REVIEW URRENT C OPINION
Left atrial anatomy and physiology: echo/Doppler assessment James B. Sewarda and Virginia B. Heblb
Purpose of review This article provides a state-of-the-art perspective of left atrial anatomy and physiology. Recent findings Left atrial structure and function can be used to reflect and quantify the physiologic state of complex disease processes. No single left atrial anatomic, functional, or clinical feature will adequately define a complex system. The state of combined left atrial structural and functional features (i.e., systems biology) defines disease clustering (i.e., commonality of underlying left atrial pathophysiology), cause and effect (i.e., left atrial dynamics impute disease events as consequences), disease classification (e.g., primary vs. secondary atrial fibrillation), and intensity of a pathophysiologic state (i.e., quantifiably infer the magnitude of a pathophysiologic perturbation), and helps explain complex pathophysiology (e.g., myocyte death vs. hibernation). Summary Individual left atrial structural and functional features do not define the state of complex systems. Systems biology and multifeature profiles of left atrial anatomy and physiology should be used to assist the prediction, management, and, ultimately, prevention of preclinical and overt complex disease processes. Keywords atrial fibrillation, left atrial anatomy and physiology, left atrial pathophysiology, systems biology
INTRODUCTION The left atrium is a complex organ system, with unique anatomic and physiologic attributes. Between 1990 and 2014, yearly publications related to left atrial anatomy and function increased by more than 600% (50 to more than 300 per year). Total left atrial publications per year now exceed 1000. The attention to left atrial size and function is related to its pervasive relationship to the unresolved ‘epidemics’ of heart failure and atrial fibrillation [1,2]. A meaningful review of recent left atrial literature must begin with an assured understanding of established left atrial pathophysiology.
ESTABLISHED LEFT ATRIAL KNOWLEDGE Left atrial pathophysiology is complex and cannot be defined by any single feature (e.g., complex processes must be defined as dynamic multifeature states) [3]. Left atrial size is best expressed as a volume indexed to body surface area [left atrial volume index (LAVi)]. Indexing accounts for variation in plasma volume in different-sized persons [4,5]. Left atrial enlargement (LAE) itself is a marker of the chronicity of volume and/or pressure
overload (e.g., left atrial size remodels relatively slowly) [4]. There are two principal pathophysiologic causes of atrial enlargement [4]: benign chronic left atrial volume overload – features: enlarged atria; normal left ventricular (LV) diastolic function; no associated major adverse events (e.g., normal athletic heart, burst atrial tachyarrhythmias, and chronic disease states) – and malignant chronic left atrial pressure overload – features: enlarged atria; abnormal LV diastolic function; clustering of associated adverse events [e.g., atrial fibrillation, stroke, hypertension (HTN), heart failure, sleep apnea, diabetes, dementia, premature death, and others]. There are two principal pathophysiologic forms of atrial fibrillation [4,6]: primary atrial fibrillation – features: variable degrees of ‘benign’ atrial volume overload; normal LV diastolic function; no serious a Department of Adult and Pediatric Cardiology and bDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
Correspondence to James B. Seward, MD, 102 S Broadway #310 EchoMetrics, Rochester, MN 55904, USA. Tel: +1 507 252 9070; fax: +1 507 252 9071; e-mail: [email protected] Curr Opin Cardiol 2014, 29:403–407 DOI:10.1097/HCO.0000000000000089
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Imaging and echocardiography
KEY POINTS
little evidence that atrial fibrillation-related LAE actually ‘causes’ the prothrombotic effect [19].
Left atrial structure and function directly reflect the impact of systemic physiologic perturbations, both benign and malignant, as part of a complex contiguous system.
NEW (2013–2014) COMPLEMENTARY LEFT ATRIAL KNOWLEDGE
To date, the use of left atrial structure and function has focused on discrete relationships, discrete features, and individual disease entities. This has yielded insufficient understanding and management of complex processes. Multifeature profiles of left atrial anatomy and physiology are predicted to substantially improve our ability to predict, manage, and, ultimately, prevent associated preclinical and overt complex disease processes.
adverse events – and secondary atrial fibrillation – features: atrial enlargement due to ‘chronic’ atrial pressure overload; abnormal LV diastolic function; associated with adverse events. There are two major causes of atrial myocyte dysfunction: ‘myocyte death’ is most commonly associated with elevated left atrial pressure, stretchinduced myocyte death, and replacement fibrosis [7]; ‘myocyte hibernation’ is caused by reduced cell contraction (e.g., atrial tachyarrhythmia and tethering). Coincident with the mechanoelectrical feedback phenomenon, myocytes dedifferentiate into a reversible state of hibernation; normalization of myocyte excursion initiates staged redifferentiation (reconstitution) of myocyte function. For example, postcardioversion ‘stunning’ is a clinical example of the mechanoelectrical feedback phenomenon and not an electrical injury phenomenon [8–10].
