Asymptomatic ventricular extrasystoles

Keywords

Premature ventricular contractions, risk assessment, treatment, ventricular arrhythmia

Abbreviation List

AAD:  anti-arrhythmic drugs

ARVC:  arrhythmogenic right ventricular cardiomyopathy

BB:  beta-blocker

CA:  catheter ablation

CCB:  calcium channel blocker

CMR:  cardiac magnetic resonance

ECG:  electrocardiogram

EF:  ejection fraction

PVC:  premature ventricular contractions

RVOT:  right ventricular outflow tract

SNE:  sympathetic nervous system

Take-home messages

1. PVCs are common and may be encountered across all medical specialties.
2. Patients with asymptomatic PVCs may potentially face the same risk for complications as symptomatic ones.
3. The decision to further examine asymptomatic patients should be based on consideration of the prognostic benefit it could imply.
4. The goals of the diagnostic evaluation should be to exclude/state underlying heart disease and to assess the risk for future complications.
5. The presence of underlying heart disease remains the most powerful negative prognostic factor. ECG and imaging findings can be used for risk assessment also in apparently healthy patients.
6. Although PVC treatment (with AAD or CA) is typically guided by symptoms, it may also be considered in certain asymptomatic patients to reduce PVC burden.            

Patient-oriented messages

• Ventricular extra-beats (PVCs) are common and can also be discovered in those without symptoms.
• While most individuals with ventricular ectopic beats and no other heart conditions have a favourable prognosis, their discovery should still prompt a medical assessment.
• The presence or absence of symptoms does not affect prognosis per se. Other factors, such as how many PVCs you have every day, can be important to evaluate your risk for complications.
• ECG and echocardiography are relatively simple and accessible methods that are recommended in the investigation.
• PVC treatment is mostly based on symptoms but can sometimes be suggested in order to diminish the PVC frequency, regardless of symptoms.

Introduction

Premature ventricular contractions (PVCs) occur when depolarisation starts in the heart’s ventricles, corresponding to abnormal QRS-complexes (broader than 120 milliseconds) with an opposite T-wave and no preceding P-wave on electrocardiogram (ECG). PVCs are frequently observed in clinical settings, although their reported prevalence varies significantly [1] and is primarily influenced by diverse methods of recording the ECG, differences in study populations, and inclusion criteria. However, it is reasonable to assume that PVCs have a high prevalence, meaning that physicians across all medical specialities are likely to encounter patients with PVCs.

PVCs may affect both individuals with and without established heart disease [2,3]. While their prognostic significance in the presence of cardiovascular pathology is well established, it is more uncertain for healthy individuals [4]. Although PVCs can occur in many different conditions, both cardiac and extra-cardiac, they share three pathophysiological mechanisms: re-entry, triggered activity and enhanced electrical automaticity. In patients with structural heart disease, re-entry is the most common mechanism. This is due to the presence of tissue with different electrophysiological features than the healthy myocardium (most commonly fibrotic areas), allowing a depolarisation wave to slow down enough to reach an area of the myocardium that is no longer refractory, thus leading to one or several extra beats. This mechanism explains why PVCs are more common in populations with higher incidence of cardiovascular disease or risk factors [3,5]. Considering that PVCs are more prevalent in the presence of structural heart disease, whether diagnosed or undetected, their finding should prompt the physician to pursue an appropriate diagnostic approach to identify or rule out any underlying conditions.

Predisposing factors other than structural heart disease

As all underlying structural or electrical heart diseases increase risk for PVC, there are also non-cardiac conditions and modifiable lifestyle factors that can affect their frequency. Amongst primary non-cardiac conditions that have been linked to an increased risk for ventricular ectopy are endocrinological disorders (hyperthyroidism and hypokalaemia being the most common), neuromuscular disease (myotonic dystrophy) and inflammatory diseases (sarcoidosis, Chagas’ disease). These should be considered if the patient presents with symptoms (beside PVCs) suggesting one of these conditions. Even psychological distress has been linked to ventricular ectopy and a special focus should be put on improving psychological well-being [6].

