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Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease characterized by thrombotic occlusion of pulmonary arteries and vasculopathy, leading to increased pulmonary vascular resistance and progressive right-sided heart failure. Thrombotic lesions in CTEPH contain CD68+ macrophages, and increasing evidence supports their role in disease pathogenesis. Macrophages are classically divided into pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages, which are involved in wound healing and tissue repair. Currently, the phenotype of macrophages and their localization within thrombotic lesions of CTEPH are largely unknown. In our study, we subclassified thrombotic lesions of CTEPH patients into developing fresh thrombi (FT) and organized thrombi (OT), based on the degree of fibrosis and remodeling. We used multiplex immunofluorescence histology to identify immune cell infiltrates in thrombotic lesions of CPTEH patients. Utilizing software-assisted cell detection and quantification, increased proportions of macrophages were observed in immune cell infiltrates of OT lesions, compared with FT. Strikingly, the proportions with a CD206+INOS- M2 phenotype were significantly higher in OT than in FT, which mainly contained unpolarized macrophages. Taken together, we observed a shift from unpolarized macrophages in FT toward an expanded population of M2 macrophages in OT, indicating a dynamic role of macrophages during CTEPH pathogenesis.
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Hipertensión Pulmonar , Macrófagos , Embolia Pulmonar , Trombosis , Humanos , Macrófagos/inmunología , Hipertensión Pulmonar/inmunología , Hipertensión Pulmonar/patología , Femenino , Masculino , Persona de Mediana Edad , Embolia Pulmonar/inmunología , Embolia Pulmonar/patología , Enfermedad Crónica , Trombosis/inmunología , Trombosis/patología , Anciano , Antígenos CD/metabolismoRESUMEN
In the field of pulmonary hypertension (PH), a well-established protocol to induce severe angioproliferation in rats (SuHx) involves combining the VEGF-R inhibitor Sugen 5416 (SU5416) with 3 wk of hypoxia (Hx). In addition, injecting monocrotaline (MCT) into rats can induce inflammation and shear stress in the pulmonary vasculature, leading to neointima-like remodeling. However, the SuHx protocol in mice is still controversial, with some studies suggesting it yields higher and reversible PH than Hx alone, possibly due to species-dependent hypoxic responses. To establish an alternative rodent model of PH, we hypothesized mice would be more sensitive to hemodynamic changes secondary to shear stress compared with Hx. We attempted to induce severe and irreversible PH in mice by combining SU5416 or monocrotaline pyrrole (MCTP) injection with pneumonectomy (PNx). However, our experiments showed SU5416 administered to mice at various time points after PNx did not result in severe PH. Similarly, mice injected with MCTP after PNx (MPNx) showed no difference in right ventricular systolic pressure or exacerbated pulmonary vascular remodeling compared with PNx alone. These findings collectively demonstrate that C57/B6 mice do not develop severe and persistent PH when PNx is combined with either SU5416 or MCTP.NEW & NOTEWORTHY We attempted to establish a mouse model of severe and irreversible pulmonary hypertension by substituting hypoxia with pulmonary overcirculation. To do so, we treated mice with either SU5416 or monocrotaline pyrrole after pneumonectomy and performed hemodynamic evaluations for PH. Despite this "two-hit" protocol, mice did not exhibit signs of severe pulmonary hypertension or exacerbated pulmonary vascular remodeling compared with PNx alone.
