The pro-resolving mediator, annexin A1 regulates blood pressure, and age-associated changes in cardiovascular function and remodeling.

Aging is associated with chronic, low-level inflammation which may contribute to cardiovascular pathologies such as hypertension and atherosclerosis. This chronic inflammation may be opposed by endogenous mechanisms to limit inflammation, for example, by the actions of annexin A1 (ANXA1), an endogenous glucocorticoid-regulated protein that has anti-inflammatory and pro-resolving activity. We hypothesized the pro-resolving mediator ANXA1 protects against age-induced changes in blood pressure (BP), cardiovascular structure and function, and cardiac senescence. BP was measured monthly in conscious mature (4-month) and middle-aged (12-month) ANXA1-deficient (ANXA1-/- ) and wild-type C57BL/6 mice. Body composition was measured using EchoMRI, and both cardiac and vascular function using ultrasound imaging. Cardiac hypertrophy, fibrosis and senescence, vascular fibrosis, elastin, and calcification were assessed histologically. Gene expression relevant to structural remodeling, inflammation, and cardiomyocyte senescence were also quantified. In C57BL/6 mice, progression from 4 to 12 months of age did not affect the majority of cardiovascular parameters measured, with the exception of mild cardiac hypertrophy, vascular calcium, and collagen deposition. Interestingly, ANXA1-/- mice exhibited higher BP, regardless of age. Additionally, age progression had a marked impact in ANXA1-/- mice, with markedly augmented vascular remodeling, impaired vascular distensibility, and body composition. Consistent with vascular dysfunction, cardiac dysfunction, and hypertrophy were also evident, together with markers of senescence and inflammation. These findings suggest that endogenous ANXA1 plays a critical role in regulating BP, cardiovascular function, and remodeling and delays cardiac senescence. Our findings support the development of novel ANXA1-based therapies to prevent age-related cardiovascular pathologies.

Cardiovascular risk factors during pregnancy impact the postpartum cardiac and vascular reverse remodeling.

Pregnant women with cardiovascular risk (CVR) factors are highly prone to develop cardiovascular disease later in life. Thus, recent guidelines suggest extending the follow-up period to 1 yr after delivery. We aimed to evaluate cardiovascular remodeling during pregnancy and determine which CVR factors and potential biomarkers predict postpartum cardiac and vascular reverse remodeling (RR). Our study included a prospective cohort of 76 healthy and 54 obese and/or hypertensive and/or with gestational diabetes pregnant women who underwent transthoracic echocardiography, pulse-wave velocity (PWV), and blood collection at the 1st trimester (1T) and 3rd trimester (3T) of pregnancy as well as at the 1st/6th/12th mo after delivery. Generalized linear mixed-effects models was used to evaluate the extent of RR and its potential predictors. Pregnant women develop cardiac hypertrophy, as confirmed by a significant increase in left ventricular mass (LVM). Moreover, ventricular filling pressure (E/e') and atrial volume increased significantly during gestation. Significant regression of left ventricular (LV) volume, LVM, and filling pressures was observed as soon as 1 mo postpartum. The LV global longitudinal strain worsened slightly and recovered at 6 mo postpartum. PWV decreased significantly from 1T to 3T and normalized at 1 mo postpartum. We found that arterial hypertension, smoking habits, and obesity were independent predictors of increased LVM during pregnancy and postpartum. High C-reactive protein (CRP) and low ST2/IL33-receptor levels are potential circulatory biomarkers of worse LVM regression. Arterial hypertension, age, and gestational diabetes positively correlated with PWV. Altogether, our findings pinpoint arterial hypertension as a critical risk factor for worse RR and CRP, and ST2/IL33 receptors as potential biomarkers of postpartum hypertrophy reversal.NEW & NOTEWORTHY This study describes the impact of cardiovascular risk factors (CVR) in pregnancy-induced remodeling and postpartum reverse remodeling (up to 1 yr) by applying advanced statistic methods (multivariate generalized linear mixed-effects models) to a prospective cohort of pregnant women. Aiming to extrapolate to pathological conditions, this invaluable "human model" allowed us to demonstrate that arterial hypertension is a critical CVR for worse RR and that ST2/IL33-receptors and CRP are potential biomarkers of postpartum hypertrophy reversal.

Cardiovascular remodeling in active and controlled acromegaly: association with sleep-disordered breathing.

