Alterations of PINK1-PRKN signaling in mice during normal aging.

The ubiquitin kinase-ligase pair PINK1-PRKN identifies and selectively marks damaged mitochondria for elimination via the autophagy-lysosome system (mitophagy). While this cytoprotective pathway has been extensively studied in vitro upon acute and complete depolarization of mitochondria, the significance of PINK1-PRKN mitophagy in vivo is less well established. Here we used a novel approach to study PINK1-PRKN signaling in different energetically demanding tissues of mice during normal aging. We demonstrate a generally increased expression of both genes and enhanced enzymatic activity with aging across tissue types. Collectively our data suggest a distinct regulation of PINK1-PRKN signaling under basal conditions with the most pronounced activation and flux of the pathway in mouse heart compared to brain or skeletal muscle. Our biochemical analyses complement existing mitophagy reporter readouts and provide an important baseline assessment in vivo, setting the stage for further investigations of the PINK1-PRKN pathway during stress and in relevant disease conditions.

Cardiac defects of hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders: a retrospective cohort study.

Background: Defective connective tissue structure may cause individuals with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorders (HSD) to develop cardiac defects. Methods: We conducted a retrospective chart review of adult patients treated in the EDS Clinic from November 1, 2019, to June 20, 2022 to identify those with cardiac defects. Echocardiogram data were collected using a data collection service. All EDS Clinic patients were evaluated by a single physician and diagnosed according to the 2017 EDS diagnostic criteria. Patient demographic, family and cardiac history were extracted from self-reported responses from a REDCap clinical intake questionnaire. Patients with at least 1 available echocardiogram (ECHO) were selected for the study (n = 568). Results: The prevalence of aortic root dilation in patients with hEDS was 2.7% and for HSD was 0.6%, with larger measurements for males than females and with age. Based on self-reported cardiac history that was verified from the medical record, patients with hEDS with bradycardia (p = 0.034) or brain aneurysm (p = 0.015) had a significantly larger average adult aortic root z-score. In contrast, patients with HSD that self-reported dysautonomia (p = 0.019) had a significantly larger average aortic root z-score. The prevalence of diagnosed mitral valve prolapse in patients with hEDS was 3.5% and HSD was 1.8%. Variants of uncertain significance were identified in 16 of 84 patients that received genetic testing based on family history. Conclusions: These data reveal a low prevalence of cardiac defects in a large cohort of well-characterized hEDS and HSD patients. Differences in cardiovascular issues were not observed between patients with hEDS vs. HSD; and our findings suggest that cardiac defects in patients with hEDS or HSD are similar to the general population.

A Possible Newly Defined and Treatable Secondary Cause of Early Morning Wake-Up Headaches in an Older Hypermobile Woman: Nutcracker Physiology with Spinal Epidural Venous Congestion.

Introduction: Left renal vein compression (nutcracker physiology) with secondary spinal epidural venous congestion is a newly recognized cause of daily persistent headache. Presently, only women with underlying symptomatic hypermobility issues appear to develop headache from this anatomic issue. The hypothesized etiology is an abnormal reset of the patient's cerebrospinal fluid (CSF) pressure to an elevated state. Headaches that occur during sleep can have a varied differential diagnosis, one of which is elevated CSF pressure. We present the case of an older woman who began to develop severe wake-up headaches at midnight. She was found to have left renal vein compression and spinal epidural venous congestion on imaging. After treatment with lumbar vein coil embolization, which alleviated the spinal cord venous congestion, her headaches alleviated. Case Report: A 61-year-old woman with a history of hypermobile Ehlers-Danlos syndrome began to be awakened with severe head pain at midnight at least several times per week. The headache was a holocranial, pressure sensation, which worsened in the supine position. The headaches were mostly eliminated with acetazolamide. Because of her hypermobility issues and pressure-like headache, she was investigated for underlying nutcracker physiology and spinal epidural venous congestion. This was confirmed using magnetic resonance (MR) angiography and conventional venography, and after lumbar vein coil embolization her wake-up headaches ceased. Conclusion: The case report suggests a possible new underlying and treatable cause for early morning, wake-up headaches: nutcracker physiology with secondary spinal epidural venous congestion. The case expands on the clinical headache presentation of nutcracker physiology.

The inflammatory spectrum of cardiomyopathies.

Infiltration of the myocardium with various cell types, cytokines and chemokines plays a crucial role in the pathogenesis of cardiomyopathies including inflammatory cardiomyopathies and myocarditis. A more comprehensive understanding of the precise immune mechanisms involved in acute and chronic myocarditis is essential to develop novel therapeutic approaches. This review offers a comprehensive overview of the current knowledge of the immune landscape in cardiomyopathies based on etiology. It identifies gaps in our knowledge about cardiac inflammation and emphasizes the need for new translational approaches to improve our understanding thus enabling development of novel early detection methods and more effective treatments.

