[Show abstract][Hide abstract] ABSTRACT: 1. Diabetes is a significant risk factor for cardiovascular disease (CVD), but the presence of comorbidities, such as hypertension, markedly increases CVD risk. The aim of the present study was to determine the effectiveness of hypertension management in patients with diabetes. 2. The cvTRAC Study was a cross-sectional study of CVD risk factors in primary care practices across Australia. General medical practitioners enrolled patients they considered to be at increased risk of CVD and reported on cardiovascular disease history, CVD risk factor levels and current therapy. 3. In all, 9857 men and 8332 women with diabetes participated in the study, with > 85% having at least two CVD risk factors in addition to diabetes and 68% having a history of hypertension. Lost therapeutic benefit in diabetes patients with hypertension was seen in those who were failing to meet targets on antihypertensive drug therapy (therapeutic inertia: > 73% of the hypertensive cohort), with a smaller proportion accounted for by those who met prescribing guidelines but were not being treated pharmacologically (treatment gap: 5.4% of the hypertensive cohort). Lack of compliance with lifestyle guidelines was estimated to account for over 8% of those not meeting blood pressure targets. Age (odds ratio (OR) 0.983, 95% confidence interval (CI) 0.980-0.986; P < 0.001), compliance with physical activity guidelines (OR 1.219, 95% CI 1.088-1.366; P = 0.001) and compliance with dietary guidelines (OR 1.298, 95% CI 1.188-1.420; P < 0.001) were independent predictors of target blood pressure attainment in the diabetic population. 4. Deficiencies in pharmacological and lifestyle-related therapeutic strategies contribute to suboptimal hypertension management in diabetes. Therapeutic inertia is a greater contributor to lost therapeutic benefit than treatment gap in this population.
Clinical and Experimental Pharmacology and Physiology 11/2008; 36(7):643-7. · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Increased arterial stiffness is observed in a number of cases. The analysis of the regional functional arterial properties is of interest to determine the role of a given risk factor on the vascular wall and in some diseases such as atherosclerosis. We analysed the pulse wave velocity (PWV) measured by the Doppler method with 2D guidance and its reproducibility in different arterial segments in 15 men with coronary artery disease. Regional Doppler PWV was defined as the distance between the extremities of a given segment divided by the transit time calculated by Doppler. Intra- and interobserver reproducibilities of the Doppler measurements were studied in all of the subjects. The variation coefficients were low, maximum at the level of ascending aorta and minimal at the level of iliac segment. This good reproducibility was validated by the Bland-Altman method. Moreover, using this Doppler technique, we found a progressive increase in PWV from the ascending aorta to the iliac segment. These data demonstrate that noninvasive Doppler analysis is a feasible and reproducible method to determine regional PWV.
Journal of Human Hypertension 07/2003; 17(6):407-12. · 2.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alterations in monoaminergic neurotransmission in the brain are thought to underlie seasonal variations in mood, behaviour, and affective disorders. We took blood samples from internal jugular veins in 101 healthy men, to assess the relation between concentration of serotonin metabolite in these samples and weather conditions and season. We showed that turnover of serotonin by the brain was lowest in winter (p=0.013). Moreover, the rate of production of serotonin by the brain was directly related to the prevailing duration of bright sunlight (r=0.294, p=0.010), and rose rapidly with increased luminosity. Our findings are further evidence for the notion that changes in release of serotonin by the brain underlie mood seasonality and seasonal affective disorder.
