Plasma Brain Natriuretic Peptide Concentration: Impact of Age and Gender

Transcription

1 Joural of the America College of Cardiology Vol. 40, No. 5, by the America College of Cardiology Foudatio ISSN /02/$22.00 Published by Elsevier Sciece Ic. PII S (02) Plasma Brai Natriuretic Peptide Cocetratio: Impact of Age ad Geder Margaret M. Redfield, MD,* Richard J. Rodeheffer, MD,* Steve J. Jacobse, MD, PHD, Douglas W. Mahoey, MS, Ket R. Bailey, PHD, Joh C. Burett, JR, MD* Rochester, Miesota Biomarkers OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS We wished to examie the effects of age ad geder o plasma brai atriuretic peptide (BNP) cocetratio i a populatio-based study. Measuremet of BNP cocetratio is approved for use i the diagosis of heart failure ad may aid i the detectio of left vetricular dysfuctio. Although BNP is approved for cliical use, there are few data regardig the rage of BNP observed i persos without cardiovascular disease or cardiac dysfuctio. These data are essetial for the iterpretatio of BNP. I 2,042 radomly selected residets of Olmsted Couty, Miesota, 44 years old, BNP (Shioogi ad Biosite assays), Doppler echocardiography, ad medical record review were performed. A ormal subset of subjects ( 767) i sius rhythm without cardiovascular, real, or pulmoary disease or diabetes; o o cardiovascular medicatios; ad with ormal systolic, diastolic, ad valvular fuctio was idetified. Withi the ormal subset, the distributio of BNP differed by age, geder, ad assay system. With both assays, BNP icreased sigificatly with age ad was sigificatly higher i wome tha me, leadig to age-, geder-, ad assay-specific referece rages. Receiver operatig characteristic aalysis for the ability of BNP to detect a ejectio fractio 40% was performed i each age/geder stratum i the etire cohort ( 2,042) ad cofirmed that discrimiatory values for BNP for detectio of reduced ejectio fractio were higher i wome ad older persos ad were differet betwee the two assays. Iterpretatio of BNP should iclude cosideratio of age-, geder-, ad assay-specific partitio values. (J Am Coll Cardiol 2002;40:976 82) 2002 by the America College of Cardiology Foudatio Brai atriuretic peptide (BNP) is a member of the family of geetically distict atriuretic peptides sythesized ad released by cardiomyocytes i respose to icreased trasmural wall stress (1). Although this respose is critical for cardioreal regulatio, the icrease i plasma BNP cocetratio has diagostic implicatios as well. Ideed, BNP may be useful for the detectio of asymptomatic left vetricular (LV) dysfuctio (2,3) ad the diagosis (4,5) ad maagemet (6) of cogestive heart failure (CHF). Whereas most previous studies have utilized a immuoradiometric assay (Shioogi), recet Food ad Drug Admiistratio approval of a poit-of-care assay (Biosite Triage) for use i the diagosis of CHF has made the possibility of usig BNP i cliical practice a reality. The rage of BNP observed i subjects without cardiovascular disease or cardiac dysfuctio has ot bee well established. Although a few studies suggest that age ad geder may ifluece circulatig atriuretic peptide levels (7 9), the magitude of these effects ad their potetial From the *Divisio of Cardiovascular Diseases, ad Sectios of, Health Sciece Research ad Biostatistics, Mayo Cliic ad Foudatio, Rochester, Miesota. This study was fuded by grats from the Public Health Service, Natioal Istitutes of Health (HL ad AR 30582), the Marriott Foudatio, the Miami Heart Research Istitute, ad the Mayo Foudatio. Gottlieb C. Friesiger II, MD, acted as guest editor for this article. Mauscript received March 4, 2002; accepted May 31, importace i the iterpretatio of BNP remais uclear. Therefore, we measured BNP with two commercially available assays i a populatio-based cohort. I subjects without cardiovascular disease or cardiac dysfuctio ( 767), we assessed the ifluece of the assay used, age, ad geder o BNP. We evaluated the ifluece of cliical factors, real fuctio, ad cardiac structural parameters o BNP, as age/geder-related chages i these factors could mediate associatios betwee BNP ad age/geder. I the etire cohort ( 2,042), we determied whether the BNP that idetified subjects havig systolic dysfuctio (ejectio fractio [EF] 40%) with optimal sesitivity ad specificity varied with age, geder, ad assay. METHODS This study was approved by the Mayo Istitutioal Review Board. Study settig. The characteristics of the Olmsted Couty, Miesota, populatio ad the uique resources for populatio-based epidemiologic research i Olmsted Couty have bee previously described (10,11). Populatio samplig, subject recruitmet, ad erollmet. A radom sample of the populatio 44 years was ivited to participate. A samplig fractio of 7% was applied withi each of the geder ad age (five-year) specific strata.

