Do level and variability of systolic blood pressure predict arterial properties or vice versa?

No longitudinal study addressed whether systolic blood pressure level (SBPL) or within-visit variability (SBPV) predict arterial properties or vice versa. In families randomly recruited from a Flemish population, we determined SBPL and SBPV from five consecutive blood pressure readings. The indexes of SBPV were variability independent of the mean, the difference between maximum and minimum SBPL, and average real variability. We measured carotid intima-media thickness and distensibility by ultrasound and carotid-femoral pulse wave velocity by tonometry (SphygmoCor, version 8.2). Effect sizes were computed for 1-s.d. increments in the predictors, while accounting for covariables and family clusters. Among 1087 participants (50.4% women; mean age, 41.8 years), followed up for 2.55 years (median), higher SBPL predicted (P < or = 0.019) higher carotid intima-media thickness (+15 µm), lower carotid distensibility (-1.53 10(-3) kPa(-1)) and faster carotid-femoral pulse wave velocity (+0.285 m s(-1)) at follow-up, whereas none of the SBPV indexes predicted the arterial traits at follow-up (P> or = 0.11). In a subset of 713 participants, followed up for another 3.14 years, lower carotid distensibility predicted (P<0.01) higher SBPL (+2.57 mm Hg), variability independent of the mean (+0.531 units), difference between maximum and minimum SBPL (+1.75 mm Hg) and average real variability (+0.654 mm Hg). Higher carotid-femoral pulse wave velocity predicted a 1.11 mm Hg increase SBPL (P=0.031). In conclusion, temporality and effect size suggest that SBPL but not within-visit SBPV cause arterial stiffness and carotid intima-media thickness. Carotid stiffness, independent of SBPL, predicts within-visit SBPV, possibly because baroreflexes originating from a stiff carotid artery wall are impaired. Finally, stiffness of the aorta contributes to the age-related SBPL possibly, because faster returning reflected waves augments SBPL.

Cross-talk between macro- and microcirculation.

Physiologically, macro- and microcirculation differ markedly as macrocirculation deals with pulsatile pressure and flow and microcirculation with steady pressure and flow. Various such haemodynamic aspects correspond to a large heterogeneity in the structure and function of the vascular tree. In the past, diseases such as hypertension and diabetes mellitus were classified on the basis of the structure and function of small and large arteries. The purpose of this paper is to review the cross-talk between the micro- and macrocirculation. We shall discuss this cross-talk from the perspective of the development, physiology and pathology of the entire arterial tree.

Renal medullary effects of transient prehypertensive treatment in young spontaneously hypertensive rats.

AIM: Transient angiotensin II receptor blockade (ARB) leads to prolonged blood pressure (BP) lowering, but the underlying mechanism remains uncertain. Long-term BP control is regulated by the medullary microcirculation with the pericyte as contractile cell. We hypothesize that the prolonged BP effect is caused by increased medullary blood flow (MBF) associated with structural alterations based on reduced medullary pericyte number. METHODS: Four-week-old spontaneously hypertensive rats (SHR) were treated for 4 weeks with losartan (SHR-Los: 20 mg kg(-1) day(-1)), hydralazine (SHR-Hyd: 15 mg kg(-1) day(-1)), losartan and pan-caspase inhibitor zVAD (SHR-Los + 1 mg kg(-1) day(-1) zVAD), losartan and glycogen synthase kinase-3beta (GSK) inhibitor valproate (SHR-Los + 10 mg kg(-1) day(-1) Val) or placebo. BP, MBF and pericyte number were determined under and after treatment (8 and 12 weeks). Apoptotic pericytes were determined with alpha-actin and TUNEL double staining. Sodium concentration was determined in renal medulla and urine. RESULTS: Antihypertensive treatment equipotently reduced BP at 8 weeks of age. After drug withdrawal (12 weeks of age) BP reduction was restricted to SHR-Los (SHR-Los: 153 +/- 5, SHR-Hyd: 177 +/- 2, SHR: 184 +/- 3 mmHg). Simultaneously, MBF was increased and pericyte number reduced, while medullary and urinary sodium concentration increased. Transient ARB in combination with zVAD or valproate resulted in more medullary pericytes and higher BP (SHR-Los/zVAD: 164 +/- 7; SHR-Los/Val: 168 +/- 6 mmHg) compared with transient ARB alone. CONCLUSION: After drug withdrawal, transient ARB leads to increased MBF and is associated with a reduction in medullary pericytes. This may be associated with pericyte apoptosis as anti-apoptosis during transient ARB increases pericyte number and BP.

