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Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts. Using genetic loss-of-function models, we demonstrate that GPNMB deficiency leads to increased mortality, cardiac rupture and rapid post-MI left ventricular dysfunction. Conversely, increasing circulating GPNMB levels through viral delivery improves heart function after MI. Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation. Additionally, we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling.

BACKGROUND: The characteristics of electrocardiogram (ECG) abnormalities related to cardiac channelopathies potentially linked to sudden cardiac death (SCD) are not widely recognized in Iran. We examined the prevalence of such ECG patterns and their related factors among adult residents of Tehran, Iran. METHODS: The clinical characteristics and 12-lead ECGs of Tehran Cohort Study participants were examined. Long QT intervals, short QT intervals, Brugada syndrome (BrS) patterns, and early repolarization (ER) were evaluated using computer-based assessment software validated by cardiologists. Logistic regression models were employed to identify the factors associated with the prevalence of different ECG patterns. RESULTS: Out of 7678 available ECGs, 7350 were included in this analysis. Long QT interval, ER pattern, BrS patterns, and short QT interval were found in 3.08%, 1.43%, 0.31%, and 0.03% of participants, respectively. The prevalence of long QT interval increased with age, opium consumption, and presence of hypertension. Younger age, lower body mass index (BMI), alcohol use and male sex were independently linked to an elevated prevalence of ER pattern. Most individuals with BrS patterns were men (95%) and had lower BMI, high- and low-density lipoprotein, and total cholesterol compared to those without the BrS pattern. At a mean follow-up of 30.2 ± 5.5 months, all-cause mortality in the group exhibiting abnormal ECG patterns (6.3%) was approximately twice as high as that in the group without such patterns (2.96%). CONCLUSION: Abnormal ECG patterns corresponding to channelopathies were relatively rare among adult residents of the Tehran population, and their prevalence was influenced by various factors. CLINICAL TRIAL NUMBER: Not applicable.

Small-conductance Ca2+-activated K+ channels (SK, KCa2) are gated solely by intracellular microdomain Ca2+. The channel has emerged as a therapeutic target for cardiac arrhythmias. Calmodulin (CaM) interacts with the CaM binding domain (CaMBD) of the SK channels, serving as the obligatory Ca2+ sensor to gate the channels. In heterologous expression systems, phosphatidylinositol 4,5-bisphosphate (PIP2) coordinates with CaM in regulating SK channels. However, the roles and mechanisms of PIP2 in regulating SK channels in cardiomyocytes remain unknown. Here, optogenetics, magnetic nanoparticles, combined with Rosetta structural modeling, and molecular dynamics (MD) simulations revealed the atomistic mechanisms of how PIP2 works in concert with Ca2+-CaM in the SK channel activation. Our computational study affords evidence for the critical role of the amino acid residue R395 in the S6 transmembrane segment, which is localized in propinquity to the intracellular hydrophobic gate. This residue forms a salt bridge with residue E398 in the S6 transmembrane segment from the adjacent subunit. Both R395 and E398 are conserved in all known isoforms of SK channels. Our findings suggest that the binding of PIP2 to R395 residue disrupts the R395:E398 salt bridge, increasing the flexibility of the transmembrane segment S6 and the activation of the channel. Importantly, our findings serve as a platform for testing of structural-based drug designs for therapeutic inhibitors and activators of the SK channel family. The study is timely since inhibitors of SK channels are currently in clinical trials to treat atrial arrhythmias.

Lipoprotein lipase (LPL) and multiple regulators of LPL activity (e.g., APOC2 and ANGPTL4) are present in all vertebrates, but GPIHBP1-the endothelial cell (EC) protein that captures LPL within the subendothelial spaces and transports it to its site of action in the capillary lumen-is present in mammals but in not chickens or other lower vertebrates. In mammals, GPIHBP1 deficiency causes severe hypertriglyceridemia, but chickens maintain low triglyceride levels despite the absence of GPIHBP1. To understand intravascular lipolysis in lower vertebrates, we examined LPL expression in mouse and chicken hearts. In both species, LPL was abundant on capillaries, but the distribution of Lpl transcripts was strikingly different. In mouse hearts, Lpl transcripts were extremely abundant in cardiomyocytes but were barely detectable in capillary ECs. In chicken hearts, Lpl transcripts were absent in cardiomyocytes but abundant in capillary ECs. In zebrafish hearts, lpl transcripts were also in capillary ECs but not cardiomyocytes. In both mouse and chicken hearts, LPL was present, as judged by immunogold electron microscopy, in the glycocalyx of capillary ECs. Thus, mammals produce LPL in cardiomyocytes and rely on GPIHBP1 to transport the LPL into capillaries, whereas lower vertebrates produce LPL directly in capillary ECs, rendering an LPL transporter unnecessary.

Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.

Minimally invasive approaches to address coronary artery disease, such as robotic coronary bypass grafting, are emerging in surgery and have been shown to be beneficial with a reduction in morbidity. The perioperative management of this subset of patients is crucial to the success of the operation as there are several preoperative and postoperative issues and considerations that need to be addressed. A meticulous preoperative workup with an extensive history, physical exam, and appropriate imaging are instrumental to ensure a successful operation. Protocolized postoperative care is also essential to garnish the most benefit from this minimally invasive approach. All of these factors, in conjunction with a heart team approach and surgeon experience, are imperative for the successful outcome of robotic coronary artery revascularization.

AIMS: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB. METHODS AND RESULTS: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up. CONCLUSION: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.

During postnatal cardiac hypertrophy, cardiomyocytes undergo mitotic exit, relying on DNA replication-independent mechanisms of histone turnover to maintain chromatin organization and gene transcription. In other tissues, circadian oscillations in nucleosome occupancy influence clock-controlled gene expression, suggesting a role for the circadian clock in temporal control of histone turnover and coordinated cardiomyocyte gene expression. We sought to elucidate roles for the master circadian transcription factor, Bmal1, in histone turnover, chromatin organization, and myocyte-specific gene expression and cell growth in the neonatal period. Bmal1 knockdown in neonatal rat ventricular myocytes decreased myocyte size, total cellular protein synthesis, and transcription of the fetal hypertrophic gene Nppb after treatment with serum or the α-adrenergic agonist phenylephrine. Depletion of Bmal1 decreased the expression of clock-controlled genes Per2 and Tcap, as well as Sik1, a Bmal1 target upregulated in adult versus embryonic hearts. Bmal1 knockdown impaired Per2 and Sik1 promoter accessibility as measured by micrococcal nuclease-quantitative PCR and impaired histone turnover as measured by metabolic labeling of acid-soluble chromatin fractions. Sik1 knockdown in turn decreased myocyte size, while simultaneously inhibiting natriuretic peptide B transcription and activating Per2 transcription. Linking these changes to chromatin remodeling, depletion of the replication-independent histone variant H3.3a inhibited myocyte hypertrophy and prevented phenylephrine-induced changes in clock-controlled gene transcription. Bmal1 is required for neonatal myocyte growth, replication-independent histone turnover, and chromatin organization at the Sik1 promoter. Sik1 represents a novel clock-controlled gene that coordinates myocyte growth with hypertrophic and clock-controlled gene transcription. Replication-independent histone turnover is required for transcriptional remodeling of clock-controlled genes in cardiac myocytes in response to growth stimuli.

Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) are powerful in vitro models to study the mechanisms underlying cardiomyopathies and cardiotoxicity. Quantification of the contractile function in single hiPSC-CMs at high-throughput and over time is essential to disentangle how cellular mechanisms affect heart function. Here, we present CONTRAX, an open-access, versatile, and streamlined pipeline for quantitative tracking of the contractile dynamics of single hiPSC-CMs over time. Three software modules enable: parameter-based identification of single hiPSC-CMs; automated video acquisition of >200 cells/hour; and contractility measurements via traction force microscopy. We analyze >4,500 hiPSC-CMs over time in the same cells under orthogonal conditions of culture media and substrate stiffnesses; +/- drug treatment; +/- cardiac mutations. Using undirected clustering, we reveal converging maturation patterns, quantifiable drug response to Mavacamten and significant deficiencies in hiPSC-CMs with disease mutations. CONTRAX empowers researchers with a potent quantitative approach to develop cardiac therapies.

BackgroundChronic sympathetic stimulation drives desensitization and downregulation of β1 adrenergic receptor (β1AR) in heart failure. We aim to explore the differential downregulation subcellular pools of β1AR signaling in the heart.Methods and resultsWe applied chronic infusion of isoproterenol to induced cardiomyopathy in male C57BL/6J mice. We applied confocal and proximity ligation assay to examine β1AR association with L-type calcium channel, ryanodine receptor 2, and SERCA2a ((Sarco)endoplasmic reticulum calcium ATPase 2a) and Förster resonance energy transfer-based biosensors to probe subcellular β1AR-PKA (protein kinase A) signaling in ventricular myocytes. Chronic infusion of isoproterenol led to reduced β1AR protein levels, receptor association with L-type calcium channel and ryanodine receptor 2 measured by proximity ligation (puncta/cell, 29.65 saline versus 14.17 isoproterenol, P

The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential energy source for normal function of cardiac muscle during each beat, as it powers ion transport, intracellular Ca2+ handling, and actin-myosin cross-bridge cycling. Despite this, the impact of excitation-contraction coupling on the intracellular ATP concentration ([ATP]i) in myocytes is poorly understood. Here, we conducted real-time measurements of [ATP]i in ventricular myocytes using a genetically encoded ATP fluorescent reporter. Our data reveal rapid beat-to-beat variations in [ATP]i. Notably, diastolic [ATP]i was

BACKGROUND: Dilated cardiomyopathy (DCM) is one of the most common causes of heart failure. Multiple identified mutations in nexilin (NEXN) have been suggested to be linked with severe DCM. However, the exact association between multiple mutations of Nexn and DCM remains unclear. Moreover, it is critical for the development of precise and effective therapeutics in treatments of DCM. RESULTS: In our study, Nexn global knockout mice and mice carrying human equivalent G645del mutation are studied using functional gene rescue assays. AAV-mediated gene delivery is conducted through systemic intravenous injections at the neonatal stage. Heart tissues are analyzed by immunoblots, and functions are assessed by echocardiography. Here, we identify functional components of Nexilin and demonstrate that exogenous introduction could rescue the cardiac function and extend the lifespan of Nexn knockout mouse models. Similar therapeutic effects are also obtained in G645del mice, providing a promising intervention for future clinical therapeutics. CONCLUSIONS: In summary, we demonstrated that a single injection of AAV-Nexn was capable to restore the functions of cardiomyocytes and extended the lifespan of Nexn knockout and G645del mice. Our study represented a long-term gene replacement therapy for DCM that potentially covers all forms of loss-of-function mutations in NEXN.

Determining the pathogenicity of hypertrophic cardiomyopathy-associated mutations in the β-myosin heavy chain (MYH7) can be challenging due to its variable penetrance and clinical severity. This study investigates the early pathogenic effects of the incomplete-penetrant MYH7 G256E mutation on myosin function that may trigger pathogenic adaptations and hypertrophy. We hypothesized that the G256E mutation would alter myosin biomechanical function, leading to changes in cellular functions. We developed a collaborative pipeline to characterize myosin function across protein, myofibril, cell, and tissue levels to determine the multiscale effects on structure-function of the contractile apparatus and its implications for gene regulation and metabolic state. The G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 33%, resulting in more myosin heads available for contraction. Myofibrils from gene-edited MYH7WT/G256E human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibited greater and faster tension development. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues. We demonstrated consistent hypercontractile myosin function as a primary consequence of the MYH7 G256E mutation across scales, highlighting the pathogenicity of this gene variant. Single-cell transcriptomic and metabolic profiling demonstrated upregulated mitochondrial genes and increased mitochondrial respiration, indicating early bioenergetic alterations. This work highlights the benefit of our multiscale platform to systematically evaluate the pathogenicity of gene variants at the protein and contractile organelle level and their early consequences on cellular and tissue function. We believe this platform can help elucidate the genotype-phenotype relationships underlying other genetic cardiovascular diseases.

The Na+-Ca2+ exchanger (NCX1) is the dominant Ca2+ extrusion mechanism in cardiac myocytes. NCX1 activity is inhibited by intracellular Na+ via a process known as Na+-dependent inactivation. A central question is whether this inactivation plays a physiological role in heart function. Using CRISPR/Cas9, we inserted the K229Q mutation in the gene (Slc8a1) encoding for NCX1. This mutation removes the Na+-dependent inactivation while preserving transport properties and other allosteric regulations. NCX1 mRNA levels, protein expression, and protein localization are unchanged in K229Q male mice. However, they exhibit reduced left ventricular ejection fraction and fractional shortening, while displaying a prolonged QT interval. K229Q ventricular myocytes show enhanced NCX1 activity, resulting in action potential prolongation, higher incidence of aberrant action potentials, a faster decline of Ca2+ transients, and depressed cell shortening. The results demonstrate that NCX1 Na+-dependent inactivation plays an essential role in heart function by affecting both cardiac excitability and contractility.

Hematopoietic stem cell transplantation can cure various disorders but poses cardiovascular risks, especially for elderly patients and those with cardiovascular diseases. Cardiovascular evaluations are crucial in pretransplantation assessments, but guidelines are lacking. This American Heart Association scientific statement summarizes the data on transplantation-related complications and provides guidance for the cardiovascular management throughout transplantation. Hematopoietic stem cell transplantation consists of 4 phases: pretransplantation workup, conditioning therapy and infusion, immediate posttransplantation period, and long-term survivorship. Complications can occur during each phase, with long-term survivors facing increased risks for late effects such as cardiovascular disease, secondary malignancies, and endocrinopathies. In adults, arrhythmias such as atrial fibrillation and flutter are the most frequent acute cardiovascular complication. Acute heart failure has an incidence ranging from 0.4% to 2.2%. In pediatric patients, left ventricular systolic dysfunction and pericardial effusion are the most common cardiovascular complications. Factors influencing the incidence and risk of complications include pretransplantation therapies, transplantation type (autologous versus allogeneic), conditioning regimen, comorbid conditions, and patient age. The pretransplantation cardiovascular evaluation consists of 4 steps: (1) initial risk stratification, (2) exclusion of high-risk cardiovascular disease, (3) assessment of cardiac reserve, and (4) optimization of cardiovascular reserve. Clinical risk scores could be useful tools for the risk stratification of adult patients. Long-term cardiovascular management of hematopoietic stem cell transplantation survivors includes optimizing risk factors, monitoring, and maintaining a low threshold for evaluating cardiovascular causes of symptoms. Future research should prioritize refining risk stratification and creating evidence-based guidelines and strategies to optimize outcomes in this growing patient population.

