Ralph R. Scholten

Exercise training and artery function in humans: nonresponse and its relationship to cardiovascular risk factors

The objectives of our study were to examine 1) the proportion of responders and nonresponders to exercise training in terms of vascular function; 2) a priori factors related to exercise training-induced changes in conduit artery function, and 3) the contribution of traditional cardiovascular risk factors to exercise-induced changes in artery function. We pooled data from our laboratories involving 182 subjects who underwent supervised, large-muscle group, endurance-type exercise training interventions with pre-/posttraining measures of flow-mediated dilation (FMD%) to assess artery function. All studies adopted an identical FMD protocol (5-min ischemia, distal cuff inflation), contemporary echo-Doppler methodology, and observer-independent automated analysis. Linear regression analysis was used to identify factors contributing to changes in FMD%. We found that cardiopulmonary fitness improved, and weight, body mass index (BMI), cholesterol, and mean arterial pressure (MAP) decreased after training, while FMD% increased in 76% of subjects (P < 0.001). Training-induced increase in FMD% was predicted by lower body weight (β = -0.212), lower baseline FMD% (β = -0.469), lower training frequency (β = -0.256), and longer training duration (β = 0.367) (combined: P < 0.001, r = 0.63). With the exception of a modest correlation with total cholesterol (r = -0.243, P < 0.01), changes in traditional cardiovascular risk factors were not significantly related to changes in FMD% (P > 0.05). In conclusion, we found that, while some subjects do not demonstrate increases following exercise training, improvement in FMD% is present in those with lower pretraining body weight and endothelial function. Moreover, exercise training-induced change in FMD% did not correlate with changes in traditional cardiovascular risk factors, indicating that some cardioprotective effects of exercise training are independent of improvement in risk factors.

Co-occurrence of cardiovascular and prothrombotic risk factors in women with a history of preeclampsia

OBJECTIVE: Formerly preeclamptic women are at increased risk for remote cardiovascular and thrombotic diseases. We studied co-occurrence of cardiovascular and prothrombotic risk factors within a cohort of formerly preeclamptic women and tested if prevalence of these risk profiles related to onset of preeclampsia in previous pregnancy. METHODS: We evaluated 1,297 nonpregnant formerly preeclamptic women (6–12 months postpartum) for the presence of four risk profiles: circulatory risk profile (hypertension or latent hypertension [low plasma volume, increased vascular resistance, or both]; metabolic syndrome (World Health Organization criteria); thrombophilia (factor V Leiden, prothrombin mutation, or protein C or S deficiency); and hyperhomocysteinemia. Trends between prevalence of these four profiles and onset of preeclampsia were studied using linear regression analysis. RESULTS: After exclusion of 63 women (4.9%) because of incomplete data, 1,234 women were included. One or more risk profiles were detected in 958 of 1,234 (77.6%) formerly preeclamptic women. Circulatory risk profile was more prevalent (66.1%) than hyperhomocysteinemia (18.7%), metabolic syndrome (15.4%), or thrombophilia (10.8%). Prevalence of circulatory risk profile, metabolic syndrome, and hyperhomocysteinemia decreased significantly with gestational age at delivery, whereas thrombophilia did not (P=.22). There was minimal overlap (less than 2%) between metabolic syndrome, thrombophilic profile, and hyperhomocysteinemia. CONCLUSION: Circulatory risk profile is present in two thirds of formerly preeclamptic women. Metabolic syndrome, thrombophilia, and hyperhomocysteinemia are prevalent in 10–20%. There is considerable overlap between circulatory risk profile and other profiles, but not among the three other profiles. Prevalence of these risk factors, except thrombophilia, decreases with gestational age at delivery in preceding pregnancy. LEVEL OF EVIDENCE: II

Cardiovascular effects of aerobic exercise training in formerly preeclamptic women and healthy parous control subjects

OBJECTIVE Women who have had preeclampsia demonstrate higher prevalence of metabolic syndrome (MetS), impaired vascular function, and increased sympathetic activity and are at increased risk of cardiovascular disease. The aim of this study was to assess the effects of 12 weeks of exercise training (70-80% maximum volume of oxygen utilization) in women who had had preeclampsia on physical fitness, components of MetS, vasculature, and autonomic functions compared with healthy control subjects. STUDY DESIGN Our prospective case-control study included 24 normotensive women who had had preeclampsia and 20 control subjects who were matched for age and postpartum interval (all 6-12 months after delivery). Before and after training, we measured all components of MetS (ie, BP, lipids, glucose/insulin, and albuminuria), carotid intima media thickness (IMT) and brachial and superficial femoral artery endothelial function that used flow-mediated dilation (FMD). Autonomic activity was quantified with power spectral analysis (low-frequency/high-frequency power [LF/HF] ratio). RESULTS At baseline, women who had had preeclampsia demonstrated higher values of most components of MetS. Compared with the control subjects, women who had had preeclampsia had increased IMT (580 ± 92 μm vs 477 ± 65 μm, respectively), impaired endothelial function (FMD brachial artery, 5.3% ± 2.2% vs 10.8% ± 3.5%, respectively; FMD superficial femoral artery, 4.9% ± 2.1% vs 8.7% ± 3.2%, respectively) and increased LF/HF power ratio (2.2 ± 1.0 vs 1.3 ± 0.4, respectively; all P < .05). In both groups, exercise training decreased values of most components of MetS and IMT, improved FMD, and concurrently reduced LF/HF. Despite these improvements, vascular and autonomic variables did not normalize by 12 weeks of training in women who had had preeclampsia. CONCLUSION This study demonstrates that exercise training in women who had had preeclampsia and control subjects improves components of MetS, endothelial function, vascular wall thickness, and autonomic control. Nonetheless, trained women who had had preeclampsia only reached a cardiovascular status that is comparable with sedentary healthy control subjects.