The Lancet 01/2003; 360(9348):1840-2. · 39.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Clinical and Experimental Pharmacology and Physiology 01/2002; 28(12):1040-3. · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
Journal of Hypertension 01/2002; 19(12):2197-203. · 4.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mechanical strain has been shown to induce mitogenesis in a rat neonatal vascular smooth muscle (VSM) cell line in a response mediated predominantly by transcription, expression, and release of platelet-derived growth factor (PDGF). We examined the effect of cyclic mechanical strain and growth factor production on mitogenic response in ovine coronary artery smooth muscle cells. Vascular smooth muscle cells were cultured from explants of left anterior descending (LAD) coronary arteries from young sheep. Cells for experiments were grown on wells with silicone-elastomer bottoms, and subjected to strain (60 cycles/min) using a vacuum actuated strain device. Tritiated thymidine incorporation was used as a measure of DNA synthesis. Cell membrane damage was assessed with differentially permeable nuclear staining dyes. We observed an increase in tritiated thymidine incorporation in response to strain with a temporal response identical to that observed in response to exogenous growth factors (PDGF-BB and basic fibroblast growth factor [bFGF]). Supernatant medium obtained from stretched cells induced a twofold increase in DNA synthesis in unstretched cells. The mitogenic response was abolished by monoclonal antibodies to bFGF, but not by antibodies to PDGF-AB. Studies of fluorescent dye exclusion indicated the stretching protocol caused no cell membrane damage. Thus, mechanical strain is an important stimulus for growth factor release in coronary VSM cells. The mitogenic response is mediated by release of bFGF.
American Journal of Hypertension 12/2001; 14(11 Pt 1):1128-34. · 3.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate whether strong cardiac sympathetic activity contributes primarily to sudden death or to worsening heart failure, and to determine the relationship of the size of cardiac noradrenaline stores to the mode of death.
The study population comprised 116 patients with congestive heart failure (ejection fraction 19+/-7%) and a mean follow-up of 18+/-19 months. Cardiac sympathetic nervous function was measured using coronary sinus blood sampling and noradrenaline isotope dilution methodology. Cardiac sympathetic activity was estimated from cardiac noradrenaline spillover, and noradrenaline stores from the overflow of the tritiated noradrenaline metabolite [(3)H]dihydroxyphenylglycol, which is produced by monoamine oxidase inside nerve endings. Small cardiac noradrenaline stores (below median) predicted death from worsening heart failure (hazard ratio=4.18, P<0.05), particularly if cardiac noradrenaline spillover was elevated (hazard ratio=2.36 per tertile, P<0.01), indicating progression of disease associated with defective sympathetic innervation. In contrast, large stores (hazard ratio=2.81, P<0.05), especially if coupled with increased noradrenaline spillover (hazard ratio=1.64 per tertile, P<0.05), were related to sudden death.
High cardiac sympathetic activity is a risk factor for sudden death, particularly in the presence of intact cardiac sympathetic innervation. Conversely, progression of myocardial disease and heart failure is closely associated with depletion of sympathetic nerves in the heart, especially if rates of noradrenaline release paradoxically remain high.
European Heart Journal 07/2001; 22(13):1136-43. · 14.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The precise mechanism by which beta-adrenoceptor blockers exert their beneficial actions in patients with heart failure remains unclear. Several possibilities have been proposed, including heart rate reduction, beta2-adrenoceptor-mediated modulation of catecholamine release, antagonism of the receptor-mediated toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics. In the present study we evaluated the effect of 3 months of carvedilol therapy on hemodynamics, total systemic and cardiac norepinephrine spillover (isotope dilution method), and myocardial metabolism (myocardial oxygen consumption and carbon dioxide release) in 10 patients with severe congestive heart failure. Although carvedilol treatment was associated with a significant improvement in left ventricular ejection fraction (17+/-1% to 28+/-3%; P<0.01) and left ventricular stroke work (87+/-13 to 119+/-21 g. m per beat; P<0.05), this effect was unrelated to changes in total systemic or cardiac norepinephrine spillover. The rise in left ventricular stroke work was accompanied by a modest rise in myocardial oxygen consumption per beat (0.33+/-0.04 to 0.42+/-0.04; P=0.05), although contractile efficiency was unchanged. The favorable effects of carvedilol on ventricular function in the failing heart are not explained by alterations in norepinephrine release or by changes in myocardial contractile efficiency.
[Show abstract][Hide abstract] ABSTRACT: 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.
