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Objective: To investigated the cross-sectional association between peripheral sensory nerve function and frailty among community-dwelling men, and examine whether type 2 diabetes (T2D) modifies this association., Methods: A sample of 349 men [mean age = 77.1 ± 6.4 years; 37 % with T2D] who previously (1990-1998) participated in the Bezafibrate Infarction Prevention (BIP) trial, underwent assessment of frailty and legs vibratory thresholds (LVT), a measure of peripheral sensory nerve function, as part of the BIP Neurocognitive study during 2011-2013. LVT was assessed using a graduated tuning fork and frailty was assessed using the Fried criteria. An ordered logistic regression model was used to assess the link between LVT and degrees of frailty and to test for effect modification by T2D., Results: Overall, 117 (33.5 %) of patients were non-frail, 134 (38.4 %) pre-frail, and 98 (28.1 %) frail. A significant interaction between LVT and T2D with regard to frailty was found. Among men with T2D, estimated OR (95%CI) for increasing frailty at the 1st, 2nd, and 3rd as compared to the top LVT quartile were 13.5 (3.4-54.3), 5.9 (1.5-23.5), and 4.4 (1.20-16.0), respectively. Among men without T2D, the estimated ORs for increasing frailty in patients at the 1st, 2nd, and 3rd quartiles compared to the top LVT quartile were 2.8 (1.1-7.4), 1.6 (0.6-4.1), and 2.5 (1.0-6.5), respectively., Conclusion: Frailty is significantly associated with worsening peripheral sensory nerve function, particularly among men with T2D., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Backgrounds and aims: Evidence from recent years highlighted the importance of the Mediterranean diet for brain health. We investigated the association between adherence to Mediterranean diet and change in cognitive functions two decades later in patients with cardiovascular disease (CVD). Methods: Participants were men with a history of CVD, who previously participated in the Bezafibrate Infarction Prevention (BIP) trial between 1990 and 1997, had a food diary record, and underwent cognitive evaluations 14.6 ± 1.9 years (T1) and 19.9 ± 1.0 years after baseline (T2) as part of the BIP Neurocognitive study ( n  = 200, mean age at 57.3 ± 6.3 years). Adherence to the Mediterranean diet was determined from the self-administered 4-day food diary record, with patients categorized into high, middle and poor levels of adherence if they received >5, 4-5 and <4 points, respectively. Cognitive function was assessed using the NeuroTrax computerized battery. Linear mixed models were applied. Results: Among the 200 patients, 52 (26%) had poor adherence, 98 (49%) had middle adherence and 50 (25%) had high levels of adherence to the Mediterranean diet. Those categorized to the poor adherence level had poorer cognitive function at T1 compared to the other groups. Additionally, poor vs. high level of adherence was associated with a greater decline in overall cognitive performance [ z -score = -0.23 and 95% confidence interval (CI), -0.43;-0.04; p  = 0.021] and in visual spatial functions (-0.46 95% CI, -0.86;-0.06; p  = 0.023). Conclusion: This study stresses the possible role of the Mediterranean diet in men with a high vascular burden and may set the ground for future intervention to reduce their risk for cognitive decline.

Introduction: Despite the impressive decline in mortality from atherosclerotic cardiovascular diseases (ASCVD), these diseases still account for a large proportion of the overall morbidity and mortality worldwide. A vast amount of research has demonstrated the key role played by circulating lipoproteins, and especially low-density lipoprotein (LDL), in the etiology of atherosclerosis, and numerous studies have proven the efficacy of interventions that lower the atherogenic lipoproteins in reducing morbidity and mortality from ASCVD. While previous guidelines placed an emphasis on the use HMG-CoA reductase inhibitors (statins) for the treatment of dyslipidemia, recent studies have shown that other LDL cholesterol lowering drugs, including ezetimibe and the PCSK9 inhibitors, can provide additional benefit when used in combination with (and in certain cases instead of) statins. These studies have also shown that blood LDL cholesterol levels lower than previously recommended targets provide additional benefit, without evidence of a threshold beyond which the benefit ceases and without excess adverse effects. The updated guidelines were formulated by a committee that consisted of representatives from the Israeli Society for the Research, Prevention and Treatment of Atherosclerosis, the Israel Society of Internal Medicine, the Israeli Heart Association, the Israeli Neurology Association and the Israel Association of Family Medicine. They provide recommendations for revised risk stratification of patients, novel target goals, and the use of evidence-based treatment and follow-up strategies with reference to specific patient sub-groups.

