Ventricular Chamber Research Articles

Long-term structural right heart remodeling following transcatheter annuloplasty for treating severe tricuspid regurgitation assessed by CT scan

Abstract Background Transcatheter tricuspid annuloplasty has emerged as an attractive percutaneous therapy for patients with severe symptomatic tricuspid regurgitation. Cardioband (Edwards) was the first dedicated CE marked percutaneous device for tricuspid regurgitation. Despite mid-long-term clinical safety and efficacy demonstrated in early feasibility trials and registries, there is no data about its impact on right heart structural remodeling using computed tomography (CT). Our aim was to assess right heart remodeling and changes in the tricuspid annulus (TA) one year after Cardioband implantation. Methods A total of 30 patients were prospectively included in the study; 21 of them had baseline and at least 1-year follow-up CT analysis. The average time from the basal CT scan and the procedure was 118±136 days, and from the intervention to follow-up CT scan was 468±251 days. 2D and 3D analyses were performed with 3mensio version 10.3 at baseline and at least 12 months after Cardioband implantation. Results There was a significant decrease in right ventricular dimensions at follow-up (right ventricular basal diameter was 53.65 ± 8.45 mm at baseline Vs 48.54 ± 9.12 mm at 1-year follow-up; right ventricular mid cavity diameter was 40.30 ± 9.10 mm at baseline Vs 34.22 ± 9.22 at the end of follow-up, and right ventricular longitudinal diameter was 75.43 ± 9.85 mm at baseline Vs 69.95 ± 9.96 mm at the end of follow-up, all of them were statistically significant). A reduction in right atrial dimension was also observed (longitudinal diameter 66.86 ± 7.63 mm at baseline Vs 64.89 ± 9.99 mm at the end of follow-up; transverse diameter of 61.62 ± 8.38 mm at baseline Vs 60.59 ± 8.3 mm at the end of follow-up, p<0.001). There was a significant decrease in the area and diameters of the dilated TA (area at baseline 16.51 ± 3.06 cm2 vs 8.90 ± 2.71 cm2 at the end of follow-up, p=0.02; septolateral diameter 45.42 ± 5.02 mm at baseline vs 33.87 ± 5.09 mm at the end of follow-up, p=0.01). Conclusions Long-term favorable right ventricular chambers and TA remodeling was observed following Cardioband implantation assessed by CT scan. This finding could explain the long-term clinical benefit demonstrated in feasibility studies.Right heart remodeling after Cardioband

Abstract 13989: Automated VT Localization System Based on Patient-Specific Integration of Two-Dimensional (2D) Intracardiac Echocardiography (ICE) and 3DElectroanatomic (EA) Mapping

Introduction: We have previously developed an intraprocedural automated localization system to identify VT-exit sites projected onto a patient-specific CT geometry using 12-lead ECGs. However, the accuracy of the system depends on a registered reconstruction of the cardiac surface. Objective: To assess the feasibility of using a registered integration of 2D ICE and 3D EA mapping to perform intraprocedural localization, while avoiding errors being introduced by registration of the CT geometry and EA map. Methods: Four patients with 7 VTs (5 LV VTs, 2 RV VTs) were enrolled. A 3D patient-specific shell of both ventricles that combines ICE and EA map was reconstructed during the ablation procedure. It was imported into the automated localization system post-procedure for offline analysis. The system was used to estimate the location of VT-exit sites on the reconstructed 3D geometry. Localization accuracy was quantified for the VT-exit sites by comparing the distance of the calculated site to the site of successful ablation or that of best pacing site match. Results: Five reentrant VT-exit sites were identified using activation and entrainment mapping, supplemented by pace-mapping at the scar margin; two focal VTs were identified by pace mapping. The proposed system achieved mean localization accuracy of 6.4 mm for 7 VTs. Conclusions: ICE and EA mapping can be successfully integrated for intraprocedural automated localization of ventricular activation in both ventricular chambers and may avoid registration errors of CT geometry integration.

