Franca Cocci

Predictive value of elevated neutrophil–lymphocyte ratio on cardiac mortality in patients with stable coronary artery disease

BACKGROUND An association between white blood cell count (WBC), severity of coronary artery disease (CAD) and survival has been described in patients with acute coronary syndrome. Our aim was to analyze the predictive ability for cardiac events of differential WBC, which is still not well characterized, against established risk factors in angiographically proven CAD patients. METHODS We prospectively evaluated complete blood count, biomarkers of inflammation [(C-reactive protein (CRP) and serum iron (SI)], glucose/lipid metabolism [(fasting glucose (FG), total, high-density lipoprotein (HDL) and low-density lipoprotein cholesterol] and established risk factors in 422 consecutive ischemic patients with angiographically documented stable CAD. On a 3-year follow-up, cardiac death and non-fatal myocardial infarction (MI) were considered as end-points. RESULTS At multivariate analysis neutrophil to lymphocyte ratio (N/L) emerged as independent predictor of cardiac death (HR 8.13; p=0.02) together with CRP, left ventricular ejection fraction (LVEF), FG, HDL and SI. CRP, LVEF, and HDL showed an independent prognostic value for cardiac death and non-fatal MI. Event-free survival according to N/L tertiles was 99% for the first tertile (1.23+/-0.26), 96.5% for the second (2.05+/-0.29), and 88.8% for the third one (5.19+/-3.81). CONCLUSIONS N/L is an independent predictor of cardiac mortality in stable CAD patients.

Genetic polymorphisms in folate and homocysteine metabolism as risk factors for DNA damage

Epidemiological studies indicated a role for polymorphisms in genes of folate and homocysteine (Hcy) metabolism in the etiology of neurodegenerative disease, congenital defects and coronary artery disease (CAD). This study investigated the effect of several polymorphisms [C677 T, A1298C of methylenetetrahydrofolate reductase (MTHFR) and A66G of methionine synthase reductase (MTRR) genes] on Hcy levels and DNA damage in 68 patients who underwent coronary angiography. Plasma Hcy concentrations were higher in patients with multivessel disease with respect to monovessel disease and no-CAD patients (19.4±2.6 vs 11.6±1.2 and 13.7±1.4 μmol/l, respectively; P=0.03). 677TT patients had higher Hcy levels than those with 677CC or 677CT genotypes (26.2±4.3 vs 13.1±1.4 and 13.0±1.4 μmol/l, respectively; P=0.0006). No significant associations were found between A1298C and A66G polymorphisms and plasma Hcy levels. Among patients with 677CC genotype, 66GG individuals tended to have higher levels of Hcy than 66AA homozygotes (14.5±1.9 vs 8.9±0.7 μmol/l, P=0.06). Multivessel disease patients showed an increased frequency of DNA damage, measured by the micronucleus (MN) frequency, as compared to monovessel disease and no-CAD subjects (12.5±1.1 vs 8.5±0.8 and 8.2±0.9, respectively; P=0.006). The MN were positively correlated with Hcy levels (r=0.33, P=0.006) and were significantly higher in subjects with the 677TT genotype compared with the 677CC or 677CT genotypes (14.4±2.0 vs 8.8±1.2 and 9.5±0.7, respectively; P=0.006). A1298C and A66G polymorphisms had no effect on MN frequency. However, among 677TT patients, 66GG subjects tended to have higher levels of MN than those 66AG and 66AA (18.2±3.6 vs 13.8±4.0 and 10.3±1.7, respectively; P=NS). Our results indicate that genetic instability may be associated with increased risk for multiple Hcy-related diseases.

Soluble receptor for advanced glycation end products in COPD: relationship with emphysema and chronic cor pulmonale: a case-control study.

