MD Wilfried Mullens
email: wilfried.mullens@zol.be

Angelo Auricchio

Pieter Martens

Klaus Witte

Martin R Cowie

Victoria Delgado

Kenneth Dickstein

Cecilia Linde

Kevin Vernooy

Francisco Leyva

Johann Bauersachs

Carsten W Israel

Lars Lund

Erwan Donal

Giuseppe Boriani

Tiny Jaarsma

Antonio Berruezo

Vassil Traykov

Zaheer Yousef

Zbigniew Kalarus

Jens Cosedis Nielsen

Jan Steffel

Panos Vardas

Andrew Coats

Petar Seferovic

Thor Edvardsen

Hein Heidbuchel

Frank Ruschitzka

Christophe Leclercq

Optimized Implementation of cardiac resynchronization therapy -a call for action for referral and optimization of care

Keywords: Cardiac resynchronization therapy, Response, Heart failure, Implementation, Utilization, Care pathways, Disease Modification, Disease management, Outcome

A. Introduction

Cardiac resynchronization therapy (CRT) is one of the most effective therapies for heart failure with reduced ejection fraction (HFrEF) resulting in improved quality of life, beneficial reverse remodeling and reductions in heart failure hospitalization rates and all-cause mortality.(1-7) Despite its well established clinical benefits and cost effectiveness, it remains a widely underutilized treatment option; recent Europe data suggest only 1 in 3 eligible patients actually receives a CRT device. [START_REF] Raatikainen | Statistics on the use of cardiac electronic devices and electrophysiological procedures in the European Society of Cardiology countries: 2014 report from the European Heart Rhythm Association[END_REF] In contrast, the topic of "non-response" to CRT ("failure to improve") has received disproportionally large research attention, with rates of non-response reported in 30% of implanted patients.(9) A binary definition of "response" classified by arbitrary magnitudes of improvements in a variety of variables of questionable clinical significance underestimates the true benefits of CRT reported in the randomized clinical trials. This is in contrast with the message from all randomized controlled CRT trials in HFrEF patients with a QRS > 130 msec, which consistently show a spectrum of stabilization or improvement of disease progression to even recovery of the disease. [START_REF] Cleland | An individual patient meta-analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure[END_REF][START_REF] Woods | Individual patient data network metaanalysis of mortality effects of implantable cardiac devices[END_REF] Moreover, in addition to this "failure to refer", optimization of both the device and the care of the patient following implant is hampered by a lack of integration of cardiological and nonspecialist care, leading to suboptimal and variable post-implant management. [START_REF] Daubert | EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management[END_REF][START_REF] Varma | Evaluation, Management, and Outcomes of Patients Poorly Responsive to Cardiac Resynchronization Device Therapy[END_REF] As a result, many heart failure patients are not exposed to the full potential benefit of CRT. This position paper aims to improve the implementation of CRT and follow-up of patients with CRT, by addressing the following topics; (i) underutilization of CRT, (ii) redefining response as disease modification of heart failure, (iii) better understanding of pre-implant patient characteristics, , (iv) integration and optimization of post-implant CRT care.

Accepted Article

B. Action plan for referral and optimization of CRT related care

Action I: overcome the underutilization of CRT

Eligibility vs actual implantation

Observational data indicate that 35 to 40% of patients with HFrEF have a prolonged QRS width (classically defined as QRS>120 ms) and 20-30% of HFrEF patients have LBBB. [START_REF] Lund | Age, prognostic impact of QRS prolongation and left bundle branch block, and utilization of cardiac resynchronization therapy: findings from 14,713 patients in the Swedish Heart Failure Registry[END_REF][START_REF] Lund | Prevalence, correlates, and prognostic significance of QRS prolongation in heart failure with reduced and preserved ejection fraction[END_REF] Since a considerable proportion of HFrEF patients do not tolerate or improve after other heart failure therapies have been introduced, ultimately 5-10% of all heart failure patients remain eligible for CRT. As such, estimates using eligibility criteria as stated in professional practice guidelines (QRS>130 ms) suggest that up to 400 patients per million inhabitants of European countries might be candidates for CRT implantation annually. [START_REF] Baldasseroni | Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian network on congestive heart failure[END_REF][START_REF] Nieminen | EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population[END_REF] Between 2005 and 2013, European and US guideline indications have expanded to also include patients with less severe symptoms (NYHA class II), and in 2016 the guidelines tightened the proportion of patients eligible to CRT by prolonging the QRS duration and altering the morphology criteria. [START_REF] Lund | Effect of expanding evidence and evolving clinical guidelines on the prevalence of indication for cardiac resynchronization therapy in patients with heart failure[END_REF] Data from the EHRA White Book indicate that within the European Union between 2010 and 2013 the average implantation rate varied between 106-123 per million inhabitants, [START_REF] Raatikainen | Statistics on the use of cardiac electronic devices and electrophysiological procedures in the European Society of Cardiology countries: 2014 report from the European Heart Rhythm Association[END_REF] and more recent data from device registries reported a rate of 56 CRT-P and 119 CRT-D implants per million inhabitants in 2018 in Europe, with a slight increase of mainly CRT-P over recent years (Figure 1). Although significant geographical differences are clearly present, these data suggest that up to two thirds of those eligible for CRT on current guidelines are not implanted. Registry data provide some insights into factors associated with the non-referral of CRT, indicating that older age (>75 years), lack of CRT implant centers, shorter duration of heart failure, absence of a heart failure nurse and non-cardiology follow-up are factors that are independently associated with non-delivery of CRT. [START_REF] Lund | Association between demographic, organizational, clinical, and socio-economic characteristics and underutilization of cardiac resynchronization therapy: results Accepted Article from the Swedish Heart Failure Registry[END_REF] One key issue is that many patients with heart failure including those eligible for CRT are managed in primary or non-specialist care where there is possibly less familiarity with the indications and benefits Accepted Article of CRT. [START_REF] Nieminen | EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population[END_REF] This lack of awareness is also illustrated in the recent Euro CRT survey II, which highlighted that most of those implanted had been identified within the cardiology department. Only a minority had been referred from other departments, including primary care. [START_REF] Dickstein | CRT Survey II: a European Society of Cardiology survey of cardiac resynchronisation therapy in 11 088 patients-who is doing what to whom and how?[END_REF] Moreover, despite the well-established benefit of CRT in women, CRT remains underused in female patients. This gender gap has remained unchanged in Europe over the past 10 years with female CRT patients representing only 27% and 24% of all implants in the ESC CRT Survey I and II, respectively.

Guidelines vs registries

Professional practice guidelines have formulated recommendations for CRT in HFrEF patients based upon morbidity and mortality reductions. [START_REF] Daubert | EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management[END_REF][START_REF] Epstein | ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society[END_REF][START_REF] Yancy | ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines[END_REF][START_REF] Brignole | ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA)[END_REF][START_REF] Ponikowski | ESC Guidelines for the diagnosis Accepted Article and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF] Guidelines offer a strong level of recommendation for patients in sinus rhythm, a wide QRS-duration or LBBB. Data

Health economic considerations

Implantable devices such as CRT are often approached with scrutiny by health care regulating agencies and payers, due to their significant up-front cost and the fact that they are implanted in a patient population (if left untreated) with a relatively limited life expectancy. The cost of any intervention needs to balance the willingness to pay, which is typically reflected in the incremental cost-effectiveness ratio (ICER). This is expressed as the amount of money which has to be spent to gain a quality adjusted life-year. A Markov-model with Monte-Carlo simulation from the CARE-HF and COMPANION trials indicates an ICER of €7,538 for

Accepted Article

CRT-P and €18,017 for CRT-D, which is below the generally accepted thresholds for costeffectiveness (€30,000-40,000 or gross domestic product (GDP) per capita) in high income countries. [START_REF] Yao | The long-term cost-effectiveness of cardiac resynchronization therapy with or without an implantable cardioverter-defibrillator[END_REF] In the REVERSE trial focusing on NYHA-class II patients, CRT was linked to 0.94 life years or 0.80 QALYs at an additional cost of €11 455, yielding an incremental costeffectiveness ratio of €14.278 per quality-adjusted life year (QALY) gained. [START_REF] Linde | Cost-effectiveness of cardiac resynchronization therapy in patients with asymptomatic to mild heart failure: insights from the European cohort of the REVERSE (Resynchronization Reverses remodeling in Systolic Left Ventricular Dysfunction)[END_REF] Despite the additional upfront cost of a CRT-D device in comparison to a CRT-P device, it is still within the accepted cost-effectiveness boundaries for the USA and Europe. [START_REF] Linde | Cost-effectiveness of cardiac resynchronization therapy in patients with asymptomatic to mild heart failure: insights from the European cohort of the REVERSE (Resynchronization Reverses remodeling in Systolic Left Ventricular Dysfunction)[END_REF][START_REF] Noyes | Cost-effectiveness of cardiac resynchronization therapy in the MADIT-CRT trial[END_REF] Data from the EHRA-white book indicate lower utilization of CRT in European countries with a lower GDP per capita, [START_REF] Raatikainen | Statistics on the use of cardiac electronic devices and electrophysiological procedures in the European Society of Cardiology countries: 2014 report from the European Heart Rhythm Association[END_REF] suggesting that supportive guidelines aiding appropriate selection between CRT-P versus CRT-D in lower GDP-countries might help to increase CRT implant rates in these areas.

Strategies to overcome the underutilization of CRT

Since one of the barriers to implantation is referral, improved strategies to identify potential eligible CRT candidates by cardiologists and non-cardiologists are urgently needed. [START_REF] Dickstein | CRT Survey II: a European Society of Cardiology survey of cardiac resynchronisation therapy in 11 088 patients-who is doing what to whom and how?[END_REF] Importantly, electrocardiogram surveillance in heart failure patients is warranted as abnormalities (which often change over time) not only provide information on etiology, but they also help to identify appropriate therapy. Furthermore, thorough and repeated education within primary and secondary care (including cardiologists less familiar with devices) about CRT, and openly addressing deeply-rooted myths that contribute to non-referral may improve CRT-implementation. (see table 1). Finally, deeper engagement with patient associations or support groups could improve the dissemination of information about therapeutic options.

Screening through automated alerts in electronic health records based on information from QRS duration, LV function and heart failure status might trigger more actionable referrals.

Given the expansion of electronic health records, screening for patients eligible for Accepted Article optimisation of heart failure therapy including CRT might be effective as it has been for other treatments for heart failure. [START_REF] Lund | Effect of expanding evidence and evolving clinical guidelines on the prevalence of indication for cardiac resynchronization therapy in patients with heart failure[END_REF][START_REF] Thorvaldsen | Focusing on Referral Rather than Selection for Advanced Heart Failure Therapies[END_REF] 2. Action II: replace "response to CRT" by "disease modification by CRT" Due to the upfront cost, life-long presence of the device, and potential device and procedure related complications, decisions for device based interventions are often delayed until all other non-device based therapies have "failed". [START_REF] Han | The Heart Team: A Powerful Paradigm for the Future Training of Cardiovascular Surgeons[END_REF] This situation is exacerbated by the unique and widespread concept of "non-response" where, based upon arbitrary cut-offs of remodeling (most often LV-end systolic volume reduction of > 15%) or symptomatic "improvement", it has been suggested that one-in-three patients do not "respond" to CRT. As a result of these factors, CRT has been approached with an unprecedented scrutiny despite its firmly established benefits on morbidity and mortality in patients with heart failure and a wide QRS (>130ms). [START_REF] Bax | Left ventricular dyssynchrony predicts benefit of cardiac resynchronization therapy in patients with end-stage heart failure before pacemaker implantation[END_REF][START_REF] Butter | Effect of resynchronization therapy stimulation site on the systolic function of heart failure patients[END_REF] This situation is especially worrisome since no consensus exists on how or when to measure response to CRT and what magnitude of change constitutes response. [START_REF] Steffel | Superresponse to cardiac resynchronization therapy[END_REF] Adding to the confusion is a long list of potential "predictors of response" of which many are based upon results of observational studies, which, due to a lack of control data, cannot conclusively determine the relation between the predictor and the clinical outcome benefit (risk reduction) from CRT.

Response parameters, agreement and timing

Numerous variables including functional, event-based, imaging or composite outcomes have been used to describe response to CRT. [START_REF] Daubert | EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management[END_REF] The importance of certain metrics might also differ according to the stakeholders, such as patients, their carers, doctors, payers or industry.

The placebo effect of an implant on functional outcomes is also often underestimated as noted after implantation during the run-in phase before LV only pacing was switched on in the GREATER-EARTH study. [START_REF] Thibault | Left ventricular versus simultaneous biventricular pacing in patients with heart failure and a QRS complex >/=120 milliseconds[END_REF] Moreover, the agreement between outcomes is remarkably poor. It is well recognized that resting LV function is poorly related to exercise capacity or symptoms [START_REF] Witte | Exercise capacity and cardiac function assessed by tissue Doppler imaging in chronic heart failure[END_REF], so it is not surprising that LV reverse remodeling poorly relates to the degree of functional improvement in many studies. [START_REF] Ypenburg | Long-term prognosis after cardiac resynchronization therapy is related to the extent of left ventricular reverse remodeling at midterm follow-up[END_REF][START_REF] Lafitte | Validation of an echocardiographic multiparametric strategy to increase responders patients after cardiac resynchronization: a multicentre study[END_REF][START_REF] Yu | Left ventricular reverse remodeling but not clinical improvement predicts long-term survival after cardiac resynchronization therapy[END_REF] Indeed, the size and shape of the ventricle is irrelevant for patients complaining of exercise intolerance. Yet, LV reverse remodeling remains a commonly used endpoint, largely based upon the close relationship between changes in LV structure and outcomes.(39) However, these data have been over interpreted to imply that patients without significant LV reverse remodeling (e.g. LV end systolic volume reduction > 15%), derive no benefit from CRT whereas up to 30% of patients lacking remodeling benefits will experience an improvement in symptoms. Importantly, even patients who fail to demonstrate reverse remodeling and require a heart failure admission, still derive hemodynamic benefit from their device, as they often deteriorate when biventricular pacing is temporarily stopped. [START_REF] Mullens | Persistent hemodynamic benefits of cardiac resynchronization therapy with disease progression in advanced heart failure[END_REF] Finally, the REVERSE trial showed a continuous reduction of both LV systolic and diastolic volumes for at least up to 2 years after CRT, which questions the appropriateness of any point-in-time assessment of therapy efficacy. [START_REF] Linde | Longterm impact of cardiac resynchronization therapy in mild heart failure: 5-year results from the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction (REVERSE) study[END_REF]

Baseline variables suggested to predict outcome following CRT

In addition to the difficulty of timing, magnitude, congruity and outcome in assessing "response", there is a plethora of pre-implantation features that are associated with certain response parameters and often wrongly drive decisions on implantation. Commonly quoted features predicting less LV reverse remodeling in observational studies include male sex, ischemic etiology, high LV volumes, low glomerular filtration rate, and absence of mechanical dyssynchrony. [START_REF] Ypenburg | Effect of total scar burden on contrast-enhanced magnetic resonance imaging on response to cardiac resynchronization therapy[END_REF][START_REF] Dupont | Differential response to cardiac resynchronization therapy and clinical outcomes according to QRS morphology and QRS duration[END_REF][START_REF] Ypenburg | Impact of viability and scar tissue on response to cardiac resynchronization therapy in ischaemic heart failure patients[END_REF][START_REF] Ter Maaten | Response to Cardiac Resynchronization Therapy Across Chronic Kidney Disease Stages[END_REF][START_REF] Molhoek | Comparison of benefits from cardiac resynchronization therapy in patients with ischemic cardiomyopathy versus idiopathic dilated cardiomyopathy[END_REF] In contrast, post-hoc analyses of the major CRT-trials powered for mortality and morbidity (CARE-HF, RAFT, COMPANION and MADIT-CRT) revealed no heterogeneity between these aforementioned baseline characteristics and benefits

Accepted Article

on mortality or heart failure admission. Therefore, these subgroups gain similar relative risk reduction with CRT despite lesser degrees of LV reverse remodeling, and should not be used to deselect patients from receiving CRT. [START_REF] Bristow | Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure[END_REF][START_REF] Cleland | The effect of cardiac resynchronization on morbidity and mortality in heart failure[END_REF][START_REF] Tang | Cardiacresynchronization therapy for mild-to-moderate heart failure[END_REF][START_REF] Moss | Cardiac-resynchronization therapy for the prevention of heart-failure events[END_REF]. More importantly, these patients often have a high risk for heart failure admission and mortality (baseline event rate) and might actually therefore have a higher absolute risk reduction after CRT. None of the studies have shown an adverse effect of CRT in patients with a QRS-width above 130msec, especially in the LBBB population. [START_REF] Beshai | Cardiac-resynchronization therapy in heart failure with narrow QRS complexes[END_REF][START_REF] Ruschitzka | Cardiacresynchronization therapy in heart failure with a narrow QRS complex[END_REF]. Finally, in the recent ADVANCE-CRT registry, patients labeled as responders, were less likely to have their therapy optimized following CRTimplant, [START_REF] Varma | Evaluation, Management, and Outcomes of Patients Poorly Responsive to Cardiac Resynchronization Device Therapy[END_REF] suggesting that there are risks from suboptimal care delivery if someone is actually labeled a responder.