2 JACC Vol. 40, No. 5, 2002 September 4, 2002: Redfield et al. BNP i Normal Subjects 977 Abbreviatios ad Acroyms BNP brai atriuretic peptide CHF cogestive heart failure CI cofidece iterval E/A early-to-late fillig velocities EF ejectio fractio HRT hormoe replacemet therapy LV left vetricular ROC receiver operatig characteristic 2-D two-dimesioal Of the 4,203 subjects ivited, 2,042 (47%) participated. Aalysis of the medical records of 500 oparticipats revealed o cliically sigificat differeces betwee participats ad oparticipats. Subjects gave writte coset ad uderwet echocardiography ad phlebotomy. Of the 2,042 participats, 1,020 had o history of cardiovascular, real, or pulmoary disease ad were o o cardiovascular medicatios. Of these, 75 were excluded because of a abormal two-dimesioal (2-D) echocardiogram, 64 were excluded by a iability to characterize diastolic fuctio, ad 114 had abormal diastolic fuctio. Thus, 767 subjects had ormal EF ( 50%), o wall motio abormalities, ormal diastolic fuctio, o valve disease, ad ormal sius rhythm; these make up the ormal subgroup. The criteria used to establish the ormal subgroup resulted i small umbers i the oldest (age 75 to 83) ormal subgroup, where there were 18 wome ad two me. I this age group, the majority of excluded subjects were excluded because of the presece of kow cardiovascular disease (72% of wome excluded, 84% of me excluded) ad a miority were excluded purely o the basis of diastolic dysfuctio (10% of wome excluded, 7% of me excluded). Medical record review. All Olmsted Couty care providers have maitaied a uified medical record, which is idexed by the Rochester Epidemiology Project. Each subject s medical record was reviewed by traied urse chart abstractors usig established criteria for hypertesio (12), myocardial ifarctio (13), ad cogestive heart failure (10). Cliical diagoses of coroary artery disease, obstructive lug disease, real failure, ad diabetes were recorded. Medicatio questioaires were completed by each subject. Doppler echocardiography. All echocardiograms were performed by oe of three registered diagostic cardiac soographers with the same echocardiographic istrumet (HP-2500) accordig to protocol ad iterpreted by a sigle echocardiologist (M. M. R.). Two-dimesioal ad color Doppler imagig were performed to scree for valvular steosis or regurgitatio. I each subject, measuremet of EF by M-mode (modified Quioes formula), quatitative 2-D (BiPlae Simpsos) ad semiquatitative 2-D (visual estimate) methods was attempted as previously described (14 17). For aalysis i the ormal subgroup, subjects had ormal EF ( 40%) by all three methods. For aalysis i the etire populatio, the visual estimatio of EF was used. Pulsed-wave Doppler examiatio of mitral (before ad with Valsalva maeuver) ad pulmoary veous iflow as well as Doppler tissue imagig of the mitral aulus was performed i each subject. Diastolic fuctio was categorized as ormal, impaired relaxatio without evidece of icreased fillig pressures ( impaired relaxatio ), impaired relaxatio associated with moderate elevatio of fillig pressures ( pseudoormal fillig ), ad advaced reductio i compliace ( restrictive fillig ), as previously described (18 21). Decreases i the ratio of the mitral early to late fillig velocities (E/A ratio) idicate a reductio i early diastolic fillig related to impairmet of LV relaxatio. We defied impaired relaxatio as a E/A ratio 0.75, reflectig the average lower cofidece iterval for the E/A ratio i subjects aged 45 years i a previous ormal cohort (22). Doppler idices used to discrimiate pseudoormal or restrictive from ormal are idepedet of age. Left vetricular dimesio ad mass (M-mode) ad left atrial volume (2-D) were idexed to body surface area. BNP aalysis. Blood for BNP was collected i the fastig state i ethyleediamietetraacetic acid-treated tubes ad placed o ice. After cetrifugatio at 2,500 rpm ad 3 C, the plasma was stored at 80 C. Plasma BNP was determied by immuoradiometric assay (oextracted) usig atibody to huma BNP (Shioogi Co. Ltd., Tokyo, Japa), as previously described (23). The itra-assay (withi-day) ad iterassay (total) Table 1. Plasma BNP (Biosite [BNP-B] ad Shioogi [BNP-S] Assays) by Age ad Geder i Normal Subjects Geder BNP Age Age Age Age Wome Biosite (10, 32) (15, 43) (19, 52) (28, 89) Shioogi (13, 55) (18, 68) (20, 111) (26, 172) Me Biosite (3, 13) (5, 20) (7, 37) 2 21 (17, 24) Shioogi (9, 34) (14, 49) (10, 58) 2 38 (31, 44) The media 25th ad 75th percetiles are show. BNP brai atriuretic peptide.