PURPOSE: We hypothesized that an unfavorable cardiovascular profile in acromegaly is associated with sleep-disordered breathing (SDB), while acromegaly control improves both respiratory sleep characteristics and the cardiovascular profile. METHODS: The patients underwent the assessment of breathing during sleep and cardiovascular profile assessment at the start of the study including arterial stiffness, blood pressure, echocardiography, nocturnal heart rate variability (HRV). The assessment was repeated in patients with acromegaly at 1 year after transsphenoidal adenectomy (TSA). RESULTS: A total of 47 patients with acromegaly and 55 control subjects were enrolled. At one year after TSA, 22 patients with acromegaly were reassessed. Multiple linear regression analysis with adjustment for age, sex and body mass index (BMI) showed the associations of insulin growth-like factor 1 (IGF-1) with obstructive apnea index (OAI: ß=0.035/h, p<0.001), but not with cardiovascular parameters, in patients with acromegaly. The analysis of combined acromegaly and control dataset with adjustment for age, sex and BMI showed the association the presence of acromegaly with diastolic blood pressure (DBP; ß=17.99 mmHg, p<0.001), ejection fraction (EF; ß=6.23%, p=0.009), left heart remodeling (left ventricle posterior wall: ß=0.81 mm, p=0.045) and the association of the presence of SDB (apnea-hypopnea index≥15/h) with left ventricular function (EF: -4.12%, p=0.040; end systolic volume: 10.12 ml, p=0.004). Control of acromegaly was accompanied by the decrease in OAI (5.9 [0.8, 14.5]/h and 1.7 [0.2, 5.1]/h, p=0.004) and nocturnal heart rate (66.1 [59.2, 69.8] bpm and 61.7 [54.0, 67.2] bpm, p=0.025) and by the increase in blood pressure (DBP: 78.0 [70.3, 86.0] mm Hg and 80.0 [80.0, 90.0] mm Hg, p=0.012). CONCLUSION: The comorbidities of acromegaly, including sleep-disordered breathing, appear to have a long-term effect on cardiovascular remodeling in active acromegaly. Future studies should investigate the applicability of the treatment of SDB for the reduction of cardiovascular risk in acromegaly.

Role of global sphericity index in evaluation of fetal cardiac remodeling in late onset fetal growth restriction and small for gestational age fetuses.

INTRODUCTION: Fetal growth restriction (FGR) fetuses develop cardiovascular remodeling and dysfunction and, in this process, heart first compensates by changing its shape from ellipsoid to spherical and then cardiac dysfunction follows. Our aim was to evaluate global sphericity index (GSI) after 32 weeks of gestation to evaluate this change in cardiac shape and correlate GSI changes associated with fetal growth abnormalities. MATERIALS AND METHODS: This was a prospective study conducted at 32-38 weeks of gestation. Women were classified into three groups-Appropriate for gestational age (AGA), small for gestational age (SGA), late onset FGR (LO FGR) and GSI was measured and perinatal outcome studied. RESULTS: Out of 217 women, 131 were of AGA, 31 were SGA, 55 were of late onset FGR. SGA and late onset FGR groups had low GSI compared to AGA group. There was no significant difference in mean GSI between late onset FGR and SGA groups. Neonatal morbidity, adverse perinatal outcomes did not significantly differ with GSI in SGA and late onset FGR groups. CONCLUSION: This study showed that late gestation small fetuses develop early stages of cardiovascular remodeling as shown by GSI changes. These changes were independent of Doppler changes. This supports the concept that atleast a proportion of them are not constitutionally small but are true forms of FGR.

Effect of Cardiotonic Steroid Marinobufagenin on Vascular Remodeling and Cognitive Impairment in Young Dahl-S Rats.

The hypertensive response in Dahl salt-sensitive (DSS) rats on a high-salt (HS) diet is accompanied by central arterial stiffening (CAS), a risk factor for dementia, and heightened levels of a prohypertensive and profibrotic factor, the endogenous Na/K-ATPase inhibitor marinobufagenin (MBG). We studied the effect of the in vivo administration of MBG or HS diet on blood pressure (BP), CAS, and behavioral function in young DSS rats and normotensive Sprague-Dawley rats (SD), the genetic background for DSS rats. Eight-week-old male SD and DSS rats were given an HS diet (8% NaCl, n = 18/group) or a low-salt diet (LS; 0.1% NaCl, n = 14-18/group) for 8 weeks or MBG (50 µg/kg/day, n = 15-18/group) administered via osmotic minipumps for 4 weeks in the presence of the LS diet. The MBG-treated groups received the LS diet. The systolic BP (SBP); the aortic pulse wave velocity (aPWV), a marker of CAS; MBG levels; spatial memory, measured by a water maze task; and tissue collection for the histochemical analysis were assessed at the end of the experiment. DSS-LS rats had higher SBP, higher aPWV, and poorer spatial memory than SD-LS rats. The administration of stressors HS and MBG increased aPWV, SBP, and aortic wall collagen abundance in both strains vs. their LS controls. In SD rats, HS or MBG administration did not affect heart parameters, as assessed by ECHO vs. the SD-LS control. In DSS rats, impaired whole-heart structure and function were observed after HS diet administration in DSS-HS vs. DSS-LS rats. MBG treatment did not affect the ECHO parameters in DSS-MBG vs. DSS-LS rats. The HS diet led to an increase in endogenous plasma and urine MBG levels in both SD and DSS groups. Thus, the prohypertensive and profibrotic effect of HS diet might be partially attributed to an increase in MBG. The prohypertensive and profibrotic functions of MBG were pronounced in both DSS and SD rats, although quantitative PCR revealed that different profiles of profibrotic genes in DSS and SD rats was activated after MBG or HS administration. Spatial memory was not affected by HS diet or MBG treatment in either SD or DSS rats. Impaired cognitive function was associated with higher BP, CAS, and cardiovascular remodeling in young DSS-LS rats, as compared to young SD-LS rats. MBG and HS had similar effects on the cardiovascular system and its function in DSS and SD rats, although the rate of change in SD rats was lower than in DSS rats. The absence of a cumulative effect of increased aPWV and BP on spatial memory can be explained by the cerebrovascular and brain plasticity in young rats, which help the animals to tolerate CAS elevated by HS and MBG and to counterbalance the profibrotic effect of heightened MBG.

