Iron metabolism and anemia may play an important role in multiple organ dysfunction syndrome in Coronavirus disease 2019 (COVID-19). We conducted a systematic review and meta-analysis to evaluate ...biomarkers of anemia and iron metabolism (hemoglobin, ferritin, transferrin, soluble transferrin receptor, hepcidin, haptoglobin, unsaturated iron-binding capacity, erythropoietin, free erythrocyte protoporphyrine, and erythrocyte indices) in patients diagnosed with COVID-19, and explored their prognostic value. Six bibliographic databases were searched up to August 3rd 2020. We included 189 unique studies, with data from 57,563 COVID-19 patients. Pooled mean hemoglobin and ferritin levels in COVID-19 patients across all ages were 129.7 g/L (95% Confidence Interval (CI), 128.51; 130.88) and 777.33 ng/mL (95% CI, 701.33; 852.77), respectively. Hemoglobin levels were lower with older age, higher percentage of subjects with diabetes, hypertension and overall comorbidities, and admitted to intensive care. Ferritin level increased with older age, increasing proportion of hypertensive study participants, and increasing proportion of mortality. Compared to moderate cases, severe COVID-19 cases had lower hemoglobin weighted mean difference (WMD), − 4.08 g/L (95% CI − 5.12; − 3.05) and red blood cell count WMD, − 0.16 × 10
12
/L (95% CI − 0.31; − 0.014), and higher ferritin WMD, − 473.25 ng/mL (95% CI 382.52; 563.98) and red cell distribution width WMD, 1.82% (95% CI 0.10; 3.55). A significant difference in mean ferritin levels of 606.37 ng/mL (95% CI 461.86; 750.88) was found between survivors and non-survivors, but not in hemoglobin levels. Future studies should explore the impact of iron metabolism and anemia in the pathophysiology, prognosis, and treatment of COVID-19.
The potential role of branched-chain amino acids (BCAAs) in the pathogenesis of cardiometabolic diseases is increasingly recognized, but the association of BCAAs with incident hypertension remains ...unknown. The aim of the present study was to explore the association of BCAAs with incident hypertension in a prospective population-based cohort study. We measured plasma concentrations of BCAAs by means of nuclear magnetic resonance spectroscopy in 4169 participants from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study. We estimated the risk of incident hypertension using multivariable-adjusted Cox regression models. After a median follow-up of 8.6 years, incident hypertension was ascertained in 924 subjects. Cox regression analyses revealed a significant association between BCAAs and incident hypertension. The hazard ratio per one SD of BCAAs was 1.11 (95% CI, 1.02-1.20;
=0.01) after full adjustment for multiple clinical variables. Likewise, the fully adjusted association remained significant when evaluated as categorical variable (hazard ratio for upper quartile with lowest quartile as reference category, 1.36; 95% CI, 1.11-1.68;
=0.003). Furthermore, the net reclassification improvement assessment improved after addition of BCAAs to a traditional risk model (
<0.001). This prospective study revealed that high plasma concentrations of BCAAs are associated with an increased risk of newly developed hypertension. The association remained after adjusting for age, sex, body mass index, and lipid profile.
Aims
There are limited data examining whether body mass index (BMI) influences the association between cardiovascular biomarkers and incident heart failure (HF).
Methods and results
Thirteen ...biomarkers representing key HF domains were measured: N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), mid‐regional pro‐A‐type natriuretic peptide (MR‐proANP), cardiac troponin T (cTnT), C‐reactive protein, procalcitonin, galectin‐3, C‐terminal pro‐endothelin‐1 (CT‐proET‐1), mid‐regional pro‐adrenomedullin, plasminogen activator inhibitor‐1, copeptin, renin, aldosterone, and cystatin‐C. Associations of biomarkers with BMI were examined using linear regression models, and with incident HF using Cox regression models. We selected biomarkers significantly associated with incident HF, and evaluated whether BMI modified these associations. Among 8202 individuals, 41% were overweight (BMI 25–30 kg/m2), and 16% were obese (BMI ≥30 kg/m2). Mean age of the cohort was 49 years (range 28–75), and 50% were women. All biomarkers except renin were associated with BMI: inverse associations were observed with NT‐proBNP, MR‐proANP, CT‐proET‐1 and aldosterone whereas positive associations were observed with the remaining biomarkers (all P ≤ 0.001). During 11.3 ± 3.1 years of follow‐up, 357 HF events were recorded. Only NT‐proBNP, MR‐proANP and cTnT remained associated with incident HF (P < 0.001), and a significant biomarker*BMI interaction was not observed (interaction P > 0.1). Combined NT‐proBNP and cTnT measurements modestly improved performance metrics of the clinical HF model in overweight (ΔC‐statistic = 0.024; likelihood ratio χ2 = 38; P < 0.001) and obese (ΔC‐statistic = 0.020; likelihood ratio χ2 = 32; P < 0.001) individuals.
