MD, PhD Elena Galli
email: elena.galli@chu-rennes.fr

MD Arnaud Hubert

Virginie Le Rolle

PhD Alfredo Hernandez

PhD Otto A Smiseth

MD, PhD b ; Philippe Mabo

MD Christophe Leclercq

PhD Erwan Donal

Henri Rue

Le Guilloux

Myocardial constructive work and cardiac mortality in resynchronization therapy candidates

Keywords: cardiac resynchronization therapy, cardiac mortality, myocardial constructive work

Background: Recent studies have shown that myocardial constructive work (CW) assessed by pressure-strain loops (PSLs) is an independent predictor of a volumetric response to cardiac resynchronization therapy (CRT). Aim of this study was to evaluate the role of CW in predicting the cardiac outcome of heart failure patients undergoing CRT.

Methods: this is a retrospective study including 166 CRT-candidates (ejection fraction ≤35%, QRS duration ≥120 ms). 2D-standard and speckle-tracking echocardiography were performed before CRT and at 6-month follow-up (FU). PSLs were used to assess myocardial constructive work (CW).

Results: After a median FU of 4 years (range: 1.3-5 years), cardiac death occurred in 14 patients (8%). A multivariable Cox regression analysis including age, coronary artery disease (CAD), and septal flash (SF) showed that CW≤888 mmHg% was the only independent predictor of cardiac mortality (HR 4.23, 95% CI: 1.08-16.5, p=0.03). After 6 months of CRT, a 15% reduction in left ventricular end-systolic volume was observed in 118 (71%) patients, and a CRT volumetric response was identified. Among CRT-responders, the concomitant presence of CW≤888 mmHg% identified a subgroup of patients at high risk of cardiac death (p=0.04 in the log-rank test). The addition of CW≤888 mmHg% to a model including age, CAD, SF, and CRT response caused a significant increase in model power for the prediction of cardiac death (χ 2 : 12.6 vs 25.7, p=0.02).

Conclusions:

The estimation of left ventricular CW by PSLs is a relatively novel tool that allows for the prediction of cardiac outcome in CRT candidates.

INTRODUCTION

Cardiac resynchronization therapy (CRT) has been demonstrated to improve the left ventricular (LV) function and outcomes of patients with both systolic heart failure (HF) and wide QRS (>120 ms) [1], whom remain symptomatic despite optimized medical therapy [2]. Despite these striking results, approximately one-third of patients do not benefit, and in some cases, may even be harmed after CRT [3]. Several studies have shown that in HF patients with wide QRS and regional mechanical discoordination derived from the estimation of LV mechanical delay, CRT might alleviate the mechanical dyssynchrony caused by LV electrical activation delay [4]. Nevertheless, the routine use of mechanical discoordination as an adjunct to the electrocardiographic criteria for the selection of CRT candidates has not gained clinical acceptance [5] and has been shown to even be detrimental in patients with normal QRS [6].

A potential explanation for these results is that the assessment of QRS duration and/or myocardial dyssynchrony does not take into account the role of residual myocardial contractility [7][8][9] as a potential source for LV functional restoration after CRT.

In recently published surveys [10] [11] we demonstrated that the noninvasive estimation of global myocardial constructive work (CW) by PSL is a predictor of LV remodeling and response to CRT over common LV dyssynchrony parameters. The association between myocardial CW and outcome after CRT is, however, unknown. The aim of the present study was to assess the predictive role of myocardial CW on cardiac mortality in HF patients undergoing CRT.

METHODS

Population

This is a retrospective, observational, monocentric study conducted on 166 patients with systolic HF undergoing CRT implantation, according to current guidelines [1]. All patients

A C C E P T E D

M A N U S C R I P T 6 were in sinus rhythm and had a good acoustic window, allowing acquisition of 2Dechocardiography and speckle tracking echocardiography with excellent image quality. At the time of CRT implantation, all patients were receiving optimized medical therapy.

Coronary artery disease (CAD) was defined as a history of myocardial infarction and coronary revascularization or angiographic evidence of multiple-vessel disease or singlevessel disease with ≥75% stenosis of the left main or proximal left anterior descending artery [12]. CRT response was indicated by a decrease in LV end-systolic volume (ESV)

>15% at the 6-month follow-up (FU) [5]. A biventricular stimulation >90% after CRT implantation was mandatory for patient inclusion in the protocol. Clinical data including age, sex, and treatments were collected for each patient. The functional status was assessed by the estimation of the New York Heart Association (NYHA) functional class. Data on the vital status of patients were collected from hospital medical records or by interview with the patients' general practitioner or relatives.

The study was conducted in accordance with the "Good Clinical Practice" guidelines of the Declaration of Helsinki and reviewed by an independent ethics committee (Regional Ethic Committee validation number: 35RC14-9767). All patients gave their written informed consent for study participation. No extramural funding was used to support this work.

The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents

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, GE

A C C E P T E D M A N U S C R I P T 7

Healthcare, Horten, Norway). LV volumes and function were measured by the biplane method, as recommended [13].

Assessment of septal flash

The presence of septal flash (SF) was visually assessed before CRT implantation. SF was defined by the presence of an early septal thickening/thinning within the isovolumic contraction period [14][15].

Myocardial work quantification

Myocardial work and related indices were estimated using a vendor-specific module assessment. The inter-observer and intra-observer concordances for the estimation of myocardial work have already been reported [10], [11].

Statistical analysis

Continuous variables are expressed as the median and standard deviation and were compared using Student's t-test. Categorical data are expressed as frequencies and percentages and were compared by the χ² test. Receiver operator characteristics curve (ROC) analysis and the Youden's index were used to determine a CW cutoff that was able to predict events.

Univariable Cox proportional hazards analysis of baseline clinical, electrocardiographic and echocardiographic characteristics was performed using cardiac mortality as endpoint. For each variable, the hazard ratio (HR) and 95% confidence intervals (CI) were calculated. Only variables with a p-value <0.05 in the univariable analysis were inserted in the multivariable Cox analysis. Freedom cardiac death was plotted for both CW groups using Kaplan-Meier curves. Between-group differences in freedom from events were tested using the log-rank ROC curve analysis showed that a cutoff value of 888 mmHg% for CW was the best predictor of cardiac death (AUC 0.71, 95% CI: 0.60-0.82, p=0.007) (Figure 2). Patients with CW≤888 mmHg were more often male (p=0.01), had more dilated LV, lower LVEF and GLS (all p<0.0001), and lower prevalence of SF (p=0.01) than patients with CW>888 mmHg. A significantly lower rate of CRT responders was observed in this group (p<0.0001).

Clinical and echocardiographic data according to CRT response.

At the 6-month FU, volumetric CRT response occurred in 118 (71%) patients. Nonresponders were more often male (81 vs 64%, p=0.002) and had a lower prevalence of LBBB (29 vs 77%, p<0.0001) and SF (67 vs 89%, p=0.006) than responders. A significant difference in indexed LV end-diastolic volume, LV end-systolic volume, LVEF, and CW was observed between the two groups at baseline and at 6-month FU. A significant improvement in LV geometry and function was observed in CRT-responders at the 6-month FU. On the contrary, a slight increase in the indexed LV end-systolic volume and decrease in WW were observed in non-responders (Table 2).

Follow-up

The median follow-up was 4 years (interquartile range: 1.3-5 years). During this time span, cardiac death occurred in 14 patients (8%); 13 patients died of refractory heart failure, and 1 died one week after a heart transplant. In the multivariable Cox regression analysis, CW was an independent predictor of cardiac death (Table 3, Model A).

A C C E P T E D M A N U S C R I P T

11 Kaplan-Meier survival curves (Figure 3) showed that CW≤888 mmHg% was highly associated with a poor outcome (log-rank p=0.008). Patients with CW≤888 mmHg% had a higher risk of cardiac death (HR 4.76,p=0.01) (Table 3). When CW≤888 mmHg% was used instead of the continuous variable to predict CRT response in the multivariable Cox regression analysis, it remained the only significant predictor of mortality (HR 4.23, 95% CI: 1.08-16.5, p=0.03).

