Myocyte Injury Research Articles

Abstract 4137609: Lentiviral shRNA Library Screen Using Human Pluripotent Stem Cell-derived Cardiomyocytes Identified Mediators of Protection via MAP4K4 Inhibition against Doxorubicin-induced Cardiotoxicity

Background: Doxorubicin (Dox) is a common component in chemotherapy for a wide range of tumors, but the cardiotoxicity has restricted its use. There is an unmet need for novel therapeutics of Dox-induced cardiotoxicity (DIC). We previously identified the protein kinase MAP4K4 as a mediator of DIC. Notably, we showed that blocking MAP4K4 activity via DMX-5804 protected against Dox-induced cell death and dysfunction in human iPSCs derived cardiomyocytes (hiPSC-CMs). As a powerful tool to study the protective mechanism, pooled library screen performs high-throughput phenotypic examination, but its potential on hiPSC-CMs is poorly explored. Hypothesis: A pooled lentiviral shRNA library screen in hiPSC-CMs treated with Dox ± DMX-5804 could identify mediators of protection against DIC. Methods: To maximize the chances to uncover key factors mediating DMX-5804 protection, we performed a high-throughput loss-of-function screen. A pooled library of 1731 lentiviral shRNAs was generated. hiPSC-CMs were transduced, then treated with Dox ± DMX-5804. Cardiac troponin I ELISA was used to examine myocyte injury. Genomic DNA was isolated, followed by amplification and sequencing of the integrated shRNAs. Log2 fold change was calculated and transformed into Z score to identify significantly shifted shRNAs. Results: To build the shRNA library we included 1) genes identified via transcriptomic analysis of hiPSC-CMs treated with Dox ± DMX-5804; 2) genes in the MAP4K4 signaling cascade; 3) previously defined pro-death or pro-survival genes in DIC. To ensure single gene silenced per cell, we used a low MOI of 0.5. After transduction, cells were treated with Dox ± DMX-5804. Confirming the cardiotoxicity and protection, Dox induced a 2-fold increase of cardiac troponin I release and DMX-5804 significantly reversed it. Next, we recovered and sequenced the integrated shRNAs, and quantified the frequency of each. We identified 146 significantly enriched or depleted shRNAs (|Z score| > 2). When comparing Dox treated group to vehicle or DMX-5804 protected group, shRNA enrichment indicates pro-death function of the targeted gene. Conversely, pro-survival genes can be inferred from shRNA depletion. Amongst the 5 most consistently targeted genes, we identified SIRT6 and GATA4 which are known pro-survival in DIC, suggesting the screen is potent to define key genes. Conclusion: We performed a proof-of-concept pooled library screen in human cardiomyocytes and identified mediators of protection against DIC.

Prediction of incident major adverse cardiac events in patients starting haemodialysis for end stage kidney disease, using clinical laboratory cardiac biomarkers - a real world analysis.

Abstract Background and Aims Despite its many advantages, haemodialysis (HD) is associated with increased cardiovascular mortality and morbidity, with some studies reporting 48% higher mortality within 2 years of starting HD. Cardiac biomarkers provide insight into cardiac structure and function, including myocyte stress, inflammation and fibrosis. We aimed to investigate the prognostic significance of routine cardiac biomarkers (troponin and natriuretic peptides) in the prediction of incident major adverse cardiac events (MACE) within 5 years if commencing HD. Methods A retrospective cohort study was performed using electronic medical records from a global federated research network from the US. The network was searched on 26th February 2023. The cohorts commenced HD post-diagnosis of end-stage kidney disease. Data censoring for MACE was invoked prior to the index event of HD. Cardiac biomarkers were the first reported result within 3 months of starting HD. Cohorts were grouped according to biomarker-specific thresholds and 1:1 propensity-score matched for age, gender and co-morbidities (hypertension, diabetes mellitus and smoking status). Logistical regression produced odds ratios with 95%CI for 5-year incident MACE. MACE was defined, a priori, as a composite of ischaemic heart disease, angina pectoris, acute myocardial infarction, heart failure, AF, stroke and all-cause mortality. All statistical analysis was performed on the online platform. Results The results are shown Tables 1(Troponin I and BNP alone) and 2 (Combined Troponin I and BNP). Results that reached statistical significance (p<0.05) are shown. Conclusion Routinely available cardiac biomarkers can predict MACE and cardiac outcomes in incident HD, although results differ between markers of myocyte injury (troponin) and stress (BNP). A combined approach may prove most beneficial. The results suggest the clinical need for CV mortality and morbidity risk profiling in incident dialysis using a combination of clinical and laboratory variables and the need for prospective validation.Table 1Table 2

