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Background: Worldwide, there are millions of chronic proton pump inhibitor (PPI) users, often without a compelling indication. Evidence indicates that PPI treatment can increase mortality, in part, due to a higher risk of heart rate–corrected QT interval-related malignant arrhythmias. Drug-induced hypomagnesemia is currently believed to be the only underlying mechanism, and, therefore, serum magnesium monitoring is recommended to minimize arrhythmic risk. However, recent data suggest that PPIs might also directly interfere with cardiac electrophysiology. To test this hypothesis, a translational study was performed using a combination of electrophysiology, molecular dynamics simulations, and population data. Methods: First, the effect of different PPIs on the human ether-a-go-go-related gene potassium channel (hERG) current was evaluated in human embryonic kidney 293 cells expressing hERG. Then, free-energy calculations were performed to investigate the binding of these drugs to hERG. Finally, the impact of PPIs on the risk of heart rate–corrected QT interval prolongation was assessed in a retrospective observational cohort of 3867 US veterans, including 1289 PPI-treated subjects. Results: Clinically relevant concentrations of different PPIs induced a significant inhibition of the hERG current in vitro, pantoprazole and lansoprazole being the most potent compounds. Atomic simulations demonstrated that such a blocking class effect is likely due to direct PPIs binding to hERG channel pore cavity. Accordingly, in a US veterans cohort, PPI treatment was independently associated with an ≈20% to 40% increased risk of heart rate–corrected QT interval prolongation, also regardless of hypomagnesemia. Moreover, a synergistic interaction between PPIs and most of the traditional QT-prolonging risk factors was demonstrated. Conclusions: Altogether, this study provides, for the first time, strong evidence that PPIs can per se promote heart rate–corrected QT interval prolongation, by directly inhibiting hERG function. A careful evaluation of the benefit/risk ratio is recommended whenever PPIs are administered in subjects with other QT-prolonging risk factors, even in the absence of hypomagnesemia.

Background Anti‐Sjögren's syndrome‐related antigen A‐antibodies (anti‐Ro/SSA‐antibodies) are responsible for a novel form of acquired long‐QT syndrome, owing to autoimmune‐mediated inhibition of cardiac human ether‐a‐go‐go‐related gene‐potassium channels. However, current evidence derives only from basic mechanistic studies and relatively small sample‐size clinical investigations. Hence, the aim of our study is to estimate the risk of QTc prolongation associated with the presence of anti‐Ro/SSA‐antibodies in a large population of unselected subjects. Methods and Results This is a retrospective observational cohort study using the Veterans Affairs Informatics and Computing Infrastructure. Participants were veterans who were tested for anti‐Ro/SSA status and had an ECG. Descriptive statistics and univariate and multivariate logistic regression analyses were performed to identify risk factors for heart rate‐corrected QT interval (QTc) prolongation. The study population consisted of 7339 subjects (61.4±12.2 years), 612 of whom were anti‐Ro/SSA‐positive (8.3%). Subjects who were anti‐Ro/SSA‐positive showed an increased prevalence of QTc prolongation, in the presence of other concomitant risk factors (crude odds ratios [OR], 1.67 [1.26–2.21] for QTc >470/480 ms; 2.32 [1.54–3.49] for QTc >490 ms; 2.77 [1.66–4.60] for QTc >500 ms), independent of a connective tissue disease history. Adjustments for age, sex, electrolytes, cardiovascular risk factors/diseases, and medications gradually attenuated QTc prolongation estimates, particularly when QT‐prolonging drugs were added to the model. Nevertheless, stepwise‐fully adjusted OR for the higher cutoffs remained significantly increased in anti‐Ro/SSA‐positive subjects, particularly for QTc >500 ms (2.27 [1.34–3.87]). Conclusions Anti‐Ro/SSA‐antibody positivity was independently associated with an increased risk of marked QTc prolongation in a large cohort of US veterans. Our data suggest that within the general population individuals who are anti‐Ro/SSA‐positive may represent a subgroup of patients particularly predisposed to ventricular arrhythmias/sudden cardiac death.

