Normal Cardiac Function Research Articles

FAM210A regulates mitochondrial translation and maintains cardiac mitochondrial homeostasis.

Mitochondria play a vital role in cellular metabolism and energetics and support normal cardiac function. Disrupted mitochondrial function and homeostasis cause a variety of heart diseases. Fam210a (family with sequence similarity 210 member A), a novel mitochondrial gene, is identified as a hub gene in mouse cardiac remodelling by multi-omics studies. Human FAM210A mutations are associated with sarcopenia. However, the physiological role and molecular function of FAM210A remain elusive in the heart. We aim to determine the biological role and molecular mechanism of FAM210A in regulating mitochondrial function and cardiac health in vivo. Tamoxifen-induced αMHCMCM-driven conditional knockout of Fam210a in the mouse cardiomyocytes induced progressive dilated cardiomyopathy and heart failure, ultimately causing mortality. Fam210a deficient cardiomyocytes exhibit severe mitochondrial morphological disruption and functional decline accompanied by myofilament disarray at the late stage of cardiomyopathy. Furthermore, we observed increased mitochondrial reactive oxygen species production, disturbed mitochondrial membrane potential, and reduced respiratory activity in cardiomyocytes at the early stage before contractile dysfunction and heart failure. Multi-omics analyses indicate that FAM210A deficiency persistently activates integrated stress response, resulting in transcriptomic, translatomic, proteomic, and metabolomic reprogramming, ultimately leading to pathogenic progression of heart failure. Mechanistically, mitochondrial polysome profiling analysis shows that FAM210A loss of function compromises mitochondrial mRNA translation and leads to reduced mitochondrial-encoded proteins, followed by disrupted proteostasis. We observed decreased FAM210A protein expression in human ischaemic heart failure and mouse myocardial infarction tissue samples. To further corroborate FAM210A function in the heart, AAV9-mediated overexpression of FAM210A promotes mitochondrial-encoded protein expression, improves cardiac mitochondrial function, and partially rescues murine hearts from cardiac remodelling and damage in ischaemia-induced heart failure. These results suggest that FAM210A is a mitochondrial translation regulator to maintain mitochondrial homeostasis and normal cardiomyocyte contractile function. This study also offers a new therapeutic target for treating ischaemic heart disease.

Interaction of Filamin C With Actin Is Essential for Cardiac Development and Function.

FLNC (filamin C), a member of the filamin family predominantly expressed in striated muscles, plays a crucial role in bridging the cytoskeleton and ECM (extracellular matrix) in cardiomyocytes, thereby maintaining heart integrity and function. Although genetic variants within the N-terminal ABD (actin-binding domain) of FLNC have been identified in patients with cardiomyopathy, the precise contribution of the actin-binding capability to FLNC's function in mammalian hearts remains poorly understood. We conducted in silico analysis of the 3-dimensional structure of mouse FLNC to identify key amino acid residues within the ABD that are essential for FLNC's actin-binding capacity. Subsequently, we performed coimmunoprecipitation and immunofluorescent assays to validate the in silico findings and assess the impact of these mutations on the interactions with other binding partners and the subcellular localization of FLNC. Additionally, we generated and analyzed knock-in mouse models in which the FLNC-actin interaction was completely disrupted by these mutations. Our findings revealed that F93A/L98E mutations completely disrupted FLNC-actin interaction while preserving FLNC's ability to interact with other binding partners ITGB1 (β1 integrin) and γ-SAG (γ-sarcoglycan), as well as maintaining FLNC subcellular localization. Loss of FLNC-actin interaction in embryonic cardiomyocytes resulted in embryonic lethality and cardiac developmental defects, including ventricular wall malformation and reduced cardiomyocyte proliferation. Moreover, disruption of FLNC-actin interaction in adult cardiomyocytes led to severe dilated cardiomyopathy, enhanced lethality and dysregulation of key cytoskeleton components. Our data strongly support the crucial role of FLNC as a bridge between actin filaments and ECM through its interactions with actin, ITGB1, γ-SAG, and other associated proteins in cardiomyocytes. Disruption of FLN-actin interaction may result in detachment of actin filaments from the extracellular matrix, ultimately impairing normal cardiac development and function. These findings also provide insights into mechanisms underlying cardiomyopathy associated with genetic variants in FLNC ABD and other regions.