Functional cardiac consequences of β-adrenergic stress-induced injury in a model of Duchenne muscular dystrophy.

Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD); however, in the mdx mouse model of DMD, the cardiac phenotype differs from that seen in DMD-associated cardiomyopathy. Although some have used pharmacologic stress to stimulate injury and enhance cardiac pathology in the mdx model, many methods lead to high mortality with variable cardiac outcomes, and do not recapitulate the structural and functional cardiac changes seen in human disease. Here, we describe a simple and effective method to enhance the cardiac phenotype model in mdx mice using advanced 2D and 4D high-frequency ultrasound to monitor cardiac dysfunction progression in vivo. mdx and wild-type mice received daily low-dose (2 mg/kg/day) isoproterenol injections for 10 days. Histopathological assessment showed that isoproterenol treatment increased myocyte injury, elevated serum cardiac troponin I levels and enhanced fibrosis in mdx mice. Ultrasound revealed reduced ventricular function, decreased wall thickness, increased volumes and diminished cardiac reserve in mdx compared to wild-type mice. Our findings highlight the utility of challenging mdx mice with low-dose isoproterenol as a valuable model for exploring therapies targeting DMD-associated cardiac pathologies.

Clinical determinants of blood biomarkers of atrial cardiomyopathy: results from the ISOLATION AF ablation cohort study

Abstract Background In patients with atrial fibrillation (AF), significant advances have been made in identifying biomarkers representing diverse pathophysiological pathways, such as inflammation, myocyte injury, collagen deposition, and fatty-fibrotic infiltration. Data on clinical determinants of biomarkers in patients with AF, however, are lacking. Objective Our primary aim was to explore the relationships between clinical determinants and biomarker levels in AF patients scheduled for catheter ablation. Methods A cross-sectional analysis was conducted in AF patients undergoing catheter ablation included in the prospective multicenter ISOLATION study between July 2020 and May 2022. Clinical characteristics, routine tests and blood samples were collected before ablation. Blood samples were analyzed for known and novel cardiovascular biomarkers, including Bone morphogenetic protein 10 (BMP10), Angiopoietin-2 (Ang-2), Fibroblast growth factor 23 (FGF-23), Dickkopf-related protein 3 (DKK-3), Endocan (ESM-1), Insulin-like growth factor-binding protein 7 (IGFBP-7), B-type natriuretic peptides (proBNP, NTproBNP), High sensitive Troponin-T (hsTnT)< Growth differentiation factor 15 (GDF-15), interleukin 6 (IL-6), Fatty acid binding protein 3 (FABP3), Cancer antigen-125 (Ca-125) (Table 1). For each biomarker we trained a lasso regression model to identify the most important clinical determinants out of all the 60 available determinants (including anthropometry, ECG, comorbidities). The strongest associations are summarized in figure 1. Results Blood samples of 508 patients were analyzed. The mean age was 63 ±9 years, and 31.1% were female. 354 patients (69.7%) had paroxysmal AF and 154 patients (30.3%) had persistent AF. Heart failure was reported in 77 patients (15.2%). 355 (72.3%) patients were in sinus rhythm during sample collection. The following clinical determinants of biomarker levels were frequently identified as important: rhythm during blood phlebotomy, age, heart failure, decreased kidney function and female sex (Figure 1). Most notably, rhythm at the time of sampling was strongly associated with various biomarker levels. Female sex was positively associated with BMP10 and FGF23 (atrial fibrosis), but negatively associated with hsTNT (cardiac injury). Conclusion In patients with AF scheduled for catheter ablation, we identified several clinical determinants of biomarker levels with potential implications for disease mechanisms. In women, pro-fibrotic biomarkers were frequently higher, while male patients more often showed signs of myocardial injury. Importantly, rhythm during blood draw is a very strong determinant of many biomarkers and should be taken into account in future biomarker studies.Figure 1.Table 1.

