Impact of fetal growth and preterm birth on the retinal microvasculature in mid-adulthood.

OBJECTIVE: We hypothesized that preterm birth and being born SGA would be associated with changes in retinal microvascular architecture and that these changes would be more marked among those born preterm. We further hypothesized that these microvascular changes would correlate with early markers of CVD in mid-adulthood. METHODS: The Cardiovascular Risk in Young Finns Study included randomly selected children from 5 Finnish University cities. Retinal microvascular architecture of participants born preterm, born at term and SGA and a control group born at term and AGA were compared (aged 34-49 years). RESULTS: In participants born preterm, arteriolar tortuosity (×10(2)) was higher-means (standard error), 0.06 (0.01) versus 0.04 (0.01), p = 0.001, arteriolar length (pixels) were greater-644.9 (35.9) versus 591.7 (33.5), p = 0.007 and arteriolar diameters (pixels) were narrower-19.9 (0.4) versus 20.3 (0.3), p = 0.034 compared to participants born AGA, after adjustment. In participants born SGA, only arteriolar tortuosity was higher-0.05 (0.01) versus 0.04 (0.01), p = 0.074 compared to participants born AGA. CONCLUSION: This study demonstrated that being born SGA and in particular preterm birth are associated with changes in retinal microvascular architecture. The prenatal and immediate postnatal environment may contribute to the mechanisms.

Excess pressure integral predicts cardiovascular events independent of other risk factors in the conduit artery functional evaluation substudy of Anglo-Scandinavian Cardiac Outcomes Trial.

Excess pressure integral (XSPI), a new index of surplus work performed by the left ventricle, can be calculated from blood pressure waveforms and may indicate circulatory dysfunction. We investigated whether XSPI predicted future cardiovascular events and target organ damage in treated hypertensive individuals. Radial blood pressure waveforms were acquired by tonometry in 2069 individuals (aged, 63±8 years) in the Conduit Artery Functional Evaluation (CAFE) substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Measurements of left ventricular mass index (n=862) and common carotid artery intima media thickness (n=923) were also performed. XSPI and the integral of reservoir pressure were lower in people treated with amlodipine±perindopril than in those treated with atenolol±bendroflumethiazide, although brachial systolic blood pressure was similar. A total of 134 cardiovascular events accrued during a median 3.4 years of follow-up; XSPI was a significant predictor of cardiovascular events after adjustment for age and sex, and this relationship was unaffected by adjustment for conventional cardiovascular risk factors or Framingham risk score. XSPI, central systolic blood pressure, central augmentation pressure, central pulse pressure, and integral of reservoir pressure were correlated with left ventricular mass index, but only XSPI, augmentation pressure, and central pulse pressure were associated positively with carotid artery intima media thickness. Associations between left ventricular mass index, XSPI, and integral of reservoir pressure and carotid artery intima media thickness and XSPI were unaffected by multivariable adjustment for other covariates. XSPI is a novel indicator of cardiovascular dysfunction and independently predicts cardiovascular events and targets organ damage in a prospective clinical trial.

Microcirculatory rarefaction in South Asians - a potential mechanism for increased cardiovascular risk and diabetes.

People of South Asian descent have an increased risk of cardiovascular disease (CVD) and diabetes, but little is known about the microcirculation in South Asian people despite evidence that this plays an important role in the aetiology of CVD. We compared the retinal microcirculation in a population-based sample of 287 middle-aged adults (144 European 143 South Asian) matched for age and sex. Retinal photographs were taken and analysed using a validated semi-automated program and microvascular measures were compared. Blood pressure, anthropometry and fasting bloods were also measured. South Asians had significantly fewer arteriolar and venular vessels and bifurcations. Arterioles and venules were longer and venules were also more tortuous in South Asians. These differences were not explained by adjustment for traditional risk factors including blood pressure, body mass index, diabetes or measures of insulin resistance. People of South Asian descent have rarefaction of the retinal microcirculation compared to age-sex matched individuals of European descent. Reduced microvascular density could contribute to the elevated risk of CVD and impaired glucose tolerance in South Asian people.

Limitations of augmentation index in the assessment of wave reflection in normotensive healthy individuals.

