Atrial myopathy is the underlying pathophysiological substrate of atrial fibrillation and contributes to the risk of heart failure as well. Atrial myopathy is caused by classic risk factors such as obesity, inflammation, diabetes, hypertension, and frequent alcohol use, in addition to structural heart and lung diseases that cause atrial pressure or volume overload. An optimal management of atrial fibrillation includes careful assessment of contributors to atrial myopathy, which can be treated by guideline-recommended medical therapies for heart failure, adequate control of congestion, and treatment of comorbid conditions such as sleep apnea syndrome. This approach works synergistically with rhythm control.
Key points
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Atrial myopathy, with its functional and structural alterations, causes atrial fibrillation and reduces cardiac reserve, predisposing to decompensation in heart failure.
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Guideline-directed medical therapies for heart failure and adequate control of congestion prevent or may even reverse harmful atrial remodeling to reduce atrial fibrillation burden, in addition to their favorable effects on heart failure.
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Optimal management of atrial fibrillation includes a focus on and treatment of the multiple pathophysiological contributors to atrial myopathy, which predispose to the arrhythmia.
Introduction
Atrial fibrillation (AF) and heart failure (HF) are important contributors to cardiovascular morbidity and mortality. The prevalence of both conditions is expected to increase, as older age is an important risk factor for both and life expectancy is increasing worldwide. Moreover, obesity and its associated comorbid conditions are a growing problem in developed countries, representing another significant risk factor that is on the rise. The reported prevalence of HF is 1% to 2%, yet this is an underestimation that considers only diagnosed and confirmed cases, while the HF prevalence increases up to 10% in subjects older than 70 years. AF on the other hand is the most common arrhythmia worldwide, affecting 2% to 4% of the population, which is predicted to increase 2.3-fold.
AF and HF are intimately intertwined, each predisposing to and adversely affecting the other. , Importantly, neither AF nor HF are simple diseases characterized by a single common pathophysiological substrate. Instead, both conditions share mutual and diverse risk factors including age, hypertension, diabetes, obesity, and structural heart disease with particular hemodynamic, electrophysiological, neurohumoral, and inflammatory alterations. A diagnosis of AF in HF is associated with a higher mortality risk across the whole spectrum of ejection fraction, which is more pronounced at higher AF burden. Vice versa, when underlying HF is more severe, AF burden becomes greater. ,
Catheter ablation effectively reduces AF burden, which is associated with symptomatic improvement, better quality of life, and potentially improved outcomes if sinus rhythm can be durably maintained. Mounting evidence suggests that this is also the case in patients with HF, despite more pronounced atrial remodeling and AF recurrence in this population. Notably, ablation (or antiarrhythmic drugs) has little impact on the initial drivers of the underlying atrial myopathy. Targeting this pathophysiological substrate therefore has the potential to work synergistically with rhythm control strategies and improve the success of ablation. Unfortunately, HF and comorbid conditions like sleep apnea syndromes or lung diseases remain underdiagnosed and undertreated in patients presenting with symptomatic AF.
This review discusses the pathophysiological intersection between AF and HF, focusing on the concept of atrial myopathy. Furthermore, the importance of guideline-directed medical therapies (GDMT) and adequate control of congestion in HF, including their favorable effect on AF burden, is reviewed. Finally, the importance of diagnosing and treating comorbid conditions that may drive atrial myopathy to cause or worsen both AF and HF is appraised.
The concept of atrial myopathy
HF is a syndrome characterized by the inability to maintain organ perfusion at a rate commensurate with the body’s needs without the requirement of elevated filling pressures. Many different underlying etiologies and disease processes may explain the functional and structural ventricular impairments that cause these hemodynamic alterations; some with dedicated treatment possibilities. Traditionally, the pathophysiological model for HF has been focused on a central role of the left ventricle. Chronic elevations in left-sided cardiac filling pressures may subsequently cause left atrial dysfunction and remodeling, translate to upstream pulmonary hypertension, increase right ventricular afterload, and ultimately lead to right ventricular failure. However, many insults that impact on the left ventricle may directly influence atrial function and structural integrity as well. In fact, in some cases, particularly of HF with preserved ejection fraction (HFpEF), the atrial disease may dominate the phenotype, hence HFpEF with an atrial myopathy phenotype. There is a clear relationship between the severity of left atrial myopathy and AF burden in HFpEF, which translates into more pronounced hemodynamic impairments and worse prognosis. Therefore, an optimal management of any patient presenting with AF should always include a broad evaluation for contributing factors to the underlying atrial myopathy that may be tackled.
