Supraventricular Arrhythmias in Pulmonary Hypertension: A Comprehensive Review From Preclinical Evidence to Clinical Practice

Authors: Abdulkadir Kiris, Peng Zhang, Peter Bronk, Kurt W. Prins, Bum‐Rak Choi, Gaurav Choudhary

Abstract

Pulmonary Hypertension (PH) is a chronic disease that causes significant structural deterioration in the right atrium and ventricle. In the past 1–2 decades, life expectancy in patients with PH has increased due to improved awareness, diagnosis and advancements in treatment. Increasingly, PH is recognized in older patients with comorbidities. With the changing demographics, supraventricular arrhythmias (SVAs), especially atrial fibrillation and flutter, are emerging as important outcomes in PH. Here, we comprehensively summarize findings from preclinical and clinical studies to define the mechanistic drivers and clinical implications of SVA. In sum, we propose early recognition and targeted management of SVA is important to improve quality of life, morbidity and mortality in patients with PH.

Introduction

Pulmonary hypertension (PH) is a progressive pulmonary vascular disease characterized by elevated pressures in the pulmonary circulation. It is defined by a mean pulmonary artery pressure (mPAP) > 20 mmHg at rest during right heart catheterization (RHC) [1]. The overall global prevalence of PH is about 1% [1, 2]. PH is classified into five categories according to underlying pulmonary arterial hypertension (PAH, group 1), related with left‐sided heart disease (group 2) or lung disease (group 3), pulmonary artery obstruction (group 4) and PH with multifactorial or unclear mechanism (Group 5) [3].

Irrespective of the etiology, persistent elevation in PA pressure leads to remodeling of the right heart and eventually resulting right heart failure. The median survival for patients with untreated PH is about 3 years, with a 5‐year survival rate ranging from 19% to 59% [4, 5]. While the main cause of morbidity and mortality associated with PH is attributed to RV failure, there is increasing recognition that supraventricular arrhythmias (SVAs) significantly impact patient outcomes in this population. Indeed, available studies show SVAs are common in all PH groups and affect morbidity and mortality [6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26].

The epidemiology of PH has evolved over time and now consists of older patients with several additional comorbidities such as systemic hypertension, coronary arterial disease (CAD) and diabetes mellitus (DM) compared to two decades ago [6, 7, 9, 10, 11, 12, 13, 14, 27, 28]. Given the aging of the PH population and the increasing prevalence of comorbid conditions, it is likely that these factors influence the incidence and prevalence of SVAs in PH patients. However, these interactions have not been clearly addressed by individual studies.

Furthermore, beyond epidemiological data, the relationship between SVAs and PH remains poorly defined in terms of pathophysiology and management, with existing studies offering fragmented insights and a cohesive framework for managing SVAs and PH is lacking.

Therefore, in this review, we aim to provide a comprehensive examination of the current literature on the epidemiology, clinical effect, pathophysiology and management strategies for SVA in PH, highlighting the gaps in our understanding and suggesting potential avenues for future research.

Epidemiology

Supraventricular arrhythmias are the most well‐studied type of arrhythmia in the PH population and appears to be much more common than ventricular arrhythmias. SVAs typically includes atrial fibrillation (AF), atrial flutter (AFL), atrial tachycardia (AT), premature atrial contraction (PAC), atrioventricular reentry tachycardia (AVRT), and atrioventricular nodal reentry tachycardia (AVNRT). Detailed epidemiological data from published studies is presented in Table 1.

The overall prevalence of SVAs is up to 39% in the PH population. Among SVAs, AF and AFL are the most common arrhythmias in each of the PH groups and in overall PH population. The next most prevalent SVA is AT, which is especially frequent in PH groups 2 and 3. In contrast, AVNRT and AVRT are rare. There is limited data on group‐specific prevalence of arrhythmias with only a few studies reporting such data [6, 22]. Fingrova et al. reported the SVAs prevalence based on the hemodynamics groups of isolated precapillary (pulmonary artery wedge pressure < 15 mmHg and pulmonary vascular resistance > 3 Wood Units, n = 641) and combined pre‐ and post‐capillary PH (n = 114) [6]. The combined PH group have more than two‐fold increased risk for AF over the precapillary PH group (51% vs 25%, p < 0.05). In the precapillary PH group, PAH with connective tissue disease such as Systemic Sclerosis (SSc‐PAH) have more frequent AF occurrence than other precapillary etiologies. In a cohort of 1000 patients, Xue et al. compared the prevalence of arrhythmias in different PH groups and found that the prevalence of SVA was 25.6% in group 1, 61.1% in group 2, 28.1% in group 3, 22.7% in group 4% and 33.3% in group 5 [22].

