Stress and Heart in Remodeling Process: Multiple Stressors at the Same Time Kill.

Myocardial remodeling is developed by increased stress in acute or chronic pathophysiologies. Stressed heart morphology (SHM) is a new description representing basal septal hypertrophy (BSH) caused by emotional stress and chronic stress due to increased afterload in hypertension. Acute stress cardiomyopathy (ASC) and hypertension could be together in clinical practice. Therefore, there are some geometric and functional aspects regarding this specific location, septal base under acute and chronic stress stimuli. The findings by our and the other research groups support that hypertension-mediated myocardial involvement could be pre-existed in ASC cases. Beyond a frequently seen predominant base, hyperkinetic tissue response is detected in both hypertension and ASC. Furthermore, hypertension is the responsible factor in recurrent ASC. The most supportive prospective finding is BSH in which a hypercontractile base takes a longer time to exist morphologically than an acutely developed syndrome under both physiologic exercise and pressure overload by transaortic binding in small animals using microimaging. However, cardiac decompensation with apical ballooning could mask the possible underlying hypertensive disease. In fact, enough time for the assessment of previous hypertension history or segmental analysis could not be provided in an emergency unit, since ASC is accepted as an acute coronary syndrome during an acute episode. Additional supportive findings for SHM are increased stress scores in hypertensive BSH and the existence of similar tissue aspects in excessive sympathetic overdrive like pheochromocytoma which could result in both hypertensive disease and ASC. Exercise hypertension as the typical form of blood pressure variability is the sum of physiologic exercise and pathologic increased blood pressure and results in increased mortality. Hypertension is not rare in patients with a high stress score and leads to repetitive attacks in ASC supporting the important role of an emotional component as well as the potential danger due to multiple stressors at the same time. In the current review, the impact of multiple stressors on segmental or global myocardial remodeling and the hazardous potential of multiple stressors at the same time are discussed. As a result, incidentally determined segmental remodeling could be recalled in patients with multiple stressors and contribute to the early and combined management of both hypertension and chronic stress in the prevention of global remodeling and heart failure.

Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma.

Tumor-associated microglia and blood-derived macrophages (TAMs) play a central role in modulating the immune suppressive microenvironment in glioma. Here, we show that GPNMB is predominantly expressed by TAMs in human glioblastoma multiforme and the murine RCAS-PDGFb high grade glioma model. Loss of GPNMB in the in vivo tumor microenvironment results in significantly smaller tumor volumes and generates a pro-inflammatory innate and adaptive immune cell microenvironment. The impact of host-derived GPNMB on tumor growth was confirmed in two distinct murine glioma cell lines in organotypic brain slices from GPNMB-KO and control mice. Using published data bases of human glioma, the elevated levels in TAMs could be confirmed and the GPNMB expression correlated with a poorer survival.

Effects of Different Inspiratory Muscle Training Protocols on Exercise Capacity, Respiratory Muscle Strength, and Health-Related Quality of Life in Patients with Hypertension.

Aim: This study aimed to explore how varying inspiratory muscle training workloads affect exercise capacity, health-related quality of life (HrQoL), depression, peripheral and respiratory muscle strength, pulmonary function, dyspnea, fatigue, and physical activity levels in hypertension (HT) patients. Methods: A randomized, controlled three-arm study. Forty-five patients (58.37 ± 8.53 y, 7F/38M) with HT received IMT (7 days/8 weeks) by POWERbreathe® Classic LR device and were randomized to control group (CG, 10% maximal inspiratory pressure (MIP), n: 15), low-load group (LLG, 30% MIP), and high-load group (HLG, %50 MIP). Exercise capacity, HrQoL, depression, peripheral and respiratory muscle strength, pulmonary function, fatigue, physical activity level, dyspnea, and sleep quality were evaluated before and after the training. Results: Exercise capacity, physical functioning, peripheral muscle strength, and resting dyspnea were statistically significantly improved in HLG and LLG after the training compared to CG (p < 0.05). Similar improvements in perception of depression, fatigue, and sleep quality were seen within and between the groups (p > 0.05). Statistically significant differences were found within all the groups in terms of MIP and PEF values of respiratory functions (p < 0.05). The superior improvement in the physical activity level was found in the HLG (p < 0.05). Discussion. High-load IMT was particularly effective in increasing physical activity level, peripheral muscle strength, exercise capacity, and improved HrQoL. Low-load IMT was effective in reducing dyspnea and improving respiratory function. Device-guided breathing exercises decreased blood pressure, improved sleep quality, and strengthened respiratory muscles. IMT, an efficient method, is suggested for inclusion in rehabilitation programs due to its capacity to increase physical activity, exercise capacity, and peripheral muscle strength, enhance HrQoL and respiratory function, and alleviate dyspnea. Also, the efficacy of IMT should be investigated with different training protocols such as endurance IMT or functional IMT in HT patients.

