Diagnostic Accuracy of Anticarbamylated Protein Antibodies in Established Rheumatoid Arthritis: A Monocentric Cross-Sectional Study.

OBJECTIVE: To evaluate the diagnostic accuracy of anticarbamylated protein antibodies (CarP), alone and in combination with traditional biomarkers (rheumatoid factor [RF] and anticitrullinated peptide antibodies [ACPA]), in established rheumatoid arthritis (RA). METHODS: A commercially available enzyme-linked immunosorbent assay (ELISA) kit was used to assess CarP concentrations in serum samples of 200 established RA and 206 controls (115 healthy donors and 55 patients with other rheumatic diseases). Main outcome measures were sensitivity, specificity, and area under the curve (AUC; 95% confidence interval [CI]). Difference in accuracy was evaluated by comparison of the respective AUCs. RESULTS: A serum CarP cut-off of 1.47 ng/ml or more differentiated patients with RA from controls with 30% sensitivity, 97.1% specificity, and good accuracy (AUC[95%CI] = 0.83[0.79-0.86], P < 0.0001). However, it showed moderate diagnostic accuracy in seronegative RA patients: sensitivity 17.9%, specificity 96.9%, and AUC (95% CI) = 0.69 (0.63-0.75). The diagnostic accuracy of CarP_ACPA and CarP_RF combinations was significantly superior to that of ACPA and RF alone (P < 0.0001 and P = 0.015, respectively), but not to that of ACPA_RF combination (P = 0.089) In addition, the CarP_ACPA_RF combination did not improve the diagnostic accuracy of the ACPA_RF combination (AUC mean difference [95% CI] = 0.006 [-0.001 to 0.015], P = 0.10). The number of positive autoantibodies (0, 1, 2, or 3) was not significantly associated with moderate-severe disease (Disease Activity Score-28 [DAS-28] > 3.2) in adjusted multiple regression analysis. CONCLUSION: CarP has good diagnostic accuracy in established RA but not in seronegative RA. The addition of CarP to ACPA and RF alone or in combination does not significantly enhance the diagnostic accuracy of ACPA_RF combination.

Humoral immunity response to human endogenous retroviruses K/W differentiates between amyotrophic lateral sclerosis and other neurological diseases.

BACKGROUND AND PURPOSE: Human endogenous retroviruses (HERV) K/W seem to play a role in fostering and exacerbation of some neurological diseases, including amyotrophic lateral sclerosis (ALS). Given these findings, the immunity response against HERV-K and HERV-W envelope surface (env-su) glycoprotein antigens in serum and cerebrospinal fluid (CSF) was investigated for ALS, multiple sclerosis (MS) and Alzheimer's disease patients and in healthy controls. METHODS: Four antigenic peptides derived respectively from HERV-K and HERV-W env-su proteins were studied in 21 definite or probable ALS patients, 26 possible or definite relapsing-remitting MS patients, 18 patients with Alzheimer's disease and 39 healthy controls. An indirect enzyme-linked immunosorbent assay was set up to detect specific antibodies (Abs) against env-su peptides. RESULTS: Amongst the measured levels of Abs against the four different HERV-K peptide fragments, only HERV-K env-su19-37 was significantly elevated in ALS compared to other groups, both in serum and CSF. Instead, amongst the Abs levels directed against the four different HERV-W peptide fragments, only HERV-W env-su93-108 and HERV-W env-su248-262 were significantly elevated, in the serum and CSF of the MS group compared to other groups. In ALS patients, the HERV-K env-su19-37 Abs levels were significantly correlated with clinical measures of disease severity, both in serum and CSF. CONCLUSIONS: Increased circulating levels of Abs directed against the HERV-W env-su93-108 and HERV-W env-su248-262 peptide fragments could serve as possible biomarkers in patients with MS. Similarly, increased circulating levels of Abs directed against the HERV-K env-su19-37 peptide fragment could serve as a possible early novel biomarker in patients with ALS.

Homologous HSV1 and alpha-synuclein peptides stimulate a T cell response in Parkinson's disease.