Arterial properties in relation to genetic variation in alpha-adducin and the renin-angiotensin system in a White population.

Earlier studies have demonstrated the interaction between ADD1 and ACE in relation to arterial properties. We investigated whether arterial characteristics might also be related to interactions of ADD1 with other renin-angiotensin system genes. Using a family-based sampling frame, we randomly recruited 1064 Flemish subjects (mean age, 43.6 years; 50.4% women). By means of a wall-tracking ultrasound system, we measured the properties of the carotid, femoral and brachial arteries. In multivariate-adjusted analyses, we assessed the multiple gene effects of ADD1 (Gly460Trp), AGT (C-532T and G-6A) and AT1R (A1166C). In ADD1 Trp allele carriers, but not in ADD1 GlyGly homozygotes (P-value for interaction < or =0.014), femoral cross-sectional compliance was significantly higher (0.74 vs 0.65 mm(2) kPa(-1); P=0.020) in carriers of the AT1R C allele than in AT1R AA homozygotes, with a similar trend for femoral distensibility (11.3 vs 10.2 x 10(-3) kPa(-1); P=0.055). These associations were independent of potential confounding factors, including age. Family-based analyses confirmed these results. Brachial diameter (4.35 vs 4.18 mm) and plasma renin activity (PRA) (0.23 vs 0.14 ng ml(-1) h(-1)) were increased (P< or =0.005) in AGT CG haplotype homozygotes compared with non-carriers, whereas the opposite was true for brachial distensibility (12.4 vs 14.4 x 10(-3) kPa(-1); P=0.011). There was no interaction between AGT and any other gene in relation to the measured phenotypes. ADD1 and AT1R interactively determine the elastic properties of the femoral artery. There is a single-gene effect of the AGT promoter haplotypes on brachial properties and PRA.

The need for combination antihypertensive therapy to reach target blood pressures: what has been learned from clinical practice and morbidity-mortality trials?

Pharmacological treatment of hypertension represents a cost-effective way for preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment blood pressure (BP) should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Most of the time such targets cannot be reached using monotherapies. This is especially true in patients who exhibit a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases BP control. Such preparations are not only efficacious, but also well tolerated, and some fixed low-dose combinations have a tolerability profile similar to placebo. This is for instance the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has recently been shown in controlled interventional trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving macrovascular stiffness. Fixed-dose combinations are becoming more and more popular and are even proposed by current hypertension guidelines as a first-line option to treat hypertensive patients.

Forearm vascular response to nitric oxide and calcitonin gene-related peptide: comparison between migraine patients and control subjects.

