What is the role of atrial remodeling and atrial cardiomyopathy in heart failure?

There is a strong association between atrial fibrillation (AF) and heart failure (HF): not only do 50% of patients with AF develop HF, but the prevalence of AF increases with the severity of HF (and with age). The prevalence of AF approximates 20% in HF trial populations and 40% in community epidemiologic studies. There is a reciprocal association between the two conditions. HF increases the risk of AF 4.5-fold and 5.9-fold in men and women, respectively.

In addition to conditions such as mitral stenosis, which have a specific and direct impact on atrial pathophysiology, the ventricular pump dysfunction and neuroendocrine changes that characterize the HF syndrome are associated with high-frequency depolarization of the fibrillating atrium. This induces atrial remodeling and has generated the concept of atrial tachycardia-dependent cardiomyopathy. Atrial remodeling refers to the constellation of atrial changes in electrophysiology, ion channels, biochemistry, anatomy, histology, and mechanics resulting from sustained bouts of atrial tachyarrhythmia interspersed with the restoration of sinus rhythm.

Experimental data

The results of animal studies in chronic AF over the last decade show strong interspecies similarities (mainly between dog and goat). In the absence of heart disease, it takes high-frequency atrial stimulation for several days or weeks to induce transient episodes of AF. Many substantial electrophysiologic changes occur in atrial myocardium in the first few hours of stimulation, notably a 1/3 reduction in the effective refractory period and a decreased ability to further reduce the refractory period and thus further shorten the cardiac cycle. The functional flexibility of the ion channels is decreased. Restoration of sinus rhythm is followed by a gradual reversal of the refractory period changes over approximately 1 week, with the inducibility of AF remaining heightened for a rather longer period.

The ion channel changes underlying these electro-physiologic responses comprise:

An up to 70% decrease in potassium currents in the first few hours of stimulation, mainly involving the ^transient outward K+ (Ao) current

A similar rapid decrease in L-type calcium channels (FcaL)

No change in sodium currents.

The electrophysiologic responses appear due to a decrease in the number of active channels rather than to any change in their functional characteristics.

More recent studies have focused on connexins (Cx), the intercellular proteins that conduct stimuli from cell to cell through gap junctions. Three myocardial connexins have been described: Cx40, Cx43 and Cx45, only the first of which is atrium-specific. Connexins are normally located at the cell extremities to facilitate longitudinal conduction of the stimulus. Their distribution is sensitive and responsive to depolarization wave direction. For example, lengthening the period of electrical stimulation modifies the distribution of gap junctions and connexins in the cell membrane. A fundamental characteristic of electrophysiologic remodeling is believed to be the redistribution of connexins. They gather in longitudinal and transverse heterogeneous heaps, substantially modifying stimulus conduction.

The main structural and anatomic changes consist of progressive dilatation, characterized histologically and histochemically by mitochondrial dilatation, glycogen accumulation, loss of sarcoplasmic reticulum, and myofibril degeneration, which together have obvious mechanical and electrophysiologic consequences.

Clinical data

The clinical data are qualitatively similar to those obtained in animals. In patients cardioverted to sinus rhythm after episodes of AF lasting weeks to 3 months, the atrial monophasic potential is shorter and does not adjust to changes in the cardiac cycle. Serial electrophysiology over 4 days after cardioversion in patients with AF for more than 6 months shows progressive lengthening of the atrial refractory period and gradual recovery of the ability of refractory periods to adjust to heart rate. Conduction velocity, on the other hand, remains essentially unchanged over the same period and markedly inferior to control population values. Recent studies on peroperative atrial biopsy samples show a heterogeneous cell population in patients with AF: the refractory period is short in some cells and longer in others, with a limited adaptability to changes in frequency, ie, atrial tissue displays marked electrophysiologic dispersion.

Studies on ion channel function show results similar to those in experimental animals:

Marked decrease in potassium channels, mainly the Aoi -fc ultra-rapid (-four) and Isustained {has) Currents.

Marked decrease in calcium channels, with significant reduction in the a] subunit in patients with AF for more than 6 months; regulatory proteins in the calcium cycle (eg phospholamban) do not appear dysfunctional.

No substantial changes in sodium channels.

Human tissue also shows connexin changes, with a decrease in Cx43 and an increase in Cx40 in parallel with a decrease in conduction velocity.

Atrial stunning

It has been know for some time that atrial mechanical function remains depressed after electrical cardioversion of AF. The time course of this effect was recently studied in greater detail using transmitral

Doppler echocardiography to measure the A wave (peak atrial systolic flow velocity) immediately after cardioversion, then at 24 hours and 7 days. After AF for less than 2 weeks, atrial systolic flow increases gradually, returning to normal in under 7 days; after AF for 2 to 6 weeks, it improves but fails to return to normal levels; after AF for more than 6 weeks, it remains very low at 7 days. Normal function may return in such patients, but only after 1 to 3 months. The modality of cardioversion pharmacologic or electrical appears irrelevant to the restoration of atrial mechanical function.

