Are ventricularly-paced patients with prolonged QTc intervals at increased risk of ventricular arrhythmia? Is there further risk with addition of QTc prolonging agents?

Comment by InpharmD Researcher

Although data is scant, retrospective studies show an association between prolonged paced-QTc intervals and risks of ventricular complications or cardiac death. Ventricular pacing can prolong the QTc and QRS interval, in which correction formulas can be used; however, the choice of formula and accuracy of correction are not quite known. It is unknown if medication use (QTc-prolonging drugs) increases the risk of adverse cardiac effects in ventricularly paced patients because studies typically included single cohorts or had no differences in medication use between groups.

Background

A 2022 review article discussed the components of QT interval assessment for arrhythmogenic risk including QT prolongation, methods for adjusting the QT interval to identify repolarization changes, methods to adjust for heart rate, and proposed a framework for medication management to assess for drug-induced long QT syndrome in patients with ventricular pacing (VP). It was emphasized that VP modifies the QT interval by extending depolarization and adjusting repolarization times, complicating the evaluation of the actual repolarization duration. The JT interval (QT-QRS), proposed for assessing repolarization in patients with conduction delay, is not prolonged with VP due to solely measuring repolarization. One study found JTc superior to QTc in monitoring drug-induced repolarization changes during VP. Correction formulas for pacing-induced QRS duration extensions lack consistent conclusions and are derived only from ventricular pacing studies, with no evaluation in cardiac resynchronization therapy (CRT) scenarios. Various heart rate correction formulas exist without a universally accepted standard. Bazett’s formula, commonly used, has shown inferiority in several studies. In the context of VP, heart rate correction becomes complex. The Framingham and Nomogram methods perform reliably with the least heart rate dependence in estimating intrinsic QTc during VP rhythms. The Spline method, derived from a large U.S. database, shows superiority in eliminating the impact of heart rate on the QT interval compared to other formulas, making it a promising choice for heart rate correction in VP scenarios despite the current absence of its validation. [1]

Assessing an individual’s risk for Torsades de Pointes (TdP)/ventricular fibrillation (VF) involves considering various factors such as age, sex, cardiac health, diuretic usage, electrolyte balance, impaired drug metabolism, and interactions with other medications. The challenge intensifies in VP due to assessment limitations of the paced QT interval. VP and CRT may increase susceptibility to ventricular arrhythmias, which may potentially not be reflected in the QT interval. Knowledge of the intrinsic conduction QT can be useful if available. In the presence of CRT pacing, elevated transmural dispersion of repolarization or QT dispersion may impact the decision to avoid QT prolongation medications, though supporting data is limited. [1]

No specific QT monitoring criteria exist for most medications causing QT prolongation, but the highest risk is typically during initiation, dose increase, or at high doses. According to clinical guidelines, caution is advised if Bazett-corrected QTc exceeds 500 ms or increases by >60 ms from baseline. To assess drug-induced long QT syndrome in paced patients, it is recommended to start with a baseline spline-modified JTc. If JTc exceeds 360 ms, an alternative medication should be considered. After initiation, if QTc increases by >60 ms or spline-modified JTc is >360 ms, carefully evaluate the dosage or drug’s relative benefits, as there are no guidelines for absolute contraindications. [1]

References:

[1] Schurr JW, Grewal PK, Fan R, Rashba E. QT interval measurement in ventricular pacing: Implications for assessment of drug effects and pro-arrhythmia risk. J Electrocardiol. 2022;70:13-18. doi:10.1016/j.jelectrocard.2021.11.029
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Are ventricularly-paced patients with prolonged QTc intervals at increased risk of ventricular arrhythmia? Is there further risk with addition of QTc prolonging agents?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-4 for your response.