BackgroundThe receptor for advanced glycation end products (RAGE) is a multiligand signal transduction receptor that can initiate and perpetuate inflammation. Its soluble isoform (sRAGE) acts as a decoy receptor for RAGE ligands, and is thought to afford protection against inflammation. With the present study, we aimed at determining whether circulating sRAGE is correlated with emphysema and chronic cor pulmonale in chronic obstructive pulmonary disease (COPD).MethodsIn 200 COPD patients and 201 age- and sex-matched controls, we measured lung function by spirometry, and sRAGE by ELISA method. We also measured the plasma levels of two RAGE ligands, N-epsilon-carboxymethyl lysine and S100A12, by ELISA method. In the COPD patients, we assessed the prevalence and severity of emphysema by computed tomography (CT), and the prevalence of chronic cor pulmonale by echocardiography. Multiple quantile regression was used to assess the effects of emphysema, chronic cor pulmonale, smoking history, and comorbid conditions on the three quartiles of sRAGE.ResultssRAGE was significantly lower (p = 0.007) in COPD patients (median 652 pg/mL, interquartile range 484 to 1076 pg/mL) than in controls (median 869 pg/mL, interquartile range 601 to 1240 pg/mL), and was correlated with the severity of emphysema (p < 0.001), the lower the level of sRAGE the greater the degree of emphysema on CT. The relationship remained statistically significant after adjusting for smoking history and comorbid conditions. In addition, sRAGE was significantly lower in COPD patients with chronic cor pulmonale than in those without (p = 0.002). Such difference remained statistically significant after adjusting for smoking history, comorbidities, and emphysema severity. There was no significant difference in the plasma levels of the two RAGE ligands between cases and controls.ConclusionssRAGE is significantly lower in patients with COPD than in age- and sex-matched individuals without airflow obstruction. Emphysema and chronic cor pulmonale are independent predictors of reduced sRAGE in COPD.

Urinary desmosine excretion is inversely correlated with the extent of emphysema in patients with chronic obstructive pulmonary disease.

An enhanced proteolysis of lung interstitium is key event in the pathogenesis of emphysema, a major constituent of chronic obstructive pulmonary disease. To assess whether urinary desmosine and/or hydroxyproline may be used as a marker of lung destruction we studied urinary excretions of these products in 20 patients with chronic obstructive pulmonary disease and in 19 appropriate controls in 24h urine collection samples. For desmosine measurements, we developed a new indirect competitive enzyme-linked immunosorbent assay. The extent of emphysema was measured in high resolution computed tomography (CT) scans, by considering lung area with CT numbers <-950 Hounsfield units (HU). Urinary desmosine excretion was significantly higher in patients with chronic obstructive pulmonary disease than in controls (294+/-121 microg versus 183+/-93 microg, P=0.003), and was unrelated with both age and smoking habits. In patients with no evidence or only mild emphysema, desmosine excretion values were significantly higher (P=0.006) than those of patients with moderate to severe emphysema. In patients with chronic obstructive pulmonary disease, urinary hydroxyproline excretion was positively correlated with urinary desmosine excretion but on the average, it was not different from that of controls. These data indicate that urinary desmosine is a sensitive biological marker of lung elastin catabolism. The relatively low levels of urinary desmosine observed in patients with severe emphysema may be accounted for a decrease in elastin catabolism due to reduced lung elastin mass. Urinary desmosine may be used to identify subjects at risk of developing emphysema and to assess the efficacy of therapeutic interventions.

Plasma N-e-(carboxymethyl)lysine levels are associated with the extent of vessel injury after coronary arterial stenting

ObjectiveIn animal models, increased tissue receptor for advanced glycation end products and its ligands, including N-ϵ-(carboxymethyl)lysine (CML), are critically implicated in postprocedural intimal hyperplasia after balloon injury. In patients undergoing percutaneous coronary interventions with stenting, we investigated whether plasma levels of CML and the soluble form of receptor for advanced glycation end products (sRAGE) changed during poststenting follow-up. MethodsWe studied 81 patients with coronary artery disease who underwent successful percutaneous coronary interventions. Plasma levels of CML and sRAGE were measured before intervention, and at 1 day and 180 days of follow-up. ResultsCML levels increased significantly at day 1 after stenting and persisted at an elevated level at 180 days (P=0.013), whereas sRAGE levels increased significantly at 180 days (P=0.011). CML levels were significantly higher in multivessel-treated patients than in single-vessel-treated patients both at 1 day and 180 days of follow-up. In addition, CML values were positively associated with the extent of stent area at 1 day and 180 days of follow-up (r=0.278, P=0.022 and r=0.315, P=0.012, respectively). In logistic regression analysis, only the extent of stent area predicted adverse clinical events at 180-day follow-up (P=0.03, odds ratio=14.25, confidence interval=1.25–162.2). ConclusionThis study supports the hypothesis that increased circulating levels of CML occurred in the presence of vascular injury. This persistent rise of CML could amplify an inflammatory phenomenon triggered by stent placement and thus contributes to coronary artery disease progression.

