J. Cardiovasc. Dev. Dis., Volume 6, Issue 4 (December 2019) – 8 articles

In diabetes patients with chronic ≥3 vessel disease, coronary artery bypass grafting (CABG) holds a class I recommendation in the American College of Cardiology and American Heart Association (ACC/AHA) 2011 guidelines, and this classification has not changed to date. Much of the literature has focused upon whether CABG or percutaneous coronary intervention (PCI) produces better outcomes; there is a paucity of data comparing the odds of receiving these procedures. A secondary analysis was conducted in a de-identified database comprised of 30,482 patients satisfying the entry criteria. Odds of occurrence (CABG, PCI) were determined as the binary dependent variable in period 1, (17 October 2009 through 31 December 2011), and period 2 (1 January 2013 through 16 March 2015), before and after the 2011 guidelines, while controlling for gender, ethnicity/race, and ischemic heart disease as covariates. The odds of performing CABG rather than PCI in period 2 were not statistically significantly different than in period 1 (p = 0.400). The logistic regression model chi-square statistic was statistically significant, with χ₂ (7) = 308.850, p < 0.0001. The Wald statistic showed that ethnicity/race (African American, Caucasian, Hispanic and Other), gender, and heart disease contributed significantly to the prediction model with p < 0.05, but ethnicity ‘Unknown’ did not. The odds of CABG versus PCI in period 2 were 0.98 times those in period 1 95% confidence interval (CI) = (0.925, 1.032), statistically controlling for covariates. There was no significant rise in the odds of undergoing a CABG among this dataset of high-risk patients with diabetes and multivessel coronary heart disease. Modern practice has evolved regarding patient choice and additional variables that impact the final revascularization method employed. The degree to which odds of occurrence of procedures are a reliable surrogate for provider compliance with guidelines remains uncertain. Full article

The outer shape of most vertebrates is normally characterized by bilateral symmetry. The inner organs, on the other hand, are normally arranged in bilaterally asymmetric patterns. Congenital deviations from the normal organ asymmetry can occur in the form of mirror imagery of the normal arrangement (situs inversus), or in the form of arrangements that have the tendency for the development of bilateral symmetry, either in a pattern of bilateral left-sidedness (left isomerism) or bilateral right-sidedness (right isomerism). The latter two forms of visceral situs anomalies are called “heterotaxy syndromes”. During the past 30 years, remarkable progress has been made in uncovering the genetic etiology of heterotaxy syndromes. However, the pathogenetic mechanisms causing the spectrum of cardiovascular defects found in these syndromes remain poorly understood. In the present report, a spontaneous case of left cardiac isomerism found in an HH-stage 23 chick embryo is described. The observations made in this case confirmed the existence of molecular isomerism in the ventricular chambers previously noted in mouse models. They, furthermore, suggest that hearts with left cardiac isomerism may have the tendency for the development of non-compaction cardiomyopathy caused by defective development of the proepicardium. Full article

Among the aortic valve diseases, the bicuspid aortic valve (BAV) occurs when the aortic valve has two leaflets (cusps), rather than three, and represents the most common form of congenital cardiac malformation, affecting 1–2% of the population. Despite recent advances, the etiology of BAV is poorly understood. We have recently shown that Krox20 is expressed in endothelial and cardiac neural crest derivatives that normally contribute to aortic valve development and that lack of Krox20 in these cells leads to aortic valve defects including partially penetrant BAV formation. Dysregulated expression of endothelial nitric oxide synthase (Nos3) is associated with BAV. To investigate the relationship between Krox20 and Nos3 during aortic valve development, we performed inter-genetic cross. While single heterozygous mice had normal valve formation, the compound Krox20+/−;Nos3+/− mice had BAV malformations displaying an in vivo genetic interaction between these genes for normal valve morphogenesis. Moreover, in vivo and in vitro experiments demonstrate that Krox20 directly binds to Nos3 proximal promoter to activate its expression. Our data suggests that Krox20 is a regulator of nitric oxide in endothelial-derived cells in the development of the aortic valve and concludes on the interaction of Krox20 and Nos3 in BAV formation. Full article

Abdominal aortic aneurysms (AAA), are usually asymptomatic until rupture causes fatal bleeding, posing a major vascular health problem. AAAs are associated with advanced age, male gender, and cardiovascular risk factors (e.g. hypertension and smoking). Strikingly, AAA and AOD (arterial occlusive disease) patients have a similar atherosclerotic burden, yet develop either arterial dilatation or occlusion, respectively. The molecular mechanisms underlying this diversion are yet unknown. As this knowledge could improve AAA treatment strategies, we aimed to identify genes and signaling pathways involved. We compared RNA expression profiles of abdominal aortic AAA and AOD patient samples. Based on differential gene expression profiles, we selected a gene set that could serve as blood biomarker or as pharmacological intervention target for AAA. In this AAA gene list we identified previously AAA-associated genes COL11A1, ADIPOQ, and LPL, thus validating our approach as well as novel genes; CXCL13, SLC7A5, FDC-SP not previously linked to aneurysmal disease. Pathway analysis revealed overrepresentation of significantly altered immune-related pathways between AAA and AOD. Additionally, we found bone morphogenetic protein (BMP) signaling inhibition simultaneous with activation of transforming growth factor β (TGF-β) signaling associated with AAA. Concluding our gene expression profiling approach identifies novel genes and an interplay between BMP and TGF-β signaling regulation specifically for AAA. Full article