Introduction: Little is known about the association between obesity and sarcopenia - age-related loss of muscle mass and function - among patients with cardiovascular disease. We investigated the association between overweight, obesity, and sarcopenia among community-dwelling men in Israel with cardiovascular disease., Methods: A subset of 337 men (mean age at baseline 56.7 [SD, 6.5]) who previously (1990-1997) participated in the Bezafibrate Infarction Prevention trial underwent a neurovascular evaluation as part of the Bezafibrate Infarction Prevention Neurocognitive Study 15.0 (SD, 3.0) years after baseline and a sarcopenia evaluation 19.9 (SD, 1.0) years after baseline. We applied a multinomial logistic model to estimate odds ratios and 95% CIs for 3 categories of sarcopenia: no evidence of sarcopenia (ie, robust), probable sarcopenia, and sarcopenia., Results: We found sarcopenia among 54.3% of participants with obesity (body mass index [BMI, in kg/m 2 ] ≥30.0), 37.0% of participants who were overweight (25.0 ≤ BMI ≤29.9), and 24.8% of participants with normal weight (BMI 18.5 to 24.9). In a comparison of BMI ≥25.0 and BMI <25.0, adjusting for covariates, the odds ratio of having probable sarcopenia was 3.27 (95% CI, 1.68-6.36) and having sarcopenia was 5.31 (95% CI, 2.50-11.27)., Conclusion: We found a positive association between obesity and late-life sarcopenia and suggest that obesity might be an important modifiable risk factor related to sarcopenia among men with cardiovascular disease.

Objective: We investigated the association between severity of angina pectoris (AP) and subsequent late-life frailty among men with cardiovascular disease (CVD)., Method: A subset of 351 men (mean age at baseline 56.7 ± 6.5 years) who previously participated in the Bezafibrate Infarction Prevention, BIP trial (1990-1997) underwent a neurovascular evaluation as part of the BIP Neurocognitive study 15.0 ± 3.0 years after baseline (T1) and a frailty evaluation according to Fried 19.9 ± 1.0 years after baseline (T2). Severity of AP was assessed at baseline of the BIP trial using the Canadian Cardiovascular Society angina classification. We assessed the odds of being in the advanced rank of frailty status (robust, pre-frail, and frail) using ordered logistic regression., Results: Among 351 participants, 134 (38.2%) were classified as pre-frail and 100 (28.5%) as frail. Frailty was found among 42% participants in the AP class ≥2 and among 26% participants in the AP class <2. Adjusting for demographic, health-related and cognitive variables, odds ratio (OR), and 95% confidence interval (95% CI) for advanced rank of frailty was 2.68 (95% CI: 1.29-5.59) comparing AP class ≥2 to AP class <2., Discussion: Among men with CVD, severity of AP should be taken into risk consideration due to its strong association with late-life frailty, particularly among inactive participants and participants with cerebral microvascular damage.

Background: Recent studies suggest that impaired cerebrovascular reactivity (CVR), a marker of cerebral microvascular damage, is associated with a higher risk of stroke, cognitive decline, and mortality. We tested whether abnormal cerebrovascular status is associated with late-life frailty among men with pre-existing cardiovascular disease., Methods: A subset of 327 men (mean age at baseline 56.7 ± 6.5 years) who previously participated in the Bezafibrate Infarction Prevention (BIP) trial (1990-1997) and then in the BIP Neurocognitive Study underwent a neurovascular evaluation 14.6 ± 1.9 years after baseline (T1) and were evaluated for frailty 19.9 ± 1.0 years after baseline (T2). CVR was measured at T1 using the breath-holding index and carotid large-vessel disease using ultrasound. Frailty status was measured at T2 according to the physical phenotype developed by Fried. Patients were categorized into CVR tertiles with cutoff points at ≤0.57, 0.58-0.94, and ≥0.95 and also as normal or impaired (<0.69) CVR. We assessed the change in the odds of being in the advanced rank of frailty status (normal, prefrail, and frail) using ordered logistic regression., Results: After adjustment, the estimated OR (95% confidence intervals) for increasing frailty in the lower tertile was 1.94 (1.09-3.46) and in the middle tertile 1.24 (0.70-2.19), compared with the higher CVR tertile. The estimated OR for increasing frailty for patients with impaired vs. normal CVR was 1.76 (1.11-2.80)., Conclusions: These findings provide support that cerebral microvascular dysfunction among patients with pre-existing cardiovascular disease is related to prefrailty and frailty and suggest an added value of assessing the cerebral vascular functional status for identifying patients at-risk of developing frailty.

