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New Insights into Cardiac and Vascular Natriuretic Peptides: Findings from Young Adults Born with Very Low Birth Weight.

Infants born before 32 weeks of gestation, or those weighing <1500 g at birth [very low birth weight (VLBW) [4]], face a range of health problems in early life, including disorders of nutrition, respiratory function, and neurological deficits (1). Improved standards of neonatal care and effective monitoring during childhood have resulted in higher survival rates into adulthood (up to 90% in some studies) but reveal increased incidence of cardiovascular disorders in later years (2). Specifically, higher prevalence of hypertension, impaired insulin sensitivity, glucose intolerance, renal impairment, and lipid disorders (2, 3) have all been reported in VLBW adults and likely contribute to the inverse association of birth weight to cardiovascular morbidity and mortality (4). Although the underlying pathogenesis remains unclear, changes in the vascular endothelium appear to play a central role (5). Early detection of those most at risk of cardiovascular disorder offers the prospect of beneficial interventions, yet reliable screening procedures in young adults remain an unmet need.

In community studies of older people without history of cardiac or vascular disease, higher concentrations of the cardiac hormones atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) have been used to identify subclinical cardiac disease as well as those most at risk of adverse outcomes (6, 7). However, there are also reports that higher BNP reduces risk of developing metabolic disorders and diabetes (8). To our knowledge, these hormones have not been studied in those born with VLBW. C-type natriuretic peptide (CNP), a vasoprotective paracrine factor (9) widely expressed in tissues including the vascular endothelium (10), is a further candidate warranting evaluation as a marker of vascular integrity (11), especially as expression of the CNP gene, NPPC5, and CNP peptide is increased in arteriosclerotic vessels (12). Unlike the cardiac hormones ANP and BNP, which have well-defined endocrine actions, products of NPPC expression, such as proCNP 1-103 (proCNP), and its processed bioactive products, CNP 51-103 (CNP 53) and CNP 81-103 (CNP 22), are thought to act locally. Bioactive forms (CNPs 53 and 22) circulate at low levels--close to limits of detection--in healthy adults, consistent with their rapid degradation at source (13). However, a presumably bioinactive aminoterminal fragment of proCNP (aminoterminal proCNP1-50, NTproCNP) escapes degradation and is readily measured in plasma (14). Once growth-plate epiphyses have closed, concentrations of NTproCNP are relatively stable in adults until the fourth decade, when they progressively increase, particularly in males (15). Positive associations with higher arterial pressure (16) and other vascular risk factors (15) suggest that plasma NTproCNP may reflect an adaptive (compensatory) response to vascular stress and therefore may precede similar adaptive changes of BNP in response to cardiac stress at a later date. If so, the response of these respective peptides may differ in young adults known to be at risk of future cardiovascular disorder.

Using a wide range of vascular and metabolic markers, as well as echocardiography, we have now evaluated BNP and CNP peptides as potential biomarkers of cardiovascular risk at age 28 years in 229 subjects born with VLBW and 100 age- and sex-matched controls. On the basis of our previous CNP findings, as well as literature reports of BNP in community studies (6), we postulated (a) that height will be reduced and blood pressure and CNP will be raised in VLBW subjects compared with controls, and (b) that across all individuals, positive associations of CNP with vascular and metabolic risk will be stronger than those with BNP.

Subjects and Methods

STUDY POPULATION

Details of the New Zealand 1986 VLBW cohort study and objectives have been published previously (1).In the current study (1), 229 participants (71% of the surviving cohort) gave informed consent for restudy at 1 center (Christchurch, New Zealand). For comparison, 100 subjects born full term in New Zealand in 1986, and who had not been admitted to an intensive care unit, were recruited through peer nomination by cohort member or via random sampling from the electoral rolls, seeking balance with respect to sex, ethnicity, and regional distribution (1). Blood sampling sufficient to undertake analyses for the present study was available for 220 VLBW cases and 97 controls. In 11 of the 317 participants, echo-cardiographic reports were unavailable. Of the VLBW participants in this study, 56% had received prenatal glucocorticoids and 32% were small for gestational age. Analysis of their impact and associations of prematurity with growth and metabolic outcome in this study population are reported separately.

