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1.  Diastolic Left Ventricular Function in Relation to Urinary and Serum Collagen Biomarkers in a General Population 
PLoS ONE  2016;11(12):e0167582.
Current knowledge on the pathogenesis of diastolic heart failure predominantly rests on case-control studies involving symptomatic patients with preserved ejection fraction and relying on invasive diagnostic procedures including endomyocardial biopsy. Our objective was to gain insight in serum and urinary biomarkers reflecting collagen turnover and associated with asymptomatic diastolic LV dysfunction. We randomly recruited 782 Flemish (51.3% women; 50.5 years). We assessed diastolic LV function from the early and late diastolic peak velocities of the transmitral blood flow and of the mitral annulus. By sequencing urinary peptides, we identified 70 urinary collagen fragments. In serum, we measured carboxyterminal propeptide of procollagen type 1 (PICP) as marker of collagen I synthesis and tissue inhibitor of matrix metalloproteinase type 1 (TIMP-1), an inhibitor of collagen-degrading enzymes. In multivariable-adjusted analyses with Bonferroni correction, we expressed effect sizes per 1-SD in urinary collagen I (uCI) or collagen III (uCIII) fragments. In relation to uCI fragments, e’ decreased by 0.183 cm/s (95% confidence interval, 0.017 to 0.350; p = 0.025), whereas E/e’ increased by 0.210 (0.067 to 0.353; p = 0.0012). E/e’ decreased with uCIII by 0.168 (0.021 to 0.316; p = 0.018). Based on age-specific echocardiographic criteria, 182 participants (23.3%) had subclinical diastolic LV dysfunction. Partial least squares discriminant analysis contrasting normal vs. diastolic LV dysfunction confirmed the aforementioned associations with the uCI and uCIII fragments. PICP and TIMP-1 increased in relation to uCI (p<0.0001), whereas these serum markers decreased with uCIII (p≤0.0006). Diastolic LV dysfunction was associated with higher levels of TIMP-1 (653 vs. 696 ng/mL; p = 0.013). In a general population, the non-invasively assessed diastolic LV function correlated inversely with uCI and serum markers of collagen I deposition, but positively with uCIII. These observations generalise previous studies in patients to randomly recruited people, in whom diastolic LV function ranged from normal to subclinical impairment, but did not encompass overt diastolic heart failure.
doi:10.1371/journal.pone.0167582
PMCID: PMC5154519  PMID: 27959898
2.  Vitamin-K-Dependent Protection of the Renal Microvasculature: Histopathological Studies in Normal and Diseased Kidneys 
Pulse  2016;4(2-3):85-91.
Vitamin-K-dependent carboxylation of matrix Gla protein (MGP) protects the macrocirculation against calcification. We recently reported in a multiethnic population study that the estimated glomerular filtration rate, a microvascular trait, decreased and the risk of chronic kidney disease increased with higher circulating levels of inactive dephospho-uncarboxylated MGP, a marker of vitamin K deficiency. These findings highlighted the possibility that vitamin K might have a beneficial effect on the renal microcirculation. To substantiate these epidemiological findings, we undertook a pilot study, in which we stained renal tissue samples obtained by biopsy from 2 healthy kidney donors and 4 patients with nephropathy for carboxylated and uncarboxylated MGP and calcium deposits. Three patients had renal calcifications, which were consistently associated with carboxylated and uncarboxylated MGP. Normal renal tissue was devoid of microcalcifications and staining for carboxylated and uncarboxylated MGP. Pending confirmation in a larger study covering a wider range of renal pathologies, these histopathological findings suggest that MGP might inhibit calcification not only in large arteries, as was known before, but in renal tissue as well, thereby highlighting potentially new avenues for promoting renal health, for instance by vitamin K supplementation.
doi:10.1159/000448008
PMCID: PMC5052692  PMID: 27752480
Calcification; Matrix Gla protein; Microcirculation; Kidney; Vitamin K
3.  Conventional and Ambulatory Blood Pressure as Predictors of Retinal Arteriolar Narrowing 
Hypertension  2016;68(2):511-520.
Supplemental Digital Content is available in the text.
At variance with the long established paradigm that retinal arteriolar narrowing trails hypertension, several longitudinal studies, all based on conventional blood pressure (CBP) measurement, proposed that retinal arteriolar narrowing indicates heightened microvascular resistance and precedes hypertension. In 783 randomly recruited Flemish (mean age, 38.2 years; 51.3% women), we investigated to what extent CBP and daytime (10 am to 8 pm) ambulatory blood pressure (ABP) measured at baseline (1989–2008) predicted the central retinal arteriolar equivalent (CRAE) in retinal photographs obtained at follow-up (2008–2015). Systolic/diastolic hypertension thresholds were 140/90 mm Hg for CBP and 135/85 mm Hg for ABP. In multivariable-adjusted models including both baseline CBP and ABP, CRAE after 10.3 years (median) of follow-up was unrelated to CBP (P≥0.14), whereas ABP predicted CRAE narrowing (P≤0.011). Per 1-SD increment in systolic/diastolic blood pressure, the association sizes were −0.95 µm (95% confidence interval, −2.20 to 0.30)/−0.75 µm (−1.93 to 0.42) for CBP and −1.76 µm (−2.95 to −0.58)/−1.48 µm (−2.61 to −0.34) for ABP. Patients with ambulatory hypertension at baseline (17.0%) had smaller CRAE (146.5 versus 152.6 µm; P<0.001) at follow-up. CRAE was not different (P≥0.31) between true normotension (normal CBP and ABP; prevalence, 77.6%) and white-coat hypertension (elevated CBP and normal ABP, 5.4%) and between masked hypertension (normal CBP and elevated ABP, 10.2%) and hypertension (elevated CBP and ABP, 6.8%). In conclusion, the paradigm that retinal arteriolar narrowing precedes hypertension can be explained by the limitations of CBP measurement, including nonidentification of masked and white-coat hypertension.
doi:10.1161/HYPERTENSIONAHA.116.07523
PMCID: PMC4956676  PMID: 27324224
ambulatory blood pressure monitoring; blood pressure; hypertension; microcirculation; population science; retina
4.  Diastolic Left Ventricular Function in Relation to Circulating Metabolic Biomarkers in a General Population 
Background
The metabolic signature associated with subclinical diastolic left ventricular (LV) dysfunction in the population remains ill defined.
