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Incidence and predictors of right ventricular pacing-induced cardiomyopathy in patients with complete atrioventricular block and preserved left ventricular systolic function

      Background

      Right ventricular (RV) pacing may worsen left ventricular cardiomyopathy in patients with reduced left ventricular ejection fraction (LVEF) and advanced atrioventricular block.

      Objective

      The objectives of this study were to calculate incidence and identify predictors of RV pacing-induced cardiomyopathy (PICM) in complete heart block (CHB) with preserved LVEF and to describe outcomes of subsequent cardiac resynchronization therapy (CRT) upgrade.

      Methods

      An analysis of consecutive patients receiving permanent pacemaker (PPM) from 2000 to 2014 for CHB with LVEF >50% was performed. PICM was defined as CRT upgrade or post-PPM LVEF ≤40%. PICM association was determined via multivariable regression analysis. CRT response was defined by LVEF increase ≥10% or left ventricular end-systolic volume decrease ≥15%.

      Results

      Of the 823 study patients, 101 (12.3%) developed PICM over the mean follow-up of 4.3 ± 3.9 years, with post-PPM LVEF being 33.7% ± 7.4% in patients with PICM vs 57.6% ± 6.1% in patients without PICM (P < .001). In multivariable analysis, lower pre-PPM LVEF (hazard ratio [HR] 1.047 per 1% LVEF decrease; 95% confidence interval [CI] 1.002–1.087; P = .042) and RV pacing % both as a continuous (HR 1.011 per 1% RV pacing; 95% CI 1.002–1.02; P = .021) and as a categorical (<20% or ≥20% RV pacing) (HR 6.76; 95% CI 2.08–22.0; P = .002) variable were independently associated with PICM. Only 29 patients with PICM (28.7%) received CRT upgrade despite an 84% responder rate (LVEF increase 18.5% ± 8.1% and left ventricular end-systolic volume decrease 45.1% ± 15.0% in responders). CRT upgrade was associated with greater post-PPM LVEF decrease, lower post-PPM LVEF, and post-PPM LVEF ≤35% (P = .006, P = .004, and P = .004, respectively).

      Conclusion

      PICM is not uncommon in patients receiving PPM for CHB with preserved LVEF and is strongly associated with RV pacing burden >20%. CRT response rate is high in PICM, but is perhaps underutilized.

