Preservation of von Willebrand Factor Activity With the ModulHeart Device.

von Willebrand Factor (VWF) destruction is common with current heart pumps. This study evaluates VWF activity with ModulHeart, a novel device using 3 micropumps in parallel. In model 1, ModulHeart was compared with Impella devices in vitro. In model 2, 3 healthy swine received ModulHeart. Model 3 includes VWF data from patients who underwent protected percutaneous coronary intervention with ModulHeart. In models 1, 2, and 3, ModulHeart resulted in preservation of VWF, whereas there was a 27% and 19% reduction in VWF activity with the Impella CP and 5.0, respectively. ModulHeart features a unique design and demonstrated preservation of VWF activity.

Hypusine Signaling Promotes Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

RATIONALE: The ubiquitous polyamine spermidine is essential for cell survival and proliferation. One important function of spermidine is to serve as a substrate for hypusination, a post-translational modification process that occurs exclusively on eukaryotic translation factor 5A (eIF5A) and ensures efficient translation of various gene products. Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive obliteration of the small pulmonary arteries (PAs) due to excessive proliferation of PA smooth muscle cells (PASMCs) and suppressed apoptosis. OBJECTIVES: To characterize the role of hypusine signaling in PAH. METHODS: Molecular, genetic, and pharmacological approaches were used both in vitro and in vivo to investigate the role of hypusine signaling in pulmonary vascular remodeling. MEASUREMENTS AND MAIN RESULTS: Hypusine forming enzymes (deoxyhypusine synthase, DHPS and deoxyhypusine hydroxylase, DOHH) and hypusinated eIF5A are overexpressed in distal PAs and isolated PASMCs from PAH patients and animal models. In vitro, inhibition of DHPS using GC7 or short hairpin RNA resulted in a decrease in PAH-PASMC resistance to apoptosis and proliferation. In vivo, inactivation of one allele of Dhps targeted to smooth muscle cells alleviates PAH in mice and that its pharmacological inhibition significantly decreases pulmonary vascular remodeling and improves hemodynamics and cardiac function in two rat models of established PAH. Using mass spectrometry, we show that hypusine signaling promotes the expression of a broad array of proteins involved in oxidative phosphorylation, thus supporting the bioenergetic requirements of cell survival and proliferation. CONCLUSIONS: These findings support inhibiting hypusine signaling as a potential treatment for PAH.

Right Ventricle and Epigenetics: A Systematic Review.

There is an increasing recognition of the crucial role of the right ventricle (RV) in determining the functional status and prognosis in multiple conditions. In the past decade, the epigenetic regulation (DNA methylation, histone modification, and non-coding RNAs) of gene expression has been raised as a critical determinant of RV development, RV physiological function, and RV pathological dysfunction. We thus aimed to perform an up-to-date review of the literature, gathering knowledge on the epigenetic modifications associated with RV function/dysfunction. Therefore, we conducted a systematic review of studies assessing the contribution of epigenetic modifications to RV development and/or the progression of RV dysfunction regardless of the causal pathology. English literature published on PubMed, between the inception of the study and 1 January 2023, was evaluated. Two authors independently evaluated whether studies met eligibility criteria before study results were extracted. Amongst the 817 studies screened, 109 studies were included in this review, including 69 that used human samples (e.g., RV myocardium, blood). While 37 proposed an epigenetic-based therapeutic intervention to improve RV function, none involved a clinical trial and 70 are descriptive. Surprisingly, we observed a substantial discrepancy between studies investigating the expression (up or down) and/or the contribution of the same epigenetic modifications on RV function or development. This exhaustive review of the literature summarizes the relevant epigenetic studies focusing on RV in human or preclinical setting.

The future of group 2 pulmonary hypertension: Exploring clinical trials and therapeutic targets.