LEFT ATRIAL MYOCYTES AND LEFT ATRIAL PRESSURE OVERLOAD Left atrial myocardium extends into the proximal pulmonary veins; this myocardium is vulnerable to pressure-induced myocyte stretch, death, fibrosis, electrical heterogeneity, and induction of ‘secondary atrial fibrillation’ [11,12]. Left atrial subendocardial pectinate muscle bundles form thin and thick myocyte ridges; thin myocardium is more vulnerable to stretch-induced cell death and fibrosis; if left atrial pressure overload is not resolved, diffuse electrical heterogeneity and secondary atrial fibrillation will logically occur [7,13]. The left atrial appendage (LAA) is a complex multiple-lobed cul-de-sac [14]. Stroke and thrombogenesis are most strongly associated with LV diastolic dysfunction, left atrial endothelial dysfunction, and low flow state; thus, spontaneous echo contrast is the strongest predictor of stroke risk [15–18]. Pressure-induced left atrial remodeling is associated with atrial fibrillation and stroke; however, association cannot be construed as cause. There is 404
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New knowledge enhances the understanding of left atrial anatomy and physiology.
MALIGNANT LEFT ATRIAL PRESSURE OVERLOAD Left atrial phenotyping requires documentation of both morphologic and physiologic features. Increased left atrial pressure is strongly related to LV diastolic dysfunction, stretch-induced myocyte death, interstitial fibrosis, atrial dysfunction, electrical heterogeneity, endothelial dysfunction, increased thrombogenicity, pulmonary venous HTN, etc. Left atrial structural and physiologic remodeling is strongly related to LV diastolic dysfunction (i.e., elevated LV filling pressure is transmitted backward into the left atrium) [20 ]. LV diastolic dysfunction contributes significantly to left atrial electroanatomical remodeling in older patients [21 ]. Depressed left atrial function is strongly related to left atrial pressure overload [22]. Interstitial fibrosis is induced by myocyte stretch and death; histopathological changes and oxidative injury relate to the development and sustainability of atrial fibrillation [23 ]. Left atrial dysfunction is a complex consequence of atrial fibrosis (myocyte death) [24] and hibernation of viable myocytes [10]. &
&
&&
CLUSTERED EVENTS ASSOCIATED WITH LEFT ATRIAL PRESSURE OVERLOAD Cardiovascular events cluster around one another when they share a self-similar physiologic milieu.
Cardioversion Lower LAVi (i.e., less severe pressure-induced left atrial dysfunction) is a strong and independent predictor of the success of cardioversion and maintenance of sinus rhythm [25]; higher LAA velocity (i.e., less left atrial dysfunction) has better cardioversion results [26]. Postoperative atrial fibrillation is strongly related to the magnitude of preoperative left atrial dysfunction [27 ]. &
Systolic hypertension HTN is strongly associated with LV diastolic dysfunction, which alters atrial dynamics and increases left atrial pressure and development of atrial fibrillation [28 ]. Left atrial remodeling is significantly greater in prehypertensive patients [29]. Left atrial pressure overload and left atrial functional remodeling are associated with preemergent HTN [30]; it &
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Left atrial anatomy and physiology Seward and Hebl
is a marker of resistant HTN heart disease and increased cardiovascular risk [31 ,32]. Poor blood pressure control and diastolic dysfunction and greater left atrial pressure remodeling predict an increased occurrence of atrial fibrillation [33 ]. &&
&
Stroke Intraatrial thrombosis accompanies left atrial pressure remodeling, which increases endocardial platelet adhesion and thrombogenicity. Left atrial fibrosis is likely a facilitator of atrial arrhythmogenicity [34 ]. Quantitative left atrial fibrosis is a stroke risk marker [35]; stroke is more strongly related to left atrial pressure remodeling and less related to actual left atrial size [36 ]. Left atrial pressure overload is associated with the presence of LAA thrombus [37]; left atrial size and dysfunction are associated with LV diastolic dysfunction and are strong predictors of clot detection [38 ]. &&
&&
&
Sleep apnea LV diastolic dysfunction and left atrial structural and functional remodeling are significantly associated with the severity of obstructive sleep apnea [39].
Diabetes Combination of LV diastolic dysfunction and left atrial dysfunction is associated with quantitative left atrial remodeling in patients with diabetes [40].
Dementia Greater left atrial size is associated with cognitive dysfunction in older adults [41]; left atrial pressureinduced enlargement (LAVi ³ 34 ml/m2) and aging are independently associated with cognitive impairment [42].
LEFT ATRIAL PRESSURE OVERLOAD AND CLINICAL DECISION MAKING Atrial pathophysiology can assist disease management.
Mitral valve regurgitation LAVi may be used for risk stratification and decision making in patients with asymptomatic mitral valve regurgitation [43].
reconstruction and improves the accuracy of outcome prediction [45].
BENIGN LEFT ATRIAL VOLUME OVERLOAD Left atrial remodeling, in the absence of increased left atrial pressure, is most commonly related to increased cardiac demands. Relatively benign left atrial volume overload is encountered in the athlete’s heart, burst atrial tachyarrhythmias (e.g., primary atrial fibrillation), chronic disease states (e.g., anemia), etc. Both athletic heart and hypertrophic cardiomyopathy have increased left atrial volume and other shared morphophysiologic features. However, hypertrophic cardiomyopathy myocyte function is abnormal compared with athletes, who have normal or hypernormal longitudinal myocyte function [46]. LAE and enhanced diastolic properties are an adaptive component of athlete’s heart [47]. Physiologic and morphologic variabilities (e.g., system biology profile), which reflect the diverse demands of different sports, can be individualized [3,48]. Speckle tracking echocardiography demonstrates increased systolic and diastolic function in athletes. Strain and strain rate parameters decrease in pathologic states [49].