The mechanism behind the link between stress/anxiety and ventricular ectopy is an increased activity of the sympathetic nervous system (SNE). An increase in SNE activity can also be seen with the intake of beverages like coffee and energy drinks, even if the effect varies largely between individuals and also depends on overall health and consumption patterns [7]. As short-term caffeine consumption may lead to increased myocardial excitability due to the stimulation of beta receptors, long-term use may create tolerance with a decrease of the pro-arrhythmic effect [8]. In a similar way, acute alcohol consumption has also been linked to an increased risk for arrhythmia, while the risk with moderate consumption in individuals without established heart disease are still debated [9].

A classic risk factor for cardiovascular disease, smoking and nicotine use, has also been associated with an increased risk for ventricular arrhythmia, even in non-ischaemic patients, so the benefits of smoking cessation should be brought into discussion when evaluating PVC patients [10]. Amongst other modifiable risk factors for PVCs, sleep disorders (including sleep apnoea), obesity, and the use of central stimulant drugs are worth mentioning and should be investigated in the patient’s history [11, 12].

Clinical presentation

This publication focuses specifically on asymptomatic PVCs. Nonetheless, when assessing a patient with a diagnosis of PVC made in contexts other than symptom-driven diagnostics (i.e., routine screening, physical exam for other conditions), it is crucial to proactively explore whether any previous PVC-related symptoms have manifested. This inquiry is essential because there is a possibility that compensatory mechanisms mitigating symptoms have developed over time. Furthermore, it is conceivable that the patient hasn’t connected their symptoms to a heart rhythm issue. Actively investigating relevant symptoms in the patient’s medical history can assist the physician in gauging the duration of PVC occurrences, which could impact risk assessment and treatment decisions.

The impact of symptoms caused by PVCs varies widely, ranging from asymptomatic to debilitating [1]. At the same time, there is no linear relationship between PVC burden and severity of symptoms, as patients with rare, isolated PVCs may be more symptomatic than patients with high or very high PVC burden. Temporary irregular heart contractions, including the sensation of the heart momentarily pausing, are the most common symptom. It is also common that one forceful beat after a compensatory pause, a phenomenon known as post-systolic potentiation, is the dominating symptom. In cases of frequent PVCs, bigeminy (where a PVC follows every normal heartbeat) or trigeminy (where a PVC regularly occurs after two normal QRS-complexes), shortness of breath or fatigue is often more pronounced than arrhythmia symptoms. This is partly because most PVCs do not significantly contribute to circulation, significantly limiting the patient’s capacity during exertion. Based on the same mechanism, some patients may experience dizziness in some situations. Given the PVCs’ haemodynamic effects and the dyssynchronous contractions of the ventricles, patients may experience pressure against their necks (atrial contractions against a closed tricuspid valve), and, in some cases, have a low palpable pulse. In fact, it is not uncommon that patients with frequent PVCs are referred to Cardiology for evaluation of bradycardia, when this clinical suspicion is solely based on palpatory findings.

When collecting a patient's history and their family history, it is paramount to explore any potential "red flag" symptoms, since PVCs increase the risk for sustained ventricular arrhythmia. Considering this, the doctor should proactively inquire about episodes with sudden loss of consciousness or unexplained deaths occurring at young age within the patient's family.

Diagnostic evaluation

The assessment of asymptomatic patients diagnosed with PVCs should focus on two primary objectives:

1. confirming or ruling out the existence of underlying heart conditions, and,
2. optimising the evaluation of future risk for complications.

