Atrial fibrillation (AF) is one of the most prevalent cardiac arrhythmias in the world. Patients with AF also suffer from heart failure (HF). The relationship between AF and HF is often considered bidirectional and both share very similar risk factors. The mechanism of AF-induced cardiomyopathy lies in 3 distinct components: tachycardia-related cardiac dysfunction, heart rhythm irregularity, and AF-induced atrial myopathy. These components are mediated by calcium mishandling, neurohormonal activation, oxidative stress, myocardial supply–demand mismatch, and irreversible fibrosis and remodeling. Managing AF-induced cardiomyopathy should focus on early rhythm control to mitigate the development of irreversible remodeling and atrial myopathy.
Key points
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Atrial fibrillation (AF) is highly prevalent in the general population and is capable of causing cardiomyopathy.
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AF induces cardiomyopathy through calcium mishandling, neurohormonal activation, oxidative stress, myocardial supply–demand mismatch from tachycardia, and heart rhythm irregularity.
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Management of AF-induced cardiomyopathy should emphasize early rhythm control to mitigate the development of irreversible remodeling.
Introduction
Atrial fibrillation (AF) is one of the most prevalent cardiac arrhythmias in the world. It is estimated that by the year 2030, a total of 12.1 million adults in the United States will suffer from AF. Longitudinal follow-up from both the Framingham Health Study (FHS) and the Biomarker for Cardiovascular Risk Assessment in Europe consortium both reported that approximately one-third of individuals will develop AF during their lifetime. , AF is often considered a disease of aging, with an increasing risk of occurrence as individuals grow older, and advanced age is considered the most potent risk modifier for AF. In the FHS cohort, individuals aged 60 to 69, 70 to 79 and 80 to 89 years had 4.98 fold, 7.35 fold, and 9.33 fold, respectively, higher risk of developing AF compared to those aged 50 to 59 years.
Often, patients with AF also suffer from heart failure (HF). Statistics from the FHS reported the lifetime risk of developing HF at the age of 40 years was around 20% to 21% in the general cohort, and this risk decreased to 11% to 15% in those without lifetime incidence of myocardial infarction. The relationship between AF and HF is often considered bidirectional and both share very similar risk factors. Patients with HF are at an increased risk of developing AF compared to those without. In HF with preserved ejection fraction (HFpEF) studies, AF prevalence ranged from 25% to 39%, while in the HF with reduced ejection fraction (HFrEF) population, it ranged from 5% to 50%. As the degree of HF worsens, measured by the New York Heart Association functional class, the prevalence of AF increases. Population-level studies from several North American cohorts have shown that existing HF diagnosis imposes 2 to 4 fold the risk of developing AF. ,
Likewise, AF can potentiate the risk of cardiomyopathy. Meta-analysis from more than 100 cohort studies involving more than 9.6 million patients (among them 587,867 patients with AF) suggested that having AF increases the risk of developing HF up to 5 times compared to those without. Interestingly, one cohort study showed that in patients with AF who develop HF, more patients develop HFpEF rather than HFrEF (61% vs 39%). This is possibly because AF is a supraventricular arrhythmia and induces atrial dysfunction first, often manifesting as diastolic dysfunction. This higher prevalence of AF in HFpEF compared to HF with mildly reduced ejection fraction and HFrEF was also observed in a Swedish registry study, which analyzed 41,446 patients (44% vs 37% vs 29% respectively). The intertwined and often symbiotic relationship between AF and HF makes it difficult for researchers and clinicians to distinguish their exact temporal association. In an attempt to describe the temporal relationship between AF and HF using the FHS cohort, 41% of patients developed HF first, 38% AF first, and 21% received both diagnoses on the same day. Nevertheless, enough evidence spanning basic molecular biology, preclinical animal studies, and clinical comparative analysis has shown that AF induces cardiomyopathy. In this review, we aim to describe the existing evidence on how AF induces cardiomyopathy.
Discussion
The mechanism of how AF induces cardiomyopathy should be conceptualized in 3 distinct components: (1) tachycardia-related cardiac dysfunction, (2) heart rhythm irregularity, and (3) AF-induced atrial myopathy.
Tachycardia-Related Cardiac Dysfunction
One of the earliest and most common manifestations of AF in the general population is rapid ventricular rate episodes. These paroxysms of tachycardia often result in overt symptoms such as palpitations, chest pain, shortness of breath and dizziness from acute hemodynamic changes. Tachycardia-induced cardiomyopathy (TIC) is not only seen in AF but also in other supraventricular arrhythmias such as incessant atrial tachycardia, or in younger populations, permanent junctional reciprocating tachycardia.
