Keywords

Atrial arrhythmia, Tachycardia-mediated cardiomyopathy, Catheter ablation, Left ventricular systolic dysfunction, Left ventricular end-diastolic dimension

Introduction

Tachycardia-induced cardiomyopathy (TCM) is a reversible disease entity of dilated cardiomyopathy. Atrial arrhythmia (AA) plays a critical role in the lead-up to TCM, and the most common etiology is atrial fibrillation (AF) with rapid ventricular response [1]. The number of patients with AA is steadily increasing [2]. AA and left ventricular systolic dysfunction (LVSD) frequently co-exist, and appear to be looming as burgeoning public health problems. The presence of AF and heart failure (HF) is associated with increased morbidity, mortality, and healthcare costs [3,4]. The restoration and maintenance of sinus rhythm (SR) in patients with AA and LVSD are known to often improve symptoms [5]. Some recent clinical studies have shown that aggressive rhythm control therapy including catheter ablation leads to reductions in all-cause mortality and hospitalization for worsening (HF) and improvements in quality of life [6-9]. Furthermore, sub-analyses have shown that rhythm control therapy improved left ventricular systolic function [10]. However, in actual clinical practice, the relationship between AA and HF represents a common conundrum for cardiologists and general physicians alike, as a kind of "chicken or egg" situation as to whether AA begets HF or vice versa.

Although TCM is generally regarded as a reversible entity, LVSD is indicated for implantable cardioverter defibrillator (ICD) implantation regardless of etiology under the current guidelines. ICD therapy is recommended to prevent sudden cardiac death (SCD) in patients with symptomatic HF (New York Heart Association (NYHA) class II-III) and LVEF ≤ 35% after ≥ 3 months of optimal medical therapy who are expected to survive for ≥ 1 year with good functional status [11,12].

The only way to diagnose TCM is to treat arrhythmias [1]. Although LVSD in patients with TCM is generally considered reversible, some clinical data have shown that LVSD is irreversible when the left ventricle is severely enlarged [13]. Reversal of cardiomyopathy by eliminating arrhythmia not only confirms the diagnosis, but may significantly improve outcomes. We hypothesized that enlarged LVDd would not represent a predictor of irreversible LVSD among patients with AA. In the present study, we performed aggressive rhythm control therapy for patients with AA and LVSD. Cardiac parameters were observed after successful rhythm control therapy.

Methods

We assessed patients with persistent AA and HF (ejection fraction (EF) < 45%) who received rhythm control therapy. Patients who were hospitalized with persistent AA and LVSD between April 2016 and October 2021 receiving aggressive rhythm control therapy were enrolled in this study. Ischemic heart disease was excluded with coronary angiography or coronary computed tomography. Echocardiographic parameters and concentrations of brain natriuretic peptide (BNP) were evaluated for those patients in whom SR was maintained. The patients with severe valvular heart disease revealed with echocardiography at baseline were excluded from the study. This study was approved by the St. Marianna University School of Medicine Ethics Committee (approval no. 5020).

Rhythm control therapy

We performed the rhythm control therapy for patients with LVSD in AA, and then tried to maintain SR as long as possible. Catheter ablation (CA) was performed in all patients except those who declined to undergo the procedure. After the procedure, a class 1 or 3 antiarrhythmic drug (AAD) was administered. For patients who did not undergo CA, AAD was used in combination with external cardioversion.

Catheter ablation

Cases with left atrium (LA) or left atrial appendage thrombus were excluded by transesophageal echocardiography and/or contrast-enhanced computed tomography before the procedure in all patients. Written informed consent for the procedure was obtained from all patients.

Circumferential pulmonary vein isolation (PVI) was mandatory as the primary method. The procedure was performed with general anesthesia or deep sedation using midazolam and continuous infusion of propofol. Esophageal temperature was monitored during the whole procedure to avoid esophageal injury. A 5-Fr decapolar catheter (BeeAT; Japan Life Line, Tokyo, Japan) was positioned in the coronary sinus through the right jugular vein. Through the right femoral vein, a steerable 8.5-Fr long sheath (Agilis; Abbott Medical, Minneapolis, MN) and a non-steerable 8.5-Fr long sheath (SL0; Abbott Medical) were introduced into the LA using single transseptal puncture guided by fluoroscopy and intracardiac echocardiography. Directly after transseptal puncture, heparin was administered intravenously at a dose of 100 U/kg body weight. Thereafter, activated clotting time (ACT) was checked every 30 min and more heparin was administered as necessary to maintain ACT > 300s.

