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\begin{document}

\title{Risk of permanent pacemaker implantation after transcatheter aortic
valve replacement: How do we manage beyond risk assessment?}



\author[1]{Alex Velasquez}%
\author[2]{Jeffrey Goldberger}%
\affil[1]{University of Miami Miller School of Medicine}%
\affil[2]{University of Miami}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\textbf{Risk of permanent pacemaker implantation after transcatheter
aortic valve replacement: How do we manage beyond risk assessment?}

\textbf{Alex Velasquez, MD\textsuperscript{1}}

\textbf{Jeffrey J. Goldberger, MD, MBA\textsuperscript{1}}

\textsuperscript{1} Cardiovascular Division, Department of Medicine,
University of Miami Leonard M. Miller School of Medicine, Miami, FL

\textbf{Corresponding author:}

Jeffrey J. Goldberger, M.D.

University of Miami Miller School of Medicine

Cardiovascular Division

1120 NW 14\textsuperscript{th} St.

Miami, FL 33136

Telephone: (305) 243-8092

Fax: (305) 243-1731

E-mail: j-goldberger@miami.edu

Aortic stenosis (AS) is the most common valve disease worldwide, with
degenerative (calcific) AS being the most common etiology in western
countries. Patients experience a high morbidity and mortality without
intervention to correct the mechanical obstruction to cardiac
output\textsuperscript{1}. Since 1960, when Dwight Harken performed the
first in-situ aortic valve replacement with a ball-in-cage mechanical
valve, cardiothoracic surgeons have been dramatically improving
patients' lives\textsuperscript{2}. The implications of how we treat
this condition will become amplified by an aging US population and an
increased incidence of AS with age. \textsuperscript{3} At its
inception, surgical aortic valve replacement was recognized to have
trade-offs including injury to the native atrioventricular(AV)
conduction system\textsuperscript{4}. The AV conduction system of the
heart resides in such close anatomic proximity to the aortic valve that
injury is often encountered. As surgical techniques improved, the rate
of significant post-operative heart block that requires permanent
pacemaker implantation (PPMI) decreased and now hovers between
3.3-6.9\%. \textsuperscript{5-7}

In the last two decades, patients deemed poor surgical candidates were
offered an opportunity of similar improvements in mortality and quality
of life when trans-catheter techniques for valve replacement were
developed. The low morbidity and mortality associated with these
techniques have driven the medical community to consider these therapies
for moderate and even low risk surgical cases.\textsuperscript{7} As the
number of patients who receive this life-saving therapy increases, so
too will its most common complication occur.

Between 10-25\% of patients that receive transcatheter aortic valve
replacement (TAVR) undergo PPMI. Understanding the pre-operative and
intra-operative case characteristics that are associated with PPMI is so
popular that Wang et al. was able to pool a total of 97,294 patients in
67 retrospective and prospective studies that examine this subject. In
this meta-analysis they concluded that pre-existing cardiac conduction
abnormality and trans-femoral pathway selection were significantly
associated with PPMI. Pre-existing left bundle branch block,
patient-prosthesis mismatch, and implantation depth were
not.\textsuperscript{8}

While the information provided in this meta-analysis is valuable, the
main question confronting the clinician managing a patient following
TAVR is whether the patient needs to have a PPMI. In the patient with
persistent complete or high-grade AV block, the clinical decision is
easy. Similarly, in those without pre-existing conduction system disease
and in those with no change in their pre-existing conduction system
disease post-TAVR, there is consensus that pacing is not required. The
challenge and management disparity lie among those with transient severe
conduction abnormalities and those with significant changes in native
conduction, including significant PR interval prolongation and those
with new left bundle branch block. Anatomically, there may be
considerable variation in the location of the AV conduction system and
left bundle in the proximity to the aortic valve\textsuperscript{9}.
Unfortunately, this major anatomic determinant of the risk of AV block
cannot be assessed or imaged prior to the procedure. The surface ECG
provides important clues. While striking changes in the QRS complex, ie
the development of left bundle branch block, are routinely recognized
and addressed, subtler changes in the PR interval may be overlooked. The
PR interval has 3 components -- intratrial conduction time from the
sinus node to the AV node, AV nodal conduction time, and His-Purkinje
system conduction time. A 50 ms increase in the PR interval from 140 to
190 ms, for example, might still be considered normal when reviewed in
isolation, but a 50 ms increase in His-Purkinje system conduction time
could be a harbinger of risk for complete AV block. Interestingly, the
meta-analysis reported an enhanced risk for PPMI in patients with first
degree AV block but not those with second degree AV block. A physiologic
explanation is that in patients with first degree AV block much of this
delay may be in the His-Purkinje system, while in those with second
degree AV block (if it is Wenckebach) this is a manifestation of AV
nodal delay and not considered pathologic. It is therefore critical to
evaluate serial changes in conduction post-TAVR and follow expert panel
guidance on management\textsuperscript{10}. Electrophysiologic testing
is sometimes necessary to assess the integrity of the conduction system
and to decide whether a pacemaker is required (see
figure)\textsuperscript{11}. Continued assessment is sometimes
necessary, as there is a possibility that late sudden cardiac deaths may
be due to heart block. It is clear that the post-procedure course and
findings are the critical factors that will determine the need for PPMI
for the individual patient.