Progression of atrial remodeling in heart failure

Experimental studies on the chronology of atrial remodeling in HF, notably in dogs subjected to various modalities of atrial stimulation, have yielded the following results:

Metabolic remodeling occurs minutes after initiating stimulation: ion concentrations change according to the frequency used, and the kinetics of channel activation and inactivation are also modified.

Electrical remodeling occurs after hours to days, caused by changes in the expression of the genes regulating ion channels and intercellular connections.

Mechanical remodeling follows after several weeks, with atrial dyskinesia, the emergence of stunning, and cellular differentiation.

Anatomic remodeling is observed after months or years, and comprises fibrosis, irreversible cellular degeneration, and a tendency to atrial dilatation; apoptosis may ensue.

Clinical implications

The above data indicate that AF occurs with particular frequency in HF due to the creation, by a combination of neuroendocrine and anatomic factors, of a favorable electrophysiologic context. The essential components are electrophysiologic heterogeneity at the cellular level and stimuli such as atrial extrasystoles or rapid focal discharges. Once triggered, AF induces changes in atrial function that both complicate the restoration of sinus rhythm and prolong the abnormalities post-cardioversion.

On the other hand, AF may simply be a single episode of destabilization, albeit clinically spectacular and patho-physiologically relevant, marking the course of a pathology, HF, with a progression of its own, much like myocardial infarction in a context of coronary heart disease. Atrial electrophysiologic signal analysis using signal averaging in patients with marked left ventricular dysfunction followed up over a mean 19-month period showed that AF developed in 32% of those with atrial

Further reading

AJIessie M, Boy den PA, Camm AJ, et al. Pathophysiology and prevention of atrial fibrillation. Circulation. 2001;103:769-777.

Dunn Ml, Marcum JL Atrial mechanical performance following internal and external cardioversion of atrial fibrillation: its relationship to peripheral embolization and acute cerebrovascular accident. Chest. 2002; 121:1-3.

Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998;82:2N-9N.

Morton JB, Byrne MJ, Power JM, Raman J, Kalman JM. Electrical remodeling of the atrium in an anatomic model of atrial flutter: relationship between substrate and triggers for conversion to atrial fibrillation. Circulation. 2002;105:258-264.

Nattel S. Atrial electrophysiological remodeling caused by rapid atrial activation: underlying mechanisms and clinical relevance to atrial fibrillation. Cardio-vascRes. 1999;42:298-308.

Pozzoli M, Cioffi G, Traversi E, Pinna GD, Cobelli F, Tavazzi L Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: a prospective study in 344 patients with baseline sinus rhythm. J Am Coll Cardiol. 1998;32:197-204. Scheinman M. Mechanisms of atrial fibrillation: is a cure at hand? J An Coll Cardiol. 2000,35:1687-1692. electrical abnormalities vs in only 2% of those without. In another prospective study in patients with HF, Pozzoli et al observed that transient echocardiographic changes in atrial kinetics were predictive of AF. These findings suggest that an atrial cardiomyopathy develops in HF which is largely asymptomatic until brought to notice when a series of factors converge to trigger AF. Our improved understanding of atrial remodeling, with particular respect to the role of ion channels and connexins, should soon generate new hypotheses and new drugs to forestall and reverse AF in patients with HF.

Schoonderwoerd BA, Van Gelder 1C, van Veldhuisen DJ, et al.

Electrical remodeling and atrial dilation during atrial tachycardia are influenced by ventricular rate: role of developing tachycardiomyopathy. J Cardiovasc Elec-trophysiol. 2001; 12:1404-1410. van der Velden HM, van Kempen MJ, Wijffels MC, et al. Altered patterns of connexin40 distribution in persistent atrial fibrillation in the goat. J Cardiovasc Eledrophysiol. 1998;9:596-607.

Van Wagoner DR, Pond AL, Lamorgese M, Rossie SS, McCarthy PM, Nerbonne JM. Atrial L-type Ca2+ currents and human atrial fibrillation. Circ Res. 1999,85:428-436.

Yamada T, Fukunami M, Shimonagata T, et al. Prediction of paroxysmal atrial fibrillation in patients with congestive heart failure: a prospective study. J Am Coll Cardiol. 2000;35:405-413.

Yue L, Melnyk P, Gaspo R, Wang Z, Nattel S. Molecular mechanisms underlyinq ionic remodelinq in a doq model of atrial fibrillation. Circ Res. 1999;84:776-784.

Zipes DP. Atrial fibrillation: a tachycardia-induced atrial cardiomyopathy. Circulation. 1997;95:562-564.


pathophysiology; atrial remodeling; cardiomyopathy; atrial fibrillation; atrial stunning; electrophysiology; neuroendocrine factor

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