Katarzyna Stolarz-Skrzypek

Fatal and Nonfatal Outcomes, Incidence of Hypertension, and Blood Pressure Changes in Relation to Urinary Sodium Excretion

CONTEXT Extrapolations from observational studies and short-term intervention trials suggest that population-wide moderation of salt intake might reduce cardiovascular events. OBJECTIVE To assess whether 24-hour urinary sodium excretion predicts blood pressure (BP) and health outcomes. DESIGN, SETTING, AND PARTICIPANTS Prospective population study, involving 3681 participants without cardiovascular disease (CVD) who are members of families that were randomly enrolled in the Flemish Study on Genes, Environment, and Health Outcomes (1985-2004) or in the European Project on Genes in Hypertension (1999-2001). Of 3681 participants without CVD, 2096 were normotensive at baseline and 1499 had BP and sodium excretion measured at baseline and last follow-up (2005-2008). MAIN OUTCOME MEASURES Incidence of mortality and morbidity and association between changes in BP and sodium excretion. Multivariable-adjusted hazard ratios (HRs) express the risk in tertiles of sodium excretion relative to average risk in the whole study population. RESULTS Among 3681 participants followed up for a median 7.9 years, CVD deaths decreased across increasing tertiles of 24-hour sodium excretion, from 50 deaths in the low (mean, 107 mmol), 24 in the medium (mean, 168 mmol), and 10 in the high excretion group (mean, 260 mmol; P < .001), resulting in respective death rates of 4.1% (95% confidence interval [CI], 3.5%-4.7%), 1.9% (95% CI, 1.5%-2.3%), and 0.8% (95% CI, 0.5%-1.1%). In multivariable-adjusted analyses, this inverse association retained significance (P = .02): the HR in the low tertile was 1.56 (95% CI, 1.02-2.36; P = .04). Baseline sodium excretion predicted neither total mortality (P = .10) nor fatal combined with nonfatal CVD events (P = .55). Among 2096 participants followed up for 6.5 years, the risk of hypertension did not increase across increasing tertiles (P = .93). Incident hypertension was 187 (27.0%; HR, 1.00; 95% CI, 0.87-1.16) in the low, 190 (26.6%; HR, 1.02; 95% CI, 0.89-1.16) in the medium, and 175 (25.4%; HR, 0.98; 95% CI, 0.86-1.12) in the high sodium excretion group. In 1499 participants followed up for 6.1 years, systolic blood pressure increased by 0.37 mm Hg per year (P < .001), whereas sodium excretion did not change (-0.45 mmol per year, P = .15). However, in multivariable-adjusted analyses, a 100-mmol increase in sodium excretion was associated with 1.71 mm Hg increase in systolic blood pressure (P.<001) but no change in diastolic BP. CONCLUSIONS In this population-based cohort, systolic blood pressure, but not diastolic pressure, changes over time aligned with change in sodium excretion, but this association did not translate into a higher risk of hypertension or CVD complications. Lower sodium excretion was associated with higher CVD mortality.

Prognostic Value of Reading-to-Reading Blood Pressure Variability Over 24 Hours in 8938 Subjects From 11 Populations

In previous studies, of which several were underpowered, the relation between cardiovascular outcome and blood pressure (BP) variability was inconsistent. We followed health outcomes in 8938 subjects (mean age: 53.0 years; 46.8% women) randomly recruited from 11 populations. At baseline, we assessed BP variability from the SD and average real variability in 24-hour ambulatory BP recordings. We computed standardized hazard ratios (HRs) while stratifying by cohort and adjusting for 24-hour BP and other risk factors. Over 11.3 years (median), 1242 deaths (487 cardiovascular) occurred, and 1049, 577, 421, and 457 participants experienced a fatal or nonfatal cardiovascular, cardiac, or coronary event or a stroke. Higher diastolic average real variability in 24-hour ambulatory BP recordings predicted (P≤0.03) total (HR: 1.14) and cardiovascular (HR: 1.21) mortality and all types of fatal combined with nonfatal end points (HR: ≥1.07) with the exception of cardiac and coronary events (HR: ≤1.02; P≥0.58). Higher systolic average real variability in 24-hour ambulatory BP recordings predicted (P<0.05) total (HR: 1.11) and cardiovascular (HR: 1.16) mortality and all fatal combined with nonfatal end points (HR: ≥1.07), with the exception of cardiac and coronary events (HR: ≤1.03; P≥0.54). SD predicted only total and cardiovascular mortality. While accounting for the 24-hour BP level, average real variability in 24-hour ambulatory BP recordings added <1% to the prediction of a cardiovascular event. Sensitivity analyses considering ethnicity, sex, age, previous cardiovascular disease, antihypertensive treatment, number of BP readings per recording, or the night:day BP ratio were confirmatory. In conclusion, in a large population cohort, which provided sufficient statistical power, BP variability assessed from 24-hour ambulatory recordings did not contribute much to risk stratification over and beyond 24-hour BP.

