Sabina Frljak

Background and aims: Vericiguat lowers cardiovascular death or heart-failure hospitalization in recently worsened heart failure with reduced ejection fraction (HFrEF), but its effects on cardiac remodeling are less well characterized. Our aim was to evaluate whether the addition of vericiguat to guideline-directed medical therapy (GDMT) promotes reverse myocardial remodeling in patients with HFrEF and recent worsening. Methods: We conducted a prospective, non-randomized, single-center study enrolling 34 consecutive patients with HFrEF who had experienced recent worsening and were on stable GDMT for at least 3 months prior to decompensation. Clinical, biochemical, and echocardiographic assessments were performed at baseline and at 6 months. Results: A total of 24 patients completed the 6-month follow-up (mean age 63 ± 9 years; 92% male), 96% of whom were in New York Heart Association (NYHA) class III or IV. After 6 months of vericiguat therapy, right ventricular systolic function improved significantly, with an increase in tricuspid annular plane systolic excursion (TAPSE) from 18.5 ± 4.3 mm to 21.4 ± 4.8 mm (p = 0.003). Left ventricular systolic function improved, with a numerical increase in left ventricular ejection fraction (LVEF) (30.1 ± 5.9% to 32.2 ± 10.5%; p = 0.122) and a significant increase in left ventricular outflow tract velocity-time integral (LVOT VTI) (14.8 ± 3.7 cm to 16.1 ± 3.8 cm; p = 0.011). Functional improvements were accompanied by structural remodeling, including reductions in right ventricular internal diameter in diastole (RVIDd) (40.5 ± 5.8 mm to 37.9 ± 6.9 mm; p = 0.002) and left ventricular end-systolic volume (LVESV) (144.0 ± 40.3 mL to 132.4 ± 61.0 mL; p = 0.031). N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels also decreased significantly (median 1829.0 ng/mL to 1241.0 ng/mL; p = 0.03). Conclusions: In patients with HFrEF and recent worsening, the addition of vericiguat to GDMT may be associated with reverse myocardial remodeling.

Background/Objectives: Sodium glucose co-transporter 2 inhibitors (SGLT2is) improve outcomes in heart failure; however, data in left ventricular non-compaction cardiomyopathy (LVNC) patients are limited. We sought to analyze the clinical effects of the SGLT2is dapagliflozin and empagliflozin in patients with LVNC. Methods: Thirty consecutive LVNC patients diagnosed by CMR were prospectively enrolled. Clinical, biochemical and echocardiography data were obtained at the initiation of the SGLT2is and at the 12-month follow-up. All patients were on stable guideline-directed medical therapy. A response to SGLT2i therapy was defined as an improvement in LVEF ≥ 5% at 12 months. Results: Of the 30 enrolled patients, 25 were male, with a mean age of 49 ± 16 years and few comorbidities. Dapagliflozin 10 mg was prescribed to 23 patients and empagliflozin 10 mg to 7 patients. Five patients experiened an adverse event during follow-up (one sudden cardiac death; four heart transplantations or LVAD implantations). During follow-up, significant improvements were observed in LVEF (32.1 ± 6.9% vs. 43.5 ± 9.7%; p = 0.003), LVOT VTI (14.8 ± 6.5 cm vs. 17.6 ± 3.3 cm; p = 0.008), E/e′ (14.8 ± 4.7 vs. 10.0 ± 4.1; p < 0.001), and TAPSE (2.0 ± 0.4 cm vs. 2.3 ± 0.4 cm; p = 0.012). NT-proBNP levels decreased significantly (2025 ± 2198 pg/mL vs. 582 ± 803 pg/mL; p = 0.005). Eighteen patients responded favorably to SGLT2i therapy (Group A), whereas seven showed no significant LVEF improvement (Group B). The groups did not differ significantly in age, sex, baseline creatinine, or bilirubin. Compared to Group B, Group A had a smaller baseline LV end-diastolic diameter (6.3 ± 0.8 cm vs. 7.1 ± 0.9 cm; p = 0.025) and lower NT-proBNP levels (1720 ± 1662 pg/mL vs. 4527 ± 4397 pg/mL; p = 0.02). Conclusions: In patients with LVNC, SGLT2i therapy is associated with significant reverse remodeling and functional improvement. Benefits may be greater in those with less advanced disease.

Background: Beyond its established inotropic effects, levosimendan has been reported to enhance renal function in patients with chronic heart failure. In this study, we investigated whether changes in renal function following levosimendan administration in patients listed for heart transplantation were associated with early post-transplant renal outcomes. Methods: We retrospectively analyzed data from 99 patients with advanced heart failure and renal insufficiency (eGFR < 90 mL/min/1.73 m²) who were listed for heart transplantation and received levosimendan therapy within 1 to 6 months prior to transplantation. Renal function was assessed immediately before and 24 h after levosimendan administration. A favorable renal response was defined as any increase in eGFR at 24 h. Post-transplant renal function was evaluated on postoperative days 1 and 7 using standard renal function parameters. Results: Favorable renal response to levosimendan prior to heart transplantation was present in 73 of 99 patients (74%, Group A), and 26 patients (26%) displayed no increase in eGFR (Group B). In the first week after heart transplantation, we found a significant improvement in renal function in Group A (ΔeGFR: +14 ± 3 mL/min/1.73 m², p < 0.001), and worsening of renal function in Group B (ΔeGFR: −4 ± 3 mL/min/1.73 m², p < 0.01). Favorable response to levosimendan prior to heart transplantation was an independent correlate of improved renal function after heart transplantation (p = 0.01). Conclusion: In patients awaiting heart transplantation, improvement in renal function after levosimendan therapy was associated with better early post-transplant renal outcomes. Levosimendan response may thus help identify reversible renal dysfunction and serve as a simple tool for transplant evaluation.

