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Premature Ventricular Complexes-induced Cardiomyopathy (PVC-CM) is a cardiomyopathy characterized by left ventricular (LV) dysfunction caused by frequent premature ventricular complexes (PVCs), with the potential for resolution with treatment. Although the mechanism of PVC-CM development involves various cellular and intercellular mechanisms along with multiple risk factors, its mechanism has not been fully elucidated. In patients who develop symptomatic and/or LV dysfunction, suppression of PVCs is indicated for treatment. Despite the use of antiarrhythmic drugs in treatment, hesitations regarding their use persist due to common side effects, including proarrhythmia. Recently introduced radiofrequency ablation therapy is both effective and has a high success rate when performed by experienced hands, and current guidelines recommend it as the first option for patients developing LV dysfunction. This review will discuss PVC-CM in detail, alongside current guidelines and studies.
Medical Faculty, Department of Cardiology, Şeyh Edebali University, Bilecik, Turkey
*Address all correspondence to: mkaplangoray@gmail.com
1. Introduction
Premature ventricular complexes (PVCs) were first described by the French physiologist Étienne-Jules Marey in the early 1800s. Marey was the first to obtain an electrocardiographic recording in animals using a capillary electrometer, through which he also described PVCs. The first electrocardiography (ECG) recording in humans was made shortly after Marey by Augustus Desiré Waller in 1887. Subsequent years saw significant advancements in the identification, significance, and treatment of arrhythmias, paralleled by technological developments and the introduction of Holter monitoring technology developed by American biophysicist Norman J. Holter [1]. PVCs are a common type of ventricular arrhythmia, and their prognostic significance is closely related to underlying cardiac diseases. For years, PVCs were considered benign in individuals without any structural heart disease. However, between the 1970s and 1980s, frequent PVCs observed post-myocardial infarction (MI) were claimed to trigger ventricular tachycardia (VT), ventricular fibrillation (VF), and sudden cardiac death, suggesting the necessity for PVC suppression therapy [2].
In the Cardiac Arrhythmia Suppression Trial (CAST), treatment of PVCs with antiarrhythmic drugs in patients who had previously experienced an MI, although successful in suppressing PVCs, was associated with increased mortality [3]. Despite the findings of this study, recent studies have shown that PVCs can cause cardiomyopathy and heart failure, and effective treatment of PVCs is associated with recovery in cardiac functions [4, 5]. PVC-induced cardiomyopathy (PVC-CM) is defined as LV dysfunction caused by frequent PVCs, with the potential for improvement with PVC suppression therapy. The absence of any underlying structural heart disease is important for differential diagnosis, making PVC-induced cardiomyopathy a sort of diagnosis of exclusion.
Before discussing the prevalence of PVC-CM, it would be better to examine the prevalence of PVCs, which are involved in the etiology of this cardiomyopathy. Data on the prevalence of PVCs come from ECG databases and Holter monitoring records intended for treatment purposes and have seen an increasing incidence in recent years. In a comprehensive community-based study involving 122,034 US Air Force personnel, where 48-second ECG records were collected, the frequency of PVCs was observed to be 7.8 per 1000 individuals and was found to increase with age [6]. In a more recent multi-ethnic cohort (ARIC [Atherosclerosis Risk in Communities] study), among 14,000 participants without a diagnosis of heart failure and based on a 10-second ECG record, the frequency of PVCs was found to be 1.8% [7]. The Cardiovascular Health Study, involving 4710 individuals aged over 65 and similarly based on a 10-second ECG record in a population-based cohort excluding heart failure patients, found the frequency of PVCs to be 5.2% [7]. It is not surprising that the prevalence of PVCs increases with longer monitoring durations. Indeed, in the ARIC study, while the prevalence was 5.5% in a 2-minute ECG record, the Framingham Heart Study found a 12% prevalence of PVCs and other complex ventricular arrhythmias in a 1-hour ECG monitoring of individuals without coronary artery disease [8, 9]. In a community-based cohort in Lichtenstein, among individuals aged 24–41 undergoing 24-hour Holter monitoring, at least one PVC was found in 69%, with a median of 2 PVCs, and the 95th percentile was 193 PVCs [10].
While a PVC burden of >24% has been proposed to have the highest sensitivity and specificity (79% and 78%, respectively) for predicting the development of PVC-CM, recent studies have suggested that this rate could be lower [5]. However, the latest guidelines on ventricular tachycardia by the ESC indicate that the minimum PVC burden for the development of PVC-CM is 10%, with the risk increasing above 20% [11].
