Symptom Burden and Quality of Life After Successful Ablation in Patients With Low Burden of Symptomatic Premature Ventricular Complexes

It is essential to enhance life quality in patients with premature ventricular complexes (PVCs) with the use of radiofrequency ablation (RFA). The aim of the study was to assess symptom burden and life quality in patients with a low PVC burden following RFA. 31 individuals with a low PVC burden in whom RFA was indicated were included in the study. At baseline and after a year following RFA, the Arrhythmia-Specic questionnaire in Tachycardia and Arrhythmia (ASTA) scale was used for appraisal. A 24-hour Holter electrocardiogram was used to detect recurrent PVCs 12 months after the RFA intervention. ASTA scores related to symptom burden, including the near-syncope score, health-related quality of life (HRQOL) scales pertaining to physical and mental health, and consequently the total HRQOL score, were all diminished a year after RFA (p<0.001). The ASTA score for syncope symptoms was also reduced (p<0.05). A fall in mean PVC burden was seen from 8.0% to 0.8% (p<0.001). The long-term clinical endpoint in individuals with a low PVC burden following RFA is reported. Symptom load, life quality and ultimate PVC burden were all enhanced. Additional studies incorporating longer follow-up and monitoring periods, respectively, would be benecial.


Introduction
In patients with premature ventricular complexes (PVCs), life quality can be enhanced by radiofrequency ablation (RFA) 1 . Objectives of cardiac rehabilitation include diminishing symptomatology and attaining superior levels of physical activity and overall health 2 .
In routine clinical work, PVCs are the most frequent cardiac dysrhythmia encountered, with a prevalence of 1.1% being documented in a telemedicine study performed in Makassar City 3

. A further study noted
PVCs in 1% and 40-75% of individuals on 12-lead and Holter electrocardiography, respectively 4 . PVCs are more common in patients of more advanced years; frequencies of a minimum of one PVC detected on 24-hour cardiac recordings were 16.7% in well individuals below the age of 30 years, and up to 69% in those above the age of 75 years 5 .
Within the overall population, the impact of PVCs on the establishment of congestive cardiac impairment or fatality is unclear. Nevertheless, a number of publications have implied that the likelihood of sudden cardiac demise, cardiovascular morbidity and systolic left ventricular impairment may be exacerbated by numerous PVCs 6 . In addition, patients may present with palpitations, fatigue, chest discomfort, dizziness, loss of conscious and symptoms of cardiac impairment. Although these issues are common in patients with a high burden of PVCs, low PVC frequency, i.e. < 5000/24 hours, can also generate signi cant symptomatology and merit treatment 7 .
Earlier clinical studies have demonstrated that an impairment in left ventricular ejection fraction (LVEF) may be associated with a higher than mean burden of PVCs. Interestingly, the frequency of PVCS did not always predict left ventricular function, with patients with a high PVC burden displaying normal cardiac performance whereas cardiomyopathy related to PVCs was at times seen in subjects with a relatively small PVC burden [8][9][10] . Currently, no speci c estimate of PVC burden has been determined to be a reliable predictor of cardiac dysfunction 7 11-13 although an arbitrary cut-off parameter of 10% PVCs with respect to the overall heart rate, as opposed to the absolute PVC frequency, has been employed in a number of studies 1114 .
RFA is an e cacious therapeutic intervention for PVCs. Contemporary pharmaceutical agents for dysrhythmias are not always effective and may have an adverse side effect pro le 15  PVCs that give rise to symptoms, reduced LVEF and in whom anti-arrhythmic agents fail 1617 .
A number of studies have provided evidence regarding the non-subjective positive endpoints following the use of RFA in individuals with a high PVC burden, although PVCs were noted to recur after a postprocedural surveillance period of at least six months 8 11 12 18 . One retrospective study followed up 44 individuals who had received RFA for a symptomatic high PVC burden for over a year; monitoring determined a positive outcome rate following RFA of 75% 19 . PVCs, arising from either a different or identical pre-ablation focus, recurred in 18.2% and 6.8% patients, respectively. RFA does not in uence mortality statistics, and therefore its clinical endpoints should be judged in relation to subjective changes in patient symptomatology. Few studies have evaluated the application of RFA in individuals who have few PVCS, particularly with respect to their symptoms and life quality. A low PVC burden may provoke symptomatology; some individuals may exhibit clinical evidence of reduced LVEF. The current research has appraised the utility of RFA with respect to the symptomatic load and life quality of individuals with symptoms pertaining to a low PVC burden. The data presented can be utilized as a foundation for establishing the utility of RFA in the clinical care of this patient cohort.