Mitochondrial extracellular vesicles, autoimmunity and myocarditis.

For many decades viral infections have been suspected as 'triggers' of autoimmune disease, but mechanisms for how this could occur have been difficult to establish. Recent studies have shown that viral infections that are commonly associated with viral myocarditis and other autoimmune diseases such as coxsackievirus B3 (CVB3) and SARS-CoV-2 target mitochondria and are released from cells in mitochondrial vesicles that are able to activate the innate immune response. Studies have shown that Toll-like receptor (TLR)4 and the inflammasome pathway are activated by mitochondrial components. Autoreactivity against cardiac myosin and heart-specific immune responses that occur after infection with viruses where the heart is not the primary site of infection (e.g., CVB3, SARS-CoV-2) may occur because the heart has the highest density of mitochondria in the body. Evidence exists for autoantibodies against mitochondrial antigens in patients with myocarditis and dilated cardiomyopathy. Defects in tolerance mechanisms like autoimmune regulator gene (AIRE) may further increase the likelihood of autoreactivity against mitochondrial antigens leading to autoimmune disease. The focus of this review is to summarize current literature regarding the role of viral infection in the production of extracellular vesicles containing mitochondria and virus and the development of myocarditis.

Exercise After Acute Myocarditis: When and How to Return to Sports.

Myocarditis is an inflammatory disease of the myocardium secondary to infectious and noninfectious insults. The most feared consequence of myocarditis is sudden cardiac death owing to electrical instability and arrhythmia. Typical presenting symptoms include chest pain, dyspnea, palpitations and/or heart failure. Diagnosis is usually made with history, electrocardiogram, biomarkers, echocardiogram, and cardiac MRI (CMR). Application of the Lake Louise criteria to CMR results can help identify cases of myocarditis. Treatment is usually supportive with medical therapy, and patients are recommended to abstain from exercise for 3 to 6 months. Exercise restrictions may be lifted after normalization on follow-up testing.

Laryngological Complaint Prevalence in Hypermobile Ehlers-Danlos or Hypermobility Spectrum Disorders.

OBJECTIVE: The aim was to study laryngological complaints in patients with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorders (HSD). METHODS: A total of 363 patients met inclusion for the study by completing questions related to voice, upper airway, and swallowing between July 7, 2020 and July 13, 2022. Demographic data, voice-related questions, and hypermobility diagnosis were analyzed retrospectively. From those, 289 patients were diagnosed with hEDS or HSD with 74 that did not meet the diagnostic criteria for either diagnosis serving as controls. RESULTS: There were no statistically significant differences between patients with hEDS and HSD regarding Voice Handicap Index (VHI-10) scores, voice, upper airway, or swallow complaints. However, more hEDS/HSD patients answered positively to the laryngeal dysfunction question versus controls (p = 0.031). 22.5% of hEDS/HSD patients (n = 65) reported hoarseness, of which 52.3% reported hoarseness >2 days/month. 33.9% (n = 98) with hEDS/HSD reported symptoms of dysphagia, and 27.0% (n = 78) reported laryngeal dysfunction symptoms. Controls demonstrated 20.3% prevalence of hoarseness, of which 46.7% reported hoarseness >2 days/month. 24.3% of controls had dysphagia and 14.9% laryngeal dysfunction symptoms. Of the 363 patients, VHI-10 scores >11 were more likely in patients reporting >2 days of hoarseness/month (p = 0.001) versus those with <2 days of hoarseness/month. There was an increased prevalence of voice, upper airway, and dysphagia symptoms in hEDS/HSD patients compared with previously reported prevalence data in the general population. CONCLUSION: A significant proportion of patients diagnosed with hypermobility due to hEDS or HSD were found to have voice, upper airway, and dysphagia symptoms. These rates are higher than those previously reported in the general population. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:773-778, 2024.

Sex differences in left-ventricular strain in a murine model of coxsackievirus B3 myocarditis.

Myocarditis is typically caused by viral infections, but most cases are thought to be subclinical. Echocardiography is often used for initial assessment of myocarditis patients but is poor at detecting subtle changes in cardiac dysfunction. Cardiac strain, such as global longitudinal strain (GLS) and global circumferential strain (GCS), represents an increasingly used set of measurements which can detect these subtle changes. Using a murine model of coxsackievirus B3 myocarditis, we characterized functional changes in the heart using echocardiography during myocarditis and by sex. We found that 2D GLS, 4D mode, and 4D strains detected a significant reduction in ejection fraction and GLS during myocarditis compared to baseline and in males compared to females. Furthermore, worse GLS correlated to increased levels of CD45+, CD11b+, and CD3+ immune cells. Our findings closely resemble published reports of GLS in patients with myocarditis indicating the usefulness of this animal model for translational studies of myocarditis.

