Associations between inflammation, coagulation, cardiac strain and injury, and subclinical vascular disease with frailty in older men: a cross-sectional study.

BACKGROUND: Inflammation, coagulation activation, endothelial dysfunction and subclinical vascular disease are cross-sectionally associated with frailty. Cardiac-specific biomarkers are less-well characterised. We assessed associations between these and frailty, in men with, and without, cardiovascular disease (CVD). METHODS: Cross-sectional analysis of 1096 men without, and 303 with, CVD, aged 71-92, from the British Regional Heart Study. Multinominal logistic regression was performed to examine the associations between frailty status (robust/pre-frail/frail) and, separately, C-reactive protein (CRP), interleukin-6 (IL-6), tissue plasminogen activator (tPA), D-dimer, von Willebrand factor (vWF), high-sensitivity cardiac troponin-T (hs-cTnT), N-terminal pro B-type natriuretic peptide (NT-proBNP) (all natural log-transformed), and, in men without CVD, carotid intima-media thickness (CIMT), carotid-femoral pulse wave velocity (cfPWV), carotid distensibility coefficient (DC), and ankle-brachial pressure index (ABPI), adjusted for age, renal function, BMI, social class, smoking, polypharmacy, cognition, multimorbidity and systolic blood pressure. Explanatory variables with p < 0.05 were carried forward into mutually-adjusted analysis. RESULTS: In men without CVD, higher CRP, IL-6, vWF, tPA, hs-cTnT, NT-proBNP, cfPWV, and lower DC were significantly associated with frailty; mutually-adjusted, log IL-6 (OR for frailty = 2.02, 95%CI 1.38-2.95), log hs-cTnT (OR = 1.95, 95%CI 1.24-3.05) and DC (OR = 0.92, 95%CI 0.86-0.99) retained associations. In men with CVD, higher CRP, IL-6, and hs-cTnT, but not vWF, tPA, NT-proBNP or D-dimer, were significantly associated with frailty; mutually-adjusted, log hs-cTnT (OR 3.82, 95%CI 1.84-7.95) retained a significant association. CONCLUSIONS: In older men, biomarkers of myocardial injury are associated with frailty. Inflammation is associated with frailty in men without CVD. Carotid artery stiffness is associated with frailty in men without CVD, independently of these biomarkers.

Glucagon-like peptide-1 receptor agonists improve biomarkers of inflammation and oxidative stress: A systematic review and meta-analysis of randomised controlled trials.

AIM: To conduct a meta-analysis and systematic review to examine the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on clinical biomarkers of inflammation and oxidative stress in patients with type 2 diabetes. METHODS: Medline, Embase and the Cochrane Library were searched for randomised controlled trials (RCTs) that examined changes with GLP-1RAs in a priori selected biomarkers of inflammation: C-reactive protein (CRP), adiponectin, tumour necrosis factor-alpha (TNFα), plasminogen activator inhibitor-1, interleukin-6, leptin; and of oxidative stress: malondialdehyde (MDA); 8-iso-prostaglandin F2α; and 8-hydroxy-2'-deoxyguanosine (8-OHdG). RESULTS: We included 40 eligible RCTs (n = 6749) with a median follow-up of 6 months, a mean participant age of 53.1 years, 56.3% females, glycated haemoglobin (HbA1c) 55.6 mmol/mol, body mass index 28.8 kg/m2 and diabetes duration 7.46 years. Analysis of GLP-1RAs versus standard diabetes therapies or placebo revealed significant reductions in CRP, TNFα and MDA, and significant increases in adiponectin for (mean difference -0.54 mg/L [-0.75, -0.34]; standard mean difference [SMD] -0.39 [-0.62, -0.15]; SMD -0.84 [-1.61, -0.06] and SMD 0.30 [0.12, 0.49], respectively [95% confidence intervals]). Systolic blood pressure decreased significantly and was significantly and strongly correlated with a reduction in CRP. Homeostatic model assessment of insulin resistance was also significantly correlated with a reduction in CRP, but HbA1c was not. CONCLUSIONS: There is strong evidence supporting clinically relevant anti-inflammatory and antioxidant effects of GLP-1RAs. This may be used to guide future targeted clinical use of GLP-1RAs and the development of medications seeking to target the cardioprotective properties of GLP-1RAs.

