Antiphospholipid Antibodies and Heart Valve Disease in Systemic Lupus Erythematosus.

Evaluation of antiphospholipid antibodies (aPL) and correlation with heart valve abnormalities among patients with systemic lupus erythematosus (SLE). Nested case-control study was conducted with 70 patients with SLE selected from a longitudinal database based on levels of aPL and presence or absence of valve disease by echocardiogram. Valvular abnormalities observed were regurgitation (52), other (14), artificial valves (4), stenosis (2), thickening (2) and no Libman-Sacks endocarditis (0). The mitral valve was the most commonly affected (30 abnormalities), followed by the tricuspid (20 abnormalities). Multivariate logistic regression for those with and without an aPL value ≥20 units/mL, adjusted for disease duration and age, showed significant differences for any valve abnormality (odds ratio [OR] = 3.1; 95% CI: 1.0-8.9; P = 0.041) and individually for the tricuspid valve (OR = 3.3; 95% CI: 1.0-11.1; P = 0.052) but not for the mitral valve (OR = 2.1; 95% CI: 0.68-6.45; P = 0.195). Levels of aPL ≥20 units/mL showed no association with aortic (P = 0.253), pulmonic (P = 1.000), tricuspid (P = 0.127), or mitral (P = 0.249) valve abnormalities. Levels of aPL correlate with certain valvular abnormalities among patients with SLE.

The association between systemic lupus erythematosus and valvular heart disease: an extensive data analysis.

BACKGROUND: Association between antiphospholipid syndrome in systemic lupus erythematosus (SLE) and valvular heart disease (VHD) is well reported, but relatively few studies have been carried out to establish the linkage between VHD and SLE itself. We aimed to investigate link between VHD and SLE and to evaluate the association of diverse factors with VHD among these patients in a large-scale population-based study. MATERIALS AND METHODS: We used the databases of the largest state-mandated health service organization in Israel. All SLE patients were included (n = 5018) as well as their age and sex-matched controls (n = 25 090), creating a cross-sectional population-based study. Medical records of all subjects were analysed for documented VHD and the presence of antiphospholipid antibodies (aPLs). A logistic regression model was carried out to evaluate the diverse factors including SLE and aPLs as independent risk factors for VHD. RESULTS: Valvular heart disease were found to be more frequent among SLE group when compared to controls (aortic stenosis, 1·08% vs. 0·35% respectively, P < 0·001; aortic insufficiency, 1·32% vs. 0·29% respectively, P < 0·001; mitral stenosis, 0·74% vs. 0·21% respectively, P < 0·001; mitral insufficiency, 1·91% vs. 0·39% respectively, P < 0·001). Male sex, hypertension, aPLs and SLE were found to be significant independent risk factors for VHD. CONCLUSION: All VHD are more prevalent among SLE patients when compared to controls. SLE and aPLs are independent risk factor for VHD (OR of 2·46 and 1·7, respectively). Physicians must be aware of such significant association, and routine echocardiography should be considered in SLE patients regardless of their aPL status.

A Rare Case of Florid Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis Involving Both Atrioventricular Valves.

Cardiac involvement is rare in antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis but can involve aortic and mitral valves. We present an unusual case of a 65-year-old woman who presented 16 years after an aortic valve replacement with severe mitral regurgitation with ACNA-associated vasculitis. The extensive nature of the pathologic condition, which extended to the tricuspid valve, prevented the replacement of the mitral valve during a surgical procedure. This is a rare case in which florid valvulopathy was observed in association with vasculitis.

Aortic Regurgitation Is Common in Ankylosing Spondylitis: Time for Routine Echocardiography Evaluation?

