[Show abstract][Hide abstract] ABSTRACT: Background:
-Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood.
Methods and results:
-Data on 141,317 participants (62,666 never, 40,669 former, 37,982 current smokers) from 23 population-based studies were included in observational and Mendelian randomisation (MR) meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure (SBP, DBP), hypertension, and resting heart rate. For the MR analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower SBP, DBP, and lower hypertension risk, but with higher resting heart rate. In observational analyses amongst current smokers, one cigarette/day higher level of smoking heaviness was associated with higher (0.21 beats/minute; 95% CI 0.19; 0.24) resting heart rate, and slightly higher DBP (0.05 mmHg; 95% CI 0.02; 0.08) and SBP (0.08 mmHg; 95% CI 0.03; 0.13). However, in MR analyses amongst current smokers, while each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 beats/minute/allele; 95% CI 0.18; 0.54), there was no strong association with DBP, SBP, or hypertension. This would suggest a 7 beats/minute higher heart rate in those who smoke 20 cigarettes/day.
-This MR meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.
[Show abstract][Hide abstract] ABSTRACT: The natriuretic peptides (NPs), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), have vasoactive functions that concern humans and most animals, but their specific effects on cerebral circulation are poorly understood. We therefore examined the responsiveness of cerebral arteries to different doses of the natriuretic peptides in animals and humans. We conducted a dose-response experiment in guinea pigs ( in vitro) and a double-blind, three-way cross-over study in healthy volunteers ( in vivo). In the animal experiment, we administered cumulative doses of NPs to pre-contracted segments of cerebral arteries. In the main study, six healthy volunteers were randomly allocated to receive two intravenous doses of ANP, BNP or CNP, respectively, over 20min on three separate study days. We recorded blood flow velocity in the middle cerebral artery (VMCA) by transcranial Doppler. In addition, we measured temporal and radial artery diameters, headache response and plasma concentrations of the NPs. In guinea pigs, ANP and BNP but not CNP showed significant dose-dependent relaxation of cerebral arteries. In healthy humans, NP infusion had no effect on mean VMCA, and we found no difference in hemodynamic responses between the NPs. Furthermore, natriuretic peptides did not affect temporal and radial artery diameters or induce headache. In conclusion, natriuretic peptides in physiological and pharmacological doses do not affect blood flow velocity in the middle cerebral artery or dilate extracerebral arteries in healthy volunteers.
[Show abstract][Hide abstract] ABSTRACT: Obesity is a strong risk factor for hypertension but the mechanism linking obesity to hypertension is not fully elucidated. In obesity, circulating concentrations of adiponectin are decreased and hypoadiponectinaemia has in some but not all studies been associated with increased risk of hypertension. Due to this inconsistency, we decided to study adiponectin from two aspects in a cross-sectional in vivo study and in an experimental in vitro study. In the cross-sectional study, 103 men with body mass index (BMI) ≥30.0 kg/m(2) were studied; 63 had 24-hr ambulatory blood pressure (ABP) ≥130/80 mmHg (ObeseHT) and 40 had 24-hr ABP <130/80 mmHg (ObeseNT). As controls, we studied 27 men with BMI between 20.0 and 24.9 kg/m(2) and 24-hr ABP <130/80 mmHg (LeanNT). Serum concentrations of adiponectin and body composition using dual energy X-ray absorptiometry scanning were determined. In vitro, the direct vasomotor response of adiponectin was tested on subcutaneous resistance arteries from human abdominal adipose tissue. The 2 obese groups had lower adiponectin concentrations compared with LeanNT (P<0.01) (median (interquartile range)): ObeseHT 6.5 (5.1-8.3) mg/L; ObeseNT 6.6 (5.2-7.8) mg/L; and LeanNT 9.4 (6.7-12.4) mg/L, with no significant difference in adiponectin concentrations (or body composition) between ObeseHT and ObeseNT (P=0.67). In vitro, recombinant human adiponectin neither had any direct vasodilatory effect nor did adiponectin affect angiotensin II-stimulated vasoconstriction. In conclusion, obese, hypertensive men have similar serum concentrations of adiponectin as obese, normotensive men. In combination with the in vitro data, these findings question a pathogenic role of adiponectin in human hypertension. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Objective: Obesity is a strong risk factor for hypertension but the mechanism linking obesity to hypertension is not fully elucidated. In obesity, circulating concentrations of adiponectin are decreased and hypoadiponectinamia has in some but not all studies been associated with increased risk of hypertension. Due to this inconsistency, we decided to study adiponectin from 2 aspects in a cross-sectional in vivo study and in an experimental in vitro study. Design and method: In the cross-sectional study, 103 men with body mass index (BMI) > = 30.0 kg/m2 were studied; 63 had 24-hr ambulatory blood pressure (AMBP) > = 130/80 mmHg (OHT) and 40 had 24-hr AMBP < 130/80 mmHg (ONT). As controls, we studied 27 men with BMI between 20.0 and 24.9 kg/m2 and 24-hr AMBP < 130/80 mmHg (LNT). Serum concentrations of adiponectin and body composition using dual energy X-ray absorptiometry scanning were determined. In the in vitro study, the direct vasomotor response of adiponectin was tested on subcutaneous resistance arteries from human abdominal adipose tissue. Results: The 2 obese groups had lower serum adiponectin concentrations compared with LNT (P < 0.01) (median (interquartile range): OHT 6.5 (5.1-8.3) mg/L; ONT 6.6 (5.2-7.8) mg/L; and LNT 9.4 (6.7-12.4) mg/L, but there was no significant difference in adiponectin concentrations (or body composition) between OHT and ONT (P = 0.67), although OHT had much higher 24-hr systolic AMBP (mean +/- SD: 137 +/- 11 mm Hg vs. 117 +/- 6 mm Hg, P < 0.001) and much higher 24-hr diastolic AMBP (mean +/- SD: 83 +/- 6 mm Hg vs. 73 +/- 4 mm Hg, P < 0.001) compared with ONT. In the in vitro study, adiponectin neither had any direct vasodilatory effect nor did adiponectin affect angiotensin II stimulated vasoconstriction. Conclusions: Despite large differences in 24-hr AMBP (and comparable body compostion), obese hypertensive men had similar serum concentrations of adiponectin as obese normotensive men, and furthermore adiponectin did not show any vasodilatory properties in human subcutaneous resistance arteries. Thus overall, our findings do not support a major role, if any, for adiponectin in human hypertension. Copyright
Journal of Hypertension 06/2015; 33:e432. DOI:10.1097/01.hjh.0000468735.75587.06 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Common diseases like essential hypertension or diabetes mellitus are complex as they are polygenic in nature, such that each genetic variation only has a small influence on the disease. Genes operates in integrated networks providing the blue-print for all biological processes and conditional of the complex genotype determines the state and dynamics of any trait, which may be modified to various extent by non-genetic factors. Thus, diseases are heterogenous ensembles of conditions with a common endpoint. Numerous studies have been performed to define genes of importance for a trait or disease, but only a few genes with small effect have been identified. The major reasons for this modest progress is the unresolved heterogeneity of the regulation of blood pressure and the shortcomings of the prevailing monogenic approach to capture genetic effects in a polygenic condition. Here, a two-step procedure is presented in which physiological heterogeneity is disentangled and genetic effects are analysed by variance decomposition of genetic interactions and by an information theoretical approach including 162 single nucleotide polymorphisms (SNP) in 84 genes in the sphingolipid metabolism and related networks in blood pressure regulation. As expected, almost no genetic main effects were detected. In contrast, two-gene interactions established the entire sphingolipid metabolic and related genetic network to be highly involved in the regulation of blood pressure. The pattern of interaction clearly revealed that epistasis does not necessarily reflects the topology of the metabolic pathways i.e. the flow of metabolites. Rather, the enzymes and proteins are integrated in complex cellular substructures where communication flows between the components of the networks, which may be composite in structure. The heritabilities for diastolic and systolic blood pressure were estimated to be 0.63 +/- 0.01 , which may in fact be the maximum heritabilities of these traits.
Frontiers in Genetics 03/2015; 6:84. DOI:10.3389/fgene.2015.00084
[Show abstract][Hide abstract] ABSTRACT: The role of the natriuretic peptides (NPs) in hypertension is complex. Thus, a higher blood NP concentration is a robust marker of pressure-induced cardiac damage in patients with hypertension, whereas genetically elevated NP concentrations are associated with a reduced risk of hypertension and overweight individuals presumably at high risk of hypertension have lower NP concentrations.
To investigate the associations between serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), used as a surrogate marker for active BNP, and prevalent as well as 5-year incident hypertension in a Danish general population sample.
Cross-sectional and prospective population-based study.
