The aim of this study was to investigate the occurrence of heart failure in patients treated with bisphosphonates.
In this nationwide retrospective cohort study from Denmark, all users of bisphosphonates and raloxifene between 1996 and 2006 (n = 102,342) were included in the ‘exposed’ group and three age- and gender-matched subjects (n = 307.026) from the general population comprised the control group. The risk of heart failure was estimated by Cox proportional hazard analyses.
The mean follow-up times were 2.8, 5.5 and 4.9 years for alendronate-, etidronate- and raloxifene-treated patients, respectively. The absolute risk of heart failure was 4.4% in the exposed group and 3.7% in the control group (P < 0.01). The relative risk (RR) of heart failure was significantly increased in users of bisphophonates: crude RR 1.71 [95% confidence interval (CI) 1.63–1.79]; adjusted hazard ratio (HR) 1.41 (95% CI 1.34–1.48). By comparison, raloxifene, which is used for the same indication but has a different mechanism of action, was not associated with an increased risk of heart failure: adjusted HR 1.07 (95% CI 0.76–1.50). When the two most commonly used bisphosphonates, alendronate and etidronate, were analysed separately, significant trends in the risk of heart failure were observed across refill compliance strata. The risk of heart failure increased significantly with increasing refill compliance for etidronate (P for trend <0.01), whereas decreased for alendronate (P for trend <0.01).
Bisphosphonate users were at increased risk of heart failure compared to age- and gender-matched control subjects. However, users of alendronate showed a dose-dependent reduction of this risk, suggesting that alendronate may reduce the risk of heart failure.
This article is protected by copyright. All rights reserved.
Treating patients or families with Fabry disease is challenging. Males with this X-linked disease experience life-threatening organ damage to the heart, kidney and cerebrovascular system, and may have advanced disease at presentation; in addition, treatment with enzyme-replacement therapy (ERT) is not only extremely expensive, it is of limited effectiveness. Furthermore, because of a manufacturing problem [1], one of the two ERT preparations was in short supply from June 2009 until 2012.
This article is protected by copyright. All rights reserved.
We thank Dr. Sen and colleagues for their Letter to the Editor [1] and their interest in our recent study of subclinical atherosclerosis in patients with psoriasis [2]. The goal of our study was to identify premature atherosclerosis using non-invasive surrogate markers in patients with psoriasis. The two modalities that we chose, coronary calcification measured by multidetector computed tomography (MDCT) and carotid intima–media thickness evaluated by carotid ultrasonography, are both well-validated surrogate markers of atherosclerosis.
This article is protected by copyright. All rights reserved.
We would like to thank Prof. Dal Moro for his valuable contribution[1]. Indeed, many patients, especially those who are older and who suffer from several concomitant diseases, are at risk of being “overtreated with good intentions”. The main problem is that the diagnosis of essential hypertension is at times assigned very liberally based on a single ambulatory measurement without taking into consideration the natural history and variation of systemic blood pressure[2]. The orthostatic intolerance is often asymptomatic and thus not being looked for. Consequently, the antihypertensive treatment may additionally reduce blood pressure on standing and lead to unexpected syncopal attacks.
This article is protected by copyright. All rights reserved.
Metastasis is an inefficient process and most cancer cells fail to colonize secondary sites. There are several possible reasons for this. First, the nature of the infiltrating cells is important as a small population of cancer stem cells has been shown to have exclusive metastasis-initiating potential. Secondly, supportive niches are required to promote the outgrowth of disseminated tumour cells. S uch niches are either produced prior to the arrival of cancer cells in the target organ or are induced ad hoc upon cell infiltration. Components of the extracellular matrix (ECM) have been found to play a role in establishing these niches. This has highlighted the importance of the ECM for metastatic progression, and suggests that such components may provide alternative targets for treatment of metastastic disease.
© 2012 The Association for the Publication of the Journal of Internal Medicine
Background and aim: Carotenoids in plasma are inversely associated with cardiovascular risk. Low levels can be explained by low dietary intake but also by a number of other factors including inflammatory activity. Given that matrix metalloproteinase (MMP)-9 has an important role in inflammation and cardiovascular disease, we hypothesized that circulating MMP-9 levels would be inversely related to total or single carotenoids in a general population cohort.
Methods: A well-characterized population-based cohort of 285 Swedish men and women (45–69 years) was used for the present study. The intake of carotenoid-rich fruits and vegetables was estimated from a food frequency questionnaire. Levels of MMP-9, C-reactive protein (CRP), interleukin (IL)-6 and six major carotenoids [β-cryptoxanthine, α-carotene, β-carotene, lutein (+ zeaxanthin) and lycopene] were determined in plasma.
Results: Lower plasma levels of total and single carotenoids were associated with lower dietary intake of carotenoids, older age, male sex, lower physical activity, higher alcohol consumption, higher body mass index (BMI), higher systolic and diastolic blood pressures, lower levels of total cholesterol and HDL cholesterol and higher levels of CRP, IL-6 and MMP-9. After multivariate adjustments, plasma levels of total carotenoids and provitamin A carotenoids (β-cryptoxanthine, α-carotene and β-carotene) remained independently associated with sex, dietary intake of carotenoids, BMI, HDL cholesterol and MMP-9, while associations with CRP and IL-6 were not maintained. Neither dietary intake of carotenoid-rich fruits and vegetables, nor vitamin supplement use was associated with MMP-9, CRP or IL-6 levels.