Conclusions
Plasma concentrations of several cardiovascular biomarkers are influenced by obesity. Only NT‐proBNP, MR‐proANP and cTnT were associated with incident HF, and BMI did not modify these associations. A combination of NT‐proBNP and cTnT improves HF risk prediction in overweight and obese individuals.
Associations of selected biomarkers with incident heart failure across body mass index categories. Models are adjusted for age, sex, smoking, diabetes mellitus, hypertension, cholesterol, body mass index, myocardial infarction, stroke, atrial fibrillation, and renal dysfunction. In analyses performed in the total population, models were also adjusted for body mass index. Hazard ratio (HR) are presented per standard deviation increase in natural log transformed biomarker. Pint represents the P‐value for biomarker*continuous body mass index interaction for heart failure outcome in the total population. CI, confidence interval; MR‐proANP, mid‐regional pro‐A‐type natriuretic peptide; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide.
Methylmalonic acid (MMA) is best known for its use as a functional marker of vitamin B12 deficiency. However, MMA concentrations not only depend on adequate vitamin B12 status, but also relate to ...renal function and endogenous production of propionic acid. Hence, we aimed to investigate to what extent variation in MMA levels is explained by vitamin B12 and eGFR and whether MMA levels are associated with mortality if vitamin B12 and eGFR are taken into account.
A total of 1533 individuals (aged 60-75 years, 50% male) were included from the Lifelines Cohort and Biobank Study. Individuals were included between 2006 and 2013, and the total follow-up time was 8.5 years.
Median IQR age of the study population was 65 62-69 years, 50% was male. At baseline, median MMA concentration was 170 138-216 nmol/L, vitamin B12 290 224-362 pmol/L, and eGFR 84 74-91 mL/min/1.73 m2. Log
vitamin B12, log
eGFR, age, and sex were significantly associated with log
MMA in multivariable linear regression analyses (model R
= 0.22). After a total follow-up time of 8.5 years, 72 individuals had died. Log
MMA levels were significantly associated with mortality (hazard ratio HR 1.67 95% CI 1.25-2.22, P < 0.001). Moreover, we found a significant interaction between MMA and eGFR with respect to mortality (P
< 0.001).
Only 22% of variation in MMA levels was explained by vitamin B12, eGFR, age, and sex, indicating that a large part of variation in MMA levels is attributable to other factors (e.g., catabolism, dietary components, or gut microbial production). Higher MMA levels are associated with an increased risk for mortality, independent of vitamin B12, eGFR, and sex. This association was more pronounced in individuals with impaired renal function.
Measuring vibration perception threshold (VPT) accurately classifies and quantifies the severity of loss of vibration perception. A biothesiometer (Bio-thesiometer.sup.#174; ; Bio Medical Instrument ...Co, Ohio, USA) appears to be the most suitable tool to determine VPT due to its low inter-rater variability and low occurence of adaption to the sensation. Different VPT values for a biothesiometer have been described, however, specification on age, height and different measurement locations is currently lacking. The objective of our study was to identify determinants of vibration perception in non-diabetic subjects, in order to provide individualized normal values of VPTs for clinical practice. Measurements of the vibration perception were performed on the big toes, insteps, lateral malleoli, and wrists. A total of 205 healthy subjects were included (108 (52.7%) males) with a median interquartile range age of 59 51;64 (range 21-80) years. Mean height was 174.45 #177; 9.20 cm and mean weight was 82.94 #177; 14.84 kg, resulting in a mean BMI of 27.19 #177; 4.00 kg/m.sup.2 . In stepwise forward linear regression analyses, age (st. beta = 0.51, p 0.001) and height (st. beta = 0.43, p 0.001) were found to be the independent unmodifiable determinants of the VPT at the big toe. Regression coefficients for quantiles of the determinants age and height were incorporated in the corresponding regression equations. This study provides equations to calculate age- and height-specific normal values for VPT that can be used in clinical practice and in large research studies.