Acute Change in Vascular Tone Alters Intima-Media Thickness

Atherosclerosis is a lifelong process involving artery wall thickening. Increased wall thickness has been widely adopted as a preclinical surrogate marker of atherosclerosis. A prerequisite for such a surrogate marker is that it is a structural characteristic of the vessel wall that is not subject to acute changes. The purpose of this study was to examine the acute effects of vasodilator drug administration on wall thickness of the carotid and superficial femoral arteries. High-resolution ultrasound was used to examine carotid and femoral artery diameters and wall thickness in 15 young (25±4 years of age) and 15 older (70±6 years of age) healthy men who were administered sublingual glyceryl trinitrate. Diameter and wall thickness were collected before and across a 10-minute period after glyceryl trinitrate administration. Glyceryl trinitrate induced a significant increase in carotid and femoral artery diameter and a decrease in wall thickness in both young and older men (both P<0.001). The latter was significantly larger than in young men (both P<0.01). The changes in carotid artery wall thickness in both young (35±23 &mgr;m) and older men (71±46 &mgr;m) approximate those considered prognostically relevant. Collectively, our data suggest that vasodilator drug administration induces a rapid and marked decrease in wall thickness, which mirrors conduit artery vasodilation in both young and older men. This finding confirms the presence of acute changes in wall thickness and has important implications for future studies that assess artery wall characteristics as a surrogate measure of atherosclerosis.

Prepregnancy low-plasma volume and predisposition to preeclampsia and fetal growth restriction.

OBJECTIVE: To estimate whether recurrence risks of preeclampsia, preterm birth, and fetal growth restriction relate to prepregnancy plasma volume. METHODS: We conducted a retrospective cohort study in 580 formerly preeclamptic women and a control group. In all women we measured plasma volume (iodine125-human serum albumin indicator dilution method) in the nonpregnant state. One hundred seventy-eight normotensive (formerly preeclamptic) women had a subsequent pregnancy within the study period (1996–2008). Odds ratios (ORs) for recurrent preeclampsia, preterm birth, and small for gestational age (SGA) neonates were estimated, using multivariable logistic regression with adjustment for confounders. RESULTS: Plasma volumes were lower in women who developed recurrent preeclampsia (1,241±158 mL/m2, 17% lower compared with women in the control group) than in women without recurrent preeclampsia (1,335±167 mL/m2, 11% lower compared with women in the control group). Logistic regression analysis demonstrated that each 100-mL/m2 difference in plasma volume was associated with an OR of 0.6 (95% confidence interval [CI] 0.5–0.8) to develop recurrent preeclampsia in subsequent pregnancy. Risk of preterm delivery (before 37 weeks of gestation) depended on preeclampsia in subsequent pregnancy, the adjusted hazard ratio for preterm birth was 0.9 (95% CI 0.7–1.1) for each 100-mL/m2 change in plasma volume. Risk of delivering an SGA neonate was independent of recurrent preeclampsia. Each 100-mL/m2 change in plasma volume was associated with an adjusted OR of 0.8 (95% CI 0.5–0.9) to deliver an SGA neonate in subsequent pregnancy. CONCLUSION: The risk of recurrent preeclampsia and fetal growth restriction in subsequent pregnancy relates inversely and linearly to prepregnancy plasma volume. LEVEL OF EVIDENCE: II

Impact of wall thickness on conduit artery function in humans: Is there a “Folkow” effect?

Regional heterogeneity in wall architecture and thickness may be present between conduit arteries in the upper and lower limbs in humans. These differences in wall architecture may, in turn, influence vascular responsiveness. Folkow proposed in the 1950s that heterogeneity in wall-to-lumen ratio (W:L) could contribute to differences in vascular responsiveness, but this hypothesis has never been directly confirmed in vivo. Our first aim was to examine wall thickness and W:L across arteries in the lower (common and superficial femoral) and upper limbs (brachial and radial) of healthy men (n=35) using high resolution ultrasound. In a subgroup (n=20) we examined the relationship between W:L of these arteries, physiological (flow-mediated dilation, FMD) and pharmacological vasodilation (glyceryl trinitrate, GTN). Diameter and wall thickness differed significantly across all arteries (ANOVA P<0.001), with smaller arteries having a relatively larger wall thickness. Moreover, we found a significant correlation between W:L and the FMD-response (r=0.55, P<0.001), which remained significant after correcting for the eliciting shear stress (r=0.47, P<0.001), indicating that W:L/FMD relationship was not primarily related to the impact of diameter on the shear rate stimulus to FMD. W:L also correlated strongly with the GTN-response (r=0.56, P<0.001) across all arteries studied. These results indicate that regional heterogeneity exists in W:L within, but also between, limbs. More importantly, differences in W:L contribute to differences in vascular functional responses, reinforcing the conceptual proposal of Folkow, who suggested that arteries with larger W:L exhibit exaggerated responses to vasoactive stimuli.