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Hipertensión Pulmonar , Indoles , Ratones Endogámicos C57BL , Monocrotalina , Neumonectomía , Pirroles , Animales , Monocrotalina/análogos & derivados , Pirroles/farmacología , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/inducido químicamente , Indoles/farmacología , Ratones , Masculino , Modelos Animales de Enfermedad , Hipoxia/patología , Remodelación Vascular/efectos de los fármacos , Pulmón/patología , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Hemodinámica/efectos de los fármacosRESUMEN
BACKGROUND: The consequences of tricuspid regurgitation (TR) for right ventricular (RV) function and prognosis in pulmonary arterial hypertension (PAH) are poorly described and effects of tricuspid valve repair on the RV are difficult to predict. METHODS: In 92 PAH patients with available cardiac magnetic resonance (CMR) studies, TR volume was calculated as the difference between RV stroke volume and forward stroke volume, i.e. pulmonary artery (PA) stroke volume. Survival was estimated from the time of the CMR scan to cardiopulmonary death or lung transplantation. In a subgroup, pressure-volume loop analysis including two-parallel elastances was applied to evaluate effective elastances, including net afterload (effective arterial elastance (E a)), forward afterload (effective pulmonary arterial elastance (E pa)) and backward afterload (effective tricuspid regurgitant elastance (E TR)). The effects of tricuspid valve repair were simulated using the online software package Harvi. RESULTS: 26% of PAH patients had a TR volume ≥30â mL. Greater TR volume was associated with increased N-terminal pro-brain natriuretic peptide (p=0.018), mean right atrial pressure (p<0.001) and RV end-systolic and -diastolic volume (both p<0.001). TR volume ≥30â mL was associated with a poor event-free survival (p=0.008). In comparison to E a, E pa correlated better with indices of RV dysfunction. Lower end-systolic elastance (E es) (p=0.002) and E TR (p=0.030), higher E pa (p=0.001) and reduced E es/E pa (p<0.001) were found in patients with a greater TR volume. Simulations predicted that tricuspid valve repair increases RV myocardial oxygen consumption in PAH patients with severe TR and low E es unless aggressive volume reduction is accomplished. CONCLUSIONS: In PAH, TR has prognostic significance and is associated with low RV contractility and RV-PA uncoupling. However, haemodynamic simulations showed detrimental consequences of tricuspid valve repair in PAH patients with low RV contractility.
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Hipertensión Arterial Pulmonar , Insuficiencia de la Válvula Tricúspide , Función Ventricular Derecha , Humanos , Insuficiencia de la Válvula Tricúspide/fisiopatología , Insuficiencia de la Válvula Tricúspide/complicaciones , Femenino , Masculino , Persona de Mediana Edad , Adulto , Hipertensión Arterial Pulmonar/fisiopatología , Hipertensión Arterial Pulmonar/complicaciones , Volumen Sistólico , Ventrículos Cardíacos/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen , Arteria Pulmonar/fisiopatología , Pronóstico , Anciano , Válvula Tricúspide/fisiopatología , Válvula Tricúspide/diagnóstico por imagen , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/diagnóstico por imagen , Imagen por Resonancia Magnética , Hipertensión Pulmonar/fisiopatología , Péptido Natriurético Encefálico/sangreRESUMEN