Assessment of Remote Heart Rhythm Sampling Using the AliveCor Heart Monitor to Screen for Atrial Fibrillation: The REHEARSE-AF Study.

BACKGROUND: Asymptomatic atrial fibrillation (AF) is increasingly common in the aging population and implicated in many ischemic strokes. Earlier identification of AF with appropriate anticoagulation may decrease stroke morbidity and mortality. METHODS: We conducted a randomized controlled trial of AF screening using an AliveCor Kardia monitor attached to a WiFi-enabled iPod to obtain ECGs (iECGs) in ambulatory patients. Patients ≥65 years of age with a CHADS-VASc score ≥2 free from AF were randomized to the iECG arm or routine care (RC). iECG participants acquired iECGs twice weekly over 12 months (plus additional iECGs if symptomatic) onto a secure study server with overread by an automated AF detection algorithm and by a cardiac physiologist and/or consultant cardiologist. Time to diagnosis of AF was the primary outcome measure. The overall cost of the devices, ECG interpretation, and patient management were captured and used to generate the cost per AF diagnosis in iECG patients. Clinical events and patient attitudes/experience were also evaluated. RESULTS: We studied 1001 patients (500 iECG, 501 RC) who were 72.6±5.4 years of age; 534 were female. Mean CHADS-VASc score was 3.0 (heart failure, 1.4%; hypertension, 54%; diabetes mellitus, 30%; prior stroke/transient ischemic attack, 6.5%; arterial disease, 15.9%; all CHADS-VASc risk factors were evenly distributed between groups). Nineteen patients in the iECG group were diagnosed with AF over the 12-month study period versus 5 in the RC arm (hazard ratio, 3.9; 95% confidence interval=1.4-10.4; P=0.007) at a cost per AF diagnosis of $10 780 (£8255). There was a similar number of stroke/transient ischemic attack/systemic embolic events (6 versus 10, iECG versus RC; hazard ratio=0.61; 95% confidence interval=0.22-1.69; P=0.34). The majority of iECG patients were satisfied with the device, finding it easy to use without restricting activities or causing anxiety. CONCLUSIONS: Screening with twice-weekly single-lead iECG with remote interpretation in ambulatory patients ≥65 years of age at increased risk of stroke is significantly more likely to identify incident AF than RC over a 12-month period. This approach is also highly acceptable to this group of patients, supporting further evaluation in an appropriately powered, event-driven clinical trial. CLINICAL TRIAL REGISTRATION: URL: https://www.isrctn.com. Unique identifier: ISRCTN10709813.

Objectively measured physical activity, sedentary time and subclinical vascular disease: Cross-sectional study in older British men.

Low physical activity (PA) and high levels of sedentary time (ST) are associated with higher cardiovascular disease (CVD) risk among older people. However, their independent contribution and importance of duration of PA and ST bouts remain unclear. We investigated associations between objectively measured PA, ST and non-invasive vascular measures, markers of CVD risk. Cross-sectional study of 1216 men from the British Regional Heart Study, mean age 78.5years, measured in 2010-2012. Carotid intima thickness (CIMT), distensibility coefficient (DC) and plaque presence were measured using ultrasound; pulse wave velocity (cfPWV) and augmentation index (AIx) using a Vicorder. PA and ST were measured using hip-worn ActiGraph GT3X accelerometers. After adjusting for covariates, each additional 1000 steps per day was associated with a 0.038m/s lower cfPWV (95% CI=-0.076, 0.0003), 0.095 10(-3) kPa(-1) higher DC (95% CI=0.006, 0.185), 0.26% lower AIx (95% CI=-0.40, -0.12) and a 0.005mm lower CIMT (95% CI=-0.008, -0.001). Moderate and vigorous PA (MVPA) was associated with lower AIx and CIMT, light PA (LPA) with lower cfPWV and CIMT and ST with higher cfPWV, AIx and CIMT and lower DC. LPA and ST were highly correlated (r=-0.62). The independence of MVPA and ST or MVPA and LPA was inconsistent across vascular measures. Bout lengths for both PA and ST were not associated with vascular measures. In our cross-sectional study of older men, all PA regardless of intensity or bout duration was beneficially associated with vascular measures, as was lower ST. LPA was particularly relevant for cfPWV and CIMT.