Although there is no consensus on the prevalence of PVC-CM, it is estimated to be higher than reported, with a prevalence of approximately 7% in patients with a PVC burden of >10% [12]. Clinical studies have reported the frequency of PVC-CM in patients referred for radiofrequency ablation (RFA) due to PVCs to be between 9% and 30% [5, 13, 14]. The CHF-STAT (Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure) study demonstrated that PVC-CM (LVEF <40% and > 10 PVCs/h) accounted for 40% of all cardiomyopathy patients [15].
Compared to tachycardia-induced cardiomyopathy, the cellular-level mechanism of PVC-CM is unclear. However, it is evident that the histopathological and cellular characteristics of PVC-CM differ from other forms of heart failure [16]. A more comprehensive evaluation from both a cellular level and clinical perspective is necessary to fully understand the mechanism.
The proposed mechanisms related to PVC-CM at the cellular level are speculative and based on animal models. Studies conducted by Wang et al. [17] in a dog model have shown that prolongation of the action potential duration and beat-to-beat variability in the action potential lead to a decrease in inward and outward (L-type calcium) currents, causing repolarization heterogeneity. These results could potentially increase the risk of sudden cardiac death by leading to triggered activity and malignant arrhythmias. Additionally, the study highlighted that the contractile dysfunction observed in PVC-CM could be explained by alterations in calcium-induced calcium release in the sarcoplasm. Another study in a dog model showed that the impairment in LVEF caused by PVCs only became apparent after three months, supporting the notion that the mechanism in PVC-CM might be more functional than structural, as myocardial fibrosis and apoptosis are observed to be minimal or absent [18, 19].
From a clinical perspective, the theory of mechanical ventricular dyssynchrony secondary to abnormal electrical activity may be a more solid theory [20, 21]. The impairment in LV function caused by left bundle branch block and right ventricular pacing is a similar example. In both cases, changes in myocardial blood flow are observed alongside asymmetrically increased wall thickness in areas activated late [22, 23].
Not all patients with PVCs develop PVC-CM, and some patients with a high burden of PVCs continue their lives symptom-free and without any impairment in LV function. Given this situation, certain predisposing factors that could play a role in the development of PVC-CM have naturally come to the forefront. We will now discuss these factors.
4.1 Characteristics of premature ventricular complexes
The QRS duration of PVCs ≥140 ms has been reported in many studies as an independent factor for the impairment of LV functions (Figure 1). These PVCs predominantly originate from the free wall or outflow tract [24, 25, 26, 27]. In contrast, PVCs originating from the fascicles and septum tend to have a narrower QRS duration. Additionally, a small-scale study has identified interpolated PVCs and PVC burden as predisposing factors for the development of PVC-CM [28].
Figure 1.
VPC QRS durations of patients with similar origin and PVC burden. A: PVC-QRS duration is 150 ms and left ventricular functions are normal. B: PVC-QRS duration is 176 ms and left ventricular ejection fraction is 40% and ECG example of the case that progressed to PVC-CM [16].
PVCs with a short coupling interval have been associated with idiopathic ventricular fibrillation [29]. Several studies have shown that interpolated PVCs and short coupling intervals, especially below 450 ms, are associated with low LVEF and pose a risk for the development of PVC-CM. Furthermore, the dispersion of the PVC coupling interval is also known to be a significant factor in the development of PVC-CM (Figure 2) [28, 30].
Figure 2.
In the ECG sample of the patient with PVC-CM, CI dispersion was measured as 144 ms (threshold value for PVC-CM development is >99 ms) [16].
4.2 Premature ventricular complex burden
The burden of PVCs is considered a major factor in the development of PVC-CM. In two major studies, a PVC burden of >16% and > 24% has been accepted as the threshold for the development of PVC-CM (with sensitivity and specificity of 79–100% and 78–87%, respectively). However, other studies have considered a minimum threshold of 10% for the development of PVC-CM, as improvements in LV function have been observed in patients with a PVC burden between 6–8%. In this context, the duration of ambulatory ECG monitoring is critically important, and when the monitoring period is maintained between 24 hours to 7 days, the number of patients reaching the 10% threshold doubles [16].
4.3 Origin of premature ventricular complexes
Del Carpio et al. demonstrated that PVCs originating from the right ventricle (RV) caused impairment in LV function with a lower daily burden of PVCs compared to those originating from the LV [25]. This could be due to greater LV dyssynchrony in RV-originating PVCs. Additionally, recent studies have shown that PVCs of epicardial origin have a higher risk of developing cardiomyopathy. As previously mentioned, this may be attributed to greater mechanical dyssynchrony in epicardial-originating PVCs [21]. Given this, detailed ECG evaluations to predict PVC localization before potential radiofrequency ablation (RFA) treatment are of great importance. Below is a brief algorithm that may be useful for PVC localization.