LA geometry was acquired using a multipolar mapping catheter (Pentaray; Biosense Webster, Diamond Bar, CA or HD Grid; Abbott Medical, Minneapolis, MN) in combination with a three-dimensional mapping system (CARTO3; Biosense Webster or EnSite; Abbott Medical) with computed tomography image integration. An open-irrigated radiofrequency (RF) ablation catheter with a contact force sensor (Surround Flow; Biosense Webster or Tacticath; Abbott Medical) was used in all cases. The ablation catheter was positioned in the LA through the Agilis sheath, and then PVI was performed. In one case, focal ablation was performed for atrial tachycardia (AT) arising from the lateral portion of the mitral annulus. PVI was not performed because no arrhythmia was inducible after the ablation of AT and SR was maintained.

Each pulse was delivered in a power-control mode. RF energy was limited to 35 W for all locations in the LA, ablation duration was limited to 60s. When esophageal temperature increased to > 39 ℃, energy delivery was stopped immediately and lower RF energy in the range of 20-25 W was applied.

The acute endpoint of AF ablation was the creation of conduction block in all PVs. Isolation of each pulmonary vein (PV) was confirmed by entrance block using the multipolar mapping catheter. When PVI was not achieved with circumferential ablation, earliest PV potential was targeted sequentially until complete isolation was achieved. Internal cardioversion using a catheter positioned in the coronary sinus was performed when SR was not achieved by ablation.

When AT remained after completion of PVI, mitral isthmus ablation, LA posterior wall isolation, and superior vena cava isolation, Cavo-tricuspid isthmus block line was added to PVI, depending on the mechanism of AT. Additional ablation lesions were made at the discretion of the operators.

After the procedure, AAD was administered, unless the patient had sinus node or atrioventricular conduction dysfunction. Efforts to maintain SR were continued even after CA.

Echocardiographic parameters

Trans-thoracic echocardiography was performed during AA at baseline and SR after rhythm control therapy. Echocardiography was performed at 3 months after the restoration of SR. Echocardiography was performed in the left lateral decubitus position using a Vivid E95 system (GE Medical Systems, Milwaukee, WI). To avoid underestimation of left ventricular systolic function during AA at baseline, calculations of all parameters were performed at the preceding RR interval > 500 ms. Left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) were measured from standard apical four-chamber views in 2D mode using a modification of Simpson's rule, then LVEF was derived [14].

Left atrial volume (LAV) was measured in the same view. Left atrial volume index (LAVI) was then calculated as LAV divided by body surface area. Left atrial dimension (LAD), left ventricular end-diastolic dimension (LVDd), and left ventricular end-systolic dimension (LVDs) were measured from the standard long-axis view in M mode. Echocardiographic data were acquired by an investigator blinded to the study protocol.

Statistical analysis

All continuous variables are expressed as mean ± standard deviation. Student's t test was used for statistical analyses. Two-tailed probability values of P < 0.01 were considered statistically significant. All statistical analyses were performed using SPSS version 23 (SPSS, Chicago, IL, USA).

Results

Aggressive rhythm control therapy was performed for 38 consecutive patients with persistent AA and LVSD (35 men; mean age, 64.3 ± 8.8 years). SR was maintained in 33 patients (86.8%) after rhythm control therapy during the observation period (mean, 5.1 ± 4.4 months). Patient characteristics are shown in Table 1. There were no cases with severe mitral regurgitation. No complications related to the procedure were encountered. An AAD was administered in 24 patients (73%). At baseline, enlarged LVDd > 60 mm was observed in 7 patients (21%). Sixteen patients (48%) displayed severe LVSD, with EF < 35%.