There is limited data on incidence and time for the development of SVA after PH (Table 2). The cumulative incidence of SVA ranges from 6.7% to 35.4%. In group 1, AF/AFL has the highest incidence, followed by AT and AVNRT. When evaluated in a combined population of groups 1 and 4, incidence of other kinds of SVA was similar to incidence of AF and AFL suggesting that AT may be more common in group 4 compared to group 1 PH. The average time from PH diagnosis to the development of arrhythmia ranges from 0 to 20 years for groups 1 and 4, and a median duration of 15.1 months was reported in the overall PH population [7, 15, 16].

The clinical predictors associated with SVAs are outlined in Table 3. Notably, right atrial (RA) pressure and size seem to be related to SVAs, especially in PAH (group 1) and chronic thromboembolic pulmonary hypertension (CTEPH, group 4). Interestingly, LA pressure and size are also predictors for SVA in precapillary PH suggesting LA remodeling might also play a role in the development of AF and AFL in this population.

On the other hand, while not systematically studied in the PH population, the prevalence of SVA in PH is likely influenced by known risk factors for SVA such as age and comorbidities such as systemic hypertension, CAD and DM in addition to PH itself. Indeed, the prevalence and incidence of SVA in the PH population over 50 years of age is higher than in those under 50 years of age (Table 2) and two studies have identified age as an independent predictor for the development of SVA [12, 22]. However, incremental effect of age, body mass index and systemic comorbidities on risk for SVAs has not been rigorously explored in PH population and further studies are needed to clarify these relationships.

Pathophysiology of SVA

In PH (most notable in pre‐capillary PH), the development of atrial arrhythmias is primarily driven by the increased right atrial pressure, which leads to a complex interaction of electrical and structural remodeling over time. Structural remodeling creates an appropriate substrate for arrhythmia development, while electrical remodeling acts as a trigger on this substrate, initiating the arrhythmia. Subsequently, structural remodeling sustains the continuation of the arrhythmia. In this process, the development of atrial inflammation and autonomic remodeling contribute significantly to the entire progression (Figure 1).

Electrical Remodeling

Elevated RA afterload in PH results in electrical remodeling in atrial myocytes. Koyama et al. published one of the early reports on ion channel remodeling in monocrotaline (MCT) induced PH in rats [29]. They reported that l‐type Ca^2+^ channels (ICaL) are downregulated and T‐type Ca^2+^ channels (ICaT), normally expressed in only conduction system cells (purkinje and pacemaker cells), are upregulated in the RA myocytes [30]. Similarly, others have reported a decrease in expression of INa, Ito, IKur and IK1 in addition to ICaL the MCT rat model [31, 32, 33].

PH induced pressure overload also changes the expression of Ca^2+^ handling proteins in the right atrium that play an important role in arrhythmogenesis [34, 35, 36]. This includes decreased expression of sarcoplasmic reticulum Ca^2+^‐ATPase (SERCA‐2a), ryanodine receptor (RyR2), phospholamban, sarcolipin and sodium‐Ca^2+^ exchanger (NCX) suggested in both clinical and preclinical studies [34, 35, 36]. In addition, Ye et al. investigated the role of transient receptor potential vanilloid type 2 (TRPV2), a non‐selective Ca^2+^ permeable cation channel, on the development of AF in the MCT rat model [33]. They found that TRPV2 is related to AF inducibility and a TRPV2 inhibitor, Tranilast, improved Ca^2+^ handling as well as electrical and structural remodeling.

Therefore, PH is associated with remodeling of Na^+^, Ca^2+^, K^+^ channels and calcium handling proteins such as SERCA‐2 and RyR2 in RA myocytes. These changes in ion channels are expected to affect action potential duration (APD) and effective refractory period (ERP). In this context, dysregulated intracellular Ca^2+^ leads to proarrhythmic mechanisms such as enhanced automaticity and early‐ and late‐ afterdepolarizations. In addition, decreased Na^+^ current also affects conduction velocity (CV), which contributes to the maintenance of arrhythmia by a reentry mechanism.