BackgroundRecently shown to regulate cardiac development, the secreted axon guidance molecule SLIT3 maintains its expression in the postnatal heart. Despite its known expression in the cardiovascular system after birth, SLIT3's relevance to cardiovascular function in the postnatal state remains unknown. As such, the objectives of this study were to determine the postnatal myocardial sources of SLIT3 and to evaluate its functional role in regulating the cardiac response to pressure overload stress.MethodsWe performed in vitro studies on cardiomyocytes and myocardial tissue samples from patients and performed in vivo investigation with SLIT3 and ROBO1 (roundabout homolog 1) mutant mice undergoing transverse aortic constriction to establish the role of SLIT3-ROBO1 in adverse cardiac remodeling.ResultsWe first found that SLIT3 transcription was increased in myocardial tissue obtained from patients with congenital heart defects that caused ventricular pressure overload. Immunostaining of hearts from WT (wild-type) and reporter mice revealed that SLIT3 is secreted by cardiac stromal cells, namely fibroblasts and vascular mural cells, within the heart. Conditioned media from cardiac fibroblasts and vascular mural cells both stimulated cardiomyocyte hypertrophy in vitro, an effect that was partially inhibited by an anti-SLIT3 antibody. Also, the N-terminal, but not the C-terminal, fragment of SLIT3 and the forced overexpression of SLIT3 stimulated cardiomyocyte hypertrophy and the transcription of hypertrophy-related genes. We next determined that ROBO1 was the most highly expressed roundabout receptor in cardiomyocytes and that ROBO1 mediated SLIT3's hypertrophic effects in vitro. In vivo, Tcf21+ fibroblast and Tbx18+ vascular mural cell-specific knockout of SLIT3 in mice resulted in decreased left ventricular hypertrophy and cardiac fibrosis after transverse aortic constriction. Furthermore, α-MHC+ cardiomyocyte-specific deletion of ROBO1 also preserved left ventricular function and abrogated hypertrophy, but not fibrosis, after transverse aortic constriction.ConclusionsCollectively, these results indicate a novel role for the SLIT3-ROBO1-signaling axis in regulating postnatal cardiomyocyte hypertrophy induced by pressure overload.

Human induced pluripotent stem cell (hiPSC) to cardiomyocyte (CM) differentiation has reshaped approaches to studying cardiac development and disease. In this study, we employed a genome-wide CRISPR screen in a hiPSC to CM differentiation system and reveal here that BRD4, a member of the bromodomain and extraterminal (BET) family, regulates CM differentiation. Chemical inhibition of BET proteins in mouse embryonic stem cell (mESC)-derived or hiPSC-derived cardiac progenitor cells (CPCs) results in decreased CM differentiation and persistence of cells expressing progenitor markers. In vivo, BRD4 deletion in second heart field (SHF) CPCs results in embryonic or early postnatal lethality, with mutants demonstrating myocardial hypoplasia and an increase in CPCs. Single-cell transcriptomics identified a subpopulation of SHF CPCs that is sensitive to BRD4 loss and associated with attenuated CM lineage-specific gene programs. These results highlight a previously unrecognized role for BRD4 in CM fate determination during development and a heterogenous requirement for BRD4 among SHF CPCs.

The heart, which is the first organ to develop, is highly dependent on its form to function1,2. However, how diverse cardiac cell types spatially coordinate to create the complex morphological structures that are crucial for heart function remains unclear. Here we integrated single-cell RNA-sequencing with high-resolution multiplexed error-robust fluorescence in situ hybridization to resolve the identity of the cardiac cell types that develop the human heart. This approach also provided a spatial mapping of individual cells that enables illumination of their organization into cellular communities that form distinct cardiac structures. We discovered that many of these cardiac cell types further specified into subpopulations exclusive to specific communities, which support their specialization according to the cellular ecosystem and anatomical region. In particular, ventricular cardiomyocyte subpopulations displayed an unexpected complex laminar organization across the ventricular wall and formed, with other cell subpopulations, several cellular communities. Interrogating cell-cell interactions within these communities using in vivo conditional genetic mouse models and in vitro human pluripotent stem cell systems revealed multicellular signalling pathways that orchestrate the spatial organization of cardiac cell subpopulations during ventricular wall morphogenesis. These detailed findings into the cellular social interactions and specialization of cardiac cell types constructing and remodelling the human heart offer new insights into structural heart diseases and the engineering of complex multicellular tissues for human heart repair.

LMNA-related dilated cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure or sudden death. The condition is caused by mutation in the Lamin A/C (LMNA) gene encoding Type-A nuclear lamin proteins involved in nuclear integrity, epigenetic regulation of gene expression, and differentiation. The molecular mechanisms of the disease are not completely understood, and there are no definitive treatments to reverse progression or prevent mortality. We investigated possible mechanisms of LMNA-related DCM using induced pluripotent stem cells derived from a family with a heterozygous LMNA c.357-2A>G splice-site mutation. We differentiated one LMNA-mutant iPSC line derived from an affected female (Patient) and two non-mutant iPSC lines derived from her unaffected sister (Control) and conducted single-cell RNA sequencing for 12 samples (four from Patients and eight from Controls) across seven time points: Day 0, 2, 4, 9, 16, 19, and 30. Our bioinformatics workflow identified 125,554 cells in raw data and 110,521 (88%) high-quality cells in sequentially processed data. Unsupervised clustering, cell annotation, and trajectory inference found complex heterogeneity: ten main cell types; many possible subtypes; and lineage bifurcation for cardiac progenitors to cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Data integration and comparative analyses of Patient and Control cells found cell type and lineage-specific differentially expressed genes (DEGs) with enrichment, supporting pathway dysregulation. Top DEGs and enriched pathways included 10 ZNF genes and RNA polymerase II transcription in pluripotent cells (PP); BMP4 and TGF Beta/BMP signaling, sarcomere gene subsets and cardiogenesis, CDH2 and EMT in CMs; LMNA and epigenetic regulation, as well as DDIT4 and mTORC1 signaling in EPDCs. Top DEGs also included XIST and other X-linked genes, six imprinted genes (SNRPN, PWAR6, NDN, PEG10, MEG3, MEG8), and enriched gene sets related to metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our complex Patient-derived iPSC model for Lamin A/C haploinsufficiency in PP, CM, and EPDC provided support for dysregulation of genes and pathways, many previously associated with Lamin A/C defects, such as epigenetic gene expression, signaling, and differentiation. Our findings support disruption of epigenomic developmental programs, as proposed in other LMNA disease models. We recognized other factors influencing epigenetics and differentiation; thus, our approach needs improvement to further investigate this mechanism in an iPSC-derived model.

Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac CaV1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

Cells interpret a variety of signals through G-protein-coupled receptors (GPCRs) and stimulate the generation of second messengers such as cyclic adenosine monophosphate (cAMP). A long-standing puzzle is deciphering how GPCRs elicit different physiological responses despite generating similar levels of cAMP. We previously showed that some GPCRs generate cAMP from both the plasma membrane and the Golgi apparatus. Here we demonstrate that cardiomyocytes distinguish between subcellular cAMP inputs to elicit different physiological outputs. We show that generating cAMP from the Golgi leads to the regulation of a specific protein kinase A (PKA) target that increases the rate of cardiomyocyte relaxation. In contrast, cAMP generation from the plasma membrane activates a different PKA target that increases contractile force. We further validated the physiological consequences of these observations in intact zebrafish and mice. Thus, we demonstrate that the same GPCR acting through the same second messenger regulates cardiac contraction and relaxation dependent on its subcellular location.

Osteogenesis imperfecta (OI) is a rare heritable connective tissue disorder of skeletal fragility with an incidence of roughly 1:15,000. Approximately 85% of the pathogenic variants responsible for OI are in the type I collagen genes, COL1A1 and COL1A2, with the remaining pathogenic OI variants spanning at least 20 additional genetic loci that often involve type I collagen post-translational modification, folding, and intracellular transport as well as matrix incorporation and mineralization. In addition to being the most abundant collagen in the body, type I collagen is an important structural and extracellular matrix signaling molecule in multiple organ systems and tissues. Thus, OI disease-causing variants result not only in skeletal fragility, decreased bone mineral density (BMD), kyphoscoliosis, and short stature, but can also result in hearing loss, dentinogenesis imperfecta, blue gray sclera, cardiopulmonary abnormalities, and muscle weakness. The extensive genetic and clinical heterogeneity in OI has necessitated the generation of multiple mouse models, the growing awareness of non-skeletal organ and tissue involvement, and OI being more broadly recognized as a type I collagenopathy. This has driven the investigation of mutation-specific skeletal and extra-skeletal manifestations and broadened the search of potential mechanistic therapeutic strategies. The purpose of this review is to outline several of the extra-skeletal manifestations that have recently been characterized through the use of genetically and phenotypically heterogeneous mouse models of osteogenesis imperfecta, demonstrating the significant potential impact of OI disease-causing variants as a collagenopathy (affecting multiple organ systems and tissues), and its implications to overall health. [ABSTRACT FROM AUTHOR]

While the pathophysiology of pre‐eclampsia has been postulated as being secondary to placental dysfunction, a cardiac origin has more recently been proposed. Although an association between fetal congenital cardiovascular disease and pre‐eclampsia has been demonstrated, no precise pathophysiologic mechanism for this association has been described. This review highlights the current biophysical (including echocardiography and Doppler indices) and biochemical (including proteomic, metabolomic and genetic/transcriptomic) markers of cardiac dysfunction that have been investigated in maternal and fetal cardiac disease and their overlap with predictors of pre‐eclampsia. Common pathways of inflammatory and anti‐angiogenesis imbalance, endothelial damage, and oxidative stress have been demonstrated in both cardiovascular disease and pre‐eclampsia and further investigation into these pathways could help to elucidate the common pathophysiologic mechanisms linking these disorders. Synopsis: Cardiac dysfunction in the mother and fetus have been linked with pre‐eclampsia. This review highlights that shared pathways can elucidate common pathophysiology linking the disorders. [ABSTRACT FROM AUTHOR]

Background and Purpose: Adenosine receptor activation induces delayed, sustained cardioprotection against ischaemia–reperfusion (IR) injury (24–72 h), but the mechanisms underlying extended cardioprotection duration remain unresolved. We hypothesized that a positive feedback loop involving adenosine receptor‐induced proteasomal degradation of adenosine kinase (ADK) and decreased myocardial adenosine metabolism extends the duration of cardioprotection. Experimental Approach: Mice were administered an ADK inhibitor, ABT‐702, to induce endogenous adenosine signalling. Cardiac ADK protein and mRNA levels were analysed 24–120 h later. Theophylline or bortezomib was administered 24 h after ABT‐702 to examine the late roles of adenosine receptors or proteasomal activity, respectively, in ADK expression and cardioprotection at 72 h. Coronary flow and IR tolerance were analysed by Langendorff technique. The potential for continuous adenosinergic cardioprotection was examined using heterozygous, cardiac‐specific ADK KO (cADK+/−) mice. Cardiac ADK expression was also examined after A1 or A3 receptor agonist, phenylephrine, lipopolysaccharide or sildenafil administration. Key results: ABT‐702 treatment decreased ADK protein content and provided cardioprotection from 24 to 72 h. ADK mRNA upregulation restored ADK protein after 96–120 h. Adenosine receptor or proteasome inhibition at 24 h reversed ABT‐702‐induced ADK protein deficit and cardioprotection at 72 h. cADK+/− hearts exhibited continuous cardioprotection. Diverse preconditioning agents also diminished cardiac ADK protein expression. Conclusion and Implications: A positive feedback loop driven by adenosine receptor‐induced ADK degradation and renewed adenosine signalling extends the duration of cardioprotection by ABT‐702 and possibly other preconditioning agents. The therapeutic potential of continuous adenosinergic cardioprotection is demonstrated in cADK+/− hearts. [ABSTRACT FROM AUTHOR]

Background: Although direct oral anticoagulants (DOACs) have been used in the adult population for over a decade, DOACs use has begun to rise in pediatric populations since FDA approval of rivaroxaban and dabigatran, DOACs offer several advantages for pediatric patients, to other anticoagulants, including a similar safety profile, minimal lab monitoring, and ease of administration. The rise in DOAC use has led to an increasing number of pediatric patients managed on DOACs presenting for elective and urgent procedures. Perioperative management of anticoagulation is often challenging for providers due to the lack of expert consensus guidelines and the difficulty in balancing a patient's thrombotic risk with bleeding risk for a given procedure. Aims: Using the most up to date literature, we provide a focused review on the perioperative management of DOACs in pediatric patients. Conclusions: This work presents a focused review for pediatric anesthesiologists on clinically available DOACs, perioperative monitoring and management of DOACs, as well as options and indications for reversal. While consensus expert practice guidelines are still needed, we hope this work will familiarize perioperative physicians with these agents, recommended uses, and potential perioperative management. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether pre- and postoperative follow-up based on lung ultrasound is associated with the respiratory and clinical evolution of patients undergoing cardiac surgery in the neonatal period. Methods: Prospective observational unicentric study from December 2020 to October 2023 in a neonatal intensive care unit, a referral center for congenital heart diseases (CHD). Neonates with CHD exposed to heart surgery or percutaneous catheterization in their first 28 days of life were included. LU follow-up was performed before surgery (LUSpre) and on days 1 (LUS_1), 3 (LUS_3), and 7 (LUS_7) afterwards by mean of a dedicated score (LUS) ranging from 0 to 3 points in 8 areas (total score 0–24). Results: Fifty-five neonates were included. Median gestational age was 39.1 weeks (37.8–40.1), birth weight 3088 g (IQR 2910–3400). Forty-nine received surgery and 6 only percutaneous catheterization. Median LUSpre score was associated with total respiratory support in the first 30 postoperative days (p = 0.034). Median postoperative LUS was significantly higher than LUSpre in the surgery cohort at all time points (p < 0.05). LUS_1 was associated with respiratory and several clinical outcomes: for each point increase in the ultrasound score, the days on invasive mechanical ventilation, the need for any respiratory support within the first 30 postoperative days, and the length of NICU stay increased significantly (p < 0.05). The presence of consolidations in any area in the postoperative lung ultrasounds was associated with worse respiratory outcomes: higher invasive mechanical ventilation duration (6.84 days), longer total respiratory support (6.07 days), and NICU admission (21.61 days). The presence of consolidations in LUS_7 was significantly associated with the occurrence of ipsilateral diaphragmatic paralysis (odds ratio of 10.25 (95% CI 2.05–51.26, p = 0.006). Conclusion: Performance of lung ultrasound follow-up in CHD in the NICU is feasible and predictive of the respiratory evolution of the patient. LUS_1 presented the highest predictive values. The presence of consolidations is associated with a worse respiratory evolution and if they persist for a week after the procedure, it may raise suspicion of ipsilateral diaphragmatic paralysis. What is known: • Lung ultrasound evaluates lung aeration and predicts respiratory outcomes in premature infants. What is new: • Follow-up based on lung ultrasound in congenital heart diseases postoperative period is associated with respiratory evolution and length of admission. [ABSTRACT FROM AUTHOR]

