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\begin{document}

\title{Tricuspid Regurgitation, the last challenge left.}



\author[1]{Takashi Kurita}%
\affil[1]{Kindai University}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Atrial fibrillation (AF) provides extremel rapid excitation frequency in
both atria, and induces several pathophysiological mechanisms by
influencing each other to promote AF. This auto-enhancing feature is
often described by the well-known concept ``AF begets AF''. The cure of
AF by creating pulmonary vein (PV) isolation may be able to reverse the
spiral and be able to achieve reverse remodeling. Because of the initial
focus on PV in the pathogenesis of AF, the effects of reverse remodeling
after catheter ablation (CA) have been investigated on improvement of
the left-sided cardiac system. On the other hand, tricuspid
regurgitation (TR), the most neglected of all valvular diseases, is
increasingly recognized as an important prognostic condition in heart
failure patients. Previous reports, which tested the role of CA for AF
patients with TR, have demonstrated that maintenance of SR provides
reverse remodeling of the right-sided cardiac system, but have yet to
prove whether this leads to improvement in patient prognosis. What is
new and noteworthy about the report by Ukita et al. in this issue is
that they found that TR improvement itself improves major event-free
survival rate (incidence of heart failure hospitalization and all-cause
mortality). However, several issues remain unresolved in their report.
They observed a low AF recurrence rate in the TR-improved group, but did
not address the possibility that AF suppression itself contributed to
improve event-free survival rate. Further investigation is required to
clarify whether TR improvement or maintenance of SR is the greater
contributor to improved prognosis in AF.%
\end{abstract}%



\sloppy


Tricuspid Regurgitation, the last challenge left.

Takashi Kurita, MD, PhD

Division of Cardiovascular Center, Kindai University, Osaka, Japan

Key words: Atrial fibrillation, Catheter ablation, Reverse remodeling,
Functional tricuspid regurgitation

Manuscripts

Since the discovery that atrial fibrillation (AF) is mostly caused by
the transition area between the left atrium (LA) and the pulmonary vein
(PV), catheter ablation (CA) of AF based on PV isolation (PVI) has
achieved remarkable success in its cure and is now established as the
principal technique for AF treatment \textsuperscript{1)}. Because of
the initial focus on LA in the pathogenesis of AF, the effects of
reverse remodeling after CA have been investigated on improvement of the
left-sided cardiac system, mitral regurgitation (MR), and left
ventricular systolic function \textsuperscript{2)}. The most extreme of
these is the concept of functional atrial MR. This final aspect of AF
indicates that this is not necessarily a benign disease, and is a useful
concept to explain the pathogenesis of AF-induced heart failure death
and sudden cardiac death \textsuperscript{3)}.

On the other hand, tricuspid regurgitation (TR), which has been the most
neglected pathophysiology among all valvular diseases in adults, is
increasingly recognized as an important prognostic condition in heart
failure patients.

Several clinical conditions such as ischemic heart disease,
cardiomyopathy, pacemaker leads, COPD, and AF are well known as causes
of functional TR \textsuperscript{4)}. The severity of TR is graded as
none/trivial, mild, moderate, and sever, and its severity is associated
with the patient's life expectancy, with the 5-year survival rate for
severe TR being reduced to 20\% \textsuperscript{5)}. It is also known
that patients with TR progression have a worse prognosis than those
without. Among the etiologies of TR, AF is extremely important as a
particular condition that cardiologists can directly intervene and
resolve.

AF provides extremely rapid excitation frequency in both atria, and
induces following four pathophysiological mechanisms: electrical
remodeling, structural remodeling, autonomic nervous system changes, and
abnormal Ca\textsuperscript{++} handling, which influence each other to
promote AF \textsuperscript{6)}. This auto-enhancing feature is often
described by the famous concept ''AF begets AF'' \textsuperscript{7)}.
In particular, structural remodeling caused by AF leads to enlargement
of both atria and atrioventricular (AV) annulus and AV valve
regurgitation (atrial functional MR, TR), which in turn lead to
ventricular enlargement and further worsen AV valve regurgitation, a
negative spiral. \textsuperscript{6)} (Figure).

Radical therapy of AF may be able to reverse the negative spiral or
prevent the patient from falling into it. And many reports have shown
its remarkable efficacy, and the therapeutic concept of reverse
remodeling has been established \textsuperscript{8-9)}.

To the best of the author's knowledge, the first report to demonstrate
that restoration of SR from AF with CA improves TR was by Itakura et al.
in January 2020 \textsuperscript{8)}. They conducted a retrospective
cohort study of 86 patients with persistent AF and found that 71
patients who were maintained in SR by CA had reductions in right atrial
(RA) area, RA diameter, tricuspid annular diameter, and resulting in
improvements of functional TR. The same effect was not observed in the
15 patients in whom SR could not be maintained, and the authors
concluded that right atrial remodeling was achieved by SR maintenance in
persistent AF patients.

Subsequently, several clinical trials have confirmed that maintenance of
SR produces similar results \textsuperscript{9,10)}. In particular,
Soulat-Dufour et al. studied 117 patients hospitalized for AF and
divided them into two groups: non-spontaneous restoration (n=86) and
spontaneous restoration of SR (n=31), with subsequent follow-up by
UCG\textsuperscript{9)}. In this study, non-spontaneous restoration
group (n=39) had worsening TR and MR, while those who underwent active
restoration by electroshock or ablation (n=47) showed significant
improvement. In this study, the spontaneous restoration group had fewer
comorbidities and significantly smaller both atria, and left ventricular
diameters, suggesting that the progression of cardiac structural
remodeling had been less pronounced in spontaneous restoration group. In
other words, once caught in the spiral of structural remodeling, CA
plays a pivotal role to reverse it.