Background Patients with gout have arterial dysfunction and systemic inflammation, even during intercritical episodes, which may be markers of future adverse cardiovascular outcomes. We conducted a prospective observational study to assess whether initiating guideline-concordant gout therapy with colchicine and a urate-lowering xanthine oxidase inhibitor (XOI) improves arterial function and reduces inflammation. Methods Thirty-eight untreated gout patients meeting American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria for gout and ACR guidelines for initiating urate-lowering therapy (ULT) received colchicine (0.6 mg twice daily, or once daily for tolerance) and an XOI (allopurinol or febuxostat) titrated to ACR guideline-defined serum urate (sU) target. Treatment was begun during intercritical periods. The initiation of colchicine and XOI was staggered to permit assessment of a potential independent effect of colchicine. Brachial artery flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD) assessed endothelium-dependent and endothelium-independent (smooth muscle) arterial responsiveness, respectively. High-sensitivity C-reactive protein (hsCRP), IL-1β, IL-6, myeloperoxidase (MPO) concentrations, and erythrocyte sedimentation rate (ESR) assessed systemic inflammation. Results Four weeks after achieving target sU concentration on colchicine plus an XOI, FMD was significantly improved (58% increase, p = 0.03). hsCRP, ESR, IL-1β, and IL-6 also all significantly improved (30%, 27%, 19.5%, and 18.8% decrease respectively; all p ≤ 0.03). Prior to addition of XOI, treatment with colchicine alone resulted in smaller numerical improvements in FMD, hsCRP, and ESR (20.7%, 8.9%, 13% reductions, respectively; all non-significant), but not IL-1β or IL-6. MPO and NMD did not change with therapy. We observed a moderate inverse correlation between hsCRP concentration and FMD responsiveness (R = − 0.41, p = 0.01). Subgroup analyses demonstrated improvement in FMD after achieving target sU concentration in patients without but not with established cardiovascular risk factors and comorbidities, particularly hypertension and hyperlipidemia. Conclusions Initiating guideline-concordant gout treatment reduces intercritical systemic inflammation and improves endothelial-dependent arterial function, particularly in patients without established cardiovascular comorbidities.

Cytopenias in systemic lupus erythematosus (SLE) require clinical and laboratory workup and bone marrow (BM) examination to determine the cause and for appropriate patient management. Common causes include an increase in SLE activity, immune-mediated hemolysis, iron deficiency, antiphospholipid antibody syndrome, infection, or the effect of medications. We retrospectively evaluated the clinical and laboratory findings of patients with SLE and cytopenias who had undergone BM studies to determine the indicators of malignancy. We retrospectively reviewed medical records of patients with SLE who presented with cytopenias for their disease course, medications, laboratory parameters and documented the spectrum of morphological changes in BM including CD34 expression. Twenty patients with SLE had undergone BM biopsy for evaluation of cytopenias. 14/20 (70%) of the patients had reactive BM, and the rest had hematologic malignancies involving the BM. Of these 14 patients, 8 had hypocellular marrow with loss of precursor cells (low CD34), 4 had left shift in myeloid lineage, 3 had serous atrophy, and 1had multilineage dysplasia. The 6 patients with hematologic malignancies included 2 with diffuse large B cell lymphoma, and one each of natural killer/T cell lymphoma, post-transplant lymphoproliferative disorder, Hodgkin lymphoma, and myelodysplastic syndrome evolving to acute myelogenous leukemia. The presence of autoantibodies, SLE activity, and lupus nephritis were comparable in patients with and without neoplasia. However, the duration of the use of multiple immunosuppressants, years since renal transplant (22 vs 10), multiple transplants, and the presence of other autoimmune diseases were greater in those with neoplasia. Two of the 14 patients with non-neoplastic BM and 1 with the neoplastic BM had nonhematological malignancy. Clinical and laboratory findings, the number of transplants, and the use of immunosuppressive agents can guide physicians to identify patients with a higher risk of developing hematologic malignancy. BM findings of cytopenia in SLE are often due to increased disease activity causing global cell death and dysmaturation. SLE patients presenting with cytopenias, with a history of long-term exposure to immunosuppressive drugs, should be regularly screened for hematologic and nonhematologic malignancies.

Ca entry through atrial L-type Calcium channels (α1C and α1D) play an important role in muscular contraction, regulation of gene expression, and release of hormones including atrial natriuretic peptide (ANP), and brain natriuretic peptide (BNP). α1D Ca channel is exclusively expressed in atria, and has been shown to play a key role in the pathogenesis of atrial fibrillation. Recent data have shown that the small conductance calcium-activated potassium channel, SK4 is also atrial specific and also contributes prominently to the secretion of ANP and BNP. However, its functional role in the heart is still poorly understood. Here we used α1D gene heterozygous (α1D+/-) mice and HL-1 cells to determine the functional contribution of SK4 channels to α1D-dependent regulation of ANP and BNP secretion in response to endothelin (ET), and/or mechanical stretch. Immunoprecipitation with α1D specific antibody and western blotting with SK4 specific antibody on the immuno-precipitated protein complex showed a band at 50 KDa confirming the presence of SK4 in the complex and provided evidence of interaction between SK4 and α1D channels. Using RT-PCR, we observed a 2.9 fold decrease in expression of Cacna1d (gene encoding α1D) mRNA in atria from α1D+/-mice. The decrease in α1D mRNA corresponded with a 4.2 fold decrease in Kcnn4 (gene encoding SK4) mRNA from α1D+/- mice. These changes were paralleled with a 77% decrease in BNP serum levels from α1D+/- mice. When α1D was knocked down in HL-1cardiomyocytes using CRISPR/Cas9 technology, a 97% decrease in secreted BNP was observed even in cells subjected to stretch and endothelin. In conclusion, our data are first to show that α1D Ca and SK4 channels are coupled in the atria, and that deletion of α1D leads to decreased SK4 mRNA and BNP secretion providing evidence for a novel role of α1D in atrial endocrine function. Elucidating the regulatory factors that underlie the secretory function of atria will identify novel therapeutic targets for treatment and prevention of cardiac arrhythmias such as atrial fibrillation.