Heart failure with preserved ejection fraction (HFpEF) is the most common cause of hospitalisation for heart failure. However, only limited effective treatments are available. Recent evidence suggests that HFpEF may result from a systemic proinflammatory state, microvascular endothelial inflammation and microvascular rarefaction. Formation of new microvasculature in ischaemic tissues is dependent on CD34+ cells, which incorporate into the newly developing vasculature and produce pro-angiogenic cytokines. In HFpEF patients, worsening of diastolic function appears to correlate with decreased numbers of CD34+ cells. Therefore, it is plausible that increasing the myocardial numbers of CD34+ cells could theoretically lead to improved microvascular function and improved diastolic parameters in HFpEF. In accordance with this hypothesis, recent pilot clinical data suggest that CD34+ cell therapy may indeed be associated with improved diastolic function and better functional capacity in HFpEF patients and could thus represent a promising novel therapeutic modality for this patient population.

Purpose of Review The purpose of this review is to discuss recent advances in the field of cell therapy in patients with heart failure with reduced ejection fraction (HFrEF) of ischemic (iCMP) and nonischemic (dCMP) etiology, heart failure with preserved ejection fraction (HFpEF), and in advanced heart failure patients undergoing mechanical circulatory support (LVAD). Recent Findings In HFrEF patients (iCMP and dCMP cohorts), autologous and/or allogeneic cell therapy was shown to improve myocardial performance, patients’ functional capacity, and neurohumoral activation. In HFpEF patient population, the concept of cell therapy in novel and remains largely unexplored. However, initial data are very encouraging and suggest at least a similar benefit in improvements of myocardial performance (also diastolic function of the left ventricle), exercise capacity, and neurohumoral activation. Recently, cell therapy was explored in the sickest population of advanced heart failure patients undergoing LVAD support also showing a potential benefit in promoting myocardial reverse remodeling and recovery. Summary In the past decade, several cell therapy-based clinical trials showed promising results in various chronic and advanced heart failure patient cohorts. Future cell treatment strategies should aim for more personalized therapeutic approaches by defining optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patient’s age and stage/duration of heart failure.

Background. We sought to evaluate the long-term effects of angiotensin receptor blocker–neprilysin inhibitor (ARNI) therapy on reverse remodeling of the failing myocardium in HFrEF patients. Methods. We performed a prospective non-randomized longitudinal study on 228 HFrEF patients treated with ARNI at our center. Prior to ARNI introduction all patients received stable doses of ACEI/ARB for at least six months. Clinical, biochemical and echocardiography data were obtained at ARNI introduction and 12-month follow-up. Results At follow-up, we found significant improvements in LVEF (29.7% ± 8% vs. 36.5% ± 9%; p < 0.001), LVOT-VTI (14.8 ± 4.2 cm vs. 17.2 ± 4.2 cm; p < 0.001), TAPSE (1.7 ± 0.5 cm vs. 2.1 ± 0.6 cm; p < 0.001) and LV-EDD (6.5 ± 0.8 cm vs. 6.3 ± 0.9 cm; p = 0.001). NT-proBNP serum levels also decreased significantly (1324 (605, 3281) pg/mL vs. 792 (329, 2022) pg/mL; p = 0.001). A total of 102 (45%) of patients responded favorably to ARNI (ΔLVEF < +5%; Group A) and 126 (55%) patients achieved ΔLVEF ≥ +5% (Group B). The two groups differed significantly in age, heart failure etiology, baseline LVEF and baseline NT-proBNP. On multivariable analysis, nonischemic heart failure, LVEF < 30% and NT-proBNP < 1500 pg/mL emerged as independent correlates of favorable response to ARNI therapy. Conclusion. ARNI therapy appears to improve echocardiographic parameters of left and right ventricular function in HFrEF patients above the effect of pre-existing optimal medical management. These effects may be particularly pronounced in patients with nonischemic heart failure, LVEF < 30% and lower degree of neurohumoral activation.

Aim of the Review. The aim of this review is to discuss recent advances in clinical aspects of stem cell therapy in chronic nonischemic heart failure (DCMP) with emphasis on patient selection, stem cell types, and delivery methods. Recent Findings. Several stem cell types have been considered for the treatment of DCMP patients. Bone marrow-derived cells and CD34⁺ cells have been demonstrated to improve myocardial performance, functional capacity, and neurohumoral activation. Furthermore, allogeneic mesenchymal stem cells were also shown to be effective in improving heart function in this patient population; this may represent an important step towards the development of a standardized stem cell product for widespread clinical use in patients with DCMP. Summary. The trials of stem cell therapy in DCMP patients have shown some promising results, thus making DCMP apparently more inviting target for stem cell therapy than chronic ischemic heart failure, where studies to date failed to demonstrate a consistent effect of stem cells on myocardial performance. Future stem cell strategies should aim for more personalized therapeutic approach by establishing the optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patient’s age and stage of the disease.