Abstract 18288: Mice Harboring a Novel De Novo Missense RBFOX2 Variant Display Abnormal Heart Development

Hypoplastic Left Heart Syndrome (HLHS) is a complex form of congenital heart disease, characterized by severe underdevelopment of the left ventricle, stenosis or atresia of the mitral and aortic valves, and hypoplasia of the ascending aorta and aortic arch. Despite advances in surgical and palliative strategies leading to improved neonatal survival outcomes, HLHS is still associated with early mortality and long-term morbidity. Elucidation of HLHS etiology is compounded by its complex inheritance mechanism and heterogenous genetic landscape, with studies indicating a multigenic etiology. We performed exome sequencing on a parent-offspring trio in which the proband was affected with HLHS and identified a novel de novo missense variant in the gene, RBFOX2, that was bioinformatically predicted to be pathogenic. RBFOX2 belongs to a family of RNA-binding proteins that is broadly expressed in all tissues and regulates splicing and transcription of many targets, including those involved in heart development. In order to determine the in vivo pathogenicity of the RBFOX2 variant, we generated a knock-in mouse model harboring orthologous missense RBFOX2 variant using CRISPR/Cas9 technology. RBFOX2 KI/KI mice were found to be embryonic lethal. Morphological analysis revealed 100% of homozygous mutants exhibit gross developmental defects. Normal Mendelian ratios are found at E9.5 but homozygous mutants display severe growth retardation from E9.5 to E11.5. Histologic analysis demonstrated underdevelopment of the ventricular chambers starting at E9.5. Overall, these mutant mice, harboring a clinically relevant human HLHS variant in RBFOX2 , display highly penetrant hypoplastic hearts with significant growth retardation. The use of this new murine model will pave the way for better cellular and molecular characterization of the deficits in RBFOX2 function that contribute to HLHS.

Abstract 13987: RBX1-CRLs Are Essential for Perinatal Heart Development by Regulating Hippo-YAP Signaling

Defects in cardiac development can lead to congenital heart diseases (CHD) or predispose the heart to cardiomyopathies in adult life. The molecular mechanisms that regulate this process remain elusive. Cullin-RING E3 ligases (CRLs) are multi-subunit complexes that are critical to maintain protein homeostasis by targeting a variety of protein substrates for proteasomal degradation. In the CRLs, RBX1 serves as the catalytic subunit that promotes the transfer of ubiquitin to the target protein. Previous animal studies uncovered a crucial role for RBX1 in development. However, its importance in the developing heart has not been explored. Here, we report for the first time the indispensable role of RBX1 in perinatal cardiac development. We created mice with cardiac-specific deletion of RBX1 driven by αMHC Cre . Compared with littermate control mice, RBX1-deficient mouse embryos exhibited no gross morphological abnormalities at E12.5 and E14.5, displayed peripheral edema at E16.5 indicative of heart failure, and eventually died around E18.5. Histological analysis revealed myocardial hypoplasia and a substantially thinner compact layer in E16.5 mutant hearts. This event was preceded by a remarkable decrease in cardiomyocyte proliferation and diminished nuclear localization of YAP, a powerful regulator of cardiomyocyte proliferation, at E14.5. In cultured cardiomyocytes, depletion of RBX1 inhibited proliferation and induced profound transcriptomic changes like the upregulation of cardiomyopathy-related genes. Mechanistically, RBX1 deficiency destabilized multiple CRLs and resulted in the accumulation of Hippo kinases and adaptor proteins such as SAV1, LATS1/2, and MOB1 leading to the inactivation of YAP by phosphorylation. We further demonstrated that RBX1 degrades the Hippo adaptors SAV1 and MOB1. Collectively, we propose that the fine-tuned, RBX1-mediated removal of Hippo components serves as a critical checkpoint to activate YAP signaling ensuring cardiac ventricular chamber development and morphogenesis.

Deep Learning–Enabled Assessment of Left Heart Structure and Function Predicts Cardiovascular Outcomes

BackgroundDeep learning interpretation of echocardiographic images may facilitate automated assessment of cardiac structure and function. ObjectivesWe developed a deep learning model to interpret echocardiograms and examined the association of deep learning–derived echocardiographic measures with incident outcomes. MethodsWe trained and validated a 3-dimensional convolutional neural network model for echocardiographic view classification and quantification of left atrial dimension, left ventricular wall thickness, chamber diameter, and ejection fraction. The training sample comprised 64,028 echocardiograms (n = 27,135) from a retrospective multi-institutional ambulatory cardiology electronic health record sample. Validation was performed in a separate longitudinal primary care sample and an external health care system data set. Cox models evaluated the association of model-derived left heart measures with incident outcomes. ResultsDeep learning discriminated echocardiographic views (area under the receiver operating curve >0.97 for parasternal long axis, apical 4-chamber, and apical 2-chamber views vs human expert annotation) and quantified standard left heart measures (R2 range = 0.53 to 0.91 vs study report values). Model performance was similar in 2 external validation samples. Model-derived left heart measures predicted incident heart failure, atrial fibrillation, myocardial infarction, and death. A 1-SD lower model-left ventricular ejection fraction was associated with 43% greater risk of heart failure (HR: 1.43; 95% CI: 1.23-1.66) and 17% greater risk of death (HR: 1.17; 95% CI: 1.06-1.30). Similar results were observed for other model-derived left heart measures. ConclusionsDeep learning echocardiographic interpretation accurately quantified standard measures of left heart structure and function, which in turn were associated with future clinical outcomes. Deep learning may enable automated echocardiogram interpretation and disease prediction at scale.