Heart failure and atrial fibrillation predispose to each other
The interplay between AF and HF is multifaceted, with each condition predisposing to the other through different mechanisms and the common denominator being atrial myopathy. Understanding this relationship is critical to appreciate the role of HF treatment in the prevention of AF ( Fig. 1 ).
Heart Failure Begets Atrial Fibrillation
HF may cause the development of AF by several mechanisms. First and foremost, HF is associated with chronic elevations of the atrial pressures, which promotes atrial stretching, dilation, scarring, and fibrosis, hence atrial myopathy. In animal studies, these anatomic changes have been associated with slowed conduction velocity, anisotropy, shortened action potential duration, and a reduced effective refractory period that facilitate re-entry and predispose to AF. Of note, atrial dysfunction and remodeling are not homogeneous across HF subtypes. In patients with reduced ejection fraction (HFrEF), more typical eccentric left atrial remodeling is observed, whereas in patients with HFpEF, increased left atrial stiffness predominates. Atrial dilation and more pronounced congestion, reflected by higher natriuretic peptide levels, are associated with increased pulmonary vein-related spontaneous firing activity, which is an important trigger of AF. On a microcellular level, HF is accompanied by important abnormalities in calcium homeostasis that may promote AF as well. Intracellular calcium is regulated primarily by the ryanodine receptor and sarcoplasmic reticulum calcium-ATPase. Atrial stretch and increased filling pressures decrease the expression of L-type calcium channels in atrial myocytes, resulting in reduced transmembrane calcium influx and calcium-induced calcium release from the sarcoplasmic reticulum, which predisposes to delayed after-depolarizations and susceptibility to AF.
Although initially adaptive, excessive neurohumoral activation is a key driver of HF progression, at least in HFrEF, which has proven to be an important treatment target with GDMT. Neurohumoral activation also plays a role in the development of AF. Higher circulating catecholamine levels, resulting in stimulation of beta-adrenergic receptors, may trigger AF by non-re-entrant mechanisms, including abnormal automaticity and triggered activity. Furthermore, angiotensin II and activation of the mineralocorticoid receptor drive adverse remodeling by activating pro-fibrotic pathways, which is the case in both the ventricles and atria, providing a substrate for AF. Moreover, peripheral congestion, which is a hallmark of the HF syndrome, causes inflammation, neurohumoral, and endothelial cell activation. The chronic pro-inflammatory state associated with HF and marked by the presence of multiple cytokines such as interleukin-6, transforming growth factor beta1, and tumor necrosis factor alpha, leads to structural and electrical remodeling of atrial myocytes that predisposes to the development of AF.
Both ventricular and atrial remodeling contribute to annular dilation, reduced closing forces of the atrioventricular valves, and increased tethering forces on the valve apparatus, causing secondary or functional atrioventricular valve regurgitation. This further amplifies the volume load imposed on the atria, which accelerates the process of atrial dilation and fibrosis, hence augmenting the AF risk.
Atrial Fibrillation Begets Heart Failure
On its turn, AF predisposes to HF through several mechanisms. The direct consequence of an increased heart rate and irregular rhythm in AF is impaired ventricular filling because of a shortened filling time and less synchronous contraction pattern. , The loss of effective atrial contractile function further worsens ventricular filling and diastolic function. The hemodynamic consequences are a decreased cardiac output and increased cardiac filling pressures. Notably, irregular ventricular rate has been associated with a ∼25% reduction in cardiac output because diastolic filling during long cycles does not offset reduced filling during short cycles. Chronic elevation of cardiac filling pressures may predispose to atrial and ventricular remodeling, which propagates abnormal atrial pressures in a vicious cycle leading to worsening AF and HF.
