Ventricular Premature Complexes

Ventricular premature complexes (VPCs) are ectopic impulses originating from an area distal to the His Purkinje system. VPCs are the most common ventricular arrhythmia. Assessment and treatment of VPCs is challenging and complex, and is highly dependent on the clinical context. The prognostic significance of VPCs is variable and, again, best interpreted in the context of the underlying cardiac condition.

The approach to the evaluation and management of VPCs has undergone dramatic changes in the last decade. Observational studies and inferences from typical electrophysiology studies were initially focused on ventricular ectopy triggering ventricular tachycardia (VT), which, in turn, can degenerate into ventricular fibrillation, as a mechanisms for sudden cardiac death. The treatment paradigm in the 1970s and 1980s was to eliminate VPCs in patients after myocardial infarction (MI). The Cardiac Arrhythmia Suppression Trial (CAST) and other arrhythmia suppression studies have demonstrated that eliminating VPCs with available antiarrhythmic drugs increases the risk of death to patients without providing any measurable benefit.[1]

Very few studies have evaluated the pathophysiology of VPCs in human subjects. Most of the information is derived from animal studies. Three common mechanisms exist for VPCs, (1) automaticity, (2) reentry, and (3) triggered activity, as follows:

• Automaticity: This is the development of a new site of depolarization in nonnodal ventricular tissue, which can lead to a VPC. In animal models, focal mechanisms without evidence of macro-reentry play a major role in the origin of ventricular arrhythmia associated with ischemic cardiomyopathy. Increased automaticity could be due to electrolyte abnormalities or ischemic myocardium.

• Reentry circuit: Reentry typically occurs when slow-conducting tissue (eg, infarcted myocardium) is present adjacent to normal tissue. The slow-conducting tissue could be due to damaged myocardium, as in the case of a healed MI.

• Triggered activity: After depolarizations triggered by a preceding impulse can lead to premature activation if the threshold is reached, and this can cause a VPC. Afterdepolarization can occur either during (early) or after (late) completion of repolarization. Early afterdepolarizations commonly are responsible for bradycardia associated VPCs, but they also can be present with ischemia and electrolyte abnormalities.

Cardiac causes of VPCs include the following:

• Acute myocardial infarction

• Valvular heart disease, especially mitral valve prolapse

• Cardiomyopathy (eg, ischemic, dilated, hypertrophic, infiltrative)[2]

• Myocardial stretch

• Cardiac contusion

• Bradycardia

• Tachycardia (high-catecholamine state)

Noncardiac causes of VPCs include the following:

• Electrolyte disturbances (hypokalemia, hypomagnesemia, or hypercalcemia)

• Medications (eg, digoxin, tricyclic antidepressants, aminophylline, amitriptyline, pseudoephedrine, fluoxetine)

• Other drugs (eg, cocaine, amphetamines, caffeine, alcohol)

• Anesthetics

• Surgery

• Infection

• Stress

United States data

The reported prevalence of VPCs varies between studies, depending on the population studied, duration of observation, and method of detection. In asymptomatic patients, VPCs are infrequently noted when only a single 12-lead ECG is used for ascertainment. The Framingham heart study (with 1-h ambulatory ECG) suggested that the prevalence rate of 1 or more VPCs per hour was 33% in men without coronary artery disease (CAD) and 32% in women without CAD. Among patients with CAD, the prevalence rate of 1 or more VPCs was 58% in men and 49% in women. Other studies using 24-hour ambulatory monitoring showed a VPC prevalence rate of 41% in healthy teenage boys aged 14-16 years, 50-60% in healthy young adults, and 84% in healthy elderly persons aged 73-82 years. VPCs also are common in patients with hypertension, ventricular hypertrophy, cardiomyopathy, and mitral valve prolapse.

International data

Data from the Gruppo Italiano per lo Studio della Sopravvivenza dell'Infarto Miocardico 2 study demonstrated that 64% of patients who had MI then had ventricular arrhythmia and 20% of patients had more than 10 VPCs per hour when 24-h Holter monitoring was used.[3, 4]

In a study evaluating the features of frequent idiopathic VPCs in the Korean, investigators reported a mean patient age of 54.7 ± 16.8 years and a slight female preponderance (54.8%).[5]  The most common typical VPC-related symptoms/signs were palpitation and a dropped beat (59.2%), whereas the most common ECG features were left bundle branch block, an inferior axis, and late precordial R-wave transition.

Sex- and age-related demographics

The Framingham heart study demonstrated increased prevalence of VPCs in men compared with women. The difference was especially higher in men with CAD than in women with CAD.

