A longitudinal 20 years of follow up showed a decrease in the survival of heart failure patients who maintained low LDL cholesterol levels.

BACKGROUND: Treatment by statins is well established for primary and secondary prevention of cardiac events but may be hazardous for patients with heart failure (HF). AIM: We studied the long-term (20 years) association between baseline low-density lipoprotein cholesterol (LDL-c) levels and clinical outcome in patients with severe HF. DESIGN: Patients were divided into those with plasma LDL-c levels 110 mg/dl (Group 1) or >110 mg/dl (Group 2). METHODS: The mean follow-up of 305 study patients with advanced HF who had an average NYHA score of 2.7 was 11.3 years (range 15 months to 20 years). Mortality during follow-up was 43%. RESULTS: Patients with the highest baseline LDL-c levels had significantly improved outcome, whereas those with the lowest LDL-c levels had the highest mortality. This paradoxical effect was prominent in patients <70 years old. The negative association of LDL-c levels and mortality was most conspicuous among the HF patients who were treated with statins. DISCUSSION AND CONCLUSION: Long-term follow-up findings showed that low LDL-c levels may predict a less favorable outcome in advanced HF, particularly in patients <70 years old and those taking statins. This negates the protocol of following an aggressive LDL-c-lowering strategy in younger patients with HF.

The association between the embolic load and atrial size in acute pulmonary embolism.

BACKGROUND: Early identification by computed tomography pulmonary angiography (CTPA) of patients with acute pulmonary embolism (PE) who have signs associated with a high embolic burden would be highly desirable. OBJECTIVES: To investigate whether an increased obstruction of the pulmonary vasculature is associated with reduced left atrial (LA) and increased right atrial (RA) areas. METHODS: We retrospectively analyzed a consecutive series of CTPA studies of 137 patients with acute PE and 38 controls without PE between October 2004 and March 2006. Left and right atrial areas and longitudinal and short axis diameters were measured and correlated with the pulmonary arterial obstruction index (PAOI) divided into tertiles (obstruction of < 12.5%, 12.5%-42.5% and ≥ 42.5%). RESULTS: There was a significant negative age- and gender-adjusted correlation between the PAOI and LA measurements, particularly the LA area (r = -0.259) and the LA short axis diameter (r = -0.331). All RA measurements had positive correlations (RA area, r = 0.279; RA short axis diameter, r = 0.313). The LA/RA area ratio correlated negatively with the PAOI (r = -0.447). All above-mentioned correlations had P < 0.002. All the LA measurements were the largest in the controls and gradually decreased with higher PAOIs. A receiver operating characteristic curve analysis demonstrated that the RV/LV diameter, LA/RA area and LA/RA short axis diameter ratios had comparable discriminative ability for higher PAOI tertiles. CONCLUSIONS: The higher the clot load in the pulmonary arteries, the smaller the LA area and the larger the RA area. Atrial area measurements by CTPA may serve as a real-time parameter in assessing the severity of PE upon diagnosis.

Low-grade systemic inflammation in patients with amyotrophic lateral sclerosis.

OBJECTIVE: To prospectively determine the intensity of systemic low-grade inflammation in patients with amyotrophic lateral sclerosis (ALS). PATIENTS AND METHODS: Patients with ALS and matched healthy controls underwent blood tests for inflammation-sensitive biomarkers: erythrocyte sedimentation rate (ESR), quantitative fibrinogen, wide-range C-reactive protein (wrCRP) concentrations, leukocyte count and neutrophil-to-lymphocyte ratio (NLR). The correlation between these inflammatory biomarkers and disability status of the patients, expressed by the ALS Functional Rating Scale (ALSFRS-R), was evaluated. RESULTS: Eighty patients with ALS and 80 matched controls were included. wrCRP, fibrinogen, ESR and NLR values were significantly elevated in patients compared with controls. There was a significant correlation between the ALSFRS-R score and wrCRP, ESR and fibrinogen levels. This correlation persisted on sequential examinations. CONCLUSIONS: A systemic low-grade inflammation was detected in patients with ALS and correlated with their degree of disability. A heightened systemic inflammatory state is apparently associated with a negative prognosis in ALS.