Objective The Rheumatology Research Foundation's Clinician Scholar Educator (CSE) award is a 3-year career development award supporting medical education research while providing opportunities for mentorship and collaboration. Our objective was to document the individual and institutional impact of the award since its inception, as well as its promise to strengthen the subspecialty of rheumatology. Methods All 60 CSE Award recipients were surveyed periodically. Fifty-six of those 60 awardees (90%) responded to requests for survey information that included post-award activities, promotions, and further funding. Data were also collected from yearly written progress reports for each grant. Results Of the total CSE recipients to date, 48 of 60 (80%) are adult rheumatologists, 11 of 60 (18%) are pediatric rheumatologists, and 1 is an adult and pediatric rheumatologist. Two-thirds of survey respondents spend up to 30% of their total time in educational activities, and one-third spend greater than 30%. Thirty-one of the 60 CSE recipients (52%) have published a total of 86 medical education papers. Twenty-six of 52 (50%) had received an academic promotion following the award. Eleven awardees earned advanced degrees. Conclusion We describe the creation and evolution of a grant program from a medical subspecialty society foundation and the impact on producing education research, individual identity formation, and ongoing support for educators. This community of rheumatology scholar educators now serves as an important resource at the national level for the American College of Rheumatology and its membership. We believe that this grant may serve as a model for other medical societies that want to promote education scholarship and leadership within their specialties.

The NYC Rheumatology Objective Structured Clinical Examination (NYC-ROSCE) is held annually to assess fellow competencies. We recently redesigned our OSCE to better assess subspecialty trainee communication skills and professionalism by developing scenarios in which the patients encountered were psychosocially or medically complex. The objective of this study is to identify which types of verbal and non-verbal skills are most important in the perception of professionalism in the patient-physician interaction. The 2012-2013 NYC-ROSCEs included a total of 53 fellows: 55 MD evaluators from 7 NYC rheumatology training programs (Hospital for Special Surgery-Weill Cornell (HSS), SUNY/Downstate, NYU, Einstein, Columbia, Mount Sinai, and North Shore/Long Island Jewish (NSLIJ)), and 55 professional actors/standardized patients participated in 5 stations. Quantitative fellow performance assessments were made on the following: maintaining composure; partnering with the patient; honesty; professionalism; empathy; and accountability. Free-text comments were solicited regarding specific strengths and weaknesses. A total of 53/53 eligible (100 %) fellows were evaluated. MD evaluators rated fellows lower for professionalism than did the standardized patients (6.8 ± 0.6 vs. 7.4 ± 0.8, p = 0.05), suggesting that physicians and patients view professionalism somewhat differently. Fellow self-evaluations for professionalism (6.6 ± 1.2) were concordant with those of the MD evaluators. Ratings of empathy by fellows themselves (6.6 ± 1.0), MD evaluators (6.6 ± 0.7), and standardized patients (6.6 ± 1.1) agreed closely. Jargon use, frequently cited by evaluators, showed a moderate association with lower professionalism ratings by both MD evaluators and patients. Psychosocially challenging patient encounters in the NYC-ROSCE permitted critical assessment of the patient-centered traits contributing to impressions of professionalism and indicate that limiting medical jargon is an important component of the competency of professionalism.

