Physiology Of Heart Research Articles

Heart function enhancement with Nrf2-activating antioxidant in acute Y-strain Chagas disease, not in chronic Colombian or Y-strain.

Oxidative stress promotes T. cruzi growth and development of chronic Chagas heart dysfunction. However, the literature contains gaps that must be fulfilled, largely due to variations in parasite DTU sources, cell types, mouse strains, and tools to manipulate redox status. We assessed the impact of oxidative environment on parasite burden in cardiomyoblasts and the effects of the Nrf2-inducer COPP on heart function in BALB/c mice infected with either DTU-II Y or DTU-I Colombian T. cruzi strains. Treatment with antioxidants CoPP, apocynin, resveratrol, and tempol reduced parasite burden in cardiomyoblasts H9C2 for both DTUI- and II-strains, while H2O2 increased it. CoPP treatment improved electrical heart function when administered during acute stage of Y-strain infection, coinciding with an overall trend towards increased survival and reduced heart parasite burden. These beneficial effects surpassed those of trypanocidal benznidazole, implying that CoPP directly affects heart physiology. CoPP treatment had beneficial impact on heart systolic function when performed during acute and evaluated during chronic stage. No impact of CoPP on heart parasite burden, electrical, or mechanical function was observed during the chronic stage of Colombian-strain infection, despite previous demonstrations of improvement with other antioxidants. Treatment with CoPP also did not improve heart function of mice chronically infected with Y-strain. Our findings indicate that amastigote growth is responsive to changes in oxidative environment within heart cells regardless of the DTU source, but CoPP influence on heart parasite burden in vivo and heart function is mostly confined to the acute phase. The nature of the antioxidant employed, T. cruzi DTU, and the stage of disease, emerge as crucial factors to consider in heart function studies.

Epitranscriptomic regulation of cardiac fibrosis via YTHDF1-dependent PIEZO2 mRNA m6A modification.

Mechanosensitive ion channels play a key role in heart development, physiology, and disease. However, little is known about the molecular mechanisms of the mechanosensitive nonselective cationic channel Piezo family in cardiac fibrosis. Mice were treated with ISO/Ang-II/TAC to induce cardiac fibrosis. AAV9 carrying POSTN promoter-driven small hairpin RNA targeting YTHDF1, and Piezo2 were administered to ISO mice to investigate their roles in cardiac fibrosis. RNA-seq, single-cell sequencing, and histological and biochemical analyses were performed to determine the mechanism by which YTHDF1 regulates Piezo2 expression in cardiac fibrosis. Piezo2 was reconstituted in YTHDF1-deficient cardiac fibroblasts and mouse hearts to study its effects on cardiac fibroblast autophagy and fibrosis. Piezo2 but not Piezo1 expression increased in experimental cardiac fibrosis and TGF-β1-induced cardiac fibroblasts. Fibroblast-specific Piezo2 deficiency ameliorated fibroblast activation and autophagy and inhibited cardiac fibrosis. Mechanistically, Piezo2 upregulation was associated with elevated m6A mRNA levels. Site-specific m6A modifications at peak_26355 were crucial for regulating the binding of YTHDF1 to Piezo2 mRNA and inducing Piezo2 translation. Notably, Piezo2 epitranscriptomic repression ameliorated experimental cardiac fibrosis. We demonstrated a novel epitranscriptomic mechanism through which YTHDF1 recognizes Piezo2 and controls cardiac fibroblast autophagy and fibrosis through m6A-dependent modulation. Our findings provide new insights for the development of preventive measures for cardiac fibrosis.

Latrophilin-2 Deletion in Cardiomyocyte Disrupts Cell Junction, Leading to D-CMP.