Real-time risk stratification of patients with acute pulmonary embolism by grading the reflux of contrast into the inferior vena cava on computerized tomographic pulmonary angiography.

OBJECTIVE: To investigate whether fast grading of reflux of contrast to the inferior vena cava (IVC) on computerized tomographic pulmonary angiography (CTPA) is a potential biomarker for real-time risk stratification. METHODS: We retrospectively identified 343 patients investigated for possible pulmonary embolism (PE) by CTPA at our medical center between September 2004 and March 2006. A total of 145 consecutive patients with PE (age 67 +/- 19 years) and 168 consecutive ones with negative CTPAs (age 64 +/- 20 years) fulfilled entry criteria. CTPAs were evaluated for retrograde reflux of contrast to the IVC by fast visual grading from 1 to 6 using the original axial images. Pulmonary obstruction index, the diameters of right and left ventricles and pulmonary artery, and patient survival data were recorded as well. RESULTS: Twenty-nine (20.0%) patients with positive CTs and 23 (13.7%) patients with negative CTs had substantial degrees (>or=4) of reflux of contrast to the IVC (P = 0.14). The Kaplan-Meier 30-day survival curves demonstrated significant reduction in survival in individuals with PE and grade >or=4 reflux of contrast to the IVC compared with lower grades (P = 0.008), but not in patients with grade >or=4 and no PE on CTPA (P = 0.26). The other cardiovascular parameters showed no significant correlation with survival in patients with and without PE. CONCLUSION: Substantial grades of reflux of contrast to the IVC during CTPA could predict early mortality in patients with acute PE. Rapid grading of reflux of contrast from the original axial CTPA images can be used for real-time risk stratification in patients with acute PE.

Dissociated effects of physical activity and weight loss on fibrinogen concentrations and markers of red blood cell aggregation. Relevance for life style modification in atherothrombosis.

It has been shown that weight loss and physical activity contribute to a better biorheological profile. Yet, the concentrations of fibrinogen are not always reduced following life style modification. We evaluated the inter-relations between fibrinogen's pro red cell aggregation potential and reduced inflammation and improved lipid profile as anti-aggregating forces in a group of 20 apparently healthy obese volunteers following 4 and 8 months of intensive life modification program which included diet and strenuous physical activity. A significant (p=0.005) weight loss (from a mean+/-SD of 121.4+/-20.9 to 98.0+/-21.3 kg) and decrease in body mass index (from 40.8+/-4.3 to 32.9+/-5.3 kg/m(2), p=0.005) was noted in fourteen individuals who completed the 8-month program. The concentrations of clottable fibrinogen rose from 318+/-96 to 387+/-72 mg/dl (p=0.012) while there was a significant reduction in the erythrocyte sedimentation rate (ESR) (from 19.0+/-12.6 to 10.8+/-7.5 mm/h, p=0.018), triglycerides (from 143+/-80 to 80+/-44 mg/dl, p=0.005), LDL cholesterol (from 128+/-34 to 103+/-17 mg/dl, p=0.005) and total cholesterol (from 211+/-40 to 171+/-17 mg/dl, p=0.007), as well as decrease in insulin concentration (from 36.1+/-21.3 to 20.6+/-8.0 microu/ml, p=0.01) and the insulin resistance index (HOMA-R, from 9.1+/-6.4 to 4.9+/-2.1 glu*ins/405, p=0.008). Despite a significant increment in the concentrations of clottable fibrinogen, a significant reduction was noted in the degree of red cell aggregation as measured by using a slide test and direct visualization of the aggregates. Our conclusion is that the pro-aggregating properties of fibrinogen following intense physical activity are probable counterbalanced by the anti-aggregatory properties of an improved lipid profile and an attenuated acute phase response.

Rheological consequences of acute infections: the rheodifference between viral and bacterial infections.

