Angiogenic T-cells and putative endothelial progenitor cells in hypertension-related cerebral small vessel disease.

BACKGROUND AND PURPOSE: Cerebral small vessel disease (CSVD) may be caused by endothelial dysfunction, whereas endothelial progenitor cells (EPC) may attenuate endothelial dysfunction. Their vitality is lower in CSVD. A subset of lymphocytes, angiogenic T-cells, is capable to stimulate EPC function. The purpose of our study was to explore the relation between CSVD manifestations, angiogenic T-cells, and EPC in hypertensive patients with CSVD. METHODS: We compared 32 essential hypertensive patients with CSVD (white matter lesions, asymptomatic lacunar infarcts, or microbleeds on 1.5-Tesla MRI) to 29 age-matched and sex-matched hypertensive controls. We counted angiogenic T-cells (CD3(+)/CD31(+)/CD184(+)) and putative EPC (CD31(+)/CD34(+)/CD45(-)/KDR(+)) by flow cytometry and determined EPC vitality by in vitro cluster formation. RESULTS: Putative EPC numbers were lower in hypertensive individuals with CSVD than in those without (10±7(.)10(3)/mL versus 13±6(.)10(3)/mL [median±interquartile range]; P=0.011). Angiogenic T-cell numbers were also lower in hypertensive individuals with CSVD than in those without (0.56±0.25(.)10(9)/mL versus 0.78±0.50(.)10(9)/mL; P=0.008). Higher angiogenic T-cell numbers independently related to absence of CSVD (odds ratio, 0.088; 95% confidence interval, 0.012-0.627). CONCLUSIONS: Our data suggest that angiogenic T-cells and putative EPC independently relate to radiological CSVD manifestations in hypertensive patients.

Autoantibodies against oxidized low-density lipoprotein in cerebral small vessel disease.

BACKGROUND AND PURPOSE: Oxidized low-density lipoprotein (oxLDL) induces endothelial dysfunction and antibody formation. Because endothelial dysfunction is involved in cerebral small vessel disease (CSVD) (dilated Virchow Robin spaces, lacunar infarcts, and white matter lesions), oxLDL antibodies could play a role in CSVD pathogenesis. Therefore, we studied oxLDL antibodies in patients with high prevalence of CSVD: lacunar stroke patients and essential hypertensive patients. METHODS: A total of 158 lacunar stroke patients, 158 hypertensive patients, and 43 healthy controls were included. We determined levels of IgG and IgM against hypochlorite (HOCl) and malondialdehyde (MDA) oxLDL using ELISA (values in optical density). RESULTS: Patients with CSVD had higher levels of IgG-HOCl-oxLDL (0.77 versus 0.70; P<0.01), as well as lower levels of IgM-MDA-oxLDL (0.55 versus 0.65; P<0.05) than patients without such lesions. Higher IgG-HOCl-oxLDL levels were only independently associated with higher numbers of Virchow Robin spaces at the level of the basal ganglia (ß=0.218; P<0.001). CONCLUSIONS: An autoinflammatory process with lower levels of IgM antibodies and higher levels of IgG antibodies against oxLDL may be involved in CSVD.

Brain microbleeds relate to higher ambulatory blood pressure levels in first-ever lacunar stroke patients.

BACKGROUND AND PURPOSE: Hypertension is an important risk factor for brain microbleeds (BMBs) in lacunar stroke patients. However, beyond the qualitative label "hypertension," little is known about the association with ambulatory blood pressure (BP) levels. METHODS: In 123 first-ever lacunar stroke patients we performed 24-hour ambulatory BP monitoring after the acute stroke-phase. We counted BMBs on T2*-weighted gradient-echo MR images. Because a different etiology for BMBs according to location has been suggested, we distinguished between BMBs in deep and lobar location. RESULTS: BMBs were seen in 36 (29.3%) patients. After adjusting for age, sex, number of antihypertensive drugs, asymptomatic lacunar infarcts, and white matter lesions, we found 24-hour, day, and night systolic and diastolic BP levels to be significantly associated with the presence and number of BMBs (odds ratios 1.6 to 2.3 per standard deviation increase in BP). Distinguishing between different locations, various BP characteristics were significantly associated with the presence of deep (or combined deep and lobar) BMBs, but not with purely lobar BMBs. CONCLUSIONS: Our results underline the role of a high 24-hour BP load as an important risk factor for BMBs. The association of BP levels with deep but not purely lobar BMBs is in line with the idea that different vasculopathies might be involved. Deep BMBs may be a particular marker of BP-related small vessel disease, but longitudinal and larger studies are now warranted to substantiate these findings.

