Pulmonary hypertension (PH) is a progressive lung disease characterized by abnormal pulmonary vascular pressure and right ventricular (RV) dysfunction. Atrial arrhythmias, including atrial fibrillation (AF) and atrial flutter, are common in patients with PH and significantly contribute to disease progression and mortality. A bidirectional pathophysiological link exists between PH and AF, encompassing shared mechanisms such as endothelial dysfunction, DNA damage, autophagy, inflammation, and oxidative stress, as well as mutual risk factors, including diabetes, obesity, heart disease, and aging. Despite these shared pathways, limited research has been conducted to fully understand the intertwined relationship between PH and AF, hindering the development of effective treatments. In this review, we provide a comprehensive overview of the epidemiology of PH, the molecular mechanisms underlying the development of AF in PH, and the overlap in their pathophysiology. We also identify novel druggable targets and propose mechanism-based therapeutic approaches to treat this specific patient group. By shedding light on the molecular connection between PH and AF, this review aims to fuel the design and validation of innovative treatments to address this challenging comorbidity.

Atrial fibrillation (AFib) reduces the quality of life and increases hospitalization frequency in patients with pulmonary hypertension (PH). Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of PH with a specific pathophysiology, treatment methods, and demographics; however, the factors that correlate with AFib in this population have not yet been determined. This study aimed to investigate the variables that influence the AFib development in patients with CTEPH and assess the impact of arrhythmia on the mortality rate in this population.

Data were obtained from the Database of Pulmonary Hypertension in the Polish Population (NCT03959748), a registry containing data on patients with pulmonary arterial hypertension and CTEPH who were diagnosed and treated in all Polish PH Centers. This study included 784 adult patients diagnosed with CTEPH. We compared echocardiographic, hemodynamic, and demographic variables between patients with and without AFib during database enrollment (retrospective arm) and with and without AFib diagnosis during follow-up (prospective arm).

A total of 106 patients (13,5%) with CTEPH were already diagnosed with AFib at enrollment to the registry. We observed a higher incidence of arterial hypertension and chronic renal disease in the arrhythmia than in the non-arrhythmia group. According to the logistic regression analysis, the independent risk factors for AFib development were only pulmonary artery wedge pressure (PAWP, odds ratio [OR] 1,27 per mmHg, 95% confidence interval [CI] 1,082-1,497, p=0,004) and Left Atrial Area (LA area, OR 1,279, 95% CI 1,109-1,476, p=0,001). AFib is associated with higher serum N-terminal prohormone of natriuretic peptide (NTproBNP) levels and is not an independent predictor of mortality.

AFib in patients with CTEPH is related to comorbidities similar to those in the general population. The independent predictors of arrhythmia occurrence are PAWP and LA area, suggesting dominant role of left heart disease in AFib development. Atrial fibrillation does not remain an independent predictor of mortality in patients with CTEPH but is associated with increased NTproBNP serum levels.

Pulmonary hypertension (PH) is a progressive disease characterized by endothelial dysfunction and vascular remodeling and is a leading cause of mortality worldwide. Although it is independently associated with multiple comorbidities, the impact of diabetes mellitus (DM) on mortality in patients with PH remains uncertain. To address this issue, we conducted a systematic review and meta-analysis to investigate the effect of DM on survival in patients with pulmonary hypertension.

To investigate the impact of diabetes mellitus on mortality in pulmonary hypertension patients.

We conducted a comprehensive search of four major electronic bibliographic databases like PubMed, Google Scholar, Scopus, and Embase, and identified 106 relevant studies, out of 1561 articles, published since the year 2000 for full-text review. Fourteen retrospective and prospective cohort studies that compared survival between patients with DM and those without DM in the context of PH were deemed eligible for inclusion in our meta-analysis. The study was registered on PROSPERO with the identifier CRD42023390232.