VPCs are uncommon in children (suggested prevalence rate of 0.8-2.2% from the Vanderbilt Medical Center; exact prevalence not known). Prevalence increases with age.

The prognosis depends on the frequency and characteristics of VPCs and on the type and severity of associated structural heart disease. Overall, VPCs are associated with an increased risk of death, especially when CAD is diagnosed, but the relationship between VPC frequency and mortality, even in this group, is not robust. Importantly, no survival benefit in in any population has been convincingly demonstrated as a consequence of suppressing VPCs .

In asymptomatic patients, frequent ventricular ectopy (defined as a run of 2 or more consecutive premature ventricular depolarizations or with premature ventricular depolarizations constituting over 10% of all ventricular depolarizations on any of the ECG recordings with the subject at rest, during exercise, or during recovery) recorded during exercise testing was associated with 2.5-fold increased risk of cardiovascular death.[6] Less frequent VPCs did not increase the risk.

In general, multimorphic VPCs connote a poorer prognosis than uniform morphologic VPCs. In patients post-MI, frequent VPCs (>10/h) are associated with increased mortality in the prethrombolytic era, but the association in patients receiving thrombolysis is weak.

In 2 studies, frequent or complex ventricular ectopy (defined as the presence of 7 or more ventricular premature beats per minute during any given stage, ventricular bigeminy, ventricular trigeminy, ventricular couplets, ventricular triplets, sustained or nonsustained ventricular tachycardia, ventricular flutter, torsade de pointes, or ventricular fibrillation) during exercise was an independent predictor of death.[6, 7] However, in another study, frequent VPCs only during exercise did not independently predict an increased risk; instead frequent VPCs during recovery was a stronger predictor of death.[8]

Frequent VPCs, especially when they occur in a bigeminal pattern, can cause or contribute to tachycardia-induced cardiomyopathy, which reversed by elimination of the PVCs through catheter ablation.[6, 9, 10, 11]  However, the extent to which this can be generalized to larger populations remains uncertain. Caution is in order, primarily because prior attempts at pharmacologic suppression were associated with unexpected and deleterious outcomes.[12]

Various symptoms are associated with VPCs, but the exact prevalence of symptoms is not known. Typical symptoms include palpitations, light-headedness, syncope, atypical chest pain, or fatigue. Palpitations are due to an augmented post-VPC beat and may be sensed as a pause rather than an extra beat.

VPCs frequently are associated with variable or decreased intensity of heart sounds. An augmented beat following a dropped beat is heard frequently. Bounding jugular pulse (cannon a wave) from a loss of atrioventricular (AV) synchrony may be present. The follow-up beat after a VPC is stronger due to the postextrasystolic compensatory pause, allowing greater left ventricular (LV) filling, which usually causes greater intensity of that beat. This is known as extrasystolic potentiation. Conversely, the VPC itself may be underperfused and consequently not perceived by radial pulse, resulting in a spurious documentation of bradycardia.

Obtain laboratory studies to evaluate or correctable causes of VPCs, such as medications, electrolyte disturbances, infection, and myocardial ischemia or MI. Obtain serum electrolyte and magnesium levels.

A 2016 population-based study of 498 individuals with ventricular ectopy activity, including PVCs, found that elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were independently associated with ventricular ectopy but not with levels of high sensitivity-troponin I (hs-TnI) or hs-C-reactive protein (hs-CRP).[13] Obtaining levels of NT-proBNP may help in the evaluation of potential adverse cardiovascular events in persons with asymptomatic ventricular arrhythmias.

Imaging studies may help to identify any underlying structural heart abnormalities that can predispose to VPCs. Assess the degree of LV dysfunction by noninvasive techniques such as echocardiography or radionuclide imaging. Echocardiography may be the preferred imaging modalitybecause it also provides structural information about the heart.

Exercise stress testing should be performed to look for coronary ischemia, exercise-induced arrhythmia, or both.

In patients suspected of having coronary artery disease, a noninvasive evaluation to rule out this possibility or even a cardiac catheterization may be helpful diagnostically. This is based on not just the presence of VPCs, but on all risk factors and symptoms. Onset in an elderly patient should be a red flag to consider the possibility of progressive structural heart disease.

The diagnosis of VPCs is typically established by electrocardiography. The presence of a VPC on a 12-lead ECG provides essential information about the origin of that extrasystole, as well as providing important information about the ventricular site-of-origin of the VPC. Accordingly, an ECG should be performed to look for pathophysiologic cardiac abnormalities as well as documenting the presence of VPCs and potentially providing information about their specific mechanism and frequency.