Latrophilin-2 (Lphn2), an adhesive GPCR (G protein-coupled receptor), was found to be a specific marker of cardiac progenitors during the differentiation of pluripotent stem cells into cardiomyocytes or during embryonic heart development in our previous studies. Its role in adult heart physiology, however, remains unclear. The embryonic lethality resulting from Lphn2 deletion necessitates the establishment of cardiomyocyte-specific, tamoxifen-inducible Lphn2 knockout mice, which was achieved by crossing Lphn2flox/flox mice with mice having MerCreMer (tamoxifen-inducible Cre recombinase) under the α-myosin heavy chain promoter. Tamoxifen treatment for several days completely suppressed Lphn2 expression, specifically in the myocardium, and induced the dilated cardiomyopathy (D-CMP) phenotype with serious arrhythmia and sudden death in a short period of time. Transmission electron microscopy showed mitochondrial abnormalities, blurred Z-discs, and dehiscent myofibrils. The D-CMP phenotype, or heart failure, worsened during myocardial infarction. In a mechanistic study of D-CMP, Lphn2 knockout suppressed PGC-1α and mitochondrial dysfunction, leading to the accumulation of reactive oxygen species and the global suppression of junctional molecules, such as N-cadherin (adherens junction), DSC-2 (desmocollin-2; desmosome), and connexin-43 (gap junction), leading to the dehiscence of cardiac myofibers and serious arrhythmia. In an experimental therapeutic trial, activators of p38-MAPK, which is a downstream signaling molecule of Lphn2, remarkably rescued the D-CMP phenotype of Lphn2 knockout in the heart by restoring PGC-1α and mitochondrial function and recovering global junctional proteins. Lphn2 is a critical regulator of heart integrity by controlling mitochondrial functions and cell-to-cell junctions in cardiomyocytes. Its deficiency leads to D-CMP, which can be rescued by activators of the p38-MAPK pathway.

The Effect of Cardiac Rehabilitation in Paediatric Fontan Circulation Patients: A Prospective Intervention Study.

Background and Objectives: The Fontan procedure, a palliative surgery for univentricular heart physiology, often reduces exercise capacity and quality of life. This study aimed to evaluate the impact of cardiac rehabilitation (CR) on improving outcomes in Fontan patients to inform evidence-based care. Materials and Methods: Fontan patients aged 8-30 participated in a structured CR program for at least three months. The program included weekly aerobic and resistance training sessions with educational and nutritional guidance. Baseline and post-CR assessments included cardiac function, fitness, daily activity, and health-related quality of life (HRQOL). Results: The cohort included ten Fontan patients, of whom six had a right systemic ventricle. CR significantly improved cardiorespiratory fitness, as seen in VO2 max (from 27.92 ± 5.15 to 34.69 ± 1.14 mL/kg/min, p = 0.0089) and percent predicted VO2 (from 0.67 ± 0.18 to 0.90 ± 0.02, p = 0.005). VCO2 increased by +8.68 ± 8.59 mL/kg/min but did not reach statistical significance (p = 0.05). Most haemodynamic and ventilatory parameters showed no significant improvement. All the SF-36 questionnaire domains showed significant HRQOL gains (p < 0.001). High adherence (85-93%), no adverse events, and reduced NT-proBNP levels supported the program's safety. Conclusions: This study's findings have important implications for the care of Fontan patients. CR significantly improved exercise capacity and HRQOL in Fontan patients across various anatomies, particularly in the right systemic ventricle. Integrating physical conditioning into standard care could reduce long-term morbidity and mortality; however, further research is needed to refine the protocols and confirm sustained benefits.

The Interplay between Mechanoregulation and ROS in Heart Physiology, Disease, and Regeneration.

Cardiovascular diseases are currently the most common cause of death in developed countries. Due to lifestyle and environmental factors, this problem is only expected to increase in the future. Reactive oxygen species (ROS) are a key player in the onset of cardiovascular diseases but also have important functions in healthy cardiac tissue. Here, the interplay between ROS generation and cardiac mechanical forces is shown, and the state of the art and a perspective on future directions are discussed. To this end, an overview of what is currently known regarding ROS and mechanosignaling at a subcellular level is first given. There the role of ROS in mechanosignaling as well as the interplay between both factors in specific organelles is emphasized. The consequences at a larger scale across the population of heart cells are then discussed. Subsequently, the roles of ROS in embryogenesis, pathogenesis, and aging are further discussed, exemplifying some aspects of mechanoregulation. Finally, different models that are currently in use are discussed to study the topics above.

Science of left ventricular unloading.