Study design
An observational, single-centre, cohort study was performed in order to assess the outcome of individuals with a low burden of PVCs treated at either the Medical Faculty of Hasanuddin University or the Dr. Wahidin Sudirohusodo Hospital, Makassar, Indonesia. The study was conducted between January and December, 2019. The study was approved by Commission on Health Research Ethics Medical Faculty of Hasanuddin University RSPTN with protocol number UH20020106. All participant will be informed of the research aims and objectives, and that con dentiality will be maintained throughout the study. Information and consent form provided at baseline and participant will be free to withdraw from the research at any time. All methods were performed in accordance with the Declaration of Helsinki. Patient characteristics All 31 study participants had a low PVC burden, as evaluated by 24-hour Holter electrocardiography and de ned as ≤ 10% PVCs per 24-hour period. Indications for RFA included continuing symptoms despite use of anti-arrhythmic agents, failure to withstand medication and patient choice. Study exclusion criteria encompassed those who had undergone former RFA or who had additional coexistent rhythm disturbances. Patient demographics were documented, i.e., gender, age, weight, height, body mass index (BMI) and additional comorbidities. Echocardiography 2-dimensional echocardiography was carried out before and after RFA intervention. LVEF and left ventricular end-diastolic dimension (LVEDd) were computed according to the Simpson method from an M-mode image obtained in the parasternal long axis plane.

Radiofrequency ablation
Following written informed consent, all patients underwent electro anatomical mapping and radiofrequency catheter ablation of the PVC foci per standard laboratory protocol and the judgment of the operator. Mapping and ablation were performed with 7Fr quadripolar electrodes and a de ectablecurve, temperature-guided ablation catheter. Activation mapping was used with 3-dimensional mapping system. Attempts were made to record an earliest endocardial activation at least 30 ms before the onset of the QRS complex from the ectopic site. The aim was to achieve a 11/12 or 12/12 identical pace mapping. Once VPCs were localized, radiofrequency power of 20 to 40 W to maintain the temperature at the catheter tip of 50°C was delivered. After ablation, all patients were kept under observation for 30 min.
Successful ablation was de ned as complete elimination of spontaneous or inducible PVC 1 .

Arrhythmia-Speci c questionnaire in Tachycardia and Arrhythmia scale
The Arrhythmia-Speci c questionnaire in Tachycardia and Arrhythmia scale (ASTA) scale was utilized in order to evaluate subjects' symptom load and impact on life quality prior to and 12 months after RFA, the latter in conjunction with a further 24-hour Holter electrocardiogram in order to identify recurrent PVCs. The questionnaire was split into three sections, which assessed: (i) the most recent arrhythmic event and ongoing drug therapy; (ii) the symptom load according to a 9-item 4-point response scale (the ASTA symptom scale); and (iii) life quality using a 6-and a 7-item subscale, i.e. 13 items in total, comprising similar 4-point response rankings, i.e. the ASTA Health-Related Quality of Life (HRQOL) scale. The second section also encompassed enquiries regarding the prevalence of events relating to PVCs, the mean length of symptoms and the most enduring event, together with any history of associated loss of consciousness, dizziness or palpitations. The ASTA HRQOL evaluation generated scores ranging between 0 and 100; the latter indicated a high symptom load and greater impact of the PVC burden on life quality 20 21 .

Statistical analysis
The Statistical Package for the Social Sciences software was used for data analysis. Mean ± standard deviation, together with minimal and maximal scores are presented for the continuous variables; frequencies are provided for the categorical data. Life quality pre-and post-RFA was compared using a paired simple t-test. Signi cance was de ned as a p value < 0.05.

Results
The study sample included 19 females (61.4%) and 12 males (38.7%). Mean age was 43.0 years; age range was 17 -74 years. Mean weight was 61.7 kg, height, 160.0 cm, and BMI, 24.3 kg/cm 2 . Comorbid factors were absent in 51.6%; hypertension, coronary heart disease and diabetes mellitus were present in 38.7%, 6.5% and 3.2%, respectively. Anti-arrhythmic medication was prescribed prior to RFA; 26 patients (83.9%) were on beta blockers, 4 (12.9%) were on amiodarone, and 1 (3.2%) was receiving a calcium channel blocker.  Table 1. Echocardiographic ndings from baseline and a year after RFA are displayed in Table 2 (Table 3). Baseline ASTA near-syncope score was 7.5; this dropped to 0 following the intervention, with no participants reporting symptoms of near-syncope or syncope during the surveillance period. All the symptom burdens measured on the ASTA score decreased (p<0.05).
Life quality was also evaluated at baseline and at one year following RFA, yielding HRQOL physical subscale values of 30.7 and 0.3 (range: 0-9.1), respectively. The mental HRQOL additionally diminished following RFA, with baseline and post-intervention values of 32.7 and 2.7 (range: 0-21.1), respectively. Thus, post-RFA, the total HRQOL scale score decreased from 32.5 to 1.5, indicating a notable improvement in life quality (p<0.001). Table 3. Symptom burden and quality of life before and 12 months after ablation *Paired t-test for comparison before and after ablation

