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SHORT SUMMARY
After atrial fibrillation conversion, long recurrences are present mostly in patients with structural atrial appendage dysfunction. Once excluded other clinical and echocardiographic determinants of stroke, the appendage velocity could select patients with normal appendage function at low embolic risk and patients with irreversible appendage dysfunction, at high risk, for lifelasting anticoagulation.
SUMMARY
In the last few decades several clinical studies evaluated the efficacy and safety of different strategies for antithrombotic prophylaxis to prevent thromboembolic events in patients with atrial fibrillation (AF).
Nowadays, a very debated point is related to the high embolic risk deriving from the asymptomatic and symptomatic AF recurrence after cardioversion or in paroxysmal AF, especially in patients with a large number of prolonged episodes of AF. In fact, after the recent AFFIRM and RACE trials, also patients after successful cardioversion at risk for thromboembolism could need life-lasting anticoagulation. Considering this, should we anticoagulate all the patients with clinical risk factors for thromboembolism with a single episode of AF, without considering the hemorrhagic risk?
Based on recent trials, it is reasonable hypothesize that long AF recurrences (>48 hours), both symptomatic and asymptomatic, are present mostly (if not exclusively) in patients with structural left atrial appendage (LAA) dysfunction and remodeling. Conversely, AF recurrences in patients without LAA dysfunction and remodeling, could be too short to allow thrombi formation in the LAA, and the anticoagulation could also be avoided. Once excluded other clinical and echocardiographic determinants of stroke, the LAA velocity could select patients with a normal appendage function at low embolic risk who could benefit from antiaggregation and patients with irreversible appendage dysfunction, at high embolic risk, who need life-lasting anticoagulation.
Echocardiographic criteria to evaluate the thromboembolic risk
in the single patient
This lack of precise indications based only on clinical criteria in a large number of patients at intermediate risk of thromboembolism focused the interest of physicians on echocardiographic predictive factors for thromboembolic risk.
Quite recently, several data have been published by the SPAF III researchers on the prognostic importance of transesophageal echocardiography (TEE) in patients with non valvular AF4. The multivariate analysis identified the presence of thrombi, spontaneous dense echocontrast, low velocity in left atrial appendage (LAA) and complex aortic plaques as independent predictors of thromboembolism. These factors are considered by the "Working Group Record" of the European Association or Heart Rhythm as facilitating factors for stroke and, therefore, indicate the anticoagulation therapy.
Hence, clinical and echocardiographic risk factors cooperate to define the individual risk profile in patients with non valvular AF. The TEE can offer adjunctive information to this goal, mostly in some subgroups of patients at intermediate risk and in all the cases where there are doubts on the risk/benefit ratio for the therapeutic choice.
All these findings recommend a cautious treatment of paroxysmal AF, as well as the use of other methods to detect patients at high risk of recurrence, such as echocardiographic left atrial appendage (LAA) parameters (see next paragraphs).
The importance of left atrial appendage function for
antithrombotic profilaxis: beyond the AFFIRM study
The recent RACE and AFFIRM trials 9,16 demonstrated a substantial embolic risk in patients with SR with a clinical history of AF, and suggested to anticoagulate both patients in persistent AF (mostly from the "rate control" arm of the trial), as well as those with recovery of SR (mostly from the "rhythm control" arm of the trial) .
All patients enrolled in these trials have been considered at "high thromboembolic risk", although the patients' selection was very heterogeneous as number and length of qualifying episodes, as well as degree of hypertension. Moreover, the results of these trials, although valid for the studied population, have sometimes been directly moved to other clinical settings, suggesting the anticoagulation therapy in almost all patients with SR and previous episodes of AF (including also paroxysmal AF , with a single or few arrhythmic events).
Although patients at high risk benefit from life-lasting anticoagulation , to date no specific studies demonstrated the usefulness of anticoagulation in patients such as a young man with well controlled moderate hypertension, cardioverted for a first episode of non-valvular AF, with a good left atrial and appendage function and without echocardiographic risk factors (aortic plaques or spontaneous atrial echocontrast). In these patients also the supplementary and significant risk for major hemorrhagic events, that has been well demonstrated in all trials studying patients on anticoagulation therapy12, has to be taken into account.
