Effects of different nitric oxide synthases on pulmonary and systemic hemodynamics in hypoxic stress rat model.

BACKGROUND: Under hypoxia, exaggerated compensatory responses may lead to acute mountain sickness. The excessive vasodilatory effect of nitric oxide (NO) can lower the hypoxic pulmonary vasoconstriction (HPV) and peripheral blood pressure. While NO is catalyzed by various nitric oxide synthase (NOS) isoforms, the regulatory roles of these types in the hemodynamics of pulmonary and systemic circulation in living hypoxic animals remain unclear. Therefore, this study aims to investigate the regulatory effects of different NOS isoforms on pulmonary and systemic circulation in hypoxic rats by employing selective NOS inhibitors and continuously monitoring hemodynamic parameters of both pulmonary and systemic circulation. METHODS: Forty healthy male Sprague-Dawley (SD) rats were randomly divided into four groups: Control group (NG-nitro-D-arginine methyl ester, D-NAME), L-NAME group (non-selective NOS inhibitor, NG-nitro-L-arginine methyl ester), AG group (inducible NOS inhibitor group, aminoguanidine), and 7-NI group (neurological NOS inhibitor, 7-nitroindazole). Hemodynamic parameters of rats were monitored for 10 min after inhibitor administration and 5 min after induction of hypoxia [15% O2, 2200 m a. sl., 582 mmHg (76.5 kPa), Xining, China] using the real-time dynamic monitoring model for pulmonary and systemic circulation hemodynamics in vivo. Serum NO concentrations and blood gas analysis were measured. RESULTS: Under normoxia, mean arterial pressure and total peripheral vascular resistance were increased, and ascending aortic blood flow and serum NO concentration were decreased in the L-NAME and AG groups. During hypoxia, pulmonary arterial pressure and pulmonary vascular resistance were significantly increased in the L-NAME and AG groups. CONCLUSIONS: This compensatory mechanism activated by inducible NOS and endothelial NOS effectively counteracts the pulmonary hemodynamic changes induced by hypoxic stress. It plays a crucial role in alleviating hypoxia-induced pulmonary arterial hypertension.

Differential hemodynamic adaptations to tilt test in patients with idiopathic atrial fibrillation.

The hemodynamic response during the transition from the supine to standing position in idiopathic atrial fibrillation (AF) patients is not completely understood. This study aimed to analyze the hemodynamic changes that occur during the head-up tilt test in idiopathic AF patients. We investigated the hemodynamic changes during the head-up tilt test with impedance cardiography in 40 AF patients (12 with AF rhythm-AFr and 28 with sinus rhythm-AFsr) and 38 non-AF controls. Patients with AFr had attenuated SVI decrease after standing when compared to AFsr and non-AF [ΔSVI in mL/m2: -1.3 (-3.4 to 1.7) vs. -6.4 (-17.3 to -0.1) vs. -11.8 (-18.7 to -8.0), respectively; p < 0.001]. PVRI decreased in AFr but increased in AFsr and non-AF [ΔPVRI in dyne.seg.m2/cm5: -477 (-1148 to 82.5) vs. 131 (-525 to 887) vs. 357 (-29 to 681), respectively; p < 0.01]. Similarly, compared with non-AF patients, AFr patients also had a greater HR and greater CI increase after standing. The haemodynamic response to orthostatic challenge suggests differential adaptations between patients with AF rhythm and those reverted to sinus rhythm or healthy controls. Characterizing the hemodynamic phenotype may be relevant for the individualized treatment of AF patients.

Maternal cardiovascular profile is altered in the preclinical phase of normotensive early and late intrauterine growth restriction.