Background: Dealing with parturient women with cardiac disease is still a challenge for anesthesiologists due to the presence of physiologic burden of pregnancy in addition to the already existing compromised cardiovascular system. A variety of cardiac indices have been utilized to forecast the risk of perioperative cardiac complications, yet limitations in their predictive value exist. Perioperative brain natriuretic peptide (BNP) level is used as a prognosticator of cardiac complications following surgery in cardiac and non-cardiac individuals. Aim of study: To compare the effect of general and spinal anesthesia during cesarean section in parturient with cardiac disease on BNP levels and on predicting adverse cardiac events. Methods: Thirty cardiac parturient with cesarean section were assigned randomly into two groups of equal size. Group A: participants received general anesthesia (GA); Group B: participants received spinal anesthesia. Preoperative and 2 and 24 h postoperative BNP levels were measured. Intraoperative and 24 h postoperative cardiac complications were observed. Results: Preoperative and 2 and 24 h postoperative BNP mean levels were similar in the two groups. In each group, the 2 and 24 h postoperative rise in BNP mean levels was insignificant compared to the preoperative mean levels of BNP. Incidence of complications was comparable in both groups, but it was associated with the already high preoperative levels of BNP. Conclusions: The study concludes that safely conducted certain type of anesthesia has no effect on the perioperative BNP levels nor incidence of complications which is associated with the already high preoperative BNP levels. [ABSTRACT FROM AUTHOR]

Purpose: Individualizing fluid resuscitation utilizing indicators that assess fluid tolerance could positively impact optimizing volemia while avoiding venous congestion in cardiac surgery. Our study aims to describe hemodynamic changes based on the assessment of venous congestion using transesophageal ultrasonography (TEUS), both before and after cardiopulmonary bypass (CPB) in patients with preserved right ventricle (RV) function. Methods: A retrospective study was conducted at the Hospital Privado Universitario de Córdoba, involving patients who underwent cardiac surgery with CPB. The study assessed ultrasonographic venous congestion parameters before and after CPB using TEUS. The measured parameters included the diameter of the inferior vena cava (IVC), the pattern of hepatic vein flow (HVF), and the pulsatility index of portal vein flow (PVF). Results: A total of 43 patients who underwent cardiac surgery between January 2021 and January 2022 were enrolled. A significant difference in the IVC diameter was observed before and after initiation of CPB (p =.0001). Comparative measurements of the HVF pattern before and after CPB revealed a significant difference, indicating modifications in congestion patterns related to CPB initiation (p =.0001). Pre‐CPB, portal flow was normal in all patients, while more than 50% of patient showed altered post‐CPB PVF. A significant difference in the PVF pulsatility index related to CPB initiation was observed, suggesting increased portal venous congestion (p =.0001). Conclusion: Our study demonstrates that extracorporeal circulation can induce signs of venous congestion, which are detectable by TEUS, in patients with preserved RV function preoperatively. [ABSTRACT FROM AUTHOR]

Purpose: Myocardial T1ρ mapping techniques commonly acquire multiple images in one breathhold to calculate a single‐slice T1ρ map. Recently, non‐selective adiabatic pulses have been used for robust spin‐lock preparation (T1ρ,adiab). The objective of this study was to develop a fast multi‐slice myocardial T1ρ,adiab mapping approach. Methods: The proposed‐sequence reduces the number of breathholds required for whole‐heart 2D T1ρ,adiab mapping by acquiring multiple interleaved slices in each breathhold using slice‐selective T1ρ,adiab preparation pulses. The proposed‐sequence was implemented with two interleaved slices per breathhold scan and was quantitatively evaluated in phantom experiments and 10 healthy‐volunteers against a single‐slice T1ρ,adiab mapping sequence. The sequence was demonstrated in two patients with myocardial scar. Results: The phantom experiments showed the proposed‐sequence had slice‐to‐slice variation of 1.62% ± 1.05% and precision of 4.51 ± 0.68 ms. The healthy volunteer cohort subject‐wise mean relaxation time was lower for the proposed‐sequence than the single‐slice sequence (137.7 ± 5.3 ms vs. 148.4 ± 8.3 ms, p < 0.001), and spatial‐standard‐deviation was better (18.7 ± 1.8 ms vs. 21.8 ± 3.4 ms, p < 0.018). The mean within‐subject, coefficient of variation was 5.93% ± 1.57% for the proposed‐sequence and 6.31% ± 1.92% for the single‐slice sequence (p = 0.35) and the effect of slice variation (0.81 ± 4.87 ms) was not significantly different to zero (p = 0.61). In both patient examples increased T1ρ,adiab (maximum American Heart Association‐segment mean = 174 and 197 ms) was measured within the myocardial scar. Conclusion: The proposed sequence provides a twofold acceleration for myocardial T1ρ,adiab mapping using a multi‐slice approach. It has no significant difference in within‐subject variability, and significantly better precision, compared to a 2D T1ρ,adiab mapping sequence based on non‐selective adiabatic spin‐lock preparations. [ABSTRACT FROM AUTHOR]

