Journal of Cardiovascular Development and Disease

22 pages, 16990 KiB

Open AccessEditor’s ChoiceReview

From Stripes to a Beating Heart: Early Cardiac Development in Zebrafish

by Cassie L. Kemmler, Fréderike W. Riemslagh, Hannah R. Moran and Christian Mosimann

J. Cardiovasc. Dev. Dis. 2021, 8(2), 17; https://doi.org/10.3390/jcdd8020017 - 10 Feb 2021

Cited by 38 | Viewed by 10429

The heart is the first functional organ to form during vertebrate development. Congenital heart defects are the most common type of human birth defect, many originating as anomalies in early heart development. The zebrafish model provides an accessible vertebrate system to study early [...] Read more.

The heart is the first functional organ to form during vertebrate development. Congenital heart defects are the most common type of human birth defect, many originating as anomalies in early heart development. The zebrafish model provides an accessible vertebrate system to study early heart morphogenesis and to gain new insights into the mechanisms of congenital disease. Although composed of only two chambers compared with the four-chambered mammalian heart, the zebrafish heart integrates the core processes and cellular lineages central to cardiac development across vertebrates. The rapid, translucent development of zebrafish is amenable to in vivo imaging and genetic lineage tracing techniques, providing versatile tools to study heart field migration and myocardial progenitor addition and differentiation. Combining transgenic reporters with rapid genome engineering via CRISPR-Cas9 allows for functional testing of candidate genes associated with congenital heart defects and the discovery of molecular causes leading to observed phenotypes. Here, we summarize key insights gained through zebrafish studies into the early patterning of uncommitted lateral plate mesoderm into cardiac progenitors and their regulation. We review the central genetic mechanisms, available tools, and approaches for modeling congenital heart anomalies in the zebrafish as a representative vertebrate model. Full article

(This article belongs to the Special Issue Zebrafish Heart Development, Regeneration, and Disease Modelling)

► Show Figures

Figure 1

17 pages, 1155 KiB

Open AccessEditor’s ChoiceReview

Atrial and Sinoatrial Node Development in the Zebrafish Heart

by Kendall E. Martin and Joshua S. Waxman

J. Cardiovasc. Dev. Dis. 2021, 8(2), 15; https://doi.org/10.3390/jcdd8020015 - 9 Feb 2021

Cited by 18 | Viewed by 5772

Abstract

Proper development and function of the vertebrate heart is vital for embryonic and postnatal life. Many congenital heart defects in humans are associated with disruption of genes that direct the formation or maintenance of atrial and pacemaker cardiomyocytes at the venous pole of [...] Read more.

Proper development and function of the vertebrate heart is vital for embryonic and postnatal life. Many congenital heart defects in humans are associated with disruption of genes that direct the formation or maintenance of atrial and pacemaker cardiomyocytes at the venous pole of the heart. Zebrafish are an outstanding model for studying vertebrate cardiogenesis, due to the conservation of molecular mechanisms underlying early heart development, external development, and ease of genetic manipulation. Here, we discuss early developmental mechanisms that instruct appropriate formation of the venous pole in zebrafish embryos. We primarily focus on signals that determine atrial chamber size and the specialized pacemaker cells of the sinoatrial node through directing proper specification and differentiation, as well as contemporary insights into the plasticity and maintenance of cardiomyocyte identity in embryonic zebrafish hearts. Finally, we integrate how these insights into zebrafish cardiogenesis can serve as models for human atrial defects and arrhythmias. Full article

(This article belongs to the Special Issue Zebrafish Heart Development, Regeneration, and Disease Modelling)

► Show Figures

Figure 1

14 pages, 3828 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Pathways Regulating Establishment and Maintenance of Cardiac Chamber Identity in Zebrafish

by Yao Yao, Amanda N. Marra and Deborah Yelon

J. Cardiovasc. Dev. Dis. 2021, 8(2), 13; https://doi.org/10.3390/jcdd8020013 - 29 Jan 2021

Cited by 8 | Viewed by 4810

Abstract

The vertebrate heart is comprised of two types of chambers—ventricles and atria—that have unique morphological and physiological properties. Effective cardiac function depends upon the distinct characteristics of ventricular and atrial cardiomyocytes, raising interest in the genetic pathways that regulate chamber-specific traits. Chamber identity [...] Read more.

The vertebrate heart is comprised of two types of chambers—ventricles and atria—that have unique morphological and physiological properties. Effective cardiac function depends upon the distinct characteristics of ventricular and atrial cardiomyocytes, raising interest in the genetic pathways that regulate chamber-specific traits. Chamber identity seems to be specified in the early embryo by signals that establish ventricular and atrial progenitor populations and trigger distinct differentiation pathways. Intriguingly, chamber-specific features appear to require active reinforcement, even after myocardial differentiation is underway, suggesting plasticity of chamber identity within the developing heart. Here, we review the utility of the zebrafish as a model organism for studying the mechanisms that establish and maintain cardiac chamber identity. By combining genetic and embryological approaches, work in zebrafish has revealed multiple players with potent influences on chamber fate specification and commitment. Going forward, analysis of cardiomyocyte identity at the single-cell level is likely to yield a high-resolution understanding of the pathways that link the relevant players together, and these insights will have the potential to inform future strategies in cardiac tissue engineering. Full article

(This article belongs to the Special Issue Zebrafish Heart Development, Regeneration, and Disease Modelling)

► Show Figures

Figure 1

11 pages, 906 KiB

Open AccessEditor’s ChoiceArticle

Lipoprotein(a), Immunity, and Inflammation in Polyvascular Atherosclerotic Disease

by Narek A. Tmoyan, Olga I. Afanasieva, Marat V. Ezhov, Elena A. Klesareva, Tatiana V. Balakhonova and Sergei N. Pokrovsky

J. Cardiovasc. Dev. Dis. 2021, 8(2), 11; https://doi.org/10.3390/jcdd8020011 - 27 Jan 2021

Cited by 13 | Viewed by 4093

Abstract

Background and aims: lipoprotein(a) (Lp(a)) is a genetically determined risk factor for coronary artery disease and its complications, although data on the association with other vascular beds and the severity of atherosclerosis is limited. The aim of this study was to evaluate the [...] Read more.

Background and aims: lipoprotein(a) (Lp(a)) is a genetically determined risk factor for coronary artery disease and its complications, although data on the association with other vascular beds and the severity of atherosclerosis is limited. The aim of this study was to evaluate the association of atherosclerosis of various vascular beds with Lp(a), as well as its autoantibodies and generalized inflammatory markers. Material and methods: this study included 1288 adult patients with clinical and imaging examination of three vascular beds (coronary, carotid, and lower limb arteries). Patients were categorized according to the number of affected vascular beds (with at least one atherosclerotic stenosis ≥50%): 0 (n = 339), 1 (n = 470), 2 (n = 315), 3 (n = 164). We assessed blood cell count, lipid profile, C-reactive protein, circulating immune complexes, Lp(a), and its autoantibodies. Results: the number of affected vascular beds was associated with an increasing level of Lp(a) and a lower level of IgM autoantibodies to Lp(a). Hyperlipoproteinemia(a) (Lp(a) ≥ 30 mg/dL) was detected more frequently in patients with atherosclerosis. In logistic regression analysis adjusted for age, sex, hypertension, type 2 diabetes, and smoking, an elevated Lp(a) level was independently associated with stenotic atherosclerosis and lesion severity. There was a positive association of the number of affected vascular beds with C-reactive protein (r = 0.21, p < 0.01) and a negative association with circulating immune complexes (r = −0.29, p < 0.01). The neutrophil-to-lymphocyte ratio was significantly higher and the lymphocyte-to-monocyte ratio was significantly lower in patients with atherosclerosis compared to the controls (p < 0.01). Conclusion: Lp(a), C-reactive protein, circulating immune complexes, and neutrophil-to-lymphocyte ratio are associated with the stenotic atherosclerosis of different vascular beds. Lp(a) levels increase and IgM autoantibodies to Lp(a) decrease with the number of affected vascular beds. Full article

(This article belongs to the Special Issue Atherosclerosis: Current Concepts of Genetic, Epigenetic and Environmental Risk Factors)

► Show Figures

Figure 1

18 pages, 1632 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Mechanisms of TTNtv-Related Dilated Cardiomyopathy: Insights from Zebrafish Models

by Celine F. Santiago, Inken G. Huttner and Diane Fatkin

J. Cardiovasc. Dev. Dis. 2021, 8(2), 10; https://doi.org/10.3390/jcdd8020010 - 25 Jan 2021

Cited by 16 | Viewed by 7370

Abstract

Dilated cardiomyopathy (DCM) is a common heart muscle disorder characterized by ventricular dilation and contractile dysfunction that is associated with significant morbidity and mortality. New insights into disease mechanisms and strategies for treatment and prevention are urgently needed. Truncating variants in the TTN [...] Read more.