Other important issues arise regarding PPMI post-TAVR. First, once a
PPMI is indicated, what kind of cardiac implanted electronic device
(CIED) is appropriate? PPMI implantation is associated with elevated
re-hospitalization and mortality risk. \textsuperscript{12} The cause of
this observation is unclear, but one could postulate that device related
complications including infection could play a role\textsuperscript{13}.
In general, 2\% of patients implanted with CIED develop a device related
infection at 5 years\textsuperscript{14}. Intravascular infection
associated with a valve prosthesis carries with it a high mortality.
Patients with prosthetic valve endocarditis experience a mean hospital
stay of 28-33 days and an in-hospital mortality of
22-27\%.\textsuperscript{15} Without pre-existing ventricular
dysfunction and sinus node dysfunction, a VDI leadless pacemaker may be
sufficient to maintain AV synchrony and reduce risk of CIED related
infection. For those with second degree AV block or high degree AV block
post TAVR, RV pacing requirements may be low and decrease over time.
Thus, a VVI leadless pacemaker may also be sufficient.

Conversely, reduction in infection risk by implanting a leadless
pacemaker may be offset by the potentially deleterious effects of right
ventricular pacing on ventricular systolic
function.\textsuperscript{16}Similarly, left bundle branch block may
also be associated with development of left ventricular systolic
dysfunction. Initially, the development of left bundle branch block was
not considered to affect morbidity and mortality post TAVR. However,
recent data suggest that mortality is worse with new-onset LBBB post
TAVR.\textsuperscript{17}The impacts of cardiac dyssynchrony, via right
ventricular pacing or LBBB, on long-term post-TAVR outcomes is unclear.
Also unclear, is whether or not early physiologic pacing would benefit
this group of patients. In the setting of LBBB and preserved left
ventricular ejection fraction, cardiac resynchronization therapy (CRT)
has not been shown to have meaningful improvement in
outcomes.\textsuperscript{18} The timing of CRT implantation for those
with LBBB and systolic dysfunction post-TAVR also requires further
investigation, since the effects of cardiac dyssynchrony are likely to
be higher in this group.

On the horizon, leadless absorbable temporary pacing is an emerging
technology that could change the way we approach risk stratification of
post-TAVR patients to further limit morbidity associated with
pacing.\textsuperscript{19} Most cardiac conduction abnormalities
improve or present within 48 hours, but some patients resolve their
cardiac conduction or present with high degree AV block beyond this
period\textsuperscript{20,21}. For patients requiring percutaneous
trans-venous temporary pacing in the perioperative period, observation
in the ICU with temporary pacing in a geriatric population comes with
its own hazard, namely, hospital-associated functional
decline.\textsuperscript{22} Pre-operative frailty in this patient
populace also influences this outcome. Even a pectoral wound and the
shoulder restrictions required to prevent lead dislodgment can conflict
with the moderate assistance measures to allow mobility. Leadless
absorbable temporary pacing could allow a longer observation period to
decide whether PPMI is necessary enabling early hospital discharge and
early mobilization.

In conclusion, while pre-procedure risk factors for PPMI following TAVR
as outlined in this meta-analysis are important for determining
procedural approaches, including choice of valve, and the risk for PPMI,
many questions about the rhythm management of these patients remain
unanswered and will require continual re-evaluation as TAVR technology
continues to evolve.



\textbf{References}

1. Schwarz F, Baumann P, Manthey J, et al. The effect of aortic valve
replacement on survival. Circulation 1982;66:1105-10.

2. Alivizatos PA. Dwight Emary Harken, MD, an all-American surgical
giant: Pioneer cardiac surgeon, teacher, mentor. Baylor University
Medical Center Proceedings 2018;31:554-7.

3. Eveborn GW, Schirmer H, Heggelund G, Lunde P, Rasmussen K. The
evolving epidemiology of valvular aortic stenosis. The Troms\selectlanguage{ngerman}ø Study.
Heart 2013;99:396-400.

4. Gannon PG, Sellers RD, Kanjuh VI, Edwards JE, Lillehei CW. Complete
heart block following replacement of the aortic valve. Circulation
1966;33:I152-I61.

