The inconvenient truth of elevated left atrial pressure and AF recurrence despite catheter ablation Saurabh Kumar, BSc(Med)/MBBS, PhD, Gregory F. Michaud, MD, FHRS From the Cardiac Arrhythmia Service, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts. Complex and progressive electrical and structural remodeling of the left atrium (LA) is critical to the formation of substrate for the maintenance and progression of atrial fibrillation (AF).1 Several well-known clinical conditions such as aging, hypertension, and heart failure create atrial substrate for AF.1 Lone AF is also associated with widespread and progressive atrial structural abnormalities,2 a process that is accentuated in persistent lone AF, suggesting a progressive remodeling process in the absence of structural heart disease.3 Atrial wall stretch (with atrial pressure as a surrogate) is an important mediator of atrial remodeling. Stretch-induced AF is mediated by mechanoelectrical feedback with increased gene expression of potassium channels, resulting in both abbreviation and spatial and temporal alternations in atrial action potential duration that is proarrhythmic.4,5 Furthermore, atrial stretch induces heterogeneous remodeling of atrial architecture characterized by cellular hypertrophy and de-differentiation, atrial fibrosis, and gap junction modulation.1,6 These changes promote widespread and site-specific atrial conduction slowing,7 conduction heterogeneity, and anisotropy, as well as creating lines of functional delay that facilitate circuitous wavefront propagation.8 Furthermore, atrial stretch may contribute to AF maintenance by stabilizing high-frequency rotors in the posterior LA and pulmonary veins (PVs).9 Atrial pressure and function is closely and intimately related to left ventricular (LV) systolic and diastolic function. The atrium modulates LV filling through its reservoir, conduit, and booster pump function; in contrast, increased LA pressure may indicate increasing LV filling pressures or impaired LV relaxation. Although the relationship between atrial stretch and AF pathogenesis is well accepted, there is little data on the effect of atrial stretch on ablation outcomes, an area addressed in a contribution by Park et al10 in this issue of HeartRhythm. The authors postulated that increased left atrial pressure Dr Kumar is a recipient of a Neil Hamilton Fairley Overseas Fellowship cofunded by the National Health and Medical Research Council and the National Heart Foundation of Australia and the Bushell Travelling Fellowship funded by the Royal Australasian College of Physicians. Address reprint requests and correspondence: Dr Gregory F. Michaud, Cardiac Arrhythmia Service, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115. E-mail address: [email protected]

1547-5271/$-see front matter B 2014 Heart Rhythm Society. All rights reserved.

(LAP) would be associated with advanced electroanatomic remodeling of the LA and poorer clinical outcomes after radiofrequency catheter ablation (RFCA). Furthermore, noninvasive prediction of elevated LAP may help identify those patients with suboptimal response to RFCA. The large study was composed of 326 patients with paroxysmal AF and 128 with persistent AF undergoing RFCA who underwent (1) invasive LAP assessment (in AF and in sinus rhythm); (2) transthoracic transmitral flow velocity (E wave, A wave), tissue Doppler assessment of peak diastolic velocity (Em), and peak systolic velocity (S0 ) of the mitral septal area; and (3) left PV flow velocity measurements during systole and diastole and LA appendage emptying velocity during transesophageal echocardiography. These were performed in conjunction with electroanatomic characterization of atrial substrate that included (1) a detailed LA voltage map, (2) assessment of atrial conduction velocity, and (3) right atrial and coronary sinus refractory periods before catheter ablation. A median value of 19 mm Hg was used to dichotomize patients into high- or low-peak LAP. As expected, high LAP was associated with an increased likelihood of persistent AF, greater LA volume, greater anterior LA dimensions, and greater LA structural remodeling characterized by lower LA voltage. Patients with high- and low-peak LAP had similar atrial effective refractory periods and, interestingly, similar linear conduction. High LAP was associated with abnormal LV systolic function (lower S0 ), and abnormal indices of both LV filling pressures and diastolic function, namely, higher E/ Em and higher diastolic PV flow velocity. Furthermore, high-peak LAP was associated with abnormal atrial mechanical function measured as lower LA appendage–emptying velocity. Particularly important and unique to this study was the observation that high-peak LAP was independently associated with a higher risk of AF recurrence after catheter ablation. Moreover, indices of abnormal LV filling and diastolic function, namely, PV diastolic flow velocity and E/Em, independently predicted high-peak LAP, suggesting the utility of noninvasive markers for identifying patients with poor response to catheter ablation. The observation of elevated LAP correlating with lower LA voltage and greater LA volume corroborates previous http://dx.doi.org/10.1016/j.hrthm.2014.03.047

