Increased Cardiac Workload in the Upright Posture in Men: Noninvasive Hemodynamics in Men Versus Women

Inc eased Ca diac Wo kload in he Up igh Pos u e in Men: Nonin asi e Hemodynamics in Men Ve sus Women Pauliina Kangas, MD; Anna Tah anainen, MD, PhD; An i Tikkakoski, MD; Jenni Koskela, MD, PhD; Ma ko Ui o, MSc; Ja i Viik, MSc, PhD; Mika K€ ah€ onen, MD, PhD; Tii K€ o€ obi, MD, PhD; Jukka Mus onen, MD, PhD; Ilkka P€ o s i, MD, PhD Backg ound-—Men and women di e in he isk o ca dio ascula disease, bu he unde lying mechanisms a e no comple ely unde s ood. We examined possible sex- ela ed di e ences in supine and up igh ca dio ascula egula ion. Me hods and Resul s-—Hemodynamics we e eco ded om 167 men and 167 women o ma ching age (45 yea s) and body mass index (26.5) du ing passi e head-up il . None had diabe es melli us o ca dio ascula disease o he han hype ension o used an ihype ensi e medica ion. Whole-body impedance ca diog aphy, onome ic adial blood p essu e, and hea a e a iabili y we e analyzed. Resul s we e adjus ed o heigh , smoking, alcohol in ake, mean a e ial p essu e, plasma lipids, and glucose. Supine hemodynamic di e ences we e mino : Men had lowe hea a e (4%) and highe s oke index (+7.5%) han women (P<0.05 o bo h). Up igh sys emic ascula esis ance was lowe (10%), bu s oke index (+15%), ca diac index (+16%), and le ca diac wo k we e clea ly highe (+20%) in men han in women (P<0.001 o all). Co esponding esul s we e obse ed in a subg oup o men and pos menopausal women (n=76, aged >55 yea s). Hea a e a iabili y analyses showed highe low:high equency a ios in supine (P<0.001) and up igh (P=0.003) posi ions in men. Conclusions-—The o emos di e ence in ca dio ascula egula ion be ween sexes was highe up igh hemodynamic wo kload o he hea in men, a finding no explained by known ca dio ascula isk ac o s o ho monal di e ences be o e menopause. Hea a e a iabili y analyses indica ed highe sympa ho agal balance in men ega dless o body posi ion. The de ia ions in up igh hemodynamics could play a ole in he di e ences in ca dio ascula isk be ween men and women. Clinical T ial Regis a ion-—URL: h p://www.clinical ials.go . Unique iden ifie : NCT01742702. (J Am Hea Assoc. 2016;5: e002883 doi: 10.1161/JAHA.115.002883) Key Wo ds: ca diac ou pu •hemodynamics •sex-specific The li e ime isk o ca dio ascula disease (CVD) is close o 50% o pe sons aged 30 yea s wi hou known CVD, 1 and i is he mos common cause o dea h o bo h men and women. 2 The isk and he ou come o CVD, howe e , di e be ween sexes; pa icula ly be o e middle age, mo bidi y and mo ali y caused by CVDs a e highe in men. 3 In he F amingham Hea S udy, he li e ime isk o co ona y hea disease a age 40 yea s was abou 49% o men and 32% o women. 4 These di e ences in CVD isk be ween sexes ha e been a ibu ed o ho monal di e ences and o he ac ha mos o he isk ac o s a e mo e a o able o women. 5 Dis inc di e ences in ca dio ascula egula ion ha e been cha ac e ized be ween sexes. In ea ly adul hood, pulse p essu e is highe in men; howe e , a olde ages, pulse p essu e becomes highe in women. 6 The myoca dial emod- eling p ocess in esponse o aging, p essu e and olume o e load, and myoca dial in a c ion appea s o be mo e a o able in women han in men. 7 In pa ien s wi h ischemic hea disease, women may be mo e p one o myoca dial ischemia in esponse o men al s ess, whe eas men may show highe inc eases in blood p essu e (BP). 