Cardiac Remodeling and Hypertension in HIV-Uninfected Infants Exposed in utero to Antiretroviral Therapy.

BACKGROUND: We aimed to assess the postnatal pattern of cardiovascular remodeling associated with intrauterine exposure to maternal HIV and antiretroviral treatment (ART). METHODS: Prospective cohort including 34 HIV-exposed uninfected (HEU) infants and 53 non-HIV-exposed infants were evaluated from fetal life up to 6 months postnatally. A cardiovascular evaluation was performed including echocardiography, blood pressure, and carotid intima media thickness (cIMT) measurement. RESULTS: ART regimens during pregnancy included 2 nucleoside reverse transcriptase inhibitors (Abacavir + Lamivudine (32.4%), Emtricitabine + Tenofovir (41.2%), and Zidovudine + Lamivudine (20.6%)). At 6 months of age, HIV-exposed uninfected infants showed thicker myocardial walls (septal wall thickness mean 5.02 mm (SD 0.85) vs 3.98 mm (0.86); P < .001), relative systolic dysfunction with decreased mitral ring displacement (8.57 mm (2.03) vs 10.34 mm (1.84); P = .002), and decreased tricuspid S' (9.71 cm/s (1.94) vs 11.54 cm/s (2.07); P = .003) together with relative diastolic dysfunction showed by prolonged left isovolumic relaxation time (58.57 ms (13.79) vs 47.94 (7.39); P < .001). Vascular assessment showed significantly higher systolic and diastolic blood pressure (102 mmHg (16.1) vs 80 mmHg (13.9); P < .001 and 64 mmHg (14.4) vs 55 mmHg (10.2); P = .045 respectively), with 50% of HIV-exposed children meeting criteria for hypertension vs 3.77% of the non-HIV-exposed group (P < .001) and thicker mean cIMT in the HIV-exposed group (0.62 µm (0.09) vs 0.51 µm (0.09); P = .015). CONCLUSIONS: Subclinical cardiac impairment together with higher blood pressure and thicker cIMT were observed in HIV-exposed infants at 6 months of age. Half of them presented hypertension. Our findings support a possible increased cardiovascular risk in HIV uninfected infants exposed in utero to ART.

NR4A3: A Key Nuclear Receptor in Vascular Biology, Cardiovascular Remodeling, and Beyond.

The mechanisms committed in the activation and response of vascular and inflammatory immune cells play a major role in tissue remodeling in cardiovascular diseases (CVDs) such as atherosclerosis, pulmonary arterial hypertension, and abdominal aortic aneurysm. Cardiovascular remodeling entails interrelated cellular processes (proliferation, survival/apoptosis, inflammation, extracellular matrix (ECM) synthesis/degradation, redox homeostasis, etc.) coordinately regulated by a reduced number of transcription factors. Nuclear receptors of the subfamily 4 group A (NR4A) have recently emerged as key master genes in multiple cellular processes and vital functions of different organs, and have been involved in a variety of high-incidence human pathologies including atherosclerosis and other CVDs. This paper reviews the major findings involving NR4A3 (Neuron-derived Orphan Receptor 1, NOR-1) in the cardiovascular remodeling operating in these diseases.

Fetal cardiac remodeling and dysfunction is associated with both preeclampsia and fetal growth restriction.

