The relation between resting heart rate and cancer incidence,cancer mortality and all-cause mortality in patients with manifest vascular disease

BackgroundPrevious studies suggest that elevated resting heart rate (RHR) is related to an increased risk of cancer mortality. The aim of this study was to evaluate the relation between RHR and cancer incidence and mortality in patients with vascular disease.MethodsPatients with manifest vascular disease (n = 6007) were prospectively followed-up for cancer incidence and mortality. At baseline, RHR was obtained from an electrocardiogram. The relation between RHR and cancer incidence, cancer mortality and total mortality was assessed using competing risks models.ResultsDuring a median follow-up of 6.0 years (interquartile range: 3.1–9.3) 491 patients (8%) were diagnosed with cancer and 907 (15%) patients died, 248 (27%) died from cancer. After adjustment for potential confounders, the hazard ratio (HR) for incident cancer per 10 beats/min increase in RHR was 1.00 (95% confidence interval [CI]: 0.93–1.07). There was a trend toward an increased risk of colorectal cancer in patients with higher RHR (HR 1.15, 95% CI 0.97–1.36). The risk of all-cause mortality was increased in patients in the highest quartile of RHR compared to the lowest quartile (HR 1.86, 95% CI 1.53–2.27), but no effect of RHR on cancer mortality was observed (HR 1.01, 95% CI 0.70–1.46).ConclusionsIn patients with manifest vascular disease, elevated RHR was related to a higher risk of premature all-cause mortality, but this was not due to increased cancer mortality. RHR was not related to risk of overall cancer incidence, although a relation between elevated RHR and incident colorectal cancer risk could not be ruled out.     

Decreased AMP-activated protein kinase activity is associated with increased inflammation in visceral adipose tissue and with whole-body insulin resistance in morbidly obese humans

Inflammation and infiltration of immune cells in white adipose tissue have been implicated in the development of obesity-associated insulin resistance. Likewise, dysregulation of the fuel-sensing enzyme AMP-activated protein kinase (AMPK) has been proposed as a pathogenetic factor for these abnormalities based on both its links to insulin action and its anti-inflammatory effects. In this study, we examined the relationships between AMPK activity, the expression of multiple inflammatory markers in visceral (mesenteric and omental) and abdominal subcutaneous adipose tissue, and whole-body insulin sensitivity in morbidly obese patients (BMI 48 ± 1.9 kg/m²) undergoing gastric bypass surgery. AMPK activity was assessed by Western-blots (P-AMPK/T-AMPK) and mRNA levels of various markers of inflammation by qRT-PCR. Patients were stratified as insulin sensitive obese or insulin-resistant obese according to their HOMA-IR values. The results indicate that AMPK activity is lower in visceral than in subcutaneous abdominal adipose tissue of these patients and that this is associated with an increased expression of multiple inflammatory genes. They also revealed that AMPK activity is lower in adipose tissue of obese patients who are insulin resistant (HOMA-IR > 2.3) than in BMI-matched insulin sensitive subjects. Furthermore, this difference was evident in all three fat depots. In conclusion, the data suggest that there are close links between reduced AMPK activity and inflammation in white adipose tissue, and whole-body insulin resistance in obese humans. Whether adipose tissue AMPK dysregulation is a causal factor for the development of the inflammation and insulin resistance remains to be determined.     

Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue

Age-related adiposity has been linked to chronic inflammatory diseases in late life. To date, the studies on adipose tissue leukocytes and aging have not taken into account the heterogeneity of adipose tissue macrophages (ATMs), nor have they examined how age impacts other leukocytes such as T cells in fat. Therefore, we have performed a detailed examination of ATM subtypes in young and old mice using state of the art techniques. Our results demonstrate qualitative changes in ATMs with aging that generate a decrease in resident type 2 (M2) ATMs. The profile of ATMs in old fat shifts toward a proinflammatory environment with increased numbers of CD206(-)CD11c(-) (double-negative) ATMs. The mechanism of this aging-induced shift in the phenotypic profile of ATMs was found to be related to a decrease in peroxisome proliferator-activated receptor-γ expression in ATMs and alterations in chemokine/chemokine receptor expression profiles. Furthermore, we have revealed a profound and unexpected expansion of adipose tissue T cells in visceral fat with aging that includes a significant induction of regulatory T cells in fat. Our findings demonstrate a unique inflammatory cell signature in the physiologic context of aging adipose tissue that differs from those induced in setting of diet-induced obesity.     

