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Atherosclerosis plays a significant role in the development of cardiovascular diseases, the leading cause of death worldwide. Modification of low-density lipoproteins (LDLs) is a critical event in atherogenesis. Native LDL undergoes several modifications that can lead to the formation of atherogenic modified LDLs. LDL modifications change their physicochemical and biological properties. Possible modifications include changes in the lipoprotein particle’s structure, size, charge, and composition. Uptake and utilization of modified LDLs are impaired in cells. Macrophages take up modified LDLs that promote forming of foam cells, one of the critical cellular components of atherosclerotic lesions. Nevertheless, the direct role of each atherogenic LDL modification in atherogenesis remains uncertain. This review highlights LDL's most critical atherogenic modifications, including oxidized, enzyme-modified, non-oxidative, desialylated, glycated and carbamylated LDLs. Studying the role of each type of LDL modification will clarify the unknown elements of atherosclerosis progression and facilitate the development of effective methods for its diagnosis, treatment, and prevention. LESS      Full article

Cerebral complications, especially intracranial hemorrhage (ICH), are critical determinants of the early outcomes of cardiac surgery for active infective endocarditis (AIE). Relevant society guidelines still recommend delaying cardiac surgery for AIE complicated by ICH for 4 weeks. Some early studies indicated that the mortality decreases when cardiac surgery for ICH is delayed. In contrast, some reported that surgical intervention should not be delayed if an early operation is indicated, even in patients with ICH. The current literature on early versus late surgery for AIE with ICH is conflicting. ICH is classified by its mechanism which includes primary intraparenchymal hemorrhage, hemorrhagic transformation of ischemic infarcts, and rupture of intracranial infectious aneurysms. Some reported that for AIE with a mycotic cerebral aneurysm, early cardiac surgery should be done after repair of the aneurysm, either surgically or endovascularly. Except for the rupture of mycotic aneurysm, primary intraparenchymal hemorrhage and hemorrhagic transformation of ischemic infarcts remain a critical and challenging dilemma. Modifying the cardiopulmonary bypass (CPB) strategy might be necessary to improve the surgical outcomes of AIE with ICH. Some studies reported that cardiac surgery using nafamostat mesylate as an alternative anticoagulant during CPB (NM-CPB) was performed successfully. The NM-CPB can be a useful option as an anticoagulant in critical situations of cardiac surgery with ICH. The timing of surgery should be decided on a case-by-case basis with multidisciplinary specialties including cardiac and neurological teams. LESS      Full article

In this review, the authors discuss the perioperative management of patients who undergo thoracoabdominal aortic aneurysm or descending thoracic aortic aneurysm repair. All major organ systems are potentially vulnerable to complications from these repairs; meticulous preoperative attention to optimizing relevant comorbidities, diligent performance of intraoperative anesthetic and surgical techniques, and careful postoperative management are necessary to maximize the likelihood of successful outcomes. Specific attention should be given to reducing the risk for spinal cord ischemia and for paraplegia. Of note, renal and respiratory systems are especially vulnerable to major complications and require a thoughtful multidisciplinary approach. Because preventing complications is the primary goal of perioperative management, deviations from the normal course must be recognized promptly and addressed aggressively to reduce the likelihood of major morbidity and death. LESS      Full article

Atherosclerosis is the major cause of occurrence and development of cardiovascular disease. Mutations in mitochondrial DNA (mtDNA) can lead to the development of several pathologies. Over the last few years, there has been increasing evidence that mitochondrial dysfunction caused by mtDNA mutations is associated with atherogenesis and other diseases of the cardiovascular system. Several therapeutic approaches have been developed for the improvement of mitochondrial function, and they are mainly associated with the cellular and tissue antioxidant defense system. However, these approaches are not targeted at mtDNA mutations, which trigger the pathogenesis of disease. Gene-editing technologies could be a promising approach for the treatment of cardiovascular disease caused by mtDNA mutations. To date, such technologies have shown considerable success in mitochondrial gene editing in cell and animal models. Gene-editing technologies allow the determination of the role of mitochondrial genome mutations in the development and complication of various chronic diseases. Nevertheless, further investigation and optimization in this field is required for future human trials. This review highlights the progress and existing challenges of modern technologies and approaches to mitochondrial gene editing. LESS      Full article

The incidence of type 2 diabetes mellitus (T2DM) is growing globally, and the major cause of morbidity and mortality in these patients is the premature development of cardiovascular disease. Consequently, medical interventions, such as coronary artery bypass graft surgery and widespread statin prescriptions, are common in this patient group. Smooth muscle cells are the major structural component of the vascular wall. They play a crucial role in post-bypass recovery to successfully revascularize the heart by switching between differentiated (contractile) and dedifferentiated (synthetic) phenotypes. However, in patients with T2DM, these cells have functional defects that may affect bypass integration. RhoA is a small GTPase that regulates many functions, such as motility and phenotypic regulation of smooth muscle cells. RhoA is dependent upon a stimulus, and it can drive the contractile smooth muscle cell phenotype present in the healthy condition or the (mal)adaptive phenotypes prevalent in disease or in response to injury. We hypothesize that RhoA deregulation plays a major role in vascular complications of T2DM. This protein is deregulated in T2DM smooth muscle cells, which may in part explain the functional defects of smooth muscle tissue and the subsequent failure rate of bypass in these patients. An important consideration in this circumstance is the use of statin therapies because these further inhibit RhoA activity. The effect of inhibition of RhoA activity in patients with T2DM who have a bypass is currently unknown. LESS      Full article