REVERSE REMODELING OF LEFT ATRIUM Left atrial volume can reverse remodel after alleviating atrial pressure and/or volume overload. Interstitial left atrial fibrosis associated with chronic atrial pressure overload limits structural remodeling. There is a complex milieu of fibrosis (irreversible) and hibernation (reversible) remodeling in patients with secondary atrial fibrillation. Primary atrial fibrillation and burst atrial tachyarrhythmias have a preponderance of reversible hibernation. The most important pretreatment objective is to define both the morphologic and the physiologic state (i.e., classify atrial enlargement as benign volume vs. malignant pressure overload).
Ablation therapy
Left atrial pressure-induced LAE can help determine functional severity and can assist in the decision to operate [44].
Successful catheter ablation is associated with variable left atrial reverse remodeling and left atrial/LAA functional recovery [50,51] (redifferentiation of hibernating myocytes would account for most of the observed functional recovery). Without correction of atrial pressure overload, secondary atrial fibrillation will logically reoccur.
Surgical left ventricular reconstruction
Mitral valve surgery
Pressure-induced left atrial remodeling is a powerful indicator of poor outcome after surgical LV
LAVi significantly decreases postoperatively. However, in patients with highest preoperative LAVi (e.g.,
Aortic valve stenosis
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Imaging and echocardiography
established fibrosis), the structural and functional remodeling is significantly impaired [52 ].
REFERENCES AND RECOMMENDED READING
MEASUREMENT OF LEFT ATRIAL SIZE
Papers of particular interest, published within the period of review, have been highlighted as: & of special interest && of outstanding interest
&
The necessity of characterizing both the left atrial physiologic and structural state reduces clinical utility of isolated measurements of left atrial size. Various volumetric techniques should not be used interchangeably or without documentation and attention to the coincident physiologic state. Minimum LAVi may have better diagnostic power in early disease assessment [53]. Three-dimensional echocardiographic methods offer moderate improvement in accuracy at the cost of more elaborate analysis [54,55]; ellipse and cube methods should be avoided. Each method is reasonably reproducible, but they should not be used interchangeably for follow-up studies [56]; left atrial sphericity is a new independent predictor of recurrent atrial fibrillation [57].
CONCLUSION The most important disclosure emanating from recent literature is that the left atrium is a dynamic component of a complex contiguous organ system and, therefore, cannot be depicted by a single anatomic, physiologic, or clinical feature. As opposed to the conventional focus on single features and discrete relationships, systems biology [3] provides a holistic approach that integrates multiple features into a singular expression of the pathophysiologic state. Systems biology ‘signatures’ are beginning to replace traditional approaches to disease diagnosis, elucidation of disease mechanisms and treatment targets, identification of preclinical disease states, and outcome prediction. The approach directly challenges the existing paradigm of human disease, but is justifiable due to the current flawed heuristic strategies [3]. Left atrial pathophysiology is strongly associated with multiple preemergent and overt disease states that substantially impact contemporary clinical practice. Understanding left atrial pathophysiology through the lens of systems biology is essential to improving our ability to predict, manage, and, ultimately, prevent associated preclinical and overt cardiovascular disease. Acknowledgements The authors are receiving no funding relevant to this review. Conflicts of interest There are no conflicts of interest. 406
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1. Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355:251–259. 2. Miyasaka Y, Barnes ME, Gersh BJ, 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. 3. Loscalzo J, Barabasi AL. Systems biology and the future of medicine. Wiley Interdiscip Rev Syst Biol Med 2011; 3:619–627. 4. Abhayaratna WP, Seward JB, Appleton CP, et al. Left atrial size: physiologic determinants and clinical applications. J Am Coll Cardiol 2006; 47:2357–2363. 5. Lang RM, Bierig M, Devereux RB, et al. 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 2005; 18:1440–1463. 6. Osranek M, Bursi F, Bailey KR, et al. Left atrial volume predicts cardiovascular events in patients originally diagnosed with lone atrial fibrillation: three-decade follow-up. Eur Heart J 2005; 26:2556–2561. 7. Corradi D, Maestri R, Macchi E, Callegari S. The atria: from morphology to function. J Cardiovasc Electrophysiol 2011; 22:223–235. 8. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res 2002; 54:230–246. 9. Ausma J, Litjens N, Lenders MH, et al. Time course of atrial fibrillationinduced cellular structural remodeling in atria of the goat. J Mol Cell Cardiol 2001; 33:2083–2094. 10. Bassingthwaighte JB, Li Z. Heterogeneities in myocardial flow and metabolism: exacerbation with abnormal excitation. Am J Cardiol 1999; 83:7H–12H. 11. Lin WS, Prakash VS, Tai CT, et al. Pulmonary vein morphology in patients with paroxysmal atrial fibrillation initiated by ectopic beats originating from the pulmonary veins: implications for catheter ablation. Circulation 2000; 101:1274–1281. 