Small Ventricle Research Articles

Ebstein's anomaly with coarctation of the aorta and a bicuspid aortic valve: a case report of a rare association with unique prenatal findings.

Ebstein's anomaly is rarely accompanied by coarctation of the aorta, although patients with Ebstein's anomaly have a relatively small left ventricle. Here, we report a rare case of Ebstein's anomaly with coarctation of the aorta and a bicuspid aortic valve. We compared the foetal echocardiographic parameters of five previous cases with Ebstein's anomaly without left heart obstruction to explore the association between left ventricular volume, Ebstein's anomaly severity, and left heart obstruction.

CMR predictors of acute right heart failure after LVAD implantation

Abstract Background Acute right heart failure (RHF) is one of the most dangerous complications after placement of left ventricular assisted device (LVAD), having a significant impact on prognosis, and is estimated to be around 3 to 35%. Even though right ventricular evaluation with hemodynamical and echocardiographic measurements is a key aspect prior to LVAD implantation, prediction of RHF remains a challenge in daily clinical practice. Purpose To identify cardiac magnetic resonance (CMR) predictors of RHF after LVAD placement. Methods We retrospectively enrolled patients referred to our centre for implantation who also underwent CMR scan prior to LVAD implantation. Acute RHF was defined according to Mechanical Circulatory Support Academy Research Consortium (MRC ARC) criteria. Baseline characteristics, preoperative laboratory, echocardiographic, right heart catheterization (RHC) and CMR parameters were obtained. Patients were divided into two groups based on the development of acute RHF. The variables showing significant differences between the two groups were analysed with the receiver operating characteristic (ROC) curves to find the best cut-offs and then combined into a risk score. Results We enrolled 54 patients who underwent continuous-centrifugal flow LVAD implantation from 2013 to 2021 in whom a CMR within median time of 30 days pre-implantation was available. Four patients were excluded due to low quality images. Among the final cohort of 50 patients, 15 (28%) developed acute RHF. Patients who developed RHF showed worse INTERMACS class, worse renal and liver function, higher central venous pressure at RHC, worse TAPSE at echocardiography and overall smaller left ventricles at the CMR analysis when compared to those who had not acute RHF. No CMR derived right ventricle parameters nor moderate to severe tricuspid regurgitation at echocardiography were different among the two groups. We found that CMR-derived LV mass indexed < 65 g/m2, left ventricular end diastolic diameter (LVEDD) < 70 mm, and LV eccentricity index >1,12 were independent predictors of acute RHF. A CMR-derived score with these three parameters was built (1 point for each). This CMR score has shown to be an independent predictor of acute RHF at multivariate analysis with an odds ratio of 7,084 (CI 95%1.614-37.734) when corrected for other clinical and instrumental predictors of acute RHF. Conclusions Our study proposes a simple scoring system based on three CMR- derived parameters (LVEDD, LV mass indexed and LV eccentricity index) to screen for acute RHF prior LVAD implantation. This score shows promise to be an independent predictor of acute RHF, even when adjusted for clinical, echocardiographic, and haemodynamic parameters. Our model is built on CMR measurement of the LV, showing how patients with smaller ventricles and a left displacement of the interventricular septum (expressed with a higher LV eccentricity index) are at higher risk of developing acute RHF.ROC curves

Staged ventricular recruitment following single-ventricular palliation in unbalanced atrioventricular septal defect with heterotaxy syndrome.

A newborn with unbalanced atrioventricular septal defect and heterotaxy syndrome underwent early surgeries for single-ventricular palliation due to a small left ventricle. Following procedures, including the modified Damus-Kaye-Stansel, there was a notable increase in left ventricular size. This progression allowed successful biventricular repair at 7 months. This case highlights potential ventricular development after palliative procedures in patients with borderline ventricular size.

The clinical significance of lack of hindbrain herniation in fetal myelomeningocele/myeloschisis patients.