Diagnostic criteria include the following:

• Wide (duration exceeding the dominant QRS complexes) and bizarre QRS complexes are present.

• No preceding premature P waves occur, and, rarely, a sinus P wave is conducted.

• The T wave usually is in the opposite direction from the R wave.

• Full compensatory pause is common.

• VPCs originating from the left ventricle typically produce a right bundle-branch block (BBB) pattern on QRS.

• VPCs originating from right ventricle typically produce left BBB-like pattern on QRS.

• Idiopathic VPCs often originate from the right ventricular outflow tract and have a left bundle inferior axis morphology. See the image below.

  Ventricular premature complexes (VPCs). Ventricular trigeminy is present. Note that the VPCs are unimorphic and that a compensatory pause follows each VPC. This patient has asymptomatic idiopathic VPCs originating from the right ventricular outflow tract.

Noninvasive mapping of cardiac arrhythmias is also possible with a 252-lead ECG and computed-tomography scan–based three-dimensional electroimaging.[14]

Newer monitoring devices

Newer monitoring devices are generally categorized in two groups. Wearable ambulatory electrocardiographic (AECG) devices and smaller cardiac implantable electronic devices (CIEDs) may be useful in patients with previously undiagnosed arrhythmias of significance.

More recent advances with miniaturized devices, rapidly expanding mobile technology (mobile cardiac telemetry [MCT]), and the availability of wearable ambulatory devices with microelectronics (eg, ZIO Patch, NUVANT MCT, and SEEQ MCT) have the potential to change the work-up algorithm for premature ventricular complexes in near future.[15]

 

In high-risk patients, ie, those with reduced ejection fraction (EF) and VPCs, a 24-hour Holter monitor may help establish the degree of electrical instability.

The severity of LV dysfunction, along with the complexity and frequency of the VPC, determines the aggressiveness of management.

Suppression of VPCs by beta-blocker or calcium blocker, together with a typical VPC morphology (inferior axis, LBBB morphology) can be helpful in establishing typical right ventricular outflow tract ectopy.

Suppressing the VPCs themselves is not the focus of treatment unless patients are significantly symptomatic.

Treatment of the underlying structural heart disease also is extremely important. This includes acute syndromes, such as ischemia and infarction, the treatment of which involves reperfusion.[16]

Electrophysiologic study (EPS) may be indicated for 2 types of patients with VPCs, (1) those with a structurally normal heart with symptomatic VPCs, for whom pharmacological treatment or catheter ablation is indicated and (2) those with VPCs and structural heart disease, for whom risk stratification for sudden cardiac death is indicated.

According to the American College of Cardiology/American Heart Association guidelines,[17, 18] class I indications for EPS are patients with CAD, low EF (< 0.36), and nonsustained VT on ambulatory ECG. Class II indications for catheter ablation apply to patients with a highly symptomatic uniform morphology of VPC, couplets, and nonsustained VT.

VPCs can be classified in different ways. The Lown classification was introduced to gauge effects of antiarrhythmic drugs and widely assumed to encapsulate prognostic significance—it is not clear that it fulfills either of these goals, but this classification is still employed.

Table 1. Lown Classification (Open Table in a new window)

 

The Lown classification does not necessarily imply a continuum of increasing risk.

Clinical classification is as follows:

• Benign

• Potentially malignant

• Malignant

Classification according to frequency is as follows:

• Frequent - 10 or more VPCs per hour (by Holter monitoring) or 6 or more per minute

• Occasional - Fewer than 10 VPCs per hour or fewer than 6 per minute

Classification according to relationship to normal beats is as follows:

• Bigeminy - Paired complexes, VPC alternating with a normal beat

• Trigeminy - VPC occurring every third beat (2 sinus beats followed by VPC)

• Quadrigeminy - VPC occurring every fourth beat (VPC following 3 normal beats)

• Couplet - 2 consecutive VPCs

• Nonsustained VT - 3 or more consecutive VPCs (< 30 s)

Classification according to origin is as follows:

• Number of foci: Unifocal/unimorphic (beats originate from 1 focus; ie, all VPCs have the same morphology) or multifocal/multimorphic (VPCs have more than one morphology and may originate from more than one site)

• Site of origin: Left or right ventricular

• Associated heart disease: None (idiopathic) or structural heart disease is present

Deciding when to treat VPCs is difficult because not all patients with VPCs are at risk of sudden death and treatment is associated with risk. The approach to VPCs depends on the frequency of VPCs, attributable symptoms, the presence or absence of underlying structural heart disease, and the estimated risk of sudden cardiac death.[19]

In the absence of significant structural heart disease (eg, normal ventricular function, no coronary or valvular heart disease) and the presence of asymptomatic VPCs, no therapy is required.

