Telomeres are the protective end caps of chromosomes and shorten with every cell division. Telomere length has been proposed as a biomarker of biological age and a risk factor for age-related ...diseases. Epidemiologic studies show an association between leukocyte telomere length (LTL) and mortality. There is solid evidence that links LTL with cardiovascular disease. Short telomeres promote atherosclerosis and impair the repair of vascular lesions. Alzheimer’s disease patients have also a reduced LTL. Telomeres measured in tumor tissue from breast, colon and prostate are shorter than in healthy tissue from the same organ and the same patient. In healthy tissue directly adjacent to these tumors, telomeres are also shorter than in cells that are more distant from the cancerous lesion. A reduced telomere length in cancer tissue from breast, colon and prostate is associated with an advanced disease state at diagnosis, faster disease progression and poorer survival. By contrast, results regarding LTL and cancer are inconsistent. Furthermore, the majority of studies did not find significant associations between LTL, bone mineral density (BMD) and osteoporosis. The present manuscript gives an overview about our current understanding of telomere biology and reviews existing knowledge regarding the relationship between telomere length and age-related diseases.
Patients on maintenance dialysis treatment experience an excess mortality, predominantly of sudden cardiac death. Poor glycemic control is associated with cardiovascular comorbidities in the general ...population. This study investigated the impact of glycemic control on cardiac and vascular outcomes in diabetic hemodialysis patients.
Glycohemoglobin A1c (HbA(1c)) was measured in 1255 hemodialysis patients with type 2 diabetes mellitus who participated in the German Diabetes and Dialysis Study (4D Study) and were followed up for a median of 4 years. Using Cox regression analyses, we determined hazard ratios to reach prespecified, adjudicated end points according to HbA(1c) levels at baseline: sudden cardiac death (n=160), myocardial infarction (n=200), stroke (n=103), cardiovascular events (n=469), death caused by heart failure (n=41), and all-cause mortality (n=617). Patients had a mean age of 66+/-8 years (54% male) and mean HbA(1c) of 6.7+/-1.3%. Patients with an HbA(1c) >8% had a >2-fold higher risk of sudden death compared with those with an HbA(1c) < or =6% (hazard ratio, 2.14; 95% confidence interval, 1.33 to 3.44), persisting in multivariate models. With each 1% increase in HbA(1c), the risk of sudden death rose significantly by 18%; similarly, cardiovascular events and mortality increased by 8%. There was a trend for higher risks of stroke and deaths resulting from heart failure, whereas myocardial infarction was not affected. The increased risks of both cardiovascular events and mortality were explained mainly by the impact of HbA(1c) on sudden death.
Poor glycemic control was strongly associated with sudden cardiac death in diabetic hemodialysis patients, which accounted for increased cardiovascular events and mortality. In contrast, myocardial infarction was not affected. Whether interventions achieving tight glycemic control decrease sudden death requires further evaluation. Clinical Trial Registration- URL: http://www.clinicalstudyresults.org. Unique identifier: CT-981-423-239.
Vitamin D deficiency is common among the elderly and may contribute to cerebrovascular diseases. We aimed to elucidate whether low vitamin D levels are predictive for fatal stroke.
The LUdwigshafen ...RIsk and Cardiovascular Health (LURIC) study includes 3316 patients who were referred to coronary angiography at baseline between 1997 and 2000. 25-Hydroxyvitamin D 25(OH)D and 1,25-dihydroxyvitamin D 1,25(OH)2D were measured in 3299 and 3315 study participants, respectively. To account for the seasonal variation of vitamin D metabolites, we calculated z values for the 25(OH)D and 1,25(OH)2D concentrations within each month of blood draw.
During a median follow-up time of 7.75 years, 769 patients died, including 42 fatal (ischemic and hemorrhagic) strokes. When compared with survivors in binary logistic-regression analyses, the odds ratios (with 95% CIs) for fatal stroke were 0.58 (0.43 to 0.78; P<0.001) per z value of 25(OH)D and 0.62 (0.47 to 0.81; P<0.001) per z value of 1,25(OH)2D. After adjustment for several possible confounders, these odds ratios remained significant for 25(OH)D at 0.67 (0.46 to 0.97; P=0.032) and for 1,25(OH)2D at 0.72 (0.52 to 0.99; P=0.047). Z values of 25(OH)D and 1,25(OH)2D were also reduced in the 274 patients who had a history of previous cerebrovascular disease events at baseline.
Low levels of 25(OH)D and 1,25(OH)2D are independently predictive for fatal strokes, suggesting that vitamin D supplementation is a promising approach in the prevention of strokes.
Circulating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the ...associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD.
The derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3-5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses. Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation SD increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval CI 1.799-2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491-1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527-1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362-1.775), renin HR 1.501 (95% CI 1.305-1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297-1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307-1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243-1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131-1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226-1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255-1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316-1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134-1.396), spondin-1 HR 1.295 (95% CI 1.156-1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237-1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129-1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307-1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490-2.056). The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events.
Profiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD.
ClinicalTrials.gov NCT00799903.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Vitamin D testing and treatment is a subject of controversial scientific discussions, and it is challenging to navigate through the expanding vitamin D literature with heterogeneous and partially ...opposed opinions and recommendations. In this narrative review, we aim to provide an update on vitamin D guidelines and the current evidence on the role of vitamin D for human health with its subsequent implications for patient care and public health issues. Vitamin D is critical for bone and mineral metabolism, and it is established that vitamin D deficiency can cause rickets and osteomalacia. While many guidelines recommend target serum 25-hydroxyvitamin D (25OHD) concentrations of ≥50 nmol/L (20 ng/mL), the minimum consensus in the scientific community is that serum 25(OH)D concentrations below 25–30 nmol/L (10–12 ng/mL) must be prevented and treated. Using this latter threshold of serum 25(OH)D concentrations, it has been documented that there is a high worldwide prevalence of vitamin D deficiency that may require public health actions such as vitamin D food fortification. On the other hand, there is also reason for concern that an exploding rate of vitamin D testing and supplementation increases costs and might potentially be harmful. In the scientific debate on vitamin D, we should consider that nutrient trials differ from drug trials and that apart from the opposed positions regarding indications for vitamin D treatment we still have to better characterize the precise role of vitamin D for human health.
Purpose
Short telomeres and B vitamin deficiencies have been proposed as risk factors for age-related diseases and mortality that interact through oxidative stress and inflammation. However, ...available data to support this concept are insufficient. We aimed to investigate the predictive role of B vitamins and homocysteine (HCY) for mortality in cardiovascular patients. We explored potential relationships between HCY, B vitamins, relative telomere length (RTL), and indices of inflammation.
Methods
Vitamin B6, HCY, interleukin-6 (IL-6), high-sensitive-C-reactive protein (hs-CRP), and RTL were measured in participants of the Ludwigshafen Risk and Cardiovascular Health Study. Death events were recorded over a median follow-up of 9.9 years.
Results
All-cause mortality increased with higher concentrations of HCY and lower vitamin B6. Patients in the 4th quartile of HCY and vitamin B6 had hazard ratios (HR) for all-cause mortality of 2.77 (95% CI 2.28–3.37) and 0.41(95% CI 0.33–0.49), respectively, and for cardiovascular mortality of 2.78 (95% CI 2.29–3.39) and 0.40 (95% CI 0.33–0.49), respectively, compared to those in the 1st quartile. Multiple adjustments for confounders did not change these results. HCY and vitamin B6 correlated with age-corrected RTL (
r
= − 0.086,
p
< 0.001;
r
= 0.04,
p
= 0.031, respectively), IL-6 (
r
= 0.148,
p
< 0.001;
r
= − 0.249,
p
< 0.001, respectively), and hs-CRP (
r
= 0.101,
p
< 0.001;
r
= − 0.320,
p
< 0.001, respectively). Subjects with the longest telomeres had a significantly higher concentration of vitamin B6, but lower concentrations of HCY, IL-6, and hs-CRP. Multiple regression analyses identified HCY as an independent negative predictor of age-corrected RTL.
Conclusions
In conclusion, hyperhomocysteinemia and vitamin B6 deficiency are risk factors for death from any cause. Hyperhomocysteinemia and vitamin B6 deficiency correlate with increased mortality. This correlation might, at least partially, be explained by accelerated telomere shortening induced by oxidative stress and systemic inflammation in these circumstances.
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DOBA, EMUNI, FIS, FSPLJ, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
This study was performed to highlight the relationship between single dietary risk factors and cardiovascular diseases (CVDs) in the WHO European Region. We used the comparative risk assessment ...framework of the Global Burden of Disease Study to estimate CVD mortality attributable to diet; comprising eleven forms of CVDs, twelve food and nutrient groups and 27 risk-outcome pairs in four GBD regions including 51 countries by age and sex between 1990 and 2016. In 2016, dietary risks were associated with 2.1 million cardiovascular deaths (95% uncertainty interval (UI), 1.7–2.5 million) in the WHO European Region, accounting for 22.4% of all deaths and 49.2% of CVD deaths. In terms of single dietary risks, a diet low in whole grains accounted for approximately 429,000 deaths, followed by a diet low in nuts and seeds (341,000 deaths), a diet low in fruits (262,000 deaths), a diet high in sodium (251,000 deaths), and a diet low in omega-3 fatty acids (227,000 deaths). Thus, with an optimized, i.e. balanced diet, roughly one in every five premature deaths could be prevented. Although agestandardized death rates decreased over the last 26 years, the absolute number of diet-related cardiovascular deaths increased between 2010 and 2016 by 25,600 deaths in Western Europe and by 4300 deaths in Central Asia. In 2016, approximately 601,000 deaths (28.6% of all diet-related CVD deaths) occurred among adults younger than 70 years. Compared to other behavioural risk factors, a balanced diet is a potential key lever to avoid premature deaths.
During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of vitamin D on CVD risk are ...puzzling: observational data indicate an inverse nonlinear association between vitamin D status and CVD events, with the highest CVD risk at severe vitamin D deficiency; however, preclinical data and randomized controlled trials (RCTs) show several beneficial effects of vitamin D on the surrogate parameters of vascular and cardiac function. By contrast, Mendelian randomization studies and large RCTs in the general population and in patients with chronic kidney disease, a high-risk group for CVD events, largely report no significant beneficial effect of vitamin D treatment on CVD events. In patients with rickets and osteomalacia, cardiovascular complications are infrequently reported, except for an increased risk of heart failure. In conclusion, there is no strong evidence for beneficial vitamin D effects on CVD risk, either in the general population or in high-risk groups. Whether some subgroups such as individuals with severe vitamin D deficiency or a combination of low vitamin D status with specific gene variants and/or certain nutrition/lifestyle factors would benefit from vitamin D (metabolite) administration, remains to be studied.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide ...meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.
Abstract
Aims
To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke ...or cataract.
Methods and results
A literature search covering 2000–2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin ≥6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5–2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case–control studies.
Conclusion
Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.
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