Hindbrain herniation (HH) is a clinical prerequisite for prenatal repair of myelomeningocele/myeloschisis; however, a subset of patients lack HH on initial fetal imaging and may ultimately progress to exhibit herniation on subsequent prenatal or postnatal imaging. The authors sought to explore the cohort of patients without HH at the time of initial fetal consultation for myelomeningocele/myeloschisis repair to define their clinical characteristics and outcome. From July 2016 to July 2022, patients evaluated at the Children's Hospital of Philadelphia Center for Fetal Diagnosis and Treatment for myelomeningocele/myeloschisis were classified into two cohorts: those with and those without HH. The diagnosis of HH was obtained from prenatal and postnatal MRI. The osseous lesion level, prenatal sac volume, and prenatal ventricular size was obtained from fetal ultrasound. The fronto-occipital horn ratio was measured on the first postnatal ultrasound. Ambulation status was obtained from postnatal evaluation in the spina bifida clinic. A total of 176 patients with prenatal HH had postnatal follow-up, of whom 95 (54%) had HH resolution and 81 (46%) had herniation persistence. Of 73 patients without prenatal HH, 9 (12%) had herniation on subsequent prenatal imaging while 64 (88%) had no herniation on prenatal imaging. Of these 64 patients, 11 (17%) had postnatal HH, 32 (50%) had no postnatal herniation, and 21 (33%) were lost to follow-up or the pregnancy was terminated. For patients without HH throughout, the sac volume was larger (9 cm3) than those who had herniation progression or initial herniation; however, the rate of talipes was not significantly different among the groups. The majority of patients were also ambulators (with assistive devices or independent), and the atrial diameter was also < 10 mm for most patients. Overall, 53% of those with initial HH compared with 35% with progression of herniation required CSF diversion, while only 25% of those without herniation required diversion. This study demonstrates the natural history of HH in patients with a prenatal diagnosis of myelomeningocele/myeloschisis. The majority of patients without any herniation had larger sac sizes but not higher rates of talipes and smaller ventricles and were ambulatory. These findings improve the ability to guide families during prenatal consultation.

Intraoperative cone-beam computed tomography for catheter placement verification in pediatric hydrocephalus: technical note.

Ventriculoperitoneal (VP) shunt placement, essential for managing hydrocephalus, often risks catheter malpositioning, especially in patients with small ventricles. We present a novel technique combining neuronavigation with intraoperative cone-beam computed tomography using the BrainLab system and Loop-X mobile imaging unit. This approach enables real-time verification of catheter placement by integrating preoperative MRI data with intraoperative CT imaging. In a 12-year-old boy with therapy-refractory idiopathic intracranial hypertension, neuronavigation was guided by the BrainLab Skull Fix and Cushing canula, ensuring precise catheter insertion into the right frontal horn. Post-placement, Loop-X facilitated immediate verification of the catheter's trajectory and positioning, corroborated by postoperative MRI. This technique demonstrated high precision and minimized radiation exposure, emphasizing its utility in reducing revision rates due to suboptimal catheter placement.

Atrioventricular Area Difference Aids Diastolic Filling in Patients with Repaired Tetralogy of Fallot.