Environmental factors are implicated in the development of Parkinson's disease (PD). The aim of this study is to investigate the role of cell-mediated immunity upon a specific immune-stimulation with HSV-1 and human alpha-synuclein homologues peptides by using the intracellular cytokine method on Parkinson's patients and healthy controls. The study showed, for the first time, a specific response to TNF-α CD8, CD4 and NK cells after stimulation in PD patients. Our data show a possible role of the immune system in the pathogenesis of Parkinson's disease, and that HSV-1 infections may lead to a progression of the disease.

Mycobacterium avium Subsp. paratuberculosis Induces Specific IgE Production in Japanese People with Allergies.

Background. The prevalence of allergies is steadily increasing worldwide; however, the pathogenesis is still unclear. We hypothesized that Mycobacterium avium subsp. paratuberculosis (MAP) may contribute to allergy development. This organism can be present in dairy foods, it can elicit an immunomodulatory switch from a Th1 to a Th2 response, and it has been speculated that it is linked to several human autoimmune diseases. To determine the contribution, sera from 99 individuals with various atopic disorders and 45 healthy nonallergic controls were assessed for total IgE levels and successively for MAP-specific IgE by ELISA. Results. The mean total serum IgE level in allergic patients was 256 ± 235 IU/mL, and in the healthy controls it was 62 ± 44 IU/mL (AUC = 0.88; p < 0.0001). Among the patient groups, 50 of the 99 subjects had increased IgE total level ≥ 150 IU/mL, while 49 subjects had IgE ≤ 150 IU/mL (mean level: 407 ± 256 IU/mL versus 106 ± 16 IU/mL; p < 0.0001). Additionally, 6 out of 50 subjects (12%) with IgE ≥ 150 IU/mL and none (0%) with IgE ≤ 150 IU/mL were positive for specific MAP IgE (AUC = 0.63; p = 0.03). Conclusion. The present study revealed that MAP has the ability to induce specific IgE and might contribute to the induction of allergic inflammation in genetically predisposed individuals.

Identification of a HERV-K env surface peptide highly recognized in Rheumatoid Arthritis (RA) patients: a cross-sectional case-control study.

Endogenous retroviruses (HERV) are believed to be pathogenic in several autoimmune diseases. Among them, HERV-K viruses have been reported recently to be involved in the pathogenesis of rheumatoid arthritis (RA). In this study we have explored the role of humoral immune response against HERV-K as a potential pathogenetic mechanism in RA. Four different peptides from the extracellular portion of the env protein of HERV-K (env-su19-37 , env-su109-126 , env-su164-186 , env-su209-226 ) were selected by bioinformatic analysis on the basis of their putative immunogenicity. Indirect enzyme-linked immunosorbent assay (ELISA) was then carried out to quantify antibodies against those peptides on blood samples of 70 consecutive RA patients and 71 healthy controls (HC). Differences between the two groups were analysed using the Mann-Whitney test. Potential correlations between RA laboratory, clinical descriptors and immunoglobulin (Ig)G levels were explored by bivariate regression analysis. Serum autoantibodies against one of four tested peptides of HERV-K (env-su19-37 ) were significantly higher in RA than in HC (19 versus 3%, P = 0·0025). Subgroup analysis showed no association between anti-HERV-K peptide humoral response and clinical, serological and clinimetric RA disease descriptors. Serum from RA patients in our series reacted significantly against HERV-K env-su19-37 peptide in comparison to the general population suggesting a role for the HERV-K- related, secondary antigenic-driven immune response in the pathogenesis of RA. Further studies are needed to confirm these results and to explore the role of this HERV-K surface peptide as a potential therapeutic target.

Impact of omega-3 polyunsaturated fatty acids on vascular function and blood pressure: Relevance for cardiovascular outcomes.

