aric is an ongoing , prospective , observational study of the natural history of cv risk factors and atherosclerotic diseases .
detailed study rationale , design , and procedures have been previously published.11 the original cohort included 15  792 participants recruited between 1987 and 1989 using probability sampling of middle - aged ( 45 to 64  years old ) men and women from 4 communities in the united states ( forsyth county , nc ; jackson , ms ; suburban minneapolis , mn ; and washington county , md ) .
enrollment of african americans varied by field center ( jackson 100% ; forsyth county 12% ; minneapolis < 1% ; washington county < 1% ) .
subsequent follow - up visits occurred at 3-year intervals up to 1998 , with annual telephone interviews conducted between visits and to the present .
institutional review boards from each site approved the study , and informed consent was obtained from all participants .
the fourth aric exam occurred between 1996 and 1998 , was attended by 11  656 participants , and is the basis for this analysis given that plasma n - terminal pro b - type natriuretic peptide ( ntprobnp ) levels were measured on samples obtained at this visit .
we excluded 2519 participants for the following reasons : missing plasma nt - probnp levels ( n=405 ) ; self - reported race other than african american or caucasian ( n=31 ) ; prevalent or missing status regarding prevalent cvd ( defined as coronary artery disease , heart failure , atrial fibrillation / flutter , or stroke ; n=1989 ) , or missing baseline characteristics of interest ( n=94 ) .
ntprobnp levels were measured using an electrochemiluminescent assay on a cobas e411 analyzer ( roche diagnostics , indianapolis , in ) , as previously described.12 the measurement range was 5 to 35  000  pg / ml , with a value of 2.5  pg / ml assigned to participants with levels below the limit of detection .
the coefficient of variation was 3.5% to 4.7%.12 established definitions for htn , obesity , dm , and smoking status , as previously described in aric , were utilized.13 annual household income was determined by participant self - report at visit 1 ( 19871989 ) .
htn was defined as systolic ( sbp ) or diastolic blood pressure ( dbp ) 140 or 90  mm  hg , respectively , or use of antihypertensive medications , which were classified according to the medispan therapeutic classification system.14 body mass index ( bmi ) was calculated from measured height and weight , with obesity defined as a bmi 30  kg / m .
creatinine and fasting glucose were measured according to standardized protocols ; estimated glomerular filtration rate ( egfr ) was calculated with the chronic kidney disease epidemiology collaboration ( ckd - epi ) equation with chronic kidney disease ( ckd ) defined as an egfr < 60  ml / min per 1.73  m.15 prevalent dm was defined as fasting glucose 126  mg / dl or nonfasting glucose 200  mg / dl , self - report of physician diagnosis of diabetes , or use of antidiabetic medications . among participants without dm ,
the homeostatic model assessment method was used to quantify insulin resistance ( homa - ir ) as fasting glucose ( mg / dl)insulin/405.16 urine microlbuminuria was measured and categorized as previously described , with microalbuminuria defined as a urine albumin - to - creatinine ratio of 30 to 300  mg / g.17 genotyping methods for estimating genetic ancestry among african americans in the aric study have been previously described.18,19 briefly , genotyping was performed on stored dna from visit 1 using the illumina beadlab platform at the center for inherited heart disease research ( johns hopkins university , baltimore , md ) .
single - nucleotide polymorphisms ( snps ) with frequencies that significantly differed between african and caucasian ancestral populations were defined as ancestry informative markers ( aims ) . among african americans , who represent an admixed population , percentage european ancestry ( pea )
. race - specific frequencies of each snp among the aims were estimated from west african and european samples to provide a bayesian prior for ancestral allele frequencies .
pea was available in 1656 ( 86% ) of african americans in the final study population for this analysis .
summary statistics for covariates were calculated as counts ( percentages ) , and medians ( interquartile ranges ; iqrs ) for categorical and continuous data , respectively .
comparisons between african americans and caucasians were made by chi - square (  ) or wilcoxon rank - sum tests , as appropriate .
a cumulative distribution plot was derived in order to compare natural log - transformed ntprobnp levels according to race .
three sensitivity analyses were performed to compare ntprobnp levels between african americans and caucasians when restricted to : ( 1 ) participants with detectable ntprobnp levels ( 5.0  pg / ml ) ; ( 2 ) healthy participants , defined as no prevalent cvd , htn , dm , ckd , past or current smoking , or use of antihypertensive medications , aspirin , or lipid - lowering therapy and bmi < 25  kg / m ; and ( 3 ) participants from forsyth county , north carolina , which was the only aric field center with substantial numbers of both african americans and caucasians .