BACKGROUND: Bone morphogenetic proteins 9 and 10 (BMP9 and BMP10), encoded by GDF2 and BMP10, respectively, play a pivotal role in pulmonary vascular regulation. GDF2 variants have been reported in pulmonary arterial hypertension (PAH) and hereditary haemorrhagic telangiectasia (HHT). However, the phenotype of GDF2 and BMP10 carriers remains largely unexplored. METHODS: We report the characteristics and outcomes of PAH patients in GDF2 and BMP10 carriers from the French and Dutch pulmonary hypertension registries. A literature review explored the phenotypic spectrum of these patients. RESULTS: 26 PAH patients were identified: 20 harbouring heterozygous GDF2 variants, one homozygous GDF2 variant, four heterozygous BMP10 variants, and one with both GDF2 and BMP10 variants. The prevalence of GDF2 and BMP10 variants was 1.3% and 0.4%, respectively. Median age at PAH diagnosis was 30â years, with a female/male ratio of 1.9. Congenital heart disease (CHD) was present in 15.4% of the patients. At diagnosis, most of the patients (61.5%) were in New York Heart Association Functional Class III or IV with severe haemodynamic compromise (median (range) pulmonary vascular resistance 9.0 (3.3-40.6)â WU). Haemoptysis was reported in four patients; none met the HHT criteria. Two patients carrying BMP10 variants underwent lung transplantation, revealing typical PAH histopathology. The literature analysis showed that 7.6% of GDF2 carriers developed isolated HHT, and identified cardiomyopathy and developmental disorders in BMP10 carriers. CONCLUSIONS: GDF2 and BMP10 pathogenic variants are rare among PAH patients, and occasionally associated with CHD. HHT cases among GDF2 carriers are limited according to the literature. BMP10 full phenotypic ramifications warrant further investigation.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Telangiectasia Hemorrágica Hereditaria , Humanos , Masculino , Femenino , Adulto , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Hipertensión Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/complicaciones , Hipertensión Pulmonar Primaria Familiar , Telangiectasia Hemorrágica Hereditaria/complicaciones , Telangiectasia Hemorrágica Hereditaria/genética , Fenotipo , Factor 2 de Diferenciación de Crecimiento/genética , Estudios Multicéntricos como AsuntoRESUMEN
INTRODUCTION: Pathogenic variants in the gene encoding for BMPR2 are a major genetic risk factor for heritable pulmonary arterial hypertension (PAH). Due to incomplete penetrance, deep-phenotyping of unaffected carriers (UCs) of a pathogenic BMPR2 variant through multi-modality screening may aid in early diagnosis and identify susceptibility traits for future development of PAH. METHODS: 28 UCs (44±16â years, 57% female) and 21 healthy controls (43±18â years, 48% female) underwent annual screening, including cardiac magnetic resonance imaging (cMRI), transthoracic echocardiography (TTE), cardiopulmonary exercise testing (CPET) and right heart catheterization (RHC). Right ventricular (RV) pressure-volume (PV) loops were constructed to assess load independent contractility and compared with a healthy control group. A transgenic Bmpr2Δ71Ex1/+ rat model was employed to validate findings in humans. RESULTS: UCs had lower indexed right ventricular end-diastolic (80±18â mL·m-2 versus 64±14â mL·m-2;p= 0.003), end-systolic (34±11â mL·m-2 versus 27±8â mL·m-2;p=0.024) and left end-diastolic volumes (69±14â mL·m-2 versus 60±11â mL·m-2;p=0.019) than control subjects. Bmpr2Δ71Ex1/+ rats were also observed to have smaller cardiac volumes than WT rats. PV loop analysis showed significantly higher afterload (Ea) (0.15±0.06 versus 0.27±0.08; p<0.001), and end-systolic elastance (Ees) 0.28±0.07 versus 0.35±0.10; p=0.047) in addition to lower RV-pulmonary artery coupling (Ees/Ea)(2.24±1.03 versus 1.36±0.37; p=0.006) in UCs. During the 4-year follow-up period, two UCs developed PAH with normal NT-proBNP and TTE indices at diagnosis. CONCLUSION: Unaffected BMPR2 mutation carriers have an altered cardiac phenotype mimicked in Bmpr2Δ71Ex1/+ transgenic rats. Future efforts in establishing an effective screening protocol for individuals at risk for developing PAH warrants longer follow-up periods.