Heart rate reduced from 98.7 ± 20.0 beats/min during AA to 58.7 ± 6.8 beats/min during SR (P < 0.001). EF and BNP were improved in all patients (EF: 30.7 ± 10.9% to 54.6 ± 7.4%, P < 0.001; BNP: 382.0 ± 251.1 pg/ml to 50.5 ± 30.7 pg/ml, P < 0.001) (Figure 1A). LA volume was reduced after maintenance of SR (45.0 ± 5.5 to 40.9 ± 4.8, P < 0.001). Significant reductions in LVDs and LVESV were also observed after maintenance of SR (LVDs: 46.5 ± 8.0 mm to 39.4 ± 6.5 mm, P < 0.001; LVESV: 80.8 ± 32.4 ml to 51.7 ± 22.9 ml, P < 0.001). On the other hand, no significant reductions were identified in LVDd and LVEDV (LVDd: 54.8 ± 7.3 mm to 54.1 ± 5.0 mm, P = 0.40; LVEDV: 118.2 ± 37.7 ml to 109.2 ± 34.9 ml, P = 0.17) (Table 2).

Among the 7 patients with severely enlarged LV (LVDd > 60 mm), LVEF and BNP were improved significantly to the same extent as patients without enlarged LV (Figure 1B). In comparisons between patients with enlarged LVDd and without enlarged LVDd, both ΔLVEF and ΔLVESV also improved (Figure 2).

Discussion

This clinical study revealed improvement of left ventricular systolic function after restoration of SR in the population of LVSD patients with AA. The main findings were as follows. First, aggressive rhythm control was able to maintain SR in 86.8% of patients with LVSD and long-lasting AA with a mean duration of 1.6 years. Second, 48% of patients had severe LVSD with EF  35%. Third, after SR had been restored and maintained, BNP and EF were significantly improved. Fourth, LV systolic function was improved even in those patients for whom LVDd was > 60 mm at baseline.

HF and tachyarrhythmia showed a strong association, particularly for AF. In general, tachyarrhythmia is a secondary consequence following advanced HF. This relationship may be partly attributable to the acute deterioration of LV function and rapid development of HF symptoms without structural remodeling. Tachyarrhythmias have long been considered part of the clinical presentation for HF. However, AA alone has been shown to result in reversible nonischemic cardiomyopathy, as so-called TCM. TCM is recognized as an entity of reversible LVSD solely due to the increase in ventricular rates, regardless of the etiology of tachycardia.

Despite AF being the most prevalent arrhythmia, clear data on the development of TCM in this population remain lacking. A single study reported TCM in 4% of patients referred for PVI [15]. AT can also be an etiological factor for TCM. TCM has been reported in 10% of patients with AT, particularly in incessant AT such as permanent junctional reciprocating tachycardia [16].

The mechanisms underlying TCM remain unclear. A previous study demonstrated that the irregular cycles of excitation and contraction with calcium mishandling induce an altered profile of gene and protein expression that are associated with functional changes at cellular and tissue levels [17]. Loss of atrial contraction, limited ventricular filling and increased filling pressure, functional mitral regurgitation, and diastolic dysfunction were considered as the mechanisms of TCM due to AA [18].

Although some mechanisms of TCM were revealed as mentioned above, no approach has been established to diagnose TCM before the treatment of tachyarrhythmia. During the persistence of AA, determining whether tachycardia leads to the LVSD or LVSD leads to the tachycardia is difficult. The coexistence of tachyarrhythmia and HF always raises a "chicken or egg" question.

The CAMERA-MRI study [19] reported the use of cardiac magnetic resonance imaging with late-gadolinium enhancement as a screening tool to predict LVSD reversibility before treatments. Absence of a ventricular scar or scar burden < 10% were predictors of the reversibility of LVSD.

TCM is a diagnosis of exclusion and should be primarily suspected in patients with nonischemic cardiomyopathy and persistent AA who do not improve after appropriate medical therapy and rate control.

