RESUMEN
BACKGROUND: The European Chronic Thromboembolic Pulmonary Hypertension registry (CTEPH), conducted between 2007 and 2012, reported the major impact of pulmonary endarterectomy (PEA) on the long-term survival of patients with CTEPH. Since then, 2 additional treatments for inoperable CTEPH have become available: balloon pulmonary angioplasty (BPA), and an approved oral drug therapy with the guanylate cyclase stimulator riociguat. The current registry aimed to evaluate the effect of these new therapeutic approaches in a worldwide context. METHODS: Participation in this international global registry included 34 centers in 20 countries. Between February 2015 and September 2016, 1009 newly diagnosed, consecutive patients were included and followed until September 2019. RESULTS: Overall, 605 patients (60%) underwent PEA and 185 (18%) underwent BPA; 76% of the 219 remaining patients not receiving mechanical intervention (ie, neither PEA nor BPA) were treated with pulmonary hypertension drugs. Oof patients undergoing PEA and BPA, 38% and 78% also received drugs for pulmonary hypertension, respectively. Median age at diagnosis was higher in the BPA and No PEA/BPA groups than in the PEA group: 66 and 69, respectively, versus 60 years. Pulmonary vascular resistance (PVR) was similar in all groups, with an average of 643 dynes/(s·cm-5). During an observation period (>3 years; ≤5.6 years), death was reported in 7%, 11%, and 27% of patients treated by PEA and BPA, and those receiving no mechanical intervention (P<0.001). In Kaplan-Meier analysis, 3-year survival was 94%, 92%, and 71% in the 3 groups, respectively. PEA 3-year survival improved by 5% from that observed between 2007 and 2012. There was no survival difference in patients receiving vitamin K antagonists and non-vitamin K oral anticoagulants (P=0.756). In Cox regression, reduced mortality was associated with: PEA and BPA in the global cohort; history of venous thromboembolism and lower PVR in the PEA group; lower right atrial pressure in the BPA group; and use of pulmonary hypertension drugs, oxygen therapy, and lower right atrial pressure, as well as functional class in the group receiving no mechanical intervention. CONCLUSIONS: This second international CTEPH registry reveals important improvement in patient survival since the introduction of BPA and an approved drug for pulmonary hypertension. The type of anticoagulation regimen did not influence survival. REGISTRATION: URL https://clinicaltrials.gov; Unique identifier: NCT02656238.
RESUMEN
BACKGROUND: Acute intraoperative hypercapnia and respiratory acidosis, which can occur during monitored anaesthesia care (MAC), pose significant cardiopulmonary risks for patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR). The goal of the present study is to assess the incidence, risk factors and impact of intraoperative hypercapnia during MAC for patients undergoing transfemoral TAVR. METHODS: Data was collected retrospectively from the electronic medical record of 201 consecutive patients with available intraoperative arterial blood gas (ABG) data who underwent percutaneous transfemoral TAVR with MAC using propofol and dexmedetomidine. ABGs (pH, arterial partial pressure of carbon dioxide (PaCO2) and arterial partial pressure of oxygen) were performed at the start of each case (baseline), immediately prior to valve deployment (ValveDepl), and on arrival to the postanaesthesia care unit. Data was analysed using Fisher's exact test, unpaired Student's t-test, Wilcoxon rank sum or univariate linear regression as appropriate based on PaCO2 and pH during ValveDepl (PaCO2-ValveDepl, pH-ValveDepl) and change in PaCO2 and pH from baseline to ValveDepl (PaCO2-%increase, pH-%decrease) to determine their association with preoperative demographic data, intraoperative anaesthetic and vasoactive medications and postoperative outcomes. RESULTS: PaCO2 increased by a mean of 28.4% and was higher than baseline in 91% of patients. Younger age, male sex, increased weight and increased propofol dose contributed to higher PaCO2-ValveDepl and greater PaCO2-%increase. Patients with PaCO2-ValveDepl>60 mm Hg, pH≤7.2 and greater pH-%decrease were more likely to receive vasoactive medications, but perioperative PaCO2 and pH were not associated with adverse postoperative outcomes. CONCLUSIONS: Transient significant hypercapnia commonly occurs during transfemoral TAVR with deep sedation using propofol and dexmedetomidine. Although the incidence of postoperative outcomes does not appear to be affected by hypercapnia, the need for vasopressors and inotropes is increased. If deep sedation is required for TAVR, hypercapnia and the need for haemodynamic and ventilatory support should be anticipated.