Cardiovascular disease risk is only elevated in hypertensive, formerly preeclamptic women

To analyse the predicted 10‐ and 30‐year risk scores for cardiovascular disease (CVD) in patients who experienced preeclampsia (PE) 5–10 years previously compared with healthy parous controls.

Metabolic syndrome and the risk for recurrent pre-eclampsia: a retrospective cohort study

To compare the prevalence of recurrent pre‐eclampsia between women who have and do not have metabolic syndrome when non‐pregnant.

Menstrual blood closely resembles the uterine immune micro-environment and is clearly distinct from peripheral blood

STUDY QUESTION Is menstrual blood a suitable source of endometrial derived lymphocytes? SUMMARY ANSWER Mononuclear cells isolated from menstrual samples (menstrual blood mononuclear cells (MMC)) are clearly distinct from peripheral blood mononuclear cells (PBMC) and show a strong resemblance with biopsy-derived endometrial mononuclear cells. WHAT IS KNOWN ALREADY A critical event in the onset of pregnancy is the implantation of the embryo in the uterine wall. The immune cell composition in the endometrium at the time of implantation is considered pivotal for success. Despite advancing knowledge on the composition of the immune cell population in the uterus, the role of endometrial immune cells in reproductive disorders is still not fully resolved, mainly due to the fact that this type of research requires invasive techniques. Here, we collected menstrual fluid and validated this unique non-invasive technique to obtain and study the endometrium-derived immune cells which would be present around the time of implantation. STUDY DESIGN, SIZE, DURATION Five healthy non-pregnant females with regular menstruation cycles and not using oral contraceptives collected their menstrual blood using a menstrual cup in five consecutive cycles. Sampling took place over the first 3 days of menses, with 12 h intervals. Peripheral blood samples, taken before and after each menstruation, were obtained for comparative analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS MMC and PBMC samples were characterized for the different lymphocyte subsets by flow cytometry, with emphasis on NK cells and T cells. Next, the functional capacity of the MMC-derived NK cells was determined by measuring intracellular production of IFN-γ, granzyme B and perforin after culture in the presence of IL-2 and IL-15. MAIN RESULTS AND THE ROLE OF CHANCE In support of their endometrial origin, MMC samples contained the typical composition of mononuclear cells expected of endometrial tissue, were phenotypically similar to the reported phenotype for biopsy-derived endometrial cells, and were distinct from PBMC. Increased percentages of NK cells and decreased percentages of T cells were found in MMC when compared with PBMC from the same female. The MMC-derived NK cells were pre-dominantly CD56(bright)/CD16(-), in contrast to the primarily CD56(dim)/CD16(+) peripheral blood NK cells. MMC-derived NK cells expressed CD103, indicating their mucosal origin. In addition, the pattern of natural cytotoxicity receptor (NCR) expression in MMC-derived NK cells was comparable with that in endometrial biopsy-derived NK cells. Compared with PBMC, the NKp30 expression was decreased, while the percentage of NKp44 positive cells was increased in MMC samples. CXCR3 and CXCR4 were hardly expressed by MMC-derived NK cells, indicating that these cells are not of PBMC origin. NK cells from MMC samples were functional as shown by their capacity to produce IFN-γ, granzyme B and perforin, upon stimulation with IL-2 and IL-15. MMC-derived T cells revealed an increased expression of CD103, CD69 and CXCR4 compared with PBMC-derived T cells. Importantly, MMC collection using a menstrual cup proved highly reliable and reproducible between women and between cycles. LIMITATIONS, REASONS FOR CAUTION Based on the parameters we studied, MMC appear similar to biopsy-derived endometrial mononuclear cells. However, sampling is not done at the exact same time in the menstrual cycle, and thus we cannot exclude some, as yet undetected, differences. Also, it should be considered that for some women, the use of the menstrual cup may be unpleasant. WIDER IMPLICATIONS OF THE FINDINGS Menstrual blood may be a source of endometrial cells and may create new opportunities to study uterine immunological cells in fertility issues. STUDY FUNDING/COMPETING INTEREST(S) No external funding was obtained for the present study. None of the authors have any conflict of interest to declare. TRIAL REGISTRATION NUMBER NA.

Pre-eclampsia : an important risk factor for asymptomatic heart failure

Pre‐eclampsia (PE) is associated with both postpartum structural asymptomatic heart disease (i.e. heart failure Stage B (HF‐B)) and conventional cardiovascular (CV) risk factors. We aimed to evaluate the extent to which PE, adjusted for conventional CV risk factors, is associated independently with asymptomatic cardiac abnormalities postpartum.