12. Ho SY, Cabrera JA, Tran VH, et al. Architecture of the pulmonary veins: relevance to radiofrequency ablation. Heart 2001; 86:265–270. 13. Ho SY, Sanchez-Quintana D, Cabrera JA, Anderson RH. Anatomy of the left atrium: implications for radiofrequency ablation of atrial fibrillation. J Cardiovasc Electrophysiol 1999; 10:1525–1533. 14. Veinot JP, Harrity PJ, Gentile F, et al. Anatomy of the normal left atrial appendage: a quantitative study of age-related changes in 500 autopsy hearts: implications for echocardiographic examination. Circulation 1997; 96:3112–3115. 15. Bernhardt P, Schmidt H, Hammerstingl C, et al. Patients with atrial fibrillation and dense spontaneous echo contrast at high risk a prospective and serial follow-up over 12 months with transesophageal echocardiography and cerebral magnetic resonance imaging. J Am Coll Cardiol 2005; 45:1807–1812. 16. Black IW, Hopkins AP, Lee LC, Walsh WF. Left atrial spontaneous echo contrast: a clinical and echocardiographic analysis. J Am Coll Cardiol 1991; 18:398–404. 17. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation 2005; 111:363–368. 18. Russo C, Jin Z, Liu R. et al. LA volumes and reservoir function are associated with subclinical cerebrovascular disease: the CABL (Cardiovascular Abnormalities and Brain Lesions) study. JACC Cardiovasc Imaging 2013; 6:313–323. 19. Nishida K, Chiba K, Iwasaki YK, et al. Atrial fibrillation-associated remodeling does not promote atrial thrombus formation in canine models. Circ Arrhythm Electrophysiol 2012; 5:1168–1175. 20. El Aouar LM, Meyerfreud D, Magalhaes P, et al. Relationship between left atrial volume and diastolic dysfunction in 500 Brazilian patients. Arq Bras & Cardiol 2013; 101:52–58. LV diastolic dysfunction contributes to left atrial remodeling. LAVi increases as an expression of severity and is independently associated with age, LV hypertrophy, systolic dysfunction, and increased filling pressures. 21. Lee JS, Shim CY, Wi J, et al. Left ventricular diastolic function is closely associated with mechanical function of the left atrium in patients with & paroxysmal atrial fibrillation. Circ J 2013; 7:697–704. Left atrial mechanical function is closely related to the degree of left atrial remodeling and LV diastolic function. Impaired LV diastolic function significantly contributes to left atrial electroanatomical remodeling in older patients with a larger left atrium. 22. Gupta S, Matulevicius SA, Ayers CR, et al. Left atrial structure and function and clinical outcomes in the general population. Eur Heart J 2013; 34:278–285.
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Left atrial anatomy and physiology Seward and Hebl 23. Yongjun Q, Huanzhang S, Wenxia Z, et al. Histopathological characteristics and oxidative injury secondary to atrial fibrillation in the left atrial && appendages of patients with different forms of mitral valve disease. Cardiovasc Pathol 2013; 22:211–218. Chronic atrial pressure overload increases the degree of atrial interstitial fibrosis. Pressure overload histopathological characteristics and oxidative injury are related to the development and sustainability of atrial fibrillation. 24. Cameli M, Lisi M, Righini FM, et al. Usefulness of atrial deformation analysis to predict left atrial fibrosis and endocardial thickness in patients undergoing mitral valve operations for severe mitral regurgitation secondary to mitral valve prolapse. Am J Cardiol 2013; 111:595–601. 25. Akdemir B, Altekin RE, Kucuk M, et al. The significance of the left atrial volume index in cardioversion success and its relationship with recurrence in patients with nonvalvular atrial fibrillation subjected to electrical cardioversion: a study on diagnostic accuracy. Anadolu Kardiyol Derg 2013; 13:18–25. 26. Kumagai K, Sakamoto T, Nakamura K, et al. Pre-procedural prediction of termination of persistent atrial fibrillation by catheter ablation as an indicator of reverse remodeling of the left atrium. Circ J 2013; 77:1416–1423. 27. Her AY, Kim JY, Kim YH, et al. Left atrial strain assessed by speckle tracking imaging is related to new-onset atrial fibrillation after coronary & artery bypass grafting. Can J Cardiol 2013; 29:377–383. Preoperative left atrial dysfunction is associated with the development of postoperative atrial fibrillation. 28. Boyd AC, Eshoo S, Richards DA, Thomas L. Hypertension accelerates the ‘normal’ aging process with a premature increase in left atrial volume. J & Am Soc Hypertens 2013; 7:149–156. HTN alters atrial dynamics significantly, with a resultant increase in left atrial volume as a consequence of altered diastolic function. The increase in left atrial volume may result in the future development of atrial fibrillation in HTN patients. 29. Akturk E, Ermis N, Yagmur J, et al. Early left atrial mechanics and volume abnormalities in subjects with prehypertension: a real time three-dimensional echocardiography study. Echocardiography 2012; 29:1211–1217. 30. Miyoshi H, Oishi Y, Mizuguchi Y, et al. Early predictors of alterations in left atrial structure and function related to left ventricular dysfunction in asymptomatic patients with hypertension. J Am Soc Hypertens 2013; 7:206–215. 31. Cuspidi C, Rescaldani M, Sala C. Prevalence of echocardiographic leftatrial enlargement in hypertension: a systematic review of recent clinical && studies. Am J Hypertens 2013; 26:456–464. LAE is a marker of hypertensive heart disease, which is associated with increased cardiovascular risk. LAE is an independent predictor of cardiovascular events and may improve the evaluation of risk in hypertensive patients. 