The Comorbidity-Driven Interleukin-6-Mediated Systemic Inflammation Hypothesis of Heart Failure With Preserved Ejection Fraction: A Decade of Testing Ends in Disappointment

In 2013, Paulus and Tschöpe proposed that the multitude of comorbidities seen in patients with heart failure with preserved ejection fraction (HFpEF) was causally responsible for triggering an interleukin-6 (IL-6)-mediated systemic inflammatory state that might lead to HFpEF, postulating the intermediary contribution of coronary microvascular disease and deficient nitric oxide/cyclic guanosine monophosphate (NO-cGMP) signaling and cytokine-mediated cardiac hypertrophy and fibrosis. The comorbidity-driven IL-6-systemic inflammation hypothesis has been extensively evaluated in randomized controlled trials. However, in these trials, most comorbidities have not been shown to represent a causal mechanism for systemic inflammation, and the treatment of comorbidities (other than obesity) has not ameliorated HFpEF. Although coronary microvascular dysfunction is common in HFpEF, it is often not endothelium-dependent, and it is not a cause of defective NO-cGMP signaling. Numerous randomized clinical trials with NO-cGMP enhancing drugs (nitrates/nitrites, phosphodiesterase 5 inhibitors and soluble guanylyl cyclase stimulators) have not provided symptomatic or exercise benefits in HFpEF. Mendelian randomization studies link IL-6 to the development of HFpEF; serum levels of IL-6 precede the development and track the severity of HFpEF; and experimental models point to IL-6 as a causal mediator of HFpEF. However, the adipokine hypothesis partitioned IL-6 and other classical cytokines from pathogenic adipokines in identifying molecular mediators of HFpEF, based on the observations that systemic IL-6 does not reliably reflect visceral adipose tissue dysfunction, and it is cosecreted with neutralizing cytokine antagonists. These observations suggested systemic IL-6 represents a distal marker, and not a mediator, of adipose tissue inflammation, and thus, unlikely to play a role in HFpEF. In proteomics analyses, heightened natural endogenous cytokine antagonists are more prominent and consistent features of HFpEF than circulating levels of the cytokines themselves. The HERMES trial tested the efficacy of the IL-6 antibody, ziltivekimab, in patients with HFpEF who were enriched for cytokine-mediated systemic inflammation, but the trial has been stopped for futility. Therefore, as a result of rigorous testing of each of its mechanistic layers, it is now difficult to support the hypothesis that HFpEF is a comorbidity-driven IL-6-mediated systemic inflammatory disorder that acts through or independently of a NO-cGMP deficiency mechanism.