Dilated cardiomyopathy (DCM) is a common heart muscle disorder characterized by ventricular dilation and contractile dysfunction that is associated with significant morbidity and mortality. New insights into disease mechanisms and strategies for treatment and prevention are urgently needed. Truncating variants in the TTN gene, which encodes the giant sarcomeric protein titin (TTNtv), are the most common genetic cause of DCM, but exactly how TTNtv promote cardiomyocyte dysfunction is not known. Although rodent models have been widely used to investigate titin biology, they have had limited utility for TTNtv-related DCM. In recent years, zebrafish (Danio rerio) have emerged as a powerful alternative model system for studying titin function in the healthy and diseased heart. Optically transparent embryonic zebrafish models have demonstrated key roles of titin in sarcomere assembly and cardiac development. The increasing availability of sophisticated imaging tools for assessment of heart function in adult zebrafish has revolutionized the field and opened new opportunities for modelling human genetic disorders. Genetically modified zebrafish that carry a human A-band TTNtv have now been generated and shown to spontaneously develop DCM with age. This zebrafish model will be a valuable resource for elucidating the phenotype modifying effects of genetic and environmental factors, and for exploring new drug therapies. Full article

(This article belongs to the Special Issue Zebrafish Heart Development, Regeneration, and Disease Modelling)

► Show Figures

Figure 1

15 pages, 2732 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Myxomatous Mitral Valve Disease with Mitral Valve Prolapse and Mitral Annular Disjunction: Clinical and Functional Significance of the Coincidence

by Nina C. Wunderlich, Siew Yen Ho, Nir Flint and Robert J. Siegel

J. Cardiovasc. Dev. Dis. 2021, 8(2), 9; https://doi.org/10.3390/jcdd8020009 - 24 Jan 2021

Cited by 24 | Viewed by 8783

Abstract

The morphological changes that occur in myxomatous mitral valve disease (MMVD) involve various components, ultimately leading to the impairment of mitral valve (MV) function. In this context, intrinsic mitral annular abnormalities are increasingly recognized, such as a mitral annular disjunction (MAD), a specific [...] Read more.

The morphological changes that occur in myxomatous mitral valve disease (MMVD) involve various components, ultimately leading to the impairment of mitral valve (MV) function. In this context, intrinsic mitral annular abnormalities are increasingly recognized, such as a mitral annular disjunction (MAD), a specific anatomical abnormality whereby there is a distinct separation between the mitral annulus and the left atrial wall and the basal portion of the posterolateral left ventricular myocardium. In recent years, several studies have suggested that MAD contributes to myxomatous degeneration of the mitral leaflets, and there is growing evidence that MAD is associated with ventricular arrhythmias and sudden cardiac death. In this review, the morphological characteristics of MAD and imaging tools for diagnosis will be described, and the clinical and functional aspects of the coincidence of MAD and myxomatous MVP will be discussed. Full article

(This article belongs to the Special Issue Mitral Valve Development and Disease)

► Show Figures

Figure 1

12 pages, 3310 KiB

Open AccessEditor’s ChoiceReview

Critical Assessment of the Concepts and Misconceptions of the Cardiac Conduction System over the Last 100 Years: The Personal Quest of Robert H. Anderson

by Eduardo Back Sternick and Damián Sánchez-Quintana

J. Cardiovasc. Dev. Dis. 2021, 8(1), 5; https://doi.org/10.3390/jcdd8010005 - 19 Jan 2021

Cited by 6 | Viewed by 4575

Abstract

Anatomical concepts regarding the conduction system of the heart have been a matter of debate since pioneering work done at the beginning of the 20th century. Robert H. Anderson was actively involved in this field for half a century. We aimed to investigate [...] Read more.

Anatomical concepts regarding the conduction system of the heart have been a matter of debate since pioneering work done at the beginning of the 20th century. Robert H. Anderson was actively involved in this field for half a century. We aimed to investigate how his own concepts evolved over time. We have assessed anatomical concepts relating to the cardiac conduction system appearing since the key contributions made in the initial decade of the 20th century, analyzing them from the perspective of Robert H. Anderson, particularly focusing on the anatomical aspects of structures such as accessory atrioventricular pathways, including the so-called Mahaim-type fibers, connections between the atrioventricular node and the atrial myocardium, and so-called “specialized” internodal atrial tracts. To accomplish this task, we have taken as our starting point the initial concepts published in the first decade of the century, along with those subsequently reported up to 1976, and assessing them in the light of our most recently published works. The concepts put forward by Robert Anderson with regard to atrioventricular nodal bypass tracts, atrioventricular nodal inputs, decrementally conducting accessory pathways, and “tracts” for internodal atrial conduction, have remained consistent along the time frame of half a century. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A special issue dedicated to Professor Robert Anderson)

► Show Figures

Figure 1

18 pages, 2075 KiB

Open AccessEditor’s ChoiceReview

Unlocking the Secrets of the Regenerating Fish Heart: Comparing Regenerative Models to Shed Light on Successful Regeneration

by Helen G. Potts, William T. Stockdale and Mathilda T. M. Mommersteeg

J. Cardiovasc. Dev. Dis. 2021, 8(1), 4; https://doi.org/10.3390/jcdd8010004 - 16 Jan 2021

Cited by 15 | Viewed by 8053

Abstract

The adult human heart cannot repair itself after injury and, instead, forms a permanent fibrotic scar that impairs cardiac function and can lead to incurable heart failure. The zebrafish, amongst other organisms, has been extensively studied for its innate capacity to repair its [...] Read more.

The adult human heart cannot repair itself after injury and, instead, forms a permanent fibrotic scar that impairs cardiac function and can lead to incurable heart failure. The zebrafish, amongst other organisms, has been extensively studied for its innate capacity to repair its heart after injury. Understanding the signals that govern successful regeneration in models such as the zebrafish will lead to the development of effective therapies that can stimulate endogenous repair in humans. To date, many studies have investigated cardiac regeneration using a reverse genetics candidate gene approach. However, this approach is limited in its ability to unbiasedly identify novel genes and signalling pathways that are essential to successful regeneration. In contrast, drawing comparisons between different models of regeneration enables unbiased screens to be performed, identifying signals that have not previously been linked to regeneration. Here, we will review in detail what has been learnt from the comparative approach, highlighting the techniques used and how these studies have influenced the field. We will also discuss what further comparisons would enhance our knowledge of successful regeneration and scarring. Finally, we focus on the Astyanax mexicanus, an intraspecies comparative fish model that holds great promise for revealing the secrets of the regenerating heart. Full article

(This article belongs to the Special Issue Zebrafish Heart Development, Regeneration, and Disease Modelling)

► Show Figures

Figure 1

15 pages, 443 KiB

Open AccessEditor’s ChoiceReview

Coconuts and Health: Different Chain Lengths of Saturated Fats Require Different Consideration

by Susan Hewlings

J. Cardiovasc. Dev. Dis. 2020, 7(4), 59; https://doi.org/10.3390/jcdd7040059 - 17 Dec 2020

Cited by 37 | Viewed by 14626

Abstract

The diet heart hypothesis has driven nutrition recommendations and policy for decades. Recent studies have questioned the hypothesis and sparked great controversy over the assumed connection between saturated fat intake and heart disease. Recent evidence suggests that dietary patterns should be the focus [...] Read more.

