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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.

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]

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]

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]

Ventricular tachycardia is an irregular heartbeat conventionally treated using invasive cardiac catheter ablation and medication. However, when standard treatments have been exhausted, cardiac SABR provides a final treatment option to this high-mortality condition. Complex diagnostic mapping and planning scans enable multi-disciplinary target delineation for a 25Gy single fraction. However, organs at risk (OAR) near the target make this treatment challenging to plan and deliver. Publications from cardiologists report the efficacy of cardiac SABR, however there is limited data on the treatment delivery and image matching of this complex procedure. Four specialist therapeutic radiographers experienced in cardiac SABR reviewed 40 CBCTs from 10 patients treated in the UK. Each therapeutic radiographer conducted five image matches: a manual match (manual), an automatic match to the heart structure (auto) and the auto match followed by manual adjustment to the PTV (PTV), all using three degrees of freedom (DoF) only. The auto and PTV matches were also repeated using 6DoF. Inter-observer variability was quantified using 95% limits of agreement from a modified Bland-Altman analysis. The limits of agreement were smallest in the automatic matches suggesting the algorithm is reliable. A manual adjustment from the auto match to the PTV is clinically appropriate to optimise target coverage. The limits of agreement were smaller in the 6DoF PTV match 1.06 mm, 1.24 mm, 1.68 mm than the 3DoF PTV match 1.57 mm, 2.06 mm, 2.11 mm (lateral, vertical, longitudinal). The 6DoF CBCT image match has less variability and therefore suggest using a 6DoF couch for treatment delivery. Cardiac SABR CBCT image matching at treatment delivery is complex, optimisation of CBCT acquisition parameters and therapeutic radiographer training is essential prior to implementation. [ABSTRACT FROM AUTHOR]

We describe the development of a bioink to bioprint human induced pluripotent stem cells (hiPSCs) for possible cardiac tissue engineering using a gelatin methacrylate (GelMA)-based hydrogel. While previous studies have shown that GelMA at a low concentration (5% w/v) allows for the growth of diverse cells, its 3D printability has been found to be limited by its low viscosity. To overcome that drawback, making the hydrogel both compatible with hiPSCs and 3D-printable, we developed an extrudable GelMA-based bioink by adding xanthan gum (XG). The GelMA-XG composite hydrogel had an elastic modulus (~9 kPa) comparable to that of cardiac tissue, and enabled 3D printing with high values of printing accuracy (83%) and printability (0.98). Tests with hiPSCs showed the hydrogel's ability to promote their proliferation within both 2D and 3D cell cultures. The tests also showed that hiPSCs inside hemispheres of the hydrogel were able to differentiate into cardiomyocytes, capable of spontaneous contractions (average frequency of ~0.5 Hz and amplitude of ~2%). Furthermore, bioprinting tests proved the possibility of fabricating 3D constructs of the hiPSC-laden hydrogel, with well-defined line widths (~800 μm). [ABSTRACT FROM AUTHOR]

Benign cardiac neoplasms are relatively uncommon. Cardiac leiomyomas are usually diagnosed as a benign metastasizing leiomyoma or as a part of intravenous leiomyomatosis spectrum. Primary cardiac leiomyomas are extremely rare and should be diagnosed after ruling out the involvement of systemic leiomyomas. Only nine cases were found in the literature that described De novo occurrence of primary intra-cardiac leiomyoma. In this study, we present a case of 60-year-old female patient with a large pedunculated mass located in the left ventricle. Histopathology examination and immunohistochemistry aid confirmed the diagnosis of benign leiomyoma. No evidence of extra cardiac lesions was detected in the patient. The patient remained healthy with no signs of recurrence four years after the surgical resection. Benign cardiac tumors are not often seen, but when they do occur, they can present a serious risk to life. This is particularly significant because these tumors can detach and cause embolization, leading to the development of strokes. Moreover, these individuals do not show any clinical symptoms, making their detection quite challenging. When there is a suspicion, it is advised to utilize echocardiography and other imaging techniques to verify the presence of a tumor. In this report, we present a rare case and provide differential diagnoses, along with a review of the literature. [ABSTRACT FROM AUTHOR]