Objective Increasing evidence indicates systemic inflammation as a new potential cause of acquired long QT syndrome (LQTS), via cytokine-mediated changes in cardiomyocyte ion channels. Torsade de pointes (TdP) is a life-threatening polymorphic ventricular tachycardia occurring in patients with LQTS, usually when multiple QT-prolonging factors are simultaneously present. Since classical risk factors cannot fully explain TdP events in a number of patients, we hypothesised that systemic inflammation may represent a currently overlooked risk factor contributing to TdP development in the general population. Methods Forty consecutive patients who experienced TdP (TdP cohort) were consecutively enrolled and circulating levels of C-reactive protein (CRP) and proinflammatory cytokines (interleukin-6 (IL-6), tumour necrosis factor alpha (TNFα), interleukin-1 (IL-1)) were compared with patients with active rheumatoid arthritis (RA), comorbidity or healthy controls. An additional 46 patients with different inflammatory conditions (acute infections, n=31; immune-mediated diseases, n=12; others, n=3) and elevated CRP (inflammatory cohort) were prospectively enrolled, and corrected QT (QTc) and cytokine levels were measured during active disease and after a CRP decrease of >75% subsequent to therapy. Results In the TdP cohort, 80% of patients showed elevated CRP levels (median: ~3 mg/dL), with a definite inflammatory disease identifiable in 18/40 cases (acute infections, n=12; immune-mediated diseases, n=5; others, n=1). In these subjects, IL-6, but not TNFα and IL-1, was ~15–20 times higher than in controls, and comparable to RA patients. In the inflammatory cohort, where QTc prolongation was common (mean values: 456.6±30.9 ms), CRP reduction was associated with IL-6 level decrease and significant QTc shortening (−22.3 ms). Conclusion The data are first to show that systemic inflammation via elevated IL-6 levels may represent a novel QT-prolonging risk factor contributing to TdP occurrence in the presence of other classical risk factors. If confirmed, this could open new avenues in antiarrhythmic therapy.

Background Hyperuricemia is associated with development of gout, hypertension, and renal disease. The impact of allopurinol, a urate-lowering therapy, on renal function is unclear, especially in patients with chronic kidney disease who are at higher risk of hypersensitivity reaction. Objectives The aim of this study was to determine the effect of allopurinol on kidney function in hyperuricemic male veterans. Methods This is a retrospective cohort study using pharmacy, medical, and laboratory records of veterans enrolled at the Veterans Administration New York Harbor Healthcare System, Brooklyn campus. Fifty patients with hyperuricemia defined as a serum uric acid greater than 7 mg/dL (average of ~9 mg/dL), newly started on allopurinol for any reason, with evidence of treatment compliance, were matched by age, race, sex, and estimated glomerular filtration rate (EGFR) to 50 hyperuricemic control subjects. The retrospective cases were observed from October 2000 until November 2006, at which time there was a change in the laboratory analyzer, making further comparisons inappropriate. Results On average, patients treated with a mean 221 (SD, 96) mg/d dose of allopurinol achieved 11.9 mL/min higher GFR (95% confidence interval, 4.8-11.9 mg/d dose; P = 0.01) than did the control group. Treatment effect was found to depend on the initial EGFR, as indicated by the significant treatment by initial EGFR interaction (P = 0.004) and increased with a higher initial EGFR. The allopurinol-treated group had a 0.10 mg/dL lower final creatinine level (95% confidence interval, 0.003-0.20 mg/dL; P = 0.04) than did the control subjects, adjusted for initial creatinine and age. The average length of follow-up was 3.4 years. There were 5 mild adverse events in the treated cases. Conclusions Treatment of hyperuricemic patients with allopurinol over an average of 3.4 years resulted in a significant improvement of kidney function in this male cohort from the Veterans Administration Healthcare System. Clinicians should consider this potential benefit of allopurinol in the treatment of patients with hyperuricemia, those with overall maintained renal function.

Mounting evidence indicates that in chronic inflammatory arthritis (CIA), QTc prolongation is frequent and correlates with systemic inflammatory activation. Notably, basic studies demonstrated that inflammatory cytokines induce profound changes in potassium and calcium channels resulting in a prolonging effect on cardiomyocyte action potential duration, thus on the QT interval on the electrocardiogram. Moreover, it has been demonstrated that in rheumatoid arthritis (RA) patients, the risk of sudden cardiac death is significantly increased when compared to non-RA subjects. Conversely, to date no data are available about torsades de pointes (TdP) prevalence in CIA, and the few cases reported considered CIA only an incidental concomitant disease, not contributing factor to TdP development. We report three patients with active CIA developing marked QTc prolongation, in two cases complicated with TdP degenerating to cardiac arrest. In these patients, a blood sample was obtained within 24 h from TdP/marked QTc prolongation occurrence, and levels of IL-6, TNFα, and IL-1 were evaluated. In all three cases, IL-6 was markedly elevated, ~10 to 100 times more than reference values. Moreover, one patient also showed high circulating levels of TNFα and IL-1. In conclusion, active CIA may represent a currently overlooked QT-prolonging risk factor, potentially contributing in the presence of other “classical” risk factors to TdP occurrence. In particular, a relevant role may be played by elevated circulating IL-6 levels via direct electrophysiological effects on the heart. This fact should be carefully kept in mind, particularly when recognizable risk factors are already present and/or the addition of QT-prolonging drugs is required.