Epidemiology

The incidence of AF in the setting of MI has hardly changed over the past 20 years. Following the arrival of thrombolysis for the management of MI in the acute phase, the 1997 GUSTO-I study, which included 40,981 patients, found an incidence of 7.9% , while the 2005 OPTIMAAL study , in 5477 patients, reported a similar incidence of 7.2%. Our team, which conducted a study on AF after non–ST-segment elevation Min (STEMI), found an incidence of 7.6% . In a recent study that evaluated the prognostic effect of AF after STEMI treated with primary angioplasty, the reported incidence was 6.4% . The factors affecting the onset of AF in the acute phase of MI are now well known; those found most frequently are indicators of left ventricular (LV) dysfunction, notably Killip class IV on admission and increased heart rate on admission, particularly when it is above 100 beats per minute.

Age is a major risk factor, and is very frequently associated with the onset of AF . Other variables, including a personal history of AF, certain cardiovascular risk factors such as hypertension or type 2 diabetes, as well as LV hypertrophy have been identified in the different studies . In contrast, MI location, type of reperfusion, and the presence of ST-segment elevation do not appear to be predictors of the onset of AF . Although the overall incidence has remained stable over time, it varies considerably from one study to another, ranging from 2.3% to 21%, because it is strongly dependent on the screening method used and the duration of screening .

The diagnosis of AF depends on the discovery of rhythm anomalies meeting the definition of AF according to European recommendations : strictly irregular RR intervals on the surface electrocardiogram (ECG); absence of identifiable P waves, with an unidentifiable isoelectric line; atrial rhythm > 300 beats per minute or an interval between two atrial activations < 200 ms. The diagnosis of AF can be made on a 12-lead surface ECG without taking the duration into account, or on an ECG readout of at least 30 seconds .

The complications associated with the onset of AF do not vary according to the type of episode. Indeed, whether the AF is paroxysmal, persistent or permanent, or symptomatic or silent, it can be complicated by serious or life-threatening thromboembolic events. Two studies have shown that episodes of AF, even silent or infraclinical AF, are associated with a significantly increased risk of stroke or other thromboembolic complications, which means that systematic screening for AF is essential in any patients with ischaemic stroke . In a study that compared different screening methods (noninvasive [3- or 7-day Holter, ECG monitor, surface ECG, etc.], invasive [implantable loop recorder] or even intracardiac recording methods [pacemaker]), the authors pointed out that the detection of AF, whether symptomatic or silent, improved with the duration of monitoring. Although there was no clear difference between the screening methods, they noted that screening by 7-day Holter was slightly superior, in that it provided continuous screening and was relatively easy to use.

Nonetheless, despite meticulous screening, there are still no recognized thresholds for AF duration or the frequency at which the thromboembolic risk becomes significant. Recommendations for the use of anticoagulants in the therapeutic management of AF, however, only take into account embolic risk factors (CHA ₂ DS ₂ -VASc score) and not AF duration or frequency .

Today, in routine clinical practice for the management of patients in the acute phase of MI, continuous ECG monitoring (CEM) is set up for the first 48 to 72 hours of their stay in the cardiac intensive care unit. The diagnosis of AF with a CEM apparatus is automatic; it is based on the application of algorithms incorporated in the software of the apparatus, which is able to detection a rhythm compatible with AF in only 15 cardiac cycles. The episode is considered significant when it lasts for at least 30 seconds. This screening system makes it possible to prolong the screening and determine the precise incidence of AF after MI. In addition, automatic detection also identifies infraclinical episodes. Recent studies have suggested that this type of AF is frequent after stroke and its consequences are far from innocuous.

Systematic screening for AF after MI therefore appears to be a key element in the management of patients. In recent studies, our team showed that systematic CEM could improve the efficacy of screening for episodes of AF after MI . Indeed, this automated screening method revealed an incidence of AF of 21%, among which three of four were episodes of silent AF, thus identified by the CEM only.

Principal mechanisms and consequences

The onset of AF in the acute phase of MI is a major event that can jeopardize the prognosis of patients in the short-, medium- and long-term; it is a powerful predictor of a poor prognosis after MI . In 2005, our team showed that the onset of AF was a predictor of poor prognosis in patients with non-STEMI . This effect on prognosis was also reported in studies on STEMI . This association was found whatever the type of reperfusion in the acute phase. Indeed, recent studies reported the harmful effect of AF onset in the acute phase of MI on mortality, even in patients treated with angioplasty . The suspected mechanism underlying this excess mortality is the drop in coronary flow linked to the acceleration and arrhythmic nature of the LV contractions, which reduce the LV ejection fraction (LVEF). The reduced LVEF could explain the frequent episodes of heart failure following the onset of AF, found in association with increased LV telediastolic pressure and increased left atrial (LA) volume . Moreover, by exacerbating LV ischaemia, AF is associated with an increased risk of severe ventricular rhythm disorders .

