George Lazaros

Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis.

We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (n=11 healthy and n=60 CAD) or placebo (n=11 healthy and n=10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (P<0.0001 for both). However, interleukin 6 was inversely correlated with FMD (P<0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (r=0.515; P<0.0001) compared with CAD (r=0.289; P=0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (P<0.0001) and ADMA (P=0.004) but lower FMD (P=0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (P<0.001) and CAD (P<0.001) subjects. FMD was reduced in healthy subjects (P<0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (P<0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans.

Anakinra for the management of resistant idiopathic recurrent pericarditis. Initial experience in 10 adult cases

Recurrent idiopathic pericarditis is a common, problematic complication of acute pericarditis, occurring in approximately 30% of cases.1 Despite appropriate management with non-steroidal anti-inflammatory drugs (NSAIDs), colchicine and corticosteroids (CS), a number of patients are either resistant to treatment requiring long-term therapy with high doses of CS or intolerant to therapy.2–4 This disease is currently viewed as an autoinflammatory disease based on its clinical and laboratory features (recurrent episodes of sterile serosal inflammation in the absence of specific autoreactive antibodies or T cells),5–7 and the preliminary results showing favourable response to intereleukin-1 (IL-1) inhibition.8–10 Anakinra, a known IL-1 receptor antagonist, has been successfully used in small series of paediatric patients8 ,9 while we have recently first reported its efficacy and safety in three adult patients.10 In this report, we extend our follow-up on these three patients, and present data on seven more adult patients treated with anakinra. …

Association of Serum Uric Acid Level With Aortic Stiffness and Arterial Wave Reflections in Newly Diagnosed, Never-Treated Hypertension

BACKGROUND Serum uric acid (UA) plays a key role in the development and progression of hypertension. We investigated the association of UA levels and indices of arterial function in a cohort of newly diagnosed, never-treated hypertensive subjects. METHODS One thousand two hundred and twenty-five patients with a new diagnosis of mild to moderate arterial hypertension for which they had never received treatment were enrolled in the study (mean age 52.9 years, 728 men). Serum UA, carotid-femoral pulse-wave velocity (cfPWV), an index of aortic stiffness and augmentation index (AIx), a composite marker of wave reflections and arterial stiffness were measured. RESULTS In univariable analysis, UA levels correlated with cfPWV (r = 0.23, P < 0.001) and AIx (r = -0.24, P < 0.001). In multiple linear regression analysis, an independent positive association of cfPWV with UA levels was observed after adjusting for confounders (standardized regression coefficient β = 0.169, P < 0.001, adjusted R² = 0.402), indicating an increase in aortic stiffness with higher values of UA. In contrast, an independent negative association of AIx with UA levels was observed after adjusting for confounders (standardized regression coefficient β = -0.064, P = 0.011, adjusted R² = 0.557), indicating a decrease in wave reflections with higher values of UA. In gender-specific analyses, UA positively correlated with cfPWV in both genders, whereas a negative correlation with AIx existed only in females. CONCLUSIONS Serum UA levels are independently associated with aortic stiffening and wave reflections in never-treated hypertensives. Future studies are warranted in order to explore its exact role on arterial function in the hypertensive setting.

Successful treatment of adult patients with idiopathic recurrent pericarditis with an interleukin-1 receptor antagonist (anakinra)

Idiopathic recurrent pericarditis (IRP) is observed in 10–30% of cases after a first episode of acute pericarditis, whereas a second recurrence appears in anevenhigher rate (~50%) [1,2]. Although severalmechanisms have been suggested to explain recurrence, most of them appear simply contributory. Today, there is increasing evidence that autoimmune and autoinflammatory pathways aremainly involved in its pathogenesis [3,4]. The optimal regimen for treating IRP has not been established [1]. Several medications either alone or in combination have been tested including nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin, colchicine, corticosteroids, and immunosuppressive agents. To date, the only available medication proved in randomized trials to decrease the recurrence rate is colchicine [2]. However, even with colchicine, a substantial proportion of patients experience recurrences [2]. Recently, Picco and et al. reported the successful use of an interleukin1β receptor antagonist anakinra in three children with resistant IRP [4]. Here, we present our experience in three adults with drug resistant or intolerant IRP. All patients were informed in detail regarding the management with anakinra and gave informed consent. Case#1: A 26-year-oldmale had suffered 8 episodes of IRP since 2004. He has received various regimens including NSAIDs, colchicine, steroids and azathioprine (Fig. 2A). In October 2006 treatment with prednisone was instituted but his symptoms recurred every time the dose was tapered below 15mg/day. Unfortunately, the patient developed steroidrelated complications including glaucoma, osteopenia and proximal myopathy of the lower extremities. In his latest admission inMarch 2010, the patient was started on anakinra (150 mg/day subcutaneously, SC) as monotherapy for 3 months and steroidswere tapered off. Administration of anakinrawas followed byan immediate and dramatic clinical response International Journal of Cardiology 160 (2012) 66–77

Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial

Importance Anakinra, an interleukin 1β recombinant receptor antagonist, may have potential to treat colchicine-resistant and corticosteroid-dependent recurrent pericarditis. Objective To determine the efficacy of anakinra for colchicine-resistant and corticosteroid-dependent recurrent pericarditis. Design, Setting, and Participants The Anakinra-Treatment of Recurrent Idiopathic Pericarditis (AIRTRIP) double-blind, placebo-controlled, randomized withdrawal trial (open label with anakinra followed by a double-blind withdrawal step with anakinra or placebo until recurrent pericarditis occurred) conducted among 21 consecutive patients enrolled at 3 Italian referral centers between June and November 2014 (end of follow-up, October 2015). Included patients had recurrent pericarditis (with ≥3 previous recurrences), elevation of C-reactive protein, colchicine resistance, and corticosteroid dependence. Interventions Anakinra was administered at 2 mg/kg per day, up to 100 mg, for 2 months, then patients who responded with resolution of pericarditis were randomized to continue anakinra (n = 11) or switch to placebo (n = 10) for 6 months or until a pericarditis recurrence. Main Outcomes and Measures The primary outcomes were recurrent pericarditis and time to recurrence after randomization. Results Eleven patients (7 female) randomized to anakinra had a mean age of 46.5 (SD, 16.3) years; 10 patients (7 female) randomized to placebo had a mean age of 44 (SD, 12.5) years. All patients were followed up for 12 months. Median follow-up was 14 (range, 12-17) months. Recurrent pericarditis occurred in 9 of 10 patients (90%; incidence rate, 2.06% of patients per year) assigned to placebo and 2 of 11 patients (18.2%; incidence rate, 0.11% of patients per year) assigned to anakinra, for an incidence rate difference of -1.95% (95% CI, -3.3% to -0.6%). Median flare-free survival (time to flare) was 72 (interquartile range, 64-150) days after randomization in the placebo group and was not reached in the anakinra group (P <.001). During anakinra treatment, 20 of 21 patients (95.2%) experienced transient local skin reactions: 1 (4.8%) herpes zoster, 3 (14.3%) transaminase elevation, and 1 (4.8%) ischemic optic neuropathy. No patient permanently discontinued the active drug. No adverse events occurred during placebo treatment. Conclusion and Relevance In this preliminary study of patients with recurrent pericarditis with colchicine resistance and corticosteroid dependence, the use of anakinra compared with placebo reduced the risk of recurrence over a median of 14 months. Larger studies are needed to replicate these findings as well as to assess safety and longer-term efficacy. Trial Registration clinicaltrials.gov Identifier: NCT02219828.

In-vivo imaging of carotid plaque neoangiogenesis with contrast-enhanced harmonic ultrasound.

We describe a case where a mild carotid atherosclerotic plaque was assessed by contrast enhanced harmonic ultrasonography and image analysis. Quantitative indices of plaque echogenicity were determined prior and after the injection of microbubbles. Changes in plaque echogenicity were detected possibly due to the flow of microbubbles through vasa vasorum within the plaque and at the plaque base at the adventitial level. Future histological studies remain to be done to link the presence and the extent of plaque and adventitial neovascularization with the visual and quantitative findings derived by contrast enhanced harmonic ultrasound and image analysis.

Distinct role of electrocardiographic criteria in echocardiographic diagnosis of left ventricular hypertrophy according to age, in the general population: the Ikaria Study.

Objective The age-dependent performance of electrocardiographic (ECG) criteria was examined for left ventricular hypertrophy (LVH) prediction. Methods During 2009, 570 middle-aged (54 ± 7 years, 45% men) and 507 elderly (75 ± 6 years, 45% men) inhabitants of the Ikaria Island were studied. Seven ECG criteria were calculated (Sokolow–Lyon voltage and product, sex-specific Cornell voltage and product, Gubner–Ungerleider voltage, Lewis voltage and Framingham), whereas LVH was defined as left ventricular mass indexed for body surface area (BSA) at least 125 g/m2 in men and at least 110 g/m2 in women or left ventricular mass indexed for height2.7 49 g/m2.7 or more in men and 45 g/m2.7 or more in women. Results The Framingham criteria had in hierarchical order the highest, although insignificant, sensitivity among the elderly individuals, either when LVH was indexed for BSA or for height2.7 (18.4 and 16.7%, respectively). Cornell voltage and product criteria had hierarchically the highest sensitivity among middle-aged participants, either when LVH was indexed for BSA (19.0 and 23.8%, respectively) or for height2.7 (17.2 and 20.3%, respectively). In the multiadjusted analysis applied in elderly participants, Cornell voltage, its product and Framingham criteria were associated with echocardiographic detection of LVH (indexed for BSA); however, when LVH was indexed for height2.7, the Sokolow–Lyon and Framingham criteria were associated with LVH detection. In contrast, among middle-aged individuals, the Cornell product was the only ECG criterion that was associated with LVH detection (irrespective of indexation). Conclusion Age should be taken into consideration in selection of appropriate ECG criteria for LVH detection. Indexation of left ventricular mass differentiates the diagnostic ability of ECG criteria, especially in older patients.