Molecular Imaging Biomarkers in Cardiooncology: A View on Established Technologies and Future Perspectives.

Novel therapeutic options have significantly improved survival and long-term outcomes in many cancer entities. Unfortunately, this improvement in outcome is often accompanied by new and increasingly relevant therapy-related cardiovascular toxicity. In this context, cardiooncology has emerged as a new field of interdisciplinary individual patient care. Important tasks are pretherapeutic risk stratification and early detection and treatment of cardiotoxicity, which comprises cardiac damage in relation to cardiovascular comorbidities, the tumor disease, and cancer treatment. Clinical manifestations can cover a broad spectrum, ranging from subtle and usually asymptomatic abnormalities to serious acute or chronic complications. Typical manifestations include acute and chronic heart failure, myo- and pericarditis, arrythmias, ischemia, and endothelial damage. They can be related to almost all current cancer treatments, including cytotoxic chemotherapy, targeted therapy, immunotherapy, hormonal therapy, and radiotherapy. Molecular imaging biomarkers can aid in pretherapeutic cardiooncologic assessment for primary prevention and personalized surveillance, detection, and differential diagnosis of cardiotoxic complications. Potential advantages over conventional diagnostics are the higher detection sensitivity for subtle changes in cardiac homeostasis, higher reproducibility, and better observer independence. Hybrid imaging with highly sensitive PET/MRI may be particularly suited for early diagnosis. Important technologies that are encouraged in current multidisciplinary guidelines are equilibrium radionuclide angiography for evaluation of ventricular function and chamber morphology, as well as myocardial perfusion imaging for additional detection of ischemia. Novel modalities that may detect even earlier signs of cardiotoxicity comprise 123I-metaiodobenzylguanidine SPECT to visualize sympathetic innervation, 18F-FDG and somatostatin receptor (68Ga-DOTATOC/DOTATATE) PET to indicate a metabolic shift and inflammation, and 68Ga-fibroblast activation protein inhibitor PET to monitor cardiac remodeling. In addition, PET imaging of mitochondrial function has recently been introduced in preclinical models and will potentially broaden the field of application through higher sensitivity and specificity and by enabling higher individualization of diagnostic concepts.

Natural history of cardiac findings in mucopolysaccharidosis type I: report from an international registry.

Mucopolysaccharidosis type I is an inborn error of glycosaminoglycan catabolism with phenotypes ranging from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes). Cardiovascular involvement is common and contributes significantly to morbidity and mortality. We conducted a retrospective analysis of the prevalence and natural history of cardiac abnormalities in treatment-naïve individuals enrolled in the international Mucopolysaccharidosis Type I Registry. Interrogation of echocardiography data (presence of cardiac valve regurgitation and/or stenosis; measurements of left ventricular chamber dimensions in diastole and systole, diastolic left ventricular posterior wall and interventricular septal thicknesses and ventricular systolic function (shortening fraction)) showed that mitral regurgitation was the most common and earliest finding for individuals with both severe (58.3%, median age 1.2 years) and attenuated (74.2%, median age 8.0 years) disease. Left-sided valve stenosis was also common in individuals with attenuated disease (mitral 30.3%; aortic 25%). Abnormal ventricular wall and septal thickness (Z-scores ≥2) were observed early in both phenotypes. Z-scores for diastolic left ventricular posterior wall and interventricular septal thicknesses increased with age in the severe phenotype (annualised slopes of 0.2777 [p = 0.037] and 0.3831 [p = 0.001], respectively); a similar correlation was not observed in the attenuated phenotype (annualised slopes of -0.0401 [p = 0.069] and -0.0029 [p = 0.875], respectively). Decreased cardiac ventricular systolic function (defined as shortening fraction <28%) was uncommon but, when noted, was more frequent in infants with the severe phenotype. While cardiac abnormalities occur early in both severe and attenuated mucopolysaccharidosis type I, the pattern of valve dysfunction and progression of ventricular abnormalities vary by phenotype.

Nrg1 Regulates Cardiomyocyte Migration and Cell Cycle in Ventricular Development.

