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Background: Falls and consequent injuries are prevalent in older adults. In this group, half of injury-related hospitalizations are associated with falls and the rate of falls increases with age. The evidence on the role of blood pressure and the use of antihypertensive treatment on the risk of falls remains unclear in oldest-old adults (≥85 years)., Objectives: To examine the association between systolic blood pressure (SBP) and incident falls with medical consequences in oldest-old adults and to analyse whether this association is modified by the use of antihypertensive treatments or the presence of cardiovascular disease., Methods: We analysed data from the Leiden 85-plus Study, a prospective, population-based cohort study with adults aged ≥85 years and a 5-year follow-up. Falls with medical consequences were reported by the treating physician of participants. We assessed the association between time-updated systolic blood pressure and the risk of falling over a follow-up period of five years using generalized linear mixed effects models with a binomial distribution and a logit link function. Subgroup analyses were performed to examine the role of antihypertensive treatment and the difference between participant with and without cardiovascular disease., Results: We analysed data from 544 oldest-old adults, 242 (44.4%) of which used antihypertensives. In 81 individuals (15%) ≥1 fall(s) were reported during the follow-up period. The odds for a fall decreased by a factor of 0.86 (95% CI 0.80 to 0.93) for each increase in blood pressure by 10 mmHg. This effect was specific to blood pressure values above 130mmHg. We did not find any evidence that the effect would be modified by antihypertensive treatment, but that there was a tendency that it would be weaker in participants with cardiovascular disease (OR 0.81, 95% CI 0.72 to 0.90 per 10mmHg) compared to those without cardiovascular disease (OR 0.94, 95% CI 0.84 to 1.05 per 10mmHg)., Conclusion: Our results point towards a possible benefit of higher blood pressure in the oldest-old with respect to falls independent of the use of antihypertensive treatments., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2023 Röthlisberger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT 4 ) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT 4 based on the risk of cardiovascular disease and mortality., Methods: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT 4 , and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT 4 , thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576., Findings: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT 4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT 4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT 4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT 4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality., Interpretation: There was a J-shaped association of FT 4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT 4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT 4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes., Funding: None., Competing Interests: Declaration of interests TIMK reports personal fees from IBSA, Meck, Berlin-Chemie, and Quidel; is an unpaid co-chair of the American Thyroid Association guidelines on thyroid and pregnancy. BBY reports grants from National Health and Medical Research Council, Fremantle Hospital Medical Research Foundation, and Ada Bartholomew Medical Research Trust. NR reports a grant from the Swiss National Science Foundation. SR reports a grant for an investigator-initiated trial by Merck; manufacturer of levothyroxine and speaker fees from Merck, Abbott Pharmaceuticals, IBSA (makers of levothyroxine). JWJ reports research grants from or was a speaker (with or without lecture fees) at (Continuing Medical Education accredited) meetings sponsored or supported by Abbott, Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Edwards Lifesciences, GE Healthcare, Johnson and Johnson, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Programme. DCB reports research grants from the National institutes of Health. DF reports a research grant from DFG SFB TR 296 LOCOTACT. RGJW reports a research grant from the Novo Nordisk Foundation Challenge Programme (NNF17OC0027812). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In the general population, an increase in low-density lipoprotein cholesterol (LDL-C) predicts higher cardiovascular disease risk, and lowering LDL-C can prevent cardiovascular disease and reduces mortality risk. Interestingly, in cohort studies that include very old populations, no or inverse associations between LDL-C and mortality have been observed. This study aims to investigate whether the association between LDL-C and mortality in the very old is modified by a composite fitness score., Methods: A 2-stage meta-analysis of individual participant data from the 5 observational cohort studies. The composite fitness score was operationalized by performance on a combination of 4 markers: functional ability, cognitive function, grip strength, and morbidity. We pooled hazard ratios (HR) from Cox proportional-hazards models for 5-year mortality risk for a 1 mmol/L increase in LDL-C. Models were stratified by high/low composite fitness score., Results: Composite fitness scores were calculated for 2 317 participants (median 85 years, 60% females participants), of which 994 (42.9%) had a high composite fitness score, and 694 (30.0%) had a low-composite fitness score. There was an inverse association between LDL-C and 5-year mortality risk (HR 0.87 [95% CI: 0.80-0.94]; p < .01), most pronounced in participants with a low-composite fitness score (HR 0.85 [95% CI: 0.75-0.96]; p = .01), compared to those with a high composite fitness score (HR = 0.98 [95% CI: 0.83-1.15]; p = .78), the test for subgroups differences was not significant., Conclusions: In this very old population, there was an inverse association between LDL-C and all-cause mortality, which was most pronounced in participants with a low-composite fitness scores., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Background and Aims: Mendelian randomization confirmed multiple risk factors for primary events of coronary artery disease (CAD), but no such studies have been performed on recurrent major coronary events despite interesting insights derived from other designs. We examined the associations between genetically-influenced classical cardiovascular risk factors and the risk of recurrent major coronary events in a cohort of CAD patients., Methods: We included all first-time CAD cases (defined as angina pectoris, chronic ischemic heart disease or acute myocardial infarction) of European ancestry from the UK Biobank. Cases were followed till the end of follow-up, death or when they developed a recurrent major coronary event (chronic ischemic heart disease or acute myocardial infarction). Standardized weighted genetic risk scores were calculated for body mass index (BMI), systolic blood pressure, LDL cholesterol and triglycerides., Results: From a total of 22,949 CAD patients (mean age at first diagnosis 59.8 (SD 7.3) years, 71.1% men), 12,539 (54.6%) reported a recurrent major coronary event within a period of maximum 17.8 years. One standard deviation higher genetically-determined LDL cholesterol was associated with a higher risk of a recurrent major coronary event (odds ratio: 1.08 [95% confidence interval: 1.05, 1.11]). No associations were observed for genetically-influenced BMI (1.00 [0.98, 1.03]), systolic blood pressure (1.01 [0.98, 1.03]) and triglycerides (1.02 [0.995, 1.05])., Conclusions: Despite the use risk-reducing medications following a first coronary event, this study provided genetic evidence that, of the classical risk factors, mainly high LDL cholesterol was associated with a higher risk of developing recurrent major coronary events., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: While randomized controlled trials have proven the benefits of blood pressure (BP) lowering in participating octogenarians, population-based observational studies suggest an association between low systolic blood pressure (SBP) and faster overall decline. This study investigates the effects of BP-lowering treatment, a history of cardiovascular diseases (CVD), and cognitive and physical fitness on the associations between SBP and health outcomes in the very old., Methods: Five cohorts from the Towards Understanding Longitudinal International older People Studies (TULIPS) consortium were included in a two-step individual participant data meta-analysis (IPDMA). We pooled hazard ratios (HR) from Cox proportional-hazards models for 5-year mortality and estimates of linear mixed models for change in cognitive and functional decline. Models were stratified by BP-lowering treatment, history of CVD, Mini-Mental State Examination scores, grip strength (GS) and body mass index (BMI)., Results: Of all 2480 participants (59.9% females, median 85 years), median baseline SBP was 149 mmHg, 64.3% used BP-lowering drugs and 47.3% had a history of CVD. Overall, higher SBP was associated with lower all-cause mortality (pooled HR 0.91 [95% confidence interval 0.88-0.95] per 10 mmHg). Associations remained irrespective of BP-lowering treatment, history of CVD and BMI, but were absent in octogenarians with above-median MMSE and GS. In pooled cohorts, SBP was not associated with cognitive and functional decline., Conclusion: While in the very old with low cognitive or physical fitness a higher SBP was associated with a lower all-cause mortality, this association was not evident in fit octogenarians. SBP was not consistently associated with cognitive and functional decline., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Disturbed cognitive function is associated with several causes of mortality; however, the association between cognitive function and the risk of cancer death has not been extensively investigated yet. We aimed to evaluate the association of cognitive function with the risk of cancer death and all-cause mortality in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) and Leiden 85-plus Study. Additionally, a systematic review and meta-analysis of longitudinal studies were conducted to evaluate the association of cognitive function and risk of cancer death., Methods: Risk of cancer death and all-cause mortality were reported using hazard ratios (HRs) with 95% confidence interval (CI) in tertiles of cognitive function of PROSPER and Leiden85-Plus Study. Additionally, PubMed, Embase, Web of Science, Cochrane, PsycINFO, Academic Search Premier, CINHAL, and Emcare were searched up to November 1st, 2020 to perform a systematic review and meta-analysis. The relative risks (RRs) with 95%CI of cancer death per each standard deviation lower performance in cognitive measurements were calculated., Results: Participants of PROSPER had 1.65-fold (95%CI 1.11-2.47) greater risk of cancer death (P for trend = 0.016) and 1.85-fold (95%CI 1.46-2.34) higher risk of all-cause mortality (P for trend<0.001), in multivariable models. Results of the Leiden-85 Plus Study showed that subjects with MMSE score below 24 had a lower chance of cancer death (HR 0.79, 95%CI 0.36-1.70, P for trend = 0.820) but had 2.18-fold (95%CI 1.57-3.02) higher risk of all-cause mortality compared to the reference group (P for trend<0.001). Besides, the results of systematic review and meta-analysis showed that per each standard deviation lower performance in cognitive function, individuals were at a 10% higher chance of cancer death (RR 1.10, 95%CI 1.00-1.20, P-value = 0.044)., Conclusions: Lower cognitive function performance is associated with a marginally increased risk of cancer death, in line with a significantly greater risk of all-cause mortality., Competing Interests: The authors have declared that no competing interests exist.

