Old and Novel Therapeutic Approaches in the Management of Hyperglycemia, an Important Risk Factor for Atherosclerosis.

Hyperglycemia is considered one of the main risk factors for atherosclerosis, since high glucose levels trigger multiple pathological processes, such as oxidative stress and hyperproduction of pro-inflammatory mediators, leading to endothelial dysfunction. In this context, recently approved drugs, such as glucagon-like-peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), could be considered a powerful tool for to reduce glucose concentration and cardiovascular risk. Interestingly, many patients with type 2 diabetes mellitus (T2DM) and insulin resistance have been found to be deficient in vitamin D. Recent studies pointed out the unfavorable prognostic values of T2DM and vitamin D deficiency in patients with cardiac dysfunction, either when considered individually or together, which shed light on the role of vitamin D in general health status. New evidence suggests that SGLT2i could adversely affect the production of vitamin D, thereby increasing the risk of fractures, which are common in patients with T2DM. Therefore, given the biological effects of vitamin D as an anti-inflammatory mediator and a regulator of endothelial function and calcium equilibrium, these new findings should be taken into consideration as well. The aim of this review is to gather the latest advancements regarding the use of antidiabetic and antiplatelet drugs coupled with vitamin D supplementation to control glucose levels, therefore reducing the risk of coronary artery disease (CAD).

A Rare Case of Isolated Right Ventricular Loeffler's Endocarditis in Primary Hypereosinophilic Syndrome.

Hypereosinophilic syndrome (HES) is a systemic disorder with various manifestations, characterized by hypereosinophilia and caused by primary or secondary conditions. Loeffler's endocarditis (LE) represents a frequent cardiac manifestation of HES, caused by infiltration of the myocardium by eosinophilic cells, which determines endocardial damage, with subsequent inflammation, thrombosis, and fibrosis of either one or both ventricles. The diagnosis of cardiac involvement is based on a multimodality approach (i.e., two-dimensional transthoracic echocardiography [2D-TTE], speckle-tracking echocardiography [STE], and cardiac magnetic resonance [CMR]), with different findings depending on the stage of disease. STE may be useful in the initial phase when traditional imaging techniques may result negative, whereas CMR allows myocardial tissue characterization along with a better definition of the right ventricle. We present a rare case of LE with isolated right ventricular involvement in a patient with HES caused by chronic eosinophilic leukemia with constitutively activated fusion tyrosine kinase on chromosome 4q12, successfully treated with imatinib mesylate.

Ventricular Septal Defect and Right-Sided Infective Endocarditis.

Right-sided infective endocarditis (IE), which represents a small but not negligible percentage of IE cases, can be observed in patients with congenital heart diseases. We discuss the case of a young woman with unrepaired perimembranous ventricular septal defect and repeated episodes of right ventricle and tricuspid valve IE with septic embolism.

The peculiar role of vitamin D in the pathophysiology of cardiovascular and neurodegenerative diseases.

Vitamin D is a hormone with both genomic and non-genomic actions. It exerts its activity by binding vitamin D receptor (VDR), which belongs to the superfamily of nuclear receptors and ligand-activated transcription factors. Since VDR has been found in various tissues, it has been estimated that it regulates approximately 3% of the human genome. Several recent studies have shown pleiotropic effects of vitamin D in various processes such as cellular proliferation, differentiation, DNA repair and apoptosis and its involvement in different pathophysiological conditions as inflammation, diabetes mellitus, and anemia. It has been suggested that vitamin D could play an important role in neurodegenerative and cardiovascular disorders. Moderate to strong associations between lower serum vitamin D concentrations and stroke and cardiovascular events have been identified in different analytic approaches, even after controlling for traditional demographic and lifestyle covariates. The mechanisms behind the associations between vitamin D and cerebrovascular and cardiologic profiles have been widely examined both in animal and human studies. Optimization of vitamin D levels in human subjects may improve insulin sensitivity and beta-cell function and lower levels of inflammatory markers. Moreover, it has been demonstrated that altered gene expression of VDR and 1,25D3-membrane-associated rapid response steroid-binding (1,25D3-MARRS) receptor influences the role of vitamin D within neurons and allows them to be more prone to degeneration. This review summarizes the current understanding of the molecular mechanisms underlying vitamin D signaling and the consequences of vitamin D deficiency in neurodegenerative and cardiovascular disorders.

Common Shared Pathogenic Aspects of Small Vessels in Heart and Brain Disease.