In some cases, AF may directly cause myocardial dysfunction with impaired contractility, resulting in tachycardia-induced cardiomyopathy. This is a reversible condition, as per definition, left ventricular systolic dysfunction resolves with the treatment of the underlying arrhythmia or tachycardia. Although the pathophysiological substrate of tachycardia-induced cardiomyopathy remains incompletely understood, impaired excitation-contraction coupling and diastolic dysfunction are postulated to result from electrical remodeling and abnormalities in calcium homeostasis. While AF represents the most common cause of tachycardia-induced cardiomyopathy, other fast and irregular arrhythmias including frequent ventricular ectopy may similarly impair left ventricular systolic function. The exact prevalence of tachycardia-induced cardiomyopathy in patients with AF remains unclear, yet some component has been observed in up to 50% of patients who simultaneously present with left ventricular dysfunction and AF.
While it is well-known that atrioventricular valve regurgitations may cause AF because of the hemodynamic stress imposed on the atria, it is less appreciated that AF directly impairs valve function as well. As described earlier, AF accelerates the process of harmful atrial remodeling that results in annular dilation, yet in addition, its presence has important consequences for annular-leaflet balance. Mitral annular dynamics are impaired in AF, with blunted presystolic narrowing (ie, annular contraction), which contributes to mitral valve regurgitation. Restauration of sinus rhythm allows gradual recovery of presystolic annular dynamics that may take some time because of atrial stunning in the post-reconversion period. Interestingly, improved annular dynamics decrease mitral valve regurgitation severity by optimizing annular-leaflet imbalance, regardless of left atrial remodeling.
Causes of development and progression of atrial myopathy
Heart Failure
The presence of AF signals an underlying pathophysiological substrate. As argued earlier, atrial myopathy most likely represents the structural substrate and underlying HF, the most likely cause. While the diagnosis of HFrEF or severe valve disease is rather obvious and not frequently missed because most patients presenting with AF will undergo an echocardiography, the assessment of HFpEF is less straightforward. Gold standard diagnostic criteria are based on invasive hemodynamic measurements including an evaluation during exercise, which is cumbersome to perform. Other diagnostic tests or strategies all suffer from imperfect negative predictive values, especially in populations with a high prevalence of HFpEF. For this reason, in many patients presenting with AF, concomitant HFpEF may go undetected, especially when dyspnea or exercise intolerance are not the most prominent complaints. Importantly, the presence of AF on its own is one of, if not the strongest predictor of underlying HFpEF. A correct and early diagnosis of HFpEF is therefore very important, especially as treatments are emerging that may have favorable consequences for AF as well.
Obesity, Hypertension, and Diabetes
A careful evaluation for underlying HFpEF with left atrial myopathy will result in many patients with lone AF being reconsidered as concomitant AF and HFpEF cases, caused by underlying left atrial myopathy. The classic HFpEF risk factors such as obesity, hypertension, and diabetes are all associated with left atrial dysfunction and remodeling in an exposure time-dependent and severity-dependent relationship. Identifying and treating those risk factors is therefore a fundamental part of both the AF and HFpEF management. ,
Alcohol Use
Alcohol consumption is embedded in Western culture, with many regular users. Observational studies show a dose-dependent relationship between alcohol intake and left atrial dilatation, fibrosis, incident AF, and AF recurrence after ablation. In a multicenter, randomized trial including adults (n = 140) who used at least 10 consumptions per week and had either paroxysmal or persistent AF, a significant reduction in AF burden was observed with abstinence. This effect was mediated by electrical, (micro) structural, and functional improvements in atrial function, again reinforcing the concept of atrial myopathy as one of the primary causes for AF.
Excessive Sporting
While regular exercise is well-recognized to have many beneficial effects on cardiovascular and general health, intense endurance sports increase the risk of atrial arrhythmias including AF, in particular for men. Although atrial (and ventricular) chamber dilation is typical in such cases, it is reversible with detraining and not associated with the classic changes of atrial myopathy including atrial fibrosis. The exact mechanisms of sport-induced atrial arrhythmias remain insufficiently elucidated, yet it probably reflects a load of hemodynamic stress during exercise that is disproportionately high for the underlying atrial functional reserve. Autonomic nervous system remodeling with consequent electrical abnormalities may also play an important role. Therefore, also in this scenario, there is likely an underlying microstructural and/or electrical substrate for AF.
