Tumour biomarkers: association with heart failure outcomes.

BACKGROUND: There is increasing recognition that heart failure (HF) and cancer are conditions with a number of shared characteristics. OBJECTIVES: To explore the association between tumour biomarkers and HF outcomes. METHODS: In 2,079 patients of BIOSTAT-CHF cohort, we measured six established tumour biomarkers: CA125, CA15-3, CA19-9, CEA, CYFRA 21-1 and AFP. RESULTS: During a median follow-up of 21 months, 555 (27%) patients reached the primary end-point of all-cause mortality. CA125, CYFRA 21-1, CEA and CA19-9 levels were positively correlated with NT-proBNP quartiles (all P < 0.001, P for trend < 0.001) and were, respectively, associated with a hazard ratio of 1.17 (95% CI 1.12-1.23; P < 0.0001), 1.45 (95% CI 1.30-1.61; P < 0.0001), 1.19 (95% CI 1.09-1.30; P = 0.006) and 1.10 (95% CI 1.05-1.16; P < 0.001) for all-cause mortality after correction for BIOSTAT risk model (age, BUN, NT-proBNP, haemoglobin and beta blocker). All tumour biomarkers (except AFP) had significant associations with secondary end-points (composite of all-cause mortality and HF hospitalization, HF hospitalization, cardiovascular (CV) mortality and non-CV mortality). ROC curves showed the AUC of CYFRA 21-1 (0.64) had a noninferior AUC compared with NT-proBNP (0.68) for all-cause mortality (P = 0.08). A combination of CYFRA 21-1 and NT-proBNP (AUC = 0.71) improved the predictive value of the model for all-cause mortality (P = 0.0002 compared with NT-proBNP). CONCLUSIONS: Several established tumour biomarkers showed independent associations with indices of severity of HF and independent prognostic value for HF outcomes. This demonstrates that pathophysiological pathways sensed by these tumour biomarkers are also dysregulated in HF.

Skin autofluorescence is elevated in acute myocardial infarction and is associated with the one-year incidence of major adverse cardiac events.

BACKGROUND.: ST-elevation myocardial infarction (STEMI) is associated with increased inflammation and oxidative stress, enhancing the formation of advanced glycation endproducts (AGEs). These encompass a characteristic fluorescence pattern, which can be non-invasively measured as skin autofluorescence (AF). In this study we investigate whether skin AF is elevated in STEMI, its association with inflammatory and glycaemic stress and its predictive value for future events. METHODS.: Skin AF was measured in 88 STEMI patients (mean age 64+/-13 years) within 72 hours and around six months after discharge, in 81 stable coronary artery disease (sCAD) patients (64+/-10 years), and in 32 healthy controls (63+/-11 years). The cumulative one-year incidence of all-cause mortality and hospitalisation for myocardial infarction or heart failure was documented. RESULTS.: Skin AF was significantly higher in STEMI compared with sCAD and controls, irrespective of confounders, and was associated with HbA1c and C-reactive protein. Skin AF decreased significantly in STEMI patients, when measured >200 days after discharge. In STEMI patients, skin AF above the median was predictive of future events (hazard ratio 11.6, 95% CI 1.5 to 90.8, p=0.019). CONCLUSION.: Skin AF is elevated in STEMI, is associated with inflammation and glycaemic stress, and predicts future major adverse cardiac events. (Neth Heart J 2009;17:162-8.Neth Heart J 2009;17:162-8.).

Acute myeloid leukaemia as a cause of acute ischaemic heart disease.

Ischaemic heart disease is almost invariably the result of atherosclerotic degeneration of the coronary arteries. However, other causes of ischaemic heart disease should always be considered. Here we describe two patients with a classic presentation of ischaemic heart disease resulting from acute leukaemia. The pathophysiological mechanisms of acute leukaemia leading to ischaemic heart disease are discussed.

[Clinical reasoning and decision-making in practice. A 31-year-old woman with transient monocular blindness and polycythaemia]. / Klinisch denken en beslissen in de praktijk. Een 31-jarige vrouw met voorbijgaande visusklachten en polycytemie.