962 animal and human data on the effect of atrial stretch on atrial structural remodeling1 but is novel in its application to patients with clinical AF. The lack of difference in atrial conduction velocity is in contrast to previous observations that atrial structural remodeling is often accompanied by widespread and site-specific conduction abnormalities.1 The study further strengthens the interdependence of LA and LV function such that diastolic dysfunction is associated with impaired atrial mechanical function, lower global LA voltage, and higher risk of AF recurrence after catheter ablation of paroxysmal AF.11 Elevated LAP can be added to the “list” of hemodynamic or imaging-derived risk factors that predict unsuccessful response to catheter ablation, such as abnormal global LA strain12 and the extent of LA fibrosis on delayed enhancement magnetic resonance imaging.13 Lack of response to catheter ablation in such patients may indicate the presence of an atrial myopathy that may progress inexorably despite catheter ablation and maintenance of sinus rhythm.14 A number of clear limitations need to be addressed. The dichotomy of high- or low-peak LAP is derived from a median value of 19 mm Hg from all patients in the cohort. The clinical utility of this exact number is unclear and may require validation from larger studies. The population is clearly heterogeneous in type of AF (paroxysmal or persistent) and presence of structural heart disease. Indeed, as acknowledged by the authors, patients with persistent AF constituted a quarter of the total population and the predictive power of LAP was driven more strongly by this subgroup of patients. In fact, when considering the paroxysmal AF cohort only, who represent 72% of the population, the relationship of LAP with AF recurrence was not statistically significant. A larger cohort may have revealed whether the relationship between LAP and AF recurrence is linear or logarithmic. The hazard ratio for AF recurrence was 1.9, with a large confidence interval (1.06–5.3), which, although significant, suggests reserved clinical utility of this marker and/or small sample size of this study. Finally, it is known that permanent PV isolation significantly reduces future atrial arrhythmia occurrence.15 It is possible that partial PV isolation, which is common at the index procedure using the technique described in this article, may be particularly ineffective in patients with high-peak LAP, indicating that better ablation strategies will be required in these patients. In summary, the findings of Park et al confirm our intuition concerning the correlation between high-peak LAP and poor response to catheter ablation for AF, and we hope it will be a clinically useful guide to future ablation approaches. Further studies are needed to contextualize the role of LAP among other markers that predict an unfavorable response to ablation.