Asunto(s)
Estenosis de la Válvula Aórtica , Hipercapnia , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Hipercapnia/etiología , Hipercapnia/epidemiología , Hipercapnia/diagnóstico , Estudios Retrospectivos , Masculino , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Reemplazo de la Válvula Aórtica Transcatéter/métodos , Femenino , Estenosis de la Válvula Aórtica/cirugía , Anciano de 80 o más Años , Factores de Riesgo , Anciano , Incidencia , Dexmedetomidina/efectos adversos , Dexmedetomidina/administración & dosificación , Propofol/efectos adversos , Propofol/administración & dosificación , Resultado del Tratamiento , Monitoreo Intraoperatorio/métodos , Anestésicos Intravenosos/efectos adversos , Anestésicos Intravenosos/administración & dosificación , Válvula Aórtica/cirugíaRESUMEN
Despite its rarity, pulmonary capillary hemangiomatosis (PCH) presents a significant diagnostic challenge. Due to its similarity to other pulmonary vascular diseases, such as pulmonary veno-occlusive disease, it is characterized by abnormal pulmonary capillary proliferation, which is a rare cause of primary pulmonary hypertension. This case was the first reported instance of PCH in Shahid Rajaee Heart Hospital in Tehran, Iran, in 2023, which was confirmed by genetic testing. It highlighted the importance of considering PCH among the differential diagnoses for pulmonary hypertension, even in adolescent patients. The 13-year-old patient's main complaints were progressive exertional dyspnea and chest pain. He had no previous medical history and had not taken any pharmaceutical or herbal medications. Critical clinical findings included a heart murmur, an electrocardiogram revealing right ventricular hypertrophy, and echocardiogram evidence of pulmonary hypertension. The main diagnosis was PCH, as shown by CT findings of pulmonary artery dilatation and diffuse nodular ground glass opacities. Genetic tests indicated pathogenic EIF2AK4 mutations and suspicion of PCH. Therapeutic intervention included vasodilator therapy, which exacerbated the patient's condition. This case emphasized the importance of maintaining a high index of suspicion for rare causes of pulmonary hypertension, such as PCH. The outcome was to prepare the patient for lung transplantation. To differentiate PCH from other pulmonary vascular diseases, a combination of clinical presentation, radiologic studies, genetic analysis, and response to treatment is required to determine appropriate management, particularly lung transplantation.
Asunto(s)
Hemangioma Capilar , Humanos , Adolescente , Masculino , Hemangioma Capilar/complicaciones , Hemangioma Capilar/fisiopatología , Hemangioma Capilar/diagnóstico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/complicaciones , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/diagnóstico , Proteínas Serina-Treonina QuinasasAsunto(s)
Biomarcadores , Monóxido de Carbono , Hipertensión Pulmonar , Capacidad de Difusión Pulmonar , Embolia Pulmonar , Humanos , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/etiología , Biomarcadores/sangre , Monóxido de Carbono/metabolismo , Embolia Pulmonar/fisiopatología , Embolia Pulmonar/complicaciones , Embolia Pulmonar/diagnóstico , Enfermedad Crónica , Microcirculación/fisiologíaAsunto(s)
Insuficiencia Cardíaca , Monitorización Hemodinámica , Arteria Pulmonar , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/diagnóstico , Arteria Pulmonar/fisiopatología , Monitorización Hemodinámica/métodos , Enfermedad Crónica , Masculino , Hemodinámica/fisiología , Femenino , Persona de Mediana Edad , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/diagnóstico , Servicios de Atención de Salud a DomicilioRESUMEN
Objectives: To evaluate the impact of Pulmonary Arterial Hypertension (PAH) therapies on the incidence of pericardial effusion and its prognostic implications for patient survival. Methods: This retrospective cohort study included 60 patients diagnosed with PAH at a high-volume tertiary care center, treated with intravenous or subcutaneous prostanoids. Data were collected from 2015 to 2019, including echocardiographic assessments, right heart catheterization, World Health Organization functional class evaluations, six-minute walk distance tests, and biomarkers such as brain natriuretic peptide and N-terminal prohormone of brain natriuretic peptide. Follow-up was conducted at least 90 days post-treatment initiation. Results: Pericardial effusion was observed in 31.7% of patients before therapy. Patients with moderate to large effusions had a significantly higher mortality risk (HR = 1.92; 95% CI 1.1-44.78; p =0.0044), while small effusions appeared protective (HR = 0.27; 95% CI 0.15-0.48; p =0.006). Survival rates declined from 89% at one year to 71% at three years post-therapy, with effusion presence correlating with more severe PAH manifestations. Conclusions: Initial pericardial effusion severity is a critical predictor of mortality in PAH patients. Early assessment and stratified management of pericardial effusion are essential for optimizing therapeutic outcomes in PAH management. Future research should explore targeted interventions for managing pericardial effusion to improve patient prognosis.