STUDY PROCEDURES

The study was approved by the Southern Health and Disability Ethics Committee, and all participants gave written informed consent. All procedures (involving a 2-day multidisciplinary evaluation) were conducted at the University of Otago, Christchurch, and Canterbury District Health Board facilities by trained staff who were blinded to the background of participants. Participants completed a standardized health questionnaire, including self-reported morbidities, and anthropometric measurements [height using a Harpenden stadiometer, weight, body mass index (BMI), waist--hip circumference] were recorded. Blood pressure (the third of 3 readings recorded within a 15-min period of resting) was measured manually by trained health professionals using a mercury sphygmomanometer with a large cuff for arm circumference >33 cm in the participants' nondominant arm while individuals were seated. Standardized transthoracic echocardiography was performed using an iE33 ultrasound machine (Philips Life Healthcare). Left ventricular (LV) elastance [systolic blood pressure/LV end systolic volume (LVESV)] and arterial elastance (systolic blood pressure/LV stroke volume) were calculated as detailed by Chantler et al. (17). Endothelial function [log normal transformed reactive hyperemic index (Ln RHI)] was measured by peripheral arterial tonometry (18). After the participants fasted overnight, venous blood was collected and rapidly separated, and plasma samples were stored frozen at minus 80 [degrees]C for assay within 6 months of receipt. Circulating aldosterone (19), plasma renin activity (20), NTproCNP (21), and NTproBNP (22) were assayed as previously described. Intraassay and interassay CVs were as follows: NTproCNP, 6.6% and 8.1% at 224 pg/mL and NTproBNP, 4.9% and 5.9% at 703 pg/mL. Plasma creatinine and glucose were determined by the Architect c8000 analyzer (Abbott Laboratories). High-sensitivity Troponin T was assayed on a Roche Cobas e411 analyzer (limits of blank and detection were 3 ng/L and 5 ng/L, respectively). Insulin was assayed on a Roche Cobas e411 analyzer after polyethylene glycol precipitation of immunoglobulins. Plasma triglycerides, HDL cholesterol, and total cholesterol were measured on an Abbott c-series analyzer using Abbott reagents. The following equation was used to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) (23) score: HOMA-IR = fasting insulin (mIU/L) X fasting glucose (mg/dL)/22.5. Estimated glomerular filtration rate was calculated by the abbreviated Modification of Diet in Renal Disease study equation (24). Body surface area was calculated using the Mosteller method (body surface area = [square root] (height X weight/3600). Exposure to tobacco was determined by the urine concentration of cotinine >500 ng/mL. The albumin creatinine ratio was determined using an early morning urine sample.

GENOTYPING

Seven single-nucleotide polymorphisms (SNPs) in genes within the natriuretic peptide system were selected from those reported in genome-wide association studies to either affect circulating ANP/BNP concentrations (25) or blood pressure (26) (see Table 1 in the Data Supplement that accompanies the online version of this article at http://www.clinchem.org/content/vol64/issue2). All SNPs (rs198389, rs1173771, rs5068, rs198358, rs17367504, rs632793, rs198388) were genotyped by Taqman[R] assays per the manufacturer's instructions, except rs198389, which was genotyped by Sequenom custom assay (Liggins Institute, University of Auckland). All SNPs were initially analyzed using an additive model, with a dominant model explored when there was a precedent from the literature.

STATISTICS

Differences between groups (VLBW cases, controls; metabolic syndrome present, absent) were determined using the Student i-test or Fisher exact test as appropriate. NT-proBNP, NTproCNP, triglyceride, and HOMA-IR data were log10-transformed to satisfy parametric assumptions. Univariate associations between natriuretic peptides and risk factors were assessed using Spearman correlation coefficients. Independence was assessed by multivariate analysis using backward stepwise regression in a model comprising 11 separate variables found significant in univariate analyses. Statistical significance was assumed when P < 0.05.

Results

COMPARISON BETWEEN VLBW ADULTS AND CONTROLS

Of 317 adults studied, the female-to-male ratio was 1.2 in the VLBW group and 1.8 in controls (P = 0.11). Ethnic distribution in VLBW adults (European, 68%; Maori/Polynesian, 31%; Asian, 1%) was similar to controls (73%, 26%, and 1%, respectively). At the time of sample collection, 6 of the VLBW adults and 4 controls were pregnant (all <27 weeks' gestation). The percentages of participants with comorbidities in the 2 groups did not differ significantly (see Table 2 in the online Data Supplement).

Clinical, hemodynamic, vascular, and metabolic risk factors, together with plasma NTproCNP and NTproBNP concentrations, are shown in Table 1. VLBW adults were significantly shorter and lighter and their systolic and pulse pressures significantly higher than in controls. Measures of heart size and stroke volume were lower in VLBW adults, whereas both LV and arterial elastance were increased. Ln RHI was lower in VLBW adults. Of the many humoral vascular and metabolic risk factors measured, including NTproBNP, only plasma NT proCNP (higher in those with VLBW) differed significantly. Analyzed according to sex (Table 2), the impact of VLBW on heart size and Ln RHI was greater in females. In both sexes, height, LV end diastolic volume, and stroke volume were all significantly lower in VLBW adults, whereas arterial elastance and plasma NT proCNP were higher compared with controls.

UNIVARIATE ASSOCIATIONS OF NATRIURETIC PEPTIDES WITH RISK FACTORS AND ECHO FINDINGS

Across all VLBW cases and control subjects combined, of the many conventional risk factors examined, natriuretic peptides were significantly associated with 7 (Table 3). All 7 factors were positively correlated with NTproCNP, whereas the associations with NTproBNP were all inverse (Fig. 1). The obverse association with systolic blood pressure is shown in Fig. 2. Similarly, arterial and LV elastance were obversely correlated--inversely with NTproBNP and positively with NTproCNP (Table 4). In VLBW adults, obverse associations were retained in 5 of the 7 conventional risk factors (Table 3) and in arterial and LV elastance (Table 4). When analyzed by sex, associations of NTproBNP in the VLBW group were all stronger in females--except for creatinine--whereas associations of NTproCNP were stronger in males. Similar trends were observed in controls (Table 3). Similarly, the associations of NTproCNP with elastance were stronger in males than in females with VLBW (Table 4).

