Clonal Hematopoiesis of Indeterminate Potential Is Associated With Coronary Microvascular Dysfunction In Early Nonobstructive Coronary Artery Disease.

BACKGROUND: Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is a risk factor for cardiovascular disease. The relationship between CHIP and coronary microvascular dysfunction (CMD) is unknown. The current study examines the association between CHIP and CH with CMD and the potential relationships in risk for adverse cardiovascular outcomes. METHODS: In this retrospective observational study, targeted next-generation sequencing was performed for 177 participants with no coronary artery disease who presented with chest pain and underwent routine coronary functional angiogram. Patients with somatic mutations in leukemia-associated driver genes in hematopoietic stem and progenitor cells were examined; CHIP was considered at a variant allele fraction ≥2%; CH was considered at a variant allele fraction ≥1%. CMD was defined as coronary flow reserve to intracoronary adenosine of ≤2. Major adverse cardiovascular events considered were myocardial infarction, coronary revascularization, or stroke. RESULTS: A total of 177 participants were examined. Mean follow-up was 12±7 years. A total of 17 patients had CHIP and 28 had CH. Cases with CMD (n=19) were compared with controls with no CMD (n=158). Cases were 56±9 years, were 68% women, and had more CHIP (27%; P=0.028) and CH (42%; P=0.001) than controls. CMD was associated with independent risk for major adverse cardiovascular events (hazard ratio, 3.89 [95% CI, 1.21-12.56]; P=0.023), and 32% of this risk was mediated by CH. The risk mediated by CH was ≈0.5× as large as the direct effect of CMD on major adverse cardiovascular events. CONCLUSIONS: In humans, we observe patients with CMD are more likely to have CHIP, and nearly one-third of major adverse cardiovascular events in CMD are mediated by CH.

Carotid Plaques From Symptomatic Patients Are Characterized by Local Increase in Xanthine Oxidase Expression.

Background and Purpose: XO (xanthine oxidase) is a key enzyme of uric acid metabolism and is thought to contribute to oxidative pathways that promote atherosclerotic plaque progression, yet its role in plaque destabilization is not well elucidated. We hypothesized that XO is expressed in carotid plaque from symptomatic patients in association with cardiovascular risk factors. Methods: Patients were stratified by symptoms, defined as presentation with an ipsilateral cerebral ischemic event. Carotid atherosclerotic plaques were obtained from 44 patients with symptomatic plaque and 44 patients without ischemic cerebral events. Protein expression of XO was evaluated by immunohistochemical staining and the percentage of cells expressing XO and CD68 (macrophage marker) compared between the groups. Biochemical and demographic cardiometabolic risk factors of study participants also were measured. Results: Carotid atherosclerotic plaques from symptomatic patients were associated with significantly higher XO expression versus asymptomatic plaque (median [interquartile range]: 1.24 [2.09] versus 0.16 [0.34]; P<0.001) and with significantly higher circulating uric acid levels (mean±SD: 7.36±2.10 versus 5.37±1.79 mg/dL; P<0.001, respectively). In addition, XO expression in atherosclerotic carotid plaque was inversely associated with serum high-density lipoproteins cholesterol levels (P=0.010, r=−0.30) and directly with circulating uric acid levels (P<0.001, r=0.45). The average percentage of macrophages that expressed XO was significantly higher in symptomatic versus asymptomatic plaques (median [interquartile range]: 93.37% [25] versus 46.15% [21], respectively; P<0.001). Conclusions: XO overexpression in macrophages is associated with increased serum uric acid and low high-density lipoproteins cholesterol levels and may potentially have a mechanistic role in carotid plaque destabilization. The current study supports a potential role for uric acid synthesis pathway as a target for management of carotid atherosclerosis in humans.

