Advertisement

Super Response to Cardiac Resynchronization Therapy in Orthotopic Heart Transplant with Atypical Right Bundle Branch Block and Cardiac Allograft Vasculopathy

Open AccessPublished:November 18, 2022DOI:https://doi.org/10.1016/j.hrcr.2022.11.008

      Keywords

      Introduction

      There is very limited data regarding the use of cardiac resynchronization therapy (CRT) in patients following cardiac transplant. We describe the use of CRT in a patient who developed cardiomyopathy, biventricular heart failure, and atypical right bundle branch block (RBBB) after orthotopic heart transplant (OHT) in the setting of cardiac allograft vasculopathy (CAV). Right ventricular (RV) function normalized, left ventricular (LV) dimension and ejection fraction (EF) significantly improved by 5 months post-CRT implant.

      Case Presentation

      A forty-five-year-old male underwent a combined heart and kidney transplant in May 2015 for end-stage heart failure secondary to non-ischemic cardiomyopathy from viral myocarditis, and advanced polycystic kidney disease. A post-transplant electrocardiogram (ECG) showed sinus rhythm and incomplete RBBB with a QRS duration of 100 ms. (Figure 1a). The early post-operative course was complicated by an acute cerebrovascular accident. The patient otherwise did well for several years after transplant with surveillance right heart catheterization (RHC) and endomyocardial biopsy (EMB) showing normal filling pressures, cardiac output, and absence of cellular or antibody mediated rejection. Annual coronary angiograms were also normal for the first 5 years after transplant. A complete atypical RBBB developed on ECG by January 2019 (Figure 1b) with no change in clinical status. However, on annual RHC in May 2020, severely elevated biventricular filling pressures with a right atrial pressure of 15 mmHg, a pulmonary-capillary wedge pressure of 29 mmHg, cardiac output of 5.1 L/min, and a cardiac index 2 L/min/m2 using the thermodilution method were noted. Coronary angiography showed evidence of mild CAV involving both the left and right coronary systems.
      Figure thumbnail gr1
      Figure1Patient Electrocardiograms, . Post-transplant ECG in May 2015 showing sinus rhythm and incomplete RBBB with a QRS of 100 ms. . ECG from January 2019 showing atypical RBBB and a QRS of 122 ms. with small S waves in leads I and aVL. . ECG from August 2020 showing sinus rhythm with atypical RBBB, a QRS duration of 150 ms, and new left axis deviation. Note: 1) S waves in leads I and aVL are < the R wave and remain < 40ms; 2) new upstroke slurring of the R wave in leads I and aVL; and 3) new QRS fractionation in leads II, III, and aVF. . Post-CRT implant 12 lead ECG, CRT = cardiac resynchronization therapy ECG = electrocardiogram, RBBB = right bundle branch block

      Investigation and early management

      EMB was performed, and blood was drawn for donor specific antibody testing, however, there remained no evidence of cellular or antibody mediated rejection. The patient reported shortness of breath symptoms with moderate exertion and compliance with anti-rejection medications. This was confirmed by a therapeutic serum tacrolimus level. Transthoracic echocardiography (TTE) showed a LV end-diastolic diameter (LVEDD) of 5.6 cm, EF of 25-30%, severe global hypokinesis of the left ventricle, and severely decreased function of the right ventricle. LV end systolic index (LVESI) was 54.8 ml/m2. In the absence of any evidence of rejection, with new heart failure and decrease in LV function, the CAV was categorized as “CAV3” per International Society for Heart and Lung Transplant classification (
      • Chih S.
      • Chong A.Y.
      • Mielniczuk L.M.
      • Bhatt D.L.
      • Beanlands R.S.
      Allograft Vasculopathy: The Achilles' Heel of Heart Transplantation.
      ). Creatinine level was slightly elevated at 1.4 mg/dL, but unchanged from measures over the prior 2 years. N-Terminal pro-brain natriuretic peptide was slightly elevated at 466 pg//ml. Total bilirubin, aspartate transaminase levels were all normal; 0.7 mg/dL, 18 U/L and 18 U/L respectively. They were admitted to the hospital after cardiac catheterization and treated with pulse dose corticosteroids, intravenous diuresis, and transitioned to oral diuretics. In addition, guideline-directed medical therapy (GDMT) with sacubitril-valsartan, carvedilol, and spironolactone was started. A new left-axis deviation with atypical RBBB and QRS duration of 150 ms. were noted on 12 lead ECG (Figure 1c). The immunosuppressive regimen was changed from tacrolimus and mycophenolate mofetil to sirolimus and mycophenolate given the CAV.