      Keywords

      Introduction

      Right ventricular (RV) pacing is known to produce electric and mechanical dyssynchrony by triggering the right ventricle to contract before the left ventricle (interventricular dyssynchrony) and the septum to contract before the lateral walls (intraventricular dyssynchrony).
      • Tops L.F.
      • Schalij M.J.
      • Bax J.J.
      The effects of right ventricular apical pacing on ventricular function and dyssynchrony implications for therapy.
      Historically, adverse clinical events were first attributed to RV pacing in patients with sinus node dysfunction, with higher rates of congestive heart failure (CHF), atrial fibrillation, and chamber dilation observed as compared to AAI pacing.
      • Nielsen J.C.
      • Andersen H.R.
      • Thomsen P.E.
      • et al.
      Heart failure and echocardiographic changes during long-term follow-up of patients with sick sinus syndrome randomized to single-chamber atrial or ventricular pacing.
      • Nielsen J.C.
      • Kristensen L.
      • Andersen H.R.
      • Mortensen P.T.
      • Pedersen O.L.
      • Pederson A.K.
      A randomized comparison of atrial and dual-chamber pacing in 177 consecutive patients with sick sinus syndrome: echocardiographic and clinical outcome.
      Thereafter, increased CHF and mortality were seen with DDDR 70 vs VVI 40 pacing in the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial,
      • Wilkoff B.L.
      • Cook J.R.
      • Epstein A.E.
      • Greene H.L.
      • Hallstrom A.P.
      • Hsia H.
      • Kutalek S.P.
      • Sharma A.
      Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial.
      a different patient population enrolling patients with left ventricular (LV) ejection fraction (LVEF) ≤40% receiving implantable cardioverter-defibrillators (ICDs) without concurrent indication for bradycardia pacing. Post hoc analyses of both the DAVID and MOST
      • Lamas G.A.
      • Lee K.L.
      • Sweeney M.O.
      • et al.
      Ventricular pacing or dual-chamber pacing for sinus-node dysfunction.
      trials,
      • Sharma A.D.
      • Rizo-Patron C.
      • Hallstrom A.P.
      • O’Neill G.P.
      • Rothbart S.
      • Martins J.B.
      • Roelke M.
      • Steinberg J.S.
      • Hreene H.L.
      Percent right ventricular pacing predicts outcomes in the DAVID trial.
      • Sweeney M.O.
      • Hellkamp A.S.
      • Ellenbogen K.A.
      • Greenspon A.J.
      • Freedman R.A.
      • Lee K.L.
      • Lamas G.A.
      Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction.
      independently identified a threshold of >40% RV pacing in DDDR mode as a predictor of CHF hospitalization. When accompanied by a decrease in LV systolic function post-RV pacing without an alternative identifiable trigger, this condition is termed pacing-induced cardiomyopathy (PICM).
      In an effort to prevent PICM in patients with preexisting LV systolic dysfunction, the BLOCK-HF trial
      • Curtis A.B.
      • Worley S.J.
      • Adamson P.B.
      • Chung E.S.
      • Niazi I.
      • Sherfesee L.
      • Shinn T.
      • Sutton M.S.
      Biventricular pacing for atrioventricular block and systolic dysfunction.
      prospectively randomized patients with high-degree atrioventricular (AV) block, preexisting CHF, and LVEF ≤50% to standard permanent pacemaker (PPM)/ICD vs biventricular PPM/ICD, referred to as cardiac resynchronization therapy (CRT). Over a mean follow-up of 3 years, a 10% higher absolute rate of CHF hospitalization and/or 15% increase in LV end-systolic volume (LVESV) index was observed in the standard RV pacing cohort. Although not yet formally integrated into current device guidelines,
      • Russo A.M.
      • Stainback R.F.
      • Bailey S.R.
      • Epstein A.E.
      • Heidenreich P.A.
      • Jessup M.
      • Kapa S.
      • Kremers M.S.
      • Lindsay B.D.
      • Stevenson L.W.
      ACCF/HRS/AHA/ASE/HFSA/SCAI/SCCT/SCMR 2013 appropriate use criteria for implantable cardioverter-defibrillators and cardiac resynchronization therapy: a report of the American College of Cardiology Foundation appropriate use criteria task force, Heart Rhythm Society, American Heart Association, American Society of Echocardiography, Heart Failure Society of America, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance.
      up-front implantation of CRT in patients with advanced AV block and LVEF ≤50% has been approved by the US Food and Drug Administration as acceptable in current clinical practice.
      US Food and Drug Administration
      FDA approves expanded indication for certain pacemakers and defibrillators used to treat heart failure [press release].
      While the risk of PICM is well established in patients with prepacing LV systolic dysfunction, the patterns of PICM warranting subsequent upgrade to CRT in patients with preserved LVEF are less certain. The PACE trial
      • Yu C.M.
      • Chan J.Y.
      • Zhang Q.
      • Omar R.
      • Yip G.W.
      • Hussin A.
      • Fang F.
      • Lam K.H.
      • Chan H.C.
      • Fung J.W.
      Biventricular pacing in patients with bradycardia and normal ejection fraction.
      prospectively randomized 177 patients with advanced AV block and normal prepacing LVEF (≥45%) to CRT vs standard PPM. At 1-year follow-up, the mean LVEF of 55% was 7% lower in the RV pacing group with 8 patients (9%) experiencing LVEF decrease to <45%. In a smaller (n = 26) study by Dreger et al
      • Dreger H.
      • Maethner K.
      • Bondke H.
      • Baumann G.
      • Melzer C.
      Pacing-induced cardiomyopathy in patients with right ventricular stimulation for >15 years.
      with a mean follow-up duration of ~25 years, the incidence of PICM was 15% (n = 4) with a mean LVEF decrease of 20%. In a larger (n = 304) descriptive cohort study by Zhang et al
      • Zhang X.H.
      • Chen H.
      • Siu C.W.
      • Yiu K.H.
      • Chan W.S.
      • Lee K.L.
      • Chan H.W.
      • Lee S.W.
      • Fu G.S.
      • Lau C.P.
      • Tse H.F.
      New-onset heart failure after permanent right ventricular apical pacing in patients with acquired high-grade atrioventricular block and normal left ventricular function.
      requiring >90% RV pacing in patients with advanced AV block and no history of CHF, new clinical CHF was observed in 26% patients.
      In this study, we analyzed consecutive data from patients undergoing PPM implantation for complete heart block (CHB) with preserved preimplant ejection fraction (≥50%) at a large, quaternary care, US academic center. The study objective was to define the incidence and predictors of PICM in this patient population, in addition to the clinical outcomes associated with subsequent CRT upgrade.

      Methods

       Study population

      After institutional review board approval, data query was performed to identify consecutive adult patients undergoing PPM implantation for CHB at Cleveland Clinic (Cleveland, OH) from 2000 to 2014. A second data query was then performed to censor patients based on the following inclusion criteria: LVEF >50% on an echocardiogram ≤6 months pre-PPM implant. Patients were excluded if (1) PPM was a reimplant, generator change, or CRT; (2) echocardiograms <6 months were discordant with respect to LVEF >50%; and (3) lack of follow-up post-PPM.