Removing the term 'response'

Apart from rare isolated situations, heart failure is incurable. CRT is therefore not a curative therapy but rather should be seen as a treatment to ameliorate the contribution of electromechanical dyssynchrony to the heart failure syndrome in the hope that this will ultimately reduce heart failure related morbidity and mortality. A slowing of a progressive disease is a positive outcome (see Figure 2). Despite frequently quoted parallels between heart failure and cancer, the important concepts of "remission" and "non-progression" seem not to have permeated to cardiology. Therefore, this position statement calls to stop the current binary approach of CRT response, but rather we suggest that CRT should be classified as a treatment for "disease modification". One step towards such an approach is the Packer hierarchical scoring system which takes into account (lack of) mortality, (lack of) hospital admission for heart failure and stable functional status (without additional diuretic therapy), where lack of deterioration and therefore "stability" is seen as a positive outcome (see supplemental figure).( 50) Furthermore, it needs to be underscored that if CRT is being Accepted Article implanted in HFrEF patients with a QRS-width above 130 msec (especially in the presence of LBBB), there is no proven patient population that experiences a negative response to CRT.(10)

Action III: Better clinical interpretation of pre-implant characteristics

Patient selection

European and American guidelines give a class I recommendation for CRT in symptomatic HFrEF patients in sinus rhythm with wide QRS (supplemental table 1). [START_REF] Brignole | ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA)[END_REF][START_REF] Ponikowski | ESC Guidelines for the diagnosis Accepted Article and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF][START_REF] Yancy | ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF] The EchoCRT and RethinQ trials showed that the benefit of CRT does not extend to patients with a narrow QRS, even in the presence of some echocardiographic characteristics indicative of LV mechanical dyssynchrony. [START_REF] Beshai | Cardiac-resynchronization therapy in heart failure with narrow QRS complexes[END_REF][START_REF] Ruschitzka | Cardiacresynchronization therapy in heart failure with a narrow QRS complex[END_REF] The 2016 HFA-guidelines reflect these data and do not recommend CRT in patients with a narrow QRS, defined as QRS < 130msec (Class of recommendation III, level of evidence A). [START_REF] Beshai | Cardiac-resynchronization therapy in heart failure with narrow QRS complexes[END_REF][START_REF] Ruschitzka | Cardiacresynchronization therapy in heart failure with a narrow QRS complex[END_REF] The observation that QRS duration is dependent on body/heart size has resulted in ongoing research to determine if QRS duration should be individualized. [START_REF] Varma | Interaction of Left Ventricular Size and Sex on Outcome of Cardiac Resynchronization Therapy Among Patients With a Narrow QRS Duration in the EchoCRT Trial[END_REF][START_REF] Varma | Sex-Specific Response to Cardiac Resynchronization Therapy: Effect of Left Ventricular Size and QRS Duration in Left Bundle Branch Block[END_REF][START_REF] Linde | The interaction of sex, height, and QRS duration on the effects of cardiac resynchronization therapy on morbidity and mortality: an individualpatient data meta-analysis[END_REF] Guidelines recommend the presence of LV ejection fraction (LVEF) below 35%, as this was a major inclusion criterion in most CRT trials. [START_REF] Brignole | ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA)[END_REF][START_REF] Ponikowski | ESC Guidelines for the diagnosis Accepted Article and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF][START_REF] Yancy | ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF] However, there is reason to believe that CRT may be effective in the higher range of reduced LVEF from both the MADIT CRT and REVERSE trial.( 56) For example, a core lab assessment of baseline LVEF from the MADIT-CRT trial indicated that 38% of patients actually had a LVEF above the entry-criteria cut-off, with LVEFs up to 45%.(57) These patients had similar benefit in terms of death and heart failure hospitalization, and might also have a greater degree of reverse remodeling. This, together with the standard error of the measurement of LVEF by echocardiography, should be taken into account when determining eligibility based upon LVEF.

Accepted Article

It is well acknowledged that visible pre-implant mechanical dyssynchrony (apical rocking, septal flash) is associated with an acute hemodynamic improvement following CRT.

(58, 59) However, using mechanical dyssynchrony for the selection of CRT does not select patients more likely to gain benefit. [START_REF] Beshai | Cardiac-resynchronization therapy in heart failure with narrow QRS complexes[END_REF][START_REF] Ruschitzka | Cardiacresynchronization therapy in heart failure with a narrow QRS complex[END_REF][START_REF] Chung | Results of the Predictors of Response to CRT (PROSPECT) trial[END_REF] As such, the absence of pre-implant mechanical dyssynchrony should not defer the implantation of a CRT device in patients with a guideline indication. Other imaging techniques or echocardiographic parameters have not been used to guide treatment in the randomized controlled trials, and should therefore not be used for the de-selection of patients otherwise eligible. That is not to say however, that preimplant imaging is not required. For instance, pre-implant magnetic resonance imaging is useful in the assessment of the risk for sudden cardiac death (e.g; mid-wall fibrosis), and might therefore be helpful in determining the choice between CRT-P vs. CRT-D. [START_REF] Gutman | Reduction in mortality from implantable cardioverter-defibrillators in non-ischaemic cardiomyopathy patients is dependent on the presence of left ventricular scar[END_REF][START_REF] Leyva | Cardiac resynchronization therapy guided by late gadolinium-enhancement cardiovascular magnetic resonance[END_REF] Additionally, echocardiography remains an indispensable tool to detect disease progression following CRT, and the mechanism(s) related to ongoing disease following implant, which might be amenable for auxiliary therapies (e.g. residual functional mitral regurgitation amendable for mitral edge-to-edge repair). [START_REF] Mullens | Sacubitril/Valsartan to Reduce Secondary Mitral Regurgitation[END_REF][START_REF] Martens | Effect of Cardiac Resynchronization Therapy on Exercise-Induced Pulmonary Hypertension and Right Ventricular-Arterial Coupling[END_REF] Guidelines state a IIa indication for CRT in patients with atrial fibrillation (AF), despite the fact that only 262 patients with AF were randomized in the original CRT-trials, which indicates that there is virtually no randomized trial data on CRT in AF patients. The RAFT trial randomized patients to an ICD vs CRT-D stratified by the presence of permanent AF. In the AF patients, there was only a trend towards fewer heart failure hospitalization in CRT treated patients, and the primary outcome of death or heart failure hospitalization between those assigned to ICD vs CRT-D was similar.(65) Despite this limited trial evidence, up to 26% of patients enrolled into the Euro CRT Survey II had AF.(20) Furthermore guidelines state that a pre-requisite for CRT to work in AF is a strategy to ensure biventricular capture is in place. [START_REF] Brignole | ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA)[END_REF][START_REF] Ponikowski | ESC Guidelines for the diagnosis Accepted Article and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF][START_REF] Yancy | ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF] Observational data indicate that AF with rapid Accepted Article conduction is the leading reason for loss of biventricular pacing.(66, 67) Furthermore, observational studies relate a low percentage of biventricular to poor outcome. Although this is often interpreted that a strategy that ensures 100% of biventricular pacing results in better prognosis, it needs to pointed out that the phenotype of patients that suffer from low percentages of biventricular pacing might be sicker. This could partially explain the observed relation between biventricular pacing percentages and outcome. Indeed to data, no randomized trial study has proven that a higher number of biventricular pacing is better than a lower percentage of biventricular pacing.