At baseline, among 5,307 participants (51.3% women, mean age 46.0±7.9 years) with a complete set of data, we recorded 1,979 cases with prevalent hypertension (PHT). Among 2,389 normotensive participants at baseline with a complete set of data, we recorded 324 cases with incident hypertension (IHT) on follow-up 5 years later. In models adjusted for age, sex, lifestyle, social, dietary, anthropometric, pulmonic, lipid, metabolic and renal risk factors, as well as heart rate and baseline blood pressure (only incident model), one standard deviation increase in baseline log-transformed NT-proBNP concentrations was on one side associated with a 21% higher risk of PHT (odds ratio [OR]: 1.21 [95% confidence interval (CI): 1.13-1.30], P<0.001), and on the other side with a 14% lower risk of IHT (OR: 0.86 [95%CI:0.76-0.98], P = 0.020).
Higher serum concentrations of NT-proBNP associate with PHT whereas lower concentrations associate with IHT. This suggests that a lower amount of circulating BNP, resulting in diminished vasodilation and natriuresis, could be involved in the pathogenesis of hypertension in its early stages.
PLoS ONE 02/2015; 10(2):e0117864. DOI:10.1371/journal.pone.0117864 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The widespread use of coronary stents has exposed a growing population to the risk of stent thrombosis, but the importance in terms of risk of ST-segment elevation myocardial infarctions (STEMIs) remains unclear.
We studied five years follow-up data for 2,098 all-comer patients treated with coronary stents in the randomized SORT OUT II trial (mean age 63.6 yrs. 74.8% men). Patients who following stent implantation were readmitted with STEMI were included and each patient was categorized ranging from definite- to ruled-out stent thrombosis according to the Academic Research Consortium definitions. Multivariate logistic regression was performed on selected covariates to assess odds ratios (ORs) for definite stent thrombosis.
85 patients (4.1%), mean age 62.7 years, 77.1% men, were admitted with a total of 96 STEMIs, of whom 60 (62.5%) had definite stent thrombosis. Notably, definite stent thrombosis was more frequent in female than male STEMI patients (81.8% vs. 56.8%, p = 0.09), and in very late STEMIs (p = 0.06). Female sex (OR 3.53 [1.01-12.59]) and clopidogrel (OR 4.43 [1.03-19.01]) was associated with increased for definite stent thrombosis, whereas age, time since stent implantation, use of statins, initial PCI urgency (STEMI [primary PCI], NSTEMI/unstable angina [subacute PCI] or stable angina [elective PCI]), and glucose-lowering agents did not seem to influence risk of stent thrombosis.
In a contemporary cohort of coronary stented patients, stent thrombosis was evident in more than 60% of subsequent STEMIs.
PLoS ONE 11/2014; 9(11):e113399. DOI:10.1371/journal.pone.0113399 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
In overweight-related hypertension, the effect of weight changes on blood pressure (BP) is believed to be mediated by insulin. To test this hypothesis, we studied 5-year changes in weight, BP, and insulin in a general population of Danish adults (n = 3443; mean age 45.7 ± 7.6 years).
We assessed the glucose-insulin metabolism by a standard oral glucose tolerance test. We divided the antihypertensive and antidiabetic medication-free participants into three groups: weight loss (n = 515), weight stable (n = 1778), and weight gain (n = 1150).
Losing on average 6.5 kg body weight, the weight loss group experienced a 28.2% reduction [(95% confidence interval [CI] -31 to -25); P < 0.001] in fasting insulin and a 23.9% reduction [(95% CI -28 to -19); P < 0.001] in 2-h insulin. Gaining on average 6.4 kg, the weight gain group experienced a 12.5% increase [(95% CI 9 to 16); P < 0.001] in fasting insulin and 32.8% increase [(95% CI 28 to 38); P < 0.001] in 2-h insulin. Using linear regression adjusting for differences in sex, age, family history of hypertension, baseline BMI, SBP and DBP, lifestyle risk factors, and their 5-year changes, weight loss was associated with a decrease in SBP of -1.8 mmHg (95% CI -2.8 to -0.7), whereas weight gain with an increase in SBP of 1.9 mmHg (95% CI 1.2 to 2.6), both with P less than 0.001. Adding fasting insulin, 2-h insulin, Δfasting insulin, and Δ2-h insulin only marginally attenuated the association, and furthermore, none of the insulin variables was significantly associated with SBP or DBP (P ≥ 0.08). The results for changes in DBP were similar to SBP.
Five-year weight changes associate with BP alterations independent of the insulin changes.
Journal of Hypertension 11/2014; 32(11):2231-2237. DOI:10.1097/HJH.0000000000000317 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
To investigate the influence of age and gender on the prevalence and cardiovascular disease (CVD) risk in Europeans presenting with the Metabolic Syndrome (MetS).