American Journal of Hypertension 06/2001; 14(6 Pt 1):573-7. · 3.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: -The predominant cause of restenosis after angioplasty is now thought to be inward remodeling, but the mechanisms responsible are unknown. Remodeling in normal vessels is regulated by the endothelium in response to altered shear stress. Although the endothelium is often damaged by angioplasty, restenosis rates after angioplasty have been correlated with impaired coronary flow. Thus, we examined how increases or decreases in blood flow through balloon catheter-injured rat carotid arteries affect vessel morphometry (4, 10, and 28 days), cell migration (4 days), and levels of promigratory mRNAs (2 and 10 days). After 28 days, the luminal area in vessels with low blood flow was significantly less than in those with normal and high blood flow (0.17+/-0.01 [low] versus 0.24+/-0.06 [normal] versus 0.30+/-0.02 [high] mm(2), P:<0.01), predominantly because of accentuated inward remodeling (or reduced area within the external elastic lamina; 0.42+/-0.02 [low] versus 0.54+/-0.07 [normal] versus 0.53+/-0.04 [high] mm(2), P:<0.05). Low flow also enhanced smooth muscle cell migration 4 days after injury by 90% above normal and high flows (P:<0.01). Two days after injury, low flow significantly increased levels of mRNAs encoding promigratory peptides (integrin alpha(v)ss(3), transforming growth factor-ss(1), CD44v6, MDC9, urokinase plasminogen activator receptor, and ss-inducible gene h3); these changes persisted 10 days after injury and were localized to the neointima. Low blood flow may promote restenosis after angioplasty because of its adverse effect on vessel remodeling, and it is associated with the augmented expression of multiple genes central to cell migration and restenosis.
[Show abstract][Hide abstract] ABSTRACT: Effects of cardiac specific overexpression of beta(2)-adrenergic receptors (beta(2)-AR) on the development of heart failure (HF) were studied in wild-type (WT) and transgenic (TG) mice following myocardial infarction (MI) by coronary artery occlusion. Animals were studied by echocardiography at weeks 7 to 8 and by catheterization at week 9 after surgery. Post-infarct mortality, due to HF or cardiac rupture, was not different among WT mice, and there was no difference in infarct size (IS). Compared with the sham-operated group (all P < 0.01), WT mice with moderate (<36%) and large (>36%) IS developed lung congestion, cardiac hypertrophy, left ventricular (LV) dilatation, elevated LV end-diastolic pressure (LVEDP), and suppressed maximal rate of increase of LV pressure (LV dP/dt(max)) and fractional shortening (FS). Whereas changes in organ weights and echo parameters were similar to those in infarcted WT groups, TG mice had significantly higher levels of LV contractility in both moderate (dP/dt(max) 4,862 +/- 133 vs. 3,694 +/- 191 mmHg/s) and large IS groups (dP/dt(max) 4,556 +/- 252 vs. 3,145 +/- 312 mmHg/s, both P < 0.01). Incidence of pleural effusion (36% vs. 85%, P < 0.05) and LVEDP levels (6 +/- 0.3 vs. 9 +/- 0.8 mmHg, P < 0.05) were also lower in TG than in WT mice with large IS. Thus beta(2)-AR overexpression preserved LV contractility following MI without adverse consequence.
[Show abstract][Hide abstract] ABSTRACT: Previous reports suggest that neuronal norepinephrine (NE) reuptake may be impaired in essential hypertension, perhaps because of dysfunction of the NE transporter, although the evidence is inconclusive. To further test this proposition, we applied phenotypically relevant radiotracer methodology, infusion of tritiated NE and quantification of NE metabolites, to 34 healthy lean subjects (body mass index <27.0 kg/m(2)), 19 overweight (body mass index >28.0 kg/m(2)) but otherwise healthy normotensive subjects, 13 untreated lean patients with essential hypertension, and 14 obesity-related hypertensives. Spillover of NE from the heart was increased in lean hypertensives only (mean+/-SD 33.4+/-20.6 versus 16.1+/-11.7 ng/min in lean normotensives, P<0.05), but this could have resulted from high cardiac sympathetic nerve firing rates, faulty NE reuptake, or both. The arterial plasma concentration of 3-methoxy-4-hydroxylphenylglycol, an extraneuronal metabolite of NE, was elevated in lean hypertensives only (3942+/-1068 versus 3055+/-888 pg/mL in healthy subjects, P:<0.05). The fractional extraction of plasma tritiated NE in passage through the heart, determined on the basis of neuronal NE uptake, was reduced in lean essential hypertensives (0.65+/-0.19 versus 0.81+/-0.11 in healthy subjects, P<0.05). Cardiac release of the tritiated NE metabolite [(3)H]dihydroxylphenylglycol, produced intraneuronally by monoamine oxidase after uptake of [(3)H]NE by the transporter, was reduced in lean hypertensives only (992+/-1435 versus 4588+/-3189 dpm/min in healthy subjects, P<0.01) These findings suggest that neuronal reuptake of NE is impaired in essential hypertension. Through amplification of the neural signal, such a defect could constitute a neurogenic variant of essential hypertension. In obesity-related hypertension, there was no phenotypic evidence of NE transporter dysfunction.