The most salient features of TIC derived from animal studies include biventricular dilatation and thinning without change in ventricular mass or hypertrophy. Preclinical animal studies compared ventricular physiology, function, and myocardial blood flow using 3 groups of pigs: control versus 3 weeks of atrial pacing at 240 beats per minute (bpm) versus 4 week recovery from atrial pacing. After each week of rapid atrial pacing, left ventricular (LV) end-diastolic volume, wall stress, and left atrial pressure increased, accompanied by decrease in left ventricular ejection fraction (LVEF). From a global hemodynamic standpoint, these changes lead to decrease in systemic blood pressure and increase in LV and pulmonary artery pressures that result in symptomatic HF after 2 to 3 weeks. In terms of myocardial blood flow, a significant reduction compared to baseline level was observed during tachycardia and did not recover to baseline level after tachycardia termination. On the myocardial cellular level, persistent tachycardia led to myocyte lengthening, decrease in the volume percent of myocytes within the ventricular wall, and the volume percent of myofibrils within myocytes. One week after termination of rapid atrial pacing, LV contractile function recovers to pre-existing levels. However, this functional recovery was mainly driven by LV hypertrophy that developed during the posttachycardia stage while LV dilation persisted. Microscopically, the recovery phase was also characterized by myocyte hypertrophy and nuclear hyperplasia. These findings were further validated in the clinical setting where patients with TIC exhibited persistent diffuse ventricular fibrosis evidenced by reduced global LV-corrected T1 time on cardiac MRI despite the cure of atrial arrhythmias. Recently, histopathological evidence of atrial biopsy, guided by electroanatomical mapping in patients with AF also demonstrated that the histologic changes involves fibrosis, myofibrillar loss, and increased intercellular space.
Heart Rhythm Irregularity
While AF is a type of supraventricular tachycardia, heart rhythm irregularity is the most important distinction of the pathogenesis of AF-induced cardiomyopathy from other tachycardia-induced cardiomyopathies. Several mechanisms have been proposed to explain the contribution of heart rhythm irregularity to the development of HF.
Calcium mishandling
Ca 2+ ions are the most crucial triggers of myocardial contraction, and abnormal influx/efflux of Ca 2+ ions impairs macroscopic chamber function. Ling and colleagues compared Ca 2+ dynamics in 2 groups of rat ventricular myocytes paced at the same frequency (2 Hz average = 120 bpm) with one group receiving regular interval pacing and the other receiving irregular pacing patterns. The irregularly paced group exhibited a 59% reduction in peak Ca 2+ transient amplitude compared to the regularly paced group after only 24 hours of pacing. In addition, there was a reduction in the expression of sarcoplasmic reticulum Ca 2+ ATPase and reduced serine-16 phosphorylation of phospholamban. Similar findings were reproduced in the LV myocardium of patients with HF in AF compared to those in sinus rhythm. In another study comparing Ca 2+ handling in patients with chronic AF and sinus rhythm, inadequate Ca 2+ flow in chronic AF is associated with impaired phosphorylation of myosin binding protein-C, leading to contractile dysfunction. One recent study showed that in patients with persistent AF, there was a loss of myofilament proteins and reduced cardiac troponin C levels. This caused diminished cytosolic Ca 2+ buffering, potentiating spontaneous Ca 2+ release, AF susceptibility, and contractile dysfunction. This evidence points to the fact that an irregular heart rhythm from AF is capable of inducing myocardial Ca 2+ mishandling independent from regularized supraventricular tachycardia.
Neurohormonal changes and oxidative stress
The sympathetic nervous system (SNS) has been implicated in the development of HF due to the enhancement of excitatory inputs that leads to abnormal hemodynamic profiles. SNS stimulates beta-1 adrenergic receptors and triggers renin-angiotensin-aldosterone system (RAAS), which is a key component in the development of LV dysfunction. Till this day, the reduction of RAAS remains one of the most fundamental therapeutics pillars in modern HF management. On this note, AF has been shown to potentiate SNS that leads to its detrimental downstream hemodynamic imbalance. In an early small study, in which 8 patients with AF were referred for electrophysiology study, sympathetic nervous activity released by efferent postganglionic muscles were recorded and showed 171 ± 40% increase during induced AF episodes compared with normal sinus rhythm. This was also accompanied by a decrease in BP and increased central venous pressure.