Association of non-alcoholic fatty liver disease with microvascular complications of type 2 diabetes.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) affects risks of type 2 diabetes (T2D), diabetes-related complications, and cardiovascular disease in a complex manner. This study is designed to clarify associations of sonographically-detected NAFLD and serum liver enzymes with diabetes-related microvascular complications. METHODS: A matched case-contorl study was designed for 440 patients with T2D and at least one of the chronic diabetes-related microvascular complications and 495 age- and gender-matched control patients with T2D. RESULTS: Considering pre-existing and newly developed chronic microvascular complications, diabetic peripheral neuropathy was found in 347 out of 935 (37.1%) study patients, diabetic retinopathy in 141/935 (15.1%), and diabetic nephropathy in 103/935 (11.0%). Diagnosis of diabetic retinopathy and diabetic nephropathy were inversely associated with the presence of NAFLD in the crude logistic regressions (OR [95% CI] = 0.18 [0.05-0.63], p value = 0.007; OR [95% CI] = 0.17 [0.04-0.59], p value = 0.011, respectively). The subgroup of NAFLD with elevated liver enzymes had lower odds of having diabetic peripheral neuropathy in the fully adjusted model (OR [95% CI] = 0.34 [0.12-0.98], p value = 0.048). CONCLUSION: Diagnosis of NAFLD with or without elevated serum liver enzymes was inversely correlated with certain chronic diabetes microvascular complications. Possible explanations for this counter-intuitive and unexpected finding are discussed and center on reverse-causality, wherein sicker patients may develop beneficial compensatory physiological and behavioral adaptations. Diversity of studied patients, in particular with regards to the ethnic and racial differences among the Western and Asian populations may also partly account for contrasting findings of the relationship between NAFLD and microvascular complications of diabetes.

Associations of Serum S100B and S100P With the Presence and Classification of Diabetic Peripheral Neuropathy in Adults With Type 2 Diabetes: A Case-Cohort Study.

OBJECTIVES: Novel biomarkers of diabetic peripheral neuropathy provide potentially useful information for early identification and treatment of diabetic neuropathy, ultimately serving to reduce the burden of disease. This study was designed to investigate the potential associations of serum S100B and S100P (calcium-modulated proteins) with the presence and classification of diabetic peripheral neuropathy in adults with type 2 diabetes. METHODS: In a case-cohort setting, the data of 44 participants diagnosed with diabetic peripheral neuropathy, 44 control participants with type 2 diabetes but free of peripheral neuropathy and 87 healthy control individuals were collected and analyzed. RESULTS: Serum S100P concentrations were elevated in participants with diabetic peripheral neuropathy compared with their controls with type 2 diabetes (median [IQR]: 2,235 pg/mL [1,497.5 to 2,680] vs. 1,200 pg/mL [975 to 1,350)], respectively; p<0.001). Conversely, serum S100B values were comparable in these 2 groups (p=0.570). Those with the typical diabetic peripheral neuropathy had significantly higher serum S100P levels compared to their counterparts with the atypical group of diabetic peripheral neuropathies (p=0.048). The independent significant association between serum S100P and diabetic peripheral neuropathy persisted into the multivariable adjusted logistic regression model (OR for S100P: 1.004 [95% CI 1.002 to 1.006]; p<0.001). CONCLUSIONS: The present study's findings demonstrated that serum S100P is a more significant indicator of peripheral neuropathy in type 2 diabetes than is serum S100B. Prospective longitudinal studies are required to confirm the prognostic value of baseline serum S100P to predict incident peripheral neuropathy in people with diabetes.

Beneficial Effects of Pentoxifylline Plus Losartan Dual Therapy in Type 2 Diabetes with Nephropathy.