C-reactive protein levels in patients at cardiovascular risk: EURIKA study.

BACKGROUND: Elevated C-reactive protein (CRP) levels are associated with high cardiovascular risk, and might identify patients who could benefit from more carefully adapted risk factor management. We have assessed the prevalence of elevated CRP levels in patients with one or more traditional cardiovascular risk factors. METHODS: Data were analysed from the European Study on Cardiovascular Risk Prevention and Management in Usual Daily Practice (EURIKA, ClinicalTrials.gov Identifier: NCT00882336), which included patients (aged ≥50 years) from 12 European countries with at least one traditional cardiovascular risk factor but no history of cardiovascular disease. Analysis was also carried out on the subset of patients without diabetes mellitus who were not receiving statin therapy. RESULTS: In the overall population, CRP levels were positively correlated with body mass index and glycated haemoglobin levels, and were negatively correlated with high-density lipoprotein cholesterol levels. CRP levels were also higher in women, those at higher traditionally estimated cardiovascular risk and those with greater numbers of metabolic syndrome markers. Among patients without diabetes mellitus who were not receiving statin therapy, approximately 30% had CRP levels ≥3 mg/L, and approximately 50% had CRP levels ≥2 mg/L, including those at intermediate levels of traditionally estimated cardiovascular risk. CONCLUSIONS: CRP levels are elevated in a large proportion of patients with at least one cardiovascular risk factor, without diabetes mellitus who are not receiving statin therapy, suggesting a higher level of cardiovascular risk than predicted according to conventional risk estimation systems. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00882336.

Higher systolic blood pressure with normal vascular function measurements in preterm-born children.

UNLABELLED: Preterm birth, low birth weight and poor foetal nutrition have been linked to cardiovascular disease, but the underlying mechanisms remain unclear. We explored prematurity and vascular function by studying a UK cohort of 14 049 children and conducting a systematic review. CONCLUSION: Systolic blood pressure was higher in subjects born preterm than term, but there were no differences in endothelial dysfunction or arterial stiffness. The systematic review revealed no clear association between prematurity and vascular function.

Single-lead ECGs (AliveCor) are a feasible, cost-effective and safer alternative to 12-lead ECGs in community diagnosis and monitoring of atrial fibrillation.

BACKGROUND: Community management of atrial fibrillation (AF) often requires the use of electrocardiographic (ECG) investigation. Patients discharged following treatment of AF with fast ventricular response (fast AF) can require numerous ECGs to monitor rate and/or rhythm control. Single-lead ECGs have been proposed as a more convenient and relatively accurate alternative to 12-lead ECGs for rate/rhythm management and also diagnosis of AF. We aimed to examine the feasibility of using the AliveCor single-lead ECG monitor for diagnosis and monitoring of AF in the community setting. METHODS: During the course of 6 months, this evaluation of a clinical service improvement pathway used the AliveCor in management of patients requiring (1) follow-up ECGs for AF with previously documented rapid ventricular rate or (2) ECG confirmation of rhythm where AF was suspected. Twelve AliveCor devices provided to the acute community medical team were used to produce 30 s ECG rhythm strips (iECG) that were electronically sent to an overreading physician. RESULTS: Seventy-four patients (mean age 82 years) were managed on this pathway. (1) The AliveCor was successfully used to monitor the follow-up of 37 patients with fast AF, acquiring a combined total of 113 iECGs (median 1.5 ±3.75 per patient). None of these patients required a subsequent 12-lead ECG and this approach saved an estimate of up to £134.49 per patient. (2) Of 53 patients with abnormal pulses, the system helped identify 8 cases of new onset AF and 19 cases of previously known AF that had reverted from sinus back into AF. CONCLUSIONS: We have demonstrated that the AliveCor system is a feasible, cost-effective, time-efficient and potentially safer alternative to serial 12-lead ECGs for community monitoring and diagnosis of AF.

