PVC induced cardiomyopathy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor-In-Chief: Farbod Zahedi Tajrishi, M.D.

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.[1][2] Although there is no clear definition for the condition, it is commonly known as either a state of decreased LVEF (<50%) in the presence of frequent PVCs that is increased by at least 15% or ≥10% or restored to more than 50% after PVC reduction therapy.[3][2] The term "frequent" is vague and not precisely explained in this definition. Different studies have considered PVC burdens of ≥10% to 29±13% as frequent, and some have suggested PVC burden >24% to be a stronger predictor for developing cardiomyopathy, although even a burden of 4% is reported to be able to cause cardiomyopathy.[3][4][5][6][7][8]

  • 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.[1] 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.[9] This hypothesis was rejected, however, because many patients with PVC-induced cardiomyopathy had normal average heart rates.[10]

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.[11]

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.[11] As a result, some investigations have even used the term "PVC-associated LV dysfunction" instead of PVC-induced cardiomyopathy.[12] 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.[13] 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.[13] Studies have reported lower ablation success rates for LVOT originated PVCs.[14][15] 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.[16]

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.

Table 1- Evidence-based risk factors of PVC-induced cardiomyopathy[3][17][18]
Risk factors (predictors)
Greater PVC burden
Longer PVC QRS duration
PVC coupling interval
Interpolated PVCs
Right ventricular PVC origin
Asymptomatic PVCs
Epicardial PVC origin
Multiform PVCs
Male sex
Presence of non-sustained VT

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.[19] 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.[19][20] 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.[21] 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.[22] 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.[23]

Predictors of ablation success:

Reports claim that PVCs originated from RVOT better respond to RFCA.[14][24][25] However, a meta-analysis has revealed no significant association between PVC site of origin and ablation success.[12]

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.[23]

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.[26] 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.[27]

Echocardiography

As mentioned earlier, LVEF (<50%) in the presence of frequent PVCs that is increased by at least 15% or ≥10% after PVC reduction therapy is characteristic of PVC-induced cardiomyopathy. Other changes such as alterations in ventricular diameters may also occur. A 2015 study by Park et al. has linked PVC QRS duration, LVEDD and the irreversibility of cardiomyopathy and concluded that left ventricular end-diastolic diameter >66mm could predict irreversible cardiomyopathy with 50% sensitivity, 100% specificity, 100% positive predictive value and 81% negative predictive value.[5] 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.[28] 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.[29] 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.[10]

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.[30][31][32][33] 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.[1]

  • 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.[17][20] 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.[2][34]