The diet heart hypothesis has driven nutrition recommendations and policy for decades. Recent studies have questioned the hypothesis and sparked great controversy over the assumed connection between saturated fat intake and heart disease. Recent evidence suggests that dietary patterns should be the focus of dietary recommendations, not any one food or nutrient. Furthermore, to classify foods as simply saturated fat, polyunsaturated or monounsaturated fats is to ignore the many other potential nutrients and health benefits. Coconut is classified as a saturated fat and therefore listed as a food to limit to reduce heart disease risk. However, different saturated fats, medium-chain or long-chain, act differently metabolically and thus have different health effects. The medium-chain fatty acids predominate in coconut are absorbed differently and have been associated with several health benefits, including improvements in cognitive function and a more favorable lipid profile compared to longer chain fatty acids. Coconuts provide a healthful source of saturated fats and should not be considered the same as foods with longer chain saturated fats. Future recommendations should take this research into consideration. It is the purpose of this review to discuss the research regarding the connection between saturated fat intake, specifically coconut consumption, and health, while focusing on dietary patterns and lifestyle behaviors. Full article

► Show Figures

Figure 1

22 pages, 1928 KiB

Open AccessEditor’s ChoiceReview

Biology and Biomechanics of the Heart Valve Extracellular Matrix

by Karthik M. Kodigepalli, Kaitlyn Thatcher, Toni West, Daniel P. Howsmon, Frederick J. Schoen, Michael S. Sacks, Christopher K. Breuer and Joy Lincoln

J. Cardiovasc. Dev. Dis. 2020, 7(4), 57; https://doi.org/10.3390/jcdd7040057 - 16 Dec 2020

Cited by 57 | Viewed by 9832

Abstract

Heart valves are dynamic structures that, in the average human, open and close over 100,000 times per day, and 3 × 10⁹ times per lifetime to maintain unidirectional blood flow. Efficient, coordinated movement of the valve structures during the cardiac cycle is [...] Read more.

Heart valves are dynamic structures that, in the average human, open and close over 100,000 times per day, and 3 × 10⁹ times per lifetime to maintain unidirectional blood flow. Efficient, coordinated movement of the valve structures during the cardiac cycle is mediated by the intricate and sophisticated network of extracellular matrix (ECM) components that provide the necessary biomechanical properties to meet these mechanical demands. Organized in layers that accommodate passive functional movements of the valve leaflets, heart valve ECM is synthesized during embryonic development, and remodeled and maintained by resident cells throughout life. The failure of ECM organization compromises biomechanical function, and may lead to obstruction or leaking, which if left untreated can lead to heart failure. At present, effective treatment for heart valve dysfunction is limited and frequently ends with surgical repair or replacement, which comes with insuperable complications for many high-risk patients including aged and pediatric populations. Therefore, there is a critical need to fully appreciate the pathobiology of biomechanical valve failure in order to develop better, alternative therapies. To date, the majority of studies have focused on delineating valve disease mechanisms at the cellular level, namely the interstitial and endothelial lineages. However, less focus has been on the ECM, shown previously in other systems, to be a promising mechanism-inspired therapeutic target. Here, we highlight and review the biology and biomechanical contributions of key components of the heart valve ECM. Furthermore, we discuss how human diseases, including connective tissue disorders lead to aberrations in the abundance, organization and quality of these matrix proteins, resulting in instability of the valve infrastructure and gross functional impairment. Full article

(This article belongs to the Special Issue Mitral Valve Development and Disease)

► Show Figures

Figure 1

17 pages, 2925 KiB

Open AccessEditor’s ChoiceArticle

The Needle in the Haystack—Searching for Genetic and Epigenetic Differences in Monozygotic Twins Discordant for Tetralogy of Fallot

by Marcel Grunert, Sandra Appelt, Paul Grossfeld and Silke R. Sperling

J. Cardiovasc. Dev. Dis. 2020, 7(4), 55; https://doi.org/10.3390/jcdd7040055 - 2 Dec 2020

Cited by 11 | Viewed by 3914

Abstract

Congenital heart defects (CHDs) are the most common birth defect in human with an incidence of almost 1% of all live births. Most cases have a multifactorial origin with both genetics and the environment playing a role in its development and progression. Adding [...] Read more.

Congenital heart defects (CHDs) are the most common birth defect in human with an incidence of almost 1% of all live births. Most cases have a multifactorial origin with both genetics and the environment playing a role in its development and progression. Adding an epigenetic component to this aspect is exemplified by monozygotic twins which share the same genetic background but have a different disease status. As a result, the interplay between the genetic, epigenetic and the environmental conditions might contribute to the etiology and phenotype. To date, the underlying causes of the majority of CHDs remain poorly understood. In this study, we performed genome-wide high-throughput sequencing to examine the genetic, structural genomic and epigenetic differences of two identical twin pairs discordant for Tetralogy of Fallot (TOF), representing the most common cyanotic form of CHDs. Our results show the almost identical genetic and structural genomic identity of the twins. In contrast, several epigenetic alterations could be observed given by DNA methylation changes in regulatory regions of known cardiac-relevant genes. Overall, this study provides first insights into the impact of genetic and especially epigenetic factors underlying monozygotic twins discordant for CHD like TOF. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A Special Issue Dedicated to Professor Adriana Gittenberger-De Groot)

► Show Figures

Figure 1

33 pages, 2728 KiB

Open AccessEditor’s ChoiceReview

The Intrinsic Cardiac Nervous System and Its Role in Cardiac Pacemaking and Conduction

by Laura Fedele and Thomas Brand

J. Cardiovasc. Dev. Dis. 2020, 7(4), 54; https://doi.org/10.3390/jcdd7040054 - 24 Nov 2020

Cited by 64 | Viewed by 14871

Abstract

The cardiac autonomic nervous system (CANS) plays a key role for the regulation of cardiac activity with its dysregulation being involved in various heart diseases, such as cardiac arrhythmias. The CANS comprises the extrinsic and intrinsic innervation of the heart. The intrinsic cardiac [...] Read more.

The cardiac autonomic nervous system (CANS) plays a key role for the regulation of cardiac activity with its dysregulation being involved in various heart diseases, such as cardiac arrhythmias. The CANS comprises the extrinsic and intrinsic innervation of the heart. The intrinsic cardiac nervous system (ICNS) includes the network of the intracardiac ganglia and interconnecting neurons. The cardiac ganglia contribute to the tight modulation of cardiac electrophysiology, working as a local hub integrating the inputs of the extrinsic innervation and the ICNS. A better understanding of the role of the ICNS for the modulation of the cardiac conduction system will be crucial for targeted therapies of various arrhythmias. We describe the embryonic development, anatomy, and physiology of the ICNS. By correlating the topography of the intracardiac neurons with what is known regarding their biophysical and neurochemical properties, we outline their physiological role in the control of pacemaker activity of the sinoatrial and atrioventricular nodes. We conclude by highlighting cardiac disorders with a putative involvement of the ICNS and outline open questions that need to be addressed in order to better understand the physiology and pathophysiology of the ICNS. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A special issue dedicated to Professor Robert Anderson)

► Show Figures

Figure 1

21 pages, 755 KiB

Open AccessEditor’s ChoiceReview

The Mesenchymal Cap of the Atrial Septum and Atrial and Atrioventricular Septation

by Ray Deepe, Emily Fitzgerald, Renélyn Wolters, Jenna Drummond, Karen De Guzman, Maurice J.B. van den Hoff and Andy Wessels

J. Cardiovasc. Dev. Dis. 2020, 7(4), 50; https://doi.org/10.3390/jcdd7040050 - 4 Nov 2020

Cited by 14 | Viewed by 4320

Abstract

In this publication, dedicated to Professor Robert H. Anderson and his contributions to the field of cardiac development, anatomy, and congenital heart disease, we will review some of our earlier collaborative studies. The focus of this paper is on our work on the [...] Read more.

In this publication, dedicated to Professor Robert H. Anderson and his contributions to the field of cardiac development, anatomy, and congenital heart disease, we will review some of our earlier collaborative studies. The focus of this paper is on our work on the development of the atrioventricular mesenchymal complex, studies in which Professor Anderson has played a significant role. We will revisit a number of events relevant to atrial and atrioventricular septation and present new data on the development of the mesenchymal cap of the atrial septum, a component of the atrioventricular mesenchymal complex which, thus far, has received only moderate attention. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A special issue dedicated to Professor Robert Anderson)

► Show Figures

Figure 1

17 pages, 4596 KiB

Open AccessEditor’s ChoiceReview

Assessing Myocardial Architecture: The Challenges and Controversies

by Peter Agger and Robert S. Stephenson

J. Cardiovasc. Dev. Dis. 2020, 7(4), 47; https://doi.org/10.3390/jcdd7040047 - 29 Oct 2020

Cited by 6 | Viewed by 3672

Abstract

In recent decades, investigators have strived to describe and quantify the orientation of the cardiac myocytes in an attempt to classify their arrangement in healthy and diseased hearts. There are, however, striking differences between the investigations from both a technical and methodological standpoint, [...] Read more.