Subclinical cardiovascular disease and risk of incident frailty: The British Regional Heart Study.

BACKGROUND/OBJECTIVES: Subclinical cardiovascular disease (CVD) is cross-sectionally associated with frailty, but the relationship between subclinical CVD and incident frailty has not been reported. We aimed to assess this prospective association. DESIGN: Longitudinal analysis of data from the British Regional Heart Study, a prospective cohort study. PARTICIPANTS: 1057 men, aged 71-92 years, robust or pre-frail at baseline, and without a clinical diagnosis of CVD. MEASUREMENTS: Participants underwent baseline measurement of carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (CIMT), carotid distensibility coefficient (DC), and ankle-brachial pressure index (ABPI), and had questionnaire-based frailty assessment after three years. Frailty status was based on the Fried phenotype. Multivariate logistic regressions examined associations between incident frailty and tertile of cfPWV, CIMT, DC, and ABPI group (<0.9, 0.9-1.4, ≥1.4). RESULTS: 865 men were examined and completed the 3 year follow-up questionnaire, of whom 78 became frail. Adjusted for age, prefrailty, body mass index, diabetes, smoking, atrial fibrillation, blood pressure, renal function, and incident CVD, higher CIMT was associated with greater odds of incident frailty (2nd tertile OR 1.62, 95% CI 0.78-3.35, 3rd tertile OR 2.61, 95% CI 1.30-5.23, p = 0.007, trend p = 0.006). cfPWV showed a weaker, non-significant association (2nd tertile OR 1.79, 95% CI 0.85-3.78, 3rd tertile OR 1.73, OR 0.81-3.72, p = 0.16, trend p = 0.20). There was no clear association between incident frailty and DC or ABPI. In subgroup analyses, CIMT was significantly associated with incident frailty in men ≥80 years (3rd tertile OR 6.99, 95%CI 1.42-34.5), but not in men aged 75-80 or < 75 years. CONCLUSION: Subclinical CVD, as measured by CIMT, is associated with greater risk of incident frailty in older men over three year follow-up, independent of the development of clinically-apparent stroke, heart failure, or myocardial infarction, and may be a modifiable risk factor for frailty. This association may be stronger in very old age.

Ultrasound- Versus Fluoroscopy-Guided Strategy for Transfemoral Transcatheter Aortic Valve Replacement Access: A Systematic Review and Meta-Analysis.

[Figure: see text].

Endothelial function predicts progression of carotid intima-media thickness.