A total of 116455 patients with PH were included in the meta-analysis, of whom 41228 suffered from DM and 75227 did not. The results of our meta-analysis indicate an elevated mortality rate among PH patients with diabetes mellitus in comparison to those without DM [odds ratio (OR) = 1.40, 95%CI: 1.15-1.70, P = 0.0006]. The meta-regression analysis unveiled a statistically significant negative association between mean age and effect size (coefficient = -0.036, P value = 0.018). Conversely, a statistically significant positive association was detected between female proportion and effect size (coefficient = 0.000, P value < 0.001).

Our meta-analysis, which included approximately 116500 PH patients, revealed that the presence of diabetes mellitus was associated with increased odds of mortality when compared to non-diabetic patients. The meta-regression analysis indicates that studies with older participants and lower proportions of females tend to exhibit smaller effect sizes. Clinically, these findings underscore the importance of incorporating diabetes status into the risk stratification of patients with PH with more aggressive monitoring and early intervention to improve prognosis potentially.

D-limonene (D-L) is the major monocyclic monoterpene in citrus plants with anti-inflammatory properties. Pulmonary hypertension (PH) can cause right heart dysfunction and increases the risk of death, partially due to inflammatory response in the heart.

To evaluate the possible protective effect of D-L on cardiac function in a rat model of monocrotaline-induced PH (MCT-PH).

Electrocardiogram was monitored in vivo. Masson Trichrome technique was deployed to verify fibrosis in the heart. Contractility function of isolated atrial tissue was studied using organ bath chamber. Real-time quantitative PCR was applied to quantify inflammation in the right ventricle.

The MCT-PH group showed electrical and structural heart remodeling, with the presence of fibrosis in the cardiac tissue and in vivo electrocardiographic changes. Treatment with D-L partially prevented the development of tissue fibrosis and the increase in P wave duration in the MCT-PH group. The contraction and relaxation velocity of isolated right and left atrium were accelerated in CTR and MCT-PH animals treated with D-L. Finally, D-L was able to prevent the abnormal expression of the key inflammatory cytokines (interleukin 1-β, interleukin 6 and tumor necrosis factor-α) in the right ventricle of MCT-PH animals. D-L was able to enhance the production of the anti-inflammatory cytokine Interleukin-10.

Our results showed that in vivo administration of D-L partially prevented the molecular, structural and functional remodeling of the heart in the MCT-PH model with attenuation of the inflammatory response in the heart.

Pulmonary arterial Hypertension (PAH) is a progressive disease marked by significant morbidity and mortality due to pulmonary vasculopathy and right ventricular (RV) dysfunction. Despite advances in PAH medical therapies which have improved clinical outcomes and survival, patients continue to face severe complications, including a notable incidence of sudden cardiac death (SCD). The high arrhythmic burden, coupled with mechanical complications such as left main compression syndrome, pulmonary artery dissection, rupture, and severe hemoptysis, significantly contribute to the risk of SCD. Close monitoring and a meticulous diagnostic approach are essential for risk stratification and timely intervention, aiming to mitigate the risk of premature death in these patients. The aim of this review is to provide a comprehensive understanding of these risks and highlight strategies for improving patient outcomes through early identification, prevention and effective management.

We aimed to evaluate the effects of radiofrequency catheter ablation (RFCA) and the factors influencing mortality after RFCA in patients with pulmonary hypertension (PH) and atrial flutter (AFL).

Fifty-eight consecutive PH patients with AFL who underwent an electrophysiological study and RFCA between April 2013 and August 2021 were selected for this study. In the study population, pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) was the most common type of PH (n = 34, 59%), followed by idiopathic pulmonary arterial hypertension (IPAH) (n = 19, 33%). Typical atrial flutter was the most common type of atrial flutter (n = 50, 86.2%). Sinus rhythm was restored in 53 (91.4%) patients during RFCA. After a mean follow-up of 33.8 months, AFL recurred in a total of 22 patients. Nine of them underwent repeat RFCA, and the site of the repeat ablation was not exactly the same as the first. At a median follow-up of 34.6 months after the last ablation, none of the patients who underwent repeat RFCA experienced AFL recurrence, and all of these patients survived. There were no procedure-related complications during hospitalization or follow-up. Univariate Cox regression analysis suggested that AFL recurrence after the last ablation was not associated with all-cause mortality. NT-proBNP (HR: 1.00024, 95% CI: 1.00008-1.00041, P = 0.004), pulmonary artery systolic pressure (PASP) (HR: 1.048, 95% CI: 1.020-1.076, P = 0.001), and IPAH (vs.