AIMS: To overview the effects of omega-3 polyunsaturated fatty acids (PUFA) on blood vessels and blood pressure (BP) and their relevance for cardiovascular prevention. DATA SYNTHESIS: The importance of omega-3 PUFA for the cardiovascular system has come under the spotlight during the last decades. These fatty acids are present in variable amounts in cell membranes of mammal species, and their content affects a variety of cellular functions. Evidence obtained in animal and human studies suggests that omega-3 PUFA affect many steps of the atherosclerotic process. In blood vessels, omega-3 PUFA improve endothelial function; promote vasodilatation through relaxation of smooth muscle cells; exert antioxidant, anti-inflammatory, and antithrombotic actions; delay development of plaques and increase their stability; and decrease wall stiffening. Omega-3 PUFA might affect BP, and studies conducted with ambulatory monitoring suggest that supplementation with these fatty acids decreases the average 24-h BP levels. This effect on BP is related to the pretreatment membrane content of omega-3 PUFA, and this might explain some inconsistencies among intervention trials. Meta-analyses indicate that omega-3 PUFA have a mild but significant BP lowering effect. While encouraging results were initially obtained with the use of omega-3 PUFA supplements in secondary prevention trials, meta-analyses have not confirmed the ability of these fatty acids to decrease the risk of coronary heart and cerebrovascular disease. CONCLUSIONS: Omega-3 PUFA are associated with significant improvement in vascular function and lowering of BP. However, the evidence currently supporting the role of these fatty acids in cardiovascular prevention is weak and needs further investigation.

Combining HLA-DRB1-DQB1 and Mycobacterium Avium Subspecies Paratubercolosis (MAP) antibodies in Sardinian multiple sclerosis patients: associated or independent risk factors?

BACKGROUND: Amongst Sardinians the human leukocyte antigen (HLA) DRB1-DQB1 haplotypes *15:02-*06:01, *16:01-*05:02, *14:01-4-*05:03 are protective for multiple sclerosis (MS), while *13:03-*03:01, *04:05-*03:01, *03:01-*02:01, *15:01-*06:02 and Mycobacterium avium subspecies paratubercolosis (MAP) are predisposing factors. We studied the correlation between MAP and HLA. METHODS: Five hundred thirty-one patients were searched for anti-MAP2694 antibodies, DRB1-DQB1 genotyping was performed. The haplotypes were classified as predisposing, neutral or protective. RESULTS: Anti-MAP2694 were found in 23 % of subjects carrying one protective HLA versus 32 % without (p = 0.04). CONCLUSIONS: We showed a lower frequency of Abs in patients with protective HLA. These haplotypes could have a protective role for both MS and MAP.

Immune response induced by Epstein-Barr virus and Mycobacterium avium subsp. paratuberculosis peptides in current and past infectious mononucleosis: a risk for multiple sclerosis?

BACKGROUND AND PURPOSE: Infectious mononucleosis (IM) caused by Epstein-Barr virus (EBV) has been associated with increased risk of multiple sclerosis (MS). However, the mechanism linking these pathologies is unclear. Different reports indicate the association of EBV, and recently Mycobacterium avium subsp. paratuberculosis (MAP), with MS. For a better understanding of the role of these pathogens, the host response induced by selected antigenic peptides in subjects with a history of IM that significantly increases the risk of MS was investigated. METHODS: Both humoral and cell-mediated response against peptides able to induce a specific immune activation in MS patients deriving from lytic and latent EBV antigens BOLF1(305-320), EBNA1(400-413), from MAP MAP_4027(18-32), MAP_0106c(121-132) and from human proteins IRF5(424-434) and MBP(85-98) in subjects with current and past IM were examined. RESULTS: EBNA1 and MAP_0106c peptides were able to induce a humoral immune response in subjects with a history of clinical IM in an independent manner. Moreover, these peptides were capable of inducing pro-inflammatory cytokine interferon γ by CD4+ and CD8+ T lymphocytes and interleukin 6 and tumour necrosis factor α by CD14+ monocyte cells. CONCLUSION: Our results highlight that EBV and MAP may be involved independently in the same causal process leading to MS in subjects with a history of IM.

Mineralocorticoid Receptor Antagonists and Clinical Outcomes in Primary Aldosteronism: As Good as Surgery?