multivariable linear regression was used to assess the associations between race and ntprobnp . given the non - normal distribution ( right - skewed ) of ntprobnp , values were natural log transformed before entry into regression models . the multiplicative effect ( percent difference ) on log ntprobnp levels
was estimated by exponentiating the beta coefficients ( 95% confidence interval [ ci ] ) for each covariate .
for example , african - american race is associated with 40% lower log ntprobnp levels than caucasians because e=0.60 .
multivariable logistic regression was used to calculate the adjusted odds of nondetectable ntprobnp levels according to race .
covariates included in multivariable models included race , age , gender , bmi , heart rate , sbp and dbp , fasting glucose , egfr , annual household income , htn , antihypertensive medication , dm , smoking status , and microalbuminuria .
in additional analyses , homa - ir was added into the multivariable logistic and linear regression models to account for the association between insulin resistance and plasma ntprobnp levels .
multivariable linear regression analyses were also repeated among african americans , with inclusion of pea as a covariate . before entry into regression models ,
all analyses were performed using stata software ( 11.2 ; stata corp , college station , tx ) .
aric is an ongoing , prospective , observational study of the natural history of cv risk factors and atherosclerotic diseases .
detailed study rationale , design , and procedures have been previously published.11 the original cohort included 15  792 participants recruited between 1987 and 1989 using probability sampling of middle - aged ( 45 to 64  years old ) men and women from 4 communities in the united states ( forsyth county , nc ; jackson , ms ; suburban minneapolis , mn ; and washington county , md ) .
enrollment of african americans varied by field center ( jackson 100% ; forsyth county 12% ; minneapolis < 1% ; washington county < 1% ) .
subsequent follow - up visits occurred at 3-year intervals up to 1998 , with annual telephone interviews conducted between visits and to the present .
institutional review boards from each site approved the study , and informed consent was obtained from all participants .
the fourth aric exam occurred between 1996 and 1998 , was attended by 11  656 participants , and is the basis for this analysis given that plasma n - terminal pro b - type natriuretic peptide ( ntprobnp ) levels were measured on samples obtained at this visit .
we excluded 2519 participants for the following reasons : missing plasma nt - probnp levels ( n=405 ) ; self - reported race other than african american or caucasian ( n=31 ) ; prevalent or missing status regarding prevalent cvd ( defined as coronary artery disease , heart failure , atrial fibrillation / flutter , or stroke ; n=1989 ) , or missing baseline characteristics of interest ( n=94 ) .
ntprobnp levels were measured using an electrochemiluminescent assay on a cobas e411 analyzer ( roche diagnostics , indianapolis , in ) , as previously described.12 the measurement range was 5 to 35  000  pg / ml , with a value of 2.5  pg / ml assigned to participants with levels below the limit of detection .
established definitions for htn , obesity , dm , and smoking status , as previously described in aric , were utilized.13 annual household income was determined by participant self - report at visit 1 ( 19871989 ) .
htn was defined as systolic ( sbp ) or diastolic blood pressure ( dbp ) 140 or 90  mm  hg , respectively , or use of antihypertensive medications , which were classified according to the medispan therapeutic classification system.14 body mass index ( bmi ) was calculated from measured height and weight , with obesity defined as a bmi 30  kg / m .
creatinine and fasting glucose were measured according to standardized protocols ; estimated glomerular filtration rate ( egfr ) was calculated with the chronic kidney disease epidemiology collaboration ( ckd - epi ) equation with chronic kidney disease ( ckd ) defined as an egfr < 60  ml / min per 1.73  m.15 prevalent dm was defined as fasting glucose 126  mg / dl or nonfasting glucose 200  mg / dl , self - report of physician diagnosis of diabetes , or use of antidiabetic medications . among participants without dm ,
the homeostatic model assessment method was used to quantify insulin resistance ( homa - ir ) as fasting glucose ( mg / dl)insulin/405.16 urine microlbuminuria was measured and categorized as previously described , with microalbuminuria defined as a urine albumin - to - creatinine ratio of 30 to 300  mg / g.17
genotyping methods for estimating genetic ancestry among african americans in the aric study have been previously described.18,19 briefly , genotyping was performed on stored dna from visit 1 using the illumina beadlab platform at the center for inherited heart disease research ( johns hopkins university , baltimore , md ) .
