Endogenous dipeptide-carnosine supplementation ameliorates hypobaric hypoxia-induced skeletal muscle loss via attenuating endoplasmic reticulum stress response and maintaining proteostasis.

High altitude is an environmental stress that is accompanied with numerous adverse biological responses, including skeletal muscle weakness and muscle protein loss. Skeletal muscle wasting is an important clinical problem, progressing to critical illness, associated with increased morbidity and mortality. The present study explores the protective efficacy of endogenous dipeptide, carnosine (CAR), supplementation in ameliorating skeletal muscle protein loss under hypobaric hypoxia (HH). Male Sprague-Dawley rats (n = 5) were randomly divided into control group, HH-exposed group (3 days HH exposure equivalent to 7,620 m), and HH-exposed rats supplemented with carnosine (3 days; 150 mg/kg b.w, orally) (HH + CAR). HH-exposed rats supplemented with CAR ameliorated HH-induced oxidative protein damage, lipid peroxidation, and maintained pro-inflammatory cytokines levels. HH-associated muscle protein degradative pathways, including calpain, ubiquitination, endoplasmic reticulum stress, autophagy, and apoptosis were also regulated in carnosine-supplemented rats. Further, the muscle damage marker, the levels of serum creatine phosphokinase were also reduced in HH + CAR co-supplemented rats which proved the protective efficacy of CAR against hypobaric hypoxia-induced muscle protein loss. Altogether, CAR supplementation ameliorated HH-induced skeletal muscle protein loss via performing multifaceted ways, mainly by maintaining redox homeostasis and proteostasis in skeletal muscle.

Microfluidic Droplet Cluster with Distributed Evaporation Rates as a Model for Bioaerosols.

Aerosols and microdroplets are known to act as carriers for pathogens or vessels for chemical reactions. The natural occurrence of evaporation of these droplets has implications for the viability of pathogens or chemical processes. For example, it is important to understand how pathogens survive extreme physiochemical conditions such as confinement and osmotic stress induced by evaporation of aerosol droplets. Previously, larger evaporating droplets were proposed as model systems as the processes in the tiny aerosol droplets are difficult to image. In this context, we propose the concept of evaporation of capillary-clustered aqueous microdroplets dispersed in a thin oil layer. The configuration produces spatially segregated evaporation rates. It allows comparing the consequences of evaporation and its rate for processes occurring in droplets. As a proof of concept, we study the consequences of evaporation and its rate using Escherichia coli (E. coli) and Bacillus subtilis as model organisms. Our experiments indicate that the rate of evaporation of microdroplets is an important parameter in deciding the viability of contained microorganisms. With slow evaporation, E. coli could mitigate the osmotic stress by K+ ion uptake. Our method may also be applicable to other evaporating droplet systems, for example, microdroplet chemistry to understand the implications of evaporation rates.

Effect of convalescent plasma therapy on mortality in moderate-to-severely Ill COVID-19 patients.

INTRODUCTION: The role of plasma therapy in the management of the COVID-19, pandemic has been speculated. However, in view of the varied response regarding its effectiveness from various multicenter studies, there is a need to conduct more single center population-specific studies. We, thus, aimed to assess the role of convalescent plasma therapy in COVID-19 patient management in a single -center. METHODS: This retrospective study was conducted using records of all COVID-19 patients who received plasma therapy over a period of 6 months in a dedicated COVID-19 hospital in Delhi. Information pertaining to transfusion, disease severity, associated comorbidities, the treatment given and patient outcome were recorded. Data was analyzed using SPSSv23. RESULTS: Of the141 patients who received plasma therapy, 62% were discharged after treatment. Mortality was found to be significantly higher in patients > 60 years of age (p < 0.001), those with severe COVID-19 infection (p < 0.05) and pre-existing renal disease (p < 0.05). The admission-transfusion interval was significantly correlated to mortality and was a sensitive parameter for predicting outcome at cut off value of < 5 days (p < 0.001). There was no significant association of mortality with patient blood group, plasma antibody levels or donor hemoglobin levels. CONCLUSIONS: We report improvement and recovery in a large number of patients who received convalescent plasma within the first 5 days of hospitalization with moderate to severe disease. Further research to compare dosage and administration protocols to delineate role of CCP in survival of COVID-19 patients is needed before it is prematurely shelved.