As NTproBNP was higher in those with lower vascular and metabolic risk but NT proCNP was lower, the association of both peptides, as well as the ratio of NT proBNP to NT proCNP, with a composite index of risk was examined. In generating this index, internationally recognized cutoff values were used for systolic blood pressure (>120 mmHg), cholesterol/HDL (>4.5), triglycerides (>150 mg/dL or >1.69 mmol/L), and HOMA-IR (<2.05) (23). Associations ([rho]) with the composite index were -0.27, 0.29, and -0.34 for NT proBNP, NT proCNP, and the ratio of NTproBNP to NT proCNP, respectively--a higher value of the ratio reflecting a more favorable vascular and metabolic status.

MULTIVARIATE ANALYSES

The relative strength of conventional risk factor associations with peptide concentrations was assessed using multivariate analysis. In addition to the 7 factors depicted in Fig. 1, the model also incorporated sex, height, weight, and status (VLBW cases vs control). These 11 factors were then subjected to backward stepwise regression. The results showed that for NTproBNP, sex (P = 0.001), diastolic blood pressure (P = 0.02), creatinine (P = 0.02), and HOMA-IR (P = 0.02) remained independently significant associations. For NTproCNP, sex (P = 0.005), cholesterol/HDL (P = 0.03), HOMA-IR (P = 0.04), creatinine (P < 0.001), and status (P < 0.001) remained significant.

ASSOCIATIONS WITH METABOLIC SYNDROME

Metabolic syndrome is a recognized adverse outcome in those born with VLBW (3). Its prevalence and impact on natriuretic peptides are shown in Table 3 of the online Data Supplement. As defined by the International Diabetes Federation (27), the prevalence of the metabolic syndrome trended higher in VLBW adults than in controls (17% and 12%, respectively; P = 0.32). Plasma NT proCNP was significantly higher (P < 0.001) in those with metabolic syndrome compared with those without. Although NTproBNP was higher in the absence of the syndrome, the difference from controls was not significant (P = 0.24).

GENETIC VARIANTS AFFECTING BNP SIGNALING PATHWAY

Genome-wide association studies in the community have identified NPPA and NPPB polymorphisms associated with lower blood pressure and higher circulating concentrations of the cardiac natriuretic peptides ANP and BNP (25). Other studies have identified NPPB SNPs associated with higher plasma BNP and decreased risk of lipid disorder, metabolic syndrome, and diabetes (28). Therefore, the inverse association we observed between NT proBNP and vascular metabolic risk factors prompted us to examine whether such SNPs were contributing to the associations described above. All 7 SNPs examined (see Table 1 in the online Data Supplement) were in Hardy-Weinberg equilibrium. Comparing VLBW cases and controls, the frequencies of minor alleles did not differ significantly for any of the SNPs investigated. In the overall cohort combining VLBW participants and controls (n = 303), there was a significant inverse association of the rs198358 minor allele (NPPA-NPPB locus; frequency, 0.24) with serum cholesterol (P = 0.02), LDL cholesterol/HDL cholesterol (P = 0.01), and triglycerides (P = 0.004). A positive association ofrs198358 with NTproBNP levels was not significant when analyzed using an additive model (P = 0.11) but was significant when analyzed in a dominant model (P = 0.04). Including the rs198358 SNP in the multivariate model, backward stepwise regression revealed that diastolic blood pressure (P < 0.001), creatinine (P = 0.008), sex (P = 0.035), waist-to-hip ratio (P = 0.015), and this SNP (P = 0.05) remained independent predictors of plasma NTproBNP. Of the other SNPs examined, positive association of rs1173771 SNP with HDL cholesterol (P = 0.03) and inverse association of rs17367504 SNP with LDL cholesterol (P = 0.04) were found. Both SNPs were also associated with a trend for higher NTproBNP, which did not reach statistical significance.

Discussion

Plasma concentrations of natriuretic peptides are currently widely used in the early detection of impaired cardiac function. Although subjects born with VLBW are known to be at risk of premature metabolic and cardiovascular disorders in adulthood, these peptides have not previously been studied systematically in this setting, nor has CNP been conclusively linked to vascular stress. Here we show that, at age 28 years, young adults born with VLBW are shorter than age-matched controls and have higher systolic blood pressure, smaller heart size, and higher levels of LV and arterial elastance, along with lower Ln RHI. Of the many humoral markers of metabolic and vascular risk measured, only plasma NT proCNP (higher in VLBW cases) differed significantly. In associative studies across all subjects, significant positive correlations ofNTproCNP were identified with each of 7 conventional risk factors. Together, these findings support our hypothesis linking NTproCNP with metabolic and vascular risk. However, the second postulate--that associations with NTproBNP would be directionally similar but weaker in these young adults--was negated by the findings that all were significantly inverse. These unexpected findings suggest that the positive link of NT proCNP reflects an adaptive response to vascular stress, whereas the inverse association of NTproBNP likely reflects beneficial genetic actions, raising levels and reducing metabolic (8) and vascular (25) risk. Notably, these obverse associations were not confined to VLBW. In fact, the directional shift was maintained for all 7 vascular risk factors in controls and was equally strong for serum creatinine and waist-to-hip ratio as observed in VLBW adults. This is not surprising in view of the relatively high prevalence of risk in the general community. Together, the results provide new insights to the contrasting underlying mechanisms affecting circulating levels and the role of these peptides in maintaining cardiac and vascular health in humans. Applying these observations--for example, the ratio of NTproBNP to NTproCNP--may provide a novel index of ideal cardiovascular health (29) that now needs to be evaluated in older age-groups. Importantly, application of this ratio in adults born with low birth weight may allow earlier preventative strategies that reduce vascular complications in later life.