BACKGROUND: The maternal cardiovascular profile of patients who develop late fetal growth restriction has yet to be well characterized, however, a subclinical impairment in maternal hemodynamics and cardiac function may be present before pregnancy and may become evident because of the hemodynamic alterations associated with pregnancy. OBJECTIVE: This study aimed to investigate if maternal hemodynamics and the cardiovascular profile might be different in the preclinical stages (22-24 weeks' gestation) in cases of early and late fetal growth restriction in normotensive patients. STUDY DESIGN: This was a prospective echocardiographic study of 1152 normotensive nulliparous pregnant women at 22 to 24 weeks' gestation. The echocardiographic evaluation included morphologic parameters (left ventricular mass index and relative wall thickness, left atrial volume index) and systolic and diastolic maternal left ventricular function (ejection fraction, left ventricular global longitudinal strain, E/A ratio, and E/e' ratio). Patients were followed until the end of pregnancy to note the development of normotensive early or late fetal growth restriction. RESULTS: Of the study cohort, 1049 patients had no complications, 73 were classified as having late fetal growth restriction, and 30 were classified as having early fetal growth restriction. In terms of left ventricular morphology, the left ventricular end-diastolic diameter was greater in uneventful pregnancies (4.84±0.28 cm) than in late (4.67±0.26 cm) and in early (4.55±0.26 cm) (P<.001) fetal growth restriction cases, whereas left ventricular end-systolic diameter was smaller in uneventful pregnancies (2.66±0.39 cm) than in late (2.83±0.40 cm) and in early (2.82±0.38 cm) (P<.001) fetal growth restriction cases. The relative wall thickness was slightly higher in early (0.34±0.05) and late (0.35±0.04) fetal growth restriction cases than in uneventful pregnancies (0.32±0.05) (P<.05). In terms of systolic left ventricular function, at 22 to 24 weeks' gestation, cardiac output was higher in uneventful pregnancies (6.58±1.07 L/min) than in late (5.40±0.97 L/min) and in early (4.76±1.05 L/min) (P<.001) fetal growth restriction cases with the lowest values in the early-onset group. Left ventricular global longitudinal strain was lower in appropriate for gestational age neonates (-21.6%±2.0%) and progressively higher in late (-20.1%±2.2%) and early (-18.5%±2.3%) (P<.001) fetal growth restriction cases. In terms of diastolic left ventricular function, the E/e' ratio showed intermediate values in the late fetal growth restriction group (7.90±2.73) when compared with the appropriate for gestational age group (7.24±2.43) and with the early fetal growth restriction group (10.76±3.25) (P<.001). The total peripheral vascular resistance was also intermediate in the late fetal growth restriction group (1300±199 dyne·s·cm-5) when compared with the appropriate for gestational age group (993±175 dyne·s·cm-5) and the early fetal growth restriction group (1488±255 dyne.s.cm-5) (P<.001). CONCLUSION: Early and late fetal growth restriction share similar maternal hemodynamic and cardiovascular profiles with a different degree of expression. These features are already present at 22 to 24 weeks' gestation and are characterized by a hypodynamic state. The degree of these cardiovascular changes may influence the timing of the manifestation of the disease; a hypovolemic, high resistance, low cardiac output state might be associated with early-onset fetal growth restriction, whereas a milder hypovolemic state seems to favor the development of the disease in the final stages of pregnancy.

Prolonged Sitting Induces Elevated Blood Pressure in Healthy Young Men: A Randomized Crossover Trial.

Introduction Prolonged sitting-induced blood pooling in the lower legs can increase blood pressure through increased sympathetic nerve activity and peripheral vascular resistance, an aspect that has been understudied as a primary outcome. This study compared the effects of prolonged sitting with those of prolonged supination on blood pressure in healthy young men. Methods This randomized crossover study included 16 healthy young men (mean age: 21.6 ± 0.7 years) who were randomly assigned to a three-hour supine (CON) or three-hour sitting (SIT) condition, followed by a washout period of at least one week. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), low-frequency/high-frequency (LF/HF) ratio derived from heart rate variability, and leg circumference were measured at 60, 120, and 180 minutes from baseline. These indices were compared by two-way (time × conditions) analysis of variance (ANOVA). Results In the SIT condition, DBP, MAP, HR, LF/HF ratio, and leg circumference increased significantly over time (P < 0.05) and were significantly higher than those in the CON condition (P < 0.05). However, SBP showed no significant change over time and between conditions. Conclusions The findings indicate the involvement of sympathetic nerve activity and increased peripheral vascular resistance induced by fluid retention in the lower legs with increased DBP and MAP in healthy young men.

Expert review: preeclampsia Type I and Type II.

Pregnancy involves an interplay between maternal and fetal factors affecting changes to maternal anatomy and physiology to support the developing fetus and ensure the well-being of both the mother and offspring. A century of research has provided evidence of the imperative role of the placenta in the development of preeclampsia. Recently, a growing body of evidence has supported the adaptations of the maternal cardiovascular system during normal pregnancy and its maladaptation in preeclampsia. Debate surrounds the roles of the placenta vs the maternal cardiovascular system in the pathophysiology of preeclampsia. We proposed an integrated model of the maternal cardiac-placental-fetal array and the development of preeclampsia, which reconciles the disease phenotypes and their proposed origins, whether placenta-dominant or maternal cardiovascular system-dominant. These phenotypes are sufficiently diverse to define 2 distinct types: preeclampsia Type I and Type II. Type I preeclampsia may present earlier, characterized by placental dysfunction or malperfusion, shallow trophoblast invasion, inadequate spiral artery conversion, profound syncytiotrophoblast stress, elevated soluble fms-like tyrosine kinase-1 levels, reduced placental growth factor levels, high peripheral vascular resistance, and low cardiac output. Type I is more often accompanied by fetal growth restriction, and low placental growth factor levels have a measurable impact on maternal cardiac remodeling and function. Type II preeclampsia typically occurs in the later stages of pregnancy and entails an evolving maternal cardiovascular intolerance to the demands of pregnancy, with a moderately dysfunctional placenta and inadequate blood supply. The soluble fms-like tyrosine kinase-1-placental growth factor ratio may be normal or slightly disturbed, peripheral vascular resistance is low, and cardiac output is high, but these adaptations still fail to meet demand. Emergent placental dysfunction, coupled with an increasing inability to meet demand, more often appears with fetal macrosomia, multiple pregnancies, or prolonged pregnancy. Support for the notion of 2 types of preeclampsia observable on the molecular level is provided by single-cell transcriptomic survey of gene expression patterns across different cell classes. This revealed widespread dysregulation of gene expression across all cell types, and significant imbalance in fms-like tyrosine kinase-1 (FLT1) and placental growth factor, particularly marked in the syncytium of early preeclampsia cases. Classification of preeclampsia into Type I and Type II can inform future research to develop targeted screening, prevention, and treatment approaches.