The concept of left ventricular unloading has its foundation in heart physiology. In fact, the left ventricular mechanics and energetics represent the cornerstone of this approach. The novel sophisticated therapies for acute heart failure, particularly mechanical circulatory supports, strongly impact on the mechanical functioning and energy consuption of the heart, ultimately affecting left ventricle loading. Notably, extracorporeal circulatory life support which is implemented for life-threatening conditions, may even overload the left heart, requiring additional unloading strategies. As a consequence, the understanding of ventricular overload, and the associated potential unloading strategies, founds its utility in several aspects of day-by-day clinical practice. Emerging clinical and pre-clinical research on left ventricular unloading and its benefits in heart failure and recovery has been conducted, providing meaningful insights for therapeutical interventions. Here, we review the current knowledge on left ventricular unloading, from physiology and molecular biology to its application in heart failure and recovery.

RNA Helicase DDX5 Maintains Cardiac Function by Regulating CamkIIδ Alternative Splicing.

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. RNA-binding proteins are identified as regulators of cardiac disease; DDX5 (dead-box helicase 5) is a master regulator of many RNA processes, although its function in heart physiology remains unclear. We assessed DDX5 expression in human failing hearts and a mouse HF model. To study the function of DDX5 in heart, we engineered cardiomyocyte-specific Ddx5 knockout mice. We overexpressed DDX5 in cardiomyocytes using adeno-associated virus serotype 9 and performed transverse aortic constriction to establish the murine HF model. The mechanisms underlined were subsequently investigated using immunoprecipitation-mass spectrometry, RNA-sequencing, alternative splicing analysis, and RNA immunoprecipitation sequencing. We screened transcriptome databases of murine HF and human dilated cardiomyopathy samples and found that DDX5 was significantly downregulated in both. Cardiomyocyte-specific deletion of Ddx5 resulted in HF with reduced cardiac function, an enlarged heart chamber, and increased fibrosis in mice. DDX5 overexpression improved cardiac function and protected against adverse cardiac remodeling in mice with transverse aortic constriction-induced HF. Furthermore, proteomics revealed that DDX5 is involved in RNA splicing in cardiomyocytes. We found that DDX5 regulated the aberrant splicing of Ca2+/calmodulin-dependent protein kinase IIδ (CamkIIδ), thus preventing the production of CaMKIIδA, which phosphorylates L-type calcium channel by serine residues of Cacna1c, leading to impaired Ca2+ homeostasis. In line with this, we found increased intracellular Ca2+ transients and increased sarcoplasmic reticulum Ca2+ content in DDX5-depleted cardiomyocytes. Using adeno-associated virus serotype 9 knockdown of CaMKIIδA partially rescued the cardiac dysfunction and HF in Ddx5 knockout mice. These findings reveal a role for DDX5 in maintaining calcium homeostasis and cardiac function by regulating alternative splicing in cardiomyocytes, identifying the DDX5 as a potential target for therapeutic intervention in HF.

Locking hERG channels into place: Using photoreactive unnatural amino acids to study voltage gating

The voltage-gated K+ channel, hERG, is a member of the Ether-a-go-go family and plays a critical role in heart physiology by repolarizing cardiac myocytes (1-4). The functional channel is comprised of four subunits, each including six transmembrane domains with large intracellular domains, a Per-ARNT-Sim (PAS) domain in the amino terminus, and the cyclic nucleotide-binding homology domain (CNBHD) in the carboxy terminus. Interactions between the PAS domain and CNBHD have been implicated in hERG channel deactivation (5-7), but how these domains interact during channel gating remains largely unknown.

Cardiac Development and Related Clinical Considerations

The anatomy, physiology, and hemodynamics of the premature heart vary along the range of gestational ages cared for in neonatal intensive care units, from 22 weeks to term gestation. Clinical management of the preterm neonate should account for this heterogenous development. This requires an understanding of the impact of ex utero stressors on immature and disorganized cardiac tissue, the different state of hemodynamics across intracardiac shunts impacting the natural transition from fetal to neonatal life, and the effects of intensive pharmacologic and non-pharmacologic interventions that have systemic consequences influencing cardiac function. This article provides a review of the increasing but still limited body of literature on the anatomy, hemodynamics, and electrophysiology of the preterm heart with relevant clinical considerations.

