Journal of Cardiovascular Development and Disease — Open Access Journal

The cardiac fibroblast is a remarkably versatile cell type that coordinates inflammatory, fibrotic and hypertrophic responses in the heart through a complex array of intracellular and intercellular signaling mechanisms. One important signaling node that has been identified involves p38 MAPK; a family of kinases activated in response to stress and inflammatory stimuli that modulates multiple aspects of cardiac fibroblast function, including inflammatory responses, myofibroblast differentiation, extracellular matrix turnover and the paracrine induction of cardiomyocyte hypertrophy. This review explores the emerging importance of the p38 MAPK pathway in cardiac fibroblasts, describes the molecular mechanisms by which it regulates the expression of key genes, and highlights its potential as a therapeutic target for reducing adverse myocardial remodeling. Full article

Plaque development and rupture are hallmarks of atherosclerotic vascular disease. Despite current therapeutic developments, there is an unmet necessity in the prevention of atherosclerotic vascular disease. It remains a challenge to determine at an early stage if atherosclerotic plaque will become unstable and vulnerable. The arrival of molecular imaging is receiving more attention, considering it allows for a better understanding of the biology of human plaque and vulnerabilities. Various plaque therapies with common goals have been tested in high-risk patients with cardiovascular disease. In this work, the process of plaque instability, along with current technologies for sensing and predicting high-risk plaques, is debated. Updates on potential novel therapeutic approaches are also summarized. Full article

Patients with cardiac diseases can achieve the greatest benefit from cardiac rehabilitation through modification of their unhealthy behaviors. This study aimed to develop and examine the psychometric properties of the Cardiac Rehabilitation Adherence Tool (CRAT), which was designed to assess patients’ adherence to cardiac rehabilitation. In this instrument development study, the items of the CRAT were extracted through a comprehensive literature review. The CRAT was assessed in terms of validity and reliability. Exploratory factor analysis was conducted to assess its construct validity, which led to the development of a tool containing 57 items and five dimensions including “acceptance of the rehabilitation center”, “being interested in health”, “feeling a need”, “personal control over the situation”, and “encouragement and advice.” These five factors accounted for 45.23% of the observed variance. The Cronbach’s alpha was 0.935. The test-retest method supported the stability of the instrument (r = 0.95). Health care professionals can use the CRAT to examine factors influencing the patient’s decision to leave cardiac rehabilitation and design strategies for improving their adherence to the rehabilitation program. Full article

Mammalian Kiaa1211 and Kiaa1211-like are a homologous pair of uncharacterized, highly conserved genes cloned from fetal and adult brain cDNA libraries. Herein we map the in utero spatiotemporal expression of mKiaa1211 and mKiaa1211L mRNA and their expression patterns in postnatal testis, skin, gastrointestinal, and adipose progenitor tissues. Significantly, mKiaa1211 is present throughout the early stages of mouse heart development, particularly in the second heart field (SHF) lineage as it differentiates from mesenchymal cells into cardiomyocytes. We also show that mKiaa1211 is expressed within several early neuronal tissues destined to give rise to central, peripheral, and sympathetic nervous system structures. Expression profiling revealed that the paralog mKiaa1211L is not expressed during the normal developmental process and that mKiaa1211 expression was noticeably absent from most adult terminally differentiated tissues. Finally, we confirm that a previously uncharacterized CRISPR/CAS-generated mKiaa1211 mouse mutant allele is hypomorphic. Full article

The American Heart Association has published a scientific statement on the effect of hookah smoking on health outcomes; nevertheless, hookah smoking continues to be popular worldwide, especially among the young. Recent reports mention a potential link between hookah smoking and obesity; however, uncertainties still surround this issue. The aim of the current study was to conduct a systematic review to clarify whether hookah smoking is associated with a higher risk of obesity among the general population. This study was conducted in compliance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, and data were collated by means of a meta-analysis and a narrative synthesis. Of the 818 articles retrieved, five large-population and low-bias studies comprising a total of 16,779 participants met the inclusion criteria and were reviewed. All included studies reported that, regardless of gender, hookah smoking increases the risk of obesity among all ages and observed an association between the two after a correction for several confounders or reported a higher prevalence of obesity among hookah smokers. This was confirmed by the meta-analysis. Therefore, hookah smoking seems to be associated with a higher risk of obesity. Public health policymakers should be aware of this for the better management of obesity and weight-related comorbidities. Full article