[Show abstract][Hide abstract] ABSTRACT: Despite providing symptomatic relief in patients with congestive heart failure (CHF), supplemental oxygen (O(2)) has been demonstrated to increase total peripheral resistance. The present study investigated the possibility that O(2) inhalation reduces nitric oxide (NO) bioavailability, using endothelium-dependent (acetylcholine) and -independent (phentolamine) vasodilators, and the antioxidant ascorbic acid. Ten patients (nine male and one female) with primary left ventricular failure participated in the study. Forearm venous occlusion plethysmography was used to study blood flow responses to acetylcholine and the alpha-adrenergic antagonist phentolamine during inhalation of either room air or 100% O(2), with and without the simultaneous infusion of ascorbic acid. Neither O(2) inhalation (3.9+/-0.4 compared with 3.8+/-0.3 ml.min(-1).100 ml(-1)) nor ascorbic acid infusion (5.2+/-0.4 compared with 5.5+/-0.4 ml.min(-1).100 ml(-1)) affected resting forearm blood flow. The percentage increase from basal blood flow after acetylcholine infusion was not altered by either O(2) inhalation or ascorbic acid infusion (room air, 140+/-55%; O(2), 118+/-46%; ascorbic acid, 147+/-39%; ascorbic acid+O(2), 109+/-31%). O(2) inhalation did, however, reduce the dilation induced by phentolamine (room air, 131+/-24%; O(2), 80+/-14%; P<0.05). These data indicate that oxygen inhalation does not increase forearm vascular resistance. Secondly, preservation of reactivity to acetylcholine during O(2) inhalation suggests that degradation of NO by O(2)-derived free radicals is not enhanced. Attenuation of phentolamine-induced vasodilation during O(2) inhalation, however, implies increased adrenergic activity, which may possibly exacerbate the detrimental effects of elevated sympathetic activity in CHF.
[Show abstract][Hide abstract] ABSTRACT: Relative contributions of remodelling and neointimal hyperplasia to restenosis after coronary angioplasty have been inferred from studies using iliofemoral arteries, despite differences in structure/function and smooth muscle cell lineage. We compared the response to balloon overstretch injury of coronary arteries (C, n = 16) and similar sized branches of the iliac arteries (I, n = 18) using preinjury vessel diameter (P). inflated balloon size in vivo (B) and the manufacturer predicted inflated size (M) to examine arterial compliance, as well as resulting injury and morphology in perfusion fixed vessels. Despite similar degrees of oversizing (M/P) in the coronary and iliac arteries (C, 1.44 +/- 0.04; I, 1.51 +/- 0.02), the compliance to overstretch (B-P/M-P) was significantly greater in the coronary than the iliac arteries (C, 0.71 +/- 0.05; I, 0.51 +/- 0.03) (P <0.05) and was associated with a higher injury score (C, 1.64 +/- 0.31; I, 0.39 +/- 0.18 P < 0.05)--only 5/18 iliac vessels had rupture of the IEL compared with 13/16 in the coronary bed. In a subgroup of animals whose vessels (C:n = 7; I:n = 8) were perfusion fixed 28 days after injury, coronary arteries had greater intimal area (C:1.03 +/- 0.42; I:0.10 +/- 0.03 mm2, P < 0.05) but larger luminal area (C:1.61 +/- 0.71; 1:0.76 +/- 0.51, P < 0.05) due to greater area within EEL (C:3.38 +/- 0.49;1:] .49 +/- 0.54, P < 0.05) or less inward remodelling. The injuries resulting from similar strategies of balloon overstretch in the coronary and the iliac arteries are different and affect healing responses--iliac arteries remodel more while coronary arteries develop more intimal hyperplasia. These results indicate that caution is warranted when extrapolating results from the iliac to the coronary artery when investigating restenosis after angioplasty.
