Left bundle branch pacing is the best approach to physiological pacing

The last decade has seen the resurgence of conduction system pacing (CSP) for patients with symptomatic bradycardia and heart failure. His-bundle pacing (HBP) is now an accepted alternative to more traditional ventricular pacing sites (right ventricular RV apex/outflow tract, coronary sinus).1Kusumoto F.M. Schoenfeld M.H. Barrett C. et al.2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society.Circulation. 2019; 140: e333-e381PubMed Google Scholar Although HBP is theoretically the ideal physiological pacing site, it has some inherent limitations. The implant technique requires greater expertise in targeting a small zone and can be challenging in patients with dilated hearts, resulting in long procedural and fluoroscopic times. The reported success rate for HBP varies from 56% to 95%, depending on the degree of conduction system disease present and the experience of the center.2Vijayaraman P. Chung M.K. Dandamudi G. et al.His bundle pacing.J Am Coll Cardiol. 2018; 72: 927-947Crossref PubMed Scopus (121) Google Scholar, 3Sharma P.S. Vijayaraman P. Ellenbogen K.A. Permanent His bundle pacing: shaping the future of physiological ventricular pacing.Nat Rev Cardiol. 2020; 17: 22-36Crossref PubMed Scopus (30) Google Scholar, 4Bhatt A.G. Musat D.L. Milstein N. et al.The efficacy of His bundle pacing: lessons learned from implementation for the first time at an experienced electrophysiology center.JACC Clin Electrophysiol. 2018; 4: 1397-1406Crossref PubMed Scopus (51) Google Scholar Successful HBP lead implantation is fraught with troubleshooting issues during follow-up.5Lustgarten D.L. Sharma P.S. Vijayaraman P. Troubleshooting and programming considerations for His bundle pacing.Heart Rhythm. 2019; 16: 654-662Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar HBP leads typically have a low R-wave amplitude that may result in oversensing of atrial or His signals and undersensing of ventricular signals. High HBP capture thresholds at implant and/or during late follow-up may result in premature battery depletion and repeated generator replacements and the associated risks.6Poole J.E. Gleva M.J. Mela T. et al.Complication rates associated with pacemaker or implantable cardioverter-defibrillator generator replacements and upgrade procedures: results from the REPLACE registry.Circulation. 2010; 122: 1553-1561Crossref PubMed Scopus (511) Google Scholar The unpredictable, delayed rise in HBP capture thresholds are a major concern, resulting in higher lead revision rates.4Bhatt A.G. Musat D.L. Milstein N. et al.The efficacy of His bundle pacing: lessons learned from implementation for the first time at an experienced electrophysiology center.JACC Clin Electrophysiol. 2018; 4: 1397-1406Crossref PubMed Scopus (51) Google Scholar,7Zanon F. Abdelrahman M. Marcantoni L. et al.Long term performance and safety of His bundle pacing: a multicenter experience.J Cardiovasc Electrophysiol. 2019; 30: 1594-1601Crossref PubMed Scopus (42) Google Scholar A subset of patients may also lose His capture during follow-up, resulting in RV septal pacing. No robust data regarding the long-term performance of HBP leads are available. In the largest observational, 2- center study, 844 patients who received HBP leads had a mean pacing capture threshold of 1.6 V at implant and 2 V at median follow-up of 3 years.7Zanon F. Abdelrahman M. Marcantoni L. et al.Long term performance and safety of His bundle pacing: a multicenter experience.J Cardiovasc Electrophysiol. 2019; 30: 1594-1601Crossref PubMed Scopus (42) Google Scholar HBP was free of any complications in 91% of patients. However, a careful appraisal of the data highlights the concerns noted in about 35%–40% of the patients. Pacing thresholds were ≥2.5 V at 1 ms in 28% of patients at median follow-up. Follow-up electrocardiography showed septal pacing in 9% of patients. Lead revision was required in 7.6% of patients. Median time for battery replacement was 5.8 years.7Zanon F. Abdelrahman M. Marcantoni L. et al.Long term performance and safety of His bundle pacing: a multicenter experience.J Cardiovasc Electrophysiol. 