       PICM

      PICM was defined as subsequent CRT upgrade or post-PPM LVEF decrease to ≤40% via echocardiography. Time to PICM was calculated from the date of PPM implant to the date of either CRT upgrade or LVEF decrease, whichever occurred first. The post-PPM LVEF threshold of ≤40% was carefully chosen to account for inherent error in LVEF estimates by echocardiography (±5% at the study site) and to maximize certainty that reported decreases in LVEF post-PPM represented true incident systolic dysfunction.

       Clinical data and measurements

      Electronic medical record chart review was performed for all patients. Collected clinical data included patient demographic characteristics; pre-PPM medical history, electrocardiographic, and echocardiographic findings; PPM indications; PPM procedural outcomes/settings; and post-PPM follow-up device diagnostics and echocardiographic findings. Intrinsic and paced QRS durations were recorded, with intrinsic QRS defined as the width of the escape rhythm or, if not available, the width of the conducted, nonpaced ventricular rhythm chronologically closest to PPM implantation. QRS morphology was classified as left or right bundle branch block, intraventricular conduction delay, or narrow QRS according to standard consensus criteria.
      • Surawicz B.
      • Childers R.
      • Deal B.J.
      • et al.
      AHA/ACCF/HRS recommendations for the standardization and interpretation of the electrocardiogram, Part III: intraventricular conduction disturbances: a scientific statement from the American Heart Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the American College of Cardiology Foundation; and the Heart Rhythm Society.
      Ventricular lead placement was classified as apical or nonapical according to the location reported in the PPM postprocedure note and was subsequently confirmed radiographically as available. PPM settings (mode, rate adaptive, rate) were recorded both at implant and at the end of follow-up. RV pacing % was recorded at the end of follow-up, censored to an earlier date if the primary outcome was reached via either CRT upgrade or LVEF decrease to ≤40%.

       Statistical analysis

      Continuous variables are expressed as mean ± SD and categorical variables as percentages. Student t and Pearson χ2 tests were used to compare continuous and categorical variables, respectively. Univariable analysis was performed on collected clinical data stratified by patients with and without PICM. Clinical data categories satisfying an a priori threshold of P < .1 were retained for multivariable logistic regression analysis. Those categories retaining P < .05 in multivariable modeling were considered statistically significant. Kaplan-Meier analysis was performed and curves were constructed demonstrating survival without PICM for both the entire cohort and the cohort stratified by RV pacing %. Analyses were performed using SPSS software Version 18, July 30, 2009 (SPSS Inc., Chicago, IL).

