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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of infections to date and has led to a worldwide pandemic. Most patients had a complete recovery from the acute infection, however, a large number of the affected individuals experienced symptoms that persisted more than 3 months after diagnosis. These symptoms most commonly include fatigue, memory difficulties, brain fog, dyspnea, cough, and other less common ones such as headache, chest pain, paresthesias, mood changes, muscle pain, and weakness, skin rashes, and cardiac, endocrine, renal and hepatic manifestations. The treatment of this syndrome remains challenging. A multidisciplinary approach to address combinations of symptoms affecting multiple organ systems has been widely adopted. This narrative review aims to bridge the gap surrounding the broad treatment approaches by providing an overview of multidisciplinary management strategies for the most common long COVID conditions.
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The pathophysiology of heart failure with preserved ejection fraction (HFpEF) driven by lipotoxicity is incompletely understood. Given the urgent need for animal models that accurately mimic cardio-metabolic HFpEF, a hyperlipidemia-induced murine model was developed by reverse engineering phenotypes seen in HFpEF patients. This model aimed to investigate HFpEF, focusing on the interplay between lipotoxicity and metabolic syndrome. Hyperlipidemia was induced in wild-type (WT) mice on a 129J strain background through bi-weekly intraperitoneal injections of poloxamer-407 (P-407), a block co-polymer that blocks lipoprotein lipase, combined with a single intravenous injection of adeno-associated virus 9-cardiac troponin T-low-density lipoprotein receptor (AAV9-cTnT-LDLR). Extensive assessments were conducted between 4 and 8 weeks post-treatment, including echocardiography, blood pressure recording, whole-body plethysmography, echocardiography (ECG) telemetry, activity wheel monitoring (AWM), and biochemical and histological analyses. The LDLR/P-407 mice exhibited distinctive features at four weeks, including diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Notably, blood pressure and renal function remained within normal ranges. Additionally, ECG and AWM revealed heart blocks and reduced activity, respectively. Diastolic function deteriorated at eight weeks, accompanied by a significant decline in respiratory rates. Further investigation into the double treatment model revealed elevated fibrosis, wet/dry lung ratios, and heart weight/body weight ratios. The LDLR/P-407 mice exhibited xanthelasmas, ascites, and cardiac ischemia. Interestingly, sudden deaths occurred between 6 and 12 weeks post-treatment. The murine HFpEF model offers a valuable and promising experimental resource for elucidating the intricacies of metabolic syndrome contributing to diastolic dysfunction within the context of lipotoxicity-mediated HFpEF.
Subject(s)
Heart Failure , Hyperlipidemias , Metabolic Syndrome , Humans , Animals , Mice , Heart Failure/etiology , Disease Models, Animal , Stroke VolumeABSTRACT
PURPOSE: Elevated hematocrit (Hct) can result in increased risk of major adverse cardiovascular events (MACE) in men receiving testosterone therapy (TTh). However, the impact of the magnitude of the change in Hct from baseline after starting TTh has never been assessed. MATERIALS AND METHODS: To assess whether an increase in Hct after initiating TTh is associated with an increased risk of MACE within 3 and 24 months of initiating TTh, we queried the TriNetX Research network database for men over the age of 18 with Hct values obtained within 6 months before starting TTh, and who had follow-up Hct measurements within 3 and 24 months after beginning TTh from 2010 to 2021. Men with and without a subsequent increase in Hct after initiating TTh were propensity matched. MACE was defined as myocardial infarction, stroke, or death. RESULTS: After matching, 10,511 men who experienced an any increase in Hct after initiating TTh and an equal number of controls who did have an increase in Hct were included. Compared to controls who did not have an increase in Hct after starting TTh, the men who had an increase in subsequent Hct had a significantly increased risk of MACE compared to men with no change in Hct. CONCLUSIONS: We demonstrate that increases in Hct from baseline are associated with increased risk of MACE, compared to men whose Hct remains stable while receiving TTh.
