Journal of Cardiovascular Development and Disease — Open Access Journal

The article will briefly introduce the high-resolution episcopic microscopy (HREM) technique and will focus on its potential for researching cardiovascular development and remodelling in embryos of biomedical model organisms. It will demonstrate the capacity of HREM for analysing the cardiovascular system of normally developed and genetically or experimentally malformed zebrafish, frog, chick and mouse embryos in the context of the whole specimen and will exemplarily show the possibilities HREM offers for comprehensive visualisation of the vasculature of adult human skin. Finally, it will provide examples of the successful application of HREM for identifying cardiovascular malformations in genetically altered mouse embryos produced in the deciphering the mechanisms of developmental disorders (DMDD) program. Full article

The zebrafish is broadly used for investigating de novo organ regeneration, because of its strong regenerative potential. Over the past two decades of intense study, significant advances have been made in identifying both the regenerative cell sources and molecular signaling pathways in a variety of organs in adult zebrafish. Epigenetic regulation has gradually moved into the center-stage of this research area, aided by comprehensive work demonstrating that DNA methylation, histone modifications, chromatin remodeling complexes, and microRNAs are essential for organ regeneration. Here, we present a brief review of how these epigenetic components are induced upon injury, and how they are involved in sophisticated organ regeneration. In addition, we highlight several prospective research directions and their potential implications for regenerative medicine. Full article

Studies over the past two decades have shown heart regeneration in zebrafish to be a dynamic process, choreographed by multiple cell types. In particular, recent work has identified revascularization of the wound to be a sentinel event during heart regeneration. The cardiac endothelium has emerged as a key orchestrator of heart regeneration, influencing cardiomyocyte hyperplasia and tissue morphogenesis. Here, we review how the coronary vasculature regenerates after injury, how signaling pathways link the cardiac endothelium to heart regeneration, and how understanding these signaling dynamics can lead to targeted therapies for heart regeneration. Full article

The embryological development of the heart is one of the most fascinating phenomena in nature and so is its final structure and function. The various ontogenetic passages form the evolutive basis of the final configuration of the heart. Each key step can be recognized in the final features, as the heart maintains a kind of “memory” of these passages. We can identify the major lines of development of the heart and trace these lines up to the mature organ. The aim of this review is to identify these key parameters of cardiac structure and function as essential elements of the heart’s proper functioning and bases for its treatment. We aim to track key steps of heart development to identify what it “remembers” and maintains in its final form as positively selected. A new vision based on the whole acquired knowledge must guide an in-depth scientific approach in future papers and guidelines on the topic and a complete, farsighted therapeutic conduct able to ensure the physiological correction of cardiac pathologies. The application of this modern, functional vision of the heart could improve the clinical treatment of heart disease, filling the gaps still present. Full article

The beating heart is subject to intrinsic mechanical factors, exerted by contraction of the myocardium (stretch and strain) and fluid forces of the enclosed blood (wall shear stress). The earliest contractions of the heart occur already in the 10-somite stage in the tubular as yet unsegmented heart. With development, the looping heart becomes asymmetric providing varying diameters and curvatures resulting in unequal flow profiles. These flow profiles exert various wall shear stresses and as a consequence different expression patterns of shear responsive genes. In this paper we investigate the morphological alterations of the heart after changing the blood flow by ligation of the right vitelline vein in a model chicken embryo and analyze the extended expression in the endocardial cushions of the shear responsive gene Tgfbeta receptor III. A major phenomenon is the diminished endocardial-mesenchymal transition resulting in hypoplastic (even absence of) atrioventricular and outflow tract endocardial cushions, which might be lethal in early phases. The surviving embryos exhibit several cardiac malformations including ventricular septal defects and malformed semilunar valves related to abnormal development of the aortopulmonary septal complex and the enclosed neural crest cells. We discuss the results in the light of the interactions between several shear stress responsive signaling pathways including an extended review of the involved Vegf, Notch, Pdgf, Klf2, eNos, Endothelin and Tgfβ/Bmp/Smad networks. Full article