A hydraulic force aids diastolic filling of the left ventricle (LV) and is proportional to the difference in short-axis area between the left ventricle and atrium; the atrioventricular area difference (AVAD). Patients with repaired Tetralogy of Fallot (rToF) and pulmonary regurgitation (PR) have reduced LV filling which could lead to a negative AVAD and a hydraulic force impeding diastolic filling. The aim was to assess AVAD and to determine whether the hydraulic force aids or impedes diastolic filling in patients with rToF and PR, compared to controls. Twelve children with rToF (11.5 [9-13] years), 12 pediatric controls (10.5 [9-13] years), 12 adults with rToF (21.5 [19-27] years) and 12 adult controls (24 [21-29] years) were retrospectively included. Cine short-axis images were acquired using cardiac magnetic resonance imaging. Atrioventricular area difference was calculated as the largest left ventricular short-axis area minus the largest left atrial short-axis area at beginning of diastole and end diastole and indexed to height (AVADi). Children and adults with rToF and PR had higher AVADi (0.3 cm2/m [-1.3 to 0.8] and -0.6 [-1.5 to -0.2]) at beginning of diastole compared to controls (-2.7 cm2/m [-4.9 to -1.7], p = 0.015) and -3.3 cm2/m [-3.8 to -2.8], p = 0.017). At end diastole AVADi did not differ between patients and controls. Children and adults with rToF and pulmonary regurgitation have an atrioventricular area difference that do not differ from controls and thus a net hydraulic force that contributes to left ventricular diastolic filling, despite a small underfilled left ventricle due to pulmonary regurgitation.

Analysis of echocardiographic features and postnatal management of fetal pulmonary valve stenosis

Objective: To investigate the echocardiographic features, consistency of diagnosis between fetal and postnatal periods and postnatal clinical outcomes of fetal pulmonary valve stenosis (PS) with different degrees. Methods: This study was a retrospective cohort study comprising 108 cases of fetal PS diagnosed during the fetal period and followed up postnatally at Xinhua Hospital, Shanghai Jiaotong University School of Medicine from November 2012 to February 2023. Echocardiographic characteristics, including morphological and hemodynamic features were collected for all fetuses who were then were followed up to at least 6 months after birth. One-way analysis of variance and Kruskal-Wallis test were used to compare the differences in the echocardiographic features among fetuses with different degrees of PS. Subsequently, McNemar test was used to assess the consistency of diagnosis between the fetal and postnatal periods. Furthermore, Logistic regression analysis was applied to explore the risk factors for neonatal intervention in fetuses with moderate PS and the receiver operating characteristic (ROC) curve was utilized to ascertain the optimal cut-off value for continuous variables. Results: The age of the mothers of the 108 fetuses at the initial assessment was (30.8±4.0) years, and the gestational age was 26.5 (24.6, 30.0) weeks. The fetuses were categorized into mild (17 cases), moderate (49 cases), and severe groups (42 cases) based on the initial echocardiographic features. Mild PS was characterized by valve thickening and hyperechogenicity combined with systolic flow acceleration or dilation of main pulmonary artery. Moderate PS exhibited both restricted valve motion and a colorful blood flow pattern at the valve orifice. The peak flow velocities of fetuses with moderate and critical PS were notably higher than those in the mild group ((2.66±0.86) and (2.77±1.30) vs. (1.43±0.59)m/s, F=14.52, P<0.001). In critical PS, all cases showed retrograde ductal flow, with a significantly higher proportion of a small right ventricle compared to the mild and moderate PS (42.9% (18/42) vs. 0 and 2.0% (1/49), χ2=31.73, P<0.001). The proportion of severe tricuspid regurgitation was also higher (35.7% (15/42) vs. 0 and 10.2% (5/49), χ2=36.94, P<0.001). Compared to mild and severe PS, the consistency of diagnosis between fetal and postnatal periods in moderate PS was lower (40.8% (20/49) vs.13/17 and 80.3% (35/42), χ2=12.45, P=0.006). The systolic flow velocity was identified as an independent risk factor for neonatal intervention in fetuses with moderate PS (OR=7.21, 95%CI2.11-24.62). A flow velocity of ≥2.18 m/s in second trimester and ≥3.15 m/s in third trimester indicated the necessity of neonatal intervention for fetal moderate PS. Among the 108 fetuses, 68 underwent surgical intervention and all survived. Additionally, 39 fetuses were regularly followed up. A sole non-surgical fatality occurred, leading to a 6-month survival rate of 99.1% (107/108). Conclusions: Various degrees of fetal PS demonstrate distinctive morphological and hemodynamic alterations in echocardiography. The disparity in severity between the postnatal and fetal stages requires ongoing monitoring for fetal PS. The prognosis for fetal PS is generally favorable.

