Florian Schrub

Frédéric Schnell

Erwan Donal

Dr Elena Galli
email: elena.galli@chu-rennes.fr

M.D Schrub Florian

M.D Schnell Frédéric

M.D Donal Erwan

M.D Galli Elena
email: gallelena@gmail.com

Myocardial work is a predictor of exercise tolerance in patients with dilated cardiomyopathy and left ventricular dyssynchrony Short title: myocardial work and exercise tolerance in dilated cardiomyopathy

Keywords: dilated cardiomyopathy, left ventricular dyssynchrony, myocardial work

come

The non-invasive assessment of myocardial work (MW) by pressure-strain loop analysis allows the evaluation of global and regional myocardial function. In patients with LV dysfunction and mechanical dyssynchrony, global and regional alterations of myocardial performance and metabolism have been observed [START_REF] Russell | A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work[END_REF], [START_REF] Russell | Assessment of wasted myocardial work: a novel method to quantify energy loss due to uncoordinated left ventricular contractions[END_REF], [START_REF] Duchenne | Left Ventricular Remodeling Results in Homogenization of Myocardial Work Distribution[END_REF]. In these patients, myocardial constructive work has shown to be associated with LV remodeling [START_REF] Galli | Role of myocardial constructive work in the identification of responders to CRT[END_REF] and survival [START_REF] Galli | Myocardial constructive work and cardiac mortality in resynchronization therapy candidates[END_REF] after cardiac resynchronisation therapy (CRT).

Previous studies have shown that myocardial constructive work correlates with exercise performance in patients with hypertrophic cardiomyopathy [START_REF] Galli | Myocardial constructive work is impaired in hypertrophic cardiomyopathy and predicts left ventricular fibrosis[END_REF]. In patients with heart failure and preserved ejection fraction, myocardial constructive work is directly related to LV on exertion and exercise capacity [START_REF] Przewlocka-Kosmala | Usefulness of myocardial work measurement in the assessment of left ventricular systolic reserve response to spironolactone in heart failure with preserved ejection fraction[END_REF]. Despite previous publications suggest an association between MW and LV contractility in CRT candidates [START_REF] Russell | A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work[END_REF], [START_REF] Russell | Assessment of wasted myocardial work: a novel method to quantify energy loss due to uncoordinated left ventricular contractions[END_REF], [START_REF] Galli | Myocardial constructive work and cardiac mortality in resynchronization therapy candidates[END_REF], no specific study has been addressed at the assessment of the relationship between MW and exercise performance in patients with LV systolic dysfunction.

In this study we investigated the relationship between myocardial work and exercise tolerance in patients with dilated cardiomyopathy (DCM) according to the presence or absence of LV dyssynchrony (LV-DYS).

A c c e p t e d m a n u s c r i p t Methods Population 51 patients with primary dilated cardiomyopathy from our Regional Competence Center of Genetic Disease were retrospectively included in this study. All the patients were in sinus rhythm and had a good acoustic window. Patients with cardiac resynchronisation therapy or pacemakers were excluded from the study. Clinical data, including age, gender, New York Heart Association (NYHA) functional class, systolic and diastolic blood pressure, lnNTproBNP, medical therapy were assessed for each patient. All patients underwent ECG enregistration, trans-thoracic echocardiography and cardiopulmonary exercice test (CPET). The study was conducted in accordance with the "Good Clinical Practice" Guidelines in the Declaration of Helsinki. All patients provided written informed consent for participation in the study.

