| 1. |
- Gavish, Benjamin, et al.
(författare)
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Predictive power of 24-h ambulatory pulse pressure and its components for mortality and cardiovascular outcomes in 11 848 participants recruited from 13 populations
- 2022
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Ingår i: Journal of Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 0263-6352 .- 1473-5598. ; 40:11, s. 2245-2255
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Tidskriftsartikel (refereegranskat)abstract
- Background: The role of pulse pressure (PP) 'widening' at older and younger age as a cardiovascular risk factor is still controversial. Mean PP, as determined from repeated blood pressure (BP) readings, can be expressed as a sum of two components: 'elastic PP' (elPP) and 'stiffening PP' (stPP) associated, respectively, with stiffness at the diastole and its relative change during the systole. We investigated the association of 24-h ambulatory PP, elPP, and stPP ('PP variables') with mortality and composite cardiovascular events in different age classes. Method: Longitudinal population-based cohort study of adults with baseline observations that included 24-h ambulatory BP. Age classes were age 40 or less, 40-50, 50-60, 60-70, and over 70 years. Co-primary endpoints were total mortality and composite cardiovascular events. The relative risk expressed by hazard ratio per 1SD increase for each of the PP variables was calculated from multivariable-adjusted Cox regression models. Results: The 11 848 participants from 13 cohorts (age 53 +/- 16 years, 50% men) were followed for up for 13.7 +/- 6.7 years. A total of 2946 participants died (18.1 per 1000 person-years) and 2093 experienced a fatal or nonfatal cardiovascular event (12.9 per 1000 person-years). Mean PP, elPP, and stPP were, respectively, 49.7, 43.5, and 6.2 mmHg, and elPP and stPP were uncorrelated (r = -0.07). At age 50-60 years, all PP variables displayed association with risk for almost all outcomes. From age over 60 years to age over 70 years, hazard ratios of of PP and elPP were similar and decreased gradually but differently for pulse rate lower than or higher than 70 bpm, whereas stPP lacked predictive power in most cases. For age 40 years or less, elPP showed protective power for coronary events, whereas stPP and PP predicted stroke events. Adjusted and unadjusted hazard ratio variations were similar over the entire age range. Conclusion: This study provides a new basis for associating PP components with outcome and arterial properties in different age groups and at different pulse rates for both old and young age. The similarity between adjusted and unadjusted hazard ratios supports the clinical usefulness of PP components but further studies are needed to assess the prognostic significance of the PP components, especially at the young age.
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| 2. |
- Greene, Chris, et al.
(författare)
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Microvascular stabilization via blood-brain barrier regulation prevents seizure activity
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Blood-brain barrier (BBB) dysfunction is associated with worse epilepsy outcomes however the underlying molecular mechanisms of BBB dysfunction remain to be elucidated. Tight junction proteins are important regulators of BBB integrity and in particular, the tight junction protein claudin-5 is the most enriched in brain endothelial cells and regulates size-selectivity at the BBB. Additionally, disruption of claudin-5 expression has been implicated in numerous disorders including schizophrenia, depression and traumatic brain injury, yet its role in epilepsy has not been fully deciphered. Here we report that claudin-5 protein levels are significantly diminished in surgically resected brain tissue from patients with treatment-resistant epilepsy. Concomitantly, dynamic contrast-enhanced MRI in these patients showed widespread BBB disruption. We show that targeted disruption of claudin-5 in the hippocampus or genetic heterozygosity of claudin-5 in mice exacerbates kainic acid-induced seizures and BBB disruption. Additionally, inducible knockdown of claudin-5 in mice leads to spontaneous recurrent seizures, severe neuroinflammation, and mortality. Finally, we identify that RepSox, a regulator of claudin-5 expression, can prevent seizure activity in experimental epilepsy. Altogether, we propose that BBB stabilizing drugs could represent a new generation of agents to prevent seizure activity in epilepsy patients.
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| 3. |
- McEvoy, John W., et al.
(författare)
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Isolated Diastolic Hypertension in the IDACO Study : An Age-Stratified Analysis Using 24-Hour Ambulatory Blood Pressure Measurements
- 2021
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Ingår i: Hypertension. - : Wolters Kluwer. - 0194-911X .- 1524-4563. ; 78:5, s. 1222-1231
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Tidskriftsartikel (refereegranskat)abstract
- The prognostic implications of isolated diastolic hypertension (IDH), as defined by 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, have not been tested using ambulatory blood pressure (BP) monitor thresholds (ie, 24-hour mean systolic BP <125 mm Hg and diastolic BP >= 75 mm Hg). We analyzed data from 11 135 participants in the IDACO (International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcomes). Using 24-hour mean ambulatory BP monitor values, we performed Cox regression testing independent associations of IDH with death or cardiovascular events. Analyses were conducted in the cohort overall, as well as after age stratification (<50 years versus >= 50 years). The median age at baseline was 54.7 years and 49% were female. Over a median follow-up of 13.8 years, 2836 participants died, and 2049 experienced a cardiovascular event. Overall, irrespective of age, IDH on 24-hour ambulatory BP monitor defined by 2017 American College of Cardiology/American Heart Association criteria was not significantly associated with death (hazard ratio, 0.95 [95% CI, 0.79-1.13]) or cardiovascular events (hazard ratio, 1.14 [95% CI, 0.94-1.40]), compared with normotension. However, among the subgroup <50 years old, IDH was associated with excess risk for cardiovascular events (2.87 [95% CI, 1.72-4.80]), with evidence for effect modification based on age (P interaction <0.001). In conclusion, using ambulatory BP monitor data, this study suggests that IDH defined by 2017 American College of Cardiology/American Heart Association criteria is not a risk factor for cardiovascular disease in adults aged 50 years or older but is a risk factor among younger adults. Thus, age is an important consideration in the clinical management of adults with IDH.