Severe form of COVID-19 in a neonate with resuscitated cardio-respiratory arrest - Case presentation

SARS-CoV-2 infection is usually a self-limiting viral infection in healthy children. Still, it’s effects on the neonatal population remain largely unknown. There has been evidence of adverse events on neonates, mostly consisting in case reports of patients with severe forms of COVID-19 and also recent cohort studied of the pediatric population including the neonatal subgroup. The clinical presentation appears different in the neonatal patients in contrast with older children, and may manifest also as a life-threatening respiratory infection with systemic complications. In this paper we present a clinical case of a premature boy with a corrected age of 40 weeks at admission to the Pediatric Infectious Diseases Clinical Department IX of the National Institute of Infectious Diseases “Prof. Dr. Matei Bals” with the diagnosis of SARS-CoV-2 infection. The positive diagnosis was established on suggestive clinical picture (fever, dry couch, rhinorrhea, loose stools and inappetence) and confirmed by SARS-CoV-2 rapid antigen test. Laboratory investigations at admission showed only moderate to severe anemia, mild inflammatory syndrome and a mild neonatal hyperbilirubinemia, with normal leukocyte count, normal glycaemia, ionograme and blood gases. Chest x-ray showed moderate interstitial pneumonia. In the second day of admission, after 24h of favorable evolution, with no fever and present appetite, he suddenly presented during defecation a presumptive vasovagal syndrome, with general hypotonia and a short period of desaturation. Laboratory investigations made during the episode showed normal glycaemia, normal ionograme, normal blood gases, moderate-severe anemia and important metabolic acidosis. A new chest x-ray showed evolution of the interstitial pneumonia. We did a blood transfusion and continued antiviral treatment, antibiotic treatment and perfusions. He maintained normal pulmonary and cardiac function for another 6 hours, after which he presented a tonic-clonic seizure and after administration of intrarectal benzodiazepines he presented cardio-pulmonary arrest. He was resuscitated, intubated and sedated and transfer to a children ICU. 2 weeks later after admission in the ICU he was discharged with favorable outcome. The case presented shows that although SARS-CoV-2 infection is often a mild condition in children, COVID-19 in neonates can have an unpredicted course. Rapid evolution to sever forms can be a possible disease outcome. Preterm birth with associated complications like bronchodysplasia or anemia, can predispose to sever evolution of the disease, and this child must be kept safe. There is also a neurotropic potential of the SARS-CoV-2 virus that has to be followed.

News from the European Journal of Therapeutics: A new issue and a new editorial board

News from the European Journal of Therapeutics: A new issue and a new editorial board

Ventricular Extrasystole in Children: Single-Center Experience.

Ventricular extrasystole is one of the most common rhythm disorders in children, and almost all of them are characterized by normal cardiac functions without structural cardiac abnormalities. The aim of this study was to assess the clinical course of ventricular extrasystole in children who did not have cardiac structural abnormalities. This retrospective study analyzed 24-hour rhythm Holter recordings performed in our clinic in children. Patients diagnosed with isolated ventricular extrasystole in Holter records and without structural heart disease on echocardiography were included in the evaluation. A total of 20 160 Holter results were evaluated in the study, and 226 patients (male; 66%) met the criteria. The mean follow-up time was 8.7 ± 3.2 years. While 81.8% of the patients were asymptomatic, the most common symptom was palpitation and 5 patients had syncope. Of the patients, 72 (31.8%) received medical therapy. Beta-blockers were the most often pre- scribed medication. Cardiomyopathy did not develop in any of the patients during the follow- up period. A partial reduction in the frequency of ventricular extrasystole was observed in 42% of the patients, while complete recovery was observed in 22%. Ventricular extrasystole in children generally has a good prognosis; most of them are asymptomatic, and the rates of spontaneous regression over time are quite high, regard- less of the origin.

Machine learning for the generation of personalized image analysis protocol in echocardiography: a pilot study in arterial hypertension

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agence National de la Recherche Europian Union-NextGenerationEU. Background Current workflow in cardiac imaging is based on protocols meant to capture a set of predefined images for a certain condition [1]. Although standardized, such approaches are not personalized, and are often time- and resource-ineffective. Reinforcement learning (RL), a subfield of machine learning that addresses decision making [2], can be used to incorporate complex, whole cardiac cycle imaging data, while optimizing costs associated to data acquisition and processing – including economy, patient safety/comfort and examination time. Our aim is to demonstrate the viability of RL to create a personalized, resource-effective data analysis routine from echocardiography to separate remodelling in arterial hypertension from normal cardiac function. Methods An echo study was performed in 189 clinically managed hypertensive (HTN) patients, and 60 non-hypertensive healthy control subjects [3]. Speckle-tracking analysis of the left ventricle was performed and deformation curves extracted. Aortic and mitral flow pulsed-wave (PW) Doppler and septal basal tissue PW Doppler velocity profiles were obtained. These whole cardiac cycle deformation and velocity curves were used as input data to the RL algorithm. RL optimized the required image analysis sequence to maximize the probability of obtaining a correct diagnosis while reducing the number of analysed images. Results The RL-generated protocol identified three separate image analysis groups to determine cardiac remodelling (Figure 1). The proposed protocol starts with the analysis of the mitral PW, and based on its velocity pattern, assigns each individual to one of the three groups. In Group 1 (G1, n=158) analysing the mitral PW acquisition was sufficient to determine disease status. HTN patients were separated based on a pattern of an inversed E/A ratio and EA fusion reflecting signs of diastolic dysfunction. In G2 (n=56), mitral flow showed a slightly decreased E/A ratio and longer E deacceleration time, and adding aortic PW was required to determine remodelling: HTN had higher aortic peak velocity and shorter peak acceleration time due to higher systemic afterload. Finally, G3 (n=19) required global longitudinal strain, which showed pathological early systolic stretching, reflecting the change in the timing of cardiac events in arterial hypertension. Fifteen (6%) participants did not match any of the groups, requiring the acquisition of remaining sequences (TDI, regional strain) to secure a correct diagnosis. In average, the protocol analysed 1.44 images per patient, out of the four available. Conclusion Through a pilot study utilizing a limited set of imaging sequences, we demonstrate a template for automated generation of efficient, tailored image analysis protocols, that minimimize the number of analyzed images to determinine patient phenotypes. RL is a promising tool to reduce analysis time, potentially saving costs in preventive screening programs.