The forearm vascular response to nitric oxide (NO) and calcitonin gene-related peptide (CGRP) was investigated in 10 migraine patients and 10 matched control subjects. Changes in forearm blood flow (FBF) during intrabrachial infusion of: (i) serotonin (releasing endogenous NO), (ii) sodium nitroprusside (SNP, exogenous NO-donor), and (iii) CGRP were measured using venous occlusion plethysmography. Flow-mediated dilation (FMD) of the brachial artery, a measure for the endogenous release of NO reactive to occlusion, was measured using ultrasound and expressed as percentage change vs. baseline diameter. FBF ratio (i.e. FBF in the infused over the control arm) at baseline (1.1 +/- 0.1) did not differ between both populations. Serotonin, SNP and CGRP induced a dose-dependent increase (P < 0.001) in FBF ratio in controls (to 2.8 +/- 0.3, 6.7 +/- 1.4 and 6.9 +/- 1.2 at the highest dose, respectively) and migraineurs (2.5 +/- 0.4, 5.6 +/- 0.8 and 6.5 +/- 1.3, respectively); these ratios did not differ between both groups. FMD was comparable in control subjects (5.8 +/- 1%) and migraine patients (5.2 +/- 1%). Based on the forearm vascular response to NO and CGRP, migraine patients do not display generalized changes in vascular function.

[Recently published European and American guidelines for the diagnosis and treatment of hypertension]. / Onlangs gepubliceerde Europese en Amerikaanse richtlijnen voor hypertensiediagnostiek en -behandeling.

The European Society of Hypertension in conjunction with the European Society of Cardiology has published new guidelines on the management of hypertension. At about the same time, the Joint National Committee in the United States updated the American hypertension guidelines. Both guidelines agree on a number of issues, such as the importance of systolic blood pressure, the necessity to take into account additional risk factors and the growing emphasis on combination treatment. As far as pharmacotherapy is concerned, however, there are major differences between the guidelines. Whereas the European report permits a choice from among several classes of drugs for initial treatment, the American guidelines still consider diuretics to be the first choice.

Maturation-dependent changes of angiotensin receptor expression in fowl.

An angiotensin (ANG) receptor homologous to the type 1 receptor (AT1) has been cloned in chickens (cAT1). We investigated whether cAT1 expression in various tissues shows maturation/age-dependent changes. cAT1 mRNA levels detected in renal glomeruli [in situ hybridization (ISH)] and kidney extract (RT-PCR) are significantly (P < 0.01) higher in 19-day embryos (EB) than in chicks (CH, 2-3 wk) and pullets/cockerels (PL/CK, 14-16 wk). The levels in adrenal glands (concentrated in subcapsular regions) are high in EB and further increased in CH and PL/CK. cAT1 mRNA is also detectable in smooth muscle (SM)/adventitia of EB and CH aorta and in the adventitia, but not SM, from PL/CK aortas. The endothelia from small arteries and arterioles, but not from aorta, express cAT1 mRNA (ISH). In all age groups, ANG II induces profound endothelium-dependent relaxation of abdominal aorta, partly (37-47%) inhibitable (P < 0.01) by Nomega-nitro-l-arginine methyl ester (l-NAME, 10(-4) M), suggesting the presence of ANG receptor in endothelium. l-NAME-resistant ANG II relaxation, examined in a limited number of EB or CH aortas, was reduced by 125 mM K+ or apamin plus charybdotoxin. The results suggest that 1) cAT1 is present in kidney, adrenal gland, and vascular endothelium (heterogeneity exists among arteries) of EB, CH, and PL/CK, and in aortic SM/adventitia of EB/CH but only in adventitia of PL/CK; 2) levels of cAT1 gene expression change during maturation in a tissue-specific manner; and 3) ANG II-induced relaxation may be partly attributable to nitric oxide and potassium channel activation.

Cranial and peripheral interictal vascular changes in migraine patients.

As migraine is associated with an increased risk for ischaemic stroke and peripheral vasospastic disorders, it was hypothesized that interictal vascular changes may be present in migraine patients. Using ultrasound and applanation tonometry, the cardiovascular properties of migraine patients were compared with those of matched control subjects. Vascular parameters of the carotid arteries, cardiac output and systemic vascular resistance did not differ between both groups. Right temporal artery diameter was larger in migraine patients (mean difference 101 micro m; 95% confidence interval (CI) 9/194 micro m; P = 0.033). At the brachial artery, migraine patients displayed a smaller distension (difference -24 micro m; 95% CI -45/-4 micro m; P = 0.021) and a decreased compliance (difference -0.025 mm2/kPa; 95% CI -0.047/-0.003 mm2/kPa; P = 0.024). Thus, migraine patients display an increased peripheral arterial stiffness. The presence of these interictal vascular changes suggests that migraine might be part of a more generalized vascular disorder.