7.720, 95% CI: 1.437-41.483, P = 0.017) were independent predictors of all-cause mortality in PH patients with AFL after RFCA. Receiver operating characteristic (ROC) curve analysis revealed that the area under the curve (AUC) of PASP for predicting all-cause mortality was 0.708. There was no significant difference in the Kaplan-Meier curves for all-cause mortality between patients with AFL recurrence after the last ablation and those without recurrence (P = 0.851). Patients with higher PASP (≥110 mmHg) and IPAH showed the lower survival rate in Kaplan-Meier curves.

Repeat ablation was safe and feasible in patients with recurrent AFL and can maintain sinus rhythm. AFL recurrence was not associated with all-cause mortality, and patients with high PASP or IPAH were at higher risk for adverse outcomes.

Arrhythmias frequently complicate the course of advanced pulmonary hypertension, often leading to hemodynamic compromise, functional impairment, and mortality. Given the importance of right atrial function in this physiology, the restoration and maintenance of sinus rhythm are of critical importance. In this review, we outline the pathophysiology of arrhythmias and their impact on right heart performance; describe considerations for antiarrhythmic drug selection, anesthetic and periprocedural management; and discuss the results of catheter ablation techniques in this complex and challenging patient population.

This study aimed to use multi-scale atrial models to investigate pulmonary arterial hypertension (PAH)-induced atrial fibrillation mechanisms. The results of our computer simulations revealed that, at the single-cell level, PAH-induced remodelling led to a prolonged action potential (AP) (ΔAPD: 49.6 ms in the right atria (RA) versus 41.6 ms in the left atria (LA)) and an increased calcium transient (CaT) (ΔCaT: 7.5 × 10-2 µM in the RA versus 0.9 × 10-3 µM in the LA). Moreover, heterogeneous remodelling increased susceptibility to afterdepolarizations, particularly in the RA. At the tissue level, we observed a significant reduction in conduction velocity (CV) (ΔCV: -0.5 m s-1 in the RA versus -0.05 m s-1 in the LA), leading to a shortened wavelength in the RA, but not in the LA. Additionally, afterdepolarizations in the RA contributed to enhanced repolarization dispersion and facilitated unidirectional conduction block. Furthermore, the increased fibrosis in the RA amplified the likelihood of excitation wave breakdown and the occurrence of sustained re-entries. Our results indicated that the RA is characterized by increased susceptibility to afterdepolarizations, slow conduction, reduced wavelength and upregulated fibrosis. These findings shed light on the underlying factors that may promote atrial fibrillation in patients with PAH.

Atrial fibrillation/flutter (AF) is common among patients with pulmonary hypertension (PH) and is associated with poor clinical outcomes. AF has been shown to occur more commonly among patients with postcapillary PH, although AF also occurs among patients with precapillary PH. The goal of this study was to evaluate the independent impact of PH hemodynamic phenotype on incident AF among patients with PH.

We retrospectively identified 262 consecutive patients, without a prior diagnosis of atrial arrhythmias, seen at the PH clinic at Mayo Clinic, Florida, between 1997 and 2017, who had right heart catheterization and echocardiography performed, with follow-up for outcomes through 2021. Kaplan-Meier analysis and Cox-proportional hazards regression modeling were used to evaluate the independent effect of PH hemodynamic phenotype on incident AF.

Our study population was classified into two broad PH hemodynamic groups: precapillary (64.9%) and postcapillary (35.1%). The median age was 59.5 years (Q1: 48.4, Q3: 68.4), and 72% were female. In crude models, postcapillary PH was significantly associated with incident AF (HR 2.17, 95% CI: 1.26-3.74, p = 0.005). This association was lost following multivariable adjustment, whereas left atrial volume index remained independently associated with incident AF (aHR 1.30, 95% CI: 1.09-1.54, p = 0.003).