 

Paced QT Interval as a Risk Factor for New-onset Left Ventricular Systolic Dysfunction and Cardiac Death After Permanent Pacemaker Implantation

Design

Retrospective, single-center, observational, case-control study

N= 491

Objective

To assess whether the prolonged paced-QTc (p-QTc) interval is associated with the development of new left ventricular systolic dysfunction (LVSD) or cardiac death after permanent pacemaker (PPM) implantation in patients with preserved LV systolic function

Study Groups

No LVSD (n= 438)

New-onset LVSD (n= 53)

Inclusion Criteria

All patients undergoing routine clinical, electrocardiographic, echocardiographic, and pacing parameters following permanent pacemaker implantation

Exclusion Criteria

 Left ventricular ejection fraction (LVEF) < 50%; lack of a paced-QRS complex on a 12-lead ECG; implantable cardioverter-defibrillator; biventricular pacemaker

Methods

This was a single-center study of patients with preserved LV systolic function following pacemaker implantation at a medical center in Korea. All patients meeting the criteria were enrolled into a prospective registry for long-term follow-up. 

All intervals of intrinsic or paced rhythms were manually measured from 12-lead ECG tracings without premature beats or significant baseline wander within 2 weeks after pacemaker implantation. The QT interval was taken from the earliest onset of the QRS complex to the end of the T-wave, where a line drawn following the down-sloping limb of the T-wave intersected the baseline; the QT was corrected for heart rate per Bazett's formula. 

Electrocardiography was performed 1 day, 2 weeks, 3 months, and every 6 months after implantation.

Duration

Enrollment: January 1995 to February 2013

Mean follow-up: 78 ± 51 months

Outcome Measures

Primary: new-onset LVSD (defined as LVEF < 40% or LV end-systolic dimension [ESD] > 40 mm if LVEF between 40-50%)

Secondary: cardiac mortality (death due to cardiac arrest or heart failure)

Baseline Characteristics

  

No LVSD (n= 438)

New-onset LVSD (n= 53)

 p-value

Age, years

 64 ± 14 65 ± 15 0.856

Male

 45% 70% 0.001

Comorbidities

Hypertension

Coronary artery disease

Atrial fibrillation

Previous valve surgery

 

44%

11%

24%

8%

 

49%

19%

23%

13%

 

0.559

0.105

1.000

0.196

Pacemaker indication

Sinus node dysfunction

Atrioventricular block

 

55%

45%

 

40%

60%

 0.041

Electrocardiography

QTc (intrinsic), ms

p-QTC, ms

QRS (intrinsic), ms

p-QRS, ms

LVEF, %

LV ESD, mm

 

441 ± 56

470 ± 51

104 ± 27

133 ± 36

64 ± 7

30 ± 5

 

456 ± 59

494 ± 39

115 ± 31

157 ± 35

59 ± 8

34 ± 6

 

0.078

< 0.001

0.008

< 0.001

< 0.001

< 0.001
There were no significant differences between the groups in terms of baseline medication use, pacemaker mode, right ventricular apical pacing, and percentage of right ventricular pacing.

Results

QTc Interval

 ≤ 450 ms (n= 160) 450-490 ms (n= 166) > 490 ms (n= 165)

New-onset LVSD

 4% 10% 19%

Cardiac death

 2% 4% 10%

New-onset LVSD or cardiac death

 5% 13% 21%

A total of 53 (11%) patients were identified who developed new-onset LVSD following pacemaker implantation.

A subgroup analysis based on p-QTc interval found a significant association between prolongation and new-LVSD (adjusted hazard ratio [aHR] 3.64; 95% confidence interval [CI] 1.29 to 10.3; p= 0.015). Similarly, there was a significant association between cardiac mortality and a prolonged p-QTc interval (aHR 5.89; 95% CI 1.22 to 28.5; p= 0.027).

The combined endpoint of new-LVSD or cardiac death had an aHR of 3.26 (95% CI 1.33 to 7.97; p= 0.010).

While the data was not presented, prolonged p-QRS followed the same trends.

Adverse Events

 N/A

Study Author Conclusions

 Prolonged p-QTc interval was closely associated with new-LVSD and cardiac death after permanent pacemaker implantation in patients with preserved LV systolic function. The rate of cardiac death significantly increased especially in patients who showed more p-QTc widening along with new-LVSD.

InpharmD Researcher Critique

This study is limited by the single-center, retrospective nature which is susceptible to confounding. The study included an Asian population, which may not be generalizable to an American population. The paced-QT interval was only corrected via Bazett's formula; Framingham, Nomogram, and Rautaharju formulae were not calculated. Baseline QTc and QRS were not available for all patients; the implications of intrinsic ECG parameters and their changes before and after the implantation were not evaluated.



References:

Cho EJ, Park SJ, Park KM, On YK, Kim JS. Paced QT interval as a risk factor for new-onset left ventricular systolic dysfunction and cardiac death after permanent pacemaker implantation. Int J Cardiol. 2016;203:158-163. doi:10.1016/j.ijcard.2015.10.128

 

Prolonged Ventricular Conduction and Repolarization During Right Ventricular Stimulation Predicts Ventricular Arrhythmias and Death in Patients With Cardiomyopathy

Design

Retrospective, single-center, observational study

N= 501

Objective

To evaluate whether prolonged ventricular conduction (paced QRS) and repolarization (paced QTc) times observed during ventricular stimulation predict ventricular arrhythmic events and death

Study Groups

Paced QRS duration ≤190 ms (n= 255)

Paced QRS duration >190 ms (n= 246)

Inclusion Criteria

Left ventricular (LV) dysfunction, underwent electrophysiological testing

Exclusion Criteria

Not disclosed

Methods

Patients undergoing electrophysiological testing during the study duration had duration changes in ventricular conduction and repolarization times during ventricular stimulation measured. Both baseline and paced QT intervals were evaluated at the same cycle length of 600 ms, then corrected for heart rate using the Bazett formula.

Included patients underwent programmed ventricular stimulation for induction of ventricular arrhythmias for diagnostic study (51.1%), ablation of supraventricular arrhythmia (12.8%), ablation of atrial fibrillation (1.8%), or ablation of ventricular extrasystoles or tachycardia (34.3%).

Duration

January 2002 through May 2014

Follow-up: until December 2014

Outcome Measures

Development of ventricular arrhythmic events, all-cause and cardiovascular death

Baseline Characteristics

  

Paced QRS duration ≤190 ms (n= 255)

Paced QRS duration >190 ms (n= 246)

  

Age, years

 65.5 ± 15.4 64.9 ± 11.7  

Male*

 191 (74.9%) 211 (85.8%)  

Comorbidities

Hypertension

Diabetes mellitus

Hyperlipidemia*

 

187 (73.3%)

75 (29.4%)

160 (62.7%)

 

183 (74.4%)

80 (32.5%)

192 (78.0%)

  

NYHA functional class*

I

II

III

IV

n= 249

76 (30.5%)

114 (45.8%)

57 (22.9%)

2 (0.8%)

n= 242

36 (14.9%)

117 (48.3%)

74 (30.6%)

15 (6.2%)

  

Drug therapy

ACE inhibitors

ARBs

Beta-blockers

Aspirin

Statin*

 

154 (60.4%)

44 (17.3%)

214 (83.9%)

182 (71.4%)

170 (66.7%)

 

157 (63.8%)

46 (18.7%)

229 (93.1%)

192 (78.0%)

197 (80.1%)

  

Electrocardiography

QRS duration (baseline), ms*

Paced QRS duration, ms*

QT interval, ms*

 

119.6 ± 30.6

168.0 ± 14.0

430.2 ± 54.1

 

155.7 ± 47.7

227.4 ± 35.4

480.3 ± 78.6

  

Echocardiography

LVEF, %*

LVEF <35%*

 

36.3 ± 8.8

114 (44.7%)

 

29.9 ± 9.3

180 (73.2%)

  

Abbreviations: ACE= angiotensin-converting enzyme; ARB= angiotensin receptor blocker; LVEF= left ventricular ejection fraction; NYHA= New York Heart Association

* p-value< 0.001

A total of 358 patients (71%) had, or subsequently underwent placement of, an implantable cardioverter-defibrillator (ICD).

