Celiac Disease, Gluten-Free Diet and Metabolic Dysfunction-Associated Steatotic Liver Disease.

Celiac disease (CD) is a chronic autoimmune disorder triggered by the ingestion of gluten-containing food by genetically predisposed individuals. Hence, treatment of CD consists of permanent avoidance of wheat, rye, barley, and other gluten-containing foods. Lifelong adherence to a gluten-free diet (GFD) improves the symptoms of CD, but recent evidence suggests it is also associated with a higher risk for hepatic steatosis and the coexistence or emergence of other cardiometabolic risk factors. Moreover, a higher risk for liver steatosis is also reported by some authors as a potential extraintestinal complication of the CD itself. Recent nomenclature changes designate the association between hepatic steatosis and at least one of five cardiometabolic risk factors as metabolic dysfunction-associated steatotic liver disease (MASLD). An extended network of potentially causative factors underlying the association between MAFLD and CD, before and after dietary therapy is implemented, was recently described. The individualized treatment of these patients is less supported by evidence, with most of the current recommendations relying on empiric clinical judgment. This review focuses on the causative associations between CD and hepatic injury, either as an extraintestinal manifestation of CD or a side effect of GFD, also referring to potential therapeutic strategies for these individuals.

Effects of Incretin-Based Treatment on the Diastolic (Dys)Function in Patients with Uncontrolled Type 2 Diabetes Mellitus: A Prospective Study with 1-Year Follow-Up.

Left ventricular diastolic dysfunction (DD) is a subclinical cardiac abnormality in patients with type 2 diabetes mellitus (T2DM) that can progress to heart failure (HF) and increase cardiovascular risk. This prospective study evaluated the DD in T2DM patients without atherosclerotic cardiovascular disease after one year of incretin-based drugs added to standard treatment. Of the 138 enrolled patients (49.30% male, mean age 57.86 ± 8.82, mean T2DM history 5 years), 71 were started on dipeptidyl peptidase-4 inhibitor sitagliptin/saxagliptin, 21 on glucagon-like peptide-1 receptor agonist exenatide, and 46 formed the control group (metformin and sulphonylurea/acarbose). At baseline, 71 patients had grade 1 DD, another 12 had grade 2 and 3 DD, and 15 had indeterminate DD. After one year, DD was evidenced in 50 cases. Diastolic function improved in 9 cases, and 27 patients went from grade 1 to indeterminate DD. The active group benefited more, especially patients treated with exenatide; their metabolic and inflammation profiles also improved the most. An in-depth analysis of echocardiographic parameters and paraclinical results in the context of literature data justifies the conclusion that early assessment of diastolic function in T2DM patients is necessary and the benefits of affordable incretin-based treatment may extend to subclinical cardiovascular manifestations such as DD.

Distinct Features of Vascular Diseases in COVID-19.

The Coronavirus Disease 2019 (COVID-19) pandemic was declared in early 2020 after several unexplained pneumonia cases were first reported in Wuhan, China, and subsequently in other parts of the world. Commonly, the disease comprises several clinical features, including high temperature, dry cough, shortness of breath, and hypoxia, associated with findings of interstitial pneumonia on chest X-ray and computer tomography. Nevertheless, severe forms of acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) are not limited to the respiratory tract but also may be extended to other systems, including the cardiovascular system. The bi-directional relationship between atherosclerosis and COVID-19 is accompanied by poor prognosis. The immune response hyperactivation due to SARS-CoV-2 infection causes an increased secretion of cytokines, endothelial dysfunction, and arterial stiffness, which promotes the development of atherosclerosis. Also, due to the COVID-19 pandemic, access to healthcare amenities was reduced, resulting in increased morbidity and mortality in patients at risk. Furthermore, as lockdown measures were largely adopted worldwide, the sedentary lifestyle and the increased consumption of processed nutrients or unhealthy food increased, and in the consequence, we might observe even 70% of overweight and obese population. Altogether, with the relatively low ratio of vaccinated people in many countries, and important health debt appeared, which is now and will be for next decade a large healthcare challenge. However, the experience gained in the COVID-19 pandemic and the new methods of patients' approaching have helped the medical system to overcome this crisis and will hopefully help in the case of new possible epidemics.

