Peripheral blood natural killer cells in sarcoidosis are associated with early cardiac involvement.

AIM: To evaluate the distribution of circulating immune cell subsets in peripheral blood of patients with sarcoidosis and investigate if there is an association with an underlying cardiac involvement. METHODS AND RESULTS: Eighty-five newly diagnosed treatment-naïve patients with sarcoidosis (50 women) were included in the study. All patients underwent a thorough cardiac investigation, including cardiac magnetic resonance imaging (CMR). Of all patients, 19 (23.53%) had myocardial involvement, and the NK subpopulation in these patients in peripheral blood was significantly decreased compared to patients without (n = 63, p = 0.001 and p = 0.003 respectively). The absolute number of NKT cells (CD3+CD16/56+ ) in patients with cardiac involvement was highly correlated with T2 map increased values in MRI (r = -686, p = 0.041) showing that low NKT cell count correlates with the inflammatory process of the heart. No difference in CD19, CD3, CD4, CD8 and CD3- NK cell counts was found between groups. Lung severity was not found to correlate with the number of NK cells. CONCLUSION: We found that low NK cell count in peripheral blood of patients with sarcoidosis is associated with cardiac involvement, and the number of NK-T cells correlates with CMR findings indicative of myocardial inflammation. This finding might have a potential clinical application in detecting clinically silent cardiac involvement in sarcoidosis and may also suggest potential targets for therapeutic interventions.

Cardiopulmonary exercise testing and prognosis in patients with systemic sclerosis without baseline pulmonary hypertension: a prospective cohort study.

Cardiopulmonary Exercise Testing (CPET) is a standardized, non-invasive procedure assessing pulmonary, cardiovascular, hematopoietic, and skeletal muscle functions during a symptom-limited test. Few studies have examined whether CPET is of prognostic value in Systemic Sclerosis (SSc), a disease characterized by highly increased cardiorespiratory morbidity and mortality. To examine the prognostic value of CPET in SSc patients without baseline pulmonary hypertension (PH). Sixty-two consecutive SSc patients underwent CPET, Pulmonary Function Tests (PFTs) and echocardiography at baseline. Four patients with Right Ventricular Systolic Pressure ≥ 40 mmHg, were excluded. Participants repeated PFTs approximately every 3 years. At the end of the follow-up period [median (IQR): 9.79 (2.78) years] patient vital status was recorded. Cox Regression analysis was used to identify predictors of deterioration of PFTs and 10-year survival. Median (IQR) age of 58 patients (90% women) at baseline was 54.0 (15.0) years, whereas 10-year survival was 88%. Baseline respiratory Oxygen uptake (VO2max) predicted PFT deterioration, defined either as a decline in FVC ≥ 10% or a combined decline in FVC 5%-9% plus DLCO ≥ 15%, during follow-up, after correction for age, gender and smoking status (HR: 0.874, 95%CI: 0.779-0.979, p = 0.021). In addition, lower baseline VO2max (HR = 0.861, 95%CI:0.739-1.003, p = 0.054) and DLCO (HR = 0.957, 95%CI: 0.910-1.006 p = 0.088), as well as male gender (HR = 5.68, 95%CI: 1.090-29.610 p = 0.039) and older age (HR = 1.069, 95%CI: 0.990-1.154, p = 0.086) were associated, after adjustment, with an increased risk for death. In the absence of baseline PH, CPET indices may predict pulmonary function deterioration and death in SSc patients during a nearly 10-year follow-up period.

Global longitudinal strain and long-term outcomes in asymptomatic extracardiac sarcoid patients with no apparent cardiovascular disease.