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| 4. |
- Melgarejo, Jesus D., et al.
(författare)
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Association of Fatal and Nonfatal Cardiovascular Outcomes With 24-Hour Mean Arterial Pressure
- 2021
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Ingår i: Hypertension. - : Wolters Kluwer. - 0194-911X .- 1524-4563. ; 77:1, s. 39-48
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Tidskriftsartikel (refereegranskat)abstract
- Major adverse cardiovascular events are closely associated with 24-hour blood pressure (BP). We determined outcome-driven thresholds for 24-hour mean arterial pressure (MAP), a BP index estimated by oscillometric devices. We assessed the association of major adverse cardiovascular events with 24-hour MAP, systolic BP (SBP), and diastolic BP (DBP) in a population-based cohort (n=11 596). Statistics included multivariable Cox regression and the generalized R-2 statistic to test model fit. Baseline office and 24-hour MAP averaged 97.4 and 90.4 mm Hg. Over 13.6 years (median), 2034 major adverse cardiovascular events occurred. Twenty-four-hour MAP levels of <90 (normotension, n=6183), 90 to <92 (elevated MAP, n=909), 92 to <96 (stage-1 hypertension, n=1544), and >= 96 (stage-2 hypertension, n=2960) mm Hg yielded equivalent 10-year major adverse cardiovascular events risks as office MAP categorized using 2017 American thresholds for office SBP and DBP. Compared with 24-hour MAP normotension, hazard ratios were 0.96 (95% CI, 0.80-1.16), 1.32 (1.15-1.51), and 1.77 (1.59-1.97), for elevated and stage-1 and stage-2 hypertensive MAP. On top of 24-hour MAP, higher 24-hour SBP increased, whereas higher 24-hour DBP attenuated risk (P<0.001). Considering the 24-hour measurements, R-2 statistics were similar for SBP (1.34) and MAP (1.28), lower for DBP than for MAP (0.47), and reduced to null, if the base model included SBP and DBP; if the ambulatory BP indexes were dichotomized according to the 2017 American guideline and the proposed 92 mm Hg for MAP, the R-2 values were 0.71, 0.89, 0.32, and 0.10, respectively. In conclusion, the clinical application of 24-hour MAP thresholds in conjunction with SBP and DBP refines risk estimates.
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| 5. |
- Melgarejo, Jesus D., et al.
(författare)
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Relative and Absolute Risk to Guide the Management of Pulse Pressure, an Age-Related Cardiovascular Risk Factor
- 2021
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Ingår i: American Journal of Hypertension. - : Oxford University Press. - 0895-7061 .- 1941-7225. ; 34:9, s. 929-938
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Pulse pressure (PP) reflects the age-related stiffening of the central arteries, but no study addressed the management of the PP-related risk over the human lifespan.METHODS In 4,663 young (18-49 years) and 7,185 older adults (>= 50 years), brachial PP was recorded over 24 hours. Total mortality and all major cardiovascular events (MACEs) combined were coprimary endpoints. Cardiovascular death, coronary events, and stroke were secondary endpoints.RESULTS In young adults (median follow-up, 14.1 years; mean PP, 45.1 mm Hg), greater PP was not associated with absolute risk; the endpoint rates were <= 2.01 per 1,000 person-years. The adjusted hazard ratios expressed per 10-mm Hg PP increments were less than unity (P <= 0.027) for MACE (0.67; 95% confidence interval [CI], 0.47-0.96) and cardiovascular death (0.33; 95% CI, 0.11-0.75). In older adults (median follow-up, 13.1 years; mean PP, 52.7 mm Hg), the endpoint rates, expressing absolute risk, ranged from 22.5 to 45.4 per 1,000 person-years and the adjusted hazard ratios, reflecting relative risk, from 1.09 to 1.54 (P < 0.0001). The PP-related relative risks of death, MACE, and stroke decreased >3-fold from age 55 to 75 years, whereas absolute risk rose by a factor 3.CONCLUSIONS From 50 years onwards, the PP-related relative risk decreases, whereas absolute risk increases. From a lifecourse perspective, young adulthood provides a window of opportunity to manage risk factors and prevent target organ damage as forerunner of premature death and MACE. In older adults, treatment should address absolute risk, thereby extending life in years and quality.
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