Rates Among Hospitalized Patients With COVID-19 Treated With Convalescent Plasma: A Systematic Review and Meta-Analysis.

Objective: To examine the association of COVID-19 convalescent plasma transfusion with mortality and the differences between subgroups in hospitalized patients with COVID-19. Patients and Methods: On October 26, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma in the literature from January 1, 2020, to October 26, 2022. Randomized clinical trials and matched cohort studies investigating COVID-19 convalescent plasma transfusion compared with standard of care treatment or placebo among hospitalized patients with confirmed COVID-19 were included. The electronic search yielded 3841 unique records, of which 744 were considered for full-text screening. The selection process was performed independently by a panel of 5 reviewers. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 5 independent reviewers in duplicate and pooled using an inverse-variance random effects model. The prespecified end point was all-cause mortality during hospitalization. Results: Thirty-nine randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants were included in the systematic review. Separate meta-analyses reported that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for both randomized clinical trials (odds ratio [OR], 0.87; 95% CI, 0.76-1.00) and matched cohort studies (OR, 0.76; 95% CI, 0.66-0.88). The meta-analysis of subgroups revealed 2 important findings. First, treatment with convalescent plasma containing high antibody levels was associated with a decrease in mortality compared with convalescent plasma containing low antibody levels (OR, 0.85; 95% CI, 0.73 to 0.99). Second, earlier treatment with COVID-19 convalescent plasma was associated with a decrease in mortality compared with the later treatment cohort (OR, 0.63; 95% CI, 0.48 to 0.82). Conclusion: During COVID-19 convalescent plasma use was associated with a 13% reduced risk of mortality, implying a mortality benefit for hospitalized patients with COVID-19, particularly those treated with convalescent plasma containing high antibody levels treated earlier in the disease course.

Sex differences in coronavirus disease 2019 myocarditis.

Myocarditis is frequently caused by viral infections, but animal models that closely resemble human disease suggest that virus-triggered autoimmune disease is the most likely cause of myocarditis. Myocarditis is a rare condition that occurs primarily in men under age 50. The incidence of myocarditis rose at least 15x during the COVID-19 pandemic from 1-10 to 150-400 cases/100,000 individuals, with most cases occurring in men under age 50. COVID-19 vaccination was also associated with rare cases of myocarditis primarily in young men under 50 years of age with an incidence as high as 50 cases/100,000 individuals reported for some mRNA vaccines. Sex differences in the immune response to COVID-19 are virtually identical to the mechanisms known to drive sex differences in myocarditis pre-COVID based on clinical studies and animal models. The many similarities between COVID-19 vaccine-associated myocarditis to COVID-19 myocarditis and non-COVID myocarditis suggest common immune mechanisms drive disease.

Reconstituted Extracellular Vesicles from Human Platelets Decrease Viral Myocarditis in Mice.

Patients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease-specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human-platelet-derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)-like module-containing mucin-like hormone receptor-like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll-like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL-1ß), transforming growth factor-beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7-9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T-cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.

COVID-19, Myocarditis and Pericarditis.

Viral infections are a leading cause of myocarditis and pericarditis worldwide, conditions that frequently coexist. Myocarditis and pericarditis were some of the early comorbidities associated with SARS-CoV-2 infection and COVID-19. Many epidemiologic studies have been conducted since that time concluding that SARS-CoV-2 increased the incidence of myocarditis/pericarditis at least 15× over pre-COVID levels although the condition remains rare. The incidence of myocarditis pre-COVID was reported at 1 to 10 cases/100 000 individuals and with COVID ranging from 150 to 4000 cases/100 000 individuals. Before COVID-19, some vaccines were reported to cause myocarditis and pericarditis in rare cases, but the use of novel mRNA platforms led to a higher number of reported cases than with previous platforms providing new insight into potential pathogenic mechanisms. The incidence of COVID-19 vaccine-associated myocarditis/pericarditis covers a large range depending on the vaccine platform, age, and sex examined. Importantly, the findings highlight that myocarditis occurs predominantly in male patients aged 12 to 40 years regardless of whether the cause was due to a virus-like SARS-CoV-2 or associated with a vaccine-a demographic that has been reported before COVID-19. This review discusses findings from COVID-19 and COVID-19 vaccine-associated myocarditis and pericarditis considering the known symptoms, diagnosis, management, treatment, and pathogenesis of disease that has been gleaned from clinical research and animal models. Sex differences in the immune response to COVID-19 are discussed, and theories for how mRNA vaccines could lead to myocarditis/pericarditis are proposed. Additionally, gaps in our understanding that need further research are raised.