PURPOSE: Global longitudinal strain (GLS) is increasingly accepted as a predictor of mortality in various clinical settings. This study tested the hypothesis that GLS is associated with increased event rate in patients with extracardiac sarcoidosis, who have no overt symptoms of cardiovascular disease and preserved ejection fraction (EF). METHODS: We retrospectively studied 117 patients with extracardiac sarcoidosis and 45 age- and sex-matched controls, who underwent comprehensive echocardiographic study, while GLS was measured by an offline speckle tracking algorithm. Patients who had signs and symptoms of cardiovascular disease at the time of the examination were excluded from the study. Patients were followed for an average of 57.1 months. Primary endpoint was defined as a composite endpoint of heart failure-related hospitalizations, need for device therapy, arrhythmias, and all-cause mortality. RESULTS: The age of patients was 42 ± 6 years old (43 men). Events were recorded in 10 patients (8.5%). Tissue Doppler revealed E/Em 7.9 ± 3.5, while EF was 54.2 ± 3.5%. Global longitudinal strain was 14.4 ± 3%, and a cutoff value ≤-13.6% for GLS was considered more associated with adverse outcomes (AUC 0.84). After adjustment for multiple potential confounders (age, gender, hypertension, diabetes, E/Em, and EF), GLS remained strongly associated with adverse outcomes (HR 0.8, 0.63 to 0.98 95% C.I, P = .04). CONCLUSIONS: In conclusion, among patients with extracardiac sarcoidosis and no symptoms of cardiovascular disease, even when EF is preserved, GLS seems to be strongly associated with adverse future events.

Vascular function and ocular involvement in sarcoidosis.

Ocular involvement occurs in sarcoidosis (Sar) patients mainly in the form of uveitis. This study was designed to determine if uveitis in Sar patients is associated with vascular impairment. We enrolled 82 Sar patients and 77, age and sex matched, control subjects (Cl). Sar patients were divided into those with ocular sarcoidosis (OS) and those without ocular sarcoidosis (WOS). Endothelial function was evaluated by flow-mediated dilation (FMD). Pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections. Although there was no significant difference in sex, age and mean arterial pressure, patients with OS compared to WOS patients and Cl subjects had impaired FMD (p<0.001), increased AIx (p=0.02) and increased PWV (p=0.001). Interestingly, impaired FMD in Sar patients was independently, from possible covariates (age, sex, smoking habits, arterial hypertension, dyslipidemia), associated with increased odds of ocular involvement (odds ratio=1.69, p=0.001). More precisely ROC curve analysis revealed that FMD had a significant diagnostic ability for the detection of OS (AUC=0.77, p<0.001) with a sensitivity of 79% and a specificity of 68% for an FMD value below 6.00%. To conclude in the present study we have shown that ocular involvement in Sar patients is associated with impaired endothelial function and increased arterial stiffness. These results strengthen the vascular theory which considers uveitis a consequence of vascular dysfunction in Sar patients and reveals a possible clinical importance of the use of endothelial function tests.

Elevated pulmonary arterial systolic pressure in patients with sarcoidosis: prevalence and risk factors.

BACKGROUND: Sarcoidosis-related pulmonary hypertension (SRPH) is an entity associated with significant morbidity and mortality irrespective of disease severity, while the pathogenic mechanisms remain poorly understood. METHODS: This cross-sectional study included consecutive patients with biopsy-proven sarcoidosis (n = 313) who were followed up in an outpatient setting from October 2002 through June 2010. All patients underwent clinical and cardiopulmonary evaluation, including cardiac MRI, to assess prevalence of SRPH and identify possible underlying pathophysiological mechanisms. RESULTS: By Doppler echocardiographic criteria, 37 (11.8 %) patients were found to have pulmonary arterial systolic pressure (PASP) >40 mmHg. Twelve of the 37 patients agreed to undergo right heart catheterization and SRPH was confirmed in nine patients. Compared to patients without SRPH, those with SRPH were significantly older and had greater lung function impairment; disease duration did not differ between patients with and without SRPH. Multiple logistic regression analysis showed that diffusing capacity for carbon monoxide (DLCO) and age were independent determinants of SRPH. Pulmonary fibrosis and left ventricular diastolic dysfunction due to cardiac sarcoidosis or other comorbidities accounted for SRPH in the majority of patients. In the nonpulmonary fibrosis group, DLCO ≤ 50.65 (% predicted) was associated with SRPH (sensitivity = 77.8 %, specificity = 72.2 %; p = 0.031, AUC = 0.759). CONCLUSION: In a large cohort of sarcoidosis patients, this study found a prevalence of SRPH of about 12 %. Pulmonary fibrosis and left ventricular diastolic dysfunction due to cardiac sarcoidosis or other comorbidities are frequent pathogenic mechanisms.