Pulmonary hypertension due to left heart disease (PH-LHD) or group 2 PH is the most common and lethal form of PH, occurring secondary to left ventricular systolic or diastolic heart failure (HF), left-sided valvular diseases, and congenital abnormalities. It is subdivided into isolated postcapillary PH (IpcPH) and combined pre- and post-capillary PH (CpcPH), with the latter sharing many similarities with group 1 PH. CpcPH is associated with worse outcomes and increased morbidity and mortality when compared to IpcPH. Although IpcPH can be improved by treatment of the underlying LHD, CpcPH is an incurable disease for which no specific treatment exists, likely due to the lack of understanding of its underlying mechanisms. Furthermore, drugs approved for PAH are not recommended for group 2 PH, as they are either ineffective or even deleterious. With this major unmet medical need, a better understanding of mechanisms and the identification of effective treatment strategies for this deadly condition are urgently needed. This review presents relevant background of the molecular mechanisms underlying PH-LHD that could translate into innovative therapeutic targets and explores novel targets currently being evaluated in clinical trials.

G9a/GLP Targeting Ameliorates Pulmonary Vascular Remodeling in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is characterized by progressive vascular remodeling of small pulmonary arteries (PAs) causing sustained elevation of PA pressure, right ventricular failure, and death. Similar to cancer cells, PA smooth muscle cells (PASMCs), which play a key role in pulmonary vascular remodeling, have adopted multiple mechanisms to sustain their survival and proliferation in the presence of stress. The histone methyltransferase G9a and its partner protein GLP (G9a-like protein) have been shown to exert oncogenic effects and to serve as a buffer against an exaggerated transcriptional response. Therefore, we hypothesized that upregulation of G9a and GLP in PAH plays a pivotal role in pulmonary vascular remodeling by maintaining the abnormal phenotype of PAH-PASMCs. We found that G9a is increased in PASMCs from patients with PAH as well as in remodeled PAs from animal models. Pharmacological inhibition of G9a/GLP activity using BIX01294 and UNC0642 significantly reduced the prosurvival and proproliferative potentials of cultured PAH-PASMCs. Using RNA sequencing, further exploration revealed that G9a/GLP promotes extracellular matrix production and affords protection against the negative effects of an overactive stress response. Finally, we found that therapeutic treatment with BIX01294 reduced pulmonary vascular remodeling and lowered mean PA pressure in fawn-hooded rats. Treatment of Sugen/hypoxia-challenged mice with BIX01294 also improved pulmonary hemodynamics and right ventricular function. In conclusion, these findings indicate that G9a/GLP inhibition may represent a new therapeutic approach in PAH.

Germline and Somatic Mutations in DNA Methyltransferase 3A (DNMT3A) Predispose to Pulmonary Arterial Hypertension (PAH) in Humans and Mice: Implications for Associated PAH.