Fish Consumption Moderates Depressive Symptomatology in Elderly Men and Women from the IKARIA Study

Background. The aim was to examine the association of depressive symptoms with fish eating habits, in elderly individuals. Methods. From June to October of 2009, we studied 330 men and 343 women, aged 65 to 100 years, permanent inhabitants of Ikaria Island. Among several characteristics, depression was assessed with the Geriatric Depression scale (GDS range 0–15), while dietary habits through a valid semiquantitative food frequency questionnaire. Results. Women had significantly higher values of the GDS compared to men (4.8 ± 3.5 versus 3.3 ± 3.1, P = .001). Participants in the upper tertile of depression scale ate less frequent fish and consumed higher quantities of alcohol, compared to those in the lowest tertile (all P < .05). Regarding fish consumption, 50% of the individuals reported consuming 1-2 times weekly, 32% 3 to 5 times weekly, 11% 2-3 times monthly, while the rest reported rare (4.5%) and everyday (1.2%) consumption. Logistic regression showed that increased fish consumption (>3 times/week versus never/rare) was inversely associated with the odds of having GDS greater the median value (i.e., 4) (odds  ratio = 0.34, 95% CI: 0.19, 0.61), after controlling for several cofounders. Conclusion. Frequent fish consumption in elderly seems to moderate depression mood.

Anakinra: an emerging option for refractory idiopathic recurrent pericarditis

Aims Accumulating evidence suggests idiopathic recurrent pericarditis as a disease of probable autoinflammatory origin, and thus anakinra could be of benefit. The goal of this systematic review was to assess the efficacy and safety of anakinra in this context. Methods Reports relevant to anakinra administration in patients with idiopathic recurrent pericarditis published up to October 2014 were searched in several databases. All references found, upon initial assessment at title and abstract level for suitability, were consequently retrieved as full reports for further appraisal. Results Among 12 citations retrieved, nine reports (four case series and five case reports with 34 patients, 20 men, mean age 26.8 years) were assessed. The mean disease duration was 31 months and the number of recurrences 8.2. Anakinra was generally administered as a daily subcutaneous injection of 100 mg or as a mean dose of 1.1 mg/kg/d in weight-adjusted regimens. The mean full-dose duration was 9.2 months. C-reactive protein normalized within 7.1 days, and steroids were withdrawn within 62 days. Dose tapering was adopted in 64.7% of patients, leading to recurrence in 26% of cases. In a 28.3-month follow-up, eight out of 34 patients (23.5%) were disease free without treatment, after having received anakinra for 10.4 months overall. Anakinra was proved well tolerated, with mild local reaction being reported in 44% of patients. Conclusion Anakinra is a highly effective, rapidly acting, well tolerated and steroid-sparing agent. Recurrences after drug discontinuation are a matter of concern. Randomized trials are required to confirm these findings and address the most effective treatment protocol.

Incidence and prognostic significance of new onset atrial fibrillation/flutter in acute pericarditis

Objective Data on the incidence of new onset atrial fibrillation and flutter (AF/f) in patients with acute pericarditis are limited. We sought to determine the incidence and prognostic significance of AF/f in this setting. Methods Between January 2006 and June 2014, consecutive new cases of acute pericarditis were included in two urban referral centres for pericardial diseases. All new cases of AF/f defined as episodes lasting ≥30 s were recorded. Events considered during follow-up consisted of AF/f and pericarditis recurrence, cardiac tamponade, pericardial constriction and death. Results 822 consecutive new cases of acute pericarditis (mean age 53±15 years, 444 men) were analysed. AF/f was detected in 35 patients (4.3%, mean age 66.5±11.3 years, 18 men). Patients with AF/f were significantly older (p=0.017) and presented more frequently with pericardial effusion (p<0.001). Arrhythmias developed within 24 h of pericarditis onset in 91.4% of cases, lasted >24 h in 25.7% and spontaneously converted in 74.3% of patients. Underlying structural heart disease was present in 17% of AF/f cases. In a 30-month follow-up, patients with history of AF/f at the initial episode had a higher rate of arrhythmia occurrence (34.3% vs 0.9%, p<0.001), mostly (75%) within 3 months. No other differences were detected in additional clinical events including haemorrhagic complications in patients receiving oral anticoagulation. Conclusions The occurrence of AF/f in acute pericarditis identifies a predisposed population to AF/f with a high recurrence risk (about 35%): in these patients, pericarditis may act as an arrhythmic trigger and oral anticoagulation should be seriously considered according to guidelines.