The prevalence of PVC is age dependent, so that it ranges from <1% in children up to >60% in the elderly persons (12). Up to 75% of subjects in standard Holter ECG recording (up to 48 hours) have PVC, while in standard 12-lead electrocardiogram the incidence is only 1% (13). PVC had been long regarded as an entirely benign phenomenon in structurally normal heart until 1998 when the beneficial effect of PVC suppressive drugs on dilated cardiomyopathy was described and when the concept of PVC-induced cardiomyopathy was developed (5). The exact prevalence of the disease is unknown, but it is certain that this entity is underdiagnosed as a cause of cardiomyopathy (CMP). It predominantly occurs in elderly people, probably due to the fact that it takes a long time for frequent PVCs to cause reduction of LV function (14). In addition to the duration of PVCs, the incidence of PVC measured as the ratio (%) or the absolute number during 24 hours, the so-called “PVC burden” is very important.

PVC-induced cardiomyopathy has some similarities to other clinical entities such as tachycardiomyopathy and cardiomyopathy induced by right ventricular electrostimulation. In the past, it was thought to be just one subtype of tachycardiomyopathy, which is a well-known phenomenon within the “fast” atrial fibrillation or undulation, other supraventricular arrhythmias or ventricular tachycardia. This pathophysiological mechanism soon faced criticism, because the average incidence in PVC-induced CMP is similar to that in sinus rhythm. It is possible that frequent and short-coupled PVCs cause changes in intracellular calcium metabolism and transmembrane ion transport thus depleting the energy supplies of myocytes. In addition, changes are made to the hemodynamics and heart rate dynamics with the associated changes in the vasculature tonus (15). The above mentioned phenomenon has been previously described as a postextrasystolic potentiation (11). The similarity to CMP in the right ventricular (RV) stimulation is reflected in eccentric activation of the ventricular myocardium caused by PVCs which leads to dyssynchrony. Compensatory pauses after PVC change the ventricular filling and discharging dynamics. Dyssynchrony results in reduced global efficiency of ventricles, asymmetric wall hypertrophy, changes in myocardial perfusion and ultimately in an increased consumption of oxygen (6).

Two models that should elucidate the exact mechanisms of this disease have been published so far, both on mongrel dogs. Akum et al. used dual chamber pacemaker (the both electrodes in the RV, one for sensing, the other for stimulation) used for simulating PVC bigeminy from the RV. Only after four weeks LV dilatation developed followed by a significant decline in systolic function (EF from 60% to 46%) (10). A similar model was used by Ellenbogen et al., where dilation and a significant decline in the LV function occurred after 12 weeks. Besides, already 2-4 weeks the cessation of stimulation was followed by the recovery of LV function. In this article, some histological studies were performed finding no signs of inflammation, fibrosis, changes in apoptosis or oxidative phosphorylation in mitochondria in subjects with cardiomyopathy, which confirms the thesis that PVC-induced cardiomyopathy is a reversible condition with no major pathohistological and mitochondrial anomalies. The change occurred in the effective refractory period of the ventricle, which is the sign of the electric remodelling. So, the most probably, it is predominantly the functional rather than structural abnormality that causes CMP (11). The fact that in canine models it took so little time for CMP to develop, casts doubt on the appropriateness of the same in case of interpolation on people where we know that it takes years for the LV function to deteriorate. A group of authors from Michigan developed a sheep model with a very similar methodology (dual chamber pacemaker and induced PVC bigeminy), but here the changes in the parameters of LV function were detected much later and were much more subtle. At the cellular level, there were only a few changes in the intracellular transport of calcium which could at least partially explain the pathophysiology of this disease (still unpublished data).

There are no strictly defined limits of incidence of PVC, which would certainly cause a decline in LV function. Some patients with very high burden do not develop CMP, while the other with a much smaller burden develop it, however, it still happens a lot less often. It is certain that the other parameters except for “PVC burden” play an important role in the development of this disease. However, patients with lowered EF have significantly greater burden than similar patients with normal EF.

Various authors have set different boundaries which define high burden, 20,000/day, >10,000/day, >10% QRS, >10/hour, etc. (6, 16, 17). It is important to note that only one third of patients with high PVC burden develop CMP. The question is whether an error in the methodology is concerned (the usual 24- hour Holter) or whether some other unknown moments are accountable. One study shows that the limit of 24% PVC a day is sufficiently specific (79%) and sensitive (78%) in dividing patients in those with and without CMP (18). The vast majority of idiopathic PVC arises from the RV outflow tract (around 2/3), but a significant proportion of arrhythmic foci is positioned in the muscular extension above the pulmonary and aortic valve (see the article by Anic in this issue (18)). Foci in LV — the free wall, papillary muscles or fascicles of the left bundle branch are somewhat rarer. Ventricular ectopia, can of course be multifocal resulting in polymorphic PVC, but often those coming from the outflow tract are dominant. It is worth noting that one study showed that much higher prevalence of LV from PVC (>20%) versus RV (>10%) was required for the development of CMP that might indicate PVC-induced dyssynchrony as a pathophysiological mechanism. In addition, PVCs of wide QRS (>150 ms) or the ones of epicardial origin are an independent predictor of the development of the CMP (19).

We noted earlier that the duration of the extrasystoles is an important predictor of the development of CMP. It takes years, not only months for very frequent PVCs to cause the development of CMP. Patients without any symptoms (they visit a doctor later) or those with a length of palpitations >60 months develop cardiomyopathy more often (20). There is still no unambiguous answer to the question concerning the impact of PVC coupling interval and PVC interpolation on the development of CMP.