Experience of Performing Systemic-to-Pulmonary Artery Shunt in Patients with Univentricular Heart Physiology and Depleted Pulmonary Blood Flow

Among patients with congenital heart disease diagnosed in infancy, 7.7% of infants have anatomical variants with functional single ventricle physiology which is often accompanied by depleted pulmonary blood flow. The type of these defects is clinically associated with cyanosis, in most cases caused not by mixing of blood at the level of the heart chambers, but by the presence of ductal-dependent pulmonary blood flow, which requires urgent surgical intervention. The aim. To evaluate the immediate and long-term outcomes of hemodynamic correction in patients with single-ventricle heart physiology with depleted pulmonary blood flow. Materials and methods. In the period from 2010 to 2022, 114 patients with reduced pulmonary blood flow underwent systemic-pulmonary anastomosis at the National Amosov Institute of Cardiovascular Surgery of the National Academy of Medical Sciences of Ukraine. Among these, 64 patients had biventricular circulation and subsequently underwent radical correction. The other 50 patients had single-ventricular heart physiology and underwent placement of systemic-pulmonary anastomosis as the first stage of the hemodynamic strategy according to Fontaine, so their data became the main material of this study. Results. Hospital mortality after systemic-pulmonary anastomosis was 8% (4 patients). An uncomplicated course of the early postoperative period was observed in 38 (76%) patients, and 16 complications were observed in the remaining 12 (24%) patients. The median follow-up period was 40 [3; 160] months. During the follow-up period, 2 (4.3%) patients died due to anastomosis thrombosis as a result of self-discontinuation of anticoagulant therapy, 3 (6.5%) patients were lost to follow-up and did not come for examination. The second stage of hemodynamic correction in the form of bidirectional cavopulmonary anastomosis was performed in 41 (82%) patients of the study group. Conclusions. Patients with single-ventricular heart physiology with depleted pulmonary blood flow are a group of extremely complex children who require an individual approach at all stages of hemodynamic correction, and early diagnosis and palliative systemic-pulmonary anastomosis continues to be a reliable alternative for these children, despite the fact that mortality after the first stage remains quite high.

History of the development of isolated heart perfusion experimental model and its pioneering role in understanding heart physiology.

The isolated heart perfusion model, a fundamental tool in cardiovascular research, has evolved significantly since its inception in the late 19th century. This review traces the development of the isolated heart model, from its early adaptations by pioneers such as Langendorff and Starling to modern advancements by researchers like Morgan and Neely. We discuss the various applications of the model in pharmacological testing, disease modeling, and educational settings, emphasizing its crucial role in understanding cardiac function and disease mechanisms. Recent technological enhancements, including high-resolution imaging, integration with bioengineering, and advanced genomic and proteomic analyses, have significantly broadened the capabilities of these models. Looking forward, we explore potential future developments such as the integration of precision medicine, stem cell research, and artificial intelligence, which promise to revolutionize the use of isolated heart perfusion models. This review highlights the model's crucial role in bridging experimental research and clinical applications.

PREVALENCE OF ELEVATED LOW DENSITY LIPOPROTEIN CHOLESTEROL (LDL–C) LEVELS IN ADULT PATIENTS WITH COMPLEX CONGENITAL HEART DISEASE

Abstract Background Thanks to advances in both medical care and surgical techniques, survival for adult patients with congenital heart disease (ACHD) has significantly increased over recent years, with about 90% of them now reaching adulthood. However, as CHD patients grow older, their relative risk of developing coronary artery disease (CAD) increases. Elevated low–density lipoprotein cholesterol (LDL–C) levels play a pivotal role in the genesis of CAD in the general population. Limited data exist on the prevalence of hyperlipidemia in the ACHD population. Patients with complex CHD should be considered at increased risk for CAD, mainly related to to the severity of the CHD and aging. For this reason, it could be reasonable to apply targets used for patients at high risk of CAD. Our study aimed at describing the overall prevalence of elevated LDL–C levels in a contemporary cohort of adult patients with complex CHD. Materials and Methods This is a single–centre retrospective study. All adults with complex CHD who attended the outpatient clinic at our tertiary centre from January 2000 to April 2023 were included. Demographic, clinical and laboratory data were obtained in all patients from medical records and our dedicated databases. Results A total of 230 patients with complex CHD were included in the present study (mean age 35±11 years, 124 male, mean follow up of 117±80 months). One hundred forty–three (63%) of them showed biventricular physiology, whereas 86 (37%) patients showed univentricular heart physiology. Eighty patients from our cohort underwent Fontan operation. Twenty patients (9%) showed oxygen saturation at rest lower than 90%. Mean levels of LDL–C was 87±28 mg/dl, with 184 patients (78%) showing LDL–C levels ≥ 55 mg/dl. Conclusion Our study demonstrated that, despite their relatively younger age, elevated LDL–C levels are not uncommon in patients with severe CHD. ACHD patients with complex anatomy, such as patients after Fontan operation, should be considered at increased risk of ischaemic events and treated accordingly. Further research and international collaboration are therefore paramount to understand whether and if these patients should be treated with lower lipid drugs as for the general population.