RESUMEN
BACKGROUND: The N6-methyladenosine (m6A) modification of RNA and its regulators have important roles in the pathogenesis of pulmonary hypertension (PH). Ythdf2 (YTH N6-methyladenosine RNA binding protein 2) is best known for its role in degrading m6A-modified mRNAs such as Hmox1 mRNA, which leads to alternative activation of macrophages in PH. Recent studies have also linked Ythdf2 to the proliferation of pulmonary artery smooth muscle cells (PASMCs). However, its specific roles in PASMCs and downstream targets during the development of PH remain unclear. METHODS: The expression and biological function of Ythdf2 in PASMCs were investigated in human and experimental models of PH. Smooth muscle cell-specific Ythdf2-deficient mice were used to assess the roles of Ythdf2 in PASMCs in vivo. Proteomic analysis, m6A sequencing, and RNA immunoprecipitation analysis were used to screen for potential downstream targets. RESULTS: Ythdf2 was significantly upregulated in human and rodent PH-PASMCs, and smooth muscle cell-specific Ythdf2 deficiency ameliorated PASMC proliferation, right ventricular hypertrophy, pulmonary vascular remodeling, and PH development. Higher expression of Ythdf2 promoted PASMC proliferation and PH by paradoxically stabilizing Myadm mRNA in an m6A-dependent manner. Loss of Ythdf2 decreased the expression of Myadm in PASMCs and pulmonary arteries, both in vitro and in vivo. Additionally, silencing Myadm inhibited the Ythdf2-dependent hyperproliferation of PASMCs by upregulating the cell cycle kinase inhibitor p21. CONCLUSIONS: We have identified a novel mechanism where the increased expression of Ythdf2 stimulates PH-PASMC proliferation through an m6A/Myadm/p21 pathway. Strategies targeting Ythdf2 in PASMCs might be useful additions to the therapeutic approach to PH.
Asunto(s)
Proliferación Celular , Hipertensión Pulmonar , Músculo Liso Vascular , Miocitos del Músculo Liso , Arteria Pulmonar , Proteínas de Unión al ARN , Remodelación Vascular , Animales , Humanos , Masculino , Ratones , Células Cultivadas , Modelos Animales de Enfermedad , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Arteria Pulmonar/metabolismo , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Remodelación Vascular/fisiología , Remodelación Vascular/genéticaRESUMEN
BACKGROUND: We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension. METHODS: In the double-blind PASSION study (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension), patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension were randomized 1:1 to receive tadalafil at a target dose of 40 mg or placebo. The primary end point was the time to the first composite event of adjudicated heart failure hospitalization or all-cause death. Secondary end points included all-cause mortality and improvements in New York Heart Association functional class or ≥10% improvement in 6-minute walking distance from baseline. RESULTS: Initially targeting 372 patients, the study was terminated early because of disruption in study medication supply. At that point, 125 patients had been randomized (placebo: 63; tadalafil: 62,). Combined primary end-point events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil (hazard ratio, 1.02 [95% CI, 0.52-2.01]; P=0.95). There was a possible signal of higher all-cause mortality in the tadalafil group (hazard ratio, 5.10 [95% CI, 1.10-23.69]; P=0.04). No significant between-group differences were observed in other secondary end points. Serious adverse events occurred in 29 participants (48%) in the tadalafil group and 35 (56%) in the placebo group. CONCLUSIONS: The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, with potential safety concerns and no observed benefits in primary and secondary end points. REGISTRATION: URL: https://www.clinicaltrialsregister.eu/; Unique identifier: 2017-003688-37. URL: https://drks.de; Unique identifier: DRKS -DRKS00014595.