Background: The outstanding capabilities of modern Positron Emission Tomography (PET) to highlight small tumor lesions and provide pathological function assessment are at peril from image quality degradation caused by respiratory and cardiac motion. However, the advent of the long axial field-of-view (LAFOV) scanners with increased sensitivity, alongside the precise time-of-flight (TOF) of modern PET systems, enables the acquisition of ultrafast time resolution images, which can be used for estimating and correcting the cyclic motion. Methods: 0.25 s so-called [18F]FDG PET histo image series were generated in the scope of for detecting respiratory and cardiac frequency estimates applicable for performing device-less data-driven gated image reconstructions. The frequencies of the cardiac and respiratory motion were estimated for 18 patients using Short Time Fourier Transform (STFT) with 20 s and 30 s window segments, respectively. Results: The Fourier analysis provided time points usable as input to the gated reconstruction based on eight equally spaced time gates. The cardiac investigations showed estimates in accordance with the measured pulse oximeter references (p = 0.97) and a mean absolute difference of 0.4 ± 0.3 beats per minute (bpm). The respiratory frequencies were within the expected range of 10–20 respirations per minute (rpm) in 16 out of 18 patients. Using this setup, the analysis of three patients with visible lung tumors showed an increase in tumor SUVmax and a decrease in tumor volume compared to the non-gated reconstructed image. Conclusions: The method can provide signals that were applicable for gated reconstruction of both cardiac and respiratory motion, providing a potential increased diagnostic accuracy. [ABSTRACT FROM AUTHOR]

Ischemic preconditioning (IPC) appears to improve exercise performance although there is uncertainty about the intensity dependence of this effect. The present study sought to clarify effects of IPC on physiological responses at and below peak oxygen uptake, including the gas exchange threshold (GET). Ten male and female participants completed five cycling ramp tests (10 W/min) to failure, with the final two tests preceded by either IPC (4 × 5 min 220 mmHg bilateral leg occlusions) or SHAM (20 mmHg), in a randomised crossover design. The rates of O2 uptake ( V ˙ O2), carbon dioxide output ( V ˙ CO2), and expired ventilation ( V ˙ E) were measured at rest and throughout exercise. Exercise data were fitted using several functions to identify GET, two ventilatory thresholds and peak V ˙ O2. IPC increased V ˙ O2 at GET by ~ 9% (IPC: 1.89 ± 0.51 L/min, SHAM: 1.73 ± 0.56 L/min; p = 0.055) and power output at GET by ~ 11% (IPC: 133 ± 36 W, SHAM: 120 ± 39 W; p = 0.022). In addition, peak power output increased by 2.4% following IPC (IPC: 217 ± 50 W, SHAM: 212 ± 51 W; p = 0.052), but there was no significant effect of IPC on peak V ˙ O2 (IPC: 2.87 ± 0.68 L/min, SHAM: 2.84 ± 0.73 L/min; p = 0.60) or the ventilatory thresholds. The present results suggest that IPC improves GET and peak power output but not peak V ˙ O2 during a maximal graded test. [ABSTRACT FROM AUTHOR]

To evaluate the effect of body position on transesophageal atrial pacing (TEAP) in dogs. Prospective, experimental trial. A total of eight mixed-breed dogs, median body mass 25 kg (range 11–31 kg). TEAP was performed using a 6 Fr (2 mm) pacing catheter introduced transorally and positioned in the lower esophagus in left lateral recumbency. The catheter was withdrawn in 5 mm increments until successful TEAP. The minimum pacing threshold (MPT) was determined at each 5 mm increment until atrial capture could not be achieved at a maximal pulse amplitude of 40 mA. The zone of capture (ZOC) was the total distance over which TEAP was achieved. The same process was repeated in right lateral, ventral and dorsal recumbency. A linear mixed model was used to assess the impact of body position on TEAP and ZOC. TEAP was achieved in all body positions. There was significant random effect of individual dogs on ZOC (p = 0.048) but not on MPT (p = 0.109). MPT was 11.56 ± 8.65 mA (mean ± SD), 8.43 ± 2.29 mA, 10.63 ± 6.91 mA and 10 ± 7.44 mA for dorsal, left and right lateral, and ventral recumbency, respectively. ZOC was 5.12 ± 2.08 cm, 6.35 ± 2.41 cm, 5.94 ± 3.23 cm and 5.31 ± 2.2 cm for dorsal, left lateral and right lateral, and ventral recumbency, respectively. Neither ZOC (p = 0.363) nor MPT (p = 0.716) varied significantly between body positions. TEAP can be performed successfully in all body positions in dogs. Body position did not significantly influence MPT or ZOC values for TEAP. Further studies are needed to compare the efficacy of TEAP with the efficacy of standard pharmacological therapy for management of bradycardia during general anesthesia in dogs. [ABSTRACT FROM AUTHOR]