Prognostic value of isolated nocturnal hypertension on ambulatory measurement in 8711 individuals from 10 populations

Background We and other investigators previously reported that isolated nocturnal hypertension on ambulatory measurement (INH) clustered with cardiovascular risk factors and was associated with intermediate target organ damage. We investigated whether INH might also predict hard cardiovascular endpoints. Methods and results We monitored blood pressure (BP) throughout the day and followed health outcomes in 8711 individuals randomly recruited from 10 populations (mean age 54.8 years, 47.0% women). Of these, 577 untreated individuals had INH (daytime BP <135/85 mmHg and night-time BP ≥120/70 mmHg) and 994 untreated individuals had isolated daytime hypertension on ambulatory measurement (IDH; daytime BP ≥135/85 mmHg and night-time BP <120/70 mmHg). During follow-up (median 10.7 years), 1284 deaths (501 cardiovascular) occurred and 1109 participants experienced a fatal or nonfatal cardiovascular event. In multivariable-adjusted analyses, compared with normotension (n = 3837), INH was associated with a higher risk of total mortality (hazard ratio 1.29, P = 0.045) and all cardiovascular events (hazard ratio 1.38, P = 0.037). IDH was associated with increases in all cardiovascular events (hazard ratio 1.46, P = 0.0019) and cardiac endpoints (hazard ratio 1.53, P = 0.0061). Of 577 patients with INH, 457 were normotensive (<140/90 mmHg) on office BP measurement. Hazard ratios associated with INH with additional adjustment for office BP were 1.31 (P = 0.039) and 1.38 (P = 0.044) for total mortality and all cardiovascular events, respectively. After exclusion of patients with office hypertension, these hazard ratios were 1.17 (P = 0.31) and 1.48 (P = 0.034). Conclusion INH predicts cardiovascular outcome in patients who are normotensive on office or on ambulatory daytime BP measurement.

Prognostic Value of the Morning Blood Pressure Surge in 5645 Subjects From 8 Populations

Previous studies on the prognostic significance of the morning blood pressure surge (MS) produced inconsistent results. Using the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcome, we analyzed 5645 subjects (mean age: 53.0 years; 54.0% women) randomly recruited in 8 countries. The sleep-through and the preawakening MS were the differences in the morning blood pressure with the lowest nighttime blood pressure and the preawakening blood pressure, respectively. We computed multivariable-adjusted hazard ratios comparing the risk in ethnic- and sex-specific deciles of the MS relative to the average risk in the whole study population. During follow-up (median: 11.4 years), 785 deaths and 611 fatal and nonfatal cardiovascular events occurred. While accounting for covariables and the night:day ratio of systolic pressure, the hazard ratio of all-cause mortality was 1.32 (95% CI: 1.09 to 1.59; P=0.004) in the top decile of the systolic sleep-through MS (≥37.0 mm Hg). For cardiovascular and noncardiovascular death, these hazard ratios were 1.18 (95% CI: 0.87 to 1.61; P=0.30) and 1.42 (95% CI: 1.11 to 1.80; P=0.005). For all cardiovascular, cardiac, coronary, and cerebrovascular events, the hazard ratios in the top decile of the systolic sleep-through MS were 1.30 (95% CI: 1.06 to 1.60; P=0.01), 1.52 (95% CI: 1.15 to 2.00; P=0.004), 1.45 (95% CI: 1.04 to 2.03; P=0.03), and 0.95 (95% CI: 0.68 to 1.32; P=0.74), respectively. Analysis of the preawakening systolic MS and the diastolic MS generated consistent results. In conclusion, a MS above the 90th percentile significantly and independently predicted cardiovascular outcome and might contribute to risk stratification by ambulatory blood pressure monitoring.