Methods and Results
In 711 randomly recruited Flemish (50.8% women; mean age, 50.8 years), we assessed echocardiographic Doppler indexes of diastolic LV function in relation to 44 circulating metabolites determined by nuclear magnetic resonance spectroscopy. In multivariable‐adjusted regression analysis with Bonferroni correction of significance levels applied, peak a’ decreased (P≤0.048) and e’/a’ increased (P≤0.044) with circulating tyrosine, high‐density lipoprotein apolipoproteins, glucose+glutamine, and an unidentified molecule. Effect sizes expressed per 1‐SD increment in the metabolite ranged from −0.277 to −0.203 cm/s for peak a’ and from +0.047 to +0.054 for e’/a’. In addition, peak a’ decreased (P≤0.031) with glucose+2‐aminobutyrate (−0.261 cm/s) and glucose+2‐phosphoglycerate (−0.209 cm/s). In partial least square discriminant analysis (PLS‐DA), metabolites associated with normal diastolic LV function (n=538) included glucose+glutamine, glucose+2‐aminobutyrate, and glucose+2‐phosphoglycerate, whereas those siding with abnormal function encompassed 4‐aminobutyrate, 4‐hydroxybutyrate, creatinine, and phosphocholine. In receiver operating characteristics plots, adding 3 latent factors identified by PLS‐DA to prohormone brain natriuretic peptide increased (P<0.0001) the area under the curve from 0.64 (95% CI, 0.58–0.68) to 0.73 (0.68–0.78).
Conclusions
In a general population, circulating metabolites indicative of energy substrate utilization and protection against oxidative stress differentiated normal from abnormal diastolic LV function. These findings improve our understanding of the pathophysiology underlying deterioration of diastolic LV function and potentially point to new targets for prevention and treatment of this condition.
doi:10.1161/JAHA.115.002681
PMCID: PMC4943244  PMID: 27025885
biomarker; diastolic left ventricular function; metabolomics; nuclear magnetic resonance spectroscopy; population science; Epidemiology; Biomarkers
5.  Vitamin K Dependent Protection of Renal Function in Multi-ethnic Population Studies 
EBioMedicine  2016;4:162-169.
Background
Following activation by vitamin K (VK), matrix Gla protein (MGP) inhibits arterial calcification, but its role in preserving renal function remains unknown.
Methods
In 1166 white Flemish (mean age, 38.2 years) and 714 South Africans (49.2% black; 40.6 years), we correlated estimated glomerular filtration (eGFR [CKD-EPI formula]) and stage of chronic kidney disease (CKD [KDOQI stages 2–3]) with inactive desphospho-uncarboxylated MGP (dp-ucMGP), using multivariable linear and logistic regression.
Results
Among Flemish and white and black Africans, between-group differences in eGFR (90, 100 and 122 mL/min/1.73 m2), dp-ucMGP (3.7, 6.5 and 3.2 μg/L), and CKD prevalence (53.5, 28.7 and 10.5%) were significant, but associations of eGFR with dp-ucMGP did not differ among ethnicities (P ≥ 0.075). For a doubling of dp-ucMGP, eGFR decreased by 1.5 (P = 0.023), 1.0 (P = 0.56), 2.8 (P = 0.0012) and 2.1 (P < 0.0001) mL/min/1.73 m2 in Flemish, white Africans, black Africans and all participants combined; the odds ratios for moving up one CKD stage were 1.17 (P = 0.033), 1.03 (P = 0.87), 1.29 (P = 0.12) and 1.17 (P = 0.011), respectively.
Interpretation
In the general population, eGFR decreases and CKD risk increases with higher dp-ucMGP, a marker of VK deficiency. These findings highlight the possibility that VK supplementation might promote renal health.
Highlights
•In Flemish, eGFR was inversely associated with dp-ucMGP and positively with t-ucMGP.•In Flemish, the risk of chronic kidney disease increased with higher dp-ucMGP.•We confirmed the inverse association of eGFR with dp-ucMGP in black South Africans.
In a multi-ethnic population study, we assessed the association of renal glomerular filtration, a microvascular trait, with circulating matrix Gla protein (MGP). In white Flemish and in South African blacks, glomerular filtration decreased and the risk of chronic kidney disease increased with higher levels of inactive desphospho-uncarboxylated MGP. Our findings support the notion that following vitamin-K dependent carboxylation active MGP not only inhibits calcification of large arteries, as was known before, but also protects the renal microcirculation. Future studies might test whether vitamin K supplementation promotes renal health in the general population.
doi:10.1016/j.ebiom.2016.01.011
PMCID: PMC4776057  PMID: 26981580
Chronic kidney disease; Glomerular filtration rate; Matrix Gla protein; Population science; Vitamin K
6.  Correlates of Peripheral Blood Mitochondrial DNA Content in a General Population 
American Journal of Epidemiology  2015;183(2):138-146.
