Double-blind randomized proof-of-concept trial of canakinumab in patients with COVID-19 associated cardiac injury and heightened inflammation

AIMS: In coronavirus disease 2019 (COVID-19), myocardial injury is associated with systemic inflammation and higher mortality. Our aim was to perform a proof of concept trial with canakinumab, a monoclonal antibody to interleukin-1β, in patients with COVID-19, myocardial injury, and heightened inflammation. METHODS AND RESULTS: This trial required hospitalization due to COVID-19, elevated troponin, and a C-reactive protein concentration more than 50 mg/L. The primary endpoint was time to clinical improvement at Day 14, defined as either an improvement of two points on a seven-category ordinal scale or discharge from the hospital. The secondary endpoint was mortality at Day 28. Forty-five patients were randomly assigned to canakinumab 600 mg ( CONCLUSION: There was no difference in time to clinical improvement at Day 14 in patients treated with canakinumab, and no safety concerns were identified. Future studies could focus on high dose canakinumab in the treatment arm and assess efficacy outcomes at Day 28

Decline in subarachnoid haemorrhage volumes associated with the first wave of the COVID-19 pandemic

BACKGROUND: During the COVID-19 pandemic, decreased volumes of stroke admissions and mechanical thrombectomy were reported. The study\u27s objective was to examine whether subarachnoid haemorrhage (SAH) hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines. METHODS: We conducted a cross-sectional, retrospective, observational study across 6 continents, 37 countries and 140 comprehensive stroke centres. Patients with the diagnosis of SAH, aneurysmal SAH, ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases, 10th Revision, codes. The 3-month cumulative volume, monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before (1 year and immediately before) and during the pandemic, defined as 1 March-31 May 2020. The prior 1-year control period (1 March-31 May 2019) was obtained to account for seasonal variation. FINDINGS: There was a significant decline in SAH hospitalisations, with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic, representing a relative decline of 22.5% (95% CI -24.3% to -20.7%, p\u3c0.0001). Embolisation of ruptured aneurysms declined with 1170-1035 procedures, respectively, representing an 11.5% (95%CI -13.5% to -9.8%, p=0.002) relative drop. Subgroup analysis was noted for aneurysmal SAH hospitalisation decline from 834 to 626 hospitalisations, a 24.9% relative decline (95% CI -28.0% to -22.1%, p\u3c0.0001). A relative increase in ruptured aneurysm coiling was noted in low coiling volume hospitals of 41.1% (95% CI 32.3% to 50.6%, p=0.008) despite a decrease in SAH admissions in this tertile. INTERPRETATION: There was a relative decrease in the volume of SAH hospitalisations, aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic. These findings in SAH are consistent with a decrease in other emergencies, such as stroke and myocardial infarction

Clinical and genetic characteristics of pulmonary arterial hypertension in Lebanon

Abstract Background Pulmonary arterial hypertension (PAH) is a rare disease with an incidence rate of 2–6 cases per million per year. Our knowledge of the disease in the Middle East and North Africa (MENA) region is limited by the small number of clinical studies and the complete absence of genetic studies. Methods Our aim was to shed light on the clinical and genetic characteristics of PAH in Lebanon and the region by using exome sequencing on PAH patients referred to the American University of Beirut Medical Center (AUBMC). Twenty-one idiopathic, hereditary and Congenital Heart Disease (CHD) PAH patients were prospectively recruited, their clinical data summarized, and sequencing performed. Results The mean age at diagnosis was 33 years with a female preponderance of 70%. The mean pulmonary artery pressure at the time of diagnosis was 55. Genetic testing showed that 5 out of 19 idiopathic and Congenital Heart Disease PAH patients had Bone Morphogenetic Protein Receptor 2 (BMPR2) mutations at 25% prevalence, with 2 of these patients exhibiting a novel mutation. It also showed the presence of 1 BMPR2 mutation with 100% penetrance in a heritable PAH family. In the remaining cases, the lack of a complete genotype/phenotype correlation entailed a multigenic inheritance; suspected interactions involved previously associated genes T-box transcription factor 4 (TBX4), Bone Morphogenic Protein 10 (BMP10) and Growth Differentiation Factor 2 (GDF2). Conclusions This is the first study that looks into the genetic causes of PAH, including known and new BMPR2 mutations, in the MENA region. It is also the first study to characterize the clinical features of the disease in Lebanon

Linezolid Toxicity and Mitochondrial Susceptibility: A Novel Neurological Complication in a Lebanese Patient

The recent rise in the use of linezolid to treat a variety of resistant pathogens has uncovered many side effects. Some patients develop lactic acidosis, myelosuppression, optic or peripheral neuropathies and myopathies. We evaluated an elderly patient who presented to the Emergency Room with linezolid toxicity and a novel neurologic complication characterized by bilateral globi pallidi necrosis. Mitochondrial ribosome inhibition was described to be the predisposing factor. The patient belongs to the mitochondrial J1 haplotype known to be associated with side effects of the drug. We recommend based on the molecular profile of the illness pretreatment considerations and complication management

Identification of several mutations in ATP2C1 in Lebanese families: insight into the pathogenesis of Hailey-Hailey disease.