single - nucleotide polymorphisms ( snps ) with frequencies that significantly differed between african and caucasian ancestral populations were defined as ancestry informative markers ( aims ) . among african americans , who represent an admixed population , percentage european ancestry ( pea )
race - specific frequencies of each snp among the aims were estimated from west african and european samples to provide a bayesian prior for ancestral allele frequencies .
pea was available in 1656 ( 86% ) of african americans in the final study population for this analysis .
summary statistics for covariates were calculated as counts ( percentages ) , and medians ( interquartile ranges ; iqrs ) for categorical and continuous data , respectively .
comparisons between african americans and caucasians were made by chi - square (  ) or wilcoxon rank - sum tests , as appropriate .
a cumulative distribution plot was derived in order to compare natural log - transformed ntprobnp levels according to race .
three sensitivity analyses were performed to compare ntprobnp levels between african americans and caucasians when restricted to : ( 1 ) participants with detectable ntprobnp levels ( 5.0  pg / ml ) ; ( 2 ) healthy participants , defined as no prevalent cvd , htn , dm , ckd , past or current smoking , or use of antihypertensive medications , aspirin , or lipid - lowering therapy and bmi < 25  kg / m ; and ( 3 ) participants from forsyth county , north carolina , which was the only aric field center with substantial numbers of both african americans and caucasians .
multivariable linear regression was used to assess the associations between race and ntprobnp . given the non - normal distribution ( right - skewed ) of ntprobnp , values were natural log transformed before entry into regression models .
the multiplicative effect ( percent difference ) on log ntprobnp levels was estimated by exponentiating the beta coefficients ( 95% confidence interval [ ci ] ) for each covariate .
for example , african - american race is associated with 40% lower log ntprobnp levels than caucasians because e=0.60 .
multivariable logistic regression was used to calculate the adjusted odds of nondetectable ntprobnp levels according to race .
covariates included in multivariable models included race , age , gender , bmi , heart rate , sbp and dbp , fasting glucose , egfr , annual household income , htn , antihypertensive medication , dm , smoking status , and microalbuminuria .
in additional analyses , homa - ir was added into the multivariable logistic and linear regression models to account for the association between insulin resistance and plasma ntprobnp levels .
multivariable linear regression analyses were also repeated among african americans , with inclusion of pea as a covariate . before entry into regression models ,
all analyses were performed using stata software ( 11.2 ; stata corp , college station , tx ) .
compared to caucasians , african americans were more likely to be female , hypertensive , and have microalbuminuria ; however , ntprobnp levels in african americans ( median , 43  pg / ml ; iqr , 18 , 88 ) were significantly lower than in caucasians ( median , 68  pg / ml ; iqr , 36 , 124 ; p<0.001 ; table 1 ; figure 1 ) .
ntprobnp levels below the limit of detection were also more frequent among african americans ( 9% ) than caucasians ( 2% ; p<0.001 ) .
significantly lower ntprobnp levels in african americans were also found when analyses were restricted to ( 1 ) participants with detectable levels of ntprobnp , ( 2 ) healthy participants , or ( 3 ) participants at the forsyth county , north carolina , field center ( data not shown ) .
baseline characteristics of african - american and caucasian participants without prevalent cardiovascular disease at aric visit 4 ( 19961998 ) data presented as percentage or median ( interquartile range ) for categorical and continuous data , respectively .
ace indicates angiotensin converting enzyme ; arb , angiotensin receptor blocker ; aric , atherosclerosis risk in communities ; bmi , body mass index ; bpm , beats per minute ; ca , calcium ; dbp , diastolic blood pressure ; egfr , estimate glomerular filtration rate ; homa - ir , homeostatic model for assessment of insulin resistance ; ntprobnp , n terminal pro b type natriuretic peptide ; sbp , systolic blood pressure ; uacr , urine albumin creatinine ratio .
natural log ntprobnp values are lower in african americans , as compared to caucasians ( p<0.001 ) . for example , the frequency of natural log ntprobnp levels 4 ( ntprobnp=54.6  pg / ml ) is 60% in african americans , compared to 40% of caucasians
. the lower limit of the natural log of ntprobnp is truncated at 0.92 based upon the lowest value of ntprobnp of 2.5  pg / ml .
