Martina Montagnana

Relation between red blood cell distribution width and inflammatory biomarkers in a large cohort of unselected outpatients.

CONTEXT A strong independent association has been recently observed between elevated red blood cell distribution width (RDW) and increased incidence of cardiovascular events. OBJECTIVE To assess whether RDW is associated with plasma markers of inflammation since the mechanism(s) underlying this association remain unknown. DESIGN We retrospectively analyzed results of RDW, hemoglobin, mean corpuscular volume, ferritin, high-sensitivity C-reactive protein (hsCRP), and erythrocyte sedimentation rate (ESR) in a large cohort of unselected adult outpatients who were consecutively referred by general practitioners for routine medical check-up. RESULTS Cumulative results of RDW and other factors were retrieved from the database of our laboratory information system for 3845 adult outpatients during a 3-year period. When participants were grouped according to RDW quartiles, there were strong, graded increases of ESR and hsCRP (P < .001), both parameters being up to 3-fold higher in the fourth versus the first quartile. Accordingly, the percentages of those with hsCRP greater than 3 mg/L (from 28% to 63%; P < .001) and ESR greater than 40 mm/h (from 8% to 40%; P < .001) increased steadily across RDW quartiles. In multivariable regression analysis, ESR and hsCRP predicted RDW independently of age, sex, mean corpuscular volume, hemoglobin, and ferritin. CONCLUSIONS To our knowledge, our study demonstrates for the first time a strong, graded association of RDW with hsCRP and ESR independent of numerous confounding factors. If confirmed in future follow-up studies, this association might provide a rationale to introduce the easy, inexpensive RDW in algorithms for cardiovascular risk prediction.

Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%–2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5′ region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10−11). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84–0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860–0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83–0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83–0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Influence of hemolysis on routine clinical chemistry testing.

Abstract Background: Preanalytical factors are the main source of variation in clinical chemistry testing and among the major determinants of preanalytical variability, sample hemolysis can exert a strong influence on result reliability. Hemolytic samples are a rather common and unfavorable occurrence in laboratory practice, as they are often considered unsuitable for routine testing due to biological and analytical interference. However, definitive indications on the analytical and clinical management of hemolyzed specimens are currently lacking. Therefore, the present investigation evaluated the influence of in vitro blood cell lysis on routine clinical chemistry testing. Methods: Nine aliquots, prepared by serial dilutions of homologous hemolyzed samples collected from 12 different subjects and containing a final concentration of serum hemoglobin ranging from 0 to 20.6g/L, were tested for the most common clinical chemistry analytes. Lysis was achieved by subjecting whole blood to an overnight freeze-thaw cycle. Results: Hemolysis interference appeared to be approximately linearly dependent on the final concentration of blood-cell lysate in the specimen. This generated a consistent trend towards overestimation of alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, creatine kinase (CK), iron, lactate dehydrogenase (LDH), lipase, magnesium, phosphorus, potassium and urea, whereas mean values of albumin, alkaline phosphatase (ALP), chloride, γ-glutamyltransferase (GGT), glucose and sodium were substantially decreased. Clinically meaningful variations of AST, chloride, LDH, potassium and sodium were observed in specimens displaying mild or almost undetectable hemolysis by visual inspection (serum hemoglobin <0.6g/L). The rather heterogeneous and unpredictable response to hemolysis observed for several parameters prevented the adoption of reliable statistic corrective measures for results on the basis of the degree of hemolysis. Conclusion: If hemolysis and blood cell lysis result from an in vitro cause, we suggest that the most convenient corrective solution might be quantification of free hemoglobin, alerting the clinicians and sample recollection.

The paradoxical relationship between serum uric acid and cardiovascular disease.

Uric acid (urate), an organic compound comprised of carbon, nitrogen, oxygen and hydrogen, is the final oxidation product of purine catabolism in humans, higher primates and in a particular species of dog (Dalmatians). For decades it has been hypothesized that the antioxidant properties of uric acid might be protective against aging, oxidative stress, and oxidative cell injury. However, recent epidemiological and clinical evidences suggest that hyperuricaemia might be a risk factor for cardiovascular disease, where enhanced oxidative stress plays an important pathophysiological role. It has also been hypothesized that hyperuricaemia might be involved in chronic heart failure and metabolic syndrome. The apparent paradox between protective and toxic effects is supported by clinical evidences that antioxidant compounds may become pro-oxidant compounds in certain situations, particularly when they are present in blood at supranormal levels. The aim of this article is to review uric acid metabolism and physiology, highlighting its association with cardiovascular disease.

The ROMA (Risk of Ovarian Malignancy Algorithm) for estimating the risk of epithelial ovarian cancer in women presenting with pelvic mass: is it really useful?

