Natriuretic Peptides, Inflammation, and Sounding the Alarm

The heart as an endocrine organ continues to emerge with the unifying concept that the heart produces and releases three structurally similar peptides with widespread pleotropic properties¹. These three peptides include atrial (ANP) and b-type (BNP) natriuretic peptides (NPs) synthesized in cardiomyocytes and c-type natriuretic peptide (CNP) produced principally in endothelial cells. All three function via membrane bound guanylyl cyclase receptors and the effector molecule 3’,5’ cyclic guanosine monophosphate (cGMP)². The wide-ranging properties include natriuresis, vasodilation, aldosterone suppression, lipolysis including anti-hypertrophic and anti-fibrotic actions. A hallmark of heart failure (HF) is the elevation in the circulation of ANP and BNP and its non-biologically active molecular forms NT-proANP and NT-proBNP^3,4. Both BNP forms have emerged as gold standard biomarkers for heart failure diagnosis and prognosis^5,6.

In the current Circulation Heart Failure, Fish-Trotter and Ferguson and co-workers take the NPs as biomarkers into the new frontier of inflammation⁷. In a comprehensive clinical biomarker investigation employing three separate studies, they examine the relationship between NT-proBNP, MR-ANP and/or BNP to specific cytokines in the general population, to cytokine activation by lipopolysaccharide (LPS) administration in healthy volunteers and in hospitalized patients with inflammatory syndromes. The major findings are that in the general population (MESA study), in healthy volunteers exposed to an inflammatory stimulus (LPS study) and in hospitalized patients with inflammation (Vanderbilt University Hospital study), cytokines representing inflammation was associated with higher circulating levels of forms of NPs. They conclude that “inflammatory conditions raise NP levels and should be considered in the clinical interpretation of NP levels in patients with and without HF.” (Figure)

Figure:

A - Under normal physiological conditions, inflammatory homeostasis is maintained by the the balance of pro-inflammatory and anti-inflammatory cytokines. In response to acute inflammatory stimuli or in chronic inflammatory conditions, pro-inflammatory cytokines such as IL-6 and TNF-α are up-regulated. In the absence of anti-inflammatory factors, a pro-inflammatory state is activated resulting contributing to disease progression. B - The findings by Fish-Trotter and Ferguson demonstrate that in response to different inflammatory stimuli, there is a strong association between pro-inflammatory cytokines and circulating levels of forms of the natriuretic peptides released by the heart and may serve as biomarkers for underlying inflammation. Given that the natriuretic peptides have been shown to have protective immune modulatory functions, we propose that increased natriuretic peptide production is an intrinsic protective mechanism to maintain inflammatory homeostasis.

A key strength of the Fish-Trotter and Ferguson findings is the association between inflammation and NP levels across different inflammatory conditions which supports the conclusion that NP levels are driven by inflammation independent of the underlying cause. Indeed, Ogawa et al. in 2004 clearly demonstrated the pivotal role for pro-inflammatory cytokines to target the BNP gene (NPPB)⁸. Specifically, pro-inflammatory cytokines such as IL-1beta and TNF-alpha rapidly increased BNP mRNA in cultured cardiomyocytes resulting in enhanced BNP secretion. In the Fish-Trotter report, in the general community there was a strong relationship between NT-proBNP, IL-6 and TNF-alpha in the absence of changes in left ventricular ejection fraction. Importantly, in the LPS study in which normal human volunteers received LPS, IL-6, NT-proBNP and MR-ANP all increased while troponin was unchanged. These two studies by Fish-Trotter are consistent with the in vitro work of Ogawa which suggests the actions of cytokines on NP release from the heart are the result of a direct non-hemodynamic mechanism⁸. Importantly, these novel observations are highly relevant to the report of elevated NT-proBNP in COVID-19 patients in whom inflammation is widespread⁹.

Beyond the strengths of the Fish-Trotter and Ferguson report, the study also presents opportunities for future studies to further examine the role of NPs in inflammation. In the MESA study, the authors observed a positive correlation between IL-6, but not CRP and NT-proBNP. CRP is a well-established and a stronger biomarker for inflammation¹⁰. The lack of correlation between CRP and NT-proBNP could be due to confounding factors such as cardiac dysfunction not detected by measuring ejection fraction causing NT-proBNP levels to be elevated. In future studies investigating the association between inflammatory cytokines and NP levels, examining echocardiographic parameters such as left atrial volume and correlating to NT-proBNP levels will help to rule out this possibility. The strong association between the circulating levels of precursor forms of NPs and inflammation observed by Fish-Trotter and Ferguson and co-authors warrants the need for a study to examine the biologically active forms of these cardiac hormones including ANP, BNP and CNP and their association with inflammation in patients with acute respiratory infections and sepsis. Such a study will provide valuable information in gaining a better understanding of the association between each of them to inflammation and help with establishing NPs as biomarkers for inflammation.

As discussed by the authors, the NPs may also serve as endogenous immunomodulators which are stimulated by inflammatory mediators. (Figure) Indeed, pioneering work done over two decades back presented clear evidence for the ability of ANP to inhibit pro-inflammatory cytokine production¹¹. Specifically, Kiemer et al. reported that ANP through generation of cGMP potently inhibited TNF-alpha production in macrophages. In a recent landmark study investigating the life-threatening complication cytokine releasing syndrome (CRS), which occurs with immunotherapies such as CAR T-Cell therapy, ANP in vitro and in vivo in mice with CRS reduced cytokine activation and mortality associated with CRS¹². Recognizing myocardial as well as renal fibrosis to be a hallmark of HF¹³, we recently reported that C53, a novel Mayo Clinic designer peptide targeting the CNP/cGMP pathway inhibited increased fibroblast proliferation produced by TGF-beta in both myocardial and renal fibroblasts¹⁴. Perhaps what Fish-Trotter and Ferguson and co-workers are observing is a compensatory myocardial endocrine response, to release upon stimulation by pro-inflammatory mediators, the NPs which function as anti-inflammatory and anti-cytokine hormones. However, the functional ability of the NPs to alleviate inflammation could vary greatly based on factors including presence of a) genetic variants, b) post translational modifications or c) the levels of endogenous NPs could still be insufficient to mount a strong anti-inflammatory response warranting the need for exogenous NP therapies. We speculate that NPs are elevated in inflammation as an immune mediator, which then modulates the inflammatory response through lowering the pro-inflammatory cytokine/anti-inflammatory cytokine ratio as well as changing the cellular components of the immune system to a more functional state to elicit anti-inflammatory functions. It should also be noted that circulating NP levels are lower in African Americans than Caucasians and we feel that such a difference could be a major contributing factor for the increased incidence of metabolic and inflammatory disease in African Americans¹⁵.

What are the next steps to address this compelling role of the NPs and inflammation as reported by Fish-Trotter and Ferguson? Prospective studies should be performed in inflammatory cardiovascular disease states with more comprehensive assessment of pro-inflammatory cytokines and relationship to both the ANP, BNP and CNP cardiac hormones. Such studies should be longitudinal and perhaps imbedded in clinical trials in HF to assess the modulating role of emerging therapies. Clearly, use of NPs as biomarkers for outcomes in inflammatory cardiovascular disease states should also be addressed. Finally, NPs as anti-inflammatory and anti-cytokine therapeutics is a clear next frontier.