aric indicates atherosclerosis risk in communities ; ntprobnp , n - terminal pro b - type natriuretic peptide . in multivariable linear regression analysis ,
adjusted log ntprobnp levels were significantly lower ( 40% ; 95% ci , 43 , 36 ) in african americans than caucasians , independent of other factors associated with ntprobnp levels ( figure 2 ) .
covariates also associated with lower ntprobnp levels included male gender , higher bmi , heart rate , and dbp , as well as higher glucose and egfr .
in contrast , covariates associated with higher levels of ntprobnp included increasing age , lower household income , beta - blocker use , current smoking , higher sbp , and presence of microalbuminuria .
with inclusion of homa - ir into the multivariable linear regression model , increased insulin resistance was also significantly associated with lower ntprobnp levels ( 14% ; 95% ci , 16 , 11 ) , although this did not attenuate the relationship between african - american race and lower plasma ntprobnp levels ( 37% ; 95% ci , 41 , 33 ) . in subgroup analyses ,
ntprobnp levels were consistently lower in african americans , as compared to caucasians ( figure 2 ) .
forest plot of percent difference in log ntprobnp levels in african americans , compared to caucasians , overall and across subgroups of aric participants .
african - american race is significantly associated with lower ntprobnp levels , as compared to caucasians , in the overall study population and within subgroups .
values shown are from multivariable adjusted linear regression analyses ( see methods for covariates ) . for the insulin - resistant subgroups ,
aric indicates atherosclerosis risk in communities ; homa - ir , homeostatic model for assessment of insulin resistance ; ntprobnp , n - terminal pro b - type natriuretic peptide .
multivariable logistic regression was performed to examine factors associated with nondetectable plasma nt - probnp levels ( table 2 ) .
after multivariable adjustment , african - american race was associated with significantly increased odds of having nondetectable levels ( multivariable adjusted odds ratio [ or ] , 5.74 ; 95% ci , 4.22 , 7.80 ) . in an additional analysis with inclusion of homa - ir in the model ,
african - american race remained significantly associated with increased odds of nondetectable ntprobnp ( or , 5.51 ; 95% ci , 3.91 , 7.77 ) . characteristics significantly associated with nondetectable plasma ntprobnp among aric participants nondetectable plasma defined as ntprobnp < 5  pg / ml .
data presented as percentage or median ( interquartile range ) for categorical and continuous data , respectively .
aric indicates atherosclerosis risk in communities ; bmi , body mass index ; bpm , beats per minute ; dbp , diastolic blood pressure ; egfr , estimate glomerular filtration rate ; ntprobnp , n terminal pro b type natriuretic peptide ; or , odds ratio . or adjusted for all covariates listed plus age , annual household income , history of hypertension , systolic blood pressure , antihypertensive medication class , diabetes mellitus , smoking status , and the presence of microalbuminuria .
ors for continuous variables reflect odds per 1 sd ( bmi=5.5  kg / m ; heart rate=9.5  bpm ; dbp=10  mm  hg ; fasting glucose=31  mg / dl ; egfr=16.5  ml / min per 1.73  m ) . among the 1656 african americans in whom
pea data were available , median pea was 15% ( iqr , 11 , 23 ) . in multivariable linear regression models , a 1 sd ( 10% )
increase in pea was associated with 7% ( 95% ci , 1 , 13 ) higher adjusted ntprobnp levels ( p=0.025 ; figure 3 ) .
the relationship between genetically determined percent european ancestry and plasma ntprobnp levels among self - reported african americans in aric . among self - reported african americans , with increasing proportion of european ancestry
aric indicates atherosclerosis risk in communities ; ntprobnp , n - terminal pro b - type natriuretic peptide .
compared to caucasians , african americans were more likely to be female , hypertensive , and have microalbuminuria ; however , ntprobnp levels in african americans ( median , 43  pg / ml ; iqr , 18 , 88 ) were significantly lower than in caucasians ( median , 68  pg / ml ; iqr , 36 , 124 ; p<0.001 ; table 1 ; figure 1 ) .
ntprobnp levels below the limit of detection were also more frequent among african americans ( 9% ) than caucasians ( 2% ; p<0.001 ) .
significantly lower ntprobnp levels in african americans were also found when analyses were restricted to ( 1 ) participants with detectable levels of ntprobnp , ( 2 ) healthy participants , or ( 3 ) participants at the forsyth county , north carolina , field center ( data not shown ) .
baseline characteristics of african - american and caucasian participants without prevalent cardiovascular disease at aric visit 4 ( 19961998 ) data presented as percentage or median ( interquartile range ) for categorical and continuous data , respectively .