Case Report: Asymptomatic SARS-COV2 infection triggering recurrent Takotsubo syndrome

Takotsubo syndrome (TTS) is a rare disease mimicking acute coronary syndrome, often triggered by physical or emotional stress, and characterized by transient left ventricular dysfunction. Recurrences are described in about 5% of cases and may have different clinical and imaging patterns. In the present report, SARS-COV-2 infection, even in the absence of symptoms and overt emotional stress, seems correlated with recurrence of TTS, due to the absence of other recognized triggers. The hypothesis is that in predisposed patients, events like catecholamine-induced myocyte injury, direct viral damage, cytokine storm, immune-mediated damage, and procoagulant state, all possibly induced by the infection, may elicit endothelial dysfunction as substrate for TTS onset.

A Review of Pediatric Cardiomyopathy.

Though pediatric cardiomyopathy is rare in children, there is significant associated morbidity and mortality. Etiology varies from inborn errors of metabolism to familial genetic mutations and myocyte injury. Major classes include dilated, hypertrophic, restrictive, and non-compaction. Diagnosis generally involves a combination of clinical history and echocardiography. The use of cross-sectional imaging is gaining popularity. Management varies between subtype and may involve a combination of medical and surgical interventions depending on clinical status.

Reduced cardiac antioxidant defenses mediate increased susceptibility to workload-induced myocardial injury in males with genetic cardiomyopathy

Ongoing cardiomyocyte injury is a major mechanism in the progression of heart failure, particularly in dystrophic hearts. Due to the poor regenerative capacity of the adult heart, cardiomyocyte death results in the permanent loss of functional myocardium. Understanding the factors contributing to myocyte injury is essential for the development of effective heart failure therapies. As a model of persistent cardiac injury, we examined mice lacking β-sarcoglycan (β-SG), a key component of the dystrophin glycoprotein complex (DGC). The loss of the sarcoglycan complex markedly compromises sarcolemmal integrity in this β-SG−/− model. Our studies aim to characterize the mechanisms underlying dramatic sex differences in susceptibility to cardiac injury in β-SG−/− mice. Male β-SG−/− hearts display significantly greater myocardial injury and death following isoproterenol-induced cardiac stress than female β-SG−/− hearts. This protection of females was independent of ovarian hormones. Male β-SG−/− hearts displayed increased susceptibility to exogenous oxidative stress and were significantly protected by angiotensin II type 1 receptor (AT1R) antagonism. Increasing general antioxidative defenses or increasing the levels of S-nitrosylation both provided protection to the hearts of β-SG−/− male mice. Here we demonstrate that increased susceptibility to oxidative damage leads to an AT1R-mediated amplification of workload-induced myocardial injury in male β-SG−/− mice. Improving oxidative defenses, specifically by increasing S-nitrosylation, provided protection to the male β-SG−/− heart from workload-induced injury. These studies describe a unique susceptibility of the male heart to injury and may contribute to the sex differences in other forms of cardiac injury.

Impact of Hemoglobin Level in Ex Vivo Heart Perfusion on Donation After Circulatory Death Hearts: A Juvenile Porcine Experimental Model.