An update on maternal cardiac hemodynamics in fetal growth restriction and pre-eclampsia.

Pre-eclampsia and fetal growth restriction (FGR) have been long related to primary placental dysfunction, caused by abnormal trophoblast invasion. Nevertheless, emerging evidence has led to a new hypothesis for the origin of pre-eclampsia and FGR. Suboptimal maternal cardiovascular adaptation has been shown to result in uteroplacental hypoperfusion, ultimately leading to placental hypoxic damage with secondary dysfunction. In this review, we summarize current evidence on maternal cardiac hemodynamics in FGR and pre-eclampsia. We also discuss the different approaches for antihypertensive treatment according to the hemodynamic phenotype observed in pre-eclampsia and FGR.

Longitudinal maternal cardiac function in hypertensive disorders of pregnancy.

BACKGROUND: Compared with gestational hypertension, preeclampsia has traditionally been considered the worse end of the spectrum of hypertensive disorders of pregnancy. It is associated with worse pregnancy outcomes and future cardiovascular morbidities. Both hypertensive disorders may be associated with cardiac maladaptation in pregnancy. However, previous studies were limited by small numbers and a paucity of longitudinal data and unaccounted for the contribution of maternal characteristics that can affect hemodynamics. OBJECTIVE: This study aimed to assess, in an unselected population, the maternal cardiac adaptation in normotensive and hypertensive pregnancies after controlling for important maternal characteristics that affect maternal cardiac function and the interaction among these covariates. STUDY DESIGN: This was a prospective, multicenter longitudinal study of maternal hemodynamics, assessed by a noninvasive bioreactance technology, measured at 11 0/7 to 13 6/7, 19 0/7 to 24 0/7, 30 0/7 to 34 0/7, and 35 0/7 to 37 0/7 weeks of gestation in 3 groups of women. Group 1 was composed of women with preeclampsia (n=45), group 2 was composed of women with gestational hypertension (n=61), and group 3 was composed of normotensive women (n=1643). A multilevel linear mixed-effects model was performed to compare the repeated measures of hemodynamic variables controlling for maternal age, height, weight, weight gain, race, previous obstetrical history, and birthweight. RESULTS: After adjusting for confounders that significantly affect maternal hemodynamics, both group 1 and group 2, compared with group 3, had pathologic cardiac adaptation. Group 1, compared with group 3, demonstrated hyperdynamic circulation with significantly higher cardiac output driven by greater stroke volume in the first trimester of pregnancy. As the pregnancies progressed to after 20 0/7 weeks of gestation, this hyperdynamic state transitioned to hypodynamic state with low cardiac output and high peripheral vascular resistance. Group 2, compared with group 3, had no significant differences in cardiac output, stroke volume, and heart rate before 20 0/7 weeks of gestation but thereafter demonstrated a continuous decline in cardiac output and stroke volume, similar to group 1. Both groups 1 and 2, compared with group 3, had persistently elevated mean arterial pressure and uterine artery pulsatility index throughout pregnancy. CONCLUSION: After adjusting for confounders that affect maternal hemodynamics in an unselected pregnant population, women with preeclampsia and gestational hypertension, compared with normotensive women, demonstrated similar cardiac maladaptation. This pathologic profile was evident after 20 0/7 weeks of gestation and at least 10 weeks before the clinical manifestation of the disease.

Smoothelin-like 1 knockout mice display sex-dependent alterations in blood flow and cardiac function.