Hypertension is the most frequently managed condition by Australian general practitioners (GP). Knowledge of hypertension and blood pressure (BP) values may motivate individuals to seek GP management. Our study aims to determine the associations of knowledge of BP values, BP perception, GP health seeking, and self-rated health (SRH) in a rural population. Two-hundred and seventy-eight (278) residents responded to the health survey on socio-demographic profile, medical history, BP knowledge and perception, SRH, and GP visit frequency. Associations were evaluated using Chi-squared test and multivariate logistic regression. Cohort mean age was 63.6 (12.4) years with 63.3% females. Hypertension (37.8%) was the most common condition. GP visits were made at least once every month (19.1%), every 2–6 months (35.6%), >6 months (11.5%), or only when needed (29.5%). Univariate analyses showed age, education, alcohol consumption, comorbidities, hypertension status, and SRH were significantly associated with visit frequency. After adjustments, hypertension status (OR = 3.6, 95% CI [1.7, 7.9]) and poor SRH (OR = 3.1, 95% CI [1.4, 7.0]) were significantly associated with frequent monthly visits. Our cohort demonstrated that having hypertension and poor self-rated health were associated with frequent monthly GP visits. The perception of high blood pressure does not drive seeking additional GP input. Full article

Aim of the study: In chronic heart failure (CHF) patients, renal congestion plays a key role in determining the progression of renal dysfunction and a worse prognosis. The aim of this study was to define the role of Doppler venous patterns reflecting renal congestion that predict heart failure progression. Methods: We enrolled outpatients affected by CHF, in stable clinical conditions and in conventional therapy. All patients underwent a clinical evaluation, routine chemistry, an echocardiogram and a renal echo-Doppler. Pulsed Doppler flow recording was performed at the level of interlobular renal right veins in the tele-expiratory phase. The venous flow patterns were divided into five groups according to the fluctuations of the flow. Type A and B were characterized by a continuous flow, whereas type C was characterized by a short interruption or reversal flow during the end-diastolic or protosystolic phase. Type D and E were characterized by a wide interruption and/or reversal flow. The occurrence of death and/or of heart transplantation and/or of hospitalization due to heart failure worsening was considered an event during follow-up. Results: During a median follow-up of 38 months, 126 patients experienced the considered end-point. Venous pattern C (HR 4.04; 95% CI: 2.14–7.65; p < 0.001), pattern D (HR 7.16; 95% CI: 3.69–13.9; p < 0.001) and pattern E (HR 8.94; 95% CI: 4.65–17.2; p < 0.001) were all associated with events using an univariate Cox regression analysis. Moreover, both the presence of pattern C (HR: 1.79; 95% CI: 1.09–2.97; p: 0) and of pattern D or E (HR: 1.90; 95% CI: 1.16–3.12; p: 0.011) remained significantly associated to events using a multivariate Cox regression analysis after correction for a reference model with an improvement of the overall net reclassification index (0.46; 95% CI 0.24–0.68; p < 0.001). Conclusions: Our findings demonstrate the independent and incremental role of Doppler venous patterns reflecting renal congestion in predicting HF progression among CHF patients, thus suggesting its possible utility in daily clinical practice to better characterize patients with cardio-renal syndrome. Full article

The last decade has seen a new condition that describes the coexistence of obesity and sarcopenia, termed sarcopenic obesity (SO). We aimed to assess the prevalence of SO in overweight and obese treatment-seeking adult women and the association with type 2 diabetes, hypertension, and dyslipidemia. A body composition assessment was conducted with an InBody bioimpedance analyser in 154 overweight and obese women referred to the Outpatient Clinic in the Department of Nutrition and Dietetics at Beirut Arab University (BAU) in Lebanon, and 30 normal-weight participants of similar age. The overweight and obese patients were then categorized as being with or without sarcopenia. Thirty-one out of the 154 overweight or obese participants met the criteria for SO and displayed a significantly higher prevalence of type 2 diabetes and hypertension than those without SO. Logistic regression analysis showed that SO increases the odds of having type 2 diabetes and hypertension by nearly 550% (odds ratio = 5.42, 95% confidence interval = 1.37–21.40, p < 0.05) after adjusting for central fat, eating habits, level of physical activity, and smoking. SO affects nearly 20% of treatment-seeking overweight and obese adult women. Moreover, SO seems to be strongly associated with type 2 diabetes and hypertension. Full article