Background: translation of the available evidence concerning primary cardiovascular prevention into clinical guidance for the heterogeneous population of older adults is challenging. With this review, we aimed to give an overview of the thresholds and targets of antihypertensive drug therapy for older adults in currently used guidelines on primary cardiovascular prevention. Secondly, we evaluated the relationship between the advised targets and guideline characteristics, including guideline quality., Methods: we systematically searched PubMed, Embase, Emcare and five guideline databases. We selected guidelines with (i) numerical thresholds for the initiation or target values of antihypertensive drug therapy in context of primary prevention (January 2008-July 2020) and (ii) specific advice concerning antihypertensive drug therapy in older adults. We extracted the recommendations and appraised the quality of included guidelines with the AGREE II instrument., Results: thirty-four guidelines provided recommendations concerning antihypertensive drug therapy in older adults. Twenty advised a higher target of systolic blood pressure (SBP) for octogenarians in comparison with the general population and three advised a lower target. Over half of the guidelines (n = 18) recommended to target a SBP <150 mmHg in the oldest old, while four endorsed targets of SBP lower than 130 or 120 mmHg. Although many guidelines acknowledged frailty, only three gave specific thresholds and targets. Guideline characteristics, including methodological quality, were not related with the recommended targets., Conclusion: the ongoing debate concerning targets of antihypertensive treatment in older adults, is reflected in an inconsistency of recommendations across guidelines. Recommended targets are largely set on chronological rather than biological age., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The cardiovascular effects of treating older adults with subclinical hypothyroidism (SCH) are uncertain. Although concerns have been raised regarding a potential increase in cardiovascular side effects from thyroid hormone replacement, undertreatment may also increase the risk of cardiovascular events, especially for patients with cardiovascular disease (CVD)., Objective: To determine the effects of levothyroxine treatment on cardiovascular outcomes in older adults with SCH., Methods: Combined data of two parallel randomised double-blind placebo-controlled trials TRUST (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism - a randomised placebo controlled Trial) and IEMO80+ (the Institute for Evidence-Based Medicine in Old Age 80-plus thyroid trial) were analysed as one-stage individual participant data. Participants aged ≥65 years for TRUST (n=737) and ≥80 years for IEMO80+ (n=105) with SCH, defined by elevated TSH with fT4 within the reference range, were included. Participants were randomly assigned to receive placebo or levothyroxine, with titration of the dose until TSH level was within the reference range. Cardiovascular events and cardiovascular side effects of overtreatment (new-onset atrial fibrillation and heart failure) were investigated, including stratified analyses according to CVD history and age., Results: The median [IQR] age was 75.0 [69.7-81.1] years, and 448 participants (53.2%) were women. The mean TSH was 6.38± SD 5.7 mIU/L at baseline and decreased at 1 year to 5.66 ± 3.3 mIU/L in the placebo group, compared with 3.66 ± 2.1 mIU/L in the levothyroxine group (p<0.001), at a median dose of 50 μg. Levothyroxine did not significantly change the risk of any of the prespecified cardiovascular outcomes, including cardiovascular events (HR 0.74 [0.41-1.25]), atrial fibrillation (HR 0.69 [0.32-1.52]), or heart failure (0.41 [0.13-1.35]), or all-cause mortality (HR 1.28 [0.54-3.03]), irrespective of history of CVD and age., Conclusion: Treatment with levothyroxine did not significantly change the risk of cardiovascular outcomes in older adults with subclinical hypothyroidism, irrespective of a history of cardiovascular disease and age., Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT01660126] (TRUST); Netherlands Trial Register: NTR3851 (IEMO80+)., Competing Interests: SM reported receiving grants from ZonMW and nonfinancial support from Merck during the conduct of the study. RP reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. DS reported receiving grants from European Union FP7 and nonfinancial support from Merck Serono during the conduct of the study. NR reported receiving grants from the Swiss National Science Foundation and the Velux Foundation during the conduct of the study. KP reported receiving grants from Netherlands Organisation for Health Research and Development (ZonMw) and the European Union FP7-HEALTH-2011 programme during the conduct of the study. T-HC reported receiving grants from the Swiss National Science Foundation during the conduct of the study. JG reported receiving grants from European Union FP7 and ZonMw (627001001) and nonfinancial support from Merck KGaA during the conduct of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zijlstra, Jukema, Westendorp, Du Puy, Poortvliet, Kearney, O’Keeffe, Dekkers, Blum, Rodondi, Collet, Quinn, Sattar, Stott, Trompet, den Elzen, Gussekloo and Mooijaart.)

