Heart Failure in Atrial Fibrillation　― An Update on Clinical and Echocardiographic Implications ―

Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia in adults and has unfavorable consequences such as stroke, heart failure (HF), and death. HF is the most common adverse event following AF and the leading cause of death. Therefore, identifying the association between AF and HF is important to establish risk stratification for HF in AF. Recent studies suggested that left atrial and ventricular fibrosis is an important link between AF and HF, and the prognostic impact may differ with respect to HF subtype, stratified with left ventricular ejection fraction (EF). Mortality risk in patients with concurrent AF and HF with reduced EF (HFrEF) appears slightly higher compared with those with concurrent AF and HF with preserved EF (HFpEF). On the other hand, the prognostic impact of HF in AF is similar between HFrEF and HFpEF. Further, left atrial size, as well as left atrial and left ventricular functional assessment, are reported to be useful for the prediction of HF in AF, incremental to the conventional risk factors. In this review, we focus on the epidemiological, pathophysiological, and prognostic associations between AF and HF, and review the clinical and echocardiographic predictors for HF in AF.

Atrial fibrillation (AF) is the most common sustained arrhythmia in adults and is a global epidemic affecting over 30 million individuals worldwide.¹ The incidence of AF increases with age,^2,3 and the prevalence of AF is expected to increase with the aging of populations.^4–8 AF often causes unfavorable consequences, such as stroke, heart failure (HF), and death.^3,9,10 Together with therapeutic advances, including oral anticoagulant agents, the reported incidence of stroke has been decreasing in AF patients;¹¹ however, the incidence and prevalence of HF and death have not improved for decades.^12–16 Further, HF subsequent to AF significantly relates to worse clinical outcomes in terms of morbidity and mortality.^12,17,18 Therefore, it is essential to identify the association between AF and HF to improve the risk stratification of AF patients, which may lead to better clinical outcomes. Recently, it was reported that echocardiographic evaluation is useful for the prediction of future HF events in patients with AF, incremental to conventional clinical risk factors.^19,20 In this review, we focus on the epidemiological, pathophysiological, and prognostic association between AF and HF, and review the clinical and echocardiographic predictors for HF in AF patients.

Epidemiology of HF and AF

AF and HF frequently coexist, and each condition promotes the other. Among patients with AF, the incident risk of HF is 2- to 5-fold higher than among those without AF.^21–24 A recent study has reported that more than one-third of the patients with new AF had HF, and more than half with new HF had AF.²⁵ In Japan, the incidence rate of HF after the diagnosis of AF has been reported to be approximately 1.5–2% per year.^26,27 The cumulative incidence rate of HF in AF is reported as 20% at 5 years, which is higher than the risk of stroke.¹² Of note, the incident risk of HF appears higher in the early phase after AF diagnosis.^12,22,27

Regarding HF subtype, stratified by left ventricular ejection fraction (LVEF), HF with preserved EF (HFpEF) is more prevalent in AF patients than HF with reduced EF (HFrEF).^28,29 Similarly, AF is more likely to occur in patients with HFpEF than in those with HFrEF.^17,25,30 According to recent data from the Swedish Heart Failure Registry, the prevalence of AF was 65%, 60%, and 53% in HFpEF (EF ≥50%), HF with mid-range EF (HFmrEF: EF 40–49%), and HFrEF (EF <40%), respectively.¹⁷

Prognostic Association Between AF and HF

Patients with concurrent HF and AF have a significantly worse prognosis compared with those with only 1 of the 2 conditions.^{17,18,25,28,31,32} The Framingham Heart Study demonstrated that subsequent HF in AF is associated with an increased risk of death with a hazard ratio (HR) of 2.7 in men and 3.1 in women.¹⁸ Similarly, another study demonstrated that subsequent HF in AF is associated with a 3.4-fold higher risk of death compared with no evidence of HF.¹² Furthermore, cardiovascular death, including HF, was reported as the leading cause of death among AF patients in some recent studies.^10,33–35 Data from a meta-analysis including 71,683 patients showed that cardiovascular death accounted for 46% of all-cause deaths in AF patients, whereas stroke accounted for only 5.7% of all deaths.³³ In the recent prospective substudy of the Effective Anticoagulation with Factor Xa Next Generation in AF-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48), which included 971 patients with a CHADS₂ score ≥2 demonstrated that hospitalization for HF was more common than for thromboembolic events (9.6% vs. 4.9%), and cardiovascular death was the most common cause of death (71.9%) in AF patients.³⁵

Notably, the impact of AF and HF on death may differ according to their temporal association. In a recent study investigating patients with AF or HF, the subsequent development of the other was associated with increased risk of death, and, also, preexisting HF negatively affected survival in patients with AF; however, preexisting AF did not have an impact on survival in patients with HF.¹⁸ Similarly, other studies have identified that the prognostic impact of AF in HF appears stronger for new-onset AF compared with concurrent or preexisting AF^13,25 (Figure A). A study in Olmsted County including 3,292 patients demonstrated that patients who developed AF after HF exhibited >2-fold increased risk of death, whereas those with AF prior to HF had a 29% increased risk of death.¹³

Figure.