Aims: To assess the relationship between physical frailty and cognitive function among elderly men with a history of cardiovascular disease (CVD)., Methods: Three-hundred-twenty-four community-dwelling men with chronic CVD (mean age 77.2 ± 6.4 years) who previously participated in the Bezafibrate Infarction Prevention (BIP) trial (1990-1998) underwent assessment of frailty and cognitive function between 2011 and 2013. Physical frailty was assessed using the Fried phenotypic model, and cognitive performance overall and in memory, executive function, visuospatial and attention domains was evaluated using a validated set of computerized cognitive tests. Linear regression models were used to assess the cross-sectional relationship of frailty status and its components (gait speed, grip strength, weight loss, exhaustion and activity) with cognitive function overall and in specific domains, adjusting for age, education, smoking status, physical activity, history of myocardial infarction, hypertension, diabetes and dyslipidemia, systolic blood pressure, BMI and depression., Results: Of the 324 men, 91 (28%) were frail and 121 (37%) were pre-frail. After controlling for potential confounders, severity of frailty was strongly associated with global cognitive function (β = -8.0, 95%CI = -11.9,-4.1 and β = -3.3, 95%CI = -6.0,-0.5 comparing frail and pre-frail to non-frail, respectively), with the most profound associations observed in executive function and attention. Gait speed was associated with overall cognitive performance and with all cognitive domains assessed in this study, and activity with none., Conclusion: Cognitive function is poor among frail and pre-frail men with CVD, particularly in non-memory domains. Future research is warranted to address mechanisms and to assess the efficacy of interventions to improve physical and cognitive health., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: To explore the association of C-reactive protein (CRP) plasma levels with subsequent cognitive performance and decline among elderly individuals with pre-existing cardiovascular disease (CVD), and to assess the role of cerebrovascular indices in this relationship., Methods: CRP levels were measured in a subgroup of individuals with chronic CVD, who previously participated in a secondary prevention trial. Cognitive performance was evaluated 14.7±1.9 and 19.9±1.0years after entry to the trial. A validated set of computerized cognitive tests was used (Neurotrax Computerized Cognitive Battery) to assess performance globally and in memory, executive function, visuospatial and attention domains. Linear regression and mixed models were used to assess the relationship of CRP plasma levels with cognitive scores and decline, respectively. In addition, we tested whether cerebrovascular reactivity, carotid intima media thickness and presence of carotid plaques modify these associations., Results: Among 536 participants (mean age at the first cognitive evaluation 72.6±6.4years; 95% males), CRP at the top tertile vs. the rest was associated with subsequent poorer performance overall (ß=-2.2±1.0; p=0.031) and on tests of executive function and attention (ß=-2.3±1.1; p=0.043 and ß=-2.0±1.4; p=0.047, respectively). Moreover, CRP levels were positively related to a greater decline in executive functions (ß=-2.4±1.1; p=0.03). These associations were independent of potential confounders and were not modified by cerebrovascular indices., Conclusion: Our findings suggest that systemic chronic inflammation, potentially associated with underlying atherosclerosis, is related to cognitive impairment and decline two decades later, in elderly individuals with pre-existing CVD., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: The role of insulin resistance (IR) in the pathogenesis of cognitive performance is not yet clear., Objective: To examine the associations between IR and cognitive performance and change in cognitive functions two decades later in individuals with cardiovascular disease with and without diabetes., Methods: A subset of 489 surviving patients (mean age at baseline 57.7±6.5 y) with coronary heart disease who previously participated in the secondary prevention Bezafibrate Infarction Prevention (BIP trial; 1990-1997), were included in the current neurocognitive study. Biochemical parameters including IR (using the homeostasis model of assessment; HOMA-IR) were measured at baseline. During 2004-2008, computerized cognitive assessment and atherosclerosis parameters were measured (T1; n = 558; mean age 72.6±6.4 years). A second cognitive assessment was performed during 2011-2013 (T2; n = 351; mean age 77.2±6.4 years). Cognitive function, overall and in specific domains, was assessed. We used linear regression models and linear mixed models to evaluate the differences in cognitive performance and decline, respectively., Results: Controlling for potential confounders, IR (top HOMA-IR quartile versus others) was associated with subsequent poorer cognitive performance overall (β= -4.45±Standard Error (SE) 1.54; p = 0.004) and on tests of memory and executive function among non-diabetic patients (β= -7.16±2.38; p = 0.003 and β= -3.33±1.84; p = 0.073, respectively). Moreover, among non-diabetic patients, IR was related to a greater decline overall (β= -0.17±0.06; p = 0.008), and in memory (β= -0.22±0.10; p = 0.024) and executive function (β= -0.19±0.08; p = 0.012). The observed associations did not differ after excluding subjects with prevalent stroke or dementia., Conclusion: IR is related to subsequent poorer cognitive performance and greater cognitive decline among patients with cardiovascular disease with and without diabetes.