3 978 Redfield et al. JACC Vol. 40, No. 5, 2002 BNP i Normal Subjects September 4, 2002: Figure 1. Plasma brai atriuretic peptide (BNP) cocetratio as a fuctio of age for each geder ad assay system. The omogram demostrates the 5th, 25th, 50th, 75th, ad 95th percetiles for BNP accordig to age. coefficiets of variatio were both 8% ad were cosistet across cocetratios of BNP. Oe-milliliter aliquots of froze plasma were shipped to Biosite Diagostics (Sa Diego, Califoria), ad the oextracted samples were batch-aalyzed by a fluorescece immuoassay (5,24). The withi-day coefficiet of variatio (9.4% to 15.2%) ad total coefficiet of variatio (10.1% to 16.2%) icreased from low to high BNP. Statistical methods. Because the variability of BNP icreased with its mea level, the atural log trasformatio was used i the regressio aalyses to satisfy modelig assumptios. Nomograms based o age ad geder were established usig the least-squares regressio fit of logtrasformed BNP with age ad geder as predictor variables. From the fitted model, the 5th, 25th, 50th, 75th, ad 95th percetiles were estimated ad back-trasformed to the atural scale. A iteractio term with age ad geder was also evaluated to determie if the associatio of age with BNP differed betwee the geders. Uadjusted ad adjusted associatios of BNP were evaluated usig Spearma s correlatio coefficiet ad liear least-squares regressio, respectively. For adjusted associatios, a model with age ad geder was fit ad, i tur, variables were added to see if there was sigificat residual associatio that could be explaied by these characteristics. The ability of BNP to detect a EF 40% was evaluated usig receiver operatig characteristic (ROC) curves withi age/geder-specific strata. The optimal discrimiatory value was idetified as the BNP value that had a combied sesitivity/specificity at the smallest distace to 100%/ 100%, respectively (23). RESULTS The associatio of BNP with age ad geder i the ormal subgroup ( 767). The distributio of the ormal subgroup by age/geder ad correspodig BNP is show i Table 1. Adjustig for age, BNP was higher i wome tha me ad icreased with age withi each geder. Plasma BNP was 32% higher i wome tha me (cofidece iterval [CI] 15% to 51%, p 0.001) by Shioogi assay ad 80% higher by Biosite assay (CI 50% to 116%, p 0.001). Nomograms for BNP as a fuctio of age, geder, ad assay are reported (Fig. 1). The age/ geder-specific referece rages (5th ad 95th percetile) for each assay as derived from the regressio fit are provided i Table 2. The associatio betwee geder ad BNP remaied similar across all age rages for both assays (p 0.90). We sought to determie if age/geder-related chages i BNP were due to age- or geder-related chages i cliical Table 2. Age ad Geder-Specific Rages (5th 95th Percetiles) for Plasma BNP (pg/ml) (Biosite ad Shioogi Assays) Derived From the Regressio Aalysis i Normal Subjects Geder BNP Age Age Age Age Wome Biosite Shioogi Me Biosite Shioogi BNP brai atriuretic peptide.