Systemic air embolism is a rare but potentially life-threatening complication of computed tomography (CT)-guided lung biopsy. The largest lung biopsy audits report an incidence rate of approximately 0.061% for systemic air embolism, with a mortality rate of 0.07-0.15%. A prompt diagnosis with high index of suspicion is essential, and hyperbaric oxygen treatment (HBOT) is the definitive management. We report the case of a 44-year-old lady who developed a lateral ST elevation myocardial infarction from coronary artery air embolism following CT-guided lung biopsy for evaluation of a left lung lesion. The biopsy was performed in the right lateral decubitus position, and the patient reported chest pain after coughing during the procedure. The clinician decided to proceed, taking four biopsy samples as no pneumothorax was identified in the intraprocedural CT image. The patient was noted to have hypotension with ongoing chest pain post-procedure. Resuscitative measures were taken to stabilise her haemodynamics, and she was successfully treated with HBOT with total resolution of air embolism. She developed a left sided pneumothorax post-treatment and needed intercostal chest drain insertion. The left lung fully re-expanded, and the patient was discharged home after day two of admission. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ischemia/reperfusion injury is one of the most challenging postoperative situations in vascular surgery, both in elective procedures with prolonged clamping time and in delayed emergency cases with vascular occlusion. The inflammatory response that develops during ischemia and the oxygen-free radicals that proliferate during reperfusion have detrimental effects on the brain, heart, and kidneys. In this study, we aimed to compare the effects of vanillic and rosmarinic acid in preventing ischemia/reperfusion injury in a lower limb ischemia-reperfusion model in rats. METHODS: Thirty-two female Sprague-Dawley rats weighing 185-240 g were randomly divided into four groups of eight animals each. Group 1 was designated as the control, Group 2 as ischemia/reperfusion (I/R), Group 3 as ischemia/reperfusion + vanillic acid (I/R + VA), and Group 4 as ischemia/reperfusion + rosmarinic acid (I/R + RA). In all groups except the control, the infrarenal abdominal aorta was clamped, and 60 minutes of ischemia followed by 120 minutes of reperfusion was performed. Vanillic acid was administered intra-abdominally 15 minutes before the start of reperfusion in Group 3, and rosmarinic acid in Group 4. At the end of the reperfusion phase, blood samples and hearts were collected, and the rats were euthanized. Histopathologically, myofibrillar edema, myocytolysis, focal hemorrhages, and infiltration of polymorphonuclear leukocytes (PMNL) in cardiac tissue were examined. Total antioxidant capacity (TAC), total oxidative status (TOS), oxidative stress index (OSI), 8-OH-deoxyguanosine, lactonase, and arylesterase activity were measured in blood samples. RESULTS: Myofibrillar edema was most pronounced in the I/R group and less pronounced in the I/R + VA and I/R + RA groups (p=0.005 and p=0.066, respectively). There was no difference between the ischemia/reperfusion groups regarding myocytolysis, focal hemorrhage, and PMNL infiltration (p>0.99). Among all groups, TOS and OSI were lowest in the control group, while TAC was highest. TAC was similar in the I/R + VA and I/R + RA groups but was significantly higher in these two groups than in the I/R group. The lactonase activity in the I/R + VA group was similar to that in the control group but was significantly higher compared to the I/R and I/R + RA groups. CONCLUSION: Our study shows that vanillic and rosmarinic acids reduce myofibrillar edema in the heart after lower limb ischemia and increase TAC. However, vanillic acid increases the activity of lactonase, an enzyme known for its antioxidant effect, more than rosmarinic acid. [ABSTRACT FROM AUTHOR]