Prognostic association between atrial fibrillation (AF) and heart failure (HF). (A) Prognostic impact is higher in new-onset AF compared with concurrent or preexisting AF. (B) Mortality risk is higher in patients with concurrent AF and HF with reduced ejection fraction (HFrEF) compared with concurrent AF and HF with preserved ejection fraction (HFpEF) or similar between these two. (C) In patients with AF, the prognostic impact is similar between new HFpEF and new HFrEF. (D) In patients with HF, the prognostic impact of AF is higher in patients with HFpEF compared with HFrEF, and similar between these 2 HF subtypes.

Differences in Prognostic Significance Between HF Subtypes

Recent studies have investigated the difference in prognostic significance based on HF subtype. There is compelling evidence of which HF subtype is the major driver for death. A study that investigated Framingham Heart Study participants between 1980 and 2012 identified a higher mortality rate in patients with concurrent AF and HFrEF than in those with concurrent AF and HFpEF²⁵ (Figure B). Similarly, in a systematic review of AF and HF, patients with concurrent AF and HFrEF had a higher mortality risk than patients with concurrent AF and HFpEF³⁶ (Figure B). However, analyses of patients with AF demonstrated that new-onset HFpEF and HFrEF appeared to have similar adverse associations with death²⁵ (Figure C). On the other hand, a meta-analysis of 152,306 HF patients reported that the increment risk of AF for death in HF was significantly higher in HFpEF compared with HFrEF (HR: 1.21 vs. 1.09)³¹ (Figure D). In the Swedish Heat Failure Registry, AF was associated with a similar increased risk of death in HFpEF, HFmrEF, and HFrEF, with HRs of 1.11, 1.22, and 1.17, respectively.¹⁷ More recently, interesting results have been shown in a study using the registry of the European Society of Cardiology. In that study, the prognostic impact of AF for combined of all-cause death or HF hospitalization was significant in patients with HFpEF (HR: 1.365, P<0.001) and HFmrEF (HR: 1.302, P=0.014), but not in patients with HFrEF (P=0.502) (Figure D); however, the survival or event-free survival rate was similar in patients with concurrent AF and HFpEF and those with concurrent AF and HFrEF, or slightly worse in those with concurrent AF and HFrEF³² (Figure B). It is assumed that the hemodynamic consequences of AF in HFpEF may be more significant because it is associated with increased myocardial wall stress compared with HFrEF. Further studies are warranted to clarify the temporal interaction between AF and HF with regard to HF subtype.

Underlying Pathophysiology of AF and HF

HF and AF share common risk factors such as age, hypertension, chronic obstructive pulmonary disease, overweight, and diabetes.^18,28,37,38 Although the underlying mechanism is rather complicated, left atrial (LA) structural, electrical, and neurohormonal remodeling is reported to be associated with AF development.^39,40 Recent studies consider LA fibrotic changes as a hallmark of LA structural remodeling.⁴¹ Indeed, the presence and severity of diastolic dysfunction are predictive of incident AF.⁴² Further, LA fibrosis is likely caused by LV diastolic dysfunction, LV myocardial stiffness, and elevated LV filling pressure, which are important substrates for the development of HF.^42–45 Therefore, myocardial fibrosis may represent a potential link between AF and HF. It is easy to speculate that in patients with significant diastolic dysfunction, who depend largely on the atrial contribution to ventricular filling, the loss of atrial function may diminish cardiac output leading to HF. Nakatani et al reported that 55% of patients with AF and preserved LVEF have reduced stroke volume index (<33 mL/m²), and persistent AF patients, who may have worse diastolic function, have a greater increment in the stroke volume index after ablation therapy than do paroxysmal AF patients.⁴⁶ However, no data are available comparing prognostic significance in patients with AF and HFpEF on outcomes with or without ablation therapy.