Cardiac ventricles provide the contractile force of the beating heart throughout life. How the primitive endocardium-layered myocardial projections called trabeculae form and mature into the adult ventricles is of great interest for biology and regenerative medicine. Trabeculation is dependent on the signaling protein Nrg1 (neuregulin-1). However, the mechanism of action of Nrg1 and its role in ventricular wall maturation are poorly understood. We investigated the functions and downstream mechanisms of Nrg1 signaling during ventricular chamber development using confocal imaging, transcriptomics, and biochemical approaches in mice with cardiac-specific inactivation or overexpression of Nrg1. Analysis of cardiac-specific Nrg1 mutant mice showed that the transcriptional program underlying cardiomyocyte-oriented cell division and trabeculae formation depends on endocardial Nrg1 to myocardial ErbB2 (erb-b2 receptor tyrosine kinase 2) signaling and phospho-Erk (phosphorylated extracellular signal-regulated kinase; pErk) activation. Early endothelial loss of Nrg1 and reduced pErk activation diminished cardiomyocyte Pard3 and Crumbs2 (Crumbs Cell Polarity Complex Component 2) protein and altered cytoskeletal gene expression and organization. These alterations are associated with abnormal gene expression related to mitotic spindle organization and a shift in cardiomyocyte division orientation. Nrg1 is crucial for trabecular growth and ventricular wall thickening by regulating an epithelial-to-mesenchymal transition-like process in cardiomyocytes involving migration, adhesion, cytoskeletal actin turnover, and timely progression through the cell cycle G2/M phase. Ectopic cardiac Nrg1 overexpression and high pErk signaling caused S-phase arrest, sustained high epithelial-to-mesenchymal transition-like gene expression, and prolonged trabeculation, blocking compact myocardium maturation. Myocardial trabecular patterning alterations resulting from above- or below-normal Nrg1-dependent pErk activation were concomitant with sarcomere actin cytoskeleton disorganization. The Nrg1 loss- and gain-of-function transcriptomes were enriched for Yap1 (yes-associated protein-1) gene signatures, identifying Yap1 as a potential downstream effector. Furthermore, biochemical and imaging data reveal that Nrg1 influences pErk activation and Yap1 nuclear-cytoplasmic distribution during trabeculation. These data establish the Nrg1-ErbB2/ErbB4-Erk axis as a crucial regulator of cardiomyocyte cell cycle progression and migration during ventricular development.

Fractalkine/CX3CR1 in Dilated Cardiomyopathy: A Potential Future Target for Immunomodulatory Therapy?

Dilated cardiomyopathy (DCM) is a cardiac condition with structural and functional impairment, where either the left ventricle or both ventricular chambers are enlarged, coinciding with reduced systolic pump function (reduced ejection fraction, rEF). The prevalence of DCM is more than 1:250 individuals, and mortality largely due to heart failure in two-third of cases, and sudden cardiac death in one-third of patients. Damage to the myocardium, whether from a genetic or environmental cause such as viruses, triggers inflammation and recruits immune cells to the heart to repair the myocardium. Examination of myocardial biopsy tissue often reveals an inflammatory cell infiltrate, T lymphocyte (T cell) infiltration, or other activated immune cells. Despite medical therapy, adverse outcomes for DCM remain. The evidence base and existing literature suggest that upregulation of CX3CR1, migration of immune cells, together with cytomegalovirus (CMV) seropositivity is associated with worse outcomes in patients with dilated cardiomyopathy. We hypothesise that this potentially occurs through cardiac inflammation and fibrosis, resulting in adverse remodelling. Immune modulators to target this pathway may potentially improve outcomes above and beyond current guideline-recommended therapy.

Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.

Pediatric cardiomyopathy (CM) represents a group of rare, severe disorders that affect the myocardium. To date, the etiology and mechanisms underlying pediatric CM are incompletely understood, hampering accurate diagnosis and individualized therapy development. Here, we identified biallelic variants in the highly conserved flightless-I (FLII) gene in 3 families with idiopathic, early-onset dilated CM. We demonstrated that patient-specific FLII variants, when brought into the zebrafish genome using CRISPR/Cas9 genome editing, resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in our patients. Importantly, using these genetic animal models, complemented with in-depth loss-of-function studies, we provided insights into the function of Flii during ventricular chamber morphogenesis in vivo, including myofibril organization and cardiomyocyte cell adhesion, as well as trabeculation. In addition, we identified Flii function to be important for the regulation of Notch and Hippo signaling, crucial pathways associated with cardiac morphogenesis and function. Taken together, our data provide experimental evidence for a role for FLII in the pathogenesis of pediatric CM and report biallelic variants as a genetic cause of pediatric CM.