[Hypertension and microcirculation]. / Hypertension et microcirculation.

The importance of the microcirculation (comprising the smallest arteries, arterioles, capillaries and venules) in hypertension and other cardiovascular diseases is well known. The small resistance arteries develop structural changes such as an increase in the wall/lumen ratio and the capillary networks of different vascular beds become rarefied in response to increased blood pressure. These changes not only contribute to hypertensive lesions of target organs but also maintain or amplify the increased blood pressure by increasing peripheral resistances, so creating a vicious circle. Microvascular changes in hypertension may also lead to an increased reflection of the pressure wave towards the heart from the peripheral reflecting sites. This reflected wave also increases systolic blood pressure without increasing the diastolic pressure, thereby increasing the pulse pressure. A high pulse pressure may induce lesions of the vessel walls and of the endothelium of the large arteries, and this is known to be a significant independent risk factor for cardiovascular mortality, especially in the elderly. Microvascular rarefaction could possibly be reversed by therapeutic angiogenesis with cytokines but this treatment is difficult to deliver to the myocardium and is not yet available in clinical practice. Some conventional antihypertensive therapies, including the association of a low dose angiotensin converting enzyme inhibitor, perindopril, and a diuretic, indapamide, may have a beneficial effect on the microcirculation. It has been demonstrated clinically that these drugs specifically reduce the pulse pressure, probably by decreasing the reflected pressure wave, and, therefore, additional benefits in terms of a reduction of cardiovascular risk can be expected.

Determination of aortic elastic modulus by pulse wave velocity and wall tracking in a rat model of aortic stiffness.

Several methods have been used to evaluate the elastic modulus of the aortic wall in the rat, but these have never been compared when used simultaneously. We measured thoracoabdominal pulse wave velocity (PWV) and changes in thoracic aorta diameter during the cardiac cycle (with wall echo-tracking) in pentobarbital-anesthetized adult male Wistar rats; half of the group had previously received vitamin D3 plus nicotine (VDN) in order to increase the stiffness of the aortic wall. The Moens-Korteweg elastic modulus (E(MK)) was calculated from PWV and the ratio of the internal diameter to the medial thickness determined by histomorphometry following in situ pressurized fixation. The incremental elastic modulus (E(inc)) was calculated from the distensibility coefficient and end-diastolic diameter measured by wall echo-tracking and the medial thickness determined by histomorphometry. Both values were higher in VDN rats than in controls: E(inc) 8.9 +/- 0.5 and 5.7 +/- 0.4.10(6) dyne/cm(2), p < 0.05; E(MK) 7.6 +/- 0.5 and 4.1 +/- 0.5.10(6) dyne/cm(2), p < 0.05. E(inc) was greater than E(MK) and this was partially due to the fact that the in vivo end-diastolic diameter measured by ultrasound was greater than the mean aortic diameter measured ex vivo by histomorphometry. In conclusion, different methods for the measurement of the elastic properties of the aortic wall gave similar results in controls and in a rat model of aortic stiffness.

Carotid and femoral artery stiffness in relation to three candidate genes in a white population.