Glucagon-like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease-Current Background, Hopes, and Perspectives.

Nonalcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease worldwide, reaching one of the highest prevalences in patients with type 2 diabetes mellitus (T2DM). For now, no specific pharmacologic therapies are approved to prevent or treat NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are currently evaluated as potential candidates for NAFLD treatment in patients with T2DM. Some representatives of this class of antihyperglycemic agents emerged as potentially beneficial in patients with NAFLD after several research studies suggested they reduce hepatic steatosis, ameliorate lesions of nonalcoholic steatohepatitis (NASH), or delay the progression of fibrosis in this population. The aim of this review is to summarize the body of evidence supporting the effectiveness of GLP-1RA therapy in the management of T2DM complicated with NAFLD, describing the studies that evaluated the effects of these glucose-lowering agents in fatty liver disease and fibrosis, their possible mechanistic justification, current evidence-based recommendations, and the next steps to be developed in the field of pharmacological innovation.

Infective Endocarditis during Pregnancy-Keep It Safe and Simple!

The diagnosis of infective endocarditis (IE) during pregnancy is accompanied by a poor prognosis for both mother and fetus in the absence of prompt management by multidisciplinary teams. We searched the electronic databases of PubMed, MEDLINE and EMBASE for clinical studies addressing the management of infective endocarditis during pregnancy, with the aim of realizing a literature review ranging from risk factors to diagnostic investigations to optimal therapeutic management for mother and fetus alike. The presence of previous cardiovascular pathologies such as rheumatic heart disease, congenital heart disease, prosthetic valves, hemodialysis, intravenous catheters or immunosuppression are the main risk factors predisposing patients to IE during pregnancy. The identification of modern risk factors such as intracardiac devices and intravenous drug administration as well as genetic diagnostic methods such as cell-free deoxyribonucleic acid (DNA) next-generation sequencing require that these cases be addressed in multidisciplinary teams. Guiding treatment to eradicate infection and protect the fetus simultaneously creates challenges for cardiologists and gynecologists alike.

Role of Chemerin and Perivascular Adipose Tissue Characteristics on Cardiovascular Risk Assessment by Arterial Stiffness Markers in Patients with Morbid Obesity.

BACKGROUND AND OBJECTIVE: The development of arterial stiffness (AS) in obesity is a multifactorial and complex process. The pleomorphic actions of adipokines and their local activity in perivascular adipose tissue (PVAT) are potential modulators of AS appearance and progression. We aimed to assess the correlations between two adipokines (chemerin, adiponectin), PVAT morphological changes (adipocyte size, blood vessel wall thickness) and AS parameters in the special subgroup of patients with morbid obesity. MATERIAL AND METHODS: We enrolled 25 patients with morbid obesity and 25 non-obese patients, who were age- and gender-matched, untreated for cardiovascular risk factors, and admitted to hospital for laparoscopic surgical procedures (bariatric surgery for morbid obesity and non-inflammatory benign pathology surgery for non-obese patients). Before the surgical procedures, we evaluated demographic and anthropometric data and biochemical parameters including the studied adipokines. Arterial stiffness was evaluated using a Medexpert ArteriographTM TL2 device. In both groups, adipocyte size and vascular wall thickness as well as local adiponectin activity were analyzed in PVAT from intraoperative biopsies. RESULTS: In our study, adiponectin (p = 0.0003), chemerin (p = 0.0001) and their ratio (p = 0.005) had statistically significant higher mean values in patients with morbid obesity compared to normal-weight patients. In patients with morbid obesity there were significant correlations between chemerin and AS parameters such as aortic pulse wave velocity (p = 0.006) and subendocardial viability index (p = 0.009). In the same group adipocyte size was significantly correlated with another AS parameter, namely, aortic systolic blood pressure (p = 0.030). In normal-weight patients, blood vessel wall thickness positively correlated with AS parameters such as brachial (p = 0.023) and aortic augmentation index (p = 0.023). An important finding was the negative adipoR1 and adipoR2 immunoexpression in PVAT adipocytes of patients with morbid obesity. Additionally, we found significant correlations between blood vessel wall thickness and blood fasting glucose (p < 0.05) in both groups. CONCLUSIONS: Chemerin and adipocyte size could be predictive biomarkers for AS in patients with morbid obesity. Given the small number of patients included, our results need further validation.