In recent decades, investigators have strived to describe and quantify the orientation of the cardiac myocytes in an attempt to classify their arrangement in healthy and diseased hearts. There are, however, striking differences between the investigations from both a technical and methodological standpoint, thus limiting their comparability and impeding the drawing of appropriate physiological conclusions from the structural assessments. This review aims to elucidate these differences, and to propose guidance to establish methodological consensus in the field. The review outlines the theory behind myocyte orientation analysis, and importantly has identified pronounced differences in the definitions of otherwise widely accepted concepts of myocytic orientation. Based on the findings, recommendations are made for the future design of studies in the field of myocardial morphology. It is emphasised that projection of myocyte orientations, before quantification of their angulation, introduces considerable bias, and that angles should be assessed relative to the epicardial curvature. The transmural orientation of the cardiomyocytes should also not be neglected, as it is an important determinant of cardiac function. Finally, there is considerable disagreement in the literature as to how the orientation of myocardial aggregates should be assessed, but to do so in a mathematically meaningful way, the normal vector of the aggregate plane should be utilised. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A special issue dedicated to Professor Robert Anderson)

► Show Figures

Graphical abstract

10 pages, 912 KiB

Open AccessEditor’s ChoiceArticle

Predictive Value of Pre-Operative 2D and 3D Transthoracic Echocardiography in Patients Undergoing Mitral Valve Repair: Long Term Follow Up of Mitral Valve Regurgitation Recurrence and Heart Chamber Remodeling

by Gloria Tamborini, Valentina Mantegazza, Marco Penso, Manuela Muratori, Laura Fusini, Sarah Ghulam Ali, Claudia Cefalù, Gianpiero Italiano, Valentina Volpato, Paola Gripari, Enrico G. Caiani, Marco Zanobini and Mauro Pepi

J. Cardiovasc. Dev. Dis. 2020, 7(4), 46; https://doi.org/10.3390/jcdd7040046 - 20 Oct 2020

Cited by 8 | Viewed by 2978

Abstract

The “ideal” management of asymptomatic severe mitral regurgitation (MR) in valve prolapse (MVP) is still debated. The aims of this study were to identify pre-operatory parameters predictive of residual MR and of early and long-term favorable remodeling after MVP repair. We included 295 [...] Read more.

The “ideal” management of asymptomatic severe mitral regurgitation (MR) in valve prolapse (MVP) is still debated. The aims of this study were to identify pre-operatory parameters predictive of residual MR and of early and long-term favorable remodeling after MVP repair. We included 295 patients who underwent MV repair for MVP with pre-operatory two- and three-dimensional transthoracic echocardiography (2DTTE and 3DTTE) and 6-months (6M) and 3-years (3Y) follow-up 2DTTE. MVP was classified by 3DTTE as simple or complex and surgical procedures as simple or complex. Pre-operative echo parameters were compared to post-operative values at 6M and 3Y. Patients were divided into Group 1 (6M-MR < 2) and Group 2 (6M-MR ≥ 2), and predictors of MR ≥ 2 were investigated. MVP was simple in 178/295 pts, and 94% underwent simple procedures, while in only 42/117 (36%) of complex MVP a simple procedure was performed. A significant relation among prolapse anatomy, surgical procedures and residual MR was found. Post-operative MR ≥ 2 was present in 9.8%: complex MVP undergoing complex procedures had twice the percentage of MR ≥ 2 vs. simple MVP and simple procedures. MVP complexity resulted independent predictor of 6M-MR ≥ 2. Favorable cardiac remodeling, initially found in all cases, was maintained only in MR < 2 at 3Y. Pre-operative 3DTTE MVP morphology identifies pts undergoing simple or complex procedures predicting MR recurrence and favorable cardiac remodeling. Full article

(This article belongs to the Special Issue Mitral Valve Development and Disease)

► Show Figures

Figure 1

19 pages, 3754 KiB

Open AccessEditor’s ChoiceReview

Embryonic Mouse Cardiodynamic OCT Imaging

by Andrew L. Lopez III, Shang Wang and Irina V. Larina

J. Cardiovasc. Dev. Dis. 2020, 7(4), 42; https://doi.org/10.3390/jcdd7040042 - 4 Oct 2020

Cited by 14 | Viewed by 6104

Abstract

The embryonic heart is an active and developing organ. Genetic studies in mouse models have generated great insight into normal heart development and congenital heart defects, and suggest mechanical forces such as heart contraction and blood flow to be implicated in cardiogenesis and [...] Read more.

The embryonic heart is an active and developing organ. Genetic studies in mouse models have generated great insight into normal heart development and congenital heart defects, and suggest mechanical forces such as heart contraction and blood flow to be implicated in cardiogenesis and disease. To explore this relationship and investigate the interplay between biomechanical forces and cardiac development, live dynamic cardiac imaging is essential. Cardiodynamic imaging with optical coherence tomography (OCT) is proving to be a unique approach to functional analysis of the embryonic mouse heart. Its compatibility with live culture systems, reagent-free contrast, cellular level resolution, and millimeter scale imaging depth make it capable of imaging the heart volumetrically and providing spatially resolved information on heart wall dynamics and blood flow. Here, we review the progress made in mouse embryonic cardiodynamic imaging with OCT, highlighting leaps in technology to overcome limitations in resolution and acquisition speed. We describe state-of-the-art functional OCT methods such as Doppler OCT and OCT angiography for blood flow imaging and quantification in the beating heart. As OCT is a continuously developing technology, we provide insight into the future developments of this area, toward the investigation of normal cardiogenesis and congenital heart defects. Full article

(This article belongs to the Special Issue Comparative Developmental Cardiovascular Biomechanics and Bioengineering)

► Show Figures

Figure 1

17 pages, 9955 KiB

Open AccessEditor’s ChoiceArticle

Cauterization as a Simple Method for Regeneration Studies in the Zebrafish Heart

by Papa K. Van Dyck, Natasha Hockaden, Emma C. Nelson, Alyssa R. Koch, Kamil L. Hester, Neil Pillai, Gabrielle C. Coffing, Alan R. Burns and Pascal J. Lafontant

J. Cardiovasc. Dev. Dis. 2020, 7(4), 41; https://doi.org/10.3390/jcdd7040041 - 3 Oct 2020

Cited by 8 | Viewed by 6368

Abstract

In the last two decades, the zebrafish has emerged as an important model species for heart regeneration studies. Various approaches to model loss of cardiac myocytes and myocardial infarction in the zebrafish have been devised, and have included resection, genetic ablation, and cryoinjury. [...] Read more.

In the last two decades, the zebrafish has emerged as an important model species for heart regeneration studies. Various approaches to model loss of cardiac myocytes and myocardial infarction in the zebrafish have been devised, and have included resection, genetic ablation, and cryoinjury. However, to date, the response of the zebrafish ventricle to cautery injury has not been reported. Here, we describe a simple and reproducible method using cautery injury via a modified nichrome inoculating needle as a probe to model myocardial infarction in the zebrafish ventricle. Using light and electron microscopy, we show that cardiac cautery injury is attended by significant inflammatory cell infiltration, accumulation of collagen in the injured area, and the reconstitution of the ventricular myocardium. Additionally, we document the ablation of cardiac nerve fibers, and report that the re-innervation of the injured zebrafish ventricle is protracted, compared to other repair processes that accompany the regeneration of the cauterized ventricle. Taken together, our study demonstrates that cautery injury is a simple and effective means for generating necrotic tissue and eliciting a remodeling and regenerative response in the zebrafish heart. This approach may serve as an important tool in the methods toolbox for regeneration studies in the zebrafish. Full article

(This article belongs to the Special Issue Zebrafish Heart Development, Regeneration, and Disease Modelling)

► Show Figures

Figure 1

15 pages, 2084 KiB

Open AccessEditor’s ChoiceArticle

Left Ventricular Noncompaction Is More Prevalent in Ventricular Septal Defect Than Other Congenital Heart Defects: A Morphological Study

by Laís Costa Marques, Gabriel Romero Liguori, Ana Carolina Amarante Souza and Vera Demarchi Aiello

J. Cardiovasc. Dev. Dis. 2020, 7(4), 39; https://doi.org/10.3390/jcdd7040039 - 25 Sep 2020

Cited by 7 | Viewed by 3762

Abstract

Left ventricular noncompaction (LVNC) is a condition characterized by prominent ventricular trabeculae and deep intertrabecular recesses and has been described as a possible substrate for arrhythmias, thromboembolism, and heart failure. Herein, we explored the prevalence of LVNC morphology among hearts with congenital heart [...] Read more.