      Results

      Of the 1147 patients initially identified by serial database queries, 323 (28.2%) were subsequently excluded, 292 because of lack of post-PPM follow-up and 32 because of insufficient evidence of preserved LVEF pre-PPM. The resultant studied population was 823 patients (71.8%).
      Baseline characteristics are listed in Table 1 for both the entire cohort and the cohort stratified by PICM vs no PICM. For the entire cohort, 58.3% of PPMs were implanted for postprocedural, as opposed to degenerative AV block. Cardiac surgery or percutaneous aortic valve procedures included 79% of patients with postprocedural CHB, AV nodal ablation an additional 14%, and the remaining 7% from other miscellaneous procedures. The mean age was 68.9 years, with sex nearly evenly distributed. The mean pre-PPM LVEF was 58% ± 5%, 91% concurrently with preserved RV function. The RV lead position was nearly distributed evenly between apical and nonapical positions. Both initial and follow-up device programming modes were predominantly DDD without rate response at implant but increasingly rate adaptive in follow-up. The mean RV pacing % in follow-up was 77% (median 99%).
      Table 1Baseline patient characteristics expressed for the entire cohort and cohort stratified by the presence or absence of PICM
      CharacteristicEntire cohort (N = 823)Cohort with PICM (n = 101)Cohort without PICM (n = 722)P
      Postprocedural CHB58.3%58.4%58.3%.996
      Age at implant (y)68.9 ± 14.271.7 ± 13.168.5 ± 14.3.028
      Sex: male54.3%62.4%53.2%.079
      Coronary artery disease37.1%43.6%36.2%.165
      Atrial arrhythmia35.6%43.6%34.5%.089
      Hypertension65.6%75.2%64.1%.020
      Diabetes mellitus23.8%27.7%23.3%.385
      Chronic kidney disease8.3%13.9%7.5%.079
      Preimplant LVEF (%)57.9 ± 5.456.7 ± 5.558.1 ± 5.4.026
      LVID diastole (cm)4.44 ± 1.684.60 ± 0.914.42 ± 1.76.153
      RV dysfunction9.4%7.9%9.6%.830
      Apical lead placement46.7%38.6%47.8%.064
      Intrinsic QRS (ms)127 ± 27125 ± 31127 ± 27.676
      Pooled QRS morphology.470
       Narrow QRS33.6%35.0%33.3%
       IVCD10.4%15.0%9.7%
       RBBB37.8%33.8%38.5%
       LBBB18.2%15.0%18.5%
       Paced QRS (ms)157 ± 25161 ± 24157 ± 25.071
      Pacing mode at implant.075
       DDD80.5%76.8%80.8%
       VVI9.2%7.3%9.4%
       AAI+MVP7.1%6.1%7.2%
       DDI2.7%3.9%2.1%
      Rate adaptive at implant35.6%36.6%35.4%.915
      Pacing mode at F/U.537
       DDD76.5%76.1%76.5%
       VVI12.6%12.0%12.7%
       AAI+MVP6.6%4.3%6.9%
       DDI3.9%6.5%3.5%
      Rate adaptive at F/U49.2%56.5%48.2%.082
      RV paced (%)77 ± 3887 ± 2776 ± 39<.001
      ≥20% RV paced (%)77.0%90.1%75.2%<.001
      ≥40% RV paced (%)74.2%86.1%72.6%<.001
      Values are presented as mean ± SD or as percentage.
      CHB = complete heart block; F/U = follow-up; IVCD = intraventricular conduction delay; LBBB = left bundle branch block; LVEF = ejection fraction; LVID = left ventricular internal diameter; MVP = managed ventricular pacing; PICM = pacing-induced cardiomyopathy; RBBB = right bundle branch block; RV = right ventricular.
      Of the 823 patients, 101 patients (12.3%) developed PICM by the end of follow-up (mean 4.3 ± 3.9 years; range 0.1–14.4 years), with post-PPM LVEF 24% lower (P < .001) in patients with PICM (33.7% ± 7.4%) vs patients without PICM (57.6% ± 6.1%) (Figure 1). At an a priori threshold of P < .1 for statistical significance in univariable analysis (Table 1), patients who developed PICM were older, more likely to be men, had higher rates of atrial arrhythmia, hypertension, and chronic kidney disease, had lower preimplant LVEF, were less likely to receive apically positioned RV leads, and had wider paced QRS complexes and higher RV pacing burdens. RV pacing burden was also compared as a categorical variable. A first dichotomous threshold of RV pacing ≥40% was selected for the analysis because of previous associations with PICM in patients with LV systolic dysfunction.
      • Sharma A.D.
      • Rizo-Patron C.
      • Hallstrom A.P.
      • O’Neill G.P.
      • Rothbart S.
      • Martins J.B.
      • Roelke M.
      • Steinberg J.S.
      • Hreene H.L.
      Percent right ventricular pacing predicts outcomes in the DAVID trial.
      • Sweeney M.O.
      • Hellkamp A.S.
      • Ellenbogen K.A.
      • Greenspon A.J.
      • Freedman R.A.
      • Lee K.L.
      • Lamas G.A.
      Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction.
      A second dichotomous cutoff of RV pacing ≥20% was also chosen for analysis, given similar rates of PICM observed in the 20%–39% RV pacing group (17.3%, n = 23) as in the ≥40% group (14.2%, n = 611) as compared with the <20% group (4.2%, n = 144). A Kaplan-Meier survival curve of freedom from PICM is depicted in Figure 2A. Follow-up was 89.1% at 3 months, 85.8% at 6 months, 77.3% at 1 year, and 44.5% at 3.65 years, the median time to PICM across the entire cohort.
      Figure 1
      Figure 1Patient flow diagram for the study population stratified by PICM, CRT upgrade, and CRT response. CRT = cardiac resynchronization therapy; LVEF = ejection fraction; LVESV = left ventricular end-systolic volume; PICM = pacing-induced cardiomyopathy; PPM = permanent pacemaker.
      Figure 2
      Figure 2Kaplan-Meier curves depicting 15-year survival without LVEF decrease to ≤40% (PICM) for (A) the entire cohort, (B) cohort stratified by <40% or ≥40% RV pacing, and (C) cohort stratified by <20% or ≥20% RV pacing. LVEF = ejection fraction; PICM = pacing-induced cardiomyopathy; RV = right ventricular.
      For multivariable logistic regression, all clinical variables meeting P < .1 in univariable analysis were included in the model with the exception of chronic kidney disease and pacing parameters. The collection and reporting of device settings was intended for descriptive purposes only; observed differences in programming modes were at maximum 3% and of questionable clinical significance. Chronic kidney disease was limited by sample size, representing <10% of the entire cohort. Three multivariable logistic regressions were performed, each identical except with inclusion of RV pacing % (continuous), RV pacing ≥40%, and RV pacing ≥20% independently. The results of the regression including RV pacing ≥20% are summarized in Table 2. With RV pacing % included as a continuous variable, the only retained variables at P < .05 were RV pacing % (hazard ratio [HR] 1.011 per 1% pacing increase; 95% confidence interval [CI] 1.002–1.020; P = .021) and pre-PPM LVEF (HR 1.045 per 1% LVEF decrease; 95% CI 1.001–1.087; P = .045). When swapped for RV pacing ≥40% as a categorical variable, the only retained variables were RV pacing ≥40% (HR 3.19; 95% CI 1.41–7.21; P = .005) and pre-PPM LVEF (HR 1.045 per 1% LVEF decrease; 95% CI 1.001–1.087; P = .046). Lastly, when swapped for RV pacing ≥20% as a categorical variable, similarly the only retained variables were RV pacing ≥20% (HR 6.76; 95% CI 2.08–22.0; P = .002) and pre-PPM LVEF (HR 1.046 per 1% LVEF decrease; 95% CI 1.002–1.087; P = .042).
      Table 2Factors predictive of incident pacing-induced cardiomyopathy via multivariable logistic regression using RV pacing % as a categorical variable with a threshold of ≥20%
      VariableHazard ratio95% CIP
      Age at implant1.010.99–1.03.265
      Sex: male1.400.87–2.26.170
      Atrial arrhythmia1.200.75–1.92.454
      Hypertension1.550.90–2.65.112
      Lower preimplant LVEF1.0471.002–1.087.042
      Apical lead placement0.700.44–1.12.139
      Paced QRS1.000.99–1.01.545
      ≥20% RV paced6.762.08–22.0.002
      CI = confidence interval; LVEF = ejection fraction; RV = right ventricular.
      Repeat Kaplan-Meier survival curves were created, stratified by RV pacing <40% or ≥40% and 20% and depicted in Figures 2B and 2C, respectively. Both curves begin to separate at ~2 years of follow-up, with increasing divergence over time. However, while at a threshold of ≥20% statistical significance at P < .05 is met (log-rank, χ2 = 4.65; P = .03), at a threshold of ≥40% statistical significance is approached but not yet met (log-rank, χ2 = 2.99; P = .03).
      Of the 101 patients with PICM, 29 (28.7%) were referred for CRT upgrade (Figure 1) 3.9 ± 3.0 years post-PPM (range 0.6–13.9 years). CRT upgrade was successful in all but 1 patient (96.6%). Post-CRT echocardiography was available in 25 of 28 patients (89.3%) over the mean follow-up of 2.9 ± 2.2 years. Twenty-one of 25 patients (84.0%) met criteria for CRT response with a mean LVEF increase of 18.5% ± 8.1% (range 10%–42%) and a mean LVESV decrease of 45.1% ± 15.0% (range 15.0%–65.3%) in responders. Referral for CRT in patients with PICM was highly associated with lower nadir post-PPM LVEF (30.1% ± 8.0% CRT vs 35.1% ± 6.7% non-CRT; P = .004), greater decrease in LVEF pre- to post-PPM (−26.9% ± 8.7% CRT vs −21.3% ± 9.1% non-CRT; P = .006), and higher likelihood of post-PPM LVEF ≤35% (79.3% CRT vs 50.0% non-CRT; P = .004). RV pacing % was greater in the CRT referral group (92.6% ± 20.3% vs 84.1% ± 29.8%) but did not meet statistical significance (P = .109).

      Discussion

      In our cohort of 823 consecutive patients undergoing PPM implantation for complete AV block with preserved pre-PPM LV systolic function, 12.3% developed PICM over 4.3 ± 3.9 years follow-up. This observed PICM incidence is in line with similar previous studies.
      • Yu C.M.
      • Chan J.Y.
      • Zhang Q.
      • Omar R.
      • Yip G.W.
      • Hussin A.
      • Fang F.
      • Lam K.H.
      • Chan H.C.
      • Fung J.W.
      Biventricular pacing in patients with bradycardia and normal ejection fraction.
      • Dreger H.
      • Maethner K.
      • Bondke H.
      • Baumann G.
      • Melzer C.
      Pacing-induced cardiomyopathy in patients with right ventricular stimulation for >15 years.
      • Khurshid S.
      • Epstein A.E.
      • Verdino R.J.
      • Lin D.
      • Goldberg L.R.
      • Marchlinski F.E.
      • Frankel D.S.
      Incidence and predictors of right ventricular pacing-induced cardiomyopathy.
      The definition of PICM used in our study (post-PPM LVEF ≤40% vs ≤50%) was purposefully conservative to minimize false positives, but may have underestimated the incidence by excluding patients with post-PPM LVEF 40%–50% and decrease in LVEF >10%. Inclusion of this patient subgroup would increase PICM incidence to 13.7% (n = 113). Nevertheless, PICM is not uncommon over extended follow-up in patients with advanced AV block and preserved LVEF. This implies that targeted surveillance of LV systolic function post-PPM may be warranted for high-risk populations (RV pacing ≥20%). However, in the most recent guidelines for appropriate use criteria for echocardiography,
      • Douglas P.S.
      • Garcia M.J.
      • Haines D.E.
      • Lai W.W.
      • Manning W.J.
      • Patel A.R.
      • Picard M.H.
      • Polk D.M.
      • Ragosta M.
      • Ward R.P.
      • Weiner R.B.
      ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011 appropriate use criteria for echocardiography: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography, American Heart Association, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Critical Care Medicine, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance.
      routine surveillance post-PPM without change in clinical status is considered inappropriate (appropriate use criteria 1–3).
      In multivariable analysis, only 2 independent predictors of PICM were identified: (1) lower pre-PPM LVEF and (2) increased RV pacing burden (Table 2). With respect to RV pacing burden, when expressed as a categorical vs continuous variable, statistical power was improved 10-fold. The initial dichotomous RV pacing threshold tested was 40%, chosen because of previous replicated associations with increased CHF rates at this level in the DAVID and MOST cohorts.
      • Sharma A.D.
      • Rizo-Patron C.
      • Hallstrom A.P.
      • O’Neill G.P.
      • Rothbart S.
      • Martins J.B.
      • Roelke M.
      • Steinberg J.S.
      • Hreene H.L.
      Percent right ventricular pacing predicts outcomes in the DAVID trial.
      • Sweeney M.O.
      • Hellkamp A.S.
      • Ellenbogen K.A.
      • Greenspon A.J.
      • Freedman R.A.
      • Lee K.L.
      • Lamas G.A.
      Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction.
      Although the 40% threshold met statistical significance in univariable (P < .001) and multivariable (P = .005) analyses, it approached statistical significance (log-rank, χ2 = 2.99; P = .08) only in Kaplan-Meier analysis (Figure 2B). Upon further inspection, we found that the incidence of PICM was similar between 20% and 39% (17.3%) and ≥40% (14.2%) RV pacing as compared with <20% RV pacing (4.2%). This prompted analysis of a second dichotomous RV pacing threshold of 20%. At RV pacing ≥20%, statistical significance was maintained throughout univariable (P < .001), multivariable (P = .005), and Kaplan-Meier (log-rank, χ2 = 4.65; P = .03) analyses (Figure 2C), suggesting that pacing burden associated with incident LV systolic dysfunction (and transitively, perhaps clinical CHF) may be lower than previously accepted. Outcome separation between PICM and no PICM began 2–3 years post-PPM, with separation widening with longer follow-up. Interestingly, an increased incidence of PICM at an RV pacing threshold of ≥20% was also seen by Khurshid et al
      • Khurshid S.
      • Epstein A.E.
      • Verdino R.J.
      • Lin D.
      • Goldberg L.R.
      • Marchlinski F.E.
      • Frankel D.S.
      Incidence and predictors of right ventricular pacing-induced cardiomyopathy.
      in a smaller (n = 257) study conducted concurrently to our study, restricted to RV pacing ≥20% (an a priori hypothesis) but not exclusive of advanced AV block. In their conclusions, the authors posit whether the RV pacing threshold for PICM might approximate the 24% PVC threshold for PVC cardiomyopathy reported by Baman et al,
      • Baman T.S.
      • Lange D.C.
      • Ilg K.J.
      • et al.
      Relationship between burden of premature ventricular complexes and left ventricular function.
      a theory strengthened only by our findings.
      With respect to pre-PPM LVEF, Khurshid et al
      • Khurshid S.
      • Epstein A.E.
      • Verdino R.J.
      • Lin D.
      • Goldberg L.R.
      • Marchlinski F.E.
      • Frankel D.S.
      Incidence and predictors of right ventricular pacing-induced cardiomyopathy.
      observed a similar trend that lower preimplant LVEF predisposed to PICM (HR 1.03 vs 1.05 per 1% LVEF decrease), but statistical significance was not met in multivariable modeling (P = .09). This was likely due to underpowering, as with a 3 times larger sample size, statistical significance was narrowly met (P = .042) in our study. Nevertheless, RV pacing burden ≥20% clearly carries a stronger association with PICM than does pre-PPM LVEF, in terms of both magnitude (HR 6.8 vs 1.05) and statistical significance (P = .002 vs P = .042). What remains unclear about pre-PPM LVEF >50%, however, is whether each incremental LVEF percentage increase above 50% is protective or only until a threshold LVEF.
      PICM risk predictors observed in other previous studies could not be replicated in our study. Khurshid et al
      • Khurshid S.
      • Epstein A.E.
      • Verdino R.J.
      • Lin D.
      • Goldberg L.R.
      • Marchlinski F.E.
      • Frankel D.S.
      Incidence and predictors of right ventricular pacing-induced cardiomyopathy.
      reported male sex (HR 2.15; P = .02) and intrinsic QRS duration (HR 1.03 per 1-ms increase; P < .001) as independent multivariable predictors of PICM, but were nonsignificant in our analysis (HR 1.40; P = .17 multivariable and P = .68 univariable). The marked difference in intrinsic QRS as a risk predictor is likely attributable to significant differences in the definition of the intrinsic QRS variable between studies. Khurshid et al included only conducted QRS complexes in a patient population not restricted to complete AV block, whereas our study included primarily the QRS duration of the escape rhythm in a patient population rarely with observed conducted QRS complexes. Zhang et al
      • Zhang X.H.
      • Chen H.
      • Siu C.W.
      • Yiu K.H.
      • Chan W.S.
      • Lee K.L.
      • Chan H.W.
      • Lee S.W.
      • Fu G.S.
      • Lau C.P.
      • Tse H.F.
      New-onset heart failure after permanent right ventricular apical pacing in patients with acquired high-grade atrioventricular block and normal left ventricular function.
      reported age (HR 1.06 per year; P < .001), coronary artery disease (HR 1.98; P < .05), and paced QRS duration (HR 1.27 per 10 ms; P = .001) as independent multivariable predictors of PICM. However, PICM was defined distinctly differently, incident clinical CHF compared to quantitative LVEF decrease post-PPM, and thus unsurprisingly, these variables were not found to be significant in our study (HR 1.01; P = .27 multivariable; P = .17 univariable; and HR 1.003; P = .545 multivariable, respectively). Lastly, with respect to RV lead positioning, the postulation that apical pacing is less physiologic and thus more likely to produce PICM has been a decade-long debate, with conflicting data both for
      • Mera F.
      • DeLurgio D.B.
      • Patterson R.E.
      • Merlino J.D.
      • Wade M.E.
      • Leon A.R.
      A comparison of ventricular function during high right ventricular septal and apical pacing after his-bundle ablation for refractory atrial fibrillation.
      • Tse H.F.
      • Yu C.
      • Wong K.K.
      • Tsang V.
      • Leung Y.L.
      • Ho W.Y.
      • Lau C.P.
      Functional abnormalities in patients with permanent right ventricular pacing: the effect of sites of electrical stimulation.
      • Shimony A.
      • Eisenberg M.J.
      • Filion K.B.
      • Amit G.
      Beneficial effects of right ventricular non-apical vs. apical pacing: a systematic review and meta-analysis of randomized-controlled trials.
      and against
      • Victor F.
      • Leclercq C.
      • Mabo P.
      • Pavin D.
      • Deviller A.
      • de Place C.
      • Pezard P.
      • Victor J.
      • Daubert C.
      Optimal right ventricular pacing site in chronically implanted patients: a prospective randomized crossover comparison of apical and outflow tract pacing.
      • Bourke J.P.
      • Hawkins T.
      • Keavey P.
      • Tynan M.
      • Jamieson S.
      • Behulova R.
      • Furniss S.S.
      Evolution of ventricular function during permanent pacing from either right ventricular apex or outflow tract following AV-junctional ablation for atrial fibrillation.
      • Stambler B.S.
      • Ellenbogen K.
      • Zhang X.
      • et al.
      Right ventricular outflow versus apical pacing in pacemaker patients with congestive heart failure and atrial fibrillation.
      • Domenichini G.
      • Sunthorn H.
      • Fleury E.
      • Foulkes H.
      • Stettler C.
      • Burri H.
      Pacing of the interventricular septum versus the right ventricular apex: a prospective, randomized study.
      this hypothesis. In our study, there was no significant difference between apical and nonapical RV lead positions (P = .139 multivariable) with less PICM associated with apical pacing (HR 0.70). Curiously, a similar pattern was seen by Khurshid et al
      • Khurshid S.
      • Epstein A.E.
      • Verdino R.J.
      • Lin D.
      • Goldberg L.R.
      • Marchlinski F.E.
      • Frankel D.S.
      Incidence and predictors of right ventricular pacing-induced cardiomyopathy.
      (HR 0.62; P = .10 univariable for apical pacing). The unimportance of apical vs nonapical pacing is consistent with the findings of the recently published PROTECT-PACE study,
      • Kaye G.C.
      • Linker N.J.
      • Marwick T.H.
      • Pollock L.
      • Graham L.
      • Pouliot E.
      • Poloniecki J.
      • Gammage G.
      Effect of right ventricular pacing lead site on left ventricular function in patients with high-grade atrioventricular block: results of the PROTECT-PACE study.
      the first of 3 large, planned prospective, randomized controlled trials
      • Kaye G.
      • Stambler B.S.
      • Yee R.
      Search for the optimal right ventricular pacing site: design and implementation of three randomized multicenter clinical trials.
      evaluating the relationship between RV pacing location and PICM.
      In patients with PICM in our study cohort, the subsequent CRT upgrade rate was only 28.7%, nearly identical (28.0%) to a similar smaller study.
      • Khurshid S.
      • Epstein A.E.
      • Verdino R.J.
      • Lin D.
      • Goldberg L.R.
      • Marchlinski F.E.
      • Frankel D.S.
      Incidence and predictors of right ventricular pacing-induced cardiomyopathy.
      CRT upgrade was technically feasible in all but 1 case, with an 84% echocardiographic response rate as defined by LVEF increase ≥10% or LVESV decrease ≥15%. Such high CRT response rates further support the pathogenesis of PICM as the etiology of the initial LVEF decrease and provide a clear signal for CRT underutilization as a treatment of PICM. Higher post-PPM LVEF, particularly at a threshold of ≥35%, was an independent risk factor for CRT nonreferral, with 38.9% referral rate for LVEF ≤35% vs 14.2% for LVEF >35% (P = .004). This may reflect a greater tendency to pursue CRT upgrade when an ICD is concurrently indicated (CRT with defibrillator) compared to biventricular pacing alone (CRT with pacemaker), yet CRT nonreferral still occurs in 61.1% of patients with PICM indicated for CRT with defibrillator. This discrepancy would only worsen with liberalized inclusion of post-PPM LVEF 41%–50% as per US Food and Drug Administration guidelines.

