Clinical guidelines. Chronic heart failure. 2024. Russian Journal of Cardiology, 2024; 29 (11): 6162. (In Russ.). doi: 10.15829/1560-4071-2024-6162

14. Russian Society of Cardiology. Stable ischemic heart disease. Clinical guidelines 2020. Russian Journal of Cardiology, 2020; 25 (11): 4076. (In Russ.). doi: 10.15829/29/1560-4071-2020-4076

15. Russian Society of Cardiology. Clinical guidelines. Stable ischemic heart disease. 2024. Russian Journal of Cardiology, 2024; 29 (9): 6110 (In Russ.). doi: 10.15829/1560-4071-2024-6110

16. Airapetian A.A., Lazareva N.V., Reitblat O.M., Mezhonov E.M., Sorokin E.V., Prints Yu.Sh., Zhirov I.V., Tereshchenko S.N., Boytsov S.A.. Comorbid conditions in patients with chronic heart failure (according to the registry of chronic heart failure in the Tyumen region). Consilium Medicum, 2023; 25 (10): 685–692. (In Russ.). doi: 10.26442/20751753.2023.10.202384

17. Zimina Yu.D., Gerasimenko O.N., Voronina E.N., Tolmacheva A.A.. Clinical, functional and molecular genetic features of patients with chronic heart failure. Therapy, 2024; 10 (4): 41–49. (In Russ.).

18. Zhdankina N.V., Abasheva E.V., Lyapina Yu.V. Clinical and demographic features of heart failure in patients with multifocal atherosclerosis. Medical Almanac, 2023; 3 (76): 24–29. (In Russ.).

19. Figueiral M., Paldino A., Fazzini L., Pereira N.L. Genetic biomarkers in heart failure: from gene panels to polygenic risk scores. Curr. Heart Fail. Rep., 2024; 21 (6): 554–569. doi: 10.1007/s11897-024-00687-5

20. Khazova E.V., Bulashova O.V., Amirov N.B. Outcomes of chronic heart failure in patients with coronary heart disease: a prospective 5-year study. Bull. Modern Clinical Med., 2023; 16 (5): 42–52. (In Russ.). doi: 10.20969/VSKM.2023.16(5).42-52

21. Salzwedel A., Jensen K., Rauch B., Doherty P., Metzendorf M.I., Hackbusch M., Völler H., Schmid J.P., Davos C.H. Effectiveness of comprehensive cardiac rehabilitation in coronary artery disease patients treated according to contemporary evidence based medicine: Update of the Cardiac Rehabilitation Outcome Study (CROS-II). Eur. J. Prev. Cardiol., 2020; 27 (16): 1756–1774. doi: 10.1177/2047487320905719

22. Aronov D.M., Bubnova M.G. Efficiency of physical rehabilitation of patients with chronic heart failure after myocardial infarction. Russian Journal of Cardiology, 2025; 30 (1): 5950. (In Russ.). doi: 10.15829/1560-4071-2025-5950

23. Pastori D., Carnevale R., Stanzione R., Nocella C., Cotugno M., Marchitti S., Bianchi F., Forte M., Valenti V., Biondi-Zoccai G., Schiavon S., Vecchio D., Versaci F., Frati G., Violi F., Volpe M., Pignatelli P., Rubattu S., Sciarretta S. T2238C atrial natriuretic peptide gene variant and cardiovascular events in patients with atrial fibrillation: A substudy from the ATHERO-AF cohort. Int. J. Cardiol.; 2021; 322: 245–249. doi: 10.1016/j.ijcard.2020.08.077

24. Barbato E., Bartunek J., Mangiacapra F., Sciarretta S., Stanzione R., Delrue L., Cotugno M., Marchitti S., Iaccarino G., Sirico G., di Castro S., Evangelista A., Lambrechts D., Sinnaeve P., de Bruyne B., van de Werf F., Janssens S., Fox K.A., Wijns W., Volpe M., Rubattu S. Influence of rs5065 atrial natriuretic peptide gene variant on coronary artery disease. J. Am. Coll. Cardiol., 2012; 59 (20): 1763–1770. doi: 10.1016/j.jacc.2012.02.017

25. Cho E.J., Han K., Lee S.P., Shin D.W., Yu S.J. Liver enzyme variability and risk of heart disease and mortality: A nationwide population-based study. Liver Int., 2020; 40 (6): 1292–1302. doi: 10.1111/liv.14432

26. Kondo T., Campbell R., Jhund P.S., Anand I.S., Carson P.E., Lam C.S.P., Shah S.J., Vaduganathan M., Zannad F., Zile M.R., Solomon S.D., McMurray J.J.V. Low natriuretic peptide levels and outcomes in patients with heart failure and preserved ejection fraction. JACC Heart Fail., 2024; 12 (8): 1442–1455.

27. Xu Y., Derakhshan A., Hysaj O., Wildisen L., Ittermann T., Pingitore A., Abolhassani N., Medici M., Kiemeney L.A.L.M., Riksen N.P., Dullaart R.P.F., Trompet S., Dörr M., Brown S.J., Schmidt B., Führer-Sakel D., Vanderpump M.P.J., Muendlein A., Drexel H., Fink H.A., Ikram M.K., Kavousi M., Rhee C.M., Bensenor I.M., Azizi F., Hankey G.J., Iacoviello M., Imaizumi M., Ceresini G., Ferrucci L., Sgarbi J.A., Bauer D.C., Wareham N., Boelaert K., Bakker S.J.L., Jukema J.W., Vaes B., Iervasi G., Yeap B.B., Westendorp R.G.J., Korevaar T.I.M., Völzke H., Razvi S., Gussekloo J., Walsh J.P., Cappola A.R., Rodondi N., Peeters R.P., Chaker L. Thyroid Studies Collaboration. The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis. Lancet Diabetes Endocrinol., 2023; 11 (10): 743–754. doi: 10.1016/S2213-8587(23)00227-9