Left ventricular noncompaction (LVNC) is a condition characterized by prominent ventricular trabeculae and deep intertrabecular recesses and has been described as a possible substrate for arrhythmias, thromboembolism, and heart failure. Herein, we explored the prevalence of LVNC morphology among hearts with congenital heart defects (CHD). We examined 259 postnatal hearts with one of the following CHD: isolated ventricular septal defect (VSD); isolated atrial septal defect (ASD); atrioventricular septal defect (AVSD); transposition of the great arteries (TGA); isomerism of the atrial appendages (ISOM); Ebstein’s malformation (EB); Tetralogy of Fallot (TF). Eleven hearts from children who died of non-cardiovascular causes were used as controls. The thickness of the compacted and non-compacted left ventricular myocardial wall was determined and the specimens classified as presenting or not LVNC morphology according to three criteria, as proposed by Chin, Jenni, and Petersen. Normal hearts did not present LVNC, but the CHD group presented different percentages of LVNC in at least one diagnostic criterium. The prevalence of LVNC was respectively, according to Chin’s, Jenni´s and Petersen´s methods: for VSD—54.2%, 35.4%, and 12.5%; ASD—8.3%, 8.3%, and 8.3%; AVSD—2.9%, 2.9%, and 0.0%; TGA—22.6%, 17%, and 5.7%; ISOM—7.1%, 7.1%, and 7.1%; EB—28.6%, 9.5%, and 0.0%; TF—5.9%. 2.9%, and 2.9%. VSD hearts showed a significantly greater risk of presenting LVNC when compared to controls (Chin and Jenni criteria). No other CHD presented similar risk. Current results show some agreement with previous studies, such as LVNC morphology being more prevalent in VSDs. Nonetheless, this is a morphological study and cannot be correlated with symptoms or severity of the CHD. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A special issue dedicated to Professor Robert Anderson)

► Show Figures

Figure 1

27 pages, 4447 KiB

Open AccessEditor’s ChoiceReview

New Concepts in the Development and Malformation of the Arterial Valves

by Deborah J. Henderson, Lorraine Eley and Bill Chaudhry

J. Cardiovasc. Dev. Dis. 2020, 7(4), 38; https://doi.org/10.3390/jcdd7040038 - 24 Sep 2020

Cited by 24 | Viewed by 5625

Abstract

Although in many ways the arterial and atrioventricular valves are similar, both being derived for the most part from endocardial cushions, we now know that the arterial valves and their surrounding structures are uniquely dependent on progenitors from both the second heart field [...] Read more.

Although in many ways the arterial and atrioventricular valves are similar, both being derived for the most part from endocardial cushions, we now know that the arterial valves and their surrounding structures are uniquely dependent on progenitors from both the second heart field (SHF) and neural crest cells (NCC). Here, we will review aspects of arterial valve development, highlighting how our appreciation of NCC and the discovery of the SHF have altered our developmental models. We will highlight areas of research that have been particularly instructive for understanding how the leaflets form and remodel, as well as those with limited or conflicting results. With this background, we will explore how this developmental knowledge can help us to understand human valve malformations, particularly those of the bicuspid aortic valve (BAV). Controversies and the current state of valve genomics will be indicated. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A special issue dedicated to Professor Robert Anderson)

► Show Figures

Figure 1

11 pages, 5106 KiB

Open AccessEditor’s ChoiceArticle

Identification and Morphogenesis of Vestibular Atrial Septal Defects

by Rohit S. Loomba, Justin T. Tretter, Timothy J. Mohun, Robert H. Anderson, Scott Kramer and Diane E. Spicer

J. Cardiovasc. Dev. Dis. 2020, 7(3), 35; https://doi.org/10.3390/jcdd7030035 - 10 Sep 2020

Cited by 8 | Viewed by 4670

Abstract

Background: The vestibular atrial septal defect is an interatrial communication located in the antero-inferior portion of the atrial septum. Reflecting either inadequate muscularization of the vestibular spine and mesenchymal cap during development, or excessive apoptosis within the developing antero-inferior septal component, the [...] Read more.

Background: The vestibular atrial septal defect is an interatrial communication located in the antero-inferior portion of the atrial septum. Reflecting either inadequate muscularization of the vestibular spine and mesenchymal cap during development, or excessive apoptosis within the developing antero-inferior septal component, the vestibular defect represents an infrequently recognized true deficiency of the atrial septum. We reviewed necropsy specimens from three separate archives to establish the frequency of such vestibular defects and their associated cardiac findings, providing additional analysis from developing mouse hearts to illustrate their potential morphogenesis. Materials and methods: We analyzed the hearts in the Farouk S. Idriss Cardiac Registry at Ann and Robert H. Lurie Children’s Hospital in Chicago, IL, the Van Mierop Archive at the University of Florida in Gainesville, Florida, and the archive at Johns Hopkins All Children’s Heart Institute in St. Petersburg, Florida, identifying all those exhibiting a vestibular atrial septal defect, along with the associated intracardiac malformations. We then assessed potential mechanisms for the existence of such defects, based on the assessment of 450 datasets of developing mouse hearts prepared using the technique of episcopic microscopy. Results: We analyzed a total of 2100 specimens. Of these, 68 (3%) were found to have a vestibular atrial septal defect. Comparable defects were identified in 10 developing mouse embryos sacrificed at embryonic data 15.5, by which stage the antero-inferior component of the atrial septum is usually normally formed. Conclusion: The vestibular defect is a true septal defect located in the muscular antero-inferior rim of the oval fossa. Our retrospective review of autopsied hearts suggests that the defect may be more common than previously thought. Increased awareness of the location of the defect should optimize its future clinical identification. We suggest that the defect exists because of failure, during embryonic development, of union of the components that bind the leading edge of the primary atrial septum to the atrioventricular junctions, either because of inadequate muscularisation or excessive apoptosis. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A special issue dedicated to Professor Robert Anderson)

► Show Figures

Figure 1

13 pages, 2300 KiB

Open AccessEditor’s ChoiceReview

Left Ventricular Blood Flow Kinetic Energy Assessment by 4D Flow Cardiovascular Magnetic Resonance: A Systematic Review of the Clinical Relevance

by Harjinder Kaur, Hosamadin Assadi, Samer Alabed, Donnie Cameron, Vassilios S. Vassiliou, Jos J. M. Westenberg, Rob van der Geest, Liang Zhong, Amardeep Dastidar, Andrew J. Swift and Pankaj Garg

J. Cardiovasc. Dev. Dis. 2020, 7(3), 37; https://doi.org/10.3390/jcdd7030037 - 10 Sep 2020

Cited by 22 | Viewed by 4676

Abstract

Background: There is an emerging body of evidence that supports the potential clinical value of left ventricular (LV) intracavity blood flow kinetic energy (KE) assessment using four-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR). The aim of this systematic review is to [...] Read more.

Background: There is an emerging body of evidence that supports the potential clinical value of left ventricular (LV) intracavity blood flow kinetic energy (KE) assessment using four-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR). The aim of this systematic review is to summarize studies evaluating LV intracavity blood flow KE quantification methods and its potential clinical significance. Methods: A systematic review search was carried out on Medline, Pubmed, EMBASE and CINAHL. Results: Of the 677 articles screened, 16 studies met eligibility. These included six (37%) studies on LV diastolic function, another six (37%) studies on heart failure or cardiomyopathies, three (19%) studies on ischemic heart disease or myocardial infarction and finally, one (6%) study on valvular heart disease, namely, mitral regurgitation. One of the main strengths identified by these studies is high reproducibility of LV blood flow KE hemodynamic assessment (mean coefficient of variability = 6 ± 2%) for the evaluation of LV diastolic function. Conclusions: The evidence gathered in this systematic review suggests that LV blood flow KE has great promise for LV hemodynamic assessment. Studies showed increased diagnostic confidence at no cost of additional time. Results were highly reproducible with low intraobserver variability. Full article

► Show Figures

Figure 1

20 pages, 24653 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Virtual Dissection: Emerging as the Gold Standard of Analyzing Living Heart Anatomy

by Justin T. Tretter, Saurabh Kumar Gupta, Yu Izawa, Tatsuya Nishii and Shumpei Mori

J. Cardiovasc. Dev. Dis. 2020, 7(3), 30; https://doi.org/10.3390/jcdd7030030 - 12 Aug 2020

Cited by 29 | Viewed by 6064

Abstract

Traditionally, gross cardiac anatomy has been described mainly based on the findings in the dissection suite. Analyses of heart specimens have contributed immensely towards building a fundamental knowledge of cardiac anatomy. However, there are limitations in analyzing the autopsied heart removed from the [...] Read more.

