Sacubitril/valsartan is the first agent in a novel pharmacologic class known as ARNIs [8]. It combines two complementary mechanisms: sacubitril, a neprilysin inhibitor, and valsartan, an ARB. Sacubitril, administered as a prodrug, inhibits neprilysin—an endopeptidase responsible for degrading vasoactive peptides such as natriuretic peptides, bradykinin, adrenomedullin, and substance P. Inhibition of neprilysin leads to elevated levels of these peptides, promoting natriuresis, diuresis, vasodilation, and inhibition of pathologic hypertrophy and fibrosis, all of which are beneficial in reverse remodeling of the myocardium in HF [9]. However, neprilysin also degrades angiotensin II partially, and its inhibition alone can paradoxically increase angiotensin II levels, potentially worsening HF. To mitigate this, valsartan is co-administered to block the angiotensin II type 1 receptor (AT₁R), thereby preventing vasoconstriction, sodium retention, and aldosterone-mediated fibrosis. The synergistic effect of this dual blockade addresses two central pathways in HF pathophysiology: the renin-angiotensin-aldosterone system (RAAS) and the natriuretic peptide system (Fig. 1). Beyond hemodynamic effects, ARNIs have shown superiority over ACE inhibitors and ARBs in promoting reverse remodeling, improving ventricular function, and reducing cardiomyocyte apoptosis and extracellular matrix remodeling. These benefits are attributed to its unique ability to preserve endogenous protective peptides while simultaneously attenuating maladaptive RAAS signaling. Mechanistically, sacubitril/valsartan also modulates G-protein–coupled receptor pathways and may influence fibrosis and inflammation at the molecular level. Importantly, the therapeutic benefit arises only when sacubitril and valsartan are used in combination; monotherapy with either component does not yield the same magnitude of clinical or biochemical improvement among adults [10]. In the PANORAMA-HF trial, ARNIs did not demonstrate superiority over enalapril in treating pediatric HF due to systemic LV systolic dysfunction, based on a global rank endpoint at 52 weeks [6]. Nonetheless, both therapies yielded clinically meaningful improvements in functional status and NT-proBNP levels, with comparable safety profiles. As the pediatric evidence base continues to grow, ARNIs therapy is increasingly recognized as a cornerstone of GDMT for children with HFrEF, aligning pediatric practice more closely with adult HF management standards. In a propensity score–matched retrospective cohort study of 1038 pediatric HF patients from the TriNetX database, sacubitril-valsartan was not associated with a reduction in 1-year all-cause mortality or heart transplantation compared to ACE/ARB therapy (13.3% vs 13.2%, p = 0.95). While hypotension was more frequent with sacubitril-valsartan (10% vs 5.2%, p = 0.006), a trend toward fewer hospitalizations per year was observed [11].

Fig. 1.

Mechanisms of action of sodium-glucose cotransporter-2 inhibitors (SGLT2is), angiotensin receptor-neprilysin inhibitors (ARNIs), and soluble guanylate cyclase (sGC) agonist in the modulation of heart failure with reduced ejection fraction (HFrEF). (Original diagram). [NHE1, sodium/hydrogen exchanger isoform 1; NHE3, sodium/hydrogen exchanger isoform 3; cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthetase; SGLT2is, sodium-glucose cotransporter-2 inhibitors; ARNIs, angiotensin receptor-neprilysin inhibitors; Na, sodium; AT₁R, angiotensin receptor 1; MRA, Mineralocorticoid receptor antagonist; BB, Beta blocker; H₂O, water; TGF$\beta$, Transforming growth factor beta].

SGLT2is, also known as gliflozins, are a novel class of antihyperglycemic agents initially developed for the management of type 2 diabetes mellitus. These agents act by inhibiting the SGLT2 protein in the renal proximal convoluted tubule, which is responsible for reabsorbing approximately 90% of filtered glucose. By blocking this transporter, SGLT2is promote glycosuria and reduce blood glucose levels independently of insulin, while also exerting natriuretic and diuretic effects. Beyond glycemic control, SGLT2is have demonstrated robust cardiovascular benefits. These benefits are thought to arise from a combination of mechanisms, including reduction in preload and afterload, improved renal hemodynamics, reduced interstitial myocardial fibrosis, and enhanced myocardial energy metabolism through increased ketone utilization and mitochondrial efficiency (Fig. 1) [12]. Importantly, these effects occur regardless of diabetic status, as demonstrated in large placebo-controlled trials such as EMPEROR-Reduced [13].

While pediatric data remain limited, emerging case series suggest that SGLT2is are safe and potentially effective in children with HF. In a single-center retrospective study by Newland et al. [14], dapagliflozin was administered to 38 pediatric patients with HF, the majority of whom had dilated cardiomyopathy (68.4%) and LVEF $\le$40% (65.8%). Patients received dapagliflozin alongside standard HF therapies, including ARNIs, BBs, MRAs, and diuretics. Over a median follow-up of 130 days, BNP levels significantly decreased from a median of 222 to 166 pg/mL, suggesting improvement in HF status. The medication was well tolerated, with no major changes in serum chemistries or vital signs. Importantly, there were no cases of hypoglycemia or hypovolemia, though 15.8% of patients experienced symptomatic urinary tract infections requiring antibiotics. In a subgroup of 16 patients with DCM, LVEF improved from 32% to 37.2% over a median follow-up of 313 days, indicating potential reverse remodeling. A second study by Konduri et al. [15] evaluated the use of SGLT2is in 14 adolescents (median age 14.5 years), including those with Fontan-associated heart failure, both with preserved and reduced EF. After an average of 4 months of therapy, reductions in BNP levels were observed without major adverse effects [15]. There were no reported incidents of genitourinary infections, hypoglycemia, diabetic ketoacidosis, or hypotension. One patient experienced significant diuresis and transient acute kidney injury, which was resolved with supportive care. These early findings suggest that SGLT2is may offer a promising therapeutic option in pediatric HF, including in complex cases such as Fontan physiology, where treatment options are limited. However, prospective trials are needed to establish safety, optimal dosing, and long-term efficacy in this population. In a recent study, the addition of dapagliflozin in 14 children significantly improved LVEF and symptoms, while demonstrating a favorable safety profile [16].

Ivabradine is a heart rate-lowering agent approved for use in patients with HFrEF who are in normal sinus rhythm and have a resting heart rate $\ge$70 bpm despite maximally tolerated BB therapy. It selectively inhibits the funny current (If) in the sinoatrial node, reducing the influx of Na⁺ and K⁺ ions during diastolic depolarization. This slows pacemaker activity, prolongs diastolic filling time, and decreases myocardial oxygen consumption [17]. Elevated resting heart rates are associated with adverse LV remodeling, impaired diastolic filling, and worse clinical outcomes in HF. A systematic review of nine randomized controlled trials including 18,972 adult HF patients demonstrated that ivabradine significantly reduced HF-related mortality (RR 0.79) and hospitalization rates (RR 0.80) compared to placebo [17]. Unlike BBs or RAAS inhibitors, Ivabradine does not act on the neurohormonal system and thus has no effect on blood pressure or myocardial contractility, making it a more selective treatment option for certain HF patients. However, ivabradine was associated with an increased incidence of bradycardia, both symptomatic and asymptomatic.

Based on large-scale clinical trials such as SHIFT and BEAUTIFUL [18, 19], the American Heart Association (AHA) and European Society of Cardiology (ESC) guidelines recommend ivabradine for symptomatic HFrEF patients (NYHA class II–IV) with LVEF $\le$35% and heart rate $\ge$70 bpm despite optimal treatment with BBs, ACE inhibitors (ACEis) or ARBs, and MRAs [4, 20]. In the pediatric population, ivabradine has shown encouraging results in improving HF outcomes. A randomized clinical trial in children with symptomatic chronic HF demonstrated significant reductions in heart rate and improvements in LVEF [21]. Based on these findings, the U.S. FDA approved ivabradine for use in children $\ge$6 months of age with symptomatic chronic HF and persistent tachycardia despite optimized BB therapy. Dosing regimens for ivabradine in children have been established by age and weight categories, ensuring safe titration. According to the 2014 ISHLT pediatric HF guidelines, ivabradine is considered reasonable (Class IIa, Level of Evidence B) for use as an adjunct therapy in children with stable HF when additional heart rate reduction is desirable [1]. More than 250 children across 19 pediatric HF centers have been treated with SGLT2 inhibitors, according to data gathered by the ACTION network. Preliminary results suggest the treatment is well tolerated, with no significant side effects reported during early follow-up.

The combination of ARNIs and SGLT2is represents a promising therapeutic strategy in the treatment of chronic HFrEF. Clinical trials in adults have demonstrated that the concomitant use of these two agents provides synergistic benefits, leading to enhanced cardiovascular outcomes compared to either therapy alone [22]. This synergism stems from the convergence of complementary mechanisms targeting multiple pathophysiological pathways in HF (Fig. 1). Both ARNIs and SGLT2is contribute to preload reduction via natriuretic and osmotic diuresis, which decreases myocardial oxygen demand and improves cardiac output. Additionally, SGLT2is increase hematocrit by stimulating erythropoietin production, thereby enhancing oxygen delivery to peripheral tissues. At the cellular level, SGLT2is enhance myocardial energetics by promoting ketone body utilization, particularly beta-hydroxybutyrate, which serves as a more oxygen-efficient substrate compared to glucose or fatty acids. This metabolic shift leads to increased Adenosine Triphosphate (ATP) production and improved cardiac efficiency [12]. Moreover, elevated ketone levels act as endogenous histone deacetylase (HDAC) inhibitors, which reduce oxidative stress, inhibit cardiac hypertrophy, and attenuate inflammatory signaling through epigenetic modulation of peroxisome proliferator-activated receptors (PPARs) and pro-inflammatory cytokines [23, 24].

Myocardial fibrosis, a hallmark of adverse remodeling in HFrEF, is mitigated through transforming growth factor-beta (TGF-$\beta$) suppression, a pathway modulated by both ARNIs and SGLT2is therapy. ARNIs further contributes to antifibrotic effects by enhancing levels of natriuretic peptides, which promote anti-remodeling and vasodilatory signaling. Another critical target is the Na⁺/H⁺ exchanger isoform 1 (NHE1) and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), both of which are upregulated in HF and contribute to pathological calcium handling and mitochondrial dysfunction. SGLT2is directly inhibit NHE1 and suppress CaMKII activity, resulting in decreased intracellular sodium and reduced calcium overload, thereby preserving mitochondrial function and calcium homeostasis [25, 26].

Furthermore, SGLT2is enhance sarcoplasmic reticulum (SR) calcium cycling, which contributes to improved myocardial contractility and reduced arrhythmogenic potential [27]. These multifaceted cellular and molecular effects underscore the potential superiority of ARNIs–SGLT2is combination therapy as a next-generation cornerstone in the pharmacologic management of pediatric HFrEF.

Vericiguat, a novel sGC stimulator, has gained increasing interest for its therapeutic potential in HF, particularly following encouraging results in adult clinical trials [28]. Unlike earlier agents, vericiguat has a dual mechanism of action: it enhances sGC sensitivity to suboptimal nitric oxide (NO) levels and directly stimulates sGC by binding to its regulatory heme domain even in the absence of NO. This dual action activates the NO–sGC–protein kinase G (PKG) signaling cascade, leading to an increase in cyclic guanosine monophosphate (cGMP) (Fig. 1), a key secondary messenger in cardiovascular homeostasis. In the failing heart, inflammation and endothelial dysfunction impair NO bioavailability, reduce sGC activity, and diminish cGMP levels. This dysregulation contributes to fibrosis, hypertrophy, and impaired myocardial relaxation [29]. sGC stimulators like vericiguat aim to restore this pathway, thereby attenuating adverse cardiac remodeling and improving hemodynamic function. In addition, when sGC is added to ARNIs and SGLT2is, there could be a more effective improvement of myocardial function and potential recovery of HFrEF.

Earlier-generation sGC stimulators, such as riociguat, were limited by short half-life and variable cGMP levels, which constrained their clinical utility in chronic HF. Vericiguat, developed through structural modifications to improve pharmacokinetics, demonstrated efficacy in the phase III VICTORIA trial, which enrolled high-risk adults with HFrEF (LVEF 45%) and recent worsening HF events [30]. Compared to placebo, vericiguat significantly reduced the composite endpoint of cardiovascular death or first HF hospitalization, earning it a Class IIb recommendation in recent adult HF guidelines [4, 20]. The drug was approved by the U.S. FDA in 2021 as an adjunct therapy for adults with symptomatic HFrEF. Despite these encouraging findings in adults, data in pediatric HF remain scarce. The ongoing VALOR-HF trial (Vericiguat in Pediatric Participants with Heart Failure Due to Systemic Left Ventricular Systolic Dysfunction) aims to bridge this gap [31]. This phase II trial evaluates the safety, efficacy, and pharmacokinetics of vericiguat in children with stable chronic HFrEF. The primary outcome is the change in NT-proBNP at 16 weeks, a surrogate marker for HF severity. Secondary outcomes include changes in log-transformed NT-proBNP at 52 weeks, time to first cardiovascular event (death, HF hospitalization, or worsening HF), adverse event profiles, and pharmacokinetics of tablet and oral suspension formulations.

Vericiguat’s unique pharmacodynamic profile—particularly its ability to function in states of low NO—makes it a compelling candidate for pediatric HF management, especially in advanced or treatment-resistant cases. If proven safe and effective, vericiguat could represent a valuable fifth pillar in the pharmacologic treatment of pediatric HFrEF. As the VALOR study progresses, collaboration among researchers, clinicians, and regulatory authorities will be pivotal to accelerate translation into pediatric practice and ultimately improve outcomes for children living with HF.

The hallmark of HFrEF is impaired myocardial contractility. While numerous agents have been developed to enhance contractile performance, traditional inotropes have been associated with increased arrhythmic risk, myocardial oxygen consumption, and mortality, limiting their long-term utility. OM represents a novel class of cardiac myosin activators, also known as myotropes, designed to increase contractility without raising intracellular calcium levels or oxygen demand [32]. OM selectively binds to the S1 domain of cardiac myosin, accelerating the rate-limiting step of ATP hydrolysis and strengthening the actin–myosin interaction. This mechanism prolongs systolic ejection time, enhances stroke volume, and improves overall cardiac output. Importantly, these effects are achieved without increasing myocardial oxygen consumption, distinguishing OM from classic inotropes. The Chronic Oral Study of Myosin Activation to Increase Contractility (COSMIC)-HF trial evaluated OM in adults with stable chronic HFrEF (EF $\le$40%) [33]. Results demonstrated favorable remodeling, including prolonged systolic ejection time, increased stroke volume, and reduced LV end-systolic and end-diastolic volumes compared to placebo, suggesting improved contractile efficiency. However, physiologic improvements do not always translate into symptom relief. The Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure (ATOMIC-AHF) trial, which tested OM in adults hospitalized for acute decompensated HF (EF 40%), did not meet its primary endpoint of dyspnea relief, although trends toward hemodynamic benefit were noted [34]. The pivotal Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility (GALACTIC)-HF trial—a multicenter, randomized, double-blind, placebo-controlled phase III study—enrolled 8256 patients with symptomatic HFrEF (NYHA class II–IV, EF $\le$35%) [35]. Participants had elevated natriuretic peptides and either a recent HF hospitalization or emergency department visit. The study found that OM significantly reduced the composite primary endpoint of time to first HF event or cardiovascular death (HR 0.92; 95% CI 0.86–0.99; p = 0.03). This benefit was primarily driven by fewer HF hospitalizations, with no significant difference in cardiovascular mortality (HR 1.01; 95% CI 0.92–1.11). Subgroup analyses revealed greater benefit in patients with lower EF and those in normal sinus rhythm. Notably, quality of life measures showed minimal overall change, although some improvement was observed in specific subpopulations (e.g., hospitalized patients). OM was associated with modestly increased troponin levels, but there was no excess in ischemic events, ventricular arrhythmias, or mortality compared to placebo, underscoring its favorable safety profile. While OM has not yet been studied in large-scale pediatric trials, its unique mechanism of enhancing contractility without increasing calcium influx or arrhythmogenic risk makes it a promising candidate for pediatric HF therapy. Further research-including pharmacokinetic, safety, and efficacy studies in children, is warranted to determine its potential role in pediatric HFrEF management.