OBJECTIVES: Augmentation index (AIx) is widely used as a measure of wave reflection. We compared the relationship between AIx and age, height and sex with 'gold standard' measures of wave reflection derived from measurements of pressure and flow to establish how well AIx measures wave reflection. MATERIALS AND METHODS: Measurements of carotid pressure and flow velocity were made in the carotid artery of 65 healthy normotensive individuals (age 21-78 yr; 43 male) and pulse wave analysis, wave intensity analysis and wave separation was performed; waveforms were classified into type A, B or C. AIx, the time of the first shoulder (T(s)), wave reflection index (WRI) and the ratio of backward to forward pressure (P(b)/P(f)) were calculated. RESULTS: AIx did not correlate with log WRI or P(b)/P(f). When AIx was restricted to positive values AIx and log WRI were positively correlated (r = 0.33; p = 0.04). In contrast log WRI and P(b)/P(f) were closely correlated (r = 0.66; p<0.001). There was no correlation between the T(s) and the timing of Pb or the reflected wave identified by wave intensity analysis. Wave intensity analysis showed that the morphology of type C waveforms (negative AIx) was principally due to a forward travelling (re-reflected) decompression wave in mid-systole. AIx correlated positively with age, inversely with height and was higher in women. In contrast log WRI and P(b)/P(f) showed negative associations with age, were unrelated to height and did not differ significantly by gender. CONCLUSIONS: AIx has serious limitations as a measure of wave reflection. Negative AIx values derived from Type C waves should not be used as estimates of wave reflection magnitude.

Differential effects of adiposity and childhood growth trajectories on retinal microvascular architecture.

OBJECTIVES: We hypothesized that trajectories of adiposity across childhood would be associated with retinal microcirculatory diameters at age 12 years, independent of BP. METHODS: The ALSPAC followed a cohort of children born in 1991-1992. The current study includes all children with retinal images acquired at the 12 years clinic and individual trajectories of PI from 0 to 2 years and BMI from 2 to 10 years. Retinal microvascular measures included retinal arteriolar and venular diameters. RESULTS: Children in this analysis had a birth weight of 3.5 ± 0.4 kg, a PI of 26.2 ± 2.4 kg/m(3) and a gestational age of 39.7 ± 1.4 weeks (mean ± SD). Analysis of growth trajectories showed that lower PI at birth was associated with narrower retinal arterioles. Higher PI at birth was associated with wider venular diameter, and a stronger positive association was evident between BMI change at 5-5.5 and 8.5-10 years with wider venular diameters. Current fat mass was also associated with wider venular diameters. CONCLUSIONS: Retinal arterioles and venules are differentially associated with growth in early life and childhood adiposity. Early adiposity may adversely affect the microcirculation, with important implications for cardiovascular risk in adulthood.

South Asians have adverse cerebrovascular haemodynamics, despite equivalent blood pressure, compared with Europeans. This is due to their greater hyperglycaemia.

BACKGROUND: South Asians have a 1.5-fold increased stroke mortality compared with Europeans, despite similar blood pressures (BP). We hypothesized that it is the greater hyperglycaemia in South Asians that increases stroke risk, by adversely affecting cerebrovascular haemodynamics. METHODS: A population-based sample of 149 Europeans and 151 South Asians underwent metabolic profiling and concurrent measurement of finger BP using a Finapres and middle cerebral artery (MCA) blood flow velocity using transcranial Doppler ultrasound. Cerebrovascular autoregulation, cerebrovascular resistance [resistive index (RI) and pulsatility index (PI)] were calculated. Means of cerebrovascular haemodynamic measures were compared by ethnicity, with the introduction of explanatory variables to a regression model to determine which variable could best account for ethnic differences. RESULTS: Cerebrovascular resistance (RI) was 12.9 × 10(3) (0.9-24.8, P = 0.04) greater in South Asians than Europeans. Systolic, diastolic and mean MCA velocities were also higher in South Asians (mean velocity 41.4 ± 8.0 cm/s vs 38.0 ± 8.0 cm/s, respectively, P = 0.001). Low frequency gain, a measure of autoregulation, was worse in South Asians compared with Europeans (0.50 ± 0.01 cm/s mm/Hg vs 0.45 ± 0.01 cm/s mm/Hg, P = 0.01). RI positively correlated with HbA(1c) (r = 0.184; P < 0.01). Adjustment for BP could not explain the higher RI in South Asians, but adjustment for HbA(1c) abolished the ethnic difference in RI (5.8 × 10(3) (-6.5 to 18.1, P = 0.4). CONCLUSIONS: Cerebrovascular resistance and autoregulation are worse in South Asians than in Europeans, despite equivalent resting BP. The greater hyperglycaemia in South Asians accounts for their adverse cerebrovascular resistance. This could explain excess stroke in South Asians but requires testing in longitudinal studies.