Asunto(s)
Insuficiencia Cardíaca , Hipertensión Pulmonar , Inhibidores de Fosfodiesterasa 5 , Volumen Sistólico , Tadalafilo , Humanos , Tadalafilo/uso terapéutico , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/fisiopatología , Masculino , Femenino , Volumen Sistólico/efectos de los fármacos , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/fisiopatología , Anciano , Persona de Mediana Edad , Método Doble Ciego , Inhibidores de Fosfodiesterasa 5/uso terapéutico , Inhibidores de Fosfodiesterasa 5/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Endothelial cell (EC) apoptosis and proliferation of apoptosis-resistant cells is a hallmark of pulmonary hypertension (PH). Yet, why some ECs die and others proliferate and how this contributes to vascular remodeling is unclear. We hypothesized that this differential response may: (1) relate to different EC subsets, namely pulmonary artery (PAECs) versus microvascular ECs (MVECs); (2) be attributable to autophagic activation in both EC subtypes; and (3) cause replacement of MVECs by PAECs with subsequent distal vessel muscularization. METHODS: EC subset responses to chronic hypoxia were assessed by single-cell RNA sequencing of murine lungs. Proliferative versus apoptotic responses, activation, and role of autophagy were assessed in human and rat PAECs and MVECs, and in precision-cut lung slices of wild-type mice or mice with endothelial deficiency in the autophagy-related gene 7 (Atg7EN-KO). Abundance of PAECs versus MVECs in precapillary microvessels was assessed in lung tissue from patients with PH and animal models on the basis of structural or surface markers. RESULTS: In vitro and in vivo, PAECs proliferated in response to hypoxia, whereas MVECs underwent apoptosis. Single-cell RNA sequencing analyses support these findings in that hypoxia induced an antiapoptotic, proliferative phenotype in arterial ECs, whereas capillary ECs showed a propensity for cell death. These distinct responses were prevented in hypoxic Atg7EN-KO mice or after ATG7 silencing, yet replicated by autophagy stimulation. In lung tissue from mice, rats, or patients with PH, the abundance of PAECs in precapillary arterioles was increased, and that of MVECs reduced relative to controls, indicating replacement of microvascular by macrovascular ECs. EC replacement was prevented by genetic or pharmacological inhibition of autophagy in vivo. Conditioned medium from hypoxic PAECs yet not MVECs promoted pulmonary artery smooth muscle cell proliferation and migration in a platelet-derived growth factor-dependent manner. Autophagy inhibition attenuated PH development and distal vessel muscularization in preclinical models. CONCLUSIONS: Autophagic activation by hypoxia induces in parallel PAEC proliferation and MVEC apoptosis. These differential responses cause a progressive replacement of MVECs by PAECs in precapillary pulmonary arterioles, thus providing a macrovascular context that in turn promotes pulmonary artery smooth muscle cell proliferation and migration, ultimately driving distal vessel muscularization and the development of PH.
Asunto(s)
Apoptosis , Autofagia , Células Endoteliales , Hipertensión Pulmonar , Arteria Pulmonar , Animales , Humanos , Hipertensión Pulmonar/patología , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/genética , Células Endoteliales/metabolismo , Células Endoteliales/patología , Ratones , Arteria Pulmonar/patología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Ratas , Proliferación Celular , Masculino , Remodelación Vascular , Ratones Noqueados , Proteína 7 Relacionada con la Autofagia/genética , Proteína 7 Relacionada con la Autofagia/metabolismo , Modelos Animales de Enfermedad , Hipoxia/metabolismo , Hipoxia/patología , Células Cultivadas , Ratones Endogámicos C57BLAsunto(s)
Fístula Arteriovenosa , Insuficiencia Cardíaca , Enfermedad Iatrogénica , Arteria Ilíaca , Humanos , Arteria Ilíaca/diagnóstico por imagen , Arteria Ilíaca/cirugía , Insuficiencia Cardíaca/etiología , Fístula Arteriovenosa/etiología , Fístula Arteriovenosa/cirugía , Fístula Arteriovenosa/diagnóstico por imagen , Vértebras Lumbares/cirugía , Masculino , Adulto , Gasto Cardíaco Elevado/etiología , Resultado del Tratamiento , FemeninoRESUMEN
BACKGROUND: Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear. METHODS: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples. RESULTS: Plasma proteomics identified high protein abundance levels of B2M (ß2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.