Smoothelin-like 1 (SMTNL1) modulates the contractile performance of smooth muscle and thus has a key role in vascular homeostasis. Elevated vascular tone, recognized as a contributor to the development of progressive cardiac dysfunction, was previously found with SMTNL1 deletion. In this study, we assessed cardiac morphology and function of male and female, wild-type (Smtnl1+/+) and global SMTNL1 knockout (Smtnl1-/-) mice at 10 weeks of age. Gross dissection revealed distinct cardiac morphology only in males; Smtnl1-/- hearts were significantly smaller than Smtnl1+/+, but the left ventricle (LV) proportion of heart mass was greater. Male Smtnl1-/- mice also displayed increased ejection fraction and fractional shortening, as well as elevated aortic and pulmonary flow velocities. The impact of cardiac stress with pressure overload by transverse aortic constriction (TAC) was examined in male mice. With TAC banding, systolic function was preserved, but the LV filling pressure was selectively elevated due to relaxation impairment. Smtnl1-/- mice displayed higher early/passive filling velocity of LV/early mitral annulus velocity ratio (E/E' ratio) and myocardial performance index along with a prolonged isovolumetric relaxation time. Taken together, the findings support a novel, sex-dimorphic role for SMTNL1 in modulating cardiac structure and function of mice.

Maternal peripheral vascular resistance at mid gestation in chronic hypertension as a predictor of fetal growth restriction.

We aimed at analyzing the relationship between maternal hemodynamics as expressed by Peripheral Vascular Resistance (PVR) at mid gestation and fetal growth at delivery in chronic hypertension. 152 chronic hypertensive patients were submitted to echocardiography noting PVR at 22-24 weeks' gestation and were followed until delivery noting birthweight centile and the diagnosis of fetal growth restriction (FGR). The logarithmic correlation analysis showed that PVR at mid gestation was strongly related to birthweight at delivery (r = -0.72; p < .001). Moreover, PVR was predictive of both a birthweight <10th centile (PVR >1466 Sensitivity 75.0%, Specificity 93.4%, AUC 0.83, p < .001) and FGR (PVR > 1355 Sensitivity 84.2%, Specificity 93.2%, AUC 0.88, p < .001). This study highlights the importance of maternal hemodynamics as expressed by PVR at mid gestation for the identification of chronic hypertensive patients at risk for developing fetal growth restriction. This observation might open new areas of intervention to treat patients with altered hemodynamics (PVR > 1355 dyne s cm-5).

Hemodynamic pathways of gestational hypertension and preeclampsia.

Gestational hypertension and preeclampsia are the 2 main types of hypertensive disorders in pregnancy. Noninvasive maternal cardiovascular function assessment, which helps obtain information from all the components of circulation, has shown that venous hemodynamic dysfunction is a feature of preeclampsia but not of gestational hypertension. Venous congestion is a known cause of organ dysfunction, but its potential role in the pathophysiology of preeclampsia is currently poorly investigated. Body water volume expansion occurs in both gestational hypertension and preeclampsia, and this is associated with the common feature of new-onset hypertension after 20 weeks of gestation. Blood pressure, by definition, is the product of intravascular volume load and vascular resistance (Ohm's law). Fundamentally, hypertension may present as a spectrum of cardiovascular states varying between 2 extremes: one with a predominance of raised cardiac output and the other with a predominance of increased total peripheral resistance. In clinical practice, however, this bipolar nature of hypertension is rarely considered, despite the important implications for screening, prevention, management, and monitoring of disease. This review summarizes the evidence of type-specific hemodynamic profiles in the latent and clinical stages of hypertensive disorders in pregnancy. Gestational volume expansion superimposed on an early gestational closed circulatory circuit in a pressure- or volume-overloaded condition predisposes a patient to the gradual deterioration of overall circulatory function, finally presenting as gestational hypertension or preeclampsia-the latter when venous dysfunction is involved. The eventual phenotype of hypertensive disorder is already predictable from early gestation onward, on the condition of including information from all the major components of circulation into the maternal cardiovascular assessment: the heart, central and peripheral arteries, conductive and capacitance veins, and body water content. The relevance of this approach, outlined in this review, openly invites for more in-depth research into the fundamental hemodynamics of gestational hypertensive disorders, not only from the perspective of the physiologist or the scientist, but also in assistance of clinicians toward understanding and managing effectively these severe complications of pregnancy.

Impact of maternal height, weight at presentation and gestational weight gain on cardiac adaptation in pregnancy.