Subject(s)
Myocardial Infarction , Stroke , Male , Humans , Adult , Middle Aged , Testosterone/adverse effects , Retrospective Studies , Hematocrit , Myocardial Infarction/chemically induced , Myocardial Infarction/epidemiology , Stroke/chemically inducedABSTRACT
The heart is susceptible to proinflammatory and profibrotic responses after myocardial injury, leading to further worsening of cardiac dysfunction. Important developments in the management of heart failure with reduced ejection fraction have reduced morbidity and mortality; however, these therapies focus on optimizing cardiac function through hemodynamic and neurohormonal pathways and not by repairing the underlying cardiac injury. The potential of cell-based therapy to reverse cardiac injury has received substantial attention. Herein are examined the phase II and III studies of bone marrow-derived mesenchymal STRO-1+ or STRO-1/STRO-3+ precursor cells in patients with ischemic and nonischemic heart failure with reduced ejection fraction, addressing the safety and efficacy of cell-based therapy throughout multiple clinical trials, the optimal dose and the steps toward revolutionizing the treatment of heart failure.
Heart disease can occur due to the blockage of blood flow to the heart muscle (heart attack). This damage reduces heart function, in part because of inflammation and fibrosis (scarring). Over time, these problems lead to heart failure and death. Advances in treating heart disease focus on maintaining heart function rather than healing the heart. A cell-based treatment designed to actually repair the heart has been used with some success. In this approach, stem cells are extracted from the bone marrow of a healthy adult, processed and then injected into a patient's diseased heart. This approach is promising, but heart repair remains incomplete. This article looks at a specific type of bone marrow stem cell that has been used as a treatment for patients with heart disease. This cell treatment was recently tested in the largest such study and the first phase III clinical trial to date in the area the DREAM-HF study. This article addresses the safety and best dosage of these cells and examines how this new approach of cell-based therapy might change how heart disease is treated.
Subject(s)
Heart Failure , Mesenchymal Stem Cell Transplantation , Ventricular Dysfunction, Left , Humans , Stroke Volume , Heart Failure/therapy , Chronic DiseaseABSTRACT
Cardiac-derived c-kit+ progenitor cells (CPCs) are under investigation in the CHILD phase I clinical trial (NCT03406884) for the treatment of hypoplastic left heart syndrome (HLHS). The therapeutic efficacy of CPCs can be attributed to the release of extracellular vesicles (EVs). To understand sources of cell therapy variability we took a machine learning approach: combining bulk CPC-derived EV (CPC-EV) RNA sequencing and cardiac-relevant in vitro experiments to build a predictive model. We isolated CPCs from cardiac biopsies of patients with congenital heart disease (n = 29) and the lead-in patients with HLHS in the CHILD trial (n = 5). We sequenced CPC-EVs, and measured EV inflammatory, fibrotic, angiogeneic, and migratory responses. Overall, CPC-EV RNAs involved in pro-reparative outcomes had a significant fit to cardiac development and signaling pathways. Using a model trained on previously collected CPC-EVs, we predicted in vitro outcomes for the CHILD clinical samples. Finally, CPC-EV angiogenic performance correlated to clinical improvements in right ventricle performance.
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INTRODUCTION: Acute myocardial infarction (AMI) remains a leading cause of death in the United States. The limited capacity of cardiomyocytes to regenerate and the restricted contractility of scar tissue after AMI are not addressed by current pharmacologic interventions. Mesenchymal stem/stromal cells (MSCs) have emerged as a promising therapeutic approach due to their low antigenicity, ease of harvesting, and efficacy and safety in preclinical and clinical studies, despite their low survival and engraftment rates. Other stem cell types, such as induced pluripotent stem cells (iPSCs) also show promise, and optimizing cardiac repair requires integrating emerging technologies and strategies. AREAS COVERED: This review offers insights into advancing cell-based therapies for AMI, emphasizing meticulously planned trials with a standardized definition of AMI, for a bench-to-bedside approach. We critically evaluate fundamental studies and clinical trials to provide a comprehensive overview of the advances, limitations and prospects for cell-based therapy in AMI. EXPERT OPINION: MSCs continue to show potential promise for treating AMI and its sequelae, but addressing their low survival and engraftment rates is crucial for clinical success. Integrating emerging technologies such as pluripotent stem cells and conducting well-designed trials will harness the full potential of cell-based therapy in AMI management. Collaborative efforts are vital to developing effective stem cell therapies for AMI patients.
