Increase in right ventricular lead pacing threshold following stereotactic ablative therapy for ventricular tachycardia

Introduction

Key Teaching Points.

• •Stereotactic ablative radiotherapy is a novel treatment modality for ventricular arrhythmias refractory to medical therapy.
• •Early evidence is in the form of case reports and small observational studies.
• •This article discussed the first reported case of a cardiac implantable electronic device complication following radiotherapy for ventricular tachycardia, with a significant rise in the right ventricular lead threshold.
• •Device function must be monitored closely following this intervention.
• •Larger studies and registry data will be necessary to determine the prevalence of this complication.

Stereotactic ablative radiotherapy (SABR) is a novel treatment modality for ventricular arrhythmias (VA) refractory to medical therapy.¹ It has primarily been used in patients in whom conventional treatments, including antiarrhythmic drugs and catheter ablation, have failed to control ventricular tachycardia (VT). Cardiac SABR (cSABR) can also be used in cases where catheter ablation is contraindicated or attempts have been unsuccessful, as well as in patients deemed clinically unsuitable for ablation procedures, which can be prolonged and include periods of hemodynamic compromise.² This treatment is in its infancy, with the clinical body of evidence being from case reports,³ retrospective series,⁴ and small prospective studies,⁵ together totaling fewer than 100 patients.¹ As such, the available data on adverse treatment effects is limited. In this report, we describe the first observed case of an adverse effect on a cardiac implantable electronic device (CIED), characterized by an increase in right ventricular lead threshold post cSABR treatment.

Case report

The patient presented is a 69-year-old female patient with a past history of a tissue aortic valve replacement (AVR) in 1991 for infective endocarditis, followed by an aortic root replacement with coronary reimplantation in 1991 for recurrent infective endocarditis, a metallic bileaflet mitral valve replacement in 2000 for severe mitral regurgitation via a right thoracotomy, and a further redo metallic AVR plus 2-vessel coronary artery bypass graft in 2007 for homograft degeneration.

Other past history included permanent atrial fibrillation and severe left ventricular (LV) systolic dysfunction with an LV ejection fraction estimated at 32%. She was originally implanted with a secondary prevention dual-chamber implantable cardioverter-defibrillator (ICD) in 2000, and subsequently upgraded to a cardiac resynchronization therapy (CRTD) device in 2012 (generator: Pacesetter St Jude promote quadra CD3239-40; right ventricular [RV] lead: Durata 7120; LV lead: Quartet 1458Q; Figure 1A). Antiarrhythmic drug therapy included bisoprolol 5 mg twice daily (BID).

Figure 1.

Baseline data. A: Chest radiograph demonstrating the positions of the cardiac implantable electronic device, anteroposterior (left panel) and lateral (right panel) views. B: Twelve-lead electrocardiogram of clinical ventricular tachycardia (VT). C: Electrocardiographic imaging maps. Modified left anterior oblique (left panel) and anterior (right panel) views. The figure shows an activation map during induced VT. The scale is displayed on the left (activation time, ms). The map demonstrates that the VT originates from the posterolateral left ventricle wall. LAD = left anterior descending artery; MV = mitral valve; TV = tricuspid valve.

The patient presented with multiple episodes of VT (12-lead electrocardiogram displayed in Figure 1B), which were treated with antitachycardia pacing and shocks via her device. VT continued despite switching medical therapy to sotalol 40 mg BID, the patient having previously not tolerated amiodarone owing to medication side effects. Further uptitration of sotalol dose was limited by intolerable lethargy at this stage. She received a total of 3 shocks via her device before treatment. Following case review at both local and national multidisciplinary meetings, a plan was made to offer first-line cSABR therapy, as the presence of an AVR in the supracoronary position as well as a mitral valve replacement made access to the left ventricle technically difficult for catheter-based radiofrequency ablation.

She underwent noninvasive programmed stimulation with concurrent electrocardiographic imaging, which suggested the VT exit site was localized to the inferolateral LV wall (Figure 1C). She underwent cardiac computed tomographic imaging with late enhancement, which defined areas of myocardial scar in the apex, apical inferior, apical septal, and mid inferoseptal walls.

The radiotherapy treatment was planned by a multidisciplinary team including a clinical oncologist, cardiologist, and medical physicist/dosimetrist using previously described techniques,⁴ collating data from the electrocardiogram, electrocardiographic imaging, and cardiac computed tomographic imaging. As per the standard in the United Kingdom, the cSABR plan underwent national peer review by a multidisciplinary team who form part of the UK Cardiac SABR Consortium, comprising clinical oncologists, cardiologists, therapeutic radiographers, and medical physicists. The planning target volume is displayed in Figure 2. This is the volume that should be within the range of 95%–140% of the prescribed dose as per the 2019 UK SABR Consortium Guidance.⁶ The patient received 25 gray (Gy) in 1 fraction with no immediate complications. The maximum dose to the RV lead tip was 6.77 Gy to 0.01 cm³ (D_0.01cc). This met our institution protocol’s mandatory dose constraint of D_0.01cc < 12 Gy, but not the optimal dose constraint of D_0.01cc < 6 Gy. Treatment was performed with a volumetric arc technique using 6 MV photons delivered via a linear accelerator (Varian© Truebeam; Varian Medical Systems, Palo Alto, CA).