References

  1. ↑ 1.0 1.1 1.2 Duffee DF, Shen WK, Smith HC (1998). "Suppression of frequent premature ventricular contractions and improvement of left ventricular function in patients with presumed idiopathic dilated cardiomyopathy". Mayo Clin Proc. 73 (5): 430–3. doi:10.1016/S0025-6196(11)63724-5. PMID 9581582.
  2. ↑ 2.0 2.1 2.2 Yokokawa M, Good E, Crawford T, Chugh A, Pelosi F, Latchamsetty R; et al. (2013). "Recovery from left ventricular dysfunction after ablation of frequent premature ventricular complexes". Heart Rhythm. 10 (2): 172–5. doi:10.1016/j.hrthm.2012.10.011. PMID 23099051.
  3. ↑ 3.0 3.1 3.2 Baman TS, Lange DC, Ilg KJ, Gupta SK, Liu TY, Alguire C; et al. (2010). "Relationship between burden of premature ventricular complexes and left ventricular function". Heart Rhythm. 7 (7): 865–9. doi:10.1016/j.hrthm.2010.03.036. PMID 20348027.
  4. ↑ Bogun F, Crawford T, Reich S, Koelling TM, Armstrong W, Good E; et al. (2007). "Radiofrequency ablation of frequent, idiopathic premature ventricular complexes: comparison with a control group without intervention". Heart Rhythm. 4 (7): 863–7. doi:10.1016/j.hrthm.2007.03.003. PMID 17599667.
  5. ↑ 5.0 5.1 Park KM, Kim J, Na H, Chun KJ, Im SI, Park SJ; et al. (2015). "Cardiomyopathy With Frequent Ventricular Premature Depolarization – Predicting Irreversible Ventricular Dysfunction". Circ J. 79 (8): 1816–22. doi:10.1253/circj.CJ-15-0171. PMID 25959434.
  6. ↑ Shanmugam N, Chua TP, Ward D (2006). "'Frequent' ventricular bigeminy--a reversible cause of dilated cardiomyopathy. How frequent is 'frequent'?". Eur J Heart Fail. 8 (8): 869–73. doi:10.1016/j.ejheart.2006.02.011. PMID 16714145.
  7. ↑ Grimm W, Menz V, Hoffmann J, Maisch B (2001). "Reversal of tachycardia induced cardiomyopathy following ablation of repetitive monomorphic right ventricular outflow tract tachycardia". Pacing Clin Electrophysiol. 24 (2): 166–71. PMID 11270695.
  8. ↑ Vijgen J, Hill P, Biblo LA, Carlson MD (1997). "Tachycardia-induced cardiomyopathy secondary to right ventricular outflow tract ventricular tachycardia: improvement of left ventricular systolic function after radiofrequency catheter ablation of the arrhythmia". J Cardiovasc Electrophysiol. 8 (4): 445–50. PMID 9106431.
  9. ↑ Ellis ER, Josephson ME (2013). "Heart failure and tachycardia-induced cardiomyopathy". Curr Heart Fail Rep. 10 (4): 296–306. doi:10.1007/s11897-013-0150-z. PMID 23963583.
  10. ↑ 10.0 10.1 Zhong L, Lee YH, Huang XM, Asirvatham SJ, Shen WK, Friedman PA; et al. (2014). "Relative efficacy of catheter ablation vs antiarrhythmic drugs in treating premature ventricular contractions: a single-center retrospective study". Heart Rhythm. 11 (2): 187–93. doi:10.1016/j.hrthm.2013.10.033. PMID 24157533.
  11. ↑ 11.0 11.1 Penela D, Van Huls Van Taxis C, Van Huls Vans Taxis C, Aguinaga L, Fernández-Armenta J, Mont L; et al. (2013). "Neurohormonal, structural, and functional recovery pattern after premature ventricular complex ablation is independent of structural heart disease status in patients with depressed left ventricular ejection fraction: a prospective multicenter study". J Am Coll Cardiol. 62 (13): 1195–202. doi:10.1016/j.jacc.2013.06.012. PMID 23850913.
  12. ↑ 12.0 12.1 Zang M, Zhang T, Mao J, Zhou S, He B (2014). "Beneficial effects of catheter ablation of frequent premature ventricular complexes on left ventricular function". Heart. 100 (10): 787–93. doi:10.1136/heartjnl-2013-305175. PMID 24670420.
  13. ↑ 13.0 13.1 Del Carpio Munoz F, Syed FF, Noheria A, Cha YM, Friedman PA, Hammill SC; et al. (2011). "Characteristics of premature ventricular complexes as correlates of reduced left ventricular systolic function: study of the burden, duration, coupling interval, morphology and site of origin of PVCs". J Cardiovasc Electrophysiol. 22 (7): 791–8. doi:10.1111/j.1540-8167.2011.02021.x. PMID 21332870.
  14. ↑ 14.0 14.1 Latchamsetty (2015). "Multicenter outcomes for catheter ablation of idiopathic premature ventricular complexes". JACC: Clinical Electrophysiology: 116–123. line feed character in |title= at position 57 (help)
  15. ↑ Ouyang F, Fotuhi P, Ho SY, Hebe J, Volkmer M, Goya M; et al. (2002). "Repetitive monomorphic ventricular tachycardia originating from the aortic sinus cusp: electrocardiographic characterization for guiding catheter ablation". J Am Coll Cardiol. 39 (3): 500–8. PMID 11823089.
  16. ↑ Nucifora G, Muser D, Masci PG, Barison A, Rebellato L, Piccoli G; et al. (2014). "Prevalence and prognostic value of concealed structural abnormalities in patients with apparently idiopathic ventricular arrhythmias of left versus right ventricular origin: a magnetic resonance imaging study". Circ Arrhythm Electrophysiol. 7 (3): 456–62. doi:10.1161/CIRCEP.113.001172. PMID 24771543.