Small-vessel disease (SVD), also known as microvascular endothelial dysfunction, is a disorder with negative consequences for various organs such as the heart and brain. Impaired dilatation and constriction of small vessels in the heart lead to reduced blood flow and ischemia independently of coronary artery disease (CAD) and are associated with major cardiac events. SVD is usually a silent form of subcortical vascular burden in the brain with various clinical manifestations, such as silent-lacunar-ischemic events and confluent white-matter hyperintensities. Imaging techniques are the main help for clinicians to diagnose cardiac and brain SVD correctly. Markers of inflammation, such as C-reactive protein, tumor-necrosis-factor α, and interleukin 6, provide insight into the disease and markers that negatively influence nitric-oxide bioavailability and promote oxidative stress. Unfortunately, the therapeutic approach against SVD is still not well-defined. In the last decades, various antioxidants, oxidative stress inhibitors, and superoxide scavengers have been the target of extensive investigations due to their potential therapeutic effect, but with unsatisfactory results. In clinical practice, traditional anti-ischemic and risk-reduction therapies for CAD are currently in use for SVD treatment.

Long-term effect of SARS-CoV-2 infection on cardiovascular outcomes and all-cause mortality.

Since the very beginning of the coronavirus disease 2019 (COVID-19) pandemic in early 2020, it was evident that patients with cardiovascular disease (CVD) were at an increased risk of developing severe illness, and complications spanning cerebrovascular disorders, dysrhythmias, acute coronary syndrome, ischemic and non-ischemic heart disease, pericarditis, myocarditis, heart failure, thromboembolic disease, stroke, and death. Underlying these was excessive systemic inflammation and coagulopathy due to SARS-COV-2 infection, the effects of which also continued long-term as evidenced by post-COVID-19 cardiovascular complications. The acute and chronic cardiovascular effects of COVID-19 occurred even among those who were not hospitalized and had no previous CVD or those with mild symptoms. This comprehensive review summarizes the current understanding of molecular mechanisms triggered by the SARS-CoV-2 virus on various cells that express the angiotensin-converting enzyme 2, leading to endothelial dysfunction, inflammation, myocarditis, impaired coagulation, myocardial infarction, arrhythmia and a multisystem inflammatory syndrome in children or Kawasaki-like disease.

Pulmonary Embolism Presenting with Pulmonary Infarction: Update and Practical Review of Literature Data.

Pulmonary infarction (PI) is a possible consequence of pulmonary embolism (PE). The real incidence of PI could be underestimated considering only non-fatal PE presentation. However, following postmortem examination, the prevalence of PI is considerably higher. This evidence suggests the necessity of proper diagnostic protocol for identifying PI. Unfortunately, PI diagnosis can sometimes be challenging, due to the overlapping of symptoms with other diseases. Nowadays, the diagnosis is mainly based on radiological evaluation, although the combination with emerging imaging techniques such as ultrasound and nuclear scanning might improve the diagnostic algorithm for PI. This review aims to summarize the available data on the prevalence of PI, the main predisposing factors for the development of PI among patients with PE, to resume the possible diagnostic tools, and finally the clinical and prognostic implications.

The Role of Exercise-Induced Molecular Processes and Vitamin D in Improving Cardiorespiratory Fitness and Cardiac Rehabilitation in Patients With Heart Failure.

Heart failure (HF) still affects millions of people worldwide despite great advances in therapeutic approaches in the cardiovascular field. Remarkably, unlike pathological hypertrophy, exercise leads to beneficial cardiac hypertrophy characterized by normal or enhanced contractile function. Exercise-based cardiac rehabilitation improves cardiorespiratory fitness and, as a consequence, ameliorates the quality of life of patients with HF. Particularly, multiple studies demonstrated the improvement in left ventricular ejection fraction (LVEF) among patients with HF due to the various processes in the myocardium triggered by exercise. Exercise stimulates IGF-1/PI3K/Akt pathway activation involved in muscle growth in both the myocardium and skeletal muscle by regulating protein synthesis and catabolism. Also, physical activity stimulates the activation of the mitogen-activated protein kinase (MAPK) pathway which regulates cellular proliferation, differentiation and apoptosis. In addition, emerging data pointed out the anti-inflammatory effects of exercises as well. Therefore, it is of utmost importance for clinicians to accurately evaluate the patient's condition by performing a cardiopulmonary exercise test and/or a 6-min walking test. Portable devices with the possibility to measure exercise capacity proved to be very useful in this setting as well. The aim of this review is to gather together the molecular processes triggered by the exercise and available therapies in HF settings that could ameliorate heart performance, with a special focus on strategies such as exercise-based cardiac rehabilitation.

Diabetes Mellitus and Vitamin D Deficiency:Comparable Effect on Survival and a DeadlyAssociation after a Myocardial Infarction.

