How do you approach treatment for patients with combined post- and pre-capillary pulmonary hypertension associated with heart failure with preserved ejection fraction? Are multidisciplinary teams, including pulmonary, pharmacy, and heart failure specialists, collaborating to manage these complex and recurring conditions that often require multiple referrals to other specialty clinics? Improving heart function in these patients remains a challenging and variable process.
Over the past decade, understanding of heart failure with preserved ejection fraction (HFpEF) has shifted toward phenotype-based models. HFpEF is now recognized as a spectrum of overlapping syndromes, including obesity-driven, pulmonary hypertension-associated, inflammatory/autoimmune, sleep apnea-related, and cardiorenal phenotypes. These frameworks have improved our understanding of pathophysiology and risk stratification. Yet, in daily clinical practice, our therapeutic approach remains strikingly uniform. Most patients receive a familiar combination of SGLT2 inhibitors, diuresis, and mineralocorticoid receptor antagonists (including non-steroidal MRAs), with selective avoidance of beta blockers or nitrates in certain contexts. Even with the emergence of GLP-1 receptor agonists targeting the obesity phenotype, true phenotype-directed therapy has yet to meaningfully influence bedside decision-making.
This gap is most apparent in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH) — a phenotype we can define precisely using invasive hemodynamics, yet have historically been unable to treat in a targeted fashion. These are patients we all recognize in practice. A typical case is the patient with HFpEF who presents with pulmonary capillary wedge pressure of 28 mmHg, pulmonary vascular resistance of 4.5 Wood units, and persistently elevated pulmonary artery pressures, who has already been optimized on SGLT2 inhibitors and mineralocorticoid receptor antagonists. Despite guideline-directed therapy, the patient remains limited, with a six-minute walk distance of about 220 meters and does not qualify for advanced therapies such as transplant due to the absence of restrictive cardiomyopathy or hypertrophic disease. These patients exist in a therapeutic gray zone; they’re clearly high-risk, clearly symptomatic, yet without a disease-specific intervention.
Historically, attempts to target this phenotype have been consistently neutral or harmful. Trials such as MELODY-1 (macitentan) demonstrated no meaningful benefit and raised concerns for fluid retention and worsening heart failure, while SIOVAC (sildenafil) showed worsened clinical outcomes in a related population of post-valvular pulmonary hypertension. Other studies evaluating endothelin receptor antagonists, prostacyclins, and cyclic GMP pathway modulators similarly failed to produce consistent benefit. The underlying limitation has been physiological: pulmonary vasodilation without regard for left-sided filling pressures, often resulting in increased pulmonary capillary wedge pressure and clinical decompensation. As a result, clinicians have developed a well-founded reluctance to initiate pulmonary vasodilator therapy in patients with HFpEF and elevated wedge pressures.
I believe that the CADENCE study, presented at this year’s American College of Cardiology Scientific Sessions and simultaneously published in Circulation, challenges this paradigm. Sotatercept, an activin-signaling inhibitor targeting pulmonary vascular remodeling, demonstrated not only a reduction in pulmonary vascular resistance but, critically, a concurrent reduction in pulmonary capillary wedge pressure. This dual hemodynamic signal represents a departure from prior therapies and suggests that the pulmonary vascular component of HFpEF may be targetable without exacerbating left-sided congestion.
The potential implications become even more apparent when considering more complex, overlapping phenotypes. Consider a second patient with rheumatoid arthritis, severe pulmonary hypertension with a pulmonary vascular resistance of eight Wood units, elevated pulmonary pressures, and a six-minute walk distance of 150 meters on supplemental oxygen, with markedly reduced quality of life. This patient also demonstrates right ventricular dilation and moderate tricuspid regurgitation, reflecting progressive RV failure in the setting of combined pulmonary vascular and left heart disease. Historically, initiating pulmonary vasodilator therapy in such a patient would be approached with significant hesitation due to concerns of worsening wedge pressure and precipitating decompensation. Yet CADENCE suggests that such patients may not only tolerate therapy but also derive meaningful benefit — potentially improving both pulmonary hemodynamics and right ventricular function without destabilizing left-sided pressures.
It is important to acknowledge that CADENCE is a Phase 2 trial, and confirmation in larger Phase 3 studies is essential. Broader enrollment, phenotype dilution, and variability in event rates remain potential challenges. However, what distinguishes CADENCE is its mechanistic coherence: simultaneous improvement in pulmonary vascular resistance, pulmonary pressures, and left-sided filling pressures, supported by signals in functional capacity and right ventricular performance. This alignment across physiologic domains strengthens the likelihood that the observed effects are biologically meaningful.
If validated, the implications extend beyond a single therapeutic agent. CADENCE may represent a transition point where HFpEF phenotyping becomes clinically actionable rather than purely descriptive. In this future paradigm, invasive hemodynamics and phenotype identification would directly inform treatment selection, particularly for high-risk subgroups such as CpcPH. It may also reduce longstanding therapeutic hesitation in patients with overlapping etiologies, where clinicians have historically been cautious about introducing pulmonary vasodilator strategies.
For me as a practicing clinician, the importance of CADENCE lies not only in its results, but in what it represents. It challenges a deeply ingrained assumption — that targeting the pulmonary vasculature in HFpEF inevitably worsens left-sided congestion — and offers a plausible alternative. While caution is appropriate and further data are needed, CADENCE may ultimately mark the point at which HFpEF management begins to shift from uniform, guideline-driven care toward truly phenotype-guided therapy at the bedside.
Dr. Abdul Latif Bikak is an advanced heart failure cardiologist and the director of Advanced Heart Failure at Wellstar Health System in Atlanta, where he leads one of the nation’s largest destination therapy LVAD programs. He focuses on building scalable, multidisciplinary programs for complex cardiomyopathies, integrating clinical care, imaging, and pharmacy pathways while advancing access to novel therapies. Dr. Bikak is an active speaker and advisor dedicated to translating emerging cardiovascular therapies into real-world clinical practice.
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