Determinants of Arterial Stiffness in Patients with Morbid Obesity. The Role of Echocardiography and Carotid Ultrasound Imaging.

Background and objective: Morbid obesity is accompanied by an increased cardiovascular (CV) risk, which justifies a multidisciplinary, integrative approach. Arterial stiffness has a well-defined additional role in refining individual CV risk. Given that echocardiography and carotid ultrasound are usual methods for CV risk characterization, we aimed to identify the imaging parameters with a predictive value for early-onset arterial stiffness. Material and methods: We conducted a study in which 50 patients (divided into two equal groups with morbid obesity and without obesity), age and gender matched, untreated for cardiovascular risk factors, were addressed to bariatric surgery or non-inflammatory benign pathology surgery. Before the surgical procedures, we evaluated demographics, anthropometric data and biochemical parameters including adipokines (chemerin, adiponectin). Arterial stiffness was evaluated using the Medexpert ArteriographTM TL2 device. Transthoracic echocardiography and carotid ultrasound were also performed. We also analyzed adipocyte size and vascular wall thickness in intraoperative biopsies. Results: Left ventricle (LV) mass index (p = 0.2851), LV ejection fraction (LVEF) (p = 0.0073), epicardial adipose tissue thickness (p = 0.0001) as echocardiographic parameters and carotid intima-media thickness (p = 0.0033), relative wall thickness (p = 0.0295), wall to lumen thickness ratio (p = 0.0930) and carotid cross-sectional area (p = 0.0042) as ultrasound parameters were significant measures in our groups and were assessed in relation to adipocyte size, blood vessel wall thickness and adipokines serum levels. Statistical analysis revealed directly proportional relationships between LV mass index (p = 0.008), carotid systolic thickness of the media (p = 0.009), diastolic thickness of the media (p = 0.007), cross-sectional area (p = 0.001) and blood vessel wall thickness. Carotid relative wall thickness positively correlates with adipocyte size (p = 0.023). In patients with morbid obesity, chemerin and adiponectin/chemerin ratio positively correlates with carotid intima-media thickness (p = 0.050), systolic thickness of the media (p = 0.015) and diastolic thickness of the media (p = 0.001). The multiple linear regression models revealed the role of epicardial adipose tissue thickness and carotid cross-sectional area in predicting adipocyte size which in turn is an independent factor for arterial stiffness parameters such as pulse wave velocity, subendocardial viability ratio and aortic augmentation index. Conclusions: Our results suggest that epicardial adipose tissue thickness, carotid intima-media thickness, relative wall thickness and carotid cross-sectional area might be useful imaging parameters for early prediction of arterial stiffness in patients with morbid obesity.

Ultrasound-Based Hepatic Elastography in Non-Alcoholic Fatty Liver Disease: Focus on Patients with Type 2 Diabetes.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and is the hepatic expression of metabolic syndrome. The development of non-invasive methods for the diagnosis of hepatic steatosis and advanced fibrosis in high-risk patients, especially those with type 2 diabetes mellitus, is highly needed to replace the invasive method of liver biopsy. Elastographic methods can bring significant added value to screening and diagnostic procedures for NAFLD in patients with diabetes, thus contributing to improved NAFLD management. Pharmacological development and forthcoming therapeutic measures that address NAFLD should also be based on new, non-invasive, and reliable tools that assess NAFLD in at-risk patients and be able to properly guide treatment in individuals with both diabetes and NAFLD. This is the first review aiming to outline and discuss recent studies on ultrasound-based hepatic elastography, focusing on NAFLD assessment in patients with diabetes.

Association of Inflammatory and Metabolic Biomarkers with Mitral Annular Calcification in Type 2 Diabetes Patients.