Should we really anticoagulate all the patients with clinical risk factors for thromboembolism with a single episode of AF, without considering the hemorrhagic risk? In the difficult decision of life-lasting anticoagulation of such a patient, we could be helped by the pathophysiologic basis of thromboembolism secondary to AF. In fact important studies showed that embolic events almost always derives by auricular thrombi due to auricular dysfunction (secondary to acute or recurrent AF), and seldom by aortic plaques or other possible sources. So the LAA dysfunction can be the ultimate pathophysiologic link between clinical risk factors and thromboembolic event , .
In patients with a history of AF appears useful, besides to the clinical evaluation of thromboembolic risk, to use echocardiography to better understand the pathophysiology of thromboembolic events. In fact, thromboembolism in patients considered at high clinical risk due to hypertension, is mediated by the increase in atrial pressure, leading to auricular remodelling, which causes an atrio-auricular dysfunction, a milieu for thrombi , .
The contractile function of LAA, both in SR and in AF, has been extensively evaluated directly (calculating the 2D fractional area change, the Mmode fractional shortening or the Doppler LAA emptying velocity) or indirectly (looking for LAA thrombi or spontaneous echocontrast, or evaluating the A wave at transmitral Doppler flow tracing) with transesophageal and transthoracic echocardiography (Figure 2).
Based on this echocardiographic analysis, the specific multivariate analysis of TEE risk factors for thromboembolic events from the SPAF III trial25, , showed that the only features independently associated with increased thromboembolic risk were appendage thrombi (relative risk [RR] 2.5, p < 0.04), dense spontaneous echo contrast (RR 3.7, p < 0.001), LAA peak flow velocities ≤20 cm/s (RR 1.7, p<0.008) and complex aortic plaque (RR 2.1, p<0.001). In patients with a high clinical risk for thromboembolic events, a TEE which excludes the predictive factors for thromboembolism (thrombi, aortic plaques or low LAA velocities) identified a population with a low annual major embolism rate (1.3%), versus the very high clinical risk for patients with predictive factors at TEE (23%)27.In addition , a very recent study on the prognosis of patients with AF demonstrated that the altered intra-atrial thrombogenic milieu (indicated by TEE parameters of left atrial thrombogenicity, namely LA thrombus and/or spontaneous echocardiographic contrast) was a marker for an increased cardiovascular death independent of clinically associated risk factors, such as hypertension, diabetes mellitus, smoking, congestive heart failure, and prior myocardial infarction . The presence of LAA dysfunction (evidenced as dense echocontrast or low emptying LAA velocities) was also associated with symptomatic, but also with silent cerebral embolisms at follow
up .
Another important limit to the interruption of anticoagulation is related to the high embolic risk deriving from the asymptomatic and symptomatic AF recurrence after cardioversion or in paroxysmal AF, especially in patients with a large number of prolonged episodes of AF, as in the AFFIRM study9. However, it is necessary to select in which patients this risk is high. .In a direct study of AF recurrence, Antonielli et al. demonstrated that a normal atrial function (with high velocities at TEE ) was the only independent factor to identify patients without AF recurrences, both in the short and in the long term . The possibility of identify patients at low risk of AF recurrence has been recently confirmed for TEE LAA velocities, but also for the high strain rate of the left atrium, obtained with transthoracic echocardiography .
Several data on the contractile post-cardioversion LAA recovery can indicate two different conditions of mechanical atrial appendage function and remodeling : A) a functional reversible one, with a preserved functional integrity of contractile apparatus (connected to an altered calcium homeostasis), typical of short term AF and B) a structural damage, with persistent – permanent damage of the contractile apparatus, often superimposed to the functional damage, typical of long term AF, with persistent hemodynamic overload.