BACKGROUND:Hailey-Hailey disease (HHD) is an inherited blistering dermatosis characterized by recurrent erosions and erythematous plaques that generally manifest in intertriginous areas. Genetically, HHD is an autosomal dominant disease, resulting from heterozygous mutations in ATP2C1, which encodes a Ca2+/Mn2+ATPase. In this study, we aimed at identifying and analyzing mutations in five patients from unrelated families diagnosed with HHD and study the underlying molecular pathogenesis. OBJECTIVES:To genetically study Lebanese families with HHD, and the underlying molecular pathogenesis of the disease. METHODS:We performed DNA sequencing for the coding sequence and exon-intron boundaries of ATP2C1. Heat shock experiments were done on several cell types. This was followed by real-time and western blotting for ATP2C1, caspase 3, and PARP proteins to examine any possible role of apoptosis in HHD. This was followed by TUNEL staining to confirm the western blotting results. We then performed heat shock experiments on neonatal rat primary cardiomyocytes. RESULTS:Four mutations were detected, three of which were novel and one recurrent mutation in two families. In order for HHD to manifest, it requires both the genetic alteration and the environmental stress, therefore we performed heat shock experiments on fibroblasts (HH and normal) and HaCaT cells, mimicking the environmental factor seen in HHD. It was found that stress stimuli, represented here as temperature stress, leads to an increase in the mRNA and protein levels of ATP2C1 in heat-shocked cells as compared to non-heat shocked ones. However, the increase in ATP2C1 and heat shock protein hsp90 is significantly lower in HH fibroblasts in comparison to normal fibroblasts and HaCaT cells. We did not find a role for apoptosis in the pathogenesis of HHD. A similar approach (heat shock experiments) done on rat cardiomyocytes, led to a significant variation in ATP2C1 transcript and protein levels. CONCLUSION:This is the first genetic report of HHD from Lebanon in which we identified three novel mutations in ATP2C1 and shed light on the molecular mechanisms and pathogenesis of HHD by linking stress signals like heat shock to the observed phenotypes. This link was also found in cultured cardiomyocytes suggesting thus a yet uncharacterized cardiac phenotype in HHD patients masked by its in-expressivity in normal health conditions

Quantification of Significant Aortic Stenosis by Echocardiography versus Four-Dimensional Cardiac Computed Tomography: A Multi-Modality Imaging Study

Transthoracic echocardiography (TTE) grading of aortic stenosis (AS) is challenging when parameters are discrepant, and four-dimensional cardiac computed tomography (4D-CCT) is increasingly utilized for transcatheter intervention workup. We compared TTE and 4D-CCT measures contributing to AS quantification. AS patients (n = 80, age 86 ± 10 years, 71% men) referred for transcatheter replacement in 2014–2017 were retrospectively studied, 20 each with high-gradient AS (HG-AS), classical and paradoxical low-flow low-gradient AS (CLFLG-AS and PLFLG-AS), and normal-flow low-gradient AS (NFLG-AS). Correlation and Bland–Altman analyses were performed between TTE and 4D-CCT parameters. There were moderate-to-high TTE versus 4D-CCT correlations for left ventricular volumes, function, mass, and outflow tract dimensions (r = 0.51–0.88), though values were mostly significantly higher by 4D-CCT (p < 0.001). Compared with 4D-CCT planimetry of aortic valve area (AVA), TTE estimates had modest correlation (r = 0.37–0.43) but were significantly lower (by 0.15–0.32 cm2). The 4D-CCT estimate of LVSVi lead to significant reclassification of AS subtype defined by TTE. In conclusion, 4D-CCT quantified values were higher than TTE for the left ventricle and AVA, and the AS subtype was reclassified based on LVSVi by 4D-CCT, warranting further research to establish its clinical implications and optimal thresholds in severe AS management

Effect of heat-shock on cardiomyocyte-ATP2C1 levels.

<p>(A) Fold change in ATP2C1 mRNA levels before and after heat-shock. (B) Fold change in Hsp90 mRNA levels before and after heat shock. (C) Variation in ATP2C1 protein levels before and after heat-shock.</p

Identification of three novel and one recurrent mutation in <i>ATP2C1</i> in Lebanese families with Hailey-Hailey disease.

<p>Identification of three novel and one recurrent mutation in <i>ATP2C1</i> in Lebanese families with Hailey-Hailey disease.</p

Heat-shock induces overexpression of ATP2C1.

<p>(A) Real-time PCR effects of heat-shock on HaCaT cells (p value = 0.004), fibroblasts from HH patient (p value = 0.003), and normal fibroblasts (p value = 0.01). (B) Hsp90 variation in expression before and after heat-shock in different cell types. (C) Western blot results; lane 1: non-heat-shocked normal fibroblasts, 2; heat-shocked normal fibroblasts, 3; non-heat-shocked Hailey-Hailey fibroblasts, 4; heat-shocked Hailey-Hailey fibroblasts. (D) ATP2C1 protein quantification (using image J software) based on the densities of the bands over GAPDH obtained through western blotting showing significant increase in normal fibroblasts (* p value = 0.01), and non-significant increase in HH fibroblasts (** p >0.05).</p

Real Time PCR primers.

<p>Real Time PCR primers.</p