High dietary salt intake increases carotid blood pressure and wave reflection in normotensive healthy young men.

Dietary salt intake is associated with high brachial blood pressure (BP) and increased risk of cardiovascular disease. We investigated whether changes in dietary salt intake are associated with changes in central BP and wave reflection in healthy volunteers. Ten healthy normotensive male volunteers (22-40 yr) participated in a 6-wk double-blind randomized crossover study to compare a low-dietary salt intake (60-80 mmol sodium/day) with a high-salt intake (low salt intake supplemented with 128 mmol sodium/day) on central BP and wave reflection. Brachial and carotid BP, carotid blood flow velocity, forward (P(f)) and backward (P(b)) pressure, wave intensity, body weight, and urinary electrolyte excretion were measured at the end of each crossover period. High salt intake significantly increased carotid systolic BP [98 (SD 11) vs. 91 mmHg (SD 13), P < 0.01] and increased wave reflection [ratio of backward to forward pressure (P(b)/P(f)) 0.13 (SD 0.02) vs. 0.11 (SD 0.03), P = 0.04] despite only small effects on brachial BP [114 (SD 9) vs. 112 mmHg (SD 6), P = 0.1]. Urinary sodium excretion and body weight were also increased following high salt intake. High salt intake disproportionately increases central BP compared with brachial BP as a result of enhanced wave reflection. These effects may contribute to the adverse effect of high dietary salt intake on the risk of cardiovascular disease.

Atorvastatin treatment is associated with less augmentation of the carotid pressure waveform in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT).

Hydroxymethylglutaryl-CoA reductase inhibitors (statins) reduce cardiovascular events in hypertensive subjects, but their effect on carotid BP, pressure augmentation, and wave reflection is unknown. We compared the effect of atorvastatin with placebo in a substudy of the lipid-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA). Hypertensive patients (n=142; age=43 to 79 years; 127 male) with total cholesterol < or = 6.5 mmol/L were randomized to atorvastatin 10 mg or placebo. Carotid BP and flow velocity were measured by tonometry and Doppler ultrasound. Augmentation index (carotid AI(x)) was calculated, and waveforms were separated into backward and forward components by wave intensity analysis. Brachial BP was similar in atorvastatin and placebo groups. Carotid AI(x) and augmentation pressure were significantly less in patients randomized to atorvastatin (mean [SD]: 21.7 [12.1] versus 25.9 [10.3] %; P=0.027 and 10.2 [6.5] versus 13.1 [6.6] mm Hg; P=0.016, respectively), and atorvastatin treatment was associated with significantly less wave reflection from the body. Carotid systolic BP was slightly lower in the atorvastatin group, but there was a statistically significant interaction between lipid-lowering and antihypertensive regimen with lower carotid systolic BP in patients randomized to amlodipine-based therapy and atorvastatin. Carotid wave velocity, timings of waves, and wave intensities did not differ significantly between atorvastatin and placebo groups. Atorvastatin treatment is associated with less augmentation of the carotid BP waveform and less wave reflection from the body. This could contribute to the reduction in risk of cardiovascular events by statins.

Differences in the magnitude of wave reflection account for differential effects of amlodipine- versus atenolol-based regimens on central blood pressure: an Anglo-Scandinavian Cardiac Outcome Trial substudy.

Antihypertensive agents may differ in their effects on central systolic blood pressure, and this may contribute to treatment-related differences in cardiovascular outcomes. In a substudy of the Anglo-Scandinavian Cardiac Outcome Trial, we investigated whether directly measured carotid systolic blood pressure differed between people randomized to amlodipine- and atenolol-based therapies and whether this is accounted for by differences in wave reflection patterns. Additional analysis was undertaken to establish whether differences in carotid systolic blood pressure predicted left ventricular mass, accounting for between-treatment differences in left ventricular mass index. Blood pressure and flow velocity were measured in the right carotid artery of 259 patients. Wave intensity analysis was used to separate and quantify forward and backward waves. Brachial blood pressure did not differ significantly between groups, but carotid systolic blood pressure (127 [12] versus 133 [15] mm Hg; P<0.001), the ratio of backward:forward pressure (0.48 [0.17] versus 0.53 [0.19]; P=0.01), and wave reflection index (19.8% [10.9%] versus 23.3% [13.3%]; P=0.02) were significantly lower in patients randomized to amlodipine-based therapy. Left ventricular mass index was also lower in this group, and adjustment for carotid blood pressure attenuated treatment differences to a greater extent than brachial blood pressure. Carotid systolic blood pressure was also a significant independent predictor of left ventricular mass index in a multivariate model. Carotid systolic blood pressure is lower in people randomized to amlodipine-based compared with atenolol-based treatment despite there being no significant difference in brachial blood pressure. This difference is attributable to a lesser magnitude of wave reflection in patients randomized to the amlodipine-based regimen.

