ABSTRACT
BACKGROUND: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. METHODS: We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro-B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. RESULTS: A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, -0.3 to 3.5) in the placebo group. The Hodges-Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. CONCLUSIONS: In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.).
Subject(s)
Pulmonary Arterial Hypertension , Recombinant Fusion Proteins , Adult , Humans , Double-Blind Method , Hypertension, Pulmonary/drug therapy , Pulmonary Arterial Hypertension/diagnosis , Pulmonary Arterial Hypertension/drug therapy , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/pharmacology , Recombinant Fusion Proteins/therapeutic use , Treatment Outcome , Vascular Resistance/drug effects , Injections, Subcutaneous , Walk Test , Exercise Tolerance/drug effects , Cardiovascular Agents/administration & dosage , Cardiovascular Agents/adverse effects , Cardiovascular Agents/pharmacology , Cardiovascular Agents/therapeutic use , Respiratory System Agents/administration & dosage , Respiratory System Agents/adverse effects , Respiratory System Agents/pharmacology , Respiratory System Agents/therapeutic useABSTRACT
BACKGROUND: Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, cellular proliferation, and poor long-term outcomes. Dysfunctional bone morphogenetic protein pathway signaling is associated with both hereditary and idiopathic subtypes. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors in the attempt to restore balance between growth-promoting and growth-inhibiting signaling pathways. METHODS: In this 24-week multicenter trial, we randomly assigned 106 adults who were receiving background therapy for pulmonary arterial hypertension to receive subcutaneous sotatercept at a dose of 0.3 mg per kilogram of body weight every 3 weeks or 0.7 mg per kilogram every 3 weeks or placebo. The primary end point was the change from baseline to week 24 in pulmonary vascular resistance. RESULTS: Baseline characteristics were similar among the three groups. The least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline to week 24 in pulmonary vascular resistance was -145.8 dyn · sec · cm-5 (95% confidence interval [CI], -241.0 to -50.6; P = 0.003). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was -239.5 dyn · sec · cm-5 (95% CI, -329.3 to -149.7; P<0.001). At 24 weeks, the least-squares mean difference between the sotatercept 0.3-mg group and the placebo group in the change from baseline in 6-minute walk distance was 29.4 m (95% CI, 3.8 to 55.0). The least-squares mean difference between the sotatercept 0.7-mg group and the placebo group was 21.4 m (95% CI, -2.8 to 45.7). Sotatercept was also associated with a decrease in N-terminal pro-B-type natriuretic peptide levels. Thrombocytopenia and an increased hemoglobin level were the most common hematologic adverse events. One patient in the sotatercept 0.7-mg group died from cardiac arrest. CONCLUSIONS: Treatment with sotatercept resulted in a reduction in pulmonary vascular resistance in patients receiving background therapy for pulmonary arterial hypertension. (Funded by Acceleron Pharma; PULSAR ClinicalTrials.gov number, NCT03496207.).
Subject(s)
Pulmonary Arterial Hypertension/drug therapy , Recombinant Fusion Proteins/therapeutic use , Transforming Growth Factor beta/antagonists & inhibitors , Vascular Resistance/drug effects , Adult , Dose-Response Relationship, Drug , Double-Blind Method , Exercise Tolerance/drug effects , Female , Humans , Injections, Subcutaneous , Least-Squares Analysis , Male , Middle Aged , Natriuretic Peptide, Brain/blood , Peptide Fragments/blood , Pulmonary Arterial Hypertension/blood , Pulmonary Arterial Hypertension/physiopathology , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/pharmacology , Thrombocytopenia/chemically induced , Walk TestABSTRACT
Nitric oxide (NO) inhalation improves pulmonary hemodynamics in participants with pulmonary arterial hypertension (PAH). Although it can reduce pulmonary vascular resistance (PVR) in PAH, its impact on the dynamic mechanics of pulmonary arteries and its potential difference between control and participants with PAH remain unclear. PA impedance provides a comprehensive description of PA mechanics. With an arterial model, PA impedance can be parameterized into peripheral pulmonary resistance (Rp), arterial compliance (Cp), characteristic impedance of the proximal arteries (Zc), and transmission time from the main PA to the reflection site. This study investigated the effects of inhaled NO on PA impedance and its associated parameters in control and monocrotaline-induced pulmonary arterial hypertension (MCT-PAH) male rats (6/group). Measurements were obtained at baseline and during NO inhalation at 40 and 80 ppm. In both groups, NO inhalation decreased PVR and increased the left atrial pressure. Notably, its impact on PA impedance was frequency dependent, as revealed by reduced PA impedance modulus in the low-frequency range below 10 Hz, with little effect on the high-frequency range. Furthermore, NO inhalation attenuated Rp, increased Cp, and prolonged transmission time without affecting Zc. It reduced Rp more pronouncedly in MCT-PAH rats, whereas it increased Cp and delayed transmission time more effectively in control rats. In conclusion, the therapeutic effects of inhaled NO on PA impedance were frequency dependent and may differ between the control and MCT-PAH groups, suggesting that the effect on the mechanics differs depending on the pathological state.NEW & NOTEWORTHY Nitric oxide inhalation decreased pulmonary arterial impedance in the low-frequency range (<10 Hz) with little impact on the high-frequency range. It reduced peripheral pulmonary resistance more pronouncedly in pulmonary hypertension rats, whereas it increased arterial compliance and transmission time in control rats. Its effect on the mechanics of the pulmonary arteries may differ depending on the pathological status.
