Association of antiphosphatidylserine/prothrombin antibodies with neuropsychiatric systemic lupus erythematosus

Neuropsychiatric manifestations in patients with systemic lupus erythematosus (SLE) are well-recognized symptoms although the pathophysiology of neuropsychiatric SLE (NPSLE) is unclear. Since an association with antiphospholipid antibodies has been reported, we examined the prevalence of antiphosphatidylserine–prothrombin antibodies (anti-PS/PT Abs), lupus anticoagulant (LA), anticardiolipin/β2-glycoprotein I antibodies (anti-β2-GPI Abs), and antiribosomal P protein antibodies (antiribosomal P Abs) in 68 SLE patients and analyzed their associations with neuropsychiatric manifestations. The prevalence of LA was significantly higher in the patients with neuropsychiatric (NP) features than those without NP features (P < 0.02). The levels of anti-PS/PT antibody were also significantly higher in the patients with NP features than those without NP features (P < 0.01). The results indicate that LA positivity and higher levels of anti-PS/PT antibody can be predictive markers for NPSLE.     

Significance of antiprothrombin antibodies in patients with systemic lupus erythematosus: clinical evaluation of the antiprothrombin assay and the antiphosphatidylserine/prothrombin assay, and comparison with other antiphospholipid antibody assays

Antibodies against prothrombin are detected by enzyme immunoassays (EIA) in sera of patients with antiphospholipid syndrome (APS). However, there are two methods for antiprothrombin EIA; one that uses high binding plates (aPT-A), and another that utilizes phosphatidylserine bound plates (aPS/PT). We aimed to evaluate and compare aPT-A and aPS/PT in a clinical setting. We performed EIA for anti-PT, anti-PS/PT, IgG, and IgM anticardiolipin antibodies (aCL), and IgG β2-glycoprotein I-dependent aCL (aβ2GPI/CL) with serum samples from 139 systemic lupus erythematosus (SLE) patients (16 with history of at least one thrombotic episode) and 148 controls. We observed that: (1) although titers of anti-PT and anti-PS/PT were significantly related with each other (P < 0.0001, ρ = 0.548), titer of anti-PT and anti-PS/PT differed greatly in some samples; (2) odds ratio and 95% confidence interval for each assay was 3.556 (1.221–10.355) for aPT-A, 4.591 (1.555–15.560) for aPS/PT, 4.204 (1.250–14.148) for IgG aCL, 1.809 (0.354–9.232) for IgM aCL, and 7.246 (2.391–21.966) for aβ2GPI/CL. We conclude that, while all EIA performed in this study except IgM aCL are of potential value in assessing the risk of thrombosis, aPS/PT and aβ2GPI/CL seemed to be highly valuable in clinical practice, and that autoantibodies detected by anti-PT and anti-PS/PT are not completely identical.     

The presence of anti-phosphatidylserine/prothrombin antibodies as risk factor for both arterial and venous thrombosis in patients with systemic lupus erythematosus

In an effort to clarify the clinical significance of anti-phospholipid antibodies (aPL) detected by enzyme-linked immunosorbent assay (ELISA), we examined the prevalence of anti-cardiolipin antibodies (aCL), anti-beta2-glycoprotein I antibodies (anti-beta2-GPI), antiprothrombin antibodies (anti-PT), and anti-phosphatidylserine/prothrombin antibodies (anti-PS/PT) in 175 patients with systemic lupus erythematosus (SLE) comprising 67 patients with thrombotic complications. The present study showed that positive results of anti-beta2-GPI-ELISA and anti-PS/PT-ELISA could serve as markers of thrombotic complications in patients with SLE, whereas aCL and anti-PT are less reliable as markers of these complications. Furthermore, results of the anti-PS/PT-ELISA correlate best with the occurrence of both arterial and venous thrombosis in patients with SLE.     

Significance of antiprothrombin antibodies in patients with systemic lupus erythematosus: clinical evaluation of the antiprothrombin assay and the antiphosphatidylserine/prothrombin assay,and comparison with other antiphospholipid antibody assays