Development of T-ARMS-PCR to Detect MYBPC3 Gene Variation in Hypertrophic Cardiomyopathy (HCM) Patients

Hypertrophic cardiomyopathy (HCM) is a common and complex, genetically inherited, cardiovascular disorder. It is typically inherited in an autosomal dominant manner with variable penetrance and mutable expression. Mutations in MYBPC3 gene is one of the genetic causes of HCM. Only 0.2% of general population suffers from HCM. The MYBPC3 gene provides instructions for making cardiac myosin binding protein C, which is imperative for the maintenance and regulation of normal cardiac functions. This study aims to explore the reported SNP rs1052373 from exon 30 of MYBPC3 gene in the population of Punjab, Pakistan. The reported SNP rs1052373 was analysed using Tetra Amplification Refractory Mutation System Polymerase Chain Reaction (T-ARMS-PCR) to find the allelic frequency in the selected population. T-ARMS-PCR is a cost effective, flexible, rapid, and accurate tool for genotyping. The specific sequences of MYBPC3 gene from exons 30 and 31 and introns 29, 30, and 31 were retrieved from NCBI (https://www.ncbi.nlm.nih.gov/). A tetra primer designing tool known as Primer 1 (http://primer1.soton.ac.uk/primer1.html) was used to design the primers for the targeted region of MYBPC3 gene. In this study, the genotyping of previously reported SNP rs1052373 showed variation in the disease group, giving CC, CT, and TT genotypes with the frequency of 0.04. The genotyping analysis of rs1052373 showed that the allelic frequency of homozygous condition T/T was 0.02 and the allelic frequency of heterozygous condition C/T was 0.02 in disease group as compared to the control group. In the latter, the homozygous T/T and heterozygous C/T genotypes were not observed in any individuals. All the individuals in control group carried homozygous C/C genotype. While, the frequency of homozygous C/C genotype was 0.96 in disease group. The findings of this study would help to find novel molecular markers for HCM diagnosis.

Long-term outcomes of left ventricular posterior wall plication for ischemic mitral regurgitation.

To evaluate the early and long-term outcomes of left ventricular posterior wall plication for ischemic mitral regurgitation. Patients with ischemic mitral regurgitation who underwent left ventricular posterior wall plication via right-sided left atriotomy at our institution between 2010 and 2020 were retrospectively reviewed. Cases with normal cardiac function, left ventricular end-systolic diameter < 50mm, and left ventriculotomy approach were excluded. The mean follow-up period was 5.3years [standard deviation (SD) = 3.5], with a maximum of 10years. Among the 21 patients enrolled, 9 had New York Heart Association (NYHA) class ≥ III. Three patients required preoperative inotrope support, while two preoperative ventilator support. The mean left ventricular ejection fraction was 31.4% (SD: 8.6), and 16 patients had mitral regurgitation grade ≥ III. All patients underwent coronary artery bypass grafting and mitral annuloplasty. Concomitant surgeries included 11 chordae cutting and 3 tricuspid annuloplasties. One in-hospital death occurred due to sepsis. At the follow-up, echocardiographic data showed significant improvement in cardiac dilation and function and good control of mitral regurgitation. The serum brain natriuretic peptide level was significantly reduced, and 85% of patients improved to NYHA class I. Four deaths occurred later due to sudden, unknown causes. The 5- and 8-year survival rates were 60.2% and 46.8%, respectively, and the 5- and 8-year hospitalization rates due to heart failure were 14.9% and 21.3%, respectively. The long-term outcomes of left ventricular posterior wall plication were satisfactory for controlling heart failure and improving survival rate and patient prognosis. The online version contains supplementary material available at 10.1007/s12055-023-01527-2.

Empiric anti-Giardia therapy in non-diarrheal protein-losing enteropathy: A focus on children with monogenic humoral immunodeficiency.