BACKGROUND: This study was designed to comparatively assess the effects of add-on pentoxifylline to losartan versus increasing the dose of losartan on serum N-terminal pro-brain natriuretic peptide (NT-proBNP), serum highly sensitive C-reactive protein (hsCRP) and the urinary albumin excretion (UAE) rate in patients with type 2 diabetes and nephropathy. METHODS: In an open-label, single-center, parallel-group, randomized clinical trial (NCT03006952), 30 patients received b.i.d. dose of pentoxifylline 400mg plus daily dose of losartan 50mg (pentoxifylline arm) and 29 patients received b.i.d. dose of losartan 50mg (losartan arm) during a 12-week follow-up period. RESULTS: Serum NT-proBNP, serum hsCRP and UAE levels all significantly decreased from baseline in both trial arms. The pentoxifylline and losartan trial arms were equally effective in reducing serum NT-proBNP levels during the course of trial (multivariable adjusted model P value = 0.864, effect size = 0.2%). There was a greater decrease in UAE and serum hsCRP levels in the pentoxifylline arm (P = 0.034, effect size = 7.8%; P = 0.009, effect size = 11.7%, respectively). Conversely, patients in the losartan arm achieved better systolic and diastolic blood pressure control (P < 0.001, effect size = 25.4%; P = 0.010, effect size = 11.3%, respectively). CONCLUSIONS: Circulating NT-proBNP levels equally and significantly reduced from baseline in the pentoxifylline and losartan treatment arms, in parallel with comparatively superior decreases of UAE and serum hsCRP in the pentoxifylline arm, and larger decreases of systolic and diastolic blood pressures in the losartan arm.

National Prevalence of Self-Reported Coronary Heart Disease and Chronic Stable Angina Pectoris: Factor Analysis of the Underlying Cardiometabolic Risk Factors in the SuRFNCD-2011.

BACKGROUND: Coronary heart disease (CHD) is one of the most common causes of mortality worldwide. The national prevalence remains unclear in most of the developing countries. OBJECTIVE: This study sought to estimate national prevalence of self-reported CHD and chronic stable angina pectoris in the general adult population of Iran using data from the fourth round of the Surveillance of Risk Factors of Non-Communicable Diseases (SuRFNCD-2011) survey. METHODS: The analysis comprised data of 11,867 civilian, nonhospitalized and noninstitutionalized residents ages 6 to 70 years of age. The calculated prevalence of self-reported CHD and chronic stable angina pectoris were extrapolated to the Iranian adult population who were >20 years old using the complex sample analysis. The factor analysis was performed for clustering of the associated cardiometabolic risk factors among people ages >40 years of age. RESULTS: The estimated national prevalence of self-reported CHD and chronic stable angina pectoris were 5.3% (95% confidence interval: 4.6 to 5.9) and 7.7% (95% confidence interval: 4.6 to 8.7), respectively. Higher prevalence of these conditions were observed among the older people, urban residents, and women. Factor analysis generated 4 distinct factors that were mainly indicators of dyslipidemia, hypertension, central obesity, hyperglycemia, and tobacco smoking. The factor incorporating hypertension was a significant correlate of self-reported CHD. CONCLUSIONS: We report concerning prevalence of self-reported CHD and chronic stable angina pectoris in the adult population of Iran. The constellation of raised systolic and diastolic blood pressures was significantly predictive of the presence of self-reported CHD.

Potential diagnostic value of 131I-MIBG myocardial scintigraphy in discrimination between Alzheimer disease and dementia with Lewy bodies.

OBJECTIVES: Clinical difficulty to discriminate between the Alzheimer disease (AD) and dementia with Lewy bodies (DLB) has led researchers to focus on highly sensitive functional imaging modalities. The aim of the present study was to assess 131I-MIBG cardiac imaging to distinguish between AD and DLB. PATIENTS AND METHODS: Seventeen patients who were known cases of dementia underwent 131I-MIBG myocardial scintigraphy to differentiate AD from DLB. Planar and 131I-MIBG SPECT were obtained 2h after the injection of 1mCi 131I-MIBG on a dual head gamma camera. The visual assessment of the heart uptake compared with lungs and the quantification based on the heart to mediastinal ratio (HMR) were done. The cardiac receiver operating characteristic (ROC) curve was designed for the optimal HMR cut-off values to predict the diagnoses of the patients. The diagnoses were clinically confirmed during the follow up of 14±8.2 months. RESULTS: Out of 17 patients (13 males; 76.5%), 10 patients had AD (7 males; 70%) and 7 patients had DLB (6 males; 85%). The pooled HMR was 1.74±0.33 in the study population; with 1.95±0.22 in the AD group and 1.43±0.20 in the DLB group to demonstrate significantly different HMR scores between patients with AD and DLB (p value=0.001). The visual interpretation was positive in 10 patients (accuracy of 88.2%). The shortest distance on the ROC curve to the optimal value corresponding to HMR=1.57 identified 10 patients with a high HMR (positive cardiac uptake) and 7 patients with a low HMR (negative cardiac uptake), the accuracy calculated at 88.2%. CONCLUSION: 131I-MIBG myocardial scintigraphy is a potential alternative diagnostic modality for discrimination between AD and DLB when 123I is not available.