8 Taken oge he , hese findings aise he ques ion o whe he u he di e ences in ca dio ascula egula ion exis be ween men and women ha could influence he hemodynamic load o he hea and subsequen ly a ec he numbe o ca dio ascula end poin s. Hype ension is mo e p e alen in young men han in young women, bu a e menopause, he isk o hype ension F om he School o Medicine, Uni e si y o Tampe e, Finland (P.K., A. Tah anainen, A. Tikkakoski, J.K., M.K., J.M., I.P.); Depa men s o In e nal Medicine (A. Tah anainen, J.K., J.M., I.P.) and Clinical Physiology (A. Tikkakoski, M.K., T.K.), Tampe e Uni e si y Hospi al, Tampe e, Finland; Depa men o Elec onics and Communica ion Enginee ing, Tampe e Uni e si y o Technology, Tampe e, Finland (M.U., J.V.). Co espondence o: Pauliina Kangas, MD, School o Medicine/In e nal Medicine, Uni e si y o Tampe e, Tampe e FIN-33014, Finland. E-mail: pauliina.kangas@fimne .fi Recei ed No embe 7, 2015; accep ed May 23, 2016. ª2016 The Au ho s. Published on behal o he Ame ican Hea Associa ion, Inc., by Wiley Blackwell. This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion-NonComme cial License, which pe mi s use, dis ibu ion and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed and is no used o comme cial pu poses. DOI: 10.1161/JAHA.115.002883 Jou nal o he Ame ican Hea Associa ion 1 ORIGINAL RESEARCH by gues on Feb ua y 7, 2017h p://jaha.ahajou nals.o g/Downloaded om is significan ly inc eased in women. 9 The li e ime bu den o hype ension on he p e alence o CVDs is subs an ial. 1 In a su ey in Finland pe o med in 2007, only 37% o he d ug- ea ed hype ensi e pa ien s had no mal BP (<140/ 90 mm Hg). 10 The subop imal con ol o hype ension aises he ques ion o whe he indi idual cha ac e is ics and possi- ble sex- ela ed di e ences in he egula ion o hemodynamics should be mo e ca e ully aken in o accoun in he ea men o ele a ed BP. Al hough a majo sha e o he ac i e li e is spen in he up igh posi ion, mos epo s on sex- ela ed di e ences in hemodynamics ha e ocused on es ing condi ions. 11–14 Only ew s udies ha e compa ed up igh hemodynamics be ween sexes. 15–17 Simila up igh inc ease in pe iphe al a e ial esis ance and dec ease in ca diac ou pu was epo ed in 9 men e sus 8 women, 15 lowe up igh splanchnic asocon- s ic ion bu co esponding dec ease in ca diac ou pu was epo ed in 14 women e sus 16 men, 17 and co esponding up igh inc ease in o ea m ascula esis ance was obse ed in 48 women e sus 41 men. 16 In mos o he p e ious s udies, he con ol o ca diac au onomic one be ween sexes was e alua ed by he use o hea a e a iabili y (HRV). In he majo i y o hese epo s, sympa ho agal balance was epo ed o be highe in men, ega dless o whe he he pa icipan s we e in supine, si ing, o s anding posi ion. 16,18– 20 The p e ious s udies compa ing hemodynamics be ween sexes we e pe o med wi h small numbe s o pa icipan s, and he g oups ha e no been uni o m in age and body mass index (BMI). 8,15–17 The apies based on indi idual sex- ela ed cha - ac e is ics could imp o e ou comes in he ea men o CVDs like hype ension, 21 and pe sonalized app oaches in he ea men o medical condi ions a e keenly sough . 22–24 Because only limi ed in o ma ion exis s abou he up igh egula ion o he ca dio ascula sys em be ween sexes, we compa ed he hemodynamic esponses o passi e head-up il in 167 men e sus 167 women wi h co esponding age and BMI. The main findings we e e ified in a la ge g oup composed o an addi ional 313 men and 231 women. A o al o 480 men and 398 women we e examined. Me hods S udy Pa icipan s All pa icipan s we e in an ongoing s udy o hemodynamics in olun ee s, wi h he p ima y aim o examining he hemody- namic changes in p ima y and seconda y hype ension and no mo ensi e con ol pa icipan s in supine and up igh posi ions (DYNAMIC s udy; ClinicalT ials.go iden ifie NCT01742702). Pa icipan s we e en olled om he pa ien s ea ed a Tampe e Uni e si y Hospi al. An announcemen o ec ui men was dis ibu ed a Tampe e Uni e si y Hospi al, he Uni e si y o Tampe e, o fices o local occupa ional heal h ca e p o ide s, and Va ala Spo s Ins i u e, and 2 announce- men s we e published in a newspape . Those who ag eed o pa icipa e we e ec ui ed in he o de in which hei con ac in o ma ion was a ailable o he esea ch nu ses. By he ime o he p esen analysis, 878 pa icipan s (480 men and 398 women) had unde gone hemodynamic mea- su emen s; o hose, 615 we e wi hou medica ions wi h di ec influence on ca dio ascula unc ion. The emaining pa icipan s included medica ed pa ien s wi h hype