Some clinical trials have shown that the CA strategy for AA resulted in early improvement of LVSD, evident at 1 month and sustained at 1 year [7,8]. This was accompanied by reversal of LV remodeling as evidenced by the reduction in ESV compared with the medical group. CA resulted in improved exercise capacity, BNP, NYHA class, HF symptoms, and quality of life compared with a medical rate control strategy [7,8,20,21]. Restoration of SR should be considered when TCM due to AA is suspected. Importantly, appropriate diagnosis and treatment of AA will improve not only LVSD with its associated morbidity and mortality, but also HF symptoms, quality of life and long-term prognosis in most patients [8,22,23].

We demonstrated that the restoration and maintenance of SR was achievable in up to 84.6% in patients with AA and LVSD. Previous studies have reported that AADs have an overall 30-50% success rate to maintain SR, with frequent discontinuation due to side effects [18]. In contrast, the CA strategy has been reported to achieve SR from 50-88% in AA patients with HF [8,18]. The achievement of SR in the present study was relatively high with treatment for persistent AA as compared to previous reports. In this study, we performed aggressive rhythm control therapy combined with CA and AADs. The results of our study were in accordance with findings from previous studies [7,8,24].

Current guidelines recommend ICD implantation for patients with severe LVSD (EF < 35%) to prevent SCD [11,12]. If guidelines were strictly complied with, 48% of patients in the present study would have been considered candidates for ICD. After rhythm control therapy, EF was improved to > 35% in all patients with severe LVSD, and no patients in this study suffered from SCD. As indications for cardiac device implantation must be determined with utmost care, careful observation after rhythm control therapy is necessary when the etiology of LVSD is suspected to be TCM.

One study identified enlargement of LVDd to > 60 mm as a predictor of irreversible LVSD [13]. Enlarged LVDd may reflect severe left ventricular structural remodeling. Recently, Stegmann, et al. reported that opposite LVEDV index and negative late gadolinium enhancement in cardiac magnetic resonance imaging were independent predictors of complete LVEF recovery [25]. The present study included 7 cases with LVDd > 60 mm (21%). Rhythm control therapy could restore SR and EF was then improved even in that population of cases with severely enlarged left ventricle. In this study, we assessed the left ventricular systolic function revealed with echocardiography. Compared to cardiac magnetic resonance imaging, echocardiograpy can be easily achievd in daily clinical practice. Among cases of LVSD and AA with severe enlargement of LVDd, that dimension alone is not a predictor of irreversible left ventricular systolic function. Restoration of SR should be considered when TCM is suspected.

Study Limitations

Several limitations to this study should be acknowledged. First, this study was a retrospective, observational study of patients from a single institute and was not a randomized study. Second, we demonstrated that LVESV and EF were improved after aggressive rhythm control therapy, whereas no reduction in LVEDV was shown. One possibility is that the observation period was too short to observe reverse remodeling after restoration of SR. Although we did not refer to the clinical course such as total mortality or admission for worsening of HF, we could refer to statistical improvements in EF and BNP levels as important clinical parameters. Larger studies are required to validate these initial results.

Conclusion

Left ventricular systolic function improved after aggressive rhythm control therapy in patients with AA and LVSD. Unnecessary cardiac device implantation may be avoidable in this population. Even in cases with severely enlarged LVDd > 60 mm, LV systolic function appears reversible when AA is present.

Conflict of Interest

The authors declare that there is no conflict of interest.