Plasma adrenomedullin concentration is increased in patients with peripheral arterial occlusive disease associated with vascular inflammation

Adrenomedullin (AM), a potent vasodepressor, is known to have anti-atherosclerotic and anti-inflammatory effects. However, there is no information about its level in severe atherosclerotic diseases, such as peripheral arterial occlusive disease (PAOD). The present study investigated the plasma concentration of AM and several inflammatory parameters in 72 patients with and without PAOD. The plasma AM concentration in patients with PAOD was significantly higher than in those without PAOD. Its concentration had significant correlations with ankle-brachial index and Fontaine's stage. The plasma AM level also correlated with high sensitive C-reactive protein and interleukin-6. As an additional study, plasma levels of two forms of AM drawn from the femoral artery and saphenous vein were measured in 27 other subjects. Both mature and intermediate forms of plasma AM in the femoral artery and saphenous vein were higher in patients with PAOD than in those without PAOD. A significant step-up of the mature form of AM from the femoral artery to the saphenous vein was observed. Our findings indicate that the plasma AM concentration was elevated in patients with PAOD in proportion to the severity of the disease and associated with vascular inflammation. An increased production of AM in PAOD may play a protective role against advanced atherosclerosis with an inflammatory signature.     

A polymorphism in the beta1 adrenergic receptor is associated with resting heart rate

Resting heart rate is significantly associated with cardiovascular morbidity and mortality. However, the extent to which resting heart rate is genetically determined is poorly understood, and no genes have been found that contribute to variation in resting heart rate. Because signaling through the beta1 adrenergic receptor is a key determinant of cardiac function, we tested whether polymorphisms in this receptor are associated with resting heart rate. A cohort of >1,000 individuals of Chinese and Japanese descent, from nuclear families, was genotyped for two polymorphisms, resulting in a serine/glycine substitution at amino acid 49 (Ser49Gly) and an arginine/glycine substitution at residue 389 (Arg389Gly), in the beta1 adrenergic receptor. For comparison, polymorphisms in the beta2 and beta3 adrenergic receptors were also evaluated. The Ser49Gly polymorphism was significantly associated (P=.0004) with resting heart rate, independent of other variables, such as body-mass index, age, sex, ethnicity, exercise, smoking, alcohol intake, hypertension status, and treatment with beta blockers. The data support an additive model in which individuals heterozygous for the Ser49Gly polymorphism had mean heart rates intermediate to those of either type of homozygote, with Ser homozygotes having the highest mean heart rate and with Gly homozygotes having the lowest. Neither the Arg389Gly polymorphism in the beta1 adrenergic receptor nor polymorphisms in the beta2 and beta3 adrenergic receptors were associated with resting heart rate. The heritability of heart rate was 39.7% +/- 7.1% (P<10-7).     

Oxidative stress is associated with decreased heart rate variability in patients with chronic kidney disease

Objectives: Elevated oxidative stress and reduced heart rate variability (HRV) is prevalent in patients with chronic kidney disease (CKD) and is associated with increased morbidity and mortality. Previous studies have identified a positive association between elevated oxidative stress and autonomic dysfunction, however this relationship has not yet been investigated in the CKD population.

Methods: Plasma was collected from 78 patients with stage 3–4 CKD (estimated glomerular filtration rate 25–60?ml/min/1.73?m²) for the assessment of oxidative stress, including plasma total F2-isoprostanes, glutathione peroxidase activity and total antioxidant capacity. Time and frequency HRV parameters were measured from a three lead electrocardiogram.

Results: Participants with elevated F2-isoprostanes had reduced HRV compared to patients with normal levels of F2-isoprostanes. A number of HRV parameters were found to be inversely correlated with F2-isoprostanes in all CKD patients, including SDNN (r?=??0.337; P?r?=??0.281, P?=?0.01), LF (r?=??0.315, P?r?=??0.288, P?=?0.01). Multiple linear regression found F2-isoprostanes to be an independent predictor of SDNN (r²?=?0.287, β?=??0.272, P?=?0.01).

