Open AccessArticle
Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy
J. Cardiovasc. Dev. Dis. 2017, 4(3), 11; doi:10.3390/jcdd4030011 -
Abstract
Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. DCM typically remains clinically silent until adulthood, yet symptomatic disease can develop in childhood. We sought to identify the genetic basis of pediatric DCM in 15 sporadic and three
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Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. DCM typically remains clinically silent until adulthood, yet symptomatic disease can develop in childhood. We sought to identify the genetic basis of pediatric DCM in 15 sporadic and three affected-siblings cases, comprised of 21 affected children (mean age, five years) whose parents had normal echocardiograms (mean age, 39 years). Twelve underwent cardiac transplantation and five died with severe heart failure. Parent-offspring whole exome sequencing (WES) data were filtered for rare, deleterious, de novo and recessive variants. In prior work, we reported de novo mutations in TNNT2 and RRAGC and compound heterozygous mutations in ALMS1 and TAF1A among four cases in our cohort. Here, de novo mutations in established DCM genes—RBM20, LMNA, TNNT2, and PRDM16—were identified among five additional cases. The RBM20 mutation was previously reported in familial DCM. An identical unreported LMNA mutation was identified in two unrelated cases, both harboring gene-specific defects in cardiomyocyte nuclear morphology. Collectively, WES had a 50% diagnostic yield in our cohort, providing an explanation for pediatric heart failure and enabling informed family planning. Research is ongoing to discover novel DCM genes among the remaining families. Full article
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Open AccessCommunication
Phosphodiesterases 3 and 4 Differentially Regulate the Funny Current, If, in Mouse Sinoatrial Node Myocytes
J. Cardiovasc. Dev. Dis. 2017, 4(3), 10; doi:10.3390/jcdd4030010 -
Abstract
Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3′,5′-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac “funny current” (If) is among the cAMP-sensitive effectors that drive pacemaking in SAMs. If is produced
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Cardiac pacemaking, at rest and during the sympathetic fight-or-flight response, depends on cAMP (3′,5′-cyclic adenosine monophosphate) signaling in sinoatrial node myocytes (SAMs). The cardiac “funny current” (If) is among the cAMP-sensitive effectors that drive pacemaking in SAMs. If is produced by hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels. Voltage-dependent gating of HCN channels is potentiated by cAMP, which acts either by binding directly to the channels or by activating the cAMP-dependent protein kinase (PKA), which phosphorylates them. PKA activity is required for signaling between β adrenergic receptors (βARs) and HCN channels in SAMs but the mechanism that constrains cAMP signaling to a PKA-dependent pathway is unknown. Phosphodiesterases (PDEs) hydrolyze cAMP and form cAMP signaling domains in other types of cardiomyocytes. Here we examine the role of PDEs in regulation of If in SAMs. If was recorded in whole-cell voltage-clamp experiments from acutely-isolated mouse SAMs in the absence or presence of PDE and PKA inhibitors, and before and after βAR stimulation. General PDE inhibition caused a PKA-independent depolarizing shift in the midpoint activation voltage (V1/2) of If at rest and removed the requirement for PKA in βAR-to-HCN signaling. PDE4 inhibition produced a similar PKA-independent depolarizing shift in the V1/2 of If at rest, but did not remove the requirement for PKA in βAR-to-HCN signaling. PDE3 inhibition produced PKA-dependent changes in If both at rest and in response to βAR stimulation. Our results suggest that PDE3 and PDE4 isoforms create distinct cAMP signaling domains that differentially constrain access of cAMP to HCN channels and establish the requirement for PKA in signaling between βARs and HCN channels in SAMs. Full article
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Open AccessArticle
A Multiparametric Approach Based on NT-proBNP, ST2, and Galectin3 for Stratifying One Year Prognosis of Chronic Heart Failure Outpatients
J. Cardiovasc. Dev. Dis. 2017, 4(3), 0009; doi:10.3390/jcdd4030009 -
Abstract
Galectin-3 and ST2 are emerging biomarkers involved in myocardial fibrosis. We evaluate the relevance of a multiparametric biomarker approach based on increased serum levels of NT-proBNP, galectin-3, and ST2 in stratifying the prognosis of chronic heart failure (CHF) outpatients. In 315 CHF outpatients
