Catheter ablation (CA) for atrial fibrillation (AF) in patients with heart failure with preserved ejection fraction (HFpEF) addresses the significant overlap of these conditions, often found in patients with comorbidities such as obesity, diabetes, and hypertension. HFpEF is characterized by diastolic dysfunction, leading to high left atrial pressures and atrial remodeling, which promotes AF. While treatments for HFpEF are limited, recent studies suggest CA can reduce AF burden, improve quality-of-life, and lower hospitalization rates. Current and upcoming randomized trials aim to establish CA’s role as a first-line therapy for AF in HFpEF, potentially transforming patient outcomes.
Key points
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The interplay between 2 pathologies: Atrial fibrillation and heart failure with preserved ejection fraction (HFpEF) are closely interconnected, sharing pathophysiologic mechanisms such as elevated left ventricular end-diastolic pressure, atrial remodeling, and fibrosis.
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Evidence on catheter ablation : Previous studies have demonstrated that CA significantly reduces arrhythmia recurrence and improves clinical outcomes compared to medical therapy.
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Risk of catheter ablation : Pulsed field ablation is a promising alternative to traditional thermal ablation methods, offering reduced risk of fibrosis and preserving atrial function in HFpEF patients.
Introduction: the mutual relationship between heart failure and atrial fibrillation
Heart failure (HF) is a complex clinical syndrome resulting from structural or functional impairments in cardiac contraction or filling. HF is prevalent in 1% to 3% of adults, with incidence increasing with age. Key symptoms include exercise intolerance and dyspnea on exertion, alongside fatigue, peripheral edema, orthopnea, paroxysmal nocturnal dyspnea, loss of appetite, and nycturia. Current guidelines classify HF based on left ventricular ejection fraction (EF), between heart failure with reduced EF (HFrEF) if EF is less than 40%, heart failure with mildly reduced EF if EF is between 41% and 49% and evidence of spontaneous or provocable increased left ventricle (LV) filling pressures, and heart failure with preserved ejection fraction (HFpEF) if EF greater than or equal to 50% and evidence of spontaneous or provokable increased LV filling pressures. Despite similar signs and symptoms, differences in pathophysiology and treatment exist between HFrEF and HFpEF. HFrEF is characterized by impaired LV contraction, leading to fatigue, exercise intolerance, and congestion due to low cardiac output and elevated end-diastolic pressure. This pressure is transferred to pulmonary, portal, and peripheral circulations, causing edema. In HFpEF, the LVEF is normal but end-diastolic pressure and congestion are severe, driven by diastolic dysfunction, subtle systolic dysfunction, atrial and LV stiffness, and reduced arterial compliance. Diagnosis of HFpEF is challenging Diagnosing HFpEF involves a comprehensive approach that includes various echocardiographic parameters and natriuretic peptide assay results, and often requires a stress test. HFpEF is defined by intricate and interconnected pathophysiologic mechanisms that need thorough understanding. This complexity likely contributes to the limited evidence-based medicine available for HFpEF compared to HF with reduced EF. Prognosis of HFpEF remains poor, with 5-year mortality around 75%, comparable to advanced cancers. While neurohumoral drugs, device therapy, and cardiac rehabilitation have improved survival in HFrEF, no treatment has consistently improved outcomes in HFpEF.