Analysis of the distribution and orientation of oxygenated and non-oxygenated blood in a double outlet right ventricle

Double outlet right ventricle (DORV) is a malformation of the fetal heart in utero that affects the ventricular chambers. It usually presents with a displacement of the aorta and more than half the circumference of both arterial valves in the right ventricle. A peculiar characteristic is given by an interventricular septal defect (VSD), which allows communication between the left ventricle and the right with consequent mixing of oxygenated and non-oxygenated blood inside the cavities. A crucial question in assessing the degree of severity of functional dysfunction concerns the percentage of oxygenated blood that is ejected into the primary circulation via the aorta, a result that depends on the details of the vortex flow pattern within the two ventricular chambers. This study analyzes a complete DORV case through the use of numerical simulations that allow to identify the concentrations of oxygenated and non-oxygenated blood passing through this geometry. Results show that the VSD presents a significant impact on the fluid dynamic performance of the two ventricles. The analysis of blood concentration allowed to quantify the presence of oxygenated blood ejected into the pulmonary artery and of non-oxygenated blood into the aortic artery. The analysis of this specific case aims to demonstrate how the fluid dynamics analysis of this rare malformation, properly coupled with imaging technology, can provide information that could not be obtained otherwise and that are relevant for a careful clinical management including timely therapeutic intervention.

Longitudinal cardiac remodeling in collegiate American football players as assessed by echocardiography during their collegiate career.

Studies on the longitudinal effects of intense physical training on cardiac remodeling are limited, especially in American collegiate football players. College-level American football training will result in remodeling in a pattern consistent of a sport with moderate static and dynamic demands with increases in both wall and chamber sizes. We studied 85 American collegiate football players who underwent transthoracic echocardiogram (TTE) for asymptomatic or mild COVID-19-related illness and compared the changes in echo dimensions to their preparticipation screening TTE. Pre- and posttraining variables were compared using a paired t-test for normally distributed variables. Mean age was 19 years ± 1 and 61% of athletes were Black. Mean follow-up between TTEs was 21 ± 13 months. There was an increase in left atrial volume index (26.4 ± 5.5 to 32.8 ± 8.4 mL/m2 , p < .001), LV end diastolic diameter (5.13 ± 0.4 to 5.27 ± 0.4 cm, p = .003), basal RV diameter (3.28 ± 0.7 to 3.83 ± 0.5 cm, p = <.001), LV mass index (86.7 ± 15.3 to 90.1 ± 15.3, p = .015), and aortic root diameter (3.1 ± 0.4 to 3.2 ± 0.3 cm, p = .03) from pre- to posttraining, with a slightly greater magnitude in athletes with >2 years of training. Presence of left atrial enlargement (≥35 mL/m2 ) increased from 2.9% to 29% pre- to postparticipation in athletes with >2 years training. No significant changes in wall thickness, diastolic function, or right ventricular systolic function were observed. American football players college-level training was associated with increases in left and right ventricular chamber sizes, left atrial size, and aortic root diameter.

Sox7-positive endothelial progenitors establish coronary arteries and govern ventricular compaction.

The cardiac endothelium influences ventricular chamber development by coordinating trabeculation and compaction. However, the endothelial-specific molecular mechanisms mediating this coordination are not fully understood. Here, we identify the Sox7 transcription factor as a critical cue instructing cardiac endothelium identity during ventricular chamber development. Endothelial-specific loss of Sox7 function in mice results in cardiac ventricular defects similar to non-compaction cardiomyopathy, with a change in the proportions of trabecular and compact cardiomyocytes in the mutant hearts. This phenotype is paralleled by abnormal coronary artery formation. Loss of Sox7 function disrupts the transcriptional regulation of the Notch pathway and connexins 37 and 40, which govern coronary arterial specification. Upon Sox7 endothelial-specific deletion, single-nuclei transcriptomics analysis identifies the depletion of a subset of Sox9/Gpc3-positive endocardial progenitor cells and an increase in erythro-myeloid cell lineages. Fate mapping analysis reveals that a subset of Sox7-null endothelial cells transdifferentiate into hematopoietic but not cardiomyocyte lineages. Our findings determine that Sox7 maintains cardiac endothelial cell identity, which is crucial to the cellular cross-talk that drives ventricular compaction and coronary artery development.