32. Armario P, Oliveras A, Hernandez-Del-Rey R, et al. Increased pulse pressure is associated with left atrial enlargement in resistant hypertensive patients. Blood Press 2013; 22:39–44. 33. Watanabe T, Kawasaki M, Tanaka R, et al. Association among blood & pressure control in elderly patients with hypertension, left atrial structure and function and new-onset atrial fibrillation: a prospective 2-year study in 234 patients. Hypertens Res 2013; 36:799–806. Poor long-term control and diastolic dysfunction are most predictive of left atrial remodeling and the occurrence of atrial fibrillation. 34. Scridon A, Tabib A, Barres C, et al. Left atrial endocardial fibrosis and intraatrial thrombosis: landmarks of left atrial remodeling in rats with spontaneous atrial && tachyarrhythmias. Rom J Morphol Embryol 2013; 54:405–411. Intraatrial thrombosis accompanies left atrial structural remodeling (fibrosis). Increased endocardial platelet adhesion molecule von Willebrand factor could contribute to increased thrombogenicity. The left atrial remodeling– atrial tachyarrhythmia relationship could be highly nonlinear; atrial fibrosis is more likely to be a facilitator of atrial arrhythmogenicity, rather than a prerequisite. 35. Velagapudi P, Turagam MK, Leal MA, et al. Atrial fibrosis: a risk stratifier for atrial fibrillation. Expert Rev Cardiovasc Ther 2013; 11:155–160. 36. Park HC, Shin J, Ban JE, et al. Left atrial appendage: morphology and && function in patients with paroxysmal and persistent atrial fibrillation. Int J Cardiovasc Imaging 2013; 29:935–944. Stroke is related to physiologic (functional) remodeling and less related to actual morphologic left atrial size. Only depressed systolic function of the LAA is significantly related to stroke/transient ischemic attack and recurrence of atrial fibrillation after catheter ablation in paroxysmal atrial fibrillation patients. 37. Karabay CY, Zehir R, Guler A, et al. Left atrial deformation parameters predict left atrial appendage function and thrombus in patients in sinus rhythm with suspected cardioembolic stroke: a speckle tracking and transesophageal echocardiography study. Echocardiography 2013; 30:572–581.
38. Zoppo F, Brandolino G, Berton A, et al. Predictors of left atrium appendage clot detection despite on-target warfarin prevention for atrial fibrillation. J & Interv Card Electrophysiol 2012; 35:151–158. Left atrial thrombus is present despite on-target warfarin. A larger left atrial size (left atrial dysfunction and abnormal diastolic function) is a strong predictor of clot detection. 39. Kim SM, Cho KI, Kwon JH, et al. Impact of obstructive sleep apnea on left atrial functional and structural remodeling beyond obesity. J Cardiol 2012; 60:475–483. 40. Kadappu KK, Kuncoro AS, Hee L, et al. Chronic kidney disease is independently associated with alterations in left atrial function. Echocardiography 2014; 31:1–9. 41. Alosco ML, Gunstad J, Jerskey BA, et al. Left atrial size is independently associated with cognitive function. Int J Neurosci 2013; 123:544–552. 42. Karadag B, Ozyigit T, Ozben B, et al. Relationship between left atrial volume index and cognitive decline in elderly patients with sinus rhythm. J Clin Neurosci 2013; 20:1074–1078. 43. Arias A, Pizarro R, Oberti P, et al. Prognostic value of left atrial volume in asymptomatic organic mitral regurgitation. J Am Soc Echocardiogr 2013; 26:699–705. 44. Lisi M, Henein MY, Cameli M, et al. Severity of aortic stenosis predicts early postoperative normalization of left atrial size and function detected by myocardial strain. Int J Cardiol 2013; 167:1450–1455. 45. Castelvecchio S, Ranucci M, Bandera F, et al. The additional prognostic value of left atrial volume on the outcome of patients after surgical ventricular reconstruction. Ann Thorac Surg 2013; 95:141–147. 46. Gabrielli L, Enriquez A, Cordova S, et al. Assessment of left atrial function in hypertrophic cardiomyopathy and athlete’s heart: a left atrial myocardial deformation study. Echocardiography 2012; 29:943–949. 47. D’Ascenzi F, Cameli M, Lisi M, et al. Left atrial remodelling in competitive adolescent soccer players. Int J Sports Med 2012; 33:795–801. 48. Moro AS, Okoshi MP, Padovani CR, Okoshi K. Doppler echocardiography in athletes from different sports. Med Sci Monit 2013; 19:187–193. 49. Simsek Z, Hakan Tas M, Degirmenci H, et al. Speckle tracking echocardiographic analysis of left ventricular systolic and diastolic functions of young elite athletes with eccentric and concentric type of cardiac remodeling. Echocardiography 2013; 30:1202–1208. 50. Machino-Ohtsuka T, Seo Y, Ishizu T, et al. Significant improvement of left atrial left atrial appendage function after catheter ablation for persistent atrial fibrillation. Circ J 2013; 77:1695–1704. 51. La Meir M, Gelsomino S, Luca F, et al. Improvement of left atrial function and left atrial reverse remodeling after minimally invasive radiofrequency ablation evaluated by 2-dimensional speckle tracking echocardiography. J Thorac Cardiovasc Surg 2013; 146:72–77. 