Different classifications of nocturnal blood pressure dipping affect the prevalence of dippers and nondippers and the relation with target-organ damage.

OBJECTIVE: We assessed how different definitions of the awake and asleep periods and use of various blood pressure (BP) indices affect the extent of the nocturnal BP dip, the prevalence of dippers and nondippers, their respective reproducibilities and the relation of nondipping with target-organ damage. METHODS: We performed 24-h ambulatory BP monitoring twice and determined the left ventricular mass index and urinary albumin excretion as indices of target-organ damage in 150 hypertensive patients (off-medication). Awake and asleep periods were assessed using fixed and diary time methods, covering all readings available (wide) or excluding morning and evening transition hours (narrow). Nondipping (BP dip < 10%) was established for systolic BP and diastolic BP, their combinations (and/or), and mean arterial pressure. RESULTS: The different awake-asleep definitions caused significant variation in both the extent of the BP dip and the number of dippers and nondippers in comparison with the wide diary definition (i.e. use of actual awake and sleep periods). The prevalences of dippers and nondippers also varied significantly with the BP index. Reproducibility analyses of the BP dip and the dipping status yielded repeatability coefficients (expressed as percentages of nearly maximal variation) between 42.39 and 48.71%, and kappa values between 0.323 and 0.459, respectively. Some classifications, but not all, discriminated significantly between consistent dippers and nondippers in terms of left ventricular mass index or urinary albumin excretion. CONCLUSIONS: Use of different definitions of awake-asleep and BP indices affects significantly the classification of nocturnal BP dipping and its relation with hypertensive target-organ damage.

Renin-angiotensin system and nitric oxide synthase gene polymorphisms in relation to stroke.

BACKGROUND: There is ample evidence that genetic factors contribute to cardiovascular disease risk. The present study aimed to assess the relation between polymorphisms of the angiotensin II type 1 receptor (AGTR1 A(1166)C) and endothelial nitric oxide synthase (NOS3 G(894)T) and the risk of stroke. METHODS: We performed a case-cohort study on all first fatal and nonfatal stroke events (n = 74) and a 10% random sample (n = 1523) of a population-based cohort of women aged 49 to 70 years (n = 15,236; median follow-up 4.3 years). Univariate and multivariate unweigthed Cox proportional hazards regression models were used to assess the relation between the polymorphisms, their interactions with coexisting risk factors, and the risk of stroke. RESULTS: The relation between the AGTR1 CC genotype and stroke risk (unadjusted hazards ratio [HR] 1.62; 95% confidence interval [CI], 0.81-3.28) was modified by increasing age (>56 years: adjusted HR 2.77; 95% CI, 1.17-6.56) and systolic blood pressure (BP) (>130 mm Hg: adjusted HR 2.58; 95% CI, 1.12-5.93). The NOS3 G(894)T polymorphism, however, was not associated with stroke risk. CONCLUSIONS: In the presence of other coexisting risk factors the AGTR1 A(1166)C but not the NOS3 G(894)T polymorphism increased the risk of stroke. The CC genotype may help identify those individuals who are at greatest risk and who may need (early) treatment or careful follow-up.

Associations of the angiotensin II type 1 receptor A1166C and the endothelial NO synthase G894T gene polymorphisms with silent subcortical white matter lesions in essential hypertension.

BACKGROUND AND PURPOSE: Silent white matter lesions (WMLs) may represent early target organ damage of the brain in patients with hypertension. Because these lesions may have a genetic background, we assessed the associations between polymorphisms of the renin-angiotensin system and the endothelial NO synthase (NOS3) genes and silent WMLs. METHODS: Ninety-three hypertensive individuals were studied. MRI of the brain was performed to obtain estimates of the total volume of subcortical and the extent of periventricular WMLs. Patients were genotyped for the angiotensinogen (M235T), the angiotensin-converting enzyme (insertion/deletion [I/D]), the angiotensin II type 1 receptor (AGTR1 A1166C), and the NOS3 (G894T) genes. A linear regression model was used to assess the relationship of these gene polymorphisms with both subtypes of WMLs. RESULTS: When adjusted for age, diabetes mellitus, and blood pressure, subcortical WML volume was lowest in the presence of 1 or 2 AGTR1 C alleles (unstandardized beta, -38.8 [95% CI, -66.1 to -11.4] and -112.6 [CI, -188.9 to -36.4], respectively), whereas it was highest in the presence of an NOS3 T allele (31.1[corrected] [CI, 3.6 to 58.4]). No interaction between these polymorphisms on WMLs could be demonstrated. No associations were present with the other polymorphisms, either with subcortical or periventricular lesions. CONCLUSIONS: We found the AGTR1 A1166C as well as the NOS3 G894T polymorphisms to be associated with silent WMLs in the subcortical area.

Effects of ACE I/D and AT1R-A1166C polymorphisms on blood pressure in a healthy normotensive primary care population: first results of the Hippocates study.

BACKGROUND: Several studies have assessed the relationship between the angiotensin-converting enzyme (ACE) I/D or angiotensin II type 1 receptor (AT(1)R)-A C polymorphisms and blood pressure (BP). Since most data have been obtained in selected populations, the present study was performed in a healthy normotensive primary care population. OBJECTIVE: To investigate the individual effects of the aforementioned polymorphisms and their interaction on BP. METHODS: This cross-sectional study included 198 healthy subjects. Office BP was measured and polymorphisms were genotyped (polymerase chain reaction). Polymorphism interaction was tested using the following model: systolic blood pressure (SBP) (or diastolic blood pressure, DBP) = b(0)+ b(1)X + b(2)Y + b(3)XY, in which X and Y represent the polymorphisms' risk alleles. RESULTS: The ACE I/D polymorphism was associated with SBP (P = 0.002) and DBP (P = 0.004); highest pressures tracked with the DD genotype. Furthermore, in multiple linear regression analysis the ACE D allele was associated with SBP (P = 0.005) and DBP (P = 0.001), when adjusted for body mass index (BMI) and age. With respect to the AT(1)R-A C polymorphism, SBP was highest in the CC genotype (P = 0.025). In linear regression analysis the C allele was not associated with SBP. No synergistic effect of ACE D and AT(1)R C alleles on BP was found. Nevertheless, highest DBP tracked with the DDCC combination in comparison with other homozygous allele combinations (P = 0.030). CONCLUSIONS: This study confirmed an association of ACE I/D and AT(1)R-A C polymorphisms with BP in a healthy normotensive primary care population. Although synergistic effect of both polymorphisms on BP does not seem to be present, an additive effect on DBP is likely.

Progression of brain microbleeds in essential hypertensive patients: a 2-year follow-up study.

BACKGROUND: Brain microbleeds (BMBs) are common in hypertensive patients and are associated with higher blood pressure (BP) levels. Little is known about risk factors for progression of BMBs, in particular the contribution of ambulatory BP levels. We aimed to determine BMB progression and the association with BP levels in a cohort of essential hypertensive patients. METHODS: At baseline and after 2 years of follow-up, 193 participants underwent brain magnetic resonance imaging (MRI) and 24-hour ambulatory BP measurement in addition to office BP measurement. The relation between BMB progression and baseline untreated BP characteristics was tested in logistic regression analyses. RESULTS: Progression of BMBs on follow-up MRI was seen in 12 (6%) participants. Patients with progression were significantly older, and the prevalence as well as total number of BMBs at baseline was greater. With correction for age and sex, baseline 24-hour systolic and diastolic BP and 24-hour pulse pressure significantly predicted progression. Similar results were seen for baseline awake and asleep BP. On additional adjustments for baseline presence of BMBs, the associations remained significant for 24-hour, awake, and asleep systolic BP, awake diastolic BP, and awake and asleep pulse pressure. Office systolic BP was also associated with progression of BMBs, whereas office diastolic BP was not. CONCLUSIONS: High ambulatory BP levels are important and possibly modifiable predictors for progression of BMBs. This warrants further study, with an adequately long follow-up period and early adequate treatment of hypertension.