We found PH hemodynamic phenotype was not significantly associated with incident AF in our patient sample; however, echocardiographic evidence of left atrial remodeling appeared to have a greater impact on AF development. Larger studies are needed to validate these findings and identify potential modifiable risk factors for AF in this population.

Atrial fibrillation (AF), typical atrial flutter (AFL), and other atrial tachycardias (ATs) are common in patients with pulmonary hypertension. Frequently, several supraventricular arrhythmias are successively observed in individual patients. We investigated the hypothesis of whether more extensive radiofrequency catheter ablation of the bi-atrial arrhythmogenic substrate instead of clinical arrhythmia ablation alone results in superior clinical outcomes in patients with pulmonary arterial hypertension (PH) and supraventricular arrhythmias.

Patients with combined post- and pre-capillary or isolated pre-capillary PH and supraventricular arrhythmia indicated to catheter ablation were enrolled in three centres and randomized 1:1 into two parallel treatment arms. Patients underwent either clinical arrhythmia ablation only (Limited ablation group) or clinical arrhythmia plus substrate-based ablation (Extended ablation group). The primary endpoint was arrhythmia recurrence >30 s without antiarrhythmic drugs after the 3-month blanking period. A total of 77 patients (mean age 67 ± 10 years; 41 males) were enrolled. The presumable clinical arrhythmia was AF in 38 and AT in 36 patients, including typical AFL in 23 patients. During the median follow-up period of 13 (interquartile range: 12; 19) months, the primary endpoint occurred in 15 patients (42%) vs. 17 patients (45%) in the Extended vs. Limited ablation group (hazard ratio: 0.97, 95% confidence interval: 0.49-2.0). There was no excess of procedural complications and clinical follow-up events including an all-cause death in the Extended ablation group.

Extensive ablation, compared with a limited approach, was not beneficial in terms of arrhythmia recurrence in patients with AF/AT and PH.

ClinicalTrials.gov; NCT04053361.

The development of atrial flutter and fibrillation (AFL/AF) in patients with pre-capillary pulmonary hypertension has been associated with an increased risk of morbidity and mortality. Rate and rhythm control strategies have not been directly compared.

Eighty-four patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) with new-onset AFL/AF were identified in the ASPIRE registry. First, baseline characteristics and rates of sinus rhythm (SR) restoration of 3 arrhythmia management strategies (rate control, medical rhythm control and DC cardioversion, DCCV) in an early (2009-13) and later (2014-19) cohort were compared. Longer-term outcomes in patients who achieved SR versus those who did not were then explored.

Sixty (71%) patients had AFL and 24 (29%) AF. Eighteen (22%) patients underwent rate control, 22 (26%) medical rhythm control and 44 (52%) DCCV. SR was restored in 33% treated by rate control, 59% medical rhythm control and 95% DCCV (p < 0.001). Restoration of SR was associated with greater improvement in functional class (FC) and Incremental Shuttle Walk Distance (p both <0.05). It also independently predicted superior survival (3-year survival 62% vs 23% in those remaining in AFL/AF, p < 0.0001). In addition, FC III/IV independently predicted higher mortality (HR 2.86, p = 0.007). Right atrial area independently predicted AFL/AF recurrence (OR 1.08, p = 0.01). DCCV was generally well tolerated with no immediate major complications.

Restoration of SR is associated with superior functional improvement and survival in PAH/CTEPH compared with rate control. DCCV is generally safe and is more effective than medical therapy at achieving SR.

The prognosis of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) remains dismal. Better risk prediction is needed. This study investigated the prognostic value of ECG characteristics.

In this single-centre prospective study, consecutive treatment-naïve patients with PAH or CTEPH were included at time of diagnosis. From the 12-lead ECG, obtained at baseline, the following parameters were collected: heart rate (HR), rhythm, QRS axis, conduction times, P-top amplitudes in II, R-top and S-wave amplitudes in V1 and V5 and repolarisation disorders. Associations between the ECG and transplant-free survival was assessed by Kaplan-Meier curves and Cox-proportional hazard regressions.