BACKGROUND: Endothelial dysfunction develops early and has been shown to predict the development of clinical complications of atherosclerosis. However, the relationship between early endothelial dysfunction and the progression of arterial disease in the general population is unknown. We investigated endothelial dysfunction, risk factors, and progression of carotid intima-media thickness (cIMT) in late-middle-aged individuals at low to intermediate cardiovascular risk in a prospective study between 1997 and 2005. METHODS AND RESULTS: Brachial artery flow-mediated dilatation and cIMT were measured in 213 nonsmoking British civil servants recruited from a prospective cohort (Whitehall II study). Participants (age, 45 to 66 years) were free of clinical cardiovascular disease and diabetes mellitus. Risk factors and Framingham Risk Score were determined at baseline. cIMT was repeated 6.2+/-0.4 years later. At baseline, age, blood pressure, low-density lipoprotein cholesterol, and Framingham Risk Score correlated with cIMT. However, only flow-mediated dilatation, not risk factors or Framingham Risk Score, was associated with average annual progression of cIMT. This relationship remained significant after adjustment for risk factors whether entered as separate variables or as Framingham Risk Score. Further adjustment for waist circumference, triglycerides, and employment grade had no significant effect. CONCLUSIONS: Systemic endothelial function was associated with progression of preclinical carotid arterial disease over a 6-year period and was more closely related to cIMT changes than conventional risk factors. Thus, the relationship between endothelial dysfunction and adverse outcome is likely to be due not only to destabilization of established disease in high-risk populations but also to its impact on the evolution of the atherosclerotic substrate. Flow-mediated dilatation testing provides an integrated vascular measure that may aid the prediction of structural disease evolution and represents a potential short- to intermediate-term outcome measure for evaluation of preventive treatment strategies.

Active Children Through Individual Vouchers Evaluation: A Mixed-Method RCT.

INTRODUCTION: Physical activity declines in adolescence, especially among those in deprived areas. Research suggests this may result from accessibility barriers (e.g., cost and locality). The Active Children Through Individual Vouchers Evaluation RCT aimed to improve the fitness and heart health of teenagers in Wales with the help of teenagers who co-produced the study. STUDY DESIGN: This study was a mixed-method RCT. SETTING/PARTICIPANTS: Before data collection, which took place at baseline, 6 months, and 12 months for both arms, 7 schools were randomized by an external statistician (4 intervention schools, n=524; 3 control schools, n=385). INTERVENTION: The Active Children Through Individual Vouchers Evaluation intervention included provision of activity vouchers (£20 per month), a peer mentoring scheme, and support worker engagement for 12 months between January and December 2017. Data analysis occurred February-April 2018. MAIN OUTCOME MEASURES: Data included measures of cardiovascular fitness, cardiovascular health (blood pressure and pulse wave analysis), motivation, and focus groups. RESULTS: The intervention showed a trend to improve the distance ran (primary outcome) and was significant in improving the likelihood of intervention teenagers being fit (OR=1.21, 95% CI=1.07, 1.38, p=0.002). There was a reduction in teenagers classified as having high blood pressure (secondary outcome) in the intervention group (baseline, 5.3% [28/524]; 12 months, 2.7% [14/524]). Data on where teenagers used vouchers and evidence from focus groups showed that teenagers wanted to access more unstructured, informal, and social activities in their local areas. CONCLUSIONS: Active Children Through Individual Vouchers Evaluation identified methods that may have a positive impact on cardiovascular fitness, cardiovascular health, and perspectives of activity. Consulting with teenagers, empowering them, and providing more local opportunities for them to take part in activities that are fun, unstructured, and social could positively impact teenage physical activity. TRIAL REGISTRATION: ISRCTN, ISRCTN75594310.

Chronic kidney disease, cardiovascular risk markers and total mortality in older men: cystatin C versus creatinine.

