The Predictive Value of A, B, and C-Type Natriuretic Peptides in People at Risk of Heart Disease: Protocol for a Longitudinal Observational Study

Abstract

Background Heart disease and stroke are major and often unheralded causes of serious morbidity and premature death in middle age. Early detection of those most at risk is an urgent unmet need for instituting preventative measures. In an earlier community study (Canterbury Health, Ageing and Life Course [CHALICE]) of healthy people aged 50 years, contrary to previous reports, low levels of the heart hormone B-type natriuretic peptide (BNP) were associated with reduced measures of heart function and higher markers of vascular risk. A specific gene variant (rs198358) was found to be an independent contributor to higher BNP levels. A closely related vascular hormone (C-type natriuretic peptide [CNP]) showed opposite associations—higher levels were correlated with higher vascular risk and reduced cardiac function. To determine whether these novel findings predict serious heart or vascular disease in later life, this proposal re-examines the same CHALICE participants 15 years later. Objective The primary objective is to determine the predictive value of (1) low plasma concentrations of the circulating cardiac hormones (atrial natriuretic peptide [ANP] and BNP) and (2) high levels of the vascular hormone CNP at age 50 years in detecting impaired cardiac and vascular function 15 years later. Secondary objectives are to determine specific associations of individual analytes (ANP, BNP, CNP, cyclic guanosine monophosphate [cGMP]) with echo-derived changes in cardiac performance at ages 50 years and 65 years. Methods All of the 348 participants (205/348, 58.9% female; 53/348, 15.2% Māori or Pacifica ethnicity) participating in the original CHALICE study—free of history of heart or renal disease at age 50 years and who consented to further study—will be contacted, recruited, and restudied as previously described. Data will include intervening health history, physical examination, heart function (speckle-tracking echocardiography), vascular status (carotid intimal thickness), and genetic status (genome-wide genotyping). Laboratory measures will include fasting blood sampling and routine biochemistry, ANP, BNP, CNP, their downstream effector (cGMP), and their bio-inactive products. Humoral metabolic-cardiovascular risk factors will be measured after an overnight fast. Primary outcomes will be analyzed using multiple linear regression. Results The study will commence in 2022 and be completed in 2024. Conclusions Proving our hypothesis—that low BNP and high CNP at any age in healthy people predict premature aging of heart and blood vessels, respectively—opens the way to early detection and improved outcomes for those most at risk. Confirmation of our hypotheses would improve current methods of screening and, in appropriate cases, enable interventions aimed at increasing natriuretic hormones and reducing risk of serious cardiovascular complications using drugs already available. Such advances in detection, and from interventional corrections, have the potential to not only improve health in the community but also reduce the high costs inevitably associated with heart failure. International Registered Report Identifier (IRRID) PRR1-10.2196/37011

Association of natriuretic peptides and receptor activity with cardio-metabolic health at middle age

“…The positive links of NPR1 activity with cardiometabolic health, and adaptive links of NPR2 activity in combatting early dysfunction, are significant new findings contributing to improved understanding of the mechanism underpinning cardiovascular health. As a baseline for a concurrent study in progress 11 of the same population 15 years later, the study has the potential to determine causal relationships as people age, and enable beneficial interventions.…”

“…This dichotomy provides the opportunity to dissect out the links of individual peptides with cGMP, and to determine contributions of cGMP to a range of tissue malfunctions emerging at middle age. Based on our previous work 7 showing that small contrived increments of plasma ANP are much more effective than BNP in raising plasma cGMP, we hypothesised 11 that ANP but not BNP will be independently associated with cGMP. Although plasma cGMP shows little or no response to large contrived increments in CNP 3 , the increasing evidence of CNP’s adaptive role in combatting myocardial stiffening 10 , 12 , 13 , prompted us to further postulate that CNP will independently predict cGMP in subjects aged 50 years 11 .…”