Ischemic preconditioning (IPC) and activation of ATP-sensitive potassium channels (K_ATP) protect cardiac myocytes from ischemia reperfusion (IR) injury. We investigated the influence of IR injury, IPC and K_ATP in isolated rat cardiac fibroblasts. Hearts were removed under isoflurane anesthesia. IR was simulated in vitro by application and removal of paraffin oil over pelleted cells. Ischemia (30, 60 and 120 min) followed by 60 min reperfusion resulted in significant differentiation of fibroblasts into myofibroblasts in culture (mean % fibroblasts ± SEM in IR vs. time control: 12 ± 1% vs. 63 ± 2%, 30 min ischemia; 15 ± 3% vs. 71 ± 4%, 60 min ischemia; 8 ± 1% vs. 55 ± 2%, 120 min ischemia). IPC (15 min ischemia, 30 min reperfusion) significantly attenuated IR-induced fibroblast differentiation (52 ± 3%) compared to 60 min IR. IPC was mimicked by opening K_ATP with pinacidil (50 μM; 43 ± 6%) and by selectively opening mitochondrial K_ATP (mK_ATP) with diazoxide (100 μM; 53 ± 3%). Furthermore, IPC was attenuated by inhibiting K_ATP with glibenclamide (10 μM; 23 ± 5%) and by selectively blocking mK_ATP with 5-hydroxydecanoate (100 μM; 22 ± 9%). These results suggest that (a) IR injury evoked cardiac fibroblast to myofibroblast differentiation, (b) IPC attenuated IR-induced fibroblast differentiation, (c) K_ATP were involved in IPC and (d) this protection involved selective activation of mK_ATP. Full article

Congenital heart disease (CHD) arises due to errors during the embryonic development of the heart, a highly regulated process involving an interplay between cell-intrinsic transcription factor expression and intercellular signalling mediated by morphogens. Emerging evidence indicates that expression of these protein-coding genes is controlled by a plethora of previously unappreciated non-coding RNAs operating in complex feedback-control circuits. In this review, we consider the contribution of long non-coding RNA (lncRNA) to embryonic cardiovascular development before discussing applications to CHD diagnostics and therapeutics. We discuss the process of lineage restriction during cardiovascular progenitor cell differentiation, as well as the subsequent patterning of the cardiogenic progenitor fields, taking as an example the regulation of NODAL signalling in left-right patterning of the heart. lncRNA are a highly versatile group. Nuclear lncRNA can target specific genomic sequences and recruit chromatin remodelling complexes. Some nuclear lncRNA are transcribed from enhancers and regulate chromatin looping. Cytoplasmic lncRNA act as endogenous competitors for micro RNA, as well as binding and sequestering signalling proteins. We discuss features of lncRNA that limit their study by conventional methodology and suggest solutions to these problems. Full article

The interleukin-1 family is associated with innate immunity and inflammation. The latter has been linked to the genesis of cardiovascular diseases. We, therefore, investigated whether interleukin-1 beta (IL-1β) is activated during arterialization of vein grafts. First, we examined the activation of IL-1β using the rat arterialized jugular vein serially sampled for up to 90 days. IL-1β expression increased 18 times on day 1 in the arterialized rat jugular vein and remained five times above nonarterialized vein levels for up to 90 days. Similarly, IL-1β expression increased early (1–5 days) in human vein graft autopsy samples compared with late phases (1–4 years). Activation was also detected in ex vivo arterialized human saphenous veins. Upon stratification of the results, we uncovered a T allele promoter attenuating effect in IL-1β activation in response to hemodynamic stress. Altogether, the results show that IL-1β is activated during arterialization of vein grafts in rats and humans, and this response is modulated by -511C/T IL-1β gene polymorphism. It is tempting to speculate that the activation of IL-1β, and consequently local inflammation, modulates early vascular remodeling and that the gene polymorphism may be useful in predicting outcomes or assisting in interventions. Full article

