Endothelial ischemia-reperfusion injury in humans: association with age and habitual exercise

Advancing age is a major risk factor for coronary artery disease. Endothelial dysfunction accompanied by increased oxidative stress and inflammation with aging may predispose older arteries to greater ischemia-reperfusion (I/R) injury. Because coronary artery ischemia cannot be induced safely, the effects of age and habitual endurance exercise on endothelial I/R injury have not been determined in humans. Using the brachial artery as a surrogate model of the coronary arteries, endothelial function, assessed by brachial artery flow-mediated dilation (FMD), was measured before and after 20 min of continuous forearm occlusion in young sedentary (n = 10, 24 ± 2 yr) and middle-aged (n = 9, 48 ± 2 yr) sedentary adults to gain insight into the effects of primary aging on endothelial I/R injury. Young (n = 9, 25 ± 1 yr) and middle-aged endurance-trained (n = 9, 50 ± 2 yr) adults were also studied to determine whether habitual exercise provides protection from I/R injury. Fifteen minutes after ischemic injury, FMD decreased significantly by 37% in young sedentary, 35% in young endurance-trained, 68% in middle-aged sedentary, and 50% in middle-aged endurance-trained subjects. FMD returned to baseline levels within 30 min in young sedentary and endurance-trained subjects but remained depressed in middle-aged sedentary and endurance-trained subjects. Circulating markers of antioxidant capacity and inflammation were not related to FMD. In conclusion, advancing age is associated with a greater magnitude and delayed recovery from endothelial I/R injury in humans. Habitual endurance exercise may provide partial protection to the endothelium against this form of I/R injury with advancing age.     

Regular aerobic exercise and the age-related increase in carotid artery intima-media thickness in healthy men.

Carotid artery intima-media thickness (IMT), an independent risk factor for stroke, increases with age. Habitual exercise is associated with a lower prevalence of stroke, but it is unclear whether this protective effect could be mediated through a favorable influence on carotid IMT. We examined this possibility using both cross-sectional and intervention approaches. First, 137 healthy men (age 18-77 yr) who were either sedentary or endurance trained were studied. In both groups, carotid IMT and IMT-to-lumen ratio were progressively higher with age (P < 0.05). There were no significant differences in measures of carotid IMT between sedentary and endurance-trained men at any age. Carotid systolic blood pressure increased progressively with age and was related to carotid IMT (r = 0.63, P < 0.01). Second, 18 healthy sedentary subjects (54 +/- 2 yr) were studied before and after 3 mo of endurance training. Carotid IMT, IMT/lumen ratio, and carotid systolic blood pressure did not change with exercise intervention. Our results do not support the hypothesis that regular aerobic exercise exerts its protective effect against stroke by attenuating the age-related increase in carotid IMT. This lack of effect on carotid IMT may be due to the apparent inability of habitual exercise to prevent or reduce the age-associated elevation in carotid distending pressure.     

Both cyclooxygenase- and cytokine-mediated inflammation are associated with carotid intima-media thickness

BACKGROUND: Common carotid artery intima-media thickness (CCA-IMT) is a valid index of atherosclerosis, which is viewed as an inflammatory disease. It is unknown if various modes of inflammation (cyclooxygenase [COX]-mediated, cytokine-mediated), oxidative stress and anti-oxidants are independently related to CCA-IMT. METHODS AND RESULTS: We investigated cross-sectional relations between CCA-IMT measured by B-mode ultrasound and COX-mediated inflammation (as measured by 15-keto-dihydro-prostaglandin F(2alpha) [PGF(2alpha)], cytokine-mediated inflammation (interleukin-6 [IL-6], high sensitivity C-reactive protein [hsCRP] and serum amyloid A protein [SAA]), oxidative stress (8-iso-PGF(2alpha), an F(2)-isoprostane; a non-enzymatic, free radical-induced product of arachidonic acid), and tocopherols (anti-oxidants) in a small subset of a population-based sample of elderly men (n=234) stating no use of anti-inflammatory medications. In a backward-stepwise regression analysis of correlates of CCA-IMT (with PGF(2alpha), hsCRP, IL-6, SAA, F(2)-isoprostanes, tocopherols, diabetes, body mass index (BMI), beta-blocker, statin treatment, smoking, hypertension and cholesterol), PGF(2alpha), CRP, beta-blocker treatment, diabetes and BMI were independently associated with CCA-IMT. There were no associations between F(2)-isoprostanes or tocopherols and CCA-IMT in this study. CONCLUSION: This study suggests both COX- and cytokine-mediated inflammation to be independently associated with increased CCA-IMT, implying that there might be more than one mode of inflammation involved in atherogenesis.     