      Follow up and subsequent management

      TTE three months later in August 2020 showed a persistently depressed LV EF at 20-30% with severe anterior, inferior and inferolateral wall hypokinesis/akinesis despite titration to target GDMT (Supplemental video 1). In the interim, the patient also developed significant proteinuria and was switched back to tacrolimus from sirolimus. Creatinine level, however, remained within the range of 1.2 – 1.4 mg/dL during titration of medical therapy. Given persistent systolic dysfunction despite optimized GDMT, New York Heart Association (NYHA) II functional class, and atypical RBBB > 150 ms. on ECG, a CRT implantable cardioverter defibrillator (ICD) was successfully inserted with the LV lead placed in a lateral mid-basal position, and simultaneous biventricular timed pre-excitation programmed (Figure 1d, Figure 2). The Q to LV time was 119 ms. ICD settings also included a DDD mode, lower rate 40 bpm, upper rate 150 bpm, sensed/paced atrioventricular delays 80 ms. and 130 ms. respectively, a single ventricular fibrillation zone > 222 bpm, and atrial tachycardia/atrial fibrillation monitor detection > 171 bpm. No changes in GDMT followed. Repeat TTE 5 months post implant showed a normalized LVEDD of 4.8 cm, LV EF increase to 42%, improvement of the previous wall motion abnormalities, save apical akinesis, and normalization of RV function. Interventricular timing was changed to left ventricle pacing early by 50 ms. based on surface 12-lead ECG QRS duration minimization at that visit as well. Echocardiography nearly 2 years post-implant showed LV EF 45-50% and LVESI 20.8 ml/m2 with a clinical status of NYHA Class I heart failure (Supplemental video 2). Repeat cardiac catheterization was additionally notable for minimal luminal irregularities in the left and right coronary systems. There were no ventricular or atrial arrhythmias noted on remote or in-person interrogation since implant. An ECG with temporary cessation of pacing at last follow-up was notable for an atypical RBBB, QRS duration of 126 ms., and absence of left axis deviation.
      Figure thumbnail gr2
      Figure 2Post-implant chest radiograph. There is mild vascular congestion present., LV = left ventricular lead, RA = right atrial lead, RV = right ventricular lead

      Discussion

      There have only been a few case reports in the literature of CRT following cardiac transplantation. Apor et al. first described a patient with CAV, heart failure, depressed EF, and left bundle branch block (LBBB) 5 years after transplant treated with CRT placement (
      • Apor A.
      • Kutyifa V.
      • Merkely B.
      • et al.
      Successful cardiac resynchronization therapy after heart transplantation.
      ). In 2010, Mariani et al. reported a patient with heart failure secondary to severe CAV with depressed EF, persistent atrial tachyarrhythmia requiring atrioventricular junction ablation, and subsequent dual chamber ICD. Further worsening of LV function and heart failure prompted an upgrade to CRT 1 week later (
      • Mariani J.A.
      • McDonald M.A.
      • Nanthakumar K.
      • Parker J.D.
      • Ross H.J.
      Cardiac resynchronization therapy after atrioventricular node ablation for rapid atrial fibrillation in a heart transplant recipient with late allograft dysfunction.
      ). Finally, in 2013 Vural et al. described a patient 5 years removed from transplant with new CAV that developed systolic heart failure, a depressed EF, and Mobitz II atrioventricular block who was implanted with CRT (
      • Vural A.
      • Ertas G.
      • Agacdiken A.
      Cardiac resynchronization treatment in a patient with hypertrophic cardiomyopathy after heart transplantation.
      ). In all 3 cases, CRT resulted in moderate improvement in ventricular function and heart failure symptoms as one might now reasonably expect given the different indications in the contemporary guidelines that would respectively apply to each of these patients: EF < 35%/Class II-III NYHA CHF/LBBB > 150 ms. on GDMT (Class I ACC/AHA/ESC), atrioventricular block with EF < 35% and expectation of RV based pacing >40% (Class IIa ACC/AHA/ESC), and following atrioventricular junction ablation EF < 35% on GDMT (Class IIa ACC/AHA, Class I ESC) (

      Yancy C, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol 2013;62(16):e147-239.