2019; 30: 1594-1601Crossref PubMed Scopus (42) Google Scholar The quest for an optimal pacing site led to a novel CSP technique described by Huang et al8Huang W. Su L. Wu S. et al.A novel pacing strategy with low and stable output: pacing the left bundle branch immediately beyond the conduction block.Can J Cardiol. 2017; 33: 1736.e1-1736.e3Abstract Full Text Full Text PDF Scopus (208) Google Scholar in 2017, where the pacing lead was implanted deep in the RV basal septum to capture the left bundle branch (LBB) area in a patient with heart failure and left bundle branch block (LBBB). Since its original description, few studies have demonstrated the feasibility of left bundle branch area pacing (LBBAP) (Table 1).9Chen K. Li Y. Dai Y. et al.Comparison of electrocardiogram characteristics and pacing parameters between left bundle branch pacing and right ventricular pacing in patients receiving pacemaker therapy.Europace. 2019; 21: 673-680Crossref PubMed Scopus (81) Google Scholar, 10Zhang J. Wang Z. Cheng L. et al.Immediate clinical outcomes of left bundle branch area pacing vs conventional right ventricular pacing.Clin Cardiol. 2019; 42: 768-773Crossref PubMed Scopus (33) Google Scholar, 11Hou X. Qian Z. Wang Y. et al.Feasibility and cardiac synchrony of permanent left bundle branch pacing through the interventricular septum.Europace. 2019; 21: 1694-1702Crossref PubMed Scopus (84) Google Scholar, 12Li X. Li H. Ma W. et al.Permanent left bundle branch area pacing for atrioventricular block: feasibility, safety, and acute effect.Heart Rhythm. 2019; 16: 1766-1773Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 13Li Y. Chen K. Dai Y. et al.Left bundle branch pacing for symptomatic bradycardia: implant success rate, safety, and pacing characteristics.Heart Rhythm. 2019; 16: 1758-1765Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 14Vijayaraman P. Subzposh F.A. Naperkowski A. et al.Prospective evaluation of feasibility and electrophysiologic and echocardiographic characteristics of left bundle branch area pacing.Heart Rhythm. 2019; 16: 1774-1782Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 15Zhang W. Huang J. Qi Y. et al.Cardiac resynchronization therapy by left bundle branch area pacing in patients with heart failure and left bundle branch block.Heart Rhythm. 2019; 16: 1783-1790Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 16Hasumi E. Fujiu K. Nakanishi K. Komuro I. Impacts of left bundle/peri-left bundle pacing on left ventricular contraction.Circ J. 2019; 83: 1965-1967Crossref PubMed Scopus (12) Google Scholar, 17Cai B. Huang X. Li L. et al.Evaluation of cardiac synchrony in left bundle branch pacing: insights from echocardiographic research.J Cardiovasc Electrophysiol January. 2020; 31: 560-569Crossref PubMed Scopus (29) Google Scholar, 18Jiang Z. Chang Q. Wu Y. Ji L. Zhou X. Shan Q. Typical BBB morphology and implantation depth of 3830 electrode predict QRS correction by left bundle branch area pacing.Pacing Clin Electrophysiol. 2020; 43: 110-117Crossref PubMed Scopus (13) Google Scholar, 19Wang J. Liang Y. Wang W. et al.Left bundle branch area pacing is superior to right ventricular septum pacing concerning depolarization-repolarization reserve.J Cardiovasc Electrophysiol. 2020; 31: 313-322Crossref PubMed Scopus (18) Google Scholar LBBAP is rapidly emerging as an alternative for failed HBP cases or as a primary strategy (in some centers) for CSP. Both anatomy (narrow target for His bundle HB vs wide target for left bundle branch area LBBA) and histology (His encased in fibrous, electrically nonconducting tissue vs LBB embedded in myocardium) favor LBBA over HB for physiological pacing.Table 1Published studies on left bundle branch area pacingStudy (year)DesignSample sizeStudy populationSuccess rateMean paced QRSd (ms)Mean LVAT (ms)LBB potentialFollow-up (mo)Lead complicationsOutcomesChen et al (2018)ProspectiveLBBAP