Primary aldosteronism (PA) is detected with increasing frequency in hypertensive patients and is associated with excess cardiovascular, renal, and metabolic complications. For these reasons, appropriate choices for treatment of this endocrine condition are mandatory. Adrenalectomy is safely performed in PA patients when adrenal venous sampling (AVS) demonstrates lateralized aldosterone secretion. AVS, however, is a complex procedure and even among worldwide referral centers there are substantial discrepancies for interpretation of results. Also, in the majority of PA patients with lateralized aldosterone secretion, hypertension may persist after adrenalectomy requiring use of additional antihypertensive agents. Treatment with mineralocorticoid receptor antagonists (MRAs) is currently recommended for PA patients with bilateral adrenal disease, but these agents effectively decrease blood pressure also in patients with unilateral disease, although concern remains for possible sex-related side effects. Prospective studies indicate that MRAs have therapeutic values comparable to surgery in the long-term, inasmuch as they effectively correct metabolic abnormalities and subclinical organ damage and reduce the risk of cardiovascular events and renal disease progression. This article overviews the clinical outcomes obtained in patients with PA with use of MRAs.

Aldosterone and Left Ventricular Remodeling.

Experimental and clinical evidence obtained in the last 2 decades clearly indicates that protracted exposure to inappropriately elevated aldosterone levels causes significant changes in left ventricular structure and function. Animal studies have demonstrated that aldosterone induces myocardial inflammatory changes and fibrosis in the presence of a high salt diet. Moreover, the effects of aldosterone on the heart have been investigated in different clinical conditions. These conditions include systolic and diastolic heart failure, essential hypertension, and primary aldosteronism that offers a unique clinical model to study the cardiac effects of excess aldosterone because these effects are isolated from those of the renin-angiotensin axis. A relatively clear picture is emerging from these studies with regard to aldosterone-related changes in left ventricular mass and geometry. Conversely, no direct effect of aldosterone on left ventricular diastolic function can be demonstrated and improvement of diastolic function obtained in some studies that have employed mineralocorticoid receptor blockers could result from left ventricular mass reduction. Animal experiments demonstrate that effects of aldosterone on the left ventricle require high salt intake to occur, but the evidence of this contribution of salt to aldosterone-induced cardiac changes in humans remains weaker and needs further research. The article reviews the results of clinical studies addressing the role of aldosterone in regulation of LV remodeling and diastolic function, and focuses on the possible relevance of salt intake.

Carotid artery stiffness is related to hyperinsulinemia and insulin-resistance in middle-aged, non-diabetic hypertensive patients.

BACKGROUND AND AIMS: Glycometabolic abnormalities are frequently found in hypertension and could affect the mechanical properties of carotid arteries. The aim of the study was to investigate the relationship of glucose tolerance, plasma insulin, and insulin sensitivity with carotid distensibility in middle-aged, non-diabetic hypertensive patients free of cardiac and vascular complications. METHOD AND RESULTS: In 93 patients with grade 1-2, uncomplicated, primary hypertension and 68 matched normotensive controls we measured plasma glucose and insulin at fast and after an oral glucose load (OGTT), calculated the HOMA-index as a marker of insulin sensitivity, and assessed distensibility of common carotid arteries by B-mode ultrasonography. Hypertensive patients were hyperinsulinemic and insulin-resistant as compared to normotensive controls. Hypertensive patients with impaired fasting glucose and/or impaired glucose tolerance had comparable distensibility of carotid arteries. Patients with decreased carotid distensibility were older and had higher body mass, fasting and post-OGTT plasma insulin, HOMA-index, and carotid IMT than the remaining patients, but no differences in glycated hemoglobin, and fasting or post-OGTT plasma glucose. Carotid coefficient of distensibility was inversely related and ß-stiffness directly related with fasting and post-OGTT plasma insulin, and HOMA-index. Multivariate logistic regression showed that age and post-OGTT plasma insulin levels predicted carotid artery stiffening independent of body mass index, sex, blood pressure, and plasma glucose levels. CONCLUSIONS: The study demonstrates that decreased insulin sensitivity and the related hyperinsulinemia but not hyperglycemia could contribute to carotid artery stiffening in middle-aged, non-diabetic hypertensive patients free of cardiovascular complications.

