Journal of Cardiovascular Development and Disease — Open Access Journal

Left-sided congenital heart defects (CHDs) are among the most common forms of congenital heart disease, but a disease-causing gene has only been identified in a minority of cases. Here, we identified a candidate gene for CHDs, KIF1A, that was associated with a chromosomal balanced translocation t(2;8)(q37;p11) in a patient with left-sided heart and aortic valve defects. The breakpoint was in the 5′ untranslated region of the KIF1A gene at 2q37, which suggested that the break affected the levels of Kif1A gene expression. Transgenic fly lines overexpressing Kif1A specifically in the heart muscle (or all muscles) caused diminished cardiac contractility, myofibrillar disorganization, and heart valve defects, whereas cardiac knockdown had no effect on heart structure or function. Overexpression of Kif1A also caused increased collagen IV deposition in the fibrous network that normally surrounds the fly heart. Kif1A overexpression in C2C12 myoblasts resulted in specific displacement of the F-actin fibers, probably through a direct interaction with G-actin. These results point to a Kif1A-mediated disruption of F-actin organization as a potential mechanism for the pathogenesis in at least some human CHDs. Full article

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

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

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

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

Mitral valve chordae tendineae forces are elevated in the setting of mitral regurgitation (MR). Ring annuloplasty is an essential component of surgical repair for MR, but whether chordal forces are reduced after mitral annuloplasty has never been validated in vivo. Here, we present an extremely rare ovine case of natural, severe chronic functional MR, in which we used force-sensing fiber Bragg grating neochordae to directly measure chordal forces in the baseline setting of severe MR, as well as after successful mitral ring annuloplasty repair. Overall, our report is the first to confirm in vivo that mitral ring annuloplasty reduces elevated chordae tendineae forces associated with chronic functional MR. Full article

Russian patients with familial hypercholesterolemia (FH) were screened for pathogenic mutations using targeted next generation sequencing. Genetic testing was performed in 52 probands with definite or probable FH based on the Dutch lipid clinic network criteria (DLCN score ≥ 6). Blood samples were studied by massive parallel sequencing (Illumina HiSeq 1500 platform) using a custom capture library related to dyslipidemia and premature atherosclerosis. Mutations considered to be responsible for monogenic FH were identified in 48% of the probands: 24 with mutations in the LDLR gene and two with a mutation in the APOB gene. There were 22 pathogenic/likely pathogenic mutations in LDLR, eight of which have not been previously described in the literature. Four patients with a clinical picture of homozygous FH had two heterozygous LDLR mutations. Although mutation-negative patients had highly elevated total cholesterol and low-density lipoprotein cholesterol levels, only half of them had a family history of hypercholesterolemia. With respect to heterozygous FH, mutation-positive patients had higher maximum total cholesterol levels (p = 0.01), more severe carotid atherosclerotic lesions, and a higher percentage of premature peripheral artery disease (p = 0.03) than mutation-negative ones. However, the number of patients who suffered from myocardial infarction was similar between the two groups. Full article

Aerobic exercise is a core component of cardiac rehabilitation (CR). Leading organizations recommend that the exercise prescriptions should be based on a symptom limited baseline graded exercise test (GXT). However, recent evidence suggests that only ~30% of CR clinics perform baseline GXTs. Consequently, exercise prescriptions including exercise progression in CR are not following standard exercise prescription guidelines. Therefore, the purpose of this review is to provide clinicians with evidence-based techniques for prescribing exercise in the absence of a baseline GXT. Intensity indicators (e.g., heart rate, perceived exertion) are reviewed, along with special exercise considerations for various disease states (e.g., heart failure, peripheral artery disease, and coronary artery disease). Baseline exercise testing remains the gold standard approach for prescribing exercise among heart disease patients, however, clinicians must be prepared to safely develop and monitor patients when a baseline GXT is not performed. Full article