In patients with HFrEF, the AF burden is suggested to be different from that of HFpEF patients. It has been indicated that AF promotes LA and LV fibrosis, and may lead to perpetuation of AF and worsening of HF.^36,41 In fact, LV fibrotic change is more pronounced in patients with persistent AF compared with those with paroxysmal AF or sinus rhythm.⁴⁷ Furthermore, it has been demonstrated that long-standing AF, which may partly include patients with AF-mediated cardiomyopathy, is related to lower LVEF.⁴⁸ Indeed, among patients with AF and HFrEF, there is a significant number of cases of LVEF improvement after recovery of sinus rhythm by ablation therapy. The CASTLE-AF trial, which investigated patients with AF and EF ≤35% who underwent ablation therapy, demonstrated a 40% reduction in the risk of HF hospitalization and death after ablation therapy.⁴⁹

Clinical Risk Factors for HF Development in AF

In previous studies, conventional risk factors for HF in the general population such as advancing age, LV hypertrophy, obesity, hypertension, diabetes, structural heart disease, and history of myocardial infarction have been shown as significant predictors for HF development in patients with AF.^26,50,51 A prospective study in Japan²⁷ including 1,942 AF patients demonstrated that organic heart disease, anemia, renal dysfunction, and diabetes mellitus were independently associated with incident HF. Additionally, it was demonstrated that a new scoring system, the H₂ ARDD score (organic heart disease: 2 points, anemia: 1 point, renal dysfunction: 1 point, diabetes: 1 point, and diuretic use: 1 point; range: 0–6 points) stratified patients’ risk for HF development (HF incidence of patients scoring 0 points: 0.2%, vs. 6 points: 40.8%), with a high predictive ability (area under the curve=0.840).²⁷ However, this score has yet to be externally validated.

Although data regarding the relationship of the type of AF to the incidence of HF remain scarce, it is common that persistent AF is more predictive of incident HF compared with paroxysmal AF. The AF population study in the Outcome Registry for Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry demonstrated that permanent AF, which was compared with paroxysmal AF, and elevated baseline heart rate were risks for incident HF, independent of conventional risk factors.²⁸ In a Japanese community-based prospective survey, the Fushimi AF Registry, sustained AF was associated with a higher incidence of the composite outcome of cardiac death and HF hospitalization compared with paroxysmal AF. Interestingly, this association was only observed in the younger AF population (age ≤74 years), and not in the older group.⁵² In the HFpEF population-based study, it was also demonstrated that persistent AF is independently associated with worse HF hospitalization-free survival, but not paroxysmal AF.⁵¹

Echocardiographic Prediction of HF Development in AF

In patients with AF, echocardiography plays a central role in screening, management, and follow-up. In addition, echocardiographic evaluation is useful for the prediction of future HF events in patients with AF, incremental to conventional clinical risk factors.^19,20 However, it is generally challenging to determine the representative heart beat for measurement of echocardiographic parameters in such patients because of the irregular heart rhythm. A guideline of the American Society of Echocardiography recommends that measurements obtained from a minimum of 5 consecutive cardiac cycles should be averaged in patients with AF.⁵³ Also, previous studies have demonstrated an index beat that has similar R-R intervals in the preceding and pre-preceding heart beats is an accurate and easy to perform echocardiographic assessment in patients with AF.^54–56

During ventricular diastole, the LA is directly exposed to LV pressure through the open mitral valve. Therefore, in patients with sinus rhythm, and without mitral valve disease or left-to-right shunts, LA size has been demonstrated as a marker of elevated LV filling pressure and the severity of LV diastolic dysfunction,^57–59 and is a well-known predictor of HF development.^60,61 However, in a previous study by Tsang et al, indexed LA volume was not a significant predictor of future cardiovascular events in AF patients, despite it being a strong predictor in sinus rhythm.⁶⁰ On the other hand, recent studies have shown conflicting results.^19,20 Potpara et al demonstrated that LA dimensions and low-normal LVEF (50–54%) were significant predictors for incident HF in patients with first-diagnosed AF and a structurally normal heart.²⁰ In our recent study, which investigated a larger cohort of AF patients with a longer mean follow-up period, indexed LA volume was a significant predictor for HF development, independent of age, LVEF, and LV mass.¹⁹ In this study, the estimated 8-year HF event-free survival rates of each group stratified by indexed LA volume (<40 mL/m², 40–60 mL/m², >60 mL/m²) were 87%, 80%, 67%, respectively.¹⁹ Although the process of LA enlargement in AF may be more complicated than in sinus rhythm, because the LA in the AF population is commonly enlarged,^62,63 and AF itself causes LA remodeling, the degree of LA enlargement may represent a susceptibility to HF development. LA size has been used as a common echocardiographic parameter and may be useful for risk stratification, but the appropriate cutoff value and clinical utility of LA volume has not been validated in AF patients, and further studies are needed.

