Effects of maternal anxiety and depression during pregnancy in Chinese women on children's heart rate and blood pressure response to stress.

Psychological disturbances, including anxiety and depression, are common during human pregnancy. Our objective was to determine whether these maternal disturbances influence cardiovascular responses of the offspring. The psychological status of 231 pregnant women was determined. Offspring (216) of these women were subsequently exposed to a video challenge stress when aged 7-9 years. Heart rate (HR) and blood pressure (BP) of the children were determined at rest, in response to video stress and during subsequent recovery. Children's resting and stress-induced increases in HR (bpm), systolic (SBP, mm Hg) and diastolic (DBP, mm Hg) BP were all greater in children whose mothers reported anxiety during pregnancy. Values (mean±s.d.) for resting HR, SBP and DBP were 75.15±5.87, 95.37±2.72 and 66.39±4.74 for children whose mothers reported no anxiety and an average of 81.62±6.71, 97.26±2.90 and 68.86±2.82 for children whose mothers reported anxiety at any level. Respective values for stress-induced increments in HR, SBP and DBP were 14.83.±2.14, 16.41±1.97 and 12.72±2.69 for children whose mothers reported no anxiety and 17.95±3.46, 18.74±2.46 and 14.86±2.02 for children whose mothers reported any level of anxiety. Effects of maternal depression were less consistent. The effects of maternal anxiety remained in multivariate analyses, which also included children's birth weight. The results indicate a long-term influence of maternal psychological status during pregnancy on the cardiovascular responses to stress among offspring. These effects may contribute to prenatal influences on subsequent health of the offspring.

Circulating vitamin D levels are associated with the presence and severity of coronary artery disease but not peripheral arterial disease in patients undergoing coronary angiography.

BACKGROUND AND AIMS: To investigate the association between vitamin D levels, angiographic severity of coronary artery disease, arterial stiffness and degree of peripheral arterial disease (PAD) as assessed by ankle brachial index (ABI). METHODS AND RESULTS: 375 patients undergoing coronary angiography from November 2012 to September 2013 were recruited. Serum 25-hydroxyvitamin D (25OHD) levels were measured as were ABI and pulse wave velocity (PWV). Based on the findings of the coronary angiogram, patients were divided into subgroups: Absent, Single, Double and Triple Vessel Disease (as defined by >50% stenosis in each major coronary artery) 0.275 patients not taking vitamin D supplements were included in the analysis. Mean age was 66.0 ± 11.2 (mean ± SD) years. Levels of 25(OH)D were significantly lower in patients with CAD when compared to patients without CAD (57.0 ± 1.73 versus 70.1 ± 2.46 nmol/L; p < 0.01). One way ANOVA revealed triple vessel disease patients had significantly lower 25(OH)D levels when compared to single vessel disease patients (50.6 ± 2.84 nmol/L versus 61.3 ± 3.16 p < 0.01) and trended to be lower when compared to double vessel disease patients (50.6 ± 2.84 versus 59.0 ± 2.99 nmol/L; p = 0.07). Stepwise regression revealed that age, gender (male), hypertension, hyperlipidemia and 25(OH)D were significant predictors of CAD (p < 0.05). Vitamin D was the most significant predictor for CAD (p < 0.001) There was no correlation between 25(OH)D levels, ABI and PWV. CONCLUSION: Among patients presenting for coronary angiography, low serum 25-hydroxyvitamin D levels are associated with the presence and extent of angiographic CAD but not arterial stiffness or PAD.

Randomized double-blind placebo-controlled crossover study to determine the effects of esomeprazole on inhibition of platelet function by clopidogrel.

BACKGROUND: Pharmacokinetic studies suggest that clopidogrel and esomeprazole are metabolized by similar hepatic enzymes; however, previous studies have not identified a biochemical interaction. OBJECTIVES: To determine whether addition of esomeprazole to patients receiving aspirin and clopidogrel reduces the antiplatelet effects of clopidogrel. PATIENT/METHODS: Patients with a history of an acute coronary syndrome who had previously received clopidogrel were recruited. Subjects were commenced on clopidogrel and randomized to one of two treatment arms (esomeprazole or placebo) for 6 weeks. Following a 2-week washout period for study medications, patients were crossed over onto the alternative treatment arm for a further 6 weeks. Platelet function tests were undertaken at baseline, following the first treatment period, after washout and following the second treatment period. RESULTS: Thirty-one patients were enrolled. Significant attenuation of clopidogrel's antiplatelet effects was seen with co-administration of esomeprazole compared with placebo. Vasodilator stimulated phosphoprotein (VASP), platelet aggregometry (area under the curve (AUC)) and VerifyNow results were 54.7% ± 2.8 platelet reactivity index (PRI), 66.3 ± 2.6 AUC units and 213.1 ± 14.1 platelet reactivity units (PRU) with esomeprazole vs. 47% ± 2.7 PRI, 59.7 ± 3.7 AUC units and 181.4 ± 14.6 PRU with placebo (P < 0.01 esomeprazole vs. placebo for all measures). There was no significant difference in platelet aggregometry (maximal aggregation) between the esomeprazole group (68.9% ± 2.7 units) and placebo-treated group (64.5% ± 4.1 units; P > 0.05). CONCLUSION: Esomeprazole when co-administered with aspirin and clopidogrel results in a significant attenuation of clopidogrel's antiplatelet effects.

Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy.

Clopidogrel has become part of the mainstay of therapy for acute coronary syndromes and in patients post stenting. Clopidogrel is a pro drug and is metabolised by liver enzymes, particularly CYP2C19, into its active form. A considerable proportion of patients have a poor response to clopidogrel and this may be due to several factors. Genetic polymorphisms involved in clopidogrel's absorption, metabolism and activity at the platelet may interfere with its antiplatelet actions. Further, proton pump inhibitors (PPI) may interfere with clopidogrel's actions by functionally reducing the ability of CYP2C19 to convert clopidogrel to its active metabolite. By attenuating clopidogrel's actions, both polymorphisms and drug interactions may increase the risk of thrombotic events during clopidogrel therapy. This review will explore the current evidence relating to the association between PPIs, genetic polymorphisms and poor response to clopidogrel. Routine genetic testing cannot be recommended for patients receiving dual antiplatelet therapy (DAPT). However, it may have a role for patients with an episode of stent thrombosis, prior to planned high-risk stenting or major bleeding. Regarding concomitant clopidogrel and PPI therapy, it is recommended that only patients with previous gastrointestinal (GI) bleeding or multiple risk factors for GI bleeding should be prescribed gastroprotection. This is due to the uncertainty surrounding the clinical significance of this interaction given the discordant biochemical and clinical data, conflicting results from observational studies and the limitations of the COGENT study. Pantoprazole seems least likely to interact with clopidogrel and most suitable for use in patients receiving DAPT.

Myocardial oxidative stress contributes to transgenic ß2-adrenoceptor activation-induced cardiomyopathy and heart failure.

BACKGROUND AND PURPOSE: While maintaining cardiac performance, chronic ß-adrenoceptor activation eventually exacerbates the progression of cardiac remodelling and failure. We examined the adverse signalling pathways mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) after chronic ß2-adrenoceptor activation. EXPERIMENTAL APPROACH: Mice with transgenic ß2-adrenoceptor overexpression (ß2-TG) and non-transgenic littermates were either untreated or treated with an antioxidant (N-acetylcysteine, NAC) or NADPH oxidase inhibitors (apocynin, diphenyliodonium). Levels of ROS, phosphorylated p38 mitogen-activated protein kinase (MAPK), pro-inflammatory cytokines and collagen content in the left ventricle (LV) and LV function were measured and compared. KEY RESULTS: ß2-TG mice showed increased ROS production, phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), expression of pro-inflammatory cytokines and collagen, and progressive ventricular dysfunction. ß2-adrenoceptor stimulation similarly increased ROS production and phosphorylation of p38 MAPK and HSP27 in cultured cardiomyocytes. Treatment with apocynin, diphenyliodonium or NAC reduced phosphorylation of p38 MAPK and HSP27 in both cultured cardiomyocytes and the LV of ß2-TG mice. NAC treatment (500 mg·kg⁻¹ ·day⁻¹) for 2 weeks eliminated the up-regulated expression of pro-inflammatory cytokines and collagen in the LV of ß2-TG mice. Chronic NAC treatment to ß2-TG mice from 7 to 10 months of age largely prevented progression of ventricular dilatation, preserved contractile function (fractional shortening 37 ± 5% vs. 25 ± 3%, ejection fraction 52 ± 5% vs. 32 ± 4%, both P < 0.05), reduced cardiac fibrosis and suppressed matrix metalloproteinase activity. CONCLUSION AND IMPLICATIONS: ß2-adrenoceptor stimulation provoked NADPH oxidase-derived ROS production in the heart. Elevated ROS activated p38 MAPK and contributed significantly to cardiac inflammation, remodelling and failure.

Knockout of beta(1)- and beta(2)-adrenoceptors attenuates pressure overload-induced cardiac hypertrophy and fibrosis.

BACKGROUND AND PURPOSE: The role of beta-adrenoceptors in heart disease remains controversial. Although beta-blockers ameliorate the progression of heart disease, the mechanism remains undefined. We investigated the effect of beta-adrenoceptors on cardiac hypertrophic growth using beta(1)- and beta(2)-adrenoreceptor knockout and wild-type (WT) mice. EXPERIMENTAL APPROACH: Mice were subjected to aortic banding or sham surgery, and their cardiac function was determined by echocardiography and micromanometry. KEY RESULTS: At 4 and 12 weeks after aortic banding, the left ventricle:body mass ratio was increased by 80-87% in wild-type mice, but only by 15% in knockouts, relative to sham-operated groups. Despite the blunted hypertrophic growth, ventricular function in knockouts was maintained. WT mice responded to pressure overload with up-regulation of gene expression of inflammatory cytokines and fibrogenic growth factors, and with severe cardiac fibrosis. All these effects were absent in the knockout animals. CONCLUSION AND IMPLICATIONS: Our findings of a markedly attenuated cardiac hypertrophy and fibrosis following pressure overload in this knockout model emphasize that beta-adrenoceptor signalling plays a central role in cardiac hypertrophy and maladaptation following pressure overload.

Raised plasma soluble P-selectin in peripheral arterial occlusive disease enhances leukocyte adhesion.

Raised levels of soluble P-selectin (sP-selectin) have been reported in the plasma of patients with vascular diseases; however, the functional importance of this ligand remains unclear. In this study we have examined a potential role for plasma sP-selectin in regulating neutrophil adhesion in patients with peripheral arterial occlusive disease (PAOD). Patients with PAOD had significantly higher levels of sP-selectin (mean+/-SD: 73.3+/-13.0 versus 16.7+/-6.4 ng/mL) and enhanced whole blood leukocyte adhesion to platelets under shear. To examine whether the raised sP-selectin levels can directly influence leukocyte adhesion, isolated neutrophils were incubated with plasma from PAOD patients before and after immunodepletion of sP-selectin. Neutrophil adhesion to fibrinogen increased 2-fold following incubation with PAOD plasma, which was abrogated on sP-selectin immunodepletion. We subsequently demonstrated that recombinant sP-selectin dose-dependently (75 to 250 ng/mL) increased leukocyte adhesion to fibrinogen and platelet monolayers. This increase was PSGL-1 and Src kinase-dependent and correlated with an increase in sP-selectin-mediated Mac-1 activation. sP-selectin-stimulated neutrophil adhesion to platelet monolayers was inversely correlated with shear, such that at low shear (50 s(-1)) a 92.7%+/-15.7 increase in adhesion was observed decreasing to 38.5%+/-11.9 at 150 s(-1) and 10.1%+/-7.4 at 300 s(-1). These studies suggest a potentially important role for sP-selectin in modulating neutrophil adhesion in patients with PAOD, particularly at sites of low shear, where it raises the possibility that raised plasma sP-selectin levels may enhance leukocyte recruitment to vascular injury and promote disease progression.

Regulation of glycosaminoglycan structure and atherogenesis.

Cardiovascular disease is the major cause of premature death in modern society, and its impact is increasing due to rising rates of obesity and type 2 diabetes. Clinical studies based on targeting metabolic abnormalities and biomarkers demonstrate significant benefits, but always an element of disease remains which is resistant to treatment. Recent evidence has strongly implicated an early interaction of atherogenic lipoproteins with vascular matrix proteoglycans as the initiating step in atherogenesis. Expert commentary has pointed to the need for vascular directed therapies to provide reductions in the residual disease component. We propose that the regulation of synthesis and thus structure of glycosaminoglycans on proteoglycans provides a potential pathway to this reduction. We review existing evidence that the vascular synthesis of glycosaminoglycan chains can be regulated in a manner which reduces lipoprotein binding and the potential application of this strategy to attenuation of the current cardiovascular disease pandemic.

Association between past infection with Chlamydia pneumoniae and body mass index, low-density lipoprotein particle size and fasting insulin.

BACKGROUND: Chlamydia pneumoniae infection has been linked to the development of coronary heart disease (CHD), but its relationship to CHD risk factors is less clear. OBJECTIVE: To determine the relationship between past infection with C. pneumoniae and risk factors for CHD, including body weight amongst subjects with and without CHD. METHODS: Antibodies to C. pneumoniae and a range of CHD risk factors were determined in 170 subjects, of whom 43 had recent onset angina. Anthropometric, haemodynamic, lipid and metabolic measurements were obtained and related to antibody status in univariate and multivariate analyses. RESULTS: IgG seropositive (n = 62) did not differ from seronegative subjects in age but were significantly heavier (26.6 +/- 0.4 vs 25.5 +/- 0.3 kg/m2, P = 0.02). The prevalence of seropositivity was similar for subjects with and without CHD and for those with or without hypertension. Subjects with fasting insulin levels greater and those with LDL diameters below the median also had a significantly higher prevalence of seropositivity (45.3 vs 27.3%, P = 0.015 and 45.0 vs 29.4%, P = 0.045 respectively). However in multivariate analysis only body mass index remained significant (P < 0.05). Results were not explained by differences in socioeconomic class. CONCLUSION: Although the study has failed to find a greater prevalence of antibodies to C. pneumoniae amongst subjects with recent onset angina there were associations with a number of cardiovascular risk factors. An increase in body weight appears to underlie these relationships.

Gender differences in the timing of arterial wave reflection beyond differences in body height.

OBJECTIVES: The timing of arterial wave reflection affects the shape of the arterial waveform and thus is a major determinant of pulse pressure. This study assessed differences in wave reflection between genders beyond the effect of body height. METHODS: From 1123 elderly (aged 71 +/- 5 years) currently untreated hypertensives, we selected 104 pairs of men and women with identical body height (average 164 +/- 4 cm). All subjects underwent echocardiography, including measurement of aortic arch expansion, automated blood pressure measurements, measurement of ascending aortic blood flow and simultaneous carotid artery tonometry. RESULTS: Women had higher pulse (80 +/- 17 versus 74 +/- 17 mmHg, P < 0.05) and lower diastolic pressure (79 +/- 11 versus 82 +/- 10 mmHg, P < 0.05). Whilst heart rate was similar, women had a longer time to the systolic peak (210 +/- 28 versus 199 +/- 34 ms, P < 0.01) and a longer ejection time (304 +/- 21 versus 299 +/- 25 ms, P < 0.001). Wave reflection occurred earlier in women (time between maxima 116 +/- 55 versus 132 +/- 47 ms, P < 0.05) and augmentation index was higher (36 +/- 11 versus 28 +/- 12%, P < 0.001). Aortic diameter was smaller in women and the aortic arch was stiffer (median Ep 386 versus 302 kN/m2, P < 0.05). Hence, systemic arterial compliance was less in women (0.8 +/- 0.2 versus 1.0 +/- 0.3 ml/mmHg). CONCLUSIONS: We conclude that elderly hypertensive men and women have a different timing of both left ventricular ejection and arterial wave reflection when both genders are matched for body height. Women have smaller and stiffer blood vessels resulting in an earlier return of the reflected wave, which is likely due to an increased pulse wave velocity in women.

Women exhibit a greater age-related increase in proximal aortic stiffness than men.

BACKGROUND: Large artery mechanical properties are a major determinant of pulse pressure and cardiovascular outcome. Sex differences in these properties may underlie the variation in cardiovascular risk profile between men and women, in relation to age. OBJECTIVE: To investigate sex differences in the age-related stiffening of large arteries. DESIGN: Cross-sectional. METHODS: One hundred and twenty healthy men and women were recruited and divided equally into tertiles by age: young (mean +/- SD, 23 +/- 5 years), middle-age (47 +/- 3 years) and older (62 +/- 7 years). Lipids, mean arterial pressure and heart rate were matched within each tertile. Carotid tonometry and Doppler velocimetry were used to measure indices of large artery stiffness. RESULTS: There was no sex difference in systemic arterial compliance (SAC) in the young group (mean +/- SEM, 0.61 +/- 0.05 arbitrary compliance units (ACU) in women compared with 0.67 +/- 0.04 ACU in men), but in the older population women had lower SAC than men (0.27 +/- 0.03 ACU compared with 0.57 +/- 0.04 ACU respectively; P < 0.001). Measures independent of aortic geometry (distensibility index and aortic impedance) indicated that stiffness was lower in young women than in men (P < 0.05), but the reverse was true in the older population (P < 0.01). This paralleled the brachial and carotid pulse pressures, which were lower in young (P < 0.01) and higher in older women compared with those in men (P < 0.05). Follicle stimulating hormone concentrations correlated strongly (r values 0.39-0.65) with all indices of central, but not peripheral, arterial function, whereas concentrations of luteinizing hormone, progesterone and oestradiol correlated less strongly. CONCLUSIONS: In men and women matched for mean pressures, the age-related stiffening of large arteries is more pronounced in women, which is consistent with changes in female hormonal status.

Carotid pressure is a better predictor of coronary artery disease severity than brachial pressure.

The mechanisms relating pulse pressure to cardiovascular outcome may include surrogacy for coronary disease severity. Although pulse pressure is typically measured at the brachial artery, central pulse pressure and its principal determinant, large-artery stiffness, may relate more closely to disease severity. This study aimed to determine the relationships between large-artery stiffness and carotid and brachial blood pressures and coronary artery disease severity. One hundred fourteen male patients with coronary artery disease (age 60+/-8 years, mean+/-SD) and 57 age-matched healthy male controls (age 59+/-9 years) were recruited. Patients were classified into 2 groups based on the magnitude of their maximum coronary stenosis: moderate (50% to 89%) and severe (>/=90%). Large-artery stiffness was assessed as systemic arterial compliance and carotid-femoral pulse wave velocity. Mean pressure was not different between the 3 groups. Systemic compliance and carotid pulse pressure were significantly different between all 3 groups, with compliance lowest and pressure highest in the severe group (P<0.05). Pulse wave velocity was higher in patients with severe stenosis than in those with moderate stenosis (P<0.01) and those in the control group (P<0.001). Brachial pulse pressure was higher in patients than in controls (P<0.05), but there was no difference between the 2 disease groups. In separate multivariate analyses, carotid pressures and systemic arterial compliance were determinants of coronary artery disease severity, independent of age, smoking status, body mass index, mean arterial pressure, heart rate, cholesterol levels (total, LDL, and HDL), triglycerides, and beta-antagonist and lipid-lowering therapy (P<0.001), whereas brachial pressures and pulse wave velocity were not. In conclusion, central blood pressures and systemic arterial compliance are more sensitive markers of coronary artery disease severity than brachial pressures.