Attention LSTM U-Net model for Drosophila melanogaster heart tube segmentation in optical coherence microscopy images.

Optical coherence microscopy (OCM) imaging of the Drosophila melanogaster (fruit fly) heart tube has enabled the non-invasive characterization of fly heart physiology in vivo. OCM generates large volumes of data, making it necessary to automate image analysis. Deep-learning-based neural network models have been developed to improve the efficiency of fly heart image segmentation. However, image artifacts caused by sample motion or reflections reduce the accuracy of the analysis. To improve the precision and efficiency of image data analysis, we developed an Attention LSTM U-Net model (FlyNet3.0), which incorporates an attention learning mechanism to track the beating fly heart in OCM images. The new model has improved the intersection over union (IOU) compared to FlyNet2.0 + with reflection artifacts from 86% to 89% and with movement from 81% to 89%. We also extended the capabilities of OCM analysis through the introduction of an automated, in vivo heart wall thickness measurement method, which has been validated on a Drosophila model of cardiac hypertrophy. This work will enable the comprehensive, non-invasive characterization of fly heart physiology in a high-throughput manner.

Suppression of Contraction Raises Calcium Ion Levels in the Heart of Zebrafish Larvae.

Zebrafish larvae have emerged as a valuable model for studying heart physiology and pathophysiology, as well as for drug discovery, in part thanks to its transparency, which simplifies microscopy. However, in fluorescence-based optical mapping, the beating of the heart results in motion artifacts. Two approaches have been employed to eliminate heart motion during calcium or voltage mapping in zebrafish larvae: the knockdown of cardiac troponin T2A and the use of myosin inhibitors. However, these methods disrupt the mechano-electric and mechano-mechanic coupling mechanisms. We have used ratiometric genetically encoded biosensors to image calcium in the beating heart of intact zebrafish larvae because ratiometric quantification corrects for motion artifacts. In this study, we found that halting heart motion by genetic means (injection of tnnt2a morpholino) or chemical tools (incubation with para-aminoblebbistatin) leads to bradycardia, and increases calcium levels and the size of the calcium transients, likely by abolishing a feedback mechanism that connects contraction with calcium regulation. These outcomes were not influenced by the calcium-binding domain of the gene-encoded biosensors employed, as biosensors with a modified troponin C (Twitch-4), calmodulin (mCyRFP1-GCaMP6f), or the photoprotein aequorin (GFP-aequorin) all yielded similar results. Cardiac contraction appears to be an important regulator of systolic and diastolic Ca2+ levels, and of the heart rate.

Abstract LB180: Non-cardiotoxic properties of annamycin, a clinically evaluated anthracycline and potent topoisomerase 2β poison