This data are confirmed by Sanders et coll , who studied separately patients with short term AF (1-6 months) and long term AF (3 years), after cardioversion to sinus rhythm. They demonstrated that LAA function (studied with the echocardiographic LAA emptying velocity) was dependent on the duration of AF. Moreover, the "short term AF" patients were able to recover LAA function when isoproterenol was infused (reversible LAA stunning), differently from "long term AF" patients.
Therefore it is reasonable hypothesize that long AF recurrences (>48 hours), both symptomatic and asymptomatic, are present mostly (if not exclusively) in patients with structural LAA dysfunction and remodeling. Conversely, AF recurrences in patients without LAA dysfunction and remodeling, could be too short to allow thrombi formation in the LAA, and the anticoagulation could also be avoided.
A low embolic risk in these patients is supported by an our recent study, although non-randomized and undersized for the detection of thromboembolism19. We found no major embolic events at 1 year follow up in the 87 patients with LAA velocity > 25 cm/sec at pre- and post-cardioversion TEE , while 3 ischemic strokes occurred in the group of 14 patients (21%) with LAA velocity < 25 cm/sec at the first or second TEE . Importantly, two of these three strokes occurred in patients who were in SR 19. A similar trend of low thromboembolic risk has also been observed in the preliminary analysis of a larger population (252 patients), also at 2 years (Figure 3) .
We can hypothesize that, in patients with normal LAA function, and with early complete recovery after AF cardioversion, the eventual asymptomatic AF recurrence would not be associated with the formation of LAA thrombi , at least during the first year, probably because the AF is not able to produce LAA remodelling and dysfunction.
The great limitation of the LAA study is due to the semi-invasive TEE method, especially if this exam has to be repeated along the time. To overcome this limitation the transthoracic echocardiography has been suggested in conjunction with contrast echocardiography or with second harmonic technology . Also a new M-mode transthoracic echocardiographic sign, obtained sampling with a single beam oriented immediately lateral to the mitral annulus, has been demonstrated to be effective . This new transthoracic 2nd harmonic M-mode parameter is easily obtainable (over 90% of feasibility) and provides information related to transesophageal LAA velocities (Figure 4).
In conclusion, the evaluation of LAA function can be useful to guide anticoagulation both in the post-cardioversion period for sustained episodes of AF and in chronic and paroxysmal AF. Once excluded other clinical and echocardiographic determinants of stroke, the LAA velocity could select patients with a normal appendage function at low embolic risk who could benefit from
antiaggregation and patients with irreversible appendage dysfunction, at high embolic risk, who need life-lasting anticoagulation.
The AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study. Circulation. 2004;109:1509-1513
Khan IA. Atrial stunning: basics and clinical considerations. Int J Cardiol 2003; 92(2-3):113-28
Omran H, Jung W, Rabahieh R, Schimpf R, Wolpert C, Hagendorff A, Fehske W, Luderitz B. Left atrial chamber and appendage function after internal atrial defibrillation: a prospective and serial transesophageal echocardiographic study. J Am Coll Cardiol 1997; 29:131-138
Zabalgoitia M, Halperin JL, Pearce, LA, Blackshear JL, Asinger RW, Hart RG for the Stroke Prevention in Atrial Fibrillation Investigators. Transesophageal echocardiographic correlates of clinical risk of thromboembolism in nonvalvular atrial fibrillation. J Am Coll Cardiol 1998;31: 1622-6.
Omran H, Jung W, Rabahieh R, Schimpf, R, Wolpert C, Hagendorff A, et al. Left atrial chamber and appendage function after internal atrial defibrillation: a prospective and serial transesophageal echocardiographic study. J Am Coll Cardiol 1997;29:131-8
Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. Ann Intern Med 1998; 128:639-647.
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Di Salvo G, Caso P, Lo Piccolo R, Fusco A, Martiniello AR, Russo MG, et al. Atrial myocardial deformation properties predict maintenance of sinus rhythm after external cardioversion of recent-onset lone atrial fibrillation. A color Doppler myocardial imaging and transthoracic and transesophageal echocardiographic study. Circulation. 2005;112:387-395
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