Background: Whether latent cytomegalovirus (CMV) infection in older adults has any substantial health consequences is unclear. Here, we sought associations between CMV-seropositivity and IgG titer with all-cause and cardiovascular mortality in 5 longitudinal cohorts., Methods: Leiden Longevity Study, Prospective Study of Pravastatin in the Elderly at Risk, Longitudinal Study of Aging Danish Twins, and Leiden 85-plus Study were assessed at median (2.8-11.4 years) follow-up . Cox regression and random effects meta-analysis were used to estimate mortality risk dependent on CMV serostatus and/or IgG antibody titer, in quartiles after adjusting for confounders., Results: CMV-seropositivity was seen in 47%-79% of 10 122 white community-dwelling adults aged 59-93 years. Of these, 3519 had died on follow-up (579 from cardiovascular disease). CMV seropositivity was not associated with all-cause (hazard ratio [HR], 1.05; 95% confidence interval [CI], .97-1.14) or cardiovascular mortality (HR, 0.97; 95% CI, .83-1.13). Subjects in the highest CMV IgG quartile group had increased all-cause mortality relative to CMV-seronegatives (HR, 1.16; 95% CI, 1.04-1.29) but this association lost significance after adjustment for confounders (HR, 1.13; 95% CI, .99-1.29). The lack of increased mortality risk was confirmed in subanalyses., Conclusions: CMV infection is not associated with all-cause or cardiovascular mortality in white community-dwelling older adults., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

With increasing age, associations between traditional risk factors (TRFs) and cardiovascular disease (CVD) shift. It is unknown which mid-life risk factors remain relevant predictors for CVD in older people. We systematically searched PubMed and EMBASE on August 16th 2019 for studies assessing predictive ability of >1 of fourteen TRFs for fatal and non-fatal CVD, in the general population aged 60+. We included 12 studies, comprising 11 unique cohorts. TRF were evaluated in 2 to 11 cohorts, and retained in 0-70% of the cohorts: age (70%), diabetes (64%), male sex (57%), systolic blood pressure (SBP) (50%), smoking (36%), high-density lipoprotein cholesterol (HDL) (33%), left ventricular hypertrophy (LVH) (33%), total cholesterol (22%), diastolic blood pressure (20%), antihypertensive medication use (AHM) (20%), body mass index (BMI) (0%), hypertension (0%), low-density lipoprotein cholesterol (0%). In studies with low to moderate risk of bias, systolic blood pressure (SBP) (80%), smoking (80%) and HDL cholesterol (60%) were more often retained. Model performance was moderate with C-statistics ranging from 0.61 to 0.77. Compared to middle-aged adults, in people aged 60+ different risk factors predict CVD and current prediction models perform only moderate at best. According to most studies, age, sex and diabetes seem valuable predictors of CVD in old-age. SBP, HDL cholesterol and smoking may also have predictive value. Other blood pressure and cholesterol related variables, BMI, and LVH seem of very limited or no additional value. Without competing risk analysis, predictors are overestimated., Competing Interests: Declaration of competing interest None., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Many oldest-old (> 80-years) with multimorbidity and polypharmacy are at high risk of inappropriate use of medication, but we know little about whether and how GPs would deprescribe, especially in the frail oldest-old. We aimed to determine whether, how, and why Swiss GPs deprescribe for this population., Methods: GPs took an online survey that presented case-vignettes of a frail oldest-old patient with and without history of cardiovascular disease (CVD) and asked if they would deprescribe any of seven medications. We calculated percentages of GPs willing to deprescribe at least one medication in the case with CVD and compared these with the case without CVD using paired t-tests. We also included open-ended questions to capture reasons for deprescribing and asked which factors could influence their decision to deprescribe by asking for their agreement on a 5-point-Likert-scale., Results: Of the 282 GPs we invited, 157 (56%) responded: 73% were men; mean age was 56. In the case-vignette without CVD, 98% of GPs deprescribed at least one medication (usually cardiovascular preventive medications) stating it had no indication nor benefit. They would lower the dose or prescribe pain medication as needed to reduce side effects. Their response was much the same when the patient had a history of CVD. GPs reported they were influenced by 'risk' and 'benefit' of medications, 'quality of life', and 'life expectancy', and prioritized the patient's wishes and priorities when deprescribing., Conclusion: Swiss GPs were willing to deprescribe cardiovascular preventive medication when it lacked indication but tended to retain pain medication. Developing tools for GPs to assist them in balancing the risks and benefits of medication in the context of patient values may improve deprescribing activities in practice.

Objectives: We previously found large variations in general practitioner (GP) hypertension treatment probability in oldest-old (>80 years) between countries. We wanted to explore whether differences in country-specific cardiovascular disease (CVD) burden and life expectancy could explain the differences., Design: This is a survey study using case-vignettes of oldest-old patients with different comorbidities and blood pressure levels. An ecological multilevel model analysis was performed., Setting: GP respondents from European General Practice Research Network (EGPRN) countries, Brazil and New Zeeland., Subjects: This study included 2543 GPs from 29 countries., Main Outcome Measures: GP treatment probability to start or not start antihypertensive treatment based on responses to case-vignettes; either low (<50% started treatment) or high (≥50% started treatment). CVD burden is defined as ratio of disability-adjusted life years (DALYs) lost due to ischemic heart disease and/or stroke and total DALYs lost per country; life expectancy at age 60 and prevalence of oldest-old per country., Results: Of 1947 GPs (76%) responding to all vignettes, 787 (40%) scored high treatment probability and 1160 (60%) scored low. GPs in high CVD burden countries had higher odds of treatment probability (OR 3.70; 95% confidence interval (CI) 3.00-4.57); in countries with low life expectancy at 60, CVD was associated with high treatment probability (OR 2.18, 95% CI 1.12-4.25); but not in countries with high life expectancy (OR 1.06, 95% CI 0.56-1.98)., Conclusions: GPs' choice to treat/not treat hypertension in oldest-old was explained by differences in country-specific health characteristics. GPs in countries with high CVD burden and low life expectancy at age 60 were most likely to treat hypertension in oldest-old. Key Points  • General practitioners (GPs) are in a clinical dilemma when deciding whether (or not) to treat hypertension in the oldest-old (>80 years of age).  • In this study including 1947 GPs from 29 countries, we found that a high country-specific cardiovascular disease (CVD) burden (i.e. myocardial infarction and/or stroke) was associated with a higher GP treatment probability in patients aged >80 years.  • However, the association was modified by country-specific life expectancy at age 60. While there was a positive association for GPs in countries with a low life expectancy at age 60, there was no association in countries with a high life expectancy at age 60.  • These findings help explaining some of the large variation seen in the decision as to whether or not to treat hypertension in the oldest-old.