Subject(s)
Induced Pluripotent Stem Cells , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Myocardial Infarction , Humans , Induced Pluripotent Stem Cells/metabolism , Myocardial Infarction/therapy , Stem Cell Transplantation , Cell- and Tissue-Based TherapyABSTRACT
Osteoarthritis (OA) is the most common cause of disability worldwide among the elderly. Alarmingly, the incidence of OA in individuals less than 40 years of age is rising, likely due to the increase in obesity and post-traumatic osteoarthritis (PTOA). In recent years, due to a better understanding of the underlying pathophysiology of OA, several potential therapeutic approaches targeting specific molecular pathways have been identified. In particular, the role of inflammation and the immune system has been increasingly recognized as important in a variety of musculoskeletal diseases, including OA. Similarly, higher levels of host cellular senescence, characterized by cessation of cell division and the secretion of a senescence-associated secretory phenotype (SASP) within the local tissue microenvironments, have also been linked to OA and its progression. New advances in the field, including stem cell therapies and senolytics, are emerging with the goal of slowing disease progression. Mesenchymal stem/stromal cells (MSCs) are a subset of multipotent adult stem cells that have demonstrated the potential to modulate unchecked inflammation, reverse fibrosis, attenuate pain, and potentially treat patients with OA. Numerous studies have demonstrated the potential of MSC extracellular vesicles (EVs) as cell-free treatments that comply with FDA regulations. EVs, including exosomes and microvesicles, are released by numerous cell types and are increasingly recognized as playing a critical role in cell-cell communication in age-related diseases, including OA. Treatment strategies for OA are being developed that target senescent cells and the paracrine and autocrine secretions of SASP. This article highlights the encouraging potential for MSC or MSC-derived products alone or in combination with senolytics to control patient symptoms and potentially mitigate the progression of OA. We will also explore the application of genomic principles to the study of OA and the potential for the discovery of OA phenotypes that can motivate more precise patient-driven treatments.
Subject(s)
Extracellular Vesicles , Mesenchymal Stem Cells , Osteoarthritis , Humans , Senotherapeutics , Extracellular Vesicles/metabolism , Osteoarthritis/therapy , Osteoarthritis/metabolism , Inflammation/metabolism , Mesenchymal Stem Cells/metabolismABSTRACT
INTRODUCTION: Female sexual dysfunction (FSD) is a complex issue affecting women of all ages; it involves several overlapping body systems and profoundly affects quality of life. The use of cell-based therapy, such as mesenchymal stem cells, has recently been investigated as a potential treatment for FSD. OBJECTIVES: This systematic review and meta-analysis aim to assess FSD outcomes following cell-based therapy. METHODS: We evaluated peer-reviewed articles from multiple online databases through November 2022 to identify studies that used cell-based therapy and reported sexual function outcomes in women. We performed a meta-analysis using data pooled from 3 clinical trials at our institution: CRATUS (NCT02065245), ACESO (NCT02886884), and CERES (NCT03059355). All 3 trials collected data from the Sexual Quality of Life-Female (SQOL-F) questionnaire as an exploratory outcome. RESULTS: Existing literature on this topic is scarce. Five clinical studies and 1 animal study were included in the systematic review, and only 2 clinical studies were considered good quality: 1 reported significant SQOL-F improvement in women 6 months after cell therapy, and 1 reported posttherapy sexual satisfaction in all women. When individual patient data were pooled in a meta-analysis from 29 women across 3 trials at our institution, the SQOL-F was not significantly improved. CONCLUSION: Despite growing interest in cell-based therapy for women's sexual health, this important issue is understudied in the literature. The optimal route, source, and dose of cell therapy to produce clinically meaningful change have yet to be determined, and further research is needed in larger randomized placebo-controlled clinical trials.