Ex vivo heart perfusion (EVHP) of donation after circulatory death (DCD) hearts has become an effective strategy in adults; however, the small circulating volume in pediatrics poses the challenge of a low-hemoglobin (Hb) perfusate. We aimed to determine the impact of perfusate Hb levels during EVHP on DCD hearts using a juvenile porcine model. Sixteen DCD piglet hearts (11-14 kg) were reperfused for 4 h in unloaded mode followed by working mode. Metabolism, cardiac function, and cell damage were compared between the low-Hb (Hb, 5.0-5.9 g/dL; n = 8) and control (Hb, 7.5-8.4 g/dL; n = 8) groups. Between-group differences were evaluated using 2-sample t -tests or Fisher's Exact tests. During unloaded mode, the low-Hb group showed lower myocardial oxygen consumption ( P < 0.001), a higher arterial lactate level ( P = 0.001), and worse systolic ventricular function ( P < 0.001). During working mode, the low-Hb group had a lower cardiac output (mean, 71% versus 106% of normal cardiac output, P = 0.010) and a higher arterial lactate level ( P = 0.031). Adjusted cardiac troponin-I ( P = 0.112) did not differ between the groups. Morphological myocyte injury in the left ventricle was more severe in the low-Hb group ( P = 0.028). Low-Hb perfusate with inadequate oxygen delivery induced anaerobic metabolism, resulting in suboptimal DCD heart recovery and declined cardiac function. Arranging an optimal perfusate is crucial to organ protection, and further endeavors to refine the priming volume of EVHP or the transfusion strategy are required.

Global identification of palmitoylating enzyme substrates in cardiomyocytes provides mechanistic insights into why upregulation of these enzymes aggravates myocyte injury in response to ischemia/reperfusion

Global identification of palmitoylating enzyme substrates in cardiomyocytes provides mechanistic insights into why upregulation of these enzymes aggravates myocyte injury in response to ischemia/reperfusion

The Introduction of the ROS Scavenger Prc-210 to Organ Preservation Solution Prior to Vca Induces Significant Reductions in Myocyte Injury and Tissue Damage.

The Introduction of the ROS Scavenger Prc-210 to Organ Preservation Solution Prior to Vca Induces Significant Reductions in Myocyte Injury and Tissue Damage.

Protective function of albiflorin against ferroptosis in exhaustive exerciseinduced myocardial injury via the AKT/Nrf2/HO-1 signaling.

It has been reported that exhaustive exercise (EE) causes myocyte injury, and eventually damages the function of the myocardia. Albiflorin (AF) has anti-inflammatory, antioxidant, and anti-apoptosis effects. In this study, we determined whether AF could mitigate the EE-induced myocardial injury and research the potential mechanisms. The rat model of EE was built by forced treadmill running method. Rats were intraperitoneally injected with AF before EE once daily for one week. The relative factors levels were examined by commercial kits. The apoptosis was appraised using a TdT-mediated dUTP nick end labeling assay kit. The ACSL4, GPX4, Nrf2, pAKT/AKT, and HO-1 contents were assessed by western blot. AF lessened EE-induced cardiac myocytes ischemic/hypoxic injury and reduced the contents of myocardial injury biomarkers in the serum. AF lessened EE-induced cardiac myocyte apoptosis, inflammatory response, oxidative stress, and ferroptosis in myocardial tissues. However, the influences of AF were overturned by the co-treatment of AF and LY294002. AF activated the AKT/Nrf2/HO-1 signaling pathway in myocardial tissues in vivo. AF could curb cardiac myocytes ferroptosis, thus diminishing the EE-induced myocardial injury through activating the AKT/Nrf2/HO-1 cascade.

Salvianolic Acid B Ameliorated Chemotherapeutic Injury of Cardiac Myocytes through the Nrf2/ARE Signaling Pathway.