Genetic Cardiomyopathies
Importantly, some genetic cardiomyopathies (eg, lamin A/C mutations) may present as AF months or years in advance of ventricular dysfunction development. Therefore, instead of concluding the presence of lone AF, a thorough search for clues of a genetic syndrome and low-threshold consideration of genetic testing should be performed in patients who lack an underlying substrate or risk factors for atrial myopathy as an explanation for AF.
Lung Diseases
Both obstructive and restrictive lung diseases are associated with a higher risk of AF development, with a stronger relationship when lung function abnormalities are more pronounced. The consequences of lung diseases for the right ventricle are well-recognized with increased afterload due to hypoxic lung diseases causing right ventricular hypertrophy and dilation (ie, cor pulmonale). However, cardiac involvement in lung diseases is not exclusively ventricular and may apply to the right atrium as well. In fact, right atrial size and function represents an important prognostic factor in patients with pulmonary hypertension, while right atrial dysfunction reflects the hemodynamic severity of a pulmonary embolism and may cause AF as a presenting symptom. On the long-term, poor control of AF resulting from predominant right atrial myopathy may promote the development of left atrial myopathy as well (or vice versa), resulting in overlapping syndromes between lung diseases and HFpEF that may conceal the initiating trigger or event.
Discussion of the management of atrial myopathy
A strategy of early rhythm control is important to prevent progression of atrial myopathy and reduce the adverse consequences of both AF and HF. Catheter ablation outperforms even the most effective drugs to reduce AF burden, especially when employed early. A more in-depth discussion of the role of catheter ablation in HF is provided elsewhere in this issue, but encouraging data promote a more liberal use. Nevertheless, the risk of AF recurrence is greater in this population and the underlying disease process might eventually become so advanced that the procedure becomes futile because sinus rhythm cannot be maintained or atrial function is so damaged that there is no mechanical contribution possible, even with sinus rhythm restored through aggressive ablation techniques. Importantly, neither ablation nor anti-arrhythmic drugs have any impact on the initial risk factors for atrial myopathy development. Therefore, it is vital to identify and address these risk factors, which often enables more successful rhythm management as well.
Guideline-Directed Medical Therapies for Heart Failure
GDMT is the cornerstone of pharmacologic management in HF, with proven benefits on cardiovascular morbidity and mortality. Importantly, GDMT for HF has shown to have concomitant beneficial effects on AF as well, by preventing or reversing underlying atrial remodeling and fibrosis.
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers
Table 1 presents the evidence in favor of renin-angiotensin system blockers to prevent AF, coming from secondary analyses of large clinical trials in patients with HF (mainly HFrEF). In the S tudies O f L eft V entricular D ysfunction (SOLVD) trial, which included 374 patients with HFrEF and no history of AF, enalapril therapy was associated with a lower incidence of AF over 2.9 years (5.4% vs 24% with placebo; P <.0001). Similarly, in a secondary analysis of the Tra ndolapril C ardiac E valuation (TRACE) trial, involving 1,577 patients with left ventricular systolic dysfunction after a previous myocardial infarction and without known AF, randomization to trandolapril was linked to a lower risk of AF development (2.8% vs 5.3% with placebo; P <.05). Comparable findings on AF prevention in HF have been reported with angiotensin receptor blockers. In an analysis from the V alsartan He art F ailure T rial (Val-HeFT) that analyzed 4,395 patients with HFrEF and sinus rhythm at baseline, randomization to valsartan was associated with less frequent occurrence of AF (5.1% vs 8.0% with placebo; P <.0002). In the C andesartan in H eart Failure A ssessment of R eduction in M ortality and Morbidity (CHARM) program that recruited 6,379 patients with symptomatic HF across the spectrum of ejection fraction who were in sinus rhythm at enrollment, candesartan treatment did reduce the risk of incident AF (5.6% vs 6.7% with placebo; P = .048). A meta-analysis of randomized clinical trials evaluating the role of renin-angiotensin system blockers in HF demonstrated similar effects of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers to prevent AF, with an overall relative risk reduction of 44%. This reduction was more pronounced when left ventricular systolic dysfunction was more severe.