Device based features have been designed to attain higher percentages of biventricular pacing through fusion pacing (RV sense will result in LV pacing), but should not be an alternative to optimal medical therapy, PVI or AV-junction ablation to ensure effective CRT in AF. Gasparini demonstrated in a small prospective study that CRT patients in permanent AF, only had improvement in LV function and functional capacity if AV-junction ablation was performed.(68) Furthermore, AV-junctional ablation has been associated with a reduced incidence of inappropriate ICD interventions. [START_REF] Gasparini | Atrioventricular junction ablation in patients with atrial fibrillation treated with cardiac resynchronization therapy: positive impact on ventricular arrhythmias, implantable cardioverter-defibrillator therapies and hospitalizations[END_REF] The use of AV-junctional ablation in clinical practice is variable, but should be considered if pharmacologic therapies fail to result in adequate percentage (target of >90-95%) of biventricular pacing. The current position paper recognizes the scarce data of CRT in AF. Nevertheless, despite the lack of large randomized clinical trials, guidelines as well as this position statement still recommend the use of CRT in permanent AF patients with similar indications as for patients in sinus rhythm, provided that AVJ ablation (or PVI if indicated) is added in those with incomplete (<90-95%) biventricular pacing. [START_REF] Cheng | Reasons for loss of cardiac resynchronization therapy pacing: insights from 32 844 patients[END_REF][START_REF] Koplan | Heart failure decompensation and all-cause mortality in relation to percent biventricular pacing in patients with heart failure: is a goal of 100% biventricular pacing necessary?[END_REF][START_REF] Hayes | Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival[END_REF]. In addition, other causes for incomplete biventricular pacing such as premature ventricular beats might need to be treated as well.

RAFT-PermAF (NCT01994252), which investigates whether CRT reduces heart size in CRT patients with permanent AF is currently ongoing.

Accepted Article

Next to selected patients in sinus rhythm and AF, guidelines recommend CRT in HFrEF patients with a classic pacing indication who are expected to receive a high burden of RV-pacing (IA-recommendation) or patients with a classic pacemaker or ICD who develop heart failure (IIa-recommendation for upgrade). [START_REF] Brignole | ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA)[END_REF][START_REF] Ponikowski | ESC Guidelines for the diagnosis Accepted Article and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF][START_REF] Yancy | ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America[END_REF] In the Euro CRT II Survey, 23% of the entire CRT-population were upgrades.( 20) ACC/AHA/HRS guidelines underscore that a high burden (eg >40%) of RV-pacing is a prerequisite for benefit of an upgrade.

Guideline directed medical therapy

The evidence for CRT lies with HFrEF patients with residual symptoms and a persistently reduced LVEF despite optimal background treatment with neurohormonal blockers. However, only a minority of patients implanted with CRT are on maximal guideline recommended doses of ACE-I/ARB (30%) and beta-blockers (20%) before CRT. [START_REF] Heywood | Comparison of medical therapy dosing in outpatients cared for in cardiology practices with heart Accepted Article failure and reduced ejection fraction with and without device therapy: report from IMPROVE HF[END_REF] Although this might be the result of inertia in care, patients might not be able to tolerate higher doses due bradycardia and hypotension. While patients with HFrEF and narrow QRS often exhibit significant reverse remodeling to medical therapy, patients with HFrEF and LBBB seem to reverse Accepted Article remodel less following initiation of neurohormonal blockers. [START_REF] Sze | Impaired Recovery of Left Ventricular Function in Patients With Cardiomyopathy and Left Bundle Branch Block[END_REF] For example, in one study, patients with LBBB experienced an improvement in LVEF of 2% whereas those with a narrow QRS had an increase of 8% after 6 months of medical therapy which might be the result of differential expression of contractile genes in those with electromechanical dyssynchrony. [START_REF] Sze | Impaired Recovery of Left Ventricular Function in Patients With Cardiomyopathy and Left Bundle Branch Block[END_REF][START_REF] St John | Left Ventricular Architecture, Long-Term Reverse Remodeling, and Clinical Outcome in Mild Heart Failure With Cardiac Resynchronization: Results From the REVERSE Trial[END_REF] Therefore, this position statement from HFA, EHRA and EACVI encourages clinicians not to postpone CRT implant too long, particularly in patients with LBBB and a QRS duration >150ms.

Role of comorbidities

Comorbidities are frequent in heart failure and affect the delivery and effect of heart failure therapy, functional status, and clinical outcomes. [START_REF] Lee | Comorbidity profiles and inpatient outcomes during hospitalization for heart failure: an analysis of the U.S. Nationwide inpatient sample[END_REF][START_REF] Martens | Impact of iron deficiency on exercise capacity and outcome in heart failure with reduced, midrange and preserved ejection fraction[END_REF][START_REF] Verbrugge | Comorbidity significantly affects clinical outcome after cardiac resynchronization therapy regardless of ventricular remodeling[END_REF][START_REF] Leyva | Survival after cardiac resynchronization therapy: results from 50 084 implantations[END_REF] Due to this competing risk patients with comorbidities derive less benefit from an ICD (see next section). However, an elegant analysis from the MADIT-CRT trial demonstrated that this was not the case for CRT, where the relative reduction in morbidity and mortality was consistent.(82) Hence, patients with comorbidities should not be denied CRT, although appropriate assessment of potential benefit of the combination of CRT with ICD therapy is particularly important in this population. [START_REF] Martens | Incremental benefit of cardiac resynchronisation therapy with versus without a defibrillator[END_REF] Certain comorbidities are of particular interest in CRT candidates as they might influence the success of the implantation procedure, choice between CRT-P vs. CRT-D, symptomatic improvement, and reverse remodeling response after implant.( 12) Although a history of valve replacement might make LV lead placement more challenging, it is not associated with less benefit from CRT.(84, 85) Furthermore, while renal disease was an exclusion criteria in the major CRT trials and early observational data suggested less reverse remodeling in patients with chronic kidney disease stage IV and V,(1, 3-6, 47) more recent data indicate that patients with chronic kidney disease derive similar mortality benefit from lesser reverse remodeling. [START_REF] Bax | Left ventricular dyssynchrony predicts benefit of cardiac resynchronization therapy in patients with end-stage heart failure before pacemaker implantation[END_REF][START_REF] Ter Maaten | Response to Cardiac Resynchronization Therapy Across Chronic Kidney Disease Stages[END_REF] Iron deficiency which is common in CRT recipients

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(around 55%) might be associated with less functional improvement and less reverse remodeling following CRT,(86) possibly due to the role of iron as an essential co-factor for protein synthesis and normal cell functioning. [START_REF] Martens | Rationale and design of the IRON-CRT trial: effect of intravenous ferric carboxymaltose on reverse remodelling following cardiac resynchronization therapy[END_REF] In conclusion, CRT selection and optimization must occur in the context of other heart failure interventions and other comorbidities. With a growing heart failure treatment armamentarium, this is becoming increasingly challenging for the cardiologist, highlighting the need for early referral to a heart failure management team. [START_REF] Lund | Effect of expanding evidence and evolving clinical guidelines on the prevalence of indication for cardiac resynchronization therapy in patients with heart failure[END_REF][START_REF] Thorvaldsen | Focusing on Referral Rather than Selection for Advanced Heart Failure Therapies[END_REF]

CRT-P vs CRT-D: individualizing choice

In order to derive maximal benefit from a ICD, patients need to have a high risk of dying from sudden cardiac death (SCD) mediated by ventricular arrhythmias, and a low risk of dying from other causes (non-SCD-mediated death). [START_REF] Daubert | There is plenty of room for cardiac resynchronization therapy devices without back-up defibrillators in the electrical treatment of heart failure[END_REF][START_REF] Levy | Should Nonischemic CRT Candidates Receive CRT-P or CRT-D?[END_REF][START_REF] Mcmurray | The ICD in Heart Failure -Time for a Rethink?[END_REF] This balance should be taken into account prior to device implantation (figure 3). For example, large areas of scar and an ischemic etiology of heart failure or a high burden of non-sustained ventricular tachyarrhythmias (NsVT) on Holter monitoring are associated with a higher risk of SCD. [START_REF] Gutman | Reduction in mortality from implantable cardioverter-defibrillators in non-ischaemic cardiomyopathy patients is dependent on the presence of left ventricular scar[END_REF][START_REF] Gupta | Myocardial Scar But Not Ischemia Is Associated With Defibrillator Shocks and Sudden Cardiac Death in Stable Patients With Reduced Left Ventricular Ejection Fraction[END_REF][START_REF] Acosta | Scar Characterization to Predict Life-Threatening Arrhythmic Events and Sudden Cardiac Death in Patients With Cardiac Resynchronization Therapy: The GAUDI-CRT Study[END_REF][START_REF] Di | Late Gadolinium Enhancement and the Risk for Ventricular Arrhythmias or Sudden Death in Dilated Cardiomyopathy: Systematic Review and Meta-Analysis[END_REF][START_REF] Mittal | The impact of nonsustained ventricular tachycardia on reverse remodeling, heart failure, and treated ventricular tachyarrhythmias in MADIT-CRT[END_REF][START_REF] Marijon | Causes-ofdeath analysis of patients with cardiac resynchronization therapy: an analysis of the CeRtiTuDe cohort study[END_REF] Monitored SCD in patients with a CRT-P device is often pre-dated by an increasing burden of NsVTs, suggesting a role for remote monitoring to detect patients" who might benefit from upgrade to a CRT-D. [START_REF] Boveda | Incidence and prognostic significance of sustained ventricular tachycardias in heart failure patients implanted with biventricular pacemakers without a back-up defibrillator: results from the prospective, multicentre, Mona Lisa cohort study[END_REF]. On the other hand, women have a lower risk of SCD, [START_REF] Rho | Important differences in mode of death between men and women with heart failure who would qualify for a primary prevention implantable cardioverter-defibrillator[END_REF] and data from the DANISH trial illustrate that a strategy for routine primary prevention ICD for patients with a non-ischemic etiology does not improve overall long-term survival. [START_REF] Kober | Defibrillator Implantation in Patients with Nonischemic Systolic Heart Failure[END_REF] This is in line with other studies indicating that the risk for SCD is intrinsically lower in patients with a non-ischemic etiology of heart failure.(99) Notably, there was an age-by-therapy interaction in DANISH suggesting that younger patients (possibly those younger than 70 years) have a greater chance of benefiting from ICD implantation than older patients probably because of lower competing risk from co-morbidities and the higher

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given the lack of head-to-head trials. Supportive guidelines aiding appropriate selection between CRT-P versus CRT-D in countries with lower GDP might help to increase CRT implant rates in these areas. The Re-evaluation of Optimal Re-synchronisation Therapy in Patients With Chronic Heart Failure (RESET-CRT, NCT03494933) trial will further provide information regarding this topic.

Action IV: organize a dedicated post-implant optimized CRT care pathway

Follow-up of CRT patients is often divided over several cardiology subspecialties and large differences exist between hospitals and healthcare systems.(109) Although a comprehensive post-CRT implant follow-up program has not been tested in randomized controlled trials, there are several easily-modifiable factors applicable directly following implant, before discharge, at early and longer follow-up that could improve short and longer-term outcomes following implantation (Figure 4 and Table 2).( 110

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among patients followed in CRT/ICD clinics. [START_REF] Lund | Effect of expanding evidence and evolving clinical guidelines on the prevalence of indication for cardiac resynchronization therapy in patients with heart failure[END_REF][START_REF] Thorvaldsen | Focusing on Referral Rather than Selection for Advanced Heart Failure Therapies[END_REF] The remainder of this section discusses major topics in the optimization of care following CRT implant.

Improvement of heart failure management

Higher doses of both beta-blockers and renin angiotensin system blockers are associated with lower event rates,(115, 116) and the benefits of dose titration is especially important in patients at highest risk.(117) Although CRT is often considered only after implementation of optimal medical HF therapy, it needs to be emphasized that in clinical practice only a minority of patients are able to tolerate maximal doses of neurohormonal blockers before CRT implant. [START_REF] Heywood | Comparison of medical therapy dosing in outpatients cared for in cardiology practices with heart Accepted Article failure and reduced ejection fraction with and without device therapy: report from IMPROVE HF[END_REF] On the other hand, the acute and chronic hemodynamic effects of CRT might significantly change tolerability and acceptance of medical therapy. For example, in the CARE-HF and COMPANION trial, CRT was associated with a 6-7 mmHg increase in systolic blood pressure.(3, 4) Furthermore, CRT protects patients against slowing of AVconduction, bradycardia and sinoatrial nodal pauses allowing safe uptitration of beta-blockers.

Two randomized controlled trials have tested higher versus lower doses of neuro-hormonal blockers in heart failure, indicating a lower event rate with higher doses.(115, 116) Attaining guideline directed doses of evidence based neurohormonal blockers is a cornerstone of the treatment of heart failure including patients with CRT devices which is insufficiently emphasized in current guidelines. Real world data indicate that 45% of patients on submaximal dose of ACE-I/ARB are able to tolerate uptitration following CRT-implant, and up to 57% of patients on submaximal dose of beta-blockers are able to tolerate higher doses after CRT-implant.(118) Although biased by the observational nature, uptitration was associated with a lower risk for heart failure hospitalization and mortality (118, 119). Furthermore, although between 73%-97% of patients were taking loop diuretics at the time of implant in the major CRT trials (1, 3, 4, 6, 47) loop diuretic down-titration is often feasible following CRT implant, with possible benefits on long term renal function.(120)

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Although initiation of sacubitril/valsartan improved outcome in the PARADIGM-HF trial, remarkably few were treated with CRT.(121) Sacubitril/valsartan use in CRT and ICD patients results in incremental reverse remodeling, and a significant reduction in the burden of VT/VF, appropriate ICD therapies, and premature ventricular complexes (PVCs) which can have additional benefits on CRT delivery.(122-124) Although often underappreciated by patients and primary care physicians, physical exercise following CRT or ICD implant has proven to be safe in the ACTION-HF trial.(125) Furthermore, observational and randomized data suggested that cardiac rehabilitation following CRT implant is associated with a larger degree of functional improvement, LV reverse remodeling and reduction in heart failure hospitalization and mortality.(126-129)

Optimal device programming

Individual programming of devices following implant and at each follow-up should be the aim. At each clinic visit an electrocardiogram and device analysis may help with assessment of patient status. (Table 3). The key target of programming has been to deliver 100% of biventricular capture in order to achieve the optimal outcomes. [START_REF] Daubert | EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management[END_REF][START_REF] Brignole | ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA)[END_REF] Although no randomized controlled trials exist comparing a lower versus a higher degree of biventricular pacing, observational data link a low degree of biventricular pacing to poorer outcome.

Although this might be to some extent a reflection of a different patient population, guidelines emphasize to try to attain a maximal percentage of biventricular pacing (Class IIa recommendation).( 23) There are a range of other programmable options including pacing mode, pacing rate, upper tracking rate, rate-adaptive pacing, capture output, atrio-ventricular (AV) and ventriculo-ventricular (VV) intervals and tachy-programming which should be reviewed at each clinic visit.

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The pacing mode depends on the underlying atrial rhythm. In patients in sinus rhythm a DDD pacing mode is preferred but the base rate should allow sensing of intrinsic sinus rhythm as much as possible to avoid unnecessary atrial pacing. Landmark CRT trials often used a lower rate of 35-40/min with hysteresis off (130, 131). Atrial support pacing (base rate of 70/min in DDDR mode) did not show benefit in the PEGASUS-CRT trial,(132) possibly because right atrial pacing is associated with left atrial dyssynchrony and progressive left atrial remodeling, which also are independent predictors for the development of AF.(133-135) Therefore, lower rates are generally programmed low (40-50/min) in patients in sinus rhythm, although in patients in whom atrial fibrillation leads to mode switch, attention should be given to program a high enough base rate when this occurs (DDIR or VDIR mode). In patients in permanent AF an inhibited mode is preferred, which can be DDIR or VVIR depending on the presence of an atrial lead. The DDDR mode should be reserved for patients with paroxysmal AF. [START_REF] Daubert | EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management[END_REF][START_REF] Brignole | ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA)[END_REF] In patients with AF who receive adequate rate control, a slightly higher base rate of 60 bpm together with rate-adaptive pacing might improve the proportion of bi-ventricular capture. [START_REF] Daubert | EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: implant and follow-up recommendations and management[END_REF][START_REF] Brignole | ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA)[END_REF] However in those with sinus rhythm, rate-adaptive pacing should be programmed off until the presence of significant iatrogenic or intrinsic chronotropic incompetence affecting exercise intolerance is proven bearing in mind that simple age-related rate-adaptive pacing does not improve exercise capacity and may be disadvantageous in some. (117,136,137) Whether rate-adaptive pacing is activated or not, the upper tracking rate should be programmed sufficiently high (e.g. 80% of maximal age predicted heart rate), to ensure persistent biventricular pacing during periods of faster intrinsic sinus rhythm (e.g. exercise).

Device diagnostics can be used to check this, although an exercise test is also useful.

LV output should be programmed with sufficient margin to ensure biventricular capture.

Modern devices are equipped with auto-capture features that might improve battery longevity in some,(138) although nocturnal threshold testing can be unpleasant if there is diaphragmatic None of these algorithms have proven to be superior to echocardiographic optimization, although a superiority study with LV fusion pacing is ongoing.(144) In the light of the neutral clinical results of a routine approach of optimizing AV and VV-intervals, one can consider this for specific patients (eg long interatrial delay). Nevertheless post-implant echocardiography with assessment of the mitral inflow pattern allows for a quick evaluation of the appropriateness of the AV-interval programming. Indeed, if the A-wave is truncated or there is a lot of wasted mechanical time (fusion of E and A wave with A-wave ending before beginning of electrical systole), this should prompt the attention that the AV-interval is not programmed correctly.

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The programming of therapies for tachycardia should be individualized based on the indication for the ICD (primary vs secondary prevention) and has been reviewed in more detail recently.(145) Adequate brady-and tachyprogramming requires specialist device knowledge and expertise which aims at preventing morbidity, rather than to react to it (e.g.

preventing ICD interventions; ensuring high biventricular-pacing; …). Therefore, these

Accepted Article patients should be followed at specialized centers having multidisciplinary collaboration (i.e. heart failure and arrhythmology) and by physicians having undergone extensive device training and certification.

Inclusion in remote monitoring

In remote monitoring of CRT devices, a distinction should be made between device related remote monitoring and monitoring of heart failure status through measurement of physiological variables. Patients with CRT have heart failure, and are therefore at an increased risk of clinical events such as ventricular or supraventricular arrhythmias which can interrupt CRT or worsen heart failure status.(146) Additionally, technical problems related to battery and leads can have an impact on patients status and prognosis, and might warrant detection and appropriate action as early as possible. These variables can be monitored by the (160-164) For example, long term follow-up of the highly-selected CASTLE-AF patients suggests that AF-ablation is associated with a lower risk of heart failure admission and allcause mortality.(161) Importantly, the benefit was demonstrated not by elimination of AF but rather by reducing overall AF burden.(161) In patients with HFrEF and AF who have a CRT device, AF-ablation could be considered for those with a high likelihood of attaining sinus rhythm and thus subsequently 100% of biventricular pacing. AV nodal ablation should be considered as a treatment strategy for patients who fail to achieve sufficient biventricular pacing despite AV-blocking medical therapy or efforts to maintain sinus rhythm (eg amiodarone or AF-ablation in selected patients).

Frequent PVCs can also result in a low percentage of biventricular pacing and further worsen

Disease progression and remission

As indicated in Figure 2, CRT can stabilize the disease trajectory but some patients have persistent symptoms and will eventually deteriorate. Some of these patients might be indicated for advanced heart failure therapies. Therefore, the CRT specialist team should not only be experienced in the management of technical aspects of the CRT devices, and medical therapy for heart failure, but should also be competent to detect and understand the mechanisms underlying disease progression (see Figure 4). Imaging plays an essential role A very small subgroup of CRT-patients demonstrate overwhelming benefit from CRT that every aspect of their heart failure disease seems to dissipate (normalization of echocardiogram and NTproBNP, and resolution of symptoms). These patients can be considered to be in "full remission". A small prospective randomized pilot trial suggested that closely supervised neurohumoral blocker withdrawal ("CRT only strategy") is feasible and safe in patients with myocardial recovery after CRT.(186) These results differ from TRED-HF in that those in TRED-HF did not have LBBB with improved LV function following CRT.(187) In contrast, data from MUSTIC and MADIT-CRT indicated that turning off biventricular pacing ("medical strategy only") led to a reoccurrence of the heart failure syndrome. [START_REF] Cazeau | Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay[END_REF]

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Patient engagement and education

CRT recipients are often older adults with multiple comorbidities. Adequate information on the purpose of CRT, the implant procedure including risk and post-implant care are essential for them and their family. A recent survey indicated that almost half of patients felt insufficiently informed about technical aspects or had worries about aspects of their implantable devices.(188) A considerable number of heart failure patients suffer from depressive symptoms which are associated with worse outcomes.(189) Psychosocial concerns and worries should be addressed in a multidisciplinary approach. Furthermore, end of life decisions such as ICD withdrawal are rarely discussed.(188) Information through healthcare providers (e.g. CRT-specialist, heart failure nurse) and paper and web-based education (e.g. www.heartfailurematters.org) might improve patients" understanding and engagement. Table 4 summarizes important patient-centered aspects regarding the education of patients and families with regard to use of CRT.

D. Future perspectives

Alternative resynchronization strategies have been developed that might also effectively treat the electromechanical dyssynchrony in HFrEF patients. Such strategies include His-Bundle and LBBB-area pacing, endocardial LV lead pacing, wireless LV stimulation or even deep interventricular septal LV-pacing. (190)(191)(192) In patients with a classical CRT-indication, pacing strategies such as His-Bundle-pacing are often propagated as an alternative because of the equipoise induced by the 30% non-response rate to CRT.(193) However, it is clear from this manuscript that this concept of non-response to CRT is intrinsically flawed. Although acute hemodynamic and short-term reverse remodeling studies with these novel pacing strategies illustrate a similar hemodynamic, functional and remodeling improvement as CRT (191,(194)(195)(196)(197)(198)(199), they will have to show at least equal benefit in terms of morbidity and Accepted Article mortality endpoints in HFrEF and be as safe in order to be implemented in clinical practice as an alternative to CRT (198). Additionally, His-Bundle is also being tested in HFrEF for other indications such as PR-prolongation.(200) Whether CRT might be of benefit in patients with heart failure patients with preserved ejection fraction is also under investigation.(201)

E. Conclusion

CRT is an underutilized lifesaving therapy, strongly recommended in guidelines for a common subgroup of HFrEF patients. This HFA, EHRA and EACVI endorsed document offers theoretical and practical strategies to achieve more comprehensive CRT referral and post-procedural care by focusing on several actionable domains. CRT is an expensive therapy CRT is a cost-effective heart failure therapy.

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Consideration of CRT should only occur after repeated (failed) attempts to achieve guideline recommended doses of RAAS-I and beta blockers Only a minority of patients included in CRT trials were on optimal doses of RAAS-I and beta blockers, and the effects of these drugs on LVEF improvement are far less pronounced in LBBB than in narrow QRS. CRT can help achieve guideline recommended doses.

Patients with multiple comorbidities derive no benefit of CRT Patients with comorbidities derive significant benefit from CRT, especially when the co-morbidities are addressed. The need for CRT-D should be dealt with openly in this population.

All patients should receive CRT-D The benefit of the ICD is determined by the risk of sudden cardiac death over the risk of non-sudden cardiac death. Those at highest risk of HF death derive no benefit from an ICD.

Physicians know when to refer patients for CRT.

Most patients are only referred within cardiology. The non-cardiology medical and allied health community and patients need education to improve referral.

Echocardiography should be used a technique to select patients that will not respond to CRT Echocardiography is poor at determining "need" or "response" to CRT. Patients should not be denied CRT based upon echocardiography.

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Access to CRT is not an issue as CRT implantation can be done by everyone who can implant a DDD-pacemakers CRT-implant does have a higher risk, and does require more training than conventional DDD-pacemakers. Efforts should be made to increase access.

Myths related to the post-implant phase of CRT

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  from the EuroCRT Survey II indicates that 67% of implanted patients had a class I indication, with 26% having a class IIa indication, 5% a class IIb indication and 2% a class III indication.It would appear that while CRT is globally underused, in clinical practice CRT is frequently offered to patients in whom the level of evidence is either less robust than a class I indication or non-existent.[START_REF] Fein | Prevalence and predictors of off-label use of cardiac resynchronization therapy in patients enrolled in the National Cardiovascular Data Registry Implantable Cardiac-Defibrillator Registry[END_REF]

  Few data are available from clinical trials. CRT was superior to conventional right ventricular pacing in patients in sinus rhythm with atrioventricular block and LV systolic dysfunction in the BLOCK-HF trial.(72) Additionally, reduced clinical manifestations of heart failure were noted with CRT pacing compared to RV pacing in heart failure patients with symptomatic permanent AF who underwent AV-junction ablation in the APAF trial.(73) Given the incremental risk of device upgrade or risk of pacemaker dependency after AV-junction ablation, the benefits and risks should be assessed individually given the rather low level of evidence. The ongoing BUDAPEST-CRT trial (NCT02270840) will determine the effects of upgrade from an ICD to a CRT-D in symptomatic HFrEF patients with RV-pacing (>20%).(74)

  Accepted Articleduration of exposure to the risk of SCD, which is reflected in the lower rate of SCD and allcause mortality.(100-102) Finally, accurate estimation of the risk of life-threatening ventricular tachyarrhythmias by risk calculators in patients with underlying genetic mutations (i.e. LMNA mutations) helps to select candidates for ICD implantation.(103) CRT-D comes at higher cost and carries the risk of inappropriate therapy (104) and all post-hoc analyses including a Bayesian network analysis suggest equivalence between the two approaches but the randomized controlled trials also point at a favorable effect of CRT alone on the risk of sudden death. For example, the CARE-HF and REVERSE-trial indicate that resynchronization therapy, and its potential to increase beta-blocking agents, diminishes VT/VF, especially in patients with extensive LV reverse remodeling,(105) possibly due to diminished electrical dispersion, early after depolarization and other cellular substrates for VT/VF.(106-108) Therefore, although factors associated with greater reverse remodeling following CRT, such as LBBB-morphology, long QRS-duration, female sex and nonischemic etiology should not be used to select candidates for CRT, they could be considered in the decision to offer CRT-P over CRT-D.(Figure 3). Advanced cardiac imaging technologies including assessment of conduction channels by cardiac resonance imaging and possibly radiomics may further help in individualizing risk of VT/VF in the future. Additional clinical factors favoring the use of CRT-P could include advanced age , more severe symptoms (NYHA class III/IV), and life-shortening co-morbidity (e.g. severe lung disease or Stage IV chronic kidney disease). Nevertheless, the difficult and currently unanswered paradox remains that whilst CRT reduces the need for ICD, it improves survival and reduces the rate of death due to HF, thereby exposing patients to an increased duration of life in which SCD can occur. As such, individualized decision making based on patient characteristics, national/local resources, and patient preference for either CRT-P or CRT-D remains important

  , 111). Furthermore, although such a comprehensive dedicated CRT follow-up program is endorsed by several cardiac societies (EHRA, Heart Rhythm Society, Heart Failure Society of America, American Society of Echocardiography, American Heart Association, EACVI and HFA), and results in improvement of workflow of a typical multi-morbid complex patient population, an ongoing barrier is the need for focused training of medical and allied health care professionals in the holistic care of patients with heart failure and device-based interventions.(112) Such training has been endorsed by the European HFA and forms part of the certification by the EHRA.(113, 114) Interestingly, just as referral for CRT is inadequate, referral for further interventions in patients who already have CRT is also inadequate, underscoring the importance of broad knowledge of the CRT-team/CRT-expert. For example, it has been shown that the need for heart transplantation and LV assist device was grossly underestimated

  capture at higher outputs. Quadripolar LV leads and their multiple vectors offer the opportunity of avoiding phrenic nerve stimulation, and output optimization to extend battery longevity,(139) whereas the use of multiple vectors simultaneously (multi-point pacing) has not shown clinical benefit whilst reducing battery life.(140) The most commonly assessed programming options include the AV and VV intervals. Poor attention to detail around especially AV delays is a contributor to reduced efficacy of CRT.(110) However, routine echocardiographic AV-interval optimization is not superior in comparison to empiric programming of a 100-120msec sensed AV-interval.(141) Most new devices from different vendors have automated algorithms that individualize AV/VVintervals, creating fusion between spontaneous conduction and LV stimulation to avoid right ventricular pacing, or optimizing AV/VV intervals using a hemodynamic sensor.(142, 143)

  device and remotely transmitted to the treating team.(147) Early detection of clinical or technical issues improved clinical outcomes in the IN-TIME trial, (148) although several larger trials failed to show benefit of remote monitoring.(149-152) Large registries have shown benefits of remote monitoring in CRT patients especially when devices are capable of collecting multiple key physiological parameters such as heart rate, respiration frequency, heart sounds and physical activity, in addition to technical checks on the device.(23, 153) This approach requires an organizational change including funding of virtual visits and training of personnel who should react appropriately to transmitted information.(154) With the recent EU General Data Protection Regulation, hospitals and physicians must be aware of certain rules that need to be complied with and agreements with manufacturers that need to be in place to implement remote monitoring. Finally, patients preference should be taken into account, as observational data indicates that around 20-35% of patients prefer in-clinic visits instead of remote monitoring.(155)Accepted ArticleManaging Arrhythmias in CRTArrhythmias are common in heart failure patients, and often have an impact on morbidity, mortality and functioning of the CRT device. Atrial tachyarrhythmias and frequent PVCs are responsible for 50% and 10% respectively of the cases of a low percentage of bi-ventricular pacing thereby further compromising LV systolic dysfunction and contributing to decompensation.[START_REF] Cheng | Reasons for loss of cardiac resynchronization therapy pacing: insights from 32 844 patients[END_REF] 156) Whether suppression of atrial tachyarrhythmia, mainly AF, in the presence of HFrEF is of benefit and which strategy might be appropriate is unknown.(157, 158) Despite concerns around long term safety and overall neutral clinical outcomes (154, 159), guidelines recommend amiodarone (IA) if a rhythm control strategy is chosen. AF-ablation has gained a lot of interest (IIA-recommendation),[START_REF] Ponikowski | ESC Guidelines for the diagnosis Accepted Article and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF] 158) due to possible improvements in LVEF, functional capacity and quality of life in comparison to rate control in heart failure patients.

  LV systolic function.(67) If despite heart failure therapy optimization, PVCs continue to cause low proportions of biventricular pacing, amiodarone or PVC-ablation can be considered.(158) A study in which patients with poor improvement after CRT and more than Accepted Article >10.000 PVCs per 24 hours were subjected to PVC-ablation showed improvements in symptoms and incremental reverse remodeling.(165) Ventricular arrhythmias are a key concern in HFrEF patients especially in those with reduced LVEF and ischemic heart disease. (83) The prevalence of ventricular arrhythmias is associated with the disease severity of HFrEF.(166-168) The event rate for mortality and heart failure admission are markedly higher following appropriate ICD-therapy, but not after inappropriate therapy,(169, 170) which indicates that a ventricular arrhythmic event in HFrEF is a marker of disease progression. Hence, heart failure therapy optimization is mandatory not only to treat, but also to prevent ventricular arrhythmias in HFrEF.(171) Additionally, triggers such as volume overload, ion disturbances, loss of biventricular pacing and others should be actively assessed and treated. Furthermore, guidelines recommend consideration of amiodarone and VT ablation in CRT-D patients after a first sustained episode.(171) Any arrhythmic event should also prompt a review of the device programming.(145)

(

  172) in identifying persistence of secondary mitral regurgitation, and progressive atrial, LV and right ventricular remodeling all of which indicate progression of the HF syndrome, and warrant consideration of appropriate interventions,(173-175) including additional device therapies such as mitral edge-to-edge repair,(176, 177) or newer medical therapies.(121, 178) Accepted Article Cardiopulmonary exercise test with determination of peak VO2 and other variables might (29, 179) provide information on prognosis and appropriate timing of more advanced interventions in selected patients.(180, 181) The CRT specialist team should be able to determine if palliative care is more suitable than onward referral for more invasive therapies.(182) CRT teams are also the best at determining whether and when the possibility for ICDinterventions should be withdrawn. For example, at time of battery depletion and box-change, patient and physician perspective might warrant consideration of withdrawal of ICD therapy by replacement of a CRT-D device with a CRT-P device. (183-185) Unfortunately, this is increasingly difficult in the absence of a DF-4 to IS-1 connector necessitating an additional right ventricular pace-sense lead implantation. Additional liability issues might occur if patients, following downgrading from CRT-D to CRT-P, die suddenly or subsequently show a deterioration in cardiac function, and therefore this should be comprehensively discussed with the expert team and with the patient and/or his family and in the light of therapeutic aims and relevant co-morbidity, such as dementia or malignancy.