Cardiotoxicity has been corroborated to be the toxic influence of cisplatin (CDDP). Oxidative stress and cardiomyocyte apoptosis play a vital part in cardiotoxicity induced by CDDP. Salvianolic acid Salvianolic acid B (SalB) is a monomeric component of Salvia miltiorrhiza, which has antioxidant and anti-inflammatory influences. In this research, we explored the mechanism of SalB in cardiotoxicity induced by CDDP. 36 Wistar rats were separated into sham subgroup, CDDP (10 mg/kg) subgroup, CDDP (10 mg/kg) + SalB (1 μM) subgroup at random, CDDP (10 mg/kg) + SalB (5 μM) subgroup and CDDP (10 mg/kg) + SalB (10 μM) subgroup, Nicotinic Acid Riboside (NAR, 5 μM), with 6 rats in each subgroup. The cardiac function of rats in each subgroup was estimated by echocardiography, and hematoxylin-eosin (HE) staining and Masson staining corroborated the pathological changes of cardiac tissue. Biochemical kits were utilized for detecting the lactate dehydrogenase (LDH), creatine kinase (CK), interleukin-1β (IL-1β), IL-18, and caspase-1 concentrations in serum, superoxide dismutase (SOD), and malondialdehyde (MDA) in myocardial tissue, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and flow cytometry were utilized for estimating the apoptosis level in myocardial tissue, western blot was used for estimating caspase-3, Bcl2-Associated X (Bax) levels in myocardial tissue and proteins levels related to Nuclear factor E2 related factor 2 (Nrf2) signal pathway. CDDP-induced cardiac dysfunction, myocardial injury, boosted LDH and CK levels in serum (p < 0.05), memorably increased oxidative stress level in myocardial tissue (p < 0.05), boosted inflammatory response (p < 0.05), boosted apoptosis rate of cardiomyocytes (p < 0.05), and declined the Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO-1) protein levels (p < 0.05). Interestingly, SalB remedy could alleviate the changes caused by CDDP in the above parameters, significantly decrease the level of myocardial oxidative stress and apoptosis (p < 0.05). SalB ameliorates the injury of cardiomyocytes induced by chemotherapy through oxidative stress mediated by the Nrf2/antioxidant response element (ARE) signal pathway.

Biomarker BMP10 profiles suggest an association of female and age with atrial endomysial fibrosis: Results from the ISOLATION AF ablation registry

Abstract Background/Introduction Atrial fibrillation has a complex pathophysiology such as inflammation, myocyte injury, collagen and lipid infiltration. Different biomarkers reflect these pathophysiological pathways. The biomarker Bone Morphogenetic Protein 10 (BMP10) is a secreted protein, expressed by myocytes, and is required for myocyte growth and development. BMP10 is associated with PITX2 and endomysial fibrosis. We recently demonstrated that BMP10 is independently associated with left atrial andomysial fibrosis. Purpose To analyze the correlation between the blood-based biomarker BMP10 with sex and age in patients with atrial fibrillation. Methods A cross-sectional analysis was conducted of atrial fibrillation patients scheduled for catheter ablation included from July 2020 through May 2022 in the prospective multicenter ISOLATION cohort study (NCT04342312). Clinical characteristics and routine tests were collected before ablation. Blood samples were taken before ablation and were analyzed for BMP10 among other known and novel cardiovascular biomarkers. We investigated the correlation between BMP10 and age in a univariate analysis and in a multivariate analysis including differences in clinical traits. In addition, we investigated the difference in BMP10 levels between males and females. Results Blood samples from 509 patients were analyzed. Their mean age was 64±9 years, and 31.2% were female. 352 patients (69.2%) had paroxysmal AF and 152 patients (29.9%) had persistent AF. Heart failure was reported in 77 patients (15%). 357 (70%) patients were in sinus rhythm at the time the blood was drawn (table 1). Univariate analysis showed that BMP10 levels increased with age (figure 1). After adjusting for sex, type of AF, heart failure and rhythm at blood drawing, BMP10 remained higher in older patients (Beta coefficient 0.77, standard error 0.14, p-value &amp;lt;0.001). In addition, univariate analysis showed that BMP10 was significantly higher in women than in men (2.16 ng/L versus 1.95 ng/l, P&amp;lt; 0.001). After adjusting for age, BMP10 remained higher in women than in men. Conclusion Elevated BMP10 levels suggest that in older patients possibly more atrial fibrosis is present and thus more substrate for AF. In addition, the different biomarker profile suggests that AF in women may more often be associated with atrial fibroses than in men.