BACKGROUND: It remains uncertain whether cystatin C is a superior marker of renal function than creatinine in older adults. We have investigated the association between estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations based on creatinine (CKD-EPIcr) and cystatin C (CKD-EPIcys), and cardiovascular risk markers and mortality in older adults. METHODS: This is a cross-sectional and prospective study of 1639 British men aged 71-92 years followed up for an average of 5 years for mortality. Cox survival model and receiving operating characteristic analysis were used to assess the associations. RESULTS: The prevalence of chronic kidney disease (CKD) was similar using the two CKD-EPI equations, although cystatin C reclassified 43.9% of those with stage 3a CKD (eGFR 45-59 mL/min/1.732, moderate damage) to no CKD. However, CKD stages assessed using both CKD-EPIcr and CKD-EPIcys were significantly associated with vascular risk markers and with all-cause and cardiovascular disease mortality. In all men with CKD (eGFR <60 mL/min/1.732), the HRs (95% CI) for all-cause mortality after adjustment for cardiovascular risk factors compared with those with no CKD were 1.53 (1.20 to 1.96) and 1.74 (1.35 to 2.23) using CKD-EPIcr and CKD-EPIcys, respectively. Comparisons of the two CKD equations showed no significant difference in their predictive ability for mortality (difference in area under the curve p=0.46). CONCLUSION: Despite reclassification of CKD stages, assessment of CKD using CKD-EPIcys did not improve prediction of mortality in older British men >70 years. Our data do not support the routine use of CKD-EPIcys for identifying CKD in the elderly British male population.

Circulating endothelial progenitor cells, vascular function, and cardiovascular risk.

BACKGROUND: Cardiovascular risk factors contribute to atherogenesis by inducing endothelial-cell injury and dysfunction. We hypothesized that endothelial progenitor cells derived from bone marrow have a role in ongoing endothelial repair and that impaired mobilization or depletion of these cells contributes to endothelial dysfunction and cardiovascular disease progression. METHODS: We measured the number of colony-forming units of endothelial progenitor cells in peripheral-blood samples from 45 men (mean [+/-SE] age, 50+/-2 years). The subjects had various degrees of cardiovascular risk but no history of cardiovascular disease. Endothelium-dependent and endothelium-independent function was assessed by high-resolution ultrasonography of the brachial artery. RESULTS: We observed a strong correlation between the number of circulating endothelial progenitor cells and the subjects' combined Framingham risk factor score (r=-0.47, P=0.001). Measurement of flow-mediated brachial-artery reactivity also revealed a significant relation between endothelial function and the number of progenitor cells (r=0.59, P<0.001). Indeed, the levels of circulating endothelial progenitor cells were a better predictor of vascular reactivity than was the presence or absence of conventional risk factors. In addition, endothelial progenitor cells from subjects at high risk for cardiovascular events had higher rates of in vitro senescence than cells from subjects at low risk. CONCLUSIONS: In healthy men, levels of endothelial progenitor cells may be a surrogate biologic marker for vascular function and cumulative cardiovascular risk. These findings suggest that endothelial injury in the absence of sufficient circulating progenitor cells may affect the progression of cardiovascular disease.

Circulating soluble receptor for advanced glycation end product: Cross-sectional associations with cardiac markers and subclinical vascular disease in older men with and without diabetes.

BACKGROUND AND AIMS: The soluble receptor for advanced glycation end products (sRAGE) has been implicated in diabetic vascular complications. We have examined the association between sRAGE and cardiac markers [NT-proBNP and cardiac troponin T (cTnT)] and subclinical vascular markers in older men with and without diabetes. METHODS: We performed a cross-sectional study of 1159 men aged 71-92 years with no history of cardiovascular disease (myocardial infarction, stroke, heart failure, coronary artery bypass graft operation or angioplasty). Prevalent diabetes included men with a doctor diagnosis of diabetes, men with fasting glucose ≥7 mmol/l or HbA1c ≥ 6.5% (N = 180). Subclinical vascular measurements included carotid intima media thickness (cIMT), arterial stiffness [pulse wave velocity (PWV)], central aortic blood pressure and arterial wave reflections [central augmentation pressure (AP) and augmentation index (AIx)]. RESULTS: sRAGE was strongly and positively associated with renal dysfunction in men with and without diabetes. sRAGE was significantly and positively associated with NT-proBNP (but not cTnT) and AP and AIx in both groups of men after adjustment for CVD risk and metabolic risk markers, renal function and inflammation. However, no association was seen between sRAGE and central aortic blood pressure, cIMT or arterial stiffness as determined by PWV in either group. CONCLUSIONS: Higher plasma sRAGE was associated with increased NT-proBNP and markers of arterial wave reflections in men both with and without diabetes. Increased sRAGE may contribute to or be a marker of worsening cardiac dysfunction or HF. Further studies with cardiac imaging data are required to confirm this.