Accumulation of mitochondrial DNA (mtDNA) mutations leads to alterations of mitochondrial biogenesis and function that might produce a decrease in mtDNA content within cells. This implies that mtDNA content might be a potential biomarker associated with oxidative stress and inflammation. However, data on correlates of mtDNA content in a general population are sparse. Our goal in the present study was to describe in a randomly recruited population sample the distribution and determinants of peripheral blood mtDNA content. From 2009 to 2013, we examined 689 persons (50.4% women; mean age = 54.4 years) randomly selected from a Flemish population (Flemish Study on Environment, Genes, and Health Outcomes). Relative mtDNA copy number as compared with nuclear DNA was measured by quantitative real-time polymerase chain reaction in peripheral blood. There was a curvilinear relationship between relative mtDNA copy number and age. mtDNA content slightly increased until the fifth decade of life and declined in older subjects (Page2 = 0.0002). mtDNA content was significantly higher in women (P = 0.007) and increased with platelet count (P < 0.0001), whereas it was inversely associated with white blood cell count (P < 0.0001). We also observed lower mtDNA content in women using estroprogestogens (P = 0.044). This study demonstrated in a general population that peripheral blood mtDNA content is significantly associated with sex and age. Blood mtDNA content is also influenced by platelet and white blood cell counts and estroprogestogen intake. Further studies are required to clarify the impact of chronic inflammation and hormone therapy on mitochondrial function.
doi:10.1093/aje/kwv175
PMCID: PMC4706678  PMID: 26702630
general population; mitochondrial DNA; peripheral blood
7.  Design and feasibility of “PREMATurity as predictor of children's Cardiovascular–renal Health” (PREMATCH): A pilot study 
Blood Pressure  2015;24(5):275-283.
Abstract
The microvasculature and macrovasculature undergo extensive, organ-specific perinatal maturation. Multiple studies show associations between low birth weight and subsequent cardiovascular dysfunction in adulthood, suggesting that extreme preterm birth interferes with this maturation process. Therefore, we designed PREMATCH (PREMATurity as predictor of Cardiovascular–renal Health) to phenotype the microcirculation and macrocirculation during childhood in former preterm infants. A well-characterized cohort of former extreme preterm birth survivors and gender- and age-matched controls (aged 8–13 years) will be investigated for microvascular and macrovascular structure and function. In addition to cognitive performance and anthropometrics, we will investigate (i) the microvascular structure and function by endothelial function (photoplethysmography), sublingual capillary glycocalyx function (sidestream dark field imaging) and retinal structure (diameters of arterioles and venules); and (ii) the macrovascular phenotype by cardiac and renal ultrasound, repeated blood pressure measurements and arterial pulse-wave recordings. The PREMATCH study is unique in its design, and ongoing recruitment demonstrates excellent feasibility. The expectation is that the results of this study will identify risk factors during childhood for subsequent cardiovascular–renal disease in the adult life of former preterm infants, while further analysis on mediators in neonatal life of this cardiovascular–renal outcome may provide new information on perinatal risk factors.
doi:10.3109/08037051.2015.1053220
PMCID: PMC4673568  PMID: 26107770
Cardiovascular system; ELBW; extremely low birth weight infants; health policy and outcome research; macrocirculation; microcirculation
8.  Left Ventricular Dysfunction and CXCR3 Ligands in Hypertension: From Animal Experiments to a Population-Based Pilot Study 
PLoS ONE  2015;10(10):e0141394.
Detecting left ventricular (LV) dysfunction at an early stage is key in addressing the heart failure epidemic. In proteome profiling experiments in mice subjected either to aortic banding or sham, the circulating CXCR3 ligands monokine induced by interferon-γ (MIG) and interferon-γ inducible protein 10 (IP10) were 5 to 40 fold up-regulated at eight weeks. We assessed the diagnostic value of circulating NT-pro BNP and CXCR3 ligands (MIG, IP10, Interferon-inducible T-cell alpha chemo-attractant [I–TAC]) in patients with hypertension (≥140/90 mm Hg) associated with subclinical (n = 19) or symptomatic (n = 16) diastolic LV dysfunction on echocardiography and healthy controls. NT–pro BNP, MIG, IP10, I–TAC all increased (p ≤ 0.014) across the categories of worsening left ventricular dysfunction. In patients with symptomatic disease, MIG, IP10, and I–TAC increased 210% (p = 0.015), 140% (p = 0.007) and 120% (p = 0.035) more than NT-pro BNP. The optimal discrimination limits, obtained by maximizing Youden’s index were 246 pmol/L, 65 pg/mL, 93 pg/mL, and 24 pg/mL, respectively. The odds ratios associated with the four biomarkers were significant (p ≤ 0.010), ranging from 4.00 for IP10 to 9.69 for MIG. With adjustment for NT–pro BNP, the CXCR3 ligands retained significance (p ≤ 0.028). Adding optimized thresholds for the CXCR3 ligands to NT–pro BNP enhanced (p ≤ 0.014) the integrated discrimination improvement and the net reclassification improvement. In conclusion, congruent with the concept that inflammation plays a key role in the pathogenesis of LV dysfunction, MIG, IP10 and I–TAC add diagnostic accuracy over and beyond NT–pro BNP.
doi:10.1371/journal.pone.0141394
PMCID: PMC4624781  PMID: 26506526
9.  Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population 
BMC Genetics  2015;16:116.
Background
In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD).
Results
In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25–2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16–3.31), 1.87 (1.20–2.91) and 3.16 (1.41–7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %).
Conclusions
Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0272-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12863-015-0272-2
PMCID: PMC4591634  PMID: 26428460
Clinical genetics; Coronary heart disease; MEOX2; Population science; TCF15; Translational research
11.  Setting Thresholds to Varying Blood Pressure Monitoring Intervals Differentially Affects Risk Estimates Associated With White-Coat and Masked Hypertension in the Population 
Hypertension  2014;64(5):935-942.
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.
doi:10.1161/HYPERTENSIONAHA.114.03614
PMCID: PMC4420482  PMID: 25135185
ambulatory blood pressure monitoring; cardiovascular risk; masked hypertension; population science; white-coat hypertension
12.  Ambulatory Hypertension Subtypes and 24-Hour Systolic and Diastolic Blood Pressure as Distinct Outcome Predictors in 8341 Untreated People Recruited From 12 Populations 
Circulation  2014;130(6):466-474.
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).
Conclusions
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.
doi:10.1161/CIRCULATIONAHA.113.004876
PMCID: PMC4414316  PMID: 24906822
ambulatory blood pressure monitoring; blood pressure component; cardiovascular diseases; population
13.  No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over 
BMC Medicine  2015;13:78.