It is suggested that LA dysfunction or LA fibrosis antedate LA enlargement,^64,65 and the prognostic utility of LA function has also been investigated.^35,40,66 In a substudy of the ENGAGE AF-TIMI 48 study,³⁵ LA dysfunction assessed by LA emptying fraction [100*(LA maximal volume−LA minimal volume)/LA maximal volume] and LA expansion index [(LA maximal volume−LA minimal volume)/LA minimal volume] were significantly associated with an increased risk for cardiovascular death, HF hospitalization, or both, with an intraobserver intraclass correlation coefficient of 0.95 (range: 0.91–0.99) and an interobserver intraclass correlation coefficient of 0.84 (range: 0.75–0.93). In that study, LA functional impairment was demonstrated as more predictive of these outcomes than LA size.³⁵ The usefulness of other myocardial functional assessments beyond LVEF to predict cardiovascular outcomes in AF patients has been also investigated, and the results are summarized in the Table. A cohort study of 190 persistent AF patients reported that a combination index using transmitral flow E and LA strain (E/LA strain) was a predictor of cardiovascular events including cardiovascular death, HF hospitalization, myocardial infarction, and stroke although they did not demonstrate intra- and interobserver reliability of E/LA strain.⁶⁶ Su et al also demonstrated that worsening global LV longitudinal strain was independently associated with an increased risk of cardiovascular events in AF, with intra- and interobserver mean percent errors for measurement of 5.3±3.5% and 6.2±3.8%, respectively. Of note, global LV longitudinal strain was still a significant predictor in the subgroup of patients with preserved EF.⁶⁷

Table. Studies Reporting Echocardiographic Predictors for HF Development in Patients With AF

Author	Year	Subjects	No. of patients	Follow-up period (years)	Outcome	Significant predictors
Potpara et al20	2013	Non-valvular AF with structurally normal heart (excluded: patients with a history of HF)	842	11.2±5.9	Incidence of HF	· History of hypertension · History of diabetes mellitus · LAD >40 mm · Low-normal EF (50–54%)
Su et al67	2013	Non-valvular AF lasting at least 7 days	196	1.7±0.8	CV events (CV death, stroke, HF)	· Age · eGFR · Indexed LV mass · E/E’ · LV GLS
Chu et al68	2015	Non-valvular AF lasting at least 7 days	196	1.5±0.7	CV events (CV death, stroke, HF)	· History of HF · E/E’ · Myocardial performance index
Hsu et al66	2016	Non-valvular AF lasting at least 7 days	190	2.4	CV events (CV death, MI, stroke, HF)	· Age · History of HF · Indexed LV mass · E/LA strain
Yang et al69	2018	Non-valvular AF lasting more than 1 year (excluded: patients with NYHA class III or IV)	252	1.7±1.1	HF exacerbation	· Indexed LV mass · E · E/E’
Hsu et al70	2018	Non-valvular AF (excluded: patients without tricuspid regurgitation)	155	2.3	CV events (CV death, stroke, HF)	· Age · LVEF · E/E’ · TRPG
Taniguchi et al19	2019	Non-valvular AF with preserved LVEF (LVEF ≥40%)	422	4.6±3.6	New-onset HF	· Age · LVEF · Indexed LV mass · Indexed LA volume
Inciardi et al35	2019	Non-valvular AF with CHADS2 score ≥2	971	2.5 (median)	CV events (CV death, HF)	· LA emptying fraction · LA expansion index

AF, atrial fibrillation; CV, cardiovascular; EF, ejection fraction; eGFR, estimated glomerular filtration rate; GLS, global longitudinal strain; HF, heart failure; LA, left atrial; LAD, left atrial dimension; LV, left ventricular; MI, myocardial infarction; NYHA, New York Heart Association; TRPG, tricuspid regurgitation pressure gradient.

From this viewpoint, LA size or LA function, as well as LV function, may add significant incremental prognostic value for HF events beyond the conventional clinical and LV parameters. However, the clinical utility of these parameters has not been well validated, and there are limited data available about which parameter is appropriate for risk assessment in AF patients. Therefore, larger-scale studies, which investigate and compare these parameters, as well as taking HF subtype into consideration, are needed to establish risk stratification of patients with AF.