Abstract Introduction. Cardiotoxicity is an important side effect limiting the clinical use of all anthracyclines, including doxorubicin (DOX). DOX targets topoisomerase II alpha (Top2α) and beta (Top2β), two enzymes that regulate DNA topology. Top2β is present in cardiomyocytes and has been proposed as a major contributor to DOX-induced cardiotoxicity. Annamycin (ANN), a novel clinically evaluated DOX analog, displays suppressed or no cardiotoxic properties in preclinical in vivo experiments. The objective of this study was to directly assess and compare the potency of DOX and ANN against Top2α and Top2β and determine their impact on physiology of human cardiomyocytes and mice hearts following chronic exposure. Our initial data are clearly aligned with lack of drug-related cardiotoxic events in ANN-treated patients in ongoing clinical trials. Methods. The potency of ANN and DOX to inhibit Top2 was tested in DNA relaxation assays using recombinant Top2α and Top2β with kinetoplast as the DNA substrate. ANN and DOX cytotoxicity was assessed in a panel of cancer cell lines cardiomyocytes (murine and human). In addition, the effects on cardiomyocyte physiology (beating rate, contraction, electric potential,) were assessed in human cardiomyocytes using the xCELLigence RTCA CardioECR. The pathophysiology of the heart after chronic exposure to the drugs was also evaluated in mice models. Cardiotoxicity of liposome formulated ANN (L-ANN) is currently being examined in ongoing clinical studies of subjects with acute myeloid leukemia (NCT05319587) or soft tissue sarcoma with metastases to the lungs (NCT04887298). Results. The nanomolar range potency of ANN in tested cancer cell lines was 2-10 times greater than that of DOX. The DNA relaxation assay demonstrated high potency of ANN against recombinant Top2α and Topβ with IC50 values 0.23±0.06 and 0.22± 0.06 µM, respectively, whereas the IC50 for DOX was 0.65± 0.22 and 0.34± 0.31µM, respectively. Importantly, ANN did not significantly affect electric potential, contractility, and viability of human cardiomyocytes up to highest tested dose of 1,500 nM (72h exposure). In contrast, DOX caused a dramatic change in heart beating rate and decreased in contractility and field potential amplitude. In rat cardiomyocyte culture (H92C), ANN was 14-fold less cytotoxic than DOX (IC50 1,264 nM for ANN vs. 88 nM for DOX). No cardiotoxicity of L-ANN was detected in myocardium of nude mice exposed weekly for 12 weeks to therapeutic doses of L-ANN (4 mg/kg, 40% of LD10). Finally, data from ongoing clinical trials revealed no drug related cardiac events in patients receiving L-ANN (confirmed by an independent review of the Duke’s ECHO core laboratory, USA). Conclusions. Our preclinical studies demonstrate non-cardiotoxic properties of ANN. These data are clearly aligned with lack of drug-related cardiotoxic events in ANN-treated patients in ongoing clinical trials. Interestingly, ANN appeared to be a significantly more potent inhibitor of Top2β than DOX, suggesting that Top2β may not be a universal mediator of cardiotoxicity of anthracyclines. Additional studies are needed to reevaluate the role of Top2β in anthracycline-induced cardiotoxicity. Citation Format: Rafal J. Zielinski, Krzysztof Grela, Roberto Cardenas-Zuniga, Stanislaw Skora, Izabela Fokt, Mihai Gagea, Wolfram Dempke, Waldemar Priebe. Non-cardiotoxic properties of annamycin, a clinically evaluated anthracycline and potent topoisomerase 2β poison [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB180.

Two-Dimensional and Doppler trans-thoracic echocardiographic patterns of suspected pediatric heart diseases at Tibebe--Ghion specialized Teaching Hospital and Adinas General Hospital, Bahir Dar, North-west Ethiopia:-An experience from an LMIC.

Transthoracic Echocardiography is the first-line, non-invasive, and accessible imaging modality to evaluate heart disease anatomy, physiology, and hemodynamics. We aim to describe the trans-thoracic echocardiography pattern of pediatric heart diseases and reasons for referral in children referred to Bahir Dar University Tibebe-Ghion Hospital and Adinas General Hospital. A descriptive cross-sectional study of the archived Transthoracic, Two Dimensional, and Doppler Echocardiography assessments of children from birth to fifteen years of age performed between June 2019 to May 2023 was done. Data were collected retrospectively from February 01, 2023 -May 31, 2023. Categorical variables like gender, referral reasons for echocardiography, and patterns of pediatric heart lesions were analyzed in the form of proportions and presented in tables and figures. Discrete variables including age were summarized as means (SD) and medians(IQR). Out of 3,647 Children enrolled; 1,917 (52.6%) were males and 1,730 (47.4%) were females. The median (IQR) age of children enrolled was 24 months (5 to 96). Cardiac murmur (33%) was the most common reason for echocardiography followed by, Respiratory Distress (18%), Syndromic Child (15%), easy fatigability/ Diaphoresis (14.3%), congestive heart failure (14%), and rheumatic fever (13.2%). Congenital heart defect (CHD) accounts for 70% of all heart diseases, followed by rheumatic heart disease (21%). Isolated ventricular septal defect(VSD) was the most common CHD (21%) followed by isolated Patent ductus arteriosus (15%), isolated atrial septal defect (10%), Isolated atrioventricular septal defect (6%) and isolated pulmonary stenosis (5%). Cyanotic CHD accounts for 11.5% of all heart diseases. Tetralogy of Fallot (30%), d-TGA (20%), and double outlet right ventricle (19%) were the most common cyanotic CHDs. In our study, congenital heart lesions are the most common diagnosis and cardiac murmurs are the most common presenting reasons for echocardiography evaluation.

