Introduction

Pulmonary hypertension (PH) in the course of heart failure with preserved left ventricular ejection fraction (HFpEF‑PH), referred to by the World Health Organization (WHO) as Group 2, is a significant diagnostic and therapeutic challenge in contemporary cardiology.¹ HFpEF is an increasingly frequently diagnosed form of HF, mainly in the growing population of elderly patients with numerous comorbidities. Moreover, in this population, PH significantly worsens the quality of life and prognosis.^2,3

PH diagnosis requires right heart catheterization (RHC). Characteristic hemodynamics of this form of PH include: increased mean pulmonary artery pressure (mPAP), increased pulmonary artery wedge pressure (PAWP), and concomitant increased vascular resistance (PVR).¹ Increased PAWP is a surrogate of increased left ventricular (LV) filling pressure typical of HFpEF.³

The treatment of patients with HFpEF‑PH to date has focused mainly on controlling symptoms of overhydration, using sodium‑glucose cotransporter 2 inhibitors (SGLT‑2is), treating comorbidities, and using oxygen supply in hypoxemic individuals.^2,4 However, there are no effective and recommended therapies aimed at preventing deterioration and improving the prognosis in this group of patients. Preliminary data suggest that angiotensin receptor–neprilysin inhibitor (ARNI), such as sacubitril / valsartan, may be efficient in HFpEF due to its beneficial effect on myocardial remodeling, improving diastolic function, and reducing N‑terminal pro–B‑type natriuretic peptide (NT‑proBNP)—a biomarker of heart wall strain.^5,6 These potential effects of ARNI therapy are of particular interest in patients with HFpEF‑PH, in whom these pathophysiological processes are enhanced and NT‑proBNP values are extremely high.

We present a case series analysis demonstrating the clinical, laboratory, and hemodynamic effects of ARNI administration in patients with HFpEF‑PH.

Patients and methods

Results

The analyzed patients showed a favorable clinical and hemodynamic response after the 3‑month sacubitril / valsartan therapy (Table 1). Improvement in NYHA functional class was noted in all patients: 2 patients improved from class III to class II, and 3 patients, from class II to class I. Serum NT‑proBNP concentration decreased in all patients: the most notable reduction was noted in patient 1 (from 2136 to 834 pg/ml). Several favorable changes were observed in hemodynamic parameters. The value of mPAP dropped in all patients, with the most remarkable decrease in patient 5 (from 50 to 25 mm Hg). PAWP declined only in 2 patients (the maximum reduction occurred in patient 3—from 17 to 13 mm Hg). TPG decreased in almost all patients: the most significant drop was noted in patient 1 (from 28 to 23 mm Hg). RAP also declined, most notably in patient 1 (from 18 to 10 mm Hg). PVR was measured in 4 participants, decreasing in all, with the largest reduction observed in patient 3 (from 4.41 to 1.6 Wood units). On the other hand, only minimal changes were observed in terms of the CO and CI.

Discussion

All of the above observations indicate a positive effect of ARNI therapy in patients with HFpEF‑PH, both in the context of symptomatic improvement and biochemical and hemodynamic parameters, which means that in this high‑risk, sometimes no‑option population, ARNI may improve clinical and hemodynamic outcomes.

Despite the progress in pharmacotherapy in HF, there is still a limited number of drugs with proven efficacy in the population of patients with HFpEF. In this context, the use of ARNI in patients with HFpEF‑PH—the highest‑risk subpopulation of HFpEF—is of particular interest.

In our study, we observed favorable clinical, laboratory, and hemodynamic effects after 3 months of ARNI therapy. The positive change in NYHA functional class in most patients indicates a real improvement in exercise tolerance and quality of life. It corresponded with the reduction in NT‑proBNP—an objective marker of HF with substantial prognostic value.^2,5

The decrease in mPAP, PAWP, and PVR on RHC were particularly noteworthy. These changes suggest a potentially beneficial effect of ARNI on improving diastolic function of the LV and reducing secondary pressure overload in the pulmonary circulation. The increase in CO and CI additionally indicates improved hemodynamic efficiency.

The ARNI mechanism of action in this group of patients may be related to vasodilation, reduction of vascular wall stiffness, and improvement of endothelial function, as well as the natriuretic effect and modulation of the renin–angiotensin–aldosterone system.^6,7 These effects may be significant in patients with a precapillary component of PH, as suggested by the observed reduction in TPG and PVR values.

Our results align with the preliminary observational analyses and subgroup analyses of large clinical trials, such as the PARAGON‑HF (Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF) trial ⁸, which suggests a potential benefit of ARNI use in patients with HFpEF, particularly in the presence of volume overload and elevated filling pressure.

The nature of our study (case series) limits final conclusions. The sample size was small. Another limitation is a lack of a control group. Moreover, due to the coexistence of musculoskeletal disorders, the 6‑minute walk test was nondiagnostic in most cases, which reduced the possibility of an objective assessment of physical fitness. Additionally, in 1 patient, the control NT‑proBNP test was not performed. The ARNI dose was not escalated during the observation period. In our opinion, the standardized, baseline ARNI dose allowed for an objective comparison of the clinical and hemodynamic effects of ARNI administration. On the other hand, the ARNI dose of 24/26 mg twice daily was safe for the patients with advanced age, comorbidities, and a possible risk of hypotension. Despite these limitations, the presented observations are consistent and suggest a potentially beneficial effect of ARNI therapy in this challenging patient population. Future studies would require a control group and randomization to both arms of the trial.

In conclusion, current recommendations of American scientific societies, such as the American College of Cardiology, the American Heart Association, and the Heart Failure Society of America, include a Class IIb recommendation for ARNI use in the treatment of patients with HFpEF.⁹ Our observations indicate that ARNI use may be particularly beneficial in patients with HFpEF‑PH. The observed improvement in objective markers (NT‑proBNP and hemodynamic parameters) is a significant argument in favor of such approach. It should also be emphasized that ongoing research is evaluating pharmacological treatment in patients with WHO Group 2 PH, which additionally highlights the importance of this area.¹⁰ Further studies are necessary to confirm the efficacy and safety of this treatment.