Conclusions

In patients with AF, HF is the most common adverse consequence, with a significantly worse prognosis. LV and LA fibrotic change is demonstrated as an important link between AF and HF, and clinical and echocardiographic risk assessment for HF is of particular interest in AF. Further studies are needed for the characterization of these prognostic factors with respect to the temporal relationship of AF and HF, as well as HF subtype, and may lead to improve AF management strategies and prognostic outcomes.

Disclosure

The authors have no conflicts of interest to disclose.

References

• 1.   Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: A Global Burden of Disease 2010 Study. Circulation 2014; 129: 837–847.
• 2.   Schnabel RB, Yin X, Gona P, Larson MG, Beiser AS, McManus DD, et al. 50 year trends in atrial fibrillation prevalence, incidence, risk factors, and mortality in the Framingham Heart Study: A cohort study. Lancet 2015; 386: 154–162.
• 3.   Magnussen C, Niiranen TJ, Ojeda FM, Gianfagna F, Blankenberg S, Njolstad I, et al. Sex differences and similarities in atrial fibrillation epidemiology, risk factors, and mortality in community cohorts: Results From the BiomarCaRE Consortium (Biomarker for Cardiovascular Risk Assessment in Europe). Circulation 2017; 136: 1588–1597.
• 4.   Guo Y, Tian Y, Wang H, Si Q, Wang Y, Lip GYH. Prevalence, incidence, and lifetime risk of atrial fibrillation in China: New insights into the global burden of atrial fibrillation. Chest 2015; 147: 109–119.
• 5.   Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol 2013; 112: 1142–1147.
• 6.   Lane DA, Skjoth F, Lip GYH, Larsen TB, Kotecha D. Temporal trends in incidence, prevalence, and mortality of atrial fibrillation in primary care. J Am Heart Assoc 2017; 6: e005155.
• 7.   Patel NJ, Deshmukh A, Pant S, Singh V, Patel N, Arora S, et al. Contemporary trends of hospitalization for atrial fibrillation in the United States, 2000 through 2010: Implications for healthcare planning. Circulation 2014; 129: 2371–2379.
• 8.   Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006; 114: 119–125.
• 9.   Piccini JP, Hammill BG, Sinner MF, Hernandez AF, Walkey AJ, Benjamin EJ, et al. Clinical course of atrial fibrillation in older adults: The importance of cardiovascular events beyond stroke. Eur Heart J 2014; 35: 250–256.
• 10.   Bassand JP, Accetta G, Camm AJ, Cools F, Fitzmaurice DA, Fox KA, et al. Two-year outcomes of patients with newly diagnosed atrial fibrillation: Results from GARFIELD-AF. Eur Heart J 2016; 37: 2882–2889.
• 11.   Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Seward JB, Bailey KR, et al. Time trends of ischemic stroke incidence and mortality in patients diagnosed with first atrial fibrillation in 1980 to 2000: Report of a community-based study. Stroke 2005; 36: 2362–2366.
• 12.   Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna W, et al. Incidence and mortality risk of congestive heart failure in atrial fibrillation patients: A community-based study over two decades. Eur Heart J 2006; 27: 936–941.
• 13.   Chamberlain AM, Redfield MM, Alonso A, Weston SA, Roger VL. Atrial fibrillation and mortality in heart failure: A community study. Circ Heart Fail 2011; 4: 740–746.
• 14.   Miyasaka Y, Barnes ME, Bailey KR, Cha SS, Gersh BJ, Seward JB, et al. Mortality trends in patients diagnosed with first atrial fibrillation: A 21-year community-based study. J Am Coll Cardiol 2007; 49: 986–992.
• 15.   Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC, et al. Forecasting the impact of heart failure in the United States: A policy statement from the American Heart Association. Circ Heart Fail 2013; 6: 606–619.
• 16.   Chamberlain AM, Gersh BJ, Alonso A, Chen LY, Berardi C, Manemann SM, et al. Decade-long trends in atrial fibrillation incidence and survival: A community study. Am J Med 2015; 128: 260–267.