Abnormal Shape and Size of the Cardiac Ventricles Are Associated with a Higher Risk of Neonatal Death in Fetuses with Isolated Left Congenital Diaphragmatic Hernia

Introduction: The objective of this study was to evaluate the association between fetal cardiac deformation analysis (CDA) and cardiac function with severe adverse perinatal outcomes in fetuses with isolated left congenital diaphragmatic hernia (CDH). Methods: CDA in each ventricle (contractility, size, and shape), evaluated by speckle tracking and novel FetalHQ software, and markers of cardiac function (E/A ratios, pulmonary and aortic peak systolic velocities, and sigmoid annular valve diameters), were evaluated in fetuses with isolated left CDH. Two evaluations were performed: at referral (CDA and function) and within 3 weeks of delivery (CDA). Severe adverse neonatal outcomes were considered neonatal death (ND) or survival with CDH-associated pulmonary hypertension (CDH-PH). Differences and associations between CDA, cardiac function, and severe adverse outcomes were estimated. Results: Fifty fetuses were included, and seventeen (34%) had severe adverse neonatal outcomes (11 ND and 6 survivors with CDH-PH). At first evaluation, the prevalence of a small left ventricle was 34% (17/50) with a higher prevalence among neonates presenting severe adverse outcomes (58.8 [10/17] vs. 21.2% [7/33]; p = 0.01; OR, 5.03 [1.4–19.1; p = 0.01]) and among those presenting with neonatal mortality (8/11 [72.7] vs. 9/39 [23.0%]; p = 0.03; OR, 8.9 [1.9–40.7; p = 0.005]). No differences in cardiac function or strain were noted between fetuses with or without severe adverse outcomes. Within 3 weeks of delivery, the prevalence of small left ventricle was higher (19/34; 55.8%) with a more globular shape (reduced transverse/longitudinal ratio). A globular right ventricle was significantly associated with ND or survival with CDH-PH (OR, 14.2 [1.5–138.3]; p = 0.02). Conclusion: Fetuses with isolated CDH at risk of perinatal death or survival with CDH-PH had a higher prevalence of a small left ventricle and abnormal shape of the right ventricle.

Acute Hemodynamic Compromise After Transcatheter Aortic Valve Replacement Due to Dynamic Left Ventricle Obstruction: A Systematic Review

Acute hemodynamic compromise post-TAVR due to dynamic left ventricle obstruction (LVO), also known as “Suicide left ventricle” is an infrequent but severe complication of transcatheter aortic valve replacement (TAVR) that is poorly defined in the literature.Understanding this complication is essential for its prompt diagnosis and optimal treatment.We conducted a systematic literature review using PubMed, Embase, Web of Science and Medline databases for studies describing acute hemodynamic compromise post-TAVR due to dynamic LVO or suicide left ventricle. Each study was reviewed by two authors individually for eligibility, and a third author resolved disagreements.From a total of 506 studies, 25 publications were considered for the final analysis. The majority of patients suffering from this condition were women, demonstrating a hypertrophic septum, a small ventricle, and hyperdynamic contractility on pre-TAVR echocardiographic assessment. An intraventricular gradient pre-TAVR was found in half of the cases. Acute hemodynamic compromise post-TAVR due to dynamic LVO manifested mainly as significant hypotension and occurred most often immediately after valve deployment. The left ventricle outflow tract (LVOT) was the most common site of obstruction. Advanced therapies were required in nearly 65% of the cases.In conclusion, acute hemodynamic compromise post-TAVR due to dynamic LVO occurred almost invariably in women. Echocardiography prior to TAVR may offer essential information to anticipate this complication. LVOT obstruction appears to carry the highest risk of developing this phenomenon. Advanced therapies should be promptly considered as a bailout strategy in patients with hemodynamic collapse refractory to medical therapy.