Current guidelines recommend symptom management with diuretics and stringent control of comorbidities like hypertension and diabetes. The prevalence of HFpEF is projected to rise due to an aging population and increasing cardiovascular risk factors. This growing prevalence, combined with a lack of effective treatments, makes HFpEF one of the most pressing unmet needs in 21st-century cardiology. HFpEF is consistently linked to left ventricular diastolic dysfunction, leading to increased LV end-diastolic pressure, elevated left atrial (LA) filling pressure, and atrial wall pressure. This cascade activates the renin-angiotensin system, disrupts calcium handling, and triggers profibrotic and proinflammatory pathways, collectively promoting electrical and structural remodeling of the atria, thereby contributing to the onset of atrial fibrillation (AF). , AF and HFpEF are closely intertwined disorders that afflict millions of people, many of whom are obese or have diabetes mellitus or hypertension. Therefore HFpEF and AF often coexist, and their comorbidity is associated with a poor prognosis. , Epidemiologic studies show a significant connection between AF and HFpEF. AF is a major precursor and predictor of HFpEF, and most HFpEF patients are likely to develop AF if they have not already. The overlap between AF and HFpEF is often underestimated because AF frequently goes undetected for years before diagnosis, and patients often experience exertional dyspnea long before HF is identified by physicians. AF is the most prevalent sustained arrhythmia both clinically and globally, with an estimated lifetime incidence of approximately 20%. In the United States (US), the total number of AF cases is projected to surpass 2.5 million by 2030 and reach 7.5 million by 2050. Additionally, AF is associated with substantial morbidity and is a leading cause of hospitalization in the US, with annual AF-related admissions exceeding 450,000 since 2010.
The left atrium, the pivotal cardiac chamber around which all functions revolve
The LA is crucial for maintaining the cardiovascular system’s physiologic integrity in 3 keyways. First, it functions as a reservoir for pulmonary venous return during LV systole and acts as a conduit from the pulmonary veins to the LV during early diastole. Its capacity to enlarge without raising chamber pressures is essential for preventing harmful increases in pulmonary venous and arterial pressures. Second, LA contraction enhances LV filling at end-diastole. This action, through the Frank–Starling mechanism, increases the force of ventricular systole without the need to maintain a high LA pressure during diastole. Third, the LA is central to the interaction of several neurohormonal systems activated by LA stretch. It is richly innervated by adrenergic and cholinergic nerves; its distension stimulates mechanoreceptors, reducing central sympathetic outflow to the kidneys and promoting natriuresis. Additionally, atrial stretch triggers the release of natriuretic peptides from the LA, contributing to volume homeostasis. All 3 critical physiologic actions are compromised in patients with LA disease such as HFpEF patients, often presenting clinically as AF. AF indicates extensive abnormalities in the LA that develop prior to and worsen with the duration of the arrhythmia. Indeed, the hemodynamically stressed atrium enlarges and becomes more spherical; this deformation predisposes it to the development of AF and recurrent AF following CA. Patients with HFrEF exhibit larger LA volumes but lower peak LA pressures, whereas those with HFpEF display greater LA stiffness, leading to smaller LA volumes despite higher peak pressures. Despite their smaller LA volumes, patients with HFpEF are more likely to develop AF, suggesting that atrial fibrosis, rather than dilatation, is the major determinant of AF under prolonged atrial stress. Fibrosis may result from the accumulation and inflammation of epicardial adipose tissue, a common feature in many HFpEF patients, which has been linked to electrical derangements in the adjacent underlying atrial myocardium. ( Fig. 1 ).
Know your enemy: stiff atrial syndrome
Initially, ablation procedures focused on creating circumferential lines around the pulmonary veins. However, ablation of “non-pulmonary vein triggers” as additional structures, distributed throughout both atria, including the posterior wall, coronary sinus, interatrial septum, left atrial appendage, superior vena cava, and crista terminalis. These structures can serve as sources of atrial ectopic beats capable of initiating AF. CA with radiofrequency aims to disrupt the propagation of AF triggers. However, in doing so, it is inevitable that some healthy atrial myocardium will also be destroyed. In patients with healthy atria who typically only have paroxysmal AF, the consequences of the injury may be modest. However, the procedure-related loss of cardiomyocytes eventually leads to replacement fibrosis. In patients with long-standing AF and severely diseased atria, ablation-induced injury can seriously impair LA structure and function. The extent of contractile tissue loss and replacement fibrosis depends on the number or extent of procedures, with up to 30% to 35% of the LA wall potentially being replaced by scar tissue following ablation. Therefore, although ablation aims to restore atrial contractile function, the procedure decreases the ability of the LA to transport pulmonary venous blood, encompassing the reservoir, conduit, and systolic phases of atrial function, especially in patients with long-standing AF and pre-existing LA fibrosis. ,
CA procedures can impair left atrial systolic function, which is closely linked to the degree of scar formation. During follow-up, 40% to 70% of patients undergoing ablation show a reduction in LA EF. In a significant proportion of patients, restoration of normal P waves on the electrocardiogram is not accompanied by hemodynamic signs of meaningful atrial systole, as indicated by the absence of ‘a waves’ on pressure tracings. Therefore, although ablation aims to restore atrial contractile function, the LA’s ability to effectively transport pulmonary venous blood is reduced by the ablation procedure especially in patients with long-standing AF and pre-existing left atrial fibrosis. In some patients, the LA distensibility is so severely compromised that the chamber becomes markedly stiff, struggling to accommodate even modest levels of pulmonary venous return.