Purpose: Diffusion encoding gradient waveforms can impart intra‐voxel and inter‐voxel dephasing owing to bulk motion, limiting achievable signal‐to‐noise and complicating multishot acquisitions. In this study, we characterize improvements in phase consistency via gradient moment nulling of diffusion encoding waveforms. Methods: Healthy volunteers received neuro (N=10$$ N=10 $$) and cardiac (N=10$$ N=10 $$) MRI. Three gradient moment nulling levels were evaluated: compensation for position (M0$$ {M}_0 $$), position + velocity (M1$$ {M}_1 $$), and position + velocity + acceleration (M1+M2$$ {M}_1+{M}_2 $$). Three experiments were completed: (Exp‐1) Fixed Trigger Delay Neuro DWI; (Exp‐2) Mixed Trigger Delay Neuro DWI; and (Exp‐3) Fixed Trigger Delay Cardiac DWI. Significant differences (p<0.05$$ p<0.05 $$) of the temporal phase SD between repeated acquisitions and the spatial phase gradient across a given image were assessed. Results: M0$$ {M}_0 $$ moment nulling was a reference for all measures. In Exp‐1, temporal phase SD for Gz$$ {G}_z $$ diffusion encoding was significantly reduced with M1$$ {M}_1 $$ (35% of t‐tests) and M1+M2$$ {M}_1+{M}_2 $$ (68% of t‐tests). The spatial phase gradient was reduced in 23% of t‐tests for M1$$ {M}_1 $$ and 2% of cases for M1+M2$$ {M}_1+{M}_2 $$. In Exp‐2, temporal phase SD significantly decreased with M1+M2$$ {M}_1+{M}_2 $$ gradient moment nulling only for Gz$$ {G}_z $$ (83% of t‐tests), but spatial phase gradient significantly decreased with only M1$$ {M}_1 $$ (50% of t‐tests). In Exp‐3, M1+M2$$ {M}_1+{M}_2 $$ gradient moment nulling significantly reduced temporal phase SD and spatial phase gradients (100% of t‐tests), resulting in less signal attenuation and more accurate ADCs. Conclusion: We characterized gradient moment nulling phase consistency for DWI. Using M1 for neuroimaging and M1 + M2 for cardiac imaging minimized temporal phase SDs and spatial phase gradients. [ABSTRACT FROM AUTHOR]

Background: The β-adrenergic augmentation of cardiac contraction, by increasing the conductivity of L-type voltage-gated CaV1.2 channels, is of great physiological and pathophysiological importance. Stimulation of β-adrenergic receptors (βAR) activates protein kinase A (PKA) through separation of regulatory (PKAR) from catalytic (PKAC) subunits. Free PKAC phosphorylates the inhibitory protein Rad, leading to increased Ca2+ influx. In cardiomyocytes, the core subunit of CaV1.2, CaV1.2α1, exists in two forms: full-length or truncated (lacking the distal C-terminus (dCT)). Signaling efficiency is believed to emanate from protein interactions within multimolecular complexes, such as anchoring PKA (via PKAR) to CaV1.2α1 by A-kinase anchoring proteins (AKAPs). However, AKAPs are inessential for βAR regulation of CaV1.2 in heterologous models, and their role in cardiomyocytes also remains unclear. Results: We show that PKAC interacts with CaV1.2α1 in heart and a heterologous model, independently of Rad, PKAR, or AKAPs. Studies with peptide array assays and purified recombinant proteins demonstrate direct binding of PKAC to two domains in CaV1.2α1-CT: the proximal and distal C-terminal regulatory domains (PCRD and DCRD), which also interact with each other. Data indicate both partial competition and possible simultaneous interaction of PCRD and DCRD with PKAC. The βAR regulation of CaV1.2α1 lacking dCT (which harbors DCRD) was preserved, but subtly altered, in a heterologous model, the Xenopus oocyte. Conclusions: We discover direct interactions between PKAC and two domains in CaV1.2α1. We propose that these tripartite interactions, if present in vivo, may participate in organizing the multimolecular signaling complex and fine-tuning the βAR effect in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Background Key Findings Conclusions There is little information on the prevalence of auscultatory abnormalities in anemic cats. This study aimed to describe the prevalence of cardiac murmurs and gallop sounds in a population of anemic and nonanemic cats presenting to an emergency room (ER) and to assess whether the prevalence of auscultatory abnormalities was influenced by the severity of anemia.Records of cats presenting to an ER between May 2021 and May 2022 or receiving a blood transfusion between September 2019 and January 2022 were retrospectively analyzed for presence of a murmur or gallop sound. Cats with known structural heart disease were excluded. A murmur was found in 56 of 185 (30%) anemic cats compared with 11 of 102 (11%) nonanemic cats (p < 0.001), with a higher proportion in cats with PCV <16% (p < 0.001). Twenty‐five of 185 (14%) anemic cats had a gallop compared with 4 of 102 (4%) nonanemic cats (p = 0.009), with the highest proportion in cats with PCV 11%–20% (p < 0.001). Echocardiography was performed on 17 of 185 anemic cats; 8 had normal echocardiograms and 9 demonstrated evidence of chamber dilation without left ventricular wall thickening, consistent with anemia.Abnormalities on auscultation are common in anemic cats presenting to the ER, with a higher prevalence in more severely anemic cats. [ABSTRACT FROM AUTHOR]

ABSTRACT Aim Design Methods Results Conclusion Implications for the Profession and/or Patient Care Impact Reporting Method Patient Contribution To explore descriptions of normalcy among individuals who have lived with mechanical circulatory support for a long time.Reflexive thematic analysis was used for this qualitative research.A parent study, utilising constructivist grounded theory, was conducted to explore the experiences of advance care planning among mechanical circulatory support individuals. Participants spontaneously shared their experiences of normalcy, which was outside the scope of the primary study. Thus, a secondary analysis using reflexive thematic analysis was performed to explore experiences of normalcy among individuals living with mechanical circulatory support for long‐term use.Twelve transcripts were purposively sampled and analysed. Three major themes were derived from the data: acquiescence, adapting to the device and restructuring family roles.Normalcy continued to evolve years after device implantation because individuals were not prepared to face ongoing psychosocial challenges. Clinicians and researchers must address the complex emotional and social needs related to changes in goal therapy and unanticipated transplant delays. This includes the development of support groups that are aligned with the various stages of the MCS trajectory.Clinicians need to engage patients in conversations about disruptions to their perceived ‘normal’ lifestyle and how they plan to adapt to complex changes. Future support groups can be organised according to individuals' duration of implantation and goal therapy to reduce social withdrawal. Additionally, clinicians should assess bridge to transplant individuals' attitudes before connecting them with transplanted volunteers. Finally, clinicians can support resilience by recognising and discussing the ongoing work required to adapt to the complex changes throughout the mechanical circulatory support trajectory.Perceptions of normalcy among mechanical circulatory support individuals are subject to ongoing change. Findings will inform clinicians of the social, emotional and familial challenges that require ongoing support and resources for long‐term mechanical circulatory support individuals.Reporting adhered to the COREQ checklist.Participants contributed to this study by sharing their experiences of normalcy after living with mechanical circulatory support for 2 years or more. [ABSTRACT FROM AUTHOR]

AIM: The "2024 AHA/ACC/ACS/ASNC/HRS/SCA/SCCT/SCMR/SVM Guideline for Perioperative Cardiovascular Management for Noncardiac Surgery" provides recommendations to guide clinicians in the perioperative cardiovascular evaluation and management of adult patients undergoing noncardiac surgery. METHODS: A comprehensive literature search was conducted from August 2022 to March 2023 to identify clinical studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE: Recommendations from the "2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery" have been updated with new evidence consolidated to guide clinicians; clinicians should be advised this guideline supersedes the previously published 2014 guideline. In addition, evidence-based management strategies, including pharmacological therapies, perioperative monitoring, and devices, for cardiovascular disease and associated medical conditions, have been developed. [ABSTRACT FROM AUTHOR]