Myocardial inflammation in Fabry disease: correlations between myocardial histology, T2 mapping, and troponin

Abstract Background Myocardial inflammation likely plays a key role in cardiac Fabry disease (FD), supported by the frequent observation using cardiac MRI (CMR) of high T2 mapping values, mainly in areas of late gadolinium enhancement, LGE), typically representing oedema, and increased troponin (myocardial injury). Purpose To characterize inflammation in FD cardiomyopathy by comparing myocardial histology, T2 mapping and troponin. Methods Fifteen FD patients (67% females; 51 years old, range 39-62), undergoing 3 tests: biopsy (either RV endomyocardial biopsy, n=10, or myectomy, n=5); CMR (1.5T: cines, LGE, native T1/T2 mapping quantified in the sampling area); and troponin assessment (high sensitivity TnI). Mapping values were compared to local healthy volunteers. Left ventricle hypertrophy (LVH) was defined as either MWT ≥12mm or indexed LV mass above sex specific reference ranges. Tissue was stained using Haematoxylin-Eosin and Azan Mallory trichrome. Inflammatory cell staining used CD68 and CD3 antibodies. An abnormal inflammatory infiltrate was defined according to ESC criteria as ≥14 leukocytes/mm2 (up to 4monocytes/mm2, CD3+T-lymphocytes&amp;gt;7cells/mm2) and its distribution classified as focal (&amp;lt;30% of the specimen), multifocal (30-60%), diffuse (&amp;gt;60%). Results Median LV ejection fraction was 63% (58-67); indexed end diastolic volume 83ml/m2 (68-91). Seven patients had LVH. 8 patients had low native T1 and 6 had infero-lateral LGE. Median septal T2 value was 50ms (47-52) with 3 (all females) above local upper limit value (ULV). TnI was increased in 6 pts (40%; median value 54ng/L [38-128]). Histology showed mild inflammatory infiltrates in 8 pts (46%), none diffuse (focal 4, multifocal 4). Seven were mixed - T lymphocytes and macrophages, one was exclusively macrophages. Inflammatory foci were quiescent (n=5), or associated to myocytes injury not typical of ischemic damage and fibrosis (n=3). None had histologically visible myocardial oedema. Patients with inflammatory infiltrates had higher T2 values (52ms [50-54] vs 47ms [46-51]; p=0.043) but the same troponin (18ng/L [3-82] vs 14ms [3-24], p=0.215) (figure 1). The 3 patients with high T2 all had inflammatory cells associated to histologic myocyte injury (figure 2). Conclusion For the first time we correlate histology with T2 and myocardial injury in FD. In this small study, mild myocardial macrophage/lymphocyte infiltrates are common in FD and are associated to higher T2 values. Abnormal T2 septal elevation is less common (it is known common in the basal inferolateral wall however) and when present, infiltration with histological myocyte damage is found.

Sevoflurane-mediated modulation of oxidative myocardial injury.

Volatile anesthetics offer protection when administered throughout an ischemic injury. We examined how volatile anesthetics modulate the cardiac myocytic injury associated with hydrogen peroxide. Forty-eight Long-Evans rats were divided into four groups depending on the treatment: none (CONT), Glibenclamide (GLB); Sevoflurane (SEV); or GLB+SEV. Each group was further divided into two, one of which was exposed to hydrogen peroxide (H2O2). Oral GLB was administered 48 hours before myocardial isolation. All rats were anesthetized by intraperitoneal injection of Ketamine, and the hearts were harvested after heparinization. Cardiomyocytes were isolated using a combination of mechanical mincing and enzymatic digestion. After isolation, the aliquots of cells were exposed to H2O2 and FeSO4 for 30 minutes. The cell suspensions were then bubbled for 10 minutes with 100% oxygen and 1.5% SEV if appropriate. Apoptosis was detected by fluorescein-bound annexin-V (ANX-V), necrosis by propidium iodide, and ELISA assessed caspase-3 activity in all groups. There was an increase in apoptosis, necrosis, and caspase-3 activity in the cells following exposure to hydrogen peroxide. SEV reduced the rate of cell necrosis and apoptosis. Pretreatment with GLB did not alter the effects of SEV. Similarly, caspase-3 activity did not change with GLB, although SEV administration reduced this enzymatic activity in response to hydrogen peroxide. In this oxidant injury model, we demonstrated that incubating isolated cardiomyocytes with SEV profoundly diminished H2O2-induced apoptotic and necrotic cells compared to their CONTs. These results support the hypothesis that KATP channels are not the sole mediators associated with anesthetic preconditioning.