Mycobacterium tuberculosis lipoarabinomannan antibodies are associated to rheumatoid arthritis in Sardinian patients.

Little is known regarding the environmental factors at play in igniting rheumatoid arthritis (RA) autoimmunity, although an association between Mycobacteria and RA has been documented. This pilot study focused on examining a possible involvement of Mycobacterium tuberculosis (MTB) and Mycobacterium avium ss. paratuberculosis (MAP) in RA. We measured out the serum levels of IgG antibody against different mycobacterial antigens in Sardinian patients and controls, by an enzyme-linked immunosorbent assay. The population study was composed of 61 RA patients under different therapies and 52 healthy controls, whereas the antigens tested were MTB lipoarabinomannan (ManLAM), MAP heath shock protein 70, and MAP protein tyrosine phosphatase. The frequencies of anti-ManLAM antibodies were higher in the RA group (23 %) compared to the healthy controls (5.7 %) (AUC = 0.7; p < 0.0001), whereas serum reactivity to MAP antigens was not observed. ManLAM antigen was also detected in the plasma of three RA patients (which were anti-ManLAM antibody positive) by Western blot analysis using anti-Man-LAM monoclonal antibodies. The data produced corroborate the hypothesis of a potential association between MTB ManLAM and RA disease, but so far, further studies are necessary to understand its role in RA pathogenesis.

HPV infection in HIV-positive females: the need for cervical cancer screening including HPV-DNA detection despite successful HAART.

PURPOSE: To identify the presence of Human Papilloma Virus (HPV) infection and evaluate the role of Highly Active Antiretroviral Treatment (HAART) in patients with HIV-HPV co-infection. We also compared cytological screening results with HPV-DNA detection to implement screening programs and prevention of invasive cervical cancer (ICC) in HIV-infected females. PATIENTS AND METHODS: We enrolled HIV-infected females presenting for routine clinical evaluation. HPV-DNA of high/intermediate and low-risk types was detected from cervical specimens by nucleic acid hybridization assay with signal-amplification. Patients were divided into two groups according to the presence of HPV co-infection (HPV+) or not (HPV-). RESULTS: We enrolled 57 HIV-infected females. Median age was 40 (IQR 35-44) years, mean CD4 count was 547 ± 227 cells/mm(3), 45 (78.9%) had undetectable HIV-RNA and 52 (91.2%) received HAART. Globally, 19/57 (33.3%) patients were HPV-infected, 16/57 (28.1%) with high/intermediate and 3/57 (5.3%) with low-risk types. Five of the 19 (26.3%) HPV+ patients carried both types. Correlating high-risk genotype HPV-DNA detection with cytology, 17.5% of women with negative cytology, 36.4% with ASCUS (Atypical Squamous Cells of Uncertain Significance) and 83.4% of women with positive cytology (50% of LSIL: low-grade squamous intraepithelial lesion and 100% of HSIL: high grade SIL) were HPV positive. No statistical difference when comparing HPV+ and HPV-patients in age, CD4 cell count, in the proportion of previous intravenous-drug use, previous AIDS and of those receiving HAART with undetectable HIV-RNA was observed. CONCLUSIONS: Cervical cancer screening including HPV-DNA detection should be implemented in HIV infected females across Europe, also when receiving successful HAART, to early identify the HIV patients at risk for ICC to be submitted to more frequent follow up and proper treatment.

Anti Mycobacterium avium subsp. paratuberculosis heat shock protein 70 antibodies in the sera of Sardinian patients with multiple sclerosis.

Heat shock protein (HSP) family members are highly conserved in both prokaryotic and eukaryotic organisms and are known to be immunodominant antigens in many bacteria. In particular, HSP70 has been linked to multiple sclerosis (MS), even if the available data are contradictory. Since different studies conducted on Sardinian subjects, have linked Mycobacterium avium subspecies paratuberculosis (MAP) presence to MS disease, and in view of the fact that human HSP70 is highly homologue to the majority of mycobacterial HSP70 proteins, we searched for anti-MAP HSP70 antibodies in the sera of 268 MS patients and 231 age and sex-matched healthy controls (HCs). All the subjects enrolled in the study were from Sardinia, which is an excellent setting for investigation since it has one of the highest prevalence of MS worldwide. HSP70 detection was carried out using ELISA methodology. A statistically significant difference was found between MS patients and HCs when analyzing the humoral response mounted against MAP HSP70 protein. Our study confirms that mycobacterial HSP70 might be involved in MS, and provides another piece of evidence sustaining the role played by MAP in MS in the context of Sardinian population.

Mycobacterium avium subsp. paratuberculosis and multiple sclerosis in Sardinian patients: epidemiology and clinical features.

BACKGROUND: Mycobacterium avium subspecies paratuberculosis (MAP) is an infectious factor recently found in association with multiple sclerosis (MS) in Sardinia. OBJECTIVES: The objectives of this study were to confirm this association and evaluate its role in clinical features. METHODS: A total of 436 patients and 264 healthy controls (HCs) were included. We examined the blood of each individual for MAPDNA and MAP2694 antibodies using IS900-specific PCR and ELISA, respectively. Differences in MAP presence between the MS group and HCs were evaluated. In MS patients, we considered: gender, age, age at onset, duration of disease, course, EDSS, therapy, relapse/steroids at study time, and oligoclonal bands (OBs). RESULTS: MAPDNA and MAP2694 antibodies were detected in 68 MS and six HCs (p = 1.14 × 10(-11)), and 123 MS and 10 HCs (p = 2.59 × 10(-23)), respectively. OBs were found with reduced frequency in MAP-positive patients (OR = 0.52; p = 0.02). MAP2694 antibodies were detected more in patients receiving MS treatments (OR = 2.26; p = 0.01), and MAPDNA in subjects on steroids (OR = 2.65; p = 0.02). CONCLUSION: Our study confirmed the association of MAP and MS in Sardinia. The low OB frequency in MAP patients suggests a peripheral role as a trigger in autoimmunity. MAP positivity might be influenced by steroids and MS therapy. Studies in other populations are needed to confirm the role of MAP in MS.

Ambulatory arterial stiffness indices and non-alcoholic fatty liver disease in essential hypertension.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) has been found to be strongly related to an increased arterial stiffness in patients with essential hypertension, suggesting a pathophysiologic link between major cardiovascular and metabolic abnormalities associated with liver steatosis and the functional and structural alterations of the arterial wall. The aim of our study was to investigate, in a group of essential hypertensive patients without additional cardiovascular risk factors, the relationship between NAFLD and arterial stiffness. METHODS AND RESULTS: Sixty-eight consecutive patients with essential hypertension underwent 24-h ambulatory blood pressure monitoring (ABPM) and were separated according to the presence (n = 40) or absence (n = 28) of NAFLD at liver ultrasonography. The Ambulatory Arterial Stiffness Index (AASI) and Symmetric AASI (Sym-AASI) were derived from ABPM tracings. Patients with diabetes, obesity, hyperlipidaemia or other risk factors for cardiovascular or liver disease were excluded. Hypertensive patients were compared with a normotensive control group.The two hypertensive groups had comparable age, sex distribution and clinic/ABPM blood pressure levels. In hypertensive patients with NAFLD, body mass index, fasting glucose, insulin, homeostasis model of assessment of insulin resistance index and triglyceride levels were higher, whereas plasma adiponectin was lower than in patients without NAFLD. In hypertensive patients, AASI and Sym-AASI were higher (P < 0.001) than in normotensive subjects, but both indices of vascular stiffness were comparable in patients with and without NAFLD. CONCLUSIONS: In essential hypertensive patients without additional cardiovascular risk factors, NAFLD is associated with insulin resistance but not with increased arterial stiffness.

Zinc transporter (ZnT)8(186-194) is an immunodominant CD8+ T cell epitope in HLA-A2+ type 1 diabetic patients.