Purpose
Although thyroid hormones are irrefutably implicated in cardiovascular physiology, the impact of within-reference range variations of thyroid function on cardiovascular disease (CVD) remains ...unclear. Elucidating this is important, since it could foster preventive treatment and reduce global CVD burden. We therefore investigated the impact of within-reference range variations of thyroid function on all-cause and cardiovascular mortality.
Methods
We included community-dwelling individuals aged 28–75 years from a prospective cohort study, without known use of thyroid-affecting therapy and with thyrotropin within reference range. Associations of thyroid function with mortality were quantified using Cox models and adjusted for sociodemographic and cardiovascular risk factors.
Results
Mean (SD) age of the 6,054 participants (52.0% male) was 53.3 (12.0) years. During 47,594 person-years of follow-up, we observed 380 deaths from all causes and 103 from CVDs. Although higher thyrotropin was not associated with all-cause mortality (adjusted HR 1.02, 95% CI 0.92–1.14), point estimates for cardiovascular mortality diverged toward increased risk in younger (<72 years) participants (1.31, 1.00–1.72) and decreased risk in elderly (≥72 years) (0.77, 0.56–1.06). Higher free thyroxine (FT
4
) was associated with all-cause mortality (1.18, 1.07–1.30) and with cardiovascular mortality only in elderly (1.61, 1.19–2.18), but not in younger participants (1.03, 0.78–1.34). Higher free triiodothyronine (FT
3
) was associated with all-cause mortality in females only (1.18, 1.02–1.35). FT
3
was not associated with cardiovascular mortality (0.91, 0.70–1.18).
Conclusions
Community-dwelling elderly individuals with high-normal thyroid function are at increased risk of all-cause and cardiovascular mortality, reinforcing the need of redefining the current reference ranges of thyroid function.
Background
Creatinine is the most widely used test to estimate the glomerular filtration rate (GFR), but muscle mass as key determinant of creatinine next to renal function may confound such ...estimates. We explored effects of 24‐h height‐indexed creatinine excretion rate (CER index) on GFR estimated with creatinine (eGFRCr), muscle mass‐independent cystatin C (eGFRCys), and the combination of creatinine and cystatin C (eGFRCr‐Cys) and predicted probabilities of discordant classification given age, sex, and CER index.
Methods
We included 8076 adults enrolled in the PREVEND study. Discordant classification was defined as not having eGFRCr <60 mL/min per 1.73 m2 when eGFRCys was <60 mL/min/1.73 m2. Baseline effects of age and sex on CER index were quantified with linear models using generalized least squares. Baseline effects of CER index on eGFR were quantified with quantile regression and logistic regression. Effects of annual changes in CER index on trajectories of eGFR were quantified with linear mixed‐effects models. Missing observations in covariates were multiply imputed.
Results
Mean (SD) CER index was 8.0 (1.7) and 6.1 (1.3) mmol/24 h per meter in male and female participants, respectively (Pdifference < 0.001). In male participants, baseline CER index increased until 45 years of age followed by a gradual decrease, whereas a gradual decrease across the entire range of age was observed in female participants. For a 70‐year‐old male participant with low muscle mass (CER index of 2 mmol/24 h per meter), predicted baseline eGFRCr and eGFRCys disagreed by 24.7 mL/min/1.73 m2 (and 30.1 mL/min/1.73 m2 when creatinine was not corrected for race). Percentages (95% CI) of discordant classification in male and female participants aged 60 years and older with low muscle mass were 18.5% (14.8–22.1%) and 15.2% (11.4–18.5%), respectively. For a 70‐year‐old male participant who lost muscle during follow‐up, eGFRCr and eGFRCys disagreed by 1.5, 5.0, 8.5, and 12.0 mL/min/1.73 m2 (and 6.7, 10.7, 13.5, and 15.9 mL/min/1.73 m2 when creatinine was not corrected for race) at baseline, 5 years, 10 years, and 15 years of follow‐up, respectively.