Abstract P1139: Remodeling Chromatin Structure To Induce And Reverse Heart Failure

Heart failure is a critical health issue that causes one in nine deaths in the United States. Despite extensive research on gene expression dynamics in the failing myocardium, the mechanisms by which the genome reorganizes itself to reconfigure transcription are poorly understood. CTCF is a crucial protein in chromatin architecture that mediates chromatin looping, acts as an enhancer insulator, and can function as either an activator or repressor of transcription. Our previous research indicates that CTCF plays a crucial role in heart failure, as cardiac-specific knockout of this protein promotes genome organization defects that result in cardiac pathology marked by reduced ejection fraction. To determine whether restoring CTCF levels could reverse this phenotype, we designed an AAV9 vector in which the cardiomyocyte-specific Troponin T promoter drives the expression of CTCF and GFP. Our results show that reintroduction of CTCF into failing CTCF-depleted mouse hearts successfully rescues the pathological phenotype of the animals, characterized by sustained improvement in ejection fraction and left ventricular chamber size in both systole and diastole. Furthermore, RNA-seq experiments reveal numerous differentially expressed genes with opposite transcriptional behavior depending on CTCF levels, including genes involved in chromatin organization (e.g., CHmgb2, Brca1, Smyd2), development of hypertrophy (e.g., Mef2a, Gata4, Mybpc3), extracellular matrix organization (e.g., Adamts5, Itgb1, Vtn) and collagen deposition (e.g., Col5a1, Col5a3). We also examined chromatin architecture through Hi-C experiments and discovered that restoration of CTCF levels remodels the global architecture of chromatin to closely resemble healthy myocyte chromatin. This finding supports the hypothesis that rescue of CTCF levels ameliorates cardiac disease by reverting the observed pathological gene expression profile through genomic reorganization. In summary, our project highlights the crucial role of CTCF in heart failure and demonstrates that structural repair of chromatin organization through modulation of CTCF levels is a novel and realistic approach to treating heart failure.

HYDROACOUSTICS OF THE MECHANICAL BILEAFLET HEART VALVE

The results of experimental researches of hydrodynamic noise generated by a jet flow through the mechanical bileaflet mitral valve prosthesis of the Italian company Sorin are given. Physical simulation was carried out in laboratory conditions on the model of the left atrial chamber and the left ventricular chamber of the heart. The hydrodynamic noise of the flow through the artificial bileaflet mitral valve increased with increasing water flow. It was found that the greatest intensity of hydrodynamic noise and its spectral components was observed near the central jet of the bileaflet mitral valve. The obtained average pressure values in the near wake of the open mitral valve near the side jet are (10 – 20) % higher than near the central jet. It was determined that the power spectral densities of pressure fluctuations near the central jet are higher than near the side jet, especially in the frequency range (10 – 100) Hz. It was established that the small-scale vortex structures, which broke away from its leaflets and generated pressure fluctuations in the frequency range (20 – 70) Hz, degenerated starting from a distance of 2.5 valve diameters downstream. Increased levels of pressure fluctuations were observed near the central jet by more than (12 – 13) dB relative to hydrodynamic noise inside the atrial chamber and by more than (5 – 7) dB higher relative to pressure fluctuations near the side jet inside the left ventricular chamber in the frequency range (12 – 15) Hz. With an increase in water flow in the near wake of the mitral valve, an increase in the spectral levels of pressure fluctuations in the frequency range (60 – 80) Hz was observed. At a distance of more than below the open mechanical bileaflet mitral valve, the hydrodynamic noises near the central and side jets became approximately equal in the entire frequency range under consideration. The research results showed that hydroacoustic diagnostics of the operation of the mechanical bileaflet heart valve can be an effective means of diagnosing thrombus formation on the artificial valve leaflets.

Preeclampsia and risk of maternal pulmonary hypertension at high altitude in Bolivia.

Women with a history of preeclampsia (PE) have a greater risk of pulmonary arterial hypertension (PAH). In turn, pregnancy at high altitude is a risk factor for PE. However, whether women who develop PE during highland pregnancy are at risk of PAH before and after birth has not been investigated. We tested the hypothesis that during highland pregnancy, women who develop PE are at greater risk of PAH compared to women undergoing healthy highland pregnancies. The study was on 140 women in La Paz, Bolivia (3640m). Women undergoing healthy highland pregnancy were controls (C, n = 70; 29 ± 3.3 years old, mean±SD). Women diagnosed with PE were the experimental group (PE, n = 70, 31 ± 2 years old). Conventional (B- and M-mode, PW Doppler) and modern (pulsed wave tissue Doppler imaging) ultrasound were applied for cardiovascular íííassessment. Spirometry determined maternal lung function. Assessments occurred at 35 ± 4 weeks of pregnancy and 6 ± 0.3 weeks after birth. Relative to highland controls, highland PE women had enlarged right ventricular (RV) and right atrial chamber sizes, greater pulmonary artery dimensions and increased estimated RV contractility, pulmonary artery pressure and pulmonary vascular resistance. Highland PE women had lower values for peripheral oxygen saturation, forced expiratory flow and the bronchial permeability index. Differences remained 6 weeks after birth. Therefore, women who develop PE at high altitude are at greater risk of PAH before and long after birth. Hence, women with a history of PE at high altitude have an increased cardiovascular risk that transcends the systemic circulation to include the pulmonary vascular bed.