Our group in 2011 presented a series of 1380 patients who have developed dyspnea and PH associated with diastolic hemodynamic abnormalities of the LA after catheter ablation of AF. We found pulmonary hypertension (PH) in 19 (1.4%) patients after the CA. LA size, mean LA pressure, and severe LA scarring were independently associated with the development of PH. Subsequent studies found the stiff left atrial syndrome in up to 10% patients undergoing ablation though the risk is likely higher in those with HF and pre-existing LA fibrosis. Stiff left atrial syndrome is a recognized complication with significant clinical implications. The exact mechanisms by which AF ablation might contribute to LA stiffness are complex and likely multifactorial. Some potential contributors include fibrosis and scarring, inflammation, and oxidative stress.
Thermal methods cause coagulative necrosis, which leads to reparative fibrosis, resulting in post-ablation scar tissue that is poorly compliant. Pulsed field ablation (PFA) has emerged as a promising alternative to traditional thermal energies used for CA. Unlike these latter, PFA destabilizes cell membranes by creating irreversible pores, leading to cell content leakage and apoptosis. This type of cell death does not elicit an inflammatory response with subsequent fibrosis. Instead, it produces homogeneous, myocardium-specific lesions while preserving the extracellular matrix architecture. A recent study by our group showed that on a cohort of 28 non-paroxysmal AF patients with preexisting pulmonary hypertension PFA did not lead to worsening hypertension compared to radiofrequency.
Special population: cardiac amyloidosis and hypertrophic cardiomyopathy
As previously written, the prevalence of HFpEF increases with age and longer life expectancy. There are 2 specific diseases that can present with HF or AF: cardiac amyloidosis and hypertrophic cardiomyopathy.
With improvements in the non-invasive diagnosis of cardiac amyloidosis, the incidence and prevalence of the same have been seen to be increasing: overall these patients show higher relapse after CA compared to control patients. However, a recently published retrospective study on patients with transthyretin amyloidosis demonstrated reduced mortality and significantly higher efficacy of CA compared to medical therapy, but only when the intervention is performed at an early stage and in patients with mild symptoms. Moreover, in this setting of patients, coexistent AF and infiltrating deposition of amyloid fibrils in the myocardium carry a high risk of intracardiac thrombus and stroke regardless of the CHA2DS2-VASc score.
In an adult with hypertrophic cardiomyopathy, AF is the most common sustained arrhythmia with a prevalence of 20% with a rapid evolution from paroxysmal to persistent AF. AF is associated with significant morbidity, impaired quality-of-life (QoL), and particularly high risk of stroke. The outcome of CA is conditioned by the persistence of strong hemodynamic triggers for left ventricular outflow tract obstruction, severe LV diastolic dysfunction, or associated myocardial infarction. Our group published a study on 43 patients with hypertrophic cardiomyopathy and AF (28% paroxysmal AF). The main findings were that pulmonary vein isolation only is not effective in preventing late (≥1 year) AF recurrences in ≈50% of patients and that trigger beyond the pulmonary vein seem to be responsible of late recurrences, supporting the appropriateness of a more extensive ablation to improve the long-term arrhythmia-free survival.