4 JACC Vol. 40, No. 5, 2002 September 4, 2002: Redfield et al. BNP i Normal Subjects 979 Table 3. Variables Examied for Associatio With Age, Geder, ad Plasma BNP Cocetratio i Normal Subjects Age Geder Log of Shioogi BNP Log of Biosite BNP Spearma CC p Value Spearma CC p Value Spearma CC p Value Spearma CC p Value Age NA NA Geder NA NA Body surface area Systolic blood pressure Diastolic blood pressure Creatiie Creatiie clearace LV dimesio idex LV mass idex LA volume idex BNP brai atriuretic peptide; CC correlatio coefficiet; LA left atrial; LV left vetricle; NA ot appropriate. factors, real fuctio, or cardiac structural parameters. Table 3 displays the variables cosidered as potetially associated with BNP. Several of these parameters were associated with BNP but were also associated with age ad/or geder, as idicated i Table 3. Oly age, geder, ad left atrial volume idex were idepedetly associated with BNP (Table 4). Withi each geder ad assay group, BNP icreased accordig to left atrial volume idex. To further evaluate the associatio betwee geder ad BNP, we determied whether BNP was differet i the presece or absece of hormoe replacemet therapy (HRT). As measured by the Biosite assay, there was a relatioship betwee HRT ad BNP amog wome. Of the 388 wome i the ormal subgroup, 186 (48%) were takig HRT. Cotrollig for age, BNP was 21% higher i wome o HRT tha i wome ot o HRT (CI 6% to 40%, p 0.005) (Fig. 2). Plasma BNP was 99% higher i wome o HRT tha i me (CI 75% to 125%, p 0.005) ad was 64% higher i wome ot o HRT tha i me (CI 44% to 85%, p 0.005). Similar treds were observed with the Shioogi assay, but the differece i BNP betwee wome with or without HRT was ot sigificat (data ot show). Discrimiatory values of BNP for the detectio of systolic dysfuctio i the etire cohort ( 2,042). Figure 3 displays the ROC curves for the detectio of a EF 40% withi each age stratum by geder ad assay. Forty subjects (eight wome) had a EF 40%. O each curve, both the BNP represetig the upper (95th percetile) referece limit, as derived from the regressio fit, ad the BNP represetig the optimal poit o the ROC curve are idicated. The values for the BNP at the upper referece limit ad at the optimal poit o the ROC curve, ad the correspodig sesitivity ad specificity for the detectio of a EF 40%, are show i Table 5. The areas uder the ROC curves were similar withi each age/geder stratum for each assay. However, i geeral the optimal discrimiatory value for BNP icreases with age ad is higher i wome. Oly eight female subjects had a EF 40% ad this sigificatly limited the power to demostrate age/ geder differeces i the optimal discrimiatory value for BNP. The available data i wome are icluded to demostrate the effect o specificity of age/geder-specific partitio values derived from the referece populatio. DISCUSSION I this populatio-based study, BNP icreased with age ad was higher i wome tha me i a subgroup of subjects without kow cardiovascular disease or detectable structural heart disease. These associatios were ot explaied by age- or geder-related chages i blood pressure, real fuctio, or cardiac structure. The associatio of female geder ad BNP appears to be i part related to estroge status, as BNP levels were higher i wome usig HRT. Although the absolute value of BNP varied betwee the two assays, the associatios with age ad geder were cosistet betwee assays. I additio, the BNP with optimal sesitivity ad specificity for the detectio of systolic dysfuctio i the etire populatio icreased with age ad was higher i wome, uderscorig the cliical relevace of the relatioship amog age, geder, ad BNP. Plasma BNP i the ormal subgroup. The mechaisms whereby age iflueces BNP are uclear. Previous studies have reported that levels of atriuretic peptides are higher i Table 4. Parameters Idepedetly Associated With BNP Regressio Coefficiet Log Shioogi BNP Stadard Error p Value Regressio Coefficiet Log Biosite BNP Stadard Error p Value Age Female geder LA volume idex Regressio coefficiets idicate effect per year of age or per ml/m 2 for LA volume idex. BNP brai atriuretic peptide; LA left atrial.