Atrial Structural Remodeling and Reentry Activity

In both clinical and preclinical studies, atrial arrhythmias are associated with remodeling and enlargement of the atria [12, 17, 19, 37]. In addition to cardiomyocyte hypertrophy and capillary rarefaction, PH results in fibrotic changes in both atria (RA more severe than LA). There are increased expression of fibrosis markers such as Collagen (Col)1a1 and Col 3a1, and profibrotic signaling markers including Platelet derived growth factor receptor a (Pdgfra) and Transforming growth factor β1 (Tgfb1) in PH [31, 32, 33, 38, 39].

PH also results in decreased expression of connexins (mainly 40 and 43) in preclinical studies [33, 38, 40]. In addition, increased levels of non phosphorylated connexin 43 and heterogeneity of connexin 43 expression in RA were reported in dogs with PAH [41]. Decreased connexin 43 expression and activity results in slowed cardiac CV and increased the risk of arrhythmia [42, 43]. Likewise, heterogeneity in spatial distribution of connexin 43 gap junctions causes non‐uniform electrical wave propagation and a tendency towards reentry [42, 43].

Therefore, structural remodeling (enlargement, fibrosis and gap‐junctions) in the atria results in electrical heterogeneity characterized by regional differences of APD, ERP, and CV, and reduces tissue voltage and fractionated local electrograms. All together lead to functional or structural regional conduction blocks that provide the necessary conditions for reentry development which is critical for arrhythmogenesis and maintenance of arrhythmias [38, 44, 45]. The combined structural and electrical remodeling in preclinical studies explain the observed electrophysiological properties in the RA of patients with idiopathic PH including increased atrial effective refractory period (ERP), slowed conduction with marked regional abnormalities, reduced tissue voltage, regions of electrical silence, fractionated electrograms and double potentials [46].

Autonomic Nervous System Remodeling

The autonomic nervous system (ANS) plays a central regulatory role in cardiac electrophysiology. Parasympathetic stimulation shortens APD and electrical wavelength by activating acetylcholine‐dependent K^+^ channels (IKACh), thereby facilitating reentry and rotor activity [44, 45]. In contrast, the effects of sympathetic stimulation on APD are more complex. β‐adrenergic activation enhances ICaL, IKur and IKs currents, prolonging APD, while α‐adrenergic signaling suppresses Ito and IK1 currents, which shortens APD. The overall effect is typically a slightly shortened or unchanged APD with a prolonged plateu phase. In parallel, sympathetic activity promotes diastolic Ca^+^ [2] leak from the SR via both direct mechanisms‐such as RYR2 phosphorylation‐and indirect mechanisms through phospholamdan (PLN) phosphorylation, which increases SERCA‐2a activity [47]. As a result, cytosolic Ca^2+^ accumulation occurs, predisposing to delayed afterdepolarizations (DADs) and triggered activity [44, 45, 48].

In AF associated with left heart disease, both sympathetic and parasympathetic systems are activated. Therefore, therapeutic modulation of autonomic input has been shown to attenuate left atrial remodeling and reduce AF risk [44, 45, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59]. However, in PH, ANS remodeling follows a distinct pattern‐marked by increased sympathetic tone and reduced parasympathetic activity‐which correlates with PH subtype, severity, and the degree of RV dysfunction [60, 61, 62, 63, 64, 65, 66, 67, 68]. The mechanism underlying this distinct autonomic prophile remain unclear. Nonetheles, experimental studies suggest that this imbalance is linked to both electrical and structural remodeling of RA, increasing susceptibility to AF and AFL, potentially through the involvement of the right anterior ganglionated plexi [41].

Atrial Inflammation

Inflammation is increasingly recognized as a key contributor to arrhythmogenesis, particularly in AF, through its direct effects on cardiomyocyte ion channels and cellular electrophysiology [69, 70, 71, 72, 73, 74, 75]. In a MCT‐induced PH model, Hiram et al. demonstrated elevated levels of inflammatory markers‐including IL1‐β, TGF‐β3, CXCL1 and CXCL2‐ along with activation of inflammasome components (ASC, CASP1, and CASP8) and increased proinflammatory M1 macrophage infiltration in RA. These changes were associated with enhanced susceptibility to atrial arrhythmias [76]. Importantly, treatment with RVD1, a specialized pro‐resolving mediator, attenuated RA remodeling and reduced AF inducibility by suppressing inflammation‐driven fibrotic and electrical remodeling.