ension, ch onic enal disease, diabe es melli us, and a he oscle o ic ascula disease. All pa icipan s we e in e iewed o eco d li es yle habi s, amily his o y, and medical his o y. Clinical examina ion o ca dio ascula s a us and ou ine labo a o y es s we e pe o med. Fo he main analysis o he p esen s udy, pa icipan s wi h an ihype ensi e medica ion, co ona y hea disease, o p e ious myoca dial in a c ion, diagnosis o diabe es melli us, ca diac insu ficiency, a he oscle o ic ascula disease, enal disease, o ce eb o ascula disease we e excluded. In addi- ion, all pa icipan s using medica ions wi h po en ial influ- ence on hemodynamics (eg, a 1 -ad enocep o blocke s o p os a e p oblems, b 2 -ad enocep o agonis s, digoxin, and opical b-blocke s o glaucoma) we e excluded. 25 To a oid con ounding caused by di e ences in age and body weigh , 26– 29 he ollowing inclusion p o ocol was applied: A emale pa icipan was chosen, ollowed by selec ion o a male pa icipan wi h co esponding age (di e ence in age ≤3 yea s) and BMI (di e ence ≤1.5 uni s). Using his app oach, 334 pa icipan s aged 21 o 67 yea s we e included (Table 1). O e all, 114 (34%) o he 334 pe sons used some medica ion (Table 2). Fo y emale pa icipan s used sys emic es ogen, p oges in, o hei combina ion ( o con acep ion o ho mone eplacemen he apy), and 1 pa icipan used ibolone. Eigh pa icipan s we e aking s a ins, and 11 eu hy oid pa icipan s we e on a s able dose o hy oid ho mone. O he medica ions (ace ylsalicylic acid, d ugs o men al p oblems, an ihis amines, p o on pump inhibi o s, in anasal o inhaled co icos e oid o as hma o alle gy) we e used by he s udy popula ion. One pa icipan who was physically well and symp omless was ea ed wi h wa a in o an iphospholipid synd ome. Addi ional analyses we e pe o med in g oups in which (1) all pa icipan s using sys emic emale ho mones o s a ins we e excluded, (2) all pa icipan s we e aged ≥55 yea s, and (3) all 878 pa icipan s who pa icipa ed in he eco ding o hemodynamics we e included. The pa icipan s ga e w i en in o med consen , and he s udy was app o ed by he e hics commi ee o Tampe e Uni e si y Hospi al (s udy code R06086M). DOI: 10.1161/JAHA.115.002883 Jou nal o he Ame ican Hea Associa ion 2 Up igh Hemodynamics in Men and Women Kangas e al ORIGINAL RESEARCH by gues on Feb ua y 7, 2017h p://jaha.ahajou nals.o g/Downloaded om Hemodynamic Measu emen s Hemodynamic measu emen s we e pe o med in a empe a- u e-con olled labo a o y. The pa icipan s we e ad ised o e ain om using ca eine-con aining p oduc s, smoking, and ea ing hea y meals o a leas 4 hou s and om d inking alcohol o a leas 24 hou s p io o he eco ding. While he pa icipan s we e es ing supine on a il able, he elec odes o impedance ca diog aphy we e placed on he body su ace, a onome ic senso o adial a e y BP on he le w is (Colin BP-508T; Colin Medical Ins umen s Co p) and an oscillome - ic b achial cu o BP calib a ion on he igh uppe a m. 25,26,31 The le a m wi h he onome ic senso was abduc ed o 90°in a suppo ha held he a m a he le el o he hea in supine and up igh posi ions. Es ima ion o cen al ao ic BP was pe o med by ma hema ical ans o - ma ion o adial onome y p essu e wi h he SphygmoCo pulse wa e moni o ing sys em (SpygmoCo PWMx; A co Medical) using a alida ed ans e unc ion. 32 Table 1. Clinical and Me abolic Cha ac e is ics in he S udy G oups Men (n=167) Women (n=167) PValue Age, y 4512 4511 0.967 Body mass index, kg/m 2 26.53.7 26.63.8 0.898 Heigh , cm 1806 1666<0.001 Weigh , kg 8812 7311 <0.001 Sys olic blood p essu e, mm Hg 13217 12718 0.006 Dias olic blood p essu e, mm Hg 7512 7212 0.026 Smoking Cu en 51 (30.5) 46 (27.5) 0.547 P e ious 22 (13.2) 17 (10.2) 0.394 Ne e 94 (56.3) 10 (62.3) 0.265 Alcohol, s anda d d inks pe week 4(1–10) 2 (0–4) <0.001 C ea inine, lmol/L 8212 659<0.001 Cys a in-C, mg/L 0.870.14 0.800.14 <0.001 eGFR, mL/min pe 1.73 m 2 99.214.5 99.314.0 0.956 To al choles e ol, mmol/L 5.11.0 5.11.0 0.804 LDL choles e ol, mmol/L 3.11.0 