Mitochondria are cellular organelles providing energy to the cells. Due to the nature of mitochondrial enzymatic repair systems, mitochondrial DNA tends to generate mutations that are repaired less efficiently than nuclear DNA mutations. There is a certain relationship between the accumulation of mitochondria with mutated DNA in tissues, the development of oxidative stress, and several pathological conditions, from specific mitochondrial diseases to an increased risk of cancer, atherosclerosis, neurodegeneration, and non-systemic inflammation. Mitophagy is the biological mechanism responsible for the degradation of dysfunctional, damaged, and mutant mitochondria. Presumably, the stimulation of mitophagy can lead to tissue cleansing from dysfunctional mitochondria, which can have a powerful therapeutic effect on the root cause of the pathology. This review examines the relationship between mitochondrial mutations and the development of oxidative stress, the mechanisms of mitophagy, and a group of chemicals that stimulate mitophagy. LESS      Full article

Atherosclerosis is the main pathological basis of most cardiovascular diseases and the leading health threat in the world. Of note, lipid-lowering therapy cannot completely retard atherosclerosis progression, even in patients treated with combined statins and PCSK9 inhibitors. This failure further impels researchers to explore other underlying therapeutic strategies except for lipid-lowering. Monocytes and macrophages are the major immune cell groups in atherosclerotic plaques. They play important roles in all stages of atherosclerosis, including the occurrence, advance, and regression. It is interesting that macrophages are demonstrated to have plastic and heterogenous characteristics within the dynamic atherosclerotic plaque microenvironment. Furthermore, the phenotype of macrophages can switch upon different microenvironmental stimulus. Therefore, macrophages have become a potential therapeutic target for anti-atherosclerosis treatment. This article reviews the phenotypic diversity of macrophages and their roles in dynamic atherosclerotic plaque microenvironment, especially the related signaling pathways involved in macrophage polarization and compounds exhibiting therapeutic effects. LESS      Full article

Aim: We retrospectively examined the impact on the rate of survival of pain-free home-based exercise in diabetic peripheral artery disease patients compared to patients receiving usual care.Methods: In total, 202 patients at Fontaine’s Stage II with diabetes were studied. Half were enrolled in a structured home-based exercise program (E), whereas the other half received walking advice as the active control group (C). Long-term clinical outcomes at five years were gathered from the Emilia-Romagna Health Service Registry, with survival probability selected as the primary outcome.Results: At baseline, the two groups did not differ for any demographic or clinical characteristics. High adherence to the program was recorded in Group E (88% of home-walking sessions executed, with an average distance walked during the program of 174 km). After five years, a survival rate of 90% for Group E and 60% for Group C was observed, with a significantly (P < 0.001) higher mortality risk for Group C [Hazard ratio (HR) = 3.92]. Additionally, among secondary outcomes, Group E showed a significantly (P = 0.048) lower rate of peripheral revascularizations than Group C (15% vs. 24%, respectively; HR = 1.91), all-cause hospitalizations (P = 0.007; 61% vs. 80%, HR = 1.58), and amputations (P = 0.049; 6% vs. 13%, HR = 2.47). In a Cox multivariate-proportional regression model of the entire population, the predictors of survival probability were age (HR = 1.05), Charlson index (HR = 1.24), lower ankle-brachial index (HR = 6.66), and control group (HR = 4.99).Conclusion: A simple sustainable program aimed at improving mobility of diabetic patients with claudication at high cardiovascular risk was associated with better survival and long-term clinical outcomes. LESS      Full article

Cerebral cavernous malformations (CCMs), one of the most common vascular malformations, are characterized by abnormally dilated intracranial microvascular capillaries resulting in increased susceptibility to hemorrhagic stroke. As an autosomal dominant disorder with incomplete penetrance, the majority of CCMs gene mutation carriers are largely asymptomatic, but, when symptoms occur, the disease has typically reached the stage of focal hemorrhage with irreversible brain damage, while the molecular “trigger” initiating the occurrence of CCM pathology remain elusive. Currently, the invasive neurosurgery removal of CCM lesions is the only option for the treatment, despite the recurrence of worse symptoms frequently occurring after surgery. Therefore, there is a grave need for the identification of molecular targets for therapeutic treatment and biomarkers as risk predictors for hemorrhagic stroke prevention. Based on the various perturbed angiogenic signaling cascades mediated by the CCM signaling complex (CSC) reported, there have been many proposed candidate drugs, targeting potentially angiogenic-relevant signaling pathways dysregulated by loss of function of one of the CCM proteins, which might not be enough to correct the pathological phenotype, hemorrhagic CCMs. In this review, we describe a new paradigm for the mechanism of hemorrhagic CCM lesions and propose a new concept for the assurance of CSC stability to prevent the devastating outcome of hemorrhagic CCMs. LESS      Full article

Cerebral cavernous malformations (CCM) can occur either as sporadic or familial form with autosomal dominant inheritance. Three CCM genes have been identified: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). In this review, we provide an overall update on genetics of cerebral cavernous malformations. We discuss the main features of these three genes and provide an updated listing of the mutations identified so far. Most of them lead to a premature stop codon regardless of the nature of the variation, including nonsense mutations, small deletions/insertions, and intronic/exonic substitutions causing an altered splicing and a frame-shift. In addition, deletions or duplications of one or more exons of CCM genes can be responsible for the disease. We examine the use of different mutation screening methods to identify all these mutations, providing a comprehensive approach to CCM genetic diagnosis. We also report the main strategies to evaluate the actual impact of the mutations on the protein function. Moreover, we recapitulate the available data on penetrance, phenotype-genotype correlations, and founder effect. Finally, we discuss the main aspects of genetic counseling, including genetic risk assessment in family members, in sporadic patients with multiple CCMs, and in the case of de novo mutations. LESS      Full article