Self-reported sleep duration and napping, cardiac risk factors and markers of subclinical vascular disease: cross-sectional study in older men.

STUDYOBJECTIVES: Daytime sleep has been associated with increased risk of cardiovascular disease and heart failure (HF), but the mechanisms remain unclear. We have investigated the association between daytime and night-time sleep patterns and cardiovascular risk markers in older adults including cardiac markers and subclinical markers of atherosclerosis (arterial stiffness and carotid intima-media thickness (CIMT)). METHODS: Cross-sectional study of 1722 surviving men aged 71-92 examined in 2010-2012 across 24 British towns from a prospective study initiated in 1978-1980. Participants completed a questionnaire and were invited for a physical examination. Men with a history of heart attack or HF (n=251) were excluded from the analysis. RESULTS: Self-reported daytime sleep duration was associated with higher fasting glucose and insulin levels (p=0.02 and p=0.01, respectively) even after adjustment for age, body mass index, physical activity and social class. Compared with those with no daytime sleep, men with daytime sleep >1 hour, defined as excessive daytime sleepiness (EDS), had a higher risk of raised N-terminal pro-brain natriuretic peptide of ≥400 pg/mL, the diagnostic threshold for HF (OR (95% CI)=1.88 (1.15 to 3.1)), higher mean troponin, reduced lung function (forced expiratory volume in 1 s) and elevated von Willebrand factor, a marker of endothelial dysfunction. However, EDS was unrelated to CIMT and arterial stiffness. By contrast, night-time sleep was only associated with HbA1c (short or long sleep) and arterial stiffness (short sleep). CONCLUSIONS: Daytime sleep duration of >1 hour may be an early indicator of HF.

Validation of a new method for non-invasive assessment of vasomotor function.

BACKGROUND: Reactive hyperaemia induces a slowing of pulse wave velocity (PWV) in conduit arteries of healthy subjects (flow-mediated slowing (FMS)). This could be an alternative method for assessing peripheral vasomotor function to the gold standard method of flow-mediated dilatation (FMD) a more expensive and technically demanding technique. We aimed to assess the reproducibility of FMS in healthy participants and to test its ability to detect differences in vasomotor function in patients with familial hypercholesterolaemia (FH) and post-lipoprotein apheresis (LA) treatment. METHODS: Altogether 25 healthy participants were studied on two occasions to assess reproducibility of FMS. In a case control study of 22 patients with FH and matched healthy controls, FMD and FMS were compared. An intervention study in 12 patients with FH looked at the impact of a single LA treatment on FMS assessed pre and post treatment. RESULTS: FMS demonstrated good reproducibility (coefficient of variation (CoV) 7.3%). Patients with FH had reduced FMS in comparison to matched healthy controls (FMS% FH -15.13 ± 5.04% vs controls -18.41 ± 5.15%, p = 0.023), with no difference in FMD% between the two groups. A single LA treatment significantly improved FMS (pre -18.81 ± 9.84 vs post -24.09 ± 7.61%, p = 0.016). CONCLUSIONS: FMS is a reproducible technique, which is able to detect differences in vasomotor function both in a condition associated with endothelial dysfunction and following an acute intervention known to improve endothelial function. This simple technique has potential for accessible assessment of vasomotor function in clinical studies.

Objectively measured physical activity and sedentary behaviour and ankle brachial index: Cross-sectional and longitudinal associations in older men.

