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.

Outflow graft obstruction after left ventricular assist device implantation: a retrospective, single-centre case series.

AIMS: Outflow graft obstruction is a poorly described complication following left ventricular assist device (LVAD) surgery. We sought to define the incidence of LVAD outflow graft obstruction and assess clinical outcomes with a percutaneous treatment strategy. METHODS AND RESULTS: From January 2012 to October 2020, 322 patients with LVAD were managed at our institution. Patients with LVAD outflow graft obstruction were identified by cardiac computed tomography with angiography and invasive haemodynamic assessment and were subsequently treated with percutaneous intervention. Poisson regression was used to analyse time-dependent differences in the incidence of LVAD outflow graft obstruction. Kaplan-Meier analysis was used to estimate survival. Twenty patients (6.2%) developed haemodynamically significant LVAD outflow graft obstruction at a rate of 0.03 events per patient-year. Outflow graft obstruction presented a median of 33 (26-49) months after surgery. Patients presented with low estimated LVAD pump flow (95%), heart failure (90%), or both (85%), and 59% developed cardiogenic shock prior to intervention. The most common aetiology identified by cardiac computed tomography with angiography was external compression of the outflow graft (78%). On presentation, the median peak gradient in the outflow graft was 78 (64-100) mmHg. Outflow graft stenting was 100% successful with no in-hospital mortality, and it reduced the peak outflow graft gradient to 10 (2-17) mmHg (P < 0.001). Outflow graft stenting was durable with two patients (10%) requiring a repeat procedure over a median follow-up of 13 (7-20) months and did not impact survival. CONCLUSIONS: Left ventricular assist device outflow graft obstruction is a relatively common and underappreciated cause of recurrent heart failure and LVAD dysfunction. Outflow graft stenting can be achieved with low morbidity and provides a long-term solution to this complication.

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.

Transthyretin Cardiac Amyloidosis and Aortic Stenosis: Connection and Therapeutic Implications.

BACKGROUND: There is a growing interest in the observed significant incidence of transthyretin cardiac amyloidosis in elderly patients with aortic stenosis. Approximately, 16% of patients with severe aortic stenosis undergoing aortic valve replacement have transthyretin cardiac amyloidosis. Outcomes after aortic valve replacement appear to be worst in patients with concomitant transthyretin cardiac amyloidosis. METHODS: Publications in PubMed, Cochrane Library, and Embase databases were systematically searched from January 2012 to September 2018 using the keywords transthyretin, amyloidosis, and aortic stenosis. All studies published in English that reported the prevalence, association and outcomes of transthyretin cardiac amyloidosis in patients with aortic stenosis undergoing were included. RESULTS/CONCLUSION: The relationship between aortic stenosis and transthyretin cardiac amyloidosis is not well understood. A few studies have proven successful surgical management when both conditions coexist. This systematic review suggests that transthyretin cardiac amyloidosis is common in elderly patients with aortic stenosis and tend to have high mortality rates after AVR. The significant incidence of the two diseases occurring simultaneously warrants further investigation to improve management strategies in the future.

ECG clues for false ST-segment elevation myocardial infarction activations.

BACKGROUND: Rapid diagnosis of ST-segment elevation myocardial infarction (STEMI) is crucial for appropriate management. Catheterization for a false STEMI activation has risks including exposure to contrast agent and radiation, increased healthcare costs and delay in treatment of the primary medical condition. PATIENTS AND METHODS: This was a single center retrospective study including all 'cath alerts' between January 2012 and December 2015. 'Cath alert' is a term used to activate the interventional cardiology team when STEMI is suspected by the emergency department physicians based on review of the initial ECG. We reviewed all STEMI alerts to understand ECG differences between true and false STEMI. RESULTS: Our study population (N = 361) included 221 (61%) men and 140 (39%) women, with average age 60 ± 4.2 years. Among the 361 STEMI alerts, 82 (22.7%) did not have acute coronary syndrome. Common ECG causes of misdiagnosis included left ventricular hypertrophy (LVH, found in 40/82, 49%), early repolarization changes (20/82, 24%), right bundle branch block (RBBB) (13/82, 16%), and Brugada pattern (3/82, 4%). Multivariate regression analysis showed that LVH and RBBB were independent predictors of nonacute coronary syndrome false STEMI (odds ratio: 0.54; 95% confidence interval: 0.32-0.93; P = 0.03 for LVH, and odds ratio: 0.26, 95% confidence interval: 0.1-0.62, P = 0.004 for RBBB). CONCLUSION: The incidence of false STEMI alerts was almost 23% at our center. This number might be reduced with additional training of emergency department physicians in ECG interpretation, and recognition of common causes of misdiagnosis such as LVH, early repolarization changes, RBBB, and Brugada pattern.

Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy.