(1) Background: Type 2 diabetes mellitus (T2DM) contributes to cardiovascular disease and related mortality through the insidious effects of insulin resistance and chronic inflammation. Mitral annular calcification (MAC) is one such degenerative process promoted by T2DM. (2) Methods: This is a post hoc analysis of insulin resistance, inflammation, and hepatic steatosis markers in T2DM patients without atherosclerotic manifestations, but with incidental echocardiographic detection of mild MAC. (3) Results: 138 consenting patients were 49.3% men, 57.86 years old, with a history of T2DM of 6.16 years and HbA1c 8.06%, of whom sixty had mild MAC (43.47%). The statistically significant differences between patients with/without MAC were higher HOMA C-peptide and C-peptide index for insulin resistance, higher TNF-α for inflammation, and lower estimated glomerular filtration rate. High-sensitive C-reactive protein (hsCRP) was significantly associated with insulin resistance and the strength of the relationship was higher in the MAC group. Predictive of MAC were TNF-α, HOMA C-peptide, and especially hepatic steatosis and hypertension. (4) Conclusions: MAC was more prevalent than reported in the literature. Insulin resistance and inflammation were predictive of MAC, but significant markers differ across studies. Widely available routine tests and echocardiographic assessments are useful in the early identification of mitral annular calcifications in diabetes patients.

New Insights into Non-Alcoholic Fatty Liver Disease and Coronary Artery Disease: The Liver-Heart Axis.

Non-alcoholic fatty liver disease (NAFLD) represents the hepatic expression of the metabolic syndrome and is the most prevalent liver disease. NAFLD is associated with liver-related and extrahepatic morbi-mortality. Among extrahepatic complications, cardiovascular disease (CVD) is the primary cause of mortality in patients with NAFLD. The most frequent clinical expression of CVD is the coronary artery disease (CAD). Epidemiological data support a link between CAD and NAFLD, underlain by pathogenic factors, such as the exacerbation of insulin resistance, genetic phenotype, oxidative stress, atherogenic dyslipidemia, pro-inflammatory mediators, and gut microbiota. A thorough assessment of cardiovascular risk and identification of all forms of CVD, especially CAD, are needed in all patients with NAFLD regardless of their metabolic status. Therefore, this narrative review aims to examine the available data on CAD seen in patients with NAFLD, to outline the main directions undertaken by the CVD risk assessment and the multiple putative underlying mechanisms implicated in the relationship between CAD and NAFLD, and to raise awareness about this underestimated association between two major, frequent and severe diseases.

From chronic pruritus to neuroendocrine tumor: A case report.

Chronic pruritus is a major and distressing symptom of many diseases of dermatological, neurological, psychogenic or systemic origin. This chronic itch could be a presenting sign of malignancy; therefore, paraneoplastic pruritus has also been associated with neuroendocrine tumors (NETs). This article focuses on a patient presenting with chronic pruritus for the past 12 months and who received numerous treatment schemes with very poor clinical improvement, that presented in the hospital for worsening of the chronic pruritus associated with skin rash and significant weight loss (approximately 6 kg over a 2-month period). The laboratory tests showed iron deficiency anemia, eosinophilia and negative tumor markers. In order to investigate the hypoanabolic and anemic syndromes, upper gastrointestinal endoscopy and colonoscopy, which showed no lesions or tumors, were employed. Skin biopsy was performed and antihistaminic and local steroid treatment was initiated. The patient's status worsened within a week and the patient was started on systemic steroid treatment with poor results. Computer tomography was performed to identify any tumor(s) located either in the pelvis or abdomen. A lesion was found in the terminal ileum, identified as a hypervascularized associating bulky lymphadenopathy. The patient was transferred to the surgical ward where right hemicolectomy with manual ileotransverse anastomosis L-L was performed. The histopathological result confirmed NET G2. The patient clinically improved, the skin lesions resolved and the itchiness disappeared. The general status improved significantly. NET G2 diagnosing was possible due to the atypic paraneoplastic sign: chronic pruritus. This case study highlights the association between itch and malignancy and presents an atypical way of NET presentation when all tumor markers remain negative.

Self-Reported Satisfaction to Treatment, Quality of Life and General Health of Type 2 Diabetes Patients with Inadequate Glycemic Control from North-Eastern Romania.