Lymphocyte DNA damage is associated with increased aortic intima-media thickness

OBJECTIVES: To investigate whether there is an association between lymphocyte DNA damage and aortic intima-media thickness (IMT). METHODS: We studied 70 patients (mean age: 41.6+/-10 years) who underwent transesophageal echocardiography for various indications. Four different grades were determined according to intima-media thickness (IMT) of thoracic aorta measured by transesophageal echocardiography. DNA damage was assessed by alkaline single cell electrophoresis (comet) assay in peripheral lymphocytes. Plasma level of total antioxidant status (TAS) was determined by using automated measurement method. High sensitive C-reactive protein and other biochemical markers were studied in all subjects. RESULTS: The major increase in lymphocyte DNA damage was observed in patients with grade 4 IMT when compared with other groups (p<0.001, for all). Lymphocyte DNA damage of patients with grade 1 IMT was also lower than patients with grade 2 IMT (p=0.013) and patients with grade 3 IMT (p<0.001). Lymphocyte DNA damage of patients with grade 2 IMT was found at low level compared with patients with grade 3 IMT (p=0.012) as well. In multiple linear regression analysis, IMT was independently correlated with lymphocyte DNA damage (beta=0.515, p<0.001), TAS level (beta=-420, p<0.001), total cholesterol (beta=0.407, p<0.001) and LDL cholesterol level (beta=287, p=0.020). CONCLUSION: Lymphocyte DNA damage may be an independent predictor for the grade of thoracic IMT, and may play a role in pathogenesis of thoracic atherosclerosis besides TAS and cholesterol levels.     

The relationships of markers of cholesterol homeostasis with carotid intima-media thickness

Background

The relationship of cholesterol homeostasis and carotid intima-media thickness (cIMT) is unknown. To address this, we assessed markers of cholesterol homeostasis (serum plant sterols and cholesterol precursor concentrations as surrogate measures of cholesterol absorption and synthesis, respectively) and cIMT in a middle-aged, statin-naive population.

Methods

In this prospective study of primary prevention cIMT was measured by ultrasound in 583 hospital employees aged 25–60 years without prevalent cardiovascular disease or lipid-modifying medication. The serum concentrations of plant sterols (as markers of cholesterol absorption) were measured by gas-liquid chromatography. Lathosterol serum concentrations were quantitated to assess hepatic cholesterol synthesis.

Results

cIMT correlated positively with serum cholesterol (r = 0.22, P<0.0005) and lathosterol-to-cholesterol (r = 0.18, P<0.001). In contrast, plant sterols, as markers of cholesterol absorption, showed a weak negative correlation to cIMT measurements (r = −0.18; P<0.001 for campesterol-to-cholesterol). Stratifying subjects by serum sterol levels, we found that cIMT increased continuously over quintiles of serum cholesterol (P<0.0005) and was positively associated to serum lathosterol-to-cholesterol levels (P = 0.007), on the other hand, plant sterol levels showed a weak negative association to cIMT (P<0.001 for campesterol-to-cholesterol).