Different genetic polymorphisms influence cardiovascular disease. We recently discovered a relationship between the intima-media thickness of the muscular femoral artery, but not the elastic common carotid artery, and the combined ACE (ACE, I/D), alpha-adducin (Gly460Trp),and aldosterone synthase (AS, C-344T) gene polymorphisms. To investigate the relationship between these polymorphisms and functional properties of the carotid artery and femoral artery, a sample of 756 subjects enrolled in a population study were genotyped for the presence of the ACE D, alpha-adducin 460Trp, and aldosterone synthase -344T alleles. Vessel wall properties were assessed using a vessel wall movement detector system in combination with applanation tonometry. Statistical analysis allowed for confounders and interaction among genes. Cross-sectional compliance of the common carotid artery was negatively associated with the ACE D allele. ACE II versus ACE DD homozygotes differed, expressed as a percentage of the population mean (7.0%; 95% confidence interval [CI], 1.6% to 12.4%; P=0.02). In multigene analysis, ACE DD subjects also deviated significantly from the population mean for the distensibility coefficient of the common carotid artery when carrying the AS/T allele (-5.5%; 95% CI, -9.3% to -1.7%; P<0.01), without a change in cross-sectional compliance. ACE DD subjects, when homozygote for alpha-adducin Gly460, had a lower femoral cross-sectional compliance (-10.4%; 95% CI, -1.9% to -18.9%; P<0.03) and a lower distensibility (-9.7%; 95% CI, -2.1% to -17.3%; P<0.02) compared with the population mean. These data show that functional large artery properties are influenced by the ACE I/D polymorphism. Cross-sectional compliance and distensibility coefficients are influenced by the ACE I/D genotype, but this influence depends on the vascular territory and genetic background.

Pulse pressure, arterial stiffness, and drug treatment of hypertension.

Epidemiological studies in the past decade have stressed the importance of pulse pressure as an independent risk factor for cardiovascular morbidity and mortality. We briefly review the epidemiological evidence and discuss in more detail the pathophysiological basis for this observation and the therapeutic consequences. We focus on the vascular determinants of increased pulse pressure. Both longitudinal and cross-sectional components of the vascular system contribute to the shape of the arterial pressure wave and, thereby, to pulse pressure. The primary longitudinal component is the architecture of the arterial tree, which determines the major reflection sites for the pressure wave. The cross-sectional architecture of the vascular system consists of a geometric (diameter) and a structural (composition vessel wall) component. Both diameter and composition of the vessel wall vary greatly when going from central to more peripheral arteries. We review the implications for the functional properties of various arterial segments. Finally, we discuss the therapeutic consequences of targeting pulse pressure rather than mean blood pressure with various drug classes. Among the antihypertensive agents, nitrates, NO donors, and drugs that interfere with the renin-angiotensin-aldosterone system may offer useful tools to lower pulse pressure, in addition to mean blood pressure. Future developments may include non-antihypertensive agents that target collagen or other components of the arterial wall matrix. However, large-scale clinical trials will have to confirm the therapeutic value of these agents in the treatment of increased pulse pressure and arterial stiffness.

Menopause and the characteristics of the large arteries in a population study.

In previous cross-sectional and longitudinal population studies, we found that the slope of systolic pressure on age was steeper in postmenopausal than in premenopausal women. We hypothesised that this observation could be due to a specific effect of menopause on the elasticity of the large arteries. We investigated 315 randomly selected women, aged 30 to 70 years. Based on 5.2 years of follow-up, 166 women were premenopausal and 149 menopausal (44 reaching menopause and 105 postmenopausal). These women were matched on age and body mass index with 315 men. We used a wall-tracking ultrasound system to measure the diameter, compliance and distensibility of the brachial and the common carotid and femoral arteries as well as carotid-femoral pulse wave velocity. Pulse pressure was determined from 24-h blood pressure recordings. Both in menopausal women (r = 0.37; P < 0.001) and in matching male controls (r = 0.16; P = 0.04), pulse pressure widened with increasing age. The slope of the 24-h pulse pressure on age was steeper in menopausal women than in their premenopausal counterparts (0.428 vs -0.066 mm Hg per year; P = 0.003) and than in the male controls (0.428 vs 0.188 mm Hg per year; P = 0.06). After adjustment for age, 24-h mean pressure, body mass index, antihypertensive drug treatment, smoking and the use of oral contraceptives or hormonal replacement therapy, postmenopausal women showed a higher carotid-femoral pulse wave velocity (7.77 vs 6.71 m/s; P = 0.02) and had a slightly greater diameter of the common carotid artery (7.09 vs 6.79 mm; P = 0.07) than their premenopausal counterparts. After similar adjustments, menopausal class was not significantly associated with other vascular measurements in women or with any vascular measurement in control men. In conclusion, menopause per se may increase aortic stiffness. We hypothesise that this phenomenon may contribute to the rise in systolic pressure and pulse pressure in women beyond age 50 and, in turn, may lead to a slight dilatation of the common carotid artery.

