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 . 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 Ca2+-induced Ca2+ release is essential to muscle contraction as a normal function. However, in the event of SR calcium overloading or excessive beta-adrenergic 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+/Ca2+ 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 .
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) . Therefore, strong SOICR inhibition would require high doses of carvedilol, which could produce excessive beta-blockade and accompanying adverse effects such as bradycardia . 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 . Pharmacologically, separating the beta-blocking and anti-SOICR activities of carvedilol could be one solution . 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 . The idiopathic VAs are thought to be caused by catecholamine-induced, cyclic adenosine monophosphate–mediated DADs and triggered activity .
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 . However, the effect of carvedilol should be tested in vivo study with other beta-blockers such as bisoprolol and metoprolol and also with placebo.