Traditionally, gross cardiac anatomy has been described mainly based on the findings in the dissection suite. Analyses of heart specimens have contributed immensely towards building a fundamental knowledge of cardiac anatomy. However, there are limitations in analyzing the autopsied heart removed from the thorax. Three-dimensional imaging allows visualization of the blood-filled heart in vivo in attitudinally appropriate fashion. This is of paramount importance for not only demonstration of cardiac anatomy for educational purposes, but also for the detailed anatomical evaluation in patients with acquired and congenital heart disease. In this review, we discuss the advantages of three-dimensional imaging, specifically focusing on virtual dissection, a volume rendering-based reconstruction technique using computed tomographic data. We highlight examples of three-dimensional imaging in both education and guiding patient management. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A special issue dedicated to Professor Robert Anderson)

► Show Figures

Figure 1

20 pages, 720 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Importance of Telomere Shortening for Atherosclerosis and Mortality

by Wolfgang Herrmann and Markus Herrmann

J. Cardiovasc. Dev. Dis. 2020, 7(3), 29; https://doi.org/10.3390/jcdd7030029 - 6 Aug 2020

Cited by 30 | Viewed by 5707

Abstract

Telomeres are the protective end caps of chromosomes and shorten with every cell division. Short telomeres are associated with older age and adverse lifestyle factors. Leucocyte telomere length (LTL) has been proposed as a biomarker of biological age. The shortening of LTL with [...] Read more.

Telomeres are the protective end caps of chromosomes and shorten with every cell division. Short telomeres are associated with older age and adverse lifestyle factors. Leucocyte telomere length (LTL) has been proposed as a biomarker of biological age. The shortening of LTL with age is the result of the end-replication problem, environmental, and lifestyle-related factors. Epidemiologic studies have shown that LTL predicts cardiovascular disease, all-cause mortality, and death from vascular causes. Age appears to be an important co-variate that explains a substantial fraction of this effect. Although it has been proposed that short telomeres promote atherosclerosis and impair the repair of vascular lesions, existing results are inconsistent. Oxidative stress and chronic inflammation can both accelerate telomere shortening. Multiple factors, including homocysteine (HCY), vitamin B6, and vitamin B12 modulate oxidative stress and inflammation through direct and indirect mechanisms. This review provides a compact overview of telomere physiology and the utility of LTL measurements in atherosclerosis and cardiovascular disease. In addition, it summarizes existing knowledge regarding the impact of oxidative stress, inflammation, HCY, and B-vitamins on telomere function. Full article

(This article belongs to the Special Issue Atherosclerosis: Current Concepts of Genetic, Epigenetic and Environmental Risk Factors)

► Show Figures

Figure 1

22 pages, 12647 KiB

Open AccessEditor’s ChoiceArticle

Early Embryonic Expression of AP-2α Is Critical for Cardiovascular Development

by Amy-Leigh Johnson, Jürgen E. Schneider, Timothy J. Mohun, Trevor Williams, Shoumo Bhattacharya, Deborah J. Henderson, Helen M. Phillips and Simon D. Bamforth

J. Cardiovasc. Dev. Dis. 2020, 7(3), 27; https://doi.org/10.3390/jcdd7030027 - 23 Jul 2020

Cited by 9 | Viewed by 4378

Abstract

Congenital cardiovascular malformation is a common birth defect incorporating abnormalities of the outflow tract and aortic arch arteries, and mice deficient in the transcription factor AP-2α (Tcfap2a) present with complex defects affecting these structures. AP-2α is expressed in the pharyngeal surface [...] Read more.

Congenital cardiovascular malformation is a common birth defect incorporating abnormalities of the outflow tract and aortic arch arteries, and mice deficient in the transcription factor AP-2α (Tcfap2a) present with complex defects affecting these structures. AP-2α is expressed in the pharyngeal surface ectoderm and neural crest at mid-embryogenesis in the mouse, but the precise tissue compartment in which AP-2α is required for cardiovascular development has not been identified. In this study we describe the fully penetrant AP-2α deficient cardiovascular phenotype on a C57Bl/6J genetic background and show that this is associated with increased apoptosis in the pharyngeal ectoderm. Neural crest cell migration into the pharyngeal arches was not affected. Cre-expressing transgenic mice were used in conjunction with an AP-2α conditional allele to examine the effect of deleting AP-2α from the pharyngeal surface ectoderm and the neural crest, either individually or in combination, as well as the second heart field. This, surprisingly, was unable to fully recapitulate the global AP-2α deficient cardiovascular phenotype. The outflow tract and arch artery phenotype was, however, recapitulated through early embryonic Cre-mediated recombination. These findings indicate that AP-2α has a complex influence on cardiovascular development either being required very early in embryogenesis and/or having a redundant function in many tissue layers. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A Special Issue Dedicated to Professor Adriana Gittenberger-De Groot)

► Show Figures

Figure 1

19 pages, 337 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Phthalates Implications in the Cardiovascular System

by Melissa Mariana and Elisa Cairrao

J. Cardiovasc. Dev. Dis. 2020, 7(3), 26; https://doi.org/10.3390/jcdd7030026 - 22 Jul 2020

Cited by 80 | Viewed by 5869

Abstract

Today’s sedentary lifestyle and eating habits have been implicated as some of the causes of the increased incidence of several diseases, including cancer and cardiovascular diseases. However, environmental pollutants have also been identified as another possible cause for this increase in recent decades. [...] Read more.

Today’s sedentary lifestyle and eating habits have been implicated as some of the causes of the increased incidence of several diseases, including cancer and cardiovascular diseases. However, environmental pollutants have also been identified as another possible cause for this increase in recent decades. The constant human exposure to plastics has been raising attention regarding human health, particularly when it comes to phthalates. These are plasticizers used in the manufacture of industrial and consumer products, such as PVC (Polyvinyl Chloride) plastics and personal care products, with endocrine-disrupting properties, as they can bind molecular targets in the body and interfere with hormonal function. Since these compounds are not covalently bound to the plastic, they are easily released into the environment during their manufacture, use, or disposal, leading to increased human exposure and enhancing health risks. In fact, some studies have related phthalate exposure with cardiovascular health, having already shown a positive association with the development of hypertension and atherosclerosis in adults and some cardiometabolic risk factors in children and adolescents. Therefore, the main purpose of this review is to present and relate the most recent studies concerning the implications of phthalates effects on the cardiovascular system. Full article

9 pages, 1209 KiB

Open AccessEditor’s ChoiceArticle

Why Some Patients Undergoing Lipoprotein Apheresis Therapy Develop New Cardiovascular Events?

by Ulrich Julius, Solveig Kuss, Sergey Tselmin, Ulrike Schatz and Stefan R. Bornstein

J. Cardiovasc. Dev. Dis. 2020, 7(3), 25; https://doi.org/10.3390/jcdd7030025 - 16 Jul 2020

Cited by 7 | Viewed by 3208

Abstract

Lipoprotein apheresis (LA) is an effective tool to reduce cardiovascular events (CVEs) in high-risk patients with elevations of low density lipoprotein-cholesterol (LDL-C) and/or Lipoprotein(a) (Lp(a)). All patients included into this retrospective analysis had experienced CVEs before the start of the LA therapy. We [...] Read more.

Lipoprotein apheresis (LA) is an effective tool to reduce cardiovascular events (CVEs) in high-risk patients with elevations of low density lipoprotein-cholesterol (LDL-C) and/or Lipoprotein(a) (Lp(a)). All patients included into this retrospective analysis had experienced CVEs before the start of the LA therapy. We compared personal and lab data in two groups: CVEx/0 (n 60) with no new events during LA therapy, CVEx/1+ (n 48) with at least one new event. Patients of Group CVEx/1+ were about 5 years older when they had started the extracorporeal therapy, and they experienced more CVEs prior to that timepoint. There was a positive correlation between the number of CVEs before and during LA therapy. No differences were seen with respect to lipid concentrations, even after a correction of LDL-C concentrations for the LDL-C transported with Lp(a) particles. LA sessions effectively reduced both LDL-C and Lp(a). Lp(a) levels measured before LA sessions were lower than those measured initially. It appeared difficult to reach the target values for LDL-C published in the ESC/EAS Guideline in 2019, although all patients were maximally treated including drugs when tolerated. In conclusion, it will be important to initiate an LA therapy earlier, at least after a second CVE and at a younger age. Full article

(This article belongs to the Special Issue Atherosclerosis: Current Concepts of Genetic, Epigenetic and Environmental Risk Factors)

► Show Figures

Figure 1

31 pages, 8409 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Validating the Paradigm That Biomechanical Forces Regulate Embryonic Cardiovascular Morphogenesis and Are Fundamental in the Etiology of Congenital Heart Disease

by Bradley B. Keller, William J. Kowalski, Joseph P. Tinney, Kimimasa Tobita and Norman Hu

J. Cardiovasc. Dev. Dis. 2020, 7(2), 23; https://doi.org/10.3390/jcdd7020023 - 12 Jun 2020

Cited by 12 | Viewed by 4851

Abstract

The goal of this review is to provide a broad overview of the biomechanical maturation and regulation of vertebrate cardiovascular (CV) morphogenesis and the evidence for mechanistic relationships between function and form relevant to the origins of congenital heart disease (CHD). The embryonic [...] Read more.