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Sexual Dysfunction, Physiological , Sexual Dysfunctions, Psychological , Female , Humans , Sexual Dysfunctions, Psychological/therapy , Quality of Life , Sexual Behavior , Women's HealthABSTRACT
People living with HIV (PLHIV) are at a higher risk of having cerebrocardiovascular diseases (CVD) compared to HIV negative (HIVneg) individuals. The mechanisms underlying this elevated risk remains elusive. We hypothesize that HIV infection results in modified microRNA (miR) content in plasma extracellular vesicles (EVs), which modulates the functionality of vascular repairing cells, i.e., endothelial colony-forming cells (ECFCs) in humans or lineage negative bone marrow cells (lin- BMCs) in mice, and vascular wall cells. PLHIV (N = 74) have increased atherosclerosis and fewer ECFCs than HIVneg individuals (N = 23). Plasma from PLHIV was fractionated into EVs (HIVposEVs) and plasma depleted of EVs (HIV PLdepEVs). HIVposEVs, but not HIV PLdepEVs or HIVnegEVs (EVs from HIVneg individuals), increased atherosclerosis in apoE-/- mice, which was accompanied by elevated senescence and impaired functionality of arterial cells and lin- BMCs. Small RNA-seq identified EV-miRs overrepresented in HIVposEVs, including let-7b-5p. MSC (mesenchymal stromal cell)-derived tailored EVs (TEVs) loaded with the antagomir for let-7b-5p (miRZip-let-7b) counteracted, while TEVs loaded with let-7b-5p recapitulated the effects of HIVposEVs in vivo. Lin- BMCs overexpressing Hmga2 (a let-7b-5p target gene) lacking the 3'UTR and as such is resistant to miR-mediated regulation showed protection against HIVposEVs-induced changes in lin- BMCs in vitro. Our data provide a mechanism to explain, at least in part, the increased CVD risk seen in PLHIV.
Subject(s)
Atherosclerosis , Circulating MicroRNA , Extracellular Vesicles , HIV Infections , MicroRNAs , Humans , Animals , Mice , HIV Infections/complications , HIV Infections/genetics , MicroRNAs/genetics , Extracellular Vesicles/genetics , Atherosclerosis/geneticsABSTRACT
Congenital heart disease remains one of the most frequently diagnosed congenital diseases of the newborn, with hypoplastic left heart syndrome (HLHS) being considered one of the most severe. This univentricular defect was uniformly fatal until the introduction, 40 years ago, of a complex surgical palliation consisting of multiple staged procedures spanning the first 4 years of the child's life. While survival has improved substantially, particularly in experienced centers, ventricular failure requiring heart transplant and a number of associated morbidities remain ongoing clinical challenges for these patients. Cell-based therapies aimed at boosting ventricular performance are under clinical evaluation as a novel intervention to decrease morbidity associated with surgical palliation. In this review, we will examine the current burden of HLHS and current modalities for treatment, discuss various cells therapies as an intervention while delineating challenges and future directions for this therapy for HLHS and other congenital heart diseases.
