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Balkan Medical Journal Jan 2024Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory coronavirus-2 (SARS-CoV-2). Several explanations for the development of... (Review)
Review
Coronavirus disease 2019 (COVID-19) is caused by the novel severe acute respiratory coronavirus-2 (SARS-CoV-2). Several explanations for the development of cardiovascular complications during and after acute COVID-19 infection have been hypothesized. The COVID-19 pandemic, caused by SARS-CoV-2, has emerged as one of the deadliest pandemics in modern history. The myocardial injury in COVID-19 patients has been associated with coronary spasm, microthrombi formation, plaque rupture, hypoxic injury, or cytokine storm, which have the same pathophysiology as the three clinical variants of Kounis syndrome. The angiotensin-converting enzyme 2 (ACE2), reninaldosterone system (RAAS), and kinin-kallikrein system are the main proposed mechanisms contributing to cardiovascular complications with the COVID-19 infection. ACE receptors can be found in the heart, blood vessels, endothelium, lungs, intestines, testes, neurons, and other human body parts. SARS-CoV-2 directly invades the endothelial cells with ACE2 receptors and constitutes the main pathway through which the virus enters the endothelial cells. This causes angiotensin II accumulation downregulation of the ACE2 receptors, resulting in prothrombotic effects, such as hemostatic imbalance via activation of the coagulation cascade, impaired fibrinolysis, thrombin generation, vasoconstriction, endothelial and platelet activation, and pro-inflammatory cytokine release. The KKS system typically causes vasodilation and regulates tissue repair, inflammation, cell proliferation, and platelet aggregation, but SARS-CoV-2 infection impairs such counterbalancing effects. This cascade results in cardiac arrhythmias, cardiac arrest, cardiomyopathy, cytokine storm, heart failure, ischemic myocardial injuries, microvascular disease, Kounis syndrome, prolonged COVID, myocardial fibrosis, myocarditis, new-onset hypertension, pericarditis, postural orthostatic tachycardia syndrome, pulmonary hypertension, stroke, Takotsubo syndrome, venous thromboembolism, and thrombocytopenia. In this narrative review, we describe and elucidate when, where, and how COVID-19 affects the human cardiovascular system in various parts of the human body that are vulnerable in every patient category, including children and athletes.
Topics: Child; Humans; COVID-19; SARS-CoV-2; Renin-Angiotensin System; Angiotensin-Converting Enzyme 2; Peptidyl-Dipeptidase A; Cytokine Release Syndrome; Endothelial Cells; Pandemics; Kounis Syndrome; Cardiovascular System
PubMed: 38173173
DOI: 10.4274/balkanmedj.galenos.2023.2023-10-25 -
Current Opinion in Clinical Nutrition... Jan 2020We would like to inform clinicians that the systematic administration of oral and intravenous L-arginine is therapeutically beneficial and clinically useful for patients... (Review)
Review
PURPOSE OF REVIEW
We would like to inform clinicians that the systematic administration of oral and intravenous L-arginine is therapeutically beneficial and clinically useful for patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), when they maintain plasma arginine concentration at least 168 μmol/l.
RECENT FINDINGS
MELAS is associated with endothelial dysfunction by decreased plasma L-arginine, nitric oxide (NO), and cyclic guanosine monophosphate. Endothelial dysfunction is also evident using flow-mediated vasodilation measurement by high-resolution Doppler echocardiography in the forearm artery in patients with MELAS. L-arginine is known to be an important precursor of NO to normalize the endothelial function in MELAS. In our clinical trial followed by 7 years follow-up study, the systematic administration of L-arginine to patients with MELAS significantly improved the survival curve of patients compared with natural history. Maintaining plasma arginine concentration at least 168 μmol/l may prevent the ictuses through the putative pathophysiologic mechanism and optimal normalization of endothelial dysfunction.
SUMMARY
Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. Therapeutic regimen of L-arginine on MELAS may be beneficial and clinically useful for patient care with MELAS.
Topics: Administration, Intravenous; Arginine; Clinical Trials as Topic; Follow-Up Studies; Humans; MELAS Syndrome; Treatment Outcome
PubMed: 31693521
DOI: 10.1097/MCO.0000000000000610 -
Annals of Medicine and Surgery (2012) Jun 2023Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS) is a rare neurodegenerative inherited disorder that is characterized by stroke-like...