Ursolic acid ameliorates hypobaric hypoxia-induced skeletal muscle protein loss via upregulating Akt pathway: An experimental study using rat model.

Hypobaric hypoxic stress leads to oxidative stress, inflammation, and disturbance in protein turnover rate. Aggregately, this imbalance in redox homeostasis is responsible for skeletal muscle protein loss and a decline in physical performance. Hence, an urgent medical need is required to ameliorate skeletal muscle protein loss. The present study investigated the efficacy of ursolic acid (UA), a pentacyclic triterpene acid to ameliorate hypobaric hypoxia (HH)-induced muscle protein loss. UA is a naturally occurring pentacyclic triterpene acid present in several edible herbs and fruits such as apples. It contains skeletal muscle hypertrophy activity; still its potential against HH-induced muscle protein loss is unexplored. To address this issue, an in vivo study was planned to examine the beneficial effect of UA supplementation on HH-induced skeletal muscle loss. Male Sprague Dawley rats were exposed to HH with and without UA supplementation (20 mg/kg; oral) for 3 continuous days. The results described the beneficial role of UA as supplementation of UA with HH exposure attenuated reactive oxygen species production and oxidative protein damage, which indicate the potent antioxidant activity. Furthermore, UA supplementation enhanced Akt, pAkt, and p70S6kinase activity (Akt pathway) and lowered the pro-inflammatory cytokines in HH exposed rats. UA has potent antioxidant and anti-inflammatory activity, and it enhanced the protein content via upregulation of Akt pathway-related proteins against HH exposure. These three biological activities of UA make it a novel candidate for amelioration of HH-induced skeletal muscle damage and protein loss.

Predictors of 30-day re-admissions in patients with infective endocarditis: a national population based cohort study.

Infective endocarditis (IE) is a life threatening disease requiring lengthy hospitalizations, complex multidisciplinary management and high health care costs. In this study, we analyzed the National Readmissions' Database (NRD) to identify infective endocarditis cases and the causative organisms, clinical determinants, length of stay, in-hospital mortality, and 30-day hospital readmission rates. The study cohort was derived from Healthcare Cost and Utilization Project's National Readmission Database between 2010-15. We queried the National Readmissions' Database using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic code for infective endocarditis (421.0) and identified a total of 187,438 index admissions. SAS 9.4 (SAS Institute Inc., Cary, NC) was utilized for statistical analyses. A total of 187,438 patients with a primary diagnosis of IE were identified over 6 years (2010-2015). Twenty-four percent (44,151 patients) were readmitted within 30 days. Most common etiologies for readmission included sepsis (14%), acute heart failure (8%), acute kidney injury (6%), intracardiac device infection (5.6%) and recurrence of IE (2.7%). Predictors of increased readmissions included female sex, staphylococcus aureus infection, diabetes, chronic lung disease, chronic liver disease, acute kidney injury, acute heart failure and anemia. In-hospital mortality for the readmission of IE was 13%, and average length of stay during the re-admission was 12 days. IE is associated with high rates of index admission mortality and for 30-day readmissions of which are associated with a substantial risk of death.

Hypertension During Pregnancy.