OBJECTIVE: To compare longitudinal maternal hemodynamic changes throughout gestation between different groups stratified according to weight at presentation and assess the relative influence of height, weight at presentation and gestational weight gain on cardiac adaptation. METHODS: This was a prospective, longitudinal study assessing maternal hemodynamics using bioreactance technology at 11 + 0 to 13 + 6, 19 + 0 to 24 + 0, 30 + 0 to 34 + 0 and 35 + 0 to 37 + 0 weeks' gestation. Women were divided into three groups according to maternal weight at presentation at the first visit at 11 + 0 to 13 + 6 weeks: Group 1, < 60.0 kg (n = 421); Group 2, 60.0-79.7 kg (n = 904); Group 3, > 79.7 kg (n = 427). A multilevel linear mixed-effects model was used to compare the repeated measures of hemodynamic variables, correcting for demographics, medical and obstetric history, pregnancy complications, maternal weight and time of evaluation. The linear mixed-effects model was then repeated using maternal height, weight at presentation and gestational weight gain Z-scores, and the standardized coefficients were used to evaluate the relative impact of each of these demographic parameters on longitudinal changes of maternal hemodynamics. RESULTS: Compared with Group 1, women in Group 3 demonstrated higher cardiac output (CO), heart rate (HR) and mean arterial pressure (MAP) throughout pregnancy. Groups 2 and 3 had higher stroke volume (SV) than Group 1 at the first visit, but their SV plateaued between the first and second visits and demonstrated an earlier significant decrease from the second visit to the third visit when compared with Group 1. Compared with Groups 1 and 2, there was a higher prevalence of pre-eclampsia, gestational hypertension and gestational diabetes in Group 3. Maternal height was the most important contributor to CO, peripheral vascular resistance (PVR), SV and HR, while weight at presentation was the most important contributor to MAP. Gestational weight gain was the second most important characteristic influencing the longitudinal changes of PVR and SV. CONCLUSIONS: Women with greater weight at presentation have a pathological hemodynamic profile, with higher CO, HR and MAP compared to women with lower weight at presentation. Height is the main determinant of CO, SV, HR and PVR, weight is the main determinant of MAP, and gestational weight gain is the second most important determinant of SV and PVR. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Maternal Cardiac Function at Midgestation and Development of Preeclampsia.

BACKGROUND: Preeclampsia (PE) is an independent risk factor for adverse maternal cardiovascular outcomes. The role of maternal cardiac function in the pathophysiology of PE remains unclear. OBJECTIVES: This study sought to describe differences in cardiac function at midgestation between women who develop PE and those with uncomplicated pregnancy and to establish whether routine cardiac assessment at midgestation can improve performance of screening for PE achieved by established biomarkers. METHODS: Mean arterial pressure was measured, medical history was obtained, and left ventricular (LV) systolic and diastolic functions were assessed using standard echocardiography and speckle tracking imaging. Uterine artery pulsatility index and serum placental growth factor and soluble fms-like tyrosine kinase-1 were measured. RESULTS: In 4,795 pregnancies, 126 (2.6%) developed PE. Following multivariable analysis, peripheral vascular resistance was significantly higher and LV global longitudinal systolic strain, ejection fraction, cardiac output, and left atrial area were mildly lower in women who developed PE compared to those who did not. There was a weak association between maternal cardiovascular indices and biomarkers of placental perfusion and function. Cardiac indices did not improve the performance of screening for PE on top of maternal risk factors, mean arterial pressure, and biomarkers of placental perfusion and function. CONCLUSION: Women who develop PE have an increase in peripheral vascular resistance and a mild reduction in LV functional cardiac indices long before PE development. However, cardiac indices do not improve the performance of screening for PE; thus, their routine clinical use is not advocated.

An integrated model of preeclampsia: a multifaceted syndrome of the maternal cardiovascular-placental-fetal array.