Abstract

Antibodies against prothrombin are detected by enzyme immunoassays (EIA) in sera of patients with antiphospholipid syndrome (APS). However, there are two methods for antiprothrombin EIA; one that uses high binding plates (aPT-A), and another that utilizes phosphatidylserine bound plates (aPS/PT). We aimed to evaluate and compare aPT-A and aPS/PT in a clinical setting. We performed EIA for anti-PT, anti-PS/PT, IgG, and IgM anticardiolipin antibodies (aCL), and IgG β2-glycoprotein I-dependent aCL (aβ2GPI/CL) with serum samples from 139 systemic lupus erythematosus (SLE) patients (16 with history of at least one thrombotic episode) and 148 controls. We observed that: (1) although titers of anti-PT and anti-PS/PT were significantly related with each other (P < 0.0001, ρ = 0.548), titer of anti-PT and anti-PS/PT differed greatly in some samples; (2) odds ratio and 95% confidence interval for each assay was 3.556 (1.221–10.355) for aPT-A, 4.591 (1.555–15.560) for aPS/PT, 4.204 (1.250–14.148) for IgG aCL, 1.809 (0.354–9.232) for IgM aCL, and 7.246 (2.391–21.966) for aβ2GPI/CL. We conclude that, while all EIA performed in this study except IgM aCL are of potential value in assessing the risk of thrombosis, aPS/PT and aβ2GPI/CL seemed to be highly valuable in clinical practice, and that autoantibodies detected by anti-PT and anti-PS/PT are not completely identical.     

High titer of anti-phosphatidylserine-prothrombin complex antibodies in patients with cutaneous polyarteritis nodosa

OBJECTIVE: To investigate possible correlations between cutaneous polyarteritis nodosa (CPN) and antiphospholipid syndrome-associated antibodies. METHODS: Sixteen patients were referred with CPN features. To investigate the possible role of antiphospholipid antibodies (aPL) in CPN, we measured serum lupus anticoagulant (LAC), IgG and IgM anticardiolipin (aCL) and anti-phosphatidylserine-prothrombin complex (anti-PS/PT) antibodies, and anti-beta(2)-glycoprotein I-dependent cardiolipin (anti-beta(2)GPI/CL) antibodies in the 16 CPN patients, 8 microscopic polyangiitis (MPA) patients, 33 systemic lupus erythematosus (SLE) patients, and 23 healthy controls. LAC was determined according to the Subcommittee on Lupus Anticoagulant/Phospholipid Dependent Antibody guidelines. Anti-PS/PT, aCL, and anti-beta(2)GPI/CL antibodies were measured by enzyme-linked immunosorbent assay. RESULTS: Anti-PS/PT antibodies and/or LAC were detected in all CPN patients, but not in any controls. Serum IgM anti-PS/PT antibody was found in 13 (81.3%) CPN patients. The mean +/- SD serum anti-PS/PT IgM level (19.9 +/- 12.4 units/ml) in CPN patients was significantly elevated compared with SLE patients (5.7 +/- 5.9 units/ml). IgG anti-PS/PT antibody was detected in 5 (31.3%) CPN patients, but not in any controls. The IgG PS/PT antibody titers were similar in CPN patients (12.3 +/- 12.0 units/ml) and SLE patients (13.8 +/- 14.3 units/ml). Three (18.8%) CPN patients were positive for IgG aCL antibody and 2 (12.5%) for IgM aCL antibody. No MPA patients had aPL. CPN skin manifestations included livedo reticularis (14 [87.5%]). Direct immunofluorescence (DIF) revealed C3 within the affected vessels in 7 (77.8%) of 9 CPN patients. CONCLUSION: Our study demonstrated that presence of anti-PS/PT antibodies and/or LAC could serve as markers in CPN patients. CPN could be dependently associated with the presence of anti-PS/PT antibody. Clinicians need to recognize these titers to permit early accurate diagnosis and treatment. We believe that anti-PS/PT antibodies will become widely recognized as a new factor when diagnosing CPN.     

Prevalence of antibodies against oxidised LDL in a cohort of 163 patients with positive anti-phospholipid antibodies and recent thrombosis

We evaluated the prevalence of anti-β₂-glycoprotein I (a-β₂-GPI), anti-phosphatidylserine/prothrombin (a-PP), anti-prothrombin (a-PT), and anti-oxidised low-density lipoprotein (a-oxLDL) antibodies in a cohort of patients with a recent thrombotic event. Among consecutive sera sent to an autoimmune laboratory for routine testing for anti-cardiolipin antibodies (aCL) 473 were found positive for IgG and/or IgM aCL. The referring physicians were requested for clinical information about thrombo-embolic events occurring within 6 months prior to testing. One hundred and sixty-three individuals of which 82 had suffered from cerebro-vascular infarction and 49 from deep venous thromboses or pulmonary emboli were included in the study. Ninety-four sera were positive for IgG aCL and 69 were negative. There was a strong correlation between the presence of IgG aCL and the three other phospholipid-related antibodies: a-β₂-GPI, a-PP, and a-PT. However, IgG a-oxLDL antibodies were almost equally distributed among sera positive and negative for IgG aCL. The presence of antibodies of all subgroups was most pronounced among patients with venous thrombo-embolic disease. In this cohort antibodies to β₂-GPI, PP, PT seem to coexist with aCL. However, a-oxLDL antibodies appear to define a subset of patients, who were older, had more arterial vascular disease, and with no apparent association to the presence of IgG aCL.     

Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion

Objectives. We aimed to test the maternal and fetal outcomeof SLE patients who suffered from recurrent spontaneous abortion(RSA) treated with intravenous immunoglobulin (IVIg) alone duringpregnancy and whether the clinical response to IVIg treatmentis accompanied by modifications of SLE-associated antibodiesand of complement levels. Methods. Twelve SLE-RSA pregnant patients were treated withhigh-dose IVIg and compared with 12 SLE-RSA pregnant patientstreated with prednisolone and NSAIDs. They were evaluated forthe clinical response [lupus activity index-pregnancy (LAI-P)scale] and for ANA, anti-dsDNA, anti Ro/SS-A or La/SS-B, aCL,LAC, C4, C3 before and during pregnancy, and before and aftereach treatment course. Pregnancy outcome in the two groups wasalso evaluated. Results. The groups characteristics were homogeneous at thebeginning of pregnancy. A beneficial clinical response followingIVIg treatment was noted in all patients and mean LAI-P decreasedfrom 0.72 ± 0.43 at the beginning of pregnancy to 0.13± 0.19 at the end of pregnancy (P < 0.0001). Antibodiesand complement levels tended to normalize in most of the patients.These clinical and laboratory improvements were significantwith respect to the control group. Pregnancy was successfullycarried out in 12/12 (100%) SLE-RSA patients with a mean Apgarscore of 8.92. Three patients in the control group got aborted(25%). Conclusions. IVIg has a high response rate among SLE-RSA pregnantpatients and may be considered safe and effective. KEY WORDS: SLE, IVIg, APS, Pregnancy Submitted 3 July 2007; revised version accepted 21 January 2008.     

Associations between gout tophus and polymorphisms 869T/C and -509C/T in transforming growth factor beta1 gene

Objectives. To investigate the associations between gout tophusand polymorphisms 869T/C and –509C/T in TGF-β1 gene. Methods. The polymorphisms 869T/C and –509C/T were determinedin 73 gout patients and 114 healthy controls among male Taiwaneseusing the PCR–restriction fragment length polymorphismmethod. Each patient was matched with 1–2 controls byage within 1–2 yrs. The tophus number was measured fromall the patients’ arms and legs. Results. Neither 869T/C nor –509C/T showed a significantassociation between patients and controls in the proportionsof genotypes, allele frequency or dominant and recessive models.The mean number of tophi for all patients was 1.53 ±3.44, showing a significant difference in distribution amongthe genotypes at polymorphism 869T/C (P = 0.006), but not thosein polymorphism –509C/T (P > 0.05). Those carryinggenotype CC at polymorphism 869T/C have a mean number of tophi0.35 (± 1.11), which is significantly lower than thosecarrying genotype TT (3.73 ± 4.67; P < 0.05). Thosewith genotype TT at polymorphism 869T/C also had 11.06 timesthe likelihood of having at least one tophus compared with thegenotype CC after adjustment of hyperuricaemia (95% CI = 1.84,66.36; P = 0.009). However, except for the tophus number, thesetwo polymorphisms did not show any significant association withthe clinical characteristics or biochemical markers. Conclusions. The polymorphism 869T/C in TGF-β1 gene hasa significant association with the occurrence of tophus in goutpatients. KEY WORDS: Tophus, TGF, Gout, Polymorphism Submitted 20 October 2007; revised version accepted 23 January 2008.     

The value of IgA antiphospholipid testing for diagnosis of antiphospholipid (Hughes) syndrome in systemic lupus erythematosus.

