Miller, Kathleen B.

A history of hypertensive disorders of pregnancy, including preeclampsia, place women at an elevated risk of developing hypertension and cognitive impairments as they age. The purpose of this study was to determine if aortic hemodynamics were related to cognition in postmenopausal women with a history of hypertensive disorders of pregnancy. We evaluated 33 postmenopausal women with a history of preeclampsia (PE: age = 59 ± 5 y; BMI = 29 ± 5 kg/m 2 ; years since last pregnancy = 35 ± 3 y) and 29 postmenopausal women with a history of normotensive pregnancy (NTP: age = 59 ± 5 y; BMI = 26 ± 5 kg/m 2 ; years since last pregnancy = 35 ± 3 y). Participants underwent a cognitive testing battery including letter‐number sequencing, trail making test B, letter fluency, and category fluency tests to evaluate executive functioning and working memory. Mean arterial pressure (MAP) was measured with a brachial blood pressure cuff. Applanation tonometry (SphygmoCor) was used to derive the aortic pressure waveform and calculate aortic systolic blood pressure (ASBP), aortic diastolic blood pressure (ADBP), augmentation index (AI), and augmented pressure (AP). There were no differences in cognitive scores between groups (p > 0.05). Brachial blood pressure (MAP: 103 ± 2 vs. 103 ± 3 mmHg) and aortic hemodynamic measures (ASBP: 123 ± 3 vs. 121 ± 3 mmHg; ADBP: 78 ± 2 vs. 77 ± 2 mmHg; AI: 31 ± 2 vs. 28 ± 1 %; AP: 17 ± 1 vs. 15 ± 1 mmHg) were also similar between PE women and NTP women, respectively (p > 0.05 for all). There were no associations between measures of aortic hemodynamics and cognitive scores in women independent of their pregnancy history (p > 0.05). When evaluating these relationships within each group, ADBP was significantly associated with worse scores for letter‐number sequencing and letter fluency in PE women (r = −0.433 and r = −0.441, respectively, p < 0.05). Taken together, our results indicate aortic hemodynamic measures are not associated with cognition in middle‐aged postmenopausal women with different pregnancy histories; however, future studies should address the influence of elevated aortic hemodynamic variables and the longitudinal change in cognitive function in postmenopausal women with different pregnancy histories. Support or Funding Information NIH AG44170, NIH 118154

Recent research focuses on the cerebrovascular response to vasodilatory stimuli as an index of cerebrovascular health; however, vasoconstrictor responses in the brain are likely equally important. We previously have shown that cerebral vasoconstrictor responses to hypocapnia are not affected by aging; however, this was evaluated in primarily sedentary adults. Therefore, we hypothesized that middle cerebral artery velocity (MCAv) vasoconstrictor responses to hypocapnia are dependent on age and habitual physical activity. We evaluated 13 young physically active (YA; age = 30±5 y; VO 2 max = 45±8 mL/kg/min), 6 young sedentary (YS; age = 29±4 y; VO 2 max = 26±3 mL/kg/min), 10 older physically active (OA; age= 61±6 y; VO 2 max =35±7 mL/kg/min) and 8 older sedentary (OS; age = 65±8 y; VO 2 max 23±2 mL/kg/min) adults during the recovery from inhaled 6% CO 2 to room air. Mean arterial pressure (MAP) end tidal CO 2 (ETCO 2 ) and MCAv were recorded throughout. Using a breath‐by breath analysis, cerebrovascular conductance index (CVCi=MCAv/MAP) reactivity was calculated as a slope of CVCi and ETCO 2 and used to quantify vasoconstrictor responses. CVCi reactivity was higher in YA adults (slope=2.74±0.9 AU) compared with both YS (slope=2.20±1.1 AU) and older groups (OA: slope=2.08±0.5 AU; OS: slope=2.07±0.7 AU; p<0.05 for all). There were no significant differences in CVCi reactivity between YS and either OA or OS (p=0.94, p=0.99 respectively). Additionally, CVCi negatively correlated with age (r=−0.38, p<0.05). Our results indicate that aging attenuates the cerebral vasoconstrictor response to hypocapnia in older adults in comparison to physically‐active young adults, but not compared to sedentary young controls. A sedentary lifestyle resulted in attenuated vasoconstrictor responses in the young sedentary group, as their responses were not different than the older adults. It remains unclear how habitual physical activity preserves the cerebral vasoconstrictor response to hypocapnia in young people, and if a structured exercise training intervention would impact this response in older adults. Support or Funding Information NIH HL118154