Background: Impaired cardiac function has been related to accelerated cognitive decline in late-life., Objective: To investigate whether higher levels of high sensitivity cardiac troponin T (hs-cTnT), a sensitive marker for myocardial injury, are associated with worse cognitive function in the oldest old., Methods: In 455 participants of the population-based Leiden 85-plus Study, hs-cTnT was measured at 86 years. Cognitive function was measured annually during four years with the Mini-Mental State Examination (MMSE)., Results: Participants in the highest gender-specific tertile of hs-cTnT had a 2.0-point lower baseline MMSE score than participants in the lowest tertile (95% confidence interval (CI) (95% CI 0.73-3.3), and had a 0.58-point steeper annual decline in MMSE during follow-up (95% CI 0.06-1.1). The associations remained after adjusting for sociodemographic and cardiovascular risk factors excluding those without a history of overt cardiac disease., Conclusion: In a population-based sample of the oldest old, higher levels of hs-cTnT were associated with worse cognitive function and faster cognitive decline, independently from cardiovascular risk factors and a history of overt cardiac disease.

Background: To date, no validated risk scores exist for prediction of recurrence risk or potential treatment effect for older people with a history of a cardiovascular event. Therefore, we assessed predictive values for recurrent cardiovascular disease of models with age and sex, traditional cardiovascular risk markers, and 'SMART risk score', all with and without addition of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Treatment effect of pravastatin was assessed across low and high risk groups identified by the best performing models., Design and Methods: Post-hoc analysis in 2348 participants (age 70-82 years) with a history of cardiovascular disease within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study. Composite endpoint was a recurrent cardiovascular event/cardiovascular mortality., Results: The models with age and sex, traditional risk markers and SMART risk score had comparable predictive values (area under the curve (AUC) 0.58, 0.61 and 0.59, respectively). Addition of NT-proBNP to these models improved AUCs with 0.07 (p for difference ((pdiff)) = 0.003), 0.05 (pdiff = 0.009) and 0.06 (pdiff < 0.001), respectively. For the model with age, sex and NT-proBNP, the hazard ratio for the composite endpoint in pravastatin users compared with placebo was 0.67 (95% confidence interval 0.49-0.90) for those in the highest third of predicted risk and 0.91 (0.57-1.46) in the lowest third, number needed to treat 12 and 115 (pdiff = 0.038) respectively., Conclusion: In secondary cardiovascular prevention in old age addition of NT-proBNP improves prediction of recurrent cardiovascular disease, cardiovascular mortality and treatment effect of pravastatin. A minimal model including age, sex and NT-proBNP predicts as accurately as complex risk models including NT-proBNP., (© The European Society of Cardiology 2015.)

Background: Although guidelines recommend secondary cardiovascular prevention irrespective of age, in older age the uptake of treatment is lower than in younger age groups., Aim: To explore the dilemmas GPs in the Netherlands encounter when implementing guidelines for secondary cardiovascular prevention in older age., Design and Setting: Qualitative study in four focus groups consisting of GPs (n = 23, from the northern part of the province South Holland) and a fifth focus group consisting of GP trainees (n = 4, from the Leiden University Medical Center)., Method: Focus group discussions were organised to elicit perspectives on the implementation of secondary cardiovascular prevention for older people. The 14 theoretical domains of the refined Theoretical Domains Framework (TDF) were used for (deductive) coding of the focus group discussions. The coded texts were analysed, content was discussed, and barriers and facilitators were identified for each domain of the TDF., Results: The main theme that emerged was 'uncertainty'. Identified barriers were guideline-related, patient-related, and organisation-related. Identified facilitators were doctor-related, patient-related, and organisation-related. The main aim of secondary preventive treatment was improvement in quality of life., Conclusion: GPs in the Netherlands are uncertain about many aspects of secondary cardiovascular prevention in older age; the guidelines themselves, their own role, patient factors, and the organisation of care. In view of this uncertainty, GPs consciously weigh all aspects of the situation in close dialogue with the individual patient, with the ultimate aim of improving quality of life. This highly-individualised care may largely explain the reduced prescription rates., (© British Journal of General Practice 2015.)