Despite continuing evidence of CNP's critical role in maintaining vascular integrity (11), there are few, if any, studies of plasma CNP products in humans at risk of vascular disease. In fact, the only previous study in this context reports that plasma NTproCNP is inversely associated with a range of vascular risk factors (including measures of arterial stiffness) in older men without history of cardiac or vascular disorders (30). Our study of young adults of mixed sex, all the same age, shows precisely the opposite--positive associations of NTproCNP

with each of 7 established vascular-metabolic risk factors. Further, blood pressure, pulse pressure, arterial elastance, and plasma NTproCNP were all significantly higher in VLBW adults compared with controls. Mechanisms whereby CNP is increased in VLBW subjects likely relate to increased arterial elastance (a measure of arterial stiffness) and augmented pulsatile pressure in the microcirculation, which upregulates NPPC gene expression as shown in ex vivo studies (31). Higher systemic pressure and endothelial dysfunction are also likely to contribute. Collectively, these results add to previous findings linking NTproCNP to vascular stress (15, 16, 32), but the wide array of tissues expressing CNP, as well as factors affecting clearance of NTproCNP from plasma, also needs consideration. Although cardiac secretion of NTproCNP has been documented in older subjects presenting with cardiac disorders (33), such contributions to circulating concentrations are trivial compared with BNP products and could arise from inflamed coronary arteries (32) because the NTproCNP arteriovenous gradient across the heart did not correlate with measures of cardiac performance (33). Renal clearance is an important determinant of plasma NTproCNP but can be excluded because serum creatinine did not differ between VLBW adults and controls. However, the well-established inverse association of plasma NTproCNP with adult height (15)--itself a vascular risk factor (34)--could be relevant. On this score, the finding that status (VLBW), and not height, was a significant independent contributor to NTproCNP across all subjects makes it unlikely that height is a major influence in the current study. Whether gene polymorphisms also affect the positive CNP associations with risk--for example, loss of function in NPR2 (15)--will be important to explore and could link the association between shorter stature and cardiovascular disease (34) with higher concentrations of NT proCNP (15).

Although many community studies of subjects without history of cardiac or vascular disorders show that higher concentrations of plasma BNP or NTproBNP can be used to identify subclinical cardiac disease, there are increasing reports showing that higher BNP in asymptomatic subjects without history of heart disease confers benefit by reducing risk of adverse metabolic events (8) but not blood pressure, which remains a positive association with this peptide in numerous previous reports (8, 35). However, large genome-wide association studies have demonstrated that polymorphisms in NPPB and NPPA, increasing respective plasma peptide concentrations, are associated with lower blood pressure (25). Aligning with these reports, despite the small numbers studied, we found the frequency (0.24) of the minor allele rs198358 closely simulated that reported in the European population 1000 Genomes project (0.214) and was an independent predictor of plasma NT-proBNP. Taken together with findings from other SNPs analyzed, we postulate that all the inverse associations identified here are largely driven by these BNP polymorphisms. The differing relationships of NTproBNP with blood pressure (current vs previous reports) likely relate to the younger population (all the same age), ethnicity (mostly European), and lower mean blood pressure in our study. Notably, we found no associations of either natriuretic peptide with BMI. Obesity is known to be associated with lower NTproBNP and, together with sex (higher concentrations are found in females), may complicate interpretation of risk using BNP products in community studies (29). Although excessive weight gain in VLBW subjects in early postnatal life is reported to pose additional cardiovascular risk (2), relationships linking systolic blood pressure, NTproCNP, or HOMA-IR with BMI did not differ in VLBW cases from those in controls in the current study. Collectively, these findings argue against an important role of adipose tissue driving natriuretic peptide concentrations in this study.