Discussion: Oxidative stress is significantly and independently associated with HRV in patients with CKD. Identifying oxidative stress in the pathogenesis of autonomic dysfunction may help target therapeutic strategies.     

Extension of coronary artery disease is associated with increased IL-6 and decreased adiponectin gene expression in epicardial adipose tissue

Epicardial adipose tissue (EAT) expresses lower levels of adiponectin in patients with CAD and higher levels of inflammatory mediators such as IL-6 and leptin than subcutaneous adipose tissue. This showed one important role of EAT in coronary artery disease. However, the relationship of EAT adiponectin and IL-6 levels to the extension of coronary artery disease has not hitherto been determined. We sought to determine whether the levels of adiponectin and interleukin-6 (IL-6) mRNA in epicardial adipose tissue are associated with the extension of coronary artery disease (CAD). Methods: Angiographic and hormones expression were evaluated from epicardial and subcutaneous adipose tissue. 92 patients (58 CAD, 34 non-CAD) who underwent cardiac surgery. Adiponectin and IL-6 mRNA levels were measured by real time RT-PCR in epicardial and subcutaneous adipose tissue (SAT) following angiographic evaluation of their coronary arteries. Results: We found that epicardial adipose tissue of CAD expressed lower levels of adiponectin mRNA and higher levels of IL-6 mRNA than that of non-CAD patients. As the number of injured arteries rose, adiponectin mRNA levels decreased (r = −0.402, p < 0.001) and IL-6 mRNA increased (r = 0.514, p < 0.001) in epicardial adipose tissue. Conclusions: The extension of CAD is significantly associated with the expression of adiponectin and IL-6 mRNA in EAT. These findings suggest that low adiponectin and high IL-6 expression by EAT may contribute to CAD extension.     

Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue

Fibroblast growth factor 21 (FGF21) has been proposed to be an antiaging hormone on the basis of experimental studies in rodent models. However, circulating FGF21 levels are increased with aging in rodents and humans. Moreover, despite the metabolic health‐promoting effects of FGF21, the levels of this hormone are increased under conditions such as obesity and diabetes, an apparent incongruity that has been attributed to altered tissue responsiveness to FGF21. Here, we investigated serum FGF21 levels and expression of genes encoding components of the FGF21‐response molecular machinery in adipose tissue from healthy elderly individuals (≥70 years old) and young controls. Serum FGF21 levels were increased in elderly individuals and were positively correlated with insulinemia and HOMA‐IR, indices of mildly deteriorated glucose homeostasis. Levels of β‐Klotho, the coreceptor required for cellular responsiveness to FGF21, were increased in subcutaneous adipose tissue from elderly individuals relative to those from young controls, whereas FGF receptor‐1 levels were unaltered. Moreover, total ERK1/2 protein levels were decreased in elderly individuals in association with an increase in the ERK1/2 phosphorylation ratio relative to young controls. Adipose explants from aged and young mice respond similarly to FGF21 “ex vivo”. Thus, in contrast to what is observed in obesity and diabetes, high levels of FGF21 in healthy aging are not associated with repressed FGF21‐responsiveness machinery in adipose tissue. The lack of evidence for impaired FGF21 responsiveness in adipose tissue establishes a distinction between alterations in the FGF21 endocrine system in aging and chronic metabolic pathologies.     

Elevation in cardiovascular disease risk in South Asians is mediated by differences in visceral adipose tissue