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Galectin-3 and ST2 are emerging biomarkers involved in myocardial fibrosis. We evaluate the relevance of a multiparametric biomarker approach based on increased serum levels of NT-proBNP, galectin-3, and ST2 in stratifying the prognosis of chronic heart failure (CHF) outpatients. In 315 CHF outpatients in stable clinical condition clinical and echocardiographic evaluations were performed. Routine chemistry and serum levels of NT-proBNP, galectin-3, and ST2 were also assessed. During a 12 month follow-up, cardiovascular death, and/or heart failure (HF) occurred in 64 patients. The presence of NT-proBNP, galectin-3, and ST2 were higher than the recommended cutoffs and were all associated with events at univariate Cox regression analysis, as well as in a multivariate analysis including the three biomarkers. When a score based on the number of biomarkers above the recommended cut-offs was used (in a range of 0–3), it was associated with events both with respect to the univariate (HR 2.96, 95% CI 2.21–3.95, p < 0.001, C-index 0.78) and the multivariate (HR 1.52, 95% CI 1.06–2.17, p: 0.023, C-index 0.87) analyses, after correction for the variables of a reference model. Our results suggest that an easy prognostic approach based on the combination of three biomarkers, although with partially-overlapping pathophysiological mechanisms, is able to identify patients with the highest risk of heart failure progression. Full article
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Open AccessReview
Multiple Species Comparison of Cardiac Troponin T and Dystrophin: Unravelling the DNA behind Dilated Cardiomyopathy
J. Cardiovasc. Dev. Dis. 2017, 4(3), 8; doi:10.3390/jcdd4030008 -
Abstract
Animals have frequently been used as models for human disorders and mutations. Following advances in genetic testing and treatment options, and the decreasing cost of these technologies in the clinic, mutations in both companion and commercial animals are now being investigated. A recent
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Animals have frequently been used as models for human disorders and mutations. Following advances in genetic testing and treatment options, and the decreasing cost of these technologies in the clinic, mutations in both companion and commercial animals are now being investigated. A recent review highlighted the genes associated with both human and non-human dilated cardiomyopathy. Cardiac troponin T and dystrophin were observed to be associated with both human and turkey (troponin T) and canine (dystrophin) dilated cardiomyopathies. This review gives an overview of the work carried out in cardiac troponin T and dystrophin to date in both human and animal dilated cardiomyopathy. Full article
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Open AccessFeature PaperReview
Development and Function of the Cardiac Conduction System in Health and Disease
J. Cardiovasc. Dev. Dis. 2017, 4(2), 7; doi:10.3390/jcdd4020007 -
Abstract
The generation and propagation of the cardiac impulse is the central function of the cardiac conduction system (CCS). Impulse initiation occurs in nodal tissues that have high levels of automaticity, but slow conduction properties. Rapid impulse propagation is a feature of the ventricular
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The generation and propagation of the cardiac impulse is the central function of the cardiac conduction system (CCS). Impulse initiation occurs in nodal tissues that have high levels of automaticity, but slow conduction properties. Rapid impulse propagation is a feature of the ventricular conduction system, which is essential for synchronized contraction of the ventricular chambers. When functioning properly, the CCS produces ~2.4 billion heartbeats during a human lifetime and orchestrates the flow of cardiac impulses, designed to maximize cardiac output. Abnormal impulse initiation or propagation can result in brady- and tachy-arrhythmias, producing an array of symptoms, including syncope, heart failure or sudden cardiac death. Underlying the functional diversity of the CCS are gene regulatory networks that direct cell fate towards a nodal or a fast conduction gene program. In this review, we will discuss our current understanding of the transcriptional networks that dictate the components of the CCS, the growth factor-dependent signaling pathways that orchestrate some of these transcriptional hierarchies and the effect of aberrant transcription factor expression on mammalian conduction disease. Full article
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Open AccessArticle