2.80.9 0.021 HDL choles e ol, mmol/L 1.40.3 1.80.4 <0.001 T iglyce ides, mmol/L 1.3 (0.7–1.5) 1.1 (0.7–1.3) 0.007 Fas ing plasma glucose, mmol/L 5.50.5 5.30.5 <0.001 Co nell ol age p oduc in ECG, ms9mm 1638615 1621509 0.779 Values a e meansSD excep o smoking, which shows he numbe o pa icipan s and pe cen ages, and o alcohol in ake and iglyce ides, which a e shown as medians (lowe and uppe qua iles) due o skewed dis ibu ion. eGFR indica es es ima ed glome ulus fil a ion a e 30 ; HDL, high-densi y lipop o ein; LDL, low-densi y lipop o ein. Table 2. Medica ions Used Regula ly by he S udy Pa icipan s (Numbe o Pa icipan s Wi h Each Type o Medica ion) Medica ion Men (n=167) Women (n=167) Ace ylsalicylic acid 3 0 Acyclo i 0 1 Allopu inol 0 1 Ami ip yline 0 1 Amoxicillin 0 1 An idep essan (SSRI o SNRI) 3 12 An ihis amine 2 5 Doxycycline (low dose) 1 0 Eze imibe 1 0 Female ho mones Sys emic (including ibolone) 0 41 Topical 0 3 Glucosamine 3 3 In anasal o inhaled co icos e oid 2 6 Iso e inoin 0 1 Le ozole 0 1 Le omep omazine 0 1 Le ono ges el ia in au e ine de ice 0 16 Lio hy onine 0 1 Lymecycline 1 0 Me loquine 0 1 Mela onin 1 1 Mepac ine 1 0 Nons e oidal an i-in lamma o y d ug 1 3 Oxybu ynine 0 1 P amipexole 0 1 P egabalin 1 1 P o on pump inhibi o 3 4 Que iapine 0 1 S a in 7 1 Thy oxine 0 10 Valp oa e 0 1 Vi amin D supplemen a ion 6 11 Wa a in 1 0 SNRI indica es se o onin–no epineph ine eup ake inhibi o ; SSRI, selec i e se o onin eup ake inhibi o . DOI: 10.1161/JAHA.115.002883 Jou nal o he Ame ican Hea Associa ion 3 Up igh Hemodynamics in Men and Women Kangas e al ORIGINAL RESEARCH by gues on Feb ua y 7, 2017h p://jaha.ahajou nals.o g/Downloaded om A whole-body impedance ca diog aphy de ice (Ci cMon; JR Medical L d) ha eco ds changes in body elec ical impedance du ing ca diac cycles was used o de e mine hea a e, s oke olume, and ca diac ou pu . 25,33–35 The desc ip ion o he me hod and elec ode configu a ion was epo ed p e iously. 25,33–35 The alues we e no malized o body su ace a ea and exp essed as ca diac index, s oke index, sys emic ascula esis ance index (SVRI), and le ca diac wo k index (LCWI). SVRI was calcula ed om he adial BP signal and ca diac index measu ed by he Ci cMon de ice. LCWI (in kg9m/min pe m 2 ) was calcula ed using ollowing o mula: 0.01439(mean ao ic p essu e–pulmona y a e y occlusion p essu e)9ca diac index. Pulmona y a e y occlusion p essu e was assumed o be 6 mm Hg (no mal), and 0.0143 is he con e sion ac o o p essu e om millime e s o me cu y o cen ime e s o wa e , olume o densi y o blood (in kg/L), and cen ime e s o me e s. 36,37 The s oke olume and ca diac ou pu measu ed using Ci cMon whole-body impedance ca diog aphy ag ee wi h alues mea- su ed using 3-dimensional ul asound and he he modilu ion me hod, espec i ely, and ag eemen wi h he la e has been shown in bo h supine and up igh posi ions. 34,36,38 An in oduc o y head-up il was pe o med be o e he eco dings. The ac ual measu emen consis ed o 3 consec- u i e 5-minu e pe iods wi h con inuous cap u e o da a: 5 minu es supine, 5 minu es o passi e head-up il o 60°, and 5 minu es supine. The epea abili y and ep oducibili y o he supine and up igh measu emen s has been shown o be good. 31 E alua ion o Ca diac Au onomic Tone HRV analysis om elec oca diog ams was used o assess ca diac au onomic one. The elec oca diog ams we e eco ded by he Ci cMon de ice a a 200-Hz sampling a e, and da a we e analyzed using Ma lab so wa e (Ma hWo ks Inc). No mal R-R in e als we e ecognized, and a bea was conside ed ec opic i he in e al di e ed >20% om he p e ious alues. The a i ac s we e p ocessed using he cubic spline in e pola ion me hod. 39 Because he da a we e collec ed om sho - e m eco dings, he equency domain me hod was applied. 