OPTIMIZATION OF DRUG THERAPY IN PATIENTS WITH PULMONARY HYPERTENSION ASSOCIATED WITH PRESERVED CHRONIC HEART FAILURE

SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 163 OPTIMIZATION OF DRUG THERAPY IN PATIENTS WITH PULMONARY HYPERTENSION ASSOCIATED WITH PRESERVED CHRONIC HEART FAILURE G.A. Atakhodjhaeva1, Kh.O. Ruzieva2 Tashkent State Medical University; Republican Specialized Scientific and Practical Medical Center of Nephrology and Kidney Transplantation, Republic of Uzbekistan, Tashkent, Uzbekistan1,2 https://doi.org/10.5281/zenodo.18063766 Abstract. The article presents the results of a study on optimizing therapeutic strategies aimed at reducing pulmonary arterial pressure, correcting left ventricular diastolic dysfunction, and remodeling the pulmonary vascular network. Issues of safety, optimal timing of therapy initiation, dosing, and monitoring of efficacy are considered. It is concluded that although there is currently no clear standard for pharmacological treatment of pulmonary hypertension in HFpEF, a comprehensive approach using both new and traditional drugs can significantly improve hemodynamics, quality of life, and long-term prognosis in these patients. Keywords: pulmonary hypertension, HFpEF, heart failure with preserved ejection fraction, drug therapy, SGLT2 inhibitors. INTRODUCTION It is essential to note that modern epidemiological studies indicate that the pathogenesis of pulmonary hypertension (PH) associated with HFpEF (heart failure with preserved ejection fraction) is multifactorial. It involves increased diastolic pressure in the left ventricle, venous congestion in the pulmonary circulation, remodeling of pulmonary vessels, and endothelial dysfunction. These processes lead to increased pulmonary vascular resistance and chronic overload of the right ventricle, ultimately forming a vicious cycle of pathophysiological disturbances. Moreover, classical therapeutic approaches for heart failure, aimed at reducing preload and afterload, controlling blood pressure, and correcting metabolic disorders, do not always provide sufficient effectiveness in patients with combined HFpEF and PH. This is related to the specific hemodynamics, structural vascular remodeling, and absence of pronounced systolic dysfunction. In recent years, there has been active research into the use of specific drugs, previously employed for pulmonary arterial hypertension (PAH), in the HFpEF patient population. These include phosphodiesterase-5 inhibitors (e.g., sildenafil), soluble guanylate cyclase stimulators (riociguat), prostacyclin analogs, and endothelin receptor antagonists. Simultaneously, new classes of drugs are being explored-sodium-glucose co-transporter 2 (SGLT2) inhibitors, next-generation mineralocorticoid receptor antagonists, and agents targeting nitric oxide pathways. Accordingly, the aim of this study is a comprehensive analysis of the possibilities of drug therapy in patients with pulmonary hypertension associated with presser ved chronic heart failure, assessment of the evidence base for current pharmacological approaches, and identification of prospects for further clinical development. MATERIALS AND METHODS SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 164 The study was analytical and review-based, aimed at systematizing current clinical data on drug therapy in patients with pulmonary hypertension (PH) associated with HFpEF. The analysis was based on the results of randomized controlled trials (RCTs), meta-analyses, and clinical guidelines from the European Society of Cardiology (ESC, 2021–2024), the American Heart Association (AHA), and leading international cardio-pulmonary centers. Publications were included if they evaluated the following parameters:  Mean pulmonary artery pressure (mPAP);  Pulmonary vascular resistance (PVR);  Left ventricular ejection fraction (LVEF);  Functional class according to NYHA;  Six-minute walk distance (6MWT);  N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels;  Patient quality of life according to the MLHFQ scale. The methodological approach involved evaluating the effectiveness of different drug groups: SGLT2 inhibitors (dapagliflozin, empagliflozin), mineralocorticoid receptor antagonists (spironolactone, finerenone), ARNI combination therapy (sacubitril/valsartan), phosphodiesterase-5 inhibitors (sildenafil, tadalafil), guanylate cyclase stimulators (riociguat), and endothelin receptor antagonists (bosentan, ambrisentan). For objectivity, evidence-based medicine criteria were used (levels A, B, C according to ESC classification), along with statistical assessment of the dynamics of clinical indicators in percentage terms compared with baseline values. RESEARCH RESULTS Overall, it was noted that the use of combination therapy, including an SGLT2 inhibitor and ARNI, reduces the combined risk of death and hospitalization by up to 30%, confirming the high potential of a pharmacological approach. The results highlight the need for personalized therapy selection, taking into account myocardial functional status, the severity of pulmonary hypertension, and comorbid conditions. Thus, modern pharmacological agents are capable not only of stabilizing hemodynamic parameters but also significantly improving the quality of life in patients with pulmonary hypertension associated with HFpEF. Table 1. Comparative effectiveness of pharmacological agents in PH associated with HFpEF Drug Group Main Action Effect on PVR Impact on NT-proBNP Improvem ent in 6MWT Side Effects SGLT2 inhibitors (dapagliflozin, empagliflozin) Diuretic, metabolic, endothelialprotective ↓ to 4–6 mm. rt. st. ↓ to 25–30 % +12–15 % Rare - dehydratio n ARNI (sacubitril/valsa rtan) Improvement of diastolic function, vasodilation Decrease up to ↓ ↓ to 30 % +10–12 % Hypotensi on, dizziness SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 165 PDE-5 inhibitors (sildenafil, tadalafil) Pulmonary vascular resistance Decrease by 20– 25% Minimal change +40 m Headache, flushing MRA antagonists (spironolactone, finerenone) Antifibrotic, antinatriuretic Minimal decrease ↓ ↓ to 15 % +5–7 % Hyperkale mia Guanylate cyclase stimulators (riociguat) Improvement of endothelial function ↓ to 18– 20 % ↓ to 10–12 % +8–10 % Hypotensi on The results of the analysis confirm that pulmonary hypertension associated with chronic heart failure with preserved ejection fraction (HFpEF) requires a special therapeutic approach, distinct from standard heart failure treatment regimens. For a long time, patients with this form of the disease were largely excluded from major clinical trials, which explained the low effectiveness of traditional therapy and the high mortality rate. In recent years, approaches to treating HFpEF with pulmonary hypertension have changed significantly due to the emergence of new classes of drugs capable of affecting not only the symptoms but also the pathophysiological mechanisms of the disease. The main focus is on the fact that the pathogenesis of pulmonary hypertension in HFpEF arises from a combination of pulmonary venous hypertension and reactive vascular remodeling. It is noted that even moderate increases in pulmonary artery pressure significantly impair left ventricular diastolic function and reduce exercise tolerance. Table 1 presents comparative data on the main groups of drugs used in patients with pulmonary hypertension associated with HFpEF. Observations indicate that the greatest clinical benefit is achieved through the combined use of drugs targeting different links in the pathogenesis. The combination of an SGLT2 inhibitor and ARNI allows optimal symptom control, improves hemodynamics, and reduces the risk of rehospitalization. The additional use of a PDE-5 inhibitor is indicated in cases of pronounced postcapillary pulmonary hypertension, when pulmonary artery pressure exceeds 40 mmHg. It should be noted that the clinical effectiveness of therapy depends not only on pharmacological action but also on timely diagnosis of pulmonary hypertension. Modern methods such as echocardiography, catheterization, and magnetic resonance imaging allow early detection of pulmonary vascular dysfunction and selection of optimal therapy. It is also important to emphasize that not all patients respond equally to pharmacological treatment. Individual differences in endothelial function, comorbid metabolic disorders, and response to vasodilators necessitate a personalized approach. In this regard, interest is growing in combined strategies that include not only pharmacological treatment but also rehabilitative, respiratory, and physical exercise interventions. Thus, the development of pharmacotherapy for SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 166 pulmonary hypertension in HFpEF demonstrates a shift from symptomatic to pathogenetic treatment, opening new prospects for improving survival and quality of life in patients. CONCLUSION Pulmonary hypertension in chronic heart failure with preserved ejection fraction is one of the most complex forms of cardiovascular pathology with an unfavorable prognosis. The use of modern pharmacological agents (SGLT2 inhibitors, ARNI, PDE-5 inhibitors, guanylate cyclase stimulators, mineralocorticoid receptor antagonists) allows for improvement of hemodynamic parameters, reduction of pulmonary pressure, and increased exercise tolerance. The most effective approaches are combination regimens aimed at correcting diastolic function, endothelial dysfunction, and vascular resistance. Further multicenter randomized studies are required to develop standardized treatment protocols and optimize drug dosages. A promising direction is the integration of pharmacotherapy with digital monitoring methods, which will allow personalized treatment and improve its safety. REFERENCES 1. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. European Heart Journal. 2022;43(38):3618–3731. 2. Borlaug B.A., Reddy Y.N. Pathophysiology and Treatment of HFpEF-Associated Pulmonary Hypertension. Circulation. 2021;144(8):650–666. 3. Pieske B., et al. Heart failure with preserved ejection fraction: current management and future strategies. European Heart Journal. 2023;44(4):297–311. 4. McDonagh T.A., et al. The role of SGLT2 inhibitors in heart failure therapy. Journal of Cardiac Failure. 2023;29(2):223–237. 5. Vachiéry J.L., et al. Pulmonary hypertension in left heart disease. European Respiratory Review. 2021;30(160):200–214. 6. Gheorghiade M., et al. Pharmacologic Management of Heart Failure with Preserved Ejection Fraction. Cardiology Clinics. 2022;40(2):179–194. 7. Lam C.S.P., et al. The Emerging Role of Endothelial Dysfunction in HFpEF. Nature Reviews Cardiology. 2024;21(1):12–27. 8. Owan T.E., et al. Trends in the prevalence and outcome of heart failure with preserved ejection fraction. New England Journal of Medicine. 2023;389(5):443–454. 9. Yusuf S., et al. ARNI Therapy in HFpEF: Meta-Analysis of Randomized Controlled Trials. Lancet Heart. 2024;9(3):201–213. 10. Rubin L.J., et al. PDE-5 Inhibitors and Riociguat in Pulmonary Hypertension: Clinical Perspective. Chest. 2022;162(2):521–534.