PVCs originating from the ventricular outflow tract musculature, especially from the RV outflow tract, are responsible for two-thirds of all idiopathic PVCs [25]. These originate from points where the myocardial tissue extends towards the aortic and pulmonary valves. The remaining one-third originate from various points such as the septum, papillary muscle, free wall, and ventricular fascicles. Outflow tract-originating PVCs have an inferior axis on surface ECG, visible with positive QRS morphology in leads II, III, and aVF. Those originating from the RV outflow tract generally exhibit a left bundle branch block pattern, though it should not be forgotten that those originating from the aortic cusp can also display the same morphology. On the other hand, the presence of a right bundle branch block morphology supports the origin of PVCs from the LV. However, it is crucial to remember that the outflow tract anatomy of the heart is complex and should be considered in three dimensions. In this context, ECG-based evaluations also gain importance in addition to these criteria.
A later transition of the QRS in precordial leads compared to the transition in normal sinus rhythm should suggest PVCs originating from the right ventricular outflow tract, and the converse may also be true. The more anterior the origin, the later the transition zone in the precordials will be [31, 32]. If both the sinus rhythm and PVCs show QRS transition in V3, then the R transition ratio can be indicative; if the ratio of the R wave in PVCs in V2 to the R wave in sinus rhythm is ≥0.6, then the PVCs are located on the left side with 95% sensitivity and 100% specificity [33].
Another criterion used to determine the location of PVCs is the maximum deflection index, which is the ratio of the maximum QRS deflection duration to the total QRS duration. If this index is above 0.55, the PVCs are likely to be of epicardial origin (Figure 3) [25].
Figure 3.
Calculation of maximum deflection index (MDI). It is obtained by dividing the QRS deflection duration by the QRS duration. In this case, MDI was measured as 0.64 [34].
4.4 Variability circadian PVCs
Circadian variability of PVCs is considered an independent risk factor for the development of PVC-CM [35]. A recent study showed that PVCs exhibiting circadian variation have a high likelihood of being induced in the electrophysiology laboratory. Additionally, individuals with a high heart rate due to PVCs responded to isoproterenol during electrophysiological studies, and these patients also had a high success rate for RFA [36]. However, the success of the procedure is lower in patients in whom there is no correlation between PVCs burden and average heart rate.
4.5 Gender
Latchamsetty et al. demonstrated that male gender is an independent risk factor for the development of PVC-CM [14]. Surksha et al. found that while the incidence of symptomatic PVCs is higher in women, the incidence of PVC-CM is similar between genders [37]. It should not be forgotten that symptoms leading to early diagnosis and thereby early initiation of treatment in symptomatic individuals may prevent the development of cardiomyopathy. The perception of symptoms in women could be a factor leading to earlier treatment initiation. The role of gender in the development of PVC-CM could also be due to hormonal differences, making this an area worthy of further research today [38].
4.6 Genetics
The fact that PVC-CM develops in some patients with a similar PVC burden while others remain unaffected suggests a genetic predisposition. For example, the faulty variation R222Q of the Nav1.5 subunit of the sodium channel, causing large and early sodium current, is thought to contribute to the rate of Purkinje-originating PVCs. This same mutation has also been shown to play a role in the response of patients with PVC-CM cardiomyopathy to amiodarone or flecainide [39].
The duration for the development of PVC-CM is unclear; it may span days or months [40, 41, 42]. In animal experiments, the development of PVC-CM has been observed within 4 weeks under continuous and high PVC burden (daily PVC burden >30%) [19, 43]. The uncertainty of the onset time and variation in PVC burden in humans make it difficult to estimate this duration.
Patients with PVC-CM may present asymptomatic or with symptoms of heart failure. Palpitations are the most common symptom among these patients. The PVC coupling interval is considered a significant factor in symptomatology, and patients with a PVC coupling interval < 0.5 are mostly symptomatic [44]. A detailed history and thorough physical examination are important factors in differential diagnosis. Apart from regular pulse, variable intensity of heart sounds, and mild signs of heart failure, specific findings may not be observed during the physical examination. The diagnosis of PVC-CM can be considered a diagnosis of exclusion, especially in patients with nonischemic cardiomyopathy and a PVC burden >10%. Another critical point is distinguishing whether PVCs are an etiology or secondary to an underlying cardiomyopathy. If PVCs are the consequence of cardiomyopathy and are frequent, they can worsen heart failure and symptoms, referred to as “PVCs-aggravated cardiomyopathy” [45, 46]. Echocardiography and PVC morphology play a significant role in differential diagnosis (Table 1).