Background
Treatment for hypertension with antihypertensive medication has been shown to reduce stroke, cardiovascular events, and mortality in older adults, but there is concern that such treatment may not be appropriate in frailer older adults. To investigate whether there is an interaction between effect of treatment for hypertension and frailty in older adults, we calculated the frailty index (FI) for all available participants from the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over, and obtained frailty adjusted estimates of the effect of treatment with antihypertensive medication on risk of stroke, cardiovascular events, and mortality.
Methods
Participants in HYVET were randomised 1:1 to active treatment with indapamide sustained release 1.5 mg ± perindopril 2 to 4 mg or to matching placebo. Data relating to blood pressure, comorbidities, cognitive function, depression, and quality of life were collected at entry into the study and at subsequent follow-up visits. The FI was calculated at entry, based on 60 potential deficits. The distribution of FI was similar to that seen in population studies of adults aged 80 years and above (median FI, 0.17; IQR, 0.11–0.24). Cox regression was used to assess the impact of FI at entry to the study on subsequent risk of stroke, total mortality, and cardiovascular events. Models were stratified by region of recruitment and adjusted for sex and age at entry. Extending these models to include a term for a possible interaction between treatment for hypertension and FI provided a formula for the treatment effect as a function of FI. For all three models, the point estimates of the hazard ratios for the treatment effect decreased as FI increased, although to varying degrees and with varying certainty.
Results
We found no evidence of an interaction between effect of treatment for hypertension and frailty as measured by the FI. Both the frailer and the fitter older adults with hypertension appeared to gain from treatment.
Conclusions
Further work to examine whether antihypertensive treatment modifies frailty as measured by the FI should be explored.
Trial registration
ClinicalTrials.gov NCT00122811 (July 2005)
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0328-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0328-1
PMCID: PMC4404571  PMID: 25880068
Ageing; Antihypertensives; Frailty; Hypertension
14.  How Many Measurements Are Needed to Estimate Blood Pressure Variability Without Loss of Prognostic Information? 
BACKGROUND
Average real variability (ARV) is a recently proposed index for short-term blood pressure (BP) variability. We aimed to determine the minimum number of BP readings required to compute ARV without loss of prognostic information.
METHODS
ARV was calculated from a discovery dataset that included 24-hour ambulatory BP measurements for 1,254 residents (mean age = 56.6 years; 43.5% women) of Copenhagen, Denmark. Concordance between ARV from full (≥80 BP readings) and randomly reduced 24-hour BP recordings was examined, as was prognostic accuracy. A test dataset that included 5,353 subjects (mean age = 54.0 years; 45.6% women) with at least 48 BP measurements from 11 randomly recruited population cohorts was used to validate the results.
RESULTS
In the discovery dataset, a minimum of 48 BP readings allowed an accurate assessment of the association between cardiovascular risk and ARV. In the test dataset, over 10.2 years (median), 806 participants died (335 cardiovascular deaths, 206 cardiac deaths) and 696 experienced a major fatal or nonfatal cardiovascular event. Standardized multivariable-adjusted hazard ratios (HRs) were computed for associations between outcome and BP variability. Higher diastolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.19), and cardiac (HR = 1.19) mortality and fatal combined with nonfatal cerebrovascular events (HR = 1.16). Higher systolic ARV in 24-hour ambulatory BP recordings predicted (P < 0.01) total (HR = 1.12), cardiovascular (HR = 1.17), and cardiac (HR = 1.24) mortality.
CONCLUSIONS
Forty-eight BP readings over 24 hours were observed to be adequate to compute ARV without meaningful loss of prognostic information.
doi:10.1093/ajh/hpt142
PMCID: PMC3848629  PMID: 23955605
ambulatory blood pressure; blood pressure; blood pressure variability; epidemiology; hypertension; population science; risk factors.
15.  Risk Associated with Pulse Pressure on Out-of-Office Blood Pressure Measurement 
Pulse  2014;2(1-4):42-51.
Background
Longitudinal studies have demonstrated that the risk of cardiovascular disease increases with pulse pressure (PP). However, PP remains an elusive cardiovascular risk factor with findings being inconsistent between studies. The 2013 ESH/ESC guideline proposed that PP is useful in stratification and suggested a threshold of 60 mm Hg, which is 10 mm Hg higher compared to that in the 2007 guideline; however, no justification for this increase was provided.
Methodology
Published thresholds of PP are based on office blood pressure measurement and often on arbitrary categorical analyses. In the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) and the International Database on HOme blood pressure in relation to Cardiovascular Outcome (IDHOCO), we determined outcome-driven thresholds for PP based on ambulatory or home blood pressure measurement, respectively.
Results
The main findings were that for people aged <60 years, PP did not refine risk stratification, whereas in older people the thresholds were 64 and 76 mm Hg for the ambulatory and home PP, respectively. However, PP provided little added predictive value over and beyond classical risk factors.
doi:10.1159/000369192
PMCID: PMC4646147  PMID: 26587443
Pulse pressure; Thresholds; Blood pressure measurement; Epidemiology; Cardiovascular diseases
16.  Left ventricular diastolic function associated with common genetic variation in ATP12A in a general population 
BMC Medical Genetics  2014;15:121.
Background
Left ventricular (LV) function depends on the activity of transmembrane electrolyte transporters. Failing human myocardium has lower Na+/K+ ATPase expression and higher intracellular sodium concentrations. The ATP12A gene encodes a catalytic subunit of an ATPase that can function as a Na+/K+ pump. We, therefore, investigated the association between LV function and common genetic variants in ATP12A.
Methods
A random sample of 1166 participants (53.7% women; mean age 49.5 years, 44.8% hypertensive) was recruited in Belgium, Poland, Italy and Russia. We measured transmitral early and late diastolic velocities (E and A) by pulsed wave Doppler, and mitral annular velocities (e’ and a’) by tissue Doppler. Using principal component analysis, we summarized 7 Doppler indexes – namely, E, A, e’ and a’ velocities, and their ratios (E/A, e’/a’, and E/e’) – into a single diastolic score. We genotyped 5 tag SNPs (rs963984, rs9553395, rs10507337, rs12872010, rs2071490) in ATP12A. In our analysis we focused on rs10507337 because it is located within a transcription factor binding site.