BACKGROUND: Preeclampsia and fetal growth restriction share some pathophysiologic features and are both associated with placental insufficiency. Fetal cardiac remodeling has been described extensively in fetal growth restriction, whereas little is known about preeclampsia with a normally grown fetus. OBJECTIVE: To describe fetal cardiac structure and function in pregnancies complicated by preeclampsia and/or fetal growth restriction as compared with uncomplicated pregnancies. STUDY DESIGN: This was a prospective, observational study including pregnancies complicated by normotensive fetal growth restriction (n=36), preeclampsia with a normally grown fetus (n=35), preeclampsia with fetal growth restriction (preeclampsia with a normally grown fetus-fetal growth restriction, n=42), and 111 uncomplicated pregnancies matched by gestational age at ultrasound. Fetal echocardiography was performed at diagnosis for cases and recruitment for uncomplicated pregnancies. Cord blood concentrations of B-type natriuretic peptide and troponin I were measured at delivery. Univariate and multiple regression analysis were conducted. RESULTS: Pregnancies complicated by preeclampsia and/or fetal growth restriction showed similar patterns of fetal cardiac remodeling with larger hearts (cardiothoracic ratio, median [interquartile range]: uncomplicated pregnancies 0.27 [0.23-0.29], fetal growth restriction 0.31 [0.26-0.34], preeclampsia with a normally grown fetus 0.31 [0.29-0.33), and preeclampsia with fetal growth restriction 0.28 [0.26-0.33]; P<.001) and more spherical right ventricles (right ventricular sphericity index: uncomplicated pregnancies 1.42 [1.25-1.72], fetal growth restriction 1.29 [1.22-1.72], preeclampsia with a normally grown fetus 1.30 [1.33-1.51], and preeclampsia with fetal growth restriction 1.35 [1.27-1.46]; P=.04) and hypertrophic ventricles (relative wall thickness: uncomplicated pregnancies 0.55 [0.48-0.61], fetal growth restriction 0.67 [0.58-0.8], preeclampsia with a normally grown fetus 0.68 [0.61-0.76], and preeclampsia with fetal growth restriction 0.66 [0.58-0.77]; P<.001). Signs of myocardial dysfunction also were observed, with increased myocardial performance index (uncomplicated pregnancies 0.78 z scores [0.32-1.41], fetal growth restriction 1.48 [0.97-2.08], preeclampsia with a normally grown fetus 1.15 [0.75-2.17], and preeclampsia with fetal growth restriction 0.45 [0.54-1.94]; P<.001) and greater cord blood B-type natriuretic peptide (uncomplicated pregnancies 14.2 [8.4-30.9] pg/mL, fetal growth restriction 20.8 [13.1-33.5] pg/mL, preeclampsia with a normally grown fetus 31.8 [16.4-45.8] pg/mL and preeclampsia with fetal growth restriction 37.9 [15.7-105.4] pg/mL; P<.001) and troponin I as compared with uncomplicated pregnancies. CONCLUSION: Fetuses of preeclamptic mothers, independently of their growth patterns, presented cardiovascular remodeling and dysfunction in a similar fashion to what has been previously described for fetal growth restriction. Future research is warranted to better elucidate the mechanism(s) underlying fetal cardiac adaptation in these conditions.

Cardiovascular remodeling in patients with hypertension with different degrees of cognitive impairment.

OBJECTIVE: Introduction: Recently, the concept of vascular cognitive impairment, combining all variants of cognitive decline due to cerebrovascular insufficiency, is actively being developed. This concept goes far beyond traditionally existing ideas about the problem of vascular cognitive disturbances. The aim of the study is to demonstrate the correlation between the indices of structural and functional rearrangement of the cardiovascular system and the state of intellectualmnemonic functions in patients with hypertension. PATIENTS AND METHODS: Materials and methods: A comprehensive survey of 146 patients with hypertension of the II and III stage according to ESH / ESC 2013, 2017, 2018 has been performed. The study included patients with mild and moderate cognitive impairment (CI). Depending on the state of the cognitive sphere and on the basis of the results of the neuronpsychological testing, The patients were divided into 3 groups depending on the state of the cognitive sphere and on the basis of the results of the neuron-psychological testing with further comparisons of their clinical and instrumental data. RESULTS: Results: According to the results of our study, it has been found that an increase of the signs of cardiovascular remodeling was observed in patients with more pronounced changes in cognitive activity. The analysis of intracardiac hemodynamic parameters in patients of the studied groups revealed more significant pathological changes in patients with cognitive impairments than in patients without them. Patients with mild and moderate CI had significantly higher heart rates, left ventricular wall thickness (LV) which led to impairment of the diastolic function of LV and had already been registered in patients without cognitive dysfunction. Moreover, it increased with the appearance (mild) and growth of the degree (moderate) cognitive impairment. The average daily values of BP (SBP, DBP) in patients of all studied groups significantly exceeded the recommended norms, while in patients with moderate CI these rates were significantly higher than those in the group with mild CI (p = 0.028). In addition, the variability of systolic blood pressure was increasing simultaneously with the deterioration of cognitive function of our patients. Also, signs of remodeling were being observed during the study of the state of peripheral vessels (increase of peripheral resistance, pulsation index, linear velocity and thickening of the intima-media complex), which is the main cause of cognitive impairment and causes their appearance and reflects their degree. CONCLUSION: Conclusions: The presented study revealed a clear correlation between the degree of cognitive impairment and the degree of changes in the daily blood pressure profile, the most important of which were the average daily systolic blood pressure and systolic blood pressure variability. On the basis of the conducted research, in the future it will be possible to predict the level of the cognitive sphere involvement, depending on the state of the daily blood pressure profile, changes of the ventricle and vessels geometry, which will enable timely diagnosis of cognitive impairment and the prescription an adequate therapy.