References

1. Huizar JF, Ellenbogen KA, Tan AY, Kaszala K (2019) Arrhythmia-induced cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol 73: 2328-2344.
2. Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, et al. (2009) Prevalence of atrial fibrillation in the general population of Japan: An analysis based on periodic health examination. Int J Cardiol 137: 102-107.
3. Silva-Cardoso J, Zharinov OJ, Ponikowski P, Naditch-Brûlé L, Lewalter T, et al. (2013) Heart failure in patients with atrial fibrillation is associated with a high symptom and hospitalization burden: The RealiseAF survey. Clin Cardiol 36: 766-774.
4. Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, et al. (2003) Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: The Framingham Heart Study. Circulation 107: 2920-2925.
5. Pedersen OD, Bagger H, Keller N, Marchant B, Køber L, et al. (2001) Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: A Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy. Circulation 104: 292-296.
6. Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, et al. (2019) Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: The CABANA randomized clinical trial. JAMA 321: 1261-1274.
7. Di Biase L, Mohanty P, Mohanty S, Santangeli P, Trivedi C, et al. (2016) Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: Results from the AATAC multicenter randomized trial. Circulation 133: 1637-1644.
8. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, et al. (2018) Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 378: 417-427.
9. Blomstrom-Lundqvist C, Gizurarson S, Schwieler J, Jensen SM, Bergfeldt L, et al. (2019) Effect of catheter ablation vs antiarrhythmic medication on quality of life in patients with atrial fibrillation: The CAPTAF randomized clinical trial. JAMA 321: 1059-1068.
10. Sohns C, Zintl K, Zhao Y, Dagher L, Andresen D, et al. (2020) Impact of left ventricular function and heart failure symptoms on outcomes post ablation of atrial fibrillation in heart failure: CASTLE-AF trial. Circ Arrhythm Electrophysiol 13: e008461.
11. Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, et al. (2015) 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 36: 2793-2867.
12. Nogami A, Kurita T, Abe H, Ando K, Ishikawa T, et al. (2021) JCS/JHRS 2019 guideline on non-pharmacotherapy of cardiac arrhythmias. J Arrhythm 37: 709-870.
13. Jeong YH, Choi KJ, Song JM, Hwang ES, Park KM, et al. (2008) Diagnostic approach and treatment strategy in tachycardia-induced cardiomyopathy. Clin Cardiol 31: 172-178.
14. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, et al. (2005) Recommendations for chamber quantification: A report from the American Society of Echocardiography's Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 18: 1440-1463.
15. Gentlesk PJ, Sauer WH, Gerstenfeld EP, Lin D, Dixit S, et al. (2007) Reversal of left ventricular dysfunction following ablation of atrial fibrillation. J Cardiovasc Electrophysiol 18: 9-14.
16. Medi C, Kalman JM, Haqqani H, Vohra JK, Morton JB, et al. (2009) Tachycardia-mediated cardiomyopathy secondary to focal atrial tachycardia: Long-term outcome after catheter ablation. J Am Coll Cardiol 53: 1791-1797.
17. Ling LH, Khammy O, Byrne M, Amirahmadi F, Foster A, et al. (2012) Irregular rhythm adversely influences calcium handling in ventricular myocardium: Implications for the interaction between heart failure and atrial fibrillation. Circ Heart Fail 5: 786-793.
18. Trulock KM, Narayan SM, Piccini JP (2014) Rhythm control in heart failure patients with atrial fibrillation: Contemporary challenges including the role of ablation. J Am Coll Cardiol 64: 710-721.
19. Prabhu S, Taylor AJ, Costello BT, Kaye DM, McLellan AJA, et al. (2017) Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction: The CAMERA-MRI Study. J Am Coll Cardiol 70: 1949-1961.
20. Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, Silverstein AP, et al. (2021) Ablation versus drug therapy for atrial fibrillation in heart failure: Results from the CABANA Trial. Circulation 143: 1377-1390.
21. Hunter RJ, Berriman TJ, Diab I, Kamdar R, Richmond L, et al. (2014) A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial). Circ Arrhythm Electrophysiol 7: 31-38.
22. Gupta S, Figueredo VM (2014) Tachycardia mediated cardiomyopathy: Pathophysiology, mechanisms, clinical features and management. Int J Cardiol 172: 40-46.
23. Watanabe H, Okamura K, Chinushi M, Furushima H, Tanabe Y, et al. (2008) Clinical characteristics, treatment, and outcome of tachycardia induced cardiomyopathy. Int Heart J 49: 39-47.
24. Verma A, Jiang CY, Betts TR, Chen J, Deisenhofer I, et al. (2015) Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 372: 1812-1822.
25. Stegmann C, Jahnke C, Lindemann F, Oebel S, Richter S, et al. (2022) Cardiovascular magnetic resonance-based predictors of complete left ventricular systolic functional recovery after rhythm restoration in patients with atrial tachyarrhythmia. Europace 24: 12-19.

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