5 980 Redfield et al. JACC Vol. 40, No. 5, 2002 BNP i Normal Subjects September 4, 2002: Figure 2. Box plot of plasma brai atriuretic peptide (BNP) cocetratios (Biosite assay) accordig to hormoe replacemet therapy (HRT) status as a fuctio of age i female (F) subjects. The box plots idicate the 5th, 25th, 50th, 75th, ad 95th percetiles. the elderly, but did ot exclude those with altered cardiac structure or fuctio (7,9). These ivestigators suggested that age-related chages i diastolic dysfuctio ifluece BNP. However, i the curret study subjects with diastolic dysfuctio ad the diseases that cause it were excluded. Although age-related alteratios i real fuctio could alter BNP, the effect of age was idepedet of real fuctio. The atria ad vetricles are sites of BNP productio, ad age-related chages i cardiac size could ifluece BNP. However, the effect of age ad geder o BNP was idepedet of atrial volume, LV dimesio, ad LV mass. These data would suggest that as yet udefied alteratios i BNP productio, secretio, or degradatio occur with age, ad further studies are eeded to elucidate the mechaism(s) resposible for this effect. A alterative explaatio is that BNP icreases i respose to age-related alteratios i cardiac structure or fuctio that are ot detectable by curret techiques. Such a mechaism remais speculative ad ot pertiet to curret diagostic use of BNP, as the progostic implicatios of BNP i the absece of detectable structural heart disease have ot bee defied. The effect of geder o BNP was also remarkable. This effect was idepedet of other factors, observed with both assay systems, ad substatial. As geder-related differeces i edotheli ad agiotesi-covertig ezyme activity have bee reported to be associated with hormoal status (25,26), we ivestigated the effect of HRT status o BNP ad foud evidece of a relatioship betwee HRT ad BNP. Although prelimiary, these data suggest that BNP productio may be sesitive to estroge regulatio ad represet a area for further study. After adjustig for age ad geder, we foud a modest but sigificat relatioship betwee BNP ad left atrial volume idex i the ormal subgroup. Thus, i the ormal state, plasma BNP may be related to the size of the glad that produces it. Although the relatioship betwee BNP ad LV mass was ot sigificat after adjustmet for age ad geder, productio of BNP by vetricular myocytes is clearly icreased i the presece of hypertrophy. Thus, a Figure 3. Receiver operatig curves defiig the sesitivity ad specificity of brai atriuretic peptide (BNP) (by Shioogi ad Biosite assays) for the detectio of systolic dysfuctio (ejectio fractio 40%) i each age strata of me ad wome. The ope circle idicates the BNP value at the upper referece limit as derived from the regressio fit i each age/geder/assay stratum. The ope triagle idicates the BNP value with optimal sesitivity ad specificity (the optimal poit ) o the receiver operatig characteristic (ROC) curve.

6 JACC Vol. 40, No. 5, 2002 September 4, 2002: Redfield et al. BNP i Normal Subjects 981 Table 5. Sesitivity ad Specificity of BNP for Detectio of Systolic Dysfuctio at the Discrimiatory Value for BNP as Determied by the ROC Aalysis ad at the 95th Percetile Referece Limit by Age, Geder, ad Assay System Me Biosite BNP Wome Biosite BNP Me Shioogi BNP Wome Shioogi BNP BNP SENS SPEC BNP SENS SPEC BNP SENS SPEC BNP SENS SPEC Discrimiatory (BNP) Age % 86% ND ND ND 91 80% 93% ND ND ND Age % 82% % 95% 89 83% 85% % 100% Age % 81% % 86% % 74% % 99% Age % 90% % 86% % 93% % 92% 95th percetile referece (BNP) Age % 95% 73 ND 96% % 95% 157 ND 94% Age % 86% % 92% % 92% % 94% Age % 79% % 90% % 84% % 91% Age % 62% % 73% % 74% % 80% BNP is i pg/ml. BNP brai atriuretic peptide; ND o systolic dysfuctio detected amog females age 45 54; SENS sesitivity; SPEC specificity. stroger relatioship betwee plasma BNP ad LV mass or left atrial volume may be apparet if subjects with