Conclusion: Plasma carotenoids were associated with a variety of factors including age, sex, dietary intake and metabolic variables. A new finding was the independent relationship in plasma between low provitamin A carotenoids and high MMP-9, suggesting a link between these carotenoids, matrix turnover and arterial remodelling.
© 2012 The Association for the Publication of the Journal of Internal Medicine
In this article, we review the current knowledge of the inherited genetics of epithelial ovarian cancer (EOC) susceptibility and clinical outcome. We focus on recent developments in identifying low-penetrance susceptibility genes and the role of the ovarian cancer association consortium (OCAC) in these discoveries. The ovarian cancer association consortium (OCAC) was established to facilitate large-scale replication analyses for reported genetic associations for EOC. Since its inception, the OCAC has conducted both candidate gene and genome wide association studies (GWAS); the latter has identified six established loci for EOC susceptibility most of which showed stronger association with the serous histological subtype. Future GWAS and sequencing studies are likely to result in the discovery of additional susceptibility loci and may result in established associations with clinical outcome. Additional rare and uncommon ovarian cancer loci will likely be uncovered from high throughput next generation sequencing studies. Applying these novel findings to establish improved preventative and clinical intervention strategies will be one of the major challenges of future work.
The individual human genome and epigenome are being defined at unprecedented resolution by current advances in sequencing technologies with important implications for human disease. This review uses examples relevant to clinical practice to illustrate the functional consequences of genetic and epigenetic variation. The insights gained from genome-wide association studies are described together with current efforts to understand the role of rare variants in common disease, set in the context of recent successes in Mendelian traits through application of whole exome sequencing. The application of functional genomics to interrogate the genome and epigenome, build up an integrated picture of the regulatory genomic landscape and inform disease association studies is discussed, together with the role of expression quantitative trait mapping and analysis of allele-specific gene expression.
Pathogenic mutations in the tumour suppressor genes BRCA1 and BRCA2 confer increased risks for breast and ovarian cancer and account for approximately 15% of the excess familial risk of breast cancer among first degree relatives of breast cancer patients. There is considerable evidence indicating that these risks vary by other genetic and environmental factors clustering in families. In the past few years, based on the availability of genome-wide association data and samples form large collaborative studies, several common alleles have been found to modify breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. These common alleles explain a small proportion of the genetic variability in breast or ovarian cancer risk for mutation carriers, suggesting more modifiers remain to be identified. We review the so far identified genetic modifiers of breast and ovarian cancer risk and consider the implications for risk prediction. BRCA1 and BRCA2 mutation carriers could be some of the first to benefit from clinical applications of common variants identified through genome-wide association studies. However, to be able to provide more individualised risk estimates, it will be important to understand how the associations vary with different tumour characteristics and their interactions with other genetic and environmental modifiers.
The pathogenetic mechanisms that cause the two types of inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), are still under investigation. Nevertheless, there is broad agreement that luminal microbes are of particular relevance in the development of these conditions. In recent years, increasing evidence has shown that defects in the innate immunity are at the centre of both types of IBD. The innate intestinal barrier is provided by the epithelium which secretes antimicrobial peptides (so-called defensins) that are retained in the mucus layer. In ileal CD, the alpha-defensins are lacking due to several Paneth cell defects. In colonic CD, the expression of beta-defensins is inadequate. This may be related to downregulation of the transcription factor PPAR-gamma and in some cohorts is associated with a reduced HBD2 gene copy number. In UC, the mucus layer, which protects the host from the enormous amounts of luminal microbes, is defective. This is accompanied by an insufficient differentiation from intestinal stem cells towards goblet cells. All these disturbances in the gut barrier shift the balance from epithelial defence towards bacterial offense. The current treatment of CD and UC is based on suppression of this secondary inflammatory process. In future, patients may benefit from new therapeutic approaches stimulating the protective innate immune system.
Haemoglobin A1c (HbA1c) has recently been adopted by the World Health Organisation into its recommended criteria for diabetes diagnosis. Much debate continues regarding the relative benefits and potential disadvantages surrounding the use of HbA1c for this purpose. There is a lack of consensus as to whether this alteration to the definition of diabetes is a step forward or whether it could add further confusion and ambiguity to the debate on the method and criteria for the diagnosis of this globally important disease. This review provides a comprehensive overview of the current issues surrounding how HbA1c is measured and reported; and of the evidence for and against its use in diagnosis.
Patients with chronic kidney disease (CKD) often present with reduced plasma HDL cholesterol (HDL-C) levels. Whether this reduction in an epiphenomenon or is involved in disease progression is unclear. The aim of this study was to investigate the relation between HDL-C levels/function and CKD progression in patients with different degrees of disease.
A total of 176 patients with CKD [glomerular filtration rate (GFR) 50.3 ± 29.1 mL min−1] were recruited and followed for up to 84 months. Lipid profile, metabolic status and kidney function were evaluated at predetermined times. Age-matched control subjects were selected from the PLIC study (n = 453). Scavenger receptor class B member 1 (SR-BI) and ATP-binding cassette transporter A1 (ABCA-1)-dependent efflux of cholesterol were measured in CKD patients and in age-matched control subjects.