Asunto(s)
Modelos Animales de Enfermedad , Insuficiencia Cardíaca , Hipertensión Pulmonar , Proteómica , Volumen Sistólico , Microglobulina beta-2 , Adulto , Anciano , Animales , Humanos , Masculino , Ratones , Persona de Mediana Edad , Microglobulina beta-2/genética , Microglobulina beta-2/sangre , Microglobulina beta-2/metabolismo , Biomarcadores/sangre , Estudios de Casos y Controles , Movimiento Celular , Proliferación Celular , Células Cultivadas , Células Endoteliales/metabolismo , Células Endoteliales/patología , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/genética , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/sangre , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/metabolismo , Proteómica/métodos , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/metabolismo , Sirtuina 3/genética , Sirtuina 3/metabolismo , Remodelación Vascular , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Inflammation is pathogenically implicated in pulmonary arterial hypertension; however, it has not been adequately targeted therapeutically. We investigated whether neuromodulation of an anti-inflammatory neuroimmune pathway involving the splenic nerve using noninvasive, focused ultrasound stimulation of the spleen (sFUS) can improve experimental pulmonary hypertension. METHODS: Pulmonary hypertension was induced in rats either by Sugen 5416 (20 mg/kg SQ) injection, followed by 21 (or 35) days of hypoxia (sugen/hypoxia model), or by monocrotaline (60 mg/kg IP) injection (monocrotaline model). Animals were randomized to receive either 12-minute-long sessions of sFUS daily or sham stimulation for 14 days. Catheterizations, echocardiography, indices of autonomic function, lung and heart histology and immunohistochemistry, spleen flow cytometry, and lung single-cell RNA sequencing were performed after treatment to assess the effects of sFUS. RESULTS: Splenic denervation right before induction of pulmonary hypertension results in a more severe disease phenotype. In both sugen/hypoxia and monocrotaline models, sFUS treatment reduces right ventricular systolic pressure by 25% to 30% compared with sham treatment, without affecting systemic pressure, and improves right ventricular function and autonomic indices. sFUS reduces wall thickness, apoptosis, and proliferation in small pulmonary arterioles, suppresses CD3+ and CD68+ cell infiltration in lungs and right ventricular fibrosis and hypertrophy and lowers BNP (brain natriuretic peptide). Beneficial effects persist for weeks after sFUS discontinuation and are more robust with early and longer treatment. Splenic denervation abolishes sFUS therapeutic benefits. sFUS partially normalizes CD68+ and CD8+ T-cell counts in the spleen and downregulates several inflammatory genes and pathways in nonclassical and classical monocytes and macrophages in the lung. Differentially expressed genes in those cell types are significantly enriched for human pulmonary arterial hypertension-associated genes. CONCLUSIONS: sFUS causes dose-dependent, sustained improvement of hemodynamic, autonomic, laboratory, and pathological manifestations in 2 models of experimental pulmonary hypertension. Mechanistically, sFUS normalizes immune cell populations in the spleen and downregulates inflammatory genes and pathways in the lung, many of which are relevant in human disease.
Asunto(s)
Hipertensión Pulmonar , Bazo , Animales , Bazo/metabolismo , Masculino , Ratas , Hipertensión Pulmonar/terapia , Hipertensión Pulmonar/metabolismo , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Ondas UltrasónicasRESUMEN
BACKGROUND: The treatment of pulmonary hypertension (PH) has improved rapidly in recent decades. There is increasing evidence to support the role of early intervention and treatment in affecting clinical outcomes in PH. OBJECTIVES: To assess treatment effects before and after the escalation of specific PH treatments using continuous heart monitoring with a Reveal LINQ loop recorder. METHODS: Patients were compared before and after treatment escalation. Treatment escalation was defined as an additional pulmonary arterial hypertension (PAH) drug, pulmonary endarterectomy, percutaneous balloon angioplasty or bilateral lung transplantation. Specifically, changes in heart rate variability (HRV), heart rate (HR) and physical activity were assessed. RESULTS: In this prospective study, 41 patients (27 with PAH and 14 with chronic thromboembolic pulmonary hypertension (CTEPH)) were enrolled. Among them, 15 (36.6%) patients underwent PH treatment escalation. Prior to escalation, patients were monitored for a median of 100 (range: 68-100) days and after therapy escalation for a median duration of 165 (range: 89-308) days. In the escalation group, there was a significant increase in HRV, physical activity indexed by daytime HR and a significant decrease in nighttime HR assessed at baseline and after treatment escalation in both the PAH and CTEPH groups. This was paralleled by significant improvements in WHO functional class, 6-min walking distance and N-terminal pro-b-type natriuretic peptide. CONCLUSIONS: This is the first study to demonstrate an association between specific PH therapies and changes in HRV, HR nighttime and physical activity. This indicates the potential of continuous monitoring in the evaluation of treatment effects in PH.