ace indicates angiotensin converting enzyme ; arb , angiotensin receptor blocker ; aric , atherosclerosis risk in communities ; bmi , body mass index ; bpm , beats per minute ; ca , calcium ; dbp , diastolic blood pressure ; egfr , estimate glomerular filtration rate ; homa - ir , homeostatic model for assessment of insulin resistance ; ntprobnp , n terminal pro b type natriuretic peptide ; sbp , systolic blood pressure ; uacr , urine albumin creatinine ratio .
natural log ntprobnp values are lower in african americans , as compared to caucasians ( p<0.001 ) . for example , the frequency of natural log ntprobnp levels 4 ( ntprobnp=54.6  pg / ml ) is 60% in african americans , compared to 40% of caucasians
. the lower limit of the natural log of ntprobnp is truncated at 0.92 based upon the lowest value of ntprobnp of 2.5  pg / ml .
aric indicates atherosclerosis risk in communities ; ntprobnp , n - terminal pro b - type natriuretic peptide .
in multivariable linear regression analysis , adjusted log ntprobnp levels were significantly lower ( 40% ; 95% ci , 43 , 36 ) in african americans than caucasians , independent of other factors associated with ntprobnp levels ( figure 2 ) .
covariates also associated with lower ntprobnp levels included male gender , higher bmi , heart rate , and dbp , as well as higher glucose and egfr .
in contrast , covariates associated with higher levels of ntprobnp included increasing age , lower household income , beta - blocker use , current smoking , higher sbp , and presence of microalbuminuria .
with inclusion of homa - ir into the multivariable linear regression model , increased insulin resistance was also significantly associated with lower ntprobnp levels ( 14% ; 95% ci , 16 , 11 ) , although this did not attenuate the relationship between african - american race and lower plasma ntprobnp levels ( 37% ; 95% ci , 41 , 33 ) . in subgroup analyses ,
ntprobnp levels were consistently lower in african americans , as compared to caucasians ( figure 2 ) .
forest plot of percent difference in log ntprobnp levels in african americans , compared to caucasians , overall and across subgroups of aric participants .
african - american race is significantly associated with lower ntprobnp levels , as compared to caucasians , in the overall study population and within subgroups .
values shown are from multivariable adjusted linear regression analyses ( see methods for covariates ) . for the insulin - resistant subgroups ,
aric indicates atherosclerosis risk in communities ; homa - ir , homeostatic model for assessment of insulin resistance ; ntprobnp , n - terminal pro b - type natriuretic peptide .
multivariable logistic regression was performed to examine factors associated with nondetectable plasma nt - probnp levels ( table 2 ) .
after multivariable adjustment , african - american race was associated with significantly increased odds of having nondetectable levels ( multivariable adjusted odds ratio [ or ] , 5.74 ; 95% ci , 4.22 , 7.80 ) . in an additional analysis with inclusion of homa - ir in the model ,
african - american race remained significantly associated with increased odds of nondetectable ntprobnp ( or , 5.51 ; 95% ci , 3.91 , 7.77 ) .
characteristics significantly associated with nondetectable plasma ntprobnp among aric participants nondetectable plasma defined as ntprobnp < 5  pg / ml .
data presented as percentage or median ( interquartile range ) for categorical and continuous data , respectively .
aric indicates atherosclerosis risk in communities ; bmi , body mass index ; bpm , beats per minute ; dbp , diastolic blood pressure ; egfr , estimate glomerular filtration rate ; ntprobnp , n terminal pro b type natriuretic peptide ; or , odds ratio . or adjusted for all covariates listed plus age , annual household income , history of hypertension , systolic blood pressure , antihypertensive medication class , diabetes mellitus , smoking status , and the presence of microalbuminuria .
ors for continuous variables reflect odds per 1 sd ( bmi=5.5  kg / m ; heart rate=9.5  bpm ; dbp=10  mm  hg ; fasting glucose=31  mg / dl ; egfr=16.5  ml / min per 1.73  m ) .
among the 1656 african americans in whom pea data were available , median pea was 15% ( iqr , 11 , 23 ) . in multivariable linear regression models , a 1 sd ( 10% ) increase in pea was associated with 7% ( 95% ci , 1 , 13 ) higher adjusted ntprobnp levels ( p=0.025 ; figure 3 ) .