Involved-Site Radiation Therapy Enables Effective Disease Control in Parenchymal Low-Grade Primary Cerebral Lymphoma.

BACKGROUND: Primary lymphoma of the central nervous system (PCNSL) encompasses a variety of lymphoma subtypes, with the majority being diffuse large B-cell lymphomas, which require aggressive systemic treatment. In contrast, low-grade lymphomas are reported infrequently and are mostly limited to dural manifestations. Very rarely, parenchymal low-grade PCNSL is diagnosed, and the cases documented in the literature show a wide variety of treatment approaches. METHODS: We screened all cases of PCNSL treated at our department (a tertiary hematooncology and neurooncology center) in the last 15 years and conducted a comprehensive literature research in the PubMed database. RESULTS: Overall, two cases of low-grade primary parenchymal PCNSL treated with irradiation were identified. The dose prescriptions ranged from 30.6 to 36 Gy for the involved site, with sparing of the hippocampal structures. Both patients had an excellent response to the treatment with a mean follow-up of 20 months. No clinical or radiological signs of treatment toxicity were detected. CONCLUSIONS: Our analysis corroborates the results from the literature and demonstrates that parenchymal low-grade PCNSL shows a good response to localized radiation treatment, enabling a favorable outcome while avoiding long-term treatment toxicity.

Systolic blood pressure ≤110 mm Hg is associated with severe coronary microvascular ischemia and higher risk for ventricular arrhythmias in hypertrophic cardiomyopathy.

Background: Coronary microvascular dysfunction (CMD) and hypertension (HTN) occur frequently in hypertrophic cardiomyopathy (HCM), but whether blood pressure (BP) influences CMD and outcomes is unknown. Objective: The purpose of this study was to test the hypothesis that HTN is associated with worse CMD and outcomes. Methods: This retrospective study included 690 HCM patients. All patients underwent cardiac magnetic resonance imaging, echocardiography, and rhythm monitoring; 127 patients also underwent rest/vasodilator stress 13NH3 positron emission tomography myocardial perfusion imaging. Patients were divided into 3 groups based on their rest systolic blood pressure (SBP) (group 1 ≤110 mm Hg; group 2 111-140; group 3 >140 mm Hg) and were followed for development of ventricular tachycardia (VT)/ventricular fibrillation (VF), heart failure (HF), death, and composite outcome. Results: Group 1 patients had the lowest age and left ventricular (LV) mass but the highest prevalence of nonobstructive hemodynamics and restrictive diastolic filling. LV scar was similar in the 3 groups. Group 1 had the lowest rest and stress myocardial blood flow (MBF) and highest SDS (summed difference score). Rest SBP was positively correlated with stress MBF and negatively correlated with SDS. Group 1 had the highest incidence of VT/VF, whereas the incidences of HF, death, and composite outcome were similar among the 3 groups. In multivariate analysis, rest SBP ≤110 mm Hg was independently associated with VT/VF (hazard ratio 2.6; 95% confidence interval 1.0-6.7; P = .04). Conclusion: SBP ≤110 mm Hg is associated with greater severity of CMD and coronary microvascular ischemia and higher incidence of ventricular arrhythmias in HCM.

Effectiveness of Device-Guided Breathing in Chronic Coronary Syndrome: A Randomized Controlled Study.

Background: Chronic coronary syndrome (CCS) is one of the most life-restricting coronary artery diseases, and symptom relief is the main goal in CCS patients who suffer from angina. Objectives: To assess the potential benefits of device-guided breathing in CCS patients with angina in this randomized, controlled, single-blinded study. Methods: Fifty-one patients with CCS received device-guided breathing for 7 days/8 weeks. Exercise capacity [exercise stress test], cardiac function [transthoracic echocardiography], and angina severity [Canadian Cardiovascular Society Classification] were evaluated initially and after the training. Device-guided breathing was performed at the lowest resistance of the device (POWERbreathe® Classic LR) for the control group (n = 17). The low load training group (LLTG; n = 18) and high load training group (HLTG; n = 16) were trained at 30% and 50% of maximal inspiratory pressure. Baseline characteristics were compared using one-way ANOVA and Kruskal-Wallis test. Categorical data were compared using the chi-square test. ANCOVA was performed to compare changes between three groups. A p value < 0.05 was considered statistically significant. Results: Metabolic equivalent values were significantly improved in both HLTG and LLTG groups (p < 0.001, p = 0.003). The Duke treadmill score significantly improved and shifted to low-risk both in the HLTG (p < 0.001) and LLTG (p < 0.001) groups. Angina severity significantly alleviated after the training in both HLTG and LLTG groups (p < 0.001, p = 0.002). Conclusions: An 8-week long program of short-term respiratory muscle training provided positive gains in exercise capacity and angina severity in CCS patients with angina. The effects of long-term training programs on CCS patients should be investigated clinically because of the possibility of helping to decrease the need for invasive treatments.

