Experimental Benefits of Sex Hormones on Vascular Function and the Outcome of Hormone Therapy in Cardiovascular Disease

Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Experimental data have shown beneficial vascular effects of estrogen including stimulation of endothelium-dependent nitric oxide, prostacyclin and hyperpolarizing factor-mediated vascular relaxation. However, the experimental evidence did not translate into vascular benefits of hormone replacement therapy (HRT) in postmenopausal women, and HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events with HRT. The lack of vascular benefits of HRT could be related to the hormone used, the vascular estrogen receptor (ER), and the subject’s age and preexisting cardiovascular condition. Natural and phytoestrogens in small doses may be more beneficial than synthetic estrogen. Specific estrogen receptor modulators (SERMs) could maximize the vascular benefits, with little side effects on breast cancer. Transdermal estrogens avoid the first-pass liver metabolism associated with the oral route. Postmenopausal decrease and genetic polymorphism in vascular ER and post-receptor signaling mechanisms could also modify the effects of HRT. Variants of cytosolic/nuclear ER mediate transcriptional genomic effects that stimulate endothelial cell growth, but inhibit vascular smooth muscle (VSM) proliferation. Also, plasma membrane ERs trigger not only non-genomic stimulation of endothelium-dependent vascular relaxation, but also inhibition of [Ca2+]i, protein kinase C and Rho kinase-dependent VSM contraction. HRT could also be more effective in the perimenopausal period than in older postmenopausal women, and may prevent the development, while worsening preexisting CVD. Lastly, progesterone may modify the vascular effects of estrogen, and modulators of estrogen/testosterone ratio could provide alternative HRT combinations. Thus, the type, dose, route of administration and the timing/duration of HRT should be customized depending on the subject’s age and preexisting cardiovascular condition, and thereby make it possible to translate the beneficial vascular effects of sex hormones to the outcome of HRT in postmenopausal CVD

Sex Difference in Cardiovascular Risk Role of Pulse Pressure Amplification

ObjectivesThe study was to explore whether the brachial/carotid pulse pressure (B/C-PP) ratio selectively predicts the sex difference in age-related cardiovascular (CV) death.BackgroundHypertension and CV complications are more severe in men and post-menopausal women than in pre-menopausal women. C-PP is lower than B-PP, and the B/C-PP ratio is a physiological marker of PP amplification between B and C arteries that tends toward 1.0 with age.MethodsThe study involved 72,437 men (ages 41.0 ± 11.1 years) and 52,714 women (39.5 ± 11.6 years). C-PP was calculated for each sex by a multiple regression analysis including B-PP, age, height and risk factors, and a method validated beforehand in a subgroup of 834 subjects. During the 12 years of follow-up, 3,028 men and 969 women died.ResultsIn the total population, the adjusted hazard ratios (HR) (95% confidence interval [CI]) of B/C-PP ratio were: 1) for all-cause mortality: men, HR: 1.51 (95% CI: 1.47 to 1.56), women; HR: 2.46 (95% CI: 2.27 to 2.67) (p < 0.0001); and 2) for CV mortality: men, HR 1.81 (95% CI: 1.70 to 1.93); women, HR: 4.46 (95% CI: 3.66 to 5.45) (p < 0.0001). The B/C-PP impact on mortality did not significantly increase from younger men to those ≥55 years of age, from: HR: 1.44 (95% CI: 1.31 to 1.58) to HR 1.65 (95% CI: 1.48 to 1.84), but increased significantly with age in women: HR: 3.19 (95% CI: 2.08 to 4.89) versus HR: 5.60 (95% CI: 4.17 to 7.50) (p < 0.01). Thus, the mortality impact of B/C-PP ratio was 3-fold higher in women than in men ≥55 years old.ConclusionsPP amplification is highly predictive of differences in CV risk between men and women. In post-menopausal women, the attenuation of PP amplification, mainly related to increased aortic stiffness, contributes to the significant increase in CV risk

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

A study of the calcium regulatory mechanisms involved in maintained agonist-induced vascular smooth muscle tone