PURPOSE OF REVIEW: Hypertensive disorders of pregnancy affect about 5-10% of pregnancies impacting maternal, fetal, and neonatal outcomes. We review the recent studies in this field and discuss the pathophysiology, diagnosis, and management of hypertension during pregnancy, as well as the short- and long-term consequences on the cardiovascular health of women. RECENT FINDINGS: Although the American College of Cardiology/American Heart Association revised their guidelines for hypertension in the general population in 2017, hypertension during pregnancy continues to be defined as a systolic blood pressure (SBP) ≥ 140 mmHg and/or a diastolic blood pressure (DBP) ≥ 90 mmHg, measured on two separate occasions. The addition of stage 1 hypertension will increase the prevalence of hypertension during pregnancy, identifying more women at risk of preeclampsia; however, more research is needed before changing the BP goal because a lower target BP has a risk of poor placental perfusion. Women with chronic hypertension have a higher incidence of superimposed preeclampsia, cesarean section, preterm delivery before 37 weeks' gestation, birth weight less than 2500 g, neonatal unit admission, and perinatal death. They also have a higher risk of developing cardiovascular disease later in life. The guidelines recommend low-dose aspirin for women with moderate and high risk of preeclampsia. While treating pregnant women with hypertension, the effectiveness of the antihypertensive agent must be balanced with risks to the fetus. Hypertensive disorders of pregnancy should be appropriately and promptly recognized and treated during pregnancy. They should further be co-managed by the obstetrician and cardiologist to decrease the long-term negative impact on the cardiovascular health of women.

Cardiorenal syndrome in heart failure with preserved ejection fraction-an under-recognized clinical entity.

Cardiorenal syndrome (CRS) results from the complex and bidirectional interaction between the failing heart and the kidneys. Limited information exists about the pathophysiology and treatment options for worsening kidney function in the setting of heart failure with preserved ejection fraction (HFpEF). This review summarizes the salient pathophysiological pathways in CRS in patients with HFpEF, with emphasis on type 1 and type 2 phenotypes, and outlines diagnostic and therapeutic strategies that are applicable in this population. Elevated central venous and intra-abdominal pressure, left ventricular hypertrophy, LV strain, RAAS activation, oxidative injury, pulmonary hypertension, and RV dysfunction play key roles in the pathogenesis of CRS in the backdrop of HFpEF. The availability of biomarkers of renal and cardiac injury offer a new dimension in accurately diagnosing and quantifying end organ damage in CRS and will improve the accuracy of goal-directed therapies in this population. Novel targeted therapies such as the development of angiotensin/neprilysin inhibitors and sodium-glucose cotransporter-2 (SGLT-2) inhibitors offer new territory in realizing potential benefits in reduction of cardio-renal adverse outcomes in this population. Future studies focusing exclusively on renal outcomes in patients with HFpEF are crucial in delivering optimal therapies in this subset of patients.

Anticoagulation for intra-cardiac thrombi in peripartum cardiomyopathy: A review of the literature.

Peripartum cardiomyopathy is a type of non-ischemic cardiomyopathy with a high rate of thromboembolic events. Guiding strategies for anticoagulation in patients with peripartum cardiomyopathy and thromboembolic events are limited. Literature for all cases of peripartum cardiomyopathy with intracardiac thrombi were reviewed and summarized from twelve case reports. Based on the available literature, we conclude that patients with peripartum cardiomyopathy with ejection fraction of less than 30% should strongly consider anticoagulation therapy to avoid thromboembolic events. Future studies may be able to further elucidate the optimal indication and duration of anticoagulation.

Renal dysfunction in Takotsubo syndrome-role of segmental left ventricle strain analysis.