OBJECTIVE: It is recognized that the presence of IgG and IgM anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC) is associated with thrombosis in patients with antiphospholipid syndrome (APS). Some reports have shown that testing for IgA anticardiolipin and anti-beta2-glycoprotein antibodies (anti-beta2-GPI) provides extra diagnostic help in patients with APS, while other authors could not support this data. We designed this cross sectional study to determine the prevalence of IgA aCL, anti-beta2-GPI, and antiprothrombin antibodies and to study their clinical significance in a large cohort of patients with systemic lupus erythematosus (SLE). METHODS: This study comprised 134 SLE patients (126 women; median age 37.5 yrs, range 16-72). The median duration of the disease was 9 years, range 0.1-38. Of these, 55 (41%) had a history of thrombotic events: 22 (40%) presented an arterial event, 22 (40%) a venous event, and 11 (20%) both arterial and venous events. Of 49 women who had been pregnant, 18 (37%) gave a history of recurrent pregnancy loss. Thrombocytopenia was present in 14/127 patients (11%). Forty patients (30%) were diagnosed as APS secondary to SLE, 23 (17%) had IgG/M aCL and/or LAC without clinical features of APS, and 71 (53%) were SLE patients who were repeatedly negative for IgG/M aCL or LAC. IgG, IgM, IgA aCL and anti-beta2-GPI were detected by ELISA. Antibodies directed to prothrombin were detected by 2 ELISA using prothrombin coated on irradiated plates (aPT) and phosphatidylserine/prothrombin complex (aPS/PT) as antigen. RESULTS: IgA aCL were found in 18/134 (13%) patients. Of these, 3 (17%) had IgA aCL as well as IgG/M aCL, and 2 (11%) had IgG/M aCL and anti-beta2-GPI. Of the 18 patients positive for IgA aCL, 8 were also positive for LAC. Of these, one (5%) patient had IgA aCL as well as other isotype of aCL, and 7 (39%) patients had both aCL and anti-beta2-GPI. None of these patients had binding of IgA aPT or aPS/PT. Of the entire group of 18 patients, 5 (28%) had IgA aCL as the sole aPL. Four of 5 of these patients were diagnosed as SLE but had no antiphospholipid (aPL) related clinical manifestations. We found no association between the presence of IgA aCL and clinical manifestations of APS. IgA anti-beta2-GPI were found in 8/134 (6%) patients. Of these, one (12.5%) had IgA anti-beta2-GPI as well as IgG/M anti-beta2-GPI and aCL. Of the 8 patients positive for IgA anti-beta2-GPI, 6 (75%) were also positive for LAC. Of these, one (12.5%) patient presented with IgA anti-beta2-GPI along with other isotypes of aCL, and 4 (50%) patients with aCL and other isotype of anti-beta2-GPI. One patient (12.5%) had IgA anti-beta2-GPI along with LAC only, and one patient (12.5%) who was diagnosed as SLE had no aPL related clinical manifestation but had IgA anti-beta2-GPI as the sole aPL. CONCLUSION: IgA aCL and anti-beta2-GPI are found in SLE, usually along with IgG and/or IgM isotypes. Testing for IgA aCL and anti-beta2-GPI is not a helpful screening test and does not contribute to the recognition of APS in SLE. IgA aPT and aPS/PT are not present in patients with SLE, therefore there is no need to test for these antibodies.     

Chronic atrial fibrillation does not influence the magnitude of sympathetic overactivity in patients with heart failure

Aims In this study we sought to assess the influence of atrialfibrillation (AF) on sympathetic nervous system overactivityin congestive heart failure (CHF) patients. Methods and results We studied 133 consecutive patients withmoderate to severe CHF. Subjects underwent haemodynamic assessment(right heart catheterization) and assessment of total systemicand cardiac sympathetic activity by the norepinephrine (NE)spillover method. The study population included 108 patientsin sinus rhythm (SR) and 25 in AF. While AF patients had a lowercardiac output (CO) (SR vs AF: 4.2±0.1 vs 3.7±0.2l/min,P<0.05), the groups were otherwise matched for systemic bloodpressure (BP), heart rate and filling pressures. In conjunction,total body NE spillover (SR vs AF: 5.8±0.4 vs 4.9±0.5nmol/min,P>0.05) and cardiac NE spillover (SR vs AF: 339±21 vs393±49pmol/min, P>0.05) were not significantly differentbetween the two groups, while the systemic clearance rate forNE was lower in the AF group (SR vs AF: 2.2±0.1 vs 1.6±0.1l/min,P<0.05). Conclusion Congestive heart failure patients in AF do not appearto have heightened sympathetic tone compared to CHF patientsin SR.     

High titer of anti–phosphatidylserine‐prothrombin complex antibodies in patients with cutaneous polyarteritis nodosa

Objective

To investigate possible correlations between cutaneous polyarteritis nodosa (CPN) and antiphospholipid syndrome–associated antibodies.

