Left ventricular function and remodeling after myocardial infarction in aging rats

1997 ◽  
Vol 273 (6) ◽  
pp. H2652-H2658 ◽  
Author(s):  
Thomas E. Raya ◽  
Mohamed Gaballa ◽  
Peter Anderson ◽  
Steven Goldman
Keyword(s):  
Myocardial Infarction ◽  
Myocardial Fibrosis ◽  
Myocardial Function ◽  
Systolic Function ◽  
Left Ventricular ◽  
Volume Index ◽  
Brown Norway ◽  
Lv Function ◽  
Mature Adult ◽  
Lv Systolic Function

— Adaptations of the aging left ventricle (LV) to hemodynamic overload are functionally and structurally distinct from those of the young organism. This study describes the influence of aging on LV hemodynamics and remodeling late after myocardial infarction (MI) in Fischer 344 Brown Norway rats. In sham rats at 23 mo, LV weight, myocyte cross-sectional area (CSA), and myocardial fibrosis were increased, whereas LV dP/d t, LV relaxation, and maximal LV systolic function declined with respect to younger rats (7, 12, and 18 mo of age). Isometric myocardial function was evaluated in papillary muscles of 12- and 23-mo-old sham rats. Myocardial systolic function was decreased in older rats. To determine how aging affects LV function and remodeling after MI, rats were infarcted at 7 and 18 mo of age and were studied 5 mo later. Infarct size was similar in each group. Right ventricular weight, LV end-diastolic pressure, and volume index were increased, whereas LV dP/d t, peak cardiac index, and peak developed LV pressure declined after MI. However, there were no significant differences between young and older rats in any variable of LV systolic function or remodeling after MI. Myocyte CSA increased in younger rats after MI but was unchanged in 23-mo-old rats. After MI, myocardial fibrosis was significantly increased from baseline only in younger rats. The negative interaction of aging and MI on myocyte hypertrophy and fibrosis was highly significant. The findings indicate that baseline LV and myocardial function decline with age. In the aging rat after MI, despite limited compensatory hypertrophy and more advanced baseline myocardial fibrosis, the long-term functional and structural adaptations to MI are similar to those of the mature adult heart.

scholarly journals Effect of cardiosphere-derived cells on segmental myocardial function after myocardial infarction: ALLSTAR randomised clinical trial

Open Heart ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. e001614
Author(s):  
Mohammad R Ostovaneh ◽  
Raj R Makkar ◽  
Bharath Ambale-Venkatesh ◽  
Deborah Ascheim ◽  
Tarun Chakravarty ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Clinical Trial ◽  
Myocardial Function ◽  
Randomised Clinical Trial ◽  
Scar Tissue ◽  
Left Ventricular ◽  
Lv Function ◽  
Cardiac Events ◽  
Lv Dysfunction ◽  
Registration Number

BackgroundMost cell therapy trials failed to show an improvement in global left ventricular (LV) function measures after myocardial infarction (MI). Myocardial segments are heterogeneously impacted by MI. Global LV function indices are not able to detect the small treatment effects on segmental myocardial function which may have prognostic implications for cardiac events. We aimed to test the efficacy of allogeneic cardiosphere-derived cells (CDCs) for improving regional myocardial function and contractility.MethodsIn this exploratory analysis of a randomised clinical trial, 142 patients with post-MI with LVEF <45% and 15% or greater LV scar size were randomised in 2:1 ratio to receive intracoronary infusion of allogenic CDCs or placebo, respectively. Change in segmental myocardial circumferential strain (Ecc) by MRI from baseline to 6 months was compared between CDCs and placebo groups.ResultsIn total, 124 patients completed the 6-month follow-up (mean (SD) age 54.3 (10.8) and 108 (87.1%) men). Segmental Ecc improvement was significantly greater in patients receiving CDC (−0.5% (4.0)) compared with placebo (0.2% (3.7), p=0.05). The greatest benefit for improvement in segmental Ecc was observed in segments containing scar tissue (change in segmental Ecc of −0.7% (3.5) in patients receiving CDC vs 0.04% (3.7) in the placebo group, p=0.04).ConclusionsIn patients with post-MI LV dysfunction, CDC administration resulted in improved segmental myocardial function. Our findings highlight the importance of segmental myocardial function indices as an endpoint in future clinical trials of patients with post-MI.Trial registration numberNCT01458405.