Electrocardiogram

The 12-lead ECG serves as initial evidence for assessing PVCs and remains the best non-invasive tool to pinpoint their origin. When a PVC has been recorded on ECG, or is suspected based on patient history or physical examination, it is beneficial to capture the PVC across all 12 leads simultaneously, by extended recording if necessary. Additionally, paying attention to other aspects of the ECG can provide insights into the underlying heart condition. For instance:

• A prolonged or shortened QT interval may suggest electric disease on genetic (Short or Long QT-syndrome) or on acquired basis.
• A Brugada pattern with coved ST-elevation followed by negative T-wave can be seen in V1-V3.
• High QRS-amplitude in precordial leads may result from hypertrophic myocardium.
• Precordial T-wave inversion or so-called epsilon wave (a late potential embedded in the end of the QRS-complex) may indicate arrhythmogenic right ventricular cardiomyopathy (ARVC).
• Pathological Q waves might reflect scarred areas, most commonly due to previous myocardial infarction.
• Conduction disease (prolonged PQ- or QRS-time) may manifest because of cardiac sarcoidosis.

Understanding of the site of origin can be important should the patient be referred for ablation and can also bear a prognostic importance (see following chapters). A precordial transition (meaning the first lead showing a predominantly positive QRS) in V1 or V2 indicates left ventricular PVCs, while a transition in V4 or later points towards a right ventricular origin. An outflow tract origin corresponds to negative QRS in aVL and aVR, and positive inferior leads, while a depolarisation front moving in the opposite direction, i.e. from the apex, will result in negative inferior leads.

Holter monitoring, historically the preferred method for quantifying premature ventricular complexes, continues to play a crucial role in assessing PVC burden. However, due to the significant day-to-day variability in the number of PVCs, there are instances where extended monitoring periods or alternative methods beyond Holter monitoring may be necessary to gain a comprehensive understanding of PVC characteristics.

Cardiac imaging

Echocardiography is the cornerstone of structural evaluation and strongly recommended in guidelines. Through echocardiography it is possible to reveal underlying structural conditions, evaluate the degree of ventricular dysfunction that can result from frequent PVCs, and identify patients who are not in need of further investigation. Given that the presence of structural disease is the stronger prognostic predictor in PVC patients, transthoracic echocardiography should be considered for all patients where prognostic assessment is relevant. However, there is increasing evidence that standard echocardiography may not always been able to detect early signs of PVC-related ventricular dysfunction, and that more advanced imaging techniques may be necessary to provide a comprehensive evaluation [13]. Notably, cardiac magnetic resonance (CMR) imaging has gained support as an important tool for advanced evaluation. Tissue characterisation through CMR, beyond improving diagnostic accuracy, also carries prognostic significance [14].

Given that CMR is more expensive and less accessible compared to echocardiography, physicians should judiciously assess which patients warrant CMR examinations. This evaluation should consider factors such as PVC burden, PVC morphology, findings from prior investigations, and, naturally, clinical suspicion. PVC burden lacks a universally agreed upon specific threshold. However, a cut-off range of 5,000 to 10,000 PVCs per day can be considered reasonable [15]. Other factors enhancing CMR indication are listed below:

• suspicion of specific diseases, such as ARVC or cardiac sarcoidosis
• suspicion of arrhythmogenic syncope
• bundle branch block at resting ECG
• PVC morphology other than typical right ventricular outflow tract (RVOT)
• polymorphic PVCs
• ventricular tachycardia

Invasive electrophysiological examination and genetic testing

Advanced diagnostic methods are rarely necessary for isolated asymptomatic PVCs. However, an electrophysiological examination can be performed with the goal of ablating the ectopic site. This procedure is never recommended for asymptomatic patients with normal left ventricular ejection fraction (EF). However, according to the latest ESC guidelines, catheter ablation holds a class I indication for patients with PVC-induced cardiomyopathy and predominantly monomorphic PVCs, irrespective of symptoms. This recommendation has been upgraded from a class IIa level in the previous 2015 guidelines. Additionally, catheter ablation may also be considered (class IIb indication) for asymptomatic patients with more than 20% daily PVCs during follow-up.

Genetic testing is a critical aspect of patient evaluation and should be approached with care. It should not be performed without specific clinical suspicion, which relies on a thorough understanding of the patient’s medical history (including family history) and previous diagnostic findings. When considering genetic testing, it serves as a crucial step in diagnosis and risk stratification of patients exhibiting phenotypes consistent with genetic conditions. In this context, factors such as imaging results (like hypertrophic or dilated myocardium) and ECG findings beyond PVCs (such as AV conduction delays at a young age or long/short QT intervals) must be carefully considered.