The aim of the present study was to explore the difference between viral and bacterial infections regarding the intensity of erythrocyte aggregation in the peripheral venous blood. Although a rheodifference in terms of erythrocyte aggregation between viral and bacterial infections has been shown by us in the past, the time from onset of disease was not included. We have presently included the time from the onset of disease in a group of 133 patients with an acute bacterial infection who showed a significantly enhanced erythrocyte aggregation as opposed to a group of 23 with viral ones and no increased erythrocyte aggregation despite of there being no significant difference in the time from onset of disease (55.7+/-55.6 hours in the bacterial group versus 50+/-35.2 in the viral one). In addition, we could match 22 patients with viral infections who presented the same fibrinogen concentrations (338+/-78 mg/dl) as those with acute bacterial ones (338+/-79 mg/dl). Although of borderline (p=0.06) significance, patients with an acute bacterial infection presented enhanced (vacuum radius=12.6+/-6.4 microns) erythrocyte aggregation as opposed to their isofibrinogenemic counterparts (vacuum radius=9.4+/-6.5 microns). Again, both groups presented no difference regarding the time from onset of disease. We conclude therefore that patients with acute bacterial infections present higher levels of erythrocyte aggregation. This is not a result of a shorter time interval from disease onset of the viral group. The known detrimental effects of increased erythrocyte aggregation regarding capillary slow flow, endothelial dysfunction and reduced tissue oxygenation might be therefore relevant in the context of patients with an acute infection, especially the bacterial ones.

Heart rate and microinflammation in men: a relevant atherothrombotic link.

OBJECTIVE AND BACKGROUND: To explore the possibility that increased resting heart rate (HR) is associated with a microinflammatory response. Such an association could explain, at least in part, the recently described worse cardiovascular prognosis in individuals with increased HR. METHODS: Concentrations of fibrinogen and high-sensitivity C-reactive protein, as well as the absolute number of polymorphonuclear leucocytes, were analysed in a cohort of 4553 apparently healthy men and in those with atherothrombotic risk factors. RESULTS: Following adjustment for age and body mass index, lipid profile and cardiovascular risk factors, a significant (p<0.001) difference was noted between individuals in the first quintile of HR (< or =58 beats/min) and those in the fifth quintile (> or =79 beats/min) regarding all the above-mentioned inflammatory biomarkers, the respective mean values being 7.38 and 8.11 micromol/l, 1.12 and 1.61 mg/l, and 4.23 and 4.74 x 10(9)/l. CONCLUSIONS: Resting HR is associated with a microinflammatory response in apparently healthy men and in those with atherothrombotic risk factors. Sympathetic activation might be a common factor explaining such an association. If confirmed in additional studies, this association might be a relevant target for therapeutic manipulations.

Wide-range C-reactive protein efficacy in acute ischemic stroke patients.

OBJECTIVE: To compare the recently introduced wide-range C-reactive protein (wr-CRP) with the widely used high-sensitivity Behring Dade method (hs-CRP) in acute stroke/transient ischemic attack (TIA) patients. MATERIALS AND METHODS: A total of 119 consecutive patients admitted to a tertiary medical center with acute ischemic stroke/TIA were included in the study. Venous blood was obtained for both assays during the first 24 h, 3-5 days, as well as 3-6 months thereafter. RESULTS: A highly significant correlation (r=0.994, P<0.0001) was found between the two methods even when analyzed at three different time points. In addition, a similar correlation was noted between these two assays and other commonly used biomarkers, including white blood cell count, Westergren's sedimentation rate and quantitative fibrinogen. CONCLUSION: Real-time, on-line and low-cost wr-CRP assay is a reasonable alternative to the Behring Dade hs-CRP method in acute stroke/TIA patients.

Increased erythropoiesis and subclinical inflammation as part of the metabolic syndrome.