LIMITATIONS

Several factors need to be considered before our findings can be applied to other populations. This is the first report on plasma concentrations of natriuretic peptides in subjects born with VLBW, which now requires confirmation preferably in larger multicenter studies. We used well-established and fully validated in-house assays of the natriuretic peptides, and it remains to be seen whether similar results are obtained using commercial assays that may have different sensitivity and specificity. However, we find excellent correspondence (36) between our NTproBNP RIA and the Roche Diagnostic assay (r = 0.95) across the concentration range found in this report. Head-to-head comparison of our in-house NTproCNP assay with the only commercial 2-site polyclonal ELISA (Biomedica) also shows good agreement (r = 0.78; n = 42), although readout was only 20% of the RIA value (21). Importantly, ethnicity may affect concentrations of NTproBNP in community studies. Values are reportedly lower in blacks and those of Chinese ancestry (37)--aligning with their higher incidence of cardiovascular disorders compared with white populations. In the current study, median concentration of plasma NTproBNP in those of Polynesian ancestry (31% of the subjects) was 107 ng/L and not significantly different from that of Europeans (97 ng/L; P = 0.6). Finally, whether the obverse relationships of the cardiac (BNP) and vascular (CNP) peptides with vascular risk we identify in young subjects will also be apparent in older people (in whom subclinical organ dysfunction is more prevalent) will be a crucial question to address. Because plasma NTproCNP is likely to reflect vascular stress, we anticipate that the positive associations we identified with all vascular risk factors will be maintained and possibly intensified in older subjects. For NTproBNP, the picture is more complicated by the intersection of genetic advantage (raising levels) and the increasing prevalence of pathological (adaptive) responses of the heart and vasculature, which also raise levels. Notably, community studies of NTproBNP show that subjects with levels in the upper quartiles are less prone to lipid disorders, diabetes, and metabolic syndrome (35) even at advanced age ([greater than or equal to] 70 years) (8). Although yet to be proven in humans, similar beneficial effects may make them less prone to hypertension and associated end-organ damage (38). Therefore, it is possible that beneficial SNPs increasing BNP concentrations in plasma may be contributing to better cardiovascular health throughout life, in which case the proposed ratio of NTproBNP to NT proCNP could still be a valid marker of ideal cardiovascular health in older age-groups in the community. Alternatively, application of an NTproBNP cutoff or threshold concentration (e.g., >100 ng/L) (39) could be used. Concentrations below the threshold may be used to distinguish beneficial (physiological) from the (higher, >100 ng/L) pathological values (40), improving discrimination. Clearly, further studies--preferably longitudinal ones--are required to capture the dynamic effects of reverse causality. Defining the boundaries that distinguish normal from pathological will be even more critical now that plasma BNP peptides are viewed as prospective markers of subclinical disease (7), with applications in decisions affecting the implementation of preventative strategies.

In conclusion, we provide new insights into the respective roles of the cardiac hormone (BNP) and the vascular peptide (CNP) in young adults at increased risk of cardiovascular disease. Positive links of CNP with risk likely reflect a compensatory response to vascular stress, whereas the negative link of BNP with risk likely reflects beneficial genetic mutations. Therefore, we postulate that measuring both peptides--for example, calculating the ratio of NTproBNP to NTproCNP--will provide a novel index of ideal cardiovascular health (29), which now needs to be evaluated as a potential marker of adverse cardiovascular outcomes in older age-groups more vulnerable to vascular disorders.

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following3 requirements: (a) significant contributions to the conception and design, acquisition Of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: L.J. Horwood, University of Otago.

Consultant or Advisory Role: None declared.

Stock Ownership: None declared.

Honoraria: None declared.

Research Funding: Cure Kids. T.C.R. Prickett, the New Zealand Lottery Grants Board, the Christchurch Heart Institute; B.A. Darlow, New Zealand Health Research Council (project grant 12-129), the Child Health Research Foundation (CHRF 5040 and CHRF 5041). Expert Testimony: None declared.

Patents: T.C.R. Prickett, WO2014027899 A1; E.A. Espiner, 14/421,423.

Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or final approval of manuscript.

Acknowledgment: The authors thank all the young adult participants for their willingness to take part in this study. They also acknowledge funding and strong logistical support from the Christchurch Heart Institute.

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Timothy C.R. Prickett, [1] * Brian A. Darlow, [2] Richard W. Troughton, [1] Vicky A. Cameron, [1] John M. Elliott, [1] Julia Martin, [2] L. John Horwood,3 and Eric A. Espiner [1]

[1] Department of Medicine, University of Otago, Christchurch, New Zealand; [2] Department of Paediatrics, University of Otago, Christchurch, New Zealand; [3] Department of Psychological Medicine, University of Otago, Christchurch, New Zealand.

* Address correspondence to this author at: Department of Medicine, University of Otago, Christchurch, 2 Riccarton Ave., PO Box4345, Christchurch 8140, New Zealand. Fax +643-364-0818; e-mail tim.prickett@otago.ac.nz.

Received August 2,2017; accepted October 2,2017.

Previously published online at DOI: 10.1373/clinchem.2017.280354

[C] 2017 American Association for Clinical Chemistry

[4] Nonstandard abbreviations: VLBW, very low birth weight; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide; NTproCNP, aminoterminal proCNP; BMI, body mass index; LV, left ventricular; Ln RHI, log normal transformed reactive hyperemic index; NTproBNP, aminoterminal proBNP; HOMA-IR, homeostatic model assessment of insulin resistance; SNP, single nucleotide polymorphism.

[5] Human genes: NPPC, C-type natriuretic peptide; NPPA, atrial natriuretic peptide; NPPB, B-type natriuretic peptide; NPR2, natriuretic peptide receptor B.

Caption: Fig. 1. Comparison of correlation coefficients of NT proBNP and NT proCNP with vascular metabolic risk factors. BP, blood pressure. * P< 0.05, ** P< 0.01.

Caption: Fig. 2. Inverse association of NTproBNP (top) and positive association of NTproCNP (bottom) with systolic blood pressure. Lines, regression line fit by the method of least squares. Spearman correlation coefficient is shown.
Table 1. Clinical, echocardiography, and laboratory findings (median
and interquartile range) in VLBW adults and controls.