AIMS/HYPOTHESIS: Anti-zinc transporter (ZnT)8 autoantibodies are commonly detected in type 1 diabetic patients. We hypothesised that ZnT8 is also recognised by CD8(+) T cells and aimed to identify HLA-A2 (A*02:01)-restricted epitope targets. METHODS: Candidate epitopes were selected by ZnT8 plasmid DNA immunisation of HLA-A2/DQ8 transgenic mice and tested for T cell recognition in peripheral blood mononuclear cells of type 1 diabetic, type 2 diabetic and healthy participants by IFN-γ enzyme-linked immunospot. RESULTS: White HLA-A2(+) adults (83%) and children (60%) with type 1 diabetes displayed ZnT8-reactive CD8(+) T cells that recognised a single ZnT8(186-194) (VAANIVLTV) epitope. This ZnT8(186-194)-reactive fraction accounted for 50% to 53% of total ZnT8-specific CD8(+) T cells. Another sequence, ZnT8(153-161) (VVTGVLVYL), was recognised in 20% and 25% of type 1 diabetic adults and children, respectively. Both epitopes were type 1 diabetes-specific, being marginally recognised by type 2 diabetic and healthy participants (7-12% for ZnT8(186-194), 0% for ZnT8(153-161)). CONCLUSIONS/INTERPRETATION: ZnT8-reactive CD8(+) T cells are predominantly directed against the ZnT8(186-194) epitope and are detected in a majority of type 1 diabetic patients. The exceptional immunodominance of ZnT8(186-194) may point to common environmental triggers precipitating beta cell autoimmunity.

Predictive factors of left ventricular mass changes after treatment of primary aldosteronism.

A variety of abnormalities that occur in patients with primary aldosteronism indicate the capability of elevated aldosterone to induce cardiac damage over that induced by hypertension itself. This study investigates factors that can predict structural and functional changes of the heart after treatment of primary aldosteronism in a post-hoc analysis of 54 patients who were enrolled in a long-term follow-up study that was conducted after either adrenalectomy or treatment with spironolactone. Cardiac ultrasound assessment was performed before treatment and after with an average follow-up of 6.4 years. During follow-up, blood pressure decreased significantly and comparably in both treatment groups. In both treatment groups, left ventricular mass decreased significantly with a trend to improved diastolic filling profile and no changes in ventricular geometry. At univariate analysis, changes in left ventricular mass induced by treatment of primary aldosteronism were directly related with changes in systolic blood pressure and pretreatment plasma aldosterone levels measured both at baseline and after an intravenous saline load. This relationship was maintained when patients treated with adrenalectomy and spironolactone were analyzed separately. Multivariate regression analysis showed that changes in systolic blood pressure and pretreatment aldosterone levels were independent predictors of left ventricular mass changes after treatment. This study strongly supports a role of aldosterone in promoting left ventricular hypertrophy that is independent of the hypertension-related hemodynamic load and suggests a practical way to predict left ventricular mass changes following surgical and medical treatment of primary aldosteronism.

Aldosterone and the heart: from basic research to clinical evidence.

Recent views suggest that long-term exposure to elevated aldosterone concentrations might result in cardiac, vascular, renal, and metabolic sequelae that occur independent of the blood pressure level. Indirect evidence of the untoward effects of aldosterone on the heart has been clearly established in clinical studies that have tested the effects of mineralocorticoid receptor antagonists in the treatment of systolic heart failure. As it has become clear in recent years, the interaction between aldosterone and the heart has to deal with additional actions of the hormone on specific cell types, cellular mechanisms, and molecules that are involved in regulation of tissue responses, leading to hypertrophy, remodeling, and fibrosis. The majority of these effects are mediated by activation of the mineralocorticoid receptors that are expressed in cardiomyocytes and cardiac fibroblasts, and mediate the genomic effects of the hormone. Evidence of interactions between aldosterone and the heart that occur independent of the renal effects of aldosterone, however, is not limited to the context of systolic heart failure and observations obtained in other disease states have led, together with findings of animal studies, to a better understanding of the potential benefits of aldosterone antagonists. In this narrative overview, we highlight the most recent findings that have been obtained in experimental animal models and in clinical conditions that include, in addition to systolic heart failure, primary aldosteronism, essential hypertension, diastolic heart failure, and arrhythmia.