South Asians have a higher risk for cardiovascular disease (CVD) that remains largely unexplained. We hypothesized that the increased CVD risk in South Asians compared to Europeans is mediated through higher levels of visceral adipose tissue (VAT) in South Asians compared to total body fat and subcutaneous abdominal adipose tissue (SAT). South Asians (207) and Europeans (201) underwent assessment for demographics, body fat, and risk factors. Linear regression models were created by sex for each risk factor to explore mediation effects of total body fat, SAT, and VAT adjusted for age, income, smoking, and BMI (menopausal status for women). Mediation was based on changes in the ethnicity β coefficient due to additional adjustment for our adipose variable of interest and the Sobel test for mediation. South Asians had worse lipid, glucose, insulin, and C-reactive protein (CRP) levels than Europeans after adjusting for confounders. Most of these differences remained even after further adjustment by either total body fat or SAT. In contrast, VAT attenuated the ethnic differences in risk factors by 16%-52%. After adjusting for VAT, there were no longer ethnic differences in total cholesterol (TC), LDL-C, TC/HDL-C, glucose, and diastolic blood pressure (BP) in men, and in HDL-C, triglycerides (TG), TC/HDL-C, and homeostasis model (HOMA) in women, and VAT was a significant mediator for these risk factors. Higher levels of risk factors for CVD in South Asians are predominantly because of the unique phenotype of South Asians having greater VAT than Europeans even at the same BMI.     

Increased signal complexity is associated with increased mating success

The evolution of complex signals has often been explored by testing multiple functional hypotheses regarding how independent signal components provide selective benefits to offset the costs of their production. In the present study, we take a different approach by exploring the function of complexity per se. We test the hypothesis that increased vibratory signal complexity—based on both proportional and temporal patterning—provides selective benefits to courting male Schizocosa stridulans wolf spiders. In support of this hypothesis, all of our quantified metrics of vibratory signal complexity predicted the mating success of male S. stridulans. The rate of visual signalling, which is mechanistically tied to vibratory signal production, was also associated with mating success. We additionally found evidence that males can dynamically adjust the complexity of their vibratory signalling. Together, our results suggest that complexity per se may be a target of female choice.     

Increased systemic and adipose tissue cytokines in patients with HIV-associated lipodystrophy

The lipodystrophy syndrome (adipose tissue redistribution and metabolic abnormalities) observed with highly active antiretroviral therapy (HAART) during human immunodeficiency virus (HIV) infection may be related to increased proinflammatory cytokine activity. We measured acute cytokine (TNF-alpha, IL-6, leptin), glycerol, and lactate secretion from abdominal subcutaneous adipose tissue (SAT), and systemic cytokine levels, in HIV-infected subjects with and without lipodystrophy (HIVL+ and HIVL-, respectively) and healthy non-HIV controls. Lipodystrophy was confirmed and characterized as adipose tissue redistribution in HIVL+ compared with HIVL- and controls, by dual-energy X-ray absorptiometry and by whole body MRI. TNF-alpha secretion from abdominal SAT and circulating levels of IL-6, soluble TNF receptors I and II, and insulin were elevated in HIVL+ relative to HIVL- and/or controls, particularly in HIVL+ undergoing HAART. In the HIV-infected group as a whole, IL-6 secretion from abdominal SAT and serum IL-6 were positively associated with visceral fat and were negatively associated with the relative amount of lower limb adipose tissue (P < 0.01). Decreased leptin and increased lactate secretion from abdominal SAT were specifically associated with HAART. In conclusion, increased cytokine secretion from adipose tissue and increased systemic proinflammatory cytokine activity may play a significant role in the adipose tissue remodeling and/or the metabolic abnormalities associated with the HIV-lipodystrophy syndrome in patients undergoing HAART.     

Proteomics of epicardial adipose tissue in patients with heart failure

Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot closely linked to the pathogenesis of heart failure (HF). But the molecular signatures related to the mechanism of HF have not been systematically explored. Here, we present comprehensive proteomic analysis of EAT in HF patients and non‐HF patients as controls. A total of 771 proteins were identified in liquid chromatography‐tandem mass spectrometry experiments. Amongst them, 17 increased in abundance in HF and seven decreased. They were involved in HF‐related processes including inflammation and oxidative stress response and lipid metabolism. Of these proteins, serine proteinase inhibitor A3 (Serpina3) levels in EAT were highly up‐regulated in HF, with HF/non‐HF ratio of 4.63 (P = .0047). Gene expression of Serpina3 via quantitative polymerase chain reaction was significantly increased in the HF group. ELISA analysis confirmed a significant increase in circulating plasma Serpina3 levels in the HF group (P = .004). In summary, for the first time, we describe that parts of EAT proteome may be reactive and work as modulators of HF. Our profiling provides a comprehensive basis for linking EAT with pathogenesis of HF. Understanding the role of EAT may offer new insights into the treatment of HF.