A Rare Presentation of Dilated Cardiomyopathy Along with Takayasu Arteritis in a Preschool Child

Dilated cardiomyopathy is the most common form of cardiomyopathy in children, is the cause of significant morbidity and mortality. Although the most common etiology of DCM remains idiopathic, it is estimated that upto 50% of cases are genetic. The pathogenesis of ventricular dilation and altered contractility seen in DCM varies depending on the underlying etiology; systolic dysfunction and myocyte injury are common. Takayasu arteritis also known as “pulseless disease”, is a chronic large vessel vasculitis of unknown etiology and predominantly involves the aorta and its major branches. This disease is most common in Asians and mostly diagnosed in adolescent age group, on average at the age of 13 years. TA is characterized by inflammation of the vessel wall starting from vasa vasorum. Persistent inflammation leads to progressive scarring and intimal proliferation and can result in stenotic or occluded vessels leading to systemic manifestations. We have reported a rare case of dilated cardiomyopathy along with Takayasu arteritis in a preschool child. The causality and association between both the conditions has not been fully understood yet. However DCM has been reported in only 5-6% cases of TA.

Evolocumab has no effects on heart failure with reduced ejection fraction injury biomarkers: The EVO-HF trial.

Patients with heart failure with reduced ejection fraction (HFrEF) have not been shown to benefit from statins. We hypothesized that, by limiting disease progression in stable HFrEF of ischaemic etiology, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab could reduce circulating troponin levels, a surrogate biomarker of myocyte injury and atherosclerosis progression. The EVO-HF multicentre prospective randomized trial compared evolocumab (420 mg/month administered subcutaneously) plus guideline-directed medical therapy (GDMT; n = 17) versus GDMT alone (n = 22) for 1 year in patients with stable coronary artery disease and left ventricular ejection fraction (LVEF) <40%, ischaemic aetiology, New York Heart Association class II, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥400 pg/ml, high-sensitivity troponin T (hs-TnT) >10 pg/ml, low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl. The primary endpoint was change in hs-TnT concentration. Secondary endpoints included NT-proBNP, interleukin-1 receptor-like 1 (ST2), high-sensitivity C-reactive protein (hs-CRP), LDL, low-density lipoprotein receptor (LDLR), high-density lipoprotein cholesterol (HDL-C), and PCSK9 levels at 1 year. Patients were mainly Caucasian (71.8%), male (79.5%), relatively young (mean age 68.1 ± 9.4 years), with a mean LVEF of 30.4 ± 6.5%, and managed with contemporary treatments. No significant changes in hs-TnT levels were observed in any group at 1 year. NT-proBNP and ST2 levels decreased in the GDMT plus evolocumab group (p = 0.045 and p = 0.008, respectively), without changes in hs-CRP, HDL-C, or LDLR. Total and LDL-C decreased in both groups, significantly higher in the intervention group (p = 0.003), and PCSK9 levels increased in the intervention group. This prospective randomized pilot trial, although with the limitation of the small sample size, does not support the benefit of evolocumab in reducing troponin levels in patients with elevated LDL-C levels, history of coronary artery disease, and stable HFrEF.

#4779 CARDIAC BIOMARKERS FOR THE PREDICTION OF INCIDENT MAJOR ADVERSE CARDIAC EVENTS IN PATIENTS STARTING HAEMODIALYSIS: A REAL-WORLD ANALYSIS