Association of BAFF and BAFF-R polymorphisms with sarcoidosis in a Greek patient cohort.

Introduction: Sarcoidosis is a disease that results from a combination of environmental and genetic factors. Its genetic basis however, is yet to be clarified. The purpose of this study is to determine whether single nucleotide polymorphisms (SNPs) of the B-cell activating factor (BAFF) and its receptor (BAFF-R) are associated with sarcoidosis. Material and methods: Blood samples from one hundred and seventy-three sarcoidosis patients and one hundred and sixty-four controls were collected. All samples were genotyped for BAFF rs2893321, rs1041569 and rs9514828, and for BAFF-R rs61756766. Results: Out of the three BAFF polymorphisms, none genotype had any significant association with sarcoidosis, although the T allele in rs1041569 and rs9514828 was overrepresented in sarcoidosis patients. A marginally significant association with sarcoidosis was found in the case of the CT genotype and T allele of BAFF-R rs61756766. Haplotype analysis of the BAFF polymorphisms was also performed, revealing an overrepresentation of the ATT, GTA and GTT haplotypes in the group of patients with cardiac involvement. Conclusions: Taken together, the results of this study suggest a possible relationship between BAFF SNPs, rs1041569 and rs9514828, and BAFF-R SNP rs61756766 with sarcoidosis susceptibility and their potential as biomarkers for the disease.

From Karl Wurm and Guy Scadding's staging to 18F-FDG PET/CT scan phenotyping and far beyond: perspective in the evading history of phenotyping in sarcoidosis.

Sarcoidosis is an inflammatory granulomatous disease of unknown etiology involving any organ or tissue along with any combination of active sites, even the most silent ones clinically. The unpredictable nature of the sites involved in sarcoidosis dictates the highly variable natural history of the disease and the necessity to cluster cases at diagnosis based on clinical and/or imaging common characteristics in an attempt to classify patients based on their more homogeneous phenotypes, possibly with similar clinical behavior, prognosis, outcome, and therefore with therapeutic requirements. In the course of the disease's history, this attempt relates to the availability of a means of detection of the sites involved, from the Karl Wurm and Guy Scadding's chest x-ray staging through the ACCESS, the WASOG Sarcoidosis Organ Assessment Instruments, and the GenPhenReSa study to the 18F-FDG PET/CT scan phenotyping and far beyond to new technologies and/or the current "omics." The hybrid molecular imaging of the 18F-FDG PET/CT scan, by unveiling the glucose metabolism of inflammatory cells, can identify high sensitivity inflammatory active granulomas, the hallmark of sarcoidosis-even in clinically and physiologically silent sites-and, as recently shown, is successful in identifying an unexpected ordered stratification into four phenotypes: (I) hilar-mediastinal nodal, (II) lungs and hilar-mediastinal nodal, (III) an extended nodal supraclavicular, thoracic, abdominal, inguinal, and (IV) all the above in addition to systemic organs and tissues, which is therefore the ideal phenotyping instrument. During the "omics era," studies could provide significant, distinct, and exclusive insights into sarcoidosis phenotypes linking clinical, laboratory, imaging, and histologic characteristics with molecular signatures. In this context, the personalization of treatment for sarcoidosis patients might have reached its goal.