Long-term outcome in relation to CRT response and septal flash

To compare the added value of CW over LV reverse remodeling for predicting the course of the disease, volumetric response to CRT was added to the Cox multivariable model (Table 3,

Model B

). In this model, CRT response was no longer a significant predictor of cardiac death, and it did not affect the HR of CW, which remained a significant predictor of cardiac mortality. Among responders, the presence of a CW≤888 mmHg% resulted in increased cardiac mortality, as shown by the log-rank test. The concomitant absence of volumetric response to CRT and CW≤888 mmHg identified a subgroup of patients with a particularly dismal prognosis (Figure 4).

The relationship between CW and outcome was independent from SF (Table 2). In patients with SF, the presence of a CW≤888 mmHg% was associated with a significantly increased CV and all-cause mortality (log-rank test: p=0.00l). Patients without SF and with CW≤888 mmHg% presented the worst prognosis (Figure 5).

Finally, to evaluate the predictive value of CW≤888 mmHg% over SF and CRT response for cardiac death, Cox regression analysis was used, and different nested models were created.

The incremental value of each model was assessed by comparing the χ² value at each step.

The accuracy of the Cox proportional hazards model in predicting cardiac mortality did not increase after adding SF and CRT response to clinical variables, but was significantly

A C C E P T E D M A N U S C R I P T
increased by the addition of CW (Figure 6). Table 4 shows the Harrell's C-concordance statistic index for each model.

DISCUSSION

In the present study, we showed that in CRT candidates, the degree of global myocardial CW is a predictor of long-term survival, independent of the presence of SF and the volumetric response to CRT.

Assessment of myocardial constructive work

PSL curves are a recently introduced tool that allow a noninvasive estimation of myocardial work. The reliability of this method with respect to the invasive estimation of myocardial work has been validated by experimental studies and mathematical models [16][20][18].

Regional differences in myocardial work assessed by PSLs have a strong correlation with the entity of myocardial glucose metabolism evaluated by FDG-PET [16]. These results support the hypothesis that the differences in CW detected by PSLs before CRT correspond to myocardial residual metabolic activity and contractile reserve and might, therefore, explain the role of baseline CW in predicting CRT response [10], [11], [16] and long-term survival after CRT.

Myocardial constrictive work as a predictor of prognosis in CRT candidates

Although CRT has a pivotal role for the treatment of patients with HF and widened QRS, the lack of response to CRT remains an important clinical problem. From a physiologic point of view, it seems reasonable to believe that the main effect of CRT might be observed when a delayed electrical activation is associated with significant LV mechanical delay.

Nevertheless, the origin of LV mechanical discoordination may arise from substrates, such as a regional myocardial scar or hypocontractility, that are unresponsive to the electrical stimulation of CRT [9]. In patients with HF undergoing CRT, Ciampi et al. demonstrated that the presence of contractile reserve assessed by dobutamine stress echocardiography was

A C C E P T E D M A N U S C

Need for physiological understanding

The absence of myocardial viability is associated with the extent of LV remodeling before CRT and with the presence of extensive myocardial remodeling and fibrosis [22].

In our population, CW≤888 mmHg% was associated with a greater LV size and reduced LVEF before CRT. This cutoff identified a subgroup of patients with a particularly dismal prognosis and limited positive remodeling after CRT implantation.

The possibility that LV stimulation might gradually recruit viable myocardium might, therefore, be the key to achieving significant LV reverse remodeling after CRT and improved survival. Myocardial viability can be assessed by several methods, including MRI, stress echocardiography and nuclear imaging. PSLs allow the assessment of myocardial

Clinical perspectives

An increasing amount of data seem to underscore that the major benefits of CRT are observed when LV mechanical dyssynchrony is induced by an electrical activation delay. The results of the present study are not in opposition to this hypothesis but underscore the importance of the concomitant evaluation of the myocardial substrate of LV dysfunction in CRT candidates.

The existence of multiple independent mechanisms governing CRT response (e.g., ECG patterns, electromechanical delay, and residual contractility) supports the hypothesis that a multimodal stepwise approach that combines clinical, electrocardiographic, and echocardiographic data might be more effective for the identification of CRT responders.

Moving in that direction, the use of myocardial work seems very promising: it integrates the load, it is an automatic measurement with associated robustness, and it could be used as a global and a regional myocardial function parameter.

Limitations

This is a monocentric, retrospective study aimed at assessing the relationship between CW and mortality in CRT candidates. With respect to previous studies, which often include all-

A C C E P T E D M A N U S C R I P T

cause mortality and heart failure hospitalization in the primary end-point, we focused specifically on the predictors of cardiac mortality. The overall cardiac mortality rate in our survey was relatively low (4%), which might be attributed to the high percentage of CRTresponders (70%), the relatively low prevalence of ischemic cardiomyopathy (29%), and the significant increase in LVEF observed in responders (Table 2). No validation cohort was created to replicate our findings on myocardial work, which currently limits its application in everyday clinical practice. Precise myocardial scar localization and extension by cardiac MRI or nuclear imaging was not investigated in the current study, as far as the relationship between scar localization and LV lead position. Such investigations may be important to further understand the relationship between regional CW and LV function improvement in CRT candidates and should be the object of a future study.

As for many other echo-parameters, the proper assessment of myocardial work requires a suitable acoustic windows, and is not applicable to patients with poor echogenicity.

Until now, the validation of the non-invasive estimation of myocardial work by pressurestrain loops analysis has been restricted to patients to CRT candidates, patients with dilated cardiomyopathy of ischemic and non-ischemic etiology, and patients with arterial hypertension [16][18][19], which limits the reliable application of this method to these specific subsets of cardiac diseases. wide QRS (>120 ms) [1], whom remain symptomatic despite optimized medical therapy [2].

CONCLUSIONS

A C C E P T E D M A N U S C R I P T

Despite these striking results, approximately one-third of patients do not benefit, and in some cases, may even be harmed after CRT [3]. Several studies have shown that in HF patients with wide QRS and regional mechanical discoordination derived from the estimation of LV mechanical delay, CRT might alleviate the mechanical dyssynchrony caused by LV electrical activation delay [4]. Nevertheless, the routine use of mechanical discoordination as an adjunct to the electrocardiographic criteria for the selection of CRT candidates has not gained clinical acceptance [5] and has been shown to even be detrimental in patients with normal QRS [6].

A potential explanation for these results is that the assessment of QRS duration and/or myocardial dyssynchrony does not take into account the role of residual myocardial contractility [7][8][9] as a potential source for LV functional restoration after CRT.

In recently published surveys [10][11] we demonstrated that the noninvasive estimation of global myocardial constructive work (CW) by PSL is a predictor of LV remodeling and response to CRT over common LV dyssynchrony parameters. The association between myocardial CW and outcome after CRT is, however, unknown. The aim of the present study was to assess the predictive role of myocardial CW on cardiac mortality in HF patients undergoing CRT.

METHODS

Population

This is a retrospective, observational, monocentric study conducted on 166 patients with systolic HF undergoing CRT implantation, according to current guidelines [1]. All patients assessment. The inter-observer and intra-observer concordances for the estimation of myocardial work have already been reported [10], [11].

Statistical analysis

Continuous variables are expressed as the median and standard deviation and were compared using Student's t-test. Categorical data are expressed as frequencies and percentages and were compared by the χ² test. Receiver operator characteristics curve (ROC) analysis and the Youden's index were used to determine a CW cutoff that was able to predict events.

Univariable Cox proportional hazards analysis of baseline clinical, electrocardiographic and echocardiographic characteristics was performed using cardiac mortality as endpoint. For each variable, the hazard ratio (HR) and 95% confidence intervals (CI) were calculated. Only variables with a p-value <0.05 in the univariable analysis were inserted in the multivariable Cox analysis. Freedom cardiac death was plotted for both CW groups using Kaplan-Meier curves. Between-group differences in freedom from events were tested using the log-rank test. Finally, the merits of CW over different nested models including clinical variables, SF, and CRT response to predict mortality were assessed with Cox regression analysis, and the incremental value of each model was assessed by the χ² test at each step, and by the Harrel's C-concordance statistics. Intra-and inter-observer reliability for the assessment of SF was estimated by the percentage of agreement and Cohen'κ in 20 randomly selected patients.

All statistical analysis was performed using a standard statistical software program (SPSS Version 20.0, IBM, Chicago, IL, USA and R statistical software, version 3.4.4). A value of p<0.05 was considered statistically significant.

A C C E P T E D M A N U S C R I P T

42

RESULTS

Baseline characteristics of the population are summarized in Table 1. In the overall population, 48 (29%) patients had ischemic cardiomyopathy. LBBB was present in 136 (82%) patients. SF was identified in 105 (63%) patients. Intra-and interobserver agreement for visual assessment of SF were 95% (κ=0.90, [95%CI: 0.71-1], p<0.0001) and 90% (κ=0.80, [95% CI: 0.58-1], p=0<0.0001), respectively.

ROC curve analysis showed that a cutoff value of 888 mmHg% for CW was the best predictor of cardiac death (AUC 0.71, 95% CI: 0.60-0.82, p=0.007) (Figure 2). Patients with CW≤888 mmHg were more often male (p=0.01), had more dilated LV, lower LVEF and GLS (all p<0.0001), and lower prevalence of SF (p=0.01) than patients with CW>888 mmHg. A significantly lower rate of CRT responders was observed in this group (p<0.0001).

Clinical and echocardiographic data according to CRT response.

At the 6-month FU, volumetric CRT response occurred in 118 (71%) patients. Nonresponders were more often male (81 vs 64%, p=0.002) and had a lower prevalence of LBBB (29 vs 77%, p<0.0001) and SF (67 vs 89%, p=0.006) than responders. A significant difference in indexed LV end-diastolic volume, LV end-systolic volume, LVEF, and CW was observed between the two groups at baseline and at 6-month FU. A significant improvement in LV geometry and function was observed in CRT-responders at the 6-month FU. On the contrary, a slight increase in the indexed LV end-systolic volume and decrease in WW were observed in non-responders (Table 2).

Follow-up

The median follow-up was 4 years (interquartile range: 1.3-5 years). During this time span, cardiac death occurred in 14 patients (8%); 13 patients died of refractory heart failure, and 1 died one week after a heart transplant. In the multivariable Cox regression analysis, CW was an independent predictor of cardiac death (Table 3, Model A).

A C C E P T E D M A N U S C R I P T

Kaplan-Meier survival curves (Figure 3) showed that CW≤888 mmHg% was highly associated with a poor outcome (log-rank p=0.008). Patients with CW≤888 mmHg% had a higher risk of cardiac death (HR 4.76,p=0.01) (Table 3). When CW≤888 mmHg% was used instead of the continuous variable to predict CRT response in the multivariable Cox regression analysis, it remained the only significant predictor of mortality (HR 4.23,p=0.03).

Long-term outcome in relation to CRT response and septal flash

To compare the added value of CW over LV reverse remodeling for predicting the course of the disease, volumetric response to CRT was added to the Cox multivariable model (Table 3, Model B). In this model, CRT response was no longer a significant predictor of cardiac death, and it did not affect the HR of CW, which remained a significant predictor of cardiac mortality. Among responders, the presence of a CW≤888 mmHg% resulted in increased cardiac mortality, as shown by the log-rank test. The concomitant absence of volumetric response to CRT and CW≤888 mmHg identified a subgroup of patients with a particularly dismal prognosis (Figure 4).

The relationship between CW and outcome was independent from SF (Table 2). In patients with SF, the presence of a CW≤888 mmHg% was associated with a significantly increased CV and all-cause mortality (log-rank test: p=0.00l). Patients without SF and with CW≤888 mmHg% presented the worst prognosis (Figure 5).

Finally, to evaluate the predictive value of CW≤888 mmHg% over SF and CRT response for cardiac death, Cox regression analysis was used, and different nested models were created.

The incremental value of each model was assessed by comparing the χ² value at each step.

The accuracy of the Cox proportional hazards model in predicting cardiac mortality did not increase after adding SF and CRT response to clinical variables, but was significantly

A C C E P T E D M A N U S C R I P T 44
increased by the addition of CW (Figure 6). Table 4 shows the Harrell's C-concordance statistic index for each model.

DISCUSSION

In the present study, we showed that in CRT candidates, the degree of global myocardial CW is a predictor of long-term survival, independent of the presence of SF and the volumetric response to CRT.

Assessment of myocardial constructive work

PSL curves are a recently introduced tool that allow a noninvasive estimation of myocardial work. The reliability of this method with respect to the invasive estimation of myocardial work has been validated by experimental studies and mathematical models [16][20][18].

Regional differences in myocardial work assessed by PSLs have a strong correlation with the entity of myocardial glucose metabolism evaluated by FDG-PET [16]. These results support the hypothesis that the differences in CW detected by PSLs before CRT correspond to myocardial residual metabolic activity and contractile reserve and might, therefore, explain the role of baseline CW in predicting CRT response [10], [11], [16] and long-term survival after CRT.

Myocardial constrictive work as a predictor of prognosis in CRT candidates

Although CRT has a pivotal role for the treatment of patients with HF and widened QRS, the lack of response to CRT remains an important clinical problem. From a physiologic point of view, it seems reasonable to believe that the main effect of CRT might be observed when a delayed electrical activation is associated with significant LV mechanical delay.

Nevertheless, the origin of LV mechanical discoordination may arise from substrates, such as a regional myocardial scar or hypocontractility, that are unresponsive to the electrical stimulation of CRT [9]. In patients with HF undergoing CRT,

Need for physiological understanding

The absence of myocardial viability is associated with the extent of LV remodeling before CRT and with the presence of extensive myocardial remodeling and fibrosis [22].

In our population, CW≤888 mmHg% was associated with a greater LV size and reduced LVEF before CRT. This cutoff identified a subgroup of patients with a particularly dismal prognosis and limited positive remodeling after CRT implantation.

Clinical perspectives

An increasing amount of data seem to underscore that the major benefits of CRT are observed when LV mechanical dyssynchrony is induced by an electrical activation delay. The results of the present study are not in opposition to this hypothesis but underscore the importance of the concomitant evaluation of the myocardial substrate of LV dysfunction in CRT candidates.

The existence of multiple independent mechanisms governing CRT response (e.g., ECG patterns, electromechanical delay, and residual contractility) supports the hypothesis that a multimodal stepwise approach that combines clinical, electrocardiographic, and echocardiographic data might be more effective for the identification of CRT responders.

Moving in that direction, the use of myocardial work seems very promising: it integrates the load, it is an automatic measurement with associated robustness, and it could be used as a global and a regional myocardial function parameter.

Limitations

This is a monocentric, retrospective study aimed at assessing the relationship between CW and mortality in CRT candidates. With respect to previous studies, which often include all-cause mortality and heart failure hospitalization in the primary end-point, we focused specifically on the predictors of cardiac mortality. The overall cardiac mortality rate in our survey was relatively low (4%), which might be attributed to the high percentage of CRTresponders (70%), the relatively low prevalence of ischemic cardiomyopathy (29%), and the significant increase in LVEF observed in responders (Table 2). No validation cohort was created to replicate our findings on myocardial work, which currently limits its application in everyday clinical practice. Precise myocardial scar localization and extension by cardiac MRI or nuclear imaging was not investigated in the current study, as far as the relationship between scar localization and LV lead position. Such investigations may be important to further understand the relationship between regional CW and LV function improvement in CRT candidates and should be the object of a future study.

As for many other echo-parameters, the proper assessment of myocardial work requires a suitable acoustic windows, and is not applicable to patients with poor echogenicity.

Until now, the validation of the non-invasive estimation of myocardial work by pressurestrain loops analysis has been restricted to patients to CRT candidates, patients with dilated cardiomyopathy of ischemic and non-ischemic etiology, and patients with arterial hypertension [16][18][19], which limits the reliable application of this method to these specific subsets of cardiac diseases.

CONCLUSIONS

( 1 ) 2 ) 3 )

 123 EchoPAC Version 202, GE Vingmed Ultrasound, Norway). Myocardial work was estimated as a function of time throughout the cardiac cycle by the combination of LV strain data obtained by speckle tracking echocardiography and a noninvasively estimated LV pressure curve, as previously described byRussel et al.[16]. A 17-segment model was used for the estimation of segmental myocardial work.The calculation of myocardial work followed several steps. LV strain analysis. 2D grayscale images were acquired in the standard apical four-, three-and two-chamber views at a frame rate ≥60 frames/s, and 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)[17]. Image quality for the enrolled patients was optimal, and no LV segments were excluded from strain analysis. Non invasive estimation of LV pressure (LVP). The profile of an empiric LVP waveform provided by the software was used for the prediction of LVP in each specific subject by the analysis of aortic and mitral valve events (mitral valve closure, aortic valve opening, aortic valve closure, mitral valve opening) during the cardiac cycle. The duration of time intervals of isovolumic contraction, LV ejection, and isovolumic A C C E P T E D M A N U S C R I P T relaxation was then determined by stretching or compressing the time axis of the averaged LVP curve to match the measured time intervals (Figure 1A, left side). The instantaneous systolic pressure value estimated by a brachial artery cuff was assumed to be equal to peak systolic LV pressure and to be uniform throughout the ventricle. This pressure value was then used to scale the normalized pressure signal in each patient (Figure 1B, right side). The reliability of this non-invasively estimated LV pressure curve was previously validated in a dog model [16], in CRT candidates, patients with dilated cardiomyopathy of ischemic and non-ischemic etiology [16][18][19], and in patients with arterial hypertension [19] Calculation of myocardial work. Strain and pressure data were synchronized using the R wave on ECG as a common time reference (Figure 1B, left side). Myocardial work was then quantified by calculating the rate of segmental shortening by differentiating the strain curve and multiplying the resulting value by the instantaneous LV-pressure (Figure 1B, right side). The result is a measure of instantaneous power, which was integrated over time to obtain myocardial work as a function of time. Work was calculated from mitral valve closure until mitral valve opening. During the isovolumic contraction and LV ejection period, segmental shortening contributes to the final LV ejection, whereas segmental stretch or lengthening do not contribute to LV ejection. As a result, the work performed by the myocardium during segmental shortening represents constructive work, whereas the work performed by the myocardium during stretch or segmental lengthening represents energy loss, which is defined as wasted work. During isovolumic relaxation, segmental lengthening contributes to LV relaxation, whereas segmental shortening doesn't. As a result, the work performed by the myocardium during segmental shortening, which doesn't promote LV relaxation, was considered wasted work, whereas the work performed by the myocardium during segmental lengthening was considered segmental A C C E P T E D M A N U S C R I P T constructive work. By averaging segmental constructive and wasted work for each segment, global constructive work (GCW) and global wasted work (GWW) were estimated for the entire LV (Figure 1B, right side)[16]. The overall process of estimation of myocardial work was quite fast, taking no more than 2 minutes after LV strain

  A C C E P T E DM A N U S C R I P T 14 performance in a rapid and effective manner and might, therefore, have a complementary role with respect to these costly investigations.Speckle tracking echocardiography allows the simultaneous assessment of LV dyssynchrony, mechanical dispersion, and GLS. Previous studies have shown that the observation of LV mechanical dispersion in speckle tracking echocardiography is a predictor of ventricular arrhythmias in CRT candidates[23] and is related to LV fibrosis[24]. LV-GLS is also a wellknown prognostic predictor in CRT candidates[23][25]. The assessment of myocardial work by PSLs can take into account the effect of afterload on LV function, which allows a comprehensive evaluation of LV performance.

Figure 1 .

 1 FIGURE CAPTIONS

Figure 2 .

 2 Figure 2. ROC curve analysis of left ventricular constructive work for the prediction of

Figure 3 .

 3 Figure 3. Kaplan-Meier estimates of the time to cardiac death displayed according to

Figure 4 .

 4 Figure 4. Kaplan-Meier estimates of the time to cardiac death in CRT-responders

Figure 5 .

 5 Figure 5. Kaplan-Meier estimates of the time to cardiac death in patients with septal

Figure 6 .

 6 Figure 6. Incremental prognostic value of myocardial work on clinical variables, septal

  Figures

6 )

 6 determined by stretching or compressing the time axis of the averaged LVP curve to match the measured time intervals (Figure1A, left side). The instantaneous systolic pressure value estimated by a brachial artery cuff was assumed to be equal to peak systolic LV pressure and to be uniform throughout the ventricle. This pressure value was then used to scale the normalized pressure signal in each patient (Figure 1B, right side). The reliability of this non-invasively estimated LV pressure curve was previously validated in a dog model [16], in CRT candidates, patients with dilated cardiomyopathy of ischemic and non-ischemic etiology [16][18][19], and in patients with arterial hypertension [19] Calculation of myocardial work. Strain and pressure data were synchronized using the R wave on ECG as a common time reference (Figure 1B, left side). Myocardial work was then quantified by calculating the rate of segmental shortening by differentiating the strain curve and multiplying the resulting value by the instantaneous LV-pressure (Figure 1B, right side). The result is a measure of instantaneous power, which was integrated over time to obtain myocardial work as a function of time. Work was calculated from mitral valve closure until mitral valve opening. During the isovolumic contraction and LV ejection period, segmental shortening contributes to the final LV ejection, whereas segmental stretch or lengthening do not contribute to LV ejection. As a result, the work performed by the myocardium during segmental shortening represents constructive work, whereas the work performed by the myocardium during stretch or segmental lengthening represents energy loss, which is defined as wasted work. During isovolumic relaxation, segmental lengthening contributes to LV relaxation, whereas segmental shortening doesn't. As a result, the work performed by the myocardium during segmental shortening, which doesn't promote LV relaxation, was considered wasted work, whereas the work performed by the myocardium during segmental lengthening was considered segmental A C C E P T E D M A N U S C R I P T constructive work. By averaging segmental constructive and wasted work for each segment, global constructive work (GCW) and global wasted work (GWW) were estimated for the entire LV (Figure 1B, right side)[16]. The overall process of estimation of myocardial work was quite fast, taking no more than 2 minutes after LV strain

AFigure 1 .

 1 FIGURE CAPTIONS

Figure 2 .

 2 Figure 2. ROC curve analysis of left ventricular constructive work for the prediction of

Figure 3 .

 3 Figure 3. Kaplan-Meier estimates of the time to cardiac death displayed according to

Figure 4 .

 4 Figure 4. Kaplan-Meier estimates of the time to cardiac death in CRT-responders

Figure 5 .

 5 Figure 5. Kaplan-Meier estimates of the time to cardiac death in patients with septal

Figure 6 .

 6 Figure 6. Incremental prognostic value of myocardial work on clinical variables, septal

  R I P T 13 associated with a better prognosis independent of the presence of LV dyssynchrony[21]. In the present study, global CW was associated with CRT response and emerged as a predictor of long-term prognosis in CRT candidates; this result was independent of well-known predictors of CRT response, namely, QRS duration, left bundle-branch block, and SF.The presence of LV dyssynchrony is traditionally considered a predictor of CRT response, and its correction by CRT is associated with good prognosis[14],[15]. In our observational study, patients with LV dyssynchrony identified by the presence of SF and CW>888 mmHg% had the best outcomes, whereas the presence of CW<888 mmHg% increased the risk of cardiac and all-cause death in patients with SF. The concomitant absence of SF and

CW ≤888 mmHg% was associated with a poor prognosis. These findings underscore the importance of the myocardial substrate of functional response beyond the assessment of LV dyssynchrony. Interestingly, the prognostic value of myocardial work persisted when CRT volumetric response is considered. In fact, the best prognosis was observed in CRT responders who also had a CW>888 mmHg% before CRT implantation; the absence of response to CRT and a CW≤888 mmHg was associated with the highest mortality.

Table 1 : Baseline characteristics of the population

 1

	Variables	All	CW> 888 mmHg%	CW≤888
		patients	(n=99, 60%)	mmHg%	p-value
		(n=166)		(n=67, 40%)
	Age, years	66±10	66±10	64±11	0.19
	Male, n	115 (69%)	61 (62%)	54 (81%)	0.01
	Ischemic disease, n	48 (29%)	27 (27%)	21 (31%)	0.60
	NYHA>II	70 (42%)	40 (40%)	30 (45%)	0.52
	Arterial Hypertension	32 (19%)	18 (18%)	13 (19%)	0.31
	Diabetes	17 (10%)	6 (6%)	11 (16%)	0.05
	Dyslipidemia	63 (38%)	35 (35%)	28 (42%)	0.40
	Creatinine, μmol/L	99±31	95±30	104±31	0.07
	QRS widths, per ms	165±19	163±16	169±23	0.07
	QRS> 150 ms	124 (75%)	75 (76%)	49 (73%)	0.55
	LBBB, n	136 (82%)	86 (87%)	50 (75%)	0.14
	LV-EF, %	28±7	30±6	24±7	<0.0001
	LV-EDV, ml/m 2	120±42	105±31	143±45	<0.0001
	LV-ESV, ml/m 2	84±36	71±25	104±39	<0.0001
	LV-GLS, %	-9±3	-9±3	-6±2	<0.0001
	SF, n	105 (63%)	71 (72%)	34 (51%)	0.01
	Constructive Work, per	1025±442	1288±329	636±171	<0.0001
	mmHg%
	Wasted work, per mmHg%	229±134	307±140	288±124	0.39
	CRT-responders, n	118 (71%)	81 (82%)	37 (55%)	<0.0001
	EDV; end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; GLS, global

longitudinal strain; LBBB, Left Bundle Branch Block; LV, left ventricle; NYHA, New York Heart Association functional class; SF, septal flash

Table 2 . Comparative data on left ventricular size, function, an myocardial work in CRT-responders and non-responders at baseline and at 6-month follow-up

 2

		Responders	Non-responders	p-value
		N=118 (71%)	N=48 (29%)
	Baseline
	LV-EDV, ml/m 2	117±42	129±41	0.037
	LV-ESV, ml/m 2	83±35	89±36	0.15
	LV-EF, %	28±7	28±8	0.62
	LV-GLS, %	-9±3	-7±3	0.0001
	Constructive work, mmHg%	1104±434	838±324	0.0001
	Wasted work, mmHg%	325±137	245±114	0.001
	After 6 months of CRT
	LV-EDV, ml/m 2	80±28*	129±38	<0.0001
	LV-ESV, ml/m 2	45±21*	91±35 †	<0.0001
	LV-EF, %	45±11*	28±9	<0.0001
	LV-GLS, %	-13±4*	-8±4	<0.0001
	Constructive work, mmHg%	1452±420*	920±372	<0.0001
	Wasted work, mmHg%	197±111*	197±102 †	0.99
	*p<0.0001 with respect to Baseline
	†<0.05 with respect to Baseline

Table 3 . Predictors of cardiac death at univariable and multivariable analysis. Two multivariate models were created: Model A not including CRT-reponse and Model B including CRT response

 3

			Univariable analysis	Multivariable analysis
					Model A		Model B
		HR	95% CI	p HR	95% CI	p HR	95% CI	p
	Age, per year	1.08	(1.01-1.15)	0.02 1.07	(1.00-1.14)	0.05 1.07	(1.00-1.15)	0.04
	Male sex	1.75	(0.49-6.27)	0.39
	Ischaemic disease	3.99 (1.34-11.94)	0.01 2.99 (0.79-11.16)	0.10 2.33	(0.71-1.15)	0.16
	NYHA>2	1.39	(0.46-4.24)	0.56
	Arterial Hypertension	0.81	(0.22-2.95)	0.75
	Diabetes	2.56	(0.69-9.45)	0.16
	Dyslipidemia	1.49	(0.49-4.56)	0.49
	Creatinine, per μmol/L	1.01	(0.99-1.93)	0.07
	QRS duration, per ms	0.99	(0.97-1.03)	0.81
	QRS>150 ms	0.48	(0.17-0.40)	0.18
	LBBB	0.87	(0.27-2.77)	0.81
	LVEF, per %	0.99	(0.92-1.08)	0.89
	LVEDV, per ml/m 2	1.01	(0.99-1.02)	0.46
	LVESV, per ml/m 2	1.01	(0.99-1.02)	0.69
	Septal flash	0.19	(0.06-0.62)	0.006 2.29	(0.54-9.71)	0.26 0.48	(0.12-1.95)	0.30
	LV-GLS	1.21	(0.99-1.47)	0.06
	Wasted work, per mmHg%	0.99	(0.99-1.01)	0.75
	Constructive Work, per	0.99	(0.99-1.00)	0.04 0.99	(0.99-1.01)	0.03 0.99	(0.99-1.00)	0.04
	mmHg%*
	Constuctive Work ≤888	4.76 (1.33-17.12)	0.01
	mmHg%
	CRT-response**	0.26 (0.09-0.78)	0.02		0.68	(0.18-2.57)	0.58

  Ciampi et al. demonstrated that the presence of contractile reserve assessed by dobutamine stress echocardiography was associated with a better prognosis independent of the presence of LV dyssynchrony[21]. In the present study, global CW was associated with CRT response and emerged as a predictor of long-term prognosis in CRT candidates; this result was independent of well-known predictors of CRT response, namely, QRS duration, left bundle-branch block, and SF.The presence of LV dyssynchrony is traditionally considered a predictor of CRT response, and its correction by CRT is associated with good prognosis[14],[15]. In our observational study, patients with LV dyssynchrony identified by the presence of SF and CW>888 mmHg% had the best outcomes, whereas the presence of CW<888 mmHg% increased the risk of cardiac and all-cause death in patients with SF. The concomitant absence of SF and CW ≤888 mmHg% was associated with a poor prognosis. These findings underscore the importance of the myocardial substrate of functional response beyond the assessment of LV

	M A N U S C R I P T
	A C C E P T E D

dyssynchrony. Interestingly, the prognostic value of myocardial work persisted when CRT volumetric response is considered. In fact, the best prognosis was observed in CRT responders who also had a CW>888 mmHg% before CRT implantation; the absence of response to CRT and a CW≤888 mmHg was associated with the highest mortality.

  The possibility that LV stimulation might gradually recruit viable myocardium might, therefore, be the key to achieving significant LV reverse remodeling after CRT and improved survival. Myocardial viability can be assessed by several methods, including MRI, stress echocardiography and nuclear imaging. PSLs allow the assessment of myocardial performance in a rapid and effective manner and might, therefore, have a complementary role with respect to these costly investigations.

	Speckle tracking echocardiography allows the simultaneous assessment of LV dyssynchrony,
	mechanical dispersion, and GLS. Previous studies have shown that the observation of LV
	mechanical dispersion in speckle tracking echocardiography is a predictor of ventricular
	arrhythmias in CRT candidates[23] and is related to LV fibrosis[24]. LV-GLS is also a well-
	known prognostic predictor in CRT candidates[23][25]. The assessment of myocardial work
	by PSLs can take into account the effect of afterload on LV function, which allows a
	comprehensive evaluation of LV performance.

Acknowledgments

The authors deeply thank the nurses and research team working at the CIC-IT1414, CHU Rennes for their skillful assistance.

Acknowledgments

The authors deeply thank the nurses and research team working at the CIC-IT1414, CHU Rennes for their skillful assistance.

Disclosures

Professor Smiseth is a co-inventor but no longer has ownership of the patent "Method for myocardial segment work analysis", which was used to calculate myocardial work. The other authors report that there are no conflicts of interest.

A C C E P T E D

M A N U S C R I P T >15% at the 6-month follow-up (FU) [5]. A biventricular stimulation >90% after CRT implantation was mandatory for patient inclusion in the protocol. Clinical data including age, sex, and treatments were collected for each patient. The functional status was assessed by the estimation of the New York Heart Association (NYHA) functional class. Data on the vital status of patients were collected from hospital medical records or by interview with the patients' general practitioner or relatives.

The study was conducted in accordance with the "Good Clinical Practice" guidelines of the Declaration of Helsinki and reviewed by an independent ethics committee (Regional Ethic Committee validation number: 35RC14-9767). All patients gave their written informed consent for study participation. No extramural funding was used to support this work.

The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents

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, GE

Healthcare, Horten, Norway). LV volumes and function were measured by the biplane method, as recommended [13].

Assessment of septal flash

The presence of septal flash (SF) was visually assessed before CRT implantation. SF was defined by the presence of an early septal thickening/thinning within the isovolumic contraction period [14][15].

Myocardial work quantification

Myocardial work and related indices were estimated using a vendor-specific module The calculation of myocardial work followed several steps.

4

) LV strain analysis. 2D grayscale images were acquired in the standard apical four-, three-and two-chamber views at a frame rate ≥60 frames/s, and 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) [17]. Image quality for the enrolled patients was optimal, and no LV segments were excluded from strain analysis.

5) Non invasive estimation of LV pressure (LVP). The profile of an empiric LVP

waveform provided by the software was used for the prediction of LVP in each specific subject by the analysis of aortic and mitral valve events (mitral valve closure, aortic valve opening, aortic valve closure, mitral valve opening) during the cardiac cycle. The duration of time intervals of isovolumic contraction, LV ejection, and isovolumic

Disclosures

Professor Smiseth is a co-inventor but no longer has ownership of the patent "Method for myocardial segment work analysis", which was used to calculate myocardial work. The other authors report that there are no conflicts of interest.

A C C E P T E D M A N U S C R I P T


Gewu Bu

Wassim Hana

Maria Potop-Butucaru

Metamorphic IOTA

Keywords: IoT, Distributed ledgers, Tangle, Energy aware

IOTA opened recently a new line of research in distributed ledgers area by targeting algorithms that ensure a high throughput for the transactions generated in IoT systems. Transactions are continuously appended to an acyclic structure called tangle and each new transaction selects as parents two existing transactions (called tips) that it approves. G-IOTA, a very recent improvement of IOTA, targets to protect tips left behind offering hence a good confidence level. However, this improvement had a cost: the use of an additional tip selection mechanism which may be critical in IoT systems since it needs additional energy consumption. In this paper we propose a new metamorphic algorithm for tip selection that offers the best guaranties of both IOTA and G-IOTA. Our contribution is two fold. First, we propose a parameterized algorithm, E-IOTA, for tip selection which targets to reduce the number of random walks executed in previous versions (IOTA and G-IOTA) while maintaining the same security guaranties as IOTA and the same confidence level and fairness with respect to tips selection as G-IOTA. Then we propose a formal analysis of the security guaranties offered by E-IOTA against various attacks mentioned in the original IOTA proposal (e.g. large weight attack, parasite chain attack and splitting attack). Interestingly, to the best of our knowledge this is the first formal analysis of the security guaranties of IOTA and its derivatives.

I. INTRODUCTION

Bitcoin blockchain technology created a new design philosophy for executing and storing transactions in a decentralized and secure fashion [1]. A blockchain is a distributed ledger that mimics the functioning of a classical traditional ledger (i.e. transparency and falsification-proof of documentation) in an untrusted environment where the computation is distributed. The set of participants to the system are not known and it varies during the execution. Moreover, each participant follows his own rules to maximize its welfare. Blockchain systems maintain a continuously-growing list of ordered blocks that include one or more transactions that have been verified by the members of the system, called miners. Blocks are linked using cryptography and the order of blocks in the blockchain is the result of a form of agreement among the system participants. Participants strongly agree only on a prefix of the blockchain, the suffix of the blockchain may be different from one participant to another.

Bitcoin technology and similar proposals (e.g Ethereum) came with several drawbacks that prevent them from being used as standard for IoT industry. In the field of IoT the main attributes that are concerned are the speed, scalability, and energy costs; all of which Bitcoin suffers from as limitations.

Hence the introduction of IOTA [2] designed specifically for the IoT industry. IOTA is a DAG (Directed Acyclic Graph) based distributed ledger, also known as the tangle, aimed to overcome limitations of Bitcoin when used in IoT environment while preserving equivalent security levels. IOTA uses tip selection algorithms for new transactions to approve two previous transactions. IOTA suffers from certain limitations in terms of security and fairness with respect to approved transactions. Therefore G-IOTA [3] was proposed as a new tips selection mechanism that combines a confidence fairness aware tips selection algorithm and a mutual supervision mechanism.

In this paper we introduce a new approach, E-IOTA, that aims at maximizing the fairness level in tip selection by approving left behind tips, and improving confidence within the main tangle. E-IOTA randomizes tip selection to reduce computational costs, as well as reduces left behind tips, and increases the security level of the tangle by avoiding a deterministic (predictable) tips selection algorithm (TSA). This makes the TSA and the tangle unpredictable for attackers. The algorithm creates a metamorphic main-chain that is as resistant to splitting attacks as IOTA and G-IOTA while reducing the costs of tip selection and hence preserving the energy of the nodes maintaining the tangle.

The organization of this paper is as follows. Section II introduces IOTA and G-IOTA and identifies their drawbacks. Section III proposes E-IOTA that is designed to overcome the drawbacks of both IOTA and G-IOTA tangles. Section IV focuses on the security analysis of E-IOTA. Section V discusses the process of evaluation and testing of E-IOTA and provides the performance analysis and the comparison between the IOTA, G-IOTA and E-IOTA tangles. Section VI concludes the paper and discusses future research directions.

II. BACKGROUND ON IOTA AND G-IOTA

In this section we present the design details of the IOTA system. Furthermore we focus its drawbacks and describe the improvement G-IOTA and its drawbacks respectively.


Oleg A Filippov

Antoine Bruneau-Voisine

Jérémy Willot

Carine Duhayon

Dmitry A Valyaev

Noël Lugan

Yves Canac

Jean-Baptiste Sortais

R Buhaibeh

A Bruneau- Voisine

J.-B Sortais

Phosphine-NHC Manganese Hydrogenation Catalyst Exhibiting a Non-Classical Metal-Ligand Cooperative H2 Activation Mode

Keywords:

A NHC-phosphine manganese complex in the presence of base is transformed into a NHC-phosphinomethanide derivative capable to easily activate dihydrogen via a nonclassical metal-ligand cooperative mode. This process is relevant for catalysis providing one of the most efficient Mn-based systems for ketone hydrogenation.