  17. ↑ 17.0 17.1 Lee AK, Deyell MW (2016). "Premature ventricular contraction-induced cardiomyopathy". Curr Opin Cardiol. 31 (1): 1–10. doi:10.1097/HCO.0000000000000236. PMID 26599061.
  18. ↑ Sharma E, Arunachalam K, Di M, Chu A, Maan A (2017). "PVCs, PVC-Induced Cardiomyopathy, and the Role of Catheter Ablation". Crit Pathw Cardiol. 16 (2): 76–80. doi:10.1097/HPC.0000000000000106. PMID 28509708.
  19. ↑ 19.0 19.1 Niwano S, Sasaki T, Kurokawa S, Kiryu M, Fukaya H, Hatakeyama Y; et al. (2009). "Predicting the efficacy of antiarrhythmic agents for interrupting persistent atrial fibrillation according to spectral analysis of the fibrillation waves on the surface ECG". Circ J. 73 (7): 1210–8. PMID 19436116.
  20. ↑ 20.0 20.1 Lamba J, Redfearn DP, Michael KA, Simpson CS, Abdollah H, Baranchuk A (2014). "Radiofrequency catheter ablation for the treatment of idiopathic premature ventricular contractions originating from the right ventricular outflow tract: a systematic review and meta-analysis". Pacing Clin Electrophysiol. 37 (1): 73–8. doi:10.1111/pace.12243. PMID 23980900.
  21. ↑ Carballeira Pol L, Deyell MW, Frankel DS, Benhayon D, Squara F, Chik W; et al. (2014). "Ventricular premature depolarization QRS duration as a new marker of risk for the development of ventricular premature depolarization-induced cardiomyopathy". Heart Rhythm. 11 (2): 299–306. doi:10.1016/j.hrthm.2013.10.055. PMID 24184787.
  22. ↑ Dukes JW, Dewland TA, Vittinghoff E, Mandyam MC, Heckbert SR, Siscovick DS; et al. (2015). "Ventricular Ectopy as a Predictor of Heart Failure and Death". J Am Coll Cardiol. 66 (2): 101–9. doi:10.1016/j.jacc.2015.04.062. PMC 4499114. PMID 26160626.
  23. ↑ 23.0 23.1 Yokokawa M, Kim HM, Good E, Chugh A, Pelosi F, Alguire C; et al. (2012). "Relation of symptoms and symptom duration to premature ventricular complex-induced cardiomyopathy". Heart Rhythm. 9 (1): 92–5. doi:10.1016/j.hrthm.2011.08.015. PMID 21855522.
  24. ↑ Mukai J, Nakagawa H, Nagata K, Karakawa S, Shimizu W, Tsuchioka Y; et al. (1993). "Long-term results of catheter ablation for idiopathic ventricular tachycardia originated from the right ventricular outflow". Jpn Circ J. 57 (10): 960–8. PMID 8230677.
  25. ↑ Klein LS, Shih HT, Hackett FK, Zipes DP, Miles WM (1992). "Radiofrequency catheter ablation of ventricular tachycardia in patients without structural heart disease". Circulation. 85 (5): 1666–74. PMID 1572025.
  26. ↑ Heeger CH, Hayashi K, Kuck KH, Ouyang F (2016). "Catheter Ablation of Idiopathic Ventricular Arrhythmias Arising From the Cardiac Outflow Tracts　- Recent Insights and Techniques for the Successful Treatment of Common and Challenging Cases". Circ J. 80 (5): 1073–86. doi:10.1253/circj.CJ-16-0293. PMID 27074752.
  27. ↑ Del Carpio Munoz F, Syed FF, Noheria A, Cha YM, Friedman PA, Hammill SC; et al. (2011). "Characteristics of premature ventricular complexes as correlates of reduced left ventricular systolic function: study of the burden, duration, coupling interval, morphology and site of origin of PVCs". J Cardiovasc Electrophysiol. 22 (7): 791–8. doi:10.1111/j.1540-8167.2011.02021.x. PMID 21332870.
  28. ↑ Krittayaphong R, Bhuripanyo K, Punlee K, Kangkagate C, Chaithiraphan S (2002). "Effect of atenolol on symptomatic ventricular arrhythmia without structural heart disease: a randomized placebo-controlled study". Am Heart J. 144 (6): e10. doi:10.1067/mhj.2002.125516. PMID 12486439.
  29. ↑ WRITING COMMITTEE MEMBERS. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE; et al. (2013). "2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines". Circulation. 128 (16): e240–327. doi:10.1161/CIR.0b013e31829e8776. PMID 23741058.
  30. ↑ Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH; et al. (1991). "Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial". N Engl J Med. 324 (12): 781–8. doi:10.1056/NEJM199103213241201. PMID 1900101.
  31. ↑ Cardiac Arrhythmia Suppression Trial II Investigators (1992). "Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction". N Engl J Med. 327 (4): 227–33. doi:10.1056/NEJM199207233270403. PMID 1377359.
  32. ↑ Waldo AL, Camm AJ, deRuyter H, Friedman PL, MacNeil DJ, Pauls JF; et al. (1996). "Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral d-Sotalol". Lancet. 348 (9019): 7–12. PMID 8691967.
  33. ↑ Køber L, Torp-Pedersen C, McMurray JJ, Gøtzsche O, Lévy S, Crijns H; et al. (2008). "Increased mortality after dronedarone therapy for severe heart failure". N Engl J Med. 358 (25): 2678–87. doi:10.1056/NEJMoa0800456. PMID 18565860.
  34. ↑ Dabbagh GS, Bogun F (2017). "Predictors and Therapy of Cardiomyopathy Caused by Frequent Ventricular Ectopy". Curr Cardiol Rep. 19 (9): 80. doi:10.1007/s11886-017-0887-1. PMID 28752278.
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