• 17.   Sartipy U, Dahlstrom U, Fu M, Lund LH. Atrial fibrillation in heart failure with preserved, mid-range, and reduced ejection fraction. JACC Heart Fail 2017; 5: 565–574.
• 18.   Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: The Framingham Heart Study. Circulation 2003; 107: 2920–2925.
• 19.   Taniguchi N, Miyasaka Y, Suwa Y, Harada S, Nakai E, Kawazoe K, et al. Usefulness of left atrial volume as an independent predictor of development of heart failure in patients with atrial fibrillation. Am J Cardiol 2019; 124: 1430–1435.
• 20.   Potpara TS, Polovina MM, Licina MM, Marinkovic JM, Lip GY. Predictors and prognostic implications of incident heart failure following the first diagnosis of atrial fibrillation in patients with structurally normal hearts: The Belgrade Atrial Fibrillation Study. Eur J Heart Fail 2013; 15: 415–424.
• 21.   Ruddox V, Sandven I, Munkhaugen J, Skattebu J, Edvardsen T, Otterstad JE. Atrial fibrillation and the risk for myocardial infarction, all-cause mortality and heart failure: A systematic review and meta-analysis. Eur J Prev Cardiol 2017; 24: 1555–1566.
• 22.   Aleong RG, Sauer WH, Davis G, Bristow MR. New-onset atrial fibrillation predicts heart failure progression. Am J Med 2014; 127: 963–971.
• 23.   Vermond RA, Geelhoed B, Verweij N, Tieleman RG, Van der Harst P, Hillege HL, et al. Incidence of atrial fibrillation and relationship with cardiovascular events, heart failure, and mortality: A community-based study from the Netherlands. J Am Coll Cardiol 2015; 66: 1000–1007.
• 24.   Odutayo A, Wong CX, Hsiao AJ, Hopewell S, Altman DG, Emdin CA. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: Systematic review and meta-analysis. BMJ (Clin Res edn) 2016; 354: i4482.
• 25.   Santhanakrishnan R, Wang N, Larson MG, Magnani JW, McManus DD, Lubitz SA, et al. Atrial fibrillation begets heart failure and vice versa: Temporal associations and differences in preserved versus reduced ejection fraction. Circulation 2016; 133: 484–492.
• 26.   Fukuda T, Yamashita T, Sagara K, Kato T, Sawada H, Aizawa T. Development of congestive heart failure in Japanese patients with atrial fibrillation. Circ J 2007; 71: 308–312.
• 27.   Suzuki S, Sagara K, Otsuka T, Matsuno S, Funada R, Uejima T, et al. A new scoring system for evaluating the risk of heart failure events in Japanese patients with atrial fibrillation. Am J Cardiol 2012; 110: 678–682.
• 28.   Pandey A, Kim S, Moore C, Thomas L, Gersh B, Allen LA, et al. Predictors and prognostic implications of incident heart failure in patients with prevalent atrial fibrillation. JACC Heart Fail 2017; 5: 44–52.
• 29.   Azadani PN, King JB, Kheirkhahan M, Chang L, Marrouche NF, Wilson BD. Left atrial fibrosis is associated with new-onset heart failure in patients with atrial fibrillation. Int J Cardiol 2017; 248: 161–165.
• 30.   Siontis KC, Yao X, Noseworthy PA. Atrial fibrillation in heart failure syndromes: Does it matter more in some than in others? Eur Heart J 2018; 39: 4285–4286.
• 31.   Cheng M, Lu X, Huang J, Zhang J, Zhang S, Gu D. The prognostic significance of atrial fibrillation in heart failure with a preserved and reduced left ventricular function: Insights from a meta-analysis. Eur J Heart Fail 2014; 16: 1317–1322.
• 32.   Zafrir B, Lund LH, Laroche C, Ruschitzka F, Crespo-Leiro MG, Coats AJS, et al. Prognostic implications of atrial fibrillation in heart failure with reduced, mid-range, and preserved ejection fraction: A report from 14 964 patients in the European Society of Cardiology Heart Failure Long-Term Registry. Eur Heart J 2018; 39: 4277–4284.
• 33.   Gomez-Outes A, Lagunar-Ruiz J, Terleira-Fernandez AI, Calvo-Rojas G, Suarez-Gea ML, Vargas-Castrillon E. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol 2016; 68: 2508–2521.
• 34.   Fauchier L, Villejoubert O, Clementy N, Bernard A, Pierre B, Angoulvant D, et al. Causes of death and influencing factors in patients with atrial fibrillation. Am J Med 2016; 129: 1278–1287.