Bradycardia arising from pacemaker dysfunction can be debilitating and life threatening. Electronic pacemakers serve as effective treatment options for pacemaker dysfunction. They however present their own limitations and complications. This has motivated research into discovering more effective and innovative ways to treat pacemaker dysfunction. Gene therapy is being explored for its potential to treat various cardiac conditions including cardiac arrhythmias. Gene transfer vectors with increasing transduction efficiency and biosafety have been developed and trialed for cardiovascular disease treatment. With an improved understanding of the molecular mechanisms driving pacemaker development, several gene therapy targets have been identified to generate the phenotypic changes required to correct pacemaker dysfunction. This review will discuss the gene therapy vectors in use today along with methods for their delivery. Furthermore, it will evaluate several gene therapy strategies attempting to restore biological pacing, having the potential to emerge as viable therapies for pacemaker dysfunction. Full article

Haploinsufficiency of the T-box transcription factor TBX1 is responsible for many features of 22q11.2 deletion syndrome. Tbx1 is expressed dynamically in the pharyngeal apparatus during mouse development and Tbx1 homozygous mutants display numerous severe defects including abnormal cranial ganglion formation and neural crest cell defects. These abnormalities prompted us to investigate whether parasympathetic (vagal) innervation of the heart was affected in Tbx1 mutant embryos. In this report, we used an allelic series of Tbx1 mouse mutants, embryo tissue explants and cardiac electrophysiology to characterise, in detail, the function of Tbx1 in vagal innervation of the heart. We found that total nerve branch length was significantly reduced in Tbx1^+/− and Tbx1^neo2/− mutant hearts expressing 50% and 15% levels of Tbx1. We also found that neural crest cells migrated normally to the heart of Tbx1^+/−, but not in Tbx1^neo2 mutant embryos. In addition, we showed that cranial ganglia IX^th and X^th were fused in Tbx1^neo2/− but neuronal differentiation appeared intact. Finally, we used telemetry to monitor heart response to carbachol, a cholinergic receptor agonist, and found that heart rate recovered more quickly in Tbx1^+/− animals versus controls. We speculate that this condition of decreased parasympathetic drive could result in a pro-arrhythmic substrate in some 22q11.2DS patients. Full article

Genetic polymorphisms are variations in DNA sequences which can influence either disease susceptibility, severity, or prognosis. Pulmonary arterial hypertension (PAH) is one of the complications that occurs in certain patients who have atrial septal defect (ASD). This study seeks to determine the association of gene polymorphisms with the pathogenesis of PAH in ASD patients. This study was conducted on 30 ASD patients with PAH, and 50 ASD patients who were not diagnosed with PAH. All respondents were Malay. Patients were selected based on stringent inclusion and exclusion criteria. Molecular analyses were done to detect the genetic polymorphisms of angiotensin converting enzyme (ACE I/D), serotonin transporter (5-HTTLPR), endothelial nitric oxide synthase (eNOS) G894T, and eNOS 4b/4a. The genotypes of these genetic polymorphisms were determined using conventional PCR and PCR-RFLP methods. The PCR products were analysed using agarose gel electrophoresis. Statistical analysis was done using SPSS Version 22. Clinical characteristics, such as the diameter of ASD, mean arterial pressure (MAP), and mean pulmonary artery pressure (mPAP) differed significantly (p < 0.05). Based on the statistical analysis, ACE I/D, eNOS G894T, and eNOS 4b/4a do not contribute to the progression of PAH amongst ASD patients (p > 0.05). However, the L allele of the 5-HTTLPR gene polymorphism may have an affect on the development of PAH in ASD patients (p < 0.05). Full article