Echocardiography

All patients underwent standard transthoracic echocardiography using a Vivid 7 or Vivid E9 and E95 ultrasound system (GE Healthcare, Horten, Norway) equipped with a 3S or M5S 3.5-mHz transducer. Two-dimensional, color Doppler, pulsed-wave and continuous-wave Doppler data were stored on a dedicated workstation for the offline analysis (EchoPAC, GEHealthcare, Horten, Norway). Leaft atrial (LA) and LV volumes and function were measured by the biplane method, as recommended [START_REF] Lang | Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF]. Peak early diastolic flow velocity (E), were measured from the apical four chamber view by pulsed-wave Doppler with the sample volume placed between the tips of the mitral leaflets. Pulsed-wave tissue Doppler was used to assess peak early diastolic tissue velocity (e'). The ratio of mitral inflow early diastolic velocity to the average e' velocity obtained from the septal and lateral portions of the mitral annulus (E/e') was calculated to estimate LV filling pressure. Tricuspid annular plane systolic A c c e p t e d m a n u s c r i p t excursion (TAPSE) was measured by M-mode echocardiography with the curson aligned along the direction of the lateral tricuspid annulus in apical 4-chamber view. In patients with detactable tricuspid regurgitation, pulmonary artery pressure (PAPs) was estimated using the maximal velocity of the tricuspid regurgitation jet (TRV max ) and an estimation of the right atrial pressure (RAP) based on the inferion vena cava size and collapsibility according to the following formula: PAPs= 4x (TRV max ) 2 + RAP [START_REF] Lang | Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging[END_REF].

LV global longitudinal strain (GLS) assessment

Two-dimensional greyscale images were acquired in the apical 4-, 3-, and 2-chamber views at a frame rate ≥60 frames/s. The recordings were processed using an acoustic-tracking dedicated software (EchoPAC version 112.99, Research Release, GE Healthcare, Horten Norway), to estimate LV global longitudinal strain (GLS).

Myocardial work evaluation.

Myocardial work (MW) and related indices were estimated using a vendor-specific module (EchoPAC Version 202, GE Vingmed Ultrasound, Norway), by the combination of LV strain data and the non-invasive estimation of the LV pressure curve as previously described [START_REF] Russell | A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work[END_REF].

The main steps for the estimation of MW are described above.

Briefly, peak systolic LV pressure is assumed to be equal to the peak arterial pressure recorded from the brachial cuff systolic pressure prior to the echocardiographic study. A patient-specific LV pressure curve is then constructed, adjusting LV pressure curve to the duration of the isovolumic and ejection phases, defined by valvular timing events.

Strain and pressure data are synchronized using the R wave on ECG as a common time reference. The area within the PSL provided an index of MW for each myocardial segment.

Constructive work (CW) was defined as MW during segmental shortening in systole, and

Assessment of left ventricular dyssynchrony.

Left ventricular dyssynchrony (LV-DYS) was defined by the presence of a septal flash (SF) and or an apical rocking (AR) in different transthoracic echocardiography views. SF was defined by the presence of early septal thickening/thinning detected by M-mode within the isovolumetric contraction period or by the presence of a rapid change of colour in tissue Doppler imaging related to the early and fast contraction of the septum occurring during the isovolumetric period [START_REF] Parsai | Toward understanding response to cardiac resynchronization therapy: left ventricular dyssynchrony is only one of multiple mechanisms[END_REF]. AR was defined as an apical transverse motion , with short initial septal contraction followed by delayed later wall activation [START_REF] Szulik | Assessment of apical rocking: a new, integrative approach for selection of candidates for cardiac resynchronization therapy[END_REF].

Cardio-pulmonary exercise testing (CPET).

All subjects underwent a progressive exercise test on an ergocycle (ERG 900; Jaeger, Hochberg, Germany) according to the recommendations [START_REF] Guazzi | EACPR/AHA Scientific Statement. Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations[END_REF]. The initial workload of 30 Watts was progressively increased by 15-25 W every 2-minutes until symptoms' onset or maximal exertion was reached. Breath-by-breath gas exchanges were analyzed using an Oxycon device (Jaeger), and the electrocardiogram (CardioSys; Marquette-Hellige, Freiburg, Germany) was continuously monitored to detect eventual arrhythmias and/or repolarization alterations. The maximal oxygen uptake (VO2 peak ) was expressed as mL/min/kg.

Statistical analysis

A c c e p t e d m a n u s c r i p t

Continuous variables are expressed by their mean and standard deviation and compared using the Student's t-test. Categorical data are expressed in terms of frequencies and percentage and compared by the χ² test. To identify correlates of VO2 peak , univariable linear regression analysis was carried out. After excluding variables showing collinearity (Pearson's coefficient ≥0.6), all the variables that were significant at univariable analysis were entered into a stepwise multivariate regression analysis. A p-value ≤0.05 indicated statistical significance. All statistical analysis was performed using a standard statistical software program (SPSS Version 20.0, IBM, Chicago -IL, USA).

Results.

Clinical, echocardiographic, and CPET data from the overall population and based on the presence of LV dyssynchrony are presented in Table 1.

In the overall population, mean age was 57±13 years, 32 (63%) patients were males and LV-DYS was observed in 16 (31%) patients. There were no significant differences between the groups in NYHA function class, therapy regimens and cardiovascular risk factors. Exercise tolerance was also similar in the two groups. LV volumes tended to be larger in patients with LV-DYS without reaching statistical significance. LVEF was significantly lower in patients with LV-DYS (28±7 vs 34±10 %, p=0.04), and GLS was much more altered in LV-DYS (-13±3 vs -10±3, p=0.001). In the LV-DYS group, GWW was significantly higher, and GWE was lower with respect to patients without LV-DYS. If we look at the regional distribution of MW, Septal CW (CW sept ), lateral CW (CW lat ) and septal WE (WE sep t) were significantly impaired in patients with LV-DYS, whereas septal (WW sept ) and lateral WW (WW lat) were significantly increased (Table 1, Figure 2 A-F). LA volume, TAPSE and PAPs were not significantly different in patients with and without LV dyssynchrony.

Parameters related with VO2 peak

A c c e p t e d m a n u s c r i p t

The main correlates of VO2 peak at univariable linear regression analysis are listed in Table 1.

In patients with LV-DYS, LVEF, WE sept and CW sept were the only correlates of VO2 peak .

In patients without LV-DYS, LVEF, age, and lnNT-proBNP emerged as correlates of VO2 peak .

At the multivariable regression analysis, WE sept (β=0.68, p=0.03 ) was the only correlate of VO2 peak in patients with LV-DYSS, wheras no LV functional parameter was able to predict VO2 peak in patients without LV dyssynchrony (Figure 3).

Discussion

The present study demonstrate that in patients with dilated cardiomyopathy, LV-DYS assessed by echocardiography is characterized by a significant increase of GWW and reduction in GWE, which are particularly altered in septum.

In these patients, the residual WE in the septum is the main correlate of exercise tolerance as assessed by the CPET.

Heart failure with reduced ejection fraction is a great therapeutic challenge. When the symptoms resist to first line medical therapy, with no or incomplete recovery of the systolic function, new therapeutics may be used, like CRT, in order to improve LV performance 6 .

Recent studies have shown that the presence of LV-DYS in CRT-candidates is a predictor of LV contractile reserve [START_REF] Stankovic | Dynamic relationship of left-ventricular dyssynchrony and contractile reserve in patients undergoing cardiac resynchronization therapy[END_REF] and is able to improve the prognostic value of guideline-based patients' selection for CRT [START_REF] Beela | Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient selection for cardiac resynchronization therapy[END_REF]. Interestingly, the predictive role of LV-DYS is maintained also in patients with QRS duration <120 ms [START_REF] Beela | Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient selection for cardiac resynchronization therapy[END_REF].

Several methods mostly based on the analysis of timing of longitudinal myocardial velocity peaks have been proposed in order to identify LV-DYS [START_REF] Mor-Avi | Current and evolving echocardiographic techniques for the quantitative evaluation of cardiac mechanics: ASE/EAE consensus statement on methodology and indications endorsed by the Japanese Society of Echocardiography[END_REF]. Nevertheless, the results of the A c c e p t e d m a n u s c r i p t PROSPECT trial have raised serious doubts regarding the robustness of these parameters, which makes their application unsuitable in everyday clinical practice [START_REF] Chung | Results of the Predictors of Response to CRT (PROSPECT) Trial[END_REF].

The visual identification of LV-DYS by the detection of SF and AR is a relatively recent tool, which have shown to be associated with the response to cardiac resynchronisation therapy (CRT) and survival in patients CRT-candidates [START_REF] Stankovic | Relationship of visually assessed apical rocking and septal flash to response and long-term survival following cardiac resynchronization therapy (PREDICT-CRT)[END_REF].

In the present study conducted on patients DCM, LV-DYS was defined by the presence of septal flash and or apical rocking and was detected in 31% of patients.

Despite the great majority of patients with LV-DYS in our population had a widened QRS, a proportion of patient with LV-DYS (25%) did not have LV conduction disturbances.