       Study limitations

      The chief limitations of our study stem from long-term loss of patient follow-up. Follow-up rates were robust at 6 and 12 months (86% and 77%, respectively), but were <50% by 3.7 years, the median time to PICM and well within the post-PPM range where Kaplan-Meier curves begin to deviate when stratified by RV pacing <30% or ≥20%. Typically, loss of follow-up predisposes to inclusion bias, as symptomatic patients are more likely to follow-up, but this is less likely in our study. Nearly 60% of the patient cohort received their pacemaker post-procedurally at a quaternary care referral center. The median drive time to the implanting center was >1 hour, with 20% of patients living more than a 5 hour drive away. As such, extended follow-up was performed elsewhere for a sizable proportion of the cohort, limiting capture of incident PICM in that subset, as well as potential outside CRT upgrades. For those patients maintaining long-term follow-up at the study site, particularly with implant date 2000–2004 (25% of the cohort), the study period spanned institutional conversion from paper to electronic medical records, and thus data availability was intermittently limited. Chart review was performed in an attempt to identify alternative explanations for LVEF decrease, but was often difficult and no such patients were identified. When accounting for the competing forces favoring overestimation (inclusion bias, potential nonexclusion of alternative triggers for LVEF decrease) and underestimation (long-term follow-up attrition, conservative LVEF cutoff of ≤40% to define PICM) of PICM incidence, the authors strongly favor underestimation of PICM incidence.
      The fact that the observed PICM incidence of 12.3% and CRT response rate of 84% is in line with previous studies is reassuring that both the reported incidence estimation is fair and, at most, few non-PICM LVEF decreases were included inappropriately as meeting the primary outcome of PICM. It should be noted, though, that the same uncertainties would not be expected to affect the clinical predictors of PICM nor CRT upgrade.

      Conclusion

      PICM is not uncommon over prolonged follow-up, with an observed incidence of 12.3% in our cohort of patients receiving PPMs for complete AV block with preserved preimplant LV systolic function. In multivariable analysis, right ventricular pacing burden ≥20% was strongly associated with the development of PICM. Subsequent upgrade to CRT is highly effective clinically but is underutilized, particularly at higher postpacing ejection fraction >35%.

      Acknowledgments

      Dr Kiehl thanks his wife, Caitlin Kiehl, for her steadfast love and support always; Bruce Lindsay, MD, FHRS, for his support and mentoring on this study; and Sherry Bissell, for her daily assistance and help in manuscript preparation.

      Appendix. Supplementary data

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