Background and Aim: Chronic giardia infection can lead to non-erosive gastrointestinal disorders, including protein-losing enteropathy (PLE). This report describes non-diarrheal PLE in chronic giardiasis in children with defective humoral immunity. Methods: The retrospective report is related to 2 children known to have a monogenic inborn error of immunity. The first patient is a 13-year-old boy with X-linked agammaglobulinemia (Patient-1), and the second is a 5-year-old boy with NF-kB inducing kinase (NIK) deficiency infection. Frequency, growth status, and serum immunoglobulin-G (IgG) trough and albumin levels were monitored (Patient-2). Results: Patient-1 had more frequency of pneumonia but reported no symptoms of gastrointestinal disease, including alteration of bowel habits, change in stool consistency, nausea, vomiting, fatigue, bloating, and abdominal pain. No clinical oedema on examination. His weight remains static at 19-20 kg for about 1.5 years. Simultaneously, hypoproteinaemia was noted (Figure-1). A trial of increasing IVIG (0.7 - 1 g/kg) and the use of subcutaneous immunoglobulin (0.2 g/kg) did not reverse the biochemical and clinical situation. Hypoproteinaemia workup revealed normal liver and kidney functions, normal cardiac function, and no proteinuria. Interestingly, his upper endoscopy showed mild duodenitis and the presence of giardia lamblia at the luminal surface (Figure-2). Following this, a 2-week course of oral metronidazole (7.5 mg/kg/dose BID) resulted in a restoration of therapeutic serum IgG trough and albumin levels. Additionally, the child's nutritional status improved, and the frequency of respiratory infections dropped. In Patient-2, progressive hypoproteinaemia was noted over nine months. Similarly, no gastrointestinal complaints; however, the family reported foul-smelling semisolid stools with regular consistency. His IgG trough level was 2 g/l, and his albumin level was 20 g/l. Despite maximizing IVIG, he developed two episodes of pneumonia and once otitis media. An empiric oral metronidazole course resulted in the amelioration of symptoms and restoration of proteinemia. Meanwhile, faeces microscopy confirmed the presence of Giardia lamblia. Conclusions: Progressive hypoproteinaemia in children with humoral immunodeficiency is a clinical concern. Routine stool microscopy can identify giardia infection despite the ambiguity of gastrointestinal symptoms in such patients. However, a trial of empiric metronidazole therapy should be considered.

Cardiac rehabilitation using a virtual trainer in patients with heart failure

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): European Union’s Horizon 2020. Background/Introduction According to WHO cardiovascular diseases (CVDs) are the leading cause of mortality. Heart attacks and strokes account for more than four out of every five CVD fatalities. Early identification of patients at risk to developing cardiovascular diseases and prompt initiation of appropiate treatment can prevent premature deaths. After a patient overcomes an acute cardiovascular event, he is referred for rehabilitation to help him restore most of his normal cardiac functions. Purpose This study is part of a European project called vCare (Virtual Coaching Activities for Rehabilitation in Elderly), which aimed to test a rehabilitation program carried out by patients at home with the help of a virtual coach. In Romania, we evaluated the effectiveness of the cardiac rehabilitation program using the vCare system in reducing cardiovascular risk and improving quality of life in patients with heart failure (HF). Methods We conducted a prospective interventional pilot study in which we enrolled a total of 30 patients with HF who were divided into 3 groups: 10 patients in the experimental group (EG), 10 patients in ambulatory group (AG) and another 10 in the control group (CG). The follow-up period lasted 3 months. The patients in the EG performed cardiac rehabilitation (CR) at home using vCare app, patients in the AG underwent conventional CR at Bagdasar Arseni Hospital and those in the CG only received advice at discharge to perform regular physical activity at home and reduced cardiovascular risk factors. At the time of inclusion (time 0) all patients were clinically examined, blood tests and echocardiography were performed and also ECG exercices test for the assessment of exercices capacity and personalization of the CR program in the case of those from EG and AG. Furthermore they filled out several questionnaires (Minnesota, HADS scale, Fagerstrom). At the end of the rehabilitation program (time 1) all patients were reassessed in the same way as at enrollment. Results Patients with HF in EG had an increase in quality of life by up to 30% from time 0 to time 1, in exercices capacity by 4% and a significant decrease in cardiovascular risk factors was identified. Similar data were observed in patients from the AG, while in patients from the CG, a decrease in exercices capacity and a worsening of anxiety and depression were found. Conclusions Patients with HF who perform cardiac rehabilitation using vCare system had similar results compared to the AG and better results compared to CG, especially in terms of quality of life and their activities of daily life. This kind of cardiac rehabilitation can represent a safe and efficient solution for ensuring continuity of medical care and access to personalized motor treatments for patients with cardiological disease.

The effects of cardiac structure, valvular regurgitation, and left ventricular diastolic dysfunction on the diagnostic accuracy of Murray law-based quantitative flow ratio.