Figure 1 :

 1 Figure 1: CRT-P and CRT-D implants in Europe between 2014 and 2018

Figure 2 :

 2 Figure 2: Role of CRT in disease modification of the heart failure disease trajectory

Figure 3 :

 3 Figure 3: Conceptual framework for individualizing of prescription of CRT-P vs CRT-D

Figure 4 :

 4 Figure 4: Structured post-implant CRT-care



  Abbreviations: AT/AF= atrial tachycardia/ atrial fibrillation, AV= atrioventricular , BiV=biventricular pacing, COPD= chronic obstructive pulmonary disease,ECG= electrocardiogram, LV= left ventricular, MR= mitral regurgitation, NsVT= non-sustained ventricular tachycardia, PA= posterior-anterior, PVC= premature ventricular complexes, RV= right ventricular, VV= interventricular, VT/VF= ventricular tachycardia/ ventricular fibrillation. Explanation: diagnostic procedures should be individualized to the patients' need and physical status and not be considered "routine" (e.g. repeat treadmill tests in older adults, or those with frailty or comorbidity, may not be helpful or useful).

Table 1 :

 1 myths and strategies for better implementation

	Common Myths of CRT	Explanation
	Myths related to the pre-implant phase of CRT
	30% of patients do not respond to CRT CRT response has been classified by arbitrary definitions:
		its effect in any one individual should be seen as
		continuous disease modification and whilst they may not
		feel "better", they are highly likely to be "better than
		without the device"
	Patients with an ischemic etiology of	On average, patients with an ischemic etiology of heart
	heart failure benefit less from CRT	failure manifest less reverse remodeling but have an equal
		relative risk reduction after CRT for HF-admission and
		death as the non-ischaemic group
	If the QRS is narrow, patients will	In patients with HFrEF, remodeling of the left ventricle is
	never have an indication for CRT	accompanied by electrical remodeling such that QRS
		duration lengthens. Follow-up ECG are necessary.
		Consideration should be given to those with poor LV
		ejection fraction and a pacing indication that will lead to
		high proportion of RV pacing.

Table 2 :

 2 Role and utility of interventions in CRT follow-upEnsure and determine BiV-paced complex (QRS width, degree of QRS reduction, capture, morphology and LV latency), ECG after implant is the template for future trouble-shooting  Consider performing at least once ECG with BiV off and LV and RV only pacing (large QRS difference between LV and RV only pacing might indicate need for VV-optimization)

	Intervention	Potential relevance
	12-lead ECG	  Positive R-wave V1? If not, rule out LV lead displacement and loss of LV
		capture, and if other cause are negative if lead was placed middle or
		anterior cardiac vein
		 Always repeat ECG following significant device changes
	Chest X-ray (PA
	and lateral)

Table 3 :

 3 Template for CRT-device analysis Diagnostics 1. Battery longevity 2. %ASVP / %APVP / %Biv vs LV only / % Biv vs RVSense respons / % Effective 3. Heart failure log: HR variability, activity, lung impedance, sleep… 4. Arrhythmias (afib, ectopy, VT, Vsense response…) 5. Impedance trends APVP= atrial pace ventricular pace, ASVP= atrial sense ventricular pace, AV= atrioventricular,BiV= biventricular, CLS= closed loop stimulation, HR= heart rate, LV= left ventricular , RV=right ventricular, VT= ventricular tachycardia, VV= interventricular,.

	Measurements
	1. Impedance
	2. Sensitivity
	3. Tresholds
	Programming
	1. Lower / upper frequency (+mode switch)
	2. R-response (accelerometer / CLS / minute ventilation)
	3. Biv vs RV vs LV only
	4. AV / VV times (manual: fixed vs dynamic / device-based)
	5. Output leads
	6. Sensitivity
	7. Biv sense response
	8. Tachysettings

Abbreviations:

Table 4 :

 4 Element of patient centered CRT-education CRT= cardiac resynchronization therapy, HF= heart failure, ICD= implantable cardioverter defibrillator.

	Pre-implantation	Early post-implantation	Living with CRT
	 Discuss the position in the HF trajectory  Include patient and caregiver in decision making  Provide information and understanding of the device indication (ask-tell-ask)  Provide information on the procedure  Discuss expectations  Provide information of consequences (long and short term)  Include family caregivers  Discussion of potential complications (lead displacement, shocks,	 Discuss questions related to discomfort, pain, placement  Discuss effect and expectations  Discuss the role of CRT in the HF treatment and consequence for treatment (lifestyle and medication changes)  Discuss how to adjust medications after implant  Inform on when to contact a health care provider  Include family caregivers	 Provide tailored follow-up  Discuss the role of CRT in the HF trajectory  Discuss consequences for survival, treatment, lifestyle, exercise  Be open for coping issues (feeling dependent on technology, anxiety for failure)  Inform the patients about relevant issues: insurance, travel  If relevant discuss deactivation of the ICD  Include family caregivers  End of life care.
	infection) with the
	patients and care-giver.

Abbreviations:

Heart failure fund has received research grants from Novartis, Vifor, Medtronic, Biotronik, Abbott and Boston Scientific. Boston Scientific, Medtronic, Philips. has received a research grant from Vifor pharma and Fonds Wetenschappelijk Onderzoek (grant number: 1127917N) and consultancy fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Novartis and Vifor pharma. Myers Squibb, Pfizer, Bayer, Astra Zeneca, and has received unconditional research support in the form of a PhD Fellowship collaboration between the University of Leeds and Medtronic UK. Research grants to institution from Astra Zeneca, Swedish Heart-Lung-foundation and Stockholm County Council. Speaker honoraria from Medtronic, Abbot, Microport, Boston Scientific, Novartis, Vifor , Impulse consultancy and speaker fees from Medtronic, Abbott, and Phillips. The department has received research and educational grants from Medtronic, Abbott and Biotronik , Abbott, Boston Scientific, Microport and Novartis. He has received research funding from Medtronic, Abbott, Boston Scientific, Microport. Medtronic; honoraria for presentations, travel/congress cost reimbursement; Abbott, Biotronik, Grants or research support: MicroPort. Lars Lund: personal fees from Merck, personal fees from Sanofi, grants and personal fees from Vifor-Fresenius, grants and personal fees from AstraZeneca, grants and personal fees from Relypsa, personal fees from Bayer, grants from Boston Scientific, grants and personal fees from Novartis, personal fees from Pharmacosmos, personal fees from Abbott, grants and personal fees from Mundipharma, personal fees from Medscape, personal fees from Myokardia, grants and personal fees from Boehringer Ingelheim, outside the submitted work; Giuseppe Boriani: declares speaker"s fees of small amount from Boston, Biotronik, Boehringer, Medtronic. has received speaker fees and research grant from Biosense. He has intellectual properties with Galgo Medical. He participates in clinical trials sponsored by Biotronik, Biosense and Circle. honoraria from Medtronic, Pfizer, Berlin Chemie Menarini and Sandoz. has received grants from the Novo Nordisk Foundation (NNF16OC0018658 and NNF17OC0029148). grants from Medtronic, Daiichi Sankyo, Boehringer-Ingelheim, Bayer, Pfizer-BMS, Biotronik, Abbott and Bracco Imaging.