Survivors after a myocardial infarction (MI), especially those with diabetes mellitus (DM),remain at high risk of further events. Identifying and treating factors that may influence survivalmay open new therapeutic strategies. We assessed the impact on prognosis of DM andhypovitaminosis D (hypovitD), alone or combined. In this prospective, observational study, 1081patients were enrolled surviving an MI and divided into four groups according to their diabetic andVitD status. The primary end-point was composite of all-cause mortality, angina/MI and heartfailure (HF). Secondary outcomes were mortality, HF and angina/MI. During a follow-up of 26.1months (IQR 6.6-64.5), 391 subjects experienced the primary end-point. Patients with DM orhypovitD had similar rate of the composite end-point. Patients with only hypovitD or DM did notdiffer regarding components of composite end-point (angina p = 0.97, HF p = 0.29, mortality p = 0.62).DM and VitD deficiency had similarly adjusted risks for primary end-point (HR 1.3, 95%CI 1.05-1.61; HR 1.3, 95% CI 1.04-1.64). The adjusted HR for primary composite end-point for patients withhypovitD and DM was 1.69 (95%CI 1.25-2.29, p = 0.001) in comparison to patients with neitherhypoD nor DM. In conclusion, DM and hypovitD, individually and synergistically, are associatedwith a worse outcome after MI.

Cardiac Biomarkers in the Emergency Department: The Role of Soluble ST2 (sST2) in Acute Heart Failure and Acute Coronary Syndrome-There is Meat on the Bone.

Soluble ST2 (sST2) has recently emerged as a promising biomarker in the field of acute cardiovascular diseases. Several clinical studies have demonstrated a significant link between sST2 values and patients' outcome. Further, it has been found that higher levels of sST2 are associated with an increased risk of adverse left ventricular remodeling. Therefore, sST2 could represent a useful tool that could help the risk stratification and diagnostic and therapeutic work-up of patients admitted to an emergency department. With this review, based on recent literature, we have built sST2-assisted flowcharts applicable to three very common clinical scenarios of the emergency department: Acute heart failure, type 1, and type 2 acute myocardial infarction. In particular, we combined sST2 levels together with clinical and instrumental evaluation in order to offer a practical tool for emergency medicine physicians.

Galectin 3 and Galectin 3 Binding Protein Improve the Risk Stratification after Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) survivors are at risk of major adverse cardiac events and their risk stratification is a prerequisite to tailored therapeutic approaches. Biomarkers could be of great utility in this setting. METHODS: We sought to evaluate the utility of the combined assessment of Galectin 3 (Gal-3) and Galectin 3 binding protein (Gal-3bp) for post-AMI risk stratification in a large, consecutive population of AMI patients. The primary outcomes were: Recurrent angina/AMI and all-cause mortality at 12 months after the index event. RESULTS: In total, 469 patients were included. The median Gal-3bp was 9.1 µg/mL (IQR 5.8-13.5 µg/mL), while median Gal-3 was 9.8 ng/mL (IQR 7.8-12.8 ng/mL). During the 12 month follow-up, 34 patients died and 41 had angina pectoris/reinfarction. Gal-3 was associated with all-cause mortality, while Gal-3bp correlated with the risk of angina/myocardial infarction even when corrected for other significant covariates. The final multivariable model for mortality prediction included patients' age, left ventricular ejection fraction (LVEF), Gal-3, and renal function. The ROC curve estimated for this model has an area under the curve (AUC) of 0.84 (95%CI 0.78-0.9), which was similar to the area under the ROC curve obtained using the GRACE score 1-year mortality. CONCLUSIONS: The integrated assessment of Gal-3 and Gal-3bp could be helpful in risk stratification after AMI.

Ghrelin Derangements in Idiopathic Dilated Cardiomyopathy: Impact of Myocardial Disease Duration and Left Ventricular Ejection Fraction.

BACKGROUND: Ghrelin may exert positive effects on cardiac structure and function in heart failure (HF) patients. METHODS: We assessed ghrelin levels in 266 dilated cardiomyopathy (DCM) patients and in 200 age, gender and body mass index (BMI) matched controls. Further, we evaluated the expression of ghrelin and growth hormone secretagogue-receptor (GHSR) in the myocardium of 41 DCM patients and in 11 controls. RESULTS: DCM patients had significantly lower levels of total, acylated and unacylated ghrelin when compared to controls (p < 0.05 for all). In controls, we observed a negative correlation of ghrelin with age, male gender and BMI. These correlations were lost in the DCM group, except for male gender. Total ghrelin was higher in patients with more recent diagnosis when compared to patients with longer duration of the DCM (p = 0.033). Further, total ghrelin was higher in patients with lower left ventricular systolic function (<40% LVEF, vs. 40% ≤ LVEF < 49% vs. LVEF ≥ 50%: 480.8, vs. 429.7, vs. 329.5 pg/mL, respectively, p = 0.05). Ghrelin prepropeptide was expressed more in DCM patients than in controls (p = 0.0293) while GHSR was expressed less in DCM patients (p < 0.001). Furthermore, ghrelin showed an inverse correlation with its receptor (= -0.406, p = 0.009), and this receptor showed a significant inverse correlation with Interleukin-1 (= -0.422, p = 0.0103). CONCLUSION: DCM duration and severity are accompanied by alterations in the ghrelin-GHSR system.