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 Table of Contents  
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 176-183

Left Atrial and Renal Functional Status as Drivers of Adverse Outcome in Heart Failure with Reduced Ejection Fraction: A Four-Chamber Deformation Study in a Small Cohort of Northern Sweden

1 Umeå University, Umeå, Sweden
2 Narayana Institute of Cardiac Sciences, Bengaluru, Karnataka, India

Date of Submission03-Aug-2020
Date of Acceptance03-Aug-2020
Date of Web Publication19-Aug-2020

Correspondence Address:
Dr. Samir Kanti Saha
Faculty of Medicine, Umeå University, Umeå 90187
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiae.jiae_37_20

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In a small cohort of patients (58 ± 12 years) with heart failure and reduced ejection fraction (HFREF), we have analyzed myocardial mechanics in all the four principal cardiac chambers to investigate the prognostic value of left atrial (LA) remodeling. We have also studied to investigate a possible prognostic role of the biochemical markers, such as estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) and N-terminal pro-brain natriuretic peptide (NT-proBNP). We used two-dimensional speckle tracking echocardiography to compute cardiac deformation in addition to measuring LA reservoir strain using two algorithms based on the type of electrocardiogram gating protocol chosen. The data have shown that not only four-chamber strain was significantly lower in HFREF compared with the controls but also LA strain predicted an adverse outcome. In addition, in the subgroup analysis, eGFR was significantly lower in patients with adverse outcome (death or cardiac transplantation). Interestingly, the contribution of the renal biomarker was as significant as NT-proBNP in this regard.

Keywords: Global longitudinal strain, heart failure, left atrial strain, right ventricular strain

How to cite this article:
Saha SK, Kiotsekoglou A, Govind SC, Lindmark K. Left Atrial and Renal Functional Status as Drivers of Adverse Outcome in Heart Failure with Reduced Ejection Fraction: A Four-Chamber Deformation Study in a Small Cohort of Northern Sweden. J Indian Acad Echocardiogr Cardiovasc Imaging 2020;4:176-83

How to cite this URL:
Saha SK, Kiotsekoglou A, Govind SC, Lindmark K. Left Atrial and Renal Functional Status as Drivers of Adverse Outcome in Heart Failure with Reduced Ejection Fraction: A Four-Chamber Deformation Study in a Small Cohort of Northern Sweden. J Indian Acad Echocardiogr Cardiovasc Imaging [serial online] 2020 [cited 2020 Oct 27];4:176-83. Available from: https://www.jiaecho.org/text.asp?2020/4/2/176/292624

  Introduction Top

Left atrial (LA) functional impairment has been implicated in heart failure (HF) in studies using standard echocardiography, strain echocardiography, as well as cardiac magnetic resonance imaging.[1] Standard echocardiography can provide data on LA active and passive emptying and other phasic measures using ECG-gated timing synchronized with mitral and aortic valve motions in systole and diastole. While standard echocardiography relies on volumetric changes during the entire cardiac cycle that requires multiple equations, strain echocardiography can provide information in a single spatio-temporal interface depicting dynamic functions, namely, reservoir, conduit, and booster pump functions, with excellent reproducibility. Strain rate imaging has the added advantage of providing conduit and booster pump functions with extremely high signal-to-noise ratio. In the recent times, two sets of normal reference values of LA strain have been published,[2],[3] and the investigators have proposed normative values that vary substantially between the normal values of LA peak systolic strain (reservoir function) in the two published reports. The difference is mainly because of different ECG gating used in the two studies: PP gating resulted in lower values,[3] whereas RR gating provided higher values.[2] It is not clear which mode of ECG gating should be used in research as well as in the clinics. In this study, we have investigated LA dynamic function in both the forms of gating to investigate the role of atrial myopathy in patients with HF with reduced ejection fraction (HFREF) hospitalized for acute decompensation, relative to dysfunction of the other chambers of the heart. Our group has previously shown the superiority of LA strain over volumes in atrial fibrillation,[4] as well as differential LA and left ventricular (LV) coupling in HFREF, in a cohort of the Chinese population.[5] Here, we present the prognostic value of strain imaging, particularly of LA strain imaging using the two gating protocols, in a small cohort of northern Sweden.

  Subjects Top

Of the 232 patients with HFREF that were hospitalized from January to December 2016 for HF decompensation, 41 patients died. Of the rest, 28 patients were post priori selected to be included in this study. The selection criteria were based on the availability of echocardiographic images within the year 2015 or 2016. Not only that, only those patients whose images were acquired in the department of clinical physiology by specialist cardiologists or sonographers on GE equipment (Vivid 7 or Vivid 9, GE Healthcare, EchoPAC, Horten, Norway) were accepted for analysis. Recent studies have shown that this provided the best LV global strain values compared with other contemporarily available equipment.[6] The patients had mixed pathologies in the background of severe HF, with dilated cardiomyopathy in 17, implantable cardioverter-defibrillator (ICD) implanted in 16, ischemic cardiomyopathy in six patients, arrhythmogenic right ventricular cardiomyopathy in one patient, Takotsubo disease in one patient, and transposition of arteries in one patient, while oncotoxic cardiomyopathy in one patient. Of the associated comorbid condition, six patients had atrial fibrillation; two patients each had Type 2 diabetes and chronic obstructive pulmonary disease, cancer, and sleep apnea; one patient each had hypertension, depression and systemic lupus erythematosus, drug abuse, and renal failure; and three patients were obese. Rest of the patients had no known major comorbid conditions. The prevalence of coronary artery disease is provided in [Table 1]. All patients received evidence-based medications for HFREF as per the current recommendations, except that none received angiotensin receptor neprilysin inhibitor, as advocated in the latest guideline of 2017 that recommends a switch from angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers.[7]
Table 1: Clinical, echocardiographic, coronary, and outcome data in the heart failure and reduced ejection fraction group

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Of the 28 study participants, two patients died: one was on the LV assist device while on the transplantation waiting list and the other patient received cardiac transplantation. These patients were grouped as having an adverse outcome, while these including 13 others that were on ICDs were grouped as those with a composite outcome.

Seventy-nine healthy younger (40 ± 9 years) volunteers served as controls to mainly compare the strain values to gauze the degree of chamber dysfunction in HFREF.

The Ethical Committee approved the study of the Umeå University, and the study was conducted as per the Helsinki declaration.

  Methods Top

Standard echocardiographic methods

All standard and speckle tracking echocardiographic images were obtained by a 2.5 MHz piezoelectric crystal probe to scan patients from parasternal long and short axes, apical long axis, subcostal, and from suprasternal windows in quiet breathing. A GE Vivid 7 or a GE Vivid 9 system was used (Horten, Norway). The machine was set with a sweep speed of 50/s and a depth of 16 cm. The gain setting was made to maximize the visualization of cardiac structures. Standard two-dimensional imaging included aortic, LA, and right ventricular (RV) and LV dimensions (linear or M-Mode, wherever applicable). The great vessels were negotiated using continuous-wave Doppler, whereas the mitral and tricuspid valves were negotiated using pulsed-wave Doppler. LA volume was assessed using the area plane method, whereas the LV systolic function was estimated using ejection fraction (EF) obtained by Simpson's biplane method. All measurements were made according to the guideline of the American Society of Echocardiography and the European Association of Echocardiography.[8] The subcostal projection was used to assess the respiratory collapsibility of the inferior vena cava to estimate right atrial pressure that was added to peak tricuspid regurgitation velocity gradient to estimate pulmonary artery systolic pressure.[9]

LV diastolic function and filling pressure was estimated by standard methods of mitral pulsed-wave Doppler. Filling pressure was estimated using the E/E´ ratio, where E (early mitral velocity) represents the numerator and E´ (average of septal and lateral tissue Doppler velocity) represents the denominator.

