PVC induced cardiomyopathy

# Overview
- Introduction
PVC-induced cardiomyopathy has been a controversial subject since its introduction. The concept of the disease is mainly based on the overwhelming evidence suggesting that frequent PVCs may cause, or at least play a role in the development of a reversible form of cardiomyopathy. Although there is no clear definition for the condition, it is commonly known as either a state of decreased LVEF (24% to be a stronger predictor for developing cardiomyopathy, although even a burden of 4% is reported to be able to cause cardiomyopathy.
- Historical Perspective
Initially, a 1998 study revealed that frequent PVCs may be the cause of, or at least associated with a reversible form of cardiomyopathy. The concept of PVC-induced cardiomyopathy was formed afterwards.
- Pathophysiology
In addition to issues in the definition of PVC-induced cardiomyopathy, the mechanism for the development of this condition is not yet well understood.
- Causes and risk factors
Greater PVC burden, longer PVC QRS duration, PVC coupling interval, interpolated PVCs, PVCs originating from the epicardium or right ventricle, asymptomatic and multiform PVCs, male sex and nonsustained VT are all associated with the disease. However, stronger evidence is needed with regards to most of these risk factors.
- Natural history, complications, and prognosis
- History and symptoms
- Physical exam
- Electrocardiogram
- Echocardiography
- Treatment
Treatment is based on PVC suppression that is achieved either by antiarrhythmic agents or radio-frequency catheter ablation. Options for medical therapy include beta-blockers, calcium channel blockers, flecainide, propafenone and amiodarone, among which amiodarone have proven most effective without affecting mortality.

# Historical perspective
In 1998, a study demonstrated that treating patients with frequent PVCs ( > 20,000 per day ) and ventricular dysfunction with amiodarone could significantly improve LVEF. This result led to the initial assumption that frequent PVCs might cause a reversible form of cardiomyopathy and thus, the concept of PVC-induced cardiomyopathy as a separate entity was formed. Since then, multiple studies have attempted to clarify the nature and the features of the disease. However, the mechanisms through which frequent PVCs can cause ventricular dysfunction remain mainly unknown. Initial studies suggested that PVC-induced cardiomyopathy was essentially a tachycardia-induced cardiomyopathy as seen with other arrhythmias such as atrial fibrillation. This hypothesis was rejected, however, because many patients with PVC-induced cardiomyopathy had normal average heart rates.

# Pathophysiology
The exact pathogenesis of PVC-induced cardiomyopathy is not fully understood. Some even argue that PVCs may NOT be the cause of cardiomyopathy. Instead, they could be the products of an underlying cardiomyopathy of unknown/undetected mechanism and origin.
Role of structural heart disease:
Hypothetically, frequent PVCs could be both a result of an underlying, undetected structural heart disease or its cause. Although both scenarios are capable of producing left ventricular dysfunction (i.e. cardiomyopathy), there is an ongoing debate on whether PVCs have a causal role or they are just an indicator of a subtle, undetectable structural heart disease. As a result, some investigations have even used the term "PVC-associated LV dysfunction" instead of PVC-induced cardiomyopathy. Nevertheless, there is not enough evidence to confirm either of these two cases and the controversy remains unsolved.
PVC site of origin:
PVCs can originate from any location within the myocardial, endocardial and epicardial surfaces and therefore can produce a variety of morphologies. Overall, approximately two thirds of idiopathic PVCs originate from the ventricular outflow tract and most commonly the RVOT. The other potential locations include periatrioventricular valvular regions, papillary muscles, fascicles, aortic valve cusps and epicardium. RVOT-originated PVCs are associated with LVEF reduction and cardiomyopathy. RVOT-originated PVCs can result in LVEF reduction in lower amounts of PCV burden in contrast to PVCs originated from LVOT.  Studies have reported lower ablation success rates for LVOT originated PVCs. Subtle myocardial structural abnormalities detected by cardiac MRI are more common in patients with LVOT-originated PVCs and may be responsible for weaker response to ablation in these patients.

# Causes and risk factors
Although all the factors listed in table 1 are proposed to be associated with developing PVC-induced cardiomyopathy, the evidence is not yet strong enough and further studies are warranted.