Significance of White-Coat Hypertension in Older Persons With Isolated Systolic Hypertension: A Meta-Analysis Using the International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes Population

The significance of white-coat hypertension in older persons with isolated systolic hypertension remains poorly understood. We analyzed subjects from the population-based 11-country International Database on Ambulatory Blood Pressure Monitoring in Relation to Cardiovascular Outcomes database who had daytime ambulatory blood pressure (BP; ABP) and conventional BP (CBP) measurements. After excluding persons with diastolic hypertension by CBP (≥90 mm Hg) or by daytime ABP (≥85 mm Hg), a history of cardiovascular disease, and persons <18 years of age, the present analysis totaled 7295 persons, of whom 1593 had isolated systolic hypertension. During a median follow-up of 10.6 years, there was a total of 655 fatal and nonfatal cardiovascular events. The analyses were stratified by treatment status. In untreated subjects, those with white-coat hypertension (CBP ≥140/<90 mm Hg and ABP <135/<85 mm Hg) and subjects with normal BP (CBP <140/<90 mm Hg and ABP <135/<85 mm Hg) were at similar risk (adjusted hazard rate: 1.17 [95% CI: 0.87–1.57]; P=0.29). Furthermore, in treated subjects with isolated systolic hypertension, the cardiovascular risk was similar in elevated conventional and normal daytime systolic BP as compared with those with normal conventional and normal daytime BPs (adjusted hazard rate: 1.10 [95% CI: 0.79–1.53]; P=0.57). However, both treated isolated systolic hypertension subjects with white-coat hypertension (adjusted hazard rate: 2.00; [95% CI: 1.43–2.79]; P<0.0001) and treated subjects with normal BP (adjusted hazard rate: 1.98 [95% CI: 1.49–2.62]; P<0.0001) were at higher risk as compared with untreated normotensive subjects. In conclusion, subjects with sustained hypertension who have their ABP normalized on antihypertensive therapy but with residual white-coat effect by CBP measurement have an entity that we have termed, “treated normalized hypertension.” Therefore, one should be cautious in applying the term “white-coat hypertension” to persons receiving antihypertensive treatment.

Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37–1.73]; combined P=2.58 · 10−13). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25–1.44; P=1.032 · 10−14). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16–3.66) for systolic and 1.40 (95% CI: 0.25–2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

Masked Hypertension in Diabetes Mellitus: Treatment Implications for Clinical Practice

Although distinguishing features of masked hypertension in diabetics are well known, the significance of antihypertensive treatment on clinical practice decisions has not been fully explored. We analyzed 9691 subjects from the population-based 11-country International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes. Prevalence of masked hypertension in untreated normotensive participants was higher ( P <0.0001) among 229 diabetics (29.3%, n=67) than among 5486 nondiabetics (18.8%, n=1031). Over a median of 11.0 years of follow-up, the adjusted risk for a composite cardiovascular end point in untreated diabetic-masked hypertensives tended to be higher than in normotensives (hazard rate [HR], 1.96; 95% confidence interval [CI], 0.97–3.97; P =0.059), similar to untreated stage 1 hypertensives (HR, 1.07; CI, 0.58–1.98; P =0.82), but less than stage 2 hypertensives (HR, 0.53; CI, 0.29–0.99; P =0.048). In contrast, cardiovascular risk was not significantly different in antihypertensive-treated diabetic-masked hypertensives, as compared with the normotensive comparator group (HR, 1.13; CI, 0.54–2.35; P =0.75), stage 1 hypertensives (HR, 0.91; CI, 0.49–1.69; P =0.76), and stage 2 hypertensives (HR, 0.65; CI, 0.35–1.20; P =0.17). In the untreated diabetic-masked hypertensive population, mean conventional systolic/diastolic blood pressure was 129.2±8.0/76.0±7.3 mm Hg, and mean daytime systolic/diastolic blood pressure 141.5±9.1/83.7±6.5 mm Hg. In conclusion, masked hypertension occurred in 29% of untreated diabetics, had comparable cardiovascular risk as stage 1 hypertension, and would require considerable reduction in conventional blood pressure to reach daytime ambulatory treatment goal. Importantly, many hypertensive diabetics when receiving antihypertensive therapy can present with normalized conventional and elevated ambulatory blood pressure that mimics masked hypertension. # Novelty and Significance {#article-title-46}Although distinguishing features of masked hypertension in diabetics are well known, the significance of antihypertensive treatment on clinical practice decisions has not been fully explored. We analyzed 9691 subjects from the population-based 11-country International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes. Prevalence of masked hypertension in untreated normotensive participants was higher (P<0.0001) among 229 diabetics (29.3%, n=67) than among 5486 nondiabetics (18.8%, n=1031). Over a median of 11.0 years of follow-up, the adjusted risk for a composite cardiovascular end point in untreated diabetic-masked hypertensives tended to be higher than in normotensives (hazard rate [HR], 1.96; 95% confidence interval [CI], 0.97–3.97; P=0.059), similar to untreated stage 1 hypertensives (HR, 1.07; CI, 0.58–1.98; P=0.82), but less than stage 2 hypertensives (HR, 0.53; CI, 0.29–0.99; P=0.048). In contrast, cardiovascular risk was not significantly different in antihypertensive-treated diabetic-masked hypertensives, as compared with the normotensive comparator group (HR, 1.13; CI, 0.54–2.35; P=0.75), stage 1 hypertensives (HR, 0.91; CI, 0.49–1.69; P=0.76), and stage 2 hypertensives (HR, 0.65; CI, 0.35–1.20; P=0.17). In the untreated diabetic-masked hypertensive population, mean conventional systolic/diastolic blood pressure was 129.2±8.0/76.0±7.3 mm Hg, and mean daytime systolic/diastolic blood pressure 141.5±9.1/83.7±6.5 mm Hg. In conclusion, masked hypertension occurred in 29% of untreated diabetics, had comparable cardiovascular risk as stage 1 hypertension, and would require considerable reduction in conventional blood pressure to reach daytime ambulatory treatment goal. Importantly, many hypertensive diabetics when receiving antihypertensive therapy can present with normalized conventional and elevated ambulatory blood pressure that mimics masked hypertension.