The goal of this review is to provide a broad overview of the biomechanical maturation and regulation of vertebrate cardiovascular (CV) morphogenesis and the evidence for mechanistic relationships between function and form relevant to the origins of congenital heart disease (CHD). The embryonic heart has been investigated for over a century, initially focusing on the chick embryo due to the opportunity to isolate and investigate myocardial electromechanical maturation, the ability to directly instrument and measure normal cardiac function, intervene to alter ventricular loading conditions, and then investigate changes in functional and structural maturation to deduce mechanism. The paradigm of “Develop and validate quantitative techniques, describe normal, perturb the system, describe abnormal, then deduce mechanisms” was taught to many young investigators by Dr. Edward B. Clark and then validated by a rapidly expanding number of teams dedicated to investigate CV morphogenesis, structure–function relationships, and pathogenic mechanisms of CHD. Pioneering studies using the chick embryo model rapidly expanded into a broad range of model systems, particularly the mouse and zebrafish, to investigate the interdependent genetic and biomechanical regulation of CV morphogenesis. Several central morphogenic themes have emerged. First, CV morphogenesis is inherently dependent upon the biomechanical forces that influence cell and tissue growth and remodeling. Second, embryonic CV systems dynamically adapt to changes in biomechanical loading conditions similar to mature systems. Third, biomechanical loading conditions dynamically impact and are regulated by genetic morphogenic systems. Fourth, advanced imaging techniques coupled with computational modeling provide novel insights to validate regulatory mechanisms. Finally, insights regarding the genetic and biomechanical regulation of CV morphogenesis and adaptation are relevant to current regenerative strategies for patients with CHD. Full article

(This article belongs to the Special Issue Comparative Developmental Cardiovascular Biomechanics and Bioengineering)

► Show Figures

Figure 1

31 pages, 1180 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Arrhythmogenic Cardiomyopathy: Molecular Insights for Improved Therapeutic Design

by Tyler L. Stevens, Michael J. Wallace, Mona El Refaey, Jason D. Roberts, Sara N. Koenig and Peter J. Mohler

J. Cardiovasc. Dev. Dis. 2020, 7(2), 21; https://doi.org/10.3390/jcdd7020021 - 26 May 2020

Cited by 25 | Viewed by 5750

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by structural and electrical cardiac abnormalities, including myocardial fibro-fatty replacement. Its pathological ventricular substrate predisposes subjects to an increased risk of sudden cardiac death (SCD). ACM is a notorious cause of SCD in young athletes, [...] Read more.

Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by structural and electrical cardiac abnormalities, including myocardial fibro-fatty replacement. Its pathological ventricular substrate predisposes subjects to an increased risk of sudden cardiac death (SCD). ACM is a notorious cause of SCD in young athletes, and exercise has been documented to accelerate its progression. Although the genetic culprits are not exclusively limited to the intercalated disc, the majority of ACM-linked variants reside within desmosomal genes and are transmitted via Mendelian inheritance patterns; however, penetrance is highly variable. Its natural history features an initial “concealed phase” that results in patients being vulnerable to malignant arrhythmias prior to the onset of structural changes. Lack of effective therapies that target its pathophysiology renders management of patients challenging due to its progressive nature, and has highlighted a critical need to improve our understanding of its underlying mechanistic basis. In vitro and in vivo studies have begun to unravel the molecular consequences associated with disease causing variants, including altered Wnt/β-catenin signaling. Characterization of ACM mouse models has facilitated the evaluation of new therapeutic approaches. Improved molecular insight into the condition promises to usher in novel forms of therapy that will lead to improved care at the clinical bedside. Full article

(This article belongs to the Special Issue Cardiomyopathy at the Sub-Cellular Level)

► Show Figures

Figure 1

24 pages, 22141 KiB

Open AccessEditor’s ChoiceArticle

Pax9 and Gbx2 Interact in the Pharyngeal Endoderm to Control Cardiovascular Development

by Catherine A. Stothard, Silvia Mazzotta, Arjun Vyas, Jurgen E. Schneider, Timothy J. Mohun, Deborah J. Henderson, Helen M. Phillips and Simon D. Bamforth

J. Cardiovasc. Dev. Dis. 2020, 7(2), 20; https://doi.org/10.3390/jcdd7020020 - 25 May 2020

Cited by 12 | Viewed by 5113

Abstract

The correct formation of the aortic arch arteries depends on a coordinated and regulated gene expression profile within the tissues of the pharyngeal arches. Perturbation of the gene regulatory networks in these tissues results in congenital heart defects affecting the arch arteries and [...] Read more.

The correct formation of the aortic arch arteries depends on a coordinated and regulated gene expression profile within the tissues of the pharyngeal arches. Perturbation of the gene regulatory networks in these tissues results in congenital heart defects affecting the arch arteries and the outflow tract of the heart. Aberrant development of these structures leads to interruption of the aortic arch and double outlet right ventricle, abnormalities that are a leading cause of morbidity in 22q11 Deletion Syndrome (DS) patients. We have recently shown that Pax9 functionally interacts with the 22q11DS gene Tbx1 in the pharyngeal endoderm for 4th pharyngeal arch artery morphogenesis, with double heterozygous mice dying at birth with interrupted aortic arch. Mice lacking Pax9 die perinatally with complex cardiovascular defects and in this study we sought to validate further potential genetic interacting partners of Pax9, focussing on Gbx2 which is down-regulated in the pharyngeal endoderm of Pax9-null embryos. Here, we describe the Gbx2-null cardiovascular phenotype and demonstrate a genetic interaction between Gbx2 and Pax9 in the pharyngeal endoderm during cardiovascular development. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A special issue dedicated to Professor Robert Anderson)

► Show Figures

Figure 1

21 pages, 5143 KiB

Open AccessEditor’s ChoiceArticle

Transforming Growth Factor Beta3 is Required for Cardiovascular Development

by Mrinmay Chakrabarti, Nadia Al-Sammarraie, Mengistu G. Gebere, Aniket Bhattacharya, Sunita Chopra, John Johnson, Edsel A. Peña, John F. Eberth, Robert E. Poelmann, Adriana C. Gittenberger-de Groot and Mohamad Azhar

J. Cardiovasc. Dev. Dis. 2020, 7(2), 19; https://doi.org/10.3390/jcdd7020019 - 24 May 2020

Cited by 25 | Viewed by 5606

Abstract

Transforming growth factor beta3 (TGFB3) gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of [...] Read more.

Transforming growth factor beta3 (TGFB3) gene mutations in patients of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD1) and Loeys-Dietz syndrome-5 (LDS5)/Rienhoff syndrome are associated with cardiomyopathy, cardiac arrhythmia, cardiac fibrosis, cleft palate, aortic aneurysms, and valvular heart disease. Although the developing heart of embryos express Tgfb3, its overarching role remains unclear in cardiovascular development and disease. We used histological, immunohistochemical, and molecular analyses of Tgfb3^−/− fetuses and compared them to wildtype littermate controls. The cardiovascular phenotypes were diverse with approximately two thirds of the Tgfb3^−/− fetuses having one or more cardiovascular malformations, including abnormal ventricular myocardium (particularly of the right ventricle), outflow tract septal and alignment defects, abnormal aortic and pulmonary trunk walls, and thickening of semilunar and/or atrioventricular valves. Ventricular septal defects (VSD) including the perimembranous VSDs were observed in Tgfb3^−/− fetuses with myocardial defects often accompanied by the muscular type VSD. In vitro studies using TGFβ3-deficient fibroblasts in 3-D collagen lattice formation assays indicated that TGFβ3 was required for collagen matrix reorganization. Biochemical studies indicated the ‘paradoxically’ increased activation of canonical (SMAD-dependent) and noncanonical (MAP kinase-dependent) pathways. TGFβ3 is required for cardiovascular development to maintain a balance of canonical and noncanonical TGFβ signaling pathways. Full article

(This article belongs to the Special Issue Leaders in Cardiovascular Research: A Special Issue Dedicated to Professor Adriana Gittenberger-De Groot)

► Show Figures

Graphical abstract

24 pages, 1594 KiB

Open AccessEditor’s ChoiceReview

Biomechanical Cues Direct Valvulogenesis

by Neha Ahuja, Paige Ostwald, David Bark and Deborah Garrity

J. Cardiovasc. Dev. Dis. 2020, 7(2), 18; https://doi.org/10.3390/jcdd7020018 - 19 May 2020

Cited by 7 | Viewed by 4130

Abstract

The vertebrate embryonic heart initially forms with two chambers, a ventricle and an atrium, separated by the atrioventricular junction. Localized genetic and biomechanical information guides the development of valves, which function to ensure unidirectional blood flow. If the valve development process goes awry, [...] Read more.