A 31-year-old woman presented with recurrent transient monocular blindness. As transient ischaemic attacks were suspected further investigations were targeted at evaluation of premature atherosclerotic lesions in the internal carotid artery. Initially laboratory tests were not performed. After referral to a cardiovascular-disease prevention outpatient clinic, laboratory evaluation disclosed a marked isolated polycythaemia that turned out to be secondary to right-left shunting through multiple pulmonary arteriovenous malformations. The ultimate diagnosis was hereditary haemorrhagic telangiectasia. Later on, physical signs such as telangiectasia and central cyanosis were noticed. In the clinical decision-making process, laboratory tests associated with causes of transient monocular visual loss were not carried out and therefore clues important for the ultimate diagnosis were not obtained. In only a minority of young patients with transient monocular visual loss can this be ascribed to premature atherosclerosis. For these reasons, a proper physical examination and laboratory tests directed towards other causes must be part of the initial diagnostic work-up in young patients with visual disturbances and suspected transient ischaemic attacks.

Circulating monocytes in patients with acute coronary syndromes lack sufficient interleukin-10 production after lipopolysaccharide stimulation.

Acute coronary syndromes (ACS) are associated with inflammation resulting from monocyte activation. We sought for differences in the production of pro- and anti-inflammatory cytokines by monocytes from patients with ACS. C-reactive protein (CRP) and neopterin were measured in 22 patients with acute coronary syndromes, 50 patients with stable vascular disease and 22 healthy controls. Production of tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 was determined after, respectively, 6 and 24 h of incubation of full blood with lipopolysaccharide (LPS). Levels of CRP [median, interquartile range (IQR)][1.5 mg/l (0.8-4.5) ACS patient versus 2.1 (0.9-3.6) stable disease versus 0.4 (0.3-1.2) healthy controls] (P < 0.001) and neopterin [7.4 nmol/l (6.0-8.7) ACS patient versus 7.1(6.0-8.9) stable disease versus 6.4 (5.6-7.3) healthy controls] (P = 0.07) were higher in both the patient groups. IL-10 production after LPS stimulation was greatly reduced in patients with acute coronary syndromes (16 175 pg/ml, 7559-28 470 pg/ml) as opposed to patients with stable disease (28 379 pg/ml, 12 601-73 968 pg/ml) and healthy controls (63 830 pg/ml, 22 040-168 000 pg/ml) (P = 0.003). TNF-alpha production was not signi fi cantly different between the groups [7313 pg/ml (4740-12 615) ACS patient versus 11 002 (5913-14 190) stable disease versus 8229 (5225-11 364) healthy controls] (P = 0.24). Circulating monocytes in unstable coronary syndromes produce equal amounts of TNF-alpha but less IL-10 after stimulation with LPS in vitro as compared with healthy controls. We hypothesize that, in acute coronary syndromes, the production proinflammatory cytokines is not counterbalanced by anti-inflammatory cytokines such as IL-10.

Increased alpha-linolenic acid intake lowers C-reactive protein, but has no effect on markers of atherosclerosis.

OBJECTIVE: To investigate the effects of increased alpha-linolenic acid (ALA)-intake on intima-media thickness (IMT), oxidized low-density lipoprotein (LDL) antibodies, soluble intercellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP), and interleukins 6 and 10. DESIGN: Randomized double-blind placebo-controlled trial. SUBJECTS: Moderately hypercholesterolaemic men and women (55 +/- 10 y) with two other cardiovascular risk factors (n = 103). INTERVENTION: Participants were assigned to a margarine enriched with ALA (fatty acid composition 46% LA, 15% ALA) or linoleic acid (LA) (58% LA, 0.3% ALA) for 2 y. RESULTS: Dietary ALA intake was 2.3 en% among ALA users, and 0.4 en% among LA users. The 2-y progression rate of the mean carotid IMT (ALA and LA: +0.05 mm) and femoral IMT (ALA:+0.05 mm; LA:+0.04 mm) was similar, when adjusted for confounding variables. After 1 and 2 y, ALA users had a lower CRP level than LA users (net differences -0.53 and -0.56 mg/l, respectively, P < 0.05). No significant effects were observed in oxidized LDL antibodies, and levels of sICAM-1, interleukins 6 and 10. CONCLUSIONS: A six-fold increased ALA intake lowers CRP, when compared to a control diet high in LA. The present study found no effects on markers for atherosclerosis. SPONSORSHIP: The Dutch 'Praeventiefonds'.

[Diagnostic image (164). A man who drank formalin by mistake. Caustic lesions of esophagus and stomach]. / Diagnose in beeld (164). Een man die per ongeluk formaline dronk. Caustisch slokdarm- en maagletsel na inname van formaline.

A 71-year-old male was admitted because of unintentional ingestion of formalin, which caused severe caustic lesions of oesophagus and stomach.

Long term angiotensin converting enzyme-inhibition in patients after coronary artery bypass grafting reduces levels of soluble intercellular cell adhesion molecule-1.