52. Hyllen S, Nozohoor S, Meurling C, et al. Determinants of left atrial reverse & remodeling after valve surgery for degenerative mitral regurgitation. J Heart Valve Dis 2013; 22:2–10. Preoperative increase in LAVi is associated with adverse events (e.g., stroke). LAVi can significantly decrease postoperatively. However, in patients with high preoperative LAVi, reverse remodeling is significantly impaired. Patients with preoperative left atrial enlargement should be closely monitored, with a low threshold for surgical admittance, as the potential for postoperative left atrial reverse remodeling decreases with increasing preoperative LAVi. 53. Wu VC, Takeuchi M, Kuwaki H, et al. Prognostic value of LA volumes assessed by transthoracic 3D echocardiography: comparison with 2D echocardiography. JACC Cardiovasc Imaging 2013; 6:1025–1035. 54. Buechel RR, Stephan FP, Sommer G, et al. Head-to-head comparison of two-dimensional and three-dimensional echocardiographic methods for left atrial chamber quantification with magnetic resonance imaging. J Am Soc Echocardiogr 2013; 26:428–435. 55. Al-Mohaissen MA, Kazmi MH, Chan KL, Chow BJ. Validation of twodimensional methods for left atrial volume measurement: a comparison of echocardiography with cardiac computed tomography. Echocardiography 2013; 30:1135––1142. 56. Nacif MS, Barranhas AD, Turkbey E, et al. Left atrial volume quantification using cardiac MRI in atrial fibrillation: comparison of the Simpson’s method with biplane area-length, ellipse, and three-dimensional methods. Diagn Interv Radiol 2013; 19:213–220. 57. Bisbal F, Guiu E, Calvo N, et al. Left atrial sphericity: a new method to assess atrial remodeling. Impact on the outcome of atrial fibrillation ablation. J Cardiovasc Electrophysiol 2013; 24:752–759.
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Left atrial anatomy and physiology: echo/Doppler assessment James B. Sewarda and Virginia B. Heblb
Purpose of review This article provides a state-of-the-art perspective of left atrial anatomy and physiology. Recent findings Left atrial structure and function can be used to reflect and quantify the physiologic state of complex disease processes. No single left atrial anatomic, functional, or clinical feature will adequately define a complex system. The state of combined left atrial structural and functional features (i.e., systems biology) defines disease clustering (i.e., commonality of underlying left atrial pathophysiology), cause and effect (i.e., left atrial dynamics impute disease events as consequences), disease classification (e.g., primary vs. secondary atrial fibrillation), and intensity of a pathophysiologic state (i.e., quantifiably infer the magnitude of a pathophysiologic perturbation), and helps explain complex pathophysiology (e.g., myocyte death vs. hibernation). Summary Individual left atrial structural and functional features do not define the state of complex systems. Systems biology and multifeature profiles of left atrial anatomy and physiology should be used to assist the prediction, management, and, ultimately, prevention of preclinical and overt complex disease processes. Keywords atrial fibrillation, left atrial anatomy and physiology, left atrial pathophysiology, systems biology
INTRODUCTION The left atrium is a complex organ system, with unique anatomic and physiologic attributes. Between 1990 and 2014, yearly publications related to left atrial anatomy and function increased by more than 600% (50 to more than 300 per year). Total left atrial publications per year now exceed 1000. The attention to left atrial size and function is related to its pervasive relationship to the unresolved ‘epidemics’ of heart failure and atrial fibrillation [1,2]. A meaningful review of recent left atrial literature must begin with an assured understanding of established left atrial pathophysiology.
ESTABLISHED LEFT ATRIAL KNOWLEDGE Left atrial pathophysiology is complex and cannot be defined by any single feature (e.g., complex processes must be defined as dynamic multifeature states) [3]. Left atrial size is best expressed as a volume indexed to body surface area [left atrial volume index (LAVi)]. Indexing accounts for variation in plasma volume in different-sized persons [4,5]. Left atrial enlargement (LAE) itself is a marker of the chronicity of volume and/or pressure
overload (e.g., left atrial size remodels relatively slowly) [4]. There are two principal pathophysiologic causes of atrial enlargement [4]: benign chronic left atrial volume overload – features: enlarged atria; normal left ventricular (LV) diastolic function; no associated major adverse events (e.g., normal athletic heart, burst atrial tachyarrhythmias, and chronic disease states) – and malignant chronic left atrial pressure overload – features: enlarged atria; abnormal LV diastolic function; clustering of associated adverse events [e.g., atrial fibrillation, stroke, hypertension (HTN), heart failure, sleep apnea, diabetes, dementia, premature death, and others]. There are two principal pathophysiologic forms of atrial fibrillation [4,6]: primary atrial fibrillation – features: variable degrees of ‘benign’ atrial volume overload; normal LV diastolic function; no serious a Department of Adult and Pediatric Cardiology and bDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA
Correspondence to James B. Seward, MD, 102 S Broadway #310 EchoMetrics, Rochester, MN 55904, USA. Tel: +1 507 252 9070; fax: +1 507 252 9071; e-mail: [email protected] Curr Opin Cardiol 2014, 29:403–407 DOI:10.1097/HCO.0000000000000089
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Imaging and echocardiography
KEY POINTS
little evidence that atrial fibrillation-related LAE actually ‘causes’ the prothrombotic effect [19].