• 35.   Inciardi RM, Giugliano RP, Claggett B, Gupta DK, Chandra A, Ruff CT, et al. Left atrial structure and function and the risk of death or heart failure in atrial fibrillation. Eur J Heart Fail 2019; 21: 1571–1579.
• 36.   Kotecha D, Chudasama R, Lane DA, Kirchhof P, Lip GY. Atrial fibrillation and heart failure due to reduced versus preserved ejection fraction: A systematic review and meta-analysis of death and adverse outcomes. Int J Cardiol 2016; 203: 660–666.
• 37.   Anter E, Jessup M, Callans DJ. Atrial fibrillation and heart failure: Treatment considerations for a dual epidemic. Circulation 2009; 119: 2516–2525.
• 38.   Hirsh BJ, Copeland-Halperin RS, Halperin JL. Fibrotic atrial cardiomyopathy, atrial fibrillation, and thromboembolism: Mechanistic links and clinical inferences. J Am Coll Cardiol 2015; 65: 2239–2251.
• 39.   Casaclang-Verzosa G, Gersh BJ, Tsang TS. Structural and functional remodeling of the left atrium: Clinical and therapeutic implications for atrial fibrillation. J Am Coll Cardiol 2008; 51: 1–11.
• 40.   Miyasaka Y. Can we predict the outcome of catheter ablation for atrial fibrillation? Circ J 2013; 77: 1681–1683.
• 41.   Dzeshka MS, Lip GY, Snezhitskiy V, Shantsila E. Cardiac fibrosis in patients with atrial fibrillation: Mechanisms and clinical implications. J Am Coll Cardiol 2015; 66: 943–959.
• 42.   Tsang TSM, Gersh BJ, Appleton CP, Tajik AJ, Barnes ME, Bailey KR, et al. Left ventricular diastolic dysfunction as a predictor of the first diagnosed nonvalvular atrial fibrillation in 840 elderly men and women. J Am Coll Cardiol 2002; 40: 1636–1644.
• 43.   Melenovsky V, Hwang SJ, Redfield MM, Zakeri R, Lin G, Borlaug BA. Left atrial remodeling and function in advanced heart failure with preserved or reduced ejection fraction. Circ Heart Fail 2015; 8: 295–303.
• 44.   Corradi D. Atrial fibrillation from the pathologist’s perspective. Cardiovasc Pathol 2014; 23: 71–84.
• 45.   Zotter-Tufaro C, Mascherbauer J, Duca F, Koell B, Aschauer S, Kammerlander AA, et al. Prognostic significance and determinants of the 6-min walk test in patients with heart failure and preserved ejection fraction. JACC Heart Fail 2015; 3: 459–466.
• 46.   Nakatani Y, Sakamoto T, Yamaguchi Y, Tsujino Y, Kataoka N, Nishida K, et al. Improvement of hemodynamic parameters in patients with preserved left ventricular systolic function by catheter ablation of atrial fibrillation: A prospective study using impedance cardiography. Circ J 2018; 83: 75–83.
• 47.   Ling LH, Kistler PM, Ellims AH, Iles LM, Lee G, Hughes GL, et al. Diffuse ventricular fibrosis in atrial fibrillation: Noninvasive evaluation and relationships with aging and systolic dysfunction. J Am Coll Cardiol 2012; 60: 2402–2408.
• 48.   Qin D, Mansour MC, Ruskin JN, Heist EK. Atrial fibrillation-mediated cardiomyopathy. Circ Arrhythm Electrophysiol 2019; 12: e007809.
• 49.   Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, et al. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018; 378: 417–427.
• 50.   Schnabel RB, Rienstra M, Sullivan LM, Sun JX, Moser CB, Levy D, et al. Risk assessment for incident heart failure in individuals with atrial fibrillation. Eur J Heart Fail 2013; 15: 843–849.
• 51.   Schonbauer R, Duca F, Kammerlander AA, Aschauer S, Binder C, Zotter-Tufaro C, et al. Persistent atrial fibrillation in heart failure with preserved ejection fraction: Prognostic relevance and association with clinical, imaging and invasive haemodynamic parameters. Eur J Clin Invest 2020; 50: e13184.
• 52.   An Y, Ogawa H, Esato M, Ishii M, Iguchi M, Masunaga N, et al. Age-dependent prognostic impact of paroxysmal versus sustained atrial fibrillation on the incidence of cardiac death and heart failure hospitalization (the Fushimi AF Registry). Am J Cardiol 2019; 124: 1420–1429.
• 53.   Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015; 28: 1–39.e14.