The study aimed to investigate the diagnostic accuracy of Murray law-based quantitative flow ratio (μQFR) from a single angiographic view in patients with abnormal cardiac structure, left ventricular diastolic dysfunction, and valvular regurgitation. μQFR is a novel fluid dynamics method for deriving fractional flow reserve (FFR). In addition, current studies of μQFR mainly analyzed patients with normal cardiac structure and function. The accuracy of μQFR when patients had abnormal cardiac structure, left ventricular diastolic dysfunction, and valvular regurgitation has not been clear. This study retrospectively analyzed 261 patients with 286 vessels that underwent both FFR and μQFR prior to intervention. The cardiac structure and function were measured using echocardiography. Pressure wire-derived FFR ≤0.80 was defined as hemodynamically significant coronary stenosis. μQFR had a moderate correlation with FFR (r = 0.73, p < 0.001), and the Bland-Altman plot presented no difference between the μQFR and FFR (0.006 ± 0.075, p = 0.192). With FFR as the standard, the diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of μQFR were 94.06% (90.65-96.50), 82.56% (72.87-89.90), 99.00% (96.44-99.88), 97.26 (89.91-99.30), and 92.96% (89.29-95.44), respectively. The concordance of μQFR/FFR was not associated with abnormal cardiac structure, valvular regurgitation (aortic valve, mitral valve, and tricuspid valve), and left ventricular diastolic function. Coronary hemodynamics showed no difference between normality and abnormality of cardiac structure and left ventricular diastolic function. Coronary hemodynamics demonstrated no difference among valvular regurgitation (none, mild, moderate, or severe). μQFR showed an excellent agreement with FFR. The effect of abnormal cardiac structure, valvular regurgitation, and left ventricular diastolic function did not correlate with the diagnostic accuracy of μQFR. Coronary hemodynamics showed no difference in patients with abnormal cardiac structure, valvular regurgitation, and left ventricular diastolic function.

P70 UNEXPLAINED TRANSIENT BIVENTRICULAR DYSFUNCTION IN A PATIENT WITH DISSEMINATED TUBERCULOSIS AND SEVERE EOSINOPHILIA

Abstract Introduction Tuberculosis (TB) is an infectious disease with significant global burden. Pericardial injury is relatively common, while myocardial involvement has only rarely been described. Case presentation A 29-years-old man from Gambia with disseminated TB, treated with isoniazid, rifampin, pyrazinamide and ethambutol, was admitted to our hospital. He denied history of heart disease, cardiovascular risk factors and voluptuary habits. Laboratory exams revealed severe eosinophilia without microbiological evidence of parasitic infection; a lymphocyte proliferation test ruled out allergic reaction to anti-TB therapy. Baseline echocardiographic evaluation showed normal cardiac function with negative troponin. The patient, subsequently, developed worsening dyspnoea and asthenia with progressive biventricular dysfunction. Therefore, he was admitted to our department for further investigations. Cardiac magnetic resonance (CMR) showed a 20% left ventricular ejection fraction and absence of myocardial oedema or fibrosis [Fig.1]. Coronary CT angiography (CCTA) was unremarkable. Endomyocardial biopsy (EMB) showed absence of TB lesions or eosinophilic infiltration. Cardiac troponin and electrocardiogram remained negative throughout. Optimal medical therapy (OMT) for heart failure was promptly initiated. After several months an almost complete recovery of cardiac function was documented [Fig.2]. Discussion In cases of ventricular dysfunction, establishing an etiological diagnosis is imperative, though sometimes challenging. When pre-test probability is low, CAD can be ruled out by CCTA. Myocarditis is a common cause of reversible cardiac dysfunction. In this case, the absence of Lake Louise criteria, negative bioptic findings, persistently negative cardiac troponin and microbiological tests argue against this diagnosis. However, the timing of investigations can affect diagnostic accuracy; furthermore, focal lesions can be missed by EMB, leading to false negative results. Alcoholic cardiomyopathy (CMP) could be an option, but it was not considered due to absence of alcohol consumption. The clinical picture was not compatible with a typical CMP phenotype. Immune-mediated reaction to anti-TB drugs was ruled out by immunological testing. Although not previously described, ethambutol and pyrazinamide direct cardiotoxicity may explain transient impairment of cardiac function. Recovery may be related to withdrawal of these drugs and introduction of guideline-directed OMT.