High serum uric acid (UA) levels are associated with numerous vascular risk factors, and vascular disease, that predispose patients to cognitive impairment, yet UA is also a major natural antioxidant and higher levels have been linked to slower progression of several neurodegenerative disease. In-order to test the association between UA and subsequent cognitive performance among patients that carry a high vascular burden, UA levels were determined by calorimetric enzymatic tests in a sub-cohort of patients with chronic cardiovascular disease who previously participating in a secondary prevention trial. After an average of 9.8±1.7 years, we assessed cognitive performance (Neurotrax Computerized Cognitive Battery) as well as cerebrovascular reactivity (CVR) and common carotid intima-media thickness (IMT). Among 446 men (mean age 62.3±6.4 yrs) mean UA levels were 5.8±1.1 mg/dL. Adjusted linear regression models revealed that low UA levels (bottom quintile) were associated with poorer cognitive performance. Adjusted differences between the bottom quintile and grouped top UA quintiles were (B coefficient±SE) -4.23±1.28 for global cognitive scores (p = 0.001), -4.69±1.81 for memory scores (p = 0.010), -3.32±1.43 for executive scores (p = 0.020) and -3.43±1.97 for visual spatial scores (p = 0.082). Significant difference was also found for attention scores (p = 0.015). Additional adjustment for impaired CVR and high common carotid IMT slightly attenuated the relationship. Stronger UA effect on cognitive performance was found for older (age>65) patients with significant age interaction for global cognitive score (p = 0.016) and for executive (p = 0.018) and attention domains (p<0.001). In conclusion, we demonstrate that low UA levels in patients with preexisting cardiovascular disease are associated with poorer cognitive function a decade later. These findings lend support to the hypothesis that oxidative stress may be involved in the pathogenesis of age-associated cognitive impairment.

