scholarly journals Relationship between right ventricular diastolic dysfunction, right atrial phasic function and ventricular filling in pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J.N Wessels ◽  
S.A Mouratoglou ◽  
J Van Wezenbeek ◽  
J.T Marcus ◽  
L.J Meijboom ◽  
...  
Keyword(s):  
Heart Rate ◽  
Pulmonary Arterial Hypertension ◽  
Right Atrial ◽  
Funding Source ◽  
Filling Volume ◽  
Ventricular Dyssynchrony ◽  
Active Strain ◽  
Filling Time ◽  
Pulmonary Arterial ◽  
Ventricular Filling

Abstract Background In pulmonary arterial hypertension (PAH) patients, the right ventricle (RV) stiffens due to hypertrophy, fibrosis and intrinsic (sarcomeric) stiffness. In these patients, end-diastolic elastance (stiffness, Eed) is associated with parameters of disease severity and predicts mortality. However, the effect of RV stiffness on RV filling and the effect of increased filling pressures on right atrial (RA) function remain elusive. Purpose To examine the relationship between RV diastolic stiffness and RA phasic function and the effect of diastolic dysfunction on ventricular filling in PAH patients. Methods Using single-beat pressure-volume analyses we determined Eed in controls (n=31) and baseline, treatment naive PAH patients (63 idiopathic, 9 hereditary and 25 connective tissue disease associated). We also measured RA reservoir, conduit and active strain by tissue tracking on cardiac magnetic resonance images. Furthermore, interventricular dyssynchrony was defined as a right to left difference in time to peak circumferential strain >52ms (97.5th percentile in controls). Results End-diastolic pressure was higher in PAH patients (16±7 mmHg) than in controls (8±4 mmHg; p<0.001). Median Eed in patients was 0.635 mmHg/mL (IQR: 0.40–0.99), while in controls it was 0.20 mmHg/mL (IQR: 0.15–0.24). In comparison with controls, patients had reduced RA reservoir (14.3±5.1% vs. 19.1±4.3%; p<0.001) and conduit strain (−5.6±3.4% vs. −12.4±3.3%; p<0.001), while RA active strain was enhanced (−9.0±4.0% vs. −7.5±2.8%; p=0.019). In patients with a stiff RV (Eed above median), RA conduit strain was worse than in patients with a more compliant RV as illustrated in figure A. However, no correlation between RA active strain and Eed was observed (Spearman rho 0.06; p=0.57). Passive filling time of the RV (end-systole until start of atrial contraction) was shorter in patients than in controls (244±136ms vs. 365±103ms; p<0.001). Higher heart rate and ventricular dyssynchrony are causes of a shorter passive filling time in patients as illustrated in figure B. When comparing patients with short vs. long passive filling time (cutoff median of 220ms), the RV passive filling volume was lower (24±15ml vs. 42±19ml; p<0.001). The active filling volume was slightly higher, although not significantly (25±17ml vs. 19±15ml; p=0.12). Conclusion Stiffening of the RV in PAH patients is accompanied by increased filling pressures and decreased RA conduit strain, while there is no correlation between Eed and RA active strain. Higher heart rate and ventricular dyssynchrony lead to shorter passive filling time of the RV, which in turn leads to lower passive filling volume. In contrast, the active filling volume is preserved in these patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Netherlands Organization for Scientific Research

scholarly journals Atrial arrhythmias are associated with increased mortality in pulmonary arterial hypertension

2018 ◽  
Vol 8 (3) ◽  
pp. 204589401879031 ◽  
Author(s):  
Benjamin Smith ◽  
Michael V. Genuardi ◽  
Agnes Koczo ◽  
Richard H. Zou ◽  
Floyd W. Thoma ◽  
...  
Keyword(s):  
Heart Rate ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Left Ventricular ◽  
Sensitivity Analyses ◽  
Right Atrial ◽  
Left Ventricular Ejection ◽  
Atrial Arrhythmias ◽  
Pulmonary Arterial ◽  
Time Varying Covariates