It Is Time to Focus on "Segmental Remodeling" with Validated Biomarkers as "Stressed Heart Morphology" in Prevention of Heart Failure.

In cardiovascular medicine, hemodynamic stress with hypertension is a major risk [...].

Targeting UDP-α-d-glucose 6-dehydrogenase alters the CNS tumor immune microenvironment and inhibits glioblastoma growth.

Glioblastoma (GBM, WHO grade IV glioma) is the most common and lethal malignant brain tumor in adults with a dismal prognosis. The extracellular matrix (ECM) supports GBM progression by promoting tumor cell proliferation, migration, and immune escape. Uridine diphosphate (UDP)-glucose 6-dehydrogenase (UGDH) is the rate-limiting enzyme that catalyzes the biosynthesis of glycosaminoglycans that are the principal component of the CNS ECM. We investigated how targeting UGDH in GBM influences the GBM immune microenvironment, including tumor-associated microglia/macrophages (TAMs) and T cells. TAMs are the main immune effector cells in GBM and can directly target tumor cells if properly activated. In co-cultures of GBM cells and human primary macrophages, UGDH knockdown in GBM cells promoted macrophage phagocytosis and M1-like polarization. In orthotropic human GBM xenografts and syngeneic mouse glioma models, targeting UGDH decreased ECM deposition, increased TAM phagocytosis marker expression, reduced M2-like TAMs and inhibited tumor growth. UGDH knockdown in GBM cells also promoted cytotoxic T cell infiltration and activation in orthotopic syngeneic mouse glioma models. The potent and in-human-use small molecule GAG synthesis inhibitor 4-methylumbelliferone (4-MU) was found to inhibit GBM cell proliferation and migration in vitro, mimic the macrophage and T-cell responses to UGDH knockdown in vitro and in vivo and inhibit growth of orthotopic murine GBM. Our study shows that UGDH supports GBM growth through multiple mechanisms and supports the development of ECM-based therapeutic strategies to simultaneously target tumor cells and their microenvironment.

Ultimate phases of hypertensive heart disease and stressed heart morphology by conventional and novel cardiac imaging.

Early recognition of hypertensive heart disease is needed to prevent macrovascular and microvascular damage. Hypertension (HTN) is a risk factor for coronary artery disease, and plays a prominent role in the development of adverse left ventricular (LV) remodeling and heart failure. Here, we review new knowledge on effects of HTN on cardiac geometry and function, obtained from multimodality cardiac imaging, including echocardiography, positron emission tomography and magnetic resonance imaging. Early recognition of changes in LV geometry and function induced by HTN could identify patients at risk for end-organ damage, who could be targeted for close monitoring and intensive therapy. Basal septal hypertrophy as the early imaging biomarker at the adaptive phase may be a specific aspect not only in hypertensive heart but stress-related conditions and called stressed heart morphology.

Hemodynamic stress and microscopic remodeling.

BACKGROUD: Heart responds to physiologic and pathologic conditions and sympathetic drive plays an important role. It has been documented that LV base is more dominantly affected by sympathetic drive compared to the other regions. LV base is more dominantly exposed to wall stress in the initial period of remodeling due to pressure-overload, since LV cavity is the largest at base. Basal septal hypertrophy (BSH) in cross-sectional data is associated with the early phase of hypertensive heart disease. BSH was confirmed by 3rd generation microscopic ultrasound in small animals. BSH as the closest location to increased afterload could be detected in variety of stress stimuli and result in a huge septal hypertrophy in advance cases possibly related to earlier exposure of hemodynamic stress to septal wall. CONCLUSION: Effective geometric and functional evaluation of initial remodeling due to hemodynamic stress is important according to both human and animal data. These findings possibly contribute to early recognition of adaptive phase of hypertensive remodeling and more effective management in a timely fashion.

Mutant IDH1 promotes phagocytic function of microglia/macrophages in gliomas by downregulating ICAM1.