Breast Cancer Clinical Trial of Chemotherapy and Trastuzumab: Potential Tool to Identify Cardiac Modifying Variants of Dilated Cardiomyopathy
J. Cardiovasc. Dev. Dis. 2017, 4(2), 6; doi:10.3390/jcdd4020006 -
Abstract
Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell
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Doxorubicin and the ERBB2 targeted therapy, trastuzumab, are routinely used in the treatment of HER2+ breast cancer. In mouse models, doxorubicin is known to cause cardiomyopathy and conditional cardiac knock out of Erbb2 results in dilated cardiomyopathy and increased sensitivity to doxorubicin-induced cell death. In humans, these drugs also result in cardiac phenotypes, but severity and reversibility is highly variable. We examined the association of decline in left ventricular ejection fraction (LVEF) at 15,204 single nucleotide polymorphisms (SNPs) spanning 72 cardiomyopathy genes, in 800 breast cancer patients who received doxorubicin and trastuzumab. For 7033 common SNPs (minor allele frequency (MAF) > 0.01) we performed single marker linear regression. For all SNPs, we performed gene-based testing with SNP-set (Sequence) Kernel Association Tests: SKAT, SKAT-O and SKAT-common/rare under rare variant non-burden; rare variant optimized burden and non-burden tests; and a combination of rare and common variants respectively. Single marker analyses identified seven missense variants in OBSCN (p = 0.0045–0.0009, MAF = 0.18–0.50) and two in TTN (both p = 0.04, MAF = 0.22). Gene-based rare variant analyses, SKAT and SKAT-O, performed very similarly (ILK, TCAP, DSC2, VCL, FXN, DSP and KCNQ1, p = 0.042–0.006). Gene-based tests of rare/common variants were significant at the nominal 5% level for OBSCN as well as TCAP, DSC2, VCL, NEXN, KCNJ2 and DMD (p = 0.044–0.008). Our results suggest that rare and common variants in OBSCN, as well as in other genes, could have modifying effects in cardiomyopathy. Full article
Open AccessReview
Lineages of the Cardiac Conduction System
J. Cardiovasc. Dev. Dis. 2017, 4(2), 5; doi:10.3390/jcdd4020005 -
Abstract
The cardiac conduction system (CCS) initiates and coordinately propagates the electrical impulse to orchestrate the heartbeat. It consists of a set of interconnected components with shared properties. A better understanding of the origin and specification of CCS lineages has allowed us to better
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The cardiac conduction system (CCS) initiates and coordinately propagates the electrical impulse to orchestrate the heartbeat. It consists of a set of interconnected components with shared properties. A better understanding of the origin and specification of CCS lineages has allowed us to better comprehend the etiology of CCS disease and has provided leads for development of therapies. A variety of technologies and approaches have been used to investigate CCS lineages, which will be summarized in this review. The findings imply that there is not a single CCS lineage. In contrast, early cell fate decisions segregate the lineages of the CCS components while they remain connected to each other. Full article
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Open AccessFeature PaperReview
On the Evolution of the Cardiac Pacemaker
J. Cardiovasc. Dev. Dis. 2017, 4(2), 4; doi:10.3390/jcdd4020004 -
Abstract
The rhythmic contraction of the heart is initiated and controlled by an intrinsic pacemaker system. Cardiac contractions commence at very early embryonic stages and coordination remains crucial for survival. The underlying molecular mechanisms of pacemaker cell development and function are still not fully
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The rhythmic contraction of the heart is initiated and controlled by an intrinsic pacemaker system. Cardiac contractions commence at very early embryonic stages and coordination remains crucial for survival. The underlying molecular mechanisms of pacemaker cell development and function are still not fully understood. Heart form and function show high evolutionary conservation. Even in simple contractile cardiac tubes in primitive invertebrates, cardiac function is controlled by intrinsic, autonomous pacemaker cells. Understanding the evolutionary origin and development of cardiac pacemaker cells will help us outline the important pathways and factors involved. Key patterning factors, such as the homeodomain transcription factors Nkx2.5 and Shox2, and the LIM-homeodomain transcription factor Islet-1, components of the T-box (Tbx), and bone morphogenic protein (Bmp) families are well conserved. Here we compare the dominant pacemaking systems in various organisms with respect to the underlying molecular regulation. Comparative analysis of the pathways involved in patterning the pacemaker domain in an evolutionary context might help us outline a common fundamental pacemaker cell gene programme. Special focus is given to pacemaker development in zebrafish, an extensively used model for vertebrate development. Finally, we conclude with a summary of highly conserved key factors in pacemaker cell development and function. Full article
