Bas van den Bogaard

Activation of Inflammation and Coagulation After Infusion of C-Reactive Protein in Humans

C-reactive protein (CRP) has been postulated to play a causal part in atherosclerosis and its acute complications. We assessed the effects of CRP-infusion on coagulation and inflammatory pathways to determine its role in atherothrombotic disease. Seven male volunteers received an infusion on two occasions, containing 1.25 mg/kg recombinant human CRP (rhCRP) or diluent, respectively. CRP-concentrations rose after rhCRP-infusion from 1.9 (0.3 to 8.5) to 23.9 (20.5 to 28.1) mg/L, and subsequently both inflammation and coagulation were activated. This sequence of events suggests that CRP is not only a well known marker of cardiovascular disease, but is also probably a mediator of atherothrombotic disease.

Effects on Peripheral and Central Blood Pressure of Cocoa With Natural or High-Dose Theobromine. A Randomized, Double-Blind Crossover Trial

Flavanol-rich cocoa products have been reported to lower blood pressure. It has been suggested that theobromine is partially responsible for this effect. We tested whether consumption of flavanol-rich cocoa drinks with natural or added theobromine could lower peripheral and central blood pressure. In a double-blind, placebo-controlled 3-period crossover trial we assigned 42 healthy individuals (age 62±4.5 years; 32 men) with office blood pressure of 130 to 159 mm Hg/85 to 99 mm Hg and low added cardiovascular risk to a random treatment sequence of dairy drinks containing placebo, flavanol-rich cocoa with natural dose consisting of 106 mg of theobromine, or theobromine-enriched flavanol-rich cocoa with 979 mg of theobromine. Treatment duration was 3 weeks with a 2-week washout. The primary outcome was the difference in 24-hour ambulatory systolic blood pressure between placebo and active treatment after 3 weeks. The difference in central systolic blood pressure between placebo and active treatment was a secondary outcome. Treatment with theobromine-enriched cocoa resulted in a mean±SE of 3.2±1.1 mm Hg higher 24-hour ambulatory systolic blood pressure compared with placebo (P<0.01). In contrast, 2 hours after theobromine-enriched cocoa, laboratory peripheral systolic blood pressure was not different from placebo, whereas central systolic blood pressure was 4.3±1.4 mm Hg lower (P=0.001). Natural dose theobromine cocoa did not significantly change either 24-hour ambulatory or central systolic blood pressure compared with placebo. In conclusion, theobromine-enriched cocoa significantly increased 24-hour ambulatory systolic blood pressure while lowering central systolic blood pressure.

Cholesterol Acyltransferase Gene Mutations Have Accelerated Atherogenesis as Assessed by Carotid 3.0-T Magnetic Resonance Imaging: Carriers of Lecithin

OBJECTIVES The aim of this study was to investigate the role of reduced lecithin: cholesterol acyltransferase (LCAT) function on atherogenesis using 3.0-T carotid magnetic resonance imaging (MRI) and B-mode ultrasound. BACKGROUND The role of low high-density lipoprotein cholesterol as a causal factor in atherogenesis has recently been questioned. LCAT plays a key role in high-density lipoprotein cholesterol metabolism. METHODS Carotid 3.0-T MRI and B-mode ultrasound measurements were performed in 40 carriers of LCAT gene mutations and 40 controls, matched for age. Patients with cardiovascular disease were excluded. RESULTS Carriers had 31% lower LCAT activity levels and 38% decreased high-density lipoprotein cholesterol levels (both p < 0.001 vs. controls). Carriers presented with a 10% higher normalized wall index (0.34 ± 0.07 vs. 0.31 ± 0.04, p = 0.002), a 22% higher mean wall area (17.3 ± 8.5 mm(2) vs. 14.2 ± 4.1 mm(2), p = 0.01), and a 22% higher total wall volume (1,039 ± 508 mm(3) vs. 851 ± 247 mm(3), p = 0.01 vs. controls) as measured by MRI. The prevalence (20 vs. 5, p = 0.002) and the total volume (102 mm(3) vs. 3 mm(3)) of atherosclerotic plaque components on MRI relating to lipid-rich tissue or calcification were also higher in carriers than in controls. All differences retained significance after adjustment for age, sex, blood pressure, low-density lipoprotein cholesterol, body mass index, smoking, and family history of cardiovascular disease. Common carotid intima-media thickness measured with ultrasound was increased in carriers by 12.5% (0.72 ± 0.33 mm vs. 0.64 ± 0.15 mm, p = 0.14). CONCLUSIONS Carriers of LCAT gene mutations exhibit increased carotid atherosclerosis, indicating an increased risk of cardiovascular disease. The present findings imply that increasing LCAT activity may be an attractive target in cardiovascular prevention strategies.