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INTRODUCTION: Chronic thromboembolic pulmonary hypertension (CTEPH) is often diagnosed late in acute pulmonary embolism (PE) survivors: more efficient testing to expedite diagnosis may considerably improve patient outcomes. The InShape II algorithm safely rules out CTEPH (failure rate 0.29%) while requiring echocardiography in only 19% of patients but may be improved by adding detailed reading of the computed tomography pulmonary angiography (CTPA) diagnosing the index PE. METHODS: Twelve new algorithms, incorporating the CTEPH prediction score, ECG reading, NT-proBNP levels and dedicated CTPA reading were evaluated in the international InShape II (n=341) and part of the German FOCUS cohort (n=171). Evaluation criteria included failure rate, defined as the incidence of confirmed CTEPH in PE patients in whom echocardiography was deemed unnecessary by the algorithm, and the overall net reclassification index (NRI) compared to the InShape II algorithm. RESULTS: The algorithm starting with CTPA reading of the index PE for 6 signs of CTEPH, followed by the ECG/NTproBNP assessment and echocardiography resulted in the most beneficial change compared to InShape II with a need for echocardiography in 20% (+5%), a failure rate of 0%, and an NRI of +3.5, reflecting improved performance over the InShape II algorithm. In the FOCUS cohort, this approach lowered echocardiography need to 24% (-6%) and missed no CTEPH cases, with an NRI of +6.0. CONCLUSION: Dedicated CTPA reading of the index PE improved the performance of the InShape II algorithm and may improve the selection of PE survivors who require echocardiography to rule out CTEPH.
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SARS-CoV-2 can induce insulin resistance, which is, among others, mediated by adipose tissue dysfunction and reduced angiotensin-converting enzyme 2 (ACE2) enzymatic activity. In SARS-CoV-2-infected mice, the tyrosine kinase inhibitor imatinib attenuates inflammation and improves insulin sensitivity. Here, we report the effects of imatinib on incident hyperglycaemia, circulating levels of glucoregulatory proteins, longitudinal insulin sensitivity and ACE-2 enzymatic activity in 385 hospitalized COVID-19 patients who participated in a randomized, double-blind, placebo-controlled clinical trial. Patients with severe hyperglycaemia had similar demographics compared to those without, but required longer hospital stays and exhibited higher invasive ventilation and mortality rates. The incidence of severe hyperglycaemia was significantly lower in patients treated with imatinib, while insulin production and central insulin sensitivity were unaffected. Imatinib increased plasma angiotensin-2 and adiponectin levels, and decreased c-Jun N-terminal protein kinase 1 (JNK1), JNK2 and interleukin-6 levels. These findings suggest that imatinib restores endocrine control of peripheral glucose uptake in COVID-19.
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COVID-19 , Hiperglucemia , Resistencia a la Insulina , Humanos , Hiperglucemia/tratamiento farmacológico , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , SARS-CoV-2RESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response and mortality in patients with COVID-19. METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort. RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumour necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1 and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively). CONCLUSIONS: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.
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COVID-19 , Humanos , Anciano , Biomarcadores , Inflamación , Citocinas , EnvejecimientoRESUMEN
Increasing evidence indicates that inflammation promotes thrombosis via a VWF (von Willebrand factor)-mediated mechanism. VWF plays an essential role in maintaining the balance between blood coagulation and bleeding, and inflammation can lead to aberrant regulation. VWF is regulated on a transcriptional and (post-)translational level, and its secretion into the circulation captures platelets upon endothelial activation. The significant progress that has been made in understanding transcriptional and translational regulation of VWF is described in this review. First, we describe how VWF is regulated at the transcriptional and post-translational level with a specific focus on the influence of inflammatory and immune responses. Next, we describe how changes in regulation are linked with various cardiovascular diseases. Recent insights from clinical diseases provide evidence for direct molecular links between inflammation and thrombosis, including atherosclerosis, chronic thromboembolic pulmonary hypertension, and COVID-19. Finally, we will briefly describe clinical implications for antithrombotic treatment.