cardiovascular disease are icluded. Implicatios for use of BNP as a diagostic test. Previous studies have reported the sesitivity ad specificity of BNP for the detectio of CHF or LV dysfuctio (2 5). These studies derived a sigle abormal (partitio) value for BNP by ROC aalysis ad have ot examied the use of age- or geder-specific partitio values. For the Biosite assay, values of 75 to 80 pg/ml have bee reported as partitio values for detectio of vetricular dysfuctio (with ad without symptoms) or diagosis of CHF (5,24). For the Shioogi assay, values of 17.9 to 79 pg/ml have bee reported for detectio of vetricular dysfuctio or CHF i highly variable populatios (2,8,23,27,28). Although we foud that the area uder the ROC curves was similar amog the age/geder strata, the optimal partitio value for the detectio of systolic dysfuctio differed by assay, age, ad geder. These data suggest that age-, geder-, ad assay-specific partitio values should be used to iterpret BNP. The ultimate partitio values used may also deped o the abormality beig screeed for (CHF vs. asymptomatic LV dysfuctio), its severity, the implicatios of false positives or egatives ad, importatly, o the populatio beig studied. The operatig characteristics of diagostic tests may vary accordig to the populatio to which they are applied (11). Eve though patiets with severe CHF have very high BNP, age/geder effects still eed to be cosidered whe choosig a partitio value. A previous study that utilized the Biosite assay to measure BNP reported that a BNP of 80 pg/ml is diagostic of CHF i symptomatic patiets presetig for urget care (5). Although the average BNP value i patiets with CHF was very high, ad the performace of the test was outstadig, the study populatio was youg (mea age 63 years) ad predomiately me (94%). I the curret study, a value of 80 pg/ml would be abormal i most male age groups (Table 2, Fig. 1) but would be well withi the 95th percetile for wome. A higher partitio value may be eeded i wome or older patiets where use of age- ad geder-specific partitio values may ehace the predictive characteristics of the test, particularly avoidig specificity problems i the elderly. Limitatios. The populatio of Olmsted Couty, Miesota, is primarily white, ad thus we are uable to ivestigate potetial ifluece of ethicity o BNP. Our study was cofied to subjects 44 years of age. Coclusios. I this populatio-based cohort, we foud that BNP icreases with age ad is higher i wome amog subjects without cardiovascular disease or cardiac dysfuctio. The magitude of the effects of age ad geder o BNP i the ormal subgroup suggested that both parameters eed to be cosidered whe iterpretig BNP, ad ideed, the optimal discrimiatory value of BNP for the detectio of systolic dysfuctio i the populatio was higher i wome ad older persos. Although the ultimate partitio value for BNP used i cliical practice will be iflueced by a umber of variables, these data suggest that age-, geder-, ad assay-specific values will be eeded. Ackowledgmets The authors are idebted to the study soographers, Trudy Wellik, Mary Wezel, ad Joa Lusk; ad the data aalysts, Ly Urba ad Matthew Johso for their techical expertise. Reprit requests ad correspodece: Dr. Margaret M. Redfield, Guggeheim 9, Mayo Cliic, 200 First Street, Southwest, Rochester, Miesota redfield.margaret@mayo.edu. REFERENCES 1. Che HH, Burett JC Jr. The atriuretic peptides i heart failure: diagostic ad therapeutic potetials. Proc Assoc Am Physicias 1999;111: McDoagh TA, Robb SD, Murdoch DR, et al. Biochemical detectio of left-vetricular systolic dysfuctio. Lacet 1998;351: Smith H, Pickerig RM, Struthers A, Simpso I, Mat D. Biochemical diagosis of vetricular dysfuctio i elderly patiets i geeral practice: observatioal study. Br Med J 2000;320: Davis M, Espier E, Richards G, et al. Plasma brai atriuretic peptide i assessmet of acute dyspoea. Lacet 1994;343:440 4.