• 54.   Govindan M, Kiotsekoglou A, Saha SK, Borgulya G, Bajpai A, Bijnens BH, et al. Validation of echocardiographic left atrial parameters in atrial fibrillation using the index beat of preceding cardiac cycles of equal duration. J Am Soc Echocardiogr 2011; 24: 1141–1147.
• 55.   Kong LY, Sun LL, Chen LL, Lv X, Liu F. Value of index beat in evaluating left ventricular systolic and diastolic function in patients with atrial fibrillation: A dual pulsed-wave Doppler study. Ultrasound Med Biol 2020; 46: 255–262.
• 56.   Kusunose K, Yamada H, Nishio S, Tomita N, Niki T, Yamaguchi K, et al. Clinical utility of single-beat E/e’ obtained by simultaneous recording of flow and tissue Doppler velocities in atrial fibrillation with preserved systolic function. JACC Cardiovasc Imaging 2009; 2: 1147–1156.
• 57.   Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002; 90: 1284–1289.
• 58.   Jais P, Peng JT, Shah DC, Garrigue S, Hocini M, Yamane T, et al. Left ventricular diastolic dysfunction in patients with so-called lone atrial fibrillation. J Cardiovasc Electrophysiol 2000; 11: 623–625.
• 59.   Leung DY, Boyd A, Ng AA, Chi C, Thomas L. Echocardiographic evaluation of left atrial size and function: Current understanding, pathophysiologic correlates, and prognostic implications. Am Heart J 2008; 156: 1056–1064.
• 60.   Tsang TS, Abhayaratna WP, Barnes ME, Miyasaka Y, Gersh BJ, Bailey KR, et al. Prediction of cardiovascular outcomes with left atrial size: Is volume superior to area or diameter? J Am Coll Cardiol 2006; 47: 1018–1023.
• 61.   Takemoto Y, Barnes ME, Seward JB, Lester SJ, Appleton CA, Gersh BJ, et al. Usefulness of left atrial volume in predicting first congestive heart failure in patients > or = 65 years of age with well-preserved left ventricular systolic function. Am J Cardiol 2005; 96: 832–836.
• 62.   Zakeri R, Borlaug BA, McNulty SE, Mohammed SF, Lewis GD, Semigran MJ, et al. Impact of atrial fibrillation on exercise capacity in heart failure with preserved ejection fraction: A RELAX trial ancillary study. Circ Heart Fail 2014; 7: 123–130.
• 63.   Lam CS, Rienstra M, Tay WT, Liu LC, Hummel YM, van der Meer P, et al. Atrial fibrillation in heart failure with preserved ejection fraction: Association with exercise capacity, left ventricular filling pressures, natriuretic peptides, and left atrial volume. JACC Heart Fail 2017; 5: 92–98.
• 64.   Kojima T, Kawasaki M, Tanaka R, Ono K, Hirose T, Iwama M, et al. Left atrial global and regional function in patients with paroxysmal atrial fibrillation has already been impaired before enlargement of left atrium: Velocity vector imaging echocardiography study. Eur Heart J Cardiovasc Imaging 2012; 13: 227–234.
• 65.   Gupta DK, Shah AM, Giugliano RP, Ruff CT, Antman EM, Grip LT, et al. Left atrial structure and function in atrial fibrillation: ENGAGE AF-TIMI 48. Eur Heart J 2014; 35: 1457–1465.
• 66.   Hsu PC, Lee WH, Chu CY, Lee HH, Lee CS, Yen HW, et al. Prognostic role of left atrial strain and its combination index with transmitral E-wave velocity in patients with atrial fibrillation. Sci Rep 2016; 6: 17318.
• 67.   Su HM, Lin TH, Hsu PC, Lee WH, Chu CY, Lee CS, et al. Global left ventricular longitudinal systolic strain as a major predictor of cardiovascular events in patients with atrial fibrillation. Heart 2013; 99: 1588–1596.
• 68.   Chu CY, Lee WH, Hsu PC, Lee HH, Chiu CA, Su HM, et al. Myocardial performance index derived from pre-ejection period as a novel and useful predictor of cardiovascular events in atrial fibrillation. J Cardiol 2015; 65: 466–473.
• 69.   Yang LT, Tsai WC, Su HM. Echocardiographic parameters versus CHA2DS2-VASc score in prediction of overall cardiac events, heart failure, and stroke in non-valvular atrial fibrillation. Cardiol J 2018; 25: 60–71.
• 70.   Hsu PC, Lee WH, Chu CY, Tsai WC, Lee HH, Lee CS, et al. Tricuspid regurgitation pressure gradient as a useful predictor of adverse cardiovascular events and all-cause mortality in patients with atrial fibrillation. Am J Med Sci 2018; 356: 147–151.