Conclusions

In this population without prevalent cardiovascular diseases or lipid-modifying medication, markers of increased endogenous cholesterol synthesis correlated positively with cIMT, while markers of cholesterol absorption showed a weakly negative correlation. These data suggest that not only total serum cholesterol levels but also differences in cholesterol homeostasis are associated with cIMT.     

Inflammation,carotid intima-media thickness and atherosclerosis in rheumatoid arthritis

Carotid intima-media thickness (cIMT) reflects early atherosclerosis and predicts cardiovascular events in the general population. An increased cIMT is present in patients with rheumatoid arthritis, compared with control individuals, from the early stages of the disease and is thought to indicate accelerated atherosclerosis, but direct evidence is not available. Whether cIMT is susceptible to rapid and potentially reversible change depending on the intensity of inflammation in states of high-grade systemic inflammation, such as rheumatoid arthritis, remains unknown. If this is the case, an increased cIMT in such disease states may not reflect structural vessel wall damage, and may not be a good predictor of future cardiovascular events in these particular populations. Prospective, long-term, longitudinal studies are needed to address these questions.     

Peak exercise stroke volume: associations with cardiac structure and diastolic function.

One of the most debilitating effects of primary aging is the decline in aerobic exercise capacity. One of its causes is an age-related decline in peak exercise stroke volume. This study's main purpose was to determine the cardiovascular adaptations to aging that most influence peak exercise stroke volume in the elderly. We hypothesized that increased left ventricular (LV) filling and mild concentric LV remodeling would be associated with an increase in peak exercise stroke volume corrected for lean body mass (LBM) and that an increased augmentation index (AI), which is a marker of arterial stiffness, would be associated with a decrease. A second aim was to determine the adaptations to aging that most influence LV concentric remodeling in the elderly. We hypothesized that AI would be a predictor of LV mass/LBM and the LV posterior wall thickness-to-LV radius ratio (h/r). We performed a cross-sectional study of cardiac and vascular adaptations to aging in 52 sedentary, elderly subjects. LV filling [as measured by the early-to-late transmitral flow velocity ratio (E/A)] was inversely correlated with and was an independent predictor of peak exercise stroke volume/LBM and was also a predictor of LV remodeling. AI was a predictor of LV remodeling (LV mass/LBM) but not of peak exercise stroke volume/LBM. We conclude that 1) maintenance of LV filling (E/A <1) is associated with a higher peak exercise stroke volume/LBM in very elderly subjects and thus may be a useful adaptation that enhances stroke volume during peak exercise, 2) LV remodeling and AI are less influential on peak exercise stroke volume/LBM, and 3) AI was the most important predictor of LV remodeling.     

Genetic associations with brain cortical thickness in multiple sclerosis

Multiple sclerosis (MS) is characterized by temporal and spatial dissemination of demyelinating lesions in the central nervous system. Associated neurodegenerative changes contributing to disability have been recognized even at early disease stages. Recent studies show the importance of gray matter damage for the accrual of clinical disability rather than white matter where demyelination is easily visualized by magnetic resonance imaging (MRI). The susceptibility to MS is influenced by genetic risk, but genetic factors associated with the disability are not known. We used MRI data to determine cortical thickness in 557 MS cases and 75 controls and in another cohort of 219 cases. We identified nine areas showing different thickness between cases and controls (regions of interest, ROI) (eight of them were negatively correlated with Kurtzke's expanded disability status scale, EDSS) and conducted genome‐wide association studies (GWAS) in 464 and 211 cases available from the two data sets. No marker exceeded genome‐wide significance in the discovery cohort. We next combined nominal statistical evidence of association with physical evidence of interaction from a curated human protein interaction network, and searched for subnetworks enriched with nominally associated genes and for commonalities between the two data sets. This network‐based pathway analysis of GWAS detected gene sets involved in glutamate signaling, neural development and an adjustment of intracellular calcium concentration. We report here for the first time gene sets associated with cortical thinning of MS. These genes are potentially correlated with disability of MS.     