the relationship between genetically determined percent european ancestry and plasma ntprobnp levels among self - reported african americans in aric . among self - reported african americans , with increasing proportion of european ancestry , there is a significant increase in plasma ntprobnp levels .
aric indicates atherosclerosis risk in communities ; ntprobnp , n - terminal pro b - type natriuretic peptide .
our principal finding is that african americans have substantially lower plasma ntprobnp levels , compared to caucasians .
the lower levels of plasma ntprobnp in african - american individuals were observed across clinically relevant subgroups and appeared to be independent of other factors associated with low levels of ntprobnp , including obesity and insulin resistance .
pea among african americans also correlated with ntprobnp levels , which not only supports the observation of racial differences in np levels , but also suggests a genetic basis for lower np levels between individuals of west - african and european ancestry .
given that previous experimental , genetic , and clinical studies support that reductions in np secretion are associated with salt - sensitive htn and incident dm,2,4 our finding of lower levels of circulating np levels in african - american individuals may , in part , explain the increased susceptibility to htn and dm .
furthermore , the relative reduction in ntprobnp level in african americans versus caucasians observed in our study ( 40% ) is comparable to that reported with obesity ( 20% to 40%),20 suggesting physiological and clinical significance .
previous studies of hospitalized patients suggest that african americans may have lower np levels than caucasians.2,79 however , these studies largely evaluated persons presenting to the emergency department , such that the coexistence of prevalent cvd and risk factors may have confounded the associations between race and np levels.7,9,21 in contrast , the aric study afforded the opportunity to examine the impact of race on np levels in a community - based cohort of more than 9000 individuals free of prevalent cvd .
this sample size also allowed adjustment for confounding factors , and we found that african americans had lower plasma ntprobnp levels than caucasians , despite greater frequencies of female gender , htn , microalbuminuria , and lower socioeconomic status among african americans , each of which correlated with higher , rather than lower , levels of np .
moreover , the finding of lower levels of plasma ntprobnp in african americans was independent of other factors previously reported to be associated with low levels of ntprobnp , including obesity , insulin resistance , and dm .
the significant and independent association between pea and ntprobnp levels among african americans also suggests a genetic basis for lower np levels in african americans .
african americans have a higher prevalence of htn , left ventricular hypertrophy , and microalbuminuria , conditions that should raise np levels.6,2224 consequently , the finding in aric that african - american individuals have lower np levels , compared to white individuals , is counterintuitive and suggests that nonhemodynamic factors may contribute .
the association between pea and ntprobnp levels among african americans indicates an underlying genetic component .
one biologically plausible way in which np levels may be decreased is through impaired synthesis or reduced release from cardiomyocytes . indeed , previous studies indicate that variations in processes related to the synthesis of ntprobnp , such as genetic polymorphisms in the nppb gene that influence transcription , translation , and/or post - translational processing , may contribute to lower ntprobnp levels , although there are limited data on racial differences in the genetics of the np system.25 alternatively , non - nppb gene variations that affect np production and processing may be involved as well . for example , corin is a protein that is partly responsible for cleavage of nps into the active carboxy - terminus hormone and inactive amino - terminus propeptide.26 variants in the corin gene are more common among african americans , and experimental mouse models overexpressing the corin variant observed in african americans demonstrate increased salt sensitivity , htn , and hypertrophy , thereby recapitulating the clinical phenotype.4,27 however , variation in the corin gene may not fully explain the observed lower levels of ntprobnp in aric given that the assay used detects both the 76-amino - acid ntprobnp as well as the full 108-amino - acid prohormone ( probnp),28 suggesting that np levels in african americans may , in part , be regulated upstream of corin .
future studies quantifying circulating probnp , ntprobnp , and bnp levels may help clarify the role of corin mutations in african americans , but are beyond the scope of this study .
clearance of ntprobnp is not mediated through the same processes that lead to clearance of the active hormone , bnp.29 therefore , it is also possible that the lower levels of ntprobnp observed among african americans may be related to enhanced clearance in african americans , compared to caucasians .
bnp levels were not measured in aric ; however , ntprobnp and bnp levels have previously been demonstrated to be highly correlated,30,31 suggesting that lower ntprobnp levels also reflect lower bnp levels , and that differences in np between races may be determined upstream of clearance in np regulation pathways . however , further studies are needed to elucidate and clarify the relative importance of synthesis , release , and clearance mechanisms to the lower np levels observed in african americans .