The role of oxidative stress and reactive oxidative species has also been explored in the association between AF and development of cardiomyopathy. Patients with AF had greater calcium/calmodulin-dependent protein kinase II (CaMKII)-Met 281/282 oxidation and increased oxidative stress in their ventricular myocardial samples compared to those without AF. Interestingly, pathologic myocardial changes from AF were improved by weeks of antioxidant treatment including beta-carotene, ascorbic acid, and alpha tocopherol, hinting at a potentially causative relationship between AF, oxidative stress, and cardiomyopathy. ,
Myocardial supply–demand mismatch
AF also causes supply–demand mismatch due to relative coronary malperfusion and decreased myocardial blood flow. In a prospective age-matched and gender-matched cohort study, patients with AF without obstructive coronary artery disease had higher thrombolysis in myocardial infarction (TIMI) frame rate counts in all 3 coronary arteries compared to those without AF, indicating decreased flow. Similar results were reproduced in another study also documenting increased coronary vascular resistance. When these patients were electrically cardioverted to sinus rhythm, myocardial blood flow improved, indicating the change in coronary perfusion was likely caused by AF. Supply–demand mismatch also results in mitochondrial dysfunction. Swine rapid atrial pacing models demonstrated reduction in Na/K ATPase activity with abnormal channel location (patchy vs uniform distribution) within myocytes. Moreover, LV myocytes had decreased response to cardiac glycosides when stimulated with ouabain. , There is also evidence of mitochondrial swelling and rupture with reduced density after 2 weeks of rapid pacing.
Atrial Fibrillation-Induced Atrial Myopathy
As evidenced by epidemiologic studies, more patients with AF develop HFpEF. One can infer that AF induces diastolic dysfunction and atrial myopathy more frequently than ventricular dysfunction. One of the most macroscopic pieces of evidence of atrial myopathy as a result of long-standing AF is left atrial dilatation. Modern multimodality imaging techniques such as cardiac MRI, high-density electroanatomical mapping (EAM), and intracardiac echocardiography combined with histopathological data are pointing toward atrial myopathy as a type of cardiomyopathy that cannot be ignored.
While the common notion that cardiac function would return to normal after the termination of atrial arrhythmias in arrhythmia-induced cardiomyopathy, some disease burden never recovers completely. Takahashi and colleagues reported one of the largest endomyocardial atrial biopsy AF cohorts to date by performing EAM-guided biopsy during AF ablation. They reported the common atrial histologic changes in AF including (1) interstitial fibrosis with the accumulation of collagen fibrils; (2) parenchymal degeneration with myofibrillar loss; (3) atrial myocardial hypertrophy greater than 12 μm with decrease in cardiomyocyte nuclear density; (4) changes in the size, shape, and numbers of mitochondria; (5) changes in connexin expression; (6) amyloid deposition; and (7) lymphomononuclear infiltration. These histologic changes lay the foundation of understanding atrial scar/fibrosis and phenotypical myopathy. Moreover, the extent of intercellular space and fibrosis was more advanced in long-standing persistent AF than in paroxysmal AF and was associated with atrial tachyarrhythmia recurrence after AF ablation.
Translating preclinical understandings to clinical management, atrial structural remodeling is identified as late gadolinium enhancement (LGE) on cardiac MRI, and extensive LGE (≥30% LA wall enhancement) predicts poor response to catheter ablation therapy for AF. In the DECAAF study, every 1% increase in left atrial fibrosis burden resulted in a 6% increased hazard ratio of arrhythmia recurrence after ablation. When the amount of fibrosis was stratified by stage 1 (<10% of the atrial wall), 2 (≥10%–<20%), 3 (≥20%–<30%), and 4 (≥30%), 1 year arrhythmia recurrence was 15.3%, 32.6%, 45.9% and 51.1%, respectively. The CAMERA-MRI study investigated the reversibility of AF-induced cardiomyopathy (LVEF ≤45%) in the persistent AF population undergoing AF ablation and found that the absence of LGE predicted greater improvements in absolute LVEF of 10.7% and higher chance of LVEF normalization (73% vs 29%). This evidence points to the necessity of early correction of AF to prevent irreversible remodeling and cardiac dysfunction. It is important to note that simply achieving rate control is not enough. As demonstrated previously, heart rhythm variability is capable of inducing cardiomyopathy alone irrespective of heart rate, therefore emphasizing the need for early rhythm control.
Management of atrial fibrillation-induced cardiomyopathy
Large randomized controlled studies have demonstrated that rhythm control through either antiarrhythmics or catheter ablation not only improves cardiac function but also mortality and hospitalization in the HF population ( Fig. 1 ). The CASTLE-AF study demonstrated that catheter ablation in the AF and HF population reduced all-cause mortality and HF hospitalization. The more recent CASTLE-HTx study took a step further to demonstrate that ablation and rhythm control should still be considered in a sicker HF population suffering from recurrent AF. The post hoc analysis of the EAST AFNET-4 study showed that the long-term use of sodium channel blocker therapy for early rhythm control appeared to be safe in selected patients with stable coronary artery disease (CAD) and HF. In this subanalysis, either flecainide or propafenone was given to 689 patients for a median duration of 1153 days, among which 177 had diagnosed HF, 41 with prior myocardial infarction (MI), coronary artery bypass graft (CABG), or percutaneous coronary intervention (PCI).