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Open AccessReview
Management of Arrhythmias in Heart Failure
J. Cardiovasc. Dev. Dis. 2017, 4(1), 3; doi:10.3390/jcdd4010003 -
Abstract
Heart failure patients are predisposed to develop arrhythmias. Supraventricular arrhythmias can exacerbate the heart failure symptoms by decreasing the effective cardiac output and their control require pharmacological, electrical, or catheter-based intervention. In the setting of atrial flutter or atrial fibrillation, anticoagulation becomes paramount
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Heart failure patients are predisposed to develop arrhythmias. Supraventricular arrhythmias can exacerbate the heart failure symptoms by decreasing the effective cardiac output and their control require pharmacological, electrical, or catheter-based intervention. In the setting of atrial flutter or atrial fibrillation, anticoagulation becomes paramount to prevent systemic or cerebral embolism. Patients with heart failure are also prone to develop ventricular arrhythmias that can present a challenge to the managing clinician. The management strategy depends on the type of arrhythmia, the underlying structural heart disease, the severity of heart failure, and the range from optimization of heart failure therapy to catheter ablation. Patients with heart failure, irrespective of ejection fraction are at high risk for developing sudden cardiac death, however risk stratification is a clinical challenge and requires a multiparametric evaluation for identification of patients who should undergo implantation of a cardioverter defibrillator. Finally, patients with heart failure can also develop symptomatic bradycardia, caused by sinus node dysfunction or atrio-ventricular block. The treatment of bradycardia in these patients with pacing is usually straightforward but needs some specific issue. Full article
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Open AccessArticle
Collagenolytic Activity Is Associated with Scar Resolution in Zebrafish Hearts after Cryoinjury
J. Cardiovasc. Dev. Dis. 2017, 4(1), 2; doi:10.3390/jcdd4010002 -
Abstract
Myocardial infarction is the major cause of cardiac injury in western countries and can result in a massive loss of heart cells, leading eventually to heart failure. A fibrotic collagen-rich scar may prevent ventricular wall rupture, but also may result in heart failure
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Myocardial infarction is the major cause of cardiac injury in western countries and can result in a massive loss of heart cells, leading eventually to heart failure. A fibrotic collagen-rich scar may prevent ventricular wall rupture, but also may result in heart failure because of its stiffness. In zebrafish, cardiac cryoinjury triggers a fibrotic response and scarring. Unlike with mammals, zebrafish heart has the striking ability to regenerate and to resolve the scar. Thus, understanding the mechanisms of scar resolution in zebrafish heart might facilitate the design of new therapeutic approaches to improve the recovery of patients. To visualize the collagenolytic activity within the zebrafish heart following cryoinjury, we used an in situ collagen zymography assay. We detected expression of mmp2 and mmp14a and these matrix metalloproteinases might contribute to the collagenase activity. Collagenolytic activity was present in the wound area, but decreased as the myocardium regenerated. Comparison with neonatal mouse hearts that failed to regenerate after transmural cryoinjury revealed a similar collagenolytic activity in the scar. These findings suggest that collagenolytic activity may be key to how the zebrafish heart resolves its scar; however, it is not sufficient in mouse hearts that lack efficient myocardial regeneration. Full article
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Open AccessEditorial
Acknowledgement to Reviewers of Journal of Cardiovascular Development and Disease in 2016
J. Cardiovasc. Dev. Dis. 2017, 4(1), 1; doi:10.3390/jcdd4010001 -
Open AccessReview
Mechanical Circulatory Support for Advanced Heart Failure: Are We about to Witness a New “Gold Standard”?