Low HDL-C levels, diabetes and hypertension were associated with reduced GFR. At follow-up, low HDL-C levels were associated with earlier entry in dialysis or doubling of the plasma creatinine level (P = 0.017); HDL-C levels were the only lipid parameter that affected the progression of CKD (hazard ratio 0.951, 95% confidence interval 0.917–0.986, P = 0.007), independently of the presence of diabetes. Only SR-BI-mediated serum cholesterol efflux was significantly reduced in the group of CKD patients with low HDL-C levels compared to the control group.
CKD patients with low levels of plasma HDL-C have a poor prognosis. HDL functionality is also impaired in renal dysfunction. These data support the relevance of HDL in influencing CKD progression.
The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards ‘hard’ clinical end-points in comparison with the natural course of the disease.
A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain.
During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min−1 per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry.
Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.
Heterozygous mutations in hepatocyte nuclear factor 1α (HNF1α) cause maturity onset diabetes of the young 3 (MODY3), an autosomal dominant form of diabetes. Deficiency of HNF1α in mice results in diabetes, hypercholesterolaemia and increased bile acid (BA) and cholesterol synthesis. Little is known about alterations in lipid metabolism in patients with MODY3. The aim of this study was to investigate whether patients with MODY3 have altered cholesterol and BA synthesis and intestinal cholesterol absorption. A secondary aim was to investigate the effects of HNF1α mutations on the transcriptional regulation of BA metabolism.
Plasma biomarkers of BA and cholesterol synthesis and intestinal cholesterol absorption were measured in patients with MODY3 (n = 19) and in matched healthy control subjects (n = 15). Cotransfection experiments were performed with several promoters involved in BA metabolism along with expression vectors carrying the mutations found in these patients.
Plasma analysis showed higher levels of BA synthesis in patients with MODY3. No differences were observed in cholesterol synthesis or intestinal cholesterol absorption. Cotransfection experiments showed that one of the mutations (P379A) increased the induction of the cholesterol 7α-hydroxylase promoter compared with HNF1α, without further differences in other studied promoters. By contrast, the other four mutations (L107I, T260M, P291fsinsC and R131Q) reduced the induction of the farnesoid X receptor (FXR) promoter, which was followed by reduced repression of the small heterodimer partner promoter. In addition, these mutations also reduced the induction of the apical sodium-dependent bile salt transporter promoter.
BA synthesis is increased in patients with MODY3 compared with control subjects. Mutations in HNF1α affect promoters involved in BA metabolism.
Poorer control of risk factors for cardiovascular disease (CVD) has been reported in diabetic women, as compared with diabetic men. It has been proposed that this finding is due to gender disparities in treatment intensity. We investigated this hypothesis in a large contemporary cohort of subjects with type 2 diabetes.
Observational, cross-sectional study.
Consecutive patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicentre study (n = 15 773), attending 19 hospital-based diabetes clinics in 2007–2008.
Traditional CVD risk factors, macro- and microvascular complications and current glucose-, lipid- and blood pressure (BP)-lowering treatments were assessed.
Although CVD was more prevalent in men, women showed a less favourable CVD risk profile and worse performance in achieving treatment targets for haemoglobin A1c, LDL, HDL and non-HDL cholesterol, systolic blood pressure (BP) and in particular obesity [body mass index (BMI) and waist circumference], but not for triglycerides and diastolic BP. However, women were more frequently receiving pharmacological treatment for hypertension and to a lesser extent hyperglycaemia and dyslipidaemia than men, and female gender remained an independent predictor of unmet therapeutic targets after adjustment for confounders such as treatments, BMI, duration of diabetes and, except for the systolic BP goal, age.
In women with type 2 diabetes from the RIACE cohort, a more adverse CVD risk profile and a higher likelihood of failing treatment targets, compared with men, were not associated with treatment differences. This suggests that factors other than gender disparities in treatment intensity are responsible.
Systemic therapeutic efficacy is central to determining the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive biomarkers to optimize efficacy whilst minimizing toxicity. The integration of a new generation of molecularly targeted drugs into the treatment of CRC, coupled with the development of sophisticated technologies for individual tumours as well as patient molecular profiling, underlines the potential for personalized medicine. In this review, we focus on the latest progress made within the genomic and proteomic fields, concerning predictive biomarkers for individualized therapy in metastatic CRC.
To investigate the independent effects of antihypertensive treatment and blood pressure (BP) levels on physical and mental health status in patients with arterial disease.
Cross-sectional analyses were conducted within the single-centre Secondary Manifestations of ARTerial disease (SMART) study, in a hospital care setting.
A total of 5877 patients (mean age 57 years) with symptomatic and asymptomatic arterial disease underwent standardized vascular screening.
The primary outcome was self-rated physical and mental health assessed using the 36-item short-form health survey.
In the total population, antihypertensive drug use and increased intensity of antihypertensive treatment were associated with poorer health status independent of important confounders including BP levels; adjusted mean differences [95% confidence interval (CI)] in physical and mental health between n = 0 and n ≥ 3 antihypertensives were −1.2 (−2.1; −0.3) and −3.5 (−4.4; −2.6), respectively. Furthermore, both lower systolic and lower diastolic BP levels were related to poorer physical and mental health status independent of antihypertensive treatment. Mean differences (95% CI) in physical and mental health status per SD decrease in systolic BP were −0.56 (−0.84; −0.27) and −0.32 (−0.61; −0.03) and per SD decrease in diastolic BP were −0.50 (−0.78; −0.23) and −0.08 (−0.36; 0.20), respectively. The association between low BP and poor health status was particularly present in patients with coronary artery disease.