Isometric tension was measured in parallel with \sp{45}Ca influx in rabbit aorta or simultaneously with (Ca\sp{2+}) \sb{\rm i} in rabbit inferior vena cava loaded with fura-2. In the presence of external Ca\sp{2+}, phenylephrine, norepinephrine and high K\sp+ caused a maintained increase in tension, \sp{45}Ca influx and (Ca\sp{2+}) \sb{\rm i} which were markedly inhibited in the absence of extracellular Ca\sp{2+}. In (Ca\sp{2+}) \sb{\rm i} vs force curves, the norepinephrine curve was shifted to the left of that of high K\sp+. The protein kinase C activator TPA induced a slow increase in tension and shifted the (K\sp+) \sb{\rm e}-force relationship to the left without any change in (Ca\sp{2+}) \sb{\rm i}. TPA alone did not maintain the contraction initiated by high K\sp+. The protein kinase C inhibitor H-7 completely inhibited the contraction induced by TPA but only partially inhibited the phenylephrine-, norepinephrine- and high K\sp+-induced contraction without changing \sp{45}Ca influx or (Ca\sp{2+}) \sb{\rm i}. In the presence of external Ca\sp{2+}, ryanodine caused a maintained increase in (Ca\sp{2+}) \sb{\rm i} which was not inhibited by diltiazem, but completely abolished by La\sp{3+} or in Ca\sp{2+}-free solution. Ryanodine caused a small increase in tension and transient decrease in the caffeine-releasable Ca\sp{2+}. Ryanodine did not enhance the high K\sp+-induced force, \sp{45}Ca influx and (Ca\sp{2+}) \sb{\rm i}. It is concluded that the maintained agonist-induced vascular tone is due to (1) Ca\sp{2+} influx from the extracellular space, (2) increased myofilament force sensitivity probably due to activation of protein kinase C, and (3) inhibition of Ca\sp{2+} buffering by the sarcoplasmic reticulum

Cellular mediators of renal vascular dysfunction in hypertension

The renal vasculature plays a major role in the regulation of renal blood flow and the ability of the kidney to control the plasma volume and blood pressure. Renal vascular dysfunction is associated with renal vasoconstriction, decreased renal blood flow, and consequent increase in plasma volume and has been demonstrated in several forms of hypertension (HTN), including genetic and salt-sensitive HTN. Several predisposing factors and cellular mediators have been implicated, but the relationship between their actions on the renal vasculature and the consequent effects on renal tubular function in the setting of HTN is not clearly defined. Gene mutations/defects in an ion channel, a membrane ion transporter, and/or a regulatory enzyme in the nephron and renal vasculature may be a primary cause of renal vascular dysfunction. Environmental risk factors, such as high dietary salt intake, vascular inflammation, and oxidative stress further promote renal vascular dysfunction. Renal endothelial cell dysfunction is manifested as a decrease in the release of vasodilatory mediators, such as nitric oxide, prostacyclin, and hyperpolarizing factors, and/or an increase in vasoconstrictive mediators, such as endothelin, angiotensin II, and thromboxane A2. Also, an increase in the amount/activity of intracellular Ca2+ concentration, protein kinase C, Rho kinase, and mitogen-activated protein kinase in vascular smooth muscle promotes renal vasoconstriction. Matrix metalloproteinases and their inhibitors could also modify the composition of the extracellular matrix and lead to renal vascular remodeling. Synergistic interactions between the genetic and environmental risk factors on the cellular mediators of renal vascular dysfunction cause persistent renal vasoconstriction, increased renal vascular resistance, and decreased renal blood flow, and, consequently, lead to a disturbance in the renal control mechanisms of water and electrolyte balance, increased plasma volume, and HTN. Targeting the underlying genetic defects, environmental risk factors, and the aberrant renal vascular mediators involved should provide complementary strategies in the management of HTN

Differential [Ca2+]i signaling of vasoconstriction in mesenteric microvessels of normal and reduced uterine perfusion pregnant rats