PVC-induced cardiomyopathy is still a diagnosis of exclusion. It is necessary to detect all potential underlying structural heart diseases that could be a cause for frequent extrasystoles. Sometimes it is very difficult to determine what precedes what, and what a primary disorder is, whether it is extrasystole causing a structural disease or vice versa. In most patients, it is not possible to determine the start of frequent extrasystoles in relation to the development of CMP (21). As PVC-induced CMP is a reversible disease, it is important to find the primary cause.

The range of symptoms that patients present with, extends from palpitations (typical heart skipping, pricking pains, unspecified precordial oppressions), presyncopal episodes, syncopes to manifest heart failure in the case of already developed CMP. At the time of diagnosis, most of the patients have structurally normal heart (1), but a standard cardiac workup should be performed anyway.

It is important to examine family medical history (familiar non-ischemic CMP) and the personal medical history that may help explain the cause of any potential CMP (toxic, ischemic — risk factors, infectious, thyroid etc.). Physical examination usually detects arrhythmic heart rate if PVCs are extremely common. The 12-lead electrocardiogram can record PVC which helps locate the focus (most commonly the RV outflow tract). Likewise, the ECG should search for signs of arrhythmogenic right ventricular dysplasia, hypertrophic cardiomyopathy, etc. The diagnosis is impossible without 24-, or 48-hour Holter ECG, because it is very important to determine the patient’s PVC burden. As the daily burden varies, Holter monitoring is to be repeated more often. Echocardiography is unavoidable not only in verifying structurally normal heart, but also in diagnosing the most common disorders within this CMP — LV dilatation and global reduction of contractilities (22). Echocardiography is also important to us to exclude any other potential causes of CMP and for further follow-up of patients. The risk factors for the development of CMP as a part to frequent PVC are still unknown, so that there are no clear guidelines for the frequency of echocardiographic follow-ups and Holter monitoring. If there are risk factors for coronary artery disease with regional wall motion abnormalities, then coronary angiography is to be performed. Furthermore, heart magnetic resonance imaging can give us the best information if you suspect the arrhythmogenic dysplasia, the history of myocarditis or infiltrative cardiac diseases.

The general consensus is that the PVC therapy is required when LV dysfunction is recorded, and there is a thorough suspicious of PVC-induced CMP, or if the PVC burden is extremely high. The therapy is indicated in case of a slightly lower PVC burden in case of pronounced symptoms that impair the quality of life. There are two treatment options, conservative medical (antiarrhythmic drugs) treatment and catheter radiofrequency (RF) ablation.

Most patients with frequent extrasystoles have structurally normal heart and once we determine it, it is primarily necessary to advise and comfort a concerned patient and explain that this it is a completely benign disorder with an excellent prognosis1. No need to rush with pharmacotherapy, which is in this case indicated only if the symptoms limit the patient’s life. Beta blockers or non-dihydropyridine calcium channel blockers are the first line of pharmacotherapy (23). In case they have no efficacy, we can use sotalol or I.b antiarrhythmics (mexiletine) or I.c (propafenone) groups which are otherwise contraindicated if CMP has already developed (24). In this case, you should always weigh any pro-arrhythmogenic effects of antiarrhythmics, as well as any possible side effects against the potential benefits. In case that we treat a patient who has experienced a decline in LV function, then the only one which is left from the antiarrhythmic drug therapy is amiodarone. In a number of studies amiodarone therapy has proved to be efficient in suppressing PVCs which resulted in normalization of LV function (5, 25).

Considering the development of new methods and options of invasive treatment of arrhythmias, including 3D navigation systems (which drastically reduce the time of fluoroscopy), the alternative sources of ablative energy (cryoablation), the advancement of epicardial access etc. the catheter ablation is becoming an increasingly attractive option of treating this disease. There are still no randomized clinical trials that compared the medical and invasive treatment. Nevertheless, there are numerous reports on the success of RF ablation in the treatment of this arrhythmia. The first group which reported on the success of RF ablation in normalizing the LV function was the one from Yarlagadde in 2005 (14). It was followed by some more reports with similar findings on a smaller numbers of patients. The group from Michigan had the largest series of patients, also with very favorable results on RF ablation. Bogun et al. have described 60 patients, of whom 48 met the criteria for successful ablation, whereas out of 22 patients with compromised function there were 18 of them successfully ablated who experienced a significant recovery of the LV function (EF 34% to 59%, LVIDd from 59 mm to 51 mm)6. Baman et al. have reported on 80% reduction of PVC burden in 174 patients with a significant improvement on the LV function (EF 35% to 54%) and reduction in LV dimensions (LVIDd from 59 mm to 54 mm) in 57 patients who had developed CMP (17).

As in case of any invasive procedure, the RF ablation of arrhythmias is followed by its complications which according to previous publications appear in up to 3% of cases and include stroke, AV block requiring electrostimulation, perforation, tamponade, local vascular complications, myocardial infarction, etc (26). In the recent literature relating to the ablation of PVC, the incidence of complications is significantly lower. For this reason, it is necessary to think it through and weigh the potential benefits and risks of the procedure. We should not forget that the medical treatment also has its disadvantages, so that modern techniques of catheter ablation with a better risk-benefit ratio are becoming increasingly attractive and more commonly used treatment options for PVC-induced cardiomyopathy.

Ventricular extrasystoles are a common and generally a benign phenomenon, especially if a structurally normal heart is concerned, but they are frequently an overlooked cause of CMP. Given that the most likely scenario is a predominantly functional disorder that is largely reversible, it is very important to recognize this entity for the treatment of one portion of patients with non-ischemic CMP. Catheter radiofrequency ablation is becoming safer and more attractive method of treatment of these patients, where we avoid lengthy, and possibly lifetime antiarrhythmic therapy. Therefore, we recommend that such patients should be referred to some of the available electrophysiology centers.