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COVID-19 , Trombosis , Enfermedades de von Willebrand , Humanos , Factor de von Willebrand/genética , Fibrinolíticos/uso terapéutico , Plaquetas , Inflamación/genéticaRESUMEN
PURPOSE: A hallmark of acute respiratory distress syndrome (ARDS) is hypoxaemic respiratory failure due to pulmonary vascular hyperpermeability. The tyrosine kinase inhibitor imatinib reversed pulmonary capillary leak in preclinical studies and improved clinical outcomes in hospitalized COVID-19 patients. We investigated the effect of intravenous (IV) imatinib on pulmonary edema in COVID-19 ARDS. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled trial. Invasively ventilated patients with moderate-to-severe COVID-19 ARDS were randomized to 200 mg IV imatinib or placebo twice daily for a maximum of seven days. The primary outcome was the change in extravascular lung water index (∆EVLWi) between days 1 and 4. Secondary outcomes included safety, duration of invasive ventilation, ventilator-free days (VFD) and 28-day mortality. Posthoc analyses were performed in previously identified biological subphenotypes. RESULTS: 66 patients were randomized to imatinib (n = 33) or placebo (n = 33). There was no difference in ∆EVLWi between the groups (0.19 ml/kg, 95% CI - 3.16 to 2.77, p = 0.89). Imatinib treatment did not affect duration of invasive ventilation (p = 0.29), VFD (p = 0.29) or 28-day mortality (p = 0.79). IV imatinib was well-tolerated and appeared safe. In a subgroup of patients characterized by high IL-6, TNFR1 and SP-D levels (n = 20), imatinib significantly decreased EVLWi per treatment day (- 1.17 ml/kg, 95% CI - 1.87 to - 0.44). CONCLUSIONS: IV imatinib did not reduce pulmonary edema or improve clinical outcomes in invasively ventilated COVID-19 patients. While this trial does not support the use of imatinib in the general COVID-19 ARDS population, imatinib reduced pulmonary edema in a subgroup of patients, underscoring the potential value of predictive enrichment in ARDS trials. Trial registration NCT04794088 , registered 11 March 2021. European Clinical Trials Database (EudraCT number: 2020-005447-23).
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COVID-19 , Edema Pulmonar , Síndrome de Dificultad Respiratoria , Humanos , COVID-19/complicaciones , Mesilato de Imatinib/efectos adversos , Pulmón , Método Doble CiegoRESUMEN
Rationale: von Willebrand factor (vWF) mediates platelet adhesion during thrombosis. While chronic thromboembolic pulmonary hypertension (CTEPH) is associated with increased plasma levels of vWF, the role of this protein in CTEPH has remained enigmatic. Objectives: To identify the role of vWF in CTEPH. Methods: CTEPH-specific patient plasma and pulmonary endarterectomy material from patients with CTEPH were used to study the relationship between inflammation, vWF expression, and pulmonary thrombosis. Cell culture findings were validated in human tissue, and proteomics and chromatin immunoprecipitation were used to investigate the underlying mechanism of CTEPH. Measurements and Main Results: vWF is increased in plasma and the pulmonary endothelium of CTEPH patients. In vitro, the increase in vWF gene expression and the higher release of vWF protein upon endothelial activation resulted in elevated platelet adhesion to CTEPH endothelium. Proteomic analysis revealed that nuclear factor (NF)-κB2 was significantly increased in CTEPH. We demonstrate reduced histone tri-methylation and increased histone acetylation of the vWF promoter in CTEPH endothelium, facilitating binding of NF-κB2 to the vWF promoter and driving vWF transcription. Genetic interference of NFκB2 normalized the high vWF RNA expression levels and reversed the prothrombotic phenotype observed in CTEPH-pulmonary artery endothelial cells. Conclusions: Epigenetic regulation of the vWF promoter contributes to the creation of a local environment that favors in situ thrombosis in the pulmonary arteries. It reveals a direct molecular link between inflammatory pathways and platelet adhesion in the pulmonary vascular wall, emphasizing a possible role of in situ thrombosis in the development or progression of CTEPH.