strengths of the present investigation include the large sample size , routine measurement of plasma ntprobnp in a community - dwelling population , standard ascertainment of clinical characteristics , use of multivariable adjusted analyses , and consistency of the finding of lower plasma ntprobnp levels across several sensitivity and subgroup analyses .
plasma ntprobnp levels in ambulatory community - dwelling participants may be below the limit of detection ; however , in a sensitivity analysis restricted to individuals with detectable levels , plasma ntprobnp remained significantly lower in african americans , as compared to caucasians .
plasma bnp was not measured in aric ; therefore , it is possible that active np hormone levels may not differ according to race .
however , ntprobnp and bnp levels are highly correlated , even within a range of values well below thresholds diagnostic of heart failure.3032 atrial natriuretic peptide ( anp ) was not measured in aric , although other studies have indicated that mid - regional pro - anp levels may also be lower in african americans , compared to caucasians.9 we did not assess cardiac structure and function with echocardiography , given that these measures were not obtained during aric visit 4 .
however , compared to caucasians , african americans tend to have greater wall thickness,24 which is typically associated with higher np levels and therefore should bias the result toward the null ; however , we found that plasma ntprobnp levels were significantly lower in african americans , lending further validity to these results .
though we adjusted for multiple factors that may contribute to ntprobnp levels , there may be residual confounding . in the estimation of pea , which is based upon samples from west africa and europe
further studies are needed to elucidate specific genetic loci related to np levels in african americans .
finally , in this cross - sectional study , we can not determine a causal association between low plasma np levels and htn , obesity , and/or dm .
however , it has previously been demonstrated in aric that low plasma np levels are associated with increased risk for dm.2,3
african americans have a higher prevalence of htn , left ventricular hypertrophy , and microalbuminuria , conditions that should raise np levels.6,2224 consequently , the finding in aric that african - american individuals have lower np levels , compared to white individuals , is counterintuitive and suggests that nonhemodynamic factors may contribute .
the association between pea and ntprobnp levels among african americans indicates an underlying genetic component .
one biologically plausible way in which np levels may be decreased is through impaired synthesis or reduced release from cardiomyocytes . indeed , previous studies indicate that variations in processes related to the synthesis of ntprobnp , such as genetic polymorphisms in the nppb gene that influence transcription , translation , and/or post - translational processing , may contribute to lower ntprobnp levels , although there are limited data on racial differences in the genetics of the np system.25 alternatively , non - nppb gene variations that affect np production and processing may be involved as well .
for example , corin is a protein that is partly responsible for cleavage of nps into the active carboxy - terminus hormone and inactive amino - terminus propeptide.26 variants in the corin gene are more common among african americans , and experimental mouse models overexpressing the corin variant observed in african americans demonstrate increased salt sensitivity , htn , and hypertrophy , thereby recapitulating the clinical phenotype.4,27 however , variation in the corin gene may not fully explain the observed lower levels of ntprobnp in aric given that the assay used detects both the 76-amino - acid ntprobnp as well as the full 108-amino - acid prohormone ( probnp),28 suggesting that np levels in african americans may , in part , be regulated upstream of corin .
future studies quantifying circulating probnp , ntprobnp , and bnp levels may help clarify the role of corin mutations in african americans , but are beyond the scope of this study .
clearance of ntprobnp is not mediated through the same processes that lead to clearance of the active hormone , bnp.29 therefore , it is also possible that the lower levels of ntprobnp observed among african americans may be related to enhanced clearance in african americans , compared to caucasians .
bnp levels were not measured in aric ; however , ntprobnp and bnp levels have previously been demonstrated to be highly correlated,30,31 suggesting that lower ntprobnp levels also reflect lower bnp levels , and that differences in np between races may be determined upstream of clearance in np regulation pathways
. however , further studies are needed to elucidate and clarify the relative importance of synthesis , release , and clearance mechanisms to the lower np levels observed in african americans .
strengths of the present investigation include the large sample size , routine measurement of plasma ntprobnp in a community - dwelling population , standard ascertainment of clinical characteristics , use of multivariable adjusted analyses , and consistency of the finding of lower plasma ntprobnp levels across several sensitivity and subgroup analyses .
plasma ntprobnp levels in ambulatory community - dwelling participants may be below the limit of detection ; however , in a sensitivity analysis restricted to individuals with detectable levels , plasma ntprobnp remained significantly lower in african americans , as compared to caucasians .
plasma bnp was not measured in aric ; therefore , it is possible that active np hormone levels may not differ according to race .