Subject(s)
Nitric Oxide , Pulmonary Artery , Vascular Resistance , Animals , Male , Nitric Oxide/metabolism , Pulmonary Artery/physiopathology , Pulmonary Artery/drug effects , Administration, Inhalation , Vascular Resistance/drug effects , Monocrotaline , Rats , Rats, Sprague-Dawley , Disease Models, Animal , Hypertension, Pulmonary/physiopathology , Hypertension, Pulmonary/chemically induced , Hypertension, Pulmonary/drug therapy , Pulmonary Arterial Hypertension/physiopathology , Pulmonary Arterial Hypertension/drug therapy , Pulmonary Arterial Hypertension/chemically induced , Arterial Pressure/drug effectsABSTRACT
Background: Living donor kidney transplantation (LDKT) is a crucial treatment for end-stage renal disease, with pre-emptive LDKT (transplantation before dialysis initiation) offering significant benefits in graft function and patient survival. The selection of a vasopressor during LDKT, particularly between norepinephrine and dopamine, and its impact on renal arterial hemodynamics measured using the renal arterial resistive index (RARI) is poorly understood. Methods: This retrospective observational cohort study enrolled 347 eligible pre-emptive LDKT recipients from the Seoul St. Mary's Hospital between January 2019 and June 2023. Utilizing propensity score matching (PSM), the patients were categorized into dopamine and norepinephrine groups to compare the effects of these vasopressors on the intraoperative RARI, postoperative estimated glomerular filtration rate (eGFR), and hourly urine output. The RARI was measured via the Doppler ultrasonography of the renal hilum and parenchyma post-graft vascular and ureteral anastomoses. Results: The preoperative differences in the recipients' and donors' characteristics were mitigated following PSM. The dopamine group exhibited higher intraoperative RARI values at the renal hilum (0.77 ± 0.11 vs. 0.66 ± 0.13, p < 0.001) and parenchyma (0.71 ± 0.1 vs. 0.6 ± 0.1, p < 0.001) compared to those of the norepinephrine group. However, these differences were not statistically significant on postoperative day 7. The norepinephrine infusion adjusted for the propensity scores was associated with significantly lower odds of an RARI > 0.8 (hilum: OR = 0.214, 95% CI = 0.12-0.382, p < 0.001; parenchyma: OR = 0.1, 95% CI = 0.029-0.348, p < 0.001). The early postoperative outcomes showed a higher eGFR (day 1: 30.0 ± 13.3 vs. 25.1 ± 17.4 mL/min/1.73 m2, p = 0.004) and hourly urine output (day 1: 41.8 ± 16.9 vs. 36.5 ± 14.4 mL/kg/h, p = 0.002) in the norepinephrine group. Furthermore, the long-term outcomes were comparable between the groups. Conclusions: Norepinephrine infusion during pre-emptive LDKT is associated with more favorable intraoperative renal arterial hemodynamics, as evidenced by a lower RARI and improved early postoperative renal function compared to those of dopamine. These findings suggest a potential preferential role for norepinephrine in optimizing perioperative management and early graft functions in LDKT recipients. Given the retrospective nature of this study, further prospective studies are needed to confirm these observations. Additionally, the study limitations include the potential for unmeasured confounding factors and the inability to determine causality due to its observational design.
Subject(s)
Dopamine , Kidney Transplantation , Living Donors , Norepinephrine , Propensity Score , Renal Artery , Humans , Kidney Transplantation/methods , Male , Female , Dopamine/therapeutic use , Dopamine/administration & dosage , Retrospective Studies , Middle Aged , Norepinephrine/therapeutic use , Norepinephrine/administration & dosage , Adult , Renal Artery/drug effects , Vasoconstrictor Agents/therapeutic use , Vasoconstrictor Agents/administration & dosage , Cohort Studies , Vascular Resistance/drug effects , Hemodynamics/drug effects , Hemodynamics/physiologyABSTRACT
We studied changes of pulmonary microhemodynamics when modeling pulmonary artery thromboembolism on perfused isolated rabbit lungs after pretreatment with ranolazine and ivabradine. The increase in pulmonary artery pressure, pulmonary vascular resistance, and pre- and postcapillary resistance was less pronounced than in control animals, but was close to that in case of pulmonary thromboembolism after pretreatment with voltage-gated Na+ channel blockers lidocaine and ropivacaine. The increase of capillary filtration coefficient inversely correlated with values of capillary hydrostatic pressure. Thus, ranolazine and ivabradine exhibit the properties of voltage-gated Na+ channel blockers mainly in smooth muscles of pulmonary arterial vessels and promote the decrease in endothelial permeability.
Subject(s)
Ivabradine , Pulmonary Artery , Pulmonary Embolism , Ranolazine , Vascular Resistance , Animals , Rabbits , Ivabradine/pharmacology , Ivabradine/therapeutic use , Pulmonary Embolism/drug therapy , Pulmonary Embolism/physiopathology , Ranolazine/pharmacology , Vascular Resistance/drug effects , Pulmonary Artery/drug effects , Pulmonary Artery/physiopathology , Lung/drug effects , Lung/blood supply , Disease Models, Animal , Male , Lidocaine/pharmacology , Voltage-Gated Sodium Channel Blockers/pharmacologyABSTRACT
[Figure: see text].