The acute phase of MI corresponds to a period of myocardial and systemic inflammation associated with elevated plasma markers . This inflammatory process activates cellular growth factors and tissue repair mechanisms, leading to atrial fibrosis and remodelling, which are likely to generate the anatomical substrate favourable for the subsequent onset of AF and its persistence over time . The ultrasound LA variables, particularly LA volume, indirectly reflect this remodelling. The follow-up of patients after MI shows that those who develop new onset AF, those whose paroxysmal AF is reactivated, or even those who present with permanent AF on admission have a higher inhospital and long-term mortality rate than patients without AF after MI . However, certain studies suggest that this mortality rate varies according to the type of AF.

Indeed, in the OPTIMAAL trial, the inhospital mortality rate in patients who developed new onset AF in the acute phase of MI was higher than that in patients without AF. This difference, however, was not found between patients with AF on admission and those without AF . Moreover, the study by Jabre et al. provided additional details, by showing that the prognosis in patients who developed de novo AF depended on when the AF occurred. Indeed, the mortality rate in patients who developed AF beyond 30 days after MI was twice that in patients without AF after MI and greater than that in patients who developed AF between the second and thirtieth day after MI . However, the early post-MI period, notably the first 48 hours, was the peak period for the onset of episodes of AF, and included 30% of such episodes. As shown above, the time to onset of AF after MI affects the prognosis. Another major element leading to excess mortality is impaired LVEF, according to data from the VALIANT study .

The principal causes of AF-associated death after MI are linked to heart failure . Moreover, the excess risk of death in these heart failure patients has also been associated with the onset of sudden death, with an odds ratio of 1.33 (95% confidence interval 1.19–1.49; P < 0.001) .

Finally, the principal complication of AF, namely stroke, has also been studied. Three important studies showed a higher incidence of stroke after MI in patients who experienced AF in the acute phase. The analysis of data from the GUSTO-I trial showed a stroke incidence of 3.1% in patients who presented with AF in the acute phase, compared with 1.3% in patients in sinus rhythm. In this study, involving more than 40,000 patients, most of the strokes were ischaemic .

The onset of AF, when it occurs during the acute phase of MI, is a serious event because it increases the risk of stroke in the medium- and long-term, and is responsible for the increased mortality most often linked to heart failure and sudden death. Although numerous studies have investigated the conditions surrounding the onset of AF, the precise physiopathological mechanisms responsible for the onset of AF in the acute phase of MI are still unclear; they notably involve atrial ischaemia, increased LV telediastolic pressure and its effect on the left atrium (LA), neurohormonal phenomena and their link with atrial hyperexcitability and, finally, oxidative stress.

Implication of oxidative stress in myocardial infarction

Oxidative stress corresponds to an imbalance between the pro-oxidant and antioxidant systems. During an ischaemia/reperfusion sequence, the oxidative balance tilts in favour of the production of free radical species, such as superoxide anion . An increase in oxidative stress, which is a target of choice for future therapies, could be an important mediator of atrial remodelling . Indeed, studies in animal models have suggested that the oxidative stress pathway is one of the pathways via which inflammation could trigger AF. In a dog model of pacemaker-induced AF, a fall in tissue antioxidant defences (ascorbic acid) and an increase in markers of nitro-oxidative stress were observed . Moreover, in a recent study in pigs subjected to rapid atrial stimulation for a week to trigger the onset of AF, the concentration of superoxide anion production in atrial tissue in the AF pigs was three times greater than that in control pigs without AF . In addition, the analysis of atrial tissue from patients after a Maze operation showed oxidative-type alterations in the myofibrils in the appendages (especially the LA appendage) in these patients with chronic AF. This damage was attributed to the release of peroxynitrites and hydroxyl radicals. These free radical species lead to the formation of carbonylated proteins and nitrotyrosine, suggesting, in humans, that an oxidative process takes place in the atrial myocardium of patients with chronic AF. This study indicates that oxidative stress has a major effect on the electrophysiological and mechanical properties of atrial myocytes, resulting in remodelling that favours the development and persistence of AF.

Age is also a major risk factor of the development of AF. Age correlates with the level of oxidative stress , thus reinforcing the hypothesis of a link between oxidative stress and AF.