The aging and elderly population are particularly susceptible to cardiovascular disease. Age is an independent risk factor for cardiovascular disease (CVD) in adults, but these risks are compounded by additional factors, including frailty, obesity, and diabetes. These factors are known to complicate and enhance cardiac risk factors that are associated with the onset of advanced age. Sex is another potential risk factor in aging adults, given that older females are reported to be at a greater risk for CVD than age-matched men. However, in both men and women, the risks associated with CVD increase with age, and these correspond to an overall decline in sex hormones, primarily of estrogen and testosterone. Despite this, hormone replacement therapies are largely shown to not improve outcomes in older patients and may also increase the risks of cardiac events in older adults. This review discusses current findings regarding the impacts of age and gender on heart disease. Full article

There is increasing recognition of a specific diabetic cardiomyopathy beyond ischemic cardiomyopathy, which leads to structural and functional myocardial abnormalities. The aim of this review is to summarize the recent literature on diagnostic findings and prognostic significance of non-invasive imaging including echocardiography, nuclear imaging, computed tomography and cardiovascular magnetic resonance in diabetic cardiomyopathy. Full article

Cardiovascular disease (CVD) is a major public health problem in Saudi Arabia. Dietary intake plays a major role in CVD incidence; however, the dietary intake status in Saudi nationals with CVD is unknown. We aimed to investigate whether the dietary patterns of Saudi males, using the Saudi dietary guidelines adherence score, in parallel with the measurement of a selective number of cardiovascular disease-related biomarkers, are contributing factors to CVD risk. Demographics, dietary adherence score, and blood biomarker levels were collected for 40 CVD patients and forty non-CVD patients. Fasting blood glucose (p = 0.006) and high-density lipoprotein levels (p = 0.03) were significantly higher in CVD patients. The adherence score to the Saudi dietary guidelines was not significantly different between the CVD and non-CVD patients; however, the specific adherence scores of fruit (p = 0.02), olive oil (p = 0.01), and non-alcoholic beer (p = 0.02) were significantly higher in the non-CVD patients. The differences in CVD family history (p = 0.02) and adherence scores to specific groups/foods between the CVD and non-CVD patients may contribute to CVD risk in Saudi males. However, as the sample size of this study was small, further research is required to validate these findings. Full article

The let-7c family of micro-RNAs (miRNAs) is expressed during embryonic development and plays an important role in cell differentiation. We have investigated the role of let-7c in heart regeneration after injury in adult zebrafish. let-7c antagomir or scramble injections were given at one day after cryoinjury (1 dpi). Tissue samples were collected at 7 dpi, 14 dpi and 28 dpi and cardiac function was assessed before cryoinjury, 1 dpi, 7 dpi, 14 dpi and 28 dpi. Inhibition of let-7c increased the rate of fibrinolysis, increased the number of proliferating cell nuclear antigen (PCNA) positive cardiomyocytes at 7 dpi and increased the expression of the epicardial marker raldh2 at 7 dpi. Additionally, cardiac function measured with echocardiography recovered slightly more rapidly after inhibition of let-7c. These results reveal a beneficial role of let-7c inhibition in adult zebrafish heart regeneration. Full article