In total, 140 patients were included (median age: 60.7 years, 63.6% female). The ECG was abnormal in 86.2%: sinus rhythm was not present in 9.3%, right QRS axis was observed in 47.8%, mean QRS duration was 101±17 ms. Only 42.5% of the patients had normal repolarisation, 34.5% had right ventricular strain and 14.4% non-specific repolarisation disorders. Over a median follow-up time of 3.49 (IQR: 1.37-6.42) years, 45 patients (32.5%) died or underwent lung transplantation. Transplant-free survival was worse in patients presenting with an abnormal ECG (64.0% vs 86.0%; p=0.037). The following ECG characteristics were associated with all-cause mortality or lung transplantation: heart rate (HR 1.02, 95% CI: 1.00 to 1.05), QRS duration >120 ms (HR 2.61, 95% CI: 1.01 to 6.71) and S-wave amplitude in V5 (HR 1.10, 95% CI: 1.04 to 1.17).

Only 13.8% of patients with PAH and CTEPH presented with a normal ECG, which is associated with favourable outcome. The ECG provides additional prognostic value to current clinical parameters and should be considered in risk prediction.

In patients with pulmonary hypertension (PH), increased pulmonary vascular resistance (PVR) may lead to increased right ventricular afterload and cardiac remodelling, potentially providing the substrate for ventricular arrhythmias. Studies dealing with long term monitoring of patients with PH are rare. The present study evaluated the incidence and the types of arrhythmias retrospectively recorded by Holter ECG in patients with newly detected PH during a long-term Holter ECG follow-up. Moreover, their impact on patient survival was evaluated.

Medical records were screened for demographic data, aetiology of PH, incidence of coronary heart disease, level of brain natriuretic peptide (BNP), results from Holter ECG monitoring, 6-minute walk test distance, echocardiographic data and hemodynamic data derived from right heart catheterization. Two subgroups were analyzed: 1. patients (n = 65) with PH (group 1 + 4) and derivation of at least 1 Holter ECG within 12 months from initial detection of PH and 2. patients (all PH etiologies, n = 59) with 3 follow-up Holter ECGs. The frequency and complexity of premature ventricular contractions (PVC) was classified into "lower" and "higher" (=non sustained ventricular tachycardia, nsVT) burden.

Holter ECG revealed sinus rhythm (SR) in most of the patients (n = 60). Incidence of atrial fibrillation (AFib) was low (n = 4). Patients with premature atrial contractions (PAC) tend to have a shorter period of survival (p = 0.098), PVC were not correlated with significant survival differences. During follow-up PAC and PVC were common in all PH groups. Holter ECG revealed non sustained ventricular tachycardia in 19/59 patients [(32.2%); n = 6 during first Holter-ECG, n = 13 during second/third Holter-ECG]. In all patients suffering from nsVT during follow-up previous Holter ECG revealed multiform/repetitive PVC. PVC burden was not linked to differences in systolic pulmonary arterial pressure, right atrial pressure, brain natriuretic peptide and results of six-minute walk test.

Patients with PAC tend to have a shortened survival. None of the evaluated parameters (BNP, TAPSE, sPAP) was correlated with the development of arrhythmias. Patients with multiform/repetitive PVC seem to be at risk for ventricular arrhythmias.