40 The ollowing a iables we e calcula ed om he eco dings in supine (0–5 minu es) and up igh (5–10 minu es) posi ions using he as Fou ie ans o ma- ion me hod: (1) o al powe , (2) powe in he low- equency (LF) ange (0.04–0.15 Hz), (3) powe in he high- equency (HF) ange (0.15–0.40 Hz), and (4) LF/HF a io. 40 Labo a o y Tes s Blood samples we e ob ained a e abou 12 hou s o as ing. Plasma glucose, c ea inine, cys a in C, iglyce ide, and o al and high- and low-densi y lipop o ein choles e ol concen a- ions we e de e mined using he Cobas In eg a 700/800 o Cobas 6000, module c501 (F. Ho mann-La Roche L d), and blood cell coun was pe o med by an ADVIA 120 o 2120 sys em (Siemens Heal hca e GmbH). In some pa icipan s, low-densi y lipop o ein was calcula ed using he F iedewald o mula. 41 C ea inine- and cys a in C–based es ima ed glome ula fil a ion a e was calcula ed using he Ch onic Kidney Disease Epidemiology Collabo a ion o mula. 30 A s anda d 12-lead elec oca diog am was eco ded, and le en icula mass was e alua ed using he Co nell ol age QRS du a ion p oduc . 21 All labo a o y alues we e missing om 3 pa icipan s, and low-densi y lipop o ein choles e ol alues we e missing om an addi ional 2 pa icipan s. S a is ical Analyses The cha ac e is ics o men e sus women we e compa ed using an independen samples es , and smoking habi s (cu en , p e ious and ne e ) we e compa ed using he Pea son chi-squa e es . Hemodynamic di e ences in supine and up igh posi ions we e examined using ANOVA o epea ed measu es, and he changes in hemodynamic alues om supine o up igh posi ion (a e age alues o las 3 minu es be o e and las 3 minu es du ing he head-up il 25 ) and HRV di e ences we e analyzed using an independen samples es and ANOVA wi h possible con ounding ac o s as co a ia es. A e age BP alues du ing he las 3 minu es o he fi s supine pe iod we e applied o he clinical cha ac- e iza ion o he BP o pa icipan s (Table 1). The analyses we e adjus ed o smoking habi s, alcohol in ake (s anda d doses pe week), as ing plasma glucose, iglyce ides, high- and low-densi y lipop o ein choles e ol, heigh , and mean a e ial p essu e, as app op ia e ( he adjus ing a iable was no used i i was included in he o mula o he a iable o in e es ). HRV analyses we e also adjus ed o hea a e. 42 In he adjus ed analyses, cu en smoking as ciga e es pe day was applied as a con inuous a iable, whe eas in he ables, he smoking habi s we e desc ibed as cu en , p e ious, and ne e smoke . Due o missing da a among he main g oup o in e es (334 pa icipan s), he numbe o pa icipan s in he adjus ed analyses anged om 311 o 324, wi h a leas 153 men and 158 women in all analyses. The skewed dis ibu ions o iglyce ides, o al powe , LF powe , HF powe , and LF/HF a io we e loga i hmically ans o med be o e s a is ical analyses. Va iables wi h no mal dis ibu ion we e epo ed as means and s anda d de ia ions (SD) o 95% CIs o he means; skewed dis ibu ions we e epo ed as medians, lowe and uppe qua iles, and ange; and ca ego ical a iables we e epo ed as numbe s o pa icipan s and pe cen ages. All es ing was 2-sided, and P DOI: 10.1161/JAHA.115.002883 Jou nal o he Ame ican Hea Associa ion 4 Up igh Hemodynamics in Men and Women Kangas e al ORIGINAL RESEARCH by gues on Feb ua y 7, 2017h p://jaha.ahajou nals.o g/Downloaded om alues <0.05 we e conside ed s a is ically significan . The da a we e analyzed using SPSS 17.0 (IBM Co p). Resul s S udy Popula ion The gene al cha ac e is ics o he s udy pa icipan s a e p esen ed in Table 1. Because o he inclusion p o ocol, men and women we e well ma ched o age and BMI. In addi ion, he e we e no significan di e ences in smoking s a us, es ima ed glome ula fil a ion a e, 30 o al choles e ol, and Co nell ol age p oduc 21 be ween he 167 men and 167 women. Men, howe e , we e cha ac e ized by somewha highe sys olic and dias olic BP, alcohol in ake, and highe as ing plasma c ea inine, cys a in C, low-densi y lipop o ein choles e ol, iglyce ide, and glucose concen a ion and lowe high-densi y lipop o ein choles e ol concen a ion han women. Supine and Up igh Hemodynamics Men had highe supine mean a e ial p essu e, s oke index, and LCWI and lowe hea a e han women