Vps4a Regulates Autophagic Flux to Prevent Hypertrophic Cardiomyopathy.

Autophagy has stabilizing functions for cardiomyocytes. Recent studies indicate that an impairment in the autophagy pathway can seriously affect morphology and function, potentially leading to heart failure. However, the role and the underlying mechanism of the endosomal sorting complex required for transport (ESCRT) family protein, in particular the AAA-ATPase vacuolar protein sorting 4a (Vps4a), in regulating myocardial autophagy remains unclear. In the present study, cardiomyocyte-specific Vps4a knockout mice were generated by crossing Vps4aflox/flox (Vps4afl/fl) with Myh6-cre transgenic mice. As a result, we observed a partially dilated left ventricular (LV) chamber, a significant increase in heart weight to body weight ratio (HW/BW), and heart weight to tibial length ratio (HW/TL), hypertrophic cardiomyopathy and early lethality starting at 3 months of age. Hematoxylin-eosin (HE), immunofluorescence assay (IFA), and Western blot (WB) revealed autophagosome accumulation in cardiomyocytes. A transcriptome-based analysis and autophagic flux tracking by AAV-RFP-GFP-LC3 showed that the autophagic flux was blocked in Vps4a knockout cardiomyocytes. In addition, we provided in vitro evidence demonstrating that Vps4a and LC3 were partially co-localized in cardiomyocytes, and the knockdown of Vps4a led to the accumulation of autophagosomes in cardiomyocytes. Similarly, the transfection of cardiomyocytes with adenovirus (Adv) mCherry-GFP-LC3 further indicated that the autophagic flux was blocked in cells with deficient levels of Vps4a. Finally, an electron microscope (EM) showed that the compromised sealing of autophagosome blocked the autophagic flux in Vps4a-depleted cardiomyocytes. These findings revealed that Vps4a contributed to the sealing of autophagosomes in cardiomyocytes. Therefore, we demonstrated that Vps4a deletion could block the autophagic flux, leading to the accumulation of degradation substances and compromised cardiac function. Overall, this study provides insights into a new theoretical basis for which autophagy may represent a therapeutic target for cardiovascular diseases.

Missense Mutation in Human CHD4 Causes Ventricular Noncompaction by Repressing ADAMTS1.

Left ventricular noncompaction (LVNC) is a prevalent cardiomyopathy associated with excessive trabeculation and thin compact myocardium. Patients with LVNC are vulnerable to cardiac dysfunction and at high risk of sudden death. Although sporadic and inherited mutations in cardiac genes are implicated in LVNC, understanding of the mechanisms responsible for human LVNC is limited. We screened the complete exome sequence database of the Pediatrics Cardiac Genomics Consortium and identified a cohort with a de novo CHD4 (chromodomain helicase DNA-binding protein 4) proband, CHD4M202I, with congenital heart defects. We engineered a humanized mouse model of CHD4M202I (mouse CHD4M195I). Histological analysis, immunohistochemistry, flow cytometry, transmission electron microscopy, and echocardiography were used to analyze cardiac anatomy and function. Ex vivo culture, immunopurification coupled with mass spectrometry, transcriptional profiling, and chromatin immunoprecipitation were performed to deduce the mechanism of CHD4M195I-mediated ventricular wall defects. CHD4M195I/M195I mice developed biventricular hypertrabeculation and noncompaction and died at birth. Proliferation of cardiomyocytes was significantly increased in CHD4M195I hearts, and the excessive trabeculation was associated with accumulation of ECM (extracellular matrix) proteins and a reduction of ADAMTS1 (ADAM metallopeptidase with thrombospondin type 1 motif 1), an ECM protease. We rescued the hyperproliferation and hypertrabeculation defects in CHD4M195I hearts by administration of ADAMTS1. Mechanistically, the CHD4M195I protein showed augmented affinity to endocardial BRG1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4). This enhanced affinity resulted in the failure of derepression of Adamts1 transcription such that ADAMTS1-mediated trabeculation termination was impaired. Our study reveals how a single mutation in the chromatin remodeler CHD4, in mice or humans, modulates ventricular chamber maturation and that cardiac defects associated with the missense mutation CHD4M195I can be attenuated by the administration of ADAMTS1.