For symptomatic VPCs, recommended treatment usually involves the following:

• Patient education and reassurance
• Avoidance of aggravating factors (eg, stress, caffeine-containing products)
• Consideration of antiarrtymic agents and
• Anxiolytic drugs if education, targeted pharmacologic treatment and avoidance of aggravating factors are ineffective. 

Step 1: Beta-blockers and nondihydropyridine calcium channel blockers (eg, verapamil, diltiazem) can be used to treat symptomatic patients. Beta-blockers with intrinsic sympathomimetic activity may be particularly helpful.[20, 21]

Step 2: The use of antiarrhythmic therapy is not typically recommended and best targeted to address limiting symptoms. The risk of the drug (including the risk of arrhythmic death from proarrhythmia) must be weighed against the benefits of VPC suppression. The risk of adverse events is higher in patients with structural heart disease.

In patients without structural heart disease who have refractory symptoms and are using beta-blockers and/or calcium channel blockers, cautious use of antiarrhythmic drugs is the appropriate next step. Class Ic drugs (flecainide and propafenone) are effective in such patients without structural heart disease or coronary heart disease.

Step 3: The next step in patients who cannot take flecainide or propafenone is to consider amiodarone or sotalol.

Because interest in VPC supression decreased when it was shown to be typically deleterious in patients with coronary artery disease, this literature is not current, and specifically the role of newer class III antiarrhythmic like dofetilide and azimilide for VPCs is unclear at present.

Presence of underlying heart disease (eg, VPCs in patients post MI)

Management in these patients Various strategies, both invasive and noninvasive, predict prognosis in patients with VPCs post-MI.

The most powerful combination of noninvasive prognostic variables that identify patients in whom invasive strategies are suitable includes the presence of 2 or more of the following variables, (1) LV EF less than 0.40, (2) ventricular late potentials (on signal-averaged ECG), and (3) repetitive VPCs.

Supportive management

Treatment should include limiting transient ischemia.

Optimal treatment for congestive heart failure (CHF), CAD, or both should be instituted.

Maintain electrolyte balance.

Blood pressure control should be obtained because LV hypertrophy is associated with increased VPCs.[22]

Ablation therapy

The 2006 ACC/AHA/ESC guideline recommends that ablation therapy should be considered in the following[18] :

• Patients with frequent, symptomatic, and monomorphic VPCs refractory to medical therapy

• Patients who choose to avoid long-term medical therapy

• Patients with ventricular arrhythmia storm that is consistently provoked by VPBs of a similar morphology

VPCs arising from the outflow tract (OT) are the most common subtype of idiopathic VPCs; more than 70-80% of premature ventricular contractions (PVCs) originate from the right ventricular (RV) OT. The remaining VPCs originate from other sites (left and right coronary cusp, mitral annulus, and on the epicardium near the left ventricular [LV] OT). Highly symptomatic and refractory cases of VPCs especially from RVOT are appropriate for ablation therapy, with success rates over 70%.

The selection of an endocardial versus an epicardial approach to target ventricular arrythmia depends on the patient’s underlying disease substrate, as well as the location of the arrhythmogenic substrate within the myocardial wall, which can be best assessed with a cardiac MRI.[23]

Diet

Recommendations depend on the underlying cardiac disease; avoidance of caffeine, nicotine, and alcohol may reduce the frequency of VPCs.

Patients deemed to be at high risk of sudden cardiac death may benefit from implantable cardioverter defibrillator (ICD) implantation.

Catheter-based renal sympathetic denervation (RSD) may have a role in reducing the arrhythmic burden of ventricular arrhythmias, including PVCs, that are refractory to pharmacotherapy.[24] In a preliminary study of 34 patients with PVCs and structurally normal hearts (20 underwent ablation RSD, 14 served as controls), investigators noted that at 3-, 6- (first month after RSD, without drugs), 7-, and 12-month (sixth month after RSD, without drugs) follow-up, those treated with RSD had significantly reduced numbers of polymorphic PVCs compared to baseline. Although neither patient group showed any changes in mean 24-hour ambulatory blood pressure monitoring (ABPM) and renal function at 12 months, the control group demonstrated a decrease in 24-hour Holter mean heart rate. The change in number of polymorphic PVCs at 6 months post RSD was significantly associated with the total number of RSD ablated sites.[24]

Consultation with a cardiac electrophysiologist may be beneficial. As described above, select patients with symptomatic idiopathic VPCs may benefit from catheter ablation. EPS may help define risk for sudden death in some patients with structural heart disease. ICD implantation is beneficial in patients at high risk of sudden cardiac death, which is typically assessed by the presence of any associated cardiovascular disease, rather than the presence of VPCs per se.