The vertebrate embryonic heart initially forms with two chambers, a ventricle and an atrium, separated by the atrioventricular junction. Localized genetic and biomechanical information guides the development of valves, which function to ensure unidirectional blood flow. If the valve development process goes awry, pathology associated with congenital valve defects can ensue. Congenital valve defects (CVD) are estimated to affect 1–2% of the population and can often require a lifetime of treatment. Despite significant clinical interest, molecular genetic mechanisms that direct valve development remain incompletely elucidated. Cells in the developing valve must contend with a dynamic hemodynamic environment. A growing body of research supports the idea that cells in the valve are highly sensitive to biomechanical forces, which cue changes in gene expression required for normal development or for maintenance of the adult valve. This review will focus on mechanotransductive pathways involved in valve development across model species. We highlight current knowledge regarding how cells sense physical forces associated with blood flow and pressure in the forming heart, and summarize how these changes are transduced into genetic and developmental responses. Lastly, we provide perspectives on how altered biomechanical cues may lead to CVD pathogenesis. Full article

► Show Figures

Figure 1

16 pages, 1360 KiB

Open AccessEditor’s ChoiceReview

Right Ventricular Function in Chronic Heart Failure: From the Diagnosis to the Therapeutic Approach

by Francesco Monitillo, Vito Di Terlizzi, Margherita Ilaria Gioia, Roberta Barone, Dario Grande, Giuseppe Parisi, Natale Daniele Brunetti and Massimo Iacoviello

J. Cardiovasc. Dev. Dis. 2020, 7(2), 12; https://doi.org/10.3390/jcdd7020012 - 9 Apr 2020

Cited by 22 | Viewed by 4617

Abstract

There is growing attention for the study of the right ventricle in cardiovascular disease and in particular in heart failure. In this clinical setting, right ventricle dysfunction is a significant marker of poor prognosis, regardless of the degree of left ventricular dysfunction. Novel [...] Read more.

There is growing attention for the study of the right ventricle in cardiovascular disease and in particular in heart failure. In this clinical setting, right ventricle dysfunction is a significant marker of poor prognosis, regardless of the degree of left ventricular dysfunction. Novel echocardiographic methods allow for obtaining a more complete evaluation of the right ventricle anatomy and function as well as of the related abnormalities in filling pressures. Specific and effective therapies for the right ventricle dysfunction are still not well defined and this represents the most difficult and important challenge. This article focuses on available diagnostic techniques for studying right ventricle dysfunction as well as on the therapies for right ventricle dysfunction. Full article

► Show Figures

Figure 1

17 pages, 1696 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Translating Translation to Mechanisms of Cardiac Hypertrophy

by Michael J. Zeitz and James W. Smyth

J. Cardiovasc. Dev. Dis. 2020, 7(1), 9; https://doi.org/10.3390/jcdd7010009 - 10 Mar 2020

Cited by 20 | Viewed by 6556

Abstract

Cardiac hypertrophy in response to chronic pathological stress is a common feature occurring with many forms of heart disease. This pathological hypertrophic growth increases the risk for arrhythmias and subsequent heart failure. While several factors promoting cardiac hypertrophy are known, the molecular mechanisms [...] Read more.

Cardiac hypertrophy in response to chronic pathological stress is a common feature occurring with many forms of heart disease. This pathological hypertrophic growth increases the risk for arrhythmias and subsequent heart failure. While several factors promoting cardiac hypertrophy are known, the molecular mechanisms governing the progression to heart failure are incompletely understood. Recent studies on altered translational regulation during pathological cardiac hypertrophy are contributing to our understanding of disease progression. In this brief review, we describe how the translational machinery is modulated for enhanced global and transcript selective protein synthesis, and how alternative modes of translation contribute to the disease state. Attempts at controlling translational output through targeting of mTOR and its regulatory components are detailed, as well as recently emerging targets for pre-clinical investigation. Full article

(This article belongs to the Special Issue Cardiomyopathy at the Sub-Cellular Level)

► Show Figures

Figure 1

26 pages, 5561 KiB

Open AccessEditor’s ChoiceReview

Follow Me! A Tale of Avian Heart Development with Comparisons to Mammal Heart Development

by Rusty Lansford and Sandra Rugonyi

J. Cardiovasc. Dev. Dis. 2020, 7(1), 8; https://doi.org/10.3390/jcdd7010008 - 7 Mar 2020

Cited by 16 | Viewed by 9141

Abstract

Avian embryos have been used for centuries to study development due to the ease of access. Because the embryos are sheltered inside the eggshell, a small window in the shell is ideal for visualizing the embryos and performing different interventions. The window can [...] Read more.

Avian embryos have been used for centuries to study development due to the ease of access. Because the embryos are sheltered inside the eggshell, a small window in the shell is ideal for visualizing the embryos and performing different interventions. The window can then be covered, and the embryo returned to the incubator for the desired amount of time, and observed during further development. Up to about 4 days of chicken development (out of 21 days of incubation), when the egg is opened the embryo is on top of the yolk, and its heart is on top of its body. This allows easy imaging of heart formation and heart development using non-invasive techniques, including regular optical microscopy. After day 4, the embryo starts sinking into the yolk, but still imaging technologies, such as ultrasound, can tomographically image the embryo and its heart in vivo. Importantly, because like the human heart the avian heart develops into a four-chambered heart with valves, heart malformations and pathologies that human babies suffer can be replicated in avian embryos, allowing a unique developmental window into human congenital heart disease. Here, we review avian heart formation and provide comparisons to the mammalian heart. Full article

(This article belongs to the Special Issue Comparative Developmental Cardiovascular Biomechanics and Bioengineering)

► Show Figures

Figure 1

11 pages, 536 KiB

Open AccessEditor’s ChoiceArticle

The Prognostic Importance of TAPSE in Early and in Stable Cardiovascular Diseases

by Paolo Giovanardi, Enrico Tincani, Marco Maioli and Stefano Tondi

J. Cardiovasc. Dev. Dis. 2020, 7(1), 4; https://doi.org/10.3390/jcdd7010004 - 15 Jan 2020

Cited by 6 | Viewed by 5705

Abstract

The identification of predictors of major cardiovascular events (MACES) represents a big challenge, especially in early and stable cardiovascular diseases. This prospective study comparatively evaluated the prognostic importance of left ventricular (LV) and right ventricular (RV) systolic and diastolic function, pulmonary artery pressure [...] Read more.

The identification of predictors of major cardiovascular events (MACES) represents a big challenge, especially in early and stable cardiovascular diseases. This prospective study comparatively evaluated the prognostic importance of left ventricular (LV) and right ventricular (RV) systolic and diastolic function, pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) in a stable patient’s cohort with cardiovascular risk factors. The LV ejection fraction, mitral annular plane systolic excursion (MAPSE), tricuspid annular plane systolic excursion (TAPSE), functional mitral regurgitation (FMR), doppler tissue imaging of mitral and tricuspid annulus with systolic and diastolic peaks estimation, tricuspid regurgitation velocity (TRV), pulmonary velocity outflow time integral (PVTI), mean pulmonary artery pressure (MPAP) and PVR were estimated at enrollment. During the follow-up, MACES and all-cause mortality were recorded. 369 subjects with or without previous MACES were enrolled. Bivariate analysis revealed LVEF, TAPSE, MPAP, TRV, PVR, LV diastolic function, and FMR were associated with the endpoints. When computing the influence of covariates to the primary endpoint (all-cause mortality and MACES) through Cox analysis, only LV diastolic function and TAPSE entered the final model; for the secondary endpoint (MACES) only TAPSE entered. TAPSE was able to predict MACES and all-cause mortality in early and stable cardiovascular diseases. The use of TAPSE should be implemented. Full article

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI