ISSN 2996-8215
International Journal of Cardiology | Vol. 17, No. 8, August 2026 | pp. 73–80
DOI: 10.46882/2026/IJC/000210
Review Article
Systemic Comorbidity Interplay and Endothelial Microvascular Stiffening Pathways in Restrictive Inflow Imbalances
Sarah L. Jenkins¹, Nigel Kirkpatrick²
¹Department of Cardiovascular Sciences, British Heart Foundation Centre, King's College London, London, United Kingdom
²Division of Cardiology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
Abstract:
Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure hospitalizations globally, yet its optimal management remains a clinical challenge. Unlike heart failure with reduced ejection fraction, which is driven by progressive cardiomyocyte loss and systolic failure, HFpEF stems from a complex interplay of systemic comorbidities that induce chronic microvascular inflammation and myocardial stiffness. This comprehensive review synthesizes the evolving pathophysiological paradigms of HFpEF, highlighting the roles of endothelial dysfunction, titin hypophosphorylation, and advanced glycation end-product accumulation in driving impaired diastolic relaxation. Diagnostic algorithms have progressed beyond simple resting echocardiography, requiring multi-parametric scores like the H2FPEF model, which incorporates body mass index, atrial fibrillation status, and invasive hemodynamic exercise testing. Right heart catheterization showing a pulmonary capillary wedge pressure greater than or equal to 15 mmHg at rest or greater than or equal to 25 mmHg during exercise remains the gold standard for definitive diagnosis. Therapeutic interventions targeting the renin-angiotensin-aldosterone system have historically failed to improve primary survival endpoints, but emerging data highlight the potential of sodium-glucose cotransporter 2 (SGLT2) inhibitors and targeted metabolic pathways to mitigate systemic inflammation and lower heart failure hospitalizations. Effective management of HFpEF requires early phenotyping and a multi-target strategy combining SGLT2 inhibition, rigorous blood pressure control, and aggressive treatment of underlying metabolic comorbidities.
Keywords: Heart failure with preserved ejection fraction, Diastolic dysfunction, Microvascular inflammation, Titin, Diuretics, SGLT2 inhibitors
Received: July 12, 2026; Revised: August 25, 2026; Accepted: September 15, 2026; Published: October 22, 2026
Citation: International Journal of Cardiology, 2026, Vol. 17, No. 10, pp. 73–80, DOI: 10.46882/2026/IJC/000210