Arterial hypoxemia and performance during intense exercise

In order to determine the level of hypoxemia which is sufficient to impair maximal performance, seven well-trained male cyclists [maximum oxygen consumption (VO_2max)51·min^–1 or 60 ml·kg^–1·min^–1] performed a 5-min performance cycle test to exhaustion at maximal intensity as controlled by the subject, under three experimental conditions: normoxemia [percentage of arterial oxyhemoglobin saturation (%S _a O₂)>94%], and artificially induced mild (%S _aO₂=90±1%) and moderate (%S _aO₂=87±1%) hypoxemia. Performance, evaluated as the total work output (Work_tot) performed in the 5-min cycle test, progressively decreased with decreasing %S _aO₂ [mean (SE) Work_tot=107.40 (4.5) kJ, 104.07 (5.6) kJ, and 102.52 (4.7) kJ, under normoxemia, mild, and moderate hypoxemia, respectively]. However, only performance in the moderate hypoxemia condition was significantly different than in normoxemia (P=0.02). Mean oxygen consumption and heart rate were similar in the three conditions (P=0.18 andP=0.95, respectively). End-tidal partial pressure of CO₂ was significantly lower (P=0.005) during moderate hypoxemia compared with normoxemia, and ventilatory equivalent of CO₂ was significantly higher (P=0.005) in both hypoxemic conditions when compared with normoxemia. It is concluded that maximal performance capacity is significantly impaired in highly trained cyclists working under an %S _aO₂ level of 87% but not under a milder desaturation level of 90%.     

Macrosomic newborns of diabetic mothers are associated with increased aortic intima-media thickness and lipid concentrations

BACKGROUND/AIMS: Exposure to diabetes in utero has been established as a significant risk factor for some of components of metabolic syndrome. A few studies have examined relationship between the metabolic syndrome and echocardiographic left ventricular (LV) mass. We aimed to investigate relationship between abdominal aortic intima-media thickness (aIMT), LV mass and lipid profile in macrosomic newborns. METHODS: Abdominal aIMT was measured in 30 macrosomic neonates of diabetic mothers (group A), 30 macrosomic neonates of healthy mothers (group B) and 30 healthy neonates (group C). Lipid profile and LV mass were determined. RESULT: Mean aIMT was significantly higher in groups A and B (0.489 +/- 0.015, 0.466 +/- 0.019 mm, respectively) than in controls (0.375 +/- 0.024 mm). Weight-adjusted aIMT in group A was significantly higher than in groups B and C. Macrosomia was associated with increased lipid concentrations. Both LV mass indexed for BSA (body surface area) and birth weight measurements were significantly increased in group A compared with control. CONCLUSIONS: Macrosomic neonates of diabetic mothers have significant aIMT and LV mass indexed for BSA and birth weight with lipid alterations. It might play a role in the pathogenesis of atherosclerosis in adult life.     

Measuring microtubule thickness: an exercise in cooperativity

Eukaryotic centromeres are propagated by incorporation of the centromere-specific histone CENP-A into centromeric chromatin. Silva et al. (2012) now show that cyclin-dependent kinases (CDKs) hold the CENP-A assembly machinery in an inactive state until mitotic exit and entry into G1, at which time new CENP-A is loaded.     

15-Lipoxygenase gene variants are associated with carotid plaque but not carotid intima-media thickness