Background: The increasing incidence of heart failure (HF) in the elderly leads to increased mortality, hospitalization, length of hospital stay, and health care costs. Older adults often face multiple drug treatments, comorbidities, frailty, and cognitive problems, which require early palliative care. However, these patients do not receive adequate palliative care. Objective: This concept analysis aimed to develop an in-depth understanding of palliative care for elderly patients with cardiac diseases in tertiary care. Design: The analysis was guided by Walker and Avant's method, and databases were searched using keywords, such as palliative care, tertiary care, elderly, and heart. Covidence was used to review the results using the inclusion and exclusion criteria. Results: The World Health Organisation's definition of palliative care is widely accepted. Palliative care for older adults with heart disease in tertiary care is preceded by chronic illness, polypharmacy, symptom burden, physical and cognitive decline, comorbidities, and psychosocial/spiritual issues. The main attributes of palliative care for this population include health care professionals and patient education, holistic patient/family-centered care, symptom management, shared decision-making, early integration, advanced care planning, and a multidisciplinary approach. Palliative care improves elderly cardiac patients' and their family satisfaction while reducing readmission, hospital stays, and unnecessary invasive procedures. Conclusion: Collaboration between hospitals, community organizations, transitional palliative care services, and research has the potential to improve early palliative care and the well-being of the elderly cardiac population. Advanced Practice Nurses (APNs) competencies play a crucial role in promoting palliative care in the elderly HF population. [ABSTRACT FROM AUTHOR]

Background: First‐pass perfusion cardiac MR imaging could reflect pulmonary hemodynamics. However, the clinical value of pulmonary transit time (PTT) derived from first‐pass perfusion MRI in light‐chain (AL) amyloidosis requires further evaluation. Purpose: To assess the clinical and prognostic value of PTT in patients with AL amyloidosis. Study Type: Prospective observational study. Population: 226 biopsy‐proven systemic AL amyloidosis patients (age 58.62 ± 10.10 years, 135 males) and 43 healthy controls (age 42 ± 16.2 years, 20 males). Field Strength/Sequence: SSFP cine and phase sensitive inversion recovery late gadolinium enhancement (LGE) sequences, and multislice first‐pass myocardial perfusion imaging with a saturation recovery turbo fast low‐angle shot (SR‐TurboFLASH) pulse sequence at 3.0T. Assessment: PTT was measured as the time interval between the peaks of right and left ventricular cavity arterial input function curves on first‐pass perfusion MR images. Statistical Tests: Independent‐sample t test, Mann–Whitney U test, Chi‐square test, Fisher's exact test, analysis of variance, or Kruskal–Wallis test, as appropriate; univariable and multivariable Cox proportional hazards models and Kaplan–Meier curves, area under receiver operating characteristic curve were used to determine statistical significance. Results: PTT could differentiate AL amyloidosis patients with (N = 188) and without (N = 38) cardiac involvement (area under the curve [AUC] = 0.839). During a median follow‐up of 35 months, 160 patients (70.8%) demonstrated all‐cause mortality. After adjustments for clinical (Hazard ratio [HR] 1.061, confidence interval [CI]: 1.021–1.102), biochemical (HR 1.055, CI: 1.014–1.097), cardiac MRI‐derived (HR 1.077, CI: 1.034–1.123), and therapeutic (HR 1.063, CI: 1.024–1.103) factors, PTT predicted mortality independently in patients with AL amyloidosis. Finally, PTT could identify worse outcomes in patients demonstrating New York Heart Association class III, Mayo 2004 stage III, and transmural LGE pattern. Data Conclusion: PTT may serve as a new imaging predictor of cardiac involvement and prognosis in AL amyloidosis. Level of Evidence: 2 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Congenital heart defects (CHDs) can have profound and potentially life‐threatening consequences on horses' health and performance capability. While CHDs are rare in the general horse population, the Arabian breed is disproportionately overrepresented and thus is widely suspected to be genetically predisposed. This review discusses the most common CHDs in Arabian horses, including ventricular septal defect (VSD), tetralogy of Fallot (TOF), patent duct arteriosus (PDA), tricuspid valve atresia (TVA) and atrial septal defect (ASD). This review also explores how future research into the genetic factors that likely underpin many CHDs can revolutionise the way these disorders are managed in Arabian horses. [ABSTRACT FROM AUTHOR]

Explainable artificial intelligence (XAI) elucidates the decision-making process of complex AI models and is important in building trust in model predictions. XAI explanations themselves require evaluation as to accuracy and reasonableness and in the context of use of the underlying AI model. This review details the evaluation of XAI in cardiac AI applications and has found that, of the studies examined, 37% evaluated XAI quality using literature results, 11% used clinicians as domain-experts, 11% used proxies or statistical analysis, with the remaining 43% not assessing the XAI used at all. We aim to inspire additional studies within healthcare, urging researchers not only to apply XAI methods but to systematically assess the resulting explanations, as a step towards developing trustworthy and safe models. [ABSTRACT FROM AUTHOR]