Associations Between TREML2 Gene Variants and Alzheimer's Disease: Biomarkers, Neuroimage, and Cognition.

Recent genetic research identified a protective factor against late-onset Alzheimer's disease (AD) in Caucasians, a variant called rs3747742-C in the TREML2 gene. However, the roles of other TREML2 variants in AD have not been fully explored. We conducted a focused analysis of 16 TREML2 variants, examining their connection to AD by studying their correlation with cerebrospinal fluid (CSF) proteins, neuroimage, and cognition in the Alzheimer's Disease Neuroimaging Initiative database (ADNI). A multiple linear regression model was utilized to estimate potential associations between TREML2 genotypes and various endophenotypes in the entire ADNI sample at baseline, with age, gender, years of education, and APOE ɛ4 status included as covariates. To examine changes in clinical outcomes over time, linear mixed-effects models were employed. We found that the SNP rs17328707-A was associated with higher ADNI-VS scores, smaller ventricles, and larger middle temporal volume at baseline. The SNP rs6915083-G was linked to lower CSF t-tau and p-tau levels, and higher CSF Aβ levels. The SNP rs9394766-G was associated with a smaller hippocampus and larger ventricles at baseline. In longitudinal cohorts, the rs6915083-G SNP was associated with changes in ADNI-MEM and ADNI-EF scores, as well as the rate of hippocampal and middle temporal atrophy. Our findings reveal that TREML2 gene variants have different effects on AD. Two variants are protective, while one may be a risk factor. This enhances our understanding of AD genetics and could guide future research and personalized treatments.

SCO-spondin knockout mice exhibit small brain ventricles and mild spine deformation

Reissner’s fiber (RF) is an extracellular polymer comprising the large monomeric protein SCO-spondin (SSPO) secreted by the subcommissural organ (SCO) that extends through cerebrospinal fluid (CSF)-filled ventricles into the central canal of the spinal cord. In zebrafish, RF and CSF-contacting neurons (CSF-cNs) form an axial sensory system that detects spinal curvature, instructs morphogenesis of the body axis, and enables proper alignment of the spine. In mammalian models, RF has been implicated in CSF circulation. However, challenges in manipulating Sspo, an exceptionally large gene of 15,719 nucleotides, with traditional approaches has limited progress. Here, we generated a Sspo knockout mouse model using CRISPR/Cas9-mediated genome-editing. Sspo knockout mice lacked RF-positive material in the SCO and fibrillar condensates in the brain ventricles. Remarkably, Sspo knockout brain ventricle sizes were reduced compared to littermate controls. Minor defects in thoracic spine curvature were detected in Sspo knockouts, which did not alter basic motor behaviors tested. Altogether, our work in mouse demonstrates that SSPO and RF regulate ventricle size during development but only moderately impact spine geometry.

Three-dimensional-printed heart model can determine univentricular repair strategy in borderline double-outlet right ventricle

BackgroundAs double-outlet right ventricle has a wide pathophysiology spectrum, its comprehensive treatment strategy is determined based on relevant factors, such as the location and size of the ventricular septal defect, ventricular volume, and relationship of the great arteries. However, for borderline double-outlet right ventricle cases, it is occasionally difficult to decide the treatment strategy preoperatively. Recently, advances in 3D printing technology based on computed tomography have enabled the creation of 3D heart models of congenital heart disease that can precisely reproduce the anatomical structure of each patient even for complex anomalies. Herein, we describe a young patient in whom univentricular repair could be decided after confirming the 3D heart model and intracardiac structure under direct vision.Case presentationWe describe a 3-year-old girl who was diagnosed with double-outlet right ventricle and severe pulmonary valve stenosis at birth and who underwent a left modified Blalock–Taussig shunt at 2 years of age. Preoperative examination revealed a borderline condition for biventricular repair characterized by a small left ventricle volume and side-by-side relationship of the great artery. After a preoperative discussion using a 3D heart model, we concurred that an intraoperative assessment would be made as to whether biventricular repair was possible or not. After confirming the intracardiac structure under direct vision, we assessed that intraventricular rerouting was not possible owing to the high risk of subvalvular aortic stenosis as there was no tissue that could be incised between the right ventricular free wall and the primary interventricular foramen, as indicated in the 3D heart model. Thus, atrial septostomy and Glenn anastomosis were performed.ConclusionsWe report a 3-year-old girl with a borderline double-outlet right ventricle in whom a univentricular repair strategy could be decided after confirming the 3D heart model and intracardiac structure under direct vision. A 3D-printed heart model can be useful in patients whose repair strategy is difficult to judge for the borderline double-outlet right ventricle.