Tumor-associated microglia/macrophages (TAMs) are the main innate immune effector cells in malignant gliomas and have both pro- and anti-tumor functions. The plasticity of TAMs is partially dictated by oncogenic mutations in tumor cells. Heterozygous IDH1 mutation is a cancer driver gene prevalent in grade II/III gliomas, and IDH1 mutant gliomas have relatively favorable clinical outcomes. It is largely unknown how IDH mutation alters TAM phenotypes to influence glioma growth. Here we established clinically relevant isogenic glioma models carrying monoallelic IDH1 R132H mutation (IDH1R132H/WT) and found that IDH1R132H/WT significantly downregulated immune response-related pathways in glioma cells, indicating an immunomodulation role of mutant IDH1. Co-culturing IDH1R132H/WT glioma cells with human macrophages promoted anti-tumor phenotypes of macrophages and increased macrophage migration and phagocytic capacity. In orthotopic xenografts, IDH1R132H/WT decreased tumor growth and prolonged animal survival, accompanied by increased TAM recruitment and upregulated phagocytosis markers, suggesting the induction of anti-tumor TAM functions. Using human cytokine arrays that query 36 proteins, we identified significant downregulation of ICAM-1/CD54 in IDH1R132H/WT gliomas, which was further confirmed by ELISA and immunoblotting analyses. ICAM1 gain-of-function studies revealed that ICAM1 downregulation in IDH1R132H/WT cells played a mechanistic role to mediate the immunomodulation function of IDH1R132H/WT. ICAM-1 silencing in IDH1 wild-type glioma cells decreased tumor growth and increased the anti-tumor function of TAMs. Together, our studies support a new TAM-mediated phagocytic function within IDH1 mutant gliomas, and improved understanding of this process may uncover novel approaches to targeting IDH1 wild type gliomas.

Predictive value of the SYNTAX score for diabetic retinopathy in stable coronary artery disease patients with a concomitant type 2 diabetes mellitus.

AIMS: Diabetic retinopathy (DR) is a serious complication of type 2 diabetes mellitus (T2DM) and is the most common cause of impaired vision for adults. DR is related to a number of risk factors. The aim of this study was to investigate the relationship between burden of coronary artery disease assessed by Syntax Score (SS) and DR in T2DM. METHODS: A total of 96 T2DM patients undergoing coronary angiography were prospectively included in the study. Presence and severity of DR were assessed by ocular fundus examination. DR was graded as no apparent retinopathy (NDR), non-proliferative (NPDR), and proliferative DR (PDR). The SS for each patient was calculated. RESULTS: The mean age was 58.0 ± 8.2 years. SS gradually increased from NDR group to PDR group. The median (IQR) value of SS was 10 (5-16) in patients with NDR, 22.8 (17-35.8) in those with NPDR, and 35.5 (28-37) in those with PDR (p < 0.001). On multivariate analysis SS [odds ratio (OR) 1.145, p = 0.001] and duration of diabetes (OR 1.753, p = 0.031) were independent factors for DR. CONCLUSIONS: The SS is independently associated with the occurrence of DR in T2DM. Ophthalmologists and cardiologists must cooperate when evaluating patients with DM because of possible complications.

Basal Septal Hypertrophy as the Early Imaging Biomarker for Adaptive Phase of Remodeling Prior to Heart Failure.

Hypertension plays a dominant role in the development of left ventricular (LV) remodeling and heart failure, in addition to being the main risk factor for coronary artery disease. In this review, we focus on the focal geometric and functional tissue aspects of the LV septal base, since basal septal hypertrophy (BSH), as the early imaging biomarker of LV remodeling due to hypertensive heart disease, is detected in cross-sectional clinic studies. In addition, the validation of BSH by animal studies using third generation microimaging and relevant clinical observations are also discussed in the report. Finally, an evaluation of both human and animal quantitative imaging studies and the importance of combined cardiac imaging methods and stress-induction in the separation of adaptive and maladaptive phases of the LV remodeling are pointed out. As a result, BSH, as the early imaging biomarker and quantitative follow-up of functional analysis in hypertension, could possibly contribute to early treatment in a timely fashion in the prevention of hypertensive disease progression to heart failure. A variety of stress stimuli in etiopathogenesis and the difficulty of diagnosing pure hemodynamic overload mediated BSH lead to an absence of the certain prevalence of this particular finding in the population.

Increased Rates of Coronary Artery Calcium Score in Patients with Non - Functioning Adrenal Incidentaloma.