Background and Purpose: Current US guideline statements regarding primary and secondary cardiovascular risk prediction and prevention use absolute risk estimates to identify patients who are at high risk for vascular disease events and who may benefit from specific preventive interventions. These guidelines do not explicitly include patients with stroke, however. This statement provides an overview of evidence and arguments supporting (1) the inclusion of patients with stroke, and atherosclerotic stroke in particular, among those considered to be at high absolute risk of cardiovascular disease and (2) the inclusion of stroke as part of the outcome cluster in risk prediction instruments for vascular disease., Methods and Results: Writing group members were nominated by the committee co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association (AHA) Stroke Council's Scientific Statements Oversight Committee and the AHA Manuscript Oversight Committee. The writers used systematic literature reviews (covering the period from January 1980 to March 2010), reference to previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard AHA criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. The guideline underwent extensive AHA internal peer review, Stroke Council leadership review, and Scientific Statements Oversight Committee review before consideration and approval by the AHA Science Advisory and Coordinating Committee. There are several reasons to consider stroke patients, and particularly patients with atherosclerotic stroke, among the groups of patients at high absolute risk of coronary and cardiovascular disease. First, evidence suggests that patients with ischemic stroke are at high absolute risk of fatal or nonfatal myocardial infarction or sudden death, approximating the ≥20% absolute risk over 10 years that has been used in some guidelines to define coronary risk equivalents. Second, inclusion of atherosclerotic stroke would be consistent with the reasons for inclusion of diabetes mellitus, peripheral vascular disease, chronic kidney disease, and other atherosclerotic disorders despite an absence of uniformity of evidence of elevated risks across all populations or patients. Third, the large-vessel atherosclerotic subtype of ischemic stroke shares pathophysiological mechanisms with these other disorders. Inclusion of stroke as a high-risk condition could result in an expansion of ≈10% in the number of patients considered to be at high risk. However, because of the heterogeneity of stroke, it is uncertain whether other stroke subtypes, including hemorrhagic and nonatherosclerotic ischemic stroke subtypes, should be considered to be at the same high levels of risk, and further research is needed. Inclusion of stroke with myocardial infarction and sudden death among the outcome cluster of cardiovascular events in risk prediction instruments, moreover, is appropriate because of the impact of stroke on morbidity and mortality, the similarity of many approaches to prevention of stroke and these other forms of vascular disease, and the importance of stroke relative to coronary disease in some subpopulations. Non-US guidelines often include stroke patients among others at high cardiovascular risk and include stroke as a relevant outcome along with cardiac end points., Conclusions: Patients with atherosclerotic stroke should be included among those deemed to be at high risk (≥20% over 10 years) of further atherosclerotic coronary events. Inclusion of nonatherosclerotic stroke subtypes remains less certain. For the purposes of primary prevention, ischemic stroke should be included among cardiovascular disease outcomes in absolute risk assessment algorithms. The inclusion of atherosclerotic ischemic stroke as a high-risk condition and the inclusion of ischemic stroke more broadly as an outcome will likely have important implications for prevention of cardiovascular disease, because the number of patients considered to be at high risk would grow substantially.

Background: The effect of combination of fibrate with statin on major adverse cardiovascular events (MACE) following acute coronary syndrome (ACS) hospitalization is unclear. The main aim of this study was to investigate the 30-day rate of MACE in patients who participated in the nationwide ACS Israeli Surveys (ACSIS) and were treated on discharge with a fibrate (mainly bezafibrate) and statin combination vs. statin alone., Methods: The study population comprised 8,982 patients from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 8,545 (95%) received statin alone and 437 (5%) received fibrate/statin combination. MACE was defined as a composite measure of death, recurrent MI, recurrent ischemia, stent thrombosis, ischemic stroke and urgent revascularization., Results: Patients from the combination group were younger (58.1±11.9 vs. 62.9±12.6 years). However, they had significantly more co-morbidities (hypertension, diabetes), current smokers and unfavorable cardio-metabolic profiles (with respect to glucose, total cholesterol, triglyceride and HDL-cholesterol). Development of MACE was recorded in 513 (6.0%) patients from the statin monotherapy group vs. 13 (3.2%) from the combination group, p = 0.01. 30-day re-hospitalization rate was significantly lower in the combination group: 68 (15.6%) vs. 1691 (19.8%) of patients, respectively; p = 0.03. Multivariable analysis identified the fibrate/statin combination as an independent predictor of reduced risk of MACE with odds ratio of 0.54, 95% confidence interval 0.32-0.94., Conclusion: A significantly lower risk of 30-day MACE rate was observed in patients receiving combined fibrate/statin treatment following ACS compared with statin monotherapy. However, caution should be exercised in interpreting these findings taking into consideration baseline differences between our observational study groups.