in unadjus ed analyses (Figu e 1A–1C and 1E). Supine ca diac index and SVRI did no di e be ween sexes (Figu e 1D and 1F). A e adjus ing o heigh , smoking habi s, alcohol in ake, mean a e ial p essu e, low- and high-densi y lipop o ein choles- e ol, iglyce ides, and glucose, only he di e ences in supine hea a e and s oke index o men and women emained significan (Figu e 1B and 1C). Du ing passi e head-up il o 60°, men had highe mean a e ial p essu e, s oke index, ca diac index, and LCWI (Figu e 1A, 1C, 1D, and 1E) and lowe SVRI (Figu e 1F) han women in unadjus ed analyses. Up igh hea a e did no di e be ween men and women (Figu e 1B). In adjus ed analyses, wi h he excep ion o mean a e ial p essu e, all o he abo e di e ences in up igh hemody- namics o men and women emained significan (Figu e 1A and 1C–1F). The magni ude o he changes in hemodynamic a iables in esponse o up igh pos u e was also analyzed (see Me hods). Unadjus ed analyses showed a g ea e inc ease in hea a e (P<0.001); less dec ease in s oke index, ca diac index, and LCWI (P<0.05 o all); and less inc ease in SVRI (P<0.001) in esponse o head-up il in men han in women. A simila inc ease in mean a e ial p essu e was obse ed in bo h sexes (P=0.812). In adjus ed analyses, he di e ences in he up igh changes in ca diac index, LCWI, and SVRI emained significan (P<0.01 o all), whe eas he changes in hea a e and s oke index we e no longe di e en be ween men and women (P=0.600 and P=0.694, espec i ely). HRV in Supine and Up igh Posi ions In supine and up igh posi ions, he e we e no significan di e ences in o al powe and in powe in he LF ange in unadjus ed analyses (Figu e 2A and 2B), whe eas men had lowe powe in he HF ange and highe LF/HF a ios han women (Figu e 2C and 2D). In adjus ed analyses, he up igh di e ences in he HF componen we e no longe significan (Figu e 2C), bu supine HF powe was lowe and bo h supine and up igh LF/HF a ios emained highe in men han in women (Figu e 2C and 2D) Supine and Up igh Hemodynamics in Addi ional Analyses Th ee addi ional analyses o hemodynamic changes in esponse o head-up il we e pe o med: (1) All pa icipan s using sys emic emale ho mones and s a ins we e excluded (n=285) (Figu e 3); (2) all included pa icipan s we e aged ≥55 yea s, and none used sys emic emale ho mones (n=76) (Figu e 4); (3) all pa icipan s who pa icipa ed in hemody- namic eco dings we e included (n=878) (Figu e 5). The las g oup was composed o 615 pa icipan s who we e wi hou medica ions wi h di ec influence on ca dio ascula unc ion and 263 medica ed pa ien s wi h hype ension, ch onic enal disease, diabe es melli us, o a he oscle o ic ascula dis- ease. The ou come o all o hese addi ional analyses was ha he sex- ela ed di e ences in up igh hemodynamics we e e y simila o hose obse ed in he 167 men and 167 women wi h ma ching age and BMI. The esul s clea ly showed a highe up igh hemodynamic wo kload o he hea in men (Figu es 3 h ough 5). Discussion Se e al p e ious s udies examined he di e ences in ca dio- ascula unc ion be ween sexes, 6–8,16,18–20,43 bu only a ew epo s compa ed he up igh hemodynamics be ween sexes. 15–17,44,45 Al hough head-up il o 5 minu es is a sho pe iod o obse a ion, we ound ha up igh hemo- dynamic adap a ion di e ed be ween men and women. In men, ca diac index and le ca diac wo k dec eased less in he up igh posi ion han in women, whe eas men also showed lowe up igh inc ease in sys emic ascula esis- ance han women. The ne ou come was ha he up igh hemodynamic wo kload o he hea was highe in men han in women. To gain unc ional insigh abou he ca dio ascula sys em, we applied a head-up il p o ocol o induce changes in au onomic one, ca diac unc ion, and pe iphe al a e ial esis ance in he s udy pa icipan s. 25,26,31,35 Because age and excess body weigh ha e majo influences on DOI: 10.1161/JAHA.115.002883 Jou nal o he Ame ican Hea Associa ion 5 Up igh Hemodynamics in Men and Women Kangas e al ORIGINAL RESEARCH by gues on Feb ua y 7, 