scholarly journals Acute recoordination rather than functional hemodynamic improvement determines reverse remodelling by cardiac resynchronisation therapy

2021 ◽  
Author(s):  
Philippe C. Wouters ◽  
Geert E. Leenders ◽  
Maarten J. Cramer ◽  
Mathias Meine ◽  
Frits W. Prinzen ◽  
...  
Keyword(s):  
Systolic Function ◽  
Cardiac Resynchronisation Therapy ◽  
Left Ventricular ◽  
Lv Function ◽  
Peak Strain ◽  
Cardiac Resynchronisation ◽  
Reverse Remodelling ◽  
Resynchronisation Therapy ◽  
Lv Systolic Function

AbstractPurpose: Cardiac resynchronisation therapy (CRT) improves left ventricular (LV) function acutely, with further improvements and reverse remodelling during chronic CRT. The current study investigated the relation between acute improvement of LV systolic function, acute mechanical recoordination, and long-term reverse remodelling after CRT. Methods: In 35 patients, LV speckle tracking longitudinal strain, LV volumes & ejection fraction (LVEF) were assessed by echocardiography before, acutely within three days, and 6 months after CRT. A subgroup of 25 patients underwent invasive assessment of the maximal rate of LV pressure rise (dP/dtmax,) during CRT-implantation. The acute change in dP/dtmax, LVEF, systolic discoordination (internal stretch fraction [ISF] and LV systolic rebound stretch [SRSlv]) and systolic dyssynchrony (standard deviation of peak strain times [2DS-SD18]) was studied, and their association with long-term reverse remodelling were determined. Results: CRT induced acute and ongoing recoordination (ISF from 45 ± 18 to 27 ± 11 and 23 ± 12%, p < 0.001; SRS from 2.27 ± 1.33 to 0.74 ± 0.50 and 0.71 ± 0.43%, p < 0.001) and improved LV function (dP/dtmax 668 ± 185 vs. 817 ± 198 mmHg/s, p < 0.001; stroke volume 46 ± 15 vs. 54 ± 20 and 52 ± 16 ml; LVEF 19 ± 7 vs. 23 ± 8 and 27 ± 10%, p < 0.001). Acute recoordination related to reverse remodelling (r = 0.601 and r = 0.765 for ISF & SRSlv, respectively, p < 0.001). Acute functional improvements of LV systolic function however, neither related to reverse remodelling nor to the extent of acute recoordination. Conclusion: Long-term reverse remodelling after CRT is likely determined by (acute) recoordination rather than by acute hemodynamic improvements. Discoordination may therefore be a more important CRT-substrate that can be assessed and, acutely restored.

scholarly journals Correlation between hemoglobin level and left ventricular systolic functions and dimensions in children with chronic severe anemia

2011 ◽  
Vol 51 (2) ◽  
pp. 79
Author(s):  
Erlina Masniari Napitupulu ◽  
Fera Wahyuni ◽  
Tina Christina L. Tobing ◽  
Muhammad Ali ◽  
Bidasari Lubis
Keyword(s):  
Systolic Function ◽  
Pearson Correlation ◽  
Systolic Dysfunction ◽  
Univariate Analysis ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Lv Function ◽  
Severe Anemia ◽  
Cross Sectional ◽  
Lv Systolic Function

Background Chronic severe anemia is a connnon disease. Cardiac output may increase when the hemoglobin (Hb) level decreases to < 7 g/dL for 3 months or more. Alteration of left ventricular (LV) function occurs frequently in children 'With chronic severe anemia, in the {onn of concentric LV hypertrophy, LV dilatation with or v.ithout LV hypertrophy, or systolic dysfunction. Objective To examine the correlation between Hb level and alteration of LV systolic function in children with chronic severe anemia. Methods We conducted a cross-sectional study in Adam Malik Hospital from October to December 2009. Subjects were chronic severely anemic children. Left ventricular systolic function (ejection fraction/EF, fractional shortening/FS) and dimensions (left ventricular end diastolic diameter/LVEDD and left ventricular end systolic diameter/LVESD) were measured using Hitachi EUB 5500 echocardiography unit. Univariate analysis  and Pearson correlation were performed.Results Thirty children were enrolled in the study. The mean of age was 113.5 months (SD 53.24). Hb values ranged from 2.1 to 6.9 g/dL with mean value of 4.6 g/dL (SD 1.44). Mean duration of anemia was 3.9 months (SD 0.70). Chronic severe anemia was not associated \\lith decreased LV systolic function [EF 62.2% (SD 9.16), r =0.296, P=0.112; FS 33.8% (SD 7.26), r =0.115, P=0.545], nor LV dimension changes [LVEDD 40.2 mm (SD 6.85), r = -0.192, P=0.308; LVESD 26.2 mm (SD 4.98), r=-0.266, P=0.156]. Conclusion There was no correlation between Hb level in chronically anemic children and changes in LV systolic function or dimension.

Abstract 15362: Epicardial Adipose Tissue Effects on Systolic Function: A Direct or Systemic Metabolic Effect?

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Shiva Reddy ◽  
Aditi Shankar ◽  
Katrin A Dias ◽  
James P Macnamara ◽  
Christopher M Hearon ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Epicardial Adipose Tissue ◽  
Systolic Function ◽  
Left Ventricular ◽  
Lv Function ◽  
Ectopic Fat ◽  
Paracrine Effects ◽  
Regional Strain ◽  
Data Points ◽  
Lv Systolic Function

Introduction: Obesity is associated with increased epicardial adipose tissue (EAT). It is unknown if this ectopic fat deposit has direct cardiotoxic paracrine effects on regional systolic function. We have previously shown that EAT mediates diastolic dysfunction via systemic effects, rather than localized effects. We similarly hypothesized regional EAT deposits would have no effect on the left ventricular (LV) strain of adjoining myocardial segments. Methods: We studied 28 obese healthy adults (mean age 48 ± 5 yrs, BMI 38.2 ± 5.0 kg/m 2 ). EAT was quantified on each individual MRI slice from base to apex and summed to obtain total volume. It was then separated into anterior, lateral, and inferior regions corresponding to the adjacent LV segments. Using MRI feature tracking, global longitudinal LV strain (GLS) and peak regional anterior, inferior, and lateral LV strain were quantified. Associations between total EAT and GLS, and between regional EAT and corresponding regional strain were determined by linear regression. Results: Mean total EAT volume was 69.6 ± 29.8 mL and mean GLS was -19.4 ± 2.0%. Individual data points for EAT and longitudinal strain are shown in the figure. Greater total EAT volume was modestly associated with decreased GLS (r2 = 0.127). However, anterior, lateral, and inferior EAT volume did not correlate with a decrease in corresponding regional strain (r2 = 0.003, r2 = 0.088, r2 = 0.016, respectively). Conclusion: In obese adults, total EAT volume was associated with a decrease in global LV systolic function measured by GLS. There was no association between regional EAT depots and corresponding regional LV function to suggest localized metabolic cardiotoxic effect. These preliminary results support our previous findings that EAT has little paracrine effect on cardiac function. Rather, EAT likely represents an additional depot of ectopic fat reflective of a general metabolic abnormality.

scholarly journals Valve Replacement for Aortic Stenosis in Patients With Poor Left Ventricular Function

Circulation ◽  
1999 ◽  
Vol 100 (suppl_2) ◽  
Author(s):  
Julian Collinson ◽  
Michael Henein ◽  
Marcus Flather ◽  
John R. Pepper ◽  
Derek G. Gibson
Keyword(s):  
Aortic Stenosis ◽  
Systolic Function ◽  
Left Ventricular ◽  
Lv Function ◽  
Valve Prosthesis ◽  
Transthoracic Doppler Echocardiography ◽  
Early Improvement ◽  
Lv Dysfunction ◽  
Lv Systolic Function ◽  
Fractional Shortening

Background —Long-standing aortic stenosis causes significant left ventricular (LV) dysfunction, which may progress irreversibly. In many cases, LV function can be salvaged by aortic valve surgery, although debate exists regarding the best valve prosthesis to use. Methods and Results —We studied 33 patients retrospectively who had significant aortic stenosis and impaired LV systolic function, as assessed by transthoracic Doppler echocardiography. Patients were assessed preoperatively and before discharge from the hospital. A total of 20 patients received a stentless (homograft or Toronto) valve, and 13, a stented valve. No patient had significant aortic regurgitation or other valvular disease. Preoperatively, fractional shortening was 18.8±5.5% in the stentless group and 18.6±3.8% in the stented group. Postoperatively, it was 25.6±6.9% ( P <0.001 compared with baseline) and 17.0±2.8%, respectively ( P <0.001 compared with stentless group). Fractional shortening improved because of a reduction in LV end-systolic and end-diastolic dimensions in the stentless group. Systolic long axis function at the LV free wall also recovered, with an increase in systolic excursion and both peak shortening and lengthening rates. No change was noted in mitral valve Doppler patterns. Conclusions —Patients who received a stentless valve demonstrated a significantly greater early improvement in LV systolic function compared with those who received a stented valve.

Plasma cardiotrophin-1 following acute myocardial infarction: relationship with left ventricular systolic dysfunction

2001 ◽  
Vol 102 (1) ◽  
pp. 9-14 ◽  
Author(s):  
Suneel TALWAR ◽  
Iain B. SQUIRE ◽  
Russell J. O'BRIEN ◽  
Paul F. DOWNIE ◽  
Joan E. DAVIES ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Acute Myocardial Infarction ◽  
Left Ventricular Systolic Dysfunction ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Clinic Visit ◽  
Left Ventricular ◽  
Lv Function ◽  
Ventricular Remodelling

The glycoprotein 130 (gp130) signalling pathway is important in the development of heart failure. Cardiotrophin-1 (CT-1), a cytokine acting via the gp130 pathway, is involved in the process of ventricular remodelling following acute myocardial infarction (AMI) in animals. The aims of the present study were to examine the profile of plasma CT-1 following AMI in humans, and its relationship with echocardiographic parameters of left ventricular (LV) systolic function. Serial measurements of plasma CT-1 levels were made in 60 patients at 14-48h, 49-72h, 73-120h and 121-192h following AMI and at a later clinic visit. LV function was assessed using a LV wall motion index (WMI) score on admission (WMI-1) and at the clinic visit (WMI-2). Compared with values in control subjects (29.5±3.6fmol/ml), the plasma CT-1 concentration was elevated in AMI patients at 14-48h (108.1±15.1fmol/ml), 49-72h (105.2±19.7fmol/ml), 73-120h (91.2±14.9fmol/ml) and 121-192h (118.8±22.6fmol/ml), and at the clinic visit (174.9±30.9 fmol/ml) (P < 0.0001). Levels were higher following anterior compared with inferior AMI. For patients with anterior AMI, CT-1 levels were higher at the clinic visit than at earlier times. WMI-1 correlated with CT-1 at all times prior to hospital discharge (P < 0.05). On best subsets analysis, the strongest correlate with WMI-1 was CT-1 level at 49-72h (R2 = 20%, P < 0.05). In conclusion, plasma levels of CT-1 are elevated soon after AMI in humans and rise further in the subsequent weeks in patients after anterior infarction. CT-1 measured soon after AMI is indicative of LV dysfunction, and this cytokine may have a role in the development of ventricular remodelling and heart failure after AMI.

scholarly journals Alteration of Cardiovascular Structure and Function in Patients Undergoing Peritoneal Dialysis

2015 ◽  
Vol 5 (2) ◽  
pp. 135-144
Author(s):  
Damir R. Rebić ◽  
Senija R. Rašić ◽  
Muamer D. Dervišević ◽  
Aida H.M. Hamzić-Mehmedbašić ◽  
Alma M. Muslimović ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Systolic Function ◽  
Intima Media Thickness ◽  
Female Gender ◽  
Left Ventricular ◽  
Lv Function ◽  
Uremic Cardiomyopathy ◽  
Lv Systolic Function ◽  
Systolic And Diastolic Function ◽  
Negative Predictor

Aims: Cardiovascular alterations contribute to a high mortality rate in patients with end-stage renal disease (ESRD). The aims of the present study are to evaluate left ventricular (LV) function and common carotid artery (CCA) parameters and to determine risk factors associated with these changes in patients undergoing peritoneal dialysis (PD). Methods: This longitudinal prospective study was conducted in 50 ESRD patients in whom PD had been initiated and who were observed for 18 months after the commencement of dialysis treatment, with echocardiography and CCA ultrasound parameter evaluation. Results: LV hypertrophy was observed in 78% of patients at baseline and in 60% after 18 months of PD treatment. LV systolic and diastolic function was found to be significantly better after 18 months of PD treatment. Examining predictors of LV systolic function, it was found that total cholesterol was an independent positive predictor and endothelin-1 (ET-1) an independent negative predictor of LV systolic function after 18 months of treatment with PD (p < 0.001). Independent negative predictors of diastolic LV function were hemoglobin and type 2 diabetes mellitus, and daily collection of urine was an independent positive predictor (p < 0.001). Female gender was an independent negative predictor of CCA intima-media thickness, whereas body mass index, ET-1 and C-reactive protein were independent positive predictors (p < 0.001). Conclusions: The results suggest several novel modifiable mechanisms related to the short-term effects of dialysis that are potentially implicated in the development of uremic cardiomyopathy.

Attenuation of left ventricular dysfunction by an ACE inhibitor after myocardial infarction in a kininogen-deficient rat model

2008 ◽  
Vol 389 (6) ◽  
Author(s):  
Matthias Koch ◽  
Klaus Bonaventura ◽  
Frank Spillmann ◽  
Andreas Dendorfer ◽  
Heinz-Peter Schultheiss ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ace Inhibitor ◽  
Diastolic Pressure ◽  
Ace Inhibition ◽  
Left Ventricular ◽  
Brown Norway ◽  
Lv Function ◽  
Maximal Rate ◽  
Lv Dysfunction

Abstract Bradykinin (BK) coronary outflow and left ventricular (LV) performance of kininogen-deficient Brown Norway Katholiek (BNK) rats and Brown Norway Hannover (BNH) controls were investigated. We analyzed whether the angiotensin-converting enzyme (ACE) inhibitor ramipril is able to attenuate LV dysfunction after induction of myocardial infarction (MI) in this animal model. Ex vivo, the basal BK content in the coronary outflow of buffer-perfused, isolated hearts was measured by specific radioimmunoassay. In vivo, left ventricular pressure (LVP), the maximal rate of LVP increase, LV end-diastolic pressure, the maximal rate of LVP decrease and heart rate were determined using a tip catheter 3 weeks after induction of MI. Compared to BNK rats, basal BK outflow was increased 30-fold in controls (p<0.01). In vivo, we found no significant differences between sham-ligated BNK and BNH rats in basal LV function. After MI, the impairment of LV function was significantly worse in BNK rats when compared to BNH rats. ACE inhibition significantly attenuated this LV dysfunction in both groups, when compared to untreated animals. Reduced basal BK level resulting from kininogen deficiency has no effect on basal LV function, but remains to be a risk factor for the ischemic heart. However, ACE inhibition is sufficient to improve LV function despite kininogen deficiency.

scholarly journals Best anesthetics for assessing left ventricular systolic function by echocardiography in mice

2015 ◽  
Vol 308 (12) ◽  
pp. H1525-H1529 ◽  
Author(s):  
Ronald E. Pachon ◽  
Bruce A. Scharf ◽  
Dorothy E. Vatner ◽  
Stephen F. Vatner
Keyword(s):  
Heart Rate ◽  
Systolic Function ◽  
Left Ventricular Systolic Function ◽  
Conscious State ◽  
Left Ventricular ◽  
Lv Function ◽  
The Past ◽  
Anesthetic Agents ◽  
Lv Systolic Function ◽  
Randomized Crossover Study