Vaccarin administration ameliorates hypertension and cardiovascular remodeling in renovascular hypertensive rats.

Sympathetic overdrive, activation of renin angiotensin systems (RAS), and oxidative stress are vitally involved in the pathogenesis of hypertension and cardiovascular remodeling. We recently identified that vaccarin protected endothelial cell function from oxidative stress or high glucose. In this study, we aimed to investigate whether vaccarin attenuated hypertension and cardiovascular remodeling. Two-kidney one-clip (2K1C) model rats were used, and low dose of vaccarin (10 mg/kg), high dose of vaccarin (30 mg/kg), captopril (30 mg/kg) were intraperitoneally administrated. Herein, we showed that 2K1C rats exhibited higher systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), left ventricular mass/body weight ratio, myocardial hypertrophy or fibrosis, media thickness, and media thickness to lumen diameter, which were obviously alleviated by vaccarin and captopril. In addition, both vaccarin and captopril abrogated the increased plasma renin, angiotensin II (Ang II), norepinephrine (NE), and the basal sympathetic activity. The AT1R protein expressions, NADPH oxidase subunit NOX-2 protein levels and malondialdehyde (MDA) content were significantly increased, whereas superoxide dismutase (SOD) and catalase (CAT) activities were decreased in myocardium, aorta, and mesenteric artery of 2K1C rats, both vaccarin and captopril treatment counteracted these changes in renovascular hypertensive rats. Collectively, we concluded that vaccarin may be a novel complementary therapeutic medicine for the prevention and treatment of hypertension. The mechanisms for antihypertensive effects of vaccarin may be associated with inhibition of sympathetic activity, RAS, and oxidative stress.

Gαq/p63RhoGEF interaction in RhoA/Rho kinase signaling: investigation in Gitelman's syndrome and implications with hypertension.

PURPOSE: Gitelman's syndrome (GS) presents normo-hypotension and absence of cardiovascular-renal remodeling despite high angiotensin II (Ang II), activation of renin-angiotensin-aldosterone system and is a human model of endogenous antagonism of Ang II signaling, opposite to hypertension. GS's clinical presentation leads to questions regarding what features might be responsible. One area of investigation involves Ang II signaling. In hypertensive patients, RhoA/Rho kinase (RhoA/ROCK) pathway activation by Ang II is involved in hypertension development/maintenance and induction of long-term consequences (cardiovascular-renal remodeling), while GS has reduced p63RhoGEF gene and protein levels and ROCK activity. Ang II signaling is mediated by Gαq, which interacts with p63RhoGEF via the α6-αN linker connecting p63RhoGEF's DH and PH domains acting as a conformational switch to activate RhoA/ROCK signaling. METHODS: We have investigated in GS patients, the presence of mutations in either p63RhoGEF's α6-αN linker domain and in Gαq's Ala253, Trp263, and Tyr356 residues, crucial for p63RhoGEF-Gαq interplay. RESULTS: No mutations have been found in specific aminoacids of p63RhoGEF α6-αN linker and Gαq, key for p63RhoGEF/Gαq interplay. CONCLUSIONS: Gitelman's syndrome normo/hypotension and lack of cardiovascular-renal remodeling are not due to mutations of p63RhoGEF α6-αN linker and Gαq interactions. This opens the way for investigations on different coding and no-coding regions (p63RhoGEF and Gαq promoters) and on altered transcriptional/post-transcriptional regulation. Clarification of how these biochemical/molecular mechanisms work/interact would provide insights into mechanisms involved in the GS's Ang II signaling fine tuning, in human physiology/pathophysiology in general and could also identify significant targets for intervention in the treatments of hypertension.

Effects of oligomeric grape seed proanthocyanidins on L-NAME-induced hypertension in pregnant mice: Role of oxidative stress and endothelial dysfunction.

The aim of this study was to investigate the effects of Grape Seed Proanthocyanidins (GSP) on Nω-Nitro-L-arginine methyl ester-induced hypertension in pregnant mice. Fifty Kunming mice were randomized into control, control + GSP, model, and model + GSP. Three weeks later, the artery systolic blood pressure was examined and the related pathological changes were detected. Aorta relaxation function was assessed by aorta ring apparatus. Blood urea nitrogen and serum creatinine were measured by an automatic biochemistry analyzer. Colorimetric analysis, enzyme-linked immunosorbent assay, immunofluorescence, and western blot were applied to detect related indicator in serum, cardiac, and kidney tissues. The results showed that GSP treatment for 3 weeks could improve cardiovascular and kidney remodeling indexes and decrease blood urea nitrogen and serum creatinine content in serum, as well as could ameliorate oxidative stress status and endothelial dysfunction. Therefore, it is for the first time found that GSP exerts protective effect against Nω-Nitro-L-arginine methyl ester-induced hypertension in pregnant mice, which provided a theoretical basis for potential application in the clinic.

Protective effects of Xinji'erkang on myocardial infarction induced cardiac injury in mice.

BACKGROUND: Myocardial infarction (MI) is a major risk factor responsible for morbidity and mortality. Xinji'erkang (XJEK) has been clinically used as an effective medication in the treatment of coronary heart disease and myocarditis. The purpose of this study was to investigate the cardioprotective effect of Xinji'erkang on MI mice. METHODS: Forty male mice were randomly assigned into four groups as follows (n = 10): sham, model, MI with administration of XJEK and fosinopril for four weeks. At the end of studies, hemodynamic parameters and electrocardiography (ECG) were recorded. Heart and body mass were measured and heart weight/body weight (HW/BW) ratio was calculated as index of hypertrophy. The hypertrophy of heart and aorta was examined using the hematoxylin and eosin (HE) staining, and the collagen deposition was evaluated using Van Gieson (VG) staining. Serum nitric oxide level (NO), superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration were assayed by colorimetric analysis. The expressions of endothelial NO synthetase (eNOS) expression in serum and cardiac tissues were determined using ELISA assay and immunohistochemistry. Angiotensin II (Ang II) in serum and cardiac tissues was measured using ELISA assay. Besides, tumor necrosis factor-α (TNF-α), interleukin1ß (IL-1ß) and interleukin10 (IL-10) were observed in cardiac tissues with ELISA assay as well. RESULTS: The administration of XJEK significantly improved cardiac dysfunction and abnormal ECG with reduced HW/BW ratio and ameliorated cardiomyocyte hypertrophy and collagen deposition compared to MI, which was partly due to the decreased SOD and increased MDA in serum. Moreover, XJEK treatment also improved endothelial dysfunction (ED) with not only enhanced eNOS activities in serum and cardiac tissues and elevated NO levels in serum, but also decreased Ang II content in serum and cardiac tissues. Finally, protein expressions of pro-inflammation cytokines, TNF-α and IL-1ß in the cardiac tissues with XJEK treatment were significantly decreased compared to model. On the contrary, IL-10, an anti-inflammatory cytokine concentrated in cardiac tissues was significantly enhanced compared to model. CONCLUSION: Xinji'erkang exerts cardioprotective effect on myocardial infarction in mice, which may be due to the improvement of endothelial dysfunction and the reduction of oxidative stress and inflammation response.

Fetal cardiovascular remodeling persists at 6 months in infants with intrauterine growth restriction.

OBJECTIVES: Intrauterine growth restriction is associated with increased cardiovascular risk later in life but the link between fetal disease and postnatal risk is not well-documented. We evaluated longitudinally the association between cardiovascular remodeling in small-for-gestational-age (SGA) fetuses and at 6 months of age. METHODS: A cohort of 80 SGA fetuses (defined by estimated fetal and birth weights < 10(th) centile) delivered > 34 weeks' gestation was compared with 80 normally grown age-matched control fetuses, with follow-up at 6 months of corrected age (i.e. 6 months from estimated date of delivery according to first-trimester crown-rump length). Cardiovascular evaluation included a comprehensive echocardiographic assessment in both fetuses and infants and blood pressure and aortic intima-media thickness (aIMT) measurement in infants. Parameters were adjusted by linear regression analysis for gender, gestational age at delivery, pre-eclampsia, prenatal glucocorticoid exposure, Cesarean delivery, admission to neonatal intensive care unit and body surface area. RESULTS: Both pre- and postnatally, when compared with controls, the SGA group showed a more globular cardiac shape (left sphericity index: controls 2.06 vs SGA 1.87 (P = 0.022) prenatally and 1.92 vs 1.67 (P = 0.007) postnatally), as well as signs of systolic longitudinal dysfunction (systolic annular peak velocity (S'): 7.2 vs 6.3 cm/s (P = 0.003) prenatally and 7.9 vs 6.4 cm/s (P < 0.001) postnatally; tricuspid annular plane systolic excursion: 7.2 vs 6.8 mm (P = 0.015) prenatally and 16.0 vs 14.2 mm (P < 0.001) postnatally) and diastolic dysfunction (left isovolumetric relaxation time: 46 vs 52 ms (P < 0.001) prenatally and 50 vs 57 ms (P = 0.034) postnatally). In addition, infants in the SGA group had increased mean blood pressure (mean: 61 vs 70 mmHg, P < 0.001) and maximum aIMT (0.57 vs 0.66 mm; P < 0.001). CONCLUSIONS: Primary cardiovascular changes are already present in the SGA fetus and persist at 6 months of age. These data support prenatal cardiovascular remodeling as a mechanistic pathway of increased risk later in life in cases of SGA, regardless of Doppler abnormalities. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