7 982 Redfield et al. JACC Vol. 40, No. 5, 2002 BNP i Normal Subjects September 4, 2002: Dao Q, Krishaswamy P, Kazaegra R, et al. Utility of B-type atriuretic peptide i the diagosis of cogestive heart failure i a urget-care settig. J Am Coll Cardiol 2001;37: Murdoch DR, McDoagh TA, Byre J, et al. Titratio of vasodilator therapy i chroic heart failure accordig to plasma brai atriuretic peptide cocetratio: radomized compariso of the hemodyamic ad euroedocrie effects of tailored versus empirical therapy. Am Heart J 1999;138: Davis KM, Fish LC, Miaker KL, Elahi D. Atrial atriuretic peptide levels i the elderly: differetiatig ormal agig chages from disease. J Gerotol A Biol Sci Med Sci 1996;51:M Lucher A, Burett JC Jr., Jougasaki M, et al. Evaluatio of brai atriuretic peptide as marker of left vetricular dysfuctio ad hypertrophy i the populatio. J Hypertes 2000;18: Sayama H, Nakamura Y, Saito N, Kioshita M. Why is the cocetratio of plasma brai atriuretic peptide i elderly ipatiets greater tha ormal? Coro Artery Dis 1999;10: Sei M, Tribouilloy CM, Rodeheffer RJ, et al. Cogestive heart failure i the commuity: a study of all icidet cases i Olmsted Couty, Miesota, i Circulatio 1998;98: Jacobse SJ, Bergstralh EJ, Guess HA, et al. Predictive properties of serum-prostate-specific atige testig i a commuity-based settig. Arch Iter Med 1996;156: Aoymous. The sixth report of the Joit Natioal Committee o prevetio, detectio, evaluatio, ad treatmet of high blood pressure (published erratum appears i Arch Iter Med 1998:158:573). Arch Iter Med 1997;157: Gillum RF, Fortma SP, Prieas RJ, Kottke TE. Iteratioal diagostic criteria for acute myocardial ifarctio ad acute stroke. Am Heart J 1984;108: Naik MM, Diamod GA, Pai T, Soffer A, Siegel RJ. Correspodece of left vetricular ejectio fractio determiatios from twodimesioal echocardiography, radiouclide agiography ad cotrast cieagiography. J Am Coll Cardiol 1995;25: Starlig MR, Crawford MH, Sorese SG, Levi B, Richards KL, O Rourke RA. Comparative accuracy of apical biplae cross-sectioal echocardiography ad gated equilibrium radiouclide agiography for estimatig left vetricular size ad performace. Circulatio 1981;63: Jese-Urstad K, Bouvier F, Hojer J, et al. Compariso of differet echocardiographic methods with radiouclide imagig for measurig left vetricular ejectio fractio durig acute myocardial ifarctio treated by thrombolytic therapy. Am J Cardiol 1998;81: Michels VV, Moll PP, Miller FA, et al. The frequecy of familial dilated cardiomyopathy i a series of patiets with idiopathic dilated cardiomyopathy. N Egl J Med 1992;326: Appleto CP, Hatle LK. The atural history of left vetricular fillig abormalities: Assessmet by two-dimesioal ad Doppler echocardiography. Echocardiography 1992;9: Nishimura RA, Tajik AJ. Evaluatio of diastolic fillig of left vetricle i health ad disease: Doppler echocardiography i the cliicia s Rosetta stoe. J Am Coll Cardiol 1997;30: Omme SR, Nishimura RA, Appleto CP, et al. The cliical utility of Doppler echocardiography ad tissue Doppler imagig i estimatio of left vetricular fillig pressures: a comparative simultaeous Doppler-catheterizatio study. Circulatio 2000;102: Hurrell DG, Nishimura RA, Ilstrup DM, Appleto CP. Utility of preload alteratio i assessmet of left vetricular fillig pressure by Doppler echocardiography: a simultaeous catheterizatio ad Doppler echocardiographic study. J Am Coll Cardiol 1997;30: Klei AL, Burstow DJ, Tajik AJ, Zachariah PK, Bailey KR. Effects of age o left vetricular dimesios ad fillig dyamics i 117 ormal persos. Mayo Cli Proc 1994;69: Yamamoto K, Burett JC Jr., Jougasaki M, et al. Superiority of brai atriuretic peptide as a hormoal marker of vetricular systolic ad diastolic dysfuctio ad vetricular hypertrophy. Hypertesio 1996; 28: Maisel AS, Koo J, Krishaswamy P, et al. Utility of B-atriuretic peptide as a rapid, poit-of-care test for screeig patiets udergoig echocardiography to determie left vetricular dysfuctio. Am Heart J 2001;141: Best PJ, Berger PB, Miller VM, Lerma A. The effect of estroge replacemet therapy o plasma itric oxide ad edotheli-1 levels i postmeopausal wome. A Iter Med 1998;128: Gallagher PE, Li P, Lehart JR, Chappell MC, Brosiha KB. Estroge regulatio of agiotesi-covertig ezyme mrna. Hypertesio 1999;33: Yamamoto K, Burett JC Jr, Bermudez EA, Jougasaki M, Bailey KR, Redfield MM. Cliical criteria ad biochemical markers of systolic dysfuctio. J Card Fail 2000;6: Cowie MR, Struthers AD, Wood DA, et al. Value of atriuretic peptides i assessmet of patiets with possible ew heart failure i primary care. Lacet 1997;350: