Biomedical subjects
Publications and source records attributed to Anthony M Dart.
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OBJECTIVE: Myocardial contractility is enhanced in transgenic (TG) mice with cardiac-restricted overexpression of the alpha1A-adrenergic receptors (alpha1A-AR). We tested the hypothesis that this enhanced inotropy protects against dysfunction and remodeling after myocardial infarction (MI). METHODS: We subjected alpha1A-TG and non-TG mice (NTG) to MI and determined changes in left ventricular (LV) function and diastolic dimension (LVDd) by echocardiography prior to and at 1, 3, 7, 12 and 15 weeks thereafter. RESULTS: Although infarct size was similar in the NTG and alpha1A-TG groups (32+/-2 vs. 29+/-2% of LV, P=NS), mortality due to heart failure was lower after MI in the alpha1A-TG (37%, n=39) than that in the NTG animals (63%, n=56, P=0.026). NTG and alpha1A-TG mice showed similar reductions in LV fractional shortening (FS) and increases in LVDd at week-1 after MI. However, whereas NTG mice showed continuous deterioration over a 15-week period after MI in FS (fell by 40%, from 30+/-2 to 18+/-1%, P<0.01) and LVDd (increased by 24%, from 4.2+/-0.1 to 5.2+/-0.1 mm, P<0.01), the changes in both FS (fell by 14%, from 42+/-2 to 36+/-2%) and LVDd (increased by 8%, from 3.8+/-0.1 to 4.1+/-0.1 mm, both changes P<0.01 vs. NTG) were significantly less severe in the alpha1A-TG mice and did not progress after 3 weeks. At 15 weeks after MI, LV catheterization revealed better preservation of dP/dtmax in the alpha1A-TG vs. NTG mice (7270+/-324, vs. 5938+/-372 mmHg/s, P<0.05). CONCLUSION: Enhanced inotropy resulting from transgenic overexpression of alpha1A-AR is well maintained chronically after MI and limits echocardiography-determined LV remodeling, preserves function, and reduces acute heart failure death.
Central arterial waveforms and related indices of large artery properties can be determined with relative ease. This would make them an attractive adjunct in the risk stratification for cardiovascular disease. Although they have been associated with some classical risk factors and the presence of coronary disease, their prospective value in predicting cardiovascular outcomes is unknown. The present study determined the relative predictive value for cardiovascular disease-free survival of large artery properties as compared with noninvasive brachial blood pressure alone in a population of elderly female hypertensive subjects. We measured systemic arterial compliance, central systolic pressure, and carotid augmentation index in a subset of female participants in the Second Australian National Blood Pressure Study (untreated blood pressure 169/88+/-12/8 mm Hg). There were a total of 53 defined events during a median of 4.1 years of follow-up in 484 women with complete measurements. Although baseline blood pressures at the brachial artery predicted cardiovascular disease-free survival (hazard ratio [HR], 2.3; 95% CI, 1.3 to 4.1 for pulse pressure > or =81 versus <81 mm Hg; P=0.01), no such relation was found for carotid augmentation index (HR, 0.80; 95% CI, 0.44 to 1.44; P value not significant) or systemic arterial compliance (HR, 1.25; 95% CI, 0.72 to 2.16; P value not significant). Blood pressure, but not noninvasively measured central arterial waveforms, predict outcome in the older female hypertensive patient. Thus, blood pressure measurement alone is superior to measurement of arterial waveforms in predicting outcome in this group.
The epidemic of obesity in the developed world over the last two decades is driving a large increase in type 2 diabetes and consequentially setting the scene for an impending wave of cardiovascular morbidity and mortality. It is only now being recognized that the major antecedent of type 2 diabetes, insulin resistance with its attendant syndrome, is the major underlying cause of the susceptibility to type 2 diabetes and cardiovascular disease. In metabolic tissues, insulin signaling via the phosphatidylinositol-3-kinase pathway leads to glucose uptake so that in insulin resistance a state of hyperglycemia occurs; other factors such as dyslipidemia and hypertension also arise. In cardiovascular tissues there are two pathways of insulin receptor signaling, one that is predominant in metabolic tissues (mediated by phosphatidylinositol-3-kinase) and another being a growth factor-like pathway (mediated by MAPK); the down-regulation of the former and continued activity of the latter pathway leads to atherosclerosis. This review addresses the metabolic consequences of the insulin resistance syndrome, its relationship with atherosclerosis, and the impact of insulin resistance on processes of atherosclerosis including insulin signaling in cells of the vasculature.
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There is some controversy regarding whether vascular responses to endothelin are altered in hypercholesterolemia. Studies performed to date have been compromised by the use of endothelin antagonists at inappropriate concentrations. In the current study, we examine the role of endothelin-1 in hypercholesterolemic patients using lower, more selective doses of specific endothelin antagonists. Twenty-two patients with hypercholesterolemia (total plasma cholesterol > 6.0 mmol/l) and 17 healthy controls were recruited. Forearm vascular responses to endothelin-1 (5 pmol/min), the endothelin A antagonist BQ-123 (10 nmol/min), and the endothelin B antagonist BQ-788 (1 nmol/min) were obtained. Endothelin-1 caused a significant vasoconstriction in both hypercholesterolemic and control subjects, an effect that was not significantly different between the two groups (P = 0.784). BQ-123 caused a significant vasodilatation that was not significantly different between the two groups (P = 0.899). Similarly, responses to BQ-788 (P = 0.774) and mean plasma endothelin-1 levels were not different (control vs. hypercholesterolemia, 1.16 +/- 0.18 vs. 1.06 +/- 0.15 fmol/ml; P = 0.64). Responses to neither exogenous nor endogenous endothelin are influenced by plasma cholesterol levels in humans. It is thus unlikely that the endothelin system contributes to early vascular disease pathology in patients with hypercholesterolemia.
OBJECTIVE: Recent studies on mice with surgically induced acute myocardial infarction (AMI) have documented the frequent occurrence of ventricular rupture, an event not previously reported in other laboratory species. We have examined the natural history, histopathology and myocardial mechanical strength in mice with AMI. METHODS: AMI was induced by coronary artery occlusion and animals were monitored for fatal events. Gross and histological examinations were undertaken. RESULTS: Rupture occurred in the left ventricular free wall at 2-6 days after AMI. Incidence of rupture in male mice varied among three strains studied (3% for FVB/N, 27% for C57B/6J, and 59% for 129sv, P<0.05) and was lower in female than male mice (23% vs. 59%, P<0.05). Histologically, ruptured hearts had rapid-occurring and severe infarct expansion, multifocal intramural hemorrhage and leucoyte infiltration at the border zone and infarcted zone. In vitro, infarcted left ventricles demonstrated a 50-60% reduction in muscle tensile strength. This reduction preceded the onset of rupture and was related to the time-window of rupture and to infarct size. CONCLUSION: LV wall rupture in the mouse occurs within a narrow time-window after AMI and is strain- and gender-dependent. Infarct expansion, regional hemorrhage with formation of hematoma and leuocyte accumulation are important pathological changes leading to reduced myocardial tensile strength.
BACKGROUND: Several new techniques exist for measuring arterial stiffness, but their association with central pulse wave velocity (PWV), an established measure of central arterial stiffness, has not been compared in the same study. The aim of this study was to compare the agreement of the new techniques with central PWV. METHODS: Fifteen men with coronary artery disease (59 +/- 2 years of age) and 15 healthy men (28 +/- 1 years of age) were recruited. The following measures were performed in a random sequence and repeated after 1 week: central and distal pulse wave velocity (PWV), large and small artery compliance (C1 and C2, respectively), and stroke volume/pulse pressure (SV/PP) (measured by HDI/PulseWave CR-2000), augmentation index (AIx) and central pulse pressure (CPR) (Sphygmocor), stiffness index (SI) (Micro Medical Pulse Trace), systemic arterial compliance (SAC) (area method), and brachial PP (Dinamap). Methods were compared using correlation coefficients and Bland-Altman analysis. RESULTS: Although all measures of arterial stiffness except PWV correlated significantly with central PWV (P < .01 for each), Bland-Altman analysis showed poor agreement (confidence interval [CI] >3 Z-scores) between central PWV and C1, C2, SV/PP, and SAC). There was good agreement (CI > 2 Z-scores) between central PWV and SI, AIx, CPP, and brachial PP. The coefficient of variation was lowest with central PWV (7.6%), brachial PP (8.0%), and SV/PP (8.6%) and was significantly higher (P < .05) in increasing order with C1 (11.3%), C2 (15.6%), SI (17.8%), SAC (19.3%), AIx (22.4%), and CPP (25.3%). CONCLUSIONS: Based on our study findings, C1, C2, SV/PP, and SAC show poor agreement with central PWV, an established measure of central arterial stiffness. Indices of this type should therefore be useful in providing a more complete understanding of arterial stiffness. In comparison, SI, AIx, and CPP are more closely related to central arterial stiffness.
BACKGROUND: Folic acid reduces plasma homocysteine and may be an important therapy for preventing cardiovascular disease. A key mechanism may be the reduction of arterial stiffness. OBJECTIVE: The effect of folic acid supplementation on blood pressure and large artery stiffness was examined in relation to methylenetetrahydrofolate reductase (MTHFR) genotype. DESIGN: Forty-one asymptomatic men with normal or high-normal ambulatory blood pressure (systolic: >130 to <145 mm Hg; diastolic: >80 to <90 mm Hg) participated. The study had a randomized, placebo-controlled, double-blind, crossover design that incorporated 3-wk treatments with 5 mg folic acid/d or matching placebo; each treatment was separated by a 4-wk washout phase. RESULTS: Folic acid reduced brachial pulse pressure by 4.7 +/- 1.6 mm Hg (P < 0.05) without changing mean arterial pressure. Systemic arterial compliance increased by 0.15 +/- 0.03 mL/mm Hg (P < 0.05) after folic acid treatment but did not change after placebo treatment. These responses did not significantly correlate with either homocysteine or folate plasma concentrations. MTHFR genotype CC homozygotes (without the 677C-->T polymorphism) with normal blood pressure had a larger reduction in homocysteine concentrations in response to folic acid than did T allele carriers. Blood pressure and arterial stiffness responses were independent of MTHFR genotype. CONCLUSION: Folic acid is a safe and effective supplement that targets large artery stiffness and may prevent isolated systolic hypertension.
OBJECTIVE: Because large artery stiffening contributes to myocardial ischemia, its determinants are of relevance as potential risk markers. This study examined whether matrix metalloproteinase (MMP)-9 (gelatinase B) genotype is associated with large artery stiffening and aortic MMP-9 gene and protein expression. METHODS AND RESULTS: MMP-9 genotype (C-1562T promoter polymorphism) was determined in 84 patients (73 male) with angiographically defined coronary artery disease (CAD). Carotid applanation tonometry was used to assess central blood pressures and, with Doppler velocimetry, to assess aortic stiffness (input and characteristic impedance). Gene expression real-time polymerase chain reaction (RT-PCR) and protein levels (Western blotting) were assessed in relation to genotype in aortic samples from a separate population. T-allele carriers (C/T and T/T) had stiffer large arteries (higher input and characteristic impedance) and higher carotid pulse and systolic blood pressure (all P<0.05) than C/C homozygotes. In aortic samples, gene expression was 5-fold higher and active protein levels were >2-fold higher in T-allele carriers. CONCLUSIONS: Because the T allele was associated with greater MMP-9 mRNA and protein levels, the greater large artery stiffness in T-allele carriers may be secondary to excessive degradation of the arterial elastic matrix. The consequent higher pulse pressure may increase susceptibility to myocardial ischemia.