5. Rosato S, Biancari F, D'Errigo P, et al. One-Year Outcomes after
Surgical versus Transcatheter Aortic Valve Replacement with Newer
Generation Devices. Journal of Clinical Medicine 2021;10:3703.

6. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or Surgical
Aortic-Valve Replacement in Intermediate-Risk Patients. New England
Journal of Medicine 2016;374:1609-20.

7. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter Aortic-Valve
Replacement with a Balloon-Expandable Valve in Low-Risk Patients. New
England Journal of Medicine 2019;380:1695-705.

8. Wang T, Ou A, Xia P, Tian J, Wang H, Cheng Z. Predictors for the risk
of permanent pacemaker implantation after transcatheter aortic valve
replacement: a systematic review and meta-analysis ~Journal of Cardiac
Surgery 2021.

9. Kawashima T, Sato F. Visualizing anatomical evidences on
atrioventricular conduction system for TAVI. International Journal of
Cardiology 2014;174:1-6.

10. Rodés-Cabau J, Ellenbogen KA, Krahn AD, et al. Management of
Conduction Disturbances~Associated With Transcatheter Aortic Valve
Replacement: JACC Scientific Expert Panel. J Am Coll Cardiol
2019;74:1086-106.

11. Ferreira T, Da Costa A, Cerisier A, et al. Predictors of high\selectlanguage{english}-degree
conduction disturbances and pacemaker implantation after transcatheter
aortic valve replacement: Prognostic role of the electrophysiological
study. Pacing and Clinical Electrophysiology 2021;44:843-55.

12. Nazif TM, Dizon M, Jose, Hahn RT, et al. Predictors and Clinical
Outcomes of Permanent Pacemaker Implantation After Transcatheter Aortic
Valve Replacement. JACC: Cardiovascular Interventions 2015;8:60-9.

13. Clementy N, Bisson A, Bodin A, et al. Outcomes associated with
pacemaker implantation following transcatheter aortic valve replacement:
A nationwide cohort study. Heart Rhythm 2021.

14. Cahill TJ, Prendergast BD. Infective endocarditis. The Lancet
2016;387:882-93.

15. Lalani T. In-Hospital and 1-Year Mortality in Patients Undergoing
Early Surgery for Prosthetic Valve Endocarditis. JAMA Internal Medicine
2013;173:1495.

16. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. 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. Circulation
2003;107:2932-7.

17. Regueiro A, Abdul-Jawad Altisent O, Del Trigo M, et al. Impact of
New-Onset Left Bundle Branch Block and Periprocedural Permanent
Pacemaker Implantation on Clinical Outcomes in Patients Undergoing
Transcatheter Aortic Valve Replacement. Circulation: Cardiovascular
Interventions 2016;9:e003635.

18. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular Pacing for
Atrioventricular Block and Systolic Dysfunction. New England Journal of
Medicine 2013;368:1585-93.

19. Choi YS, Yin RT, Pfenniger A, et al. Fully implantable and
bioresorbable cardiac pacemakers without leads or batteries. Nature
Biotechnology 2021;39:1228-38.

20. Kaplan RM, Yadlapati A, Cantey EP, et al. Conduction recovery
following pacemaker implantation after transcatheter aortic valve
replacement. Pacing and Clinical Electrophysiology 2018.

21. Ream K, Sandhu A, Valle J, et al. Ambulatory Rhythm Monitoring
to~Detect~Late High-Grade Atrioventricular Block Following Transcatheter
Aortic~Valve~Replacement. Journal of the American College of Cardiology
2019;73:2538-47.

22. Cohen Y, Zisberg A, Chayat Y, et al. Walking for Better Outcomes and
Recovery: The Effect of WALK-FOR in Preventing Hospital-Associated
Functional Decline Among Older Adults. The Journals of Gerontology:
Series A 2019;74:1664-70.

1. Stewart BF, Siscovick D, Lind BK, et al. Clinical Factors Associated
With Calcific Aortic Valve Disease. Journal of the American College of
Cardiology 1997;29:630-4.

2. Alivizatos PA. Dwight Emary Harken, MD, an all-American surgical
giant: Pioneer cardiac surgeon, teacher, mentor. Baylor University
Medical Center Proceedings 2018;31:554-7.

3. Eveborn GW, Schirmer H, Heggelund G, Lunde P, Rasmussen K. The
evolving epidemiology of valvular aortic stenosis. The Tromso Study.
Heart 2013;99:396-400.

4. Gannon PG, Sellers RD, Kanjuh VI, Edwards JE, Lillehei CW. Complete
heart block following replacement of the aortic valve. Circulation
1966;33:I152-I61.