Objective: Analysis and presentation of the capabilities of the new ultrasound technique —the index of volume remodeling (IRV), which allows comprehensive assessing of pathological remodeling of the heart as an integrated functional anatomical system. Materials and methods: For this study 316 patients with acquired mitral valve disease (MVD) were examined prior to and following mitral valve replacement with bileaflet, disc-, and bioprostheses. Key parameters of the heart were measured in classical echocardiographic projections (end systolic area, end-diastolic area, end systolic volume, and end diastolic volume of ventricles, ventricular ejection fraction, atrial volume, and the ratio of ventricular to atrial volumes). The patients were examined 1–2 days prior to and following the surgery—before discharge, 6 months later, 1 year later, and then annually within next 5 years. The examination data were collected in one- and two-dimensional modes by using Philips EpiQ-7, iE33, HDI, Siemens Acuson, and HP Sonos 2500 diagnostic ultrasound machines equipped with 2.5 and 3.5 MHz transthoracic sensors. Results: A comprehensive study of structural geometric remodeling parameters of heart cavities in the context of acquired MVD allowed identifying new patterns in changes of the heart chambers geometry. These changes are reflected in the IRV, a digital indicator of the severity of cardiac pathological remodeling. Analysis of the dynamics of post-operative vs. pre-operative IRV-based remodeling data also showed that the index is highly sensible to the hemodynamic features of through-flows in various designs of prostheses. The IRV has a pronounced prognostic power and allows predicting the long-term outcome of surgical treatment with an accuracy of 82.35%. Conclusions: The IRV predictive accuracy formed the basis of the original classification of types of cardiac remodeling, which can assist both in determining the optimal timing for surgery, and in conjunction with other clinical diagnostic data, in predicting the long-term outcome of heart geometry restoration depending on the type of surgical correction. The IRV can be used in evaluation of the heart geometry for any cardiac pathology. It makes the approach to the analysis of pathological remodeling of the heart understandable, consistent, and universal, and also opens up opportunities for further expanding the diagnostic capabilities of radiology in cardiac surgery at all stages of the diagnostic process. Full article

Congenital heart defects (CHDs) occur with such a frequency that they constitute a significant cause of morbidity and mortality in both children and adults. A significant portion of CHDs can be attributed to aberrant development of the cardiac outflow tract (OFT), and of one of its cellular progenitors known as the cardiac neural crest cells (NCCs). The gene regulatory networks that identify cardiac NCCs as a distinct NCC population are not completely understood. Heart and neural crest derivatives (HAND) bHLH transcription factors play essential roles in NCC morphogenesis. The Hand1^PA/OFT enhancer is dependent upon bone morphogenic protein (BMP) signaling in both cranial and cardiac NCCs. The Hand1^PA/OFT enhancer is directly repressed by the endothelin-induced transcription factors DLX5 and DLX6 in cranial but not cardiac NCCs. This transcriptional distinction offers the unique opportunity to interrogate NCC specification, and to understand why, despite similarities, cranial NCC fate determination is so diverse. We generated a conditionally active transgene that can ectopically express DLX5 within the developing mouse embryo in a Cre-recombinase-dependent manner. Ectopic DLX5 expression represses cranial NCC Hand1^PA/OFT-lacZ reporter expression more effectively than cardiac NCC reporter expression. Ectopic DLX5 expression induces broad domains of NCC cell death within the cranial pharyngeal arches, but minimal cell death in cardiac NCC populations. This study shows that transcription control of NCC gene regulatory programs is influenced by their initial specification at the dorsal neural tube. Full article

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

Carotid and/or femoral atherosclerotic plaques (AP) assessment through imaging studies is an interesting strategy for improving individual cardiovascular risk (CVR) stratification and cardiovascular disease (CVD) and/or events prediction. There is no consensus on who would benefit from image screening aimed at determining AP presence, burden, and characteristics. Aims: (1) to identify, in asymptomatic and non-treated subjects, demographic factors, anthropometric characteristics and cardiovascular risk factors (CRFs), individually or grouped (e.g., CVR equations, pro-atherogenic lipid ratios) associated with carotid and femoral AP presence, burden, geometry, and fibro-lipid content; (2) to identify cut-off values to be used when considering the variables as indicators of increased probability of AP presence, elevated atherosclerotic burden, and/or lipid content, in a selection scheme for subsequent image screening. Methods: CRFs exposure and clinical data were obtained (n = 581; n = 144 with AP; 47% females). Arterial (e.g., ultrasonography) and hemodynamic (central [cBP] and peripheral blood pressure; oscillometry/applanation tonometry) data were obtained. Carotid and femoral AP presence, burden (e.g., AP number, involved territories), geometric (area, width, height) and fibro-lipid content (semi-automatic, virtual histology analysis, grayscale analysis and color mapping) were assessed. Lipid profile was obtained. Lipid ratios (Total cholesterol/HDL-cholesterol, LDL-cholesterol/HDL-cholesterol, LogTryglicerides(TG)/HDL-cholesterol) and eight 10-years [y.]/CVR scores were quantified (e.g., Framingham Risk Scores [FRS] for CVD). Results: Age, 10-y./CVR and cBP showed the highest levels of association with AP presence and burden. Individually, classical CRFs and lipid ratios showed almost no association with AP presence. 10-y./CVR levels, age and cBP enabled detecting AP with large surfaces (˃p75th). Lipid ratios showed the largest association with AP fibro-lipid content. Ultrasound evaluation could be considered in asymptomatic and non-treated subjects aiming at population screening of AP (e.g., ˃ 45 y.; 10-y./FRS-CVD ˃ 5–8%); identifying subjects with high atherosclerotic burden (e.g., ˃50 y., 10-y./FRS-CVD ˃ 13–15%) and/or with plaques with high lipid content (e.g., LogTG/HDL ˃ 0.135). Full article