OBJECTIVES: The aim of this study was to assess the prevalence of aortic regurgitation and any relation to disease activity and specific human leukocyte antigen (HLA)-B27 subtypes in patients with ankylosing spondylitis. METHODS: Transthoracic echocardiography was performed in 187 patients (105 men), mean age (SD) 50 (13) years, and mean disease duration 24 (13) years, and was related to demographic, clinical, radiographic, electrocardiographic, and laboratory data. RESULTS: Aortic regurgitation was found in 34 patients (18%; 95% confidence interval [CI], 12%-24%): mild in 24, moderate in 9, and severe in one. The prevalence was significantly higher than expected from population data. Conduction system abnormalities were documented in 25 patients (13%; 95% CI, 8%-18%), and significantly more likely in the presence of aortic regurgitation (P = .005), which was related to increasing age and longstanding disease, and increased from ~20% in the 50s to 55% in the 70s. It was also independently associated with disease duration, with higher modified Stoke Ankylosing Spondylitis Spine Score, and with a history of anterior uveitis. HLA-B27 was present in similar proportions in the presence vs absence of aortic regurgitation. For comparison, clinically significant coronary artery disease was present in 9 patients (5%; 95% CI, 2%-8%). CONCLUSION: Patients with ankylosing spondylitis frequently have cardiac abnormalities, but they more often consist of disease-related aortic regurgitation or conduction system abnormalities than manifestations of atherosclerotic heart disease. Because aortic regurgitation or conduction abnormalities might cause insidious symptoms not easily interpreted as of cardiac origin, we suggest that both electrocardiography and echocardiography evaluation should be part of the routine management of patients with ankylosing spondylitis.

Autoantibodies to oxidized low-density lipoprotein in patients with aortic regurgitation: association with aortic diameter size.

BACKGROUND: Aortic regurgitation (AR) is a condition associated with volume overload, causing left-ventricular (LV) remodeling, eccentric LV hypertrophy and eventually heart failure. LV remodeling associated with AR is regulated by mechanical stress, neurohormonal activation, inflammation and oxidative stress. Since anti-oxidized low-density lipoprotein (LDL) antibodies (Abs) are a measurable marker of oxidative stress, we hypothesized that an increased level of circulating oxidized LDL (oxLDL) Abs may be related to remodeling of the left ventricle in patients with significant AR. METHODS: We assessed IgG anti-oxLDL Abs in 31 patients with significant AR and compared them to 30 patients with similar risk factors and no valvular disease. Abs to oxLDL were determined by ELISA. RESULTS: The 2 groups had similar clinical characteristics. There was no difference between patients with AR and patients with no AR in the level of anti-oxLDL Abs. However, in all patients and controls, anti-oxLDL Abs correlated positively with the diameter of the ascending aorta (AA; r = 0.32, p = 0.016) and the level of oxLDL Abs was significantly higher in patients with an AA diameter ≥39 mm. On multivariate analysis, only white blood cell count and AA diameter were related to anti-oxLDL Abs in all patients. CONCLUSIONS: We did not find a difference in the level of anti-oxLDL Abs between patients with AR and controls; however, there was a strong correlation between anti-oxLDL Abs and AA diameter.

A case of microscopic polyangiitis associated with aortic valve insufficiency.

Microscopic polyangiitis (MPA) is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by inflammation of small-sized vessels. Although there have been some reports of ANCA-associated vasculitis presenting as aortitis syndrome, MPA rarely involves large-sized vessels such as the aorta. We report an unusual case of MPA combined with severe acute aortic valve insufficiency in a 56-year-old man. He initially presented with prolonged fever, skin rash, and rapidly progressive glomerulonephritis. P-ANCA and anti-myeloperoxidase (MPO) antibodies were positive, but the c-ANCA and anti-proteinase-3 antibodies were negative. Skin biopsy of the lower leg showed necrotizing arteritis. Kidney biopsy was also performed, which revealed diffuse necrotizing and crescentic glomerulonephritis (GN) consistent with pauci-immune ANCA-associated GN. Serial echocardiographic evaluations revealed aortic valve changes and worsening acute aortic valve insufficiency over a two-month period. Despite intensive treatment, our patient developed sudden cardiac arrest and died. Our patient demonstrated typical clinical features and histopathologic findings for systemic vasculitis and had a positive anti-MPO antibody, all of which were consistent with the diagnosis of MPA. Thus, MPA may have been the cause of acute aortic valve insufficiency in this case.

Notch ligand delta-like 4 blockade attenuates atherosclerosis and metabolic disorders.

Atherosclerosis and insulin resistance are major components of the cardiometabolic syndrome, a global health threat associated with a systemic inflammatory state. Notch signaling regulates tissue development and participates in innate and adaptive immunity in adults. The role of Notch signaling in cardiometabolic inflammation, however, remains obscure. We noted that a high-fat, high-cholesterol diet increased expression of the Notch ligand Delta-like 4 (Dll4) in atheromata and fat tissue in LDL-receptor-deficient mice. Blockade of Dll4-Notch signaling using neutralizing anti-Dll4 antibody attenuated the development of atherosclerosis, diminished plaque calcification, improved insulin resistance, and decreased fat accumulation. These changes were accompanied by decreased macrophage accumulation, diminished expression of monocyte chemoattractant protein-1 (MCP-1), and lower levels of nuclear factor-κB (NF-κB) activation. In vitro cell culture experiments revealed that Dll4-mediated Notch signaling increases MCP-1 expression via NF-κB, providing a possible mechanism for in vivo effects. Furthermore, Dll4 skewed macrophages toward a proinflammatory phenotype ("M1"). These results suggest that Dll4-Notch signaling plays a central role in the shared mechanism for the pathogenesis of cardiometabolic disorders.

Treatment of relapsing polychondritis in the era of biological agents.

Relapsing polychondritis (RP) is a rare disorder, often requiring high doses of immunosuppressive therapy to control its potentially life-threatening consequences. The advent of biological agents has added to the armamentarium available to treat RP, but the lack of controlled trials, along with the small numbers of patients and disease heterogeneity means that new therapies are prescribed without the benefits of rigorous clinical research. Thus, information on individual cases is of value in expanding our knowledge of the use of biologic agents in rare conditions. We report on the use of rituximab in a patient who subsequently developed catastrophic aortic incompetence, and we review the literature in relation to the use of this drug in RP.

Unknown ankylosing spondylitis with only cardiac involvement in patient with surgical indication: Call for patient and family members immunological screening.

Aortic regurgitation (AR) and first-degree atrioventricular heart block (FDAVB) are encountered in ankylosing spondylitis (AS). This rheumatological disease also presents in 90% of the cases an immunogenetic marker that is Human Leucocyte Antigen-B27 (HLA-B27). In this report we describe a case of a patient presenting with AR, FDAVB, aneurysm and thinning of the ascending aortic wall, aneurysm of the sinuses of Valsalva and inferior myocardial infarction-like electrocardiographic pattern with unknown cardiac AS and absence of other AS-related systemic manifestations.

Cardiopulmonary bypass for complex cardiac surgery using bivalirudin anticoagulation in a patient with heparin antibodies.

BACKGROUND: The presence of antibodies directed against heparin necessitates the use of an alternative anticoagulant in patients undergoing cardiac surgery. Bivalirudin is a short-acting direct thrombin inhibitor that has been used successfully in routine cardiac surgical cases. Experience in complicated cases requiring extended cardiopulmonary bypass is limited, however. We report the successful use of bivalirudin in a patient who underwent complex cardiac surgery. METHOD: A 42-year-old patient with aortic regurgitation due to endocarditis who had heparin antibodies underwent a Ross procedure for aortic valve replacement using bivalirudin as anticoagulant during cardiopulmonary bypass (CPB). Bivalirudin was given with a bolus of 1 mg/kg and a continuous infusion of 2.5 mg/kg/hours during CPB. Monitoring of bivalirudin was performed using the ecarin clotting time (ECT). RESULTS: After 128 minutes of extracorporeal circulation, the patient was weaned from CPB without problems. After termination of CPB, modified ultrafiltration (MUF) was commenced. Perioperatively, six units of fresh frozen plasma were transfused. The 12-hour postoperative blood loss was 550 mL. The postoperative course was uneventful and the patient was discharged from hospital after 5 days. CONCLUSION: Bivalirudin can be safely used for anticoagulation during CPB even in complex cardiac surgery.