Methods

Sixteen patients were referred with CPN features. To investigate the possible role of antiphospholipid antibodies (aPL) in CPN, we measured serum lupus anticoagulant (LAC), IgG and IgM anticardiolipin (aCL) and anti–phosphatidylserine‐prothrombin complex (anti‐PS/PT) antibodies, and anti–β₂‐glycoprotein I–dependent cardiolipin (anti‐β₂GPI/CL) antibodies in the 16 CPN patients, 8 microscopic polyangiitis (MPA) patients, 33 systemic lupus erythematosus (SLE) patients, and 23 healthy controls. LAC was determined according to the Subcommittee on Lupus Anticoagulant/Phospholipid Dependent Antibody guidelines. Anti‐PS/PT, aCL, and anti‐β₂GPI/CL antibodies were measured by enzyme‐linked immunosorbent assay.

Results

Anti‐PS/PT antibodies and/or LAC were detected in all CPN patients, but not in any controls. Serum IgM anti‐PS/PT antibody was found in 13 (81.3%) CPN patients. The mean ± SD serum anti‐PS/PT IgM level (19.9 ± 12.4 units/ml) in CPN patients was significantly elevated compared with SLE patients (5.7 ± 5.9 units/ml). IgG anti‐PS/PT antibody was detected in 5 (31.3%) CPN patients, but not in any controls. The IgG PS/PT antibody titers were similar in CPN patients (12.3 ± 12.0 units/ml) and SLE patients (13.8 ± 14.3 units/ml). Three (18.8%) CPN patients were positive for IgG aCL antibody and 2 (12.5%) for IgM aCL antibody. No MPA patients had aPL. CPN skin manifestations included livedo reticularis (14 [87.5%]). Direct immunofluorescence (DIF) revealed C3 within the affected vessels in 7 (77.8%) of 9 CPN patients.

Conclusion

Our study demonstrated that presence of anti‐PS/PT antibodies and/or LAC could serve as markers in CPN patients. CPN could be dependently associated with the presence of anti‐PS/PT antibody. Clinicians need to recognize these titers to permit early accurate diagnosis and treatment. We believe that anti‐PS/PT antibodies will become widely recognized as a new factor when diagnosing CPN.     

IgG and IgM isotypes of anti-cardiolipin and anti-β 2-glycoprotein i antibodies reflect different forms of recent thrombo-embolic events

We correlated the distribution and levels of serum anti-cardiolipin (aCL) and anti-₂-glycoprotein-1 antibodies (anti-₂-GPI) of the IgG and IgM isotypes to the clinical spectrum of recent (<6 months) thrombo-embolic events in a cohort of 162 patients. Clinical information was obtained by questionnaires from the referring physicians. Cerebro-vascular infarction (CVI) had taken place in 82 patients, deep venous thrombosis (DVT) in 34, pulmonary embolism (PE) in 14, myocardial infarction (MI) in four, and other thromboses in 28 patients. SLE was the most commonly associated rheumatic disease and accounted for 20 (12%) patients. In 124 (77%) patients no underlying rheumatic disease was identified. Isolated IgG aCL was found in 31 of 48 patients with DVT/PE (65%), but in only 21 of 82 patients with CVI (26%); p<0.0001. IgG anti-₂-GPI were detected in 23 (48%) DVT/PE patients, but in only 13 (16%) CVI patients; p<0.001. The IgG class anti-₂-GPI positive patients had significantly higher levels of IgG aCL (mean 65 units) compared to IgG anti-₂-GPI negative patients (mean 29 units); p<0.0001. In contrast, isolated IgM aCL was found in nine (19%) patients with DVT/PE, but in 46 (56%) CVI patients; p<0.0001. Only ten patients had IgM anti-₂-GPI. The present study shows that the IgG and IgM aCL isotypes seem to define different clinical subsets of patients with thrombo-embolic events with IgG aCL being most prevalent in the group having DVT/PE, IgM aCL being found primarily among CVI patients.     