In a population of patients with asymptomatic and symptomatic arterial disease, antihypertensive treatment and lower BP levels are independently associated with poorer self-rated physical and mental health. These findings suggest that different underlying mechanisms may explain these independent associations.
Obesity increases the risk of metabolic diseases, including insulin resistance and type 2 diabetes, as well as cardiovascular disease. In addition to lipid accumulation in adipose tissue, obesity is associated with increased lipid storage in ectopic tissues, such as skeletal muscle and liver. Furthermore, lipid accumulation in the heart may result in cardiac dysfunction and heart failure. It has recently been demonstrated that intracellular lipid accumulation in ectopic tissues leads to pathological responses and impaired insulin signalling. Here, we will review the current understanding of how lipid storage and lipid droplet physiology affect the risk of developing metabolic diseases.
Excess body weight and a sedentary lifestyle are associated with the development of several diseases, including cardiovascular disease, diabetes and cancer in women. One proposed mechanism linking obesity to chronic diseases is an alteration in adipose-derived adiponectin and leptin levels. We investigated the effects of 12-month reduced calorie, weight loss and exercise interventions on adiponectin and leptin concentrations.
Overweight/obese postmenopausal women (n = 439) were randomized as follows: (i) a reduced calorie, weight-loss diet (diet; N = 118), (ii) moderate-to-vigorous intensity aerobic exercise (exercise; N = 117), (iii) a combination of a reduced calorie, weight-loss diet and moderate-to-vigorous intensity aerobic exercise (diet + exercise; N = 117), and (iv) control (N = 87). The reduced calorie diet had a 10% weight-loss goal. The exercise intervention consisted of 45 min of moderate-to-vigorous aerobic activity 5 days per week. Adiponectin and leptin levels were measured at baseline and after 12 months of intervention using a radioimmunoassay.
Adiponectin increased by 9.5% in the diet group and 6.6% in the diet + exercise group (both P ≤ 0.0001 vs. control). Compared with controls, leptin decreased with all interventions (diet + exercise, −40.1%, P < 0.0001; diet, −27.1%, P < 0.0001; exercise, −12.7%, P = 0.005). The results were not influenced by the baseline body mass index (BMI). The degree of weight loss was inversely associated with concentrations of adiponectin (diet, P-trend = 0.0002; diet + exercise, P-trend = 0.0005) and directly associated with leptin (diet, P-trend < 0.0001; diet + exercise, P-trend < 0.0001).
Weight loss through diet or diet + exercise increased adiponectin concentrations. Leptin concentrations decreased in all of the intervention groups, but the greatest reduction occurred with diet + exercise. Weight loss and exercise exerted some beneficial effects on chronic diseases via effects on adiponectin and leptin.
To our knowledge, no randomized toxicity studies have been conducted to compare myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) in allogeneic haematopoietic stem cell transplantation (HSCT).
Adult patients ≤60 years of age with myeloid leukaemia were randomly assigned (1 : 1) to treatment with RIC (n = 18) or MAC (n = 19) in this Phase II single-centre toxicity study.
There was a maximum median mucositis grade of 1 in the RIC group compared with 4 in the MAC group (P < 0.001). Haemorrhagic cystitis occurred in eight of the patients in the MAC group and none in the RIC group (P < 0.01). Results of renal and hepatic tests did not differ significantly between the two groups. RIC-treated patients had faster platelet engraftment (P < 0.01) and required fewer erythrocyte and platelet transfusions (P < 0.001) and less total parenteral nutrition (TPN) than those treated with MAC (P < 0.01). Cytomegalovirus (CMV) infection was more common in the MAC group (14/19) than in the RIC group (6/18) (P = 0.02). Donor chimerism was similar in the two groups with regard to CD19 and CD33, but was delayed for CD3 in the RIC group. Five-year transplant-related mortality (TRM) was approximately 11% in both groups, and rates of relapse and survival were not significantly different. Patients in the MAC group with intermediate cytogenetic acute myeloid leukaemia had a 3-year survival of 73%, compared with 90% among those in the RIC group.
Reduced-intensity conditioning had several advantages compared with MAC, including less mucositis, less haemorrhagic cystitis, faster platelet engraftment, the need for fewer transfusions and less TPN, and fewer CMV infections. Both regimens were tolerated and TRM was low.
To evaluate the proportion of cardiovascular disease (CVD) incidence that is explained by genetic variation at chromosome 9p21 and to test whether such variation adds incremental information with regard to CVD prediction, beyond traditional risk factors.
rs4977574 on chromosome 9p21 was genotyped in 24 777 subjects from the Malmö Diet and Cancer study who were free from CVD prior to the baseline examination. Association between genotype and incident CVD (n = 2668) during a median follow-up of 11.7 years was evaluated in multivariate Cox proportional hazard models. Analyses were performed in quartiles of baseline age, and linear trends in effect size across age groups were estimated in logistic regression models.
In additive models, chromosome 9p21 significantly predicted CVD in the entire population (hazard ratio 1.17 per G allele, 95% confidence interval 1.11–1.23, P < 0.001). Effect estimates increased from the highest (Q4) to the lowest quartile (Q1) of baseline age, but this trend was not significant. The overall population attributable risk conferred by chromosome 9p21 in fully adjusted models was 13%, ranging from 17% in Q1 to 11% in Q4. Addition of chromosome 9p21 to traditional risk factors only marginally improved predictive accuracy.
