Atrial Fibrillation in Mitral Regurgitation Patients: A Harbinger for Poorer Outcomes

Atrial fibrillation (AF) is one of the most common arrhythmias in the general population and is associated with increased mortality.1Benjamin EJ Wolf PA D’Agostino RB Silbershatz H Kannel WB Levy D Impact of atrial fibrillation on the risk of death: the Framingham heart study.Circulation. 1998; 98: 946-952Google Scholar Among a community cohort of over 9,700 individuals with AF, 27.5% had significant valvular heart disease, the majority of which had mitral regurgitation (MR). The combination of MR and AF in this cohort was associated with 8.6 deaths per 100 patient-years.2Thomas KL, Jackson LR 2nd, Shrader P, et al. Prevalence, characteristics, and outcomes of valvular heart disease in patients with atrial fibrillation: insights from the ORBIT-AF (Outcomes Registry for Better Informed Treatment for Atrial Fibrillation). J Am Heart Assoc. 2017; 6(12). doi:10.1161/JAHA.117.006475.Google Scholar In this issue of Structural Heart, Megaly et al.3Megaly M, Abraham B, Saad M, et al. Impact of atrial fibrillation on the outcomes after MitraClip®: a meta-analysis. Struct Heart. 2018;2: this issue.Google Scholar present the results of a meta-analysis to evaluate the impact of atrial fibrillation on outcomes following transcatheter mitral valve repair for MR using the MitraClip device. The meta-analysis combined results from four observational studies with a total of 1510 patients and a mean follow-up of 10.2 months. Patients were older (mean age > 75 years), and secondary MR was the predominant etiology. At follow-up, the presence of AF was associated with an increased risk of mortality, OR 1.54 (95% CI 1.16, 2.04, p = 0.003) and major adverse cardiac events OR 1.46 (95% CI 1.03, 2.07 p = 0.03). There was no effect of AF on procedural success or stroke at 14-month follow-up. The data are interesting and certainly raise questions as to the impact of AF on outcomes of transcatheter treatment of MR. There are however important limitations. The analysis did not present any information related to previous history of heart failure or left ventricular function, which is a powerful predictor of mortality in patients treated with MitraClip.4Azzalini L Millan X Khan R et al.Impact of left ventricular function on clinical outcomes of functional mitral regurgitation patients undergoing transcatheter mitral valve repair.Catheter Cardiovasc Interv. 2016; 88 (doi: 10.1002/ccd.26460.): 1124-1133Google Scholar In addition, procedural success was only 88%, low by contemporary standards, and there were no data on residual MR post-intervention, also a predictor of long-term outcomes following MitraClip.5Kaneko H Neuss M Weissenborn J Butter C Impact of residual mitral regurgitation after MitraClip implantation.Int J Cardiol. 2017; 227 (doi: 10.1016/j.ijcard.2016.10.054.): 813-819Google Scholar Despite the limitations of this work, this observational meta-analysis demands the review of the relationship between AF and MR as well as their interaction with heart failure (Figure 1) and begs the question as to whether we need to adjust the timing of transcatheter treatment for MR. MR results in a volume overload of the left ventricle (LV) that causes increased LV wall stress. As a result, the LV dilates and there is increased fractional shortening to maintain normal diastolic pressures in the chronic compensated state. Over time as the disease progresses and MR severity increases, irreversible dilatation of the LV may occur, and filling pressures become elevated in both the left atrium and left ventricle leading to heart failure and atrial fibrillation, both of which are associated with reduced survival.6El Sabbagh A Reddy YNV Nishimura RA Mitral valve regurgitation in the contemporary era: insights into diagnosis, management, and future directions.JACC Cardiovasc Imaging. 2018; 11 (doi: 10.1016/j.jcmg.2018.01.009.): 628-643Google Scholar AF may also cause MR. Persistent AF may lead to atrial remodeling, resulting in mitral annular dilation and secondary MR also described as atrial functional MR. Patients with atrial MR tend to be older, with dilated left atria and persistent AF. Atrial MR has been shown to improve with restoration of sinus rhythm7Gertz ZM Raina A Saghy L et al.Evidence of atrial functional mitral regurgitation due to atrial fibrillation: reversal with arrhythmia control.J Am Coll Cardiol. 2011; 58 (doi: 10.1016/j.jacc.2011.06.032.): 1474-1481Google Scholar and has been treated successfully with surgical mitral valve repair.8Takahashi Y Abe Y Sasaki Y et al.Mitral valve repair for atrial functional mitral regurgitation in patients with chronic atrial fibrillation.Interact Cardiovasc Thorac Surg. 2015; 21 (doi: 10.1093/icvts/ivv119.): 163-168Google Scholar For those patients with primary MR in sinus rhythm, a long-term study on medical therapy demonstrated that the risk of developing AF was high, 18 ± 3% at 5 years and 48 ± 6% at 10 years. Development of AF was associated with a high risk of cardiac death or heart failure (adjusted risk ratio 2.23, p = 0.025).9Grigioni F Avierinos J-F Ling LH et al.Atrial fibrillation complicating the course of degenerative mitral regurgitation.J Am Coll Cardiol. 