PVC during exercise

Exercise testing plays a role in the diagnostic evaluation of PVC patients. Asymptomatic patients may also be referred for PVC evaluation if PVCs appear during exercise tests conducted for other reasons. Traditionally, PVCs that decrease in frequency during exertion have been considered benign. However, it’s important to know that experiencing PVC during exercise has not been shown to be significantly associated with a poorer prognosis in meta-analyses, while PVCs during recovery were associated with higher risk of death and cardiovascular events [16].

It is common for PVC patients to experience PVC-related symptoms that tend to resolve or diminish during exertion. However, it is plausible that patients predominantly notice PVCs while at rest due to their supine position, which allows closer contact between the heart and the thoracic wall, coupled with the absence of other stimuli. During exertion, the increased physiological demands are primarily met through an elevated heart rate, diminishing the significance of AV synchrony. Consequently, PVCs during exertion are typically less symptomatic and exercise tests can provide an objective analysis of PVC patterns under stress conditions.

In cases of exercise-induced PVCs, whether occurring during or after strain, it is generally prudent to pursue further investigation, regardless of symptoms. The primary focus should be on excluding structural conditions such as coronary artery disease or aortic stenosis. Additionally, specific conditions—such as genetically caused ARVC or catecholaminergic polymorphic ventricular tachycardia—may lead to an elevated number of PVCs and even ventricular tachycardia during exertion. Although uncommon, considering these diagnoses is therefore wise in such clinical scenarios.

Risks and factors affecting prognosis

PVC patients, including those who are free of symptoms, face the risk of developing complications such as cardiomyopathy, heart failure, and malignant ventricular arrhythmias. In the Framingham Heart study, asymptomatic ventricular arrhythmia was associated with a two-fold increased risk of death and major adverse cardiovascular events [17]. Additionally, there is evidence linking PVCs, regardless of symptoms, to an increased risk of cerebrovascular events [18]. Therefore, an adequate risk assessment should be conducted, irrespective of symptoms.

As previously mentioned, the most significant predictor of adverse events in patients with PVCs is the presence of underlying heart disease, whether structural or electrical. However, even in healthy patients, a variety of clinical and diagnostic findings can influence prognosis and dictate the need for follow-up. The impact of PVC burden has been investigated in various studies, revealing a potential linear correlation between the number of PVCs per day and clinical outcomes. However, no specific cut-off point exists for the development of complications. While PVC burden provides crucial information, it alone is insufficient for determining follow-up strategies. Additionally, the width of the QRS complex during PVCs has also been linearly associated with clinical outcomes. A ‘broad’ PVC can serve as both a risk factor, exacerbating dissynchrony, and a risk marker, indicating a sick or fibrotic myocardium. Furthermore, a broad QRS complex may indicate an epicardial site of origin, which is more challenging to ablate. Although no precise cut-off value exists in this scenario, a rough limit of 150 milliseconds can be used to dichotomise and facilitate decision-making. Polymorphic PVCs have traditionally been regarded as a risk factor. However, this association appears to be most pronounced in patients with underlying heart disease, while it is more uncertain in healthy patients.

Other electrophysiological characteristics may significantly impact risk assessment. Notably, interpolation refers to a situation where the PVC does not reset the sinus node and is not followed by a compensatory pause. Additionally, a highly irregular coupling interval can have distinct implications as short intervals from the native QRS complex to PVCs may elevate the risk for malignant arrhythmias through the R-on-T phenomenon. Conversely, long coupling intervals can increase the risk of ventricular dysfunction [19].

Imaging findings also contribute to risk assessment, with the most robust indicator being the presence of fibrosis at CMR [14].