PVC-aggravated cardiomyopathies
PVC-CM
Patient characteristics
Older and have known heart disease
Healthy otherwise
Comorbidities
CAD, other types of cardiomyopathy, hypertension
No cardiac disease
Echocardiogram
Segmental hypokinesis, LVEF <25%
Global hypokinesis, LVEF 37 ± 10%
Cardiac magnetic resonance imaging (late-gadolinium enhancement)
Significant scar
Absence or minimal scar burden
PVC frequency
<5000/24 h (<5%)
≥ 10,000/24 h (≥ 10%)
PVC pattern
Multifocal
Monomorphic
QRS morphology
Nonspecific
RVOT/LVOT/epicardial
Response to PVC suppression
No change in LV function
Improvement of LV function
Table 1.
Clinical, electrocardiographic and imaging features of PVC-CM and PVC-aggravated cardiomyopathies.
ECG and prolonged ambulatory ECG monitoring are fundamental tools for diagnosis. Loring et al. suggest that a minimum of 6 days of monitoring is necessary to maximize the detection of PVC burden [47]. Correspondingly, nearly half of potential PVC-CM patients may be missed in the conventional 24-hour ambulatory ECG monitoring [47].
PVC-CM does not have specific echocardiographic findings, but mild to moderate LV ejection fraction (LVEF) impairment, LV dilatation, mild mitral regurgitation, and left atrial dilatation are commonly observed echocardiographic findings. Improvements in these findings are generally seen weeks after PVC suppression therapy [16]. Cardiac imaging is an important diagnostic tool in patients with a PVC burden >10% and should be performed promptly. Cardiac magnetic resonance (CMR) imaging can identify scar or fibrosis load through late-gadolinium enhancement (LGE). Scar load is considered a significant parameter in response to PVC suppression therapy [48]. In subclinical PVC-CMP forms (LVEF ≥50%), speckle tracking has shown improvement in radial, circumferential, and longitudinal strains after RFA therapy [49, 50]. These findings are consistent with translational studies showing a mild and linear decrease in LV systolic functions at PVC burdens of 7%, 14%, and 25% [43].
In recent years, myocarditis has been proposed to trigger frequent PVCs and cardiomyopathy. Increased hs-CRP has been reported as an independent factor for PVCs in the Chinese population [51, 52]. Therefore, whether inflammatory processes are a cause or consequence of PVCs remains unclear.
As mentioned earlier, PVCs can cause impairment in LV functions in those with structural heart disease. It should not be forgotten that in patients with structural heart disease undergoing CRT implantation, PVCs can reduce the effectiveness of optimal CRT. In differential diagnosis, a small left ventricular diastolic diameter and a short QRS complex duration support the diagnosis of PVC-CM. CMR is a valuable diagnostic tool in differentiating PVC-CM from PVC-aggravated cardiomyopathy, with the presence of LGE supporting the latter diagnosis. Additionally, PVCs with a right bundle branch block pattern show a strong correlation with LGE, and CMR is recommended in these patients. Another way to distinguish PVC-CM from PVC-aggravated cardiomyopathy is that PVC-CM shows improvement after PVC suppression therapy (Tables 1 and 2) [11].
Recommendation
Class
Level
Diagnostic evaluation
In patients with an unexplained reduced EF and a PVC burden of at least 10%, PVC-induced cardiomyopathy should be considered
IIa
C
In patients with suspected PVC-induced cardiomyopathy, CMR should be considered
IIa
B
Treatment
In patients with a cardiomyopathy suspected to be caused by frequent and predominately monomorphic PVCs, catheter ablation is recommended
I
C
In patients with a cardiomyopathy suspected to be caused by frequent and predominately monomorphic PVCs, treatment with AADsa should be considered if catheter ablation is not desired, suspected to be high-risk, or unsuccessful
IIa
C
In patients with SHD in whom predominately monomorphic frequent PVCs are suspected to be contributing to the cardiomyopathy, AAD (amiodarone) treatment or catheter ablation should be considered.
IIa
B
In non-responders to CRT with frequent, predominately monomorphic PVCs limiting optimal biventricular pacing despite pharmacological therapy, catheter ablation or AADs should be considered.
IIa
C
Table 2.
In the 2022 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death, there are diagnostic evaluation and treatment recommendations for cardiomyopathies induced or exacerbated by premature ventricular complexes.