Age-associated pro-inflammatory remodeling and functional phenotype in the heart and large arteries.

The aging population is increasing dramatically. Aging-associated stress simultaneously drives proinflammatory remodeling, involving angiotensin II and other factors, in both the heart and large arteries. The structural remodeling and functional changes that occur with aging include cardiac and vascular wall stiffening, systolic hypertension and suboptimal ventricular-arterial coupling, features that are often clinically silent and thus termed a silent syndrome. These age-related effects are the result of responses initiated by cardiovascular proinflammatory cells. Local proinflammatory signals are coupled between the heart and arteries due to common mechanical and humoral messengers within a closed circulating system. Thus, targeting proinflammatory signaling molecules would be a promising approach to improve age-associated suboptimal ventricular-arterial coupling, a major predisposing factor for the pathogenesis of clinical cardiovascular events such as heart failure.

Pregnancy induces persistent changes in vascular compliance in primiparous women.

OBJECTIVE: Pregnancy induces rapid, progressive, and substantial changes to the cardiovascular system. The low recurrence risk of preeclampsia, despite familial predisposition, suggests an adaptation associated with pregnancy that attenuates the risk for subsequent preeclampsia. We aimed to evaluate the persistent effect of pregnancy on maternal cardiovascular physiology. STUDY DESIGN: Forty-five healthy nulliparous women underwent baseline cardiovascular assessment before conception and repeated an average of 30 months later. After baseline evaluation, 17 women conceived singleton pregnancies and all delivered at term. The remaining 28 women comprised the nonpregnant control group. We measured mean arterial blood pressure, cardiac output, plasma volume, pulse wave velocity, uterine blood flow, and flow-mediated vasodilation at each visit. RESULTS: There was a significant decrease in mean arterial pressure from the prepregnancy visit to postpartum in women with an interval pregnancy (prepregnancy, 85.3±1.8; postpartum, 80.5±1.8 mm Hg), with no change in nonpregnant control subjects (visit 1, 80.3±1.4; visit 2, 82.8±1.4 mm Hg) (P=.002). Pulse wave velocity was significantly decreased in women with an interval pregnancy (prepregnancy, 2.73±0.05; postpartum, 2.49±0.05 m/s), as compared with those without an interval pregnancy (visit 1, 2.56±0.04; visit 2, 2.50±0.04 m/s) (P=.005). We did not observe a residual effect of pregnancy on cardiac output, plasma volume, uterine blood flow, or flow-mediated vasodilation. CONCLUSION: Our observations of decreased mean arterial pressure and reduced arterial stiffness following pregnancy suggest a significant favorable effect of pregnancy on maternal cardiovascular remodeling. These findings may represent a mechanism by which preeclampsia risk is reduced in subsequent pregnancies.

Role of 8-nitro-cGMP and its redox regulation in cardiovascular electrophilic signaling.

Structural and morphological changes of the cardiovascular systems (cardiovascular remodeling) are a major clinical outcome of cardiovascular diseases. Many lines of evidences have implied that transfiguration of reduction/oxidation (redox) homeostasis due to excess production of reactive oxygen species (ROS) and/or ROS-derived electrophilic metabolites (electrophiles) is the main cause of cardiovascular remodeling. Gasotransmitters, such as nitric oxide (NO) and endogenous electrophiles, are considered major bioactive species and have been extensively studied in the context of physiological and pathological cardiovascular events. We have recently found that hydrogen sulfide-related reactive species function as potent nucleophiles to eliminate electrophilic modification of signaling proteins induced by NO-derived electrophilic byproducts (e.g., 8-nitroguanosine 3',5'-cyclic monophosphate and nitro-oleic acid). In this review, we discuss the current understanding of redox control of cardiovascular pathophysiology by electrophiles and nucleophiles. We propose that modulation of electrophile-mediated post-translational modification of protein cysteine thiols may be a new therapeutic strategy of cardiovascular diseases. This article is part of a Special Issue entitled "Redox Signalling in the Cardiovascular System".