Background: Visit-to-visit variability in blood pressure is an independent predictor of cardiovascular disease. This study investigates biological correlates of intra-individual variability in blood pressure in older persons., Methods: Nested observational study within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) among 3,794 male and female participants (range 70-82 years) with a history of, or risk factors for cardiovascular disease. Individual visit-to-visit variability in systolic and diastolic blood pressure and pulse pressure (expressed as 1 SD in mm Hg) was assessed using nine measurements over 2 years. Correlates of higher visit-to-visit variability were examined at baseline, including markers of inflammation, endothelial function, renal function and glucose homeostasis., Results: Over the first 2 years, the mean intra-individual variability (1 SD) was 14.4mm Hg for systolic blood pressure, 7.7mm Hg for diastolic blood pressure, and 12.6mm Hg for pulse pressure. After multivariate adjustment a higher level of interleukin-6 at baseline was consistently associated with higher intra-individual variability of blood pressure, including systolic, diastolic, and pulse pressure. Markers of endothelial function (Von Willebrand factor, tissue plasminogen activator), renal function (glomerular filtration rate) and glucose homeostasis (blood glucose, homeostatic model assessment index) were not or to a minor extent associated with blood pressure variability., Conclusion: In an elderly population at risk of cardiovascular disease, inflammation (as evidenced by higher levels of interleukin-6) is associated with higher intra-individual variability in systolic, diastolic, and pulse pressure., (© American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To assess the influence vulnerability and severity of cardiovascular disease (CVD), on prescription rates of secondary cardiovascular preventive drugs in old age., Design: Population-based observational study within the ISCOPE study., Setting: General practices in the Netherlands., Subjects: A total of 1350 patients with a history of CVD (median age 81 years, 50% female)., Main Outcome Measures: One-year prescription rates of lipid-lowering drugs and antithrombotics were obtained from the electronic medical records of 46 general practitioners (GPs). Prescription of both drugs for ≥ 270 days per year was considered optimal. GPs made a judgement of vulnerability. Severity of CVD was expressed as major (myocardial infarction, stroke, or arterial surgery) versus minor (angina, transient ischaemic attack, or claudication)., Results: GPs considered 411 (30%) participants to be vulnerable and 619 (55%) participants had major CVD. Optimal treatment was prescribed to 680 (50%) participants, whereas 370 (27%) received an antithrombotic drug only, 53 (4%) a lipid-lowering drug only, and 247 (18%) received neither. Optimal treatment was lower in participants aged ≥ 85 years (OR 0.37 [95% CI 0.29-0.48]), in females (OR 0.63 [0.50-0.78]), in vulnerable persons (OR 0.79 [0.62-0.99]) and in participants with minor CVD (OR 0.65 [0.53-0.81]). Multivariate ORs remained similar whereas vulnerability lost its significance (OR 0.88 [0.69-1.1])., Conclusion: In old age, GPs' judgement of vulnerability is not independently associated with lower treatment rates of both lipid-lowering drugs and antithrombotics, whereas a history of minor CVD is. Individual proactive re-evaluation of preventive treatment in older (female) patients, especially those with a history of minor CVD, is recommended. Key points Prescriptions of lipid-lowering drugs and antithrombotics in secondary cardiovascular prevention tend to decline with age. In this study with median age 81 years, 50% of participants received optimal treatment with both lipid-lowering drugs and antithrombotics. GPs' judgement of vulnerability was not independently associated with optimal treatment. A history of less severe cardiovascular disease was independently associated with lower prescription rates of lipid-lowering drugs and antithrombotics. Proactive individual re-evaluation of cardiovascular preventive treatment in older (female) patients, especially patients with less severe cardiovascular disease, is recommended.

Objective: Elevated levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) are associated with cognitive impairment, which might be explained by cardiovascular diseases or risk factors. The aim of this study was to investigate the association of NT-proBNP with cognitive function and decline in older adults at high risk of cardiovascular disease., Methods: We studied 5,205 men and women (mean age = 75 years) who were recruited into the PROspective Study of Pravastatin in the Elderly at Risk. All participants had pre-existing cardiovascular disease or risk factors thereof. Four domains of cognitive function were tested at baseline and repeated during a follow-up period of 3.2 years., Results: Participants with higher NT-proBNP (≥450ng/l) had worse baseline cognitive function, including reaction time (mean difference high vs low group = 3.07 seconds, 95% confidence interval [CI] = 0.83 to 5.32), processing speed (-1.02 digits coded, 95% CI = -1.65 to -0.39), and immediate memory (-0.13 pictures remembered, 95% CI = -0.29 to 0.04). There was no significant difference in delayed memory (-0.14, 95% CI = -0.38 to 0.10) between the NT-proBNP groups. Participants with higher NT-proBNP had a steeper cognitive decline, including reaction time (mean annual change high vs low group = 0.60 seconds, 95% CI = 0.14 to 1.07), processing speed (-0.15 digits coded, 95% CI = -0.25 to -0.05), immediate memory (-0.05 pictures remembered, 95% CI = -0.09 to 0.00), and delayed memory (-0.05 pictures remembered, 95% CI = -0.11 to 0.01). Associations were independent of cardiovascular diseases and risks., Interpretation: Higher NT-proBNP associates with worse cognitive function and steeper cognitive decline, independent of cardiovascular diseases and risks. Further studies to unravel the underlying mechanisms are warranted., (© 2014 American Neurological Association.)

In the aging society, it is important to identify very old persons at high risk of functional decline, cardiovascular disease and mortality. However, traditional risk markers lose their predictive value with age. We investigated whether plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels predict change in functional status, cardiovascular morbidity and mortality in very old age. Here we present an observational prospective cohort study (Leiden 85-plus Study, 1997-2004) in a population-based sample of 560 individuals aged 85 years with a 5-year complete follow-up for functional status, cardiovascular morbidity and cause-specific mortality. Median NT-proBNP for men was 351 pg/ml (cutoff values for low-medium tertiles 201 pg/ml and medium-high tertiles 649 pg/ml) and, for women, 297 pg/ml (cutoffs 204 and 519 pg/ml, respectively). During the 5-year follow-up, participants with high NT-proBNP had an accelerated cognitive decline and increase of activities of daily living (ADL) disability over time (all at p < 0.01) and an increased risk of incident heart failure [hazard ratio (HR) 3.3 (95 % confidence interval (CI) 1.8-6.1)], atrial fibrillation [HR 4.1 (2.0-8.7)], myocardial infarction [HR 2.1 (1.2-3.7)], stroke [HR 3.4 (1.9-6.3)], cardiovascular mortality [HR 5.5 (3.1-10)], non-cardiovascular mortality [HR 2.0 (1.4-3.0)] and all-cause mortality [HR 2.9 (2.1-4.0)], independent of other known risk markers. All results remained similar after exclusion of participants with heart failure at baseline. In very old age, high-NT-proBNP levels predict accelerated cognitive and functional decline, as well as cardiovascular morbidity and mortality. Results suggest that NT-proBNP can help clinicians to identify very old people at high risk of functional impairment and incident cardiovascular morbidity.

Background: In the aging population cardiovascular disease (CVD) is highly prevalent. Identification of very old persons at high risk of recurrent CVD is difficult, since traditional risk markers loose predictive value with age., Methods: In a population-based sample of 282 85-year old participants with established CVD from the Leiden 85-plus Study, we studied predictive values of traditional cardiovascular risk markers, a history of major CVD (myocardial infarction, stroke or arterial surgery), and new cardiovascular biomarkers (estimated glomerular filtration rate (MDRD), C-reactive protein (CRP), homocysteine and N-terminal pro B-type natriuretic peptide (NT-proBNP)) regarding 5-year risk of recurrent cardiovascular events and mortality (composite endpoint)., Results: During complete 5-year follow-up 157 (56%) participants died. 109 (39%) had a cardiovascular event or died from cardiovascular causes. Individually related to the composite endpoint were: a history of major CVD (HR 1.5 (95%CI 1.03-2.3)), CRP (HR 1.3 (95%CI 1.03-1.5)), homocysteine (HR 1.4 (95%CI 1.2-2.6)) and NT-proBNP (HR 1.7 (95%CI 1.4-2.1)). A prediction model including all traditional risk markers yielded a C-statistic of 0.59 (95%CI 0.52-0.66). Of all five new markers only addition of NT-proBNP improved the C-statistic (0.67 (95%CI 0.61-0.74, p=0.023)). The categoryless net reclassification improvement for NT-proBNP was 39% (p=0.001), for a history of major CVD 27.2% (p=0.03) and for homocysteine 24.7% (p=0.04)., Conclusions: Among very old subjects with established CVD, NT-proBNP was the strongest risk marker for cardiovascular events and cardiovascular mortality. When estimating risk in secondary prevention in very old age, use of NT-proBNP should be considered.