Acute management

Treatment steps for VPC include looking for and correcting the reversible causes (eg, hypoxia, hypokalemia, hypomagnesemia).

Long-term treatment

The long-term treatment of VPCs is highly controversial. Class I drugs affect fast sodium channels; they are classified into A, B, and C groups according to effects on phase 0 of the action potential, repolarization, and conduction.

Class IA drugs (eg, procainamide, quinidine, disopyramide) are moderately effective but have proarrhythmic effects. Procainamide is associated with a high incidence of allergic reactions, and quinidine is poorly tolerated due to adverse effects.

Class IB drugs (eg, mexiletine) may have less proarrhythmic effect (although one post-MI trial showed higher mortality for mexiletine than placebo) than class I antiarrhythmic drugs. They have a high incidence of adverse noncardiac effects. These drugs may show reasonable efficacy in some patients.

Class IC drugs (eg, flecainide, propafenone) are effective for reducing ventricular ectopy and are relatively well tolerated in patients with normal or minimally reduced LV function and no ischemic heart disease. They are not recommended in patients with ischemic heart disease because of the adverse outcome observed in the Cardiac Arrhythmia Suppression Trial (CAST). In CAST II, moricizine (Ethmozine) demonstrated neither benefits nor adverse effects long term, but, in the early use of the drug, increased mortality on moricizine occurred. Moricizine was discontinued in July 2007 because of diminished market demand.

Class II drugs (beta-blockers) are the drugs of choice in patients who are symptomatic but do not have structural heart disease. Also, class II drugs are considered the first choice of therapy for patients with underlying heart disease, especially if their EF is reduced. Beta-blockers or calcium blockers often suppress VPCs of right ventricular outflow tract origin.

Drug of choice in patients with VPC postmyocardial infarction

Class III drugs (eg, amiodarone, sotalol) are approved for use only in life-threatening arrhythmia. Recent data suggest that amiodarone is safe post-MI for patients with VPCs, but does not reduce mortality. Amiodarone is the drug of choice in patients who can not tolerate beta-blockers. A meta-analysis comparing efficacy and safety of amiodarone and metoprolol in the treatment of VPC concluded that the response rate of amiodarone did not seem to be superior to metoprolol; amiodarone was associated with higher incidence of adverse reactions.[25, 26]

Class IV drugs (calcium channel blockers), in general, have a limited role in the treatment of VPCs. However, occasionally, these drugs may suppress triggered automaticity or idiopathic VPCs. Verapamil is recommended for treatment of idopathic LVOT VPCs. 

Currently, no evidence supports treatment of asymptomatic VPCs after MI with medication other than beta-blockers. Treatment considerations include symptoms caused by VPC, other prognostic variables (ie, presence or absence and type of structural heart disease, CAD, and LV dysfunction), and adverse effects (specifically proarrhythmic effects of medications).

Clinical trials have suggested that type I antiarrhythmic agents and racemic sotalol increase mortality in patients post-MI. Amiodarone may have no adverse effect on mortality in this setting.[27]

Class Summary

Alter the electrophysiologic mechanisms responsible for arrhythmia.

Amiodarone (Cordarone, Pacerone)

Class III antiarrhythmic. Has antiarrhythmic effects that overlap all 4 Vaughn-Williams antiarrhythmic classes. May inhibit A-V conduction and sinus node function. Prolongs action potential and refractory period in myocardium and inhibits adrenergic stimulation. Only agent proven to reduce incidence and risk of cardiac sudden death, with or without obstruction to LV outflow. Very efficacious in converting atrial fibrillation and flutter to sinus rhythm and in suppressing recurrence of these arrhythmias.

Has low risk of proarrhythmia effects, and any proarrhythmic reactions generally are delayed. Used in patients with structural heart disease. Most clinicians are comfortable with inpatient or outpatient loading with 400 mg PO tid for 1 wk because of low proarrhythmic effect, followed by weekly reductions with goal of lowest dose with desired therapeutic benefit (usual maintenance dose for AF 200 mg/d). During loading, patients must be monitored for bradyarrhythmias. Prior to administration, control the ventricular rate and CHF (if present) with digoxin or calcium channel blockers.

Oral efficacy may take weeks. With exception of disorders of prolonged repolarization (eg, LQTS), may be DOC for life-threatening ventricular arrhythmias refractory to beta-blockade and initial therapy with other agents.

Metoprolol (Lopressor, Toprol XL)

Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions.