Teemu J. Niiranen

Outcome-Driven Thresholds for Home Blood Pressure Measurement: International Database of HOme blood pressure in relation to Cardiovascular Outcome

The lack of outcome-driven operational thresholds limits the clinical application of home blood pressure (BP) measurement. Our objective was to determine an outcome-driven reference frame for home BP measurement. We measured home and clinic BP in 6470 participants (mean age, 59.3 years; 56.9% women; 22.4% on antihypertensive treatment) recruited in Ohasama, Japan (n=2520); Montevideo, Uruguay (n=399); Tsurugaya, Japan (n=811); Didima, Greece (n=665); and nationwide in Finland (n=2075). In multivariable-adjusted analyses of individual subject data, we determined home BP thresholds, which yielded 10-year cardiovascular risks similar to those associated with stages 1 (120/80 mm Hg) and 2 (130/85 mm Hg) prehypertension, and stages 1 (140/90 mm Hg) and 2 (160/100 mm Hg) hypertension on clinic measurement. During 8.3 years of follow-up (median), 716 cardiovascular end points, 294 cardiovascular deaths, 393 strokes, and 336 cardiac events occurred in the whole cohort; in untreated participants these numbers were 414, 158, 225, and 194, respectively. In the whole cohort, outcome-driven systolic/diastolic thresholds for the home BP corresponding with stages 1 and 2 prehypertension and stages 1 and 2 hypertension were 121.4/77.7, 127.4/79.9, 133.4/82.2, and 145.4/86.8 mm Hg; in 5018 untreated participants, these thresholds were 118.5/76.9, 125.2/79.7, 131.9/82.4, and 145.3/87.9 mm Hg, respectively. Rounded thresholds for stages 1 and 2 prehypertension and stages 1 and 2 hypertension amounted to 120/75, 125/80, 130/85, and 145/90 mm Hg, respectively. Population-based outcome-driven thresholds for home BP are slightly lower than those currently proposed in hypertension guidelines. Our current findings could inform guidelines and help clinicians in diagnosing and managing patients.nn# Novelty and Significance {#article-title-32}The lack of outcome-driven operational thresholds limits the clinical application of home blood pressure (BP) measurement. Our objective was to determine an outcome-driven reference frame for home BP measurement. We measured home and clinic BP in 6470 participants (mean age, 59.3 years; 56.9% women; 22.4% on antihypertensive treatment) recruited in Ohasama, Japan (n=2520); Montevideo, Uruguay (n=399); Tsurugaya, Japan (n=811); Didima, Greece (n=665); and nationwide in Finland (n=2075). In multivariable-adjusted analyses of individual subject data, we determined home BP thresholds, which yielded 10-year cardiovascular risks similar to those associated with stages 1 (120/80 mm Hg) and 2 (130/85 mm Hg) prehypertension, and stages 1 (140/90 mm Hg) and 2 (160/100 mm Hg) hypertension on clinic measurement. During 8.3 years of follow-up (median), 716 cardiovascular end points, 294 cardiovascular deaths, 393 strokes, and 336 cardiac events occurred in the whole cohort; in untreated participants these numbers were 414, 158, 225, and 194, respectively. In the whole cohort, outcome-driven systolic/diastolic thresholds for the home BP corresponding with stages 1 and 2 prehypertension and stages 1 and 2 hypertension were 121.4/77.7, 127.4/79.9, 133.4/82.2, and 145.4/86.8 mm Hg; in 5018 untreated participants, these thresholds were 118.5/76.9, 125.2/79.7, 131.9/82.4, and 145.3/87.9 mm Hg, respectively. Rounded thresholds for stages 1 and 2 prehypertension and stages 1 and 2 hypertension amounted to 120/75, 125/80, 130/85, and 145/90 mm Hg, respectively. Population-based outcome-driven thresholds for home BP are slightly lower than those currently proposed in hypertension guidelines. Our current findings could inform guidelines and help clinicians in diagnosing and managing patients.