Effects of ACE inhibitor therapy on derived central arterial waveforms in hypertension.

Large artery properties constitute an important component of left ventricular afterload in hypertension. The present study examined whether such properties were particularly responsive to angiotensin converting enzyme inhibitor therapy. A prospective, randomized, 12-week study in 138 previously treated hypertensive subjects, in 67 of whom usual treatment (UC) was replaced with perindopril (P) therapy. Large artery properties were assessed as central arterial pressure augmentation determined by applanation tonometry of the radial artery and a transfer function. At baseline both augmentation index (AI, %) and pressure (AP, mm Hg) were related to body size, heart rate, and gender. In addition AP was related to age and systolic blood pressure (BP). After 12 weeks of treatment AP decreased significantly in both perindopril and UC groups, whereas AI only decreased significantly (151.7%+/-2.3% to 144.9%+/-2.6%) in those treated with perindopril. Decreases in AP (-4.2+/-0.9 mm Hg v -1.9+/-0.7 mm Hg) and AI (-6.8%+/-2.2% v -2.2%+/-2.5%) from week 0 to week 12 were greater in the perindopril-treated group, but differences between groups failed to reach statistical significance (P = .05 and .09, respectively). The change in AI during the 12-week treatment period was dependent on the initial heart rate (P < .001), systolic BP (P < .05), weight (P < .001), and sex (P < .001), but not on treatment group (P > .5). Al at 12 weeks was negatively correlated with heart rate but regression slopes for the association were virtually identical for perindopril and UC groups. Perindopril treatment produces a greater decrease in AI than continuation with previous therapy, but this can be largely explained by hemodynamic changes rather than direct arterial effects.

Aerobic exercise training does not modify large-artery compliance in isolated systolic hypertension.

The present study characterized large-artery properties in patients with isolated systolic hypertension (ISH) and determined the efficacy of exercise training in modifying these properties. Twenty patients (10 male and 10 female) with stage I ISH and 20 age- and gender-matched control subjects were recruited, and large-artery properties were assessed noninvasively. Ten ISH patients (5 male and 5 female) were enrolled in a randomized crossover study comparing 8 weeks of moderate intensity cycling with 8 weeks of sedentary activity. Brachial and carotid systolic, diastolic, mean, and pulse pressures were higher in the ISH group than in the control group. Systemic arterial compliance (0.43+/-0.04 versus 0.29+/-0.02 arbitrary compliance units for the control versus ISH groups, respectively; P=0.01) was lower, and carotid-to-femoral pulse-wave velocity (9.67+/-0.36 versus 11.43+/-0.51 m. s(-1) for the control versus ISH groups, respectively; P=0.007), input impedance (2.39+/-0.19 versus 3.27+/-0.34 mm Hg. s. cm(-1) for the control versus ISH groups, respectively; P=0.04), and characteristic impedance (1.67+/-0.17 versus 2.34+/-0.27 mm Hg. s. cm(-1) for the control versus ISH groups, respectively; P=0.05) were higher in the ISH group than in the control group. Training increased maximal oxygen consumption by 13+/-5% (P=0.04) and maximum workload by 8+/-4% (P=0.05); however, there was no effect on arterial mechanical properties, blood lipids, or left ventricular mass or function. These results suggest that the large-artery stiffening associated with ISH is resistant to modification through short-term aerobic training.

Correction of carotid augmentation index for heart rate in elderly essential hypertensives. ANBP2 Investigators. Australian Comparative Outcome Trial of Angiotensin-Converting Enzyme Inhibitor- and Diuretic-Based Treatment of Hypertension in the Elderly.