Sodium current preserves electrical excitability in the heart of hibernating ground squirrel (Citellus undulatus)

Hibernating mammals are capable of maintaining normal cardiac function at low temperatures. Excitability of cardiac myocytes crucially depends on the fast sodium current (INa), which is decreased in hypothermia due to both depolarization of resting membrane potential and direct negative effect of low temperature. Therefore, INa in hibernating mammals should have specific features allowing to maintain excitability of myocardium at low temperatures. The current-voltage dependence of INa, its steady-state inactivation and activation and recovery from inactivation were studied in winter hibernating (WH) and summer active (SA) ground squirrels and in rats using whole-cell patch clamp at 10 °C and 20 °C. INa peak amplitude and the parameters of steady-state activation and inactivation curves did not differ between SA and WH ground squirrels at both temperatures. However, at both temperatures strong positive shift of activation and inactivation curves by 5–12 mV was observed in both WH and SA ground squirrels if compared to rats. This peculiarity of cardiac INa in ground squirrels helps to maintain excitability in conditions of depolarized resting membrane potential. The time course of INa recovery from inactivation at 10 °C was faster in WH than in SA ground squirrels, which could ensure normal activation of myocardium during hibernation.

Concentric hypertrophy geometry is a significant determinant of impaired global longitudinal strain in patients with normal cardiac structure and function

BackgroundIn recent years, the assessment of global longitudinal strain (GLS) derived by speckle-tracking analysis has become a clinically feasible alternative to left ventricular (LV) ejection fraction (LVEF) for the assessment of myocardial function. However, the determinant factors of impaired GLS in structurally and functionally normal patients are unclarified. The objective of this study was to elucidate the determinant factors of impaired GLS in structurally and functionally normal patients. MethodsWe evaluated structurally and functionally normal patients scheduled to undergo noncardiac surgery. The evaluated patient characteristics were age, sex, presence of hypertension, presence of diabetes mellitus, presence of hyperlipidemia, systolic blood pressure, and body mass index. The concentrations of B-type natriuretic peptide and high-sensitivity troponin I were measured. Echocardiography was performed to determine the LVEF, GLS, transmitral early diastolic velocity/transmitral atrial velocity ratio, LV mass index (LVMI), and relative wall thickness (RWT). Patients with preserved LVEF (≥50%) were divided into the normal GLS group (GLS ≤ -20%) and the impaired GLS group (GLS > -20%). On the basis of the RWT and LVMI values, the patients were categorized as having four types of LV geometry. Logistic regression analysis was performed to ascertain the determinant factors of impaired GLS. ResultsThe study cohort comprised 75 structurally and functionally normal patients (age 67.7 ± 12.6 years, 45 men). The GLS was normal in 43 patients and impaired in 32 patients. There was a significant difference in RWT between the impaired and normal GLS groups. The evaluation based on the LV geometry showed that six of seven patients with concentric hypertrophy geometry had impaired GLS, and the GLS was significantly more impaired in patients with concentric hypertrophy geometry than in patients with normal geometry or eccentric hypertrophy geometry. Logistic regression analysis revealed that LV concentric hypertrophy geometry was a significant determinant factor of impaired GLS (odds ratio 22.4, P = 0.042). ConclusionsGlobal longitudinal strain is more impaired in structurally and functionally normal patients with concentric hypertrophy geometry compared with those with eccentric hypertrophy geometry or normal geometry. In addition, concentric hypertrophy geometry is a significant determinant for impaired GLS in patients with normal cardiac structure and function.

Targeting p21-activated kinase 1 for development of a novel anti-arrhythmic drug class.

Evidence accumulated over the past decade suggests that p21-activated kinase 1 (PAK1) is a critical cardiac-protective signalling molecule. The present article provides an updated review of recent findings regarding the role of PAK1 in maintaining normal cardiac electrophysiological function through its regulation of membrane and Ca2+ clocks. We first overviewed the PAK1 activation mechanism. We then discussed recent updated results showing the action mechanisms of PAK1 signalling on Cav1.2/Cav1.3 (ICaL)-mediated Ca2+ entry, ryanodine receptor type 2-mediated sarcoplasmic reticulum (SR) Ca2+ release, transcriptional regulation of SR Ca2+-ATPase 2a, Na+/Ca2+ exchangers, and Ca2+/calmodulin-dependent protein kinase II. Finally, we proposed a new and exciting route for developing a PAK1-based therapeutic strategy for cardiac arrhythmias. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Tree elements: Branching hopes after tissue injury in regenerative medicine