This study aimed to explore the prognosis of very old people depending on their cardiovascular disease (CVD) history. This observational prospective cohort study included 570 participants aged 85 years from the general population with 5-year follow-up for morbidity, functional status, and mortality. At baseline, participants were assigned to three groups: no CVD history, "minor" CVD (angina pectoris, transient ischemic attack, intermittent claudication, and/or heart failure), or "major" CVD (myocardial infarction [MI], stroke, and/or arterial surgery). Follow-up data were collected on MI, stroke, functional status, and cause-specific mortality. The composite endpoint included cardiovascular events (MI or stroke) and cardiovascular mortality. At baseline, 270 (47.4 %) participants had no CVD history, 128 (22.4 %) had minor CVD, and 172 (30.2 %) had major CVD. Compared to the no CVD history group, the risk of the composite endpoint increased from 1.6 (95 % confidence interval [CI], 1.1-2.4) for the minor CVD group to 2.7 (95 % CI, 2.0-3.9) for the major CVD group. Similar trends were observed for cardiovascular and all-cause mortality risks. In a direct comparison, the major CVD group had a nearly doubled risk of the composite endpoint (hazard ratio, 1.8; 95 % CI, 1.2-2.7), compared to the minor CVD group. Both minor and major CVD were associated with an accelerated decline in cognitive function and accelerated increase of disability score (all p < 0.05), albeit most pronounced in participants with major CVD. CVD disease status in very old age is still of important prognostic value: a history of major CVD (mainly MI or stroke) leads to a nearly doubled risk of poor outcome, including cardiovascular events, functional decline, and mortality, compared with a history of minor CVD.

Aims: Resting heart rate is a promising modifiable cardiovascular risk marker in older adults, but the mechanisms linking heart rate to cardiovascular disease are not fully understood. We aimed to assess the association between resting heart rate and incident heart failure (HF) and cardiovascular mortality, and to examine whether these associations might be attributable to systemic inflammation and endothelial dysfunction., Methods and Results: We studied 4084 older adults aged 70-82 years with known cardiovascular risk factors or previous cardiovascular disease, without pre-existing HF or beta-blockers in the PROSPER study. Over a 3.2-year follow-up period, we examined incident HF hospitalization and cardiovascular mortality according to resting heart rate, along with C-reactive protein (CRP), interleukin-6 (IL-6), tissue plasminogen activator (tPA), and von Willebrand factor (vWf). Mean heart rate was 67 b.p.m. for men and 70 b.p.m. for women. CRP, IL-6, tPA, and vWf levels were all positively correlated with heart rate. After multivariate adjustment, heart rate was associated with HF hospitalization [hazard ratio (HR) 1.78 for highest vs. lowest distribution third, 95% confidence interval (CI) 1.21-2.63, P= 0.003] and cardiovascular mortality (HR 1.74, 95% CI 1.23-2.47, P= 0.002). Further adjustment for both IL-6 and vWf levels decreased HR to 1.60 (95% CI 1.08-2.38, P= 0.020) for HF and to 1.50 (95% CI 1.04-2.15, P= 0.028) for cardiovascular mortality., Conclusion: Increased heart rate is associated with increased systemic inflammation and endothelial dysfunction. These factors are likely to contribute to, but do not fully explain, the risk of HF and cardiovascular death associated with increased heart rate in older age.

In the 2011 revision of the multidisciplinary guideline 'Cardiovascular Risk Management', the new age category '70-year olds' was added to the risk chart. Virtually all people aged 70 years and over have a 10-year risk of cardiovascular mortality and morbidity that exceeds 20%, and are therefore eligible for preventive medication when lifestyle changes fail. In view of the attenuating predictive value of classic risk factors with age, the authors of this commentary discuss the lack of a more age-differentiated approach for older persons. They underline the importance of including differences in the levels of vulnerability in older patients when making medication decisions. The risk of undue medicalisation of a large segment of the population is discussed. Alternative approaches are conveyed: the use of age-dependent thresholds for different risk categories, the use of relative risk charts, and the search for better risk markers in (very) old age.

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70-82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1-1.4; hazard ratio 1.1, 95% confidence interval 1.1-1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2-1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1-1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1-1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1-1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0-1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0-1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0-1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects.

Background: The production of erythropoietin is triggered by impaired oxygen delivery to the kidney, either because of anemia or hypoxemia. High erythropoietin levels have been shown to predict the risk of death among patients with chronic heart failure. We investigated the prognostic value of elevated erythropoietin levels on mortality among very elderly people in the general population., Methods: The Leiden 85-plus Study is a population-based prospective follow-up study involving 599 people aged 85 years in Leiden, the Netherlands, enrolled between September 1997 and September 1999. Erythropoietin levels were determined at age 86. For this analysis, we included 428 participants with a creatinine clearance of at least 30 mL/min. Mortality data, recorded until Feb. 1, 2008, were obtained from the municipal registry., Results: During follow-up, 324 (75.7%) participants died. Compared with participants whose erythropoietin levels were in the lowest tertile (reference group), those whose levels were in the middle tertile had a 25% increased risk of death (hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.95-1.64), and those whose levels were in the highest tertile had a 73% increased risk (HR 1.73, 95% CI 1.32-2.26) (p value for trend < 0.01). The association between erythropoietin levels and mortality remained largely unchanged after we adjusted for sex, creatinine clearance, hemoglobin level, comorbidity, smoking status and C-reactive protein level, and was similar for deaths from cardiovascular and noncardiovascular causes., Interpretation: Among people aged 85 years and older, elevated erythropoietin levels were associated with an increased risk of death, independent of hemoglobin levels.