Hyperleptinaemia in chronic heart failure: Relationships with insulin

Background Leptin, a product of theobgene, is known to increaseenergy expenditure. Given that chronic heart failure is a hypercatabolicstate, we sought to determine whether congestive heart failureinvolves elevations in plasma leptin levels. Since leptin secretionis up-regulated by insulin, we also explored whether in congestiveheart failure, a hyperinsulinaemic state, plasma leptin levelsrelate to plasma insulin levels. Methods Male patients with weight-stable congestive heart failure(n=25, aged 55·5±2·0, mean±SEM,body mass index=27·4±0·8, radionuclideleft ventricular ejection fraction=29·3±3·0%)and 18 controls, matched for age, sex and body fat (dual energyX-ray absorp-tiometry), underwent measurement of fasting plasmaleptin (radioimmunoassay) and insulin levels. Results Compared to controls, patients with congestive heartfailure had higher plasma leptin [8·12 (–1·12,+1·31)vs 4·48 (–0·61,+0·70) ng.ml^–1,mean±asymmetrical SEM,P=0·003], 41·5% higherplasma leptin per percent body fat mass (P<0·001),and higher fasting insulin levels [67·8 (–11·1,+13·3)vs 32·9 (–5·7,+6·9) pmol.l^–1,P=0·010].In the congestive heart failure group, plasma leptin correlatedwith total body fat (r=0·66) and fasting insulin (r=0·68)(bothP<0·001). In multivariate regression analysesof the congestive heart failure group, fasting insulin (standardizedcoefficient=0·41,P=0·011) emerged as a predictorof plasma leptin levels, independent of total body fat (standardizedcoefficient=0·73,P=0·002, R²=0·66,P<0·001). Conclusions Plasma leptin levels are raised in patients withcongestive heart failure. The observation of a positive relationshipbetween plasma leptin and insulin concentrations suggests thatthe insulin–leptin axis may be related to the increasedenergy expenditure observed in patients with congestive heartfailure.     

Both endothelium-dependent and endothelium-independent function is impaired in patients with angina pectoris and normal coronary angiograms

Background The aim of this study was to investigate both endothelium-dependentand endothelium-independent vasodilatation in syndrome X patients.Recently selective impairment of endothelium-dependent functionhas been reported in a small number of syndrome X patients.However, other investigators have reported impaired endothelium-independentfunction. Methods We infused the endothelium-independent vasodilatorspapaverine and glyceryl trinitrate, and endothelium-dependentvasodilator acetyicholine in the left coronary artery of 35patients with syndrome X and in 17 control subjects (atypicalchest pain, negative exercise test, and normal coronary angiograms).Coronary blood flow was measured with an intracoronary Dopplercatheter positioned in the proximal left anterior descendingcoronary artery, and the artery diameter was assessed usingquantitative coronary angiography. Result The mean increase in coronary blood flow in responseto a 12 mg dose of papaverine was significantly less in thesyndrome X group (185±74% vs 411 ± 59%, P0·001).The increase in coronary blood flow in response to acetylcholine,at doses of 1, 3, 10, and 30 µg. min^–1, was alsosignificantly lower in the syndrome X group (12±13 (P>0·05),41 ± 33, 57 ± 68, and 124 ± 87% (P>0·001))as compared to the control group (76 ± 49, 214 ±116, 355 ± 115, and 361 ± 74%). Conclusion These findings demonstrate that both endothelium-dependentand endothelium-independent dilatation of the coronary microvasculatureis impaired in syndrome X.     

The BNP assay does not identify mild left ventricular diastolic dysfunction in asymptomatic diabetic patients

Aims We examined the usefulness of BNP for screening for leftventricular (LV) diastolic dysfunction in a sample of type 2diabetic patients, without structural heart disorder, who havenever presented symptoms or signs of heart failure (HF). Methods and results Seventy-six consecutive patients admittedto the Outpatient Diabetes Clinic were studied. Blood sampleswere analyzed using the Triage BNP fluorescence immunoassay(Biosite Diagnostics, La Jolla, CA, USA). Echocardiography examinationswere performed, with no knowledge of the BNP value. A totalof 39 patients out of 76 (51%) were diagnosed with LV diastolicdysfunction and 23 (30%) with LV hypertrophy. Of the patientswith LV diastolic dysfunction, impaired relaxation and pseudonormalpattern accounted for 97 and 3% of the cases, respectively.BNP levels among subjects with LV diastolic dysfunction (26±22pg/ml,n=39) were not significantly different from patients with normalLV function (24±23pg/ml, n=37pg/ml; Mann–WhitneyU-test, Z=–0.4, n.s.). Conclusions Our data confirm alarmingly high prevalence of LVdiastolic dysfunction in asymptomatic individuals with diabetes.Identification of patients with preclinical diabetic cardiomyopathyshould be a research and clinical priority. BNP levels cannotbe used to detect mild LV diastolic dysfunction in this subsetof patients, which requires Doppler echocardiography to be detected.     