Carotid augmentation index (AI) is used as a surrogate measure of arterial stiffness. Although arterial stiffness has been shown to either remain unchanged or increase with an increase in heart rate, AI decreases as heart rate increases. This study aimed to quantify this confounding effect of heart rate on AI. We investigated 873 hypertensives, mean age 72 +/- 5 years, 44% men, mean brachial blood pressure 161 +/- 21/82 +/- 11 mm Hg. Carotid artery tonometry with simultaneous continuous wave Doppler measurement of ascending aortic blood flow was performed. AI was calculated from the carotid pressure waveform. Waveforms were decomposed into their forward and backward components and the time to reflection between the maxima of the forward and backward pressure waves was measured. AI showed a stronger (P < .001) association with ejection time (r = 0.48, P < .001) than with heart rate (r = -0.28, P < .001). Although AI is strongly related to the time to reflection (r = -0.51, P < .001), only a weak association was seen between time to reflection and heart rate (r = 0.16, P < .001) or ejection time (r = -0.12, P < .001). Our analysis in an elderly cohort of patients with essential hypertension demonstrates that AI is related to the time to reflection. It also reiterates that AI is confounded by heart rate without any underlying heart rate-dependent change in wave reflection. In population-based studies the confounding effect of heart rate can potentially be corrected. AI remains strongly (r = -0.52) related to time to reflection after correction for the effects of ejection time on AI.

Cardiac output in mice overexpressing beta2-adrenoceptors or with myocardial infarct.

1. The aims of the present study were to characterize cardiac output (CO) in transgenic mice that overexpress the beta2-adrenoceptor and to evaluate ultrasonic flowmetery for continuous CO measurement in the mouse in vivo. 2. Under conditions of anaesthesia, open chest and positive ventilation, CO was determined with a transonic flowmeter at baseline and during dobutamine administration and intravenous volume loading in wild-type mice (n = 17) and beta2-adrenoceptor transgenic (n = 9) and wild-type mice with chronic myocardial infarct (n = 16). 3. Compared with wild-type mice, beta2-adrenoceptor transgenic mice with markedly enhanced ventricular contractility had a significantly higher CO, heart rate (HR) and maximal acceleration of aortic flow. Both dobutamine and volume loading increased CO in the two groups and higher levels of CO were measured in transgenic mice during the interventions. At baseline or during interventions, stroke volume was similar between beta2-adrenoceptor transgenic and wild-type mice. Infarcted mice with impaired cardiac function had a significantly lower CO under basal and stress conditions. 4. Thus, beta2-adrenoceptor transgenic mice revealed higher CO that was largely attributable to a significantly higher HR but not to an increase in stroke volume. Transonic flowmetery can detect differences in CO among mice in various functional states and is suitable for evaluation of cardiac functional reserve in mice in vivo by continuous monitoring of CO responses to different interventions.

Pulse pressure--a review of mechanisms and clinical relevance.

The goal of this study was to review the origin, clinical relevance and treatment of pulse pressure (PP). Elevated PP is increasingly being recognized as a risk factor for cardiovascular, particularly coronary, disease. Pulse pressure is discussed in terms of both Windkessel and distributive models of the arterial circulation. Pulse pressure arises from the interaction of cardiac ejection (stroke volume) and the properties of the arterial circulation. An increased stiffness of the aorta and large arteries leads to an increase in PP through a reduction in arterial compliance and effects on wave reflection. A number of factors are known to influence arterial wall behavior and, therefore, PP. In addition to the effects of aging and blood pressure on arterial wall elasticity, there is some evidence that atherosclerosis, per se, amplifies these effects. Thus, the relationship between PP and coronary disease may be bidirectional. A number of dietary and lifestyle interventions have been shown to modify large artery behavior. These include aerobic exercise training and consumption of n-3 fatty acids. Conversely, strength training is associated with an increase in arterial stiffness and a higher PP. The effects of antihypertensive medication have been extensively studied, but many studies are difficult to interpret because of concomitant change in blood pressure, and to a lesser degree, heart rate. However a number of studies do suggest direct arterial wall effects, particularly for angiotensin-converting enzyme inhibitors. A distributed compliance model of the arterial circulation provides a framework for understanding the causes, effects and potential treatment of elevations in PP.