1. Ivabradine selectively reduces heart rate (HR) by inhibiting the cardiac pacemaker I(f) current, thus prolonging the duration of spontaneous depolarization in the sinus node. The activity of ivabradine under conditions of enhanced sympathoadrenergic activity has been addressed by investigating the effects of repeated oral administration in mice with sympathoadrenergic activation due to either stress, cardiac-restricted overexpression of beta(2)-adrenergic receptors (beta(2)AR), or beta-agonist administration. HR and left ventricular fractional shortening (FS) were determined by echocardiography. 2. Initial experiments showed that the conscious restrained state was associated with stress-mediated sympathetic activation, while sympathetic withdrawal occurred under anaesthetized conditions. In wild-type mice, ivabradine reduced HR under both conscious and anaesthetized states, with a similar degree in absolute reduction under both states. FS was unchanged by the treatment. 3. Ivabradine was similarly effective in reducing HR in the beta(2)AR transgenic mice. Further, ivabradine at 10 mg kg(-1) day(-1) reduced the maximal HR increase in response to the beta-agonist isoproterenol, without modifying the response of contractile parameters. 4. These data indicate that oral administration of ivabradine in mice reduces HR while ventricular performance is maintained. This specific HR-reducing action of ivabradine is well preserved under conditions that are associated with significant activation of the sympathoadrenergic system.
OBJECTIVE: Previous studies have demonstrated a prognostic role of large artery stiffness in hypertensive subjects and increased stiffness in subjects with coronary artery disease. Although plasma cholesterol is an established risk factor for cardiovascular disease, its relationship with large artery properties in a hypertensive population is unclear. METHODS AND RESULTS: Plasma cholesterol and large artery properties were measured at baseline in a subset of participants of a randomized controlled trial (ANBP2) evaluating hypertension treatment in older (65 to 84 years) subjects. Noninvasive measures of large artery behavior were central augmentation index (AI), systemic arterial compliance (SAC), and transverse expansion of the aortic arch (aortic distensibility). Arterial waveforms acceptable for analysis were obtained in approximately 80% of cases yielding valid measurements of AI in 868, SAC in 846, and aortic distensibility in 680 subjects. Mean total and high-density lipoprotein (HDL) concentrations were 5.5+/-1.0 and 1.4+/-0.5 mmol L(-1). Total and HDL cholesterol and AI were greater in females than males, whereas SAC and aortic distensibility were greater in males. In multiple regression analyses there were no significant associations between stiffness parameters and total or HDL cholesterol. Significant independent associations in such analyses were found for mean arterial blood pressure, gender, age, height, and heart rate, in keeping with previous findings. CONCLUSIONS: In the largest cohort of elderly hypertensive subjects studied to date, plasma cholesterol per se was not associated with large artery stiffness. Such independence from cholesterol increases the potential for artery stiffness measurements to additionally contribute to cardiovascular risk assessment in this population.
