J. Cardiovasc. Dev. Dis., Volume 5, Issue 2 (June 2018) – 16 articles

The precise nature of packing together of the cardiomyocytes within the ventricular walls has still to be determined. The spiraling nature of the chains of interconnected cardiomyocytes has long been recognized. As long ago as the end of the nineteenth century, Pettigrew had emphasized that the ventricular cone was not arranged on the basis of skeletal muscle. Despite this guidance, subsequent anatomists described entities such as “bulbo-spiral muscles”, with this notion of subunits culminating in the suggestion that the ventricular cone could be unwrapped so as to produce a “ventricular myocardial band”. Others, in contrast, had suggested that the ventricular walls were arranged on the basis of “sheets”, or more recently “sheetlets”, with investigators seeking to establishing the angulation of these entities using techniques such as magnetic resonance imaging. Our own investigations, in contrast, have shown that the cardiomyocytes are aggregated together within the supporting fibrous matrix so as to produce a three-dimensional myocardial mesh. In this review, we summarize the previous accounts, and provide the anatomical evidence we have thus far accumulated to support the model of the myocardial mesh. We show how these anatomic findings underscore the concept of the myocardial mesh functioning in antagonistic fashion. They lend evidence to support the notion that the ventricular myocardium works as a muscular hydrostat. Full article

Cardiac dynamics are traditionally linked to a left ventricle, right ventricle, and septum morphology, a topography that differs from the heart’s five-century-old anatomic description of containing a helix and circumferential wrap architectural configuration. Torrent Guasp’s helical ventricular myocardial band (HVMB) defines this anatomy and its structure, and explains why the heart’s six dynamic actions of narrowing, shortening, lengthening, widening, twisting, and uncoiling happen. The described structural findings will raise questions about deductions guiding “accepted cardiac mechanics”, and their functional aspects will challenge and overturn them. These suppositions include the LV, RV, and septum description, timing of mitral valve opening, isovolumic relaxation period, reasons for torsion/twisting, untwisting, reasons for longitudinal and circumferential strain, echocardiographic sub segmentation, resynchronization, RV function dynamics, diastolic dysfunction’s cause, and unrecognized septum impairment. Torrent Guasp’s revolutionary contributions may alter future understanding of the diagnosis and treatment of cardiac disease. Full article

Rheumatic heart disease (RHD) is a preventable disease that is prevalent in developing regions of the world. Its eradication from most of the developed world indicates that this disease can be controlled and eliminated. Aim: To conduct an in-depth analysis of the trends and challenges of controlling RHD in the Eastern Mediterranean region (EMR). Methodology: Global data from the World Health Organization (WHO) data banks were retrieved for total deaths and age standardized death rate per 100,000 (ASDR) by age group, sex, and year (from 2000 to 2015). The data was compared with the five other WHO regions of the world. We also performed in-depth analysis by socio-economic groups in relation to other attributes in the region related to population growth, illiteracy, and nutritional status. Indicators of service delivery were correlated with ASDR from RHD. Findings: Prevalence of RHD in 2015 in the EMR region was one-third of that of the total deaths reported in the Asian and West Pacific regions. The total deaths for the region peaked twice: in early adulthood and again later in old age, and was higher in females than in males. There was a rising trend in deaths from RHD from 2000 to 2015. The highest total deaths were reported from Egypt, Pakistan, Iran, Afghanistan, and Yemen, representing 80% of the total death rates for the region (35,248). The highest ASDR was Afghanistan (27.5), followed by Yemen (18.78) and Egypt (15.59). The ASDR for RHD was highest in low income countries. It correlated highly, in all income groups, with anemia during pregnancy. Conclusions: Trends and patterns of deaths from RHD in the EMR have shifted to a later age group and are linked with poverty related to inequalities in development and service delivery for certain age groups and gender. Full article