Background: Mutations are found in 10-20% of idiopathic PAH (IPAH) patients, but none are consistently identified in connective tissue disease-associated PAH (APAH), which accounts for ∼45% of PAH cases. TET2 mutations, a cause of clonal hematopoiesis of indeterminant potential (CHIP), predispose to an inflammatory type of PAH. We now examine mutations in another CHIP gene, DNMT3A , in PAH. Methods: We assessed DNMT3A mutation prevalence in PAH Biobank subjects as compared with controls, first using whole exome sequencing (WES)-derived CHIP calls in 1832 PAH Biobank patients versus 7509 age-and sex-matched gnomAD controls. We then performed deep, targeted panel sequencing of CHIP genes on a subset of 710 PAH Biobank patients and compared the prevalence of DNMT3A mutations therein to an independent pooled control cohort (N = 3645). In another cohort of 80 PAH patients and 41 controls, DNMT3A mRNA expression was studied in peripheral blood mononuclear cells (PBMCs). Finally, we evaluated the development of PAH in a conditional, hematopoietic, Dnmt3a knockout mouse model. Results: DNMT3A mutations were more frequent in PAH cases versus control subjects in the WES dataset (OR 2.60, 95% CI: 1.71-4.27). Among PAH patients, 33 had DNMT3A variants, most of whom had APAH (21/33). While 21/33 had somatic mutations (female:male 17:4), germline variants occurred in 12/33 (female:male 11:1). Hemodynamics were comparable with and without DNMT3A mutations (mPAP=58±21 vs. 52±18 mmHg); however, patients with DNMT3A mutations were unresponsive to acute vasodilator testing. Targeted panel sequencing identified that 14.6% of PAH patients had CHIP mutations (104/710), with DNMT3A accounting for 49/104. There was a significant association between all CHIP mutations and PAH in analyses adjusted for age and sex (OR 1.40, 95% CI: 1.09-1.80), though DNMT3A CHIP alone was not significantly enriched (OR:1.15, 0.82-1.61). DNMT3A expression was reduced in patient-derived versus control PAH-PBMCs. Spontaneous PAH developed in Dnmt3a -/- mice, and it was exacerbated by 3 weeks of hypoxia. Dnmt3a -/- mice had increased lung macrophages and elevated plasma IL-13. The IL-1ß antibody canakinumab attenuated PAH in Dnmt3a -/- mice. Conclusions: Germline and acquired DNMT3A variants predispose to PAH in humans. DNMT3A mRNA expression is reduced in human PAH PBMCs. Hematopoietic depletion of Dnmt3a causes inflammatory PAH in mice. DNMT3A is a novel APAH gene and may be a biomarker and therapeutic target.

An integrated proteomic and transcriptomic signature of the failing right ventricle in monocrotaline induced pulmonary arterial hypertension in male rats.

Aim: Pulmonary arterial hypertension (PAH) is an obstructive pulmonary vasculopathy that results in death from right ventricular failure (RVF). There is limited understanding of the molecular mechanisms of RVF in PAH. Methods: In a PAH-RVF model induced by injection of adult male rats with monocrotaline (MCT; 60 mg/kg), we performed mass spectrometry to identify proteins that change in the RV as a consequence of PAH induced RVF. Bioinformatic analysis was used to integrate our previously published RNA sequencing data from an independent cohort of PAH rats. Results: We identified 1,277 differentially regulated proteins in the RV of MCT rats compared to controls. Integration of MCT RV transcriptome and proteome data sets identified 410 targets that are concordantly regulated at the mRNA and protein levels. Functional analysis of these data revealed enriched functions, including mitochondrial metabolism, cellular respiration, and purine metabolism. We also prioritized 15 highly enriched protein:transcript pairs and confirmed their biological plausibility as contributors to RVF. We demonstrated an overlap of these differentially expressed pairs with data published by independent investigators using multiple PAH models, including the male SU5416-hypoxia model and several male rat strains. Conclusion: Multiomic integration provides a novel view of the molecular phenotype of RVF in PAH which includes dysregulation of pathways involving purine metabolism, mitochondrial function, inflammation, and fibrosis.

Macrophage-NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)-macrophage activation may promote RVF in PAH. Objectives: Evaluating the contribution of the NLRP3 inflammasome in RV macrophages to PAH RVF. Methods: Rats with decompensated RV hypertrophy (monocrotaline [MCT] and Sugen-5416 hypoxia [SuHx]) were compared with compensated RV hypertrophy rats (pulmonary artery banding). Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptides, and fibrosis were evaluated by microscopy or flow cytometry. NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot and in vitro strategies. MCT rats were treated with SC-144 (a GP130 antagonist) or MCC950 (an NLRP3 inhibitor). Macrophage-NLRP3 activity was evaluated in patients with PAH RVF. Measurements and Main Results: Macrophages, fibrosis, and atrial natriuretic peptides were increased in MCT and SuHx RVs but not in left ventricles or pulmonary artery banding rats. Although MCT RV macrophages were inflammatory, lung macrophages were antiinflammatory. CCR2+ macrophages (monocyte-derived) were increased in MCT and SuHx RVs and highly expressed NLRP3. The macrophage-NLRP3 pathway was upregulated in patients with PAH with decompensated RVs. Cultured MCT monocytes showed NLRP3 activation, and in coculture experiments resulted in cardiomyocyte mitochondrial damage, which MCC950 prevented. In vivo, MCC950 reduced NLRP3 activation and regressed pulmonary vascular disease and RVF. SC-144 reduced RV macrophages and NLRP3 content, prevented STAT3 (signal transducer and activator of transcription 3) activation, and improved RV function without regressing pulmonary vascular disease. Conclusions: NLRP3-macrophage activation occurs in the decompensated RV in preclinical PAH models and patients with PAH. Inhibiting GP130 or NLRP3 signaling improves RV function. The concept that PAH RVF results from RV inflammation rather than solely from elevated RV afterload suggests a new therapeutic paradigm.