Humans are poor model systems for studying tissue regeneration. Unlike their amphibians or rodent counterparts, humans are deficient in this quality, making the repair process following a tissue injury infrequent and limited. Most human tissues or organs, except the liver, lack in their regenerative potential. This tends to be a serious problem in organ damage until recently with the identification of enhancer regulatory elements that engage in regenerating tissue. Tissue regeneration enhancer elements (TREEs) trigger gene expression in injury sites and can be engineered to modulate the regenerative potential of vertebrate organs. TREE orchestrates selective gene expression at the injury sites, thereby modulating the regenerative activities and potential of vertebrate organs. Using a genetic screen of a zebrafish-based tissue injury model, Kang et al., identified the gene expression signature associated with regeneration. This concept is being tried and tested to see its possibility in regenerating injured myocardium following myocardium infraction leading to ischemia and tissue damage. TREEs displayed specificity and efficacy in a systemically delivered recombinant AAV vector system in mice and can be used as a gene-therapy module to repair damaged tissue. A team of researchers at the Duke School of Medicine, USA, headed by Ken Poss, reported their findings in cell stem cell, 2022. These researchers further took a step ahead to actually orchestrate a damaged myocardium repair and the growth of new muscles to restore normal cardiac function. Even more spectacular is that tissue growth is selective only at injury sites and becomes quiescent once the damage is repaired. HOW THIS MAY IMPACT REGENERATIVE MEDICINEUsing a TREE-based system, one can attempt to use gene therapy with viral vectors to enhance heart tissue cell proliferation and growth, thus improving cardiac regeneration. This system will further strengthen by incorporating better gene payloads, thereby opening new possibilities to rescue scar tissue and restore function. According to the World Health Organization, MI-related death in India accounts for one-fifth of deaths worldwide, which is alarmingly higher in the younger population. The age-standardized cardiovascular disease (CVD) death rate of 272/100,000 in India is much higher than the global average of 235. Under these circumstances, these findings seem extremely relevant. Although we may not fix a broken heart, engineered TREE elements might at least fix a damaged myocardium branching hopes for numeroussuffering from CVD.

The role of purine nucleotide metabolism in cardiac failure

Normal cardiac function requires ATP to be synthesized at a sufficient rate to drive the molecular processes underlying electromechanical coupling. Myocardial metabolic dysfunction observed during heart failure leads to reductions in the chemical potential at which ATP is synthesized. We have observed reductions in oxidative capacity, and total adenine nucleotide (TAN) levels in a rat aortic constriction (TAC) induced heart failure model that parallel changes seen in large mammal models and humans with heart failure. Computer simulations of cardiac mechano-energetics also predict a marked increase in inorganic phosphate levels in diseased hearts compared to healthy control hearts. Furthermore, simulations predict that restoring the impaired energetic dysfunction of TAC rats improves systolic function. Metabolomic and proteomic analysis reveal increases in purine degradation by-products and AMP deaminase 3 (AMPD3) levels in failing versus control hearts. AMPD activity has been hypothesized to play a role in skeletal muscle in type 2 diabetes, however, there is still a need to decern the role, if any, of AMPD3 in the heart and in failure. A cardiac ventricle specific AMPD3 conditional knock out (cKO) rat model was developed to test the hypothesis that decreasing AMPD3 activity in the failing heart will lead to a preservation of TAN and improvement in cardiac mechanical function. Cardiac hypertrophy and decomposition were induced by placing a clip (TAC) in three-week old female and male rats. In the cKO model, AMPD3 exon 6 is flanked by loxP sites, and are either heterozygous for cre recombinase driven by the cardiac myosin light chain promoter (cre+/-) or lack the cre enzyme (cre-/-). Tamoxifen was administered to all rats both pre-surgery and post-surgery to induce AMPD3 knock down. Echocardiography was performed at 2- and 18-weeks post-surgery. At 18 weeks post-surgery, hearts were harvested for mitochondrial capacity, metabolite measurements, AMPD activity, and protein and mRNA measurements. Knock down efficiency in cre +/- animals compared to cre -/- was assessed based on enzyme activity, mRNA expression, and protein abundance. There is a 45% decrease in total AMPD activity in the AMPD3 cKO rats, where measured AMPD activity reflects the sum activity of all present AMPD isoforms. Additionally, there is 52% decrease in protein abundance and a 72% reduction in AMPD3 mRNA expression. Preliminary observations reveal significant differences in oxidative capacity and in cardiac function between TAC and sham rats, consistent with the hypothesis that knock down of AMDP3, an enzyme that is upregulated during TAC induced heart failure in rodents, results in preservation of myocardial nucleotide pools and improve cardiac mechanical function. Research is supported by the NIH grants HL144657 and F31-HL154605 (RL). We are grateful for support from the post-baccalaureate research program (2R25GM086262-09), the Systems and Integrative Biology (T32-GM008322) training grant and the Cardiovascular Research and Entrepreneurship training grant (T32-HL125242) and the University of Michigan Rackham Merit Fellowship. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Connexin 43 dephosphorylation at serine 282 induces spontaneous arrhythmia and increases susceptibility to ischemia/reperfusion injury