Results
In the population-based analyses while adjusting for covariables and accounting for family clusters and country, rs10507337 C allele carriers had significantly higher E/A (P = 0.003), e’ (P = 5.8×10−5), e’/a’ (P = 0.003) and diastolic score (P = 0.0001) compared to TT homozygotes. Our findings were confirmed in the haplotype analysis and in the family-based analyses in 74 informative offspring.
Conclusions
LV diastolic function as assessed by conventional and tissue Doppler indexes including a composite diastolic score was associated with genetic variation in ATP12A. Further experimental studies are necessary to clarify the role of ATP12A in myocardial relaxation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12881-014-0121-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12881-014-0121-6
PMCID: PMC4411923  PMID: 25366262
Epidemiology; Echocardiography; Diastolic function; ATP12A
17.  Left ventricular diastolic function in relation to the urinary proteome: A proof-of-concept study in a general population 
International Journal of Cardiology  2014;176(1):158-165.
Background
In previous studies, we identified two urinary proteomic classifiers, termed HF1 and HF2, which discriminated subclinical diastolic left ventricular (LV) dysfunction from normal. HF1 and HF2 combine information from 85 and 671 urinary peptides, mainly up- or down-regulated collagen fragments. We sought to validate these classifiers in a population study.
Methods
In 745 people randomly recruited from a Flemish population (49.8 years; 51.3% women), we measured early and late diastolic peak velocities of mitral inflow (E and A) and mitral annular velocities (e' and a') by conventional and tissue Doppler echocardiography, and the urinary proteome by capillary electrophoresis coupled with mass spectrometry.
Results
In the analyses adjusted for sex, age, body mass index, blood pressure, heart rate, LV mass index and intake of medications, we expressed effect sizes per 1-SD increment in the classifiers. HF1 was associated with 0.204 cm/s lower e' peak velocity (95% confidence interval, 0.057–0.351; p = 0.007) and 0.145 higher E/e' ratio (0.023–0.268; p = 0.020), while HF2 was associated with a 0.174 higher E/e' ratio (0.046–0.302; p = 0.008). According to published definitions, 67 (9.0%) participants had impaired LV relaxation and 96 (12.9%) had elevated LV filling pressure. The odds of impaired relaxation associated with HF1 was 1.38 (1.01–1.88; p = 0.043) and that of increased LV filling pressure associated with HF2 was 1.38 (1.00–1.90; p = 0.052).
Conclusions
In a general population, the urinary proteome correlated with diastolic LV dysfunction, proving its utility for early diagnosis of this condition.
Highlights
•Aim: to validate urinary proteomic markers for LV dysfunction in a population.•Result: LV diastolic dysfunction was associated with the urinary proteome.•Perspective: Screening for subclinical LV dysfunction becomes possible.
doi:10.1016/j.ijcard.2014.07.014
PMCID: PMC4155932  PMID: 25065337
Diastolic dysfunction; Urinary proteomics; Population science
18.  Heart ‘omics’ in AGEing (HOMAGE): design, research objectives and characteristics of the common database 
Journal of Biomedical Research  2014;28(5):349-359.
Abstract
Heart failure is common in older people and its prevalence is increasing. The Heart ‘omics’ in AGEing (HOMAGE) project aims to provide a biomarker approach that will improve the early diagnosis of heart failure. A large clinical database, based on (1) prospective population studies or (2) cross-sectional, prospective studies or randomized controlled trials (RCTs) of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising ‘omics’-based biomarkers to identify the risk of developing heart failure and/or comorbidities. Population studies, patient cohorts and RCTs are eligible for inclusion in the common database, if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors. Currently, the HOMAGE database includes 43,065 subjects, from 20 studies in eight European countries, including healthy subjects from three population studies in France, Belgium and Italy (n  =  7,124), patients with heart failure (n  =  4,312) from four cohorts in the UK, Spain and Switzerland and patients at high risk for cardiovascular disease (n  =  31,629) in 13 cohorts. It is anticipated that more partners will join the consortium and enlarge the pooled data. This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure.
doi:10.7555/JBR.28.20140045
PMCID: PMC4197385  PMID: 25332706
left ventricle; heart failure; heart failure with reduced ejection fraction; heart failure with preserved ejection fraction; population science; morbidity; mortality
19.  Estimation of Glomerular Filtration Rate Based on Serum Cystatin C versus Creatinine in a Uruguayan Population 
Background. Estimation of glomerular filtration rate (eGFR) from biomarkers has evolved and multiple equations are available to estimate renal function at bedside. Methods. In a random sample of 119 Uruguayans (54.5% women; 56.2 years (mean)), we used Bland and Altman's method and Cohen's kappa statistic to assess concordance on a continuous or categorical (eGFR < 60 versus ≥60 mL/min/1.73 m2) scale between eGFRcys (reference) and eGFR derived from serum creatinine according to the Modification of Diet in Renal Disease (eGFRmdrd) or the Chronic Kidney Disease Epidemiology Collaboration equations (eGFRepi) or from both serum cystatin C and creatinine (eGFRmix). Results. In all participants, eGFRmdrd, eGFRepi, and eGFRmix were, respectively, 9.7, 11.5, and 5.6 mL/min/1.73 m2 higher (P < 0.0001) than eGFRcys. The prevalence of eGFR <60 mL/min/1.73 m2 was the highest for eGFRcys (21.8%), intermediate for eGFRmix (11.8%), and the lowest for eGFRmdrd (5.9%) and eGFRepi (3.4%). Using eGFRcys as reference, we found only fair agreement with the equations based on creatinine (Cohen's kappa statistic 0.15 to 0.23). Conclusion. Using different equations we reached clinically significant differences in the estimation of renal function. eGFRcys provides lower estimates, resulting in higher prevalence of eGFR <60 mL/min/1.73 m2.
doi:10.1155/2014/837106
PMCID: PMC4158300  PMID: 25215234
20.  Randomised Double-Blind Comparison of Placebo and Active Drugs for Effects on Risks Associated with Blood Pressure Variability in the Systolic Hypertension in Europe Trial 
PLoS ONE  2014;9(8):e103169.