Blood pressure variability in relation to outcome in the International Database of Ambulatory blood pressure in relation to Cardiovascular Outcome

Ambulatory blood pressure (BP) monitoring provides information not only on the BP level but also on the diurnal changes in BP. In the present review, we summarized the main findings of the International Database on Ambulatory BP in relation to Cardiovascular Outcome (IDACO) with regard to risk stratification based on BP variability. The predictive accuracy of daytime and nighttime BP and the night-to-day BP ratio depended on the disease outcome under study and treatment status, and differed for fatal outcomes compared with the composite of fatal and nonfatal diseases. An exaggerated morning surge, exceeding the 90th percentile of the population, is an independent risk factor for mortality and cardiovascular and cardiac events. Conversely, a sleep-trough or preawakening morning surge in systolic BP below 20 mm Hg is probably not associated with an increased risk of death or cardiovascular events. BP variability as captured by the average of the daytime and nighttime s.d. weighted for the duration of the daytime and nighttime interval (s.d.dn) and the average real variability (ARV24) predicted the outcome, but improved the prediction of the composite of all cardiovascular events by only 0.1%. In conclusion, the IDACO observations support the concept that BP variability adds to risk stratification, but above all highlight that 24-h ambulatory BP level remains the main predictor to be considered in clinical practice.

Arterial stiffness, central hemodynamics, and cardiovascular risk in hypertension.

This review summarizes several scientific contributions at the recent Satellite Symposium of the European Society of Hypertension, held in Milan, Italy. Arterial stiffening and its hemodynamic consequences can be easily and reliably measured using a range of noninvasive techniques. However, like blood pressure (BP) measurements, arterial stiffness should be measured carefully under standardized patient conditions. Carotid-femoral pulse wave velocity has been proposed as the gold standard for arterial stiffness measurement and is a well recognized predictor of adverse cardiovascular outcome. Systolic BP and pulse pressure in the ascending aorta may be lower than pressures measured in the upper limb, especially in young individuals. A number of studies suggest closer correlation of end-organ damage with central BP than with peripheral BP, and central BP may provide additional prognostic information regarding cardiovascular risk. Moreover, BP-lowering drugs can have differential effects on central aortic pressures and hemodynamics compared with brachial BP. This may explain the greater beneficial effect provided by newer antihypertensive drugs beyond peripheral BP reduction. Although many methodological problems still hinder the wide clinical application of parameters of arterial stiffness, these will likely contribute to cardiovascular assessment and management in future clinical practice. Each of the abovementioned parameters reflects a different characteristic of the atherosclerotic process, involving functional and/or morphological changes in the vessel wall. Therefore, acquiring simultaneous measurements of different parameters of vascular function and structure could theoretically enhance the power to improve risk stratification. Continuous technological effort is necessary to refine our methods of investigation in order to detect early arterial abnormalities. Arterial stiffness and its consequences represent the great challenge of the twenty-first century for affluent countries, and “de-stiffening” will be the goal of the next decades.

Setting thresholds to varying blood pressure monitoring intervals differentially affects risk estimates associated with white-coat and masked hypertension in the population

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.