Challenges with asymptomatic patients

Assessing asymptomatic patients with PVCs presents a significant challenge due to their underrepresentation in outcome-focused studies. Typically, thorough evaluations that aim to identify and exclude structural heart disease occur at secondary or tertiary medical centres, where patients are often referred due to symptoms. This limitation becomes even more pronounced in studies involving patients referred for invasive electrophysiological examination and ablation. However, as previously mentioned, it is reasonable to assume that asymptomatic patients face similar risks as symptomatic ones. In fact, there is evidence suggesting that the absence of typical PVC-related symptoms may be linked to a higher risk for ventricular dysfunction [20]. Consequently, physicians assessing patients with asymptomatic PVCs should have two primary goals: excluding underlying heart disease and performing a reasonable evaluation of future risks, which significantly impacts treatment decisions and follow-up strategies.

Most patients with PVCs experience a benign course, and the development of complications typically occurs over an extended period. Therefore, a decision for further examination must be carefully balanced with other medical and ethical considerations, including age, comorbidities, and, importantly, the patient’s preferences. After thoughtful deliberation of these factors, if the patient is deemed to benefit from additional investigation, the suggested algorithm in Figure 1 can be employed.

Figure 1. Evaluation and management of asymptomatic patients.

CMR: cardiac magnetic resonance imaging; ECG:electrocardiogram; EF: ejection fraction; PVC: premature ventricular contractions; RVOT: right ventricular outflow tract

Treatment

The management of PVCs is primarily guided by the patient’s symptoms. In asymptomatic cases, treatment may still be considered, particularly with the aim of reducing PVC burden in the hope of achieving favourable prognostic outcomes. If there are indications that lifestyle-related factors are contributing to the onset or exacerbation of PVCs —such as caffeinated beverages, inadequate sleep, or stress—the initial step should be to minimise or eliminate these triggers.

Beta-blockers (BB) are first-line drugs that can be used both in patients with and without structural heart disease and are particularly effective when PVCs are triggered by SNE-activation. Selective β1-receptor blockers, such as bisoprolol or metoprolol, should be preferred. If the effect from beta-blockers is insufficient despite an adequate dose, or the patient is experiencing side effects, a non-dihydropyridine calcium channel blocker (CCB), diltiazem or verapamil, can be used in patients without structural heart disease, especially in patients with fascicular PVCs.  If treatment with BB and/or CCB does not yield success, the consideration of class I or III anti-arrhythmic drugs (AAD) becomes relevant. These medications are potent but come with a potential pro-arrhythmic effect, necessitating follow-up by an experienced cardiologist. Importantly, there is no conclusive evidence supporting prognostic benefits from these drugs, which is why they are rarely used in asymptomatic cases. Class I-AAD drugs are often effective in reducing premature PVC burden, but they cannot be administered in the presence of structural heart disease. Additionally, treatment with class I-AAD drugs may require concurrent medication with BB. Among the class III-AADs, sotalol stands out due to its ability to block β-receptors and suitability for patients with ischaemic heart disease.

Catheter ablation (CA) serves as an effective alternative to pharmacological treatment, particularly in cases of monomorphic ectopy. It is recommended when medications are either ineffective, not well-tolerated, or not preferred by the patient. Notably, CA can even be considered as a first-line treatment for asymptomatic patients with left ventricular dysfunction caused by frequent premature ventricular contractions (PVCs). Despite its invasiveness, CA is a safe procedure with a low complication frequency. However, it is crucial to carefully weigh the risk of complications. While CA has demonstrated effectiveness, especially in EF recovery for patients with PVC-mediated cardiomyopathy, no impact on hard clinical endpoints has been conclusively established yet.

Other aspects

• In specific conditions, such as genetic diseases with a risk for activity-triggered PVCs or chronic ischaemic heart disease, participation in high-intensity exercise is not recommended. However, for individuals without these specific conditions, physical exercise as part of a healthy lifestyle should be encouraged.
• PVCs during pregnancy tend to increase towards the end of pregnancy and to diminish or disappear after childbirth. New-onset ventricular arrhythmia during pregnancy should prompt structural investigation. If indicated, metoprolol and bisoprolol can be used during pregnancy.
• Asymptomatic ventricular extrasystoles in athletes warrant specialised management, a topic not covered in this publication.