Neutrophil-Lymphocyte Ratio as an Independent Predictor of Survival in Pulmonary Arterial Hypertension: An Exploratory Study.

Background: The blood neutrophil-to-lymphocyte ratio (NLR) has recently emerged as a powerful predictor of adverse outcomes in some cardiovascular and lung diseases. Pulmonary arterial hypertension (PAH) is a lethal vasculopathy associated with increased inflammation. Although PAH exhibits a higher prevalence among women, men have a poorer prognosis. We investigated the NLR as an independent predictor of transplant-free survival in PAH. Methods: We performed a retrospective analysis of 78 PAH patients from the Quebec PAHBiobank (71% female). We used univariate and multivariate (adjusted for age, sex, renal function, and disease severity) Cox regression analyses to assess the relationship between the NLR and transplant-free survival, in the whole sample, and according to sex. The NLR was categorized as high (≥ 4.8) or low (< 4.8) using receiver operating characteristic analysis. Unadjusted Kaplan-Meier analysis estimated survival per NLR category. Results: The NLR was higher in patients who died, compared to that in patients who had transplant-free survival (P < 0.05). The NLR was an independent predictor of event-free survival in PAH (unadjusted hazard ratio: 1.11, 95% confidence interval: 1.04-1.18, which remained significant after adjustment for covariates). The high-NLR group had lower 1-, 3-, and 5-year survival compared to those with a low NLR (P < 0.001). The NLR remains a predictor of survival in women. Conclusions: The NLR is an independent predictor of transplant-free survival in PAH. We report a potential sexual dimorphism in the ability of the NLR to predict mortality in PAH, emphasizing the importance of considering sex-related differences in the development of biomarkers in PAH.

Contexte: Le rapport neutrophiles/lymphocytes (RNL) s'est récemment imposé comme un puissant facteur prédictif de l'issue défavorable de certaines maladies cardiovasculaires et pulmonaires. L'hypertension artérielle pulmonaire (HTAP) est une vasculopathie mortelle associée à une inflammation accrue. Bien que sa prévalence soit plus élevée chez les femmes, son pronostic est plus défavorable chez les hommes. Nous avons étudié le RNL en tant que prédicteur indépendant de la survie sans greffe chez des sujets atteints d'HTAP. Méthodologie: Nous avons effectué une analyse rétrospective du matériel sur l'HTAP de la Biobanque du Québec se rapportant à 78 patients (71 % de femmes). Des analyses de régression de Cox univariées et multivariées (ajustées en fonction de l'âge, du sexe, de la fonction rénale et de la gravité de la maladie) nous ont permis d'évaluer la relation entre le RNL et la survie sans greffe dans l'ensemble de l'échantillon et selon le sexe. Le RNL a été classé comme élevé (≥ 4,8) ou faible (< 4,8) au terme d'une analyse des caractéristiques de fonctionnement du récepteur. Une analyse non ajustée effectuée selon la méthode de Kaplan-Meier a servi à estimer la survie par catégorie de RNL. Résultats: Le RNL était plus élevé chez les patients décédés que chez les patients ayant survécu sans greffe (p < 0,05). Le RNL était un prédicteur indépendant de la survie sans événement chez les patients atteints d'HTAP (rapport des risques instantanés non ajusté : 1,11, intervalle de confiance à 95 % : 1,04-1,18, demeuré significatif après ajustement en fonction des covariables). La survie à 1, 3 et 5 ans a été inférieure au sein du groupe présentant un RNL élevé comparativement au groupe présentant un RNL faible (p < 0,001). Le RNL demeure un prédicteur de la survie chez les femmes. Conclusions: Le RNL est un facteur prédictif indépendant de la survie sans greffe chez les sujets atteints d'HTAP. Selon nos observations, un dimorphisme sexuel potentiel le caractérise en tant que prédicteur de la mortalité chez les sujets atteints d'HTAP. Il importe donc de tenir compte des différences liées au sexe dans le développement des biomarqueurs de l'HTAP.