Abstract 16850: Suicide Left Ventricle After Transcatheter Aortic Valve Replacement. A Systematic Review

Introduction: Suicide left ventricle (LV) is an infrequent but severe complication of transcatheter aortic valve replacement (TAVR) that is poorly defined. It is generally referred to as hemodynamic collapse following valve deployment due to acute LV dynamic obstruction. Understanding this complication is essential for its prompt diagnosis and treatment. Methods: We conducted a systematic literature review for studies describing suicide LV (i.e., severe hypotension causing hemodynamic collapse and/or end-organ failure in the setting of a new or worsened dynamic intraventricular gradient after TAVR). Two authors reviewed each study for eligibility, and a third author resolved disagreements. Results: Of 506 studies, 27 publications were considered for the final analysis. Most patients that met the inclusion criteria of suicide LV were women (96%), demonstrating a small ventricle (70%), a hypertrophic septum (81%), and hyperdynamic contractility (50%) on pre-TAVR echocardiographic assessment. An intraventricular gradient pre-TAVR was found in half of the cases. Suicide LV manifested as severe hypotension occurred most often immediately after valve deployment. The LV outflow tract was the most common site of obstruction (85%) (i.e., LVOTO), compared to midventricular obstruction (MVO). Advanced therapies were required in nearly 70% of the cases. The most common advanced therapies were alcohol septal ablation and ventricular pacing. Conclusions: LV suicide after TAVR occurred almost invariably in women. The use of echocardiography before TAVR may be essential to anticipate this complication. Although previous studies report MVO being a more common site of dynamic intraventricular gradient after TAVR, LVOTO appears to carry the highest risk of suicide LV. Further research is required to predict better the risk of suicide LV to improve the ability to perform a bailout strategy in patients with hemodynamic collapse refractory to medical therapy.

Benchtop Models of Patient-Specific Intraventricular Flow During Heart Failure and LVAD Support.

The characterization of intraventricular flow is critical to evaluate the efficiency of fluid transport and potential thromboembolic risk but challenging to measure directly in advanced heart failure (HF) patients with left ventricular assist device (LVAD) support. The study aims to validate an in-house mock loop (ML) by simulating specific conditions of HF patients with normal and prosthetic mitral valves (MV) and LVAD patients with small and dilated left ventricle volumes, then comparing the flow-related indices result of vortex parameters, residence time (RT), and shear-activation potential (SAP). Patient-specific inputs for the ML studies included heart rate, end-diastolic and end-systolic volumes, ejection fraction, aortic pressure, E/A ratio, and LVAD speed. The ML effectively replicated vortex development and circulation patterns, as well as RT, particularly for HF patient cases. The LVAD velocity fields reflected altered flow paths, in which all or most incoming blood formed a dominant stream directing flow straight from the mitral valve to the apex. RT estimation of patient and ML compared well for all conditions, but SAP was substantially higher in the LVAD cases of the ML. The benchtop system generated comparable and reproducible hemodynamics and fluid dynamics for patient-specific conditions, validating its reliability and clinical relevance. This study demonstrated that ML is a suitable platform to investigate the fluid dynamics of HF and LVAD patients and can be utilized to investigate heart-implant interactions.