Background
In the Systolic Hypertension in Europe trial (NCT02088450), we investigated whether systolic blood pressure variability determines prognosis over and beyond level.
Methods
Using a computerised random function and a double-blind design, we randomly allocated 4695 patients (≥60 years) with isolated systolic hypertension (160–219/<95 mm Hg) to active treatment or matching placebo. Active treatment consisted of nitrendipine (10–40 mg/day) with possible addition of enalapril (5–20 mg/day) and/or hydrochlorothiazide (12.5–25.0 mg/day). We assessed whether on-treatment systolic blood pressure level (SBP), visit-to-visit variability independent of the mean (VIM) or within-visit variability (WVV) predicted total (n = 286) or cardiovascular (n = 150) mortality or cardiovascular (n = 347), cerebrovascular (n = 133) or cardiac (n = 217) endpoints.
Findings
At 2 years, mean between-group differences were 10.5 mm Hg (p<0.0001) for SBP, 0.29 units (p = 0.20) for VIM, and 0.07 mm Hg (p = 0.47) for WVV. Active treatment reduced (p≤0.048) cardiovascular (−28%), cerebrovascular (−40%) and cardiac (−24%) endpoints. In analyses dichotomised by the median, patients with low vs. high VIM had similar event rates (p≥0.14). Low vs. high WVV was not associated with event rates (p≥0.095), except for total and cardiovascular mortality on active treatment, which were higher with low WVV (p≤0.0003). In multivariable-adjusted Cox models, SBP predicted all endpoints (p≤0.0043), whereas VIM did not predict any (p≥0.058). Except for an inverse association with total mortality (p = 0.042), WVV was not predictive (p≥0.15). Sensitivity analyses, from which we excluded blood pressure readings within 6 months after randomisation, 6 months prior to an event or both were confirmatory.
Conclusions
The double-blind placebo-controlled Syst-Eur trial demonstrated that blood-pressure lowering treatment reduces cardiovascular complications by decreasing level but not variability of SBP. Higher blood pressure level, but not higher variability, predicted risk.
Trial Registration
ClinicalTrials.gov NCT02088450
doi:10.1371/journal.pone.0103169
PMCID: PMC4121168  PMID: 25090617
21.  Prognostic Value of Left Ventricular Diastolic Dysfunction in a General Population 
Background
New techniques of Tissue Doppler Imaging (TDI) enable the measurement of myocardial velocities and provide information about left ventricular (LV) diastolic function. Recent studies explored the prognostic role of TDI‐derived indexes. However, these studies considered only total mortality and did not provide information on cardiovascular mortality and morbidity. Therefore, we investigated in continuous and categorical analyses whether Doppler diastolic indexes contained any prognostic information over and beyond traditional cardiovascular risk factors in a general population.
Methods and Results
We measured early and late diastolic peak velocities of mitral inflow (E and A) by conventional Doppler, and the mitral annular velocities (e' and a') by TDI in 793 participants (mean age 50.9 years). We calculated multivariable‐adjusted hazard ratios for conventional and TDI Doppler indexes, while accounting for family cluster and cardiovascular risk factors. Median follow‐up was 4.8 years (5th to 95th percentile, 3.0 to 5.4). With adjustments applied for covariables, e' velocity was a significant predictor of fatal and nonfatal cardiovascular (n=59; P=0.004) and cardiac events (n=40; P=0.001). TDI e' yielded a net reclassification improvement of 54.2% for cardiovascular and 64.0% for cardiac events. Hazard ratios of all cardiovascular (2.21; P=0.042) and cardiac (4.50; P=0.002) events were significantly elevated in participants with increased LV filling pressure compared with subjects with normal diastolic function.
Conclusions
TDI e' velocity is a significant predictor of fatal and nonfatal cardiovascular events in a general population. Furthermore, we observed an increase in all cardiovascular events in the diastolic dysfunction group characterized by elevated LV filling pressure.
doi:10.1161/JAHA.114.000789
PMCID: PMC4309065  PMID: 24780207
diastole; echocardiography; epidemiology; survival; tissue Doppler imaging
22.  Heritability and Clinical Determinants of Serum Indoxyl Sulfate and p-Cresyl Sulfate, Candidate Biomarkers of the Human Microbiome Enterotype 
PLoS ONE  2014;9(5):e79682.
Background
Indoxyl sulfate and p-cresyl sulfate are unique microbial co-metabolites. Both co-metabolites have been involved in the pathogenesis of accelerated cardiovascular disease and renal disease progression. Available evidence suggests that indoxyl sulfate and p-cresyl sulfate may be considered candidate biomarkers of the human enterotype and may help to explain the link between diet and cardiovascular disease burden.
Objective and Design
Information on clinical determinants and heritability of indoxyl sulfate and p-cresyl sulfate serum is non-existing. To clarify this issue, the authors determined serum levels of indoxyl sulfate and p-cresyl sulfate in 773 individuals, recruited in the frame of the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO study).
Results
Serum levels of indoxyl sulfate and p-cresyl sulfate amounted to 3.1 (2.4–4.3) and 13.0 (7.4–21.5) μM, respectively. Regression analysis identified renal function, age and sex as independent determinants of both co-metabolites. Both serum indoxyl sulfate (h2 = 0.17) and p-cresyl sulfate (h2 = 0.18) concentrations showed moderate but significant heritability after adjustment for covariables, with significant genetic and environmental correlations for both co-metabolites.
Limitations
Family studies cannot provide conclusive evidence for a genetic contribution, as confounding by shared environmental effects can never be excluded.
Conclusions
The heritability of indoxyl sulfate and p-cresyl sulfate is moderate. Besides genetic host factors and environmental factors, also renal function, sex and age influence the serum levels of these co-metabolites.
doi:10.1371/journal.pone.0079682
PMCID: PMC4029585  PMID: 24850265
23.  Association of digital vascular function with cardiovascular risk factors: a population study 
BMJ Open  2014;4(3):e004399.