BACKGROUND: Takotsubo syndrome (TTS) is a peculiar clinical condition often resembling an acute coronary syndrome and mostly affecting postmenopausal women. We sought to describe the prevalence of acute kidney injury and acute renal failure in TTS patients during index event and assess the usefulness of speckle tracking echocardiography in predicting subjects at risk of developing acute kidney insult. METHODS: We conducted a retrospective descriptive study reviewing study with the discharge diagnosis of TTS between 2003-2016 at our Institution. One hundred and two patients met the Modified Mayo Clinic. Acute kidney injury (AKI) was defined as an increment of serum creatinine 2 times greater than baseline and/or at least 50% reduction in baseline eGFR. Acute renal failure (ARF) was defined as an increment of serum creatinine 3 times greater than baseline and/or at least 75% reduction in baseline eGFR as per RIFLE Classification. RESULTS: AKI/ARF patients had longer length of stay (24 vs 10 days, P = 0.02), had higher mean peak troponin (16.7 ng/mL vs 3.2, P < 0.05) and later peak creatinine day (10 vs 3, P < 0.05). LV Longitudinal strain in the basal segment and apex upon admission was significantly worse in the AKI/ARF group (-4.7 and -6.5, respectively, vs -8.6 and -9.1 in the non-AKI/ARF group, P < 0.05). CONCLUSIONS: One in every 10 TTS patients may develop AKI/ARF during the acute episode. Segmental longitudinal strain by speckle tracking may have important prognostic value in identifying TTS patients at risk of developing AKI/ARF.

Cholesterol embolization syndrome: An under-recognized entity in cardiovascular interventions.

Cholesterol embolization syndrome (CES) is a multi-systemic disease caused by embolization of atherosclerotic plaque contents from proximal large-caliber artery to distal small to medium arteries, occurring spontaneously or more commonly after vascular intervention. This report is a comprehensive review of the reported cases of CES found in our literature search. We discuss the risk factors, clinical manifestations, management, and prognosis of CES. The major predisposing factors for CES include older age, male sex, atherosclerotic cardiovascular risk factors, anticoagulation, and femoral access route. The composite incidence of atheroembolic renal disease was 92% and mortality 63%. Our review highlights the importance to recognize this disease entity for the cardiologist and nephrologist.

Pericardium: The Forgotten Space During Acute Myocardial Infarction.

BACKGROUND: Acute pericardial pathologies, such as pericardial effusion, pericarditis, and cardiac tamponade, have been reported rarely in patients presenting as ST-elevation myocardial infarction (STEMI). We present a series of 3 patients with STEMI, where an undiagnosed pericardial effusion led to pericardial tamponade and subsequent cardiocirculatory collapse. CASE REPORTS: This is a case series of 3 patients, all women, aged 72, 64, and 54 years who presented to the emergency department with chest pain or syncope and were found to have STEMI with hemodynamic instability. They were taken to the catheterization laboratory for urgent coronary revascularization requiring mechanical circulatory support (intra-aortic balloon pump or impella). During catheterization, all 3 patients were diagnosed with large pericardial effusion using hemodynamic parameters and bedside transesophageal echocardiogram. Commonly ignored, pericardial tamponade and acute large pericardial effusion can be the cause of cardiocirculatory collapse. Two of the 3 patients survived with aggressive interventions requiring pericardial drains, long-term mechanical circulatory support, and effective postoperative rehabilitation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: It is important for treating clinicians, including emergency physicians, intensivist, and cardiologist, to consider the differential of a cardiac tamponade due to a pericardial effusion as a potential cause for hypotension in patients with an acute STEMI.

Utility of Dobutamine Stress Echocardiography in Cardiac Risk Stratification of Patients Undergoing Orthotopic Liver Transplantation.