Subject(s)
Kynurenine/pharmacology , Pre-Eclampsia/drug therapy , Vascular Resistance/drug effects , Vasodilation , Vasodilator Agents/pharmacology , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/antagonists & inhibitors , Adenylyl Cyclase Inhibitors/pharmacology , Adult , Calcium Channel Blockers/pharmacology , Endothelium, Vascular/drug effects , Female , Humans , Indoles/pharmacology , Muscle, Smooth, Vascular/cytology , Myometrium/blood supply , Omentum/blood supply , Peptides/pharmacology , Pre-Eclampsia/physiopathology , Pregnancy , Ryanodine Receptor Calcium Release Channel/drug effects , Vascular Resistance/physiology , Vasoconstrictor Agents/antagonists & inhibitors , Vasodilation/drug effects , Vasodilation/physiologyABSTRACT
Rationale: An initial oral combination of drugs is being recommended in pulmonary arterial hypertension (PAH), but the effects of this approach on risk reduction and pulmonary vascular resistance (PVR) are not known.Objectives: To test the hypothesis that a low-risk status would be determined by the reduction of PVR in patients with PAH treated upfront with a combination of oral drugs.Methods: The study enrolled 181 treatment-naive patients with PAH (81% idiopathic) with a follow-up right heart catheterization at 6 months (interquartile range, 144-363 d) after the initial combination of endothelin receptor antagonist + phosphodiesterase-5 inhibitor drugs and clinical evaluation and risk assessments by European guidelines and Registry to Evaluate Early and Long-Term PAH Disease Management scores.Measurements and Main Results: Initial combination therapy improved functional class and 6-minute-walk distance and decreased PVR by an average of 35% (median, 40%). One-third of the patients had a decrease in PVR <25%. This poor hemodynamic response was independently predicted by age, male sex, pulmonary artery pressure and cardiac index, and at echocardiography, a right/left ventricular surface area ratio of greater than 1 associated with low tricuspid annular plane systolic excursion of less than 18 mm. A low-risk status at 6 months was achieved or maintained in only 34.8% (Registry to Evaluate Early and Long-Term PAH Disease Management score) to 43.1% (European score) of the patients. Adding criteria of poor hemodynamic response improved prediction of a low-risk status.Conclusions: A majority of patients with PAH still insufficiently improved after 6 months of initial combinations of oral drugs is identifiable at initial evaluation by hemodynamic response criteria added to risk scores.
Subject(s)
Antihypertensive Agents/therapeutic use , Endothelin Receptor Antagonists/therapeutic use , Hemodynamics/drug effects , Phosphodiesterase 5 Inhibitors/therapeutic use , Pulmonary Arterial Hypertension/diagnosis , Pulmonary Arterial Hypertension/drug therapy , Vascular Resistance/drug effects , Administration, Oral , Aged , Aged, 80 and over , Drug Combinations , Endothelin Receptor Antagonists/administration & dosage , Female , Humans , Male , Middle Aged , Phosphodiesterase 5 Inhibitors/administration & dosage , Risk Reduction Behavior , Treatment OutcomeABSTRACT
PURPOSE: Previous work suggests that endurance-trained athletes have superior pulmonary vasculature function as compared to untrained individuals, which may contribute to their greater maximal oxygen uptake ([Formula: see text]O2max). Inhaled nitric oxide (iNO) reduces pulmonary vascular resistance in healthy individuals, which could translate into greater cardiac output and improved [Formula: see text]O2max, particularly in untrained individuals. The purpose of the study was to examine whether iNO improved [Formula: see text]O2max in endurance trained and untrained individuals. METHODS: Sixteen endurance-trained and sixteen untrained individuals with normal lung function completed this randomized double-blind cross-over study over four sessions. Experimental cardiopulmonary exercise tests were completed while breathing either normoxia (placebo) or 40 ppm of iNO, on separate days (order randomized). On an additional day, echocardiography was used to determine pulmonary artery systolic pressure at rest and during sub-maximal exercise (60 Watts) while participants breathed normoxia or iNO. RESULTS: Right ventricular systolic pressure was significantly reduced by iNO during exercise (Placebo: 34 ± 7 vs. iNO: 32 ± 7; p = 0.04). [Formula: see text]O2max was greater in the endurance trained group (Untrained: 3.1 ± 0.7 vs. Endurance: 4.3 ± 0.9 L min-1; p < 0.01), however, there was no effect of condition (p = 0.79) and no group by condition interaction (p = 0.68). Peak cardiac output was also unchanged by iNO in either group. CONCLUSION: Despite a reduction in right ventricular systolic pressure, the lack of change in [Formula: see text]O2max with iNO suggests that the pulmonary vasculature does not limit [Formula: see text]O2max in young healthy individuals, regardless of fitness level.
Subject(s)
Endurance Training , Nitric Oxide/administration & dosage , Nitric Oxide/pharmacology , Oxygen Consumption/physiology , Vascular Resistance/drug effects , Administration, Inhalation , Adult , Echocardiography , Exercise Test , Female , Healthy Volunteers , Humans , Male , Respiratory Function TestsABSTRACT
In pulmonary arterial hypertension (PAH), progressive structural remodeling accounts for the pulmonary vasculopathy including the obliteration of the lung vasculature that causes an increase in vascular resistance and mean blood pressure in the pulmonary arteries ultimately leading to right heart failure-mediated death. Deciphering the molecular details of aberrant signaling of pulmonary vascular cells in PAH is fundamental for the development of new therapeutic strategies. We aimed to identify kinases as new potential drug targets that are dysregulated in PAH by means of a peptide-based kinase activity assay. We performed a tyrosine kinase-dependent phosphorylation assay using 144 selected microarrayed substrate peptides. The differential signature of phosphopeptides was used to predict alterations in tyrosine kinase activities in human pulmonary arterial smooth muscle cells (HPASMCs) from patients with idiopathic PAH (IPAH) compared with healthy control cells. Thereby, we observed an overactivation and an increased expression of Jak2 (Janus kinase 2) in HPASMCs from patients with IPAH as compared with controls. In vitro, IL-6-induced proliferation and migration of HPASMCs from healthy individuals as well as from patients with IPAH were reduced in a dose-dependent manner by the U.S. Food and Drug Administration-approved Jak1 and Jak2 inhibitor ruxolitinib. In vivo, ruxolitinib therapy in two experimental models of pulmonary arterial hypertension dose-dependently attenuated the elevation in pulmonary arterial pressure, partially reduced right ventricular hypertrophy, and almost completely restored cardiac index without signs of adverse events on cardiac function. Therefore, we propose that ruxolitinib may present a novel therapeutic option for patients with PAH by reducing pulmonary vascular remodeling through effectively blocking Jak2-Stat3 (signal transducer of activators of transcription)-mediated signaling pathways.
Subject(s)
Hypertension, Pulmonary/metabolism , Janus Kinases/metabolism , STAT Transcription Factors/metabolism , Signal Transduction/physiology , Animals , Cells, Cultured , Humans , Hypertension, Pulmonary/drug therapy , Hypertrophy, Right Ventricular/metabolism , Male , Mice , Mice, Inbred C57BL , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , Nitriles , Pulmonary Artery/drug effects , Pulmonary Artery/metabolism , Pyrazoles/pharmacology , Pyrimidines , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effects , Vascular Remodeling/drug effects , Vascular Remodeling/physiology , Vascular Resistance/drug effects , Vascular Resistance/physiologyABSTRACT
The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase-2 (COX-2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX-2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX-2 overexpression by COX-2-dependent PGE2-EP2-ERK1/2-NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX-2-independent LKB1-AMPK-NRF2-HO-1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX-2-dependent and COX-2-independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.
Subject(s)
Celecoxib/therapeutic use , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Hypertension, Portal/drug therapy , Hypertension, Portal/metabolism , Oxidative Stress/drug effects , Vascular Resistance/drug effects , Animals , Antioxidants/pharmacology , Antioxidants/therapeutic use , Celecoxib/pharmacology , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2 Inhibitors/therapeutic use , Disease Management , Disease Models, Animal , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Gene Expression Regulation/drug effects , Heme Oxygenase (Decyclizing)/metabolism , Hemodynamics/drug effects , Hepatic Stellate Cells/drug effects , Hepatic Stellate Cells/metabolism , Humans , Hypertension, Portal/diagnosis , Hypertension, Portal/etiology , Male , Models, Biological , Nitric Oxide/metabolism , Rats , Reactive Oxygen Species/metabolism , Signal Transduction/drug effectsABSTRACT
BACKGROUND & AIMS: In advanced chronic liver disease (ACLD), deregulated hepatic necroinflammatory processes play a key role in the development of liver microvascular dysfunction, fibrogenesis, and increased hepatic vascular tone, resulting in progression of ACLD and portal hypertension. Given the current lack of an effective treatment, we aimed to characterise the effects of the pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist lanifibranor in 2 preclinical models of ACLD, as well as in liver cells from patients with ACLD. METHODS: Cirrhotic rats (thioacetamide or common bile duct ligation; TAA or cBDL) randomly received lanifibranor (100 mg/kg/day, po) or vehicle for 14 days (n = 12/group). PPAR expression, systemic and hepatic haemodynamics, presence of ascites, liver sinusoidal endothelial cell (LSEC) phenotype, hepatic stellate cell (HSC) activation, serum transaminases and albumin, hepatic macrophage infiltration, cytokine expression, and liver fibrosis were determined. Hepatic cells were isolated from the livers of patients with cirrhosis and their phenotype was evaluated after treatment with either lanifibranor or vehicle. RESULTS: TAA-cirrhotic rats receiving lanifibranor showed significantly lower portal pressure compared with vehicle-treated animals (-15%; p = 0.003) without decreasing portal blood flow, indicating improved hepatic vascular resistance. Moreover, lanifibranor-treated TAA-rats showed decreased ascites, improved LSEC and HSC phenotypes, ameliorated hepatic microvascular function, reduced hepatic inflammation, and significant fibrosis regression (-32%; p = 0.020). These findings were confirmed in the cBDL rat model as well as in human liver cells from patients with cirrhosis, which exhibited phenotypic improvement upon treatment with lanifibranor. CONCLUSIONS: Lanifibranor ameliorates fibrosis and portal hypertension in preclinical models of decompensated cirrhosis. Promising results in human hepatic cells further support its clinical evaluation for the treatment of ACLD. LAY SUMMARY: Advanced chronic liver disease (ACLD) constitutes a serious public health issue for which safe and effective treatments are lacking. This study shows that lanifibranor improves portal hypertension and liver fibrosis, 2 key elements of the pathophysiology of ACLD, in preclinical models of the disease. Evaluation of lanifibranor in liver cells from patients with ACLD further supports its beneficial effects.
Subject(s)
Benzothiazoles/pharmacology , Hypertension, Portal , Liver Cirrhosis , Peroxisome Proliferator-Activated Receptors/agonists , Sulfonamides/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Antifibrotic Agents/pharmacology , Antihypertensive Agents/pharmacology , Cells, Cultured , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Hypertension, Portal/drug therapy , Hypertension, Portal/etiology , Hypertension, Portal/metabolism , Liver/drug effects , Liver/pathology , Liver Cirrhosis/complications , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Portal Pressure/drug effects , Rats , Vascular Resistance/drug effectsABSTRACT
BACKGROUND/AIMS: Sex dependent differences in coronary artery vasoregulation may be due to variations in responses to endogenous vasoactive compounds including endothelin (ET-1) and nitric oxide (NO). METHODS: Septal coronary arteries (<200 µm) from healthy, sexually mature male, female and ovariectomized (i.e. surgical menopause) Sprague-Dawley rats were used. Myogenic tone, measured by pressure myography, was initially determined for all vessel segments studied before and after exposure to the nonselective ETA/ETB receptor blocker, bosentan (1 µM). Vasoconstrictor responses (vascular endothelium intact) to cumulative ET-1 (10-12 - 10-9 M) were assessed in a separate set of septal coronary vessels. Additional studies, examined the vasoconstrictor effects of ET-1 after NO blockade with L-NAME (200 µM). RESULTS: Myogenic tone was 26 ± 7% in male, 20 ± 7% in female (p = 0.04 versus male) and 24 ± 3% in ovariectomized (p = NS versus male/female) vessels. Antagonism of ET-1 receptors produced a greater reduction in myogenic tone in male, compared to female rats over a similar range of intraluminal pressure (20-80 mmHg). Robust constrictor responses to cumulative concentrations of ET-1 were observed in all vessels; however, male rats exhibited greater sensitivity to vasoconstrictor effects of ET-1. After exposure to L-NAME vessel responses to ET-1 were normalized in male and female (not studied in ovariectomized) groups. CONCLUSIONS: These findings confirm marked sex differences for myogenic tone and vessel constrictor responses to ET-1 in coronary resistance vessels. Results also suggest greater sensitivity to vasoconstrictor effects of ET-1 in male coronary resistance vessels.
Subject(s)
Coronary Vessels/drug effects , Endothelin-1/pharmacology , Sex Characteristics , Vascular Resistance , Vasoconstriction/drug effects , Animals , Bosentan/pharmacology , Endothelin A Receptor Antagonists/pharmacology , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiology , Female , Male , Myography , Nitric Oxide/metabolism , Ovariectomy , Rats , Rats, Sprague-Dawley , Receptor, Endothelin A/metabolism , Vascular Resistance/drug effectsABSTRACT
Impaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity, yet underlying mechanisms and potential therapeutic strategies remain poorly understood. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Whether MR blockade improves in vivo regulation of coronary flow, a process involving voltage-dependent K+ (Kv) channel activation, or reduces coronary structural remodeling in obesity is unclear. Thus, the goals of this investigation were to determine the effects of obesity on coronary responsiveness to reductions in arterial PO2 and potential involvement of Kv channels and whether the benefit of MR blockade involves improved coronary Kv function or altered passive structural properties of the coronary microcirculation. Hypoxemia increased coronary blood flow similarly in lean and obese swine; however, baseline coronary vascular resistance was significantly higher in obese swine. Inhibition of Kv channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. Chronic MR inhibition in obese swine normalized baseline coronary resistance, did not influence hypoxemic coronary vasodilation, and did not restore coronary Kv function (assessed in vivo, ex vivo, and via patch clamping). Lastly, MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density and changes in cardiac function. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of Kv channel function and is associated with mitigation of obesity-mediated coronary arteriolar stiffening.
Subject(s)
Aldosterone/pharmacology , Coronary Artery Disease/prevention & control , Coronary Circulation/drug effects , Coronary Vessels/drug effects , Mineralocorticoid Receptor Antagonists/pharmacology , Obesity/drug therapy , Potassium Channels, Voltage-Gated/metabolism , Vascular Resistance/drug effects , Animals , Arterioles/drug effects , Arterioles/metabolism , Arterioles/physiopathology , Coronary Artery Disease/etiology , Coronary Artery Disease/metabolism , Coronary Artery Disease/physiopathology , Coronary Vessels/metabolism , Coronary Vessels/physiopathology , Disease Models, Animal , Female , Male , Microcirculation/drug effects , Obesity/complications , Obesity/metabolism , Obesity/physiopathology , Sus scrofa , Vascular Stiffness/drug effectsABSTRACT
Herein we report in a sample of healthy young men (n = 14) and women (n = 12) that hyperinsulinemia induces time-dependent decreases in total peripheral resistance and its contribution to the maintenance of blood pressure. In the same participants, we observe profound vasodilatory effects of insulin in the lower limb despite concomitant activation of the sympathetic nervous system. We hypothesized that this prominent peripheral vasodilation is possibly due to the ability of the leg vasculature to escape sympathetic vasoconstriction during systemic insulin stimulation. Consistent with this notion, we demonstrate in a subset of healthy men (n = 9) and women (n = 7) that systemic infusion of insulin blunts sympathetically mediated leg vasoconstriction evoked by a cold pressor test, a well-established sympathoexcitatory stimulus. Further substantiating this observation, we show in mouse aortic rings that insulin exposure suppresses epinephrine and norepinephrine-induced vasoconstriction. Notably, we found that such insulin-suppressing effects on catecholamine-induced constriction are diminished following ß-adrenergic receptor blockade. In accordance, we also reveal that insulin augments ß-adrenergic-mediated vasorelaxation in isolated arteries. Collectively, these findings support the idea that sympathetic vasoconstriction can be attenuated during systemic hyperinsulinemia in the leg vasculature of both men and women and that this phenomenon may be in part mediated by potentiation of ß-adrenergic vasodilation neutralizing α-adrenergic vasoconstriction.
Subject(s)
Adrenergic Agents/pharmacology , Hyperinsulinism/drug therapy , Sympathetic Nervous System/drug effects , Vasoconstriction/drug effects , Adult , Blood Pressure/drug effects , Female , Humans , Male , Norepinephrine/pharmacology , Regional Blood Flow/drug effects , Regional Blood Flow/physiology , Sympathetic Nervous System/physiology , Vascular Resistance/drug effectsABSTRACT
Preeclampsia (PE) is characterized by maternal hypertension, intrauterine growth restriction, and increased cytolytic natural killer cells (cNKs), which secrete interferon γ (IFNγ). However, the precise role of IFNγ in contributing to PE pathophysiology remains unclear. Using the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia, we tested the hypothesis that neutralization of IFNγ in RUPPs will decrease placental reactive oxygen species (ROS) and improve vascular function resulting in decreased MAP and improved fetal growth. On gestation day (GD) 14, the RUPP procedure was performed and on GDs 15 and 18, a subset of normal pregnant rats (NP) and RUPP rats were injected with 10 µg/kg of an anti-rat IFNγ monoclonal antibody. On GD 18, uterine artery resistance index (UARI) was measured via Doppler ultrasound and on GD 19, mean arterial pressure (MAP) was measured, animals were euthanized, and blood and tissues were collected for analysis. Increased MAP was observed in RUPP rats compared with NP and was reduced in RUPP + anti-IFNγ. Placental ROS was also increased in RUPP rats compared with NP rats and was normalized in RUPP + anti-IFNγ. Fetal and placental weights were reduced in RUPP rats, but were not improved following anti-IFNγ treatment. However, UARI was elevated in RUPP compared with NP rats and was reduced in RUPP + anti-IFNγ. In conclusion, we observed that IFNγ neutralization reduced MAP, UARI, and placental ROS in RUPP recipients. These data suggest that IFNγ is a potential mechanism by which cNKs contribute to PE pathophysiology and may represent a therapeutic target to improve maternal outcomes in PE.
Subject(s)
Antibodies, Monoclonal/pharmacology , Arterial Pressure/drug effects , Interferon-gamma/antagonists & inhibitors , Killer Cells, Natural/drug effects , Oxidative Stress/drug effects , Placenta/blood supply , Placenta/drug effects , Pre-Eclampsia/prevention & control , Uterine Artery/drug effects , Vascular Resistance/drug effects , Angiogenic Proteins/metabolism , Animals , Disease Models, Animal , Female , Fetal Growth Retardation/metabolism , Fetal Growth Retardation/physiopathology , Fetal Growth Retardation/prevention & control , Interferon-gamma/metabolism , Ischemia/metabolism , Ischemia/physiopathology , Killer Cells, Natural/metabolism , Placenta/metabolism , Placental Circulation , Pre-Eclampsia/metabolism , Pre-Eclampsia/physiopathology , Pregnancy , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Uterine Artery/metabolism , Uterine Artery/physiopathologyABSTRACT
BACKGROUND: In the EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial) treatment with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin significantly reduced heart failure hospitalization (HHF) in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The early separation of the HHF event curves within the first 3 months of the trial suggest that immediate hemodynamic effects may play a role. However, hitherto no data exist on early effects of SGLT2 inhibitors on hemodynamic parameters and cardiac function. Thus, this study examined early and delayed effects of empagliflozin treatment on hemodynamic parameters including systemic vascular resistance index, cardiac index, and stroke volume index, as well as echocardiographic measures of cardiac function. METHODS: In this placebo-controlled, randomized, double blind, exploratory study patients with T2D were randomized to empagliflozin 10 mg or placebo for a period of 3 months. Hemodynamic and echocardiographic parameters were assessed after 1 day, 3 days and 3 months of treatment. RESULTS: Baseline characteristics were not different in the empagliflozin (n = 22) and placebo (n = 20) group. Empagliflozin led to a significant increase in urinary glucose excretion (baseline: 7.3 ± 22.7 g/24 h; day 1: 48.4 ± 34.7 g/24 h; p < 0.001) as well as urinary volume (1740 ± 601 mL/24 h to 2112 ± 837 mL/24 h; p = 0.011) already after one day compared to placebo. Treatment with empagliflozin had no effect on the primary endpoint of systemic vascular resistance index, nor on cardiac index, stroke volume index or pulse rate at any time point. In addition, echocardiography showed no difference in left ventricular systolic function as assessed by left ventricular ejections fraction and strain analysis. However, empagliflozin significantly improved left ventricular filling pressure as assessed by a reduction of early mitral inflow velocity relative to early diastolic left ventricular relaxation (E/e') which became significant at day 1 of treatment (baseline: 9.2 ± 2.6; day 1: 8.5 ± 2.2; p = 0.005) and remained apparent throughout the study. This was primarily attributable to reduced early mitral inflow velocity E (baseline: 0.8 ± 0.2 m/s; day 1: 0.73 ± 0.2 m/sec; p = 0.003). CONCLUSIONS: Empagliflozin treatment of patients with T2D has no significant effect on hemodynamic parameters after 1 or 3 days, nor after 3 months, but leads to rapid and sustained significant improvement of diastolic function. Trial registration EudraCT Number: 2016-000172-19; date of registration: 2017-02-20 (clinicaltrialregister.eu).
Subject(s)
Benzhydryl Compounds/therapeutic use , Cardiovascular Diseases/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Glucosides/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Ventricular Function, Left/drug effects , Ventricular Pressure/drug effects , Aged , Benzhydryl Compounds/adverse effects , Cardiovascular Diseases/diagnostic imaging , Cardiovascular Diseases/physiopathology , Diabetes Mellitus, Type 2/diagnosis , Double-Blind Method , Female , Germany , Glucosides/adverse effects , Heart Failure/drug therapy , Heart Failure/physiopathology , Humans , Male , Middle Aged , Patient Admission , Pilot Projects , Prospective Studies , Recovery of Function , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Stroke Volume/drug effects , Time Factors , Treatment Outcome , Vascular Resistance/drug effectsABSTRACT
The obese Zucker rat (OZR) manifests multiple risk factors for impaired cerebrovascular function, including hypertension and insulin resistance although how they combine to produce integrated vascular function is unclear. As studies have suggested that myogenic activation (MA) severity for middle cerebral arteries (MCAs) may be proportional to hypertension severity, we hypothesized that MA will negatively correlate with dilator reactivity in OZR. MA of MCA from OZR was divided into low, medium, and high based on the slope of MA, while MCA reactivity and vascular metabolite bioavailability were assessed in all groups. Endothelium-dependent dilation of MCA in OZR was attenuated and correlated with the MA slope. Treatment of OZR MCA with TEMPOL (antioxidant) improved dilation in low or medium MA groups, but had less impact on high MA. Alternatively, treatment with gadolinium to normalize MA in OZR had reduced impact on dilator reactivity in MCA from low and medium MA groups, but improved responses in the high group. Treatment with both agents resulted in dilator responses that were comparable across all groups. These results suggest that, under conditions with stronger MA, endothelial function may receive some protection despite the environment, potentially from the ability of MCA to reduce wall tension despite increased pressure.
Subject(s)
Cerebrovascular Circulation , Endothelium, Vascular/physiopathology , Metabolic Syndrome/physiopathology , Middle Cerebral Artery/physiopathology , Muscle, Smooth, Vascular/physiopathology , Vascular Resistance , Vasodilation , Animals , Antioxidants/pharmacology , Cerebrovascular Circulation/drug effects , Disease Models, Animal , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Male , Metabolic Syndrome/metabolism , Middle Cerebral Artery/drug effects , Middle Cerebral Artery/metabolism , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Rats, Zucker , Vascular Resistance/drug effects , Vasodilation/drug effects , Vasodilator Agents/pharmacologyABSTRACT
Cardiovascular diseases are among the main causes of mortality in the world. There is evidence of cardiovascular harm after exposure to low lead or mercury concentrations, but the effects of chronic exposure to the association of low doses of these toxic metals are still unknown. This work evaluated after 4 weeks, the association effects of low concentrations of lead and mercury on blood pressure and vascular resistance reactivity. Wistar rats were exposed for 28 days to lead acetate (1st dose of 4 µg/100 g and subsequent doses of 0.05 µg /100 g/day to cover daily losses) and mercury chloride (1st dose of 2.17 µg/kg and subsequent doses of 0.03 µg/kg/ day to cover daily losses) and the control group received saline, i.m. Results showed that treatment increased blood pressure and induced left ventricular hypertrophy. The mesenteric vascular reactivity to phenylephrine and the endothelium-dependent vasodilator response assessed by acetylcholine did not change. Additionally, reduced involvement of vasoconstrictor prostanoids derived from cyclooxygenase was observed in the PbHg group. By other regulatory routes, such as potassium channels, the vessel showed a greater participation of BKCa channels, and a reduction in the participation of Kv channels and SKCa channels. The endothelium-independent smooth muscle relaxation was significantly impaired by reducing cGMP, possibly through the hyperstimulation of Phosphodiesterase-5 (PDE5). Our results suggested that exposure to low doses of lead and mercury triggers this compensatory mechanism, in response to the augment of arterial pressure.
Subject(s)
Arterial Pressure/drug effects , Cyclic GMP/metabolism , Mercuric Chloride/toxicity , Muscle, Smooth, Vascular/drug effects , Organometallic Compounds/toxicity , Vasodilation/drug effects , Animals , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Down-Regulation , Hypertension/chemically induced , Hypertension/metabolism , Hypertension/physiopathology , Hypertrophy, Left Ventricular/chemically induced , Hypertrophy, Left Ventricular/metabolism , Hypertrophy, Left Ventricular/physiopathology , Mesenteric Arteries/drug effects , Mesenteric Arteries/metabolism , Mesenteric Arteries/physiopathology , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/physiopathology , Rats, Wistar , Second Messenger Systems , Time Factors , Vascular Resistance/drug effectsABSTRACT
The heart exhibits the highest basal oxygen (O2) consumption per tissue mass of any organ in the body and is uniquely dependent on aerobic metabolism to sustain contractile function. During acute hypoxic states, the body responds with a compensatory increase in cardiac output that further increases myocardial O2 demand, predisposing the heart to ischemic stress and myocardial dysfunction. Here, we test the utility of a novel engineered protein derived from the heme-based nitric oxide (NO)/oxygen (H-NOX) family of bacterial proteins as an O2 delivery biotherapeutic (Omniox-cardiovascular [OMX-CV]) for the hypoxic myocardium. Because of their unique binding characteristics, H-NOX-based variants effectively deliver O2 to hypoxic tissues, but not those at physiologic O2 tension. Additionally, H-NOX-based variants exhibit tunable binding that is specific for O2 with subphysiologic reactivity towards NO, circumventing a significant toxicity exhibited by hemoglobin (Hb)-based O2 carriers (HBOCs). Juvenile lambs were sedated, mechanically ventilated, and instrumented to measure cardiovascular parameters. Biventricular admittance catheters were inserted to perform pressure-volume (PV) analyses. Systemic hypoxia was induced by ventilation with 10% O2. Following 15 minutes of hypoxia, the lambs were treated with OMX-CV (200 mg/kg IV) or vehicle. Acute hypoxia induced significant increases in heart rate (HR), pulmonary blood flow (PBF), and pulmonary vascular resistance (PVR) (p < 0.05). At 1 hour, vehicle-treated lambs exhibited severe hypoxia and a significant decrease in biventricular contractile function. However, in OMX-CV-treated animals, myocardial oxygenation was improved without negatively impacting systemic or PVR, and both right ventricle (RV) and left ventricle (LV) contractile function were maintained at pre-hypoxic baseline levels. These data suggest that OMX-CV is a promising and safe O2 delivery biotherapeutic for the preservation of myocardial contractility in the setting of acute hypoxia.
Subject(s)
Heme/therapeutic use , Hypoxia/therapy , Oxygen/therapeutic use , Animals , Biological Therapy/methods , Heart/physiology , Heart Rate/drug effects , Heart Ventricles/drug effects , Lung , Muscle Contraction/drug effects , Myocardial Contraction/drug effects , Myocardium/metabolism , Nitric Oxide/metabolism , Nitric Oxide/therapeutic use , Oxygen/metabolism , Oxygen Consumption/physiology , Protein Engineering/methods , Sheep , Vascular Resistance/drug effectsABSTRACT
RATIONALE: Pulmonary vascular resistance fails to decrease appropriately during exercise in patients with heart failure with preserved ejection fraction (HFpEF). Interventions that enhance pulmonary vasodilation might be beneficial in this cohort but could also worsen left atrial hypertension, exacerbating lung congestion. Intravenous ß-agonists reduce pulmonary vascular resistance but are not suitable for chronic use. OBJECTIVE: We hypothesized that the inhaled ß-adrenergic agonist albuterol would improve pulmonary vasodilation during exercise in patients with HFpEF, without increasing left heart filling pressures. METHODS AND RESULTS: We performed a randomized, double-blind, placebo-controlled trial testing the effects of inhaled albuterol on resting and exercise hemodynamics in subjects with HFpEF using high-fidelity micromanometer catheters and expired gas analysis. The primary end point was pulmonary vascular resistance during exercise. Subjects with HFpEF (n=30) underwent resting and exercise hemodynamic assessment and were then randomized 1:1 to inhaled, nebulized albuterol or placebo. Rest and exercise hemodynamic testing was then repeated. Albuterol improved the primary end point of exercise pulmonary vascular resistance as compared with placebo (-0.6±0.5 versus +0.1±0.7 WU; P=0.003). Albuterol enhanced cardiac output reserve and right ventricular pulmonary artery coupling, reduced right atrial and pulmonary artery pressures, improved pulmonary artery compliance, and enhanced left ventricular transmural distending pressure (all P <0.01), with no increase in pulmonary capillary hydrostatic pressures. CONCLUSIONS: Albuterol improves pulmonary vascular reserve in patients with HFpEF without worsening left heart congestion. Further study is warranted to evaluate the chronic efficacy of ß-agonists in HFpEF and other forms of pulmonary hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02885636.