Background: The timing for initiation of effective antithrombotic therapy relative to the onset of arterial thrombosis may influence outcomes. This report investigates the hypothesis that early administration of heparin anticoagulation relative to the onset of thrombotic occlusion will effect a reduction in occlusion. Methods: A standard rat model of experimental thrombosis induction was used, injuring the carotid artery exposure with FeCl₃-saturated filter paper, followed by flow monitoring for onset of occlusion and subsequent embolization events. Intravenous heparin administration (200 units/mL) was timed relative to the initiation of injury or onset of near occlusion, compared with controls (no heparin administration). Results: No occlusion was found for delivery of heparin 5 min prior to thrombus induction, whereas all vessels occluded without heparin. Unstable (embolic) thrombi were seen with heparin given at or shortly after initial occlusion. Only 9% (1/11) of the vessels had permanent occlusion when heparin was given at the time of thrombotic onset (p < 0.0001 vs. unheparinized), while 50% occluded when heparin was delayed by 5 min (p > 0.05). Conclusions: These findings provide evidence that antithrombotic therapy may need to be administered prior to the onset of anticipated loss of patency, with less effectiveness when given after occlusion has occurred. Full article

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

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

Background: Recent European guidelines on diabetes, prediabetes, and cardiovascular disease developed for the European Society of Cardiology (ESC) in collaboration with the European Association for the Study of Diabetes (EASD) significantly changed some concepts on risk stratification, lipid goals, and recommendations for the use of lipid-lowering drugs. The objectives of this work were to describe the lipid-lowering treatment prescribed for patients with diabetes and to determine the percentage of patients that achieved the lipid goals recommended by the 2019 ESC/EASD Guidelines on Diabetes in real and simulated scenarios. Methods: A multicenter, cross-sectional study was performed. Subjects >18 years with type 2 diabetes were included. The recommendations of the 2019 ESC/EASD Guidelines were followed. The real and simulated (ideal setting using adequate doses of statins ± ezetimibe) scenarios were analyzed. Results: Overall, 528 patients were included. In total, 62.5% of patients received statins (17.1% high intensity). Most patients were stratified as “very high risk” (54.2%) or “high risk” (43.4%). Only 13.3% achieved the double lipid goal (LDL-C and non-HDL-C goals according to the risk categories). In the simulation analysis, the proportion of subjects that did not reach the therapeutic objective decreased in all risk strata, although a considerable proportion of subjects persisted outside the target. Conclusion: The difficulty of achieving lipid goals in diabetic patients was considerable when applying the new guidelines. The situation would improve if we optimized treatment, but the prescription of new lipid-lowering drugs could be limited by their high cost. Full article

Attrition is a major cause of failure in obesity treatment, which is still not fully understood. The identification of factors related to this outcome is of clinical relevance. We aimed to assess the relationship between sarcopenic obesity (SO) and early attrition. Early attrition was assessed at six months, and two groups of patients were selected from a large cohort of participants with overweight or obesity enrolled at the Outpatient Clinic of the Department of Nutrition and Dietetics at Beirut Arab University (Lebanon). Body composition was measured using a bioimpedance analyser (Tanita BC-418) and participants at baseline were categorized as having or not having SO. The “dropout group” included 72 participants (cases) compared to 31 participants (controls) in the “completer group”, with the former displaying a higher prevalence of SO than the latter (51.0% vs. 25.8%; p = 0.016). In the same direction, Poisson regression analysis showed that SO increased the relative risk of dropout by nearly 150% (RR = 1.45; 95% CI = 1.10–1.89; p = 0.007) after adjustment for age, gender, body mass index (BMI), age at first dieting, sedentary habits and weight-loss expectation. In conclusion, in a “real-world” outpatient clinical setting, the presence of SO at baseline increases the risk of dropout at six months. New directions of future research should be focused on identifying new strategies to reduce the attrition rate in this population. Full article

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