INTRODUCTION

Pacemaker implantation is indicated for bradycardia caused by sinus node dysfunction (SND) as chronic therapy when other potential treatable or reversible etiologies have been excluded. Pacemaker implantation is intended to increase heart rate and improve symptoms.¹ However, long-term use of right ventricle pacing is reported to induce ventricular dyssynchrony which causes disturbances in left ventricular systolic function which further leads to heart failure syndrome or what is called pacing-induced cardiomyopathy (PICM).² PICM is defined as a heart failure syndrome characterized by: (i). left ventricular systolic dysfunction (LVEF < 50%) and LVEF reduction ≥10% after pacemaker implantation or (ii). No other cause of left ventricular dysfunction. Incidence of PICM is estimated to occur in 5-20% of patients using right ventricular pacing for more than two years.^{3, 4} Symptoms that may appear in patients who develop PICM include dyspnea on exertion, paroxysmal nocturnal dyspnea, unexplained weight gain, and edema on the extremity. Physical examination may show signs of jugular venous pressure elevation, auscultatory crackles, S3 gallop, ascites, pulmonary edema, or pleural effusion.⁴ Patients with PICM have higher probability of all cause death, HF admission, and cardiac death compared to non-PICM, so observation and intervention are needed.⁵ This study was conducted to provide the latest updates on diagnosing patients with PICM and the best management that can be done in patients by looking at the conditions in each hospital.

Predictors and Risk Factors of Pacing Induced Cardiomyopathy (PICM)

Patient who undergoes RV pacing has up to 26% chance develop LV systolic dysfunction. Many studies have been conducted to find out about the risk factors for PICM. These studies found that men are more likely to experience PICM than women. History of heart diseases such as myocardial infarction, atrioventricular block, atrial fibrillation, and pre-existing LV systolic dysfunction.^5–8 LBBB at baseline ECG, lower baseline LVEF, wider paced QRS duration and pre-LVESD, and higher burden of right ventricular pacing were predictors of PICM.^{6, 7, 9, 10} The study shows patient with baseline LVEF under 55% before pacing, wider paced QRS duration (>160msec), and pacing burden more than 33% has a higher risk for developing PICM.⁹

Mechanism of Pacing-Induced Cardiomyopathy (PICM)

Permanent pacing is indicated for patients with total AV block (TAVB) as well as bradycardia caused by SND. Symptomatic SND requiring GDMT or with bradycardia with significant comorbid, single chamber ventricular pacing is recommended unless there is reason to avoid the RV lead (IIa).¹ Studies have found that in patients with higher ventricular pacing burden (> 40%), it is more common to have a decreased LVEF, which causes symptoms of heart failure. This is supported by predictive factors such as lower baseline LVEF and wider-paced QRS duration.^{10, 11} Pacing in the distal part of the conduction system disrupts physiological conduction. Conduction does not pass through the his-purkinje system, but rather through the ventricular myocardium which causes ventricular dyssynchrony. Ventricular dyssynchrony furthermore causes abnormal contraction of the ventricle which leads to LV remodeling. Ventricular dilatation, functional MR, reduced LVEF, myocardial fibrosis, and neuro-hormonal activation play a role in LV remodeling.¹² A study conducted by the author previously found that there were neuro-hormonal changes in the remodeling process of LV. The authors found that there was a decrease in miR-155, and an increase in interleukin-6 (IL-6), soluble tumor necrosis factor 2 (sTNFR-2), matrix metalloproteinase-9 (MMP-9), N-cadherin (N-Cad), Occludens Zone-1 (ZO-1).¹³

Diagnosis of Pacing Induced Cardiomyopathy (PICM)

PICM is generally defined as a fall in Left Ventricle Ejection Fraction (LVEF) after implantation of a cardiac pacemaker. This results in symptoms of heart failure such as; dyspnea on exertion, paroxysmal nocturnal dyspnea, unexplained weight gain, edema on extremity, and physical examination may show elevation of jugular venous pressure, auscultatory crackles, S3 gallop, ascites, pulmonary edema or pleural effusion. PICM happens mostly in patients with high right ventricle pacing burden and may happen in months to years following implantation of the pacemaker. No consensus has been reached in determining the diagnostic criteria of PICM. Current literature uses varying criteria for diagnosing PICM. A systematic review and meta-analysis done by Somma et al, states that there are 15 unique diagnostic criteria found in the current literature.⁶ Based on a review by Mizner et al, these are the most often used diagnostic criteria for PICM.¹⁴