Active standing reduces wave reflection in the presence of increased peripheral resistance in young and old healthy individuals.

Objective Pressure wave reflections are age-dependent and generally assumed to increase with increasing peripheral resistance. We sought to determine the effect of standing on wave reflection in healthy older and younger individuals and the influence of increased peripheral resistance. Methods During supine rest and active standing, continuous finger arterial blood pressure was measured. Data obtained in the supine period and after 1 and 5 min standing were analysed. Aortic pressure and flow, calculated from finger pressure, were used to derive forward and backward pressure waves, reflection magnitude (ratio of backward and forward pressure waves), augmentation index, and peripheral resistance. Results Fifteen healthy older (aged 53 ± 7 years) and 15 healthy younger (aged 29 ± 5 years) individuals were included. In both groups, upon standing, stroke volume, cardiac output and pulse pressure decreased with an increase in heart rate and in diastolic pressure. In the older group peripheral resistance increased from 1.3 ± 0.4 to 1.5 ± 0.4 and 1.5 ± 0.4 for supine, 1 and 5 min standing, whereas reflection magnitude decreased from 0.67 ± 0.1 to 0.61 ± 0.1 and 0.61 ± 0.1, and augmentation index from 33 ± 11 to 23 ± 12 and 25 ± 11. In the younger group peripheral resistance increased from 0.9 ± 0.2 to 1.1 ± 0.2 and 1.1 ± 0.2, whereas reflection magnitude decreased from 0.55 ± 0.05 to 0.48 ± 0.05 and 0.49 ± 0.05 and augmentation index from 18 ± 11 to 1 ± 18 and 4 ± 19. Conclusion With standing, haemodynamic variables change similarly in older and younger individuals. The opposite changes in reflection magnitude and peripheral resistance suggest that reflection and pressure augmentation are not solely dependent on peripheral resistance.

Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality: systematic review and meta-analysis.

Thiazide diuretics are recommended as first-line therapy for hypertension and are among the most commonly prescribed drugs worldwide. According to their molecular structure, thiazide diuretics can be divided in thiazide-type (TT) and thiazide-like (TL) diuretics. TL diuretics have a longer elimination half-life compared with TT diuretics and have been shown to exert additional pharmacological effects, which may differently affect cardiovascular risk. In this meta-analysis, we compared the effects of TT and TL diuretics on cardiovascular events and mortality. Randomized, controlled studies in adult hypertensive patients that compared TT or TL diuretics with placebo or antihypertensive drugs and had ≥1 year follow-up were included. Primary outcome was cardiovascular events; secondary outcomes included coronary events, heart failure, cerebrovascular events, and all-cause mortality. Meta-regression analysis was used to identify confounders and correct for the achieved blood pressure reductions. Twenty-one studies with >480 000 patient-years were included. Outcomes were not affected by heterogeneity in age, sex, and ethnicity among included studies, whereas larger blood pressure reductions were significantly associated with increased risk reductions for all outcomes (P<0.001). Corrected for differences in office blood pressure reductions among trials, TL diuretics resulted in a 12% additional risk reduction for cardiovascular events (P=0.049) and a 21% additional risk reduction for heart failure (P=0.023) when compared with TT diuretics. The incidence of adverse events was comparable among TT, TL diuretics, and other antihypertensive therapy. Our data suggest that the best available evidence seems to favor TL diuretics as the drug of choice when thiazide treatment is considered for hypertension.

Vascular Aspects of Fabry Disease in Relation to Clinical Manifestations and Elevations in Plasma Globotriaosylsphingosine