Similarly, in both MCT and SU5416/hypoxia‐induced PH models, Ye et al. reported increased infiltration of proinflammatory immune cells‐CD68^+^ macrophages and MPO^+^ neutrophils‐and upregulation of inflammatory cytokines such as TNF‐α, IL1‐β, CXCL1 and CXCL2 in the RA [33]. Therapeutic suppression of atrial inflammation in these models resulted in decreased AF inducibility and reduced AF duration, in parallel with improvements in structural and electrical remodeling. Additionally, increased macrophage infiltration was observed in the RA of pulmonary artery‐banded pigs, further supporting the relevance of inflammation across PH models [77].

Clinical Impact

Available data suggests that the development of SVA is frequently associated with significant clinical deterioration in PH, particularly in precapillary PH (group 1 and 4), as assessed by symptoms such as dyspnea, signs of right heart failure, and exercise intolerance, compared to other PH groups [7, 11, 15, 16, 17, 18, 19, 20, 21, 22, 23, 25, 78, 79]. Moreover, restoration of sinus rhythm in patients with PH improves clinical and laboratory findings associated with RV failure such as NT‐proBNP level and cardiac index (CI) [7, 15, 16, 17, 18, 19, 80].

A possible mechanism underlying the severe clinical deterioration observed in PH patients with SVA may involve RV remodeling, which not only affects the structure of the RV but also significantly impairs its function, akin to the pathophysiological relationship between SVA and left heart failure with preserved ejection fraction (HFpEF). In patients with HFpEF, a prototype of diastolic ventricular dysfunction, SVA such as AF leads to severe clinical deterioration by adversely affecting atrial contraction, heart rate, and atrioventricular synchronicity, all necessary to maintain left heart filling [81]. Similar mechanisms may underlie the effect of SVA in the PH population related to the effects of PH on the RV. Increased RV afterload in PH is associated with increased RV diastolic stiffness and diastolic dysfunction, which makes RV filling sensitive to changes in diastolic filling time and atrial contraction, both of which are adversely affected by SVA contributing to decreased cardiac output and higher RA pressures [82, 83, 84] (Figure 2). Indeed, passive diastolic RV filling is decreased and the contribution of active filling by RA contraction is increased in PH [85]. RA contraction may be responsible for up to 51% of RV systolic function (as assessed by tricuspid annular plane systolic excursion, TAPSE) in patients with PH compared to 32% in normal subjects. Therefore, loss of RA contraction, as seen in AF, contributes to decreased RV cardiac output and systolic function as measured by TAPSE [17, 86]. Presence of SVA can also exacerbate the oxygen supply/demand mismatch and further impair RV function. Even without SVA, the hypertrophied RV in PH has a higher oxygen consumption, yet the oxygen delivery to the RV is decreased due to capillary rarefaction and reduced right coronary artery flow [80, 87, 88, 89, 90, 91]. The irregular and/or increased heart rate due to SVA can further increase the oxygen demand and shorten diastole, when the coronary flow is maximum, reducing oxygen supply [92, 93, 94].

In addition to contributing to worsening clinical status, the occurrence of SVA might be a marker of worsening underlying PH and need for an escalation of specific therapy. In patients that develop clinical deterioration associated with SVA, up to half of the patients may require intensification of PAH specific drug therapy in addition to restoration of sinus rhythm [16, 19]. Additionally, the presence of SVA has been reported to be the third most common reason for ICU hospitalization, after RVF and infection (11%, 53.3%, 17.4%, respectively) in patients with PAH [23].