Current evidence of atrial fibrillation ablation in patients with heart failure with preserved ejection fraction
The latest guidelines recommend CA as a first-line treatment when HF symptoms are attributed to AF in HFrEF.
Recent trials specifically studying patients with AF and HFrEF have demonstrated the superiority of ablation over antiarrhythmic drugs (AADs). These studies have shown significant benefits in terms of hard outcomes, such as mortality and cardiovascular hospitalizations, as well as improvements in QoL and LVEF. Furthermore, recent research has shown substantial improvement in multiple clinical outcomes for patients with end-stage heart failure. Although HF may elevate the risk of CA complications, CA has been shown to reduce AF burden, mortality, and rehospitalization rates in AF patients with HFrEF, without significantly increasing adverse events.
However only few study aimed to assess the superiority of CA over AAD. Various meta-analyses have compared the efficacy of CA in AF patients with HFpEF and HFrEF, revealing similar efficacy and safety profiles between the 2 groups.
A retrospective analysis by Arora and colleagues including 63,299 HFrEF and 56,395 HFpEF showed no significant difference in the composite outcome of HF readmission and mortality at 1 y between ablation and non-ablation groups for both HFrEF (hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.91–1.13, P = .81) and HFpEF (HR 0.90, 95% CI 0.78–1.04, P = .15). However, CA significantly reduced AF readmissions at 1 y in both HFrEF (HR 0.41, 95% CI 0.33–0.49, P <.001) and HFpEF (HR 0.54, 95% CI 0.44–0.65, P <.001) groups.
Conversely, non randomized studies on CA in patients with AF and HFpEF have shown improvements in QoL and even in survival when compared to medical therapy alone. ,
A prospective study by Cha and colleagues evaluated 3 different groups of patients undergoing CA for AF: those with HFrEF, those with HFpEF, and patients without HF. The results showed that at 1 y, AF elimination was achieved in 75% of patients with diastolic dysfunction, compared to 62% in those with systolic dysfunction and 84% in those with normal LV function. Additionally, all groups experienced significant improvements in QoL, with mean physical component summary scores increasing to 69.3±21.8 in the diastolic dysfunction group, 77.1±17.5 in the systolic dysfunction group, and 77.3±16.2 in the normal LV function group.
Another retrospective study by Rattka and colleagues showed that CA significantly reduced arrhythmia recurrence (HR: 0.47; P =.016) and composite primary endpoint of HF hospitalization and death (HR: 0.30; P =.003) compared to medical therapy. Moreover, clinical parameters such as HF symptoms and New York Heart Association (NYHA) class, as well as echocardiographic parameters including mitral peak E-wave and A-wave velocities, E/E′ ratio, improved significantly after CA. Notably, 35% of CA-treated patients experience improvement of HFpEF compared to 9% in the medical group ( P =.008).
A prospective study by Fukui and colleagues tried to assess the impact of CA in HFpEF patients; 35 patients received CA versus 50 received conventional AADs; in this study CA significantly reduced HF rehospitalization, with 9% of ablated patients re-hospitalized compared to 48% in the AADs group ( P <.001). Multivariate analysis identified CA as the only preventive factor for HF rehospitalization (odds ratio = 0.15; P <.001).
A recent observational study demonstrated that restoring sinus rhythm through CA led to improvements in invasive hemodynamic parameters and a reversal of HFpEF in a subset of patients. In a subanalysis of the CABANA study involving patients with baseline HF symptoms (NYHA Class ≥ II, with 79% having LVEF ≥ 50%), CA significantly improved outcomes of arrhythmia recurrence, QoL, and survival compared to AADs. Specifically, in the subgroup of HFpEF patients (LVEF ≥ 50%), CA was associated with a 60% reduction in mortality compared to AADs. Another randomized trial demonstrated that, in patients with HFpEF and concomitant paroxysmal or persistent AF, CA significantly improved invasive hemodynamic parameters such as pulmonary capillary wedge pressure and exercise capacity like peak relative O2 compared to medical therapy ( Table 1 ).