Pulmonary arterial hypertension (PAH) is a deadly vascular disease, characterized by increased pulmonary arterial pressures and right heart failure. Considering prior non-US studies of atrial arrhythmias in PAH, this retrospective, regional multi-center US study sought to define more completely the risk factors and impact of paroxysmal and non-paroxysmal forms of atrial fibrillation and flutter (AF/AFL) on mortality in this disease. We identified patients seen between 2010 and 2014 at UPMC (Pittsburgh) hospitals with hemodynamic and clinical criteria for PAH or chronic thromboembolic pulmonary hypertension (CTEPH) and determined those meeting electrocardiographic criteria for AF/AFL. We used Cox proportional hazards regression with time-varying covariates to analyze the association between AF/AFL occurrence and survival with adjustments for potential cofounders and hemodynamic severity. Of 297 patients with PAH/CTEPH, 79 (26.5%) suffered from AF/AFL at some point. AF/AFL was first identified after PAH diagnosis in 42 (53.2%), identified prior to PAH diagnosis in 27 (34.2%), and had unclear timing in the remainder. AF/AFL patients were older, more often male, had lower left ventricular ejection fractions, and greater left atrial volume indices and right atrial areas than patients without AF/AFL. AF/AFL (whether diagnosed before or after PAH) was associated with a 3.81-fold increase in the hazard of death (95% CI 2.64–5.52, p < 0.001). This finding was consistent with multivariable adjustment of hemodynamic, cardiac structural, and heart rate indices as well as in sensitivity analyses of patients with paroxysmal versus non-paroxysmal arrhythmias. In these PAH/CTEPH patients, presence of AF/AFL significantly increased mortality risk. Mortality remained elevated in the absence of a high burden of uncontrolled or persistent arrhythmias, thus suggesting additional etiologies beyond rapid heart rate as an explanation. Future studies are warranted to confirm this observation and interrogate whether other therapies beyond rate and rhythm control are necessary to mitigate this risk.

Optimal Timing for Lung Transplantation: Why Not Include RVEF As an Indicator?

2012 ◽  
Vol 11 (1) ◽  
pp. 47-48
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Lung Transplantation ◽  
Severity Of Illness ◽  
Right Atrial ◽  
Optimal Time ◽  
Optimal Timing ◽  
Predictors Of Outcome ◽  
Donor Organ ◽  
Pulmonary Arterial ◽  
Rv Function

One of the most challenging questions to answer in pulmonary arterial hypertension (PAH) is: “When is the optimal time to proceed with lung transplantation?” The current lung allocation scoring (LAS) system prioritizes donor organ resources based on severity of illness. Factors used to assign LAS do not account for known predictors of outcome for PAH patients—including determinants of right ventricular (RV) function. It has been recognized that the system places PAH patients at a distinct disadvantage, and concerted efforts are being made to correct this by considering variables that reflect RV function, specifically mean right atrial pressure (mRAP) and cardiac index (CI).

Pulmonary arterial hypertension in families with hereditary hemorrhagic telangiectasia: a 13-year follow-up study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y.-P Zhou ◽  
X Jiang ◽  
Y.-X Zhang ◽  
K Sun ◽  
T.-Y Lian ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Hereditary Hemorrhagic Telangiectasia ◽  
Clinical Status ◽  
Development Program ◽  
Resistance Index ◽  
Walking Distance ◽  
Funding Source ◽  
Free Survival ◽  
Pulmonary Arterial

Abstract Background Pulmonary arterial hypertension (PAH) can occur in families with hereditary hemorrhagic telangiectasia (HHT), but it has not been well-characterized. Purpose This study sought to characterize the genetic defects, clinical and hemodynamic features, and outcomes of PAH patients in HHT families. Methods All HHT families with at least one case of PAH investigated in our center from January 2006 to December 2018 were enrolled in the study. We did whole-exome sequencing (WES) or whole-genome sequencing (WGS) to every proband and available family members. The clinical data, hemodynamic features and outcomes of PAH patients were reviewed. Results A total of 64 PAH patients in 57 families were enrolled. Only 7 (12.3%) families had more than one case of PAH. Activin-receptor-like kinase 1 (ALK-1) mutation and Endoglin (ENG) mutation were confirmed in 49 (86.0%) and 3 (5.3%) families and other 5 (8.8%) had no known mutation associated with HHT or PAH. The median age when PAH diagnosis was 22 [9–33] years and female was dominant (70.3%). Most patients (84.4%) had signs of HHT and anemia was recorded in 14 (21.9%) patients. Remarkably, these patients showed severely compromised hemodynamics with elevated mean pulmonary artery pressure (62 [51, 77] mm Hg) and pulmonary vascular resistance index (17.0 [11.2, 22.8] Wood units*m2). Also, impaired exercise capacity was recorded at diagnosis with decreased six-minute walking distance (410 [342–485] meters) and over half (54.7%) were in WHO functional class III or IV. The 1-, 3-, 5- and 10-year transplantation-free survival for the overall PAH patients was 95.0%, 75.9%, 67.1% and 36.4%, respectively. Anemia (HR: 4.24 [1.32–13.65], p=0.016) and CI &lt;2.5 l/min/m2 (HR: 4.39 [1.20–16.09], p=0.026) were independent risk factors for mortality. Conclusions PAH in HHT families is a devastating condition characterized by a young age at PAH diagnosis, poor clinical status and outcomes mainly underlying ALK-1 mutation, which emphasizes the importance to pay attention to this group of patients. Transplantation-free survival Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Beijing Natural Science Foundation (7181009), the National Key Research and Development Program of China (2016YFC0901502)