These findings are in line with previous publications on this topic [START_REF] Beela | Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient selection for cardiac resynchronization therapy[END_REF] , [START_REF] Menet | Is mechanical dyssynchrony a therapeutic target in heart failure with preserved ejection fraction?[END_REF], and support the concept that specific sign of mechanical dyssynchrony assessend by echocardiography can be present regardeless of QRS width.

In our population, LV-DYS was associated with a significant increase in GWW and reduction in GWE, which were paricularly pronounced in the septum. This redistribution of MW has already been observed [START_REF] Russell | A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work[END_REF], [START_REF] Russell | Assessment of wasted myocardial work: a novel method to quantify energy loss due to uncoordinated left ventricular contractions[END_REF], [START_REF] Duchenne | Left Ventricular Remodeling Results in Homogenization of Myocardial Work Distribution[END_REF] in patients with LV-DYS and is associated with a significant decrease of the metabolic activity of the septum with respect to the lateral LV wall [START_REF] Russell | Assessment of wasted myocardial work: a novel method to quantify energy loss due to uncoordinated left ventricular contractions[END_REF] , [START_REF] Duchenne | Left Ventricular Remodeling Results in Homogenization of Myocardial Work Distribution[END_REF].

As a matter of fact, previous studies shown that typical LV-DYS is associated with a specific septal deformation pattern, which is caracterised by an early shortening followed by a rebound stretch. The entity of this rebound stretch, is an indirect measure of septal viability and is associated with CRT-reponse [START_REF] Boeck | Septal rebound stretch reflects the functional substrate to cardiac resynchronization therapy and predicts volumetric and neurohormonal response[END_REF]and prognosis [START_REF] Lumens | Differentiating Electromechanical From Non-Electrical Substrates of Mechanical Discoordination to Identify Responders to Cardiac Resynchronization Therapy[END_REF]. These alterations in septal mechanics are associated with local modifications in the metabolic activity and overall myocardial performance. Moreover, experimental studies have shown that LV dyssynchrony in failing hearts generates a "molecular polarization" between the septum and the lateral A c c e p t e d m a n u s c r i p t wall, which may contribute to the heterogeneity of electromechanics observed in patients with LV-DYS [START_REF] Szulik | Assessment of apical rocking: a new, integrative approach for selection of candidates for cardiac resynchronization therapy[END_REF].

As a matter of fact, patients with DCM without LV mechanical dyscoordination had a more homogenous distribution of MW-derived parameters.

In patients with HF and reduced LVEF, VO2 peak assessed by CPET has shown to be associated with LV contractile reserve during exercise [START_REF] Moneghetti | Contractile reserve and cardiopulmonary exercise parameters in patients with dilated cardiomyopathy, the two dimensions of exercise testing[END_REF] and with prognosis 11 .

In current study, LVEF and age were predictors of VO2 peak only in patients without LV-DYS.

On the contrary, WE sept emerged as the only predictor of exercise performance in patients with LV-DY, irrespective of the fact that LVEF and GLS were significantly more impaired in these patients. Despite the indeniable relationship between LVEF and prognosis in cardiac patients, decreased LVEF is a late and insensitive finding in the natural history of DCM. This might be particularly evident in patients with LV mechanical discoordination, who have significant alteration in regional LV mechanics and local metabolic activity [START_REF] Russell | A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work[END_REF] , [START_REF] Russell | Assessment of wasted myocardial work: a novel method to quantify energy loss due to uncoordinated left ventricular contractions[END_REF] , [START_REF] Duchenne | Left Ventricular Remodeling Results in Homogenization of Myocardial Work Distribution[END_REF].

Aalen et al. have shown that the dyssynchronous ventricle is particularly sensitive to

increase in LV afterload. This is particularly evident in the septum with respect to the lateral wall [START_REF] Aalen | Afterload Hypersensitivity in Patients With Left Bundle Branch Block[END_REF], and might explain the relationship between septal work efficiency and exercise performance in patients with LV-DYS. In a small cohort of patients undergoing CRT, Zweerink et al. have shown that the contribution of the septum to LV work varies widely in CRT candidates and that the lower is the septal contribution to myocardial work at baseline, the higher is the acute pump function improvement that can be achieved with CRT [START_REF] Zweerink | Prediction of Acute Response to Cardiac Resynchronization Therapy by Means of the Misbalance in Regional Left Ventricular Myocardial Work[END_REF].

Myocardial work efficiency represents the portion of myocardial energy which is correctly used for the stroke work during LV ejection. This support the hypothesis that exercice impairement in patients with LV-DYS is directly linked to the suboptimal use of energy due to heterogenous electromechanical activation and metabolical distribution. This

Limitations

Our survey have several limitations.1) This is a monocentric, retrospective study conducted on a very limited number of patients. 2) Brachial cuff pressure was used as a non-invasive LV pressure derivative to calculate MW. This might impact the accuracy of the estimation of myocardial work. Nevertheless, the non-invasive method for the estimation of myocardial work has been validated by previous studies and in different hemodynamics condictions [START_REF] Russell | A novel clinical method for quantification of regional left ventricular pressure-strain loop area: a non-invasive index of myocardial work[END_REF], [START_REF] Hubert | Estimation of myocardial work from pressure-strain loops analysis: an experimental evaluation[END_REF].

3) Patients with atrial fibrillation and myocardial ischemia were excluded from the study. This has the merit of making our population quite homogenoeous, but limits the external validity of our study.

Conclusions

In patients with dilated cardiomyopathy, the presence of LV-DYS assessed by echocardiography is associated with a significant increase of GWW, a decrease in GWE, and an heterogeneous distribution of MW. Septal WE was the best predictor of exercise performance in patients with LV-DYS. Further studies should explore whether the relationship between MW, exercise performance and LV contractility has any utility in predicting CRT response in patients with LV-DYS.

Introduction

  The relationship between myocardial performance and exercise tolerance in patients with LV dysfunction and mechanical dyssynchrony has not yet been well understood.

  s c r i p t segmental lenghtening during the isovolumic relaxation time. Wasted work (WW) was defined as the work performed during lengthening in systole and shortening in isovolumic relaxation, associated with energy loss. Work efficiency was defined as the ratio between myocardial CW and the sum of CW and WW. By averaging segmental work data for each segment, global constructive work (GCW), wasted work (GWW) , WE (GWE), and work index were estimated for the entire LV. An example of the estimation of myocardial work efficiency in a patient with and without left ventricular dyssynchrony is depicted in Figure 1.

A

  c c e p t e d m a n u s c r i p t interpretation can explain why patients who have higher septal work efficiency have better exercise performances.

A c c e p t e d m a n u 14 A

 14 s c r i p t FL.S., participated in the conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article ; E.G. participated in the conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article, critical revision for important intellectual content, final approval of the version to be submitted. F.S, E.D participated in the critical revision of the article for important intellectual content, and final approval of the version to be submittedEtichal standarsThis study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All patients included in the study gave their informed consent prior to their inclusion in the study. All details that might disclose the identity of the subjects have been omitted.

A c c e p t e d m a n u s c r i p t Figure captions Figure 1 . 20 A c c e p t e d m a n u s c r i p tFigure 2 A 21 A c c e p t e d m a n u s c r i p t

 captions120221 Figure captions

Figure 3 : 22 A c c e p t e d m a n u s c r i p t

 322 Figure 3 : Association between septal work efficiency (WE sept ) and VO2 Peak

Table 1 . Main characteristics of the overall population and according to the presence of intraventricular dyssynchrony

 1 tricuspid annular plane systolic excursion; VO2 peak, maximal oxygen uptake; WE lat , work efficiency lateral wall; WE sept , work efficiency septal wall; WW lat , wasted work lateral wall, WW sept , wasted work septal wall. *Tricuspid regurgitation jet was detactable in 24 (47%) patients, 16 (45%) without LV dyssyncrhony and 8 (50%) with LV dyssynchrony.

		All	No-dyssynchrony	LV-Dyssynchrony
		n=51	n=35 (69%)	n=16 (31%)	p-value
	Clinical data
	Age	57±13	57±13	57±15	0.91
	Males NYHA lnNT-proBNP, pg/ml Hypertension, n(%) Diabetes, n(%) Dyslipidemia, n(%) Beta-blockers, n(%) Antialdosteronics, n(%) ACEI/ARB, n(%) LBBB/RBBB, n(%) Echocardiographic data LVEDV, ml LVESV, ml LVEF, % E/e' LAV i , ml/m 2 TAPSE, mm PAPs, mmHg*	32 (63) 1.7±0.5 6.2±1.2 9 (18) 6 (12) 11 (22) 51 (100) 15 (29) 45 (88) 22 (43) 190±75 129±56 32±9 12±6 42±15 20±4 32±10	24 (69) 1.7±0.5 6.1±1.1 4 (11) 5 (14) 9 (26) 35 (100) 11 (31) 31 (89) 10 (29) 178±66 122±53 34±10 12±6 42±15 20±4 30±9 m a n u s c r i p t 8 (50) 0.17 1.7±0.5 0.85 6.4±1.5 0.51 5 (31) 0.09 1 (6) 0.38 2 (13) 0.25 16 (100) -4 (27) 0.51 14 (88) 0.62 12 (75) 0.002 216±86 0.92 144±62 0.19 28±7 0.04 12±5 0.60 41±17 0.84 22±5 0.18 34±11 0.43
	GLS, % GCW, mmHg% GWW, mmHg% GWE, % CW sept , mmHg% CW lat , mmHg% WW sept , mmHg% WW lat , mmHg% WE sept , % WE lat , % VO2 data Maximal workload, Watt VO2 peak , ml/min/Kg HR max , bpm ACEi, angiotensin conversion enzym inhibitor; ARB, angiotensin receptor blocker; BNP, brain -12±3 -13±3 -10±3 0.001 1325±398 1342±354 1287±491 0.65 201±147 154±95 304 ±191 <0.0001 85±9 88±7 78 ±10 <0.0001 1172±459 1274±398 949±516 0.017 1518 471 1472±386 1620±622 0.30 283±275 174±98 522 ±376 <0.0001 135±88 117±81 176±92 0.02 78±16 84±9 62± 18* <0.0001 90±7 91±7 88±7 0.16 112±43 114±45 107±41 0.58 21±6 22±6 21±7 0.79 138±24 139±26 135±23 0.85 natriuretic peptide; CW lat , constructive work lateral wall; CW sept , constructive work septal A c c e p t e d
	wall; GCW, global constructive work; GWE, global work efficiency; GWW, global wasted
	work; HR, heart rate; LAV i , indexed left atrial volume; LBBB, left bundle branch bloch; LV, left

ventricle; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVEF : left ventricular ejection fraction; NYHA, New York heart association funtional class; PAPs, estimated pulmonary artery pressure; RBBB, right buldle branch block; TAPSE,

Table 2 . Univariable and multivariable association of exercise capacity (peakVO2) according to left ventricular dyssynchrony.

 2

	Variables			LV dyssynchrony				No LV dyssynchrony
			Univariable	Multivariable		Univariable	Multivariable
					Model R 2 = 0.55,				Model R 2 = 0.36,
					p=0.02				p=0.01
		β	R 2 p-value	β	p-value	β	R 2 p-value	p-value
	Age	-0.34	0.11	0.20			-0.40	0.16	0.02	-0.42	0.04
	LnNTproBNP	-0.31	0.09	0.30			-0.43	0.18	0.02	0.12	0.64
	LVESV	-0.27	0.08	0.44			-0.29	0.08	0.09
	LVEDV	-0.21	0.04	0.31			-0.18	0.03	0.10
	LVEF	0.52	0.27	0.04 0.23	0.48	0.47	0.20	0.005	0.47	0.05
	GLS	-0.36	0.13	0.17			-0.26	0.07	0.13
	GCW	0.25	0.06	0.36			0.11	0.01	0.52
	GWW	-0.34	0.11	0.20			-0.16	0.03	0.35
	GWE*	0.60	0.37	0.01			0.27	0.07	0.11
	CW sept	0.53	0.29	0.03 0.02	0.94	0.11	0.01	0.51
	CW lat	-0.01	0.00	0.97			0.09	0.01	0.62
	WW sept	-0.42	0.17	0.11			-0.09	0.01	0.58
	WW lat	-0.14	0.02	0.60			-0.13	0.02	0.45
	WE sept	0.71	0.50	0.002 0.68	0.03	0.20	0.04	0.25
	WE lat	0.17	0.03	0.53			0.21	0.04	0.24

Conflict of Interest

There are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

Disclosures

All authors made substantial contributions to the study.