BackgroundConnexin 43 (Cx43), the predominant gap junction protein in hearts, is modified by specific (de)phosphorylation events under physiological and pathological states to affect myocardium function and structure. Previously we found that deficiency in Cx43 S282 phosphorylation could impair intercellular communication and contribute to cardiomyocyte apoptosis by activating p38 mitogen-activated protein kinase (p38 MAPK)/factor-associated suicide (Fas)/Fas-associating protein with a novel death domain (FADD) pathway, which is involved in myocardium injury in ischemia/reperfusion (I/R) heart. In addition, mutant at Cx43 S282 substituted with alanine heterozygous mice (S282A+/−) exhibited different degrees of ventricular arrhythmias and only some underwent myocardium apoptosis. In this study, we aimed to investigate the role of Cx43 pS282 in different cardiac pathological phenotypes. MethodsWe examined cardiac function, structure, and relevant protein expression in S282A+/− mice (aged 2, 10 and 30 weeks) by electrocardiograph, echocardiography, histological staining, and co-immunoprecipitation followed by Western blot. Intraperitoneal isoprenaline injection and I/R surgery were applied in S282A+/− mice as external stimulus. 2,3,5-triphenyltetrazolium chloride staining was used for myocardium infarction evaluation. ResultsAdult S282A+/− mice (aged 10 and 30 weeks) still exhibited spontaneous arrhythmia. Unlike neonatal stage (aged around 2 weeks), no apoptosis-related manifestations and the activation of p38 MAPK-Fas-FADD apoptotic pathway were observed in adult S282A+/− hearts. S282A+/− neonatal mice with cardiomyocytes apoptosis exhibited more than 60% dephosphorylation at Cx43 S282 than WT mice, while less than 40% S282 dephosphorylation were found in adult S282A+/− mice. In addition, although S282A+/− mice displayed normal cardiac function, they were highly susceptible to isoproterenol-induced ECG alternans and prone to cardiac injury and deaths upon I/R attack. ConclusionsThese results reinforce that Cx43 S282 dephosphorylation acts as a susceptibility factor in regulating cardiomyocyte survival and cardiac electrical homeostasis in basal conditions and contributes to myocardium injury in the setting of I/R. Cx43 S282 phosphorylation was competent to induce spontaneous arrhythmias, cardiomyocyte apoptosis and deaths based on the degree of S282 dephosphorylation.

Subcutaneous white adipose tissue expression of HuR mediates cardiac pathology via adipose tissue-derived extracellular vesicles

Obesity is a rapidly growing epidemic worldwide, especially in the United States, and is associated with cardiovascular disease (CVD), diabetes, cancer, and a multitude of other comorbidities. Adipose tissue has been shown to act as an endocrine organ in the body and to mediate cardiac physiology. We have previously shown that deletion of HuR specifically in adipocytes (Adipo-HuR KO) induces cardiac fibrosis in mice, independent of traditional adipose/obesity co-morbidities (dyslipidemia, hypertension, diabetes).​ Deletion of HuR in the adipocyte affects both brown adipose tissue (BAT) depots as well as subcutaneous white adipose tissue (scWAT) depots. We have shown that HuR deletion in BAT (using a UCP1-driven cre model) maintains normal cardiac function compared to Adipo-HuR KO mice. This points toward scWAT being the primary mediator of cardiac pathology from adipose tissue, which is consistent with our previously published bioinformatic analysis suggesting HuR-dependent adipose tissue-derived extracellular vesicles (Ad-EVs) as the mechanism by which this occurs.The goal of this work is to identify the mechanisms by which HuR expression in subcutaneous white adipose tissue (scWAT) mediates cardiac function via Ad-EVs. Here, we show that Ad-EVs isolated from scWAT depots of our Adipo-HuR KO model induce significant hypertrophic signaling in vitro, compared to wild-type littermates. We also show that expression of HuR in scWAT specifically is decreased with obesity and age, suggesting a potential mechanistic link between obesity, HuR expression in scWAT, and CVD.In conclusion, our results demonstrate that loss of HuR expression in scWAT is sufficient to induce cardiac hypertrophy and fibrosis, in part through endocrine-mediated Ad-EV signaling. In addition, we are beginning to identify HuR-dependent gene expression patterns in human scWAT which may potentially play a significant role in this signaling axis. This work was supported by NIH grants R01-HL132111 and HL158671 (MT). RD is supported by a Peter Lauf Travel Award from the Ohio Physiological Society. SP is supported by an NIH Training grant T32HL125204 (PIs: Molkentin and Kranias). ARG was supported by American Heart Association Predoctoral Fellowship (916812). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Extracorporeal Membrane Oxygenation in an Adolescent with Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children is a rare and potentially life-threatening disease that is associated with SARS-CoV-2 infection, characterized by hyperinflammation and multiorgan involvement. Cardiovascular involvement is common, including myocardial dysfunction often leading to cardiogenic shock. We present the case of a 17-year-old boy with fever, odynophagia, maculopapular rash and abdominal pain who developed a cardiogenic shock. Due to progressive deterioration of cardiac function despite optimized vasoactive support, veno-arterial extracorporeal membrane oxygenation support was initiated 12 hours after admission, with successful decannulation after seven days and discharge after 23 days, with normal cardiac function. The patient received corticosteroids and intravenous immunoglobulin. Early recognition and intensive care support are crucial for ensuring a successful outcome in severe cases of multisystem inflammatory syndrome. In cases of severe cardiogenic shock, extracorporeal membrane oxygenation support can be critical for survival and rapid recovery.