Minimal residual disease (MRD) is of growing interest in light chain (AL) amyloidosis and is associated with higher rates of cardiac response. A new graded cardiac response criteria has been proposed for better assessment of cardiac improvement. We evaluated MRD status in 63 patients with cardiac AL amyloidosis using next generation flow cytometry (sensitivity ≥ 1*10–5) within four cycles after treatment initiation and cardiac response kinetics. All patients were treated with first-line proteasome inhibitor (100%) and predominantly bortezomib (87.3%). The overall early MRD negative rates were 33.3%. Patients who achieved early MRD negativity were less likely to harbor t(11;14) (21.1% vs 57.5%, P = 0.009). The MRD negative rates amongst patients in hematologic complete response were 66.7% (14/21), and in very good partial response 29.2% (7/24). Early MRD negativity was associated with a higher likelihood of achieving ≥ cardiac partial response (≥ CarPR) (66.7% vs 38.1%, P = 0.032) and ≥ cardiac very good partial response (≥ CarVGPR) (38.1% vs 11.9%, P = 0.023) throughout first-line therapy. The cumulative incidence curve of achieving ≥ CarPR (P = 0.034) and ≥ CarVGPR (P = 0.026) showed significant difference between early MRD negative and positive group. After a median follow-up time of 27.2 months, the median progression free survival was longer in early MRD negative group (not reached vs 31.3 months, P = 0.033). Early MRD eradication in cardiac AL amyloidosis generated deeper and faster cardiac organ response. [ABSTRACT FROM AUTHOR]

Due to the current organ shortage waitlist, alternatives to allotransplantation are necessary. Xenotransplantation is currently being pursued as one such alternative in adults in need of kidney or heart transplantation. Cardiac xenotransplantation of genetically modified pig hearts has been conducted twice in adults under the United States Food and Drug Administration (FDA) expanded access criteria. Because of the shortage of transplantable hearts for children as well as the lack of mechanical circulatory support in this population, pediatric researchers are exploring FDA expanded access in high‐risk neonates and infants who lack alternative options for survival. The adult cardiac xenotransplantation experience with expanded access can provide lessons and highlight nuances for researchers preparing pediatric application. This includes aspects of informed consent, biosurveillance, and protection of bystanders from potential xenozoonoses. [ABSTRACT FROM AUTHOR]

Background: Congenital heart disease (CHD) is one the most common congenital anomalies, with a prevalence of 8-10 cases per 1000 live births in the United States. Congenital heart disease has been recognized as a risk factor for poor perioperative and postoperative outcomes in non-cardiac surgery. We aimed to determine if documentation of CHD-related diagnosis codes was associated with similar risks for trauma surgery. Methods: Data were acquired from the 2010-2019 American College of Surgeons' Trauma Quality Programs Participant Use Files. This study included trauma patients of all ages with one or more surgical procedures and at least one documented non-trauma (comorbidity) International Classification of Diseases code. Patients were stratified based on presence of CHD-related comorbidity codes vs any other comorbidity. Outcomes included mortality, hospital length of stay (LOS), discharge disposition, and in-hospital complications. Results: Using 1:1 propensity score matching, we matched 215 cases with CHD-related comorbid diagnoses to non-CHD controls. Compared to patients with other comorbidities, patients with CHD-related comorbidites were less likely to be discharged home to self-care (odds ratio: 0.44, 95% confidence interval [CI]: 0.25, 078 P = .005) and tended to have prolonged hospital LOS (incidence rate ratio [IRR]: 1.06, 95% CI: 1.001, 1.13, P = .046). Conclusions: We present the first quantitative multicenter analysis correlating documentation of comorbid CHD-related diagnoses with higher risk of adverse outcomes after trauma surgery. These results support the need to routinely acknowledge and document CHD as comorbidity in trauma admissions that could lead to surgical intervention and for trauma centers to prepare for patients with a possible CHD comorbidity. [ABSTRACT FROM AUTHOR]

• Minor ECG abnormalities are common in children evaluated in the emergency center. • Epilepsy and increased respiratory support are independent factors for abnormal ECGs. • Increased respiratory support is associated with abnormal ECGs in the epilepsy group. • Impaired respiration may have independent, adverse cardiac effects in epilepsy. We sought to examine the effects of acute seizures and respiratory derangement on the cardiac electrical properties reflected on the electrocardiogram (ECG); and to analyze their potential interactions with a diagnosis of epilepsy in children. Emergency center (EC) visits with seizure or epilepsy diagnostic codes from 1/2011–12/2013 were included if they had ECG within 24 h of EC visit. Patients were excluded if they had pre-existing cardiac conditions, ion channelopathy, or were taking specific cardiac medications. Control subjects were 1:1 age and gender matched. Abnormal ECG was defined as changes in rhythm, PR, QRS, or corrected QT intervals; QRS axis or morphology; ST segment; or T wave morphology from normal standards. We identified independent associations between clinical factors and abnormal ECG findings using multivariable logistic regression modeling. Ninety-five children with epilepsy presented to the EC with seizures, respiratory distress, and other concerns. Three hundred children without epilepsy presented with seizures. There was an increased prevalence of minor ECG abnormalities in children with epilepsy (49 %) compared to the control subjects (29 %) and those without epilepsy (36 %). Epilepsy (OR: 1.61, 95 %CI: 1.01–2.6), need for supplemental oxygen (OR 3.06, 95 % CI: 1.45–6.44) or mechanical ventilation (OR: 2.5, 95 % CI: 1.03–6.05) were independently associated with minor ECG abnormalities. Secondary analyses further demonstrated an independent association between level of respiratory support and ECG abnormalities only in the epilepsy group. Independent association of increased respiratory support with minor ECG abnormalities suggests a potential respiratory influence on the hearts of children with epilepsy. [ABSTRACT FROM AUTHOR]

We report a case of a giant tortuous right coronary artery to coronary sinus fistula with severe tricuspid regurgitation in a 78-year-old female. The initial working diagnosis was based on clinical manifestations and echocardiography, further supported with computed tomography coronary angiography. The fistula was surgically closed with satisfactory results. This case highlights the rarity and complexity of giant right coronary artery fistulas, and the current challenges of diagnosing and managing these fistulas, particularly in older adults. It explores the role of imaging in clinical evaluation, and the ongoing need for research and monitoring of long-term postoperative outcomes. [ABSTRACT FROM AUTHOR]