Our review of the literature of the major cardiovascular journals for the past three years showed that for all studies using anesthesia for mouse echocardiography, the predominant anesthetic was isoflurane, which was used in 76% of the studies. The goal of this investigation was to determine if isoflurane is indeed the best anesthetic. Accordingly, we compared isoflurane with 2,2,2-tribromoethanol (Avertin), ketamine-xylazine, and ketamine on different days in the same 14 mice, also studied in the conscious state without anesthesia. A randomized crossover study design was employed to compare the effects on left ventricular (LV) systolic function and heart rate of the four different anesthetic agents assessed by transthoracic echocardiography. As expected, each anesthetic depressed LV ejection fraction and heart rate when compared with values in conscious mice. Surprisingly, isoflurane was not the best, but actually second to last in maintaining normal LV function and heart rate. The anesthetic with the least effect on LV function and heart rate was ketamine alone at a dose of 150 mg/kg, followed by Avertin at 290 mg/kg, isoflurane at 3% induction and 1 to 2% maintenance, and lastly ketamine-xylazine at 100 and 10 mg/kg, respectively. In summary, these results indicate that ketamine alone exerts the least depressant effects on LV function and heart rate, with Avertin second, suggesting that these anesthetics should be used when it is not feasible to study the animals in the conscious state as opposed to the most commonly used anesthetic, isoflurane.

scholarly journals Longitudinal mechanics as predictors of left ventricular systolic function in the early postoperative period after surgical perimembranous ventricular septal defect closure in children aged <1 year

2019 ◽  
Vol 23 (1) ◽  
pp. 17
Author(s):  
Yu. S. Sinelnikov ◽  
E. N. Orekhova ◽  
T. V. Matanovskaya
Keyword(s):  
Postoperative Period ◽  
Septal Defect ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Left Ventricular Systolic Function ◽  
Left Ventricular ◽  
Early Postoperative Period ◽  
Volume Index ◽  
Perimembranous Ventricular Septal Defect ◽  
Lv Systolic Function

<p><strong>Aim.</strong> To evaluate left ventricular systolic function in the early postoperative period after surgical perimembranous ventricular septal defect (VSD) closure in children aged &lt;1 year using longitudinal mechanics.</p><p><strong>Methods.</strong> Between 2014 and 2017, we examined 65 children aged 2–11 months with perimembranous VSD (mean diameter = 8.6 ± 1.7 mm) and a pulmonary-to-systemic blood flow ratio of &gt;1.5/1. The longitudinal mechanics of the left ventricle (LV) were assessed using vector velocity imaging. All the children underwent surgical perimembranous VSD closure. Echocardiographic studies were performed preoperatively, immediately postoperatively, and 1 and 20 days postoperatively.</p><p><strong>Results.</strong> In all the children, significant decreases in the LV end-systolic volume index, end-diastolic volume index, stroke volume index (SVI), and ejection fraction (EF) were identified immediately postoperatively when compared with the preoperative findings. One day postoperatively, the LV volume data normalized; however, in 10.8% of the children, the SVI and EF remained impaired. The percentage EF reduction showed weak correlations with the childrens’ weights (Rs = 0.3; p = 0.039), aortic cross-clamping durations (Rs = 0.36; p = 0.03), and VSD sizes (Rs = 0.33; p = 0.006). Twenty days postoperatively, the LV volumetric parameters normalized; however, the EF did not reach the initial value. The longitudinal strain and strain rate were reduced preoperatively when compared with normal values. For the prediction of a postoperatively significant EF reduction (≤35%), the preoperative LV strain had a sensitivity of 88%, specificity of 98.2%, and cutoff value of –9.2%; the LV strain rate had a sensitivity of 87.8%, specificity of 94.7%, and cutoff value of –0.47 s<sup>−</sup><sup>1</sup>.</p><p><strong>Conclusion.</strong> Children aged &lt;1 year with perimembranous VSD showed reductions in the longitudinal mechanics of the LV, reflecting subclinical systolic dysfunction. One day after surgical correction, a transient decrease in LV systolic function was noted in all the children; however, a significantly impaired LV systolic function was noted in 10.8% of the children. Our findings indicate that the longitudinal mechanics of the LV can predict LV systolic dysfunction in the early postoperative period with high sensitivity and specificity.</p><p>Received 17 January 2019. Revised 18 April 2019. Accepted 25 April 2019.</p><p><strong>Funding:</strong> The study did not have sponsorship.</p><p><strong>Conflict of interest:</strong> Authors declare no conflict of interest.</p>

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