OBJECTIVE: to examine the effect of angiotensin converting enzyme inhibition (ACEI) on soluble intercellular adhesion molecule 1 (sICAM-1) and C-reactive protein (CRP) in patients requiring coronary artery bypass grafting (CABG). METHOD: subgroup analysis of 42 patients randomised to Quinapril (40 mg daily determined) and 45 to placebo. sICAM-1 and CRP were > or = 4 weeks before and 1 year after surgery. RESULTS: there was no difference in sICAM-1 at baseline (142.2 microg/L vs 136.6 microg/L). There was significant reduction in s-ICAM-1 in patients receiving quinapril (142.2+/-10.8 microg/L vs 125.6+/-9.4 microg/L, p<0.05) but not placebo (136.6+/-10.2 microg/L vs 131.2+/-11.7 microg/L, p=NS). Levels of C-reactive protein remained unchanged in both groups (3.70+/-0.85 vs 2.73+/-0.32 mg/L, 2.85+/-0.48 vs 3.16+/-0.50 mg/L). CONCLUSIONS: ACEI reduces sICAM-1 in patients undergoing CABG. The benefits of ACEI may partly be due to a reduction of the vascular inflammatory response.

[Diagnostic image (111). A dyspnoeic man with fever and a sore throat. Lemierre's syndrome]. / Diagnose in beeld (III). Een kortademige man met koorts en keelpijn. Syndroom van Lemierre.

An 18-year-old man was admitted because of high fever, a sore throat and dyspnoea. Additional investigations revealed tonsillitis, lung abscesses and thrombophlebitis of the internal jugular vein. Lemierre's syndrome was diagnosed.

AECA and ANCA in patients with premature atherosclerosis.

UNLABELLED: Autoimmunity is suggested to play a pathogenetic role in premature atherosclerosis. Since atherosclerosis and vasculitis seem pathogenetically related, we hypothesized that ANCA, an important antibody in vasculitis, plays a role in atherosclerosis as well. We therefore investigated the prevalence of ANCA in patients with premature atherosclerosis and related the presence of these antibodies to levels of AECA and markers of inflammation. METHODS & RESULTS: In a cohort of 286 patients with premature atherosclerosis the prevalence of ANCA was 5.6% (16/286). All had perinuclear ANCA. More females were ANCA-positive (8M/8F vs. 200M/70F, p = 0.03). In a nested case-control study, comparing the 16 ANCA-positive patients with 32 controls, levels of AECA were higher in the first (7.32 +/- 0.91U vs. 5.52 +/- 0.41U, p < 0.05). CONCLUSION: ANCA does not seem to play a major role in premature atherosclerosis. Whether elevated levels of AECA in ANCA-positive patients with premature atherosclerosis reflect more extended vascular disease remains to be determined.

Antineutrophil cytoplasmatic antibodies in patients with premature atherosclerosis: prevalence and association with risk factors.

OBJECTIVES: Autoimmunity is suggested to play a role in premature atherosclerosis. Antineutrophil cytoplasmatic antibodies (ANCA) are a group of autoantibodies found in several inflammatory disorders in which they supposedly amplify the inflammatory process. In this study the hypothesis is tested that ANCA play a role in premature atherosclerosis. DESIGN: Cross-sectional study followed by nested case-control study. In a total of 286 consecutive patients with premature atherosclerosis (age < 55 years) ANCA were tested. Within the same cohort, a nested case-control study in 16 ANCA-positive patients and 32 ANCA-negative controls matched for sex, and site of atherosclerosis, was executed. SETTING: University hospital outpatient clinic for lipids and premature atherosclerosis. SUBJECTS: A total of 286 consecutive patients with premature atherosclerosis (age < 55 years). RESULTS: Prevalence of ANCA was 5.6% (16 of 286). All cases had perinuclear ANCA (pANCA); no cytoplasmatic ANCA was found. Mean age was 42 +/- 7 in the ANCA-positive vs. 42 +/- 9 years in the ANCA-negative group (P=ns). More female parents were ANCA-positive (8M/8F vs. 200M/70F, P=0.03). Patients with ANCA had more often peripheral vascular disease (37.5 vs. 15.2%, P=0.03). In the case-control study levels of Lp(a) were higher (43.8 vs. 15.6% >300 mg x L(-1), P=0.05), whereas levels of HDL-c were lower in ANCA-positive patients (0.84 +/- 0.26 vs. 1.06 +/- 0.27 mmol x L(-1), P=0.01). Markers of inflammation, C-reactive protein (CRP) and serum amyloid A (SAA), did not differ, nor did antibodies against oxidized-LDL and malondialdehyde (MDA)-LDL, markers for the extent of atherosclerosis. CONCLUSIONS: Our results suggest that ANCA do not appear to play a major role in premature atherosclerosis as there was no increased prevalence of the autoantibody. Moreover, no differences in the incidence of classical cardiovascular risk factors nor in serum levels of markers of inflammation were found between the ANCA-positive group as compared with the ANCA-negative group.

Giant cell myocarditis: a fatal cause of dyspnea in pregnancy.

The clinical course of a pregnant patient, who presented with progressive dyspnea and heart failure is described. Despite intensive care and resuscitative efforts to mother and child, both expired. The autopsy revealed giant cell myocarditis in the mother. Giant cell myocarditis can affect pregnant patients and should therefore be considered in the differential diagnosis of progressive dyspnea.

Secondary prevention with fluvastatin decreases levels of adhesion molecules, neopterin and C-reactive protein.

BACKGROUND: Treatment of hypercholesterolaemia with HMG-CoA reductase inhibitors results in an earlier reduction of morbidity and mortality than expected from trials using conventional cholesterol-lowering therapies. Possible explanations for this effect include stimulation of angiogenesis, improvement of endothelial function, plaque stabilisation, inhibition of coagulation and/or thrombocyte aggregation and inhibition of the inflammatory response associated with atherosclerosis. METHODS: We investigated whether statins exert their effects by inhibition of endothelial activation, inflammation and/or monocyte/macrophage activation by measuring plasma levels of soluble cell adhesion molecules, neopterin and C-reactive protein upon treatment with fluvastatin for a period of 12 months in patients with established atherosclerosis and hypercholesterolaemia. RESULTS: Blood samples were taken at baseline and at 3 and 12 months after starting treatment with fluvastatin 80 mg daily. Upon treatment, a reduction of s-ICAM-1 (956.3+/-123.6 vs. 745.4+/-127.4 vs. 674.9+/-70.8 ng/ml, P<0.05) and s-E-selectin (58.6+/-6.7 vs. 47.0+/-6.1 vs. 44.9+/-3.2 ng/ml, P<0.01) was observed. In addition, levels of neopterin decreased, albeit transiently (7.1+/-0.7 vs. 6.0+/-0.5 vs. 6.5+/-0.8 nmol/l, P=0.02), suggesting a reduction in monocyte/macrophage activity. Moreover, we found a decrease in levels of C-reactive protein during follow-up (5.21+/-2.0 vs. 3.18+/-0.7 vs. 1.95+/-0.3 mg/l, P<0.05), compatible with a reduction in inflammatory activity. CONCLUSION: We conclude that statins have a combined beneficial effect on monocyte/macrophage activity, endothelial function and systemic inflammatory activity.

No long-lasting or intermittent mast cell activation in acute coronary syndromes.

BACKGROUND: Unstable coronary syndromes, such as acute myocardial infarction and unstable angina pectoris are mostly due to rupture of an atherosclerotic plaque. Recently mast cells were found to participate actively in the inflammatory process of atherosclerosis by excreting proteolytic and pro-inflammatory substances with the ability to cause plaque instability and rupture. Mast cell activity can be determined by measuring serum levels of tryptase, as has been demonstrated in patients with anaphylaxis and mastcytosis. HYPOTHESIS: Acute coronary events (acute myocardial infarction and unstable angina pectoris) are associated with increased mast cell activity, reflected by elevated serum tryptase levels. METHODS: Serum levels of tryptase were determined in the following three groups of patients: 13 patients with acute myocardial infarction, 10 patients with unstable angina pectoris, and 14 patients without ischaemic cardiovascular disease who were used as controls. Patients with known IgE mediated allergic diseases and/or anti-histaminical drugs were excluded. RESULTS: The groups were comparable for sex, blood pressure, smoking and cholesterol levels. The controls tended to be younger (P=0.05). Levels of tryptase did not differ between patients with acute myocardial infarction (7.9+/-4.6 microg/l), unstable angina pectoris (6.0+/-2.1 microg/l) or controls (6.9+/-4.1 microg/l), nor could a relation with levels of C-reactive protein be demonstrated. CONCLUSION: Serum levels of tryptase are not elevated in patients with acute coronary syndromes. This implies that increased mast cell activity, if any, in unstable coronary syndromes is not reflected systemically. Other, more specific methods will be needed to determine the activity of the mast cell in vivo.