Vascular inflammation in cerebral small vessel disease.

Cerebral small vessel disease (CSVD) is considered to be caused by an increased permeability of the blood-brain barrier and results in enlargement of Virchow Robin spaces (VRs), white matter lesions, brain microbleeds, and lacunar infarcts. The increased permeability of the blood-brain barrier may relate to endothelial cell activation and activated monocytes/macrophages. Therefore, we hypothesized that plasma markers of endothelial activation (adhesion molecules) and monocyte/macrophage activation (neopterin) relate to CSVD manifestations. In 163 first-ever lacunar stroke patients and 183 essential hypertensive patients, we assessed CSVD manifestations on brain magnetic resonance imaging (MRI) and levels of C-reactive protein (CRP), neopterin, as well as circulating soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin, sP-selectin). Neopterin, sICAM-1 and sVCAM-1 levels were higher in patients with extensive CSVD manifestations than in those without (p < 0.01). Neopterin levels independently related to higher numbers of enlarged Virchow Robin spaces (p < 0.001). An inflammatory process with activated monocytes/macrophages may play a role in the increased permeability of the blood brain barrier in patients with CSVD.

Subjective sleep disturbance increases the nocturnal blood pressure level and attenuates the correlation with target-organ damage.

OBJECTIVE: We aimed to investigate whether subjective sleep disturbance during overnight blood pressure (BP) monitoring results in higher night-time BP levels, and whether this affects the correlation between nocturnal BP and hypertensive target-organ damage. METHODS: In 203 untreated hypertensive patients (104 men) without a history of cardiovascular disease, with a mean age of 52.1 ± 12.5 years, and with office BP levels of 170 ± 23/104 ± 12 mmHg, we performed duplicate ambulatory BP monitoring (ABPM), assessed subjective sleep quality using the Groningen Sleep Quality Scale, and obtained information on hypertension-related cardiac damage by echocardiography. RESULTS: Overnight BP monitoring disturbed sleep significantly, but habituation to nocturnal measurements occurred on the second ABPM. Participants whose subjective sleep quality was less than usual on either ABPM did not have higher nocturnal BP levels than those who slept similar to usual (P > 0.05). When comparing the nocturnal BP levels between the first and second ABPM, we found that participants whose subjective sleep quality was less on the second ABPM had significantly higher pressure levels and a smaller BP dip than participants with a similar sleep quality for both ABPMs (P < 0.05). Accordingly, the correlations between the nocturnal BP and cardiac damage tended to be weaker based on the ABPM with the lowest sleep quality. CONCLUSIONS: Subjectively assessed sleep disturbance during overnight BP monitoring increases the nocturnal BP level and potentially attenuates the correlation with hypertension-related cardiac damage, even though habituation to overnight BP monitoring occurs.

[Diagnostic image. A man with tongue deviation following a motorcycle accident]. / Een man met tongdeviatie na een motorongeval.

A 49-year-old man complained of headache, dysarthria and difficulty in swallowing following a motorcycle accident. He had a tongue deviation to the right due to a traumatic lesion of the right hypoglossal nerve which was caused by a right occipital condyle fracture.

Haptoglobin phenotype correlates with the extent of cerebral deep white matter lesions in hypertensive patients.

Cerebral white matter lesions (WMLs), due to small vessel disease, can be regarded as an early "silent" sign of hypertensive cerebral end-organ damage. As haptoglobin (Hp) phenotype has earlier been associated with symptomatic vascular disease, we now examined the relationship between Hp phenotype and asymptomatic cerebral small vessel disease, manifested by deep and periventricular WMLs, in hypertensive patients. We determined Hp phenotype using starch gel electrophoresis in 152 hypertensive patients without symptomatic vascular disease. We found 26 (17.1%) Hp1-1, 89 (58.6%) Hp2-1 and 37 (24.3%) Hp2-2. Volumes of deep and periventricular WMLs were quantitatively measured on brain MR images. Patients were ranked in 5 categories according to ascending WMLs volumes. Compared to Hp2-2, Hp1-1 was associated with larger deep WMLs volumes when adjusted for age, gender, brain volume, 24-hour mean arterial pressure, duration of hypertension and previous antihypertensive treatment (ordinal regression analysis, OR 2.77, 95%CI 1.08-7.11, p=0.034). No association was found between Hp phenotype and periventricular WMLs. Hp1-1 phenotype correlates with the extent of hypertensive deep white matter damage. One of the possibilities is that this is related to lower regenerating power against endothelial injury in Hp1-1 individuals.