Maternal tolerance of the semiallogenic fetus necessitates conciliation of competing interests. Viviparity evolved with a placenta to mediate the needs of the fetus and maternal adaptation to the demands of pregnancy and to ensure optimal survival for both entities. The maternal-fetal interface is imagined as a 2-dimensional porous barrier between the mother and fetus, when in fact it is an intricate multidimensional array of tissues and resident and circulating factors at play, encompassing the developing fetus, the growing placenta, the changing decidua, and the dynamic maternal cardiovascular system. Pregnancy triggers dramatic changes to maternal hemodynamics to meet the growing demands of the developing fetus. Nearly a century of extensive research into the development and function of the placenta has revealed the role of placental dysfunction in the great obstetrical syndromes, among them preeclampsia. Recently, a debate has arisen questioning the primacy of the placenta in the etiology of preeclampsia, asserting that the maternal cardiovascular system is the instigator of the disorder. It was the clinical observation of the high rate of preeclampsia in hydatidiform mole that initiated the focus on the placenta in the etiology of the disease. Over many years of research, shallow trophoblast invasion with deficient remodeling of the maternal spiral arteries into vessels of higher capacitance and lower resistance has been recognized as hallmarks of the preeclamptic milieu. The lack of the normal decrease in uterine artery resistance is likewise predictive of preeclampsia. In abdominal pregnancies, however, an extrauterine pregnancy develops without remodeling of the spiral arteries, yet there is reduced resistance in the uterine arteries and distant vessels, such as the maternal ophthalmic arteries. Proponents of the maternal cardiovascular model of preeclampsia point to the observed maternal hemodynamic adaptations to pregnancy and maladaptation in gestational hypertension and preeclampsia and how the latter resembles the changes associated with cardiac disease states. Recognition of the importance of the angiogenic-antiangiogenic balance between placental-derived growth factor and its receptor soluble fms-like tyrosine kinase-1 and disturbance in this balance by an excess of a circulating isoform, soluble fms-like tyrosine kinase-1, which competes for and disrupts the proangiogenic receptor binding of the vascular endothelial growth factor and placental-derived growth factor, opened new avenues of research into the pathways to normal adaptation of the maternal cardiovascular and other systems to pregnancy and maladaptation in preeclampsia. The significance of the "placenta vs heart" debate goes beyond the academic: understanding the mutuality of placental and maternal cardiac etiologies of preeclampsia has far-reaching clinical implications for designing prevention strategies, such as aspirin therapy, prediction and surveillance through maternal hemodynamic studies or serum placental-derived growth factor and soluble fms-like tyrosine kinase-1 testing, and possible treatments to attenuate the effects of insipient preeclampsia on women and their fetuses, such as RNAi therapy to counteract excess soluble fms-like tyrosine kinase-1 produced by the placenta. In this review, we will present an integrated model of the maternal-placental-fetal array that delineates the commensality among the constituent parts, showing how a disruption in any component or nexus may lead to the multifaceted syndrome of preeclampsia.

Apelin improves cardiac function mainly through peripheral vasodilation in a mouse model of dilated cardiomyopathy.

There is growing evidence that apelin plays a role in the regulation of the cardiovascular system by increasing myocardial contractility and acting as a vasodilator. However, it remains unclear whether apelin improves cardiac contractility in a load-dependent or independent manner in pathological conditions. For this purpose we investigated the cardiovascular effects of apelin in α-actin transgenic mice (mActin-Tg mice), a model of cardiomyopathy. [Pyr1]apelin-13 was administered by continuous infusion at 2 mg/kg/d for 3 weeks. Effects on cardiac function were determined by echocardiography and a Pressure-Volume (PV) analysis. mActin-Tg mice showed a dilated cardiomyopathy (DCM) phenotype similar to that encountered in patients expressing the same mutation. Compared to WT animals, mActin-Tg mice displayed cardiac systolic impairment [significant decrease in ejection fraction (EF), cardiac output (CO), and stroke volume (SV)] associated with cardiac ventricular dilation and diastolic dysfunction, characterized by an impairment in mitral flow velocity (E/A) and in deceleration time (DT). Load-independent myocardial contractility was strongly decreased in mActin-Tg mice while total peripheral vascular resistance (TPR) was significantly increased. As compared to vehicle-treated animals, a 3-week treatment with [Pyr1]apelin-13 significantly improved EF%, SV, E/A, DT and corrected TPR, with no significant effect on load-independent indices of myocardial contractility, blood pressure and heart rate. In conclusion [Pyr1]apelin-13 displayed no intrinsic contractile effect but improved cardiac function in dilated cardiomyopathy mainly by reducing peripheral vascular resistance, with no change in blood pressure.

Effect of maternal age on cardiac adaptation in pregnancy.

OBJECTIVE: To compare longitudinal maternal hemodynamic changes throughout gestation between different age groups. METHODS: This was a prospective longitudinal study assessing maternal hemodynamics using a bioreactance technique at 11 + 0 to 13 + 6, 19 + 0 to 24 + 0, 30 + 0 to 34 + 0 and 35 + 0 to 37 + 0 weeks' gestation. Women were divided into four groups according to maternal age at the first visit at 11 + 0 to 13 + 6 weeks: Group 1, < 25.0 years; Group 2, 25.0-30.0 years; Group 3, 30.1-34.9 years; and Group 4, ≥ 35.0 years. A multilevel linear mixed-effects model was performed to compare the repeat measurements of hemodynamic variables, correcting for demographics, medical and obstetric history, pregnancy complications, maternal age and gestational-age window. RESULTS: The study population included 254 women in Group 1, 442 in Group 2, 618 in Group 3 and 475 in Group 4. Younger women (Group 1) had the highest cardiac output (CO) and lowest peripheral vascular resistance (PVR), and older women (Group 4) had the lowest CO and highest PVR throughout pregnancy. The higher CO seen in younger women was achieved through an increase in heart rate alone and not with a concomitant rise in stroke volume. Although the youngest age group demonstrated an apparently more favorable hemodynamic profile, it had the highest incidence of a small-for-gestational-age neonate. There was no significant difference between the groups in the incidence of pre-eclampsia. CONCLUSION: Age-specific differences in maternal hemodynamic adaptation do not explain the differences in the incidence of a small-for-gestational-age neonate between age groups. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Maternal cardiac adaptation and fetal growth.