Low wall shear stress predicts subsequent development of wall hypertrophy in lower limb bypass grafts.

BACKGROUND: Venous grafts commonly develop myointimal hyperplasia, which can lead to stenoses and, ultimately, with expression of adhesion molecules, lumenal occlusion. The aim of the present study was to investigate whether wall shear stress measured post-operatively would predict subsequent myointimal hypertrophy in lower limb venous bypass grafts. METHODS: Magnetic resonance imaging and ultrasound were performed in a cohort of patients following lower limb venous bypass graft surgery for peripheral arterial disease at baseline (1-2 weeks) and at follow-up (9-12 months). Wall shear stress was determined at baseline using computational fluid dynamics techniques and intima-media thickness along the length of the graft was measured by ultrasound at baseline and follow up. RESULTS: Complete follow-up was possible in eight patients, in whom low wall shear stress at baseline predicted high intima-media thickness. The relationship between wall shear stress (WSS) and intima-media thickness (IMT) was curvilinear with IMT increasing sharply at lower levels of WSS (IMT >1.0 mm at <0.3 Pa). CONCLUSIONS: Low wall shear stress is associated with subsequent increase in myointimal thickness in lower limb venous bypass grafts. This is believed to be the first prospective study in humans to demonstrate the relationship between low wall shear stress and myointimal thickening and indicates a likely causative role for low wall shear stress in the development of myointimal hyperplasia.

Ethnicity and left ventricular diastolic function in hypertension an ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) substudy.

OBJECTIVES: We investigated whether diastolic function differs between hypertensive patients of African-Caribbean or white European origin and established whether differences could be explained by confounding variables. BACKGROUND: African Caribbeans are known to have a higher prevalence of heart failure than white Europeans but it is unclear whether this is a result of known risk factors. Tissue Doppler technology now allows accurate quantification of diastolic function, which is recognized as an important factor in the development of heart failure. METHODS: Participants from a single center participating in the ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial), composed of patients with hypertension but no evidence of heart failure, were studied. Left ventricular structure and function were measured in 509 patients using conventional and tissue Doppler echocardiography. Diastolic function was assessed using the tissue Doppler early diastolic velocity E' (averaged from 3 left ventricular segments) and the ratio of this and the transmitral early filling velocity E (E/E'). RESULTS: In African-Caribbean patients, mean E' was significantly lower (7.7 cm/s vs. 8.6 cm/s, p = 0.003) and mean E/E' was significantly higher (8.85 vs. 7.93, p = 0.003). After adjustment for confounding variables-age, gender, systolic blood pressure, pulse pressure, cholesterol, smoking, ejection fraction, left ventricular mass index, and diabetes mellitus-the effect of African-Caribbean ethnicity on diastolic function remained highly significant (E': 7.52 vs. 8.51; p < 0.001; E/E': 8.89 vs. 7.93; p = 0.003; African Caribbeans vs. white Europeans for both comparisons). CONCLUSIONS: Diastolic function is significantly worse in hypertensive patients of African-Caribbean origin than in white Europeans. This difference in diastolic performance is not due to known confounding variables.

Effect of antihypertensive treatment on retinal microvascular changes in hypertension.

OBJECTIVE: Hypertension causes arteriolar narrowing and rarefaction in the retinal circulation, but the extent to which these changes are reversible by antihypertensive treatment is not well studied. We compared the effect of antihypertensive treatment with a calcium-channel-blocker-based regimen and an angiotensin-converting-enzyme-inhibitor-based regimen on the retinal microvasculature. METHODS: Twenty-five patients (17 men, age range 24-71 years) with untreated hypertension were randomized to treatment with an amlodipine-based (n = 12) or lisinopril-based (n = 13) regimen in a double-blind, prospective parallel limb trial for 52 weeks. Measurements of blood pressure and the retinal microvasculature were made at baseline and at the end of the study. RESULTS: Both the amlodipine-based and lisinopril-based treatments reduced blood pressure to similar extents. Blood pressure reduction was associated with a reduction in arteriolar narrowing, a widening of arteriolar branch angle and an increase in arteriolar density. There were no significant differences between the two treatment regimens. CONCLUSION: Antihypertensive treatment is associated with improvement in arteriolar narrowing and rarefaction. Improved microvascular structure may contribute to the beneficial effects of antihypertensive treatment in hypertension.