Endometrial angiogenesis throughout the human menstrual cycle.

BACKGROUND: The timing and mechanisms of new blood vessel formation in the endometrium during the menstrual cycle are still largely unknown. In the present study we used the chick embryo chorioallantoic membrane (CAM) as an in-vivo assay for angiogenesis to assess the angiogenic potential of endometrium obtained at different stages of the menstrual cycle. METHODS: Endometrial fragments were explanted onto the CAM and, after 4 days of incubation, slides of the treated area were taken in ovo through a microscope for computerized image analysis. The vascular density index (VDI), a stereological estimate of vessel number and length, was obtained by counting the intersections of vessels with five concentric circles of a circular grid superimposed on the computerized image. RESULTS: We demonstrated that human endometrium has angiogenic potential throughout the menstrual cycle. Furthermore, there was a significant difference in angiogenic response between the stages of the menstrual cycle (P = 0.01). The VDIs of the early proliferative, early and late secretory stage were significantly higher than the VDI of the late proliferative phase. CONCLUSIONS: Elongation of existing vessels during the early proliferative phase as well as growth and coiling of the spiral vessels during the secretory phase may demand far higher angiogenic activity than outgrowth and maintenance of vessels during the late proliferative phase.

Dihydroergotamine: discrepancy between arterial, arteriolar and pharmacokinetic data.

AIMS: To investigate the peripheral vascular effects and pharmacokinetics of dihydroergotamine (DHE) 0.5 mg after a single subcutaneous administration in humans. METHODS: A double-blind, placebo-controlled cross-over study was performed in 10 healthy male subjects. A wash-out period of 2 weeks separated the two study periods. During each period, just before and at regular intervals after drug administration, vascular measurements were performed and venous blood samples were drawn. Vessel wall properties were assessed at the brachial artery, by ultrasound and applanation tonometry. Blood pressure and heart rate were recorded with an oscillometric device. Forearm blood flow was measured with venous occlusion plethysmography. For all parameter-time curves the area under the curve (AUC) was calculated. Differences in AUC after placebo and DHE (DeltaAUC) were analysed and the time-course of the difference assessed. DHE pharmacokinetics were analysed according to a two-compartment open model with an absorption phase. RESULTS: AUC for blood pressure, heart rate and forearm vascular resistance did not change after DHE. Brachial artery diameter and compliance decreased (P < 0.01); DeltaAUC (95% confidence interval) equalled -8.81 mm h (-12.97/-4.65) and -0.98 mm2 kPa(-1) h (-1.61/-0.34), respectively. Diameter decreased (P < 0.05) from 1 until 24 h after DHE (peak decrease 9.7% at 10 h); compliance from 2 until 32 h (24.8% at 2 h). Time to reach maximum plasma concentration of DHE averaged 0.33 +/- 0.08 h (+/- s.e.mean); terminal half-life was 5.63 +/- 1.15 h. CONCLUSIONS: DHE decreased diameter and compliance of the brachial artery whereas forearm vascular resistance remained unchanged. Thus, DHE acts on conduit arteries without affecting resistance arteries. Furthermore, a discrepancy was demonstrated between the plasma concentrations of DHE which rapidly reach peak levels and quickly decline, and its long lasting vasoconstrictor activity.