PARP1-PKM2 Axis Mediates Right Ventricular Failure Associated With Pulmonary Arterial Hypertension.

The authors show that increased poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) and pyruvate kinase muscle isozyme 2 (PKM2) expression is a common feature of a decompensated right ventricle in patients with pulmonary arterial hypertension and animal models. The authors find in vitro that overactivated PARP1 promotes cardiomyocyte dysfunction by favoring PKM2 expression and nuclear function, glycolytic gene expression, activation of nuclear factor κB-dependent proinflammatory factors. Pharmacologic and genetic inhibition of PARP1 or enforced tetramerization of PKM2 attenuates maladaptive remodeling improving right ventricular (RV) function in multiple rodent models. Taken together, these data implicate the PARP1/PKM2 axis as a critical driver of maladaptive RV remodeling and a new promising target to directly sustain RV function in patients with pulmonary arterial hypertension.

Inhibiting pyruvate kinase muscle isoform 2 regresses group 2 pulmonary hypertension induced by supra-coronary aortic banding.

INTRODUCTION: Group 2 pulmonary hypertension (PH) has no approved PH-targeted therapy. Metabolic remodelling, specifically a biventricular increase in pyruvate kinase muscle (PKM) isozyme 2 to 1 ratio, occurs in rats with group 2 PH induced by supra-coronary aortic banding (SAB). We hypothesize that increased PKM2/PKM1 is maladaptive and inhibiting PKM2 would improve right ventricular (RV) function. METHODS: Male, Sprague-Dawley SAB rats were confirmed to have PH by echocardiography and then randomized to treatment with a PKM2 inhibitor (intraperitoneal shikonin, 2 mg/kg/day) versus 5% DMSO (n = 5/group) or small interfering RNA-targeting PKM2 (siPKM2) versus siRNA controls (n = 7/group) by airway nebulization. RESULTS: Shikonin-treated SAB rats had milder PH (PAAT 32.1 ± 1.3 vs 22.1 ± 1.2 ms, P = .0009) and lower RV systolic pressure (RVSP) (31.5 ± 0.9 vs 55.7 ± 1.9 mm Hg, P < .0001) versus DMSO-SAB rats. siPKM2 nebulization reduced PKM2 expression in the RV, increased PAAT (31.7 ± 0.7 vs 28.0 ± 1.3 ms, P = .025), lowered RVSP (30.6 ± 2.6 vs 42.0 ± 4.0 mm Hg, P = .032) and reduced diastolic RVFW thickness (0.69 ± 0.04 vs 0.85 ± 0.06 mm, P = .046). Both shikonin and siPKM2 regressed PH-induced medial hypertrophy of small pulmonary arteries. CONCLUSION: Increases in PKM2/PKM1 in the RV contribute to RV dysfunction in group 2 PH. Chemical or molecular inhibition of PKM2 restores the normal PKM2/PKM1 ratio, reduces PH, RVSP and RVH and regresses adverse PA remodelling. PKM2 merits consideration as a therapeutic cardiac target for group 2 PH.

Commentary on: Xbp1s-Ddit3, DNA damage and pulmonary hypertension.

In this commentary, we discuss new observations stating that spliced X-box-binding protein 1 (Xbp1s)-DNA damage-inducible transcript 3 (Ddit3) promotes monocrotaline (MCT)-induced pulmonary hypertension (Jiang et al., Clinical Science (2021) 135(21), https://doi.org/10.1042/CS20210612). Xbp1s-Ddit3 is involved in the regulation of endoplasmic reticulum stress but is also associated with DNA damage repair machinery. Pathologic DNA damage repair mechanisms have emerged as critical determinants of pulmonary hypertension development. We discuss the potential relationship among Xbp1s-Ddit3, DNA damage, and pulmonary hypertension. Although Xbp1s-Ddit3 contributes to the regulation of cell proliferation and apoptosis and the development of vascular lesions, whether Xbp1s is a friend or foe remains controversial.

Potential for inhibition of checkpoint kinases 1/2 in pulmonary fibrosis and secondary pulmonary hypertension.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterised by exuberant tissue remodelling and associated with high unmet medical needs. Outcomes are even worse when IPF results in secondary pulmonary hypertension (PH). Importantly, exaggerated resistance to cell death, excessive proliferation and enhanced synthetic capacity are key endophenotypes of both fibroblasts and pulmonary artery smooth muscle cells, suggesting shared molecular pathways. Under persistent injury, sustained activation of the DNA damage response (DDR) is integral to the preservation of cells survival and their capacity to proliferate. Checkpoint kinases 1 and 2 (CHK1/2) are key components of the DDR. The objective of this study was to assess the role of CHK1/2 in the development and progression of IPF and IPF+PH. METHODS AND RESULTS: Increased expression of DNA damage markers and CHK1/2 were observed in lungs, remodelled pulmonary arteries and isolated fibroblasts from IPF patients and animal models. Blockade of CHK1/2 expression or activity-induced DNA damage overload and reverted the apoptosis-resistant and fibroproliferative phenotype of disease cells. Moreover, inhibition of CHK1/2 was sufficient to interfere with transforming growth factor beta 1-mediated fibroblast activation. Importantly, pharmacological inhibition of CHK1/2 using LY2606368 attenuated fibrosis and pulmonary vascular remodelling leading to improvement in respiratory mechanics and haemodynamic parameters in two animal models mimicking IPF and IPF+PH. CONCLUSION: This study identifies CHK1/2 as key regulators of lung fibrosis and provides a proof of principle for CHK1/2 inhibition as a potential novel therapeutic option for IPF and IPF+PH.

Recent advancements in pulmonary arterial hypertension and right heart failure research: overview of selected abstracts from ATS2020 and emerging COVID-19 research.

Each year the American Thoracic Society (ATS) Conference brings together scientists who conduct basic, translational and clinical research to present on the recent advances in the field of respirology. Due to the Coronavirus Disease of 2019 (COVID-19) pandemic, the ATS2020 Conference was held online in a series of virtual meetings. In this review, we focus on the breakthroughs in pulmonary hypertension research. We have selected 11 of the best basic science abstracts which were presented at the ATS2020 Assembly on Pulmonary Circulation mini-symposium "What's New in Pulmonary Arterial Hypertension (PAH) and Right Ventricular (RV) Signaling: Lessons from the Best Abstracts," reflecting the current state of the art and associated challenges in PH. Particular emphasis is placed on understanding the mechanisms underlying RV failure, the regulation of inflammation, and the novel therapeutic targets that emerged from preclinical research. The pathologic interactions between pulmonary hypertension, right ventricular function and COVID-19 are also discussed.

PINK1-induced phosphorylation of mitofusin 2 at serine 442 causes its proteasomal degradation and promotes cell proliferation in lung cancer and pulmonary arterial hypertension.