Diabetes in Iran: Prospective Analysis from First Nationwide Diabetes Report of National Program for Prevention and Control of Diabetes (NPPCD-2016).

We estimated proportions of different types of diabetes, comorbidities, treatment (the use of oral glucose-lowering agents and insulin), control (hyperglycemia, dyslipidemia and hypertension) and chronic microvascular and macrovascular complications among people with diabetes presenting to the tertiary-care academic diabetes outpatient clinics in Iran. This study is the prospective analysis of data (n = 30,202) from the registry of university-affiliated adult outpatient diabetes clinics in the country during 2015-2016. The proportions of type 1 diabetes, types 2 diabetes, and other types of diabetes were 11.4%, 85.5%, and 1.3%, respectively. The frequencies of drug-naivety, use of oral agents, insulin monotherapy and insulin combination therapy were 2.9%, 60.5%, 11.5%, and 25.1%, respectively. Around 13.2%, 11.9% and 43.3% of patients with diabetes had controlled hyperglycemia, hyperlipidemia and hypertension, respectively. The proportions of retinopathy, nephropathy, peripheral neuropathy, diabetic foot, and ischemic heart disease were 21.9%, 17.6%, 28.0%, 6.2%, and 23.9%, respectively. Despite the wide availability of medications and insulin coverage in Iran, the estimated national control of hyperglycemia, hyperlipidemia and hypertension (especially for young men and old women) remains subpar. The present study further suggests that the frequencies of chronic vascular complications among patients with diabetes are relatively high in Iran.

Glioblastoma Multiforme: an Advanced Analysis of 153 Patients and Review of the Literature

Objective Glioblastoma multiforme (GBM) is an aggressive primary tumor with frequent recurrences that leaves patients with a short survival time and a low quality of life. The aim of this study was to review the prognostic factors in patients with glioblastoma multiforme. Material and Methods The focus of this retrospective study was a group of 153 patients with supratentorial GBM tumors, who were admitted to a tertiary-care referral academic center from 2005 to 2013. The factors associated with survival and local recurrence were assessed using the hazard ratio (HR) function of Cox proportional hazards regression and neural network analysis. Results Out of the 153 patients, 99 (64.7%) weremale. The average age of the patients was 55.69 15.10 years. The median overall survival (OS) and progression-free survival (PFS) rates were 14.0 and 7.10 months respectively. In the multivariate analysis, age (HR » 2.939, p < 0.001), operative method (HR » 7.416, p < 0.001), temozolomide (TMZ, HR » 11.723, p < 0.001), lomustine (CCNU, HR » 8.139, p < 0.001), occipital lobe involvement (HR » 3.088, p < 0.001) and Karnofsky Performance Status (KPS, HR » 4.831, p < 0.001) scores were shown to be significantly associated with a higher OS rate. Furthermore, higher KPS (HR » 7.292, p < 0.001) readings, the operative method (HR » 0.493, p » 0.005), the use of CCNU (HR » 2.047, p » 0.003) and resection versus chemotherapy (HR » 0.171, p < 0.001) were the significant factors associated with the local recurrence of the tumor. Conclusion Our findings suggest that the use of CCNU and TMZ, the operative method and higher KPS readings are associated with both higher survival and lower local recurrence rates.