Purpose: Fasting or postprandial hypertriglyceridemia is considered an independent cardiovascular disease (CVD) risk factor. The intestinal fatty acid binding protein (FABP2) is involved in the intracellular transport and metabolism of fatty acids. The presence of the Ala54Thr polymorphism of the FABP2 gene appears to be involved in postprandial hypertriglyceridemia. We explored the possible association of the Ala54Thr polymorphism with fat intolerance in apparently healthy, fasting, normolipidemic subjects with normal body-mass index and without diabetes. Methodology: A total of 158 apparently healthy individuals were classified as fat tolerant (n = 123) or intolerant (n = 35) according to their response (plasma triglycerides) to an oral abbreviated tolerance test with blood samples taken at 0, 2 and 4 h. At 0 h, all subjects ingested 26.3 g of fats. Presence of the Ala54Thr polymorphism of the FABP2 gene was evaluated by polymerase chain reaction–restriction fragment length (PCR–RFLP). Results: The group with fat intolerance (postprandial hypertriglyceridemia group) showed an increased frequency of the Thr54Thr genotype when compared with the group with normal fat tolerance (control group) (23% vs. 4%, respectively, OR: 16.53, 95% CI: 4.09–66.82, p: 0.0001, pc: 0.0003). Carriers of at least one Thr54 allele were up to six times more prevalent in the fat intolerant group than in the non-carriers. (OR: 6.35; 95% CI: 1.86–21.59, p: 0.0003, pc: 0.0009). The levels of plasma triglycerides (Tg) at 4 h after the test meal were higher in carriers of at least one 54Thr allele than in carriers of the Ala54 allele (p < 0.05). Conclusions: There is a significant association between postprandial hypertriglyceridemia and the presence of at least one 54Thr allele of the FABP2 gene. In addition, subjects with this genotype showed an increased ratio of Tg/HDL-cholesterol. This parameter is a marker of increased CVD risk and insulin resistance. Full article

That form and function are related is a maxim of anatomy and physiology. Yet, form-function relations can be difficult to prove. Human subjects with excessive trabeculated myocardium in the left ventricle, for example, are diagnosed with non-compaction cardiomyopathy, but the extent of trabeculations may be without relation to ejection fraction. Rather than rejecting a relation between form and function, we may ask whether the salient function is assessed. Is there a relation to electrical propagation, mean arterial blood pressure, or propensity to form blood clots? In addition, how should the extent of trabeculated muscle be assessed? While reviewing literature on trabeculated muscle, we applied Tinbergen’s four types of causation—how does it work, why does it work, how is it made, and why did it evolve—to better parse what is meant by form and function. The paper is structured around cases that highlight advantages and pitfalls of applying Tinbergen’s questions. It further uses the evolution of lunglessness in amphibians to argue that lung reduction impacts on chamber septation and it considers the evolution of an arterial outflow in fishes to argue that reductions in energy consumption may drive structural changes with little consequences to function. Concerning trabeculations, we argue they relate to pumping function in the embryo in the few weeks before the onset of coronary circulation. In human fetal and postnatal stages, a spectrum of trabeculated-to-compact myocardium makes no difference to cardiac function and in this period, form and function may appear unrelated. Full article

Cardiovascular diseases (CVDs) are as menacing as ever and still continue to kill adults worldwide, notwithstanding tremendous efforts to decrease their consequent mortality and morbidity. Lately, a growing body of research indicated that inflammation plays a pivotal role in the pathogenesis and complications of CVDs. A receptor of the immunoglobulin superfamily, triggering receptors expressed on myeloid cells-1 (TREM-1) was shown to induce and amplify the inflammation in both acute and chronic disease’ pathogenesis and progression, which hence makes it one of the most important complication factors of CVDs. Thus, studies endeavored to investigate the role played by TREM-1 in CVDs with respect to their etiologies, complications, and possible therapeutics. We examined here, for the first time, the most relevant studies regarding TREM-1 involvement in CVDs. We critically analyzed and summarized our findings and made some suggestions for furtherance of the investigations with the aim to utilize TREM-1 and its pathways for diagnostic, management, and prognosis of CVDs. Overall, TREM-1 was found to be involved in the pathogenesis of acute and chronic cardiovascular conditions, such as acute myocardial infarction (AMI) and atherosclerosis. Although most therapeutic approaches are yet to be elucidated, our present research outcome displays a promising future to utilizing the TREM-1 pathway as a potential target for understanding and managing CVDs. Full article

It is now well over 100 years since Sunao Tawara clarified the location of the axis of the specialised myocardium responsible for producing coordinated ventricular activation. Prior to that stellar publication, controversies had raged as to how many bundles crossed the place of the atrioventricular insulation as found in mammalian hearts, as well as the very existence of the bundle initially described by Wilhelm His Junior. It is, perhaps surprising that controversies continue, despite the multiple investigations that have taken place since the publication of Tawara’s monograph. For example, we are still unsure as to the precise substrates for the so-called slow and fast pathways into the atrioventricular node. Much has been done, nonetheless, to characterise the molecular make-up of the specialised pathways, and to clarify their mechanisms of development. Of this work itself, a significant part has emanated from the laboratory coordinated for a quarter of a century by Antoon FM Moorman. In this review, which joins the others in recognising the value of his contributions and collaborations, we review our current understanding of the anatomy, development, and evolution of the atrioventricular conduction axis. Full article