Subject(s)
Heart Failure , Hypoplastic Left Heart Syndrome , Infant, Newborn , Child , Humans , Hypoplastic Left Heart Syndrome/surgery , Ventricular Function, Right , Retrospective StudiesABSTRACT
Heart failure (HF) with preserved ejection fraction (HFpEF) represents a major unmet medical need owing to its diverse pathophysiology and lack of effective therapies. Potent synthetic, agonists (MR-356 and MR-409) of growth hormone-releasing hormone (GHRH) improve the phenotype of models of HF with reduced ejection fraction (HFrEF) and in cardiorenal models of HFpEF. Endogenous GHRH exhibits a broad range of regulatory influences in the cardiovascular (CV) system and aging and plays a role in several cardiometabolic conditions including obesity and diabetes. Whether agonists of GHRH can improve the phenotype of cardiometabolic HFpEF remains untested and unknown. Here we tested the hypothesis that MR-356 can mitigate/reverse the cardiometabolic HFpEF phenotype. C57BL6N mice received a high-fat diet (HFD) plus the nitric oxide synthase inhibitor (l-NAME) for 9 wk. After 5 wk of HFD + l-NAME regimen, animals were randomized to receive daily injections of MR-356 or placebo during a 4-wk period. Control animals received no HFD + l-NAME or agonist treatment. Our results showed the unique potential of MR-356 to treat several HFpEF-like features including cardiac hypertrophy, fibrosis, capillary rarefaction, and pulmonary congestion. MR-356 improved cardiac performance by improving diastolic function, global longitudinal strain (GLS), and exercise capacity. Importantly, the increased expression of cardiac pro-brain natriuretic peptide (pro-BNP), inducible nitric oxide synthase (iNOS), and vascular endothelial growth factor-A (VEGF-A) was restored to normal levels suggesting that MR-356 reduced myocardial stress associated with metabolic inflammation in HFpEF. Thus, agonists of GHRH may be an effective therapeutic strategy for the treatment of cardiometabolic HFpEF phenotype.NEW & NOTEWORTHY This randomized study used rigorous hemodynamic tools to test the efficacy of a synthetic GHRH agonist to improve cardiac performance in a cardiometabolic HFpEF. Daily injection of the GHRH agonist, MR-356, reduced the HFpEF-like effects as evidenced by improved diastolic dysfunction, reduced cardiac hypertrophy, fibrosis, and pulmonary congestion. Notably, end-diastolic pressure and end-diastolic pressure-volume relationship were reset to control levels. Moreover, treatment with MR-356 increased exercise capacity and reduced myocardial stress associated with metabolic inflammation in HFpEF.
Subject(s)
Heart Failure , Animals , Mice , Cardiomegaly , Disease Models, Animal , Fibrosis , Growth Hormone-Releasing Hormone , Inflammation , NG-Nitroarginine Methyl Ester , Stroke Volume/physiology , Vascular Endothelial Growth Factor A , Ventricular Function, LeftABSTRACT
Aims: Hypoplastic left heart syndrome (HLHS) survival relies on surgical reconstruction of the right ventricle (RV) to provide systemic circulation. This substantially increases the RV load, wall stress, maladaptive remodelling, and dysfunction, which in turn increases the risk of death or transplantation. Methods and results: We conducted a phase 1 open-label multicentre trial to assess the safety and feasibility of Lomecel-B as an adjunct to second-stage HLHS surgical palliation. Lomecel-B, an investigational cell therapy consisting of allogeneic medicinal signalling cells (MSCs), was delivered via intramyocardial injections. The primary endpoint was safety, and measures of RV function for potential efficacy were obtained. Ten patients were treated. None experienced major adverse cardiac events. All were alive and transplant-free at 1-year post-treatment, and experienced growth comparable to healthy historical data. Cardiac magnetic resonance imaging (CMR) suggested improved tricuspid regurgitant fraction (TR RF) via qualitative rater assessment, and via significant quantitative improvements from baseline at 6 and 12 months post-treatment (P < 0.05). Global longitudinal strain (GLS) and RV ejection fraction (EF) showed no declines. To understand potential mechanisms of action, circulating exosomes from intramyocardially transplanted MSCs were examined. Computational modelling identified 54 MSC-specific exosome ribonucleic acids (RNAs) corresponding to changes in TR RF, including miR-215-3p, miR-374b-3p, and RNAs related to cell metabolism and MAPK signalling. Conclusion: Intramyocardially delivered Lomecel-B appears safe in HLHS patients and may favourably affect RV performance. Circulating exosomes of transplanted MSC-specific provide novel insight into bioactivity. Conduct of a controlled phase trial is warranted and is underway.Trial registration number NCT03525418.