Besides clinical deterioration, newly diagnosed SVA (AF, AFL and AT) in idiopathic PAH has also been reported to be associated with higher overall mortality rate (40% vs 17%) and lower estimated survival at 1, 3, and 6 years compared to patients without SVA [19]. Similarly, Baskar et al. reported an increased risk of all‐cause mortality rate related to cardiac arrhythmias in Eisenmenger syndrome [10], and Cannillo et al. found SVA is independently associated with all‐cause mortality and rehospitalization (HR = 2.82, p = 0.018) in a cohort of patients with group 1, 3 and 4 and newly diagnosed SVA (mostly AF and AFL) [7]. In addition, in a retrospective analysis of a cohort of patients with group 1 and 4 PH and SVT, Tongers et al. report the mortality rate is much lower (6.3%, follow‐up 26 ± 23 months) when sinus rhythm was restored in contrast to patients with sustained AF (mortality rate of 82%, follow‐up 11 ± 8 months) [15]. Beyond that, the presence of arrhythmia is also reported to be independently related to maternal and fetal/neonatal mortality in patients with PH [24]. In line with these findings, the presence of SVA, RV diameter, pulmoner vascular resistance, total bilirubin and World health Organization (WHO) functional class III/IV appear to be critical parameters related to poor prognosis in the PH patients with SVA (Table 4). In contrast, Fingrova et al. did not find any relationship between SVA and mortality in their cohort, which included overall PH patients [6].

Additionally, the duration of the arrhythmia and whether it is transient or persistent may influence the relationship between SVA and mortality. In a study of relatively large population of PH including iPAH and SSc‐PAH, the authors report that newly diagnosed atrial arrhythmias (91% of cases was AF and AFL, mostly transient) has no significant effect on mortality [11]. Also, Andersen et al. reports no deaths due to SVA (mostly transient) in their study using insertable cardiac rhythm monitors [21]. In line with these, Olsson et al. report an increase in mortality rate (Hazard ratio = 2.1, p = 0.03) in sustained AF and AFL compared to transient AF/AFL [18] These studies suggest that transient SVA may have minimal impact of on mortality compared to persistent SVA [18, 19, 21].

Apart from arrhythmia being transient, patients with better functional capacity (NYHA functional class and 6MWD), or those on stable therapy likely have better survival despite having SVA. For example, in patients with CTEPH undergoing pulmonary endarterectomy, SVA does not increase the hazards of mortality after adjustment for confounders presubmable because of near normalization of haemodynamics post surgery [20].

Management of SVA

Diagnosis and Screening

Currently, no formal guidelines exist for arrhythmia screening in patients with PH. Electrocardiography (ECG), ambulatory (Holter) monitoring, and event recorders have been employed to evaluate symptomatic individuals with suspected arrhythmias in this population [6, 7, 8, 9, 10, 11, 12, 14, 15, 17, 18, 19, 20, 22]. Prolonged rhythm surveillance using insertable cardiac monitors (ICMs) and serial Holter recordings detect a higher burden of SVAs compared to isolated assessments [8, 21]. Although an optimal screening strategy remains undefined, a risk‐based approach appears prudent. Asymptomatic patients at low risk may be adequately monitored with only routine ECGs during PH based clinical visits, while extended monitoring (ie. Holter and ICM) should be considered for individuals with structural heart disease, symptoms suggestive of arrhythmia, or changes in clinical status along with routine ECG checking.

Clinical Management

Acute Management

SVA episodes in patients with PH are frequently symptomatic and often precipitate significant clinical deterioration compared to the general population [11, 15, 16, 18, 19]. Therefore, acute restoration of sinus rhythm is commonly required, followed by maintenance strategies aimed at preventing recurrence.

AVNRT and AVRT are relatively uncommon forms of SVA in patients with PH. In the acute setting, these arrhythmias are typically managed successfully with medical cardioversion using antiarrhythmic medications or with direct current cardioversion (DCCV) [11, 19].

Atrial tachycardia, while more prevalent than AVNRT and AVRT in this population, remains understudied in terms of management. Acute interventions often include medical cardioversion with amiodarone, sotalol, or class 1c antiarrhythmic agents, as well as DCCV.

In AFL, acute rhythm control has been achieved via overdrive pacing, DCCV, antiarrhythmic medication, and RF ablation [7, 15, 18, 19, 25]. Commonly used agents include amiodarone, dronedarone, sotalol, and flecainide were generally well‐tolerated in PH. However, among acute strategies, DCCV has demonstrated higher success rates compared to antiarrhythmic medications [25]. All these approaches were reported to be safe in restoring sinus rhythm, with success rates for the initial attempt varying between 46% and 100%.