Objectives
Vasodilation of the peripheral arteries during reactive hyperaemia depends in part on release of nitric oxide from endothelial cells. Previous studies mainly employed a fingertip tonometric device to derive pulse wave amplitude (PWA) and PWA hyperaemic changes. An alternative approach is based on photoplethysmography (PPG). We sought to evaluate the correlates of digital PPG PWA hyperaemic responses as a measure of peripheral vascular function.
Design
The Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) is a population-based cohort study.
Setting
Respondents were examined at one centre in northern Belgium.
Participants
For this analysis, our sample consisted of 311 former participants (53.5% women; mean age 52.6 years; 43.1% hypertensive), who were examined from January 2010 until March 2012 (response rate 85.1%).
Primary outcome measures
Using a fingertip PPG device, we measured digital PWA at baseline and at 30 s intervals for 4 min during reactive hyperaemia induced by a 5 min forearm cuff occlusion. We performed stepwise regression to identify correlates of the hyperaemic response ratio for each 30 s interval after cuff deflation.
Results
The maximal hyperaemic response was detected in the 30–60 s interval. The explained variance for the PPG PWA ratio ranged from 9.7% at 0–30 s interval to 22.5% at 60–90 s time interval. The hyperaemic response at each 30 s interval was significantly higher in women compared with men (p≤0.001). The PPG PWA changes at 0–90 s intervals decreased with current smoking (p≤0.0007) and at 0–240 s intervals decreased with higher body mass index (p≤0.035). These associations with sex, current smoking and body mass index were mutually independent.
Conclusions
Our study is the first to implement the new PPG technique to measure digital PWA hyperaemic changes in a general population. Hyperaemic response, as measured by PPG, is inversely associated with traditional cardiovascular risk factors such as male sex, smoking and obesity.
doi:10.1136/bmjopen-2013-004399
PMCID: PMC3975759  PMID: 24662447
population; endothelial function; vasodilation; photoplethysmography
24.  Risk Stratification by Self-Measured Home Blood Pressure across Categories of Conventional Blood Pressure: A Participant-Level Meta-Analysis 
PLoS Medicine  2014;11(1):e1001591.
Jan Staessen and colleagues compare the risk of cardiovascular, cardiac, or cerebrovascular events in patients with elevated office blood pressure vs. self-measured home blood pressure.
Please see later in the article for the Editors' Summary
Background
The Global Burden of Diseases Study 2010 reported that hypertension is worldwide the leading risk factor for cardiovascular disease, causing 9.4 million deaths annually. We examined to what extent self-measurement of home blood pressure (HBP) refines risk stratification across increasing categories of conventional blood pressure (CBP).
Methods and Findings
This meta-analysis included 5,008 individuals randomly recruited from five populations (56.6% women; mean age, 57.1 y). All were not treated with antihypertensive drugs. In multivariable analyses, hazard ratios (HRs) associated with 10-mm Hg increases in systolic HBP were computed across CBP categories, using the following systolic/diastolic CBP thresholds (in mm Hg): optimal, <120/<80; normal, 120–129/80–84; high-normal, 130–139/85–89; mild hypertension, 140–159/90–99; and severe hypertension, ≥160/≥100.
Over 8.3 y, 522 participants died, and 414, 225, and 194 had cardiovascular, cardiac, and cerebrovascular events, respectively. In participants with optimal or normal CBP, HRs for a composite cardiovascular end point associated with a 10-mm Hg higher systolic HBP were 1.28 (1.01–1.62) and 1.22 (1.00–1.49), respectively. At high-normal CBP and in mild hypertension, the HRs were 1.24 (1.03–1.49) and 1.20 (1.06–1.37), respectively, for all cardiovascular events and 1.33 (1.07–1.65) and 1.30 (1.09–1.56), respectively, for stroke. In severe hypertension, the HRs were not significant (p≥0.20). Among people with optimal, normal, and high-normal CBP, 67 (5.0%), 187 (18.4%), and 315 (30.3%), respectively, had masked hypertension (HBP≥130 mm Hg systolic or ≥85 mm Hg diastolic). Compared to true optimal CBP, masked hypertension was associated with a 2.3-fold (1.5–3.5) higher cardiovascular risk. A limitation was few data from low- and middle-income countries.
Conclusions
HBP substantially refines risk stratification at CBP levels assumed to carry no or only mildly increased risk, in particular in the presence of masked hypertension. Randomized trials could help determine the best use of CBP vs. HBP in guiding BP management. Our study identified a novel indication for HBP, which, in view of its low cost and the increased availability of electronic communication, might be globally applicable, even in remote areas or in low-resource settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, hypertension (high blood pressure) is the leading risk factor for cardiovascular disease and is responsible for 9.4 million deaths annually from heart attacks, stroke, and other cardiovascular diseases. Hypertension, which rarely has any symptoms, is diagnosed by measuring blood pressure, the force that blood circulating in the body exerts on the inside of large blood vessels. Blood pressure is highest when the heart is pumping out blood (systolic blood pressure) and lowest when the heart is refilling (diastolic blood pressure). European guidelines define optimal blood pressure as a systolic blood pressure of less than 120 millimeters of mercury (mm Hg) and a diastolic blood pressure of less than 80 mm Hg (a blood pressure of less than 120/80 mm Hg). Normal blood pressure, high-normal blood pressure, and mild hypertension are defined as blood pressures in the ranges 120–129/80–84 mm Hg, 130–139/85–89 mm Hg, and 140–159/90–99 mm Hg, respectively. A blood pressure of more than 160 mm Hg systolic or 100 mm Hg diastolic indicates severe hypertension. Many factors affect blood pressure; overweight people and individuals who eat salty or fatty food are at high risk of developing hypertension. Lifestyle changes and/or antihypertensive drugs can be used to control hypertension.
Why Was This Study Done?