Many studies have assessed the implication of cluster of differentiation 14 (CD14) molecules and its single nucleotide polymorphism rs2569190A>G with different complex diseases, such as diabetes and cardiovascular diseases (CVDs). In this study, we investigated the association of rs2569190A>G in CD14 with cardiovascular disease risk factors (hypercholesterolemia and hypertension) in 460 individuals from the general Lebanese population (Middle Eastern multiethnic population). Using a multiple logistic regression model adjusted for six covariates (under additive and recessive assumptions), we found that the G allele of rs2569190 in CD14 was associated with increased levels of total cholesterol (OR = 3.10, p = 0.009), low-density lipoprotein cholesterol (OR = 3.87, p = 0.003), and decreased levels of high-density lipoprotein cholesterol (OR = 0.38, p = 0.001). In contrast, no significant relationship was found with hypertension. Thus, we concluded that rs2569190G in CD14 is associated with a higher risk of developing hypercholesterolemia. Full article

Acute rheumatic fever (ARF) is an autoimmune disease affecting the heart-valve endocardium in its final stage. Although rare in developing countries, ARF persists in third-world countries, particularly Senegal, where rheumatic heart diseases (RHDs) are the most common pediatric cardiovascular pathology. This study aimed to investigate mutations in MT-CYB in ARF and RHD in Senegalese patients. MT-CYB was amplified from blood samples from ARF patients at the Clinical of Thoracic and Cardiovascular Surgery of Fann National University Hospital Centre, Dakar, Senegal (control group, healthy individuals) and sequenced. More than half of the MT-CYB mutations (58.23%) were heteroplasmic. Transitions (61.67%) were more frequent than transversions (38.33%), and non-synonymous substitutions represented 38.33% of mutations. Unoperated RHD patients harbored frequent MT-CYB polymorphisms (7.14 ± 14.70 mutations per sample) and accounted for 72.73% of mutations. Paradoxically, subjects undergoing valvular replacement harbored infrequent polymorphisms (1.39 ± 2.97 mutations per patient) and lacked 36 mutations present in unoperated subjects. A genetic differentiation was observed between these two populations, and the mutations in operated subjects were neutral, while those in unoperated subjects were under positive selection. These results indicate a narrow link (perhaps even causal) between MT-CYB mutations and ARF and its complications (i.e., RHDs) and that these mutations are largely deleterious. Full article

The extracellular matrix (ECM) provides structural support and a microenvironmentfor soluble extracellular molecules. ECM is comprised of numerous proteins which can be broadly classified as fibrillar (collagen types I and III) and non-fibrillar (basement membrane, proteoglycans, and glycoproteins). The basement membrane provides an interface between the cardiomyocytes and the fibrillar ECM, while proteoglycans sequester soluble growth factors and cytokines. Myocardial fibrosis was originally only linked to accumulation of fibrillar collagens, but is now recognized as the expansion of the ECM including the non-fibrillar ECM proteins. Myocardial fibrosis can be reparative to replace the lost myocardium (e.g., ischemic injury or myocardial infarction), or can be reactive resulting from pathological activity of fibroblasts (e.g., dilated or hypertrophic cardiomyopathy). Contribution of fibrillar collagens to fibrosis is well studied, but the role of the non-fibrillar ECM proteins has remained less explored. In this article, we provide an overview of the contribution of the non-fibrillar components of the extracellular space of the heart to highlight the potential significance of these molecules in fibrosis, with direct evidence for some, although not all of these molecules in their direct contribution to fibrosis. Full article

Cardiac fibrosis is the excessive deposition of extracellular matrix proteins by cardiac fibroblasts and myofibroblasts, and is a hallmark feature of most heart diseases, including arrhythmia, hypertrophy, and heart failure. This maladaptive process occurs in response to a variety of stimuli, including myocardial injury, inflammation, and mechanical overload. There are multiple signaling pathways and various cell types that influence the fibrogenesis cascade. Fibroblasts and myofibroblasts are central effectors. Although it is clear that Ca²⁺ signaling plays a vital role in this pathological process, what contributes to Ca²⁺ signaling in fibroblasts and myofibroblasts is still not wholly understood, chiefly because of the large and diverse number of receptors, transporters, and ion channels that influence intracellular Ca²⁺ signaling. Intracellular Ca²⁺ signals are generated by Ca²⁺ release from intracellular Ca²⁺ stores and by Ca²⁺ entry through a multitude of Ca²⁺-permeable ion channels in the plasma membrane. Over the past decade, the transient receptor potential (TRP) channels have emerged as one of the most important families of ion channels mediating Ca²⁺ signaling in cardiac fibroblasts. TRP channels are a superfamily of non-voltage-gated, Ca²⁺-permeable non-selective cation channels. Their ability to respond to various stimulating cues makes TRP channels effective sensors of the many different pathophysiological events that stimulate cardiac fibrogenesis. This review focuses on the mechanisms of Ca²⁺ signaling in fibroblast differentiation and fibrosis-associated heart diseases and will highlight recent advances in the understanding of the roles that TRP and other Ca²⁺-permeable channels play in cardiac fibrosis. Full article