Recurrence of PVCs 12 months after ablation
If the burden of PVCs remained over 80% of the baseline value on the 24-hour Holter electrocardiogram after 12 months or PVCs noted on the monitor were symptomatic, the RFA was deemed to be a failure and PVCs to have recurred. Ten of the 30 participants who underwent RFA exhibited PVCs on the followup 24-hour Holter recording, of whom 5 were described as having a good ablation outcome with an 80% reduction in PVCs, and 5 were considered to have a poor procedural endpoint, with a PVC burden fall of less than 80%. Eight subjects ful lled the parameters for PVC recurrence, whereas the remaining two did not as their PVCs had been ameliorated by over 80%. Despite the evident PVCs, these individuals reported no symptoms. Thus, the proportion of subjects who presented with recurrent PVCs was documented to be 26.6% (8/30) ( Table 4). In this patient sample, the proportion of females experiencing symptoms from a low PVC burden was higher than males. Gender differences in the prevalence of PVCs have been reported in previous studies, e.g. the ARIC study and a study published by Kerola et al. 22 ; both concluded that being male increased the likelihood of PVCs. The results from the current study concur with several studies pertaining to the incidence of PVCs 23 24 25 . Of 30 patients with numerous PVCs who were treated with RFA, females reported a higher number of related symptoms. It is possible that the latter show a heightened awareness of milder disturbances associated with PVCs and are therefore more likely to present than males, although to date, there are no data to support this theory.
PVCs can be detected in individuals at any life stage, but research has implied that they become more common with advancing years. In this study, the mean age of the population with low burden PVCs was over 40 years. A similar mean age was noted by Darrieux et al. 26 in 30 patients who were treated with RFA for symptomatic multiple PVCs. The observation of age being a predictor of symptomatic PVC prevalence was also reported by a number of other researchers 242527 , and could be associated with the overall heightened cardiovascular risk pro le in the elderly, together with the onset of additional generalized symptomatology that leads individuals to seek clinical review.
The PVC site is strongly associated with symptom prevalence, a positive interventional outcome and a reduced rate of complications. Despite an underlying structurally normal heart, Darrieux et al. 26 a rmed that PVCs arising from the ROVT (PVC-RVOT) were most likely to generate symptoms 23 27 . Farzaneh et al. 28 noted that 80% of individuals with PVC-RVOT were free from structural cardiac pathology. Earlier research ndings are in keeping with the current study. Despite the fact that patients with a low PVC burden were selected for this study, the majority had PVCs originating from the RVOT. All the subjects reported symptoms; only a single individual was noted to have underlying cardiac structural abnormality.
These observations are disparate to those found by Xu et al. 29 ; these authors reported the presence of a high PVC burden in patients with PVC-RVOT.
It has been demonstrated that individuals with an impaired LVEF have a greater average PVC burden than those with an LVEF within the normal range, i.e. 29-37% and 8-13%, respectively 11 14 . Cardiomyopathy precipitated by PVCs has been occasionally noted in subjects with relatively few PVCs 8 . The data presented in the current study are in agreement, in that the participants with a mean PVC burden of 8% demonstrated a normal LEVF of 62.9% and LVEDd of 43.8 mm on echocardiography. These two parameters remained stable following RFA indicative of the absence of PVC-related cardiac impairment prior to the procedure.
Only a single individual was noted to have a low LVEF of 29% and dilated LVEDd of 67 mm prior to RFA owing to concurrent coronary artery disease. Subjects in whom a reduced LVEF was identi ed only demonstrated a rise of LVEF of up to 15% on the yearly follow-up scan, despite a positive outcome from RFA de ned by the drop in PVC burden from 9.8% to 0%. PVC-related cardiomyopathy is presumed if the diminished baseline LVEF rises by a minimum of 15% or returns to the normal range, i.e. > 50%, following RFA 11 . It was therefore surmised that the cardiac impairment seen in this individual was unlikely to be a result of PVCs or concomitant structural cardiac pathology.

