N-Terminal Pro C-Type Natriuretic Peptide (NTproCNP) And ... - PLOS

Discussion

In this analysis, we evaluated the utility of NTproCNP as a biomarker of myocardial function in aged community adults. Among community adults, NTproCNP was independently associated with impaired myocardial relaxation, a common manifestation of myocardial ageing in ageing adults[23]. With ageing, left ventricular filling tends to decrease in early diastole, reducing the mitral ratio of peak early to late diastolic filling velocity.

This community cohort of elderly adults did not have clinical cardiovascular disease, such as heart failure, as suggested by relatively low NTproBNP levels. These low levels of NTproBNP are below suggested cut points for excluding asymptomatic heart failure in elderly adults, of particular relevance to our study[24]. Therefore, the myocardial alterations seen in this asymptomatic study population represent changes related to ageing processes.

Age-related diastolic dysfunction has been attributed to an increased passive stiffness, which is associated with increases in left ventricular fibrosis[25]. Lower NTproCNP levels were associated with worsening early to late diastolic filling velocity in our study. This is in agreement with observations in ageing rodents which reported reciprocal increases in left ventricular fibrosis associated with declines in circulating CNP levels[26].

Currently, there are limited studies on NTproCNP in cardiovascular disease in pre-specified cohorts. Our study advances current understanding on NTproCNP as a potential biomarker for cardiovascular states. To the best of our knowledge, we are the first to show a direct association between NTproCNP and measures of myocardial function in community elderly adults. Existing studies exploring NTproCNP as a novel biomarker have largely focused their attention on cohorts with clinical cardiovascular disease [27–29], with hardly any evidence available in relatively healthy human beings. Our results show promise for using NTproCNP in non-disease cohorts, such as in community based asymptomatic adults. Specifically, our results contribute to the current lack of tools available in the investigation of cardiac ageing processes in the humans, and introduce the potential to use NTproCNP as a biomarker of cardiac ageing in human cohorts.

Notably, despite the well-established role of NTproBNP as a diagnostic and prognostic biomarker of heart disease such as heart failure[30], we did not observe associations between myocardial function and NTproBNP in our study sample. NTproBNP levels were similar among those with or without impaired myocardial relaxation in our study. This reinforces the critical need for alternative biomarkers, rather than biomarkers established for clinical disease, to antedate processes prior to expression of clinical disease. Given that impaired myocardial relaxation probably represents early changes within the myocardium with ageing, its distinct association with NTproCNP suggests that NTproCNP may be useful as an ‘upstream’ biomarker useful for charting myocardial ageing.

Our hypothesis-generating observations are interesting and deserve clarification from future mechanistic studies. However, we postulate that our observations may be explained by differences in functional characteristics between NTproBNP and NTproCNP. NTproBNP is primarily secreted by cardiomyocytes in response to increased ventricular stretching and serves a natriuretic function, particularly observed in heart failure states, where natriuretic function is critical in restoring fluid balance in heart failure. On the other hand, in non-heart failure states, NTproCNP may represent a ‘protective’ function, such as in cardioprotection, to maintain cardiovascular function in health[31,32]. CNP has been found to inhibit endothelin-1 induced cardiac myocyte hypertrophy via a cGMP-dependent mechanism, with antihypertrophic and antifibrotic effects on the heart[33]. Studies show that CNP fulfils this function via regulating vascular homeostasis, promoting cardiomyocyte relaxation, stimulating endothelial cell regeneration, inducing coronary vasodilation, inhibiting vascular smooth muscle proliferation and migration, and suppressing cardiac fibroblast proliferation[28,34–37] (Fig 1). Thus, lower levels of NTproCNP may represent lower levels of cardioprotection. The question as to whether NTproCNP is merely a bystander representing healthy myocardium or a key player involved in preservation/protection of myocardial function requires future mechanistic studies.

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Fig 1. Function of C-type natriuretic peptide.

CNP is an endothelium-derived peptide that is believed to have a cardioprotective function in both healthy and disease states. While BNP directly causes natriuresis in addition to other functions, CNP acts primarily on the heart and blood vessels. In the heart, CNP induces coronary vasodilation, promotes cardiomyocyte relaxation, and exerts antihypertrophic and antifibrotic effects. In the vessels, CNP relaxes smooth muscle and inhibits its proliferation and migration, while also inhibiting catecholaminergic effects, stimulating endothelial cell regeneration, and regulating vascular homeostasis. (BNP–B-type natriuretic peptide, CNP–C-type natriuretic peptide).

https://doi.org/10.1371/journal.pone.0209517.g001

Further, in the evaluation of NTproCNP as a potential biomarker of myocardial function in ageing, our study attempted to determine a cut-off value of NTproCNP that could identify impaired myocardial relaxation with reasonable specificity. Larger studies in the future are necessary to confirm our observations about appropriate cut-offs for NTproCNP, adjusted to specificity or sensitivity thresholds. However, our data provides a glimpse of how NTproCNP levels may be handled in similar investigations.

We acknowledge limitations of our study. Firstly, NTproCNP levels are assumed to reflect levels of CNP. It is possible that NTproCNP and CNP levels do not correlate perfectly in milieu. However, prior reports have suggested significant correlations observed between NTproCNP and CNP such that NTproCNP could be used as a suitable substitute for assessment of CNP status in the circulation[19]. Secondly, our cross-sectional observations preclude causal inferences between NTproCNP and myocardial function. Longitudinal observations investigating changes in NTproCNP in relation to myocardial function in the same cohort, in addition to mechanistic studies, may provide stronger causal inferences in the future. Thirdly, our results are only applicable to elderly community adults, and results may differ in other community cohorts of different age and ethnicity. Fourth, we only studied one aspect of myocardial function, which is impaired myocardial relaxation. The association between NTproCNP may differ according to the type of cardiovascular dysfunction studied. Finally, while we observed statistically significant associations, the sample size was small and limited our ability to perform subgroup analyses.

In summary, our findings suggest that NTproCNP could be a suitable candidate biomarker for cardiac ageing, advancing our understanding of mechanisms involved in cardiac ageing.