Abstract: Deprotonation of the Mn(I) NHC-phosphine complex fac-[MnBr(CO)3(κ 2 P,Ĉ-Ph2PCH2NHC)] ( 2) under a H2 atmosphere readily gives the hydride fac-[MnH(CO)3(κ 2 P,Ĉ-Ph2PCH2NHC)] ( 3) via the intermediacy of the highly reactive 18-e NHC-phosphinomethanide complex fac-[Mn(CO)3(κ 3 P,C,Ĉ-Ph2PCHNHC)] (6a). DFT calculations revealed that the preferred reaction mechanism involves the unsaturated 16-e mangana-substituted phosphonium ylide complex fac-[Mn(CO)3(κ 2 P,Ĉ-Ph2P=CHNHC)] (6b) as key intermediate able to activate H2 via a non-classical mode of metalligand cooperation implying a formal  5 -P - 3 -P phosphorus valence change. Complex 2 is shown to be one of the most efficient pre-catalysts for ketone hydrogenation in the Mn(I) series reported to date (TON up to 6200).

Cooperative activation of inert chemical bonds is a topical concern in modern chemistry and homogeneous catalysis. Since the discovery of Shvo-type catalysts, [1] a wide variety of transition metal complexes bearing non-innocent ligands was exploited for E-H bond activation, [2] recently supplemented by related reactivity of frustrated Lewis pairs [3] and main-group ambiphiles. [4] Among all these transformations, the activation of H2 is of utmost importance because of its essential role in catalytic [transfer] hydrogenation [START_REF]Handbook of Homogeneous Hydrogenation[END_REF] and hydrogen borrowing [6] processes relevant in fine chemicals industry. While the seminal contribution of Noyori and coll. involving an amide/amine interplay in the coordination sphere of transition metals (Scheme 1, (a)) still is the most ubiquitous system for heterolytic H2 splitting, [7] similar transformations implying phosphorous analogues remain scarce (Scheme 1, (b)). [8] By contrast, the association of N-and P-moieties for such application was more developed (Scheme 1, (c)). In this regard, as mostly demonstrated in pincer-type series, the species resulting from deprotonation of the methylene bridge in phosphine-pyridine complexes are capable to activate H2 across the metal and the ligand arm though a mechanism in which the rearomatization of the pyridine moiety actually plays a key role (Scheme 1, (c)). [9] We report herein that a non-classical metalla-substituted phosphonium ylide obtained upon C-H deprotonation of a chelating NHC-phosphine ligand in the Mn coordination sphere can easily activate H2 (Scheme 1, (d)), thus providing the first evidence of the involvement of [START_REF]Handbook of Homogeneous Hydrogenation[END_REF] -P species in metal-ligand cooperation. Thanks to this non-classical mode of H2 activation, the NHC-phosphine Mn(I) complex behaves as a powerful catalyst for the hydrogenation of ketones.

Scheme 1. H2 activation by non-innocent ligands via metal-ligand cooperation.

Compassing our recent investigations on the application of Mn(I) complexes supported by bidentate ligands in hydrogenation-type catalysis, [10] we turned our attention to the use of ligand systems now associating phosphine and NHC donors. Complex 2 was readily obtained in 86% yield from the corresponding phosphineimidazolium salt [1]OTs [11] through the sequential addition of KHMDS and [Mn(CO)5Br] (Scheme 2). According to IR and NMR spectroscopy, the air stable complex 2 forms as a single isomer (P71.3 ppm (s), C 197.7 ppm (d, 2 JPC = 17.5 Hz, CN 2 C)), presenting a facial arrangement of the three carbonyl ligands as confirmed by an XRD study (Figure 1a). [12] To explore the chemical behaviour of 2 towards H2, the latter complex was first reacted with KHMDS in toluene at 0 °C under 1 atm. of H2. Under these conditions, 2 was rapidly converted into the corresponding Mn(I) hydride complex 3 (Scheme 2, up) isolated in 78% yield, standing up as the first example of a Mn hydride complex bearing a NHC ligand. The 1 H NMR spectrum of 3 displays a doublet at H -7.25 ppm with a 2 JPH constant of 53.8 Hz agreeing with the cis arrangement of hydride and phosphine moieties. The 31 P NMR signal of 3 (P 94.2 ppm) was found shifted downfield compared to the bromide precursor 2 (P 71.3 ppm). A similar trend was observed for the carbenic resonance in the [START_REF] Van Der Vlugt | For methylation of dearomatized PNP complex[END_REF] C NMR spectrum (3: C 205.4 ppm (d, 2 JPC = arrangement of the three carbonyls co-ligands of complex 3 was univocally confirmed by an XRD study (Figure 1b). Noteworthy, performing the previous reaction under D2 atmosphere led to complex 3 D2 with a full incorporation of deuterium at the hydride (Mn-D) and at the CH2 positions (CH-D, see the S.I.).

In order to further characterize the acidic site in the complex 2, i.e. the one that undergoes the deprotonation different trapping experiments were carried out. For this purpose, complex 2 was first treated with KHMDS followed by the addition of an excess of classical alkylating agent such as MeI. [START_REF] Van Der Vlugt | For methylation of dearomatized PNP complex[END_REF] The resulting complex 4 showing methylation of the carbon atom linking the phosphine and NHC moieties was isolated as a mixture of two diastereomers (ratio 6:1) differing by the position of the methyl group with respect to the iodine atom (Scheme 2, middle). Both isomers of complex 4 (major isomer: P 73.0 ppm (s); C 195.9 ppm (d, 2 JPC = 16.6 Hz, CN 2 C)) display similar spectroscopic features compared to the bromide precursor 2. An XRD analysis of 4 evidenced the presence of the anti-isomer in the solid state (Figure 1c). In a second time, the deprotonated species was exposed to CO2 (1 atm.) affording the complex 5 in 89% yield (Scheme 2, bottom) whose solid state structure highlights the existence of a tripodal NHC-phosphine-carboxylate scaffold with a facial arrangement of the carbonyl ligands (Figure 1d). [14,[START_REF] Filonenko | Related adducts of dearomatized pincer complexes with nitriles: a)[END_REF] These results clearly indicated that the deprotonation of 2 occurs at the CH2 bridge forming a sufficiently nucleophilic carbon species to react with electrophiles such as MeI or CO2.

Yet, after proving the involvement of a deprotonated intermediate 6 of general formulae [Mn(CO)3(Ph2PCHNHC)] for the formation of complexes 3-5 from 2, arose the question of its structure. Despite its relative instability (t1/2 of ca. 0.5 h at r.t., decomposition at -30 °C over 16 h), optimization of reaction parameters allowed to prepare suitable samples for complete spectroscopic characterization. The IR spectrum of 6 in toluene exhibits two CO bands at 1993 (s) and 1901 (vs) cm -1 consistent with the presence of three CO ligands in a facial arrangement. Despite all our efforts, single crystals of complex 6 could not be obtained. Its structure was therefore investigated by theoretical calculations. DFT study at the BP86/def2-TZVP level revealed five minima on the PES. The global minimum corresponds to the strongly distorted octahedral 18-e complex fac-[Mn(CO)3(κ 3 P,C,Ĉ-Ph2PCHNHC)] (6a, Figure 2 (left)) featuring a facially coordinated, 5-e donor, NHC-phosphinomethanide ligand. [16,[START_REF] Devillard | Related complexes with chelating methanide ligands: a)[END_REF] Calculated metrical parameters within the MnPC moiety are comparable to those experimentally found in the related [(κ 2 P,C-Ph2PCH2)Mn(CO)4] complex. [16a] The other minima correspond to the four possible isomerstwo fac and two merof square pyramidal 16-e [Mn(CO)3(κ 2 P,Ĉ-Ph2P=CHNHC)] complex 6b showing an unusual bidentate NHC-phosphonium ylide ligand

Accepted Manuscript

(see the SI for details). The most thermodynamically stable isomer of NHC-ylide complexes fac-6b, yet being destabilized by +7.5 kcal.mol -1 relative to 6a, is depicted in Figure 2 (right). The calculated P-C bond length in fac-6b (1.741 Å) is consistent with an ylidic P-C bond, in agreement with experimental values found in a related iron-substituted phosphonium ylide complex (1.766(11) Å) [18] and in other metal complexes bearing more conventional NHC-ylide ligands (1.750(7)-1.794(8) Å). [19] According to ETS-NOCV study, the P-Mn bond in fac-6b is significantly stronger than that in complexes 2-3 featuring a conventional phosphine-metal dative bond (see the SI for details). Very significantly, the relatively constrained coordination of the NHC-phosphinomethanide ligand in 6a results in a strong distortion of yaw angle θ [20] for the NHC ligation (6a: θ 29.5° vs. 2-4, 6b: 6.2-7.2°). Considering that the shielding of the [START_REF] Van Der Vlugt | For methylation of dearomatized PNP complex[END_REF] C NMR chemical shift of carbenic carbon atoms in metal complexes increases as the value of θ, [21] the signal recorded at C 178.0 ppm for 6 in solution (vide supra) appears to be totally consistent with the most stable structure 6a. In addition, computed [START_REF] Van Der Vlugt | For methylation of dearomatized PNP complex[END_REF] C NMR chemical shift for the carbenic atom in complex 6a (C 181.5 ppm) matches well with the experimental value (C 178.0 ppm), a value significantly different from that computed for complex fac-6b (C 215.1 ppm) (see Table S5 for details), thus the deprotonation product of 2 was be assigned to complex 6a. The mechanism of H2 activation by 6a was then investigated by DFT calculations. Among the different activation pathways considered, the process showing the lowest energy profile is depicted in Scheme 3 (see the SI for alternative mechanisms). Complex 6a is first converted into the 16-e NHC-ylide species fac-6b with an energy barrier of 15.7 kcal.mol -1 (TS1) which then coordinate H2 to form the dihydrogen complex 7 via a TS2 of 11.3 kcal.mol -1 . [START_REF] Liu | Other η 2 -H2 Mn(I) complexes evidenced by DFT calculations: a) C[END_REF] Finally, complex 7 undergoes a facile heterolytic cleavage of the H-H bond through the low-lying transition state TS3 with an energy barrier of only 3.2 kcal.mol -1 affording finally the experimentally observed Mn(I) hydride 3. Having established that complex 2 could effectively activate H2 in basic conditions, we next focused our attention on the hydrogenation of ketones as benchmark reaction. [10a,23] Gratifyingly, at 60 °C, in toluene, in the presence of 1.0 mol% of 2 and 2.0 mol% of KHMDS, acetophenone was fully reduced to 1-phenylethanol (see Table S1 for optimization details). Notably, Scheme 3. The preferred mechanism of H2 activation with 6 (BP86/def2-TZVP, toluene SMD model, Gibbs energies are given in kcal.mol -1 and referred to 6a.

in toluene or t-AmOH the loading of 2 could be decreased to 0.1 mol% at 60 °C or even to 0.05 mol% at 100 °C keeping a full conversion. A maximum TON of 6200 was achieved with 0.01 mol% in t-AmOH, showing that this catalyst is competitive with the best Mn-based systems for this reaction reported to date [23b-c] No reaction took place in the presence of the sole hydride complex 3, while catalytic activity could be restored in the presence of base, showing its critical role in the catalytic cycle. [10,23,24] We then enlarged the synthetic scope of this catalytic transformation ( Table 1) and found that a large variety of aryl(alkyl)ketones could be readily reduced (entries 1-18), including sterically hindered representatives (entries 2-4, 7) inaccessible using our previous Mn catalyst based on a chelating phosphine-aminopyridine ligand. [10c] Interestingly, the reaction is tolerant to aryl groups substituted with halogen atoms (F, Cl, Br, I) and CF3 moiety (entries 9-14). Aliphatic 2-decanone was hydrogenated in the efficient manner albeit at 100 °C (entry 19). The heterocyclic substrates bearing potentially coordinating groups can also be reduced (entries 20-22) but with lower efficiency.

Table 1. Scope of hydrogenation of ketones catalyzed by Mn complex 2 [a].

Entry

Substrate Cat. (%) Method Conv. [b] 1 2 3

R = Me R = i-Pr R = t-Bu 0.1 0.5 0.5 [c] A A A >98 (91) >98 (
R = 2-Me R = 3-Me R = 4-Me R = 2,4,6-Me3 R = 4-OMe R = 4-F R = 4-Cl R = 2-Br R = 4-Br R = 4-I R = 4-CF3
0.5 [d] 0.2 [d] 0.1 0.5 [c] 0.5 [d] 0.1 0.5 [d] 0.2 [d] 0.2 [d] 0.5 [e]] 0.5 [c] A 97) >98 ( 93) >98 ( 72) >98 ( 98) >98 (97) >98 ( 83) 94 (81) >98 ( 99) 94 (79) >98 (92) 15 0.2 [d] B 90 (65) 16 0.2 [d] A 66 (52) 17 0.2 [d] B 78 (71) 18 0.5 [d] A 50 (37) 19 0.5 [c] A >98 (98) 20 1.0 [f] A 75 21 1.0 [f] B 40 22 1.0 [f] B 10

A A A B A A A B A A >98 (93) >98 (
[a] Typical procedure: an autoclave was charged with pre-catalyst 2 (0.1 mol%), ketone (2.0 mmol), base (1.0 mol%; A: t-BuOK, B: KHMDS), solvent (2 mL, A: t-AmOH, B: toluene), in this order and then rapidly pressurized with H2 (50 bar) and heated under stirring at 60 °C for 20h; [b] conversion determined by 1 H NMR, isolated yield in parenthesis; [c]

Accepted Manuscript

In conclusion, we have shown that a Mn(I) complex of a easily accessible bidentate phosphine-NHC ligand can be selectively deprotonated at the carbon position located between the two donor moieties to afford an original 18-e NHCphosphinomethanide complex. The latter can serve as a reservoir for an unconventional 16-e NHC-phosphonium ylide complex able to activate H2 through a metal-ligand cooperation mode based on the formal interplay between  5 -and  3 -P species. Homogeneous catalysis can take advantage of this new mode of H2 activation, as demonstrated by the development of one of the most efficient Mn-based catalytic systems for hydrogenation of ketones. Taking into account the ubiquitous presence of the 'R2PCH2' motif in transition metal complexes, an awareness of its potential as a non-innocent ligand could now open new perspectives in homogeneous catalysis.

  The 31 P{ 1 H} NMR spectrum recorded in a [D8]toluene solution at -30 °C revealed the complete conversion of 2 (P 71.7 ppm) into 6, the latter being characterized by a shielded chemical shift at P 51.6 ppm. The deprotonation site was finally revealed by the concomitant presence of doublets at H 3.55 ( 2 JPH = 8.6 Hz, 1H) and at C 22.7 ppm ( 1 JPC = 18.2 Hz) in the 1 H and 13 C{ 1 H} NMR spectra respectively, consistent with the presence of a CH group in the α-position of P-atom and confirming that the deprotonation does take place at the CH2 bridge. Noticeably, while the 13 C{ 1 H} NMR spectrum displays three distinct resonances for CO ligands at standard chemical shifts, the carbenic carbon atom appears to be strongly shielded (C 178.0 ppm, d, 2 JPC = 14.2 Hz) by ca. 20-25 ppm compared to the antecedent complexes 2-5.

Figure 1 .

 1 Figure 1. Molecular geometry of complexes fac-2 (a), fac-3 (b), fac-4 (c), and 5 (d) (30% probability ellipsoids, aryl groups represented as a wireframe).

Figure 2 .

 2 Figure 2. Structures and DFT optimized geometries of complexes 6a and fac-6b (BP86/def2-TZVP, toluene SMD model).

Acknowledgements

We thank the CNRS and the IUF (France) for general support of this project. R. B. is grateful to the Embassy of Yemen in Paris for a PhD fellowship. Computational studies were performed using HPC resources from CALMIP (Grant no. P18038).

Keywords: Metal-ligand cooperation • Phosphonium ylides • N-heterocyclic carbenes • Manganese • DFT calculations