Background: The prevalence and severity of chronic kidney disease (CKD) in primary care patients with diabetes or hypertension is unknown., Aim: To assess the prevalence and severity of CKD in patients with diabetes and hypertension; and identify whether age, sex, diabetes, and hypertension are associated with CKD., Design of Study: Cross-sectional survey., Setting: Two Dutch primary health care centres (15 954 enlisted patients)., Method: Patients, aged ≥ 25 years, with known diabetes type 2 (n = 471) or hypertension (n = 960), were selected on 1 October 2006. Initial screening uptake rates were assessed from the electronic patient records, and patients were invited when blood or urine measurements were missing. The presence of albuminuria was determined, glomerular filtration rate estimated, and clinical characteristics extracted., Results: Initial screening uptake rates were 93% and 69% for diabetes and hypertension, respectively, and increased to 97% (n = 455) and 87% (n = 836) after active invitation. The prevalence of CKD was 28% in diabetes and 21% in hypertension only. The presence of diabetes was independently associated with albuminuria (odds ratio [OR] 4.23; 95% confidence interval [CI] = 2.67 to 6.71), but not with decreased estimated GFR (eGFR) (OR 0.75; 95% CI = 0.54 to 1.04). Age showed the strongest association with decreased eGFR (OR 2.73; 95% CI = 2.02 to 3.70)., Conclusion: In primary care, more than one-quarter of patients with diabetes and about one-fifth of patients with hypertension have CKD. The high prevalence justifies longitudinal follow-up in order to evaluate whether intensified cardiovascular risk management is beneficial in this primary care population.

Objectives: To investigate whether plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) remains a specific marker of cardiac illness in very old age and can be used to identify very elderly people at high risk for death independent of the presence of known cardiac diagnoses., Design: Prospective, observational, population-based follow-up study within the Leiden 85-Plus Study of a 2-year birth cohort (1912-1914)., Setting: General population, municipality of Leiden, the Netherlands., Participants: Two hundred seventy-four participants were followed up from age 90 onward (median follow-up 42.3 months, interquartile range 20.2-50.2 months)., Measurements: Plasma NT-proBNP level, indicators of general health and functioning, and specific cardiac diagnoses at age 90 and mortality from age 90 onward., Results: Plasma levels of NT-proBNP were not correlated with indicators of poor health or poor functioning, but the level of NT-proBNP increased significantly with increasing numbers of cardiac diagnoses (P<.001). High NT-proBNP was associated with overall mortality in participants with (hazard ratio (HR)=2.8, 95% confidence interval (CI)=1.5-5.2) and without (HR=3.5, 95% CI=1.6-7.5) specific cardiac diagnoses. This was also found for cardiovascular mortality risks (with specific cardiac diagnoses HR=4.1, 95% CI=1.5-11 vs without HR=5.6, 95% CI=1.0-30) and noncardiovascular mortality risks (with specific cardiac diagnoses HR=1.9, 95% CI=0.84-4.5 vs without HR=3.4, 95% CI=1.3-8.6)., Conclusion: Plasma NT-proBNP is a disease-specific marker of cardiac illness in nonagenarians and can possibly be used as a predictor of mortality in elderly people with and without specific cardiac diagnoses.

Objectives: To investigate the performance of classic risk factors, and of some new biomarkers, in predicting cardiovascular mortality in very old people from the general population with no history of cardiovascular disease., Design: The Leiden 85-plus Study (1997-2004) is an observational prospective cohort study with 5 years of follow-up., Setting: General population of the city of Leiden, the Netherlands., Participants: Population based sample of participants aged 85 years (215 women and 87 men) with no history of cardiovascular disease; no other exclusion criteria. Main measurements Cause specific mortality was registered during follow-up. All classic risk factors included in the Framingham risk score (sex, systolic blood pressure, total and high density lipoprotein cholesterol, diabetes mellitus, smoking and electrocardiogram based left ventricular hypertrophy), as well as plasma concentrations of the new biomarkers homocysteine, folic acid, C reactive protein, and interleukin 6, were assessed at baseline., Results: During follow-up, 108 of the 302 participants died; 32% (35/108) of deaths were from cardiovascular causes. Classic risk factors did not predict cardiovascular mortality when used in the Framingham risk score (area under receiver operating characteristic curve 0.53, 95% confidence interval 0.42 to 0.63) or in a newly calibrated model (0.53, 0.43 to 0.64). Of the new biomarkers studied, homocysteine had most predictive power (0.65, 0.55 to 0.75). Entering any additional risk factor or combination of factors into the homocysteine prediction model did not increase its discriminative power., Conclusions: In very old people from the general population with no history of cardiovascular disease, concentrations of homocysteine alone can accurately identify those at high risk of cardiovascular mortality, whereas classic risk factors included in the Framingham risk score do not. These preliminary findings warrant validation in a separate cohort.

The high prevalence and incidence of cardiovascular disease in the oldest old justify consideration of both primary and secondary prevention measures in this age group. However, evidence for the effectiveness of any preventive intervention is lacking. Regarding primary prevention, it is also unknown which elderly are actually at risk of developing new cardiovascular disease.

Objective: To evaluate whether routinely performed ECGs in older people from the general population have added value for cardiovascular risk management beyond the information that is already available from their medical records., Design: Observational, prospective cohort study., Setting: General population., Subjects: A total of 566 participants aged 85 years (377 women, 189 men)., Methods: Lifelong history of cardiovascular disease was assessed through medical records obtained from general practitioners. Baseline ECGs were evaluated for prior myocardial infarction and atrial fibrillation. During a 5-year follow-up period, complete cardiovascular mortality and morbidity data were gathered., Results: During 5 years of follow-up, 262/566 (46%) participants died, of whom 102/262 (39%) died from cardiovascular disease. Participants with a history of cardiovascular disease at age 85 years (284/566, 50%) had an increased cardiovascular mortality (HR 2.7, 95% CI 1.8-4.1) and morbidity (HR (myocardial infarction) 2.1, 95% CI 1.3-3.6; HR (stroke) 2.7, 95% CI 1.6-4.9) compared with those without such a history. Participants with major ECG abnormalities (102/566, 18%) had an increased cardiovascular mortality (HR 1.8, 95% CI 1.1-2.8), but no increase of cardiovascular morbidity compared with those without major ECG abnormalities. In both participants with and without a history of cardiovascular disease, the presence of major ECG abnormalities was not associated with increased cardiovascular mortality or morbidity., Conclusions: In older people from the general population, a history of cardiovascular disease is a strong predictor of cardiovascular mortality and morbidity. Although abnormal findings on routine ECGs predict cardiovascular mortality, they do not provide additional prognostic information beyond the information available from medical records. Therefore, when accurate medical records are available, programmatic ECG recording is not effective in older people.

