Effect of carvedilol on premature ventricular complexes originating from the ventricular outflow tract

Carvedilol is one of the most effective beta-blockers in reducing ventricular tachyarrhythmias and mortality in patients with heart failure. One of the possible antiarrhythmic mechanisms of carvedilol is the suppression of store overload-induced Ca2+ release, especially for the triggered activity. Premature ventricular complex (PVC) originating from the ventricular outflow tract (OT) is the most common form of idiopathic PVC, and its main mechanism is related to triggered activity. We evaluate the efficacy of carvedilol to suppress the OT PVC. The electronic medical records at our hospital were screened to identify OT PVC patients treated with carvedilol. Clinical, electrocardiographic, and Holter monitoring studies were reviewed. A total of 25 patients who underwent Holter monitoring before and after carvedilol administration were found and enrolled. The mean age of the patients was 54.9 ± 13.9 years, and the mean dose of carvedilol was 18.2 ± 10.2 mg (sustained release formulation, 8/16/32 mg). The 24-h burden of PVC in 18 (72%) of 25 patients was significantly reduced from 12.2 ± 9.7% to 4.4 ± 6.7% (P = 0.006). In seven patients, the burden of PVC was changed from 7.1 ± 6.1% to 9.8 ± 8.4% (P = 0.061). There was no difference in age, carvedilol dose, duration of treatment, ventricular function, and left atrial size between responding and non-responding groups. In this retrospective pilot study, treatment with carvedilol showed PVC suppression in 72% of patients. Now, we are conducting a prospective, randomized, multicenter study to evaluate the effect of carvedilol on OT PVC (Clinical trial registration: FOREVER trial, Clinical-Trials.gov: NCT03587558).


Introduction
Carvedilol is one of the most effective beta-blockers to reduce ventricular arrhythmia and mortality in patients with heart failure [1,2]. Antioxidative and alpha-blockade effects, along with nonselective beta-blockade, have been proposed, but the exact mechanism is still unknown. Recently, inhibition of store overload-induced calcium release (SOICR) has been suggested as an antiarrhythmic effect of carvedilol [3]. The SOICR may cause significant

Open Access
International Journal of Arrhythmia *Correspondence: swhan@dsmc.or.kr † Jongmin Hwang and Kyoungmin Lee have contributed equally to this work 1 Cardiovascular Center, Keimyung University Dongsan Hospital, 1035 Dalgubeol-daero, Dalseo-gu, Daegu 42601, Republic of Korea Full list of author information is available at the end of the article arrhythmia by the triggered activity, which is induced by activating the Na + /Ca 2+ exchanger. Among various beta-blockers, only carvedilol is known to be a drug that can directly inhibit the release of SOICR along with the beta-blockade effect. Premature ventricular complex (PVC) occurring in the ventricular outflow tract (OT) is the most common arrhythmia among the idiopathic ventricular arrhythmias (VAs), and its mechanism is related to intracellular calcium overload and delayed afterdepolarizations that leads to triggered activity [4]. The OT PVCs associated with disruptive symptoms and frequent OT PVCs can lead to cardiomyopathy. Therefore, the OT PVC often requires treatment. The purpose of this study was to evaluate the effect of carvedilol on patients with OT PVC as a retrospective study and to obtain basic data for the future prospective randomized study.

Methods
Patients who had a diagnosis of "ventricular premature complex (I49.3 in ICD-10)" were retrospectively identified by systematic screening of the Keimyung University Dongsan Hospital electronic medical records review. A manual chart review was performed on this subset of patients to identify those who were prescribed carvedilol for the treatment of OT PVC. The OT PVC was defined as PVC showing a tall R wave in II/III/aVF lead in the 12-lead electrocardiogram. Of these, patients treated with carvedilol and who underwent Holter monitoring before and after treatment were identified. Clinical, electrocardiographic, and Holter monitoring studies were reviewed and analyzed.

Statistical analysis
Continuous variables are expressed as the mean value ± standard deviation. The median and interquartile range were used for continuous variables that did not follow a normal distribution. Categorical variables are expressed as numbers and percentages. To compare the continuous variables, paired or independent sample t test was performed. For categorical variables, the Chi-square test was used. All statistical analyses were performed by the MedCalc statistical software version 19.1.7 (MedCalc Software Ltd, Ostend, Belgium). A P value < 0.05 was considered statistically significant.

Study population
A total of 25 patients were reviewed and analyzed. The baseline characteristics of the study population are shown in Table 1. The mean age of the patients was 54.3 ± 12.4 years, and eight patients (32%) were male. All patients had structurally normal hearts, and a mean LV ejection fraction was 64.5 ± 5.0%. The enrolled patients in our study did not have significant comorbidities, and all patients did not take concomitant medications that would affect the PVC burden.