The impact of atrial fibrillation and atrial tachycardias (AF/AT), and their optimal treatment strategy in PH patients is still being discussed. The goal of this study was to evaluate the effect of AF/AT termination on the hemodynamic parameters in PH patients. We compared patients with pre-capillary pulmonary hypertension (PH group), left ventricular heart failure (LV-HF group), and a Control group. A repeated right heart catheterization was performed during the catheter ablation (CA) procedure. The first measurement was done in arrhythmia, the second after the sinus rhythm (SR) was restored. High frequency atrial stimulation was used to simulate AT in patients without arrhythmia presence at the time of the CA. The variation of pressure parameters in PH patients did not differ significantly from the Controls. There was a significant increase in the right ventricle pressure after the SR restoration in the LV-HF group compared to the Controls and PH group (+4 vs. -2 vs. -3 mmHg, p<0.05). The cardiac index (CI) variation was not significant when compared between the study groups. An increase of the CI after the SR restoration was found in those patients with AF (+0.31 l/min/m2 [IQR 0.18; 0.58]) in contrast to those patients with organized AT/high frequency atrial stimulation ( 0.09 l/min/m2, [IQR - 0.45; 0.19]). This difference was statistically significant (p<0.05). The acute hemodynamic response to arrhythmia termination was not significantly different in the PH patients when compared to the Controls. In contrast to AT/high frequency stimulation, the restoration of SR in AF patients leads to an increased CI, irrespective of the presence or absence of PH.

Arrhythmia is not uncommon among pulmonary hypertension (PH) population, and may be associated with disease severity.

To investigate different spectrums and prevalence of arrhythmias in different clinical PH groups in Chinese population.

Patients diagnosed with PH between April 15, 2019, and August 2, 2021, were enrolled prospectively. The prevalence of different types of arrhythmias in PH patients were calculated. Logistic regression analyses were conducted to determine independent predictors for arrhythmia.

One thousand patients were enrolled. The prevalence of any arrhythmia, sinus node dysfunction, sinus tachycardia, atrial fibrillation, atrial flutter, other types of atrial tachycardia, atrioventricular block, and ventricular tachycardia is 44.4%, 12.2%, 15.2%, 8.1%, 4.1%, 10.2%, 7.1%, and 2.5%. Logistic regression analyses revealed that older age and larger right ventricle (odds ratio: 1.111 and 1.095, p < .05) were independently related with higher probability of supraventricular arrhythmia; Complicating with coronary artery disease, larger right ventricle, and increased left ventricular end-diastolic diameter (odds ratio: 19.540, 1.106, and 1.085, p < .05) were independently correlated with sinus node dysfunction/atrioventricular block in patients with pulmonary arterial hypertension.

Nearly half of PH patients experienced at least one type of arrhythmia. The most common seen arrhythmias were supraventricular arrhythmia, sinus tachycardia, and sinus node dysfunction. Older age and larger right ventricle were independently related with higher probability of supraventricular arrhythmia; Complicating with coronary artery disease, larger right ventricle and increased left ventricular end-diastolic diameter were independently correlated with higher probability of sinus node dysfunction/atrioventricular block in patients with pulmonary arterial hypertension.

Atrial fibrillation and atrial tachycardias (AF/AT) have been reported as a common condition in patients with pulmonary hypertension (PH). As yet, limited data exists about the significance of the borderline post-capillary pressure component on the occurrence of AF / AT in patients with isolated pre-capillary PH. We retrospectively studied the prevalence of AF / AT in 333 patients (mean age 61 ± 15 years, 44% males) with pre-capillary idiopathic / familiar pulmonary arterial hypertension, and inoperable chronic thromboembolic pulmonary hypertension. The prevalence of AF / AT was analyzed in different categories of pulmonary artery wedge pressure (PAWP). In the study population overall, the mean PAWP was 10.5 ± 3 mmHg, median of 11 mmHg, range 2-15 mmHg. AF / AT was diagnosed in 79 patients (24%). The proportion of AF / AT among patients with PAWP below the median (?11 mmHg) was lower than in subjects with PAWP between 12 and 15 mmHg, 30 (16%) vs. 46 (35%), p = 0.0001. Compared to the patients with PAWP?11 mmHg, subjects with PAWP between 12 and 15 mmHg were older (65 ± 13 years vs. 58 ± 16), with more prevalent arterial hyperte\nsion [100 (70%) vs. 106 (55%)] and diabetes mellitus [50 (35%) vs. 48 (25%)], showed larger size of the left atrium (42 ± 7 vs. 40 ± 6 mm), and higher values of right atrium pressure (12 ± 5 vs. 8 ± 5 mm Hg), p < 0.05 in all comparisons. The prevalence of AF / AT in the group studied increased with the growing post-capillary component.