Sin3a associated protein 130kDa, sap130, plays an evolutionary conserved role in zebrafish heart development.

Hypoplastic left heart syndrome (HLHS) is a congenital heart disease where the left ventricle is reduced in size. A forward genetic screen in mice identified SIN3A associated protein 130kDa (Sap130), part of the chromatin modifying SIN3A/HDAC complex, as a gene contributing to the etiology of HLHS. Here, we report the role of zebrafish sap130 genes in heart development. Loss of sap130a, one of two Sap130 orthologs, resulted in smaller ventricle size, a phenotype reminiscent to the hypoplastic left ventricle in mice. While cardiac progenitors were normal during somitogenesis, diminution of the ventricle size suggest the Second Heart Field (SHF) was the source of the defect. To explore the role of sap130a in gene regulation, transcriptome profiling was performed after the heart tube formation to identify candidate pathways and genes responsible for the small ventricle phenotype. Genes involved in cardiac differentiation and cardiac function were dysregulated in sap130a, but not in sap130b mutants. Confocal light sheet analysis measured deficits in cardiac output in MZsap130a supporting the notion that cardiomyocyte maturation was disrupted. Lineage tracing experiments revealed a significant reduction of SHF cells in the ventricle that resulted in increased outflow tract size. These data suggest that sap130a is involved in cardiogenesis via regulating the accretion of SHF cells to the growing ventricle and in their subsequent maturation for cardiac function. Further, genetic studies revealed an interaction between hdac1 and sap130a, in the incidence of small ventricles. These studies highlight the conserved role of Sap130a and Hdac1 in zebrafish cardiogenesis.

Heart Failure with Preserved Left Ventricular Ejection Fraction: A Complex Conundrum Simply Not Limited to Diastolic Dysfunction.

Over the last two decades, the changing paradigm of heart failure with preserved ejection fraction (HFpEF) has transformed our understanding not only of the pathophysiology of this clinical entity but also the diagnostic and therapeutic approaches aimed at treating this complex patient population. No longer HFpEF should be seen as simply left ventricular diastolic dysfunction but as a group of that in addition of having small and thick left ventricles with abnormal diastolic filling patterns as their main pathophysiologic abnormality; they also have whole host of different abnormalities. In fact, this heterogeneous clinical entity embodies numerous mechanisms and is linked to multiorgan dysfunction, with hypertension and obesity playing a major role. Although we have gained an enormous amount of understanding not only on the causes but also the downstream effects of HFpEF, there is still much to be learned before we can fully comprehend this complex clinical entity. It is the main intention of this review to synthesize the most recent attributes, mechanism, diagnostic tools, and most useful therapeutic alternatives to be considered when evaluating patients either complaining of dyspnea on exertion as well as exercise intolerance or those recently admitted with HF symptoms but with normal LVEF in the absence of any other valvular abnormalities.

SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission.

SLC4A10 is a plasma-membrane bound transporter that utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of CSF. Using next generation sequencing on samples from five unrelated families encompassing nine affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorder including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioural abnormalities including delayed habituation and alterations in the two-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggest an important role of SLC4A10 in the production of the CSF. However, it is notable that despite diverse roles of the CSF in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies, which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10-/- mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties.

More than just a small left ventricle: the right ventricular fibroblast and ECM in health and disease.

Fibroblasts intricately organize and regulate the extracellular matrix (ECM) in cardiac health and disease. Excess deposition of ECM proteins causes fibrosis, resulting in disrupted signaling conduction and contributing to the development of arrhythmias and impaired cardiac function. Fibrosis is causally involved in cardiac failure in the left ventricle (LV). Fibrosis likely occurs in right ventricle (RV) failure, yet mechanisms remain unclear. Indeed, RV fibrosis is poorly understood with mechanisms often extrapolated from the LV to the RV. However, emerging data suggest that the LV and RV are distinct cardiac chambers and differ in regulation of the ECM and response to fibrotic stimuli. In the present review, we will discuss differences in ECM regulation in the healthy RV and LV. We will discuss the importance of fibrosis in the development of RV disease in pressure overload, inflammation, and aging. During this discussion, we will highlight mechanisms of fibrosis with respect to the synthesis of ECM proteins while acknowledging the importance of considering collagen breakdown. We will also discuss current knowledge of antifibrotic therapies in the RV and the need for additional research to help delineate the shared and distinct mechanisms of RV and LV fibrosis.