BACKGROUND: Associations between bouts of physical activity (PA), sedentary behaviour (SB) and cardiovascular disease, and their mutual independence are not well defined. A low ankle brachial index (ABI ≤0.9) indicates peripheral arterial disease (PAD) and is predictive of cardiovascular events and functional impairment. We investigated the independence of PA and SB and the importance of bout duration in relation to ABI using objective measures. METHODS: 945 men from the British Regional Heart Study, mean age 78.4 y, had concurrent measurements of ABI (Vicorder) and physical activity (Actigraph GT3X accelerometer); 427 men also had accelerometer measurements one year previously and contributed data to longitudinal analyses. RESULTS AND CONCLUSION: In cross-sectional analyses, after adjusting for covariates each extra 10 min of moderate and vigorous PA per day was associated with an OR of 0.81 (95% CI 0.72, 0.91) for a low ABI, a stronger association than for light PA (OR 0.85, 95% CI 0.75, 0.98). Each extra 30 min of SB was associated with an OR of 1.19 (95% CI 1.07, 1.33) for a low ABI. Associations between moderate and vigorous PA and ABI persisted after adjustment for light PA or SB. Bout lengths for PA and SB were not associated with a low ABI. One year changes in PA or SB were not associated with low ABI. All physical activity and lower levels of SB, regardless of bout duration were inversely associated with ABI; more intense PA showed a stronger association. No associations between changes in PA and ABI were observed, but power may have been limited.

Beyond the laboratory: clinical implications for statin pleiotropy.

Results from large-scale clinical trials of lipid lowering with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have led to a revolution in the management of atherosclerosis. In addition to their potent effect on serum lipid levels, statins influence several other cellular pathways, including those involving inflammatory, oxidative, and thrombotic processes. These effects clearly have the potential to beneficially modify the atherogenic process, and it has been suggested that they contribute to the impressive results seen in the clinical trials. We review the clinical evidence for benefits of statin therapy that are distinct from their effect on lipid biology. In particular, we address three key issues: the role of statins in diseases not traditionally associated with elevated cholesterol levels; whether clinical benefits are seen with statin therapy before an effect on lipid levels; and whether the magnitude of clinical benefit observed with statin therapy is unrelated to the degree of cholesterol reduction. At present, low-density-lipoprotein lowering seems to be the primary mechanism underlying the clinical benefits of statin therapy and should remain the focus of risk-reduction strategies in clinical practice.

Predisposition to atherosclerosis by infections: role of endothelial dysfunction.

BACKGROUND: Several microorganisms have been implicated in the pathogenesis of atherosclerosis. We hypothesized that infections may predispose to atherosclerosis by inflicting endothelial injury. METHODS AND RESULTS: Of 375 patients undergoing coronary angiography, 218 had assessment of endothelial function using intracoronary acetylcholine (ACH) and of endothelium-independent function with sodium nitroprusside and adenosine. Immunoglobulin-G antibody titers to cytomegalovirus, Chlamydia pneumoniae, Helicobacter pylori, hepatitis A virus, and herpes simplex virus-1 were measured. Pathogen burden was defined as the number of positive antibodies. Although positive serology to individual pathogens tended to be associated with increased incidence of coronary arteriosclerosis (CAD), the pathogen burden correlated with the presence of CAD, even after adjustment for risk factors (OR 1.3; 95% CI, 1.05 to 1.6, P=0.018). Moreover, the severity of CAD was independently associated with the pathogen burden (P=0.001). Pathogen burden was an independent predictor of endothelial dysfunction, determined as the percent change in coronary vascular resistance in response to ACH (P=0.009) but not the responses to sodium nitroprusside or adenosine. Pathogen burden was also an independent determinant of endothelial function in the subgroup with angiographically normal coronary arteries. CONCLUSIONS: The immunoglobulin-G antibody response to multiple pathogens (pathogen burden) is an independent risk factor for endothelial dysfunction and the presence and severity of CAD. Endothelial dysfunction provides the crucial link by which pathogens may contribute to atherogenesis.