The high population attributable risk conferred by chromosome 9p21 suggests that future interventions interfering with downstream mechanisms of the genetic variation may affect CVD incidence over a broad range of ages. However, variation of chromosome 9p21 alone does not add clinically meaningful information in terms of CVD prediction beyond traditional risk factors at any age.
Patients with decompensated cirrhosis are susceptible to bacterial infections, which are associated with organ failure and a high mortality rate. Reliable biomarkers are needed to identify patients who require intensified treatment. Our objective was to study the regulation and prognostic relevance of elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) in patients with advanced cirrhosis.
We examined the associations between serum and ascitic fluid (AF) suPAR and liver function, bacterial infection, and short-term mortality in 162 consecutive patients with decompensated cirrhosis undergoing diagnostic paracentesis in a tertiary health care centre in Germany.
Twenty-eight-day mortality.
Circulating suPAR levels were increased in patients with decompensated cirrhosis and correlated with the severity of liver dysfunction and systemic inflammation but were not indicative of bacterial infection. Circulating suPAR levels >14.4 ng mL−1 predicted 28-day mortality, even after adjustment for liver function and confounders [HR = 3.05 (1.35–6.90); P = 0.0076] equal to the MELD score (AUC = 0.71; 95% CI = 0.61–0.81; P < 0.001). Cut-off levels derived from cohorts without liver disease were not applicable due to the low specificity. AF suPAR levels were elevated during spontaneous bacterial peritonitis (SBP), but not during episodes in which bacteria or bacterial DNA was translocated into the ascites. AF suPAR levels correlated poorly with systemic suPAR but were associated with a more severe course of SBP and a worse outcome. In vitro experiments revealed that monocytes, and to a lesser extent neutrophils, secrete suPAR after Toll-like-receptor ligation, which led to rapid urokinase plasminogen activator receptor cleavage followed by increased synthesis.
Blood and ascitic suPAR levels provide distinct, but relevant prognostic information on the severity of complications in patients with end-stage liver disease.
Inflammation is involved in the pathogenesis of cardiovascular disease and cognitive decline. Interleukin-6 (IL-6) has a role in cardiovascular disease, but the association of IL-6 concentration and the functional IL-6 -174 polymorphism with cognitive decline has not been demonstrated unequivocally. The objective of this study was to investigate the associations between both high concentration of IL-6 and the -174 promoter polymorphism, and increased cognitive decline in old age.
Over 5000 participants of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) with a mean age of 75 years and a history of cardiovascular disease or its risk factors were included in this study. We determined baseline concentrations of IL-6 and genotype of the IL-6 -174 polymorphism, of which the C allele was previously shown to be associated with higher circulating concentrations of IL-6. A cognitive test battery was administered at baseline and repeatedly during follow-up (mean 39 months).
In the cross-sectional analysis of 5653 participants, higher IL-6 concentration was associated with worse executive cognitive function (P < 0.001), independent of cardiovascular disease status and risk factors. No association was found between IL-6 concentration and memory function (P > 0.14). In the prospective analysis, higher IL-6 concentration was associated with an increased rate of cognitive decline in both executive function (P = 0.002) and memory function (P = 0.002), again independent of cardiovascular disease status and risk factors. Although not associated with IL-6 concentrations, the IL-6 -174 CC genotype was associated with worse performance on the Stroop test (P = 0.045).
Higher circulating levels of IL-6 were associated with worse cognitive function and steeper cognitive decline and provide preliminary genetic evidence for a potential causal association. The findings support the importance of the need for further investigation of the IL-6 pathway in cognitive decline.
Ectopic fat accumulation in liver and skeletal muscle may be an essential link between abdominal obesity, insulin resistance and increased risk of cardiovascular disease after menopause. We hypothesized that a diet containing a relatively high content of protein and unsaturated fat [mainly monounsaturated fatty acids (MUFAs)] but limited carbohydrates and saturated fat would reduce lipid content in liver and muscle and increase insulin sensitivity in postmenopausal women.
Ten healthy, nonsmoking postmenopausal women with a body mass index (BMI) >27 (28–35) kg m−2 were included in the study.
Participants were instructed to consume an ad libitum Palaeolithic-type diet intended to provide approximately 30 energy percentage (E%) protein, 40 E% fat (mainly MUFAs) and 30 E% carbohydrate. Intramyocellular lipid (IMCL) levels in calf muscles and liver triglyceride levels were quantified using proton magnetic resonance spectroscopy (1H-MRS) before and 5 weeks after dietary intervention. Insulin sensitivity was estimated by homoeostasis model assessment (HOMA) indices and the euglycaemic hyperinsulinaemic clamp technique.
Mean energy intake decreased by 25% with a weight loss of 4.5 kg. BMI, waist and hip circumference, waist/hip ratio and abdominal sagittal diameter also decreased significantly, as did diastolic blood pressure (mean −7 mmHg), levels of fasting serum glucose, cholesterol, triglycerides, LDL/HDL cholesterol, apolipoprotein B (ApoB) and apolipoprotein A1 (ApoA1), urinary C-peptide and HOMA indices. Whole-body insulin sensitivity did not change. Liver triglyceride levels decreased by 49%, whereas IMCL levels in skeletal muscle were not significantly altered.