AIM: We evaluated cardiovascular (CV) risk stratification for nonfunctioning adrenal incidentalomas (NFAIs) via the coronary-artery-calcium (CAC) score. MATERIALS AND METHODS: The participants were patients with NFAI (n = 55). They were compared to patients with chest pain, a low-intermediate Framingham-risk score, and a non-diagnostic treadmill- exercise test, which served as the control group (n = 49). Subsequently, the NFAI group was subdivided according to a CAC score of <100 Agatston units - mild coronary-artery calcification (n = 40) - and ≥100 Agatston units - moderate-to-severe calcification (n = 15). RESULTS: Similar rates of traditional risk factors were observed between the NFAI and control groups, and lower low-density lipoprotein cholesterol rates were observed in the NFAI group. The CAC score was significantly higher for the NFAI group than the control group. Glucose, potassium, adrenocorticotropic-hormone, and basal-cortisol levels were higher in those with a CAC score of ≥100. High-density-lipoprotein cholesterol estimated glomerular filtration rate and ejection fraction (EF) were higher in those with a CAC score of <100. Adenoma size and location were similar between the groups. Age, EF, and glucose were the most significant variables related to CAC score in patients with NFAI, at ≥100 Agatston units. DISCUSSION: Patients with a low-intermediate CV risk profile and NFAI have a higher risk of atherosclerosis when compared to patients with a low-intermediate CV risk profile, but no NFAI. CONCLUSION: In patients with NFAI, CAC score evaluation may be used to predict increased atherosclerosis, especially in patients of an older age with higher glucose and decreased EF.

Tenascin-C Function in Glioma: Immunomodulation and Beyond.

First identified in the 1980s, tenascin-C (TNC) is a multi-domain extracellular matrix glycoprotein abundantly expressed during the development of multicellular organisms. TNC level is undetectable in most adult tissues but rapidly and transiently induced by a handful of pro-inflammatory cytokines in a variety of pathological conditions including infection, inflammation, fibrosis, and wound healing. Persistent TNC expression is associated with chronic inflammation and many malignancies, including glioma. By interacting with its receptor integrin and a myriad of other binding partners, TNC elicits context- and cell type-dependent function to regulate cell adhesion, migration, proliferation, and angiogenesis. TNC operates as an endogenous activator of toll-like receptor 4 and promotes inflammatory response by inducing the expression of multiple pro-inflammatory factors in innate immune cells such as microglia and macrophages. In addition, TNC drives macrophage differentiation and polarization predominantly towards an M1-like phenotype. In contrast, TNC shows immunosuppressive function in T cells. In glioma, TNC is expressed by tumor cells and stromal cells; high expression of TNC is correlated with tumor progression and poor prognosis. Besides promoting glioma invasion and angiogenesis, TNC has been found to affect the morphology and function of tumor-associated microglia/macrophages in glioma. Clinically, TNC can serve as a biomarker for tumor progression; and TNC antibodies have been utilized as an adjuvant agent to deliver anti-tumor drugs to target glioma. A better mechanistic understanding of how TNC impacts innate and adaptive immunity during tumorigenesis and tumor progression will open new therapeutic avenues to treat brain tumors and other malignancies.

Synergistic Toll-like Receptor 3/9 Signaling Affects Properties and Impairs Glioma-Promoting Activity of Microglia.

In murine experimental glioma models, TLR3 or TLR9 activation of microglial/macrophages has been shown to impair glioma growth, which could, however, not been verified in recent clinical trials. We therefore tested whether combined TLR3 and TLR9 activation of microglia/macrophages would have a synergistic effect. Indeed, combined TLR3/TLR9 activation augmented the suppression of glioma growth in organotypic brain slices from male mice in a microglia-dependent fashion, and this synergistic suppression depended on interferon ß release and phagocytic tumor clearance. Combined TLR3/TLR9 stimulation also augmented several functional features of microglia, such as the release of proinflammatory factors, motility, and phagocytosis activity. TLR3/TLR9 stimulation combined with CD47 blockade further augmented glioma clearance. Finally, we confirmed that the coactivation of TLR3/TLR9 also augments the impairment of glioma growth in vivo Our results show that combined activation of TLR3/TLR9 in microglia/macrophages results in a more efficient glioma suppression, which may provide a potential strategy for glioma treatment.SIGNIFICANCE STATEMENT Glioma-associated microglia/macrophages (GAMs) are the predominant immune cells in glioma growth and are recently considered as antitumor targets. TLRs are involved in glioma growth, but the TLR3 or TLR9 ligands were not successful in clinical trials in treating glioma. We therefore combined TLR3 and TLR9 activation of GAMs, resulting in a strong synergistic effect of tumor clearance in vitro, ex vivo, and in vivo Mechanisms of this GAM-glioma interaction involve IFNß signaling and increased tumor clearance by GAMs. Interfering with CD47 signaling had an additional impact on tumor clearance. We propose that these signaling pathways could be exploited as anti-glioma targets.