Abstract Background and Aims Despite its advantages, haemodialysis (HD) is associated with increased cardiovascular mortality and morbidity, with some studies reporting 48% higher mortality within 2 years of starting HD. Currently, there are no established prognostic models to stratify cardiovascular risk in incident HD. Cardiac biomarkers provide insight into cardiac structure and function, including myocyte injury, stress, inflammation and fibrosis. We aimed to investigate the prognostic significance of routine cardiac biomarkers (troponin and natriuretic peptides) in the prediction of incident Major Adverse Cardiovascular Events (MACE) within 5 years of commencing HD. Method A retrospective cohort study was performed using electronic medical records from a global federated research network from the US (TriNetX). The TriNetX network was searched on 31st January 2023. The cohorts commenced HD post-diagnosis of End-Stage Kidney Disease. Data censoring for MACE was invoked prior to the index event of HD. Cardiac biomarkers were the first reported result within 3 months of starting HD. Cohorts were grouped according to biomarker-specific thresholds and 1:1 propensity-score matched for age, gender, and co-morbidities (hypertension, diabetes mellitus and smoking status). Logistical regression produced odds ratios with 95%CI for 5-year incident MACE. MACE was defined, a priori, as a composite of ischaemic heart disease, angina pectoris, acute myocardial infarction, heart failure, AF, stroke, and all-cause mortality. All statistical analysis was performed on the TriNetX online platform. Results The results are shown in Table 1. Results that reached statistical significance (p&amp;lt;0.05) are shown. Conclusion Routinely available cardiac biomarkers can predict incident MACE and outcomes in incident HD, although results differ between markers of myocyte injury (troponin) and stress (NTproBNP). The results suggest the clinical need for CV mortality and morbidity risk profiling in incident dialysis using a combination of clinical and laboratory variables.

Biomarkers in Heart Failure: From Research to Clinical Practice.

The aim of this narrative review is to summarize contemporary evidence on the use of circulating cardiac biomarkers of heart failure (HF) and to identify a promising biomarker model for clinical use in personalized point-of-care HF management. We discuss the reported biomarkers of HF classified into clusters, including myocardial stretch and biomechanical stress; cardiac myocyte injury; systemic, adipocyte tissue, and microvascular inflammation; cardiac fibrosis and matrix remodeling; neurohumoral activation and oxidative stress; impaired endothelial function and integrity; and renal and skeletal muscle dysfunction. We focus on the benefits and drawbacks of biomarker-guided assistance in daily clinical management of patients with HF. In addition, we provide clear information on the role of alternative biomarkers and future directions with the aim of improving the predictive ability and reproducibility of multiple biomarker models and advancing genomic, transcriptomic, proteomic, and metabolomic evaluations.

1053 PHARMACOLOGICAL REDUCTION OF OXIDATIVE STRESS COUNTERACTS CARDIAC DISFUNCTION IN A MURINE MODEL OF DYSTROPHIC CARDIOMIOPATHY

Abstract Introduction Dystrophic cardiomyopathy culminates in heart failure and arrhythmias and is a major burden for Duchenne muscular dystrophy (DMD) patients. Mechanism-driven therapies designed to contrast the development of muscle and cardiac dysfunction are still missing. Antioxidant treatments counteract myocyte injury in mdx mice, a genetic model of DMD, supporting the possible role of enhanced reactive oxygen species (ROS) in the pathophysiology of muscular dystrophies. Previous evidence shows that monoamine oxidases (MAO) represent an important source of ROS, thus contributing to cardiomyocyte damage and dysfunction in different models of heart disease. Objectives we tested whether MAO-induced ROS formation contributes to the progression of pathology in dystrophic hearts. Materials and methods wild type (WT) and mdx mice at 3 and 12 months of age were employed. Cardiac function was determined by echocardiography measuring: fractional shortening, ejection fraction and left ventricle strain. Cardiac structure and fibrosis amount were assessed through histology (H&amp;E, Masson's Trichrome). To test whether reduction in ROS burden could ameliorate cardiac structure and function in mdx mice, MAO-B inhibitor safinamide was administered to WT and mdx mice respectively at 3 and 12 months of age. Results We found that fractional shortening (FS) and ejection fraction (EF) were reduced by 1.2- and 2-fold at 3 and 12 months of age, respectively, in mdx mice vs their WT counterpart. In addition, left ventricle (LV) strain was impaired in mdx mice already at 3 months of age. This functional impairment was accompanied by a 5-fold increase in fibrosis in mdx hearts, evident already at 3 months. Safinamide administration for 30 days, led to a significant improvement of FS, EF and LV strain in mdx mice. Half of the mice in the safinamide cohort showed reduced levels of myocardial fibrosis. Conclusions Taken together, these results suggest that pharmacological MAO-B inhibition improves cardiac function in a genetic model of DMD and may represent a clinically relevant target for the treatment of dystrophic cardiomyopathies.