5. Rosato S, Biancari F, D'Errigo P, et al. One-Year Outcomes after
Surgical versus Transcatheter Aortic Valve Replacement with Newer
Generation Devices. Journal of Clinical Medicine 2021;10:3703.

6. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or Surgical
Aortic-Valve Replacement in Intermediate-Risk Patients. New England
Journal of Medicine 2016;374:1609-20.

7. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter Aortic-Valve
Replacement with a Balloon-Expandable Valve in Low-Risk Patients. New
England Journal of Medicine 2019;380:1695-705.

8. Wang T, Ou A, Xia P, Tian J, Wang H, Cheng Z. Predictors for the risk
of permanent pacemaker implantation after transcatheter aortic valve
replacement: a systematic review and meta-analysis ~Journal of Cardiac
Surgery 2021.

9. Kawashima T, Sato F. Visualizing anatomical evidences on
atrioventricular conduction system for TAVI. International Journal of
Cardiology 2014;174:1-6.

10. Rodes-Cabau J, Ellenbogen KA, Krahn AD, et al. Management of
Conduction Disturbances~Associated With Transcatheter Aortic Valve
Replacement: JACC Scientific Expert Panel. J Am Coll Cardiol
2019;74:1086-106.

11. Ferreira T, Da Costa A, Cerisier A, et al. Predictors of high\selectlanguage{english}-degree
conduction disturbances and pacemaker implantation after transcatheter
aortic valve replacement: Prognostic role of the electrophysiological
study. Pacing and Clinical Electrophysiology 2021;44:843-55.

12. Nazif TM, Dizon M, Jose, Hahn RT, et al. Predictors and Clinical
Outcomes of Permanent Pacemaker Implantation After Transcatheter Aortic
Valve Replacement. JACC: Cardiovascular Interventions 2015;8:60-9.

13. Clementy N, Bisson A, Bodin A, et al. Outcomes associated with
pacemaker implantation following transcatheter aortic valve replacement:
A nationwide cohort study. Heart Rhythm 2021.

14. Cahill TJ, Prendergast BD. Infective endocarditis. The Lancet
2016;387:882-93.

15. Lalani T. In-Hospital and 1-Year Mortality in Patients Undergoing
Early Surgery for Prosthetic Valve Endocarditis. JAMA Internal Medicine
2013;173:1495.

16. Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. 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. Circulation
2003;107:2932-7.

17. Regueiro A, Abdul-Jawad Altisent O, Del Trigo M, et al. Impact of
New-Onset Left Bundle Branch Block and Periprocedural Permanent
Pacemaker Implantation on Clinical Outcomes in Patients Undergoing
Transcatheter Aortic Valve Replacement. Circulation: Cardiovascular
Interventions 2016;9:e003635.

18. Curtis AB, Worley SJ, Adamson PB, et al. Biventricular Pacing for
Atrioventricular Block and Systolic Dysfunction. New England Journal of
Medicine 2013;368:1585-93.

19. Choi YS, Yin RT, Pfenniger A, et al. Fully implantable and
bioresorbable cardiac pacemakers without leads or batteries. Nature
Biotechnology 2021;39:1228-38.

20. Kaplan RM, Yadlapati A, Cantey EP, et al. Conduction recovery
following pacemaker implantation after transcatheter aortic valve
replacement. Pacing and Clinical Electrophysiology 2018.

21. Ream K, Sandhu A, Valle J, et al. Ambulatory Rhythm Monitoring
to~Detect~Late High-Grade Atrioventricular Block Following Transcatheter
Aortic~Valve~Replacement. Journal of the American College of Cardiology
2019;73:2538-47.

22. Cohen Y, Zisberg A, Chayat Y, et al. Walking for Better Outcomes and
Recovery: The Effect of WALK-FOR in Preventing Hospital-Associated
Functional Decline Among Older Adults. The Journals of Gerontology:
Series A 2019;74:1664-70.

Figure. ECG and electrophysiology recordings from a 76 year old woman
who underwent TAVR with an Edwards S3 valve. Post-TAVR ECGs showed PR
prolongation of 30 ms and a left bundle branch block (LBBB). At
electrophysiology study, Panel A shows the LBBB was intermittent in
sinus rhythm. In panel B, there is no difference in HV interval between
the first beat with LBBB and the second beat without LBBB (HV was 55
ms). Panel C shows 6 beats of atrial pacing at 100 bpm with normal
conduction (no LBBB). When pacing stops, sinus rhythm resumes at a much
lower rate and the LBBB resumes. This phenomenon of
bradycardia-dependent LBBB is known as phase 4 block. Based on these
findings a pacemaker was not recommended.\selectlanguage{english}
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