2017h p://jaha.ahajou nals.o g/Downloaded om hemodynamics, 26–29 we ini ially pe o med analyses in 167 men and 167 women wi h co esponding age and BMI; howe e , he findings showing highe ca diac wo kload du ing head-up il in men emained simila in pa icipan s no using s a ins o ho mone eplacemen he apy, in pa icipan s aged ≥55 yea s, and in a la ge g oup composed o 878 pa icipan s. Figu e 1. Line g aphs show mean a e ial p essu e (A), hea a e (B), s oke index (C), ca diac index (D), le ca diac wo k index (E), and sys emic ascula esis ance index (F) in 167 men and 167 women du ing supine posi ion and passi e head-up il (means and 95% CIs o he mean). P alues deno e di e ences be ween sexes in unadjus ed analysis and in analyses adjus ed o low- and high-densi y lipop o ein choles e ol, iglyce ides, glucose, mean a e ial p essu e, smoking habi s, alcohol in ake, and heigh . DOI: 10.1161/JAHA.115.002883 Jou nal o he Ame ican Hea Associa ion 6 Up igh Hemodynamics in Men and Women Kangas e al ORIGINAL RESEARCH by gues on Feb ua y 7, 2017h p://jaha.ahajou nals.o g/Downloaded om We examined ca diac au onomic one using he equency domain analyses o HRV. 16,18–20 The HF componen eflec s ca diac pa asympa he ic ac i i y, 46–48 whe eas he LF com- ponen p edominan ly eflec s sympa he ic ac i i y, al hough i con ains pa asympa he ic con ibu ions. 40,46,48 The LF/HF a io is a ma ke o sympa ho agal balance, 40,46 bu his ma e emains con o e sial, and conclusions should be d awn wi h cau ion. 47,48 In he p esen s udy, he equency domain analysis o HRV showed highe LF/HF a ios in men bo h supine and up igh , sugges ing inc eased sympa ho agal balance. The di e ences in ca diac au onomic one la gely esul ed om dec eased HF powe , namely, lowe ca diac pa asympa he ic one in men han women. The e has been con o e sy abou whe he he indices o HRV a e highe in men o in women. In pa icipan s aged <30 yea s, he ime domain measu es o HRV we e highe in men han in women 49 ; howe e , mos published epo s on equency domain measu es o HRV ha e ound ha he alues o LF powe a e highe in men, 18–20,50 whe eas he alues o HF powe a e highe in women. 16,19,50 Highe LF/HF a ios du ing supine and s anding posi ions ha e been epo ed in 156 men e sus 206 women, 20 and he majo i y o epo s ha e sugges ed ha sympa ho agal balance is highe in men. 15,16,18–20,43,50–52 The p esen findings s ess he ole o di e ences in ca diac pa asympa he ic egula ion be ween sexes. Highe sympa ho agal balance in men ag ees wi h highe up igh ca diac wo kload bu aises ques ions abou lowe Figu e 2. Box plo s o hea a e a iabili y in men and women du ing 5 minu es in supine and up igh posi ions: o al powe (A), LF powe (B), HF powe (C), and LF/HF a io (D) (median [line inside box], 25 h o 75 h pe cen ile [box], and ange [whiske s); ou lie s we e excluded om he figu e bu we e included in he s a is ics). P alues deno e di e ences be ween sexes in unadjus ed analysis and in analyses adjus ed o low- and high-densi y lipop o ein choles e ol, iglyce ides, glucose, hea a e, 42 mean a e ial p essu e, smoking habi s, alcohol in ake, and heigh . HR indica es high equency; LF, low equency. DOI: 10.1161/JAHA.115.002883 Jou nal o he Ame ican Hea Associa ion 7 Up igh Hemodynamics in Men and Women Kangas e al ORIGINAL RESEARCH by gues on Feb ua y 7, 2017h p://jaha.ahajou nals.o g/Downloaded om up igh SVRI in men. Bo h a e ies and eins a e inne a ed by au onomic ne es. Au onomic inne a ion o he esis ance a e ies consis s o sympa he ic and senso y–mo o ne es, whe eas pa asympa he ic ascula inne a ion is nonexis en o e y limi ed. 53 I highe sympa ho agal balance would be ansmi ed o he esis ance a e ies simila ly in men and women, highe ca diac ou pu would esul in an excessi e up igh ise o a e ial p essu e in men, wi h subsequen ac i a ion o ba o ecep o s. 54 This would limi he inc ease in ascula esis ance, and he compa ison o ba o eflexes be ween men and women is a subjec o u he s udies. P e iously, ba o ecep o sensi i i y du ing o hos asis has been epo ed o be highe in men han in women. 