Níveis de citocinas proinflamatórias e seus antagonistas em pacientes com insuficiência aórtica crônica importante / Proninflamatory cytokine and antagonists levels with chronic severe aortic regurgitation

Realizamos estudo transversal com um grupo homogêneo constituído de 90 pacientes com insuficiência aórtica crônica importante, de etiologia reumática. Foram realizadas dosagens plasmáticas de citocinas proninfmamatórias a saber : Fator de necrose tumoral alfa( TNF ), receptores solúveis de TNF tipo I e II ( sTNFRI e sTNFRII ), interleucina 6 ( IL-6 ) e seu receptor solúvel ( IL-6R ), inteleucina 1-beta ( IL-1B ), antagonista do receptor de IL-1 ( IL1-RA ) e endotelina-1. Realizado o polimorfismo –308 do gene do TNF. Observamos níveis aumentados de TNF, IL-6 e sTNFRI em relação a indivíduos normais. Pacientes sintomáticos e assintomáticos tiveram níveis semelhantes de citocinas. O polimorfismo TNF 1/2 foi mais frequente em indivíduos assintomáticos. O aumento dos diâmetros ventriculares correlacionou-se a diminuição dos níveis de sTNFR II. /We made a transversal study in a homogeneous group of rheumatic patients with chronic severe aortic regurgitation. We determined plasma levels of the following proinflamatory cytokines : Tumor necrosis factor-alpha ( TNF ) and its soluble receptors type I and II ( sTNFR I and sTNFR II ), Interleukin-6 ( IL-6 ) and its soluble receptor ( IL-6R ), interleukin-1 beta ( IL-1 beta ), antagonist of the IL-1 receptor ( IL1-RA ) and endothelin-1. The -308 genetic polimorphism os the TNF gene was made. Plasma levels of TNF, IL-6 and sTNFRI were increased in asymptomatic and symptomatic in relation to controls. There were similar levels of cytokines in asymptromatic and symptomatic patients. The polimorphism TNF 1/2 was more frequent in asymptomatic patients. Increase of ventricular diameters was correlated to decrease...

HLA class II associations with rheumatic heart disease among clinically homogeneous patients in children in Latvia.

Genetic control of immune reactions has a major role in the development of rheumatic heart disease (RHD) and differs between patients with rheumatic fever (RF). Some authors think the risk of acquiring RHD is associated with the HLA class II DR and DQ loci, but other views exist, due to the various HLA-typing methods and ways of grouping cases. Our goal was to determine the relations between HLA class II alleles and risk of or protection from RF in patients with relatively homogeneous clinical manifestations. A total of 70 RF patients under the age of 18 years were surveyed in Latvia. HLA genotyping of DRB1*01 to DRB1*18 and DQB1*0201-202, *0301-305, *0401-402, *0501-504, and *0601-608 was performed using polymerase chain reaction sequence-specific primers. Data for a control group of 100 healthy individuals typed for HLA by the same method were available from the databank of the Immunology Institute of Latvia. Of the RF patients, 47 had RHD and 8 had Sydenham's chorea. We concluded that HLA class II DRB1*07-DQB1*0401-2 and DRB1*07-DQB1*0302 could be the risk alleles and HLA class II DRB1*06 and DQB1*0602-8, the protective ones. Patients with mitral valve regurgitation more often had DRB1*07 and DQB1*0401-2, and patients with multivalvular lesions more often had DRB1*07 and DQB1*0302. In Sydenham's chorea patients, the DQB1*0401-2 allele was more frequent. Genotyping control showed a high risk of RF and RHD in patients with DRB1*01-DQB1*0301-DRB1*07-DQB1*0302 and DRB1*15-DQB1*0302-DRB1*07-DQB1*0303.

HLA-B27 positive juvenile arthritis with cardiac involvement preceding sacroiliac joint changes.