Co-occurrence between hereditary angioedema and multiple sclerosis: Therapeutic management of both diseases with fingolimod.

BACKGROUND: Hereditary angioedema (HAE) related to C1 esterase-inhibitor deficiency activates the classic complement pathway and results to edematous crises. Although HAE is usually associated with multiple immunoregulatory disorders, neurologic manifestations are rare. CASE REPORT: We report on the case study of a 33-year-old man diagnosed with HAE (SERPIN1G gene mutation) and multiple sclerosis (MS), followed up for at least 6 years. After a first clinical attack of HEA with scrotal edema, MS disease exacerbation was observed. Treatment with glatiramer acetate could not prevent either MS or HAE clinical attacks with recurrent exacerbations been observed. Remission of MS and significant amelioration of HAE attacks were achieved under fingolimod treatment. CONCLUSIONS: Herein we provide long term evaluation of an extremely rare case of concomitant existence of HAE and MS and present the effects of MS current disease-modifying therapies in HAE attacks. Our case highlights the possible effect of fingolimod in immunoregulatory-mechanisms implicated in both diseases.

Clinico-radiologic features and therapeutic strategies in tumefactive demyelination: a retrospective analysis of 50 consecutive cases.

AIMS: Our goal was to expand the spectrum of clinico-radiologic characteristics and the possible therapeutic choices in patients with tumefactive demyelinating lesions (TDLs). METHODS: A retrospective analysis of 50 patients with at least one TDL was performed at an academic neurology center (2008-2020). RESULTS: Our cohort comprised mostly women (33/50) with a mean age of 38 years at TDL onset. The mean follow-up time was 76 months. The mean Expanded Disability Status Scale score at TDL onset and at the latest neurological evaluation was 3.7 and 2.3, respectively. We subcategorized the patients into seven groups based mainly on the clinical/radiological findings and disease course. Group A included patients presenting with a Marburg-like TDL (n = 4). Groups B and C comprised patients presenting with monophasic (n = 7) and recurrent TDLs (n = 12), respectively. Multiple sclerosis (MS) patients who subsequently developed TDL (n = 16) during the disease course were categorized as Group D. Group E comprised patients who initially presented with TDL and subsequently developed a classical relapsing-remitting MS without further evidence of TDL (n = 5). Groups F (n = 2) and G (n = 4) involved MS patients who developed TDL during drug initiation (natalizumab, fingolimod) and cessation (interferon, fingolimod), respectively. Regarding long-term treatments applied after corticosteroid administration in the acute phase, B-cell-directed therapies were shown to be highly effective especially in cases with recurrent TDLs. Cyclophosphamide was spared for more aggressive disease indicated by a poor response to corticosteroids and plasma exchange failure. CONCLUSION: Tumefactive central nervous system demyelination is an heterogenous disease; its stratification into distinct groups according to different phenotypes can establish more efficient treatment strategies, thus improving clinical outcomes in the future.

IgG4-related autoimmune manifestations in Alemtuzumab-treated multiple sclerosis patients.

We aimed to determine whether Alemtuzumab-induced immune reconstitution affects immunoglobulin and complement levels in the serum of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. IgG4-levels were increased 24-months after treatment initiation compared to baseline levels in twenty-nine patients. Alemtuzumab-treated patients with the highest IgG4-levels were more prone to thyroid-related autoimmune manifestations and specific autoimmune adverse events such as Crohn's disease, Graves' disease, and hemolytic anemia. Compared to baseline, total IgG-levels showed a trend towards reduced levels following two-courses of Alemtuzumab, but no significant change of C3 and/or C4-levels was observed. In conclusion, monitoring of IgG4-levels can serve as a marker for secondary autoimmunity risk in multiple sclerosis patients treated with Alemtuzumab.

X-linked dilated cardiomyopathy: the important role of genetic tests and imaging in the early diagnosis and treatment.