Flecainide only in selected patients (ICD recipients, only moderate LV dysfunction)
Currently, treating patients with PVC-CM with RFA or antiarrhythmic drug therapy (AAD) is a widely accepted strategy [53]. However, the situation is not as clear in asymptomatic individuals with a PVC burden >10% without life-threatening arrhythmias. Data on this group of patients is limited, and even if asymptomatic, they should be closely monitored every 6 to 12 months. If any heart failure symptoms develop, prolonged ambulatory ECG monitoring and echocardiography should be performed. Although there is no assessment of spontaneously resolving PVCs, the CHF-STAT study showed significant improvements in PVC burden in 12% of patients in the placebo group after 6 months [15].
An 80% reduction in PVC burden from the initial load indicates the real effect of the treatment [54], as spontaneous changes in PVC burden are not expected at this rate. It should be noted that these criteria are based on 24-hour ambulatory ECG monitoring data, and data from longer-term monitoring are limited. As mentioned at the beginning, RFA and AAD therapy are recommended for PVC suppression treatment today, and both treatment options have nearly the same success rate (70–80%) [16].
The success rate of RFA is lower for PVCs originating from the papillary muscle, epicardium, near the coronary artery, and the conduction system [14, 30, 55]. Therefore, 5–15% of patients may need AAD therapy after RFA [14]. PVC suppression therapy, both AAD and RFA, carries a low risk. The complication rate with RFA is between 5–8%, while the discontinuation rate of AADs due to long-term side effects is around 10% [56].
Randomized clinical trials of AADs in this field date back to a time before PVC-CM was defined. The Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that class IC AADs used in patients with frequent PVCs following acute myocardial infarction increased mortality. However, studies such as the GESICA (Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina), CAMIAT (Canadian Amiodarone Myocardial Infarction Arrhythmia Trial), and CHF-STAT have indicated that amiodarone treatment post-acute myocardial infarction and in nonischemic cardiomyopathies showed a trend towards reduced mortality [15, 57].
Currently, there are no randomized studies comparing RFA and AAD treatments. However, a recent retrospective study showed a greater reduction in PVC burden with RFA treatment compared to AAD treatment (mean reduction: RFA 15.5 ± 1.3% vs. AADs 4.8 ± 0.8; p < 0.001). A single-center small study also demonstrated that RFA treatment was more effective in patients with a low PVC burden [30].
After PVC suppression therapy, improvements in left ventricular function, left ventricular dilatation, and mitral regurgitation have been observed, along with a decrease in BNP levels. Even in superimposed cardiomyopathies, RFA treatment has resulted in an increase in LVEF of between 10–15% [16]. A recent multicenter study of 245 patients with nonischemic cardiomyopathy and frequent PVCs showed that RFA treatment improved left ventricular functions in 67% of the patients [58].
The success rate of RFA for PVC suppression therapy today ranges between 90–75%. Therefore, the latest ESC arrhythmia guidelines recommend RFA as the first option for treating PVC-CM. The success rate of RFA is related to the origin of PVCs (highest for outflow tract PVCs), diversity of PVC morphology, and the presence of late gadolinium enhancement (LGE) on CMR [11].
AADs used in PVC suppression therapy have also been shown to increase LVEF. A randomized study demonstrated that amiodarone provided more PVC suppression and was associated with greater improvements in LVEF compared to placebo [59]. Sodium channel blockers are also effective agents in PVC suppression therapy [30]. One study showed that treatment with flecainide reduced the PVC burden from 36–10% and increased LVEF from 37–49% [56]. However, it should not be forgotten that flecainide’s organ toxicities and its use post-acute myocardial infarction have been associated with increased mortality [34]. In selected patients with PVC-CM or PVC-aggravated CMP and those implanted with ICDs, flecainide may be considered an option for PVC suppression therapy.
PVC-CM is a type of cardiomyopathy with a unique pathophysiology that can be fully corrected with treatment. A detailed patient history, 12-lead ECG, Holter-ECG (preferably long-term), echocardiography, and CMR are fundamental tools for the diagnosis of this cardiomyopathy. The development of PVC-CM requires a minimum PVC burden of at least 10%, and the risk increases further when the PVC burden exceeds 20%. Although there is an option for AAD or RFA treatment for PVCs, RFA, which is more effective especially in cases with developed LV dysfunction, should be considered the primary option.
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Written By
Mustafa Kaplangoray
Submitted: 19 February 2024Reviewed: 25 February 2024Published: 14 May 2024
Open access peer-reviewed chapter - ONLINE FIRST