Diurnal variation in endothelium-dependent vasodilatation is not apparent in coronary artery disease.

BACKGROUND: Acute coronary syndromes present with an increased incidence from 6:00 AM to 12:00 noon. Whether endothelial function follows a diurnal rhythm and whether this rhythm is impaired in coronary artery disease (CAD) has not previously been studied. METHODS AND RESULTS: Diurnal variation in endothelium-dependent vasodilatation was examined in 10 CAD patients and 10 control subjects. Forearm blood flow responses to acetylcholine, sodium nitroprusside, and N(G)-monomethyl-L-arginine were determined by plethysmography at 8:00 AM, 2:00 PM, and 8:00 PM. Heart rate, blood pressure, plasma cortisol, and inflammatory markers were also determined. Heart rate and the low-frequency component of heart rate variability were greatest in the morning in control subjects, suggesting a diurnal variation in sympathetic activity. Basal forearm blood flows were significantly reduced in control subjects at 8:00 PM compared with 8:00 AM and 2:00 PM (1.2+/-0.2 versus 2.1+/-0.2 [8:00 AM] and 2.1+/-0.3 [2:00 PM] mL. 100 mL(-1). min(-1); P<0.05) but unchanged in the CAD group. Acetylcholine (37 microgram/min) responses were greater at 8:00 AM than at 8:00 PM in control subjects (12.5+/-3.7 versus 19.6+/-2.9 mL. 100 mL(-1). min(-1), respectively; P<0.05), but these responses were not time dependent in the CAD group. Responses to sodium nitroprusside were similar at all time points and between those with and without CAD. CONCLUSIONS: Thus, normal volunteers have a diurnal variation in their endothelium-dependent vasodilatation that may counteract other, potentially adverse, diurnal variations in hemodynamic and other parameters. In contrast, CAD patients who had presented with acute coronary syndromes showed a loss of this protective mechanism.

Large artery stiffness: structural and genetic aspects.

1. Large artery stiffness is a principal determinant of pulse pressure and both are related to cardiovascular mortality independently of other major risk factors. A clearer understanding of the structural and genetic processes that contribute to large artery properties may provide novel approaches to therapy. 2. Age, atherosclerosis and gender are three important factors that contribute to large artery stiffening. Each influences the artery elastic matrix and its relationship to medial smooth muscle cells. Genetic and hormonal modulation of the extracellular matrix proteins and their regulators, including matrix metalloproteinases (MMPs), may account for some interindividual differences. 3. In a study of 213 healthy individuals and 105 patients with coronary artery disease (CAD), we examined whether stromelysin-1 (MMP-3) genotype, determined by the 5A/6A promoter polymorphism, influences large artery stiffening. In healthy individuals, the 5A/5A genotype was linked with stiffer large arteries and higher systolic blood pressure compared with other genotypes. 4. Genetic variation in the extracellular matrix protein fibrillin-1, using a pentanucleotide repeat polymorphism, was assessed as a potential determinant of large artery stiffness in patients with CAD. The 2-3 genotype was associated with stiffer large arteries, higher pulse pressure and more severe CAD than other genotypes. 5. Females experience a greater increase in large artery stiffness with age than males, with a time-course suggestive of sex steroid modulation. The mechanisms mediating such gender differences have not been established, but the known regulatory role of sex steroids with respect to MMPs likely contributes. 6. The demonstration that genetic and hormonal modulation of extracellular matrix components and MMPs contributes to age, atherosclerotic and gender-related differences in large artery mechanical properties suggests these proteins may be important targets for therapy.