Using 36 cohorts from the MORGAM-Project with baseline between 1982–1997, 69094 men and women aged 19–78 years, without known CVD, were included. During 12.2 years of follow-up, 3.7%/2.1% of men/women died due to CVD. The corresponding percentages for fatal and nonfatal coronary heart disease (CHD) and stroke were 8.3/3.8 and 3.1/2.5.
The prevalence of MetS, according to modified definitions of the International Diabetes Federation (IDF) and the revised National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII), increased across age groups for both genders (P<0.0001); with a 5-fold increase in women from ages 19–39 years to 60–78 years (7.4%/7.6% to 35.4%/37.6% for IDF/NCEP-ATPIII) and a 2-fold increase in men (5.3%/10.5% to 11.5%/21.8%). Using multivariate-adjusted Cox regressions, the associations between MetS and all three CVD events were significant (P<0.0001). For IDF/NCEP-ATPIII in men and women, hazard ratio (HR) for CHD was 1.60/1.62 and 1.93/2.03, for CVD mortality 1.73/1.65 and 1.77/2.06, and for stroke 1.51/1.53 and 1.58/1.77. Whereas in men the HRs for CVD events were independent of age (MetS*age, P>0.05), in women the HRs for CHD declined with age (HRs 3.23/3.98 to 1.55/1.56; MetS*age, P = 0.01/P = 0.001 for IDF/NCEP-ATPIII) while the HRs for stroke tended to increase (HRs 1.31/1.25 to 1.55/1.83; MetS*age, P>0.05).
In Europeans, both age and gender influenced the prevalence of MetS and its prognostic significance. The present results emphasise the importance of being critical of MetS in its current form as a marker of CVD especially in women, and advocate for a redefinition of MetS taking into account age especially in women.
PLoS ONE 09/2014; 9(9):e107294. DOI:10.1371/journal.pone.0107294 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mean daytime ambulatory blood pressure (BP) values are considered to be lower than conventional BP values, but data on this relation among younger individuals <50 years are scarce. Conventional and 24-hour ambulatory BP were measured in 9550 individuals not taking antihypertensive treatment from 13 population-based cohorts. We compared individual differences between daytime ambulatory and conventional BP according to 10-year age categories. Age-specific prevalences of white coat and masked hypertension were calculated. Among individuals aged 18 to 30, 30 to 40, and 40 to 50 years, mean daytime BP was significantly higher than the corresponding conventional BP (6.0, 5.2, and 4.7 mm Hg for systolic; 2.5, 2.7, and 1.7 mm Hg for diastolic BP; all P<0.0001). In individuals aged 60 to 70 and ≥70 years, conventional BP was significantly higher than daytime ambulatory BP (5.0 and 13.0 mm Hg for systolic; 2.0 and 4.2 mm Hg for diastolic BP; all P<0.0001).The prevalence of white coat hypertension exponentially increased from 2.2% to 19.5% from those aged 18 to 30 years to those aged ≥70 years, with little variation between men and women (8.0% versus 6.1%; P=0.0003). Masked hypertension was more prevalent among men (21.1% versus 11.4%; P<0.0001). The age-specific prevalences of masked hypertension were 18.2%, 27.3%, 27.8%, 20.1%, 13.6%, and 10.2% among men and 9.0%, 9.9%, 12.2%, 11.9%, 14.7%, and 12.1% among women. In conclusion, this large collaborative analysis showed that the relation between daytime ambulatory and conventional BP strongly varies by age. These findings may have implications for diagnosing hypertension and its subtypes in clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Outcome-driven recommendations about time intervals during which ambulatory blood pressure should be measured to diagnose white-coat or masked hypertension are lacking. We cross-classified 8237 untreated participants (mean age, 50.7 years; 48.4% women) enrolled in 12 population studies, using ≥140/≥90, ≥130/≥80, ≥135/≥85, and ≥120/≥70 mm Hg as hypertension thresholds for conventional, 24-hour, daytime, and nighttime blood pressure. White-coat hypertension was hypertension on conventional measurement with ambulatory normotension, the opposite condition being masked hypertension. Intervals used for classification of participants were daytime, nighttime, and 24 hours, first considered separately, and next combined as 24 hours plus daytime or plus nighttime, or plus both. Depending on time intervals chosen, white-coat and masked hypertension frequencies ranged from 6.3% to 12.5% and from 9.7% to 19.6%, respectively. During 91 046 person-years, 729 participants experienced a cardiovascular event. In multivariable analyses with normotension during all intervals of the day as reference, hazard ratios associated with white-coat hypertension progressively weakened considering daytime only (1.38; P=0.033), nighttime only (1.43; P=0.0074), 24 hours only (1.21; P=0.20), 24 hours plus daytime (1.24; P=0.18), 24 hours plus nighttime (1.15; P=0.39), and 24 hours plus daytime and nighttime (1.16; P=0.41). The hazard ratios comparing masked hypertension with normotension were all significant (P<0.0001), ranging from 1.76 to 2.03. In conclusion, identification of truly low-risk white-coat hypertension requires setting thresholds simultaneously to 24 hours, daytime, and nighttime blood pressure. Although any time interval suffices to diagnose masked hypertension, as proposed in current guidelines, full 24-hour recordings remain standard in clinical practice.