Results

Paced QRS duration and ventricular arrhythmic events:

Paced QRS duration >190 ms patients had a higher risk of ventricular arrhythmic events vs. ≤190 ms patients (OR 5.7; 95% CI 3.7 to 8.9; p< 0.001). The Kaplan-Meier analysis of time to ventricular arrhythmic event found that >190 ms patients had significantly lower event-free survival vs. ≤190 ms patients (log-rank test, p< 0.001), regardless of the degree of left ventricular dysfunction.

Paced QRS duration and cardiovascular and all-cause death:

Risk of cardiovascular death was significantly higher for >190 ms patients vs. ≤190 ms patients (OR 2.2; 95% CI 1.3 to 3.8; p= 0.002). The Kaplan-Meier analysis of time to cardiovascular death found that >190 ms patients had significantly higher risk vs. ≤190 ms patients (log-rank test, p< 0.001).

Time to composite endpoint of all-cause death or ventricular arrhythmic event was significantly shorter in >190 ms patients vs. ≤190 ms patients (log-rank test, p< 0.001).

The risk of death or arrhythmias was 1.1 times higher per every 10-ms increase in paced QRS duration after adjusting for potential confounders (HR 1.1; 95% CI 1.04 to 1.13; p< 0.001). Similarly, >190 ms patients were associated with a higher risk of events (HR 2.12; 95% CI 1.5 to 3.0; p< 0.001).

A logistic regression analysis found that RV-paced QTc interval cutoff of 620 ms had a sensitivity of 59% and a specificity of 77% to predict ventricular arrhythmic events. 

Abbreviations: CI= confidence interval; HR= hazard ratio; OR= odds ratio

Adverse Events

Not disclosed

Study Author Conclusions

The present study found that prolonged paced QRS and paced QTc interval duration are associated with a higher risk of ventricular arrhythmias and death. Further studies are required to validate these findings and explore the role of these parameters for risk stratification of ventricular arrhythmias and sudden cardiac death.

InpharmD Researcher Critique

As the study is retrospective in nature, it may be subject to inherent biases, confounding variables, and potential missing data. Results were also obtained using intentional ventricular stimulation; patients were not already ventricularly paced.



References:

Del-Carpio Munoz F, Gharacholou SM, Scott CG, et al. Prolonged Ventricular Conduction and Repolarization During Right Ventricular Stimulation Predicts Ventricular Arrhythmias and Death in Patients With Cardiomyopathy. JACC Clin Electrophysiol. 2017;3(13):1580-1591. doi:10.1016/j.jacep.2017.06.003

 

Corrected QT in Ventricular Paced Rhythms: What Is the Validation for Commonly Practiced Assumptions?

Design

Prospective, observational study

N= 23

Objective

To investigate the accuracy of the commonly used clinical practice of subtracting 50 ms from the corrected QT (QTc) in ventricular paced rhythms

Study Groups

All patients (n = 23)

Inclusion Criteria

Aged >18 years who were followed in the pacemaker clinic after the implantation of the device, clinically stable outpatients in sinus rhythm with no change in their medications for at least 1 month prior to the investigation

Exclusion Criteria

Patients with an underlying QRS of >120 ms, atrial fibrillation, pacemaker dependence (such as a high-degree atrioventricular block), decompensated heart failure, or a recent history of atrial or ventricular tachyarrhythmia 

Methods

Four 12-lead ECGs were performed for each participant, with 2 taken at their native rate. The uncorrected QT interval in every patient was determined by identifying the maximum QT value among the 12 leads. A blinded investigator utilized Bazett's formula to compute the QTc for each ECG. The lead exhibiting the lengthiest QT interval was selected for the QTc calculation. The averaged QTc in the ventricular-paced rhythm was then compared with the non-ventricular-paced QTc for individual subjects.