BACKGROUND: Pregnancies with small-for-gestational-age fetuses are at increased risk of adverse maternal-fetal outcomes. Previous studies examining the relationship between maternal hemodynamics and fetal growth were mainly focused on high-risk pregnancies and those with fetuses with extreme birthweights, such as less than the 3rd or 10th percentile and assumed a similar growth pattern in fetuses above the 10th percentile throughout gestation. OBJECTIVE: This study aimed to evaluate the trends in maternal cardiac function, fetal growth, and oxygenation with advancing gestational age in a routine obstetrical population and all ranges of birthweight percentiles. STUDY DESIGN: This was a prospective, longitudinal study assessing maternal cardiac output and peripheral vascular resistance by bioreactance at 11+0 to 13+6, 19+0 to 24+0, 30+0 to 34+0, and 35+0 to 37+0 weeks' gestation, sonographic estimated fetal weight in the last 3 visits and the ratio of the middle cerebral artery by umbilical artery pulsatility indices or cerebroplacental ratio in the last 2 visits. Women were divided into the following 5 groups according to birthweight percentile: group 1, <10th percentile (n=261); group 2, 10 to 19.9 percentile (n=180); group 3, 20 to 29.9 percentile (n=189); group 4, 30 to 69.9 percentile (n=651); and group 5, ≥70th percentile (n=508). The multilevel linear mixed-effects model was performed to compare the repeated measures of hemodynamic variables and z scores of the estimated fetal weight and cerebroplacental ratio. RESULTS: In visit 2, compared with visit 1, in all groups, cardiac output increased, and peripheral vascular resistance decreased. At visit 3, groups 1, 2, and 3, compared with 4 and 5, demonstrated an abrupt decrease in cardiac output and increase in peripheral vascular resistance. From visit 2, group 1 had a constant decline in estimated fetal weight, coinciding with the steepest decline in maternal cardiac output and rise in peripheral vascular resistance. In contrast, in groups 4 and 5, the estimated fetal weight had a stable or accelerative pattern, coinciding with the greatest increase in cardiac output and lowest peripheral vascular resistance. Groups 2 and 3 showed a stable growth pattern with intermediate cardiac output and peripheral vascular resistance. Increasing birthweight was associated with higher cerebroplacental ratio. Groups 3, 4, and 5 had stable cerebroplacental ratio across visits 3 and 4, whereas groups 1 and 2 demonstrated a significant decline (P<.001). CONCLUSION: In a general obstetrical population, maternal cardiac adaptation at 32 weeks' gestation parallels the pattern of fetal growth and oxygenation; babies with birthweight<20th percentile have progressive decline in fetal cerebroplacental ratio, decline in maternal cardiac output, and increase in peripheral vascular resistance.

Exercise training ameliorates adrenergic control in spontaneously hypertensive rats.

The goal of this study was to examine vascular control after sympathetic stimulation by tyramine infusion in hypertensive rats submitted to swimming training. To this end, male rats were assigned to the following groups: sedentary (SN) and trained normotensive (TN), sedentary (SH) and trained hypertensive (TH). Arterial pressure (AP), heart rate (HR), HR variability (HRV), AP variability (APV), and cardiac autonomic function were recorded. Following, infusion of tyramine was administrated. The TN and TH showed a lower resting HR compared with their respective sedentary groups (p < .05). Pressure levels were less in TH than SH (p < .05). The TH showed a higher HRV together with a lower APV in comparison to SH (p < .05). The sympathetic modulation of HRV and APV was lower in TH than in SH (p < .05). Both trained groups presented an increased parasympathetic modulation of HRV compared with their respective sedentary groups (p < .05). The TN and TH groups had a higher vagal effect in comparison with their respective sedentary groups (p < .001). The sympathetic effect was lower in TH than in SH (p < .001). Pressor and HR responses to tyramine in different doses were attenuated in TH (p < .001). Further analysis showed a significant association between infusion of tyramine and normalized LF component of HRV (r = 0.84, p < .001), systolic APV (r = 0.58, p < .001) and diastolic APV (r = 0.49, p < .001). In conclusion, exercise training provokes less pressor response variation by tyramine infusion in hypertensive animals suggesting sympathetic nerve endings adjustments and decrease of the vasoconstrictor effect attenuates injury caused by hypertension improving cardiovascular autonomic dysfunction, which can be associated with sympathetic attenuation.