Objetivo Glioblastoma multiforme (GBM) é um tumor primário agressivo com recorrências frequentes que deixam pacientes com uma curta sobrevida e baixa qualidade de vida. O objetivo deste estudo é rever fatores de prognóstico em pacientes com glioblastoma multiforme. Material e Métodos O foco deste estudo retrospectivo foi um grupo de 153 pacientes com tumores GBM supratentoriais, os quais deram entrada em um centro acadêmico de atendimento de referência de 2005 a 2013. Fatores associados com a sobrevivência e a recorrência local foram avaliados usando a razão de risco (RR) da regressão de risco proporcional de Cox e análise de redes neurais. Resultados Dos 153 pacientes, 99 (64,7%) eram homens. A média de idade foi de 55,69 15,10 anos. A sobrevida geral (SG) mediana e a sobrevida de livre progressão (SLP) foram 14,0 e 7,10 meses, respectivamente. Na análise multivariada, idade (RR » 2,939, p < 0,001), método operatório (RR » 7,416, p < 0,001), temozolomida (TMZ, RR » 11,723, p < 0,001), lomustina (CCNU, RR » 8,139, p < 0,001), envolvimento do lobo occipital (RR » 3,088, p < 0,001) e Índice de Desempenho de Karnofsky (IDK, RR » 4,831, p < 0,001) foram identificados como significativamente associados a uma SG maior. Além disso, leituras maiores de IDK (RR » 7,292, p < 0,001), o método operatório (RR » 0,493, p » 0,005), o uso de CCNU (RR » 2,047, p » 0,003) e ressecção versus quimioterapia (RR » 0,171, p < 0,001) foram fatores significativos associados à recorrência local de tumor. Conclusão Nossos resultados sugerem que o uso de CCNU e TMZ, o método operatório e leituras maiores de IDK estão associados tanto à maior sobrevida quanto à menor recorrência local.

Association of peripheral nesfatin-1 with early stage diabetic nephropathy.

BACKGROUND: Nesfatin-1 is a newly found anorectic neuropeptide with potent metabolic regulatory effects that its circulating levels are shown to be elevated in diabetes. We compared serum nesfatin-1 in patients with type 2 diabetes and microalbuminuria (30mg/day≤urinary albumin excretion (UAE) <300mg/day) with their control patients with type 2 diabetes and normoalbuminuria (UAE <30mg/day). PATIENTS AND METHODS: In a cross sectional setting, 44 adult patients with type 2 diabetes and microalbuminuria and 44 control patients with type 2 diabetes and normoalbuminuria were evaluated. Serum levels of nesfatin-1 along with demographic, clinical and biochemical factors associated with diabetes was measured. RESULTS: Mean peripheral concentrations of nesfatin-1 were significantly higher in patients with diabetes who had microalbuminuria compared to normoalbuminuric control patients (175.27±25.96pg/ml vs. 134.66±23.18pg/ml, respectively; p value<0.001). Significant positive correlations were found between circulating nesfatin-1 levels and the following case-mix variables: duration of diabetes, glycated hemoglobin, plasma creatinine, UAE and serum uric acid. In the multivariate logistic regression and after adjustment for a constellation of potentially confounding variables associated with diabetic kidney disease (DKD), circulating nesfatin-1 was the only variable significantly associated with microalbuminuria (odds ratio [95% confidence interval]=1.224 [1.007-1.487], p value=0.042). CONCLUSION: In patients with type 2 diabetes, circulating nesfatin-1 appears to be associated with microalbuminuria independent of other established risk factors of DKD. The underlying pathophysiological mechanisms and the prognostic significance of this association remain to be elucidated.

Systemic Kikuchi-Fujimoto disease bordering lupus lymphadenitis: A fresh look?

A 31-year old woman with persistent fever for 6 weeks and unresponsive to antibiotic therapy came for rheumatologic investigation. After computed tomography (CT) studies of her neck, thorax and abdomen revealed bilateral cervical, axillary and retroperitoneal lymph node enlargements, histopathologic evaluation of the resected nodes showed features of histiocytic necrotizing lymphadenopathy suggestive of Kikuchi-Fujimoto's lymphadenopathy. Kikuchi-Fujimoto Disease (KFD) involving the retroperitoneal nodes is extremely unusual and even more challenging to diagnose when there are no early signs of extranodal involvement or abdominopelvic pain. We present a case of systemic KFD involving the cervical, axillary and retroperitoneal lymph nodes and emphasize the clinical interest to properly differentiate between the benign condition of KFD that requires no more than minimal to low dosage steroid therapy and the potentially life-threatening lupus lymphadenitis that mandates intensive immunosuppressive treatment.