Donepezil attenuates progression of cardiovascular remodeling and improves prognosis in spontaneously hypertensive rats with chronic myocardial infarction.

The acetylcholinesterase inhibitor donepezil restores autonomic balance, reduces inflammation, and improves long-term survival in rats with chronic heart failure (CHF) following myocardial infarction (MI). As arterial hypertension is associated with a significant risk of cardiovascular death, we investigated the effectiveness of donepezil in treating CHF in spontaneously hypertensive rats (SHR). CHF was induced in SHR by inducing permanent MI. After 2 weeks, the surviving SHR were randomly assigned to sham-operated (SO), untreated (UT), or oral donepezil-treated (DT, 5 mg/kg/day) groups, and various vitals and parameters were monitored. After 7 weeks of treatment, heart rate and arterial hypertension reduced significantly in DT rats than in UT rats. Donepezil treatment improved 50-day survival (41% to 80%, P = 0.004); suppressed progression of cardiac hypertrophy, cardiac dysfunction (cardiac index: 133 ± 5 vs. 112 ± 5 ml/min/kg, P < 0.05; left ventricular end-diastolic pressure: 12 ± 3 vs. 22 ± 2 mmHg, P < 0.05; left ventricular +dp/dtmax: 5348 ± 338 vs. 4267 ± 114 mmHg/s, P < 0.05), systemic inflammation, and coronary artery remodeling (wall thickness: 26.3 ± 1.4 vs. 34.7 ± 0.7 µm, P < 0.01; media-to-lumen ratio: 3.70 ± 0.73 vs. 8.59 ± 0.84, P < 0.001); increased capillary density; and decreased plasma catecholamine, B-type natriuretic peptide, arginine vasopressin, and angiotensin II levels. Donepezil treatment attenuated cardiac and coronary artery remodeling, mitigated cardiac dysfunction, and significantly improved the prognosis of SHR with CHF.

Impact of Sex on Cardiovascular Adaptations to Exercise: JACC Review Topic of the Week.

Routine exercise leads to cardiovascular adaptations that differ based on sex. Use of cardiac testing to screen athletes has driven research to define how these sex-based adaptations manifest on the electrocardiogram and cardiac imaging. Importantly, sex-based differences in cardiovascular structure and outcomes in athletes often parallel findings in the general population, underscoring the importance of understanding their mechanisms. Substantial gaps exist in the understanding of why cardiovascular adaptations and outcomes related to exercise differ by sex because of underrepresentation of female participants in research. As female sports participation rates have increased dramatically over several decades, it also remains unknown if differences observed in older athletes reflect biological mechanisms vs less lifetime access to sports in females. In this review, we will assess the effect of sex on cardiovascular adaptations and outcomes related to exercise, identify the impact of sex hormones on exercise performance, and highlight key areas for future research.

Quercetin decreases cardiac hypertrophic mediators and maladaptive coronary arterial remodeling in renovascular hypertensive rats without improving cardiac function.

Oxidative stress and MMP activity are found in the hearts and arteries in hypertension and contribute to the resulting hypertrophy and dysfunction. Quercetin is a flavonoid that reduces MMP-2 activity and ameliorates hypertrophic vascular remodeling of hypertension. The hypothesis is that treatment of hypertensive rats with quercetin ameliorates coronary maladaptive remodeling and decreases hypertrophic cardiac dysfunction by decreasing oxidative stress and MMP activity. Male Sprague-Dawley two-kidney, one-clip (2K1C) and Sham rats were treated with quercetin (10 mg/kg/day) or its vehicle for 8 weeks by gavage. Rats were analyzed at 10 weeks of hypertension. Systolic blood pressure (SBP) was examined by tail-cuff plethysmography. Cardiac left ventricles were used to determine MMP activity by in situ zymography and oxidative stress by dihydroethidium. Immunofluorescence was performed to detect transforming growth factor (TGF)-ß and nuclear factor kappa B (NFkB). Morphological analyses of heart and coronary arteries were done by H&E and picrosirius red, and cardiac function was measured by Langendorff. SBP was increased in 2K1C rats, and quercetin did not reduce it. However, quercetin decreased both oxidative stress and TGF-ß in the left ventricles of 2K1C rats. Quercetin also decreased the accentuated MMP activity in left ventricles and coronary arteries of 2K1C rats. Quercetin ameliorated hypertension-induced coronary arterial hypertrophic remodeling, although it did not reduce cardiac hypertrophic remodeling and dysfunction. Quercetin decreases cardiac oxidative stress and TGF-ß and MMP activity in addition to improving coronary remodeling, yet does not ameliorate cardiac dysfunction in 2K1C rats.