Abstract Background: The study is aimed at evaluating the performance of the predictive model ROMA (Risk of Ovarian Malignancy Algorithm), which utilizes the combination of human epididymis protein 4 (HE4) and CA125 values to assess the risk of epithelial ovarian cancer (EOC) in women with a pelvic mass. Methods: One hundred and four women diagnosed with a pelvic mass (55 EOC and 49 benign cases) and scheduled to have surgery were enrolled, along with 49 healthy females. Preoperative serum concentrations of HE4 and CA125 were measured. Separate logistic regression algorithms ROMA for pre-menopausal and post-menopausal women were used to categorize patients into low- and high-risk groups for EOC. The area under the curve (AUC), sensitivity and specificity were calculated for HE4, CA125 and ROMA for the diagnosis of ovarian cancer using receiver operating characteristic (ROC) analysis. Results: The median CA125 and HE4 serum concentrations were significantly higher among EOC patients than in healthy females (both p<0.05) and those with a benign mass (both p<0.05). The pre-menopausal group included 36 benign cases (29 of which were classified by ROMA as low-risk with a specificity of 80.6%; 95% CI: 64.0%–91.8%), and 15 EOC (eight of which were classified by ROMA as high-risk, with a sensitivity of 53.3%; 95% CI: 26.6%–78.7%). The post-menopausal group enclosed 13 benign cases (11 of which were classified by ROMA as low-risk with a specificity of 84.6%; 95% CI: 54.6%–98.0%), and 40 EOC (33 of which were classified by ROMA as high-risk with a sensitivity of 82.5%; 95% CI: 67.2%–92.7%). In the pre-menopausal group, the AUC was 0.64 (p=0.12, 95% CI: 0.44–0.83) for CA125, 0.77 (p=0.003, 95% CI: 0.62–0.92) for HE4 and 0.77 (p=0.002, 95% CI: 0.63–0.92) for ROMA. In the post-menopausal group, the AUC was 0.84 (p=0.0003, 95% CI: 0.73–0.94) for CA125, 0.94 (p<0.0001, 95% CI: 0.88–0.99) for HE4 and 0.92 (p<0.0001, 95% CI: 0.85–0.99) for ROMA. Conclusions: The ROMA is a simple scoring system which shows excellent diagnostic performance for the detection of EOC in post-menopausal women, but not in pre-menopausal women. Moreover, the dual marker combination of HE4 and CA125 (ROMA) does not show better performance than HE4 alone.

The role of red blood cell distribution width in cardiovascular and thrombotic disorders

Abstract The red blood cell (RBC) distribution width (RDW) is a measurement of the size variation as well as an index of the heterogeneity of the erythrocytes (i.e., anysocytosis), which is typically used in combination with the mean corpuscular volume to troubleshoot the cause of an underlying anemia. Reliable data emerged from a variety of clinical studies have, however, disclosed a new and unpredictable scenario in the clinical usefulness of this measure, supporting the hypothesis that RDW might be a useful parameter for gathering meaningful clinical information, either diagnostic or prognostic, on a variety of cardiovascular and thrombotic disorders. Highly significant associations have been described between RDW value and all-cause, non-cardiac and cardiac mortality in patients with coronary artery disease, acute and chronic heart failure, peripheral artery disease, stroke, pulmonary embolism and pulmonary arterial hypertension. It is however still unclear whether anysocytosis might be the cause, or a simple epiphenomenon of an underlying disease, such as inflammation, impaired renal function, undernutrition, oxidative damage, or perhaps an element of both. Nevertheless, RDW is an easy, inexpensive, routinely reported test, whose assessment might allow the acquisition of significant diagnostic and prognostic information in patients with cardiovascular and thrombotic disorders.

Relationship between red blood cell distribution width and kidney function tests in a large cohort of unselected outpatients

Objective. A strong, independent, association has recently been shown between higher red blood cell distribution width (RDW) and the risk of all‐cause death and cardiovascular events. However, the mechanism(s) underlying this association remains unclear. Since impaired kidney function is a well‐known risk factor for cardiovascular disease, we assessed whether RDW is associated with decreased kidney function. Material and methods. We cross‐sectionally assessed results of RDW, haemoglobin, main corpuscular volume (MCV) and serum creatinine levels in a large cohort of unselected adult outpatients consecutively referred by general practitioners for routine medical check‐up. Glomerular filtration rate (GFR) was estimated using the abbreviated Modification of Diet in Renal Disease (MDRD) equation. Results. Cumulative results of RDW, creatinine and other variables were retrieved from the database of our Laboratory Information System for 8,585 adult outpatients over a 3‐year period. When participants were grouped according to RDW quartiles, there was a strong, graded, decrease in estimated GFR levels (ranging from 87±18 to 81±32 mL/min/1.73 m2; p<0.0001). Accordingly, the percentage of participants with estimated GFR<60 mL/min/1.73 m2 increased steadily across RDW quartiles (from 5 % to 19 %; p<0.0001). In logistic regression analysis, lower estimated GFR strongly predicted higher RDW levels (p<0.0001) independently of age, gender, MCV and haemoglobin values. Conclusions. Our findings suggest that there is an inverse, graded, association between RDW and kidney function tests in a large cohort of unselected adult outpatients.

