The Comorbidity-Driven Interleukin-6-Mediated Systemic Inflammation Hypothesis of Heart Failure With Preserved Ejection Fraction: A Decade of Testing Ends in Disappointment
Abstract
Efforts to validate the comorbidity-driven interleukin-6-mediated systemic inflammation framework have been unable to support the postulated sequence of pathophysiological events. The treatment of comorbidities (other than obesity) has not alleviated systemic inflammatory biomarkers or ameliorated the course of HFpEF. Additionally, drugs that exert systemic anti-inflammatory effects by interfering with the effects of classical cytokines have not improved exercise tolerance or reduced the risk of worsening heart failure events. Only one-third of patients with HFpEF show coronary microvascular dysfunction that is endothelium-dependent, and drugs that act to reverse the consequences of coronary microvascular endothelial dysfunction by augmenting NO-cGMP signaling (nitrates, nitrites, soluble guanylate cyclase stimulators or phosphodiesterase 5 inhibitors) do not exert favorable effects on symptoms, exercise capacity or health status in HFpEF. The recently announced findings from the HERMES and ATHENA trials with interleukin-6 antagonism with ziltivekimab reinforce the premise that systemic inflammation produced by classical cytokines may not have pathogenic significance in HFpEF.
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BibTeX
@article{packer2026comorbiditydriven,
title = {{The Comorbidity-Driven Interleukin-6-Mediated Systemic Inflammation Hypothesis of Heart Failure With Preserved Ejection Fraction: A Decade of Testing Ends in Disappointment}},
author = {Milton Packer and Javed Butler and Faiez Zannad and Muthiah Vaduganathan and Barry A Borlaug},
journal = {Journal of Cardiac Failure},
year = {2026},
month = oct,
doi = {10.1016/j.cardfail.2026.09.029},
url = {https://hal.univ-lorraine.fr/hal-05789194v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The Comorbidity-Driven Interleukin-6-Mediated Systemic Inflammation Hypothesis of Heart Failure With Preserved Ejection Fraction: A Decade of Testing Ends in Disappointment
AU - Milton Packer
AU - Javed Butler
AU - Faiez Zannad
AU - Muthiah Vaduganathan
AU - Barry A Borlaug
PY - 2026
DA - 2026/10/09
JO - Journal of Cardiac Failure
DO - 10.1016/j.cardfail.2026.09.029
UR - https://hal.univ-lorraine.fr/hal-05789194v1
AB - Efforts to validate the comorbidity-driven interleukin-6-mediated systemic inflammation framework have been unable to support the postulated sequence of pathophysiological events. The treatment of comorbidities (other than obesity) has not alleviated systemic inflammatory biomarkers or ameliorated the course of HFpEF. Additionally, drugs that exert systemic anti-inflammatory effects by interfering with the effects of classical cytokines have not improved exercise tolerance or reduced the risk of worsening heart failure events. Only one-third of patients with HFpEF show coronary microvascular dysfunction that is endothelium-dependent, and drugs that act to reverse the consequences of coronary microvascular endothelial dysfunction by augmenting NO-cGMP signaling (nitrates, nitrites, soluble guanylate cyclase stimulators or phosphodiesterase 5 inhibitors) do not exert favorable effects on symptoms, exercise capacity or health status in HFpEF. The recently announced findings from the HERMES and ATHENA trials with interleukin-6 antagonism with ziltivekimab reinforce the premise that systemic inflammation produced by classical cytokines may not have pathogenic significance in HFpEF.
SN - 1071-9164
ER -