                                   VLBW               Controls

Variable                         n = 220               n = 97

Age, year                    28.3 (27.4-29.2)     28.2 (27.6-28.9)
Height, cm                  168 (162-176) (a)      171 (167-178)
Weight, kg                    71 (60-85) (b)         75 (65-88)
BMI                          24.2 (21.5-27.8)     25.7 (23.2-29.7)
Waist/hip ratio              0.83 (0.77-0.89)     0.82 (0.76-0.86)
Systolic BP, mmHg           112 (106-121) (a)       108 (102-114)
Diastolic BP, mmHg             72 (68-80)            72 (68-78)
Pulse pressure, mmHg          40 (32-46) (a)         38 (30-42)
LV ejection fraction, %         65 (62-67)           65 (62-67)
Heart rate, beats/min          70 (62-81)            70 (61-78)
LVEDV (c), mL              57.8 (50.5-64.2) (a)   61.8 (55.5-70.3)
LVESV (c), mL              20.2 (17.1-23.6) (b)   21.8 (19.7-25.7)
LV mass (c), g               89.4 (77.9-103)       92.5 (78.4-106)
LV stroke volume (c), mL   37.2 (32.5-41.4) (a)   40.3 (34.7-45.5)
LV elastance (c), mmHg/mL    5.6 (4.8-6.6) (a)       5.0 (4.1-5.8)
E/e'                          7.0 (6.0-8.0)        7.1 (6.0-8.2)
LA area (c), [cm.sup.2]        9.3 (8.2-10.3)       9.5 (8.7-10.8)
Arterial elastance (c),      3.1 (2.7-3.5) (a)       2.7 (2.4-3.1)
  mmHg/mL
Hs Troponin, ng/L              <5 (<5-5.4)          <5 (<5-5.8)
Ln RHI                     0.58 (0.41-0.77) (b)   0.67 (0.49-0.85)
Aldosterone, ng/dL            7.0 (4.7-10.2)       6.3 (4.3-8.4)
Plasma renin                    49 (35-70)           44 (35-65)
  activity, ng/mL/h
Glucose, mg/dL                  92(85-97)            88 (83-94)
Insulin, [micro]U/mL          8.2 (5.6-12.1)       7.7 (5.4-11.6)
HOMA-IR                        1.9 (1.2-2.8)        1.7 (1.2-2.5)
Cholesterol/HDL                3.6 (3.1-4.5)        3.6 (3.0-4.3)
Triglycerides, mg/dL            97 (71-142)          80 (62-115)
eGFR, mL/min/1.73               86 (78-94)           84 (76-92)
  [m.sup.2]
Creatinine, mg/dL            0.95 (0.86-1.04)     0.94 (0.87-1.01)
NTproCNP, ng/L               101 (87-118) (a)        90 (79-105)
NTproBNP, ng/L                 99 (54-167)          100 (61-155)
Urine ACR                     0.6 (0.4-1.2)         0.5 (0.3-0.8)
Urine cotinine, % + ve              33                   24

Comparison of VLBW cases and controls using Student t-test or Fisher
exact test as appropriate.

To convert mg/dL to mmol/L, multiply by 0.0113 for triglycerides, by
0.088 for creatinine, and by 0.0555 for glucose.

(a) P <0.001.

(b) P <0.05.

(c Values indexed to body surface area.

BP, blood pressure; LA, left atrium; LVEDV, left ventricular end/
diastolic volume; LVESV, left ventricular end/systolic volume; E/e',
ratio of transmitral Doppler early filling velocity to tissue Doppler
early diastolic mitral annular velocity; Hs Troponin, high
sensitivity Troponin; eGFR, estimated glomerular filtration rate;
ACR, urine albumin creatinine ratio.

Table 2. Sex-dependent variables in VLBW cases and controls. (a)

                                  VLBW               Controls
Females                         n = 120               n = 63

Height, cm                 163 (159-166) (b)       168(165-172)
Weight, kg                   64 (55-81) (c)         73 (65-87)
Waist/hip ratio             0.79(0.75-0.85)      0.80 (0.75-0.83)
Systolic BP, mmHg             110(100-116)         104(100-112)
Diastolic BP, mmHg             72(64-78)            72 (66-76)
Pulse pressure, mmHg         36 (32-44) (c)         36 (30-39)
LV ejection fraction, %        66(63-68)            65 (62-67)
LVEDV (d), mL                55 (49-62) (b)         61 (57-68)
LVESV (d), mL             19.1 (16.4-21.3) (b)    21.6(19.8-25)
LV mass (d), g                 80 (71-94)           88(77-105)
LV stroke volume (d), mL   35.9 (31.7-40.0) (c)   40.1 (35.5-43.4)
LV elastance (d), mmHg/mL   5.7 (4.9-6.7) (b)      5.0 (4.2-5.5)
LA area (d), [cm.sup.2]       9.4 (8.3-10.4)        9.6(9-10.8)
Arterial elastance (d),     3.0 (2.7-3.5) (c)      2.6 (2.4-3.0)
  mmHg/mL
Hs Troponin, ng/L (e)               <5                   <5
Ln RHI                    0.57 (0.34-0.75) (c)   0.69 (0.43-0.89)
NTproCNP, ng/L              93 (81-104) (c)         84 (76-99)
NTproBNP, ng/L                128(86-213)          121 (76-184)