Comparison between patients with reduced PVC group and not-reduced group
The burden of PVC was not reduced in seven patients (7.1 ± 6.1-9.8% ± 8.4, P = 0.061). There was no difference in baseline clinical characteristics between carvedilol treatment responding and non-responding groups (Table 3). In patients with PVC reduction, maximal heart rate was also significantly reduced (Additional file 1: Supplement Table 1).

Effect of carvedilol according to dosage
The degree of PVC suppression according to carvedilol dosage was as follows: − ∆1.9% ± 3.7% in 8 mg group, − ∆7.0% ± 9.7% in 16 mg group, − ∆6.0% ± 10.1 in 32 mg group. The comparison between three groups on the degree of PVC suppression did not reach statistical significance (P = 0.098, using ANOVA, Scheffe test). Figure 2 illustrates the mean 24-h PVC burden on Holter monitoring before and after carvedilol use according to dosage.

Discussion
In this cohort of 25 patients with OT PVC, carvedilol treatment significantly reduced the PVC burden. Overall, 72% of patients showed a decrease in PVC, and the average reduced burden of PVC compared to baseline was 71.5% ± 32.3%.
The mechanism underlying the favorable antiarrhythmic effect of carvedilol remains unclear. The antioxidant and alpha-blocking activities of carvedilol have been suggested to contribute to its beneficial effects, but those were not corroborated by clinical studies [5,6]. Recently, inhibition of SOICR has been suggested as an antiarrhythmic effect of carvedilol [3]. Stimulation of the beta-receptor leads to the entry of calcium into the cell by opening the L-type calcium channel. The influx of calcium through the L-type calcium channel also increases calcium release from SR (sarcoplasmic reticulum) through the ryanodine receptor (RyR). This Ca 2+ -induced Ca 2+ release is essential to  muscle contraction as a normal function. However, in the event of SR calcium overloading or excessive betaadrenergic receptor stimulation, spontaneous calcium release, which is not associated with the depolarization, known as SOICR, can occur through the RyR. This phenomenon may cause severe arrhythmia of triggered activity by activating the Na + /Ca 2+ exchanger. Indeed, SOICR-evoked delayed afterdepolarizations (DADs) cause catecholaminergic polymorphic ventricular tachycardia, which is associated with naturally occurring RyR2 mutations [7,8]. Among various beta-blockers, only carvedilol is known to be a drug that can directly inhibit the release of SOICR along with the beta-blockade effect [3].
One of the major limitations of using carvedilol for anti-SOICR effect is its dose. The concentrations of carvedilol required to suppress SOICR (0.3-1 μM) are much higher than those required for beta-blockade (~ 1 nM) [9]. Therefore, strong SOICR inhibition would require high doses of carvedilol, which could produce excessive beta-blockade and accompanying adverse effects such as bradycardia [10]. However, it has been reported that carvedilol has a high degree of lipophilicity and shows a large volume of distribution, so it accumulates at a higher concentration in the cardiac muscle than in plasma [11][12][13]. In addition, the longer the exposure to carvedilol, the smaller the dose of carvedilol can inhibit SOICR [3]. Pharmacologically, separating the beta-blocking and anti-SOICR activities of carvedilol could be one solution [3]. In our study, carvedilol is thought to have a higher effect on suppressing PVC at 16 mg or more than 8 mg. In addition, comparisons of electrocardiographic and Holter monitoring parameters before and after carvedilol use according to dosage showed a tendency of dose-dependent response in suppressing maximal heart rate (Additional file 1: Supplement Table 2). However, 8 mg of carvedilol also showed a significant decrease in maximal heart rate. Further studies are needed to conclude optimal dosage and inter-individual difference of carvedilol to suppress the PVC.
The VAs most frequently occur in patients with structural heart disease. However, some VAs can occur in patients without structural heart disease and those are called idiopathic VAs. The most common origins of idiopathic VAs are the right and left ventricular outflow tracts [14]. The idiopathic VAs are thought to be caused by catecholamine-induced, cyclic adenosine monophosphate-mediated DADs and triggered activity [15].
Under this background, we hypothesized that carvedilol, which can reduce triggered activity by inhibiting SOICR, would be effective for OT PVC. To confirm this hypothesis, we designed this retrospective study and the results were impressive. Now, we are conducting a prospective, randomized, multicenter study to evaluate the effect of carvedilol on OT PVC (FOREVER trial, Clinical-Trials.gov: NCT 03587558) and are expecting the results.
Our study has some limitations. The main problem is the small number of total patients and retrospective study design for the conclusion. In one in vitro study, carvedilol is the only beta-blocker tested that can effectively suppress SOICR [3]. However, the effect of carvedilol should be tested in vivo study with other beta-blockers such as bisoprolol and metoprolol and also with placebo.

Conclusion
In our retrospective, pilot study, carvedilol showed good efficacy for suppressing OT PVCs. Large, prospective, randomized studies are needed to demonstrate the effect of carvedilol on PVC suppression.