Abnormal endothelium-dependent vasodilatation is well documented in coronary artery disease (CAD), as are significant increases of acute phase inflammatory proteins and other soluble hepatic and endothelium derived proteins. In the current study we investigated whether there is a relationship between endothelium-dependent vasodilatation and the plasma levels of such proteins. Further we examined the association between these proteins, together with age, cholesterol and endothelium function, and participant status (i.e. healthy, smoker, coronary artery disease). Three groups of participants were recruited: healthy controls (n = 20), cigarette smokers (n = 20) and patients with coronary artery disease (n = 20). Forearm vascular dilatation responses to the endothelium-dependent agonist acetylcholine were obtained using venous occlusion plethysmography. Blood was sampled at the time of study for the measurement of the serological proteins described above. Responses to acetylcholine were significantly dampened in patients with CAD when compared with control and smoker groups (forearm blood flow at acetylcholine 37 microg/min): control, smokers, CAD, 12.14 +/- 2.14, 12.35 +/- 09.4, 5.12 +/- 0.81, ANOVA, P < 0.05). Responses to acetylcholine were not different between controls and smokers. C-reactive protein (C-RP) levels (controls, smokers, CAD, 1.40 +/- 0.19, 2.27 +/- 0.71, 4.73 +/- 1.09, P < 0.05) and protein S levels were significantly higher in the CAD group compared with the other two groups. There was a significant inverse correlation between forearm blood flow responses to acetylcholine and C-reactive proteins. Both responses to acetylcholine and C-RP levels demonstrated a significant association with participant status with the r value increasing from 0.405 for responses to acetylcholine to 0.491 for the combination of responses to acetylcholine and C-RP. We conclude that there is an inverse correlation between C-reactive protein, but not protein S, VCAM-1, P-selectin nor von Willebrand factor, levels and abnormal endothelium-dependent vasodilation and further that responses to acetylcholine together with C-RP protein have a strong association with cardiovascular risk and disease.
OBJECTIVES: Monitoring of brachial blood pressure during exercise-electrocardiogram (ECG) testing is mandatory and changes in blood pressure (BP) can provide critical management evidence. Patient movement, mechanical vibration, artifactual sounds and observer variability make standard manual techniques problematic. This was an investigator-initiated study to assess an automated auscultatory technique of BP assessment [Tango exercise blood pressure monitor (SunTech Medical Instruments, NC, USA)] to adequately measure BP during stress-ECG testing. METHODS: Initially five fit young male volunteers underwent invasive right brachial artery BP recording using a low-compliance fluid-filled catheter with simultaneous manual and automated assessment. Secondarily, during exercise-ECG testing, the system was assessed against beat-to-beat brachial blood pressures obtained from a catheter-tip solid-state pressure manometer positioned in the ipsilateral brachial artery. RESULTS: In the supine study overall mean difference (+/-SEM) between invasive and manual blood pressures was 3.26 (1.53) and 3.89 (1.90) mmHg for diastolic BP (DBP) and systolic BP (SBP) respectively. Corresponding differences between invasive and automated results, and manual and automated were 3.68 (0.84) and -7.31 (1.83) mmHg, and -0.64 (+/-1.43) and -11.42 (+/-1.59) mmHg. During treadmill exercise-ECG testing the combined mean difference (+/-SEM) between invasive and automated SBP and DBP was 4.79 (+/-0.14) and 6.33 (+/-0.10) mmHg, respectively. CONCLUSION: Automated BP assessment during exercise-ECG testing is feasible with the use of appropriate automatic devices likely to be at least as accurate as manual BP registration. The Tango device is tolerant to exercise and provides reliable automatic BP assessment with absolute differences within an acceptable clinical range.
OBJECTIVES: To determine whether sex differences in large-artery stiffness contribute to the greater prevalence of systolic hypertension in elderly women than in elderly men. DESIGN: During a single visit arterial stiffness was assessed in the unmedicated state using four parameters. PARTICIPANTS: Three hundred seventy-four women with a mean age+/-standard deviation of 72+/-5 and 296 men aged 71+/-5 participated. SETTING: Hypertensive patients were recruited from general practice as part of the second Australian National Blood Pressure Study in Melbourne, Australia. MEASUREMENTS: Large-artery stiffness was assessed using multiple methodologies, including aortic arch stiffness (beta-index) using M-mode ultrasound and arterial compliance and augmentation index using noninvasive carotid pressure and aortic flow measurements. RESULTS: Women had greater carotid and brachial pulse pressure (PP) than men (P<.001), despite higher mean arterial pressure in men. Mean arterial compliance was lower in women (0.20+/-0.12 vs 0.28+/-0.16 mL/mmHg, P<.001) even after correction for aortic area, and aortic arch stiffness was higher (30+/-36 vs 23+/-22; P<.01). Consistent with both a stiffer proximal circulation and a shorter distance to reflection sites, women had higher augmentation index (38+/-11% vs 29+/-12%, P<.001). In multivariate analysis, sex was an independent determinant of all arterial stiffness indices. CONCLUSION: Independently of known confounders, elderly hypertensive women have stiffer large arteries, greater central wave reflection, and higher PP than elderly men. Stiffer large arteries likely contribute to the greater prevalence of systolic hypertension in elderly women and may partly explain the acceleration in postmenopausal cerebrovascular and cardiac complications.
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Transgenic (TG) mice with cardiac specific 200-fold overexpression of beta(2)-adrenoceptors (beta(2)-AR) have a facilitated development of heart failure following thoracic aortic constriction (TAC). We have studied the alterations of intracellular Ca(2+) transients and myocyte size in wild-type (WT) and TG mice after TAC. Cardiomyocytes were isolated from mice 9 weeks after TAC or sham operation, and incubated with Fura 2/AM. The Ca(2+) transients were determined by Spex dual wavelength Spectrometer during electrical stimulation. The cell size was also determined planimetrically. Cells of sham operated TG mice displayed higher systolic Ca(2+) amplitude than respective WT group (DeltaF(340)/F(380) ratio: 1.05+/-0.08 vs. 0.63+/-0.05; P<0.01), a finding in keeping with enhanced ventricular contractility in the TG mice. However, hypertrophied and failing myocytes of TG animals showed a fall in Ca(2+) transients from sham-operated control levels and there was no difference between TG and WT groups following TAC. In sham-operated groups, the cell size of TG mice was significantly bigger than in WT animals (3212+/-139 vs. 2605+/-162 microm(2); P<0.05). The cell size increased to a similar extent in both groups after TAC (4715+/-216 vs. 5027+/-365 microm(2), P=n.s.). In summary, hypertrophy of cardiomyocytes was present in beta(2)-AR TG mice under baseline conditions. A further hypertrophy occurred during pressure overload to an extent similar to that in WT animals. However, the increased intracellular Ca(2+) transient, seen in sham-operated TG mice, was no longer detectable following development of severe hypertrophy and heart failure. These findings provide explanation on the lack of hemodynamic benefit in beta(2)-AR TG mice subjected to pressure overload.
Previous experiments in animals demonstrated a novel sympatholytic action of acute intravascular amiodarone (AM). It is not known if this action also occurs in humans. Twelve male volunteers performed handgrip for 10 min before and after 300 mg intravenous (IV) AM over 60 min. The effect of handgrip was determined from changes in blood pressure (BP), heart rate (HR), and cardiac noradrenaline (NA) spillover. Changes in cardiac spillover of dihydroxyphenylglycol (DHPG), the metabolite of NA, were measured during AM infusion. The electrophysiological effects of AM were determined from changes to the A-H intervals during right atrial stimulation (100 beats/min). Handgrip increased HR (63 +/- 2 to 84 +/- 5 beats/min and 65 +/- 3 to 84 +/- 4 beats/min), systolic BP (141 +/- 4 to 179 +/- 6 mm Hg and 140 +/- 4 to 179 +/- 7 mm Hg), and cardiac NA spillover (11.9 +/- 4 to 44.3 +/- 13 ng/min and 17.3 +/- 4 to 55.5 +/- 11 ng/min) before and after AM, respectively (P < 0.02 in all groups). There was good correlation between increases in cardiac NA spillover and HR (r2 = 0.86) and systolic BP (r2 = 0.87). AM increased the A-H interval (95.5 +/- 18 to 107.8 +/- 20 ms, P < 0.02). There was no difference in hemodynamic or NA response to handgrip before or after the AM infusion. There was also no change in DHPG cardiac spillover during AM infusion. Acute IV AM did not exert a sympatholytic action in humans, with no attenuation in hemodynamic or NA response to handgrip or increase in DHPG production, despite producing an electrophysiologic response.