Both antiarrhythmic medications and DCCV have been employed for acute and long‐term rhythm control in AF. Relevant data are summarized in Table 5. Reported success rates of cardioversion in patents with PH vary widely, ranging from 15% to 87%, which is notably lower than rates observed in classical left‐sided AF populations (> 90% for DCCV and 50%–70% for medications) [7, 15, 18, 19, 25, 95].

Chronic Management

Rhythm Versus Rate Control

AVNRT, AVRT and AT often need acute rhytm control during tachycardia episode. Therefore, their chronic management mainly depends on rhythm control by means of medication use or catheter ablation rather than rate control. In AF and AFL patients, both rhythm and rate control strategies are employed in PH. However, rhythm control is often prioritized and attempted at least once in nearly all patients due to significant hemodynamic and symptomatic deterioration, and the restoration of sinus rhythm appeared to be associated with clinical improvement and improved outcomes [6, 7, 11, 15, 16, 18, 19]. Notably, Sammut et al. compared rhythm and rate control strategies in patients with PAH and CTEPH [25]. Their findings indicated that restoration of sinus rhythm was associated with greater improvements in functional class, 6‐min walking distance, and patient‐reported outcomes. Moreover, several other studies have demonstrated a reduction in mortality with successful rhythm control in patients with PH [7, 15, 18, 19, 25]. These data are in contrast with findings in patients with left heart disease‐related AF, where rhythm control has not been consistently shown to reduce mortality. However, maintaining sinus rhythm post‐cardioversion poses a greater challenge in PH patients, with recurrence rates during follow‐up studies ranging from 31% to 100%. By comparison, recurrence rates in classical AF cohorts have been reported as as 26% and 52% at 1 and 5 years, respectively [96].

Medications in Chronic Management

Atrioventricular nodal blocking agents including beta‐blockers, calcium channel antagonists and digoxin are cornerstone medications for rate control strategies in patients with AF and AFL. However, their use is challenging in patients with PH, especially in those with PAH, and is not recommended by guidelines because of their potential to cause hypotension and hemodynamic compromise [1]. In PH, RV remodeling leads to RV stiffening and loss of elasticity, causing stroke volume to remain relatively constant and RV output becomes dependent on heart rate. A decrease in heart rate reduces RV output, which can activate RV failure and lead to hemodynamic instability. However, the presence of arrhythmias themselves can contribute to hemodynamic deterioration, especially in cases where AV synchronization is impaired, such as in AF and AFL. Therefore, current guidelines suggest that decision should be individualized, and beta‐blockers and/or digoxin may be used at low doses for rate control in selected patients [1]. The use of various AV‐blocking agents including beta‐blockers (metoprolol, carvedilol and bisoprolol), calcium channel antagonists (verapamil and diltiazem) and digoxin for rate control in PH patients have been reported without any PH‐specific adverse effects in observational studies [6, 11, 15, 25]. These data suggest that when needed their use appears to be relatively safe.

On the other hand, achieving and maintaining a stable sinus rhythm is the primary hemodynamic goal particularly in atrial arrhythmias where AV synchronization is impaired. Therefore, various antiarrhythmic drugs including amiodarone, dronedarone, sotalol, flecainide and propafenone have been used in various PH populations [6, 7, 11, 15, 17, 18, 25]. Amiodarone is the most commonly used agent, typically as monotherapy, and in some cases, in combination with digoxin or calcium channel antagonists. Although current studies have not identified any specific adverse effects related to PH, limitations such as small sample sizes and lack of detailed data regarding the severity of underlying heart disease complicate the interpretation. Furthermore, some antiarrhythmic agents are contraindicated in the presence of structural heart disease and coronary artery disease, which adds complexity to drawing definitive conclusions. As the most frequently used antiarrhythmic in PH, amiodarone appears relatively safe and may be considered the most rational choice [1]. However, given the role of APD and ERP prolongation in PH‐related atrial fibrillation and amiodarone's potential to prolong the QT interval, careful close monitoring for QT prolongation is recommended in PH patients receiving amiodarone.

Role of Interventions and Ablation

Although data on long‐term management in PH is limited, catheter‐based ablation has demonstrated high success rates in patients with AVNRT, offering durable arrhythmia control with a low complication rate [6, 7, 15, 26].

In AT patients, RF catheter ablation is generally reserved for those with recurrent or drug‐refractory episodes [6, 19, 26]. Reported success rates for RF ablation in PH range from 72% to 100%, with no major procedural complications [6, 26].