Vascular resistance and blood pressure (BP) are reduced during late normal pregnancy (Norm-Preg). In contrast, studies in human preeclampsia and in animal models of hypertension in pregnancy (HTN-Preg) have suggested that localized reduction in uterine perfusion pressure (RUPP) in late pregnancy is associated with increased systemic vascular resistance and BP; however, the vascular mechanisms involved are unclear. Because Ca2+ is a major determinant of vascular contraction, we hypothesized that the intracellular free calcium concentration ([Ca2+]i) signaling of vasoconstriction is differentially regulated in systemic microvessels during normal and RUPP in late pregnancy. Pressurized mesenteric microvessels from Norm-Preg and RUPP rats were loaded with fura 2 in preparation for simultaneous measurement of diameter and [Ca2+]i (presented as fura 2 340/380 ratio). Basal [Ca2+]i was lower in RUPP (0.73 ± 0.03) compared with Norm-Preg rats (0.82 ± 0.03). Membrane depolarization by 96 mM KCl, phenylephrine (Phe, 10−5 M), angiotensin II (ANG II, 10−7 M), or endothelin-1 (ET-1, 10−7 M) caused an initial peak followed by maintained vasoconstriction and [Ca2+]i. KCl caused similar peak vasoconstriction and [Ca2+]i in Norm-Preg (45.5 ± 3.3 and 0.89 ± 0.02%) and RUPP rats (46.3 ± 2.1 and 0.87 ± 0.01%). Maximum vasoconstriction to Phe, ANG II, and ET-1 was not significantly different between Norm-Preg (28.6 ± 4.8, 32.5 ± 6.3, and 40 ± 4.6%, respectively) and RUPP rats (27.8 ± 5.9, 34.4 ± 4.3, and 38.8 ± 4.1%, respectively). In contrast, the initial Phe-, ANG II-, and ET-1-induced 340/380 ratio ([Ca2+]i) was reduced in RUPP (0.83 ± 0.02, 0.82 ± 0.02, and 0.83 ± 0.03, respectively) compared with Norm-Preg rats (0.95 ± 0.04, 0.93 ± 0.01, and 0.92 ± 0.02, respectively). Also, the [Ca2+]i-vasoconstriction relationship was similar in KCl-treated but shifted to the left in Phe-, ANG II-, and ET-1-treated microvessels of RUPP compared with Norm-Preg rats. The lower agonist-induced [Ca2+]i signal of vasoconstriction and the leftward shift in the [Ca2+]i-vasoconstriction relationship in microvessels of RUPP compared with Norm-Preg rats suggest activation of [Ca2+]i sensitization pathway(s). The similarity in vasoconstriction in RUPP and Norm-Preg rats suggests that such a [Ca2+]i sensitization pathway(s) may also provide a feedback effect on Ca2+ mobilization/homeostatic mechanisms to protect against excessive vasoconstriction in systemic microvessels during RUPP in late pregnancy

Mechanisms of lower extremity vein dysfunction in chronic venous disease and implications in management of varicose veins

Chronic venous disease (CVD) is a common venous disorder of the lower extremities. CVD can be manifested as varicose veins (VVs), with dilated and tortuous veins, dysfunctional valves and venous reflux. If not adequately treated, VVs could progress to chronic venous insufficiency (CVI) and lead to venous leg ulcer (VLU). Predisposing familial and genetic factors have been implicated in CVD. Additional environmental, behavioral and dietary factors including sedentary lifestyle and obesity may also contribute to CVD. Alterations in the mRNA expression, protein levels and proteolytic activity of matrix metalloproteinases (MMPs) have been detected in VVs and VLU. MMP expression/activity can be modulated by venous hydrostatic pressure, hypoxia, tissue metabolites, and inflammation. MMPs in turn increase proteolysis of different protein substrates in the extracellular matrix particularly collagen and elastin, leading to weakening of the vein wall. MMPs could also promote venous dilation by increasing the release of endothelium-derived vasodilators and activating potassium channels, leading to smooth muscle hyperpolarization and relaxation. Depending on VVs severity, management usually includes compression stockings, sclerotherapy and surgical removal. Venotonics have also been promoted to decrease the progression of VVs. Sulodexide has also shown benefits in VLU and CVI, and recent data suggest that it could improve venous smooth muscle contraction. Other lines of treatment including induction of endogenous tissue inhibitors of metalloproteinases and administration of exogenous synthetic inhibitors of MMPs are being explored, and could provide alternative strategies in the treatment of CVD