                                  VLBW               Controls
Males                           n = 100               n = 34

Height, cm                 176 (172-180) (b)      181 (177-185)
Weight, kg                     77 (67-89)           80 (70-95)
Waist/hip ratio             0.87(0.83-0.92)      0.86 (0.83-0.91)
Systolic BP, mmHg          120 (112-126) (c)       114(106-120)
Diastolic BP, mmHg             77(72-84)            73 (70-80)
LV ejection fraction, %     64.1 (61.0-66.9)     64.6 (62.2-67.2)
Pulse pressure, mmHg           42 (38-50)           39 (34-42)
LVEDV (d), mL                 61 (54-68) (c)         63 (55-77)
LVESV (d), mL                21.5(19.1-25.1)      22.4(18.9-28.8)
LV mass (d), g                  97(87-108)          103 (88-117)
LV stroke volume (d), mL      38 (34-43) (c)         41(34-51)
LV elastance (d), mmHg/mL     5.2 (4.4-6.4)        5.0 (3.9-6.0)
LA area (d), [cm.sup.2]       9.1 (8.0-10.2)       9.2 (8.4-10.5)
Arterial elastance (d),     3.1 (2.7-3.5) (c)      2.7 (2.3-3.5)
  mmHg/mL
Hs Troponin, ng/L (e)          <5 (<5-6.2)          <5 (<5-6.3)
Ln RHI                      0.58 (0.44-0.78)     0.64 (0.51-0.80)
NTproCNP, ng/L              112 (99-131) (c)       103 (90-111)
NTproBNP, ng/L                71 (42-117)          62 (46-100)

(a) Values are median (interquartile range).

(b) P <0.001.

(c) P <0.05.

(d) Indexed to body surface area.

(e) 79% and 60% of Hs Troponin measurements for females and males,
respectively, were below the limit of detection. There was no
difference in the fraction of those with undetectable values in the
VLBW and control groups.

BP, blood pressure; LA, left atrium; LVEDV, left ventricular end-
diastolic volume; LVESV, left ventricular end-systolic volume; Hs
Troponin, high sensitivity Troponin.

Table 3. Associations between vascular risk factors and aminoterminal
natriuretic peptides.

                               sBP           dBP       Triglycerides
All subjects (n = 317)#

  NTproBNP                 -0.32 (a)#    -0.29 (a)#     -0.11 (b)#
  NTproCNP                 0.27 (a)#     0.20 (a)#      0.20 (a)#
Female (n = 183)
  NTproBNP                 -0.25 (a)#    -0.28 (a)#        -0.04
  NTproCNP                    0.04          0.04           0.14
Male (n = 134)
  NTproBNP                    -0.15         -0.09          -0.04
  NTproCNP                    0.16          0.11           0.13
VLBW (n = 220)#
  NTproBNP                 -0.33 (a)#    -0.30 (a)#        -0.08
  NTproCNP                 0.29 (a)#     0.22 (b)#      0.20 (b)#
Female (n = 120)
  NTproBNP                 -0.24 (b)#    -0.27 (b)#        -0.04
  NTproCNP                    0.02          0.01           0.12
Male (n = 100)
  NTproBNP                    -0.15         -0.09          0.01
  NTproCNP                 0.24 (b)#        0.12           0.13
Control (n = 97)#
  NTproBNP                 -0.32 (b)#    -0.24 (b)#        -0.19
  NTproCNP                    0.16          0.14           0.16
Female (n = 63)
  NTproBNP                 -0.33 (b)#    -0.31 (b)#        -0.08
  NTproCNP                    0.01          0.16           0.11
Male (n = 34)
  NTproBNP                    -0.10         -0.15          -0.20
  NTproCNP                    -0.14         -0.08          0.01

                           Cholesterol/   Creatinine      HOMA-IR
All subjects (n = 317)#     HDL ratio

NTproBNP                   -0.22 (a)#     -0.34 (a)#    -0.16 (b)#
NTproCNP                    0.22 (a)#     0.48 (a)#     0.12 (b)#
Female (n = 183)
NTproBNP                   -0.19 (b)#        -0.12      -0.21 (b)#
NTproCNP                       0.14       0.35 (a)#        0.09
Male (n = 134)
  NTproBNP                    -0.07       -0.25 (b)#       -0.17
  NTproCNP                     0.13       0.22 (b)#     0.22 (b)#
VLBW (n = 220)#
  NTproBNP                 -0.23 (a)#     -0.33 (a)#    -0.20 (b)#
  NTproCNP                  0.29 (a)#     0.50 (a)#        0.13
Female (n = 120)
  NTproBNP                 -0.22 (b)#        -0.07      -0.31 (a)#
  NTproCNP                     0.16       0.39 (a)#        0.03
Male (n = 100)
  NTproBNP                    -0.04       -0.25 (b)#       -0.15
  NTproCNP                     0.18       0.21 (b)#     0.33 (a)#
Control (n = 97)#
  NTproBNP                    -0.18       -0.38 (a)#       -0.06
  NTproCNP                     0.08       0.45 (a)#        0.09
Female (n = 63)
  NTproBNP                    -0.14          -0.22         -0.02
  NTproCNP                     0.17       0.35 (b)#        0.18
Male (n = 34)
  NTproBNP                    -0.28          -0.25         -0.18
  NTproCNP                    -0.26          0.19          -0.13