      ,

      Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021;42:3427-3520.

      ). CRT also resulted in significant improvement in LV and RV dysfunction in this case. In contrast to the prior reports, the indication was for QRS > 150 ms., Class II NYHA CHF, EF < 35% on GDMT that correlated with worsening of cardiac function (Class IIb ACC/AHA, Class IIa ESC) (

      Yancy C, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol 2013;62(16):e147-239.

      ,

      Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021;42:3427-3520.

      ). Specifically, the indication and response in our case likely related to observations of CRT in atypical RBBB in which a delayed LV activation was additionally present, which may partly manifest as a slurred R wave in leads I and aVL (
      • Fantoni C.
      • Kawabata M.
      • Massaro R.
      • et al.
      Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: a detailed analysis using three-dimensional non-fluoroscopic electroanatomic mapping system.
      ), absent or small S waves < 40 ms. in lateral leads I and aVL,a prolonged Q to local LV time (
      • Pastore G.
      • Morani G.
      • Maines M.
      • et al.
      Patients with right bundle branch block and concomitant delayed left ventricular activation respond to cardiac resynchronization therapy.
      ) and of a QRS duration dependent response in non-LBBB patients (

      Rickard J, Bassiouny M, Cronin EM, et al. Predictors of response to cardiac resynchronization therapy in patients with a non-left bundle branch block morphology. Am J Cardiol. 2011;108:1576–1580.

      ). Regardless of the indications, each of the 4 cases demonstrated similar initial benefit.
      Interestingly, in a 2009 national survey of 59 cardiac transplant programs, 48% of respondents did not support the use of CRT in patients following OHT and in whom CAV with depressed EF had developed (
      • McDowell D.L.
      • Hauptman P.J.
      Implantable defibrillators and cardiac resynchronization therapy in heart transplant recipients: results of a national survey.
      ). A clearer idea presently as to the likelihood of response to CRT versus that known in 2009 may partly explain this finding. However, this may also relate to experience with non-response to CRT in OHT. Admittedly the long-term data on CRT use in CAV with OHT is unknown. Reports of non-response to CRT in OHT are lacking in the literature.
      Are we delaying the inevitable in CAV? By most definition there was a super response to CRT therapy nearly 2 years from implant, and with no apparent progression of CAV in our case (
      • Steffel J.
      • Ruschitzka F.
      Super response to cardiac resynchronization therapy.
      ). CRT use for approved indications may lead to enough improvement in LV function to delay the need for re-transplant, or improve symptoms and outcomes until another donor heart is available. CAV is an accelerated and progressive fibroproliferative disorder with underlying immune and non-immune risk factors that involves both epicardial and intramural vessels (
      • Chih S.
      • Chong A.Y.
      • Mielniczuk L.M.
      • Bhatt D.L.
      • Beanlands R.S.
      Allograft Vasculopathy: The Achilles' Heel of Heart Transplantation.
      ). Thus, it is unlikely that CRT affects the natural course of CAV progression itself, but rather is still able to effect reverse remodeling from improved dyssynchrony in spite of CAV. As regards implantation of CRT with additional defibrillation capability the evidence for ICD use in general for OHT patients affected with cardiomyopathy and CAV is neither strongly supportive for, or against (

      Al-Khatib SM, Stevenson WG, Ackerman MJ et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2018;15:e73-e189.

      ). Ventricular fibrillation accounts for approximately 10% of sudden cardiac death cases in OHT with allograft dysfunction. Asystole and pulseless electrical activity are rather the predominant rhythms in allograft dysfunction sudden cardiac death (
      • Vaseghi M.
      • Lellouche N.
      • Ritter H.
      • et al.
      Mode and mechanisms of death after orthotopic heart transplantation.
      ,
      • DeFilippis E.M.
      • Rubin G.
      • Farr M.A.
      • et al.
      Cardiac Implantable Electronic Devices Following Heart Transplantation.
      ,
      • Garg J.
      • Shah K.
      • Turagam M.K.
      • et al.
      Implantable cardioverter-defibrillators in cardiac transplant recipients: A systematic review from the Electrophysiology Collaborative Consortium for Meta-analysis-ELECTRAM investigators.
      ). However, it is not known what, if any impact, CRT may have on mortality in OHT.