15 Al hough sympa he ic ne es a e p edominan ly asocons ic o ne es, hey can induce asodila ion in skele al muscles, 53 and he ne e ec o sympa he ic s imula ion on pe iphe al esis ance depends on he ci cula o y balance be ween skele al muscles and o he o gans. S udies o muscle sympa he ic ne e ac i i y ha e shown ha he associa ion o sympa he ic one wi h hemodynamics is no s aigh o wa d. 14,15 In younge men and women (aged <40 yea s), no ela ionship was ound be ween muscle sympa he ic ne e ac i i y and BP, al hough a clea ela ionship was obse ed in olde pa icipan s (aged ≥40 yea s). 14 In younge men, muscle sympa he ic ne e ac i i y was posi i ely ela ed o pe iphe al ascula esis- ance and nega i ely ela ed o ca diac ou pu , whe eas in younge women, no ela ionship was ound be ween muscle sympa he ic ne e ac i i y and pe iphe al ascula esis ance Figu e 3. Pa icipan s using s a ins o ho mone eplacemen he apy we e excluded. Line g aphs show mean a e ial p essu e (A), ca diac index (B), le ca diac wo k index (C), and sys emic ascula esis ance index (D) in 160 men and 125 women du ing supine posi ion and passi e head-up il (means and 95% CIs o he mean). P alues deno e di e ences be ween sexes in unadjus ed analysis and in analyses adjus ed o low- and high-densi y lipop o ein choles e ol, iglyce ides, glucose, mean a e ial p essu e, smoking habi s, alcohol in ake, age, and body mass index. DOI: 10.1161/JAHA.115.002883 Jou nal o he Ame ican Hea Associa ion 8 Up igh Hemodynamics in Men and Women Kangas e al ORIGINAL RESEARCH by gues on Feb ua y 7, 2017h p://jaha.ahajou nals.o g/Downloaded om o ca diac ou pu . 14 Finally, au onomic inne a ion is no he sole egula o o esis ance a e ial one; endo helium- dependen mechanisms, myogenic egula ion, and humo al ac o s also con ibu e o ascula esis ance. 53,55 The p esen findings p o ide ano he pu a i e explana ion o he highe isk o ca diac e en s in men. Co ona y hea disease and myoca dial in a c ion accoun o a hi d o hal o he ini ial p esen a ions o CVD, and male sex pa icula ly p edisposes o myoca dial in a c ion in hose aged <60 yea s. 56 The mo e un a o able up igh hemodynamic load o he hea could lead o ea lie clinical mani es a ion o co ona y hea disease in men han in women. O no e, he co ona y findings in hose who expe ienced sudden dea h also di e be ween sexes. In 442 cases o sudden co ona y dea h, he p e alence o acu e h ombosis and plaque up u e was highe in men han in women (53% e sus 46% and 71% e sus 33%, espec i ely), whe eas plaque e osion as a cause o h ombosis was less equen in men han in women (24% e sus 58%). 57 Finally, e en he p ognosis o hea ailu e has been epo ed o be wo se in men han in women. 58,59 This is no explained by he e iology o he hea ailu e o by di e ences in le en icula ejec ion ac ion. 60 Di e ences in he up igh hemodynamic load o he hea could pa ially explain some o he a o emen ioned di e ences in ca dio as- cula isk be ween men and women. An ob ious di e ence be ween men and women is ho monal unc ion, and bo h endogenous and exogenous sex ho mones ha e e ec s on he ascula u e. 9,61 Figu e 4. All included pa icipan s aged ≥55 yea s. Line g aphs show mean a e ial p essu e (A), ca diac index (B), le ca diac wo k index (C), and sys emic ascula esis ance index (D) in 43 men and 33 women (no ho mone eplacemen he apy in use) du ing supine posi ion and passi e head-up il (means and 95% CIs o he mean). P alues deno e di e ences be ween sexes in unadjus ed analysis and in analyses adjus ed o low- and high-densi y lipop o ein choles e ol, iglyce ides, glucose, mean a e ial p essu e, smoking habi s, alcohol in ake, age, and body mass index. DOI: 10.1161/JAHA.115.002883 Jou nal o he Ame ican Hea Associa ion 9 Up igh Hemodynamics in Men and Women Kangas e al ORIGINAL RESEARCH by gues on Feb ua y 7, 2017h p://jaha.ahajou nals.o g/Downloaded om