We previously reported how the loss of CHIP expression (Carboxyl terminus of Hsc70-Interacting Protein) during pressure overload resulted in robust cardiac dysfunction, which was accompanied by a failure to maintain ATP levels in the face of increased energy demand. In this study, we analyzed the cardiac metabolome after seven days of pressure overload and found an increase in long-chain and medium-chain fatty acid metabolites in wild-type hearts. This response was attenuated in mice that lack expression of CHIP (CHIP^−/−). These findings suggest that CHIP may play an essential role in regulating oxidative metabolism pathways that are regulated, in part, by the nuclear receptor PPARα (Peroxisome Proliferator-Activated Receptor alpha). Next, we challenged CHIP^−/− mice with the PPARα agonist called fenofibrate. We found that treating CHIP^−/− mice with fenofibrate for five weeks under non-pressure overload conditions resulted in decreased skeletal muscle mass, compared to wild-type mice, and a marked increase in cardiac fibrosis accompanied by a decrease in cardiac function. Fenofibrate resulted in decreased mitochondrial cristae density in CHIP^−/− hearts as well as decreased expression of genes involved in the initiation of autophagy and mitophagy, which suggests that a metabolic challenge, in the absence of CHIP expression, impacts pathways that contribute to mitochondrial quality control. In conclusion, in the absence of functional CHIP expression, fenofibrate results in unexpected skeletal muscle and cardiac pathologies. These findings are particularly relevant to patients harboring loss-of-function mutations in CHIP and are consistent with a prominent role for CHIP in regulating cardiac metabolism. Full article

Elastic extra-aortic wrapping is a potential non-pharmacological way to improve aortic compliance and treat isolated systolic hypertension associated with a stiffened aorta. We aimed to use computer simulations to re-evaluate whether there is aortic shape distortion in aortic wrapping to achieve greater elasticity of the wrapped aortic segment. Non-linear transient numerical analysis based on an idealized hyper-elastic single-layered aorta model was performed to simulate the force/displacement regimes of external aortic wrapping. Pressure-displacement relationships were used to establish model aortic wall distensibilities of 4.3 and 5.5 (10⁻³ mmHg⁻¹). A physiological pulsatile lumen pressure was employed to estimate the potential improvements in aortic distensibility by compression forces representing elastic aortic wrapping. In the less distensible model of the aortic wall there was increased systolic expansion in the wrapped segment. We found a risk of creasing of the aortic luminal wall with wrapping. Sufficient unloading of a thick and elastic aortic wall to induce increased compliance, as observed in elastic wrapping, is associated with the potential risk of over compression and folding (creasing) inside the lumen. Full article

Background: According to the ventricular myocardial band model, the diastolic isovolumetric period is a contraction phenomenon. Our objective was to employ speckle-tracking echocardiography (STE) to analyze myocardial deformation of the left ventricle (LV) and to confirm if it supports the myocardial band model. Methods: This was a prospective observational study in which 90 healthy volunteers were recruited. We evaluated different types of postsystolic shortening (PSS) from an LV longitudinal strain study. Duration of latest deformation (LD) was calculated as the time from the start of the QRS complex of the ECG to the latest longitudinal deformation peak in the 18 segments of the LV. Results: The mean age of our subjects was 50.3 ± 11.1 years. PSS was observed in 48.4% of the 1620 LV segments studied (19.8%, 13.5%, and 15.1% in the basal, medial, and apical regions, respectively). PSS was more frequent in the basal, medial septal, and apical anteroseptal segments (>50%). LD peaked in the interventricular septum and in the basal segments of the LV. Conclusions: The pattern of PSS and LD revealed by STE suggests there is contraction in the postsystolic phase of the cardiac cycle. The anatomical location of the segments in which this contraction is most frequently observed corresponds to the main path of the ascending component of the myocardial band. This contraction can be attributed to the protodiastolic untwisting of the LV. Full article