Left atrial structure and function directly reflect the impact of systemic physiologic perturbations, both benign and malignant, as part of a complex contiguous system.
NEW (2013–2014) COMPLEMENTARY LEFT ATRIAL KNOWLEDGE
To date, the use of left atrial structure and function has focused on discrete relationships, discrete features, and individual disease entities. This has yielded insufficient understanding and management of complex processes. Multifeature profiles of left atrial anatomy and physiology are predicted to substantially improve our ability to predict, manage, and, ultimately, prevent associated preclinical and overt complex disease processes.
adverse events – and secondary atrial fibrillation – features: atrial enlargement due to ‘chronic’ atrial pressure overload; abnormal LV diastolic function; associated with adverse events. There are two major causes of atrial myocyte dysfunction: ‘myocyte death’ is most commonly associated with elevated left atrial pressure, stretchinduced myocyte death, and replacement fibrosis [7]; ‘myocyte hibernation’ is caused by reduced cell contraction (e.g., atrial tachyarrhythmia and tethering). Coincident with the mechanoelectrical feedback phenomenon, myocytes dedifferentiate into a reversible state of hibernation; normalization of myocyte excursion initiates staged redifferentiation (reconstitution) of myocyte function. For example, postcardioversion ‘stunning’ is a clinical example of the mechanoelectrical feedback phenomenon and not an electrical injury phenomenon [8–10].
LEFT ATRIAL MYOCYTES AND LEFT ATRIAL PRESSURE OVERLOAD Left atrial myocardium extends into the proximal pulmonary veins; this myocardium is vulnerable to pressure-induced myocyte stretch, death, fibrosis, electrical heterogeneity, and induction of ‘secondary atrial fibrillation’ [11,12]. Left atrial subendocardial pectinate muscle bundles form thin and thick myocyte ridges; thin myocardium is more vulnerable to stretch-induced cell death and fibrosis; if left atrial pressure overload is not resolved, diffuse electrical heterogeneity and secondary atrial fibrillation will logically occur [7,13]. The left atrial appendage (LAA) is a complex multiple-lobed cul-de-sac [14]. Stroke and thrombogenesis are most strongly associated with LV diastolic dysfunction, left atrial endothelial dysfunction, and low flow state; thus, spontaneous echo contrast is the strongest predictor of stroke risk [15–18]. Pressure-induced left atrial remodeling is associated with atrial fibrillation and stroke; however, association cannot be construed as cause. There is 404
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New knowledge enhances the understanding of left atrial anatomy and physiology.
MALIGNANT LEFT ATRIAL PRESSURE OVERLOAD Left atrial phenotyping requires documentation of both morphologic and physiologic features. Increased left atrial pressure is strongly related to LV diastolic dysfunction, stretch-induced myocyte death, interstitial fibrosis, atrial dysfunction, electrical heterogeneity, endothelial dysfunction, increased thrombogenicity, pulmonary venous HTN, etc. Left atrial structural and physiologic remodeling is strongly related to LV diastolic dysfunction (i.e., elevated LV filling pressure is transmitted backward into the left atrium) [20 ]. LV diastolic dysfunction contributes significantly to left atrial electroanatomical remodeling in older patients [21 ]. Depressed left atrial function is strongly related to left atrial pressure overload [22]. Interstitial fibrosis is induced by myocyte stretch and death; histopathological changes and oxidative injury relate to the development and sustainability of atrial fibrillation [23 ]. Left atrial dysfunction is a complex consequence of atrial fibrosis (myocyte death) [24] and hibernation of viable myocytes [10]. &
&
&&
CLUSTERED EVENTS ASSOCIATED WITH LEFT ATRIAL PRESSURE OVERLOAD Cardiovascular events cluster around one another when they share a self-similar physiologic milieu.
Cardioversion Lower LAVi (i.e., less severe pressure-induced left atrial dysfunction) is a strong and independent predictor of the success of cardioversion and maintenance of sinus rhythm [25]; higher LAA velocity (i.e., less left atrial dysfunction) has better cardioversion results [26]. Postoperative atrial fibrillation is strongly related to the magnitude of preoperative left atrial dysfunction [27 ]. &
Systolic hypertension HTN is strongly associated with LV diastolic dysfunction, which alters atrial dynamics and increases left atrial pressure and development of atrial fibrillation [28 ]. Left atrial remodeling is significantly greater in prehypertensive patients [29]. Left atrial pressure overload and left atrial functional remodeling are associated with preemergent HTN [30]; it &
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Left atrial anatomy and physiology Seward and Hebl
is a marker of resistant HTN heart disease and increased cardiovascular risk [31 ,32]. Poor blood pressure control and diastolic dysfunction and greater left atrial pressure remodeling predict an increased occurrence of atrial fibrillation [33 ]. &&
&
Stroke Intraatrial thrombosis accompanies left atrial pressure remodeling, which increases endocardial platelet adhesion and thrombogenicity. Left atrial fibrosis is likely a facilitator of atrial arrhythmogenicity [34 ]. Quantitative left atrial fibrosis is a stroke risk marker [35]; stroke is more strongly related to left atrial pressure remodeling and less related to actual left atrial size [36 ]. Left atrial pressure overload is associated with the presence of LAA thrombus [37]; left atrial size and dysfunction are associated with LV diastolic dysfunction and are strong predictors of clot detection [38 ]. &&
&&
&
Sleep apnea LV diastolic dysfunction and left atrial structural and functional remodeling are significantly associated with the severity of obstructive sleep apnea [39].