Familial dilated cardiomyopathy predominantly affects younger adults and may cause advanced heart failure and sudden cardiac death. Therefore, detailed family history, family members screening, appropriate genetic testing and counselling may allow correct identification of cardiac remodeling etiology, as well as earlier disease detection. Accordingly, we present a case with an early diagnosis of an X-linked dilated cardiomyopathy guided by clinical features, cardiac MRI and genetic testing. The diagnostic workup was guided by the positive family history of cardiomyopathy and sudden cardiac deaths. Clinical implications including early management, better arrythmia risk stratification and the revealing of a potential endemic entity clustering in several male subjects of a community on Crete island are further discussed.

Recurrent Fulminant Tumefactive Demyelination With Marburg-Like Features and Atypical Presentation: Therapeutic Dilemmas and Review of Literature.

Atypical forms of demyelinating diseases with tumor-like lesions and aggressive course represent a diagnostic and therapeutic challenge for neurologists. Herein, we describe a 50-year-old woman presenting with subacute onset of left hemiparesis, memory difficulties and headache. Brain MRI revealed a tumefactive right frontal-parietal lesion with perilesional edema, mass effect and homogenous post-contrast enhancement, along with other small atypical lesions in the white-matter. Brain biopsy of cerebral lesion ruled out lymphoma or any other neoplastic process and patient placed on corticosteroids with complete clinical/radiological remission. Two years after disease initiation, there was disease exacerbation with reappearance of the tumor-like mass. The patient initially responded to high doses of corticosteroids but soon became resistant. Plasma-exchange sessions were not able to limit disease burden. Resistance to therapeutic efforts led to a second biopsy that showed perivascular demyelination, predominantly consisting of macrophages, with a small number of T and B lymphocytes, and the presence of reactive astrocytes, typical of Creutzfeldt-Peters cells. The patient received high doses of cyclophosphamide with substantial clinical/radiological response but relapsed after 7-intensive cycles. She received 4-weekly doses of rituximab with disease exacerbation and brainstem involvement. She eventually died with complicated pneumonia. We present a very rare case of recurrent tumefactive demyelinating lesions, with atypical tumor-like characteristics, with initial response to corticosteroids and cyclophosphamide, but subsequent development of drug-resistance and unexpected exacerbation upon rituximab administration. Our clinical case raises therapeutic dilemmas and points to the need for immediate and appropriate immunosuppression in difficult to treat tumefactive CNS lesions with Marburg-like features.

Blood Pressure Deviation from the Golden Ratio φ and All-cause Mortality: A Pythagorean View of the Arterial Pulse.

INTRODUCTION: There is one mathematical element with strong historical and philosophical background that exhibits remarkable properties and applications; the golden ratio (phi). Mathematically, the golden ratio equals approximately 1.61803. A rather provocative geometrical analysis of the arterial pulse according to the golden ratio was recently described, and herein, we aim to set out the hypothesis that individuals with blood pressure (BP) values that follow the golden ratio may have different prognosis than those whose BPs deviate from the divine proportions. MATERIALS AND METHODS: We used published data from the National Health and Nutrition Examination Survey during 1999-2010. RESULTS: We found that the deviation of the BP values from the golden ratio is independently associated with all-cause mortality. CONCLUSIONS: This observation stimulates further research of the potential utility of the golden ratio of BP values on the diagnosis and prediction of BP-related abnormalities and risk.

Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology.

Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM, HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with preserved ejection (HFpEF) affects most patients with obstructive, and ∼10% of patients with non-obstructive HCM. A timely treatment is important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in cardiomyopathies.

Association of the 894G>T polymorphism in the endothelial nitric oxide synthase gene with risk of acute myocardial infarction.