A modified Palaeolithic-type diet has strong and tissue-specific effects on ectopic lipid deposition in postmenopausal women.
Cystatin C is a novel marker of cardiovascular disease (CVD); however, the underlying mechanisms remain unclear. Here, we prospectively investigated whether plasma levels of cystatin C predict new-onset metabolic syndrome (MetS) as well as long-term progression and incidence of the different components of the MetS.
Cystatin C was measured in 1502 individuals included in the Malmö Diet and Cancer cardiovascular cohort (mean age 56 years, 59% women) who were free from the MetS at baseline and subsequently underwent a follow-up examination after a median of 16 years. MetS was defined according to the NCEP-ATP-III guidelines. Logistic regression was used to adjust for covariates.
Metabolic syndrome and long-term progression as well as incidence of the different components of the MetS.
During follow-up, 428 subjects developed new-onset MetS. In age- and sex-adjusted analysis, compared with the lowest quartile of cystatin C, the odds ratios (95% confidence interval) for incident MetS in subjects with cystatin C levels in quartiles 2, 3 and 4 were 1.00 (0.71–1.40), 1.48 (1.06–2.07) and 1.91 (1.37–2.68), respectively (Ptrend < 0.001); this linear association remained significant even after full multivariate adjustment (Ptrend = 0.041). Interestingly, in this fully adjusted model, long-term progression of abdominal obesity was the only component of the MetS significantly associated with increasing quartiles of baseline cystatin C levels (Ptrend = 0.008).
These findings suggest that cystatin C may adversely affect metabolic factors, particularly abdominal obesity, thus contributing to development of the MetS. Our results may help to explain the link between cystatin C and development of CVD.
Different healthy food patterns may modify cardiometabolic risk. We investigated the effects of an isocaloric healthy Nordic diet on insulin sensitivity, lipid profile, blood pressure and inflammatory markers in people with metabolic syndrome.
We conducted a randomized dietary study lasting for 18–24 weeks in individuals with features of metabolic syndrome (mean age 55 years, BMI 31.6 kg m−2, 67% women). Altogether 309 individuals were screened, 200 started the intervention after 4-week run-in period, and 96 (proportion of dropouts 7.9%) and 70 individuals (dropouts 27%) completed the study, in the Healthy diet and Control diet groups, respectively. Healthy diet included whole-grain products, berries, fruits and vegetables, rapeseed oil, three fish meals per week and low-fat dairy products. An average Nordic diet served as a Control diet. Compliance was monitored by repeated 4-day food diaries and fatty acid composition of serum phospholipids.
Body weight remained stable, and no significant changes were observed in insulin sensitivity or blood pressure. Significant changes between the groups were found in non-HDL cholesterol (−0.18, mmol L−1 95% CI −0.35; −0.01, P = 0.04), LDL to HDL cholesterol (−0.15, −0.28; −0.00, P = 0.046) and apolipoprotein B to apolipoprotein A1 ratios (−0.04, −0.07; −0.00, P = 0.025) favouring the Healthy diet. IL-1 Ra increased during the Control diet (difference −84, −133; −37 ng L−1, P = 0.00053). Intakes of saturated fats (E%, beta estimate 4.28, 0.02; 8.53, P = 0.049) and magnesium (mg, −0.23, −0.41; −0.05, P = 0.012) were associated with IL-1 Ra.
Healthy Nordic diet improved lipid profile and had a beneficial effect on low-grade inflammation.
The findings of experimental studies suggest that the immune system plays a key role in atherosclerosis, but the clinical importance of different immune cells in cardiovascular disease remains poorly characterized. In this study we investigated the association between CD8+ T cells and carotid disease as well as development of cardiovascular disease events.
The study cohort comprised 700 subjects from the cardiovascular arm of the Malmö Diet and Cancer Study. Peripheral blood mononuclear cells, obtained at the 1991–1994 baseline investigation and stored at −140 °C, were thawed and the different CD8+ T-cell populations analysed by flow cytometry. Baseline carotid intima–media thickness and stenosis were assessed by ultrasonography and clinical events were monitored through validated national registers.
Subjects with a high fraction of CD8+ T cells were characterized by decreased cytokine release from activated leucocytes, metabolic signs of insulin resistance and increased incidence of coronary events; hazard ratios (95% confidence intervals) for the second and third tertiles of CD8+ T cells were 2.57 (1.16, 5.67) and 2.61 (1.19, 5,71), respectively, in a Cox proportional hazards regression model. Correlations were found between the fraction of CD8+CD25+ T cells and the degree of carotid stenosis (r = 0.11, P < 0.01), and between the CD8+CD56−IFN-γ+ T-cell fraction and the degree of stenosis (r = −0.18, P < 0.005). The association between CD8+CD56−IFN-γ+ T cells and carotid stenosis remained significant after controlling for major cardiovascular disease risk factors.
This study provides prospective clinical evidence for a role of CD8+ T cells in cardiovascular disease and suggests the existence of CD8+ T-cell subsets with different pathological functions.