Risk Stratification by Self-Measured Home Blood Pressure across Categories of Conventional Blood Pressure: A Participant-Level Meta-Analysis

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

Sex Differences and Similarities in Atrial Fibrillation Epidemiology, Risk Factors, and Mortality in Community Cohorts Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe)

Background: Atrial fibrillation (AF) is a common cardiac disease in aging populations with high comorbidity and mortality. Sex differences in AF epidemiology are insufficiently understood. Methods: In N=79u2009793 individuals without AF diagnosis at baseline (median age, 49.6 years; age range, 24.1–97.6 years; 51.7% women) from 4 community-based European studies (FINRISK, DanMONICA, Moli-sani Northern Sweden) of the BiomarCaRE consortium (Biomarker for Cardiovascular Risk Assessment in Europe), we examined AF incidence, its association with mortality, common risk factors, biomarkers, and prevalent cardiovascular disease, and their attributable risk by sex. Median follow-up time was 12.6 (to a maximum of 28.2) years. Results: Fewer AF cases were observed in women (N=1796; 4.4%), than in men (N=2465; 6.4%). Cardiovascular risk factor distribution and lipid profile at baseline were less beneficial in men than in women, and cardiovascular disease was more prevalent in men. Cumulative incidence increased markedly after the age of 50 years in men and after 60 years in women. The lifetime risk was similar (>30%) for both sexes. Subjects with incident AF had a 3.5-fold risk of death in comparison with those without AF. Multivariable-adjusted models showed sex differences for the association of body mass index and AF (hazard ratio per standard deviation increase, 1.18; 95% confidence interval [CI], 1.12–1.23 in women versus 1.31; 95% CI 1.25–1.38 in men; interaction P value of 0.001). Total cholesterol was inversely associated with incident AF with a greater risk reduction in women (hazard ratio per SD, 0.86; 95% CI, 0.81–0.90 versus 0.92; 95% CI, 0.88–0.97 in men; interaction P value of 0.023). No sex differences were seen for C-reactive protein and N-terminal pro B-type natriuretic peptide. The population-attributable risk of all risk factors combined was 41.9% in women and 46.0% in men. About 20% of the risk was observed for body mass index. Conclusions: Lifetime risk of AF was high, and AF was strongly associated with increased mortality both in women and men. Body mass index explained the largest proportion of AF risk. Observed sex differences in the association of body mass index and total cholesterol with AF need to be evaluated for underlying pathophysiology and relevance to sex-specific prevention strategies.

Optimal Number of Days for Home Blood Pressure Measurement

BACKGROUNDnCurrent guidelines make no outcome-based recommendations on the optimal measurement schedule for home blood pressure (BP).nnnMETHODSnWe enrolled 4,802 randomly recruited participants from three populations. The participants were classified by their (i) cross-classification according to office and home BP (normotension, masked hypertension, white-coat hypertension, and sustained hypertension) and (ii) home BP level (normal BP, high normal BP, grade 1 and 2 hypertension), while the number of home measurement days was increased from 1 to 7. The prognostic accuracy of home BP with an increasing number of home BP measurement days was also assessed by multivariable-adjusted Cox models.nnnRESULTSnAgreement in classification between consecutive measurement days indicated near perfect agreement (κ ≥ 0.9) after the sixth measurement day for both office and home BP cross-classification (97.8% maintained classification, κ = 0.97) and home BP level (93.6% maintained classification, κ = 0.91). Over a follow-up of 8.3 years, 568 participants experienced a cardiovascular event, and the first home BP measurement alone predicted events significantly (P ≤ 0.003). The confidence intervals (CIs) were too wide and overlapping to show superiority of multiple measurement days over the first measurement day (hazard ratios per 10mm Hg increase in systolic BP at initial day, 1.11 [CI 1.07-1.16]; that at 1-7 days, 1.18 [CI 1.12-1.24]). Masked hypertension, but not white-coat hypertension, was associated with increased cardiovascular risk, irrespective of the number of home measurement days.nnnCONCLUSIONnEven a single home BP measurement is a potent predictor of cardiovascular events, whereas seven home measurement days may be needed to reliably diagnose hypertension.

Relative Contributions of Arterial Stiffness and Hypertension to Cardiovascular Disease: The Framingham Heart Study

Background The presence and implications of abnormal arterial stiffness, a potential independent predictor of outcomes, in community‐dwelling treated hypertensives is unknown. Furthermore, limited data exist regarding the risk of cardiovascular disease (CVD) associated with arterial stiffness across the entire range of blood pressure. Methods and Results We measured carotid‐femoral pulse wave velocity (PWV) and classical CVD risk factors in 2127 community‐dwelling participants (mean age 60 years, 57% women) of The Framingham Offspring Cohort. The participants were divided into 4 groups according to hypertension (yes/no, defined as blood pressure ≥140/90 mm Hg or use of antihypertensive treatment) and PWV status (high/low based on age‐ and sex‐specific median values) and followed up for CVD events (CVD death, myocardial infarction, unstable angina, heart failure, and stroke). Sixty percent (233 of 390) of controlled and 90% (232 of 258) of uncontrolled treated hypertensives had high PWV. The multivariable‐adjusted risk for CVD events (n=248, median follow‐up 12.6 years) rose from normotension with low PWV (reference) to normotension with high PWV (hazard ratio 1.29, 95% CI 0.83–2.00) and from hypertension with low PWV (hazard ratio 1.54, 95% CI 1.01–2.36) to hypertension with high PWV (hazard ratio 2.25, 95% CI 1.54–3.29). Conclusions A substantial proportion of treated hypertensives have high arterial stiffness, a finding that may explain some of the notable residual CVD risk associated with even well‐controlled hypertension. High PWV is associated with a trend towards increasing CVD risk in both nonhypertensives and hypertensives, a finding that may support the use of arterial stiffness measurements in both populations.

Risk for hypertension crosses generations in the community: a multi-generational cohort study

AimsnParental hypertension is known to predict high blood pressure (BP) in children. However, the extent to which risk for hypertension is conferred across multiple generations, notwithstanding the impact of environmental factors, is unclear. Our objective was therefore to evaluate the degree to which risk for hypertension extends across multiple generations of individuals in the community.nnnMethods and resultsnWe studied three generations of Framingham Heart Study participants with standardized blood pressure measurements performed at serial examinations spanning 5 decades (1948 through 2005): First Generation (nu2009=u20091809), Second Generation (nu2009=u20092631), and Third Generation (nu2009=u20093608, mean age 39 years, 53% women). To capture a more precise estimate of conferrable risk, we defined early-onset hypertension (ageu2009<55 years) as the primary exposure. In multinomial logistic regression models adjusting for standard risk factors as well as physical activity and daily intake of dietary sodium, risk for hypertension in the Third Generation was conferred simultaneously by presence of early-onset hypertension in parents [OR 2.10 (95% CI, 1.66-2.67), Pu2009<u20090.001] as well as in grandparents [OR 1.33 (95% CI, 1.12-1.58), Pu2009<u20090.01].nnnConclusionnEarly-onset hypertension in grandparents raises the risk for hypertension in grandchildren, even after adjusting for early-onset hypertension in parents and lifestyle factors. These results suggest that a substantial familial predisposition for hypertension exists, and this predisposition is not identical when assessed from one generation to the next. Additional studies are needed to elucidate the mechanisms underlying transgenerational risk for hypertension and its clinical implications.

Heritability and risks associated with early onset hypertension: multigenerational, prospective analysis in the Framingham Heart Study

Objective To determine the role of early onset versus late onset hypertension as a risk factor for hypertension in offspring and cardiovascular death. Design Multigenerational, prospective cohort study. Setting Framingham Heart Study. Participants Two generations of community dwelling participants with blood pressure measurements performed at serial examinations spanning six decades: 3614 first generation participants with mortality data and 1635 initially non-hypertensive second generation participants with data available on parental blood pressure. Main outcome measures The main outcome measures were relation of parental early onset hypertension (age <55 years) with incidence of hypertension in offspring, using regression analyses, and relation of age at hypertension onset with cause specific mortality using a case (cardiovascular death) versus control (non-cardiovascular death) design. Results In second generation participants, having one or both parents with late onset hypertension did not increase the risk of hypertension compared with having parents with no hypertension; by contrast, the hazard ratios of hypertension were 2.0 (95% confidence interval 1.2 to 3.5) and 3.5 (1.9 to 6.1) in participants with one and both parents with early onset hypertension, respectively. In first generation decedents, 1151 cardiovascular deaths occurred (including 630 coronary deaths). The odds of cardiovascular death increased linearly with decreasing age of hypertension onset (P<0.001 for trend). Compared with non-hypertensive participants, hypertension onset at age <45 years conferred an odds ratios of 2.2 (1.8 to 2.7) for cardiovascular death and 2.3 (1.8 to 2.9) for coronary death, whereas hypertension onset at age ≥65 years conferred a lower magnitude odds ratios of 1.5 (1.2 to 1.9) for cardiovascular death and 1.4 (0.98 to 1.9) for coronary death (P≤0.002 for differences in odds ratios between hypertension onset at age <45 and age ≥65). Conclusions Early onset and not late onset hypertension in parents was strongly associated with hypertension in offspring. In turn, early onset compared with late onset hypertension was associated with greater odds of cardiovascular, and particularly coronary, death. These findings suggest it may be important to distinguish between early onset and late onset hypertension as a familial trait when assessing an individual’s risk for hypertension, and as a specific type of blood pressure trait when estimating risk for cardiovascular outcomes in adults with established hypertension.

Incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities : a nationwide population-based study

BACKGROUNDnScant data exist on incidence rates, correlates, and prognosis of electrocardiographic P-wave abnormalities in the general population.nnnMETHODSnWe recorded ECG and measured conventional cardiovascular risk factors in 5667 Finns who were followed up for incident atrial fibrillation (AF). We obtained repeat ECGs from 3089 individuals 11years later.nnnRESULTSnThe incidence rates of prolonged P-wave duration, abnormal P terminal force (PTF), left P-wave axis deviation, and right P-wave axis deviation were 16.0%, 7.4%, 3.4%, and 2.2%, respectively. Older age and higher BMI were associated with incident prolonged P-wave duration and abnormal PTF (P≤0.01). Higher blood pressure was associated with incident prolonged P-wave duration and right P-wave axis deviation (P≤0.01). During follow-up, only prolonged P-wave duration predicted AF (multivariable-adjusted hazard ratio, 1.38; P=0.001).nnnCONCLUSIONSnModifiable risk factors associate with P-wave abnormalities that are common and may represent intermediate steps of atrial cardiomyopathy on a pathway leading to AF.

Multisystem Trajectories Over the Adult Life Course and Relations to Cardiovascular Disease and Death

BackgroundnComprehensive conjoint characterization of long-term trajectories representing several biological systems are lacking.nnnMethodsnWe measured serially indicators representing 14 distinct biological systems in up to 3453 participants attending four Framingham Study examinations: bone mineral density, body mass index (BMI), C-reactive protein, glomerular filtration rate, forced vital capacity (FVC), one-second forced expiratory volume/FVC ratio (FEV1/FVC), gait speed, grip strength, glycosylated hemoglobin (HbA1c), heart rate, left ventricular mass, Mini-Mental State Examination (MMSE), pulse pressure, and total/high-density lipoprotein cholesterol ratio (TC/HDL).nnnResultsnWe observed that correlations among the 14 sex-specific trajectories were modest (r<0.30 for 169 of 182 sex-specific correlations). During follow-up (median 8 years), 232 individuals experienced a CVD event and 393 participants died. In multivariable regression models, CVD incidence was positively related to trajectories of BMI, HbA1c, TC/HDL, gait time, and pulse pressure (P<0.06); mortality risk was related directly to trajectories of gait time, C-reactive protein, heart rate, and pulse pressure but inversely to MMSE, and FEV1/FVC (P<0.006). A unit increase in the trajectory risk score was associated a 2.80-fold risk of CVD (95% confidence interval [CI], 2.04-3.84, P<0.001), and a 2.71-fold risk of death (95% CI, 2.30-3.20, P<0.001). Trajectory risk scores were suggestive of a greater increase in model c-statistic compared to single occasion measures (delta-c compared to age- and sex-adjusted models: 0.032 vs. 0.026 for CVD; 0.042 vs. 0.030 for mortality).nnnConclusionnBiological systems age differentially over the life course. Longitudinal data on a parsimonious set of biomarkers reflecting key biological systems may facilitate identification of high-risk individuals.

Genome-wide association study of nocturnal blood pressure dipping in hypertensive patients

BackgroundReduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported.MethodsTo study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (nu2009=u2009204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo. Associations with Pu2009<u20091u2009×u200910−u20095 were further tested in two independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (nu2009=u2009183) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) (nu2009=u2009180). We also tested the genome-wide significant single nucleotide polymorphism (SNP) for association with left ventricular hypertrophy in GENRES.ResultsIn GENRES GWAS, rs4905794 near BCL11B achieved genome-wide significance (βu2009=u2009−u20094.8%, Pu2009=u20099.6u2009×u200910−u20099 for systolic and βu2009=u2009−u20094.3%, Pu2009=u20092.2u2009×u200910−u20096 for diastolic night-to-day BP ratio). Seven additional SNPs in five loci had P values <u20091u2009×u200910−u20095. The association of rs4905794 did not significantly replicate, even though in DYNAMIC the effect was in the same direction (βu2009=u2009−u20090.8%, Pu2009=u20090.4 for systolic and βu2009=u2009−u20091.6%, Pu2009=u20090.13 for diastolic night-to-day BP ratio). In GENRES, the associations remained significant even during administration of four different antihypertensive drugs. In separate analysis in GENRES, rs4905794 was associated with echocardiographic left ventricular mass (βu2009=u2009−u20097.6xa0g/m2, Pu2009=u20090.02).Conclusionsrs4905794 near BCL11B showed evidence for association with nocturnal BP dipping. It also associated with left ventricular mass in GENRES. Combined with earlier data, our results provide support to the idea that BCL11B could play a role in cardiovascular pathophysiology.