Routine laboratory tests to risk-stratify patients with chronic coronary artery disease

BACKGROUND Several biohumoral variables, taken individually, are predictors of prognosis in patients with chronic coronary artery disease (CAD). We hypothesized that taken together, laboratory tests provide prognostic information that is additive to a complete diagnostic work-up. METHODS We prospectively examined 2370 consecutive patients with chronic CAD, as shown by a >50% coronary stenosis (in 95% of patients), previous coronary revascularization (in 31% of patients), and/or previous myocardial infarction (MI, in 54% of patients). We tested the ability of laboratory and clinical variables to predict future cardiac events (cardiac death and non-fatal MI). RESULTS During follow-up (median, 46 months), 147 patients (6.2%) died from cardiac causes and 81 (3.4%) experienced a non-fatal MI. Using multivariate analysis, after adjustment for clinical variables (including left ventricular ejection fraction and angiographic extent of coronary stenoses), a high-density lipoprotein cholesterol (HDLc) concentration<35 mg/dL (p<0.0001), a neutrophil-to-lymphocyte ratio >2.4 (p=0.0014), and an fT3 serum level<2.1 pg/mL with normal thyrotropin (low-T3 syndrome) (p=0.0260) showed an independent and incremental prognostic value, and were associated with an increase in the rate of cardiac events of 86%, 57% and 41%, respectively. When these variables were added to clinical and instrumental variables, the prognostic power of the model increased significantly (global chi-square improvement: from 157.01 to 185.07, p<0.0001). CONCLUSION Low HDLc, high neutrophil-to-lymphocyte ratio and low-T3 syndrome, both individually and taken together, provide prognostic information that is independent of and incremental to the main clinical and instrumental findings.

α-1 Protein evaluation to stratify heart failure patients.

Heart failure is a pathological condition characterized by cardiac dysfunction and neuroendocrine system activation. The aim of this study was to evaluate serum α-1 proteins in the characterization of heart failure patients. The study included 69 patients with documented heart failure disease and 44 healthy individuals. We included 12 out of 69 patients with preserved (>50%) left ventricular ejection fraction. α-1 protein levels were evaluated using routine capillary electrophoresis. Markers of inflammation, such as interleukin-6 (IL-6) and tumor necrosis factor-α, were measured with UltraSensitive ELISA Kits. C-reactive protein and brain natriuretic peptide were determined by automated assays. No difference in α-1 protein levels between patients with reduced versus preserved left ventricular ejection fraction was observed. IL-6, tumor necrosis factor-α, and C-reactive protein concentrations were significantly increased in patients with respect to the control group (P <0.001, P <0.01, and P <0.05, respectively). A progressive increase in α-1 protein levels across NYHA classes (P = 0.0077) was observed. Brain natriuretic peptide median value of the patient group was 287 ng/l (92–602 ng/l) and was significantly associated with α-1 proteins and IL-6 levels (P <0.05 and P <0.01, respectively). Considering recent findings and our preliminary data, we hypothesized that the overexpression of α-1 antitrypsin (AAT) protein (and probably elevated AAT levels) is a compensatory mechanism as a consequence of the loss of the antiprotease activity, induced by the increase of oxidative stress in heart failure patients. In conclusion, we assume that α-1 proteins and AAT could contribute to the prognostic stratification of heart failure patients.

Arterial Blood Pressure and the Renin-Angiotensin-Aldosterone System during Postural Changes in Hypertensive Patients with Unilateral Renal Mobility

Unilateral renal mobility was identified in 27 out of 100 essential hypertensive patients by examination of renal scintiphotos. The pattern of response to postural changes of blood pressure (BP), plasma renin activity (PRA) and plasma aldosterone concentration (PAC) was investigated in 11 patients with renal mobility and without treatment and compared with that of an age- and sex-matched group of untreated hypertensives without renal mobility. The patients with renal mobility had higher BP levels (X +/- SD mm Hg: supine 185 +/- 39/112 +/- 18 vs. 149 +/- 18/97 +/- 14; upright 167 +/- 38/108 +/- 17 vs. 144 +/- 7/93 +/- 10; p less than 0.05). Significant correlations were obtained in the patients with renal mobility (but not in those without renal mobility) between upright PRA and PAC (p less than 0.001), their postural variations (p less than 0.01) and between upright PRA (and PAC) and BP levels (p less than 0.05). The high prevalence of renal mobility in hypertension and the relationship observed between the activated renin-angiotensin-aldosterone system and BP in this condition suggest the importance of searching for unilateral renal mobility when examining the renin-angiotensin-aldosterone system in hypertensive patients, particularly during postural manoeuvres.

Major determinants of plasma aldosterone levels in chronic uremia on dialytic treatment.

Several variables were determined in 18 uremic patients undergoing dialytic treatment in order to investigate their relative importance in the regulation of aldosterone secretion by single and multipl