Recent studies have suggested the insulin resistance might be accompanied by enhanced erythropoiesis. We have examined this association in individuals with the metabolic syndrome (MS) who in addition to insulin resistance harbor a chronic low grade inflammation. This study is relevant because chronic inflammation might have a suppressive effect on erythropoiesis. 280 and 554 non-smoking women and men with respective age of 46.4+/-9.3 (mean+/-S.D.) and 44.0+/-11.0 years are included. A significant correlation was noted between the numbers of the components of the MS and the inflammatory biomarkers including the white blood cell count, high sensitivity C-reactive protein, fibrinogen concentrations and the erythrocyte sedimentation rate. In addition, a significant correlation (r=0.157, p=0.008) was noted between the number of components of the MS and the number of red blood cells in the peripheral blood in women. The same was true for men (r=0.192, p<0.0005). We conclude that enhanced erythropoiesis could be a new, hitherto unrecognized component of the MS. The enhanced erythropoiesis could give an erroneous impression of general "good" health in these individuals.

Obesity-related correlation between C-reactive protein and the calculated 10-y Framingham Coronary Heart Disease Risk Score.

OBJECTIVE: To clarify the role of body mass index (BMI, kg/m(2)) adjustment in predictive models for cardiovascular events that add high-sensitivity C-reactive protein (hs-CRP) to the 10-y Framingham Coronary Heart Disease Risk Score (FCRS). DESIGN: A cross-sectional study in a group of apparently healthy individuals. SUBJECTS: In all, 1512 apparently healthy individuals (955 men and 557 women) at a respective age of 49.7+/-10.6 and 50.6+/-9.6 y. RESULTS: The Pearson correlation between hs-CRP and the calculated 10-y FCRS was lower when adjusted for BMI. This reduction was especially noted in women where it dropped from 0.247 to 0.09. The dominant role of hs-CRP concentrations was also noted in a linear regression model, again, especially noted in women (drop of the standardized coefficient from 0.517 for BMI to 0.08 for the FCRS). CONCLUSIONS: The correlation between hs-CRP and the 10-y FCRS is partly related to the presence of obesity. We raise the possibility that the addition of BMI to the predictive model of FCRS might attenuate the cost-effectiveness of CRP measurements for this specific risk assessment.

Oral temperature in daily life. A new look in the era of microinflammation.

It has been repeatedly shown that apparently healthy individuals and those with atherothrombotic risk factors harbor a low grade subclinical internal inflammation (microinflammation). This low grade acute phase response is relevant for the presence of atherothrombosis and future vascular events. Since these events are associated with a febrile response, we thought that it is relevant to clarify whether the microinflammatory response has an influence on the oral temperature. Included were 2,340 men and 1,280 women in whom the white blood cell count (WBCC) and differential, as well as the erythrocyte sedimentation rate (ESR), quantitative fibrinogen and high sensitivity C-reactive protein (hs-CRP) were determined in addition to the oral temperature in quiescent conditions. There was no association between these inflammatory biomarkers, except from a weak association with the absolute number of polymorphonuclear leukocytes. This association could be, however, related to the stress of the examination itself. Thus, it is unlikely that the microinflammatory response in daily life is associated, to a significant degree, with an enhanced oral temperature. The results are relevant for the findings of elevated oral temperature during conditions of acute ischemia/infarction where the temperature is probably related to the event itself and not to the patient's background microinflammation.

Serum lipids as minor determinants of the degree of erythrocyte adhesiveness/aggregation in the peripheral blood of individuals with low grade inflammation and moderately increased serum lipids.

Both lipids and inflammation sensitive proteins have been reported to affect the aggregation of red blood cells yet their relative importance in this regard have not been determined. We have included high sensitive C-reactive protein, erythrocyte sedimentation, fibrinogen concentrations as well as various serum lipid concentrations and the degree of erythrocyte adhesiveness/aggregation in the peripheral blood in a linear regression analysis. Partial Pearson correlation coefficients were included as well. In a group of 674 individuals with various atherosclerotic risk factors, low grade inflammation and moderately increased serum lipids, a relatively low correlation was noted between red blood cell adhesiveness/aggregation and triglycerides concentrations. A negative correlation was noted for HDL cholesterol. None of the lipid variables turned significant in the regression analysis. In a group of individuals with atherosclerotic risk factors, low grade inflammation and moderately increased serum lipids, the degree of erythrocyte adhesiveness/aggregation in the peripheral blood correlates much better with the presence of inflammation sensitive proteins than with the presence of increased lipid concentrations.