BACKGROUND: High altitude associated hypobaric hypoxia is one of the cellular and environmental perturbation that alters proteostasis network and push the healthy cell towards loss of muscle mass. The present study has elucidated the robust proteostasis network and signaling mechanism for skeletal muscle atrophy under chronic hypobaric hypoxia (CHH). METHODS: Male Sprague Dawley rats were exposed to simulated hypoxia equivalent to a pressure of 282 torr for different durations (1, 3, 7 and 14 days). After CHH exposure, skeletal muscle tissue was excised from the hind limb of rats for biochemical analysis. RESULTS: Chronic hypobaric hypoxia caused a substantial increase in protein oxidation and exhibited a greater activation of ER chaperones, glucose-regulated protein-78 (GRP-78) and protein disulphide isomerase (PDI) till 14d of CHH. Presence of oxidized proteins triggered the proteolytic systems, 20S proteasome and calpain pathway which were accompanied by a marked increase in [Ca2+]. Upregulated Akt pathway was observed upto 07d of CHH which was also linked with enhanced glycogen synthase kinase-3ß (GSk-3ß) expression, a negative regulator of Akt. Muscle-derived cytokines, tumor necrosis factor-α (TNF-α), interferon-ϒ (IFN-©) and interleukin-1ß (IL-1ß) levels significantly increased from 07d onwards. CHH exposure also upregulated the expression of nuclear factor kappa-B (NF-κB) and E3 ligase, muscle atrophy F-box-1 (Mafbx-1/Atrogin-1) and MuRF-1 (muscle ring finger-1) on 07d and 14d. Further, severe hypoxia also lead to increase expression of ER-associated degradation (ERAD) CHOP/ GADD153, Ub-proteasome and apoptosis pathway. CONCLUSIONS: The disrupted proteostasis network was tightly coupled to degradative pathways, altered anabolic signaling, inflammation, and apoptosis under chronic hypoxia. Severe and prolonged hypoxia exposure affected the protein homeostasis which overwhelms the muscular system and tends towards skeletal muscle atrophy.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio Predict Acute Cellular Rejection in the Kidney Allograft.

BACKGROUND Kidney transplantation is the treatment of choice for end stage kidney disease, but acute rejection remains a limiting factor in optimizing allograft and patient survival. Needle biopsy is the current standard of care for this diagnosis. The potential for complications with repeat biopsies limits the ability to obtain temporal immune surveillance of the allograft. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been shown to be strong predictors of inflammation and of worse prognosis in a variety of conditions. MATERIAL AND METHODS This is a single center retrospective case control study which included all patients who underwent a "for -cause biopsy" of a transplanted kidney. NLR and PLR were calculated 1 month prior, at the time, and 6 months and 1 year after the biopsy. RESULTS A total of 159 biopsies were reviewed; 127 (79.9%) of these satisfied all inclusion and exclusion criteria, and 63.0% of the sample cohort (n=80) demonstrated acute cellular rejection (ACR). Patients without evidence of ACR had an average NLR of 26.8, which was approximately 7-fold greater than those patients with findings of ACR (P<0.01). A similar trend was found for PLR, where patients without ACR had a 5.5-fold greater PLR compared to those with rejection (P<0.01). The ROC showed AUC of 0.715 and 0.716 respectively. The NLR cutoff of 9.5 had a positive predictive value (PPV) of 80% and a negative predictive value (NPV) of 77.8%; the PLR cutoff of 380 had a PPV of 75% and a NPV of 100%. CONCLUSIONS This study showed that NLR and PLR are easily obtainable and reproducible predictors of ACR in the kidney allograft. Serial monitoring of these ratios will help identify subclinical inflammation before evidence of allograft dysfunction.

Role of defective Ca2+ signaling in skeletal muscle weakness: Pharmacological implications.

The misbehaving attitude of Ca2+ signaling pathways could be the probable reason in many muscular disorders such as myopathies, systemic disorders like hypoxia, sepsis, cachexia, sarcopenia, heart failure, and dystrophy. The present review throws light upon the calcium flux regulating signaling channels like ryanodine receptor complex (RyR1), SERCA (Sarco-endoplasmic Reticulum Calcium ATPase), DHPR (Dihydropyridine Receptor) or Cav1.1 and Na+/Ca2+ exchange pump in detail and how remodelling of these channels contribute towards disturbed calcium homeostasis. Understanding these pathways will further provide an insight for establishing new therapeutic approaches for the prevention and treatment of muscle atrophy under stress conditions, targeting calcium ion channels and associated regulatory proteins.

Hyperplastic Polyps and Gastroduodenal Pseudomelanosis.

Pseudomelanosis is a rare endoscopic finding of the upper gastrointestinal tract characterized by hemosiderin deposits in histiocytes of lamina propria. We report a case of 72-year-old lady on chronic oral iron supplementation diagnosed with gastric hyperplastic polyps with background pseudomelanosis of stomach and duodenum. Concomitant occurrence of gastric pseudomelanosis, duodenal pseudomelanosis, and gastric hyperplastic polyps has never been reported. Its presence in the absence of gastritis raises question if pseudomelanosis could be associated with hyperplastic polyp. With limited literature on its etiology and prognosis, these patients should be prospectively followed and reported to study the natural history of the disease.

Overt Lower Gastrointestinal Bleeding and Pseudotumor: A Rare Presentation of Cytomegalovirus Infection.

Cytomegalovirus (CMV) is a ubiquitous organism which can infect multiple organs of the body. In an immunocompromised patient, it can have a myriad of gastrointestinal manifestations. We report a case of recurrent hematochezia and concomitant pseudotumor in an AIDS (acquired immunodeficiency syndrome) patient attributable to CMV infection. A 62-year-old man with a history of AIDS, noncompliant with highly active antiretroviral therapy (HAART), presented with bright red blood per rectum. Index colonoscopy showed presence of multiple ulcers, colonic stenosis, and mass-like appearing lesion. Biopsy confirmed CMV infection and ruled out malignancy. Cessation of dual antiplatelet therapy and compliance with HAART lead to clinical cessation of bleeding and endoscopic healing of ulcers with complete resolution of colon mass on follow-up colonoscopy.