Conclusions
Low muscle mass may cause considerable overestimation of single measurements of eGFRCr. Muscle wasting may cause spurious overestimation of repeatedly measured eGFRCr. Implementing muscle mass‐independent markers for estimating renal function, like cystatin C as superior alternative to creatinine, is crucial to accurately assess renal function in settings of low muscle mass or muscle wasting. This would also eliminate the negative consequences of current race‐based approaches.
Background Magnesium supplements may have beneficial effects on arterial stiffness. Yet, to our knowledge, no head-to-head comparison between various magnesium formulations in terms of effects on ...arterial stiffness has been performed. We assessed the effects of magnesium citrate supplementation on arterial stiffness and blood pressure and explored whether other formulations of magnesium have similar effects. Methods and Results In this randomized trial, subjects who were overweight and slightly obese received either magnesium citrate, magnesium oxide, magnesium sulfate, or placebo for 24 weeks. The total daily dose of magnesium was 450 mg/d. The primary outcome was carotid-to-femoral pulse wave velocity, which is the gold standard method for measuring arterial stiffness. Secondary outcomes included blood pressure and plasma and urine magnesium. Overall, 164 participants (mean±SD age, 63.2±6.8 years; 104 63.4% women) were included. In the intention-to-treat analysis, neither magnesium citrate nor the other formulations had an effect on carotid-to-femoral pulse wave velocity or blood pressure at 24 weeks compared with placebo. Magnesium citrate increased plasma (+0.04 mmol/L; 95% CI, +0.02 to +0.06 mmol/L) and urine magnesium (+3.12 mmol/24 h; 95% CI, +2.23 to +4.01 mmol/24 h) compared with placebo. Effects on plasma magnesium were similar among the magnesium supplementation groups, but magnesium citrate led to a more pronounced increase in 24-hour urinary magnesium excretion than magnesium oxide or magnesium sulfate. One serious adverse event was reported, which was considered unrelated to the study treatment. Conclusions Oral magnesium citrate supplementation for 24 weeks did not significantly change arterial stiffness or blood pressure. Magnesium oxide and magnesium sulfate had similar nonsignificant effects. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03632590.
High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC ...are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend on kidney function. However, many studies with vitamin K-status parameters do not structurally adjust for baseline kidney function, and detailed studies on kidney function-dependence of vitamin K-status markers are lacking. We therefore measured plasma dp-ucMGP using a chemiluminescent assay in 578 kidney transplant recipients (41% females, age 56 ± 13y, 7.5 (3.2 to 13.7)y after transplantation, eGFR 49 ± 17 mL/min/1.73 m2) participating in the prospective TransplantLines Cohort Studies. Additionally, dp-carboxylated MGP, ucOC and carboxylated OC were measured using ELISA in plasma of a subgroup of 60 participants. Finally, dp-ucMGP was measured in a separate cohort of 124 kidney transplant recipients before and three months after kidney transplantation. Dp-ucMGP positively correlated with creatinine, cystatin C, and negatively with eGFR (Spearman’s ρ 0.54, 0.60, and −0.54, respectively, p < 0.001 for all), and each 10 mL/min/1.73 m2 increase in eGFR was associated with a 14.0% lower dp-ucMGP. Additionally, dp-ucMGP strongly declined after kidney transplantation (pretransplantation: 1252 (868 to 1744) pmol/L to posttransplantation: 609 (451 to 914) pmol/L, p < 0.001). Proportions of dp-ucMGP over total MGP and ucOC over total OC were not associated with eGFR. This study highlights that dp-ucMGP is strongly associated with kidney function, and that levels strongly decrease after kidney transplantation. We therefore propose adequate adjustment for kidney function, or the use of kidney function-independent parameters such as proportion of uncarboxylated MGP or OC in the assessment of vitamin K-status in clinical practice and research.
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