Cardiovascular diseases are a major cause of morbidity and mortality in patients after orthotopic liver transplantation (OLT). This review includes major original articles published in the English-language literature of patients who underwent dobutamine stress echocardiography (DSE) before OLT for cardiac risk stratification. Of a total of 10 original articles (total 1699 patients undergoing DSE), 6 studies used DSE to predict major adverse cardiac events (MACE) in patients undergoing OLT and 4 reported the role of DSE in coronary artery disease (CAD) prediction in patients with end-stage liver disease. The composite incidence of MACE was 11.4%. In predicting postoperative MACE, DSE had a composite sensitivity of 0.12 (95% CI, 0.07-0.19), a specificity of 0.96 (95% CI, 0.94-0.97), a positive predictive value (PPV) of 0.26 (95% CI, 0.16-0.38), and a negative predictive value (NPV) of 0.89 (95% CI, 0.88-0.91). The presence of known CAD in a patient was shown to increase the risk of cardiac events after OLT significantly in three of six studies. The average prevalence of CAD was 14.4%. In predicting CAD, DSE had a composite sensitivity of 0.47 (95% CI, 0.32-0.62), specificity of 0.74 (95% CI, 0.68- 0.79), PPV of 0.23 (95% CI, 0.15-0.33), and NPV of 0.89 (95% CI, 0.84-0.93). This review emphasizes the need for standardizing cardiac risk stratification protocol to screen and prevent cardiac morbidity after OLT, standardizing MACE definition to allow more uniform reporting, and the need for safer and efficacious alternatives to DSE in the evaluation of OLT candidates.

Interactions, Structure, and Dynamics of Polymer-Tethered Nanoparticle Blends.

We report on the structure, jamming, and dynamics of blends of self-suspended hairy silica nanoparticles grafted with poly(ethylene glycol) (PEG) and poly(methyl methacrylate) (PMMA). We find that favorable enthalpic attraction between tethered PEG and PMMA chains augment previously reported entropic attractions between tethered polymer chains in self-suspended suspensions to enhance particle-particle correlations, increase jamming, and slow down chain dynamics. As with their single-component counterparts, the hairy SiO2-PEG/SiO2-PMMA nanoparticle blends exhibit soft glassy rheological behavior and both the energy dissipated at yielding and the plateau elastic modulus display strong maxima in the symmetric case. A comparison of the small angle X-ray scattering (SAXS) measurements with theoretical analysis from density functional theory (DFT) reveals that the addition of SiO2-PMMA to a self-suspended SiO2-PEG suspension initially leads to a higher degree of stretching of the corona chains, which produces stronger interdigitation of the tethered chains, enhanced jamming, and slower polymer relaxation than observed in the single-component materials. By means of an analysis of the heat of mixing released upon blending tethered and untethered PEG and PMMA chains, we find that the strong enthalpic attraction between the grafted polymer chains enhances entropic attractive forces produced by the space-filling constraint on tethered ligands in self-suspended suspensions to produce entangled-polymer-like physical properties in polymers with molecular weights below the thresholds normally associated with the transition to an entangled state.

Self-suspended suspensions of covalently grafted hairy nanoparticles.

Dispersions of small particles in liquids have been studied continuously for almost two centuries for their ability to simultaneously advance understanding of physical properties of fluids and their widespread use in applications. In both settings, the suspending (liquid) and suspended (solid) phases are normally distinct and uncoupled on long length and time scales. In this study, we report on the synthesis and physical properties of a novel family of covalently grafted nanoparticles that exist as self-suspended suspensions with high particle loadings. In such suspensions, we find that the grafted polymer chains exhibit unusual multiscale structural transitions and enhanced conformational stability on subnanometer and nanometer length scales. On mesoscopic length scales, the suspensions display exceptional homogeneity and colloidal stability. We attribute this feature to steric repulsions between grafted chains and the space-filling constraint on the tethered chains in the single-component self-suspended materials, which inhibits phase segregation. On macroscopic length scales, the suspensions exist as neat fluids that exhibit soft glassy rheology and, counterintuitively, enhanced elasticity with increasing temperature. This feature is discussed in terms of increased interpenetration of the grafted chains and jamming of the nanoparticles.

Dynamics and yielding of binary self-suspended nanoparticle fluids.

Yielding and flow transitions in bi-disperse suspensions of particles are studied using a model system comprised of self-suspended spherical nanoparticles. An important feature of the materials is that the nanoparticles are uniformly dispersed in the absence of a solvent. Addition of larger particles to a suspension of smaller ones is found to soften the suspensions, and in the limit of large size disparities, completely fluidizes the material. We show that these behaviors coincide with a speeding-up of de-correlation dynamics of all particles in the suspensions and are accompanied by a reduction in the energy dissipated at the yielding transition. We discuss our findings in terms of ligand-mediated jamming and un-jamming of hairy particle suspensions.

Impella RP Flex: Rescue for the Failing Right Ventricle After Heart Transplantation-Case Report.

Right ventricular (RV) dysfunction (RVD) after orthotopic heart transplantation (OHT) is a common cause of morbidity and mortality. Impella RP Flex was recently approved for RV support as a temporary mechanical circulatory device. We present the first case of its use in managing RVD in a patient after OHT. Here, a 40 year old male patient with familial dilated cardiomyopathy and factor V Leiden mutation presented with Society for Cardiovascular Angiography & Interventions (SCAI) stage B cardiogenic shock. Hemodynamics at admission were indicative of need for intra-aortic balloon pump (IABP) support. Hemodynamics improved and patient underwent OHT. Postoperative day (POD) 1, IABP support was changed to 1:2 and eventually removed. Hemodynamics deteriorated quickly, requiring pharmacologic RV support and diuresis, but refractory RV failure persisted. Impella RP Flex was chosen due to the patient's small size and was placed via the right internal jugular vein on POD 12. The procedure was well tolerated, with the patient ambulatory the following day (POD 13). Impella was removed on POD 25 after 13 days of support. Patient achieved normal kidney, intrinsic rhythm improved sinus rhythm, and ultimately discharged on POD 50. Impella RP flex has emerged as a promising future indication as single or biventricular support postcardiac transplantation.

Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization.

AIMS: Human pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) provide a platform to identify and characterize factors that regulate the maturation of CMs. The transition from an immature foetal to an adult CM state entails coordinated regulation of the expression of genes involved in myofibril formation and oxidative phosphorylation (OXPHOS) among others. Lysine demethylase 5 (KDM5) specifically demethylates H3K4me1/2/3 and has emerged as potential regulators of expression of genes involved in cardiac development and mitochondrial function. The purpose of this study is to determine the role of KDM5 in iPSC-CM maturation. METHODS AND RESULTS: KDM5A, B, and C proteins were mainly expressed in the early post-natal stages, and their expressions were progressively downregulated in the post-natal CMs and were absent in adult hearts and CMs. In contrast, KDM5 proteins were persistently expressed in the iPSC-CMs up to 60 days after the induction of myogenic differentiation, consistent with the immaturity of these cells. Inhibition of KDM5 by KDM5-C70 -a pan-KDM5 inhibitor, induced differential expression of 2372 genes, including upregulation of genes involved in fatty acid oxidation (FAO), OXPHOS, and myogenesis in the iPSC-CMs. Likewise, genome-wide profiling of H3K4me3 binding sites by the cleavage under targets and release using nuclease assay showed enriched of the H3K4me3 peaks at the promoter regions of genes encoding FAO, OXPHOS, and sarcomere proteins. Consistent with the chromatin and gene expression data, KDM5 inhibition increased the expression of multiple sarcomere proteins and enhanced myofibrillar organization. Furthermore, inhibition of KDM5 increased H3K4me3 deposits at the promoter region of the ESRRA gene and increased its RNA and protein levels. Knockdown of ESRRA in KDM5-C70-treated iPSC-CM suppressed expression of a subset of the KDM5 targets. In conjunction with changes in gene expression, KDM5 inhibition increased oxygen consumption rate and contractility in iPSC-CMs. CONCLUSION: KDM5 inhibition enhances maturation of iPSC-CMs by epigenetically upregulating the expressions of OXPHOS, FAO, and sarcomere genes and enhancing myofibril organization and mitochondrial function.

Anaerobic digestion of fruit and vegetable waste: a critical review of associated challenges.