                             Waist/
All subjects (n = 317)#     hip ratio

NTproBNP                   -0.31 (a)#
NTproCNP                   0.24 (a)#
Female (n = 183)
NTproBNP                   -0.26 (a)#
NTproCNP                      -0.01
Male (n = 134)
  NTproBNP                    0.03
  NTproCNP                    0.16
VLBW (n = 220)#
  NTproBNP                 -0.33 (a)#
  NTproCNP                 0.21 (a)#
Female (n = 120)
  NTproBNP                 -0.32 (a)#
  NTproCNP                    -0.15
Male (n = 100)
  NTproBNP                    0.03
  NTproCNP                 0.24 (b)#
Control (n = 97)#
  NTproBNP                 -0.23 (b)#
  NTproCNP                 0.32 (a)#
Female (n = 63)
  NTproBNP                    -0.13
  NTproCNP                    0.24
Male (n = 34)
  NTproBNP                    0.07
  NTproCNP                    -0.14

a P <0.001.

b P <0.05.

sBP, systolic blood pressure; dBP, diastolic blood pressure.
Statistically significant Spearman correlation coefficients are in
bold.

Note: Statistically significant Spearman correlation coefficients are in
bold is indicated with #.

Table 4. Associations between echocardiography parameters and
aminoterminal natriuretic peptides.

                                                          LV
                         LVEDV (a)      LVESV (a)      mass (a)
All subjects (n = 306)
  NTproBNP                  0.06          -0.00         -0.12 (b)#
  NTproCNP               -0.13 (b)#       -0.08          0.02
Female (n = 175)
  NTproBNP                  0.14          -0.05          0.09
  NTproCNP               -0.22 (b)#    -0.18 (b)#       -0.18 (b)#
Male (n = 131)
  NTproBNP                  0.12           0.16          -0.10
  NTproCNP               -0.28 (b)#    -0.27 (b)#        -0.12
VLBW (n =211)
  NTproBNP                  0.07          -0.03       -0.17 (b)#
  NTproCNP                  -0.09         -0.04          0.08
Female (n = 114)
  NTproBNP                  0.13           0.10          0.04
  NTproCNP                  -0.17         -0.14          -0.15
Male (n = 97)
  NTproBNP                  0.22b       0.26 (b)#        -0.09
  NTproCNP                 -0.31b      -0.31 (b)#        -0.06
Control (n = 95)
  NTproBNP                  -0.01         -0.13          -0.04
  NTproCNP                  -0.07         -0.04          -0.06
Female (n = 61)
  NTproBNP                  0.23          -0.03          0.18
  NTproCNP                  -0.16         -0.10          -0.18
Male (n = 34)
  NTproBNP                  -0.15         -0.14          -0.11
  NTproCNP                  -0.08         -0.12          -0.22

                             LV             LA         Arterial
                          elastance      area (a)      elastance
All subjects (n = 306)
  NTproBNP               -0.13 (b)#      0.28 (c)#    -0.23 (c)#
  NTproCNP                0.20 (c)#      -0.16 (b)#      0.23 (c)#
Female (n = 175)
  NTproBNP                  -0.14        0.28 (c)#    -0.27 (c)#
  NTproCNP               0.19 (b)#        -0.09       0.22 (b)#
Male (n = 131)
  NTproBNP               -0.22 (b)#     0.19 (b)#        -0.16
  NTproCNP                0.30 (c)#     -0.20 (b)#     0.22 (b)#
VLBW (n =211)
  NTproBNP               -0.18 (b)#      0.31 (c)#     -0.25 (c)#
  NTproCNP               0.18 (b)#     -0.16 (b)#     0.22 (b)#
Female (n = 114)
  NTproBNP               -0.19 (b)#      0.33 (c)#      -0.24 (b)#
  NTproCNP                  0.14          -0.01          0.16
Male (n = 97)
  NTproBNP               -0.31 (b)#     0.22 (b)#     -0.23 (b)#
  NTproCNP                0.37 (c)#      -0.29 (b)#     0.27 (b)#
Control (n = 95)
  NTproBNP                  -0.00       0.22 (b)#        -0.19
  NTproCNP                  0.08          -0.16          0.11
Female (n = 61)
  NTproBNP                  -0.08          0.22        -0.43 (c)#
  NTproCNP                  0.07          -0.23          0.19
Male (n = 34)
  NTproBNP                  0.09           0.10          0.04
  NTproCNP                  0.07           0.09          -0.04

(a) Indexed to body surface area.

(b)  P <0.05.

(c)  P <0.001.

Bracketed values denote number of subjects. Statistically significant
Spearman correlation coefficients are in bold.

Note: Statistically significant Spearman correlation coefficients are in
bold is indicated with #.
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Title Annotation:Lipids, Lipoproteins, and Cardiovascular Risk Factors
Author:Prickett, Timothy C.R.; Darlow, Brian A.; Troughton, Richard W.; Cameron, Vicky A.; Elliott, John M.
Publication:Clinical Chemistry
Date:Feb 1, 2018
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