While cardiovascular disease develops in up to 50% of adult patients with ankylosing spondylitis, it is very uncommon in its juvenile counterpart. Regarding the early stage of the disease, before onset of sacroiliac joint changes, only two cases with aortic incompetence have been published while reports of mitral valve involvement are not available. A 13 year old boy is described with an HLA-B27 positive asymmetric oligoarthritis and enthesitis, without back pain or radiographic evidence of sacroiliitis. Echocardiography showed an echogenic structure measuring 8 x 11 x 20 mm at the fibrous continuity between the aortic and mitral valves extending through a false tendon into an echogenic thickened posterior papillary muscle, causing a grade II aortic and grade I/II mitral regurgitation. Short term corticosteroid and long term non-steroidal anti-inflammatory drug and disease modifying antirheumatic drug treatments efficiently controlled the symptoms. The cardiac findings remained unchanged during a follow up of 20 months. Careful cardiac evaluation appears to be mandatory even in these young patients.

Acute aortic insufficiency associated with Wegener granulomatosis.

Cardiac valvular involvement associated with Wegener granulomatosis is uncommon. We describe a 17-year-old male adolescent who sought medical attention because of a sore throat, arthralgias, low-grade fever, and fatigue of 3 weeks' duration. A rash was noted on his elbows, hands, and ankles; subsequently, a crusting lesion was noted in his internal nares, and infiltrates were detected on chest radiography. Blood cultures were negative for pathogens. An echocardiogram disclosed mild left ventricular enlargement with grade 2 aortic insufficiency, and Wegener granulomatosis was diagnosed based on an antineutrophil cytoplasmic antibody titer of 1:512. When blood cultures are negative for aortic valve endocarditis, a high index of clinical suspicion and antineutrophil cytoplasmic antibody testing may lead to the diagnosis of acute aortic insufficiency associated with Wegener granulomatosis.

Cardiac valve endothelial cells: relevance in the long-term function of biologic valve prostheses.

OBJECTIVE: For reasons that are still unclear, biologic heart valve prostheses undergo degeneration after implantation. We studied the possible role of the immune system in this process. METHODS: We examined the expression of immunologically relevant molecules by human cardiac valve endothelium in situ and in vitro and studied re-endothelialization of implanted allogeneic and xenogeneic valvular surfaces using explanted bioprostheses and valves obtained from donor hearts at cardiac retransplantation. RESULTS: We demonstrate that human cardiac valve endothelial cells express molecules capable of initiating immune responses and might therefore play a role in the degeneration of viable cardiac valve prostheses. Also, we show evidence of re-endothelialization on the surfaces of xenografts and allografts but not on valves obtained from previously transplanted hearts. CONCLUSION: Inasmuch as valves from previously transplanted hearts seem to be free from degeneration, we conclude that reduction of the immunogenicity of allograft valve prostheses by HLA matching or immunosuppressive treatment might further improve long-term results after allograft valve replacement.

Cardiac involvement in Behçet's disease.

To assess the prevalence and the extent of cardiac involvement in patients with Behçet's disease and to investigate the possible causes that may predispose to this involvement, 30 patients affected by Behçet's disease and 30 normal control subjects were submitted to M-mode, two-dimensional, and Doppler echocardiographic evaluation. Moreover, antinuclear and anticardiolipin autoantibodies were determined in the sera of both patients and control subjects. Finally, HLA-B51 positivity was assessed in the patients and in a historical control group. Mitral valve prolapse was observed in 50% and proximal aorta dilatation in 30% of the patients. There was a significant difference in the rate of these abnormalities in comparison with the control group. Left ventricular function parameters were similar between the two groups. The positivity rate of antinuclear and anticardiolipin autoantibodies was very low (7%), without differences between the groups. HLA-B51 was detected in 82.7% of the patients versus 21.7% in the control group (p < 0.00001). In conclusion, this study demonstrates a high rate of cardiac abnormalities in patients with Behçet's disease.

[Relationship between postoperative prognosis and preoperative immunological factors in aortitis syndrome].