J. Cardiovasc. Dev. Dis. 2016, 3(4), 35; doi:10.3390/jcdd3040035 -
Abstract
The impact of left ventricular assist devices (LVADs) for the treatment of advanced heart failure has played a significant role as a bridge to transplant and more recently as a long-term solution for non-eligible candidates. Continuous flow left ventricular assist devices (CF-LVADs), based
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The impact of left ventricular assist devices (LVADs) for the treatment of advanced heart failure has played a significant role as a bridge to transplant and more recently as a long-term solution for non-eligible candidates. Continuous flow left ventricular assist devices (CF-LVADs), based on axial and centrifugal design, are currently the most popular devices in view of their smaller size, increased reliability and higher durability compared to pulsatile flow left ventricular assist devices (PF-LVADs). The trend towards their use is increasing. Therefore, it has become mandatory to understand the physics and the mathematics behind their mode of operation for appropriate device selection and simulation set up. For this purpose, this review covers some of these aspects. Although very successful and technologically advanced, they have been associated with complications such as pump thrombosis, haemolysis, aortic regurgitation, gastro-intestinal bleeding and arterio-venous malformations. There is perception that the reduced arterial pulsatility may be responsible for these complications. A flow modulation control approach is currently being investigated in order to generate pulsatility in rotary blood pumps. Thrombus formation remains the most feared complication that can affect clinical outcome. The development of a preoperative strategy aimed at the reduction of complications and patient-device suitability may be appropriate. Patient-specific modelling based on 3D reconstruction from CT-scan combined with computational fluid dynamic studies is an attractive solution in order to identify potential areas of stagnation or challenging anatomy that could be addressed to achieve the desired outcome. The HeartMate II (axial) and the HeartWare HVAD (centrifugal) rotary blood pumps have been now used worldwide with proven outcome. The HeartMate III (centrifugal) is now emerging as the new promising device with encouraging preliminary results. There are now enough pumps on the market: it is time to focus on the complications in order to achieve the full potential and selling-point of this type of technology for the treatment of the increasing heart failure patient population. Full article
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Open AccessReview
Current Perspectives in Cardiac Laterality
J. Cardiovasc. Dev. Dis. 2016, 3(4), 34; doi:10.3390/jcdd3040034 -
Abstract
The heart is the first organ to break symmetry in the developing embryo and onset of dextral looping is the first indication of this event. Looping is a complex process that progresses concomitantly to cardiac chamber differentiation and ultimately leads to the alignment
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The heart is the first organ to break symmetry in the developing embryo and onset of dextral looping is the first indication of this event. Looping is a complex process that progresses concomitantly to cardiac chamber differentiation and ultimately leads to the alignment of the cardiac regions in their final topology. Generation of cardiac asymmetry is crucial to ensuring proper form and consequent functionality of the heart, and therefore it is a highly regulated process. It has long been known that molecular left/right signals originate far before morphological asymmetry and therefore can direct it. The use of several animal models has led to the characterization of a complex regulatory network, which invariably converges on the Tgf-β signaling molecule Nodal and its downstream target, the homeobox transcription factor Pitx2. Here, we review current data on the cellular and molecular bases of cardiac looping and laterality, and discuss the contribution of Nodal and Pitx2 to these processes. A special emphasis will be given to the morphogenetic role of Pitx2 and to its modulation of transcriptional and functional properties, which have also linked laterality to atrial fibrillation. Full article
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Open AccessReview
Management of Mechanical Ventilation in Decompensated Heart Failure
J. Cardiovasc. Dev. Dis. 2016, 3(4), 33; doi:10.3390/jcdd3040033 -
Abstract
Mechanical ventilation (MV) is a life-saving intervention for respiratory failure, including decompensated congestive heart failure. MV can reduce ventricular preload and afterload, decrease extra-vascular lung water, and decrease the work of breathing in heart failure. The advantages of positive pressure ventilation must be
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Mechanical ventilation (MV) is a life-saving intervention for respiratory failure, including decompensated congestive heart failure. MV can reduce ventricular preload and afterload, decrease extra-vascular lung water, and decrease the work of breathing in heart failure. The advantages of positive pressure ventilation must be balanced with potential harm from MV: volutrauma, hyperoxia-induced injury, and difficulty assessing readiness for liberation. In this review, we will focus on cardiac, pulmonary, and broader effects of MV on patients with decompensated HF, focusing on practical considerations for management and supporting evidence. Full article