vs RVP20SND: 75%AV/infranodal block: 20%NR111 ± 1069 ± 955%3A/C: NoneStable lead parametersZhang et al (2019)ProspectiveLBBAP vs RVP23SND: 48%AVB: 38%87%112 ± 12NRNRNRA: NoneC: NRAcute success rate and pacing characteristicsHou et al (2019)Prospective56SND: 29%AVB: 37%AF with SVR: 34%NR118 ± 1176 ± 1467%4.5A: 1 lead dislodgment intraoperativeC: NoneStable lead parametersLBBAP patients with potential had LV mechanical synchrony similar to that of HBP based on phase analysis of gated SPECT MPIStable LVEFLi et al (2019)Retrospective33AVB: 100%91%113 ± 1182 ± 1526.7%3A: 1 LV septal perforationC: NoneStable lead parametersStable LVEFLi et al (2019)Prospective87SND: 68%AVB: 32%80%113 ± 1079.7 ± 8.566%3A/C: NoneStable lead parametersVijayaraman et al (2019)Prospective100SND: 23%AVB: 54%AVN ablation: 7%CRT: 11%HBP failure: 7%93%136 ± 1775 ± 1663%3A: 3 lead dislodgments within 24 h requiring revision; 3 LV septal perforationsC: NoneStable lead parametersZhang et al (2019)Prospective11HF with reduced EF and LBBB: 100%NR129 ± 1680.9 ± 9.950%6.7A/C: NoneStable lead parametersImprovement in LVEF by >5% from baseline in all, >20% from baseline in 7 patientsImprovement in LV synchrony by pulsed-wave Doppler and tissue synchronization imagingHasumi et al (2019)Retrospective21Advanced AVB: 100%Failed HBP81%116 ± 8.3NRNR6A/C: NoneStable lead parametersCai et al (2020)ProspectiveObservationalLBBAP vs RVP40SND: 100%90%101 ± 8.79LBBAP with normal axis: 59 ± 6; left-axis deviation: 64 ± 4.580%Echocardiogram on day 3NRLBBAP preserved mechanical synchrony similar to native conductionLBBAP leads to favorable hemodynamic effectsRVP resulted in electrical and mechanical dyssynchrony and worse hemodynamic effectsJiang et al (2020)Retrospective73BBB with QRSd >130 msAtypical BBB:13.6%5 LBBB and 5 RBBBTypical BBB: 86.4%30 LBBB and33 RBBB30%82.5%133 ± 14118 ± 14103 ± 2385 ± 1510%28.6%NRA: 4 LV septal perforationsC: NoneTypical BBB morphology (Strauss criteria) predicts successful QRS correction with LBBAPWang et al (2020)ProspectiveRandomizedLBBAP vs RVP66SND: 32%AVB: 54%AF with SVR: 14%94%121 ± 9.867.8 ± 6.875%6A: 1 lead perforation at 1 month requiring revisionC: 2 lead dislodgments (1 at 2 mo, 1 at 4 mo)Stable lead parametersLBBAP resulted in narrower QRSd, shorter QT and QTc interval, lower QTD and QTcD shorter Tpeak-end interval compared with RVP, suggesting better depolarization-repolarization reserveTotal5306 lead dislodgments9 septal perforationsA = acute; AF with SVR = atrial fibrillation with slow ventricular rate; AV = atrioventricular; AVN = atrioventricular node; AVB = atrioventricular block; BBB = bundle branch block; C = chronic; CRT = cardiac resynchronization therapy; EF = ejection fraction; HBP = His-bundle pacing; HF = heart failure; LBB = left bundle branch; LBBAP = left bundle branch area pacing; LBBB = left bundle branch block; LV = left ventricle; LVAT = left ventricular activation time; LVEF = left ventricular ejection fraction; NR = not reported; QTc = corrected QT interval; QTD = QT dispersion; QTcD = corrected QT dispersion; RBBB = right bundle branch block; RVP = right ventricular pacing; SND = sinus node dysfunction; SPECT MPI = in a A = acute; AF with SVR = atrial fibrillation with slow ventricular rate; AV = atrioventricular; AVN = atrioventricular node; AVB = atrioventricular block; BBB = bundle branch block; C = chronic; CRT = cardiac resynchronization therapy; EF = ejection fraction; HBP = His-bundle pacing; HF = heart failure; LBB = left bundle branch; LBBAP = left bundle branch area pacing; LBBB = left bundle branch block; LV = left ventricle; LVAT = left ventricular activation time; LVEF = left ventricular ejection fraction; NR = not reported; QTc = corrected QT interval; QTD = QT dispersion; QTcD = corrected QT dispersion; RBBB = right bundle branch block; RVP = right ventricular pacing; SND = sinus node dysfunction; SPECT MPI = LBBAP is a 3830 pacing lead the or the The and the from the pacing lead are and on an system The in the implant area as His-bundle potential is on the right fluoroscopic the and the 3830 and the fluoroscopic is for the His-bundle potential is to the or or can be as a is and the the RV basal septum and pacing is to for an ideal site for lead a paced morphology of with a in the in lead and/or of lead and in lead lead and the are the lead is to the RV septum by pacing is to the ideal paced QRS morphology and to of the lead in the RV pacing is is to the septum and to the to the septum 1 in the right and in the left an the in also be by a the pacing lead is rapidly pacing is to the paced QRS morphology and pacing are 1 or 2 at a the paced QRS morphology right bundle branch conduction or right bundle branch block in lead or the lead the the and as the lead the LBBA the by about pacing capture the of the electrode in the septum LBB potential is present The and are LBBAP is by W. Chen X. Su L. Wu S. X. Vijayaraman P. A to permanent left bundle branch pacing.Heart Rhythm. 2019; 16: Full Text Full Text PDF PubMed Scopus Google of through the can be in the left fluoroscopic to the RV septal and the lead depth in the interventricular septum The between the and the electrode is an of lead depth in pacing capture a of lead depth in the Lead depth can also be on the LBBAP are not lead depth in the septum or the lead not deep septum or to the lead be to a on the are to left ventricular to capture the The not to to the ideal the can be for better and 4 successful LBBAP in with and mechanical and replacement by heart heart block with right bundle branch block and left bundle branch block left bundle branch area pacing lead implant during pacing. the in QRS morphology in lead from to at V at is to of Follow-up of 1 month in the at 2 V at was the pacing with QRSd of ms and in suggesting and LBBA was V at showed normal left ventricular ejection ventricular pacing with ejection Heart Association left bundle branch block on therapy for cardiac resynchronization the coronary sinus lead implant A left bundle branch area pacing lead was sinus and LBBB with QRSd Pacing with AV at ms resulted in bundle branch area capture with right bundle branch block in lead with QRSd of Pacing with AV at ms resulted in of QRSd to is to between right bundle branch conduction and LBBA pacing. Follow-up in the in 1 month during threshold showed in lead during pacing with capture threshold of V at pacing with AV at ms and at 2 V at ms of QRS with QRSd of was V at was the day Follow-up 2 showed ejection of The patient required heart failure and reported Heart Association 5 et M. Y. et al.Feasibility and acute hemodynamic of left ventricular septal pacing by through the interventricular Electrophysiol. PubMed Scopus Google Scholar demonstrated the feasibility of LV septal pacing a lead implanted in LV septal pacing resulted in a narrower QRS ± and acute hemodynamic over RV pacing. Both LV septal pacing and LBBAP can result in a QRS with CSP is it is to LBBA However, clinical outcomes between LV septal pacing and LBBAP to be The for LBBA capture are and to be in future Huang et W. Chen X. Su L. Wu S. X. Vijayaraman P. A to permanent left bundle branch pacing.Heart Rhythm. 2019; 16: Full Text Full Text PDF PubMed Scopus Google Scholar to LBBA Successful LBBAP is of the are morphology of RBBB of LBB ventricular activation time from to of in lead and at and (1 pacing and of and LBB pacing and and from No from for LBB capture LBBAP results in capture of the LBB and the to its in the et M. P. A. et deep septal a novel for the of left bundle branch capture during permanent pacing.J Cardiovasc Electrophysiol. 2020; 31: PubMed Scopus Google Scholar described to LBB capture vs LV septal capture based on were during sinus or an at ms with a interval, was by to premature was as the paced QRS morphology to capture with and/or with in in or LBB the paced QRS morphology to a morphology by a or LBB was of LBBA capture and was noted in of the patients with M. P. A. et deep septal a novel for the of left bundle branch capture during permanent pacing.J Cardiovasc Electrophysiol. 2020; 31: PubMed Scopus Google Scholar HBP is the physiological of pacing that or electrical and mechanical synchrony by activation of M.J. et resynchronization pacing in patients with heart failure and left bundle branch Am Coll Cardiol. 2018; 72: PubMed Scopus Google Scholar In LBBAP by capture of the LBB or physiological activation of the RBBB conduction is noted with a QRS The of RBBB during LBBAP is and between LBB and L. of the His PubMed Scopus Google P. within the His bundle and the bundle PubMed Scopus Google Scholar activation of His and during and electrode S. Zhou X. bundle branch pacing: of the Am Coll Cardiol. 2019; PubMed Scopus Google Scholar the delayed RV activation from LBBAP result in interventricular dyssynchrony and is studies have LV mechanical synchrony with LBBAP similar to that of HBP based on phase analysis of gated X. Qian Z. Wang Y. et al.Feasibility and cardiac synchrony of permanent left bundle branch pacing through the interventricular septum.Europace. 2019; 21: 1694-1702Crossref PubMed Scopus (84) Google Scholar to that of native conduction based on echocardiographic B. Huang X. Li L. et al.Evaluation of cardiac synchrony in left bundle branch pacing: insights from echocardiographic research.J Cardiovasc Electrophysiol January. 2020; 31: 560-569Crossref PubMed Scopus (29) Google Scholar and LV mechanical synchrony in patients with LBBB and heart failure based on echocardiographic W. Su L. Wu S. et al.A novel pacing strategy with low and stable output: pacing the left bundle branch immediately beyond the conduction block.Can J Cardiol. 2017; 33: 1736.e1-1736.e3Abstract Full Text Full Text PDF Scopus (208) Google W. Huang J. Qi Y. et al.Cardiac resynchronization therapy by left bundle branch area pacing in patients with heart failure and left bundle branch block.Heart Rhythm. 2019; 16: 1783-1790Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar The results of small studies on LBBAP are (Table The success rate from High success rates were in patients with conduction system Lead parameters capture thresholds stable during follow-up. LBBAP in cardiac resynchronization therapy in patients with heart failure and W. Su L. Wu S. et al.A novel pacing strategy with low and stable output: pacing the left bundle branch immediately beyond the conduction block.Can J Cardiol. 2017; 33: 1736.e1-1736.e3Abstract Full Text Full Text PDF Scopus (208) Google W. Huang J. Qi Y. et al.Cardiac resynchronization therapy by left bundle branch area pacing in patients with heart failure and left bundle branch block.Heart Rhythm. 2019; 16: 1783-1790Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar In a of patients with heart failure and LBBAP resulted in LBB correction with of QRS from a mean of ± ms to ± W. Huang J. Qi Y. et al.Cardiac resynchronization therapy by left bundle branch area pacing in patients with heart failure and left bundle branch block.Heart Rhythm. 2019; 16: 1783-1790Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar the lead parameters and was in left ventricular ejection and dyssynchrony on echocardiographic at mean follow-up of W. Huang J. Qi Y. et al.Cardiac resynchronization therapy by left bundle branch area pacing in patients with heart failure and left bundle branch block.Heart Rhythm. 2019; 16: 1783-1790Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar LBBAP is an emerging pacing and the safety is the cases (Table lead dislodgments (1 3 within 24 1 at 2 and 1 at 4 and septal and 1 at 1 have X. Qian Z. Wang Y. et al.Feasibility and cardiac synchrony of permanent left bundle branch pacing through the interventricular septum.Europace. 2019; 21: 1694-1702Crossref PubMed Scopus (84) Google X. Li H. Ma W. et al.Permanent left bundle branch area pacing for atrioventricular block: feasibility, safety, and acute effect.Heart Rhythm. 2019; 16: 1766-1773Abstract Full Text Full Text PDF PubMed Scopus (92) Google P. Subzposh F.A. Naperkowski A. et al.Prospective evaluation of feasibility and electrophysiologic and echocardiographic characteristics of left bundle branch area pacing.Heart Rhythm. 