Beta3-adrenergic stimulation restores endothelial mitochondrial dynamics and prevents pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Oliver ◽  
S.F Rocha ◽  
M Spaczynska ◽  
D.V Lalama ◽  
M Gomez ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Therapeutic Strategy ◽  
Mitochondrial Dynamics ◽  
Systolic Pressure ◽  
Funding Source ◽  
Pulmonary Arterial

Abstract Background Endothelial dysfunction is one of the most important hallmarks of pulmonary arterial hypertension (PAH). This leads to anomalous production of vasoactive mediators that are responsible for a higher vascular tone and a subsequent increase in pulmonary artery pressure (PAP), and to an increased vascular permeability that favors perivascular inflammation and remodeling, thus worsening the disease. Therefore, preservation of the endothelial barrier could become a relevant therapeutic strategy. Purpose In previous studies, others and we have suggested the pharmacological activation of the β3-adrenergic receptor (AR) as a potential therapeutic strategy for pulmonary hypertension (PH) due to left heart disease. However, its potential use in other forms of PH remain unclear. The aim of the present study was to elucidate whether the β3-AR agonist mirabegron could preserve pulmonary endothelium function and be a potential new therapy in PAH. Methods For this purpose, we have evaluated the effect of mirabegron (2 and 10 mg/kg·day) in different animal models, including the monocrotaline and the hypoxia-induced PAH models in rats and mice, respectively. Additionally, we have used a transgenic mouse model with endothelial overexpression of human β3-AR in a knockout background, and performed in vitro experiments with human pulmonary artery endothelial cells (HPAECs) for mechanistic experiments. Results Our results show a dose dependent effect of mirabegron in reducing mean PAP and Right Ventricular Systolic Pressure in both mice and rats. In addition, the use of transgenic mice has allowed us to determine that pulmonary endothelial cells are key mediators of the beneficial role of β3-AR pathway in ameliorating PAH. Mechanistically, we have shown in vitro that activation of β3-AR with mirabegron protects HPAECs from hypoxia-induced ROS production and mitochondrial fragmentation by restoring mitochondrial fission/fusion dynamics. Conclusions This protective effect of mirabegron would lead to endothelium integrity and preserved pulmonary endothelial function, which are necessary for a correct vasodilation, avoiding increased permeability and remodeling. Altogether, the current study demonstrates a beneficial effect of the β3-AR agonist mirabegron that could open new therapeutic avenues in PAH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Programa de Atracciόn de Talento, Comunidad de Madrid

scholarly journals Study of the effect of Occlutech Atrial Flow Regulator on symptoms, hemodynamics, and echocardiographic parameters in advanced pulmonary arterial hypertension

2021 ◽  
Vol 11 (1) ◽  
pp. 204589402198996
Author(s):  
Kothandam Sivakumar ◽  
Gopalavilasam R. Rohitraj ◽  
Monica Rajendran ◽  
Nithya Thivianathan
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
High Risk ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Right Atrial ◽  
Echocardiographic Parameters ◽  
Procedural Complications ◽  
Pulmonary Arterial ◽  
Flow Regulator ◽  
Risk Predictors

Optimal sized balloon atrial septostomy improves hemodynamics in advanced pulmonary arterial hypertension. Occlutech Atrial Flow Regulator is designed to provide an atrial septal fenestration diameter titrated according to the age and right atrial pressures. This observational study analyzed symptoms, exercise distance, oxygen saturations, hemodynamics and echocardiographic parameters after Atrial Flow Regulator implantation in patients with syncope or right-heart failure. Patients with high-risk predictors of mortality during septostomy were scrutinized. Thirty-nine patients (9 children) with syncope (34/39) or right-heart failure (27/39) underwent Atrial Flow Regulator implantation without procedural complications. Six-minute walk distance increased from 310 ± 158.2 to 376.4 ± 182.6 m, none developed syncope. Oxygen saturations reduced from 96.4 ± 6.4% to 92 ± 4.9% at rest and further to 80.3 ± 5.9% on exercise. Right atrial pressures reduced from 9.4 ± 5 (2–27) mmHg to 6.9 ± 2.6 (1–12) mmHg, while cardiac index increased from 2.4 ± 0.8 (0.98–4.3) to 3 ± 1 (1.1–5.3) L/min/m2 and systemic oxygen transport increased from 546.1 ± 157.9 (256.2–910.5) to 637.2 ± 191.1 (301.3–1020.2) ml/min. Echocardiographic improvement included significant reduction of pericardial effusion and inferior caval congestion at a median follow-up of 37 months. Overall survival improved except two early and one late deaths in high-risk patients. Five of seven patients with advanced disease and key hemodynamic predictors of mortality survived. Acute hemodynamic benefits in pulmonary arterial hypertension after Atrial Flow Regulator were improved cardiac output, systemic oxygen transport, and reduced right atrial pressures. Improvement of symptoms especially syncope, exercise duration, and right ventricular systolic function as well as device patency were sustained on mid-term follow-up. Implantation was safe in all including young children without procedural complications. Mortality was noted only in patients who had high-risk predictors and patients at advanced stage of the disease.

Right ventricular longitudinal strain with CMR can more accurately estimate right ventricular functional reserve in rats with pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Sato ◽  
Y Someya ◽  
Y Takahashi ◽  
K Kumasaka ◽  
W Sato ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Longitudinal Strain ◽  
Weight Ratio ◽  
Contractile Properties ◽  
Funding Source ◽  
Functional Reserve ◽  
Pulmonary Arterial ◽  
Cmr Imaging

Abstract Background Right ventricular (RV) function is an important prognostic factor in patients with pulmonary arterial hypertension (PAH). Recently, CMR has become an attractive modality for follow up and providing prognosis in the patients, and strain has been used as a newer parameter to assess contractile properties of ventricle. It has not yet been established, however, whether RV strain with CMR can estimate RV functional reserve in the patients with PAH. Purpose We focused on CMR imaging of RV, investigating whether RV longitudinal strain can estimate RV functional reserve using a rat model with PAH. Method Rats were given a subcutaneous injection of 60 mg/kg monocrotaline (MCT-rats) or solvent (Ctr-rats). Four weeks after the injection, 25% of MCT-rats died due to RV failure. In the survivors of MCT- (n=19) and Ctr-rats (n=5), retrospective ECG-gated cine MR (16 phases/beat) was imaged with a 7T scanner. Subsequently, we measured RV pressure (RVP) via right internal jugular vein and dissected trabeculae (length = 1.45±0.07 mm, width = 334±27 μm, thickness = 114±6 μm) from RVs. We calculated weight ratio of RV free wall to left ventricle (LV) by RV/(LV+septum). Trabeculae were electrically stimulated with 2-s stimulus intervals, and force was measured using a silicon strain gauge (0.7 mM extracellular Ca2+, 24°C). To determine contractile properties of RV muscle, dF/dt was calculated. Using CMR imaging, we measured RV ejection fraction (RVEF) and RV longitudinal strain (RVLS). To modulate RVP, we intravenously injected 5 nmol endothelin-1 (ET-1) and again measured RVEF and RVLS. Results MCT-rats showed higher systolic RVP (62.5±16.6 vs. 25.9±1.86 mmHg, p&lt;0.01) and higher weight ratio of RV (0.60±0.03 vs. 0.28±0.02, p&lt;0.05). In CMR imaging, MCT-rats showed lower RVEF (36.1±11.2 vs. 64.8±8.4%, p&lt;0.001) and lower RVLS (−18±9 vs. −30±1%, p&lt;0.05). In trabeculae from RVs, MCT-rats showed lower developed force and lower dF/dt (p&lt;0.01). Correlation between RVLS and dF/dt was higher (n=20, r=0.53, p&lt;0.05) than that between RVEF and dF/dt (r=0.24). In addition, RVLS and dF/dt had already been decreased in 5 MCT-rats with relatively preserved RVEF (&gt;50%), suggesting that RVLS decreases earlier than RVEF in MCT-rats. Ten minutes after the injection of ET-1, RVP was increased from 49.4±7.9 to 57.9±6.4 mmHg in MCT-rats (n=6). In MCT-rats with preserved RVEF and decreased RVLS, the increase in RVP chiefly decreased RVEF while it did not change RVLS and RVEF in Ctr-rats, meaning that RV functional reserve had been decreased in MCT-rats. In trabeculae, developed force and dF/dt were increased after the addition of 0.1 μM ET-1 in MCT- (n=11, p&lt;0.01) and Ctr-rats (n=4, p&lt;0.01). Conclusion These results suggest that in rats with PAH, RVLS obtained from CMR can estimate RV functional reserve earlier and more accurately than RVEF. Therefore, RV strain with CMR may become an important parameter to assess RV functional reserve in patients with PAH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant-in-Aid for Young Scientists