Cardiovascular development is a complex developmental process starting with the formation of an early straight heart tube, followed by a rightward looping and the configuration of atrial and ventricular chambers. The subsequent step allows the separation of these cardiac chambers leading to the formation of a four-chambered organ. Impairment in any of these developmental processes invariably leads to cardiac defects. Importantly, our understanding of the developmental defects causing cardiac congenital heart diseases has largely increased over the last decades. The advent of the molecular era allowed to bridge morphogenetic with genetic defects and therefore our current understanding of the transcriptional regulation of cardiac morphogenesis has enormously increased. Moreover, the impact of environmental agents to genetic cascades has been demonstrated as well as of novel genomic mechanisms modulating gene regulation such as post-transcriptional regulatory mechanisms. Among post-transcriptional regulatory mechanisms, non-coding RNAs, including therein microRNAs and lncRNAs, are emerging to play pivotal roles. In this review, we summarize current knowledge on the functional role of non-coding RNAs in distinct congenital heart diseases, with particular emphasis on microRNAs and long non-coding RNAs. Full article

In its classical view, the renin angiotensin system (RAS) was defined as an endocrine system involved in blood pressure regulation and body electrolyte balance. However, the emerging concept of tissue RAS, along with the discovery of new RAS components, increased the physiological and clinical relevance of the system. Indeed, RAS has been shown to be expressed in various tissues where alterations in its expression were shown to be involved in multiple diseases including atherosclerosis, cardiac hypertrophy, type 2 diabetes (T2D) and renal fibrosis. In this chapter, we describe the new components of RAS, their tissue-specific expression, and their alterations under pathological conditions, which will help achieve more tissue- and condition-specific treatments. Full article

Obesity in terms of excess fat mass is associated with increased morbidity, disability and mortality due to obesity-related disorders, including hypertension. Many hypertensive individuals are overweight and often receive their advice to lose weight related to body-fat, in order to lower their blood pressure. However, it is still unclear whether there is a strong association of adipose tissue measured by adiposity indicators with hypertension in the Thai population. Various adiposity indices have been published to distinguish the distribution of body fat with disparate properties. This study examined nine adiposity markers and their association with hypertension in 15,842 Thai adults ≥35 years old. Data were obtained from the nationwide Thai National Health Examination Survey 2009. Accuracy performance and associations of indexes with hypertension were analyzed by Area Under Curve (AUC) and logistic regression analyses. Regardless of gender, the best methods to distinguish performance were waist-to-height ratio (WHtR) [AUC: 0.640 (0.631–0.649)], followed by lipid accumulation product (LAP) [AUC: 0.636 (0.627–0.645)], waist circumference (WC) [AUC: 0.633 (0.624–0.641)], and Conicity index (C-Index) [AUC: 0.630 (0.621–0.639)]. Linear regression analysis exhibited the independent association of the top four indices, WC, WHtR, C-Index, and LAP with higher systolic and diastolic blood pressure. Those indices’ quartiles were graded in a dose-response manner which significantly increased at the higher quartiles. The indicator’s cutoff point carried the odds ratio of presence hypertension in the range of 1.7 to 2.5 (p < 0.001). Among the nine obesity indices, WHtR (cutoff >0.52) in both genders was the simplest and most practical measurement for adiposity in association with hypertension in middle-aged and elderly Thais. Full article

The early embryonic heart is a multi-layered tube consisting of (1) an outer myocardial tube; (2) an inner endocardial tube; and (3) an extracellular matrix layer interposed between the myocardium and endocardium, called “cardiac jelly” (CJ). During the past decades, research on CJ has mainly focused on its molecular and cellular biological aspects. This review focuses on the morphological and biomechanical aspects of CJ. Special attention is given to (1) the spatial distribution and fiber architecture of CJ; (2) the morphological dynamics of CJ during the cardiac cycle; and (3) the removal/remodeling of CJ during advanced heart looping stages, which leads to the formation of ventricular trabeculations and endocardial cushions. CJ acts as a hydraulic skeleton, displaying striking structural and functional similarities with the mesoglea of jellyfish. CJ not only represents a filler substance, facilitating end-systolic occlusion of the embryonic heart lumen. Its elastic components antagonize the systolic deformations of the heart wall and thereby power the refilling phase of the ventricular tube. Non-uniform spatial distribution of CJ generates non-circular cross sections of the opened endocardial tube (initially elliptic, later deltoid), which seem to be advantageous for valveless pumping. Endocardial cushions/ridges are cellularized remnants of non-removed CJ. Full article