Characterizing the Causal Pathway From Childhood Adiposity to Right Heart Physiology and Pulmonary Circulation UsingLifecourse Mendelian Randomization.

Observational epidemiological studies have reported an association between childhood adiposity and altered cardiac morphology and function in later life. However, whether this is due to a direct consequence of being overweight during childhood has been difficult to establish, particularly as accounting for other measures of body composition throughout the lifecourse can be exceptionally challenging. In this study, we used human genetics to investigate this using a causal inference technique known as lifecourse Mendelian randomization. This approach allowed us to evaluate the effect of childhood body size on 11 measures of right heart and pulmonary circulation independent of other anthropometric traits at various stages in the lifecourse. We found strong evidence that childhood body size has a direct effect on an enlarged right heart structure in later life (eg, right ventricular end-diastolic volume: β=0.24 [95% CI, 0.15-0.33]; P=3×10-7) independent of adulthood body size. In contrast, childhood body size effects on maximum ascending aorta diameter attenuated upon accounting for body size in adulthood, suggesting that this effect is likely attributed to individuals remaining overweight into later life. Effects of childhood body size on pulmonary artery traits and measures of right atrial function became weaker upon accounting for adulthood fat-free mass and childhood height, respectively. Our findings suggest that, although childhood body size has a long-term influence on an enlarged heart structure in adulthood, associations with the other structural components of the cardiovascular system and their function may be largely attributed to body composition at other stages in the lifecourse.

Superior cavopulmonary shunt via right vertical axillary mini-thoracotomy.

We present 2 cases of patients with univentricular heart physiology of different anatomic variants who successfully underwent minimally invasive bidirectional cavopulmonary anastomosis via the right vertical axillary mini-thoracotomy.

Ex Vivo Working Porcine Heart Model.

Ex vivo working porcine heart models allow for the study of a heart's function and physiology outside the living organism. These models are particularly useful due to the anatomical and physiological similarities between porcine and human hearts, providing an experimental platform to investigate cardiac disease or assess donor heart viability for transplantation. This chapter presents an in-depth discussion of the model's components, including the perfusate, preload, and afterload. We explore the challenges of emulating cardiac afterload and present a historical perspective on afterload modeling, discussing various methodologies and their respective limitations. An actively controlled afterload device is introduced to enhance the model's ability to rapidly adjust pressure in the large arteries, thereby providing a more accurate and dynamic experimental model. Finally, we provide a comprehensive experimental protocol for the ex vivo working porcine heart model.

Noninvasive Quantification of Contractile Dynamics in Cardiac Cells, Spheroids, and Organs-on-a-Chip Using High-Frequency Ultrasound.

Cell-based models that mimic in vivo heart physiology are poised to make significant advances in cardiac disease modeling and drug discovery. In these systems, cardiomyocyte (CM) contractility is an important functional metric, but current measurement methods are inaccurate and low-throughput or require complex setups. To address this need, we developed a standalone noninvasive, label-free ultrasound technique operating at 40-200 MHz to measure the contractile kinetics of cardiac models, ranging from single adult CMs to 3D microtissue constructs in standard cell culture formats. The high temporal resolution of 1000 fps resolved the beat profile of single mouse CMs paced at up to 9 Hz, revealing limitations of lower speed optical based measurements to resolve beat kinetics or characterize aberrant beats. Coupling of ultrasound with traction force microscopy enabled the measurement of the CM longitudinal modulus and facile estimation of adult mouse CM contractile forces of 2.34 ± 1.40 μN, comparable to more complex measurement techniques. Similarly, the beat rate, rhythm, and drug responses of CM spheroid and microtissue models were measured, including in configurations without optical access. In conclusion, ultrasound can be used for the rapid characterization of CM contractile function in a wide range of commonly studied configurations ranging from single cells to 3D tissue constructs using standard well plates and custom microdevices, with applications in cardiac drug discovery and cardiotoxicity evaluation.