# Natural history, complications, and prognosis
Studies describing the natural history of frequent PVCs are too few. Furthermore, the factors contributing to the development of the subsequent cardiomyopathy remain, for the most part, unclear. As mentioned earlier, the main hypothesis is that frequent PVCs progress into a reversible form of cardiomyopathy. A prospective study on patients with frequent PVCs demonstrated that PVC burden did not significantly change per patient over a mean follow-up of approximately 6 years. They further indicated that LVEF decreased in patients with very frequent PVCs (burden > 20,000/24h) over the follow-up period, which was significant in comparison to patients with fewer PVCs. Another study reported a 38% decline in LVEF during a median follow-up of 14 months, confirming the depression of LVEF over time in patients with frequent PVCs. In addition, Dukes et al. demonstrated that patients with the highest quartile of PVCs had a threefold increased risk for developing depressed LVEF over a period of 5 years compared with patients with the lowest quartile of PVCs. They also found that more frequent PVCs were associated with increased risk of developing heart failure as well as increased mortality. The time course for the onset of the disease has not been clearly identified either. However, longitudinal studies have demonstrated a course of months to years rather than weeks to months for the development of PVC-induced cardiomyopathy.
Predictors of ablation success:
Reports claim that PVCs originated from RVOT better respond to RFCA. However, a meta-analysis has revealed no significant association between PVC site of origin and ablation success.

# History and symptoms
A significant portion of patients will not experience the expected symptoms such as palpitations. These patients are specifically at risk of developing PVC-induced cardiomyopathy, simply because they do not notice their condition and therefore do not refer to the physician in the absence of symptoms. Prolonged periods of frequent PVCs would then gradually affect the heart and develop into cardiomyopathy. Evidence confirms this theory by directly linking longer durations of symptoms with a higher likelihood for developing PVC-induced cardiomyopathy in symptomatic patients.

# Physical exam

# Electrocardiogram
PVCs can produce a variety of morphologies based on their site of origin. Moreover, depending on whether the PVCs originate from single or multiple foci, they can appear as monomorphic or polymorphic on ECG. PVCs originated from ventricular outflow tract are often monomorphic. The surface ECG can provide several clues that can help determine the PVC origin. Despite its limitations, ECG is a valuable tool for pre-procedural evaluation of patients undergoing RFA. RVOT-originated PVCs mainly present with LBBB morphology and inferior axis. PVCs from LVOT less commonly occur and mostly present with RBBB or LBBB, inferior axis and early R-S transition in precordial leads.

# Echocardiography
As mentioned earlier, LVEF (66mm could predict irreversible cardiomyopathy with 50% sensitivity, 100% specificity, 100% positive predictive value and 81% negative predictive value. As a mechanism, they proposed that long QRS duration results from slower myocardial electrical conduction, that could in turn be a reason of left ventricular dilation. Nevertheless, the evidence is not enough with this regard and further studies aiming to reveal other echocardiographic alterations and their mechanisms are required.

# Treatment
Treatment for PVC-induced cardiomyopathy focuses on suppressing PVCs and reducing PVC burden, that could subsequently result in ventricular function improvement. Treatment methods include pharmacological therapy with anti-arrhythmic drugs and catheter ablation.
- Medical therapy:
Pharmacotherapy is the first treatment option for asymptomatic or mildly symptomatic patients without any structural heart disease. There are several anti-arrhythmic drugs available such as beta-blockers, calcium channel blockers, flecainide, propafenone and amiodarone with varying effectiveness and side effects. Beta-blockers, especially sotalol, are usually considered as a first line therapy, due to their low adverse effects and potential secondary benefits. In patients with no symptoms of heart failure, non-dihydropyridine calcium channel blockers are reasonable alternatives. However, these two groups have only modest efficacy in reducing PVC burden. Moreover, whether they could significantly improve LVEF is still among debate. For instance, a study reported a 36% reduction of PVC burden with beta-blockers and no effect on LVEF.
Antiarrhythmic drugs are stronger PVC suppressors. Studies have demonstrated reduced PVC counts by 83% in patients treated with class I antiarrhythmics compared with 70% reduction with sotalol. Amiodarone had the highest efficacy with an 84% reduction of PVC counts. Except for amiodarone, antiarrhythmic medicarions have no role in improving survival despite their higher efficacy. Due to their adverse effects such as negative inotropic and proarrhythmic effects, they are not recommended for treating frequent PVCs in CHF patients. Amiodarone, however, is the most effective drug to reduce PVC burden without increasing mortality rate in patients with advanced CHF. It is also effective on left ventricular function improvement.
- Ablation:
Radiofrequency catheter ablation (RFCA) is a medical procedure in which part of the electrical conduction system of the heart is ablated using the heat generated from medium frequency alternating current. Evidence suggests ablation is an effective therapeutic tool to reduce frequent PVCs and restore LV function in patients with with idiopathic LV dysfunction and frequent PVCs. Complete elimination of PVCs is not necessary, however, and reducing the PVC burden to <10% can greatly increase the chance of LVEF recovery over a course of up to to 48 months or longer. LVEF improvement begins within 4 months post-ablation in most patients and takes longest when an epicardial origin of PVCs is present.