High overlap in patients diagnosed with hypermobile Ehlers-Danlos syndrome or hypermobile spectrum disorders with fibromyalgia and 40 self-reported symptoms and comorbidities.

Background: Joint pain is a common symptom in patients with hypermobile Ehlers-Danlos Syndrome (hEDS), hypermobility spectrum disorders (HSD) and fibromyalgia. The goal of this study was to determine whether symptoms and comorbidities overlap in patients diagnosed with hEDS/HSD and/or fibromyalgia. Methods: We retrospectively examined self-reported data from an EDS Clinic intake questionnaire in patients diagnosed with hEDS/HSD, fibromyalgia, or both vs. controls with an emphasis on joint issues. Results: From 733 patients seen at the EDS Clinic, 56.5% (n = 414) were diagnosed with hEDS/HSD and fibromyalgia (Fibro), 23.8% (n = 167) hEDS/HSD, 13.3% (n = 98) fibromyalgia, or 7.4% (n = 54) none of these diagnoses. More patients were diagnosed with HSD (76.6%) than hEDS (23.4%). Patients were primarily White (95%) and female (90%) with a median age in their 30s (controls 36.7 [18.0, 70.0], fibromyalgia 39.7 [18.0, 75.0], hEDS/HSD 35.0 [18.0, 71.0], hEDS/HSD&Fibro 31.0 [18.0, 63.0]). There was high overlap in all 40 symptoms/comorbidities that we examined in patients diagnosed with fibromyalgia only or hEDS/HSD&Fibro, regardless of whether they had hEDS or HSD. Patients that only had hEDS/HSD without fibromyalgia had far fewer symptoms/comorbidities than patients with hEDS/HSD&Fibro. The top self-reported issues in patients that only had fibromyalgia were joint pain, hand pain when writing or typing, brain fog, joint pain keeping from daily activities, allergy/atopy and headache. Five issues that significantly and uniquely characterized patients diagnosed with hEDS/HSD&Fibro were subluxations (dislocations in hEDS patients), joint issues like sprains, the need to stop sports due to injuries, poor wound healing, and migraine. Conclusion: The majority of patients seen at the EDS Clinic had a diagnosis of hEDS/HSD plus fibromyalgia that was associated with more severe disease. Our findings indicate that fibromyalgia should be routinely assessed in patients with hEDS/HSD and vis-a-versa to improve patient care.

Sex and gender differences in myocarditis and dilated cardiomyopathy: An update.

In the past decade there has been a growing interest in understanding sex and gender differences in myocarditis and dilated cardiomyopathy (DCM), and the purpose of this review is to provide an update on this topic including epidemiology, pathogenesis and clinical presentation, diagnosis and management. Recently, many clinical studies have been conducted examining sex differences in myocarditis. Studies consistently report that myocarditis occurs more often in men than women with a sex ratio ranging from 1:2-4 female to male. Studies reveal that DCM also has a sex ratio of around 1:3 women to men and this is also true for familial/genetic forms of DCM. Animal models have demonstrated that DCM develops after myocarditis in susceptible mouse strains and evidence exists for this progress clinically as well. A consistent finding is that myocarditis occurs primarily in men under 50 years of age, but in women after age 50 or post-menopause. In contrast, DCM typically occurs after age 50, although the age that post-myocarditis DCM occurs has not been investigated. In a small study, more men with myocarditis presented with symptoms of chest pain while women presented with dyspnea. Men with myocarditis have been found to have higher levels of heart failure biomarkers soluble ST2, creatine kinase, myoglobin and T helper 17-associated cytokines while women develop a better regulatory immune response. Studies of the pathogenesis of disease have found that Toll-like receptor (TLR)2 and TLR4 signaling pathways play a central role in increasing inflammation during myocarditis and in promoting remodeling and fibrosis that leads to DCM, and all of these pathways are elevated in males. Management of myocarditis follows heart failure guidelines and there are currently no disease-specific therapies. Research on standard heart failure medications reveal important sex differences. Overall, many advances in our understanding of the effect of biologic sex on myocarditis and DCM have occurred over the past decade, but many gaps in our understanding remain. A better understanding of sex and gender effects are needed to develop disease-targeted and individualized medicine approaches in the future.

Exercise After Acute Myocarditis: When and How to Return to Sports.

Myocarditis is an inflammatory disease of the myocardium secondary to infectious and noninfectious insults. The most feared consequence of myocarditis is sudden cardiac death owing to electrical instability and arrhythmia. Typical presenting symptoms include chest pain, dyspnea, palpitations and/or heart failure. Diagnosis is usually made with history, electrocardiogram, biomarkers, echocardiogram, and cardiac MRI (CMR). Application of the Lake Louise criteria to CMR results can help identify cases of myocarditis. Treatment is usually supportive with medical therapy, and patients are recommended to abstain from exercise for 3 to 6 months. Exercise restrictions may be lifted after normalization on follow-up testing.

Extracellular vesicles as personalized medicine.

Extracellular vesicles (EVs) are released from all cells in the body, forming an important intercellular communication network that contributes to health and disease. The contents of EVs are cell source-specific, inducing distinct signaling responses in recipient cells. The specificity of EVs and their accumulation in fluid spaces that are accessible for liquid biopsies make them highly attractive as potential biomarkers and therapies for disease. The duality of EVs as favorable (therapeutic) or unfavorable (pathological) messengers is context dependent and remains to be fully determined in homeostasis and various disease states. This review describes the use of EVs as biomarkers, drug delivery vehicles, and regenerative therapeutics, highlighting examples involving viral infections, cancer, and neurological diseases. There is growing interest to provide personalized therapy based on individual patient and disease characteristics. Increasing evidence suggests that EV biomarkers and therapeutic approaches are ideal for personalized medicine due to the diversity and multifunctionality of EVs.

The Impact of a Group Telemedicine Program for Chronic Disease: A Retrospective Cohort Survey Study on Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorder.

Background: We present an innovative care model for telehealth by creating a video conference group telemedicine program for patients with chronic disease and discuss findings from a post-program survey that was instrumental in understanding the response to telemedicine in a group setting. Methods: All patients who attended the group telemedicine program had a diagnosis of Hypermobile Ehlers-Danlos Syndrome or Hypermobility Spectrum Disorder and were requested to complete survey responses at the close of the program. Surveys were completed anonymously and electronically by REDCap. Elements of the Press Ganey, Consumer Assessment of Healthcare Providers and Systems, and Utah Telehealth Network patient satisfaction surveys were modified to construct the survey. Results: A total of 102 patients completed the post-telehealth program survey between August 20, 2021, and February 11, 2022. Around 93.1% stated that they gained a better understanding of the chronic condition, 88.3% stated that the program gave them the tools to improve, and 76.5% indicated the program addressed their specific needs. Approximately 92.1% found it easy to interact with the program facilitator and 79.4% found it easy to interact with program members. Around 93.1% said they would recommend the program to others. Discussion: We created a group telemedicine program for a complex chronic medical condition. The foundation of knowledge provided by the telemedicine program allowed more time during face-to-face encounters for individual assessment of the patient, and increased access to care. Overall, the program has improved the treatment process by reducing treatment burden and empowering patients with self-management skills to help reach our fundamental treatment goal of improving quality of life.

Convalescent plasma and COVID-19: Time for a second-second look?

In this short narrative, we highlight some of our experiences leading the US Convalescent Plasma Program at the beginning of the pandemic in the spring and summer of 2020. This includes a brief summary of how the program emerged and high-level lessons we learned. We also share our impressions about why convalescent plasma was used at scale in the United States, early in the pandemic and share ideas that might inform the use of convalescent plasma in future outbreaks of novel infectious diseases.

The evolving regulatory landscape in regenerative medicine.

Regenerative medicine as a field has emerged as a new component of modern medicine and medical research that encompasses a wide range of products including cellular and acellular therapies. As this new field emerged, regulatory agencies like the Food and Drug Administration (FDA) rapidly adapted existing regulatory frameworks to address the transplantation, gene therapy, cell-based therapeutics, and acellular biologics that fall under the broader regenerative medicine umbrella. Where it has not been possible to modify existing regulation and processes, entirely new frameworks have been generated with the intention of providing flexible, forward-facing systems to regulate this rapidly growing field. This review discusses the current state of FDA regulatory affairs in the context of stem cells and extracellular vesicles by highlighting gaps in the current regulatory system and then discussing where regulatory science in regenerative medicine may be headed based on these gaps and the FDA's historical ability to deal with emerging fields. Lastly, we utilize case studies in stem cell and acellular based treatments to demonstrate how regulatory science has evolved in regenerative medicine and highlight the ongoing clinical efforts and challenges of these therapies.