Another pathway probably implicated in the onset of AF is endothelial dysfunction. Indeed, Kim et al. showed that nitric oxide synthase decoupling was implicated in the production of superoxide anion by myocardial tissue of the atria of patients with AF . This excess of free radical species causes damage to the myofibrils responsible for structural remodelling, leading to the development of AF and the subsequent risk of thrombus formation .

Among the factors likely to modulate the bioavailability of nitric oxide, certain derivatives of L-arginine, including asymmetric N ^G ,N ^G -dimethyl L-arginine (ADMA) and its stereoisomer symmetric N ^G ,N’ ^G -dimethyl L-arginine (SDMA), have recently been proposed as new biomarkers in cardiovascular diseases . In 1998, Usui et al. reported high circulating concentrations of ADMA in heart failure patients with permanent AF . Cengel et al. also showed that ADMA concentrations in patients who developed de novo AF were higher than those in patients with chronic AF . Goette et al. very recently showed a fall in ADMA concentrations after cardioversion . This modification in circulating concentrations of ADMA could be a consequence of the AF, but also a cause of the onset of AF. Indeed, certain studies have shown that high ADMA concentrations were associated with a more frequent recurrence of AF after cardioversion or a radiofrequency ablation procedure . In patients with ischaemic heart disease and AF, a high concentration of ADMA was shown to be a risk factor for cardiovascular adverse events, including ischaemic stroke or cardiovascular death. A high concentration of ADMA (> 0.55 μmol/L) is a risk factor that is independent of LA size and the CHA ₂ DS ₂ -VASc score .

It therefore appears that the methylated derivatives of L-arginine could potentially be implicated in the onset of AF and its effect on the prognosis of patients. In a recent study, we were able to show that the plasma concentration of ADMA was an independent predictive factor of the onset of AF in the acute phase of MI. This study was the first to suggest that ADMA was a possible cause of AF onset, and not just a consequence of a local increase in oxidative stress linked to the loss of atrial systole and LA stretching .

Ultrasound left atrial size variables: value in atrial fibrillation

LA enlargement has long been known as a risk factor for the onset and persistence of AF . Ultrasound evaluation of LA variables quickly became the reference method to determine LA enlargement in this context. Complementary studies provided evidence of the direct prognostic effect of this variable , by identifying LA enlargement as an independent predictor of a poor prognosis, associated with increases in all-cause mortality after MI, in the risk of stroke and in rehospitalization for cardiac decompensation in patients with heart failure . To explain this association, it was suggested that LA enlargement was a marker of the severity and chronicity of high LA filling pressure and thus diastolic dysfunction of the left ventricle (LV) .

Different threshold values for LA enlargement, assessed according to diameter, area and volume, have been proposed by the European Association of Cardiovascular Imaging and the American Society of Echocardiography . LA volume, especially when its value is indexed to body area, is a particularly robust variable for determining LA enlargement, and was validated by comparison with measurements by computed tomography or cardiac magnetic resonance imaging. LA volume appears to correlate better with cardiovascular diseases, probably because it provides a better evaluation of the sometimes asymmetrical remodelling of the left atrium . These data were confirmed by a study in patients in sinus rhythm, which compared the value of LA size evaluated using either the diameter, area or volume as a predictor of a poor prognosis . Our studies showed that the area of the LA indexed to body area could also be an excellent tool in routine practice to evaluate the risk of AF onset in patients in the acute phase of MI. In multivariable analysis, this variable appeared to be an independent predictor of AF, and this beyond the indexed volume . These results can probably be explained by the accuracy of ultrasound measurements. The area in apical four-chamber and two-chamber views is measured directly by the operator, while the volume is calculated from the areas and longitudinal diameters obtained in the apical four-chamber and two-chamber views. The longitudinal diameters, however, may vary considerably depending on the view, the moment in the cardiac cycle and even the quality of the image obtained.

In our study, LA enlargement was an independent risk factor for inhospital death at 1 year after the acute phase. This major result underlines the central role of the LA in the onset of AF and in its prognostic consequences in the acute phase of MI .

In light of these data, it seemed interesting to evaluate LA function more precisely using more robust tools, such as speckle tracking of the LA. Indeed, this variable, which is easy to assess using current ultrasound techniques, has shown its predictive value in the maintenance of sinus rhythm after cardioversion using external electric shock . Moreover, in patients after non-STEMI, the impairment of LA function evaluated by speckle tracking was significantly greater than that caused by simple enlargement evaluated by the usual variables. In addition, this impaired deformation of the LA was significantly associated with impaired LV function , suggesting that it could help us to understand the mechanisms leading to the onset of AF after MI.