Background: Over the past years it has been recognized that insulin resistance (IR) is an independent risk factor for the development of diabetes, whereas its association with cardiovascular events remains controversial. The aim of our study was to explore the association between IR per se and cardiovascular events among patients with preexisting coronary artery disease., Methods: The mean follow-up period of this prospective study was 6.2 years. Metabolic and inflammatory parameters were analyzed from stored frozen plasma samples obtained at baseline from 2938 patients aged 45 to 74 years. The homeostatic index of IR (HOMA-IR) was calculated according to the homeostasis model assessment., Results: New major cardiovascular events (fatal and nonfatal myocardial infarction and sudden death) were recorded in 108 (11.1%) patients from the lowest IR tertile, in 147 (14.7%) from the intermediate tertile, and in 166 (17.2%) from the highest tertile (P = .0002). The linear trend for total and cardiac death across the tertiles of HOMA-IR was significant as well (P = .02 and P = .009, respectively). The highest age-adjusted rates for major cardiovascular events and new diabetes were found among patients within the top tertile of HOMA-IR (57% and 130% higher rates, respectively, tertile 3 vs tertile 1, P < .0001 for both). Multivariable analysis identified HOMA-IR (tertile 3 vs tertile 1) as an independent predictor of increased risk of major cardiovascular events and new diabetes with hazard ratios (95% CI) of 1.4 (1.1-1.8) and 1.5 (1.1-2.0), respectively., Conclusions: Insulin resistance per se is an independent risk factor for cardiovascular events and new diabetes in patients with preexisting coronary artery disease.

Background and purpose: Coronary artery calcium is an independent predictor of all-cause mortality. We sought to examine the determinants of intracranial cerebral artery calcification (CAC) and its association with long-term outcome in a large prospective cohort of stroke patients. Methods: Consecutive patients hospitalized because of acute stroke (ischaemic and intracerebral hemorrhage) or TIA throughout a large medical center were systematically assessed and followed up for 1 year. Intracranial CAC was assessed from baseline brain CT blinded to clinical data. Patients were categorized to no, mild, and severe CAC according to their total CAC score. Determinants of CAC were studied with logistic regression analysis. Risk of death, Barthel Index ≤ 60 or death and living in a nursing facility or death were assessed. Results: Amongst 1049 patients (mean age: 70 ± 13 years, 59% males) CAC was present in 727 (69%) patients. The main determinants of CAC were increasing age (OR 1.4, 95% CI 1.3-1.6, per 5 years), diabetes (OR: 2.1, 1.4-3.0), smoking (1.4, 1.0-2.2), hypertension (1.4, 1.0-2.1), and prior coronary heart disease (1.9, 1.3-2.9). CAC was associated with mortality and poor outcome amongst patients with ischaemic stroke; however, after adjusting for age and stroke severity, no significant association was observed. In patients with intracerebral hemorrhage, outcomes were not related to CAC. Conclusions: Intracranial CAC is highly prevalent in patients with acute stroke and its main determinants are older age, diabetes, smoking, hypertension, and prior coronary heart disease. Associations between CAC and mortality or poor functional outcome in the first year after ischaemic stroke are mainly age- and stroke severity-driven. [ABSTRACT FROM AUTHOR]

Background: C-reactive protein (CRP) elevated in inflammation is associated with atherosclerotic disease. We describe the distribution of CRP and its association with coronary heart disease (CHD) risk factors in a large CHD patient group. Methods: This analysis comprises 2,723 male and 256 female CHD patients, included in the Bezafibrate Infarction Prevention (BIP) study. High sensitive CRP levels were determined in frozen plasma samples. Results: CRP distribution, was normalized upon log transformation. Levels among women were higher than in men in the entire group (4.4 vs. 3.5 mg/l) and in each age group. Co-morbidities, smoking, lower education level, and use of cardiovascular drugs, were associated with elevated CRP levels in both sexes. The correlation between CRP and body mass index (BMI), insulin and glucose was stronger among women. The explained variability in CRP level was larger in women (20%) compared to men (13%). Among women, BMI explained 10% of CRP variability, whereas the contribution of each variable among men was significantly smaller. Conclusions: Among men and women with CHD, CRP level was correlated with traditional risk factors and to a lesser degree to manifestation of CHD. BMI is the main contributor to CRP variability, explained by these factors among women. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]