1. Decrease of LVEF below 50%, regardless of patients’ symptoms, or a reduction of LVEF by 10% or more.

2. Decrease of LVEF below 45%, or reduction of LVEF by 10% or more after implantation of pacemaker device.

3. Decrease of LVEF below 40%, or an indication of upgrading to cardiac resynchronization therapy (CRT).

4. Reduction of LVEF by 5% or more, with signs and symptoms of heart failure, without other etiology of heart failure.

It is estimated that about 6-22% of patients with a permanent pacemaker will fulfill the criteria for PICM within 3-16 years. The wide prevalence of PICM is attributed to differences in diagnostic criteria used, variability of patients included in the studies, and different follow-up duration.¹⁴ One study by Kaye et al, found that in 118 patients with permanent pacemakers and follow-up echocardiography with mean duration of three and a half years, using three unique definitions of PICM, the prevalence of PICM is 5.9% – 39%. This study demonstrates that just based on the diagnostic criteria used, the resulting prevalence may differ exponentially.¹¹

Yu et al observed that after one year, 9% of individuals with a right ventricular pacemaker will develop PICM.¹⁵ Khurshid et al, reported a prevalence of 19.5% after a median followup of 3.3 years.⁴ Zhang et al also reported a prevalence of 26% in patients with a median follow-up of 7.8 years.¹⁶ These three studies mentioned found that the shortest time a patient develops PICM is one month after the implantation of the pacemaker, and the longest time a patient is diagnosed with PICM is nine years following the implantation of pacemaker, suggesting PICM may occur even years after PPM.^{4, 15, 16} A systematic review conducted by the author previously, found that the incidence of PICM increases proportionally with the duration of PPM.¹⁷

Early Detection of Ventricular Dyssynchrony

PICM may occur as soon as one month after PPM implantation.⁴ Therefore, detecting pathophysiological changes and identifying risk factors is crucial in the prevention and treatment of PICM.

RV pacing, especially with apex location of the pacemaker, induces a slow myocyte-to-myocyte electrical signal transmission. This electrical signal propagates slowly, through the myocardium and bypasses the physiological conduction system causing disproportional RV and LV contraction. Initial depolarization happens near the pacing site followed by delayed depolarization of more remote segments. This nonphysiological cardiac contraction is known as ventricular dyssynchrony.¹⁴

There are two different types of ventricular dyssynchrony, interventricular (between right and left ventricle) and intraventricular (within one side of the ventricle). Interventricular dyssynchrony can be visualized as delayed aortopulmonary valve opening times and can be assessed with routine Doppler echocardiographic imaging. While an intraventricular dyssynchrony is a delay of mechanical activation between the various segments of the ventricle, and is harder to assess, requiring a Tissue Doppler imaging (TDI) or 2D speckletracking strain analysis and real-time 3D echocardiography.¹⁴

Interventricular dyssynchrony is identified to be an important predictor of ≥10% decrease in LVEF along with high burden RV pacing (>60%) in a study by Bansal et al.18 Another parameter in echocardiography that may predict LV dysfunction which precedes a decrease in LVEF is the Global Longitudinal Scale (GLS). GLS using 2D echocardiography has high sensitivity (92%) and specificity (89%) for detecting early LV systolic dysfunction. Iqbal et al demonstrate that there is a significant decrease in GLS of patients with PPM after one month, especially those with high RV pacing burden (40%) and apical pacemaker location.¹⁹ This is supported by the PAVD study which found one-month GLS reduction to be highly predictive in assessing patients after implantation of PPM with risk of LV dysfunction and subsequent cardiomyopathy.²⁰

Traditionally, ventricular dyssynchrony is assessed with a simple 12-lead ECG. Wide-paced QRS duration (QRSd) (>160msec) is identified as a predictor for PICM. Unfortunately, QRSd is limited as to what it can provide as it is not able to assess separate right and left ventricle activation.¹⁴ Vectorcardiography measuring QRS Area (QRSa) is a parameter that may be acquired using a 12-lead ECG or orthogonal chest leads. Vectorcardiography too is unable to assess separate right and left ventricle activation but may help in CRT optimization as large QRS areas have been found to be associated with better CRT responses and failure to achieve large QRS area reduction is associated with poorer survival and echocardiographic outcomes.^{21, 22}

Other more complex and non-invasive modalities to assess ventricular dyssynchrony are the ECG belt system (EBS) and ECG imaging (ECGi). Both use body surface potential mapping (BSPM) to measure a variety of parameters. EBS uses 53 body surface electrodes to produce isochronal activation maps reflecting spatial propagation of ventricular activation as reflected on the body surface.²³ While an ECGi is a more complex and resource-consuming modality, needing 252 body surface electrodes and a CT-Scan to construct 1500 epicardial unipolar electrograms.²⁴ Both are currently still novel technologies and see the bulk of their use in research rather than clinical settings.

In accordance with the results of the author’s previous study which found neurohormonal changes in patients after ppm with LV dysfunction assessed by GLS, the author suggests measuring these biomarkers to assess LV dysfunction in patients after PPM implantation.¹³