Sex differences in the expression of haemorheological determinants in individuals with atherothrombotic risk factors and in apparently healthy people.

BACKGROUND: Increased red cell aggregation can be detrimental, leading to slow capillary blood flow and tissue hypoxaemia. Sex differences in the degree of erythrocyte adhesiveness/aggregation in the peripheral blood have not been clearly shown. OBJECTIVES: To determine whether there are sex differences in the expression of erythrocyte adhesiveness/aggregation in the peripheral blood in individuals with atherothrombotic risk factors and in apparently healthy people. METHODS: From a cohort of 965 participants in the Tel Aviv Medical Centre inflammation survey, 192 pairs of different sex were matched for age, body mass index, hip and waist circumferences, cardiovascular risk factors, and the intake of active cardiovascular drugs. RESULTS: Women had an enhanced degree of red cell aggregation (p < 0.0005) as well as increased concentrations of inflammation sensitive proteins including fibrinogen and C reactive protein. Women had a lower haemoglobin concentration than men, but this did not affect the degree of erythrocyte adhesiveness/aggregation. CONCLUSIONS: The significant increase in red blood cell adhesiveness/aggregation in the peripheral blood of women with atherothrombosis could be relevant to the more eventful course that some women experience during and following acute ischaemic disease.

Increased erythrocyte adhesiveness/aggregation in the peripheral venous blood of patients with ischaemic heart disease and an eventful course.

OBJECTIVE: To determine whether increased erythrocyte aggregability has prognostic implications in patients with established ischaemic heart disease. METHODS AND RESULTS: We have adopted a simple slide test and image analysis to reveal the state of erythrocyte adhesiveness/aggregation (EAA) in the peripheral blood of patients with ischaemic heart disease and an eventful course (n=46) as opposed to those with an uneventful (n=43) course. A significant correlation was noted between the results of the erythrocyte adhesiveness/aggregation test (EAAT) and either erythrocyte sedimentation or fibrinogen concentration. When we sampled the results of fibrinogen in the group of eventful course they were not significantly different from the results obtained in the uneventful one. This was the case with the results of the erythrocyte sedimentation rate. However, the variables of the EAAT showed a significant difference, the values in the eventful group being higher than those observed in the uneventful one. CONCLUSIONS: The EAAT is a valuable tool to disclose the presence of increased red blood cell aggregability in patients with ischaemic heart disease. Increased EAA might have prognostic implications in patients with ischaemic heart disease.

The multiplicity of atherosclerotic risk factors corresponds to the appearance of increased leukocyte count in the peripheral blood: relevance to the pathogenesis of the disease.

White blood cells may have a role in the aetiopathogenesis of atherosclerosis disease in patients with risk factors for this disease. We examined the white blood cell count in a group of 331 patients and controls of the same age group (139 women and 192 men), the numbers of individuals with no, one, two or more atherosclerotic risk factors being 29, 47, 35 and 28 for women and 50, 45, 68 and 29 for men, respectively. The risk factors included were hypertension, hyperlipidaemia, current smoking and diabetes mellitus. A stepwise increment in the white blood cell count was found in both women and men, the respective values for no, one, two or more risk factors being 6.3 +/- 1.5, 7.6 +/- 1.9, 7.5 +/- 1.8, 7.3 +/- 1.4 and 6.6 +/- 1.6, 6.9 +/- 1.9, 7.4 +/- 2.1, 8.1 +/- 2.6 (absolute number of cells per cm x 103). The one-way analysis variance was found to be significant for both women (P=0.01) and men (P=0.01), as well as the entire cohort (P=0.03). We conclude that the multiplicity of risk factors for atherosclerosis is associated with the appearance of an increased number of white blood cells in the peripheral blood. These findings might represent an enhanced inflammatory response in these individuals and at the same time reveal a potential harmful role of the cells in the aetiopathogenesis of the disease.

The inflammation meter: novel technology to detect the presence of infection/inflammation in patients without leukocytosis but with increased leukocyte adhesiveness/aggregation.

OBJECTIVES: To reveal the presence of infection/inflammation in patients with relatively normal white blood cell count (WBCC) by using the leukocyte adhesiveness/aggregation test (LAAT). METHODS: The LAAT was performed by using a simple slide test and image analysis (Inflamet), the WBCC, by an electronic cell analyzer, C-reactive protein, by Laser nephelometry and CD11b/CD18 by whole blood flow cytometry. RESULTS: Forty out of a cohort of 121 patients with nonviral acute febrile illness had a WBCC within normal limits. The intensity of the inflammatory response in these individuals as judged by either C-reactive protein, or fibrinogen concentrations, erythrocyte sedimentation or polymorphonuclear leukocyte CD11b/CD18 expression was similar to that observed in patients with a leukocytic response. Our present finding that 63% out of the group with documented infection/inflammation and no leukocytosis had a significantly increased LAAT suggest that the lack of leukocytosis is in part a pseudoleukopenia, or is associated with some degree of uncompensated tissue leukostasis. CONCLUSIONS: The lack of a leukocytic response in a patient with nonviral infection/inflammation is by no means a sign of a less inflammatory response. The increased state of leukocyte adhesiveness/aggregation might help to disclose the presence of inflammation in these individuals.

Activated polymorphonuclear leukocytes and monocytes in the peripheral blood of patients with ischemic heart and brain conditions correspond to the presence of multiple risk factors for atherothrombosis.

OBJECTIVE: Risk factors like hypertension, diabetes mellitus, dyslipidemia and smoking contribute to the pathogenesis of atherothrombosis. We investigated whether the multiplicity of risk factors for atherothrombosis is associated with leukocyte activation. METHODS: We examined the availability of CD11b/CD18 antigen on the surface of peripheral blood polymorphonuclear leukocytes and monocytes in patients with acute ischemic heart and brain conditions. RESULTS: There was a highly significant (p<0.00001) increment in the availability of the CD11b/CD18 antigen on the surface of the polymorphonuclear leukocytes in patients with multiple (2 or more) vascular risk factors [mean fluorescence intensity (MFI) +/- SD, 210+/-102] as opposed to individuals with none or 1 risk factor for atherothrombosis (MFI 159+/-73). Similar results were observed on the monocytes: 309+/-151 and 235+/-97, respectively (p<0. 00001). CONCLUSION: The multiplicity of risk factors for atherothrombosis is associated with the up-regulation of CD11b/CD18 antigen on the surface of peripheral blood polymorphonuclear leukocytes and monocytes, suggesting the presence of an increased inflammatory response and leukocyte activation in these individuals.

Combined leukocyte and erythrocyte aggregation in the peripheral venous blood during sepsis. An indication of commonly shared adhesive protein(s).

We have used a simple slide test and image analysis to reveal the state of leukocyte and erythrocyte adhesiveness/aggregation in the peripheral blood of 28 patients with sepsis and 28 controls. A significant (P<0.00001) increment in both leukocyte and erythrocyte adhesiveness/aggregation was noted in patients compared with controls. Moreover, a significant (r=0.73, n=56, P<0.001) correlation was noted between the two adhesiveness/aggregation variables themselves, suggesting a common mechanism responsible for these adhesive phenomena. The significant correlation with fibrinogen suggests that this protein might be such a "non-specific glue." Our results indicate that a simple slide technique and image analysis can assess the aggregability of both white and red blood cells in septic patients. This might have clinical application when interventions to reduce cell aggregability are planned in order to improve blood flow in the microcirculation.