[Show abstract][Hide abstract] ABSTRACT: Allergy is a systemic inflammatory disease that could theoretically affect the risk of cardiovascular disease (CVD) and diabetes through inflammatory pathways or mast cell-induced coronary spasm. Whether allergy is associated with an increased risk of CVD and diabetes is largely unknown. We investigated the association between atopy as assessed by IgE sensitization, a well-accepted biomarker of allergy, and incidence of ischemic heart disease, stroke, and diabetes in five Danish population-based cohorts. A total of 14,849 participants were included in the study. Atopy was defined as serum-specific IgE positivity to inhalant allergens. The Danish National Diabetes Register enabled identification of incident diabetes. Likewise, the Danish Registry of Causes of Death and the Danish National Patient Register provided information on fatal and non-fatal ischemic heart disease and stroke. Data were analyzed by Cox regression analyses with age as underlying time axis and adjusted for study cohort, gender, education, body mass index, alcohol intake, smoking habits, physical activity during leisure time, serum lipids, and blood pressure. The prevalence of atopy was 26.9 % (n = 3,994). There were 1,170, 817, and 1,063 incident cases of ischemic heart disease, stroke, and diabetes, respectively (median follow-up 11.2 years). The hazard ratios, HRs (95 % confidence intervals, CIs) for atopics versus non-atopics: for ischemic heart disease (HR 1.00, 95 % CI 0.86, 1.16), stroke (HR 1.18, 95 % CI 0.99, 1.41), and diabetes (HR 1.06, 95 % CI 0.91, 1.23). Our results did not support the hypothesis that atopy is associated with higher risk of ischemic heart disease, stroke, or diabetes. However, a small-moderately increased risk cannot be excluded from our data.
[Show abstract][Hide abstract] ABSTRACT: Background:
Data on risk associated with 24-hour ambulatory diastolic (DBP24) versus systolic (SBP24) blood pressure are scarce.
Methods and results:
We recorded 24-hour blood pressure and health outcomes in 8341 untreated people (mean age, 50.8 years; 46.6% women) randomly recruited from 12 populations. We computed hazard ratios (HRs) using multivariable-adjusted Cox regression. Over 11.2 years (median), 927 (11.1%) participants died, 356 (4.3%) from cardiovascular causes, and 744 (8.9%) experienced a fatal or nonfatal cardiovascular event. Isolated diastolic hypertension (DBP24≥80 mm Hg) did not increase the risk of total mortality, cardiovascular mortality, or stroke (HRs≤1.54; P≥0.18), but was associated with a higher risk of fatal combined with nonfatal cardiovascular, cardiac, or coronary events (HRs≥1.75; P≤0.0054). Isolated systolic hypertension (SBP24≥130 mm Hg) and mixed diastolic plus systolic hypertension were associated with increased risks of all aforementioned end points (P≤0.0012). Below age 50, DBP24 was the main driver of risk, reaching significance for total (HR for 1-SD increase, 2.05; P=0.0039) and cardiovascular mortality (HR, 4.07; P=0.0032) and for all cardiovascular end points combined (HR, 1.74; P=0.039) with a nonsignificant contribution of SBP24 (HR≤0.92; P≥0.068); above age 50, SBP24 predicted all end points (HR≥1.19; P≤0.0002) with a nonsignificant contribution of DBP24 (0.96≤HR≤1.14; P≥0.10). The interactions of age with SBP24 and DBP24 were significant for all cardiovascular and coronary events (P≤0.043).
The risks conferred by DBP24 and SBP24 are age dependent. DBP24 and isolated diastolic hypertension drive coronary complications below age 50, whereas above age 50 SBP24 and isolated systolic and mixed hypertension are the predominant risk factors.