Purpose: The low-density lipoprotein receptor is responsible for the binding and uptake of plasma LDL particles and plays a critical role in maintaining cellular cholesterol homeostasis. LDLR gene SNP rs688 has been reported to be associated with increased plasma total and LDL cholesterol in several populations and can lead to elevated plasma LDL levels, resulting in an increased risk for atherosclerosis and coronary artery disease. This study aimed to explore genetic LDLR variant rs688 for its potential roles in coronary artery disease. Methodology: This study recruited 200 coronary artery disease patients and 200 healthy individuals. Genotyping of LDLR-rs688C > T gene variations was performed using the allele specific PCR method. Correlation of LDLR-rs688C > T gene variants with different clinicopathological features of coronary artery disease patients was performed. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the correlation of this microRNA polymorphism with coronary artery disease risk. Results: A significant difference was observed in genotype distribution among the coronary artery disease and matched healthy controls (p = 0.003). The frequencies of all three genotypes CC, CT, TT reported in the patient samples were 14%, 65% and 21% and in the healthy controls samples were 18%, 73% and 9%, respectively. The increased risk of developing CAD in Indian patients was found to be associated with LDLR rs688 TT genotype (OR = 3.0, 95% CI, 1.43 × 6.2; p = 0.003) RR 1.87 (1.20–2.91) p = 0.0037) and also the increased risk of developing CAD was reported to be associated with LDLR rs688 T allele (OR = 0.74, 95% CI, 1.57–0.97; p = 0.03) RR 0.85 (0.73–0.99) p = 0.03) compared to the C allele. Therefore, it was observed that more than a 3.0- and 0.74-fold increase risk of developing CAD was associated with TT genotype and T allele in Indian coronary artery disease patients. Conclusion: The findings indicated that LDLR rs688 TT genotype and T allele are associated with an increased susceptibility to coronary artery disease patients. LDLR-rs688C > T gene variation can be used as a predisposing genetic marker for coronary artery disease. Further studies with larger sample sizes are necessary to confirm our findings. Full article

Apolipoprotein (apo) E stands out among plasma apolipoproteins through its unprecedented ability to protect against atherosclerosis. Although best recognized for its ability to mediate plasma lipoprotein clearance in the liver and protect against macrophage foam cell formation, our recent understanding of the influence that apoE can exert to control atherosclerosis has significantly widened. Among apoE’s newfound athero-protective properties include an ability to control exaggerated hematopoiesis, blood monocyte activation and aortic stiffening in mice with hyperlipidemia. Mechanisms responsible for these exciting new properties extend beyond apoE’s ability to prevent cellular lipid excess. Rather, new findings have revealed a role for apoE in regulating microRNA-controlled cellular signaling in cells of the immune system and vascular wall. Remarkably, infusions of apoE-responsive microRNA mimics were shown to substitute for apoE in protecting against systemic and vascular inflammation to suppress atherosclerosis in mice with hyperlipidemia. Finally, more recent evidence suggests that apoE may control the release of microvesicles that could modulate cellular signaling, inflammation and atherosclerosis at a distance. These exciting new findings position apoE within the emerging field of intercellular communication that could introduce new approaches to control atherosclerosis cardiovascular disease. Full article

Mounting evidence confirms the compartmentalized structure of evolutionarily conserved 3′–5′-cyclic adenosine monophosphate (cAMP) signaling, which allows for simultaneous participation in a wide variety of physiological functions and ensures specificity, selectivity and signal strength. One important player in cAMP signaling is soluble adenylyl cyclase (sAC). The intracellular localization of sAC allows for the formation of unique intracellular cAMP microdomains that control various physiological and pathological processes. This review is focused on the functional role of sAC-produced cAMP. In particular, we examine the role of sAC-cAMP in different cellular compartments, such as cytosol, nucleus and mitochondria. Full article

The heart is the first organ system to form in the embryo. Over the course of development, cardiomyocytes with differing morphogenetic, molecular, and physiological characteristics are specified and differentiate and integrate with one another to assemble a coordinated electromechanical pumping system that can function independently of any external stimulus. As congenital malformation of the heart presents the leading class of birth defects seen in humans, the molecular genetics of heart development have garnered much attention over the last half century. However, understanding how genetic perturbations manifest at the level of the individual cell function remains challenging to investigate. Some of the barriers that have limited our capacity to construct high-resolution, comprehensive models of cardiac physiological maturation are rapidly being removed by advancements in the reagents and instrumentation available for high-speed live imaging. In this review, we briefly introduce the history of imaging approaches for assessing cardiac development, describe some of the reagents and tools required to perform live imaging in the developing heart, and discuss how the combination of modern imaging modalities and physiological probes can be used to scale from subcellular to whole-organ analysis. Through these types of imaging approaches, critical insights into the processes of cardiac physiological development can be directly examined in real-time. Moving forward, the synthesis of modern molecular biology and imaging approaches will open novel avenues to investigate the mechanisms of cardiomyocyte maturation, providing insight into the etiology of congenital heart defects, as well as serving to direct approaches for designing stem-cell or regenerative medicine protocols for clinical application. Full article

Lipoprotein apheresis (LA) is a therapeutic approach to save the lives of patients who are at an extremely high risk of developing cardiovascular events (CVE), especially after all other therapeutic options were not tolerated, or appeared not to be effective enough. Homozygous familial hypercholesterolemia represents a clear indication to start LA therapy. Another recognized indication is a severe hypercholesterolemia, which induced CVE, often in association with other risk factors. In the last years, an expressive elevation of lipoprotein(a) (Lp(a)) emerged as an indication for LA. In Germany, progress of atherosclerosis should have been documented before the permission to start LA therapy is given in these patients. Usually, all LA methods acutely decrease both LDL-C and Lp(a). However, specific columns which reduce only Lp(a) are available. Case reports and prospective observations comparing the situation before and during LA therapy clearly show a high efficiency with respect to the reduction of CVE, especially in patients with high Lp(a) levels. PCSK9 inhibitors may reduce the need for LA in patients with heterozygous or polygenetic hypercholesterolemia, but in some patients, a combination of these drugs with LA will be necessary. In the future, an antisense oligonucleotide against apolipoprotein(a) may offer an alternative therapeutic approach. Full article

Congenital heart disease (CHD) is a leading cause of death in children <1 year of age. Despite intense effort in the last 10 years, most CHDs (~70%) still have an unknown etiology. Conotruncal based defects, such as Tetralogy of Fallot (TOF), a common complex of devastating heart defects, typically requires surgical intervention in the first year of life. We reported that the noncoding transcriptome in myocardial tissue from children with TOF is characterized by significant variation in levels of expression of noncoding RNAs, and more specifically, a significant reduction in 12 small cajal body-associated RNAs (scaRNAs) in the right ventricle. scaRNAs are essential for the biochemical modification and maturation of small nuclear RNAs (spliceosomal RNAs), which in turn are critical components of the spliceosome. This is particularly important because we also documented that splicing of mRNAs that are critical for heart development was dysregulated in the heart tissue of infants with TOF. Furthermore, we went on to show, using the zebrafish model, that altering the expression of these same scaRNAs led to faulty mRNA processing and heart defects in the developing embryo. This review will examine how scaRNAs may influence spliceosome fidelity in exon retention during heart development and thus contribute to regulation of heart development. Full article

3′-5′-cyclic adenosine monophosphate (cAMP) is a signaling messenger produced in response to the stimulation of cellular receptors, and has a myriad of functional applications depending on the cell type. In the heart, cAMP is responsible for regulating the contraction rate and force; however, cAMP is also involved in multiple other functions. Compartmentation of cAMP production may explain the specificity of signaling following a stimulus. In particular, transverse tubules (T-tubules) and caveolae have been found to be critical structural components for the spatial confinement of cAMP in cardiomyocytes, as exemplified by beta-adrenergic receptor (β-ARs) signaling. Pathological alterations in cardiomyocyte microdomain architecture led to a disruption in compartmentation of the cAMP signal. In this review, we discuss the difference between atrial and ventricular cardiomyocytes in respect to microdomain organization, and the pathological changes of atrial and ventricular cAMP signaling in response to myocyte dedifferentiation. In addition, we review the role of localized phosphodiesterase (PDE) activity in constraining the cAMP signal. Finally, we discuss microdomain biogenesis and maturation of cAMP signaling with the help of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Understanding these mechanisms may help to overcome the detrimental effects of pathological structural remodeling. Full article

Human beings are characterized by a left–right asymmetric arrangement of their internal organs, and the heart is the first organ to break symmetry in the developing embryo. Aberrations in normal left–right axis determination during embryogenesis lead to a wide spectrum of abnormal internal laterality phenotypes, including situs inversus and heterotaxy. In more than 90% of instances, the latter condition is accompanied by complex and severe cardiovascular malformations. Atrioventricular canal defect and transposition of the great arteries—which are particularly frequent in the setting of heterotaxy—are commonly found in situs solitus with or without genetic syndromes. Here, we review current data on morphogenesis of the heart in human beings and animal models, familial recurrence, and upstream genetic pathways of left–right determination in order to highlight how some isolated congenital heart diseases, very common in heterotaxy, even in the setting of situs solitus, may actually be considered in the pathogenetic field of laterality defects. Full article

Aortic stiffness during cardiac contraction is defined by the rigidity of the aorta and the elastic resistance to deformation. Recent studies suggest that aortic stiffness may be associated with changes in cholesterol efflux in endothelial cells. This alteration in cholesterol efflux may directly affect endothelial function, extracellular matrix composition, and vascular smooth muscle cell function and behavior. These pathological changes favor an aortic stiffness phenotype. Among all of the proteins participating in the cholesterol efflux process, ATP binding cassette transporter A1 (ABCA1) appears to be the main contributor to arterial stiffness changes in terms of structural and cellular function. ABCA1 is also associated with vascular inflammation mediators implicated in aortic stiffness. The goal of this mini review is to provide a conceptual hypothesis of the recent advancements in the understanding of ABCA1 in cholesterol efflux and its role and association in the development of aortic stiffness, with a particular emphasis on the potential mechanisms and pathways involved. Full article

Pathological cardiac hypertrophy and dysfunction is a response to various stress stimuli and can result in reduced cardiac output and heart failure. Cyclic nucleotide signaling regulates several cardiac functions including contractility, remodeling, and fibrosis. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing the hydrolysis of cyclic nucleotides, are critical in the homeostasis of intracellular cyclic nucleotide signaling and hold great therapeutic potential as drug targets. Recent studies have revealed that the inhibition of the PDE family member PDE1 plays a protective role in pathological cardiac remodeling and dysfunction by the modulation of distinct cyclic nucleotide signaling pathways. This review summarizes recent key findings regarding the roles of PDE1 in the cardiac system that can lead to a better understanding of its therapeutic potential. Full article

Bicuspid aortic valve (BAV) patients have an increased incidence of developing aortic dilation. Despite its importance, the pathogenesis of aortopathy in BAV is still largely undetermined. Nowadays, intense focus falls both on BAV morphology and progression of valvular dysfunction and on the development of aortic dilation. However, less is known about the relationship between aortic valve morphology and aortic dilation. A better understanding of the molecular pathways involved in the homeostasis of the aortic wall, including the extracellular matrix, the plasticity of the vascular smooth cells, TGFβ signaling, and epigenetic dysregulation, is key to enlighten the mechanisms underpinning BAV-aortopathy development and progression. To date, there are two main theories on this subject, i.e., the genetic and the hemodynamic theory, with an ongoing debate over the pathogenesis of BAV-aortopathy. Furthermore, the lack of early detection biomarkers leads to challenges in the management of patients affected by BAV-aortopathy. Here, we critically review the current knowledge on the driving mechanisms of BAV-aortopathy together with the current clinical management and lack of available biomarkers allowing for early detection and better treatment optimization. Full article

Cyclic GMP regulates multiple cell types and functions of the cardiovascular system. This review summarizes the effects of cGMP on the growth and survival of vascular smooth muscle cells (VSMCs), which display remarkable phenotypic plasticity during the development of vascular diseases, such as atherosclerosis. Recent studies have shown that VSMCs contribute to the development of atherosclerotic plaques by clonal expansion and transdifferentiation to macrophage-like cells. VSMCs express a variety of cGMP generators and effectors, including NO-sensitive guanylyl cyclase (NO-GC) and cGMP-dependent protein kinase type I (cGKI), respectively. According to the traditional view, cGMP inhibits VSMC proliferation, but this concept has been challenged by recent findings supporting a stimulatory effect of the NO-cGMP-cGKI axis on VSMC growth. Here, we summarize the relevant studies with a focus on VSMC growth regulation by the NO-cGMP-cGKI pathway in cultured VSMCs and mouse models of atherosclerosis, restenosis, and angiogenesis. We discuss potential reasons for inconsistent results, such as the use of genetic versus pharmacological approaches and primary versus subcultured cells. We also explore how modern methods for cGMP imaging and cell tracking could help to improve our understanding of cGMP’s role in vascular plasticity. We present a revised model proposing that cGMP promotes phenotypic switching of contractile VSMCs to VSMC-derived plaque cells in atherosclerotic lesions. Regulation of vascular remodeling by cGMP is not only an interesting new therapeutic strategy, but could also result in side effects of clinically used cGMP-elevating drugs. Full article

Epicardium-derived cells (EPDCs) are an important pool of multipotent cardiovascular progenitor cells. Through epithelial-to-mesenchymal-transition (EMT), EPDCs invade the subepicardium and myocardium and further differentiate into several cell types required for coronary vessel formation. We previously showed that epicardial hypoxia inducible factor (HIF) signaling mediates the invasion of vascular precursor cells critical for patterning the coronary vasculature. Here, we examine the regulatory role of hypoxia (1% oxygen) on EPDC differentiation into vascular smooth muscle cells (VSMCs). Results: Hypoxia stimulates EMT and enhances expression of several VSMC markers in mouse epicardial cell cultures. This stimulation is specifically blocked by inhibiting transforming growth factor-beta (TGFβ) receptor I. Further analyses indicated that hypoxia increases the expression level of TGFβ-1 ligand and phosphorylation of TGFβ receptor II, suggesting an indispensable role of the TGFβ pathway in hypoxia-stimulated VSMC differentiation. We further demonstrate that the non-canonical RhoA/Rho kinase (ROCK) pathway acts as the main downstream effector of TGFβ to modulate hypoxia’s effect on VSMC differentiation. Conclusion: Our results reveal a novel role of epicardial HIF in mediating coronary vasculogenesis by promoting their differentiation into VSMCs through noncanonical TGFβ signaling. These data elucidate that patterning of the coronary vasculature is influenced by epicardial hypoxic signals. Full article