2002; 40: 84-92Google Scholar As a result, new onset of AF is included as a IIa indication for surgical intervention of asymptomatic primary MR.10Nishimura RA Otto CM Bonow RO et al.2014 AHA/ACC guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association task force on practice guidelines.J Am Coll Cardiol. 2014; 63 (doi: 10.1016/j.jacc.2014.02.537.): 2438-2488Google Scholar Surgical studies of mainly primary MR have documented a prevalence of pre-operative AF in 50% of patients. Patients with AF and MR were older with more left atrial dilatation than those in sinus rhythm.12Lim E Barlow CW Hosseinpour AR et al.Influence of atrial fibrillation on outcome following mitral valve repair.Circulation. 2001; 104: I59-I63Google Scholar Although there were no early differences in mortality, the presence of AF was associated with higher mortality at 3 and 5 years with a strong interaction between poor left ventricular function and mortality.12Lim E Barlow CW Hosseinpour AR et al.Influence of atrial fibrillation on outcome following mitral valve repair.Circulation. 2001; 104: I59-I63Google Scholar AF frequently coexists in patients with heart failure, with an estimated prevalence of 13–27%.13Anter E Jessup M Callans DJ Atrial fibrillation and heart failure: treatment considerations for a dual epidemic.Circulation. 2009; 119 (doi: 10.1161/CIRCULATIONAHA.108.821306.): 2516-2525Google Scholar The prevalence of AF in patients with secondary MR is less well documented. In a registry of Japanese patients with heart failure and secondary MR, 40% had documented AF.14Kaneko H Suzuki S Uejima T et al.Prevalence and the long-term prognosis of functional mitral regurgitation in Japanese patients with symptomatic heart failure.Heart Vessels. 2013; 29 (doi: 10.1007/s00380-013-0448-5.): 801-807Google Scholar For those patients with secondary MR and an indication for resynchronization therapy for heart failure, AF has been implicated as a cause of non-response to therapy.15van der Bijl P, Vo NM, Leung M, et al. Impact of atrial fibrillation on improvement of functional mitral regurgitation in cardiac resynchronization therapy. Heart Rhythm. 2018. doi:10.1016/j.hrthm.2018.07.012.Google Scholar Is atrial fibrillation a risk factor for increased mortality in the setting of MR or just a marker for a worse prognosis? To date there have been no randomized trials of restoring sinus rhythm in patients with MR however the surgical literature does provide insight with the results of surgical maze at the time of mitral valve surgery. For those patients with mechanical mitral valve replacement requiring systemic anticoagulation, concomitant maze was compared to valve replacement alone in a retrospective study of over 500 patients. Freedom from AF was higher in those treated with the maze procedure, 80% versus 20% (p < 0.001) compared to valve replacement only. At 5-year follow-up however, there was no difference in adjusted all-cause mortality or readmission for heart failure in those with maze procedure compared to those without.16Bum Kim J Suk Moon J Yun SC et al.Long-term outcomes of mechanical valve replacement in patients with atrial fibrillation: impact of the maze procedure.Circulation. 2012; 125 (doi: 10.1161/CIRCULATIONAHA.111.082347.): 2071-2080Google Scholar Data are more encouraging with radiofrequency catheter ablation of AF in heart failure. In the randomized CASTLE-AF trial, patients with heart failure, LV ejection fraction less than 35%, and predominantly persistent AF were assigned to radiofrequency AF ablation or medical therapy. After a median follow-up of 3 years, AF ablation was associated with lower all-cause mortality, HR 0.53; 95% CI, 0.32–0.86; p = 0.01 and reduced hospitalizations for heart failure HR 0.56; 95% CI, 0.37–0.83; p = 0.004.16Bum Kim J Suk Moon J Yun SC et al.Long-term outcomes of mechanical valve replacement in patients with atrial fibrillation: impact of the maze procedure.Circulation. 2012; 125 (doi: 10.1161/CIRCULATIONAHA.111.082347.): 2071-2080Google Scholar At 5-year follow-up, 63.1% of the patients in the ablation group and 21.7% in the medical-therapy group (p < 0.001) were in sinus rhythm. It is important to note that only one-third of patients had an AF duration greater than 1 year, and no mention was made of the presence of MR. Atrial fibrillation is clearly associated with increased mortality in patients with MR despite surgical valvular intervention and Megaly et al. have presented observational data suggesting a similar relationship following MitraClip. In the absence of data confirming causality, the presence of AF may be an “early warning sign” of worse outcomes and should potentially prompt earlier transcatheter intervention. As for interventions to restore sinus rhythm in this population, the jury is still out.… A. W. Asgar is a consultant for Abbott Vascular, Medtronic and Edwards LifeSciences.

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