Speckle tracking echocardiography (two-dimensional strain)

Chambers of interests were manually traced along the endocardial border at end diastole in a way that the motion of the tracking border was in synchrony with that of the cardiac chamber (RV, LV, or LA). Upon successful tracking, the quality of the tracking was approved upon which segmental strain curves in color, representing the segments tracked, were auto-generated and displayed with an excellent spatio-temporal resolution, in a single interface. A global strain value was represented in white and is used in all analyses in this study. In case the segments were not appropriately tracked, manual corrections were made whenever needed to ensure accurate tracking. For the LV, global longitudinal strain (GLS) was obtained by tracking the apical four-, three-, and two-chamber images [Figure 1].
Figure 1: Bull's eye distribution: LV GLS (upper left: normal LV with 20% strain; upper right with greatly depressed global strain of a failing LV with a strain of just 5%). Lower left: Segmental strain obtained from a failing LV (apical three-chamber view); lower right: RV longitudinal strain. The white curve represents global strain, while colored curves represent segmental strain. RV free wall strain is derived by taking the average of basal, mid, and apical strain. LV: Left ventricle, RV: Right ventricular

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LA strain was computed using two protocols: (1) by using the P-wave (P-P gating) and (2) by the use of R-wave of the QRS complex (R-R gating) [Figure 2]. The two protocols provide two different sets of LA strain values,[2] with lower reference values published using the P-P gating.[3] As there are no standard available as of now, we used both forms of strain measurements.
Figure 2: LA strain in a patient with HFREF: Left panel shows strain curve obtained using the R-R algorithm, while the right panel shows the same using P-P algorithm with lower peak reservoir strain, though the booster component is unfolded below the baseline. LA: Left atrium, HFREF: Heart failure and reduced ejection fraction

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RV free wall strain was computed as the average of basal, mid, and apical longitudinal strain, while RV-GLS % was the average of RV free wall and LV septal wall strain [Figure 1], lower right panel].

Statistical methods

Data were expressed as mean ± standard deviation unless otherwise stated. Quantitative comparisons were made using independent sample t-test, whereas qualitative comparisons were made using Fisher´ s exact test. Pearson´ s correlation assessed the association between variables. Logistic regression was used to detect the odds ratio of variables accounting for adverse and composite outcomes. Survival analysis was performed either using the Kaplan–Meier survival estimate or Cox proportional-hazards regression. Bland–Altman (B–A) curves were constructed to find out the bias and 95% limits of agreement between the two protocols (RR vs. PP gating) of LA strain quantification. Receiver operating characteristic (ROC) analysis was used to predict the adverse or composite outcome of death, cardiac transplantation, and ICD implantation. P < 0.05 was set to reject the null hypothesis. We used a PC-based software MedCalc Statistical Software version 19.4. 1 (MedCalc Software bv, Ostend, Belgium) for statistical analysis.

  Results Top

[Table 1] shows the demographic, clinical, echocardiographic, and biochemical features of the study participants. HFREF patients were older than the controls (data not shown).

[Figure 1] shows the Bull´ s eye distribution of LV GLS in controls and HFREF, as well as LV and RV longitudinal strain. [Figure 2] shows LA strain using the two protocols.

Comparisons of echocardiographic and clinical measures between those with adverse events and those without are presented in [Table 2].
Table 2: Comparisons of means between those with adverse outcome versus those without

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Comparison of strain percent measures

In HFREF and controls, LV ejection fraction (LVEF) was 27 ± 13% versus 64 ± 8%; the LA volume (mL) was 28 ± 9 versus 83 ± 27; LV-GLS (%) was 8 ± 4 versus 19 ± 2; and RV free wall strain (%) was 14 ± 8 versus 24 ± 4. LA-reservoir strain (%) with R-R gating was 12 ± 7 versus 33 ± 7 and was 8 ± 5 versus 23 ± 8 with PP gating. RV GLS % was 11 ± 5% versus 20 ± 3 (all P < 0.001 vs. controls) [Figure 3].
Figure 3: Left panel: Bar diagram showing differences of strain values between controls and HFREF - right panel. Bar diagram of strain values and LVEF%, and all calculated strain values. LV: Left ventricle, RV: Right ventricle, LA: Left atrium, Res: Reservoir strain (vide [Figure 2] and [Figure 3]). LAV: LA volume, LVEF: LV ejection fraction, HFREF: Heart failure and reduced ejection fraction. Data in the right panels show differences between adverse outcome and those with no adverse outcome

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In patients with adverse outcome, LA volume (mL) was statistically significantly higher compared with those without [112 ± 28 vs. 81 ± 27; P < 0.05, [Figure 3], right panel]. On the other hand, LVEF (%) was statistically significantly lower in ICD bearers than those without (21 ± 11 vs. 31 ± 13; P < 0.05). For the prediction of the composite outcome, ROC analysis showed only LVEF% to have the highest area under the curve (AUC) (0.7) when all echo measures were added in the analysis. However, when only ICD implantation was considered, the same analysis identified both LVEF% and LA reservoir strain (P-P gating) with AUCs of 0.75 and 0.74, respectively, as predictors. The latter also predicted the adverse outcome with an AUC of 0.71 that was inferior to that of LA volume (AUC, 0.8; P < 0.05) [Figure 4].
Figure 4: ROC analysis showing predictive value of LA volume for death or requirement of cardiac transplantation with a significant AUC value, while LA reservoir strain (P-P gated) did not have significant discriminatory power despite a good AUC value. AUC for R-R gated LA strain % was much worse at 0.5! A statistically significant difference between the two AUCs remains at P < 0.05. ROC: Receiver operating characteristic, LA: Left atrium, AUC: Area under the curve

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R-R gated LA reservation strain showed a trend to predict the adverse outcome, while a combination of LA volume and LA reservoir strain showed a cumulative hazard of 1.96 for adverse events [Figure 5].
Figure 5: Survival analysis. Left panel: Cox proportional-hazards regression data showing a trend to predict adverse outcome. Right panel: Kaplan–Meier survival statistics obtained by taking both LA volume and LA reservoir strain cutoffs that resulted in a nonsignificant trend of adverse outcome. Cutoffs were chosen based on optimal sensitivity and specificity values on ROC analysis. ROC: Receiver operating characteristic, LA: Left atrium

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Kidney function in heart failure and reduced ejection fraction

Estimated glomerular filtration rate (eGFR) (mL/min/1.73 m2) was statistically significantly lower in patients with adverse outcome (41 ± 14 vs. 67 ± 22; P < 0.05). On logistic regression analysis, with all clinical, biochemical, and strain variables having been entered in the analysis, only eGFR predicted adverse outcome with an odds ratio (OR) of 0.9 (95% confidence interval [CI]: 0.9–1.0) and with an AUC of 0.84 (95% CI: 0.6–0.9; P < 0.05). eGFR was also lower in patients with the composite outcome (55 ± 18 vs. 74 ± 27; P = 0.05). The AUC for N-terminal pro-brain natriuretic peptide (NT-proBNP) did not differ in the ROC analysis [Figure 6].
Figure 6: Comparative ROC analysis with biochemical markers for prediction of adverse outcome. ROC: Receiver operating characteristic

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B–A plot depicts variable bias and 95% limits of agreement between the two LA strain protocols, with controls showing a greater disparity between P-P and R-R gating versus HFREF [Figure 7].
Figure 7: B–A plots showing much smaller bias and 95% limits of agreements in HFREF (right panel) than in controls (left panel). HFREF: Heart failure and reduced ejection fraction, B–A: Bland–Altman

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[Figure 8] shows disparate LA and LV mechanical coupling using the two different LA strain gating protocols.
Figure 8: Pearson's correlation showing slightly discordant coupling between atrio-ventricular coupling in the entire cohort: trend line approaches line of unity when P-P gated LA strain is entered into the equation (left panel). LA: Left atrium

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[Figure 9] shows the comparison of eGFR values in the two groups.
Figure 9: Comparison of eGFR in the study participants. eGFR: Estimated glomerular filtration rate

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  Discussion Top

The principal findings of the study are: (1) biventricular longitudinal strain, LA volume, and LA reservoir strain irrespective of whether this was computed using P-P or R-R gating were significantly lower in HFREF; (2) while LA volume had the superior discriminatory power to predict adverse outcome than P-P gated LA strain, Cox proportional-hazards regression data showed a trend to predict adverse outcome using R-R gated LA reservoir strain; (3) a combination of LA volume (cutoff 87 mL) and R-R gated LA strain (cutoff being 14%) impacted survival with a hazard ratio of 1.96 (95% CI: 0.2–18.9); (4) LA strain irrespective of the method of computing had a significant correlation with LVGLS%, albeit with a better r value with RR gated LA strain, and, finally, (5) renal function estimated by glomerular filtration rate had a similar impact on outcome compared with the biomarker NT-proBNP.

Left atrium reservoir strain A marker of “global atrial failure”?

Typically, atria have a phasic function characterized by reservoir, conduit, and booster pump functions. While volumetric assessment of these functions requires many formulae, speckle tracking strain unfolds the three dynamic phases in real time. In this study using strain imaging, we have assessed reservoir function that corresponds to the passive stretching of the LA wall during early filling. This phase has been reported to correlate with the cath-based estimation of pulmonary artery wedge pressure.[10] However, it has been suggested [11] and disputed [12] that depressed atrial contraction (booster pump function) independently of GLS, may guide to ICD implantation in severe HF. Clinically, as the guideline suggests, ICDs were implanted in our patients based on severe LV failure. Hence, it is not surprising that LA reservoir strain (as a marker of elevated filling pressure) was indeed very low in the presence of markedly remodeled LA, to suggest a form of atrial stunning or atrial “exhaustion,” according to the proposition of Smiseth.[12] Though there is no consensus as to whether LA strain should be computed using P-P or R-R-gated protocols, our study has shown the value of both the protocols to assess the prognosis in severe HF.

Although we do not know the reason behind a pathognomonic role of the LA in HFREF, LA function both by CMR and STE has been reported to be associated with LV filling and even LV fibrosis and has been discussed in a review.[13] Furthermore, LA functional status has been suggested to be a “powerful biomarker” in atrial fibrillation and HF.[14] Taken as a whole, the findings of this study may support the concept of “global LA failure”[15] that is obvious in this small Swedish cohort of HFREF.

Left atrial reservoir versus left ventricular global longitudinal strain

The maintenance of LV systolic function is governed by preload, afterload, heart rate, and of course its intrinsic contractility. Whether LA mechanical integrity contributes to preserving LV systolic function has not been studied in a similar extent as with other deterministic factors of LV systolic function. The advent of echocardiographic postprocessing using speckle tracking echocardiography has made it possible to quantitatively and noninvasively study the mechanical coupling between the two left-sided chambers. In the current project, we have shown that P-P gated LA reservoir strain may have a steeper relationship with LV GLS, than P-P gated LA strain in HFREF, while in the controls, there is a gating-independent positive correlation. It is, however, difficult to ascertain whether this is because of a lower value of P-P gated strain coping with a very poorly functioning LV. It may also be of interest to mention here that in LV failure due to predominant ischemic etiology, left-sided LA/LV coupling is stronger than the right-sided heart, as we have shown in the Chinese population with HFREF.[5]

In a prospective observational cohort study, the investigators have shown that in a mixed population of HFREF and HFPEF (mean age 71 years), LV GLS was independently associated with LA reservoir and conduit strain but not with LA pump (booster) strain.[16] These data combined with our current data may indicate that in chronic disease states, dysfunction of multiple cardiac chambers is involved in sustaining a disease state (in this case, chronic HF) often with a worse outcome with variable coupling between the chambers engaged on either side of the heart. In other disease states such as in acute myocardial infarction, such relationship may not exist.[17]

The right ventricle in severely depressed left-sided function

Dysfunctional RV mechanics have been shown to correlate with the degree of myocardial fibrosis in patients with severe LV failure requiring cardiac transplantation.[18] In the present study, though RV free wall strain was very low, this did not impact the outcome, neither was it any better than other cardiac mechanical chambers, notably LA, in the ROC analysis. However, in a recently published study on over 200 consecutive patients with chronic HFREF, RV free wall strain of 9.2% resulted in a significantly lower event-free survival rate. Not only that RV free wall strain was superior to the conventional measure of RV systolic function using tricuspid annular plane systolic excursion.[19] Although the link between RV dysfunction and left-sided HF may not yet be obvious, an elegant review has proposed that chronic renal disease may produce inflammatory agents to alter the loading state of the LV in the genesis of HF, especially in HF with preserved EF.[20] As our study participants belong to HFREF phenotype, we can only speculate that chronic inflammation may be the link between the collusion of the two ventricles to herald an adverse outcome.

Estimated glomerular filtration rate versus N-terminal pro-brain natriuretic peptide Two sides of the same coin in heart failure and reduced ejection fraction?

A recently published international study has shown the association between a biomarker of renal dysfunction and incident HFREF.[21] In that study, the investigators have used plasma cystatin as a marker of tubular damage, while in our study, we have measured creatinine clearance as a marker of glomerular filtration rate. Despite the discrepancy, kidneys do play a significant role not only in sustaining HF but also in predicting an adverse outcome, as we have shown in our data on the Chinese population.[5] It may be mentioned here that though inflammation may induce HF in chronic renal dysfunction, we believe that in the current study, the primary pathology has been LV systolic dysfunction that has resulted in low eGFR. It is also possible that once renal dysfunction sets in, a vicious cycle comes into play to where LV dysfunction ushers in more renal dysfunction and thereby inducing more LV dysfunction.

  Conclusions Top

Strain echocardiography has come a long way in clinical and research arena from the identification of subclinical myocardial disease in many noncardiac conditions, such as diabetes [22] to make a clear distinction between physiologic LV remodeling versus hypertrophic cardiomyopathy and cardiac amyloidosis.[23]

Application of strain imaging in HF may provide valuable clinical and prognostic insight in better understanding the pathophysiology of HF in combination with clinical and biochemical markers. Because we now have three different phenotypes of HF, principally based on LVEF, multichamber strain analysis may provide additional prognostic value in the clinical management of HF in the setting of comorbidities.[5]

Limitations of the study

Although we did not report the classic left diastolic parameters, we presume that all patients in this cohort had high LV filling pressure, as the LA strain, which has been reported to correlate with wedge pressure, was very low, irrespective of the protocol used (R-R or P-P gating). The burden of comorbidity in this cohort matched well with that of the published report of downhill prognosis in HFREF.[24]

The study results are limited by the fact that the results were obtained from a small cohort and are restricted for one single year of hospitalization. The RV and LV data presented are during systole only. Diastolic LV function was not compared as the patients had not only bi-ventricular but also severe LA dysfunction. In addition, in acute decompensated LV failure, the value of diastolic indices remains questionable.[25] Despite such limitations, we have been able to show the importance of LA volumetric and mechanical dysfunction in predicting worse prognosis in HFREF with equipotent roles of eGFR and NT-proBNP.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Habibi M, Chahal H, Opdahl A, Gjesdal O, Helle-Valle TM, Heckbert SR, et al. Association of CMR-measured LA function with heart failure development: Results from the MESA study. JACC Cardiovasc Imaging 2014;7:570-9.  Back to cited text no. 1
Pathan F, D'Elia N, Nolan MT, Marwick TH, Negishi K. Normal ranges of left atrial strain by speckle-tracking echocardiography: A systematic review and meta-analysis. J Am Soc Echocardiogr 2017;30:59-70 e8.  Back to cited text no. 2
Miglioranza MH, Badano LP, Mihăilă S, Peluso D, Cucchini U, Soriani N, et al. Physiologic determinants of left atrial longitudinal strain: A two-dimensional speckle-tracking and three-dimensional echocardiographic study in healthy volunteers. J Am Soc Echocardiogr 2016;29:1023-34 e3.  Back to cited text no. 3
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]

  [Table 1], [Table 2]


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