A history of preeclampsia (PE) places women at higher risk for future cardiovascular disease and cognitive decline. We have previously shown that postmenopausal women with a history of PE demonstrated a reduced cerebral blood flow response to hypercapnia compared with postmenopausal women with a history of a normotensive pregnancy (NP). These findings suggest cerebrovascular effects of PE 30+ years postpartum. In addition, we have reported that women with a history of PE did not have an exaggerated pressor response to a sympathoexcitatory stimulus. However, it is possible that women with a history of PE may have an altered cerebral blood flow response to a sympathoexcitatory stimulus. In this study, middle cerebral artery blood velocity (MCAv) and beat‐to‐beat mean arterial blood pressure (MAP) were measured during isometric handgrip to fatigue (IHG) at 30% of maximal voluntary contraction followed by post‐exercise ischemia (PEI) for 90 seconds and a two minute recovery period (REC). Participants were postmenopausal women with a history of PE (n = 21; age at study = 58±5 y; years since last pregnancy = 35±3 y) and NP (n = 27; age at study = 58±5 y; years since last pregnancy = 35±3 y). Baseline MAP and MAP responses to IHG and PEI were similar between groups (p>0.05). PE women demonstrated lower MCAv at baseline (NP: 72±3 cm/s vs. PE: 57±4 cm/s), IHG (NP: 78±4 cm/s vs. PE: 63±4 cm/s), PEI (NP: 74±4 cm/s vs. PE: 60±4 cm/s), and REC (NP: 70±3 cm/s vs. PE: 58±4 cm/s) compared with NP women (p<0.05 for all). MCAv, when calculated as a percent change from baseline, was elevated during IHG in both PE and NP women as expected (p<0.05); however, PE women had an augmented MCAv response during the last third of IHG compared with NP women (NP: 9±2 % vs. PE: 13±2 %; p<0.05). PE women also had a higher MCAv response during REC compared with NP women (NP:−2±2% vs. PE: 3±2%; p<0.05). Importantly, these elevated MCAv responses occurred despite the fact that MAP was not different between groups. In summary, PE women demonstrated a lower basal cerebral blood velocity but an elevated cerebrovascular response to a sympathoexcitatory stimulus compared with NP women. This suggests that in postmenopausal women, there is an effect of pregnancy history on the sensitivity of the cerebral blood flow response to a sympathoexcitatory stimulus. Support or Funding Information NIH: AG 044170. This investigation was supported by the National Institutes of Health, under Ruth L. Kirschstein National Research Service Award T32 HL 007936 from the National Heart Lung and Blood Institute to the University of Wisconsin‐Madison Cardiovascular Research Center. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Cerebrovascular reactivity to hypercapnia declines with age and low reactivity may be a biomarker of cognitive decline. Central elastic arteries that perfuse the brain stiffen with age, increasing their transmission of pulsatile mechanical forces into the cerebral microvasculature and impairing cerebral microvessel function. Habitual physical activity, however, has been shown to reduce central arterial stiffness and is associated with better cognitive function. Therefore, the purpose of this study was to evaluate cerebrovascular reactivity in young and older healthy adults who habitually exercise. We hypothesized that older adults who habitually exercised would have similar cerebrovascular reactivity when compared with young adults. However, because the underlying mechanisms of cerebral blood flow regulation may differ with age, we also evaluated blood pressure and central hemodynamic measures. We recruited 25 young (YA: age = 27 ± 1 y) and 20 older (OA: age = 59 ± 1 y) habitual exercisers. Middle cerebral artery velocity (MCAv) was recorded using transcranial Doppler ultrasound. In order to assess cerebrovascular reactivity, mean arterial pressure (MAP), end‐tidal carbon dioxide (ETCO 2 ), and MCAv were continuously recorded at rest and during stepwise elevations of inhaled CO 2 . Cerebrovascular conductance index (CVCi) was calculated as MCAv/MAP. Reactivity was calculated as the linear relationship between the change in ETCO 2 and the change in each variable of interest (MCAv, CVCi and MAP). Central arterial stiffness (carotid‐femoral pulse wave velocity, PWV) and central hemodynamics (augmentation index, AIx) were assessed by applanation tonometry. Older adults had higher MAP (YA: 85 ± 2 mmHg; OA: 90 ± 3 mmHg; p<0.05) and AIx (YA: 0 ± 3 %; OA: 20 ± 2 %; p<0.05) at rest compared with young adults. PWV was not statistically different between groups (YA: 4.9 ± 0.3 cm/s; OA: 5.7 ± 0.5 cm/s; p=0.18). MCAv and CVCi reactivity to hypercapnia were similar between young and older adults (MCAv reactivity, YA: 2.0 ± 0.2 cm/s/mmHg; OA: 2.2 ± 0.1 cm/s/mmHg; p=0.46, CVCi reactivity, YA: 0.018 ± 0.002 cm/s/mmHg 2 ; OA: 0.016 ± 0.001 cm/s/mmHg 2 ; p=0.42); however, older adults demonstrated higher MAP reactivity to hypercapnia (YA: 0.3 ± 0.1 a.u.; OA: 0.8 ± 0.1 a.u.; p<0.05). PWV and AIx were not associated with MCAv, CVCi, or MAP reactivity to hypercapnia (p>0.05). Our results suggest that habitual exercise preserves cerebrovascular reactivity; however, MAP reactivity is augmented with aging allowing older adults to sufficiently increase cerebral blood flow during hypercapnia. Support or Funding Information Supported by National Institute of Health grant HL118154 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Abstract BACKGROUND Studies demonstrate an association between aortic hemodynamics and cognitive function. The impact of pregnancy history on this association is unknown. METHODS Postmenopausal women (age 59 ± 5 years; years since last pregnancy 35 ± 3) with either a history of preeclampsia (PE; n = 34) or a history of a normotensive pregnancy (NP; n = 30) underwent cognitive testing: Letter-Number Sequencing, Digit Span, Trail Making Test, and letter and category fluency. Applanation tonometry was used to derive aortic systolic and diastolic blood pressure and augmentation index. RESULTS Distribution of cognitive scores and aortic hemodynamic measures was similar between the PE and NP groups. Principal component (PC) analysis was used to reduce the 3 aortic hemodynamic measures and the 5 cognitive variables to single summary indices, each representing a weighted average of their respective constituent variables. Using a multivariable linear model based on these PCs that adjusted for pregnancy history and body mass index, the composite index of aortic hemodynamics was associated with the summary cognitive index, whether taking into account a potential interaction with pregnancy history (P = 0.035) or not (P = 0.026) (interaction P = 0.178). Multivariable modeling of individual cognitive tests revealed a differential association for letter fluency by pregnancy history (test for interaction P = 0.023); this score correlated with the aortic hemodynamic index in the PE (partial R2 = 0.20), but not the NP (partial R2 = 0.00) group. CONCLUSIONS Elevated aortic hemodynamics may negatively impact cognitive function in postmenopausal women with specific executive functions, such as letter fluency, being impacted more by a pregnancy history of PE.

