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............................................................. RBBB.272277 Patients with RBBB do not benefit from CRT278 unless they show a so-called masked LBBB on ECG,277 characterized by a broad, slurred, sometimes notched R wave on leads I and aVL, together with a leftward axis deviation. Individualized positioning of the LV lead is crucial in these patients.

An important recent notion is the possible role played by a prolonged PR in HF patients with non-LBBB. A few single-centre studies and two post-hoc analyses of large RCTs (COMPANION and MADIT-CRT) indicated a potential benefit of implanting CRT in this patient subgroup.244,279,280 In MADIT-CRT, the subgroup of non- LBBB patients who had a prolonged PR did benefit from CRT-D, with a 73% reduction in the risk of HF or death and an 81% reduction in the risk of all-cause mortality compared with ICD-only therapy.279 In non LBBB patients with normal PR, CRT-D was associated with a trend towards an increased risk of HF or death and a >2-fold higher mortality compared with ICD therapy, suggesting a bidirectional significant interaction. However, the data are too limited to give a recommendation.279 The results of the MADIT-CRT, REVERSE, and RAFT trials suggest that in patients with LBBB, there is likely to be potential benefit in all patients with LBBB regardless of QRS duration, and that no cut-off point can be identified clearly to exclude patients who will not respond according to the QRS duration.272,273,275 In contrast, any benefit of CRT in patients with non-LBBB is evident mostly in those with a QRS duration >_150 ms. Importantly, as shown in the MADIT- CRT long-term study and RAFT, the benefit in patients with QRS <150 ms appeared later during follow-up.265,273 The Echocardiography Guided Cardiac Resynchronization Therapy (Echo-CRT) trial suggested possible harm from CRT when baseline echocardiographic mechanical dyssynchrony in patients with QRS duration <130 ms is used.264,281 Therefore, selection of CRT patients based solely on the use of cardiac imaging data is strongly discouraged in patients with so-called ‘narrow’ QRS (i.e. <130 ms). Individual patient data pooled from three CRT-D vs. ICD trials enrolling predominantly patients with NYHA class II HF showed that women are more likely to respond than men.282 In the US Food and Drug Administration meta-analysis of patient-level data, Zusterzeel et al.283 found that the main difference occurred in patients with LBBB and a QRS of 130149 ms. In this group, women had a 76% reduction in HF or death [absolute CRT-D to ICD difference, 23% (HR 0.24, 95% CI 0.110.53; P < 0.001)] and a 76% reduction in death alone [absolute difference 9% (HR 0.24, 95% CI 0.060.89; P = 0.03)], whereas there was no significant benefit in men for HF or death [absolute difference 4% (HR 0.85, 95% CI 0.601.21; P = 0.38)] or death alone [absolute difference 2% (HR 0.86, 95% CI 0.491.52; P = 0.60)]. A possible explanation for the greater benefit of CRT in women has been attributed to sex difference in LV size, as sex-specific differences in response disappear when QRS duration is normalized to LV end-diastolic volume.284 Recently, computer modelling confirmed that sex differences in the LV size account for a significant proportion of the sex difference in QRS duration, and provided a possible mechanistic explanation for the sex difference in CRT response.285,286 Simulations accounting for the smaller LV size in female CRT patients predict 9 - 13 ms lower QRS duration thresholds for females. As with other ECG parameters (e.g. duration of QT and corrected QT), it is conceivable that QRS duration also has to reflect sex difference. ECG criteria of intraventricular conduction disturbance, LBBB, and non-LBBB have not been consistently defined and reported in any of the past CRT studies.287,288 Similarly, the modality of QRS measurement (automatic or manual, and ECG recording machine) was not reported in CRT studies. However, the selection of ECG criteria appears to influence hard endpoints.287290 Similarly, ECG recording modality and ECG manufacturer have been shown to possibly affect the automatically measured QRS duration.

Finally, CRT is considered in patients on optimal medical treatment (OMT), including beta-blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers, and mineralocorticoid receptor antagonists. However, a study raises the question of the timing of CRT, because the efficacy of the medical treatment can be limited in patients with LBBB, suggesting considering CRT sooner.291 Moreover, whereas everyday clinical practice supports the use of sacubitril/valsartan, ivabradine, and sodiumglucose co-transporter- 2 inhibitors, it must be emphasized that in the landmark trials documenting the efficacy of these drugs, very few patients had an indication for CRT. Thus, there are no strong data to support the mandatory use of these drugs before considering CRT.292295

Recommendations for cardiac resynchronization therapy in patients in sinus rhythm

Recommendations Classa Levelb

LBBB QRS morphology CRT is recommended for symptomatic patients with HF in SR with LVEF <_35%, QRS duration >_150 ms, and LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity and mortality.37,39,40,254266,283,284 I A CRT should be considered for symptomatic patients with HF in SR with LVEF <_35%, QRS duration 130149 ms, and LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity and mortality.37,39,40,254266,283,284 IIa B Non-LBBB QRS morphology CRT should be considered for symptomatic patients with HF in SR with LVEF <_35%, QRS duration >_150 ms, and non-LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity.37,39,40,254266,283,284 IIa B CRT may be considered for symptomatic patients with HF in SR with LVEF <_35%, QRS duration 130149 ms, and non-LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity.273278,281 IIb B QRS duration CRT is not indicated in patients with HF and QRS duration <130 ms without an indication for RV pacing.264,282 III A

CRT = cardiac resynchronization therapy; HF = heart failure; LBBB = left bundle branch block; LVEF = left ventricular ejection fraction; OMT = optimal medical therapy; SR = sinus rhythm. aClass of recommendation. bLevel of evidence. ESC 2021

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