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 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 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 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 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% 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++ handling, which influence each other to
promote AF 6). This auto-enhancing feature is often
described by the famous concept ”AF begets AF” 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. 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 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 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 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 UCG9). 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 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 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 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
- Haïssaguerre 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.
- 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
- 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
- Henning RJ. Tricuspid valve regurgitation: current diagnosis and
treatment. Am J Cardiovasc Dis 2022;12:1-18. www.AJCD.us
/ISSN:2160-200X/AJCD0139835
- 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
- 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
- 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.
- 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.
- 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
- 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
- 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
- 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/
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