The major underlying cause of CHD is atherosclerosis, and oxidised LDL is known to play an important role in its development. We examined the role of three single nucleotide polymorphisms (SNPs) in the 15-lipoxygenase gene (ALOX15), in atherosclerosis. We genotyped three SNPs in the ALOX15 promoter in two Western Australian samples—1,111 community-based individuals and 556 with CHD. SNPs and haplotypes were tested for an association with carotid plaque, intima-media thickness and risk of CHD. The −611GG genotype was associated with increased likelihood of carotid plaque in CHD patients (OR = 4.01, 95%CI = 1.39–11.53, P = 0.005) and the C alleles of the G-220C and G-189C SNPs were associated with decreased likelihood of plaque among cases (OR = 0.66, 95%CI = 0.43–0.99, P = 0.05 and OR = 0.51, 95%CI = 0.34–0.78, P = 0.002 respectively). The GGG haplotype was associated with increased risk of carotid plaque in CHD patients (OR = 5.77, 95%CI = 1.82–18.29, P = 0.0007) and in community-based individuals under 53 years (OR = 4.15, 95%CI = 1.23–14.08, P = 0.02). No association was observed between ALOX15 SNPs or haplotypes and intima-media thickness. This study is novel as it is the first to examine the association between 15-lipoxygenase polymorphisms and atherosclerotic indicators. These findings suggest a possible role of ALOX15 polymorphisms in focal plaque formation.     

Acute and habitual caffeine ingestion and metabolic responses to steady-state exercise.

This study compared the exercise catecholamine and metabolic responses to a caffeine challenge in trained subjects before and after a 6-wk period of increased caffeine ingestion. Trained subjects (n = 6) were challenged with 500 mg of caffeine followed by prolonged exercise before and after 6 wk of increased caffeine ingestion (500 mg ingested before each daily run). A control group (n = 6) of trained subjects followed the same protocol except for caffeine ingestion. Acute caffeine ingestion resulted in increased plasma epinephrine and decreased respiratory exchange ratio (RER) during exercise. After 6 wk of caffeine supplementation, the epinephrine response to exercise or caffeine plus exercise was decreased, although the latter still resulted in a lower RER value compared with exercise without caffeine ingestion. Activity of key metabolic enzymes (hexokinase, citrate synthase, phosphorylase, and 3-hydroxyacyl-coenzyme A dehydrogenase) from biopsies of the gastrocnemius showed no response to 6 wk of this increased adrenergic receptor stimulation and, on the basis of the lower RER, enhanced fat metabolism. This study suggests that caffeine ingestion by trained subjects causes increases in plasma epinephrine and reduces the RER during exercise. However, habitual stimulation results in a general dampening of the epinephrine response to caffeine or exercise. There was no indication that increased adrenergic stimulation and fat oxidation caused any adaptation in the activity of metabolic enzymes.     

Increased carotid artery intima-media thickness and myeloperoxidase level in children with newly diagnosed juvenile idiopathic arthritis

IntroductionJuvenile idiopathic arthritis (JIA) is a frequent childhood rheumatic disease characterized by chronic inflammation. The latter has been related to impairment of arterial functional-structural properties, atherogenesis and later cardiovascular events. The objective of this study was to examine intima-media thickness (IMT) and the parameters of arterial stiffness in children with JIA at diagnosis and their correlation with JIA subtype and markers of inflammation and atherosclerosis.MethodsThirty-nine newly diagnosed patients with JIA (26 girls; mean age, 13.2 ± 2.6 years) and 27 healthy controls (9 girls; mean age, 13.6 ± 3.4 years) were included in the study. Twelve patients had oligoarthritis, fifteen had extended oligoarthritis and twelve had rheumatoid factor–negative polyarthritis. IMT of the common carotid artery was determined by ultrasonography, carotid-femoral pulse wave velocity (cfPWV) and augmentation index adjusted to a heart rate of 75 beats/min (AIx@75) were determined by applanation tonometry. The serum levels of atherosclerosis-related biomarkers, such as asymmetric dimethylarginine (ADMA), myeloperoxidase (MPO) and adiponectin, were measured by enzyme-linked immunosorbent assay.ResultsMean IMT (0.46 ± 0.04 vs. 0.42 ± 0.04 mm; p = 0.0003) and MPO concentration (115.2 [95 % confidence interval {95 % CI}, 97.4–136.3] vs. 57.6 [95 % CI, 47.1–70.3] ng/ml; p < 0.0001) were higher in the patients with JIA than in the control subjects. The cfPWV, AIx@75 and serum ADMA and adiponectin levels did not significantly differ between the groups and JIA subtypes. Serum adiponectin level correlated negatively with AIx@75 in patients with JIA (r = −0.38; p < 0.05).ConclusionsPatients with JIA have increased mean IMT and elevated MPO levels at early stages of the disease. AIx@75 was inversely independently associated with adiponectin level in the patients, suggesting that lower adiponectin levels might influence arterial subclinical stiffening in patients with newly diagnosed JIA.     