Considerable efforts have been made to understand the role of oxidative stress in age-related diseases and ageing. The mitochondrial free radical theory of ageing, which proposes that damage to mitochondrial DNA (mtDNA) and other macromolecules caused by the production of reactive oxygen species (ROS) during cellular respiration drives ageing, has for a long time been the central hypothesis in the field. However, in contrast with this theory, evidence from an increasing number of experimental studies has suggested that mtDNA mutations may be generated by replication errors rather than by accumulated oxidative damage. Furthermore, interventions to modulate ROS levels in humans and animal models have not produced consistent results in terms of delaying disease progression and extending lifespan. A number of recent experimental findings strongly question the mitochondrial free radical theory of ageing, leading to the emergence of new theories of how age-associated mitochondrial dysfunction may lead to ageing. These new hypotheses are mainly based on the underlying notion that, despite their deleterious role, ROS are essential signalling molecules that mediate stress responses in general and the stress response to age-dependent damage in particular. This novel view of ROS roles has a clear impact on the interpretation of studies in which antioxidants have been used to treat human age-related diseases commonly linked to oxidative stress.
Lupus erythematosus (LE) is an autoimmune disease with diverse clinical manifestations ranging from limited cutaneous (CLE) to potentially life-threatening systemic disease (SLE). Susceptibility to LE arises from genetic variation in multiple loci, and disease activity is provoked by exogenous or endogenous trigger(s), the best characterized of which is exposure to ultraviolet radiation (UVR). Amongst patients with LE, a cluster of photosensitive subjects with cutaneous lesions and positivity for anti-Ro/SSA autoantibodies have been described. The Ro52 antigen belongs to the tripartite motif protein family and has E3 ligase activity. New data reveal that Ro52 ubiquitinates interferon regulatory factors and modulates their transcriptional activity, indicating an important role for Ro52 in inflammation as a negative feedback regulator. Our findings indicate that UVR exposure induces upregulation of Ro52 in the CLE target cell, the keratinocyte, and that Ro52 is upregulated in spontaneous and UVR-induced CLE lesions. Recently described functional analysis of Ro52-deficient mice revealed that loss of Ro52 results in uncontrolled inflammation in response to minor skin injury leading to an LE-like condition. In summary, emerging data suggest that abnormal function or regulation of Ro52 contributes to the pathogenesis of UVR-induced CLE in genetically susceptible individuals. Ro52 may thus be an interesting therapeutic target, as its activation could contribute to downregulation of the chronic inflammatory process in LE. Here, we review the available data on the pathogenesis of CLE and, in particular, the role of the Ro52 autoantigen.
Heparan sulphate (HS) polysaccharides are covalently attached to the core proteins of various proteoglycans at cell surfaces and in the extracellular matrix. They are composed of alternating units of hexuronic acid and glucosamine, with sulphate substituents in complex and variable yet cell-specific patterns. Whereas HS is produced by virtually all cells in the body, heparin, a highly sulphated HS variant, is confined to connective-tissue-type mast cells. The polysaccharides interact with a multitude of proteins, mainly through ionic binding, and thereby control key processes in development and homoeostasis. Similar interactions also implicate HS in various pathophysiological settings, including cancer, amyloid diseases, infectious diseases, inflammatory conditions and some developmental disorders. Prospects for the development of HS-based drugs, which are still largely unrealized, are discussed.
Cardiac disease is the most common cause of mortality in Western countries, with most deaths due to out-of-hospital cardiac arrest (OHCA). In Sweden, 5000–10 000 OHCAs occur annually. During the last decade, the time from cardiac arrest to start of cardiopulmonary resuscitation (CPR) and defibrillation has increased, whereas survival has remained unchanged or even increased. Resuscitation of OHCA patients is based on the ‘chain-of-survival’ concept, including early (i) access, (ii) CPR, (iii) defibrillation, (iv) advanced cardiac life support and (v) post-resuscitation care. Regarding early access, agonal breathing, telephone-guided CPR and the use of ‘track and trigger systems’ to detect deterioration in patients' condition prior to an arrest are all important. The use of compression-only CPR by bystanders as an alternative to standard CPR in OHCA has been debated. Based on recent findings, guidelines recommend telephone-guided chest compression-only CPR for untrained rescuers, but trained personnel are still advised to give standard CPR with both compressions and ventilation, and the method of choice for this large group remains unclear and demands for a randomized study. Data have shown the benefit of public access defibrillation for dispatched rescuers (e.g. police and fire fighters) but data are not as strong for the use of automated defibrillators (AEDs) by trained or untrained rescuers. Postresuscitation, use of therapeutic hypothermia, the importance of specific prognostic survival factors in the intensive care unit and the widespread use of percutaneous coronary intervention have all been considered. Despite progress in research and improved treatment regimens, most patients do not survive OHCA. Particular areas of interest for improving survival include (i) identification of high-risk patients prior to their arrest (e.g. early warning symptoms and genes); (ii) increased use of bystander CPR training (e.g. in schools) and simplified CPR techniques; (iii) better identification of high-incidence sites and better recruitment of AEDs (via mobile phone solutions?); (iv) improved understanding of the use of therapeutic hypothermia; (v) determining which patients should undergo immediate coronary angiography on hospital admission; and (vi) clarifying the importance of extracorporeal membrane oxygenation during CPR.
Combinations of inhaled corticosteroids (ICSs) and long-acting β2-agonists (LABAs) are recommended for patients with moderate and severe chronic obstructive pulmonary disease (COPD). However, it is not known whether different fixed combinations are equally effective. The aim of this study was to investigate exacerbation rates in primary care patients with COPD treated with budesonide/formoterol compared with fluticasone/salmeterol.