Diabetes Combination of LV diastolic dysfunction and left atrial dysfunction is associated with quantitative left atrial remodeling in patients with diabetes [40].
Dementia Greater left atrial size is associated with cognitive dysfunction in older adults [41]; left atrial pressureinduced enlargement (LAVi ³ 34 ml/m2) and aging are independently associated with cognitive impairment [42].
LEFT ATRIAL PRESSURE OVERLOAD AND CLINICAL DECISION MAKING Atrial pathophysiology can assist disease management.
Mitral valve regurgitation LAVi may be used for risk stratification and decision making in patients with asymptomatic mitral valve regurgitation [43].
reconstruction and improves the accuracy of outcome prediction [45].
BENIGN LEFT ATRIAL VOLUME OVERLOAD Left atrial remodeling, in the absence of increased left atrial pressure, is most commonly related to increased cardiac demands. Relatively benign left atrial volume overload is encountered in the athlete’s heart, burst atrial tachyarrhythmias (e.g., primary atrial fibrillation), chronic disease states (e.g., anemia), etc. Both athletic heart and hypertrophic cardiomyopathy have increased left atrial volume and other shared morphophysiologic features. However, hypertrophic cardiomyopathy myocyte function is abnormal compared with athletes, who have normal or hypernormal longitudinal myocyte function [46]. LAE and enhanced diastolic properties are an adaptive component of athlete’s heart [47]. Physiologic and morphologic variabilities (e.g., system biology profile), which reflect the diverse demands of different sports, can be individualized [3,48]. Speckle tracking echocardiography demonstrates increased systolic and diastolic function in athletes. Strain and strain rate parameters decrease in pathologic states [49].
REVERSE REMODELING OF LEFT ATRIUM Left atrial volume can reverse remodel after alleviating atrial pressure and/or volume overload. Interstitial left atrial fibrosis associated with chronic atrial pressure overload limits structural remodeling. There is a complex milieu of fibrosis (irreversible) and hibernation (reversible) remodeling in patients with secondary atrial fibrillation. Primary atrial fibrillation and burst atrial tachyarrhythmias have a preponderance of reversible hibernation. The most important pretreatment objective is to define both the morphologic and the physiologic state (i.e., classify atrial enlargement as benign volume vs. malignant pressure overload).
Ablation therapy
Left atrial pressure-induced LAE can help determine functional severity and can assist in the decision to operate [44].
Successful catheter ablation is associated with variable left atrial reverse remodeling and left atrial/LAA functional recovery [50,51] (redifferentiation of hibernating myocytes would account for most of the observed functional recovery). Without correction of atrial pressure overload, secondary atrial fibrillation will logically reoccur.
Surgical left ventricular reconstruction
Mitral valve surgery
Pressure-induced left atrial remodeling is a powerful indicator of poor outcome after surgical LV
LAVi significantly decreases postoperatively. However, in patients with highest preoperative LAVi (e.g.,
Aortic valve stenosis
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Imaging and echocardiography
established fibrosis), the structural and functional remodeling is significantly impaired [52 ].
REFERENCES AND RECOMMENDED READING
MEASUREMENT OF LEFT ATRIAL SIZE
Papers of particular interest, published within the period of review, have been highlighted as: & of special interest && of outstanding interest
&
The necessity of characterizing both the left atrial physiologic and structural state reduces clinical utility of isolated measurements of left atrial size. Various volumetric techniques should not be used interchangeably or without documentation and attention to the coincident physiologic state. Minimum LAVi may have better diagnostic power in early disease assessment [53]. Three-dimensional echocardiographic methods offer moderate improvement in accuracy at the cost of more elaborate analysis [54,55]; ellipse and cube methods should be avoided. Each method is reasonably reproducible, but they should not be used interchangeably for follow-up studies [56]; left atrial sphericity is a new independent predictor of recurrent atrial fibrillation [57].
CONCLUSION The most important disclosure emanating from recent literature is that the left atrium is a dynamic component of a complex contiguous organ system and, therefore, cannot be depicted by a single anatomic, physiologic, or clinical feature. As opposed to the conventional focus on single features and discrete relationships, systems biology [3] provides a holistic approach that integrates multiple features into a singular expression of the pathophysiologic state. Systems biology ‘signatures’ are beginning to replace traditional approaches to disease diagnosis, elucidation of disease mechanisms and treatment targets, identification of preclinical disease states, and outcome prediction. The approach directly challenges the existing paradigm of human disease, but is justifiable due to the current flawed heuristic strategies [3]. Left atrial pathophysiology is strongly associated with multiple preemergent and overt disease states that substantially impact contemporary clinical practice. Understanding left atrial pathophysiology through the lens of systems biology is essential to improving our ability to predict, manage, and, ultimately, prevent associated preclinical and overt cardiovascular disease. Acknowledgements The authors are receiving no funding relevant to this review. Conflicts of interest There are no conflicts of interest. 406
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