Fabry disease is an X-linked hereditary lysosomal storage disorder attributed to a deficiency of &agr;-galactosidase A leading to increased plasma levels of globotriaosylsphingosine (lysoGb3). The disease presents as a vascular disease, with cerebral, cardiac, and renal complications. Carotid intima-media thickness (IMT), brachial flow-mediated dilation (FMD), pulse wave velocity, and advanced glycation end products were measured in 57 classically affected patients (22 men and 35 women), 55 healthy matched controls (20 men and 35 women), and 10 atypical Fabry disease patients (5 men and 5 women). Most patients received enzyme replacement therapy. In classically affected male patients, brachial FMD was decreased (2.9% [95% CI, 0.8% to 7.9%] versus 5.9% [2.1% to 8.5%] in controls; P=0.01), and carotid IMT was increased (0.67 mm [95% CI, 0.50–0.96 mm] versus 0.59 mm [95% CI, 0.40–0.76 mm] in controls; P=0.01). In women and atypical patients these vascular parameters were comparable with controls. Pulse wave velocity was not different; advanced glycation end products were only slightly increased in atypical patients. In classically affected women, a small increase in lysoGb3 was associated with an increase in IMT independent of age. In the classically affected men, all with increased IMT and high levels of plasma lysoGb3, lysoGb3 levels did not add to a higher IMT, suggestive of a ceiling effect. For FMD, elevated lysoGb3 levels (>7 nmol/L) contributed to a 2.9% lower FMD independent of age and sex (P=0.02). Increased carotid IMT and decreased brachial FMD occur in classic Fabry disease, which is associated with plasma lysoGb3 level independent of age and sex. These observations still exist despite enzyme replacement therapy.

Patients with low HDL-cholesterol caused by mutations in LCAT have increased arterial stiffness

OBJECTIVE Carriers of a functional mutation in LCAT, encoding lecithin:cholesterol acyl transferase, are exposed to lifelong low high-density lipoprotein cholesterol (HDL-c) levels. We investigated whether LCAT mutation carriers have increased arterial stiffness as a marker of cardiovascular disease and whether arterial stiffness was associated with carotid wall thickening. METHODS We assessed 45 carriers of LCAT mutations (mean age ± SD 46 ± 13 yrs) and 45 age-matched controls. Probands referred with established cardiovascular disease were excluded. We measured carotid-fermoral pulse wave velocity (PWV) and carotid artery wall thickening by ultrasound and 3.0 T magnetic resonance imaging. RESULTS In carriers, HDL-c was lower (32 ± 12 vs. 59 ± 16 mg/dl; p < 0.0001) and triglycerides were higher (median 116 [IQR 80-170] vs. 71 [IQR 53-89] mg/dl; p < 0.001) vs. controls. PWV was higher in carriers vs. controls (7.9 ± 2.0 m/s vs. 7.1 ± 1.6 m/s; p < 0.01). This difference retained significance in multivariate analysis including age, sex, mean arterial pressure and body mass index, and after exclusion of carriers and controls with cardiovascular disease. Both in carriers and controls, PWV was correlated with wall thickening of the carotid arteries as assessed by ultrasound (R 0.50, p < 0.001 for carriers and R 0.36, p < 0.04 for controls) and 3.0 T magnetic resonance imaging (R 0.54, p < 0.001 for carriers and R 0.58, p < 0.001 for controls). CONCLUSION Pulse wave velocity is increased in LCAT mutation carriers with low HDL-c and is associated with carotid wall thickening.

Carriers of lecithin cholesterol acyltransferase gene mutations have accelerated atherogenesis as assessed by carotid 3.0-T magnetic resonance imaging [corrected].

OBJECTIVES The aim of this study was to investigate the role of reduced lecithin: cholesterol acyltransferase (LCAT) function on atherogenesis using 3.0-T carotid magnetic resonance imaging (MRI) and B-mode ultrasound. BACKGROUND The role of low high-density lipoprotein cholesterol as a causal factor in atherogenesis has recently been questioned. LCAT plays a key role in high-density lipoprotein cholesterol metabolism. METHODS Carotid 3.0-T MRI and B-mode ultrasound measurements were performed in 40 carriers of LCAT gene mutations and 40 controls, matched for age. Patients with cardiovascular disease were excluded. RESULTS Carriers had 31% lower LCAT activity levels and 38% decreased high-density lipoprotein cholesterol levels (both p < 0.001 vs. controls). Carriers presented with a 10% higher normalized wall index (0.34 ± 0.07 vs. 0.31 ± 0.04, p = 0.002), a 22% higher mean wall area (17.3 ± 8.5 mm(2) vs. 14.2 ± 4.1 mm(2), p = 0.01), and a 22% higher total wall volume (1,039 ± 508 mm(3) vs. 851 ± 247 mm(3), p = 0.01 vs. controls) as measured by MRI. The prevalence (20 vs. 5, p = 0.002) and the total volume (102 mm(3) vs. 3 mm(3)) of atherosclerotic plaque components on MRI relating to lipid-rich tissue or calcification were also higher in carriers than in controls. All differences retained significance after adjustment for age, sex, blood pressure, low-density lipoprotein cholesterol, body mass index, smoking, and family history of cardiovascular disease. Common carotid intima-media thickness measured with ultrasound was increased in carriers by 12.5% (0.72 ± 0.33 mm vs. 0.64 ± 0.15 mm, p = 0.14). CONCLUSIONS Carriers of LCAT gene mutations exhibit increased carotid atherosclerosis, indicating an increased risk of cardiovascular disease. The present findings imply that increasing LCAT activity may be an attractive target in cardiovascular prevention strategies.