Patients with physician-diagnosed COPD and a record of postdiagnosis treatment with a fixed combination of budesonide/formoterol or fluticasone/salmeterol were included. Data from primary care medical records were linked to those from Swedish national hospital, drug and cause of death registers. Pairwise (1 : 1) propensity score matching was carried out at the index date (first prescription) by prescribed fixed ICS/LABA combination. Exacerbations were defined as hospitalizations, emergency visits and collection of oral steroids or antibiotics for COPD. Yearly event rates were compared using Poisson regression.
Matching of 9893 patients (7155 budesonide/formoterol and 2738 fluticasone/salmeterol) yielded two cohorts of 2734 patients, comprising 19 170 patient-years. The exacerbation rates were 0.80 and 1.09 per patient-year in the budesonide/formoterol and fluticasone/salmeterol groups, respectively (difference of 26.6%; P < 0.0001); yearly rates for COPD-related hospitalizations were 0.15 and 0.21, respectively (difference of 29.1%; P < 0.0001). All other healthcare outcomes were also significantly reduced with budesonide/formoterol versus fluticasone/salmeterol.
Long-term treatment with fixed combination budesonide/formoterol was associated with fewer healthcare utilization-defined exacerbations than fluticasone/salmeterol in patients with moderate and severe COPD.
Metabolic syndrome (MetS) has been shown to predict both risk and CVD events. We have identified sex-specific values for the triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio associated with an unfavourable cardio-metabolic risk profile, but it is not known whether it also predicts CVD outcome.
To quantify risk for CVD outcomes associated with a high TG/HDL-C ratio and to compare this risk with that predicted using MetS, a population longitudinal prospective observational study was performed in Rauch City, Buenos Aires, Argentina. In 2003 surveys were performed on a population random sample of 926 inhabitants. In 2012, 527 women and 269 men were surveyed again in search of new CVD events. The first CVD event was the primary endpoint. Relative risks for CVD events between individuals above and below the TG/HDL-C cut-points, and with or without MetS, were estimated using Cox proportional hazard.
The first CVD event was the primary endpoint. Relative risks for CVD events between individuals above and below the TG/HDL-C cut-points, and with or without MetS, were estimated using Cox proportional hazard.
The number of subjects deemed at ‘high’ CVD risk on the basis of an elevated TG/HDL-C ratio (30%) or having the MetS (35%) was relatively comparable. The unadjusted hazard risk was significantly increased when comparing ‘high’ versus ‘low’ risk groups no matter which criteria was used, although it was somewhat higher in those with the MetS (HR = 3.17, 95% CI:1.79–5.60 vs. 2.16, 95% CI:1.24–3.75). However, this difference essentially disappeared when adjusted for sex and age (HR = 2.09, 95% CI:1.18–3.72 vs. 2.01, 95% CI:1.14–3.50 for MetS and TG/HDL-C respectively).
An elevated TG/HDL-C ratio appears to be just as effective as the MetS diagnosis in predicting the development of CVD.
The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms, including all eight natural vitamin E congeners (four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects.
Overall, 81 patients with AD, 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study. MRI and plasma vitamin E data were acquired at baseline. MRI scans were analysed using Freesurfer, an automated segmentation scheme which generates regional volume and cortical thickness measures. Orthogonal partial least squares to latent structures (OPLS), a multivariate data analysis technique, was used to analyse MRI and vitamin E measures in relation to AD and MCI diagnosis.
The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects: 98.2% (sensitivity 98.8%, specificity 97.7%) for AD versus CTL, and 90.7% (sensitivity 91.8%, specificity 89.5%) for MCI versus CTL. This combination of measures also identified 85% of individuals with MCI who converted to clinical AD at follow-up after 1 year.
Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI patients from CTL subjects, and to prospectively predict MCI conversion into AD. Our results suggest the potential role of nutritional biomarkers detected in plasma–tocopherols and tocotrienols–as indirect indicators of AD pathology, and the utility of a multimodality approach.
In a review based on estimations and assumptions, to report the estimated number of survivors after out-of-hospital cardiac arrest (OHCA) in whom cardiopulmonary resuscitation (CPR) was started and to speculate about possible future improvements in Sweden.
An observational study.
All ambulance organisations in Sweden.
Patients included in the Swedish Cardiac Arrest Registry who suffered an OHCA between January 1, 2008 and December 31, 2010. Approximately 80% of OHCA cases in Sweden in which CPR was started are included.
None
In 11 005 patients, the 1-month survival rate was 9.4%. There are approximately 5000 OHCA cases annually in which CPR is started and 30-day survival is achieved in up to 500 patients yearly (6 per 100 000 inhabitants). Based on findings on survival in relation to the time to calling for the Emergency Medical Service (EMS) and the start of CPR and defibrillation, it was estimated that, if the delay from collapse to (i) calling EMS, (ii) the start of CPR, and (iii) the time to defibrillation were reduced to <2 min, <2 min, and <8 min, respectively, 300–400 additional lives could be saved.
Based on findings relating to the delay to calling for the EMS and the start of CPR and defibrillation, we speculate that 300–400 additional OHCA patients yearly (4 per 100 000 inhabitants) could be saved in Sweden.