[Show abstract][Hide abstract] ABSTRACT: Silent myocardial ischaemia (SI) is recognised as an important prognostic factor in patients with coronary artery disease (CAD). Postprandial angina is related to severity of CAD. The effect of postprandial metabolic changes in the pathogenesis of SI is unclear. We studied the postprandial changes in glucose, insulin and triglyceride, and non-esterified fatty acids (NEFA) in relation to postprandial SI and exercise capacity, in patients with CAD. Forty elderly volunteers (63 +/- 1 years) mean age +/- s.e.m., with a history of angina were selected on the basis of a Rose questionnaire and a positive exercise stress test (modified Bruce protocol). The test meal contained 45% fat. The meal was consumed at 9.00 am and hourly blood samples were taken for glucose, insulin, triglyceride and NEFA. Continuous Holter monitoring for SI was conducted using a Spacelabs 2000 monitor. Twenty-five percent of the subjects had episodes of silent ischaemia. Postprandial glucose, insulin, triglyceride, and NEFA were not significantly different in the patients with SI (group 1, n = 10) compared with those without SI (group 2, n = 30). The mean exercise time was 6.1 +/- 0.8 min in group 1 compared with 6.8 +/- 0.5 minutes in group 2 (P = 0.48). The time to onset of ST depression during exercise test was also not significantly different in the two groups. The occurrence of postprandial SI cannot be related to changes in plasma levels of glucose, triglyceride, insulin, and NEFA. The explanation is not apparent from this study but may relate to a haemodynamic changes such as mesenteric steal. Journal of Human Hypertension (2000) 14, 391-394
Journal of Human Hypertension 07/2000; 14(6):391-4. · 2.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Whether adrenaline acts as a sympathetic nervous cotransmitter in humans and stimulates beta2-adrenoceptors to augment neuronal noradrenaline release remains a subject of considerable dispute. The aim of this study was to test if adrenaline is released from regional sympathetic nerves (in the heart) in patients with essential hypertension, and to investigate whether locally released adrenaline might enhance cardiac noradrenaline release.
Using dual isotope dilution methodology, adrenaline and noradrenaline plasma kinetics was measured for the whole body and in the heart in 13 untreated patients with essential hypertension and 27 healthy volunteers. All research participants underwent cardiac catheterization under resting conditions.
At rest, there was negligible adrenaline release from the sympathetic nerves of the heart in healthy subjects, 0.27 +/- 1.62 ng/min. In contrast, in patients with essential hypertension, adrenaline was released from the heart at a rate of 1.46 +/- 1.73 ng/min, equivalent on a molar basis to approximately 5% of the associated cardiac noradrenaline spillover value. Cardiac noradrenaline spillover was higher in hypertensive patients, 24.9 +/- 17.0 ng/min compared to 15.4 +/- 11.7 ng/min in healthy volunteers (P< 0.05). Among patients, rates of cardiac adrenaline and noradrenaline spillover correlated directly (r= 0.59, P< 0.05).
This study, in demonstrating release of adrenaline from the heart in patients with essential hypertension, and in disclosing a proportionality between rates of cardiac adrenaline and noradrenaline release, provides perhaps the most direct evidence to date in support of the 'adrenaline hypothesis' of essential hypertension.
Journal of Hypertension 06/2000; 18(6):717-23. · 4.22 Impact Factor