Arterial stiffness is increased in families with premature coronary artery disease

Objective A positive family history of premature coronary artery disease (CAD) is a risk factor for cardiovascular disease (CVD), independent of traditional risk factors. Therefore, currently used risk algorithms poorly predict risk in these individuals. Novel methods are thus needed to assess cardiovascular risk. Pulse-wave velocity (PWV) might be such a method, but it is unknown whether PWV is increased in first-degree relatives of patients with premature CAD. Design Observational case–control study. Setting Academic hospital. Patients Patients with premature CAD and a positive family history of premature CVD (n=50), their first-degree relatives without CVD (n=50) and unrelated controls (n=50). Interventions None. Main Outcome Measures PWV was measured with using an Arteriograph system. Differences in PWV were assessed by a generalised linear model and multinomial logistic regression. Results Patients with premature CAD had a higher PWV compared with first-degree relatives and controls (9.69±2.90 m/s vs 8.15±1.96 m/s and 7.38±1.08 m/s; p<0.05 patients vs all groups). Linear regression showed all groups related to PWV, with patients having the highest PWV and controls the lowest (p<0.0001). Furthermore, PWV was associated with first-degree relatives (OR 1.32, 95% CI 1.02 to 1.72; p<0.05) and premature CAD (OR 1.72, 95% CI 1.32 to 2.24; p<0.05) compared with controls. These findings were independent of blood pressure and other traditional risk factors. Conclusions Patients with premature CAD and their first-degree relatives had higher PWV compared with controls, independent of other risk factors. This holds promise for the future, in which arterial stiffness might play a role in risk prediction within families with premature CAD.

Lack of difference between nebivolol/hydrochlorothiazide and metoprolol/hydrochlorothiazide on aortic wave augmentation and central blood pressure.

Background: The vasodilating beta-blocker nebivolol is thought to be superior in lowering wave reflection and central blood pressure (BP) compared to nonvasodilating beta-blockers. The results from studies comparing nebivolol with either metoprolol or atenolol, with or without hydrochlorothiazide (HCTZ), are not unequivocal. Methods: We examined the effects of nebivolol 5 mg and metoprolol 100 mg with HCTZ 12.5 mg on aortic wave augmentation, central BP and hemodynamics using a randomized, double-blind, crossover design. We included 22 patients (17 men, age 59.9 ± 6.4 years) with office SBP of 155 ± 16 mmHg and DBP of 93 ± 10 mmHg. Radial applanation tonometry and noninvasive, continuous finger arterial BP measurement was performed at baseline and after 4 weeks of treatment with either drug regimen, separated by a 4-week washout period. Results: Neither treatment affected aortic wave augmentation significantly. Augmentation index increased 1.0 ± 7.8% (P = 0.5) for nebivolol/HCTZ and 2.4 ± 6.6% (P = 0.07) for metoprolol/HCTZ. Nebivolol/HCTZ lowered central SBP by 15.8 ± 14.9 mmHg and DBP 10.5 ± 8.4 mmHg, and with metoprolol/HCTZ by 13.5 ± 12.3 mmHg for SBP and 9.5 ± 6.8 mmHg for DBP (all P < 0.001). Heart rate was lowered 8.1 ± 5.4 beats/min by nebivolol/HCTZ and 8.6 ± 4.9 beats/min by metoprolol/HCTZ. Peripheral BP was reduced to a similar extent as central BP. Peripheral BP decreased by 16.3 ± 14.9 mmHg systolic and 10.1 ± 8.2 mmHg diastolic with nebivolol/HCTZ, and by 15.2 ± 13.0 mmHg systolic and 9.1 ± 6.9 mmHg diastolic with metoprolol/HCTZ. Both treatment modalities had a similar effect on stroke volume, cardiac output, left-ventricular contractility and peripheral resistance. Conclusion: Nebivolol was not superior to metoprolol in reducing aortic wave augmentation or central BP when combined with HCTZ.