Valve detachment or pseudoaneurysm is a well known complication of surgical treatment for cardiovascular disease due to aortitis syndrome. Although the preoperative management of inflammation by steroid therapy is very important, occasionally, the operation in active phase might be recommended because of progressive heart failure or impending rupture of aortic aneurysm. The pathology of aortitis syndrome is related to immunological abnormality, but there has been little information concerning the immunological factors. In order to evaluate the relationship between immunological factors and surgical results in patients with aortitis syndrome, immunological examination was obtained before surgery in 12 patients. Cardiovascular lesions due to aortitis syndrome were aortic regurgitation in 6 patients, annuloaortic ectasia in 1 patient, aortic arch aneurysm in 1 patient, mitral regurgitation in 2 patients, and coronary artery disease in 2 patients. Hospital mortality including initial operative death was not found. However, 6 late death (50%) occurred at late time with the mean of 23.8 months because of severe complications such as valve detachement or pseudoaneurysm after operation. In a comparison of the preoperative immunological values between survival group and late death group, immunoglobulins such as IgG, IgA, C3 and C4 were significantly higher in late death group. According to the recurrence of inflammation, the patients were divided into three groups. Group A included 3 patients who remains in active phase after initial operation in active phase. Group B included 3 patients who changed to active phase after initial operation in inactive phase. Group C included 6 patients who remains in inactive phase after initial operation. In a comparison among 3 groups, IgG and C4 showed no significant difference. However, IgA and C3 of group C were significantly lowest among three groups. This outcome is considered to be related to existence of latent inflammation. At operation, insertion of rigid prosthesis to fragile position due to latent inflammation may stimulate immunological reactions. We conclude that the preoperative values of the immunological factors, especially IgA and C3, are reliable predictors in postoperative prognosis.

Familial calcification of aorta and calcific aortic valve disease associated with immunologic abnormalities.

We report three patients of the same family with linear calcification of the ascending aorta, severe calcific mixed aortic valve disease associated with increased levels of globulins, lambda-chain gammopathy, an increased T4/T8 lymphocyte ratio, and other immunologic abnormalities. None of the patients had syphilis, atherosclerosis, abnormalities of calcium or phosphorus metabolism, lymphadenopathy, or other systemic diseases. It is postulated that these cases and some previously reported in the literature as idiopathic represent a distinct pathologic entity, familial or sporadic, in which localized vascular and valvular calcific disease is associated with an underlying immunologic disorder or autoimmune process.

Prevalence of anticardiolipin antibody in isolated mitral or aortic regurgitation, or both, and possible relation to cerebral ischemic events.

Anticardiolipin antibodies (acLa) are associated with a thrombotic tendency (often involving cerebral ischemic events), are frequently present with systemic lupus erythematosus and have been found together with cardiac valve abnormalities. Previous studies evaluated patients characterized by the presence of acLa or lupus, precluding assessment of the frequency of acLa in those with valvular disease. This study aims to establish the prevalence of acLa in patients with valve disease in the absence of lupus and, furthermore, to determine the influence of acLa on the risk of cerebral events in valve disease. Eighty-seven consecutive patients with mitral or aortic regurgitation, or both, prospectively underwent enzyme-linked immunosorbent assay testing for immunoglobulin G (IgG) and M acLa, as did 24 normal subjects. AcLa values greater than or equal to 3 SD above the normal mean were considered "positive." Prior cerebral events were defined retrospectively. Of 87 patients with valvular disease, 26 had positive IgG acLa levels compared with 0 of 24 normal subjects (p less than 0.01). AcLa values did not vary with valve disease etiology. Focal cerebral events had occurred in 8 patients and were embolic or probably embolic in 7, including 7 of 26 IgG acLa-positive and 1 of 60 IgG acLa-negative patients (p less than 0.001). In the absence of lupus, IgG acLa is highly prevalent among patients with aortic or mitral regurgitation, or both; this association may indicate a relatively high risk for cerebral emboli.