P437 HEART AND RHEUMATOLOGICAL DISEASE: A PICTURE OF ACUTE HEART FAILURE

Abstract Systemic sclerosis is a connective tissue disease characterized by endothelial dysfunction, hyper reactivity of fibroblasts and immunity abnormality in both humoral and mediated cells. Clinically, in addition to the typical skin involvement, mainly the face and fingers, is frequent involvement of lungs, heart and kidneys. Cardiac involvement, in combination with lung involvement, is considered to be the most important determinant of the prognosis of these patients. Cardiac involvement occurs in 15– 35% of cases but in autopsy surveys the incidence reaches 80%. The case we present concerns a woman of 65 years, admitted in December at the Department of Cardiology of our AOU for an episode of low–output heart failure with epigastralgia, sweating, and breathlessness. The cardiological history was almost silent; instead, it presented a history of chronic thyroiditis and a recent infection with SARS COV 2. The objective examination presented hypokinesis of basal pulmonary fields and pitting edema. The blood tests showed an increase in myocardial necrosis, BNP, creatininemia and inflammatory indices (VES, PCR, beta 2 microglobulin, ferritin, fibrinogen), normocytic normochromic anemia, hypogammaglobulinemia, hyperuricemia and proteinuria and hematuria. The echocardiogram showed severe biventricular dysfunction and moderate–grade mitral insufficiency. A coronary examination was performed that showed epicardial coronary vessels free from significant injury. The cardiac magnetic resonance showed a widespread late enhancement subendocardial of the ventricular and atrial chambers with non–vascular distribution suggestive of pathology on an autoimmune basis. Upon closer examination, multiple small telangiectasias were observed in the face, slight hyperpigmentation of the chest and back, and swelling of the hands. The antibody panel showed positivity of ANA and anti Scl70. The patient was thus addressed to a multi–specialist management in which therefore cardiologist and rheumatologist compare and support the treatment of this pathology with the goal of reducing the high mortality and morbidity that characterizes systemic scleroderma with cardiac involvement.

P358 FATAL CONSPIRACY: MIDVENTRICULAR OBSTRUCTIVE HYPERTROPHIC CARDIOMYOPATHY COMPLICATED BY GIANT APICAL ANEURYSM AND SEVERE MITRAL REGURGITATION

Abstract This case refers to a 69–year–old woman with a history of hypertrophic cardiomyopathy (HCM) with severe mid–ventricular obstruction complicated by apical aneurysm and restrictive phenotype. This patient had no left ventricular outflow tract obstruction and previous examinations showed moderate mitral regurgitation (MR) with suboptimal echocardiographic follow–up. ICD was previously implanted for primary prevention. Disease progression was complicated by episodes of acute heart failure (HF) caused by atrial fibrillation/tachycardia (AF or AT) with rapid ventricular response despite pharmacological therapy and a transcatheter ablation attempt. The patient was admitted to our Cardiac Intensive Care Unit with acute pulmonary oedema and extreme general frailty. EKG showed normal sinus rhythm alternating with AT with high ventricular rate. Transthoracic (TTE) and transesophageal (TEE) echocardiograms gave evidence of severe hypertrophy of left ventricular (LV) mid–cavity segments (mid IVS = 26 mm) with mid–ventricular systolic obliteration (with no more evidence of significant gradient) and a large apical aneurysm (37x35 mm) resulting in an “hourglass” shaped LV cavity (Figure 1). In addition the examinations highlighted systolic dysfunction with severe stroke volume reduction and severe MR caused by annulus dilatation with anterior jet direction due to leaflets abnormal coaptation (Figure 2). HF was multifactorial, caused not only by MR and atrial tachyarrhythmias but also due to the abnormal large apical aneurysm and the small left ventricular chamber with low compliance. The anatomical features obtained from TEE and cardiac CT (Figure 3) were analyzed by the Heart Team. Surgery with aneurysmectomy and mitral valve repair or replacement was excluded due to patient‘s frailty. Despite the suboptimal valve and LV chamber anatomy, percutaneous mitral valve repair with MitraClip was considered but also deferred owing to the unstable hemodynamic conditions. Further hemodynamic deterioration led to the patient’s exitus. Discussion HCM with mid–ventricular obstruction may be complicated by apical aneurysm. Large apical aneurysms can reduce LV contractile efficiency and the combination with severe MR can cause further loss of anterograde cardiac output leading to a progressive and fatal deterioration. A better outcome can only be achieved through careful follow–up and early detection and management of disease complications.