Heart failure (HF) remains a significant global health challenge, characterized by the heart’s inability to pump sufficient blood to meet the body’s demands.

Despite advances in treatment, it continues to cause high rates of morbidity and mortality.

Updated Pharmacologic Therapies

The foundation for treating heart failure with reduced ejection fraction (HFrEF) has long involved four staple drug classes: β-blockers, angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor-neprilysin inhibitors (ARNI), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 inhibitors (SGLT2i).

In recent years, these therapies have been refined with the introduction of new agents and combinations demonstrating enhanced outcomes. Notably, sacubitril/valsartan (an ARNI) has become instrumental, showing superiority over enalapril in lowering death risk and hospital admissions related to heart failure.

Additionally, emerging non-steroidal MRAs such as finerenone have exhibited promising reductions in worsening heart failure events, especially among patients with preserved or mildly reduced ejection fraction. Ongoing trials are exploring balcinrenone, combined with SGLT2 inhibitors like dapagliflozin, targeting patients with kidney impairment and chronic heart failure, aiming to further optimize cardiac and renal health.

Artificial Intelligence and Device Integration

Mechanical circulatory‑support devices such as the Impella 5.5 are increasingly used in advanced heart‑failure management. The Impella 5.5 with SmartAssist collects detailed pump and hemodynamic data, and researchers have highlighted the potential for artificial‑intelligence (AI)‑driven algorithms to optimise device management and patient outcomes. However, while these applications are promising, full clinical validation in this setting is still forthcoming.

Gene Therapy and Genomic Interventions

A groundbreaking frontier in heart‑failure and cardiomyopathy treatment involves gene‑editing technologies such as CRISPR‑Cas9, which hold promise for directly targeting genetic causes of cardiac dysfunction. One of the most advanced applications is Nexiguran Ziclumeran (nex‑z), an investigational, single‑dose CRISPR‑based therapy for Transthyretin amyloidosis with cardiomyopathy (ATTR‑CM) or polyneuropathy (ATTRv‑PN).

In Phase 1 trials, a single IV infusion of nex‑z produced a mean ~90 % reduction in serum TTR levels at 12 months, with durability observed in some patients. While clinical outcome data are still emerging, this represents one of the most promising examples of gene editing entering cardiology.

Metabolic Modulation and Anti-Obesity Agents

Recognizing the interplay between metabolic health and heart failure, novel treatments are increasingly focused on metabolic modulation. GLP‑1 receptor agonists, originally developed for diabetes and weight‑loss, have demonstrated significant cardiovascular benefits — in meta‑analysis showing reductions in major adverse cardiovascular events (MACE) of ~10‑15% (and up to ~20% in some analyses) in high‑risk patients.

These drugs act via multiple mechanisms: promoting weight loss, improving blood pressure and glycaemic control, and modulating inflammatory and metabolic pathways — all of which are relevant to heart‑failure progression. While integration of GLP‑1 RAs into heart‑failure treatment is emerging rather than fully established, this evolving approach reflects a deeper understanding of cardiovascular disease mechanisms and a more holistic strategy in care.

As heart‑failure specialist Dr. Michele E. Mancini notes, the horizon of heart‑failure treatment is rapidly expanding — moving beyond simply prolonging life to improving its quality by addressing the condition from multiple angles, including molecular correction and personalized medicine.

The current decade is witnessing transformative shifts in heart failure management, fueled by innovative drug development, advanced bioengineering devices augmented by AI, genetic therapies, and metabolic-focused treatments. Each modality addresses different aspects of heart failure pathophysiology—from preventing cardiac remodeling and mitigating inflammation to restoring myocardial function at the genetic level.