Metabolic syndrome is associated with abnormal left ventricular diastolic function independent of left ventricular mass

Aim To characterize the extent to which metabolic syndrome criteriapredict left ventricular (LV) structure and function. Methods and results Metabolic syndrome criteria were assessedin 607 adults with normal LV function. The cohort was groupedaccording to the number of criteria satisfied: (1) Absent (0criteria, n = 110); (2) Pre-Metabolic Syndrome (1–2 criteria,n = 311); and (3) Metabolic Syndrome (3 criteria, n = 186).Echocardiography was used to assess LV structure (LV mass) andsystolic (LVEF, Vs) and diastolic function, by pulse-wave Doppler(E/A ratio) and tissue Doppler imaging (Ve). LV volumes andLVEF were similar between groups. However, LV mass increasedsignificantly and progressively (LVM/Ht^2.7, in g/m^2.7: 34.9± 6.7, 41.0 ± 9.5, 46.3 ± 11.0, P <0.001); LV relaxation decreased progressively (Ve_global', incm/s: 13.5 ± 2.8, 12.1 ± 3.0, 10.5 ± 2.2,P < 0.001) from Absent to Pre-Metabolic Syndrome to MetabolicSyndrome groups, respectively. Multiple variable analyses showedthat diastolic blood pressure, waist circumference, and triglyceridelevels were independent predictors of Ve after adjustment forLV mass. Conclusion Patients with metabolic syndrome have LV diastolicdysfunction independent of LV mass. These functional abnormalitiesmay partially explain the increased cardiovascular morbidityand mortality associated with metabolic syndrome.     

Haematocrit, type 2 diabetes, and endothelium-dependent vasodilatation of resistance vessels

Aims In conditions such as type 2 diabetes, hypertension, andsmoking, in which haematocrit (Hct) tends to be higher, endothelialfunction is impaired. In vitro, haemoglobin neutralizes nitricoxide very effectively. Whether red blood cells participatein the regulation of endothelial function in vivo has not beenestablished. Methods and results Clinical and haematological parameters andforearm blood flow responses to acetylcholine (ACh) and sodiumnitroprusside (SNP) were measured in 84 type 2 diabetic patientsand 19 control subjects. Diabetics showed blunted dose–responsecurves to both SNP and ACh. In diabetics, across quartiles ofHct, ACh blood flow responses were progressively lower (881±96,652±81, 513±54, 307±46%, P</0.0001),and maximal SNP responses tended to be lower (706±72,578±61, 607±69, 499±53%, P=0.06) despitesimilar age, body mass index, glycated haemoglobin (HbA_1c),blood pressure, serum total and HDL-cholesterol levels, indicesof insulin sensitivity, and markers of inflammation. After normalizingthe ACh response for the SNP response (ACh/SNP ratio), a progressivereduction across Hct quartiles (1.54±0.23, 1.22±0.15,0.93±0.09, 0.66±0.09, P<0.0001) was still observed,with patients in the III and IV quartile showing a blunted responsecompared with controls (1.44±0.08). Both in diabeticsand controls, the ACh/SNP ratio was reciprocally related toHct (r=–0.46 and r=–0.66, respectively, P<0.002for both). This association was independent of comorbidities,gender, metabolic control, plasma lipids, or concomitant treatments,was stronger in the subjects with preserved endothelium-dependentdilatation, and was unchanged when haemoglobin replaced Hct. Conclusion Both in diabetics and non-diabetics, haematocritis inversely related to small vessel endothelium-dependent dilatation.Thus, in addition to blood rheology, a direct negative effecton nitric oxide availability might explain the link betweenhigh Hct and cardiovascular disease.     

Anti-atherogenic and anti-inflammatory properties of high-density lipoprotein are affected by specific antibodies in systemic lupus erythematosus

Objective. To determine whether antibodies against high-densitylipoprotein (aHDL) and apolipoprotein A-I (aApo A-I) interferewith the anti-atherogenic functions of high-density lipoprotein(HDL) and relate to disease activity and damage in SLE. Methods. Seventy-seven SLE patients were compared with an age-and sex-frequency matched control group. Immunoglobulin G (IgG)aHDL, IgG aApoA-I, soluble vascular cell and intracellular celladhesion molecules (VCAM-1 and ICAM-1, respectively) were measuredby ELISA, paraoxonase (PON) activity by spectrophotometry, nitricoxide (NOx) metabolites by the Griess reaction, and total anti-oxidantcapacity (TAC) by chemiluminescence. Results. Compared with controls, SLE patients showed highertitres of IgG aHDL (P < 0.0001) and IgG aApo A-I (P <0.0001), lower PON activity (P < 0.0001), increased NOx (P< 0.0001), VCAM-1 (P < 0.0001) and ICAM-1 (P = 0.0008)and lower TAC (P = 0.0006). Titres of IgG aHDL positively correlatedwith IgG aApo A-I (r = 0.64, P < 0.0001), NOx (r = 0.32,P = 0.007), inversely correlated with PON activity (r = –0.34,P = 0.002) and TAC (r = –0.43, P = 0.0004) and were independentlyassociated with ICAM-1 (t = 3.509, P = 0.001). IgG aApo A-Ititres correlated positively with NO (r = 0.37, P = 0.007),inversely with PON activity (r = –0.31, P = 0.006), TAC(r = –0.47, P < 0.0001) and were independently associatedwith HDL (t = –2.747, P = 0.008) and VCAM-1 (t = 3.311,P = 0.002), the latter alongside NOx (T = 2.271, P = 0.02).Elevated titres of IgG aHDL and IgG aApo A-I and reduced PONactivity related to increased disease score (BILAG) and damageindex (SLICC/ACR DI). Conclusion. In SLE, IgG aHDL and aApo A-I associate with diseaseactivity and damage and interfere with the anti-oxidant andanti-inflammatory functions of HDL favouring atherogenesis. KEY WORDS: Systemic lupus, Antibodies against high-density lipoprotein, Antibodies against Apolipoprotein A-I, Paraoxonase, Nitric oxide, Endothelial dysfunction Submitted 6 March 2008; revised version accepted 15 September 2008.     