Duration

Not specified 

Outcome Measures

 Mean difference in QTc between ventricular-paced and non-ventricular-paced 

Baseline Characteristics

  

All patients (n =23)

 

    

Age, years

 78 ±4      

Female

43%      

Results

ECG parameters (QRS duration, QT interval and RR interval) for the paced and nonpaced rhythms at slow and accelerated HR

Type of rhythm and HR

 Mean HR, bpm  Mean QRS duration, ms Mean uncorrected QT, ms Mean RR interval, ms

Nonpaced at slow HR

 66±8 85.3±8 410.4±9  0.94

Paced at slow HR

 66.8±8 135.7±12 450.4±13 0.92
Nonpaced at rapid HR 99.2±14 82.6±9 386.7±11 0.6
Paced at rapid HR 98.4±14 141.3±11 450.7±10 0.6

Mean QTc intervals for the nonpaced and paced rhythms at baseline and accelerated HR
  Mean nonpaced QTc, ms Mean paced QTc, ms Mean difference, ms (95% CI) p-value
Baseline HR of 66 bpm 424.15 472.43 48.27 (31.97–64.58) <0.001
Accelerated HR of 99 bpm 499.19 580.5 81.31 (35.8–126.82) 0.002
HR = Heart rate

Adverse Events

N/A

Study Author Conclusions

The QTc measurement during ventricular pacing confirms the current 50-ms subtraction assumption rule within a range of ±16 ms at an average heart rate of 66 bpm. However, at faster heart rates, the 50-ms adjustment may underestimate the QTc discrepancy between a wide and normal QRS.

InpharmD Researcher Critique

The study has limitations due to a small patient population and the reliance on a conceptual hypothesis for the QTc subtraction rule. Validation of its prognostic significance requires prospective studies. 



References:

Chakravarty S, Kluger J, Chhabra L, Ramu B, Coleman C. Corrected QT in ventricular paced rhythms: what is the validation for commonly practiced assumptions?. Cardiology. 2015;130(4):207-210. doi:10.1159/000370026

 

Nearly fatal ventricular arrhythmia following pacemaker implantation in a young female with complete heart block

Design

 Case report

Case presentation

A 24‐year‐old female patient with a past medical history of a complete heart block underwent dual‐chamber pacemaker implantation. No known family history of cardiomyopathy, conduction defects, neuromuscular disorders, long QT syndrome, or sudden cardiac death was documented. The device was programmed in DDD pacing mode at a lower rate of 50 beats per minute. An electrocardiogram prior to discharge showed sinus rhythm and a paced-QRS with a normal QTc (404 and 423 ms per Bogossian and Wang Formulas, respectively).

A few weeks post-implantation, the patient was admitted to the emergency department due to syncope occurring at rest, as well as convulsions secondary to the syncope. Although vital signs, physical examination, and lab markers were unremarkable, a 12-lead electrocardiogram revealed sinus rhythm and elevated paced‐QRS duration (136 ms vs. 130 ms post-implantation). T wave inversion in the inferior and chest leads with prolonged QTc (472 and 493 ms per Bogossian and Wang Formulas, respectively) were discovered, and pacemaker investigation revealed a prolonged episode of ventricular fibrillation or polymorphic ventricular tachycardia that lasted up to 2 minutes with spontaneous termination, triggered by late premature ventricular beats.

The patient was admitted to the intensive care unit for monitoring. After a discussion with the patient and family, a decision was made to upgrade her pacing system to a dual‐chamber defibrillator. The patient was recommended to undergo genetic testing, and was discharged on beta‐blocker therapy. No subsequent arrhythmic events occurred during a follow-up period of 3 months.

Study Author Conclusions

This case highlights other intriguing phenomena in the puzzle of cardiac repolarization and how pacing therapy may alter this complex process providing arrhythmic substrate in vulnerable subjects. Though such arrhythmic events are clinically rare, vulnerable patients or with suspected myocardial disease that may cause QT prolongation should be carefully followed in the course of pacing therapy.

 

References:

Ali H, Lupo P, Foresti S, et al. Nearly fatal ventricular arrhythmia following pacemaker implantation in a young female with complete heart block. J Arrhythm. 2019;35(5):766-769. Published 2019 Jul 18. doi:10.1002/joa3.12220