The depletion of fossil fuels coupled with stringent environmental laws has encouraged us to develop sustainable renewable energy. Due to its numerous benefits, anaerobic digestion (AD) has emerged as an environment-friendly technology. Biogas generated during AD is primarily a mixture of CH4 (65-70%) and CO2 (20-25%) and a potent energy source that can combat the energy crisis in today's world. Here, an attempt has been made to provide a broad understanding of AD and delineate the effect of various operational parameters influencing AD. The characteristics of fruit and vegetable waste (FVW) and its feasibility as a potent substrate for AD have been studied. This review also covers traditional challenges in managing FVW via AD, the implementation of various bioreactor systems to manage large amounts of organic waste and their operational boundaries, microbial consortia involved in each phase of digestion, and various strategies to increase biogas production.

Clinical Reasoning: Acute Monocular Vision Loss in a Patient With Ipsilateral Extracranial Chronic Internal Carotid Artery Occlusion.

We report the case of a middle-aged man who presented with acute painless monocular vision loss. His medical history was remarkable for chronic total occlusion of the ipsilateral internal carotid artery (ICA) and a recent carotid endarterectomy (CEA) on the contralateral ICA. In a stepwise multidisciplinary approach assessment, we review the differential diagnosis of acute vision loss and investigate how the patient's intracranial and extracranial hemodynamic reorganization after chronic ICA occlusion may affect the clinical reasoning. Early complications of CEA and the differential diagnosis of new-onset anisocoria are also discussed.

Histone demethylase KDM5 regulates cardiomyocyte maturation by promoting fatty acid oxidation, oxidative phosphorylation, and myofibrillar organization.

Rationale: Human pluripotent stem cell-derived CMs (iPSC-CMs) are a valuable tool for disease modeling, cell therapy and to reconstruct the CM maturation process and identify, characterize factors that regulate maturation. The transition from immature fetal to adult CM entails coordinated regulation of the mature gene programming, which is characterized by the induction of myofilament and OXPHOS gene expression among others. Recent studies in Drosophila , C. elegans, and C2C12 myoblast cell lines have implicated the histone H3K4me3 demethylase KDM5 and its homologs, as a potential regulator of developmental gene program and mitochondrial function. We speculated that KDM5 may potentiate the maturation of iPSC-CMs by targeting a conserved epigenetic program that encompass mitochondrial OXPHOS and other CM specific maturation genes. Objectives: The purpose of this study is to determine the role of KDM5 in iPSC-CM maturation. Methods and Results: Immunoblot analysis revealed that KDM5A, B, and C expression was progressively downregulated in postnatal cardiomyocytes and absent in adult hearts and CMs. Additionally, KDM5 proteins were found to be persistently expressed in iPSC-CMs up to 60 days after the onset of myogenic differentiation, consistent with the immaturity of these cells. Inhibition of KDM5 by KDM5-C70 -a pan-KDM5 inhibitor-resulted in differential regulation of 2,372 genes including upregulation of Fatty acid oxidation (FAO), OXPHOS, and myogenic gene programs in iPSC-CMs. Likewise, genome-wide profiling of H3K4me3 binding sites by the CUT&RUN assay revealed enriched H3K4me3 peaks at the promoter regions of FAO, OXPHOS, and sarcomere genes. Consistent with the chromatin and gene expression data, KDM5 inhibition led to increased expression of multiple sarcomere proteins, enhanced myofibrillar organization and improved calcium handling. Furthermore, inhibition of KDM5 increased H3K4me3 deposits at the promoter region of the ESRRA gene, which is known to regulate OXPHOS and cardiomyocyte maturation, and resulted in its increased RNA and protein levels. Finally, KDM5 inhibition increased baseline, peak, and spare oxygen consumption rates in iPSC-CMs. Conclusions: KDM5 regulates the maturation of iPSC-CMs by epigenetically regulating the expression of ESRRA, OXPHOS, FAO, and sarcomere genes and enhancing myofibril organization and mitochondrial function.