Preeclampsia (PE) is a hypertensive disorder of pregnancy described as a condition of excessive sympathoexcitation. PE places a woman at increased risk for lifelong hypertension and cognitive impairment. Cerebral blood velocity is blunted in response to a vasoactive stimulus in women with a history of PE. This study investigated how a sympathoexcitatory stimulus affects cerebral blood velocity in women with a history of PE. Middle cerebral artery blood velocity (MCAv) and beat-to-beat mean arterial blood pressure (MAP) were measured in postmenopausal women with a history of PE ( n = 21; age = 59 ± 5 yr) and a history of a normotensive pregnancy (NP; n = 27; age = 58 ± 4 yr), at baseline, during isometric handgrip to fatigue (IHG) followed by postexercise ischemia (PEI), and a recovery period (REC). Baseline MAP and MAP responses to IHG and PEI did not differ between groups. MCAv at baseline and throughout the stimulus was lower in PE women compared with NP women ( P < 0.05 for all). MCAv increased during IHG in both groups ( P < 0.05). This increase in MCAv was greater in PE compared with NP women during IHG and REC (IHG: PE 13 ± 2% vs. NP 9 ± 2%; REC: PE 3 ± 2% vs. NP −2 ± 2%; P < 0.05 for both). Thus, a history of PE is associated with low baseline cerebral blood velocity but an augmented response to a sympathoexcitatory stimulus. These changes in cerebral blood flow regulation may lead to an increased risk for cognitive impairment in women with a history of PE.

Cerebrovascular reactivity (CVR) is reduced in patients with cognitive decline. Women with a history of preeclampsia are at increased risk for cognitive decline. This study examined an association between pregnancy history and CVR using a subgroup of 40 age- and parity-matched pairs of women having histories of preeclampsia (n=27) or normotensive pregnancy (n=29) and the association of activated blood elements with CVR. Middle cerebral artery velocity was measured by Doppler ultrasound before and during hypercapnia to assess CVR. Thirty-eight parameters of blood cellular elements, microvesicles, and cell–cell interactions measured in venous blood were assessed for association with CVR using principal component analysis. Middle cerebral artery velocity was lower in the preeclampsia compared with the normotensive group at baseline (63±4 versus 73±3 cm/s; P =0.047) and during hypercapnia ( P =0.013–0.056). CVR was significantly lower in the preeclampsia compared with the normotensive group (2.1±1.3 versus 2.9±1.1 cm·s·mm Hg; P =0.009). Globally, the association of the 7 identified principal components with preeclampsia ( P =0.107) and with baseline middle cerebral artery velocity ( P =0.067) did not reach statistical significance. The interaction between pregnancy history and principal components with respect to CVR ( P =0.084) was driven by a nominally significant interaction between preeclampsia and the individual principal component defined by blood elements, platelet aggregation, and interactions of platelets with monocytes and granulocytes ( P =0.008). These results suggest that having a history of preeclampsia negatively affects the cerebral circulation years beyond the pregnancy and that this effect was associated with activated blood elements.