Background: Depression in old age is associated with an increased mortality risk of cardiovascular disease but the mortality risk from non-cardiovascular causes is disputed., Objective: To investigate the effect of depression on cardiovascular and non-cardiovascular mortality in old age., Methods: We prospectively followed 500 subjects from age 85 years onwards within the population-based Leiden 85-plus Study. Depressive symptoms were assessed annually with the 15-item Geriatric Depression Scale (GDS-15). Mortality risks were estimated in a Cox proportional-hazards model with the annual assessment of depression (GDS-15> or =4 points) as a time-dependent covariate., Results: During 1654 person-years of follow-up (mean per person, 3.2 years), depression was associated with a two-fold increase of all cause mortality [Relative Risk (RR), 1.83; 95% Confidence Interval (CI), 1.24-2.69] that was not explained by comorbid conditions. Both cardiovascular mortality and non-cardiovascular mortality contributed equally to the excess mortality (RR 1.95 and 1.75 respectively)., Conclusion: Depression in old age contributes to an increase of both cardiovascular and non-cardiovascular mortality. Motivational depletion may play an important role in the increased mortality in elderly with depression.

With the increase in life expectancy, death from cardiovascular disease has risen greatly. There is increasing evidence that inflammation plays an important role in cardiovascular disease. We postulate that the development of cardiovascular disease in old age is a late consequence of evolutionary programming for a pro-inflammatory response to resist infections in early age. In 311 women, aged 85 yr old, the production of the pro- and anti-inflammatory cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 was determined in lipopolysaccharide-stimulated whole blood samples and studied prospectively in association with cardiovascular mortality. High TNF-alpha was a risk factor for death from cardiovascular disease (relative risk [RR] = 1.56; 95% confidence interval [CI]: 1-2.40), whereas high IL-10 was protective (RR = 0.58; 95% CI: 0.40-0.85). A genetic variant of the IL-10 gene promoter, which is associated with lower IL-10 production, was found to predispose to a 2.8-fold higher cardiovascular mortality risk (95% CI: 1.17-6.60). Reproductive success, which was studied as a measure of evolutionary programming because it trades off with early survival by pro-inflammatory resistance genes, was negatively associated with an increasing production of TNF-alpha (RR = 0.77; 95% CI: 0.68-0.88), while a positive association with IL-10 was found (RR = 1.22; 95% CI: 1.05-1.41). We suggest that cardiovascular mortality is a late consequence of evolutionary programming for a pro-inflammatory response.

Background: The C282Y mutation in the gene for haemochromatosis (HFE) has been associated with various diseases at middle age. However, recent studies indicate that penetrance of the C282Y mutation is low. We explored the association between the C282Y mutation, iron metabolism, and morbidity and mortality in participants of the Leiden 85-plus., Study Design: A cross-sectional comparison and prospective follow-up was conducted in two unselected cohorts of 661 and 552 subjects. All subjects were aged 85 years and over. We determined the prevalence of C282Y homozygous and heterozygous subjects, and the association between the C282Y mutation and iron metabolism, all-cause and specific causes of death., Results: Prevalence of C282Y homozygosity in both cohorts was 0.2% (1/661 and 1/552, respectively) and of C282Y heterozygosity was 12.4% (82/661) and 11.4% (63/552), respectively. These estimates coincide exactly with reported estimates in younger age groups. Median ferritin level was 97 microg L-1 (IQR 39-162) for heterozygous carriers and 89 microg L-1 (IQR 41-157) for noncarriers (P = 0.66). The serum ferritin concentration for one C282Y homozygous subject, a woman aged 86 years at the time of enrollment in 1986, was 392 microg L-1. Cardiovascular morbidity was comparable between the C282Y heterozygous subjects and the noncarriers in both study cohorts. All-cause and cardiovascular mortality of carriers of the C282Y mutation was similar to that in noncarriers., Conclusions: We found two C282Y homozygous subjects, illustrating that homozygosity can be compatible with survival in very old ages. C282Y heterozygosity was not associated with history of cardiovascular disease morbidity, all cause mortality, cardiovascular mortality, or biochemical phenotype of haemochromatosis at old age.

The common apolipoprotein E (APOE) alleles epsilon2, epsilon3, and epsilon4 are associated with the risk of dementia and cardiovascular disease. Recently, two functional variants (- 219G/T and -491A/T) were identified in the promoter of the APOE gene that enable a further characterization of the role of the APOE locus in disease. We investigated the contribution of these APOE gene variants to dementia and cardiovascular mortality in old age using a population-based cohort of 648 subjects aged 85 years and over (Leiden 85-Plus Study). Genotypes containing an APOE epsilon4 allele were associated with a 4.1-fold (95% CI, 2.2-7.7) increased risk of dementia as compared to the epsilon3/epsilon3 genotype in old subjects. Moreover, homozygosity for the -219T allele was found to be associated with a 2.4-fold (95% CI, 1.0-5.8) increased risk independently of epsilon2 and epsilon4; the -491A/T variant was not associated with dementia. Over a 10-year follow-up period, the risk of cardiovascular mortality was not increased among epsilon4 carriers (RR, 0.6; 95% CI, 0.4-1.0) or -219T homozygous subjects (RR, 1.1; 95% CI, 0.7-1.7), nor did it decrease among -491T homozygous subjects (RR, 1.4; 95% CI, 0.6-3.1). In conclusion, both the APOE epsilon2/epsilon3/epsilon4 and the -219G/T variant were identified as risk factors for dementia but not cardiovascular mortality in old age. Our results support the hypothesis that both the isoform and the amount of APOE may influence the risk of dementia. Furthermore, they emphasize that variation at the APOE locus has a higher impact on the risk of dementia than on the risk of cardiovascular disease in old age., (Copyright 2001 Wiley-Liss, Inc.)

Objectives: To evaluate survival and causes of death in subjects with idiopathic senile gait disorders., Design: A population-based longitudinal study., Setting: Survival analysis of the oldest old within the Leiden 85-plus Study., Participants: We distinguished three different groups according to their gait: subjects with a normal gait (n = 25), subjects with senile gait disorders (n = 14), and subjects with gait disorders due to known disease (n = 87). The mean age was 90 years in all groups (range 87 to 97 years)., Measurements: The risk of all cause mortality and cardiovascular mortality was estimated over 5 years of follow-up in a Cox-proportional hazards model, adjusted for age and sex., Results: Eighty-nine of 126 subjects died during follow-up. Mean survival differed among the three groups (P log-rank = .01). All cause mortality risk was increased in subjects with senile gait disorders compared with subjects with a normal gait (RR = 2.8; 95% CI, 1.1-7.3, P = .03) and was similar to subjects with gait disorders caused by known disease (RR = 1.2; 95% CI: .6-2.5, P = .6). Mortality caused by cardiovascular disease also differed among the three groups (P log-rank = .03). The risk of cardiovascular death in subjects with senile gait disorders was twofold greater than in subjects with a normal gait (RR = 2.1; 95% CI, 0.4-10.3)., Conclusions: Senile gait disorders are related to subclinical, perhaps cardiovascular, disease. Senile gait disorders should not be accepted as an inevitable, benign concomitant of the normal aging process.