Reduced systolic wave generation and increased peripheral wave reflection in chronic heart failure.

In human heart failure the role of wave generation by the ventricle and wave reflection by the vasculature is contentious. The aim of this study was to compare wave generation and reflection in normal subjects with patients with stable compensated heart failure. Twenty-nine normal subjects and 67 patients with heart failure (New York Heart Association class II or III) were studied by noninvasive techniques applied to the common carotid artery. Data were analyzed by wave intensity analysis to determine the nature and direction of waves during the cardiac cycle. The energy carried by an early systolic forward compression wave (S wave) generated by the left ventricle and responsible for acceleration of flow in systole was significantly reduced in subjects with heart failure (P < 0.001), and the timing of the peak of this wave was delayed. In contrast, reflection of this wave was increased in subjects with heart failure (P < 0.001), but the timing of reflections with respect to the S wave was unchanged. The energy of an expansion wave generated by the heart in protodiastole was unaffected by heart failure. The carotid artery wave speed and the augmentation index did not significantly differ between subjects with heart failure compared with normal individuals. The ability of the left ventricle to generate a forward compression wave is markedly impaired in heart failure. Increased wave reflection serves to maintain systolic blood pressure but also places an additional load on cardiac function in heart failure.

Indian Asian men have less peripheral arterial disease than European men for equivalent levels of coronary disease.

OBJECTIVES: Indian Asians have high rates of heart disease and stroke, but risks of peripheral arterial disease appear to be low. This paradox, and reasons for it, have not been explored. We compared ethnic differences in peripheral arterial disease for a given level of coronary disease. METHODS: We studied 83 European and 84 Indian Asian men with a range of coronary disease. Extent of coronary atheroma was quantified by coronary artery calcification score on multislice CT. Femoral intima-media thickness (IMT) was measured by ultrasound. RESULTS: Femoral IMT was 1.58, 2.06, 2.12, and 2.69 mm in Europeans, and 0.61, 1.41, 1.81 and 2.29 in Indian Asians by increasing categories of coronary atheroma (p=0.003 for ethnic difference, adjusted for age and lumen diameter). Adjustment for smoking and systolic blood pressure, the only risk factors adversely distributed in Europeans, only partly accounted for this ethnic difference (p=0.05). Other risk factors, including lipids, obesity, insulin and glycaemic status, more adversely distributed in Indian Asians, could not account for ethnic differences. Prevalence of abnormal ankle brachial index and lower limb atherosclerotic plaque was also greater in Europeans. CONCLUSIONS: For a given level of coronary disease, Indian Asians have less lower limb atherosclerosis than Europeans, unexplained by established risk factors. Further study of these populations would help tease out relative contributions of risk factors to atherosclerosis in different vessel beds.

Comparison between three-dimensional volume-selective turbo spin-echo imaging and two-dimensional ultrasound for assessing carotid artery structure and function.

PURPOSE: To compare a volume-selective three-dimensional turbo spin echo (TSE) technique with ultrasound (US) for assessing carotid artery wall structure and function. MATERIALS AND METHODS: A three-dimensional volume-selective TSE technique was used to image the carotid artery in 10 healthy subjects and five hypertensive subjects (each of whom were scanned three times while they received different hypertension treatments). Lumen and wall area were measured on MR images. Two-dimensional US measurements of the intima-media thickness (IMT) and lumen diameter were taken in three orientations through a single cross section. The lumen area change over the cardiac cycle was used to determine distension. For validation, a Bland-Altman analysis was used to compare the vessel wall and lumen areas measured by three-dimensional MRI volumes with those obtained by US scans. RESULTS: Agreement between the two methods was found. The mean difference in distension between US and MRI was 1.2% (+/-5.1%). For the wall area measurements, good agreement was shown, but there was a systematic difference due to the visualization of the adventitia by MRI. Both techniques offer an easy way to objectively measure lumen indices. MRI can provide the complete circumference over the length of a vessel, while US is flexible and relatively inexpensive. The application of US is limited, however, when subjects are poorly echogenic. A difference between hypertensive and healthy subjects was found. CONCLUSION: There was a good agreement between MRI and the clinically established two-dimensional US method. The MRI method has the advantage of providing increased vessel coverage, which permits one to assess localized abnormalities without assuming vessel uniformity.