Previous reports have demonstrated that maintenance of SR in patients
with AF provides reverse remodeling of the right-sided cardiac system,
but have yet to prove whether this leads to improvement in patient
prognosis. What is new and noteworthy about the report by Ukita et al.
in this issue is that they found that TR improvement is more likely to
be obtained in patients whose remodeling is not so significant, and that
TR improvement itself improves patient prognosis \textsuperscript{11)}.
By defining improvement in TR as an improvement of at least one-grade,
they found that patients in the TR-improved group were significantly
younger than those in the non-improved group in their baseline data,
with 71 years old being the best cutoff value. Although no significant
difference was observed, the duration of AF in the TR-improved group
tended to be shorter, suggesting that early detection of AF was less
likely in elderly AF patients, and that structural remodeling may have
had progressed. One of the most important implications in this study is
that the major event-free survival rate (incidence of heart failure
hospitalization and all-cause mortality) was significantly better in the
TR-improved group, but no difference in prognosis was observed between
the groups when the subjects were divided by MR or LVEF improvement.
This suggests that TR improvement may be an independent factor that
determines the prognosis of post-CA patients with AF.

However, several issues remain unresolved even by the report of Ukita et
al \textsuperscript{11)}. They observed a low AF recurrence rate in the
TR-improved group, but did not address the possibility that AF
suppression itself contributed to improve event-free survival rate.
Further investigation is required to clarify whether TR improvement or
maintenance of SR is the greater contributor to improved prognosis in AF
patients. Also, the conclusion that improvement in left-sided cardiac
parameters was not associated with prognosis should be interpreted with
caution, since it is clear that most AF substrates are located in the
LA, and theoretically, a reduction in over load on the LA due to MR
reduction and restoration of left ventricular function should have a
more direct favorable effect \textsuperscript{12)}. Future studies are
needed to examine the mechanisms of how the improvement of TR
contributes to the improvement of the ''substrate'' present in LA and
how the occurrence of TR results in a worse prognosis for patients with
AF.

Reference

\begin{enumerate}
\tightlist
\item
  Ha\selectlanguage{ngerman}ïssaguerre M, Jaïs P, Shah DC, et al. Spontaneous initiation of
  atrial fibrillation by ectopic beats originating in the pulmonary
  veins. N Engl J Med 1998;339:659-66.
\item
  Gertz ZM, Raina A, Mountantonakis SE, et al. The impact of mitral
  regurgitation on patients undergoing catheter ablation of atrial
  fibrillation. Europace. (2011) 13:1127--32. doi:
  10.1093/europace/eur098
\item
  Marijon E, MD, Heuzey J-Y L, Connolly S, et al. Causes of death and
  influencing factors in patients with atrial fibrillation. A
  competing-risk analysis from the randomized evaluation of long-term
  anticoagulant therapy study. Circulation. 2013;128:2192-2201. doi:
  10.1161/CIRCULATIONAHA.112.000491
\item
  Henning RJ. Tricuspid valve regurgitation: current diagnosis and
  treatment. Am J Cardiovasc Dis 2022;12:1-18. www.AJCD.us
  /ISSN:2160-200X/AJCD0139835
\item
  Bannehr M, Edlinger CR, Kahn U, et al. Natural course of tricuspid
  regurgitation and prognostic implications. Open Heart 2021;8:e001529.
  doi:10.1136/ openhrt-2020-001529
\item
  Nattel S, Harada M. Atrial remodeling and atrial fibrillation. Recent
  advances and translational perspectives. J Am Coll Cardiol
  2014;63:2335--45. http://dx.doi.org/10.1016/j.jacc.2014.02.555
\item
  Wijffels M C, Kirchhof C J, Dorland R and Allessie MA. Atrial
  fibrillation begets atrial fibrillation. A study in awake chronically
  instrumented goats Allesie AF begets AF. Circulation 1995;92:1954-68.
  doi: 10.1161/01.cir.92.7.1954.
\item
  Itakura K, Hidaka T, Nakano Y, et al. Successful catheter ablation of
  persistent atrial fibrillation is associated with improvement in
  functional tricuspid regurgitation and right heart reverse remodeling.
  Heart Vessels. 2020;35:842-851.
\item
  Soulat-Dufour L, Lang S, Addetia K, et al. Restoring Sinus Rhythm
  Reverses Cardiac Remodeling and Reduces Valvular Regurgitation in
  Patients With Atrial Fibrillation. J Am Coll Cardiol. 2022;79:951-961
\item
  Markman TM, Plappert T, Alsina A, et al. Improvement in tricuspid
  regurgitation following catheter ablation of atrial fibrillation. J
  Cardiovasc Electrophysiol. 2020;31:2883--2888. doi: 10.1111/jce.14707
\item
  Ukita K, Egami Y, Nohara H, et al. Predictors and outcomes of
  tricuspid regurgitation improvement after radiofrequency catheter
  ablation for persistent atrial fibrillation. J Cardiovasc
  Electrophysiol. 2023;XXXXXXXX
\item
  Gottlieb LA, Coronel R, Dekker LRC. Reduction in atrial and pulmonary
  vein stretch as a therapeutic target for prevention of atrial
  fibrillation. Heart Rhythm 2023;20:291--298.
  http://creativecommons.org/licenses/by-nc-nd/4.0/
\end{enumerate}

Figure legend Title: Pathophysiology of atrial fibrillation and the
remodeling of the heart. ANS: Autonomic nervous system APD: Action
potential duration CM: Cardiomyopathy MR: Mitral regurgitation RAA:
Renin-Angiotensin-Aldosterone TR: Tricuspid regurgitation

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