P109: Influence Of Body Surface Area, And Ventricular Dimensions On Impella 5.5 Outcomes

Background: There has been an increase in the use of the Impella 5.5 pump for patients with refractory cardiogenic shock in a number of different patient scenarios. There is a scarcity of data on the influence of patient Body Surface Area (BSA) and ventricular dimensions prior to implant on overall pump efficiency, safety, and outcomes. Methods: Patients undergoing Impella 5.5 implantation at a single institution between August 2020 and November 2022 were included. Patient BSA was collected at the time of pump implantation, as well as ventricular dimensions from the pre-Impella echocardiography or cardiac MRI. Other clinical data included death within 30 days, and other demographic variables, as well as suspected hemolysis defined as an LDH value of over 1000 IU/L. Left Ventricular Diastolic and Systolic Dimensions (LVEDD, LVESD) were indexed by dividing them by the BSA as iLVEDD and iLVESD, respectively. Results: One hundred patients with complete data were reviewed, of which, the analysis was limited to patients with chronic heart failure (n=75). The median LVESD was 5.8 cm (IQR 4.5, 6.2), and LVEDD 6.3 cm (5.3, 6.8). 17 patients (23%) died within 30 days of Impella implantation, with no difference in gender, age, BSA, or occurrence of hemolysis in those that died vs alive at 30 days. Patients that died within 30 days had smaller indexed LVEDD (2.6 vs 2.93, p=0.01), and smaller indexed LVESD (2.14 vs 2.79, p=0.002). Conclusion: Patients with smaller indexed LVEDD and indexed LVESD at time of Impella implantation have a higher risk of 30 day mortality that appears to be independent of hemolysis risk. This maybe due to less efficient pump function in small ventricles in higher BSA individuals requiring higher levels of forward flow.

Cardiac toxicity of phenanthrene depends on developmental stage in Atlantic cod (Gadus morhua)

Complex mixtures like crude oil, and single components such as Phenanthrene (Phe), induce cardiotoxicity by interfering with excitation-contraction coupling. However, recent work has demonstrated that the timing of pollutant exposure during embryogenesis greatly impacts the degree of cardiac dysfunction caused. Here, we aimed to clarify the temporal dependence of Phe toxicity and the downstream effects of cardiac dysfunction using Atlantic cod (Gadus morhua). Phe (nominal concentration, 1.12 μmol/L), or the L-type‑calcium channel blocker Nicardipine (Nic) (nominal concentration, 2 and 4 μmol/L), were individually applied to cod embryos either during cardiogenesis (early) or after the onset of cardiac function (late). Phe toxicity was highly dependent on the timing of exposure. Exposure after the onset of cardiac function (i.e. late) caused more severe cardiac and extracardiac abnormalities at 3 days post hatching (dph) than early exposure. Late Phe exposure resulted in a smaller ventricle, eliminated ventricular contraction, and reduced atrial contraction. In contrast, early Phe exposure did not have an effect on cardiac development and function. This temporal difference was not as evident in the Nic treatment. Early Nic exposure created similar morphological phenotypes to the late Phe exposure. The two treatments (early Nic and late Phe) also shared a cardiofunctional phenotype, comprised of eliminated ventricular, and reduced atrial, contraction. These data suggest that extracardiac abnormalities, such as the craniofacial deformities seen after late embryonic exposure to cardiotoxic oil components and mixtures, are mostly downstream effects of cardiac dysfunction.