Detection of silent cerebrovascular disease refines risk stratification of hypertensive patients.

OBJECTIVE: Detection of preclinical hypertension-related cardiorenal damage has been recommended in the identification of patients most at risk of cardiovascular complications. The inclusion of silent cerebrovascular disease (SCD) as an additional marker of hypertensive organ involvement might improve risk stratification. METHODS: In 192 hypertensive patients (98 men) without a history of cardiovascular and cerebrovascular disease, a mean age of 51.6 +/- 12.3 years and untreated office blood pressure levels of 170 +/- 23/104 +/- 12 mmHg, we obtained detailed information on preclinical cardiac (left ventricular hypertrophy), renal (microalbuminuria, impaired kidney function or both) and cerebrovascular damage (white matter hyperintensities, infarcts, microbleeds or all), and estimated the associated cardiovascular risk on the basis of the presence of common cardiovascular risk factors. RESULTS: Hypertensive target-organ damage involved the heart in 41 (21%), the kidneys in 50 (26%) and the brain in 84 (44%) participants. When considering only patients with demonstrable cardiac, renal damage or both (n = 72), 42 participants (58%) had also SCD. Of the remaining 120 participants without cardiorenal damage, 42 (35%) had brain damage. In other words, half of all patients with SCD were classified as having no target-organ (i.e., cardiorenal) involvement. The cardiovascular risk score of patients without cardiorenal but with brain damage was significantly higher than that of participants without any organ involvement (37 +/- 11 versus 27 +/- 11, P < 0.001), and similar to the risk score of those with cardiorenal damage (38 +/- 14, P > 0.05). CONCLUSION: These data suggest that SCD should be recognized as an additional, independent and prognostically relevant marker of preclinical hypertensive target-organ damage.

Associations of ambulatory blood pressure levels with white matter hyperintensity volumes in hypertensive patients.

OBJECTIVE: High daytime and nighttime blood pressure (BP) levels, and apparently also an abnormal nocturnal BP dip, coincide with a greater extent of cerebral white matter hyperintensities (WMHs). We assessed the relationship between ambulatory BP and volumes of WMH, and distinguished between periventricular and deep WMH because of their supposedly different cause. METHODS: A total of 210 hypertensive patients (106 men) without cardiovascular and cerebrovascular disease, with a mean age of 52.5 +/- 12.5 years, and untreated office BP levels of 170 +/- 24/104 +/- 12 mmHg underwent duplicate 24-h ambulatory blood pressure monitoring (off medication) and brain MRI to quantify the WMHs (total, periventricular, and deep) and brain volumes. We performed linear regression analyses to relate the mean 24-h, awake, and asleep BPs, and the relative nocturnal BP dip to the different volumes of WMHs, while adjusting for age, sex, brain volume, and vascular risk factors. RESULTS: Higher 24-h, awake, and asleep BP levels were continuously, without distinct thresholds, and independently associated with a greater volume of total (all P < 0.001), periventricular (P < 0.001), and, to a lesser extent, deep (P < 0.05) WMHs. Nocturnal BP dipping was not related to the volume of WMHs. CONCLUSION: Higher 24-h, daytime, and nighttime BP levels are independently associated with WMH volumes.

Brain microbleeds are associated with ambulatory blood pressure levels in a hypertensive population.