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Open AccessReview
Genetic and Epigenetic Mechanisms Linking Air Pollution and Congenital Heart Disease
J. Cardiovasc. Dev. Dis. 2016, 3(4), 32; doi:10.3390/jcdd3040032 -
Abstract
Epidemiological studies strongly suggest that parental air pollutants exposure during the periconceptional period may play a major role in causing fetal/newborn malformations, including a frequent heterogeneity in the methods applied and a difficulty in estimating the clear effect of environmental toxicants. Moreover, only
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Epidemiological studies strongly suggest that parental air pollutants exposure during the periconceptional period may play a major role in causing fetal/newborn malformations, including a frequent heterogeneity in the methods applied and a difficulty in estimating the clear effect of environmental toxicants. Moreover, only some couples exposed to toxicants during the pre-conception period give birth to a child with congenital anomalies. The reasons for such phenomena remain elusive but they can be explained by the individual, innate ability to metabolize these contaminants that eventually defines the ultimate dose of a biological active toxicant. In this paper, we reviewed the major evidence regarding the role of parental air pollutant exposure on congenital heart disease (CHD) risk as well as the modulating effect on detoxification systems. Finally, major epigenetic alterations induced by adverse environment contaminants have been revised as possible mechanisms altering a correct heart morphogenesis. Full article
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Open AccessReview
Myocarditis in Paediatric Patients: Unveiling the Progression to Dilated Cardiomyopathy and Heart Failure
J. Cardiovasc. Dev. Dis. 2016, 3(4), 31; doi:10.3390/jcdd3040031 -
Abstract
Myocarditis is a challenging and potentially life-threatening disease associated with high morbidity in some paediatric patients, due to its ability to present as an acute and fulminant disease and to ultimately progress to dilated cardiomyopathy. It has been described as an inflammatory disease
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Myocarditis is a challenging and potentially life-threatening disease associated with high morbidity in some paediatric patients, due to its ability to present as an acute and fulminant disease and to ultimately progress to dilated cardiomyopathy. It has been described as an inflammatory disease of the myocardium caused by diverse aetiologies. Viral infection is the most frequent cause of myocarditis in developed countries, but bacterial and protozoal infections or drug hypersensitivity may also be causative agents. The prompt diagnosis in paediatric patients is difficult, as the spectrum of clinical manifestation can range from no myocardial dysfunction to sudden cardiac death. Recent studies on myocarditis pathogenesis have revealed a triphasic nature of this disease, which influences the diagnostic and therapeutic strategies to adopt in each patient. Endomyocardial biopsy remains the gold standard for diagnosing myocarditis, and several non-invasive diagnostic tools can be used to support the diagnosis. Intravenous immunoglobulin has become part of routine practice in the treatment of myocarditis in paediatric patients at many centres, but its true effect on the cardiac function has been the target of many studies. The aim of this review is to approach the recently discovered facets of paediatric myocarditis regarding its progression to dilated cardiomyopathy. Full article
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Open AccessReview
Large Mammalian Animal Models of Heart Disease
J. Cardiovasc. Dev. Dis. 2016, 3(4), 30; doi:10.3390/jcdd3040030 -
Abstract
Due to the biological complexity of the cardiovascular system, the animal model is an urgent pre-clinical need to advance our knowledge of cardiovascular disease and to explore new drugs to repair the damaged heart. Ideally, a model system should be inexpensive, easily manipulated,
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Due to the biological complexity of the cardiovascular system, the animal model is an urgent pre-clinical need to advance our knowledge of cardiovascular disease and to explore new drugs to repair the damaged heart. Ideally, a model system should be inexpensive, easily manipulated, reproducible, a biological representative of human disease, and ethically sound. Although a larger animal model is more expensive and difficult to manipulate, its genetic, structural, functional, and even disease similarities to humans make it an ideal model to first consider. This review presents the commonly-used large animals—dog, sheep, pig, and non-human primates—while the less-used other large animals—cows, horses—are excluded. The review attempts to introduce unique points for each species regarding its biological property, degrees of susceptibility to develop certain types of heart diseases, and methodology of induced conditions. For example, dogs barely develop myocardial infarction, while dilated cardiomyopathy is developed quite often. Based on the similarities of each species to the human, the model selection may first consider non-human primates—pig, sheep, then dog—but it also depends on other factors, for example, purposes, funding, ethics, and policy. We hope this review can serve as a basic outline of large animal models for cardiovascular researchers and clinicians. Full article