Role of Vascular Adaptation in Determining Systolic Blood Pressure in Young Adults.

Background Two individuals can have a similar pulse pressure (PP) but different levels of systolic blood pressure (SBP), although the underlying mechanisms have not been described. We hypothesized that, for a given level of PP, differences in SBP relate to peripheral vascular resistance (PVR); and we tested this hypothesis in a large cohort of healthy young adults. Methods and Results Demographic, biochemical, and hemodynamic data from 3103 subjects were available for the current analyses. In both men and women, for a given level of PP, higher SBP was associated with significantly higher body weight, body mass index, heart rate, and PVR (P<0.05 versus those with lower BP for all comparisons). Moreover, stratifying individuals by quartiles of PP and PVR revealed a stepwise increase in SBP from the lowest to highest quartile for each variable, with the highest SBP occurring in those in the highest quartile of both PP and PVR (P<0.001 for overall trend for both sexes). PVR was also increased with increasing tertile of minimum forearm vascular resistance, in both men (P=0.002) and women (P=0.03). Conclusions Increased PVR, mediated in part through altered resistance vessel structure, strongly associates with the elevation of SBP for a given level of PP in young adults. An impaired ability to adapt PVR appropriately to a given level of PP may be an important mechanism underlying elevated SBP in young adults.

Maternal cardiac function in women at high risk for pre-eclampsia treated with 150 mg aspirin or placebo: an observational study.

OBJECTIVE: To compare maternal haemodynamics in women at low and high risk for preterm pre-eclampsia (PE), and between those at high risk who are randomised to aspirin or placebo. DESIGN: Prospective, longitudinal observational study. SETTING: Maternity units in six UK hospitals. POPULATION: Women participating in the Aspirin for Prevention of Preterm Pre-eclampsia (ASPRE) trial. The population comprised three groups of women: low risk for preterm PE (n = 1362), high risk for preterm PE treated with aspirin (n = 208) and high risk for preterm PE on placebo (n = 220). METHODS: Women had four visits during pregnancy: 11-14, 19-24, 30-34, and 35-37 weeks' gestation. Blood pressure was measured with a device validated for pregnancy, and PE and maternal haemodynamics were assessed with a bioreactance monitor at each visit. A multilevel linear mixed-effects analysis was performed to examine longitudinal changes of maternal haemodynamic variables, controlling for demographic characteristics, past medical history and medication use. MAIN OUTCOME MEASURES: Longitudinal changes of cardiac output (CO), mean arterial pressure (MAP), and peripheral vascular resistance (PVR). RESULTS: The low-risk group demonstrated the expected changes with an increase in CO and reduction in MAP and PVR, with a quadratic change across gestation. In contrast, the high-risk groups had a declining CO, and higher MAP and PVR during pregnancy. The administration of aspirin did not appear to affect maternal haemodynamics. CONCLUSIONS: Women screened as high risk for preterm PE have a pathological cardiac adaptation to pregnancy and the prophylactic use of aspirin (150 mg oral daily from the first trimester) in this group may not alter this haemodynamic profile. TWEETABLE ABSTRACT: In women at high risk of pre-eclampsia, prophylactic use of aspirin may not alter the impaired maternal cardiac adaptation.

Chronic Low-Level Lead Exposure Increases Mesenteric Vascular Reactivity: Role of Cyclooxygenase-2-Derived Prostanoids.

Lead (Pb) exposure causes hazardous effects as hypertension and other cardiovascular diseases. We evaluated whether chronic Pb exposure alters the peripheral vascular resistance measuring the vascular reactivity of mesenteric resistance arteries in rats to identify the underlying mechanisms that are associated to the development of Pb-induced hypertension. Mesenteric resistance arteries from lead-treated and untreated Wistar rats (1st dose: 10 µg/100 g; subsequent doses: 0.125 µg/100 g, intramuscular, 30 days) were used. Contractile responses to phenylephrine increased, while acetylcholine and sodium nitroprusside-induced relaxation was not affected by lead treatment. Endothelium removal and inhibition of NO synthase by L-NAME similarly enhanced the response to phenylephrine in untreated and lead-treated rats. The antioxidants apocynin and superoxide dismutase (SOD) did not affect vasoconstriction in either group. The vascular expression of cyclooxygenase-2 (COX-2) protein increased after lead exposure. The respective non-specific or specific COX-2 inhibitors indomethacin and NS398 reduced more strongly the response to phenylephrine in treated rats. Antagonists of EP1 (SC19220), TP (SQ29548), IP (CAY10441) and angiotensin II type 1 (losartan) receptors reduced vasoconstriction only in treated rats. These conclusions present further evidence that lead, even in small concentration, produces cardiovascular hazards being an environmental contaminant that account for lead-induced hypertension.