Plasma lecithin:cholesterol acyltransferase and carotid intima-media thickness in European individuals at high cardiovascular risk

Lecithin:cholesterol acyltransferase (LCAT) is the enzyme responsible for cholesterol esterification in plasma. LCAT is a major factor in HDL remodeling and metabolism, and it has long been believed to play a critical role in macrophage reverse cholesterol transport (RCT). The effect of LCAT on human atherogenesis is still controversial. In the present study, the plasma LCAT concentration was measured in all subjects (n = 540) not on drug treatment at the time of enrollment in the multicenter, longitudinal, observational IMPROVE study. Mean and maximum intima-media thickness (IMT) of the whole carotid tree was measured by B-mode ultrasonography in all subjects. In the entire cohort, LCAT quartiles were not associated with carotid mean and maximum IMT (P for trend 0.95 and 0.18, respectively), also after adjustment for age, gender, HDL-cholesterol (HDL-C), and triglycerides. No association between carotid IMT and LCAT quartiles was observed in men (P=0.30 and P=0.99 for mean and maximum IMT, respectively), whereas carotid IMT increased with LCAT quartiles in women (P for trend 0.14 and 0.019 for mean and maximum IMT, respectively). The present findings support the concept that LCAT is not required for an efficient reverse cholesterol transport and that a low plasma LCAT concentration and activity is not associated with increased atherosclerosis.     

Increased aortic intima-media thickness is related to lipid profile in newborns with intrauterine growth restriction

BACKGROUND AND AIM: Low birth-weight is known to be associated with an increase in cardiovascular risk similar to that seen with major environmental risk factors, such as cigarette smoking or hypertension. Much epidemiological evidence has linked low birth-weight with hypertriglyceridaemia. METHOD: We measured aortic wall thickness by ultrasonography and lipid profile in 40 newborn babies with intrauterine growth restriction and 40 controls. RESULTS: Maximum and mean aortic intima-media thickness were significantly higher in the babies with intrauterine growth retardation (0.58 +/- 0.06, 0.52 +/- 0.03 mm, respectively) than in controls (0.44 +/- 0.05, 0.40 +/- 0.03 mm, p < 0.0001, p < 0.0001, respectively), more so after adjustment for birth-weight (maximum intima-media thickness: 0.23 +/- 0.03 mm/kg vs. 0.12 +/- 0.02 mm/kg, p < 0.0001; mean intima-media thickness: 0.21 +/- 0.02 mm/kg vs. 0.11 +/- 0.01 mm/kg, p < 0.0001). Serum triglyceride levels were significantly higher in the intrauterine growth retardation group (48.9 +/- 14.8 mg/dl) compared with the control group (32.5 +/- 9.8 mg/dl, p < 0.0001). The mean body mass index, prepregnancy weight, weight gain during pregnancy, maternal LDL cholesterol level and, height of the mothers were significantly lower in the intrauterine growth retardation group compared with the control group. For maximum aIMT, significant associations included the ponderal index (p = <0.01), length (p = 0.01) and serum triglyceride levels of infants (p = 0.02). CONCLUSION: Newborn babies with growth restriction have significant maximum aortic thickening with hypertriglyceridaemia, suggesting that prenatal events might predispose to later cardiovascular risk.