UNLABELLED
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS) is a rare neurodegenerative inherited disorder that is characterized by stroke-like episodes, seizures, endocrine, and multiple system involvement. It is important to consider it as a differential diagnosis in a young patient with stroke-like episodes as it is progressive and has multiple complications.
CASE PRESENTATION
A 28-year-old male presented with slurring of speech and drowsiness for 7 h. He was a diagnosed case of type 2 diabetes mellitus, Wolf-Parkinson-White syndrome, and bilateral hearing loss.
CLINICAL FINDINGS AND INVESTIGATIONS
The patient had expressive aphasia with impaired fluency, repetition, and naming. After being discharged, he represented with loss of consciousness and involuntary movements of the whole body. MRI and MRS showed extension of hyperintense lesions to parieto-occipital regions from temporal regions not limited by vascular territories. MELAS was considered, which was confirmed by molecular genetic analysis. Coenzyme Q10 was used for MELAS. Insulin, Linagliptin, and levetiracetam were used for diabetes and seizures. Regular follow-up was advised to the patient.MELAS is an important syndrome to consider in any young patient presenting with unexplained stroke disorders. A high index of suspicion is needed in an appropriate clinical setting to avoid misdiagnosis.
PubMed: 37363571
DOI: 10.1097/MS9.0000000000000712 -
Frontiers in Neurology 2022Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes, and other features (short stature, headaches, seizures, and sensorineural hearing loss)...
Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes, and other features (short stature, headaches, seizures, and sensorineural hearing loss) constitute characteristics of MELAS syndrome. MELAS is a rare condition due to mutations in maternally inherited mitochondrial DNA with levels of heteroplasmy possibly related to late adulthood presentation. A previously reported MELAS case coexisted with presumed Antiphospholipid Antibody Syndrome (APLAS), but the connection between MELAS and a potential APLAS is unclear. A 29-year-old woman presented with mild right-sided sensorimotor symptoms and mixed aphasia in November 2021. She presented again in May 2022 for unrelenting headaches and was found to have a new right hemisphere syndrome with mild left-sided sensorimotor symptoms, hemineglect, and anosognosia. Characteristic lab and imaging studies were obtained. During the first presentation (October 2021), the discovery of anticardiolipin IgM antibodies (aCL) (and their replication 3 months later) led to a diagnosis of APLAS, and Warfarin was initiated. During the second admission (May 2022), a new stroke-like lesion on the right hemisphere with characteristic features not suggestive of ischemia was detected, which led to a diagnosis of MELAS (m3243A > G mutation). Although MELAS and APLAS could co-exist, alternatively, it is possible that antiphospholipid antibodies might be generated when the strongly anionic Cardiolipin-Hydroperoxide from the inner mitochondrial membrane is exposed to immune component cells upon cell lysis. Thus, the presence of aCL in patients with stroke-like lesions might masquerade as an APLAS, but should probably be questioned if only aCL are repeatedly found and imaging findings are not characteristic for ischemic lesions.
PubMed: 36588908
DOI: 10.3389/fneur.2022.1043695 -
American Journal of Ophthalmology Case... Jun 2022Retro-mode illumination imaging can provide good visualization of chorio-retinal atrophy and of the retinal pigment epithelial alterations occurring in m.3243A > G...
Retro-mode illumination imaging can provide good visualization of chorio-retinal atrophy and of the retinal pigment epithelial alterations occurring in m.3243A > G associated retinopathy.
PubMed: 35282600
DOI: 10.1016/j.ajoc.2022.101411 -
Biology Sep 2022Advances in data acquisition via high resolution genomic, transcriptomic, proteomic and metabolomic platforms have driven the discovery of the underlying factors... (Review)
Review
Advances in data acquisition via high resolution genomic, transcriptomic, proteomic and metabolomic platforms have driven the discovery of the underlying factors associated with metabolic disorders (MD) and led to interventions that target the underlying genetic causes as well as lifestyle changes and dietary regulation. The review focuses on fourteen of the most widely studied inherited MD, which are familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, Maple syrup urine disease, Metachromatic leukodystrophy, Mitochondrial encephalopathy lactic acidosis stroke-like episodes (MELAS), Niemann-Pick disease, Phenylketonuria (PKU), Porphyria, Tay-Sachs disease, Wilson's disease, Familial hypertriglyceridemia (F-HTG) and Galactosemia based on genome wide association studies, epigenetic factors, transcript regulation, post-translational genetic modifications and biomarker discovery through metabolomic studies. We will delve into the current approaches being undertaken to analyze metadata using bioinformatic approaches and the emerging interventions using genome editing platforms as applied to animal models.
PubMed: 36138787
DOI: 10.3390/biology11091308 -
Annals of Clinical and Translational... Jun 2023To explore the clinical characteristics of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) caused by mitochondrial DNA-encoded complex...
OBJECTIVE
To explore the clinical characteristics of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) caused by mitochondrial DNA-encoded complex I subunit (mt-ND) variants.
METHODS
In this retrospective study, the clinical, myopathological and brain MRI features of patients with MELAS caused by mt-ND variants (MELAS-mtND) were collected and compared with those of MELAS patients carrying the m.3243A > G variant (MELAS-A3243G).
RESULT
A total of 18 MELAS-mtND patients (female: 7; median age: 24.5 years) represented 15.9% (n = 113) of all patients with MELAS caused by mtDNA variants in our neuromuscular center from January 2012 to June 2022. In this MELAS-mtND cohort, the two most common variants were m.10191 T > C (4/18, 22.2%) and m.13513 G > A (3/18, 16.7%). The most frequent symptoms were seizures (14/18, 77.8%) and muscle weakness (11/18, 61.1%). Compared with 87 MELAS-A3243G patients, MELAS-mtND patients were significantly more likely to have a variant that was absent in blood cells (40% vs. 1.4%). Furthermore, MELAS-mtND patients had a significantly lower MDC score (7.8 ± 2.7 vs. 9.8 ± 1.9); less hearing loss (27.8% vs. 54.0%), diabetes (11.1% vs. 37.9%), and migraine (33.3% vs. 62.1%); less short stature (males ≤ 165 cm; females ≤ 155 cm; 23.1% vs. 60.8%) and higher body mass index (20.4 ± 2.5 vs. 17.8 ± 2.7). MELAS-mtND patients had significantly more normal muscle pathology (31.3% vs. 4.1%) and fewer RRFs/RBFs (62.5% vs. 91.9%), COX-deficient fibers/blue fibers (25.0% vs. 85.1%) and SSVs (50.0% vs. 81.1%). Moreover, brain MRI evaluated at the first stroke-like episode showed significantly more small cortical lesions in MELAS-mtND patients (66.7% vs. 12.2%).
INTERPRETATION
Our results suggested that MELAS-mtND patients have distinct clinical, myopathological and brain MRI features compared with MELAS-A3243G patients.
Topics: Adult; Female; Humans; Male; Young Adult; Brain; Magnetic Resonance Imaging; MELAS Syndrome; Muscles; Retrospective Studies; Stroke
PubMed: 37221696
DOI: 10.1002/acn3.51787 -
Stem Cell Research & Therapy Jun 2022Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage in the retinal pigment epithelium (RPE) have been implicated in the pathogenesis of age-related macular...
BACKGROUND
Mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage in the retinal pigment epithelium (RPE) have been implicated in the pathogenesis of age-related macular degeneration (AMD). However, a deeper understanding is required to determine the contribution of mitochondrial dysfunction and impaired mitochondrial autophagy (mitophagy) to RPE damage and AMD pathobiology. In this study, we model the impact of a prototypical systemic mitochondrial defect, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), in RPE health and homeostasis as an in vitro model for impaired mitochondrial bioenergetics.
METHODS
We used induced pluripotent stem cells (iPSCs) derived from skin biopsies of MELAS patients (m.3243A > G tRNA leu mutation) with different levels of mtDNA heteroplasmy and differentiated them into RPE cells. Mitochondrial depletion of ARPE-19 cells (p cells) was also performed using 50 ng/mL ethidium bromide (EtBr) and 50 mg/ml uridine. Cell fusion of the human platelets with the p cells performed using polyethylene glycol (PEG)/suspension essential medium (SMEM) mixture to generate platelet/RPE "cybrids." Confocal microscopy, FLowSight Imaging cytometry, and Seahorse XF Mito Stress test were used to analyze mitochondrial function. Western Blotting was used to analyze expression of autophagy and mitophagy proteins.
RESULTS
We found that MELAS iPSC-derived RPE cells exhibited key characteristics of native RPE. We observed heteroplasmy-dependent impairment of mitochondrial bioenergetics and reliance on glycolysis for generating energy in the MELAS iPSC-derived RPE. The degree of heteroplasmy was directly associated with increased activation of signal transducer and activator of transcription 3 (STAT3), reduced adenosine monophosphate-activated protein kinase α (AMPKα) activation, and decreased autophagic activity. In addition, impaired autophagy was associated with aberrant lysosomal function, and failure of mitochondrial recycling. The mitochondria-depleted p cells replicated the effects on autophagy impairment and aberrant STAT3/AMPKα signaling and showed reduced mitochondrial respiration, demonstrating phenotypic similarities between p and MELAS iPSC-derived RPE cells.
CONCLUSIONS
Our studies demonstrate that the MELAS iPSC-derived disease models are powerful tools for dissecting the molecular mechanisms by which mitochondrial DNA alterations influence RPE function in aging and macular degeneration, and for testing novel therapeutics in patients harboring the MELAS genotype.
Topics: Autophagy; DNA, Mitochondrial; Energy Metabolism; Epithelial Cells; Humans; Induced Pluripotent Stem Cells; MELAS Syndrome; Macular Degeneration; Mitochondria; Retinal Pigment Epithelium; Retinal Pigments
PubMed: 35715869
DOI: 10.1186/s13287-022-02937-6 -
Journal of the Belgian Society of... 2022Microhemorrhages have not been described in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) on magnetic resonance imaging...
INTRODUCTION
Microhemorrhages have not been described in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) on magnetic resonance imaging (MRI). Main symptoms and/or important findings: A MELAS-patient had a rapid succession of 3 stroke-like episodes with dysphasia, visual field deficits and paresis of the right arm. MRI showed a lesion with corticosubcortical vasogenic edema without reduced diffusion, conforming to a stroke-like MELAS-lesion. Microhemorrhages within MELAS-lesions were detected on MRI. The main diagnoses, therapeutic interventions, and outcomes: Microhemorrhages are an atypical imaging finding in MELAS. The patient was treated with L-arginine.
CONCLUSION
Microhemorrhages can present on MRI in (sub)acute MELAS lesions and may reflect mitochondrial microangiopathy.
PubMed: 36248725
DOI: 10.5334/jbsr.2891 -
Nature Metabolism Dec 2023Nuclease-mediated editing of heteroplasmic mitochondrial DNA (mtDNA) seeks to preferentially cleave and eliminate mutant mtDNA, leaving wild-type genomes to repopulate...
Nuclease-mediated editing of heteroplasmic mitochondrial DNA (mtDNA) seeks to preferentially cleave and eliminate mutant mtDNA, leaving wild-type genomes to repopulate the cell and shift mtDNA heteroplasmy. Various technologies are available, but many suffer from limitations based on size and/or specificity. The use of ARCUS nucleases, derived from naturally occurring I-CreI, avoids these pitfalls due to their small size, single-component protein structure and high specificity resulting from a robust protein-engineering process. Here we describe the development of a mitochondrial-targeted ARCUS (mitoARCUS) nuclease designed to target one of the most common pathogenic mtDNA mutations, m.3243A>G. mitoARCUS robustly eliminated mutant mtDNA without cutting wild-type mtDNA, allowing for shifts in heteroplasmy and concomitant improvements in mitochondrial protein steady-state levels and respiration. In vivo efficacy was demonstrated using a m.3243A>G xenograft mouse model with mitoARCUS delivered systemically by adeno-associated virus. Together, these data support the development of mitoARCUS as an in vivo gene-editing therapeutic for m.3243A>G-associated diseases.
Topics: Humans; Animals; Mice; DNA, Mitochondrial; MELAS Syndrome; Mitochondria; Mutation
PubMed: 38036771
DOI: 10.1038/s42255-023-00932-6