Right Ventricular Failure Houston, Brian A.; Brittain, Evan L.; Tedford, Ryan J.
The New England journal of medicine,
03/2023, Letnik:
388, Številka:
12
Journal Article
Recenzirano
The authors discuss the mechanisms, clinical presentation, and evaluation of right ventricular failure, as well as its management.
Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor β (TGF-β) family of ligands. Although required for normal heart valve ...development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2E-KO) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2E-KO mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.
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•Induction of EndoMT triggers a reduction in FAO•FAO is required to maintain endothelial acetyl-CoA levels•FAO modulates in vitro and in vivo EndoMT
Xiong et al. demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of endothelial-to-mesenchymal transition (EndoMT) and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.
Mobile health (mHealth) technologies are modernizing medicine by affording greater patient engagement, monitoring, outreach, and health-care delivery. The cardiopulmonary fields have led the ...integration of mHealth into clinical practice and research. mHealth technologies in these areas include smartphone applications, wearable devices, and handheld devices, among others, and provide real-time monitoring of numerous important physiological measurements and other key parameters. Use of mHealth-compatible devices has increased in recent years, and age and socioeconomic gaps of ownership are narrowing. These tools provide physicians and researchers with a better understanding of an individual’s health and well-being. mHealth interventions have shown utility in the prevention, monitoring, and management of atrial fibrillation, heart failure, and myocardial infarction. With the growing prevalence of cardiopulmonary disease, mHealth technologies may become a more essential element of care within and outside of traditional health-care settings. mHealth is continuously developing as a result of technologic advancements and better understandings of mHealth utility. However, there is little regulation on the mHealth platforms available for commercial use and even fewer guidelines on implementing evidence-based practices into mHealth technologies. Online security is another challenge and necessitates development in data collection infrastructure to manage the extraordinary volume of patient data. Continued research on long-term implications of mHealth technology and the integration of effective interventions into clinical practice is required.
Pulmonary arterial hypertension (PAH) is a deadly disease with no cure. Alternate conversion of angiotensin II (AngII) to angiotensin-(1-7) (Ang-(1-7)) by angiotensin-converting enzyme 2 (ACE2) ...resulting in Mas receptor (Mas1) activation improves rodent models of PAH. Effects of recombinant human (rh) ACE2 in human PAH are unknown. Our objective was to determine the effects of rhACE2 in PAH.We defined the molecular effects of Mas1 activation using porcine pulmonary arteries, measured AngII/Ang-(1-7) levels in human PAH and conducted a phase IIa, open-label pilot study of a single infusion of rhACE2 (GSK2586881, 0.2 or 0.4 mg·kg
intravenously).Superoxide dismutase 2 (SOD2) and inflammatory gene expression were identified as markers of Mas1 activation. After confirming reduced plasma ACE2 activity in human PAH, five patients were enrolled in the trial. GSK2586881 was well tolerated with significant improvement in cardiac output and pulmonary vascular resistance. GSK2586881 infusion was associated with reduced plasma markers of inflammation within 2-4 h and increased SOD2 plasma protein at 2 weeks.PAH is characterised by reduced ACE2 activity. Augmentation of ACE2 in a pilot study was well tolerated, associated with improved pulmonary haemodynamics and reduced markers of oxidant and inflammatory mediators. Targeting this pathway may be beneficial in human PAH.
Background Recent studies have demonstrated a continuum in clinical risk related to mean pulmonary artery pressure that begins at >19 mm Hg, which is below the traditional threshold used to define ...pulmonary hypertension ( PH ) of 25 mm Hg. Because of the implications on patient diagnosis and prognosis, the generalizability and validity of these data need further confirmation. Methods and Results Databases were searched from inception through January 31, 2018, to identify studies comparing all-cause mortality between patients with mildly elevated mean pulmonary artery pressure near but <25 mm Hg versus the referent group. The meta-analysis included 15 nonrandomized studies and 16 482 patients (7451 45.2% with measured or calculated mean pulmonary artery pressure of 19-24 mm Hg by right heart catheterization n=6037 and echocardiography n=1414 mild PH ). The mean duration of follow-up was 5.2 years. Compared with the referent group, mild PH was associated with an increased risk of mortality (risk ratio, 1.52; 95% confidence interval, 1.32-1.74; P<0.001; I
=47%). Secondary analysis using risk-adjusted time-to-event estimates showed a similar result (hazard ratio, 1.19; 95% confidence interval, 1.09-1.31; P<0.001; I
=42%). The findings were consistent between subgroups of right heart catheterization and echocardiography studies ( P
>0.05). There was evidence of publication bias; however, this did not influence the risk estimate (Duval and Tweedie's trim and fill adjusted risk ratio, 1.34; 95% confidence interval, 1.15-1.56). Conclusions The risk of mortality is increased in patients with mild PH , defined as measured or calculated mean pulmonary artery pressure >19 mm Hg. These data emphasize a need for diagnosing patients with mild PH with consideration to enrollment in PH clinical studies investigating pharmacological and nonpharmacological interventions to attenuate clinical risk and improve outcomes.
Abstract Background Pulmonary hypertension (PH) is a common and morbid complication of left heart disease with 2 subtypes: isolated post-capillary pulmonary hypertension (Ipc-PH) and combined ...post-capillary and pre-capillary pulmonary hypertension (Cpc-PH). Little is known about the clinical or physiological characteristics that distinguish these 2 subphenotypes or if Cpc-PH shares molecular similarities to pulmonary arterial hypertension (PAH). Objectives The goal of this study was to test the hypothesis that the hemodynamic and genetic profile of Cpc-PH would more closely resemble PAH than Ipc-PH. Methods Vanderbilt University’s electronic medical record linked to a DNA biorepository was used to extract demographic characteristics, clinical data, invasive hemodynamic data, echocardiography, and vital status for all patients referred for right heart catheterization between 1998 and 2014. Shared genetic variants between PAH and Cpc-PH compared with Ipc-PH were identified by using pre-existing single-nucleotide polymorphism data. Results A total of 2,817 patients with PH (13% Cpc-PH, 52% Ipc-PH, and 20% PAH) were identified. Patients with Cpc-PH were on average 6 years younger, with more severe pulmonary vascular disease than patients with Ipc-PH, despite similar comorbidities and prevalence, severity, and chronicity of left heart disease. After adjusting for relevant covariates, the risk of death was similar between the Cpc-PH and Ipc-PH groups (hazard ratio: 1.14; 95% confidence interval: 0.96 to 1.35; p = 0.15) when defined according to diastolic pressure gradient. We identified 75 shared exonic single-nucleotide polymorphisms between Cpc-PH and PAH enriched in pathways involving cell structure, extracellular matrix, and immune function. These genes are expressed, on average, 32% higher in lungs relative to other tissues. Conclusions Patients with Cpc-PH develop pulmonary vascular disease similar to patients with PAH, despite younger age and similar prevalence of obesity, diabetes mellitus, and left heart disease compared with patients with Ipc-PH. An exploratory genetic analysis in Cpc-PH identified genes and biological pathways in the lung known to contribute to PAH pathophysiology, suggesting that Cpc-PH may be a distinct and highly morbid PH subphenotype.
Determining the cause for pulmonary hypertension is difficult in many patients. Pulmonary arterial hypertension (PAH) is differentiated from pulmonary venous hypertension (PVH) by a wedge pressure ...(PWP)>15 mm Hg in PVH. Patients undergoing right heart catheterization for evaluation of pulmonary hypertension may be dehydrated and have reduced intravascular volume, potentially leading to a falsely low measurement of PWP and an erroneous diagnosis of PAH. We hypothesized that a fluid challenge during right heart catheterization would identify occult pulmonary venous hypertension (OPVH).
We reviewed the results of patients undergoing fluid challenge in our pulmonary hypertension database from 2004 to 2011. Baseline hemodynamics were obtained and repeated after infusion of 0.5 L of normal saline for 5 to 10 minutes. Patients were categorized as OPVH if PWP increased to >15 mm Hg after fluid challenge. Baseline hemodynamics in 207 patients met criteria for PAH. After fluid challenge, 46 patients (22.2%) developed a PWP>15 mm Hg and were reclassified as OPVH. Patients with OPVH had a greater increase in PWP compared with patients with PAH, P<0.001, and their demographics and comorbid illnesses were similar to patients with PVH. There were no adverse events related to fluid challenge.
Fluid challenge at the time of right heart catheterization is easily performed, safe, and identifies a large group of patients diagnosed initially with PAH, but for whom OPVH contributes to pulmonary hypertension. These results have implications for therapeutic trials in PAH and support the routine use of fluid challenge during right heart catheterization in patients with risk factors for PVH.
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