The current guidelines for the diagnosis and management of hypertension recommend risk stratification based on conventionally measured blood pressure (CBP, the average of two consecutive measurements made at a clinic). However, self-measured home blood pressure (HBP) more accurately predicts outcomes because multiple HBP readings are taken and because HBP measurement avoids the “white-coat effect”—some individuals have a raised blood pressure in a clinical setting but not at home. Could risk stratification across increasing categories of CBP be refined through the use of self-measured HBP, particularly at CBP levels assumed to be associated with no or only mildly increased risk? Here, the researchers undertake a participant-level meta-analysis (a study that uses statistical approaches to pool results from individual participants in several independent studies) to answer this question.
What Did the Researchers Do and Find?
The researchers included 5,008 individuals recruited from five populations and enrolled in the International Database of Home Blood Pressure in Relation to Cardiovascular Outcome (IDHOCO) in their meta-analysis. CBP readings were available for all the participants, who measured their HBP using an oscillometric device (an electronic device for measuring blood pressure). The researchers used information on fatal and nonfatal cardiovascular, cardiac, and cerebrovascular (stroke) events to calculate the hazard ratios (HRs, indicators of increased risk) associated with a 10-mm Hg increase in systolic HBP across standard CBP categories. In participants with optimal CBP, an increase in systolic HBP of 10-mm Hg increased the risk of any cardiovascular event by nearly 30% (an HR of 1.28). Similar HRs were associated with a 10-mm Hg increase in systolic HBP for all cardiovascular events among people with normal and high-normal CBP and with mild hypertension, but for people with severe hypertension, systolic HBP did not significantly add to the prediction of any end point. Among people with optimal, normal, and high-normal CBP, 5%, 18.4%, and 30.4%, respectively, had a HBP of 130/85 or higher (“masked hypertension,” a higher blood pressure in daily life than in a clinical setting). Finally, compared to individuals with optimal CBP without masked hypertension, individuals with masked hypertension had more than double the risk of cardiovascular disease.
What Do These Findings Mean?
These findings indicate that HBP measurements, particularly in individuals with masked hypertension, refine risk stratification at CBP levels assumed to be associated with no or mildly elevated risk of cardiovascular disease. That is, HBP measurements can improve the prediction of cardiovascular complications or death among individuals with optimal, normal, and high-normal CBP but not among individuals with severe hypertension. Clinical trials are needed to test whether the identification and treatment of masked hypertension leads to a reduction of cardiovascular complications and is cost-effective compared to the current standard of care, which does not include HBP measurements and does not treat people with normal or high-normal CBP. Until then, these findings provide support for including HBP monitoring in primary prevention strategies for cardiovascular disease among individuals at risk for masked hypertension (for example, people with diabetes), and for carrying out HBP monitoring in people with a normal CBP but unexplained signs of hypertensive target organ damage.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001591.
This study is further discussed in a PLOS Medicine Perspective by Mark Caulfield
The US National Heart, Lung, and Blood Institute has patient information about high blood pressure (in English and Spanish) and a guide to lowering high blood pressure that includes personal stories
The American Heart Association provides information on high blood pressure and on cardiovascular diseases (in several languages); it also provides personal stories about dealing with high blood pressure
The UK National Health Service Choices website provides detailed information for patients about hypertension (including a personal story) and about cardiovascular disease
The World Health Organization provides information on cardiovascular disease and controlling blood pressure; its A Global Brief on Hypertension was published on World Health Day 2013
The UK charity Blood Pressure UK provides information about white-coat hypertension and about home blood pressure monitoring
MedlinePlus provides links to further information about high blood pressure, heart disease, and stroke (in English and Spanish)
doi:10.1371/journal.pmed.1001591
PMCID: PMC3897370  PMID: 24465187
25.  Double Product Reflects the Predictive Power of Systolic Pressure in the General Population: Evidence from 9,937 Participants 
American journal of hypertension  2013;26(5):665-672.
BACKGROUND
The double product (DP), consisting of the systolic blood pressure (SBP) multiplied by the pulse rate (PR), is an index of myocardial oxygen consumption, but its prognostic value in the general population remains unknown.
METHODS
We recorded health outcomes in 9,937 subjects (median age, 53.2 years; 47.3% women) randomly recruited from 11 populations and enrolled in the International Database on Ambulatory blood pressure in relation to Cardiovascular Outcomes (IDACO) study. We obtained the SBP, PR, and DP for these subjects as determined through 24-hour ambulatory monitoring.
RESULTS
Over a median period of 11.0 years, 1,388 of the 9,937 study subjects died, of whom 536 and 794, respectively, died of cardiovascular (CV) and non-CV causes, and a further 1,161, 658, 494, and 465 subjects, respectively, experienced a CV, cardiac, coronary, or cerebrovascular event. In multivariate-adjusted Cox models, not including SBP and PR, DP predicted total, CV, and non-CV mortality (standardized hazard ratio [HR], ≥ 1.10; P ≤ 0.02), and all CV, cardiac, coronary, and stroke events (HR, ≥ 1.21; P < 0.0001). For CV mortality (HR, 1.34 vs. 1.30; P = 0.71) and coronary events (1.28 vs. 1.21; P = 0.26), SBP and the DP were equally predictive. As compared with DP, SBP was a stronger predictor of all CV events (1.39 vs. 1.27; P = 0.002) and stroke (1.61 vs. 1.36; P < 0.0001), and a slightly stronger predictor of cardiac events (1.32 vs. 1.22; P = 0.06). In fully adjusted models, including both SBP and PR, the predictive value of DP disappeared for fatal endpoints (P ≥ 0.07), coronary events (P = 0.06), and stroke (P = 0.12), or DP was even inversely associated with the risk of all CV and cardiac events (both P ≤ 0.01).
CONCLUSION
In the general population, we did not observe DP to add to risk stratification over and beyond SBP and PR.
doi:10.1093/ajh/hps119
PMCID: PMC3792705  PMID: 23391621
blood pressure; double product; systolic blood pressure; cardiovascular risk; hypertension; general population

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