Asunto(s)
Frecuencia Cardíaca , Hipertensión Pulmonar , Humanos , Femenino , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Frecuencia Cardíaca/fisiología , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/terapia , Resultado del Tratamiento , Endarterectomía/métodos , Anciano , Antihipertensivos/uso terapéutico , Factores de Tiempo , Angioplastia de Balón/métodos , Adulto , Trasplante de Pulmón , Electrocardiografía Ambulatoria/métodos , Arteria Pulmonar/fisiopatologíaRESUMEN
BACKGROUND: Pregnancy in patients with pulmonary hypertension (PH) is associated with a heightened risk of medical complications including right heart failure, pulmonary edema, and arrhythmias. Our study investigated the association between PH and these complications during delivery. METHODS AND RESULTS: The National Inpatient Sample was used to identify delivery hospitalizations from 2011 to 2020. Multivariable logistic regression was performed to study the association of PH with the primary outcomes of in-hospital medical and obstetric complications. A total of 37 482 207 delivery hospitalizations in women ≥18 years of age were identified, of which 9593 patients had PH. Pregnant patients with PH had higher incidence of complications during delivery including preeclampsia/eclampsia, arrhythmias, and pulmonary edema among others, compared with those without PH. Pregnant patients with PH also had a higher incidence of in-hospital mortality compared with those without PH (0.51% versus 0.007%). In propensity-matched analyses, PH was still significantly associated with a higher risk of in-hospital mortality (odds ratio [OR], 5.02 [95% CI, 1.82-13.90]; P=0.001), pulmonary edema (OR, 9.11 [95% CI, 6.34-13.10]; P<0.001), peripartum cardiomyopathy (OR, 1.85 [95% CI, 1.37-2.50]; P<0.001), venous thromboembolism (OR, 12.60 [95% CI, 6.04-26.10]; P<0.001), cardiac arrhythmias (OR, 6.11 [95% CI, 4.97-7.53]; P<0.001), acute kidney injury (OR, 3.72 [95% CI, 2.86-4.84]; P<0.001), preeclampsia/eclampsia (OR, 2.24 [95% CI, 1.95-2.58]; P<0.001), and acute coronary syndrome (OR, 2.01 [95% CI, 1.06-3.80]; P=0.03), compared with pregnant patients without PH. CONCLUSIONS: Delivery hospitalizations in patients with PH are associated with a high risk of mortality, pulmonary edema, peripartum cardiomyopathy, venous thromboembolism, arrhythmias, acute kidney injury, preeclampsia/eclampsia, and acute coronary syndrome.
Asunto(s)
Mortalidad Hospitalaria , Hospitalización , Hipertensión Pulmonar , Complicaciones Cardiovasculares del Embarazo , Humanos , Femenino , Embarazo , Hipertensión Pulmonar/epidemiología , Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/terapia , Adulto , Estados Unidos/epidemiología , Hospitalización/estadística & datos numéricos , Hospitalización/tendencias , Complicaciones Cardiovasculares del Embarazo/epidemiología , Complicaciones Cardiovasculares del Embarazo/terapia , Mortalidad Hospitalaria/tendencias , Incidencia , Adulto Joven , Factores de Riesgo , Estudios Retrospectivos , Parto Obstétrico/estadística & datos numéricos , Parto Obstétrico/efectos adversos , Edema Pulmonar/epidemiología , Edema Pulmonar/etiología , Edema Pulmonar/mortalidad , Arritmias Cardíacas/epidemiología , Arritmias Cardíacas/terapia , Arritmias Cardíacas/mortalidad , Medición de RiesgoRESUMEN
PURPOSE: This study examines the hepatic extracellular volume fraction (ECV) disparity between the left and right lobes (ECV_left and ECV_right) in patients with chronic thromboembolic pulmonary hypertension (CTEPH), its association with right heart catheterization (RHC) metrics, and with intolerance to increased pulmonary hypertension (PH)-targeted medication dosages. METHODS: We retrospectively analyzed 72 CTEPH-diagnosed patients who underwent equilibrium-phase abdominal dual-energy CT (DECT) and RHC. Hepatic ECVs, derived from DECT's iodine maps using circular regions of interest in the liver and aorta, were correlated with RHC parameters via Spearman's rank correlation and lobe differences through the Wilcoxon signed-rank test. Logistic regression assessed cases with ECV_left exceeding ECV_right by > 0.05, while receiver operating characteristic curve analysis gauged ECVs' predictive power for medication intolerance. RESULTS: Of the 72 patients (57 females; median age 69), ECV_total (0.24, IQR 0.20-0.27) moderately correlated with RHC parameters (rs = 0.28, -0.24, 0.3 for mean pulmonary arterial pressure, cardiac index [CI], and pulmonary vascular resistance index, respectively). ECV_left significantly surpassed ECV_right (0.25 vs. 0.22, p < 0.001), with a greater ECV_left by > 0.05 indicating notably lower CI (p < 0.001). In 27 patients on PH medication, ECV_left effectively predicted medication intolerance (AUC = 0.84). CONCLUSION: In CTEPH patients, hepatic ECV correlated with RHC metrics, where elevated left lobe ECV suggested reduced CI and potential medication intolerance.
Asunto(s)
Cateterismo Cardíaco , Hipertensión Pulmonar , Hígado , Valor Predictivo de las Pruebas , Embolia Pulmonar , Humanos , Femenino , Masculino , Estudios Retrospectivos , Anciano , Persona de Mediana Edad , Embolia Pulmonar/diagnóstico por imagen , Embolia Pulmonar/fisiopatología , Embolia Pulmonar/complicaciones , Hipertensión Pulmonar/fisiopatología , Hipertensión Pulmonar/diagnóstico por imagen , Hipertensión Pulmonar/etiología , Enfermedad Crónica , Hígado/diagnóstico por imagen , Hígado/patología , Arteria Pulmonar/diagnóstico por imagen , Arteria Pulmonar/fisiopatología , Antihipertensivos/uso terapéutico , Presión Arterial , Angiografía por Tomografía ComputarizadaRESUMEN
BACKGROUND: Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling, which involves aberrant proliferation and apoptosis resistance of the pulmonary arterial smooth muscle cells (PASMCs), resembling the hallmark characteristics of cancer. In cancer, the HMGB2 (high-mobility group box 2) protein promotes the pro-proliferative/antiapoptotic phenotype. However, the function of HMGB2 in PH remains uninvestigated. METHODS: Smooth muscle cell (SMC)-specific HMGB2 knockout or HMGB2-OE (HMGB2 overexpression) mice and HMGB2 silenced rats were used to establish hypoxia+Su5416 (HySu)-induced PH mouse and monocrotaline-induced PH rat models, respectively. The effects of HMGB2 and its underlying mechanisms were subsequently elucidated using RNA-sequencing and cellular and molecular biology analyses. Serum HMGB2 levels were measured in the controls and patients with pulmonary arterial (PA) hypertension. RESULTS: HMGB2 expression was markedly increased in the PAs of patients with PA hypertension and PH rodent models and was predominantly localized in PASMCs. SMC-specific HMGB2 deficiency or silencing attenuated PH development and pulmonary vascular remodeling in hypoxia+Su5416-induced mice and monocrotaline-treated rats. SMC-specific HMGB2 overexpression aggravated hypoxia+Su5416-induced PH. HMGB2 knockdown inhibited PASMC proliferation in vitro in response to PDGF-BB (platelet-derived growth factor-BB). In contrast, HMGB2 protein stimulation caused the hyperproliferation of PASMCs. In addition, HMGB2 promoted PASMC proliferation and the development of PH by RAGE (receptor for advanced glycation end products)/FAK (focal adhesion kinase)-mediated Hippo/YAP (yes-associated protein) signaling suppression. Serum HMGB2 levels were significantly increased in patients with PA hypertension, and they correlated with disease severity, predicting worse survival. CONCLUSIONS: Our findings indicate that targeting HMGB2 might be a novel therapeutic strategy for treating PH. Serum HMGB2 levels could serve as a novel biomarker for diagnosing PA hypertension and determining its prognosis.
Asunto(s)
Modelos Animales de Enfermedad , Proteína HMGB2 , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular , Miocitos del Músculo Liso , Arteria Pulmonar , Remodelación Vascular , Animales , Proteína HMGB2/genética , Proteína HMGB2/metabolismo , Humanos , Masculino , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Arteria Pulmonar/patología , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Ratas , Ratones , Proliferación Celular , Índice de Severidad de la Enfermedad , Transducción de Señal , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/fisiopatología , Ratas Sprague-Dawley , Femenino , Células Cultivadas , Persona de Mediana Edad , Hipertensión Pulmonar/metabolismo , Hipertensión Pulmonar/fisiopatologíaRESUMEN
Tricuspid valve disease is an often underrecognized clinical problem that is associated with significant morbidity and mortality. Unfortunately, patients will often present late in their disease course with severe right-sided heart failure, pulmonary hypertension, and life-limiting symptoms that have few durable treatment options. Traditionally, the only treatment for tricuspid valve disease has been medical therapy or surgery; however, there have been increasing interest and success with the use of transcatheter tricuspid valve therapies over the past several years to treat patients with previously limited therapeutic options. The tricuspid valve is complex anatomically, lying adjacent to important anatomic structures such as the right coronary artery and the atrioventricular node, and is the passageway for permanent pacemaker leads into the right ventricle. In addition, the mechanism of tricuspid pathology varies widely between patients, which can be due to primary, secondary, or a combination of causes, meaning that it is not possible for 1 type of device to be suitable for treatment of all cases of tricuspid valve disease. To best visualize the pathology, several modalities of advanced cardiac imaging are often required, including transthoracic echocardiography, transesophageal echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging, to best visualize the pathology. This detailed imaging provides important information for choosing the ideal transcatheter treatment options for patients with tricuspid valve disease, taking into account the need for the lifetime management of the patient. This review highlights the important background, anatomic considerations, therapeutic options, and future directions with regard to treatment of tricuspid valve disease.
Asunto(s)
American Heart Association , Válvula Tricúspide , Humanos , Válvula Tricúspide/diagnóstico por imagen , Válvula Tricúspide/patología , Estados Unidos , Enfermedades de las Válvulas Cardíacas/terapia , Enfermedades de las Válvulas Cardíacas/diagnóstico por imagen , Insuficiencia de la Válvula Tricúspide/diagnóstico por imagen , Insuficiencia de la Válvula Tricúspide/terapia , Implantación de Prótesis de Válvulas CardíacasRESUMEN
BACKGROUND: The precise origin of newly formed ACTA2+ (alpha smooth muscle actin-positive) cells appearing in nonmuscularized vessels in the context of pulmonary hypertension is still debatable although it is believed that they predominantly derive from preexisting vascular smooth muscle cells (VSMCs). METHODS: Gli1Cre-ERT2; tdTomatoflox mice were used to lineage trace GLI1+ (glioma-associated oncogene homolog 1-positive) cells in the context of pulmonary hypertension using 2 independent models of vascular remodeling and reverse remodeling: hypoxia and cigarette smoke exposure. Hemodynamic measurements, right ventricular hypertrophy assessment, flow cytometry, and histological analysis of thick lung sections followed by state-of-the-art 3-dimensional reconstruction and quantification using Imaris software were used to investigate the contribution of GLI1+ cells to neomuscularization of the pulmonary vasculature. RESULTS: The data show that GLI1+ cells are abundant around distal, nonmuscularized vessels during steady state, and this lineage contributes to around 50% of newly formed ACTA2+ cells around these normally nonmuscularized vessels. During reverse remodeling, cells derived from the GLI1+ lineage are largely cleared in parallel to the reversal of muscularization. Partial ablation of GLI1+ cells greatly prevented vascular remodeling in response to hypoxia and attenuated the increase in right ventricular systolic pressure and right heart hypertrophy. Single-cell RNA sequencing on sorted lineage-labeled GLI1+ cells revealed an Acta2high fraction of cells with pathways in cancer and MAPK (mitogen-activated protein kinase) signaling as potential players in reprogramming these cells during vascular remodeling. Analysis of human lung-derived material suggests that GLI1 signaling is overactivated in both group 1 and group 3 pulmonary hypertension and can promote proliferation and myogenic differentiation. CONCLUSIONS: Our data highlight GLI1+ cells as an alternative cellular source of VSMCs in pulmonary hypertension and suggest that these cells and the associated signaling pathways represent an important therapeutic target for further studies.