however , ntprobnp and bnp levels are highly correlated , even within a range of values well below thresholds diagnostic of heart failure.3032 atrial natriuretic peptide ( anp ) was not measured in aric , although other studies have indicated that mid - regional pro - anp levels may also be lower in african americans , compared to caucasians.9 we did not assess cardiac structure and function with echocardiography , given that these measures were not obtained during aric visit 4 .
however , compared to caucasians , african americans tend to have greater wall thickness,24 which is typically associated with higher np levels and therefore should bias the result toward the null ; however , we found that plasma ntprobnp levels were significantly lower in african americans , lending further validity to these results .
though we adjusted for multiple factors that may contribute to ntprobnp levels , there may be residual confounding . in the estimation of pea , which is based upon samples from west africa and europe
further studies are needed to elucidate specific genetic loci related to np levels in african americans . finally , in this cross - sectional study
, we can not determine a causal association between low plasma np levels and htn , obesity , and/or dm .
however , it has previously been demonstrated in aric that low plasma np levels are associated with increased risk for dm.2,3
the lower ntprobnp levels observed in african americans , compared to caucasians , may help to explain racial disparities in cardiometabolic risk given that lower np levels may increase the risk of htn , obesity , and dm , conditions more prevalent among african americans . however , further studies are needed to confirm the causal role of nps and clarify the mechanisms leading to lower levels of np , of which our results suggest that genetic variation likely contributes .
ultimately , augmentation of the np system in individuals with a relative np deficiency may prove to be an efficacious strategy for the prevention of cardiometabolic risk .
the atherosclerosis risk in communities study is carried out as a collaborative study supported by national heart , lung , and blood institute ( nhlbi ) contracts ( hhsn268201100005c , hhsn268201100006c , hhsn268201100007c , hhsn268201100008c , hhsn268201100009c , hhsn268201100010c , hhsn268201100011c , and hhsn268201100012c ) .
its contents are solely the responsibility of the authors and do not necessarily represent official views of the ncats or the national institutes of health .
 backgroundnatriuretic peptides promote natriuresis , diuresis , and vasodilation . 
 experimental deficiency of natriuretic peptides leads to hypertension ( htn ) and cardiac hypertrophy , conditions more common among african americans . 
 hospital - based studies suggest that african americans may have reduced circulating natriuretic peptides , as compared to caucasians , but definitive data from community - based cohorts are lacking.methods and resultswe examined plasma n - terminal pro b - type natriuretic peptide ( ntprobnp ) levels according to race in 9137 atherosclerosis risk in communities ( aric ) study participants ( 22% african american ) without prevalent cardiovascular disease at visit 4 ( 19961998 ) . 
 multivariable linear and logistic regression analyses were performed adjusting for clinical covariates . among african americans , percent european ancestry was determined from genetic ancestry informative markers and then examined in relation to ntprobnp levels in multivariable linear regression analysis . 
 ntprobnp levels were significantly lower in african americans ( median , 43  pg / ml ; interquartile range [ iqr ] , 18 , 88 ) than caucasians ( median , 68  pg / ml ; iqr , 36 , 124 ; p<0.0001 ) . 
 in multivariable models , adjusted log ntprobnp levels were 40% lower ( 95% confidence interval [ ci ] , 43 , 36 ) in african americans , compared to caucasians , which was consistent across subgroups of age , gender , htn , diabetes , insulin resistance , and obesity . 
 african - american race was also significantly associated with having nondetectable ntprobnp ( adjusted or , 5.74 ; 95% ci , 4.22 , 7.80 ) . in multivariable analyses in african americans , 
 a 10% increase in genetic european ancestry was associated with a 7% ( 95% ci , 1 , 13 ) increase in adjusted log ntprobnp.conclusionsafrican americans have lower levels of plasma ntprobnp than caucasians , which may be partially owing to genetic variation . 
 low natriuretic peptide levels in african americans may contribute to the greater risk for htn and its sequalae in this population . 
Methods
Study Population
NTproBNP
Covariates
Percent European Ancestry Among African Americans
Statistical Analyses
Results
Plasma NTproBNP Levels
Race and Plasma NTproBNP Levels: Multivariable Analyses
Influence of Genetic Ancestry on Plasma NTproBNP Levels Among African Americans
Discussion
Mechanisms for Reduced NTproBNP Levels in African Americans
Strengths and Limitations
Conclusion
Source of Funding
Disclosures