Given the high recurrence rate of AFL (up to 67%) with pharmacological long‐term rhythm maintenance efforts, RF ablation is increasingly favored for long‐term rhythm control. Bradfield et al. reported an acute success rate of 80% and 75% 1‐year freedom from AFL following RF ablation in a small population with PAH [97]. Similarly, Kamada et al. observed a 94% acute success rate and improved long‐term outcomes in a mixed PH cohort undergoing ablation in a small population of PAH and CTEPH patients [26]. However, cavotricuspid isthmus dependent AFL ablation in patients with PAH may be associated with longer procedure duration and a greater amount of cumulative tissue ablation compared to patients without PH [98].

While catheter‐based ablation techniques‐including RF and cryoballoon ablation are well‐established for long‐term rhythm control in patients with classical left‐sided AF, experience with these modalities in PH remains limited [7]. Recently, Boyle et al. published the first study evaluating the feasibility, safety and efficacy of AF ablation specifically in the PH population [99]. In this cohort, 20 pulmonary vein isolation procedures were performed‐18 using RF ablation and 2 using cryablation, with some patients receiving additional ablation of non‐pulmonary vein triggers or cavotricuspid isthmus. At the 3‐year follow‐up, single‐procedure freedom from AF was 50%, increasing to 70% after multiple procedures. Notably, these success rates are comparable to those reported in the classical left‐sided AF population, despite the absence of RA ablation beyond the isthmus. These findings suggest that, even in the context of significant RA remodeling in PH, left atrial mechanisms may continue to play a dominant role in AF pathogenesis‐though the precise mechanistic basis remains unclear.

Anticoagulation for Atrial Fibrillation

Limited studies have addressed anticoagulant use in PH patients with AF and AFL. There is insufficient data regarding potential PH‐specific factors, such as patient selection for anticoagulant therapy, choice of anticoagulant agents, and interactions with specific PAH medications. Further research is needed to address these issues and provide clearer guidance.

Effect of Specific PAH Treatment on Rhythm Control

To date, the association between use of PAH‐specific therapy and development of arrhythmias has not been directly investigated. While Smith et al. and Mercurio et al. found no significant difference in the use of PAH‐specific therapies between patients with and without atrial arrhythmias [11, 12], Xue et al. reported that patients without SVAs were more frequently treated with endothelin receptor antagonists and phosphodiesterase type 5 inhibitors [22]. Additionally, Wen et al identified combination therapy as a potential risk factor for SVAs in Cox regression analysis, although the association lost significance in multivariable models [19]. Collectively, these findings are indirect and inconclusive, and the retrospective studies are prone to confounding and bias. Robust, prospective studies are needed to clarify whether specific PAH therapies influence arrhythmia risk.

Novel Therapeutic Approaches in SVA Management

Since atrial remodeling in PH is typically severe and sustained, contributing to high rates of arrhythmia recurrence even after restoration of sinus rhythm, rhythm control remains a critical therapeutic goal in this population. Given the multifactorial mechanisms underlying arrhythmogenesis in PH several novel agents have shown promise in preclinical models.

Resolvin‐D1, a pro‐resolving lipid mediator derived from docosahexaenoic acid (DHA), has been shown to suppress atrial inflammation and attenuate both electrical remodeling and fibrosis in an MCT rat model [76, 100]. Similarly, pinocembrin, a flavonoid with anti‐inflammatory and antioxidant properties improved right atrial electrical remodeling, reduced atrial fibrosis and cardiomyocyte apoptosis, and reversed autonomic remodeling, leading to lower inducibility and duration of AF in the same model [32, 101].

Dapagliflozin, a sodium‐glucose cotransporter 2 inhibitor (SGLT2i) with established antiarrhythmic benefits in patients with diabetes mellitus, heart failure, and chronic kidney disease [102, 103, 104] has also demonstrated efficacy in PH models. In MCT‐indıced PH, dapagliflozin alleviated structural remodeling in the pulmonary artery, right ventricle, and right atrium, while improving atrial electrical remodeling and reducing AF susceptibility [31].