Heart Rhythm, Vol 11, No 6, June 2014

References 1. Kumar S, Teh AW, Medi C, Kistler PM, Morton JB, Kalman JM. Atrial remodeling in varying clinical substrates within beating human hearts: relevance to atrial fibrillation. Prog Biophys Mol Biol 2012;110:278–294. 2. Stiles MK, John B, Wong CX, Kuklik P, Brooks AG, Lau DH, Dimitri H, Roberts-Thomson KC, Wilson L, De Sciscio P, Young GD, Sanders P. Paroxysmal lone atrial fibrillation is associated with an abnormal atrial substrate: characterizing the “second factor.” J Am Coll Cardiol 2009;53:1182–1191. 3. Teh AW, Kistler PM, Lee G, Medi C, Heck PM, Spence SJ, Sparks PB, Morton JB, Kalman JM. Electroanatomic remodeling of the left atrium in paroxysmal and persistent atrial fibrillation patients without structural heart disease. J Cardiovasc Electrophysiol 2012;23:232–238. 4. Saygili E, Rana OR, Saygili E, Reuter H, Frank K, Schwinger RH, MullerEhmsen J, Zobel C. Losartan prevents stretch-induced electrical remodeling in cultured atrial neonatal myocytes. Am J Physiol Heart Circ Physiol 2007;292: H2898–H2905. 5. Tsai CT, Chiang FT, Tseng CD, Yu CC, Wang YC, Lai LP, Hwang JJ, Lin JL. Mechanical stretch of atrial myocyte monolayer decreases sarcoplasmic reticulum calcium adenosine triphosphatase expression and increases susceptibility to repolarization alternans. J Am Coll Cardiol 2011;58:2106–2115. 6. De Jong AM, Maass AH, Oberdorf-Maass SU, Van Veldhuisen DJ, Van Gilst WH, Van Gelder IC. Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation. Cardiovasc Res 2011;89: 754–765. 7. John B, Stiles MK, Kuklik P, Brooks AG, Chandy ST, Kalman JM, Sanders P. Reverse remodeling of the atria after treatment of chronic stretch in humans: implications for the atrial fibrillation substrate. J Am Coll Cardiol 2010;55: 1217–1226. 8. Roberts-Thomson KC, Stevenson I, Kistler PM, Haqqani HM, Spence SJ, Goldblatt JC, Sanders P, Kalman JM. The role of chronic atrial stretch and atrial fibrillation on posterior left atrial wall conduction. Heart Rhythm 2009;6: 1109–1117. 9. Yamazaki M, Mironov S, Taravant C, Brec J, Vaquero LM, Bandaru K, Avula UM, Honjo H, Kodama I, Berenfeld O, Kalifa J. Heterogeneous atrial wall thickness and stretch promote scroll waves anchoring during atrial fibrillation. Cardiovasc Res 2012;94:48–57. 10. Park J, Joung B, Uhm JS, Shim CY, Hwang C, Lee MH, Pak HN. High left atrial pressures are associated with advanced electroanatomical remodeling of left atrium and independent predictors for clinical recurrence of atrial fibrillation after catheter ablation. Heart Rhythm 2014;11:953–960. 11. Hu YF, Hsu TL, Yu WC, Huang SH, Tsao HM, Tai CT, Lin YJ, Chang SL, Lo LW, Tuan TC, Chang CJ, Tsai WC. The impact of diastolic dysfunction on the atrial substrate properties and outcome of catheter ablation in patients with paroxysmal atrial fibrillation. Circ J 2010;74:2074–2078. 12. Hammerstingl C, Schwekendiek M, Momcilovic D, Schueler R, Sinning JM, Schrickel JW, Mittmann-Braun E, Nickenig G, Lickfett L. Left atrial deformation imaging with ultrasound based two-dimensional speckle-tracking predicts the rate of recurrence of paroxysmal and persistent atrial fibrillation after successful ablation procedures. J Cardiovasc Electrophysiol 2012;23:247–255. 13. Marrouche NF, Wilber D, Hindricks G, Jais P, Akoum N, Marchlinski F, Kholmovski E, Burgon N, Hu N, Mont L, Deneke T, Duytschaever M. Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: the DECAAF study. JAMA 2014;311: 498–506. 14. Teh AW, Kistler PM, Lee G, Medi C, Heck PM, Spence SJ, Morton JB, Sanders P, Kalman JM. Long-term effects of catheter ablation for lone atrial fibrillation: progressive atrial electroanatomic substrate remodeling despite successful ablation. Heart Rhythm 2012;9:473–480. 15. Lee G, Wu H, Kalman JM, Esmore D, Williams T, Snell G, Kistler PM. Atrial fibrillation following lung transplantation: double but not single lung transplant is associated with long-term freedom from paroxysmal atrial fibrillation. Eur Heart J 2010;31:2774–2782.

The inconvenient truth of elevated left atrial pressure and AF recurrence despite catheter ablation.

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