Changes in symptom burden and quality of life in low burden PVC patients 12 months after ablation
It was observed that both symptom load and life quality improved within the year after RFA in patients with a low initial PVC burden, which was in keeping with the recorded reduction in PVC burden following the procedure. Earlier studies have additionally demonstrated the success of RFA in diminishing PVC frequency, and in alleviating symptoms and enhancing life quality in patients with a relatively high PVC burden 1 30 . In one study in which 30 patients with a high PVC burden causing symptoms underwent RFA, PVC frequency and symptoms were reduced and a superior life quality was reported a year following the intervention 24 ; these were similar results to those obtained in the current study on subjects with a low PVC burden. At follow-up, two-thirds of patients were symptom-free; in the remaining third, their symptoms had been ameliorated and they reported no physical or psychological disruptions to their life quality.

Changes in PVC burden 12 months after ablation
Earlier work has presented evidence to demonstrate that RFA has a higher e cacy than pharmaceutical therapy for the eradication of PVCs. However, these studies were generally performed on individuals with a high PVC burden. Specialist recommendations published by the European Heart Rhythm Association The current study has demonstrated a fall in PVC prevalence a year following RFA as documented using 24-hour Holter monitoring. These data are in keeping with former research on populations with a high PVC burden 8,12,13,31 . In a study of 30 patients, a fall in the high PVC burden of 23.1% to 1% was noted at 3-4 months follow-up 32 . A similar decrease in high PVC burden, from 19% to 1.1% was noted in 50 individuals in a study published by Baser et al. 25 .

Recurrence incidence 12 months after ablation of low burden PVC patients
Statistics have revealed that individuals who exhibit over 12 PVCs on a daily basis have an increased mortality rate from all etiologies and a higher number of in-patient admissions for cardiac pathologies, including myocardial infarctions, when judged against subjects with a lower number of PVCs 6 . A RFA intervention is deemed successful if the PVC burden were diminished by 80% of the baseline total 11 25 . There is a range of parameters that have been used to determine PVC resumption following RFA; current research has predominantly used populations with a high PVC burden. The de nition of recurrence in this study was failure to decrease the PVC burden by 80% of the baseline value as recognized by 24-hour Holter electrocardiography, or the resumption of PVC-related symptomatology documented during the Holter monitoring period.
According to the above criteria, 26.6% were noted to have recurrent PVCs a year after RFA. A number of earlier researchers have demonstrated the frequency of PVC recurrence following RFA to be between 10-20%, although it was slightly higher in one study 24 , which documented a recurrence rate of 26% (8/30 participants). Patients with recurring PVCs reported symptoms, although on additional analysis, the residual symptomatology was less intense than prior to RFA and failed to impact life quality. Those who were deemed to have recurrent PVCs owing to less than 80% PVC reduction but who were symptom-free implied that the subjective parameters relating to the presence or absence of symptoms could not be utilized in isolation.

Strengths and limitations of the study
The life quality of individuals with a low PVC burden who underwent PVC was assessed. This research therefore forms the foundation for establishing the application of RFA in this patient cohort. Subjective bias from patients self-completing the questionnaire cannot be entirely excluded. Furthermore, the Holter system utilized was only a seven-lead system, which has restrictions with respect to recognizing the focal loci of PVCs in those individuals in whom recurrence was suspected. This is signi cant, as RFA may have been effective in ablating earlier PVCs but detected de novo PVCs may have arisen from a different site.

Conclusions
In patients with a low PVC burden, RFA offered a symptom burden reduction and enhanced life quality after a year following the intervention. The PVC burden was diminished at this juncture; PVC recurrence was identi ed in 26.6% subjects.
Thus, it can be concluded that patients with a low PVC burden but who experience symptoms should be treated with RFA. A more prolonged monitoring period is favored, i.e. a minimum of 48 hours. Additional studies are merited to establish the impact of RFA on the burden of symptoms and life quality in patients with only a low PVC burden; patients should be followed up long-term and studies should incorporate larger population sizes.

Declarations
Ethics approval and consent to participate The Commission on Health Research Ethics Medical Faculty of Hasanuddin University RSPTN gave ethical approval for this research (protocol number: UH20020106). All study subjects were provided information pertaining to the aims and objectives of the study; their anonymity was guaranteed. Informed consent was obtained from all participants at baseline. Subjects were reassured that they could leave the study at any juncture.

Consent for Publication
Not applicable Availability of data and material Datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The author (s) declare no competing interests.

Funding
No external monetary support was required for this study.

Authors contributions
The manuscript was written by all the authors. MA, PK and MNIS were responsible for study design, data collection, analysis and interpretation, and manuscript drafting. PT, IJP and SMZ contributed to data analysis and interpretation, and the writing of the manuscript. The nal manuscript was read, critiqued, revised and ultimately approved by all authors.