      Conclusion

      In heart transplant patients with allograft dysfunction, clinical symptoms of heart failure, and otherwise fulfilling Class I and IIa/b contemporary indications, CRT may result in improvement in cardiac function and symptoms, and should be considered. The long-term effect on outcomes for CRT in this population remains unknown.

      Acknowledgements:

      The authors would like to thank Colleen McMullen for assistance in manuscript preparation.

      Supplementary material

      References

        • Chih S.
        • Chong A.Y.
        • Mielniczuk L.M.
        • Bhatt D.L.
        • Beanlands R.S.
        Allograft Vasculopathy: The Achilles' Heel of Heart Transplantation.
        J Am Coll Cardiol. 2016; 68: 80-91
        • Apor A.
        • Kutyifa V.
        • Merkely B.
        • et al.
        Successful cardiac resynchronization therapy after heart transplantation.
        Europace. 2008; 10: 1024-1025
        • Mariani J.A.
        • McDonald M.A.
        • Nanthakumar K.
        • Parker J.D.
        • Ross H.J.
        Cardiac resynchronization therapy after atrioventricular node ablation for rapid atrial fibrillation in a heart transplant recipient with late allograft dysfunction.
        J Heart Lung Transplant. 2010; 29: 704-706
        • Vural A.
        • Ertas G.
        • Agacdiken A.
        Cardiac resynchronization treatment in a patient with hypertrophic cardiomyopathy after heart transplantation.
        Turk Kardiyol Dern Ars. 2013; 41: 72-74
      1. Yancy C, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol 2013;62(16):e147-239.

      2. Glikson M, Nielsen JC, Kronborg MB, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021;42:3427-3520.

        • Fantoni C.
        • Kawabata M.
        • Massaro R.
        • et al.
        Right and left ventricular activation sequence in patients with heart failure and right bundle branch block: a detailed analysis using three-dimensional non-fluoroscopic electroanatomic mapping system.
        J Cardiovasc Electrophysiol. 2005; 16: 112-119
        • Pastore G.
        • Morani G.
        • Maines M.
        • et al.
        Patients with right bundle branch block and concomitant delayed left ventricular activation respond to cardiac resynchronization therapy.
        Europace. 2018; 20: e171-178
      3. Rickard J, Bassiouny M, Cronin EM, et al. Predictors of response to cardiac resynchronization therapy in patients with a non-left bundle branch block morphology. Am J Cardiol. 2011;108:1576–1580.

        • McDowell D.L.
        • Hauptman P.J.
        Implantable defibrillators and cardiac resynchronization therapy in heart transplant recipients: results of a national survey.
        J Heart Lung Transplant. 2009; 28: 847-8450.9
        • Steffel J.
        • Ruschitzka F.
        Super response to cardiac resynchronization therapy.
        Circulation. 2014; 130: 87-90
      4. Al-Khatib SM, Stevenson WG, Ackerman MJ et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm 2018;15:e73-e189.

        • Vaseghi M.
        • Lellouche N.
        • Ritter H.
        • et al.
        Mode and mechanisms of death after orthotopic heart transplantation.
        Heart Rhythm. 2009; 6: 503-509
        • DeFilippis E.M.
        • Rubin G.
        • Farr M.A.
        • et al.
        Cardiac Implantable Electronic Devices Following Heart Transplantation.
        JACC Clin Electrophysiol. 2020; 6: 1028-1042
        • Garg J.
        • Shah K.
        • Turagam M.K.
        • et al.
        Implantable cardioverter-defibrillators in cardiac transplant recipients: A systematic review from the Electrophysiology Collaborative Consortium for Meta-analysis-ELECTRAM investigators.
        Pacing Clin Electrophysiol. 2020; 43: 1529-1537