Type 2 diabetes mellitus (T2DM) undermines health and quality of life (QoL). This cross-sectional study surveyed 138 consenting T2DM patients from North-Eastern Romania with regard to their satisfaction with treatment, diabetes-related impact on QoL, and general health. The Romanian versions of Diabetes Treatment Satisfaction Questionnaire (DTSQ), Audit of Diabetes Dependent Quality of Life (ADDQoL-19), and 36-Item Short Form Health Survey (SF-36) questionnaires were used. Self-reports were analyzed in conjunction with clinical and metabolic profiling. The patients were 57.86 ± 8.82 years old, 49.3% men, treated with oral glucose-lowering drugs, presenting with inadequate glycemic control but without cardiovascular manifestations. The mean DTSQ and ADDQoL scores were 25.46 ± 0.61 and -2.22 ± 1.2, respectively. Freedom to eat, holidays, journeys, leisure, physical health, sex life, freedom to drink, and feelings about the future scored below average. The mean SF-36 physical and mental health scores were 47.78 ± 1.03 and 50.44 ± 1.38, respectively. The mean SF-6D score was 0.59 ± 0.04 (generated retrospectively using SF-36 data). Negative associations were significant between ADDQoL, age (r = -0.16), and body mass index (r = -0.23), p < 0.01. Overall scores did not correlate with diabetes duration (except DTSQ, r = -1.18, p = 0.02) or HbA1c. The results confirm other researchers' findings in Europe and nearby countries. Our patients seemed satisfied with treatment despite glycemic imbalance and viewed diabetes as a burden on QoL and especially freedom to eat.

Biomarker Utility for Peripheral Artery Disease Diagnosis in Real Clinical Practice: A Prospective Study.

Peripheral arterial disease (PAD) is a common manifestation of generalized atherosclerosis, which affects more than 200 million patients worldwide. Currently, there is no ideal biomarker for PAD risk stratification and diagnosis. The goal of this research was to investigate the levels of inflammation biomarkers and cystatin C and to explore their utility for the diagnosis of PAD. The study included 296 participants, distributed in two groups: 216 patients diagnosed with PAD and 80 patients without PAD as controls. All studied biomarker levels (C-reactive protein, CRP; fibrinogen; erythrocyte sedimentation rate, ESR; neopterin; beta 2-microglobulin, B2-MG; and cystatin C) were significantly higher in the PAD group and indirectly correlated with the ankle-brachial index (ABI). The final logistic regression model included an association of neopterin, fibrinogen, and cystatin C as the most efficient markers for the prediction of PAD diagnosis. When comparing the area under the curve (AUC) for all biomarkers, the value for neopterin was significantly higher than those of all the other analyzed biomarkers. In agreement with previous studies, this research shows that markers such as fibrinogen, CRP, ESR, B2-MG, and cystatin C have significant value for the diagnosis of PAD, and also clearly underlines the accuracy of neopterin as a leading biomarker in PAD prediction.

Association of Antihyperglycemic Therapy with Risk of Atrial Fibrillation and Stroke in Diabetic Patients.

Type 2 diabetes mellitus (DM) is associated with an increased risk of cardiovascular disease (CVD). Atrial fibrillation (AF) and stroke are both forms of CVD that have major consequences in terms of disabilities and death among patients with diabetes; however, they are less present in the preoccupations of scientific researchers as a primary endpoint of clinical trials. Several publications have found DM to be associated with a higher risk for both AF and stroke; some of the main drugs used for glycemic control have been found to carry either increased, or decreased risks for AF or for stroke in DM patients. Given the risk for thromboembolic cerebrovascular events seen in AF patients, the question arises as to whether stroke and AF occurring with modified incidences in diabetic individuals under therapy with various classes of antihyperglycemic medications are interrelated and should be considered as a whole. At present, the medical literature lacks studies specifically designed to investigate a cause-effect relationship between the incidences of AF and stroke driven by different antidiabetic agents. In default of such proof, we reviewed the existing evidence correlating the major classes of glucose-controlling drugs with their associated risks for AF and stroke; however, supplementary proof is needed to explore a hypothetically causal relationship between these two, both of which display peculiar features in the setting of specific drug therapies for glycemic control.