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AIMS: To test the hypothesis that the activation of the growth hormone-releasing hormone (GHRH) receptor signalling pathway within the myocardium both prevents and reverses diastolic dysfunction and pathophysiologic features consistent with heart failure with preserved ejection fraction (HFpEF). Impaired myocardial relaxation, fibrosis, and ventricular stiffness, among other multi-organ morbidities, characterize the phenotype underlying the HFpEF syndrome. Despite the rapidly increasing prevalence of HFpEF, few effective therapies have emerged. Synthetic agonists of the GHRH receptors reduce myocardial fibrosis, cardiomyocyte hypertrophy, and improve performance in animal models of ischaemic cardiomyopathy, independently of the growth hormone axis. METHODS AND RESULTS: CD1 mice received 4- or 8-week continuous infusion of angiotensin-II (Ang-II) to generate a phenotype with several features consistent with HFpEF. Mice were administered either vehicle or a potent synthetic agonist of GHRH, MR-356 for 4-weeks beginning concurrently or 4-weeks following the initiation of Ang-II infusion. Ang-II-treated animals exhibited diastolic dysfunction, ventricular hypertrophy, interstitial fibrosis, and normal ejection fraction. Cardiomyocytes isolated from these animals exhibited incomplete relaxation, depressed contractile responses, altered myofibrillar protein phosphorylation, and disturbed calcium handling mechanisms (ex vivo). MR-356 both prevented and reversed the development of the pathological phenotype in vivo and ex vivo. Activation of the GHRH receptors increased cAMP and cGMP in cardiomyocytes isolated from control animals but only cAMP in cardiac fibroblasts, suggesting that GHRH-A exert differential effects on cardiomyocytes and fibroblasts. CONCLUSION: These findings indicate that the GHRH receptor signalling pathway(s) represents a new molecular target to counteract dysfunctional cardiomyocyte relaxation by targeting myofilament phosphorylation and fibrosis. Accordingly, activation of GHRH receptors with potent, synthetic GHRH agonists may provide a novel therapeutic approach to management of the myocardial alterations associated with the HFpEF syndrome.
Subject(s)
Cardiomyopathies , Heart Failure , Mice , Animals , Heart Failure/metabolism , Stroke Volume/physiology , Cardiomyopathies/metabolism , Cardiomegaly/metabolism , Myocytes, Cardiac/metabolism , Growth Hormone-Releasing Hormone/metabolism , FibrosisABSTRACT
HYPOTHESIS: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action. KEY PREDICTIONS: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). STRATEGY AND KEY RESULTS: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments. INTERPRETATION: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials.
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Alzheimer Disease , Humans , Alzheimer Disease/drug therapy , Treatment Outcome , Double-Blind Method , BiomarkersABSTRACT
Sustained oxidative stress in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustained CSF1R inhibition (CSF1Ri) is limited as a monotherapy. We hypothesized that one of the underlying causes for the reduced efficacy of CSF1Ri and increased oxidation in CRPC is the upregulation and uncoupling of endothelial nitric oxide synthase (NOS3). Here we show that in high-grade PCa human specimens, NOS3 abundance positively correlates with CSF1-CSF1R signaling and remains uncoupled. The uncoupling diminishes NOS3 generation of sufficient nitric oxide (NO) required for S-nitrosylation of CSF1R at specific cysteine sites (Cys 224, Cys 278, and Cys 830). Exogenous S-nitrosothiol administration (with S-nitrosoglutathione (GSNO)) induces S-nitrosylation of CSF1R and rescues the excess oxidation in tumor regions, in turn suppressing the tumor-promoting cytokines which are ineffectively suppressed by CSF1R blockade. Together these results suggest that NO administration could act as an effective combinatorial partner with CSF1R blockade against CRPC. In this context, we further show that exogenous NO treatment with GSNOR successfully augments the anti-tumor ability of CSF1Ri to effectively reduce the overall tumor burden, decreases the intratumoral percentage of anti-inflammatory macrophages, myeloid-derived progenitor cells and increases the percentage of pro-inflammatory macrophages, cytotoxic T lymphocytes, and effector T cells, respectively. Together, these findings support the concept that the NO-CSF1Ri combination has the potential to act as a therapeutic agent that restores control over TME, which in turn could improve the outcomes of PCa patients.
Subject(s)
Prostatic Neoplasms, Castration-Resistant , Receptor, Macrophage Colony-Stimulating Factor , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Cysteine , Humans , Macrophage Colony-Stimulating Factor , Male , Nitric Oxide , Nitric Oxide Synthase Type III , S-Nitrosoglutathione , Tumor MicroenvironmentABSTRACT
Adults born preterm have an increased risk of pulmonary vascular disease. Extreme preterm infants often require supplemental oxygen but they also exhibit frequent intermittent hypoxemic episodes (IH). Here, we test the hypothesis that neonatal IH induces lung endothelial cell mitochondrial DNA (mitDNA) damage and contributes to long-term pulmonary vascular disease and pulmonary hypertension (PH). Newborn C57BL/6J mice were assigned to the following groups: 1) normoxia, 2) hyperoxia (O2 65%), 3) normoxia cycling with IH (O2 21% + O2 10%), and 4) hyperoxia cycling with IH (O2 65% + O2 10%) for 3 wk. IH episodes were initiated on postnatal day 7. Lung angiogenesis, PH, and mitDNA lesions were assessed at 3 wk and 3 mo. In vitro, the effect of IH on tubule formation and mitDNA lesions was evaluated in human pulmonary microvascular endothelial cells (HPMECs). Data were analyzed by ANOVA. In vitro, IH exposure reduced tubule formation and increased mitDNA lesions in HPMECs. This was most marked in HPMECs exposed to hyperoxia cycling with IH. In vivo, neonatal IH increased lung mitDNA lesions, impaired angiogenesis, and induced PH in 3-wk-old mice. These findings were pronounced in mice exposed to hyperoxia cycling with IH. At 3 mo follow-up, mice exposed to neonatal IH had persistently increased lung mitDNA lesions and impaired lung angiogenesis, even without concomitant hyperoxia exposure. Neonatal IH induces lung endothelial cell mitDNA damage and causes persistent impairment in lung angiogenesis. These findings provide important mechanistic insight into the pathogenesis of pulmonary vascular disease in preterm survivors.NEW & NOTEWORTHY Our current study demonstrates that neonatal intermittent hypoxia (IH) alters lung endothelial cell function, induces mitochondrial DNA lesions, and impairs lung vascular growth into adulthood. Moreover, when superimposed on hyperoxia, neonatal IH induces a severe lung vascular phenotype that is seen in preterm infants with PH. These findings suggest that neonatal IH contributes to PH in adults born preterm and importantly, that mitochondrial protection strategies may mitigate these deleterious effects.