BACKGROUND: This study was designed to investigate the association of the 894G>T polymorphism in the eNOS gene with risk of acute myocardial infarction (AMI), extent of coronary artery disease (CAD) on coronary angiography, and in-hospital mortality after AMI. METHODS: We studied 1602 consecutive patients who were enrolled in the GEMIG study. The control group was comprised by 727 individuals, who were randomly selected from the general adult population. RESULTS: The prevalence of the Asp298 variant of eNOS was not found to be significantly and independently associated with risk of AMI (RR = 1.08, 95%CI = 0.77-1.51, P = 0.663), extent of CAD on angiography (OR = 1.18, 95%CI = 0.63-2.23, P = 0.605) and in-hospital mortality (RR = 1.08, 95%CI = 0.29-4.04, P = 0.908). CONCLUSION: In contrast to previous reports, homozygosity for the Asp298 variant of the 894G>T polymorphism in the eNOS gene was not found to be associated with risk of AMI, extent of CAD and in-hospital mortality after AMI.

Aortic dissection and third-degree atrioventricular block in a patient with a hypertensive crisis.

A 55-year-old man with a history of uncontrolled hypertension was admitted because of an episode of severely elevated blood pressure. An electrocardiogram revealed complete atrioventricular block while imaging showed a dissecting aneurysm of the descending thoracic and abdominal aorta, type B according to the Stanford classification. Laboratory tests revealed significant increases in serum C-reactive protein. Coronary arteriography was performed and was negative for coronary artery disease. A VDD pacemaker was placed, and a combination of 4 antihypertensive agents was used as treatment. Type B aortic dissection may present with a wide range of manifestations. The authors suggest that measurement of C-reactive protein may be used in hypertensive patients to help reflect vascular injury and its degree, progression, and prognosis. Disorders of intraventricular conductivity are rarely seen in both types of dissection of the aorta (type A, B). Atrioventricular conductivity disorders that result in complete atrioventricular block have been reported only in patients with type A dissection (before the bifurcation of the subclavian artery). In this particular case, however, the authors diagnosed an atrioventricular conductivity disorder causing atrioventricular block in a patient with type B dissection. Consequently, the authors speculate that myocardial fibrosis, as a result of long-standing hypertension, could be the main pathogenetic mechanism leading to the development of such phenomena, resulting from a potential expanding of the fibrotic process to the atrioventricular conduction system.

Avian flu: how informed are children in Greece?

OBJECTIVES: The current cluster of avian influenza outbreaks in birds has occurred in areas where humans live in proximity to poultry. Dissemination of accurate information may be the cornerstone for proper community preparation. In the herein presented study, we attempted to asses the information level among Greek children regarding avian flu. METHODS: A descriptive study was carried out in 2006 in ten Greek prefectures to determine the information level among students about transmission ways, symptoms and prevention measures of avian flu. RESULTS: A total of 1400 Greek students participated in the study. Approximately 75% of the students reported to know what bird flu is and 53% reported to know that there has been at least one case of avian flu in Greece. More than half (55.6%) reported that an effective vaccine against avian flu does exist; of the students asked, 47% reported that avian flu can be transmitted from human to human whereas 21.4% believed that humans can suffer from avian flu. Media contribution in providing information was very high among students. CONCLUSION: The level of information about avian flu among Greek students was found inadequate especially in some questions regarding serious aspects of avian flu. This study highlights the need for adaptation of health programs in Greek schools, which should include the provision of accurate information.

Ischemic stroke as an uncommon complication of Cor triatriatum.

Cor triatriatum (CT) is a rare congenital heart disease characterized by a fibromuscular membrane that divides the left atrium into two distinct chambers and mostly manifests during infancy mimicking mitral valve stenosis. We present the uncommon case of cardioembolic ischemic stroke in an adult man on the grounds of an otherwise asymptomatic CT with intra-atrial thrombus formation, which was established by means of transesophageal echocardiography and cardiac magnetic resonance imaging. Because exact diagnosis and surgical treatment is feasible, we suggest CT as a rare, but potentially treatable source of cerebral embolism in adult patients with stroke and dilatated left atrium.