Left Ventricular Diastolic Dysfunction in Type 2 Diabetes-Progress and Perspectives.

In-depth understanding of early cardiovascular manifestations in diabetes is high on international research and prevention agendas given that cardiovascular events are the leading cause of death for diabetic patients. Our aim was to review recent developments in the echocardiographic assessment of left ventricular diastolic dysfunction (LVDD) as a telltale pre-clinical disturbance preceding diabetic cardiomyopathy. We analyzed papers in which patients had been comprehensively assessed echocardiographically according to the latest LVDD guidelines (2016), and those affording comparisons with previous, widely used recommendations (2009). We found that the updated algorithm for LVDD is more effective in predicting adverse cardiovascular events in patients with established LVDD, and less specific in grading other patients (labelled "indeterminate"). This may prove instrumental for recruiting "indeterminate" LVDD cases among patients with type 2 diabetes mellitus (T2DM) in future screening programs. As an interesting consideration, the elevated values of the index E/e' can point to early diastolic impairment, foretelling diabetic cardiomyopathy. Identifying subclinical signs early makes clinical sense, but the complex nature of T2DM calls for further research. Specifically, longitudinal studies on rigorously selected cohorts of diabetic patients are needed to better understand and predict the subtle, slow onset of cardiac manifestations with T2DM as a complicating backdrop.

The Mediterranean Diet: From an Environment-Driven Food Culture to an Emerging Medical Prescription.

The Mediterranean diet originates in the food cultures of ancient civilizations which developed around the Mediterranean Basin and is based on the regular consumption of olive oil (as the main source of added fat), plant foods (cereals, fruits, vegetables, legumes, tree nuts, and seeds), the moderate consumption of fish, seafood, and dairy, and low-to-moderate alcohol (mostly red wine) intake, balanced by a comparatively limited use of red meat and other meat products. A few decades ago, the Mediterranean diet drew the attention of medical professionals by proving extended health benefits. The first reports ascertained cardiovascular protection, as multiple large-scale clinical studies, starting with Ancel Keys' Seven Countries Study, showed a marked reduction of atherosclerotic clinical events in populations with a Mediterranean dietary pattern. Ensuing trials confirmed favorable influences on the risk for metabolic syndrome, obesity, type 2 diabetes mellitus, cancer, and neurodegenerative diseases. While its health benefits are universally recognized today by medical professionals, the present state of the Mediterranean diet is challenged by major difficulties in implementing this protective dietary pattern in other geographical and cultural areas and keeping it alive in traditional Mediterranean territories, also tainted by the unhealthy eating habits brought by worldwide acculturation.

Bidirectional Relationship between Gastric Emptying and Plasma Glucose Control in Normoglycemic Individuals and Diabetic Patients.

Gastric emptying and glycemic control pathways are closely interrelated processes. Gastric chyme is transferred into the duodenum with velocities depending on its solid or liquid state, as well as on its caloric and nutritional composition. Once nutrients enter the intestine, the secretion of incretins (hormonal products of intestinal cells) is stimulated. Among incretins, glucagon-like peptide-1 (GLP-1) has multiple glycemic-regulatory effects that include delayed gastric emptying, thus triggering a feedback loop lowering postprandial serum glucose levels. Glycemic values also influence gastric emptying; hyperglycemia slows it down, and hypoglycemia accelerates it, both limiting glycemic fluctuations. Disordered gastric emptying in diabetes mellitus is understood today as a complex pathophysiological condition, with both irreversible and reversible components and high intra- and interindividual variability of time span and clinical features. While limited delays may be useful for reducing postprandial hyperglycemias, severely hindered gastric emptying may be associated with higher glycemic variability and worsened long-term glycemic control. Therapeutic approaches for both gastric emptying and glycemic control include dietary modifications of meal structure or content and drugs acting as GLP-1 receptor agonists. In the foreseeable future, we will probably witness a wider range of dietary interventions and more incretin-based medications used for restoring both gastric emptying and glycemic levels to nearly physiological levels.