Effect of CPAP on Blood Pressure in Patients With OSA/Hypopnea: A Systematic Review and Meta-analysis

BACKGROUND CPAP is considered the therapy of choice for OSA, but the extent to which it can reduce BP is still under debate. We undertook a systematic review and meta-analysis of randomized controlled trials (RCTs) to quantify the effect size of the reduction of BP by CPAP therapy compared with other passive (sham CPAP, tablets of placebo drug, conservative measures) or active (oral appliance, antihypertensive drugs) treatments. METHODS We searched four different databases (MEDLINE, EMBASE, Web of Science, and the Cochrane Library) with specific search terms and selection criteria. RESULTS From 1,599 articles, we included 31 RCTs that compared CPAP with either passive or active treatment. In a random-effects meta-analysis vs passive treatment (29 RCTs, 1,820 subjects), we observed a mean±SEM net difference in systolic BP of 2.6±0.6 mm Hg and in diastolic BP of 2.0±0.4 mm Hg, favoring treatment with CPAP (P<.001). Among studies using 24-h ambulatory BP monitoring that presented data on daytime and nighttime periods, the mean difference in systolic and diastolic BP was, respectively, 2.2±0.7 and 1.9±0.6 mm Hg during daytime and 3.8±0.8 and 1.8±0.6 mm Hg during nighttime. In meta-regression analysis, a higher baseline apnea/hypopnea index was associated with a greater mean net decrease in systolic BP (beta±SE, 0.08±0.04). There was no evidence of publication bias, and heterogeneity was mild ( I2, 34%-36%). CONCLUSIONS Therapy with CPAP significantly reduces BP in patients with OSA but with a low effect size. Patients with frequent apneic episodes may benefit the most from CPAP.

Quality Standards for Sample Collection in Coagulation Testing

Preanalytical activities, especially those directly connected with blood sample collection and handling, are the most vulnerable steps throughout the testing process. The receipt of unsuitable samples is commonplace in laboratory practice and represents a serious problem, given the reliability of test results can be adversely compromised following analysis of these specimens. The basic criteria for an appropriate and safe venipuncture are nearly identical to those used for collecting blood for clinical chemistry and immunochemistry testing, and entail proper patient identification, use of the correct technique, as well as appropriate devices and needles. There are, however, some peculiar aspects, which are deemed to be particularly critical when collecting quality specimens for clot-based tests, and these require clearer recognition. These include prevention of prolonged venous stasis, collection of nonhemolyzed specimens, order of draw, and appropriate filling and mixing of the primary collection tubes. All of these important preanalytical issues are discussed in this article, and evidence-based suggestions as well as recommendations on how to obtain a high-quality sample for coagulation testing are also illustrated. We have also performed an investigation aimed to identify variation of test results due to underfilling of primary blood tubes, and have identified a clinically significant bias in test results when tubes are drawn at less than 89% of total fill for activated partial thromboplastin time, less than 78% for fibrinogen, and less than 67% for coagulation factor VIII, whereas prothrombin time and activated protein C resistance remain relatively reliable even in tubes drawn at 67% of the nominal volume.

Mental Depression and Cardiovascular Disease: A Multifaceted, Bidirectional Association

The association between cardiovascular disease and mental depression is multifaceted and likely bidirectional. Depressed patients are at significantly higher risk for cardiac morbidity and mortality even in the absence of a diagnosis of major depression, whereas mental depression is nearly 3 times more frequent in patients after an acute myocardial infarction and contributes to a worse prognosis. Therefore, depressed patients might become trapped in a harmful loop, where mental symptoms might be worsened by the synergistic effects of stress and cardiovascular risk factors, and where they are otherwise vulnerable to acute cardiovascular events due to the synergistic effects of mental stress and an underlying atherothrombotic disorder. Although the exact pathway(s) underlying the interplay between depression and cardiovascular disease remains to be elucidated, the mechanisms most often implicated include hormonal variations, metabolic abnormalities, hypercoagulability, increased platelet aggregation, inflammation, and endothelial dysfunction. This article aims to review the biological and clinical links between depression and cardiovascular disease.