The aim of the study was to evaluate the presenting complaint, cardiovascular sequelae prevalence and type and demographic characteristics of patients who had no previous disease and had cardiac complaints after COVID-19, and to show the presence of cardiac sequelae objectively by evaluating every patient without chronic diseases by echocardiography and electrocardiography. In this study, we evaluated symptomatic patients by using echocardiography. In this study, there were included patients who recovered from COVID-19 disease and presented to the cardiology outpatient clinics. These patients were divided into two groups: those presenting within the first 30 days after recovery and those presenting between 30 and 60 days after recovery. Thirty patients who had not had COVID-19 before, who applied to the cardiology outpatient clinics, were selected as the control group. The rate of dizziness, palpitations, chest pain and blood pressure dysregulation did not differ si gnificantly between group I(patients presenting within 30 days after recovery), group II(patients presenting between 30 and 60 days after recovery), and group III(control group) (p> 0.05). Dyspnea rate in group I was significantly higher than group II and group III. There was a difference between groups in left ventricular ejection fraction. In group III, sPAP ≥ 35 mmHg ratio was significantly lower than group I and group II (p <0.05). sPAP ≥ 35 mmHg ratio did not differ significantly (p> 0.05) between group I and group II. While dyspnea was an important complaint in the first periods, it decreased over time. In addition, it was observed that right ventricular functions and left ventricular diastolic functions improved over time. It is noteworthy that there are more patients with pericardial effusion compared to the control group, which shows us that the inflammation process is continuing. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are a major cause of death worldwide. Advanced in vitro models can be the key stone for a better understanding of the mechanisms at the basis of the different pathologies, supporting the development of novel therapeutic protocols. In particular, the implementation of induced pluripotent stem cell (iPSC) technology allows for the generation of a patient-specific pluripotent cell line that is able to differentiate in several organ-specific cell subsets while retaining the patient genetic background, thus putting the basis for personalized in vitro modeling toward personalized medicine. The design of iPSC-based models able to recapitulate the complexity of the cardiac environment is a critical goal. Here, we review some of the published efforts to exploit three dimensional (3D) iPSC-based methods to recapitulate the relevant cardiomyopathies, including genetically and non-genetically determined cardiomyopathies and cardiotoxicity studies. Finally, we discuss the actual method limitations and the future perspectives in the field. [ABSTRACT FROM AUTHOR]

Background Mesenteric ischemia (Me-Is) after cardiac surgery is underreported in present literature but has still earned the bad reputation of a dismal prognosis. This study adds clinical outcomes in a large patient cohort. Methods Between 2009 and 2019 of the 22,590 patients undergoing cardiac surgery at our facility 106 (0.47%) developed Me-Is postoperatively. Retrospective patient data was analyzed. Additionally, patients were stratified by outcome—survivors and nonsurvivors. Results Patients were predominantly male (n = 68, 64.2%), mean age was 71.2 ± 9.3 years. Most procedures were elective (n = 85, 80.2%) and comprised of more complex combined procedures (50.9%) and redos (17.9%). Mean EuroSCORE II averaged 10.9 ± 12.2%. Survival at 30 days was 49.1% (n = 52). Clinical baseline and procedural characteristics did not differ significantly between survivors and nonsurvivors. The median postoperative interval until symptom onset was 5 days in both groups. Survivors were more frequently diagnosed by computed tomography and nonsurvivors based on clinical symptoms. Me-Is was predominantly nonocclusive (n = 84, 79.2%). Laparotomy was the main treatment in both groups (n = 45, 78.8% vs. n = 48, 88.9%, p = 0.94). Predictors of mortality were maximum norepinephrine doses (hazard ratio [HR] 8.29, confidence interval [CI] 3.39–20.26, p < 0.0001), lactate levels (HR 1.06, CI 1.03–1.09), and usage of inotropes (HR 2.46, CI 1.41–4.30). Conclusion The prognosis of Me-Is following cardiac surgery is poor—independently from diagnostic or treatment patterns. There exists a significant asymptomatic time period postoperatively, in which pathophysiologic processes seem to cross the Rubicon. After clinical demarcation, the further course can almost no longer be influenced. [ABSTRACT FROM AUTHOR]

A routine measurement in heart examination is that of the heart wall thickness. This study investigated whether histology can be used to estimate heart wall thickness measured in a post-mortem examination, and therefore assess the utility of this method in the post-mortem report peer review process. This study compared 30 consecutive adult heart measurements (left and right free wall thickness and interventricular wall thickness). It showed that heart wall thickness measurements on histology slides were non-repeatable, non-reproducible, and unreliable, with overall poor to moderate intraclass correlation coefficient (<0.60, p < 0.05). The 95% confidence interval in the difference between histology and post-mortem examination was 1–3.5 mm for left ventricle and interventricular wall thickness, and −1–0.5 mm for the right ventricle. This study showed limited utility in using histology in estimating heart wall thickness. However, in instances where histology was the only modality available to estimate heart wall, marking where the measurements were taken, citing the confidence intervals, and noting the limitations thereof is recommended. [ABSTRACT FROM AUTHOR]

This review provides a detailed examination of original research and previously published reviews regarding cardiovascular involvement in systemic sclerosis (SSc). Our study aims to evaluate the current understanding of SSc-associated heart involvement (SHI), focusing on its most prevalent forms, diagnostic methods and treatment options. A comprehensive search of PUBMED, Medline, Web of science, Scopus and DOAJ databases was conducted, involving articles published between January 2019 and August 2024, available in English, both original research and reviews. Additionally, the authors examined the references cited in the selected articles, reviewed relevant literature, and included key publications dating back to 2010. Systemic Sclerosis (SSc) is an autoimmune connective tissue disease characterized by skin and internal organs fibrosis with accompanying vasculopathy. SHI encompasses both primary and secondary cardiac disease with a prevalence rate of up to 39%. It constitutes one of the leading causes of death among affected individuals. Systemic sclerosis- primary heart involvement comprises a wide range of conditions including arrhythmias, heart failure, pericardial disease, valvular abnormalities, and myocardial inflammation. However, its subclinical course, often misinterpreted as other forms of cardiomyopathy, poses true diagnostic challenges, requiring diagnostic tools like transthoracic echocardiography with tissue Doppler echocardiography and cardiac magnetic resonance imaging. The review underscores the importance of SHI and a holistic approach to managing patients with systemic sclerosis. Furthermore, it emphasizes the need for further investigation into potential pathogenetic mechanisms and biomarkers crucial for targeted treatment to fully optimize recommendations for this patient subgroup. [ABSTRACT FROM AUTHOR]

Background: Gastrostomy creation is a common pediatric surgical procedure, but the time to initiation of feeds and to goal feeding volumes postoperatively varies greatly. Delays in reaching goal feeding volumes promote malnutrition and may prolong hospital length of stay. We hypothesized that implementing an accelerated, standardized post-gastrostomy feeding protocol would allow patients to reach goal feeding volumes sooner, without increasing postoperative complications. Methods: We conducted a retrospective cohort study of children who underwent gastrostomy tube placement between 1/1/2022 and 11/30/2023. The feeding protocol was implemented on 11/16/2022, with patients separated into pre- and post-protocol cohorts. Abstracted data included comorbidities, time to initiation of enteral feeds, time to goal feeding volume, and postoperative complications. Results: 322 patients were included: 166 pre-protocol and 156 post-protocol. The post-protocol cohort had a greater proportion of patients with gastrointestinal and/or cardiac comorbidities (P < .001). Through the protocol, postoperative enteral feeds were initiated significantly faster (5.4 hrs [IQR 43-7.7] vs 7.0 hrs [IQR 5.6-14.3]; P < .001). The postprotocol cohort also achieved goal feeding volumes sooner (12.8 hrs [IQR 9.1-25.3] vs 26.3 hrs [IQR 21.6-38.9]; P < .001). Postoperative complication rates did not differ between cohorts. Sub-analysis of children with complex cardiac conditions also demonstrated faster time to goal nutrition without an associated increase in postoperative events. Discussion: These findings demonstrate that our accelerated post-gastrostomy feeding protocol was effective in achieving goal enteral nutrition earlier without increasing postoperative adverse outcomes. This protocol may be used by other centers to safely expedite time to goal enteral feeds in children postoperatively. [ABSTRACT FROM AUTHOR]