Additionally, upregulation of stretch sensitive TRPV2 channels has been implicated in PH‐induced AF through calcium overload [105, 106] and subsequent pro‐fibrotic and pro‐inflammatory pathways [106, 107]. TRPV2 is overexpressed in the right atrium and contributes to PH‐induced AF in an MCT rat model [33]. Tranilast, a TRPV inhibitor, reduced TRPV2 expression and significantly improved both electrical and structural remodeling, thereby decreasing AF inducibility in MCT‐treated rats [108, 109].

Although these agents demonstrate favorable effects on atrial remodeling and arrhythmia burden in experimental models of PH, further translational research is needed to assess their safety, efficacy, and therapeutic potential in patients.

Gaps in Knowledge and Research Priorities

The available literature reveals significant gaps both in understanding the arrhythmogenic mechanisms of SVA and in their management in patients with PH. From an arrhythmogenic perspective, most available mechanistic data is derived from preclinical models that predominantly stimulate PAH. This limits the generalizability of findings to other PH types, such as postcapillary or combined pre‐and postcapillary PH, which may exhibit distinct remodeling patterns and electrophysiolgical properties. Moreover, the initiating triggers of AF in PH are not well‐defined. For instance, while ectopic activity in pulmonary vein myocytes is a well‐established trigger for left atrial AF, it remains uncertain whether similar mechanisms are involved in PH‐associated AF. Furthermore, although precapillary PH induces structural remodeling in both the right and left atria, the mechanisms underlying left atrial changes, particularly in the absence of elevated left heart pressures, are poorly understood.

Important gaps in our knowledge also exist with respect to management of SVAs. The evidence supporting rhythm control as superior to rate control in AF and AFL largely derives from relatively small observational studies. Data regarding the safety, efficacy, and selection of antiarrhythmic agents and AV blocking drugs used for rhythm and rate control are mainly based on secondary data from observational studies. Therefore, there is a pressing need for further studies to better evaluate the safety and efficacy of these medications in PH‐related arrhythmias. Additionally, the role and effectiveness of catheter ablation, which has become a cornerstone therapy for classical left atrium‐origin AF, remains an important and underexplored issue.

Key Messages for Clinical Practice

PH is associated with a higher prevalence of SVAs, with AF and AFL being the most common type of SVA. They occur more frequently in the presence of left heart disease (isolated or combined post‐capillary PH).Considering the high frequence of SVA and its potential to cause significant clinical deterioration, it is crucial to monitor for symptoms and signs associated with SVA after the diagnosis of PH and during the follow‐up.SVA may also contribute to PH progression and may necessitate an increase in specific treatment for PAH.SVAs, particularly AF and AFL, appear to be associated with increased mortality in patients with PH, especially when persistent and when associated with precapillary PH (group 1 and 4).Restoring sinus rhythm appers to reduce symptoms, functional deterioration, and mortality.Both antiarrhythmic medications and DCCV are feasible options for restoring sinus rhythm in patients with PH and AF. However, compared to classical left‐sided AF, antiarrhythmic medications demonstrate lower success rates, and overall recurremce rates remain higher in PH (Table 5).

Conclusion

SVA is relatively frequent in PH with AF and AFL being most common. Structural and electrical remodeling of the atria in PH creates both substrate and triggers necessary for SVA development. The presence of SVA is associated with both clinical deterioration and may reflect or contribute to PH progression. Rhythm control strategies, including DCCV and RF catheter ablation, have shown effectiveness in achieving long‐term rhythm control for reentrant tachycardias such as AVRT, AFL and focal AT. In contrast, more complex arrhythmias, particularly AF and multifocal AT, are related to higher recurrence rates, increased procedural risk, and reduced long‐term efficacy. Aggressive management of the underlying PH and early identification of patients at risk for SVAs may mitigate the adverse clinical impact of SVAs. However, further research is needed to define optimal screening strategies, characterize high‐risk populations, and develop targeted therapies to address RA remodeling and improve atrial rhythm control in PH.

Author Contributions

Study conception and Gaurav Choudhary, Abdulkadir Kiris. Drafting of Manuscript: Gaurav Choudhary, Abdulkadir Kiris. Acquisition, analysis, or interpretation of data, and Critical Review of Manuscript: Abdulkadir Kiris, Peng Zhang, Peter Bronk, Kurt W. Prins, Bum‐Rak Choi, and Gaurav Choudhary.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Guarantor

The Guarantor of this report is Gaurav Choudhary.