Impaired mitochondrial fusion, due in part to decreased mitofusin 2 (Mfn2) expression, contributes to unrestricted cell proliferation and apoptosis-resistance in hyperproliferative diseases like pulmonary arterial hypertension (PAH) and non-small cell lung cancer (NSCLC). We hypothesized that Mfn2 levels are reduced due to increased proteasomal degradation of Mfn2 triggered by its phosphorylation at serine 442 (S442) and investigated the potential kinase mediators. Mfn2 expression was decreased and Mfn2 S442 phosphorylation was increased in pulmonary artery smooth muscle cells from PAH patients and in NSCLC cells. Mfn2 phosphorylation was mediated by PINK1 and protein kinase A (PKA), although only PINK1 expression was increased in these diseases. We designed a S442 phosphorylation deficient Mfn2 construct (PD-Mfn2) and a S442 constitutively phosphorylated Mfn2 construct (CP-Mfn2). The effects of these modified Mfn2 constructs on Mfn2 expression and biological function were compared with those of the wildtype Mfn2 construct (WT-Mfn2). WT-Mfn2 increased Mfn2 expression and mitochondrial fusion in both PAH and NSCLC cells resulting in increased apoptosis and decreased cell proliferation. Compared to WT-Mfn2, PD-Mfn2 caused greater Mfn2 expression, suppression of proliferation, apoptosis induction, and cell cycle arrest. Conversely, CP-Mfn2 caused only a small increase in Mfn2 expression and did not restore mitochondrial fusion, inhibit cell proliferation, or induce apoptosis. Silencing PINK1 or PKA, or proteasome blockade using MG132, increased Mfn2 expression, enhanced mitochondrial fusion and induced apoptosis. In a xenotransplantation NSCLC model, PD-Mfn2 gene therapy caused greater tumor regression than did therapy with WT-Mfn2. Mfn2 deficiency in PAH and NSCLC reflects proteasomal degradation triggered by Mfn2-S442 phosphorylation by PINK1 and/or PKA. Inhibiting Mfn2 phosphorylation has potential therapeutic benefit in PAH and lung cancer.

Venous thromboembolism in COVID-19 compared to non-COVID-19 cohorts: A systematic review with meta-analysis.

BACKGROUND: Many studies confirmed an association between COVID-19 and venous thromboembolism (VTE). Whether the risk of VTE significantly differed between COVID-19 cohorts and non-COVID-19 cohorts with similar disease severity remains unknown. OBJECTIVES: The aim of this systematic review with meta-analysis was to compare the rate of VTE between COVID-19 and non-COVID-19 cohorts with similar disease severity. METHODS: A systematic literature search (MEDLINE, Embase and Google Scholar) was conducted from January 1, 2020 to March 31, 2021 to identify studies reporting VTE in COVID-19. Relative risks (RR) were estimated for the effect measure with 95% confidence intervals. RESULTS: Seven studies (41,768 patients) evaluated VTE in COVID-19 cohorts compared to non-COVID-19 cohorts. The overall risk of VTE (RR 1.18; 95%CI 0.79-1.77; p = 0.42; I2 = 54%), pulmonary embolism (RR 1.25; 95%CI 0.77-2.03; p = 0.36; I2 = 52%) and deep venous thrombosis (RR 0.92; 95%CI 0.52-1.65; p = 0.78; I2 = 0%) did not significantly differ between COVID-19 and non-COVID-19 cohorts. However, subgroup analyses suggested an increased risk of VTE amongst CODID-19 versus non COVID-19 cohorts when only patients hospitalized within the intensive care unit (ICU) were considered (RR 3.10; 95%CI 1.54-6.23), which was not observed in cohorts of predominantly non-ICU patients (RR 0.95; 95%CI 0.81-1.11) (Pinteraction = 0.001). CONCLUSION: There was no signal for a difference in VTE in COVID-19 cohorts compared to non-COVID-19 cohorts, except for the subgroup of patients hospitalized in the ICU. These results should be viewed as exploratory and further studies are needed to confirm these results.