Cardiogenesis is interdependent with blood flow within the embryonic system. Recently, a number of studies have begun to elucidate the effects of hemodynamic forces acting upon and within cells as the cardiovascular system begins to develop. Changes in flow are picked up by mechanosensors in endocardial cells exposed to wall shear stress (the tangential force exerted by blood flow) and by myocardial and mesenchymal cells exposed to cyclic strain (deformation). Mechanosensors stimulate a variety of mechanotransduction pathways which elicit functional cellular responses in order to coordinate the structural development of the heart and cardiovascular system. The looping stages of heart development are critical to normal cardiac morphogenesis and have previously been shown to be extremely sensitive to experimental perturbations in flow, with transient exposure to altered flow dynamics causing severe late stage cardiac defects in animal models. This paper seeks to expand on past research and to begin establishing a detailed baseline for normal hemodynamic conditions in the chick outflow tract during these critical looping stages. Specifically, we will use 4-D (3-D over time) optical coherence tomography to create in vivo geometries for computational fluid dynamics simulations of the cardiac cycle, enabling us to study in great detail 4-D velocity patterns and heterogeneous wall shear stress distributions on the outflow tract endocardium. This information will be useful in determining the normal variation of hemodynamic patterns as well as in mapping hemodynamics to developmental processes such as morphological changes and signaling events during and after the looping stages examined here. Full article

Hypoplastic left heart syndrome occurs in up to 3% of all infants born with congenital heart disease and is a leading cause of death in this population. Although there is strong evidence for a genetic component, a specific genetic cause is only known in a small subset of patients, consistent with a multifactorial etiology for the syndrome. There is controversy surrounding the mechanisms underlying the syndrome, which is likely due, in part, to the phenotypic variability of the disease. The most commonly held view is that the “decreased” growth of the left ventricle is due to a decreased flow during a critical period of ventricular development. Research has also been hindered by what has been, up until now, a lack of genetically engineered animal models that faithfully reproduce the human disease. There is a growing body of evidence, nonetheless, indicating that the hypoplasia of the left ventricle is due to a primary defect in ventricular development. In this review, we discuss the evidence demonstrating that, at least for a subset of cases, the chamber hypoplasia is the consequence of hyperplasia of the contained cardiomyocytes. In this regard, hypoplastic left heart syndrome could be viewed as a neonatal form of cardiomyopathy. We also discuss the role of the endocardium in the development of the ventricular hypoplasia, which may provide a mechanistic basis for how impaired flow to the developing ventricle leads to the anatomical changes seen in the syndrome. Full article

It is now established that the entity often described as an “aortopulmonary septal complex” is better considered as an “outflow tract septal complex”. This change is crucial for appropriate understanding of not only malformations of the outflow tract, but also ventricular septal defects. Thus, the embryonic outflow tract, as it develops, is separated into its two components by fusion of a protrusion from the dorsal wall of the aortic sac with the distal end of the outflow cushions. The key point with regard to morphogenesis is that, with ongoing development, these structures lose their septal integrity, although they can still be identified as septal structures when the ventricular septum itself is deficient. In the normal postnatal heart, however, the aortic and pulmonary components have their own walls throughout the length of the outflow tracts. All of this is of clinical significance, since some current concepts of categorisation of the ventricular septal defects are based on the existence in the normal heart of a “conal septum”, along with a “septum of the atrioventricular canal”. In this review, we show how analysis of postnatal hearts reveals the definitive ventricular septum to possess only muscular and fibrous components in the absence of either discrete outflow or inlet components. We also show that this information regarding development, in turn, is of major significance in determining whether categorisation of ventricular septal defects is best approached, in the first instance, on the basis of the borders of the defects or the fashion in which they open to the right ventricle. Full article