Change of myocardial fluorodeoxyglucose uptake distribution after specific therapy of pulmonary arterial hypertension patients

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
R Kazimierczyk ◽  
P Szumowski ◽  
L.M Malek ◽  
P Blaszczak ◽  
D Jurgilewicz ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Glucose Uptake ◽  
Funding Source ◽  
Hemodynamic Parameters ◽  
Fdg Uptake ◽  
Baseline Visit ◽  
Pulmonary Arterial ◽  
Rv Function

Abstract Background Right ventricular (RV) function is a major determinant of survival in patients with pulmonary arterial hypertension (PAH). In our previous study, we confirmed that increased RV fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) (presented as higher ratio of FDG uptake of RV to LV) was associated with progressive RV dysfunction and preceded hemodynamic and clinical deterioration in PAH patients. Now, we obtained second PET/MRI assessments of the study group after 2-years of PAH-targeted treatment. Aim The aim of the study was to obtain change of cardiac FDG uptake in PAH patients after follow-up period and to indicate factors mainly affecting this change. Methods Twenty-eight PAH patients (51.32±15.91 years) had simultaneous PET/MRI scans performed during baseline visit. FDG was used and its uptake was quantified as mean standardized uptake value (SUV) for both left (LV) and RV. Second PET/MRI assessments were done after 2 years in the group of twenty patients (four deaths, four patients did not agree to perform additional scans). Results After follow-up period, we observed significant change of MRI-derived RV ejection fraction (45±10% to 51.2±12.7%, p=0.03), and improvement in hemodynamic parameters obtained from right heart catheterization (RHC) e.g. mean pulmonary artery pressure, mPAP (48.5±17.2 to 41.8±17.1 mmHg, p=0.01) and pulmonary vascular resistance, PVR (8.7±5.3 to 7.0±4.2 WU, p=0.04). Follow-up SUVRV/SUVLV ratio significantly correlated with follow-up RV hemodynamic parameters confirming relationship between RV function and cardiac metabolic alterations (Table 1). Interestingly, patients who had improvement in SUVRV/SUVLV (lower follow-up value than baseline, n=11) had significantly higher mPAP at baseline visit (58.9±18.7 vs 40.3±11.8 mmHg, p=0.02), suggesting that RV FDG accumulation in advanced PAH may decrease after the PAH-specific treatment in accordance with the degree of reduction in the pulmonary vascular resistance. Conclusion Impaired RV function is associated with increased glucose uptake of RV myocytes estimated by FDG PET in PAH patients. Targeted treatment may improve RV function and thus affect previously altered cardiac glucose uptake. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Polish National Science Centre

scholarly journals Lower plasma melatonin levels predict worse long-term survival in pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Z Cai ◽  
T Klein ◽  
L.W Geenen ◽  
L Tu ◽  
S Tian ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Funding Source ◽  
Cardiovascular Research ◽  
Term Survival ◽  
Long Term Survival ◽  
Treatment Naïve ◽  
Pulmonary Arterial ◽  
Endogenous Melatonin

Abstract Background Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms may be involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve pulmonary arterial hypertension (PAH) patients and their clinical significance are still unknown. Methods and results Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in treatment-naïve PAH patients (n=43) and healthy controls (n=111). Melatonin levels were higher in PAH patients when compared with controls (Median 118.9 [IQR 109.3–147.7] versus 108.0 [102.3–115.2] pM, P&lt;0.001) (Figure 1A). The overall mortality was 26% (11/43) during a median long-term follow-up of 42 [IQR: 32–58] months. When PAH patients were stratified into 4 groups according to the quartiles of melatonin levels, the mortality from below 1st quartile to above 4th quartile was 55% (6/11), 10% (1/10), 0% (0/12), and 40% (4/10), respectively (Figure 1B). Kaplan-Meier analysis further showed that patients with melatonin levels below the 1st quartile (&lt;109.3 pM) had a worse long-term survival than patients with melatonin levels above the 1st quartile (Mean survival times were 46 [95% CI: 30–65] versus 68 [58–77] months, Log-rank, p=0.026) (Figure 1C). Conclusion Endogenous melatonin levels were increased in treatment-naïve PAH patients, and lower levels of melatonin were associated with worse long-term survival in patient with PAH, however, whether exogenous melatonin supplements may be effective as a therapeutic strategy in human PAH remains to be established. Figure 1 Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): This work was supported by the China Scholarship Council (201606230252) as well as the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-11, RECONNECT), and German Center for Cardiovascular Research (DZHK81Z0600207). Instrumentation support was received from AB Sciex, ltd. for LC-MS/MS analyses performed in this study.

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