2019; 16: 1774-1782Abstract Full Text Full Text PDF PubMed Scopus (127) Google Z. Chang Q. Wu Y. Ji L. Zhou X. Shan Q. Typical BBB morphology and implantation depth of 3830 electrode predict QRS correction by left bundle branch area pacing.Pacing Clin Electrophysiol. 2020; 43: 110-117Crossref PubMed Scopus (13) Google J. Liang Y. Wang W. et al.Left bundle branch area pacing is superior to right ventricular septum pacing concerning depolarization-repolarization reserve.J Cardiovasc Electrophysiol. 2020; 31: 313-322Crossref PubMed Scopus (18) Google Scholar No major complications associated with and have as and delayed threshold have not potential as coronary of septal of the and of lead to be in future clinical on the clinical LBBAP to be the to physiological pacing and of the noted with HBP (Table The target site, challenging lead shorter procedural and fluoroscopic Y. Chen K. Dai Y. et al.Left bundle branch pacing for symptomatic bradycardia: implant success rate, safety, and pacing characteristics.Heart Rhythm. 2019; 16: 1758-1765Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar higher success to or LV X. Qian Z. Wang Y. et al.Feasibility and cardiac synchrony of permanent left bundle branch pacing through the interventricular septum.Europace. 2019; 21: 1694-1702Crossref PubMed Scopus (84) Google W. Huang J. Qi Y. et al.Cardiac resynchronization therapy by left bundle branch area pacing in patients with heart failure and left bundle branch block.Heart Rhythm. 2019; 16: 1783-1790Abstract Full Text Full Text PDF PubMed Scopus (62) Google B. Huang X. Li L. et al.Evaluation of cardiac synchrony in left bundle branch pacing: insights from echocardiographic research.J Cardiovasc Electrophysiol January. 2020; 31: 560-569Crossref PubMed Scopus (29) Google Scholar stable lead parameters with LBBAP for LBBAP to be the of physiological pacing.Table between HBP and target zone target electrically or RV and LV or LV rates in AV and to thresholds or to the conduction system as pacing beyond the site of septum LBB of oversensing atrial or His of undersensing ventricular higher as through a be unpredictable, with a delayed thresholds ≥2.5 V ms seen in of to of be in of conduction system revision to be AV capture thresholds safety pacing or in patients with LBBB to safety pacing generator associated of His of LBBAP = atrioventricular; HBP = His-bundle pacing; LBB = left bundle branch; LBBAP = left bundle branch area pacing; LBBB = left bundle branch block; LV = left ventricle; RV = right in a AV = atrioventricular; HBP = His-bundle pacing; LBB = left bundle branch; LBBAP = left bundle branch area pacing; LBBB = left bundle branch block; LV = left ventricle; RV = right The rate of LBBAP technique in clinical is In of CSP cases in were S. Zhou X. bundle branch pacing: of the Am Coll Cardiol. 2019; PubMed Scopus Google Scholar In a of patients to an experienced center for CSP in 1 received LBBAP leads failed to an result with M. P. A. et deep septal a novel for the of left bundle branch capture during permanent pacing.J Cardiovasc Electrophysiol. 2020; 31: PubMed Scopus Google Scholar experience at also a regarding the site of CSP. HBP leads were implanted at over a is in to LBBAP leads implanted over a to the experience with LBBAP has with success stable and major complications to LBBAP is the 3830 lead and or of were for in technique and are for of success The for LBBA capture to be and The long-term safety lead and of of deep septal LBBAP leads to be The of LBBAP in patients requiring cardiac resynchronization therapy to be in clinical The are to Vijayaraman for the left bundle branch area pacing with is the to the also be by a The pacing lead is rapidly with to the lead the with of through the in the fluoroscopic the RV septal and the lead depth in the of the lead is in the with LBBA pacing lead in a patient with LBB and the LBB pacing lead the septal and at the LV with lead the lead not deep septum or to In it be to the lead to