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Hipertensión Pulmonar , Factor de von Willebrand , Células Endoteliales/metabolismo , Endotelio Vascular , Epigénesis Genética , Humanos , Agregación Plaquetaria , Proteómica , Factor de von Willebrand/análisis , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismoRESUMEN
Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis. Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation (n = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants (n = 162) or no identified variants in PAH-associated genes (n = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases. Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared with loss-of-function effects (P = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation (P = 0.005) and increased incidence of interstitial lung disease (P = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group (P = 0.022), although age had a significant effect in the hazard model (P = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age (P < 0.001) and had worse baseline lung function (FEV1, FVC) (P = 0.009) than the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.
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Mutación con Ganancia de Función , Enfermedades Pulmonares , Humanos , Proteínas de Dominio T Box/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/genética , Fenotipo , Enfermedades Pulmonares/genética , Mutación/genética , GenotipoRESUMEN
Right ventricular (RV) wall tension in pulmonary arterial hypertension (PAH) is determined not only by pressure, but also by RV volume. A larger volume at a given pressure generates more wall tension. Return of reflected waves early after the onset of contraction, when RV volume is larger, may augment RV load. We aimed to elucidate: (1) the distribution of arrival times of peak reflected waves in treatment-naïve PAH patients; (2) the relationship between time of arrival of reflected waves and RV morphology; and (3) the effect of PAH treatment on the arrival time of reflected waves. Wave separation analysis was conducted in 68 treatment-naïve PAH patients. In the treatment-naïve condition, 54% of patients had mid-systolic return of reflected waves (defined as 34-66% of systole). Despite similar pulmonary vascular resistance (PVR), patients with mid-systolic return had more pronounced RV hypertrophy compared to those with late-systolic or diastolic return (RV mass/body surface area; mid-systolic return 54.6 ± 12.6 g m-2 , late-systolic return 44.4 ± 10.1 g m-2 , diastolic return 42.8 ± 13.1 g m-2 ). Out of 68 patients, 43 patients were further examined after initial treatment. At follow-up, the stiffness of the proximal arteries, given as characteristic impedance, decreased from 0.12 to 0.08 mmHg s mL-1 . Wave speed was attenuated from 13.3 to 9.1 m s-1 , and the return of reflected waves was delayed from 64% to 71% of systole. In conclusion, reflected waves arrive at variable times in PAH. Early return of reflected waves was associated with more RV hypertrophy. PAH treatment not only decreased PVR, but also delayed the timing of reflected waves. KEY POINTS: Right ventricular (RV) wall tension in pulmonary arterial hypertension (PAH) is determined not only by pressure, but also by RV volume. Larger volume at a given pressure causes larger RV wall tension. Early return of reflected waves adds RV pressure in early systole, when RV volume is relatively large. Thus, early return of reflected waves may increase RV wall tension. Wave reflection can provide a description of RV load. In PAH, reflected waves arrive back at variable times. In over half of PAH patients, the RV is exposed to mid-systolic return of reflected waves. Mid-systolic return of reflected waves is related to RV hypertrophy. PAH treatment acts favourably on the RV not only by reducing resistance, but also by delaying the return of reflected waves. Arrival timing of reflected waves is an important parameter for understanding the relationship between RV load and its function in PAH.
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Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Ventrículos Cardíacos , Humanos , Hipertrofia , Disfunción Ventricular Derecha/etiología , Función Ventricular Derecha , Presión VentricularRESUMEN
For more than 2 years, COVID-19 has been holding the world at awe with new waves of infections, novel mutants, and still limited (albeit improved) means to combat SARS-CoV-2-induced respiratory failure, the most common and fatal presentation of severe COVID-19. In the present perspective, we draw from the successes and-mostly-failures in previous acute respiratory distress syndrome (ARDS) work and the experiences from COVID-19 to define conceptual barriers that have so far hindered therapeutic breakthroughs in this deadly disease, and to open up new avenues of thinking and thus, ultimately of therapy.
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COVID-19 , Síndrome de Dificultad Respiratoria , Humanos , SARS-CoV-2RESUMEN
Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-ß (TGF-ß)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-ß/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-ß signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-ß signalling in monocrotaline + shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-ß/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.
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Hipertensión Pulmonar , Animales , Modelos Animales de Enfermedad , Células Endoteliales , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Isomerasa de Peptidilprolil , Arteria Pulmonar , Ratas , Factor de Crecimiento Transformador beta , Remodelación VascularRESUMEN
Endothelial barrier dysfunction leads to edema and vascular leak, causing high morbidity and mortality. Previously, Abl kinase inhibition has been shown to protect against vascular leak. Using the distinct inhibitory profiles of clinically available Abl kinase inhibitors, we aimed to provide a mechanistic basis for novel treatment strategies against vascular leakage syndromes. We found that the inhibitor bosutinib most potently protected against inflammation-induced endothelial barrier disruption. In vivo, bosutinib prevented lipopolysaccharide (LPS)-induced alveolar protein extravasation in an acute lung injury mice model. Mechanistically, mitogen-activated protein 4 kinase 4 (MAP4K4) was identified as important novel mediator of endothelial permeability, which signaled via ezrin, radixin and moesin proteins to increase turnover of integrin-based focal adhesions. The combined inhibition of MAP4K4 and Abl-related gene (Arg, also known as ABL2) by bosutinib preserved adherens junction integrity and reduced turnover of focal adhesions, which synergistically act to stabilize the endothelial barrier during inflammation. We conclude that MAP4K4 is an important regulator of endothelial barrier integrity, increasing focal adhesion turnover and disruption of cell-cell junctions during inflammation. Because it inhibits both Arg and MAP4K4, use of the clinically available drug bosutinib might form a viable strategy against vascular leakage syndromes.
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Adhesiones Focales , Preparaciones Farmacéuticas , Uniones Adherentes , Compuestos de Anilina , Animales , Permeabilidad Capilar , Ratones , Nitrilos , QuinolinasRESUMEN
Despite high levels of CXCR3 ligands in mechanically ventilated COVID-19 patients, BALF CD8 T cells were not enriched in CXCR3+ cells but rather CCR6+ , likely due to high CCL20 levels in BALF, and had very high PD-1 expression. In mechanically ventilated, but not ward, patients Th-1 immunity is impaired. â.
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Linfocitos T CD8-positivos/inmunología , COVID-19/inmunología , Quimiocina CCL20/inmunología , Pulmón/inmunología , Receptores CCR6/inmunología , Respiración Artificial , SARS-CoV-2/inmunología , Anciano , Anciano de 80 o más Años , Linfocitos T CD8-positivos/patología , COVID-19/patología , COVID-19/terapia , Femenino , Humanos , Pulmón/patología , Recuento de Linfocitos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Pulmonary arterial hypertension (PAH) patients have altered right atrial (RA) function and right ventricular (RV) diastolic stiffness. This study assessed the impact of RV diastolic stiffness on RA-RV interaction. METHODS: PAH patients with low or high end-diastolic elastance (Eed) (n=94) were compared with controls (n=31). Treatment response was evaluated in 62 patients. RV and RA longitudinal strain, RA emptying and RV filling were determined and diastole was divided into a passive and active phase. Vena cava backflow was calculated as RA active emptying-RV active filling and RA stroke work as RA active emptying×RV end-diastolic pressure. RESULTS: With increased Eed, RA and RV passive strain were reduced while active strain was preserved. In comparison to controls, patients had lower RV passive filling but higher RA active emptying and RA stroke work. RV active filling was lower in patients with high Eed, resulting in higher vena cava backflow. Upon treatment, Eed was reduced in ~50% of the patients with high Eed, which coincided with larger reductions in afterload, RV mass and vena cava backflow and greater improvements in RV active filling and stroke volume in comparison with patients in whom Eed remained high. CONCLUSIONS: In PAH, RA function is associated with changes in RV function. Despite increased RA stroke work, severe RV diastolic stiffness is associated with reduced RV active filling and increased vena cava backflow. In 50% of patients with high baseline Eed, diastolic stiffness remained high, despite treatment. A reduction in Eed coincided with a large reduction in afterload, increased RV active filling and decreased vena cava backflow.
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Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Disfunción Ventricular Derecha , Función del Atrio Derecho , Diástole , Hipertensión Pulmonar Primaria Familiar , Humanos , Función Ventricular DerechaRESUMEN
BACKGROUND: Imatinib reduced 90-day mortality in hospitalised coronavirus disease 2019 (COVID-19) patients in a recent clinical trial, but the biological effects that cause improved clinical outcomes are unknown. We aimed to determine the biological changes elicited by imatinib in patients with COVID-19 and what baseline biological profile moderates the effect of imatinib. METHODS: We undertook a secondary analysis of a randomised, double-blind, placebo-controlled trial of oral imatinib in hospitalised, hypoxaemic COVID-19 patients. Mediating effects of changes in plasma concentration of 25 plasma host response biomarkers on the association between randomisation group and 90-day mortality were studied by combining linear mixed effect modelling and joint modelling. Moderation of baseline biomarker concentrations was evaluated by Cox regression modelling. We identified subphenotypes using Ward's method clustering and evaluated moderation of these subphenotypes using the aforementioned method. RESULTS: 332 out of 385 participants had plasma samples available. Imatinib increased the concentration of surfactant protein D (SP-D), and decreased the concentration of interleukin-6, procalcitonin, angiopoietin (Ang)-2/Ang-1 ratio, E-selectin, tumour necrosis factor (TNF)-α, and TNF receptor I. The effect of imatinib on 90-day mortality was fully mediated by changes in these biomarkers. Cluster analysis revealed three host response subphenotypes. Mortality benefit of imatinib was only present in the subphenotype characterised by alveolar epithelial injury indicated by increased SP-D levels in the context of systemic inflammation and endothelial dysfunction (hazard ratio 0.30, 95% CI 0.10-0.92). CONCLUSIONS: The effect of imatinib on mortality in hospitalised COVID-19 patients is mediated through modulation of innate immune responses and reversal of endothelial dysfunction, and possibly moderated by biological subphenotypes.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19 , Mesilato de Imatinib , Inmunomodulación , Humanos , Biomarcadores , COVID-19/mortalidad , Mesilato de Imatinib/uso terapéutico , Proteína D Asociada a Surfactante PulmonarRESUMEN
ABSTRACT: Although previous studies support the clinical benefit of imatinib regarding respiratory status in hospitalized patients with COVID-19, potential cardiotoxicity may limit its clinical application. This study aimed to investigate the cardiac safety of imatinib in COVID-19. In the CounterCOVID study, 385 hospitalized hypoxemic patients with COVID-19 were randomly assigned to receive 10 days of oral imatinib or placebo in a 1:1 ratio. Patients with a corrected QT interval (QTc) >500 ms or left ventricular ejection fraction <40% were excluded. Severe cardiac adverse events were monitored for 28 days or until death occurred. Electrocardiogram measurements and cardiac biomarkers were assessed repeatedly during the first 10 days. A total of 36 severe cardiac events occurred, with a similar incidence in both treatment groups. No differences were observed in the computer-generated Bazett, manually interpreted Bazett, or Fridericia-interpreted QTcs. No clinically relevant alterations in other electrocardiogram parameters or plasma high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations were observed. Similar findings were observed in a subgroup of 72 patients admitted to the intensive care unit. In the univariate and multivariable linear mixed models, treatment with imatinib was not significantly associated with QT interval duration, hs-cTnT, or NT-proBNP levels. In conclusion, imatinib treatment did not result in more cardiac events, QT interval prolongation, or altered hs-cTnT or NT-proBNP levels. This suggests that treatment with imatinib is safe in hospitalized patients with COVID-19 with a QTc duration of less than 500 ms and left ventricular ejection fraction >40%.