Subject(s)
Hyperoxia , Hypertension, Pulmonary , Humans , Infant, Newborn , Infant , Mice , Animals , Adult , Hyperoxia/complications , Endothelial Cells/pathology , DNA, Mitochondrial , Animals, Newborn , Mice, Inbred C57BL , Infant, Premature , Lung , Hypoxia/complications , OxygenABSTRACT
Background The pathways of diastolic dysfunction and heart failure with preserved ejection fraction driven by lipotoxicity with metabolic syndrome are incompletely understood. Thus, there is an urgent need for animal models that accurately mimic the metabolic and cardiovascular phenotypes of this phenogroup for mechanistic studies. Methods and Results Hyperlipidemia was induced in WT-129 mice by 4 weeks of biweekly poloxamer-407 intraperitoneal injections with or without a single intravenous injection of adeno-associatedvirus 9-cardiac troponin T-low-density lipoprotein receptor (n=31), or single intravenous injection with adeno-associatedvirus 9-cardiac troponin T-low-density lipoprotein receptor alone (n=10). Treatment groups were compared with untreated or placebo controls (n=37). Echocardiography, blood pressure, whole-body plethysmography, ECG telemetry, activity wheel monitoring, and biochemical and histological changes were assessed at 4 to 8 weeks. At 4 weeks, double treatment conferred diastolic dysfunction, preserved ejection fraction, and increased left ventricular wall thickness. Blood pressure and whole-body plethysmography results were normal, but respiration decreased at 8 weeks (P<0.01). ECG and activity wheel monitoring, respectively, indicated heart block and decreased exercise activity (P<0.001). Double treatment promoted elevated myocardial lipids including total cholesterol, fibrosis, increased wet/dry lung (P<0.001) and heart weight/body weight (P<0.05). Xanthelasma, ascites, and cardiac ischemia were evident in double and single (p407) groups. Sudden death occurred between 6 and 12 weeks in double and single (p407) treatment groups. Conclusions We present a novel model of heart failure with preserved ejection fraction driven by dyslipidemia where mice acquire diastolic dysfunction, arrhythmia, cardiac hypertrophy, fibrosis, pulmonary congestion, exercise intolerance, and preserved ejection fraction in the absence of obesity, hypertension, kidney disease, or diabetes. The model can be applied to dissect pathways of metabolic syndrome that drive diastolic dysfunction in this lipotoxicity-mediated heart failure with preserved ejection fraction phenogroup mimic.
Subject(s)
Cardiomyopathies , Heart Failure , Hyperlipidemias , Metabolic Syndrome , Animals , Disease Models, Animal , Hyperlipidemias/complications , Lipoproteins, LDL , Mice , Stroke Volume/physiology , Troponin T , Ventricular Function, Left/physiologyABSTRACT
Over 10 million doses of COVID-19 vaccines based on RNA technology, viral vectors, recombinant protein, and inactivated virus have been administered worldwide. Although generally very safe, post-vaccine myocarditis can result from adaptive humoral and cellular, cardiac-specific inflammation within days and weeks of vaccination. Rates of vaccine-associated myocarditis vary by age and sex with the highest rates in males between 12 and 39 years. The clinical course is generally mild with rare cases of left ventricular dysfunction, heart failure and arrhythmias. Mild cases are likely underdiagnosed as cardiac magnetic resonance imaging (CMR) is not commonly performed even in suspected cases and not at all in asymptomatic and mildly symptomatic patients. Hospitalization of symptomatic patients with electrocardiographic changes and increased plasma troponin levels is considered necessary in the acute phase to monitor for arrhythmias and potential decline in left ventricular function. In addition to evaluation for symptoms, electrocardiographic changes and elevated troponin levels, CMR is the best non-invasive diagnostic tool with endomyocardial biopsy being restricted to severe cases with heart failure and/or arrhythmias. The management beyond guideline-directed treatment of heart failure and arrhythmias includes non-specific measures to control pain. Anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs, and corticosteroids have been used in more severe cases, with only anecdotal evidence for their effectiveness. In all age groups studied, the overall risks of SARS-CoV-2 infection-related hospitalization and death are hugely greater than the risks from post-vaccine myocarditis. This consensus statement serves as a practical resource for physicians in their clinical practice, to understand, diagnose, and manage affected patients. Furthermore, it is intended to stimulate research in this area.