Changes in platelet size and count in unstable angina compared to stable angina or non-cardiac chest pain

Aims An increase in platelet aggregability is associated withunstable angina and myocardial infarction. Platelet size andactivity correlate and mean platelet volume was found to beincreased before acute myocardial infarction. We measured themean platelet volume and platelet count in patients with stableangina, unstable angina and non-cardiac chest pain. Methods and results We studied 981 patients (734 men; 247 women)defined clinically as stable angina (n=688), unstable angina(n=108) and unstable angina requiring immediate angioplasty(n=52). After coronary angiography the patients were subdividedinto single (n=269), double (n=304) and triple-vessel disease(n=311) and the control group of non-cardiac chest pain (n=97).There was no significant difference in platelet count betweenthe control group and patients with 1, 2, or 3-vessel disease.However, the platelet size in patients with coronary arterydisease was significantly larger (single: 8·7±1·19fl;double: 8·7±1·12fl; triple-vessel disease:8·8±1·18fl) than the control group (8·2±0·95fl)(P<0·01). Patients with stable angina similarly hadno significant difference in platelet count compared to thecontrol group but did have a significantly increased mean plateletvolume (8·7±1·13;P<0·01). Incontrast, patients with unstable angina had a decreased plateletcount (245±56x10/l) compared to either stable angina(262±62x10/l;P<0·05) or the control group (261±58x10/l;P<0·05);furthermore, the mean platelet volume (9·4±1·23fl)was significantly greater than for stable angina (P<0·01).Patients with unstable angina requiring immediate PTCA had aneven lower platelet count (231±55x10/l) and higher meanplatelet volume (10·4±1·03fl) (P<0·01)than the rest of the population with unstable angina. Conclusions In stable angina the platelet count is unchangedcompared to patients with normal coronary arteries but the plateletsize is increased. However, in unstable angina there is a decreasein platelet count and an even larger increase in platelet size.We interpret this as meaning that unstable angina might be associatedor preceded by an increase in platelet destruction rate thatis not completely compensated for by an increase in plateletproduction rate. The large, more reactive platelets might becausally related to an ongoing coronary artery obstruction inunstable angina.     

Evaluation of Cerebrospinal Fluid for the Presence of Anticardiolipin Antibodies (aCL) in NP-SLE Patients

Many neurological or psychiatric manifestations of SLE (NP-SLE) are related to the presence of anticardiolipin antibodies (aCL) in the patient’s sera. The aim of this study was to evaluate the presence of aCL in cerebrospinal fluid (CSF) in SLE patients with NP features. Fifteen SLE patients were studied, all with NP features. CSF was evaluated for intrathecal IgG synthesis, oligoclonal IgG, and blood–brain barrier impairment. Sera and CSF were tested by ELISA for the presence of aCL-IgG and aCL-IgM with and without β₂ glycoprotein (β₂ GPI) cofactor. CSF and sera of 50 low back pain patients served as controls. Six patients were aCL(+) and nine aCL(–). In all patients the general CSF examination was normal. In all patients the value of indices of intrathecal IgG synthesis were normal but oligoclonal protein was present in the CSF of three patients. In none of the patients was the blood–brain barrier impaired. Neither aCL-IgG nor aCL-IgM was detected in the CSF of any NP-SLE patient. Mean levels of aCL in patients without cofactor β₂ GPI and with cofactor were as follows: for IgG class 0.005 and 0.057 OD (negative); for IgM class 0.004 and 0.024 OD (negative). We could not detect aCL in the CSF of patients with NP-SLE, even if sera were positive for aCL. Received: 6 July 1999 / Accepted: 18 January 2000