Open AccessFeature PaperReview
The Dorsal Mesenchymal Protrusion and the Pathogenesis of Atrioventricular Septal Defects
J. Cardiovasc. Dev. Dis. 2016, 3(4), 29; doi:10.3390/jcdd3040029 -
Abstract
Congenital heart malformations are the most common type of defects found at birth. About 1% of infants are born with one or more heart defect on a yearly basis. Congenital Heart Disease (CHD) causes more deaths in the first year of life than
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Congenital heart malformations are the most common type of defects found at birth. About 1% of infants are born with one or more heart defect on a yearly basis. Congenital Heart Disease (CHD) causes more deaths in the first year of life than any other congenital abnormality, and each year, nearly twice as many children die in the United States from CHD as from all forms of childhood cancers combined. Atrioventricular septal defects (AVSD) are congenital heart malformations affecting approximately 1 in 2000 live births. Babies born with an AVSD often require surgical intervention shortly after birth. However, even after successful surgery, these individuals typically have to deal with lifelong complications with the most common being a leaky mitral valve. In recent years the understanding of the molecular etiology and morphological mechanisms associated with the pathogenesis of AVSDs has significantly changed. Specifically, these studies have linked abnormal development of the Dorsal Mesenchymal Protrusion (DMP), a Second Heart Field-derived structure, to the development of this congenital defect. In this review we will be discuss some of the latest insights into the role of the DMP in the normal formation of the atrioventricular septal complex and in the pathogenesis of AVSDs. Full article
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Open AccessFeature PaperReview
Part and Parcel of the Cardiac Autonomic Nerve System: Unravelling Its Cellular Building Blocks during Development
J. Cardiovasc. Dev. Dis. 2016, 3(3), 28; doi:10.3390/jcdd3030028 -
Abstract
The autonomic nervous system (cANS) is essential for proper heart function, and complications such as heart failure, arrhythmias and even sudden cardiac death are associated with an altered cANS function. A changed innervation state may underlie (part of) the atrial and ventricular arrhythmias
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The autonomic nervous system (cANS) is essential for proper heart function, and complications such as heart failure, arrhythmias and even sudden cardiac death are associated with an altered cANS function. A changed innervation state may underlie (part of) the atrial and ventricular arrhythmias observed after myocardial infarction. In other cardiac diseases, such as congenital heart disease, autonomic dysfunction may be related to disease outcome. This is also the case after heart transplantation, when the heart is denervated. Interest in the origin of the autonomic nerve system has renewed since the role of autonomic function in disease progression was recognized, and some plasticity in autonomic regeneration is evident. As with many pathological processes, autonomic dysfunction based on pathological innervation may be a partial recapitulation of the early development of innervation. As such, insight into the development of cardiac innervation and an understanding of the cellular background contributing to cardiac innervation during different phases of development is required. This review describes the development of the cANS and focuses on the cellular contributions, either directly by delivering cells or indirectly by secretion of necessary factors or cell-derivatives. Full article
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Open AccessReview
Heart Failure in Patients with Preserved Ejection Fraction: Questions Concerning Clinical Progression
J. Cardiovasc. Dev. Dis. 2016, 3(3), 27; doi:10.3390/jcdd3030027 -
Abstract
Over the last two decades, important advances have been made in explaining some pathophysiological aspects of heart failure with preserved ejection fraction (HFpEF) with repercussions for the successful clinical management of the syndrome. Despite these gains, our knowledge for the natural history of
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Over the last two decades, important advances have been made in explaining some pathophysiological aspects of heart failure with preserved ejection fraction (HFpEF) with repercussions for the successful clinical management of the syndrome. Despite these gains, our knowledge for the natural history of clinical progression from the pre-clinical diastolic dysfunction (PDD) until the final clinical stages is significantly limited. The subclinical progression of PDD to the clinical phenotype of HFpEF and the further clinical progression to some more complex clinical models with multi-organ involvement, similar to heart failure with reduced ejection fraction (HFrEF), continue to be poorly understood. Prospective studies are needed to elucidate the natural history of clinical progression in patients with HFpEF and to identify the exact left ventricular remodeling mechanism that underlies this progression. Full article
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