Brain microbleeds, indicative of cerebral small-vessel disease, may occur with increased frequency in patients with hypertension. However, little is known about the relation of these abnormalities with blood pressure levels. We assessed the relation between ambulatory measured blood pressure and the presence of microbleeds in a cohort of hypertensive patients without a history of cerebrovascular disease. A total of 218 participants (110 males, age 52.5+/-12.6 years) underwent 24-hour ambulatory blood pressure monitoring twice (off-medication) and brain MRI to detect microbleeds and coexisting white matter hyperintensities. We performed logistic regression analyses to relate the following blood pressure components (based on both recordings) to microbleeds: the mean 24-hour, awake, and asleep blood pressures; nocturnal hypertension (asleep pressure >or=120/70 mm Hg); nocturnal blood pressure dipping. Models were adjusted for age and sex, and additionally for cardiovascular risk factors and white matter hyperintensities. We detected microbleeds in 35 participants (16.1%; 95% confidence interval, 11.1% to 21.0%). On average, each standard deviation increment in blood pressure, whether 24-hour, awake, or asleep, was significantly and independently associated with a 1.8- to 1.9-fold higher likelihood for microbleeds (all models P<0.05). Similarly, the adjusted odds ratio for microbleeds was 5- to 6-fold higher in subjects diagnosed with nocturnal hypertension (all models P<0.05). Microbleeds were not associated with nocturnal dipping. In conclusion, brain microbleeds are frequently found in hypertensive patients without a history of cerebrovascular disease, and are independently associated with higher daytime as well as night-time blood pressure levels.

Increased aortic pulse wave velocity is associated with silent cerebral small-vessel disease in hypertensive patients.

Aortic stiffness predicts an excess risk of stroke, supposedly via cerebral small-vessel disease. White matter hyperintensities, silent lacunar infarcts, and brain microbleeds, manifestations of cerebral small-vessel disease on neuroimaging, may precede overt cerebrovascular disease. Therefore, we assessed whether aortic stiffness is also related to such lesions. In 167 hypertensive patients (85 men) without a history of cardiovascular or cerebrovascular disease, a mean age of 51.8+/-13.1 years, and untreated office blood pressure levels of 169+/-25/104+/-12 mm Hg, we determined aortic pulse wave velocity and office and ambulatory 24-hour pulse pressure (off medication), as well as the volume of white matter hyperintensities and the presence of lacunar infarcts and microbleeds using brain MRI. Linear and logistic regression analyses were performed to assess the relationships between the arterial stiffness measures and brain lesions. Aortic stiffness and pulse pressure were significantly related to each of the brain lesions in univariate analyses (P<0.05). Multivariate analyses, adjusted for age, sex, brain volume, mean arterial pressure, and heart rate, showed that a higher pulse wave velocity was significantly associated with a greater volume of white matter hyperintensities (unstandardized regression coefficient: 0.041; 95% CI: 0.005 to 0.078; P<0.05) and the presence of lacunar infarcts (odds ratio [per SD increase in pulse wave velocity]: 1.78; 95% CI: 1.06 to 2.99; P<0.05) but not with microbleeds. The models for pulse pressure failed to reach statistical significance in multivariate analyses. In conclusion, aortic stiffness is independently associated with manifestations of cerebral small-vessel disease in hypertensive patients, linking systemic large- to cerebral small-artery disease.

Genetic risk of atherosclerotic renal artery disease: the candidate gene approach in a renal angiography cohort.

It is largely unknown to what extent genetic abnormalities contribute to the development of atherosclerotic renal artery disease. Among the potential candidate genes, those of the renin-angiotensin system and the endothelial nitric oxide synthase (eNOS) rank high because of their importance in the atherosclerotic process. We investigated the association of polymorphisms in these genes (the angiotensinogen Met235Thr, the angiotensin-converting enzyme insertion/deletion, the angiotensin II type-1 receptor A1166C, and the eNOS Glu298Asp) with the presence or absence of atherosclerotic renovascular disease in 456 consecutive hypertensive patients referred for renal angiography on the suspicion of renovascular hypertension. Nondiseased normotensive (n=200) and hypertensive (n=154) patients from a family practice served as external controls. Renal artery disease was present in 30% of our angiography group. The Asp allele of the eNOS Glu298Asp polymorphism was associated with atherosclerotic renal artery stenosis with an odds ratio of 1.44 (95% confidence interval 1.00 to 2.09) versus hypertensives with angiographically proven patent arteries, of 1.89 (1.24 to 2.87) versus hypertensive family practice controls, and of 2.09 (1.29 to 3.38) versus normotensive family practice controls. However, this allele also differed significantly between patients with patent renal arteries and normotensive and hypertensive controls. No differences were found with respect to the other genetic polymorphisms. We hypothesize that the Asp allele of the Glu298Asp polymorphism may predispose to the development of atherosclerotic lesions but that renal artery involvement depends on other factors, also.