Figure 2.

Computed tomography images of the planning target volume (PTV) outlined in red with a color-wash view displaying dose distribution over the target: axial view (top left); coronal view (bottom left); sagittal view (bottom right); and 3-dimensional reconstruction (top right). The right ventricular lead tip is outlined in purple.

The patient underwent regular pacing clinic follow-up, via both home monitoring and in-person device interrogations (Figure 3 and Table 1). There was a subacute increase in RV lead threshold from 1.5 V at a pulse width (PW) of 1 ms, which peaked at 2.63 V (PW 1 ms) at day 41 post-treatment. At most recent follow-up (day 406 post-treatment) the threshold was 2.5 V (PW 1 ms).

Figure 3.

Right ventricular lead threshold (volts) vs time (blue line being day of stereotactic ablative radiotherapy treatment). The patient had a generator change in February 2022.

Table 1.

Right and left ventricular lead parameters pre- and post-radiotherapy

Day post-treatment	Right ventricular lead			Left ventricular lead
	Sensing (mV)	Threshold (V) @ pulse width (ms)	Impedance (ohms)	Sensing (mV)	Threshold (V) @ pulse width (ms)	Impedance (ohms)
-106	11.4	1.25 @ 1	380	2	1.25 @ 0.5	740
0	11.4	1.5 @ 1	390	2	1.25 @ 0.5	750
7	11.4	1.63 @ 1	360	2	1.13 @ 0.5	760
34	11.4	2 @ 1	360	2	1.25 @ 0.5	790
41	11.8	2.63 @ 1	390	2	1.25 @ 0.5	760
70	11.8	2.13 @ 1	390	2	1.25 @ 0.5	760
101	11.8	1.75 @ 1	390	2.25	1.25 @ 0.5	760
130	11.8	2.5 @ 1	390	2.25	1.25 @ 0.5	750
185	9.5	1.88 @ 1	380	2.25	1.25 @ 0.5	730
250	11.8	2.5 @ 1	410	2.25	-	790
349	11.8	1.63 @ 1	410	2.25	-	690
406	11.8	2.5 @ 1	440	2.5	1.5 @ 0.5	760

The LV lead threshold remained stable during follow-up at 1.25–1.5 V (PW 0.5 ms). The maximum dose to the LV lead tip was 6.76 Gy to 0.01 cm³. Plain chest radiographs showed no macroscopic RV lead displacement or fracture (Supplemental Figure S1).

In terms of clinical outcomes, following treatment, the sotalol dose was reduced to 40 mg once per day owing to side effects of lethargy. On day 117 post-treatment the patient experienced a prolonged VT episode requiring several bursts of antitachycardia pacing and 3 shocks. Sotalol was increased to 40 mg BID. On day 160 post-treatment the patient experienced a further episode of VT requiring shocks. At this stage, alternative potential treatments having been exhausted, sotalol was uptitrated to 160 mg BID and mexiletine 200 mg BID was initiated. The patient has since been free from VT requiring ICD therapy.

Discussion

cSABR is an emerging intervention that shows promise for the management of refractory VA and in some cases has been shown to provide valuable symptomatic benefit to a high-risk and comorbid group of patients who have limited or no other treatment options. The available data on the safety and efficacy of this technique are scarce. Here, we present a complication that is as yet unreported in the literature.

The effects of photon beam radiotherapy on cardiac tissue and its time course remain incompletely characterized. It has been studied in both animal models and human data collected from patients whose hearts have undergone histological analysis following cSABR treatment. Histopathological analysis in animal models indicates that cSABR may be expected to induce target site fibrosis, although the time course over which this develops is thought to be several months at the minimum.⁷ Histopathological studies from human subjects have demonstrated a range of acute effects on myocardial tissue, including subendocardial morphological necrosis and microvascular injury following cSABR.⁸ Preclinical studies have demonstrated that very high-dose radiation can induce acute conduction block in tissue such as the atrioventricular node, and clinical-range doses can induce atrioventricular block appearing after several months,⁷ while recent data suggest that 25 Gy single fraction irradiation can induce an acute and persistent increase in myocardial conduction velocity, via upregulation of connexin-43 and the Notch signaling pathway.⁹ Importantly, it has been consistently observed that the antiarrhythmic effect of cSABR precedes the time frame over which fibrosis is expected to develop.⁸ Acute, subacute, and chronic effects on tissue at the lead tip–myocardial interface may be expected to produce changes in the device sensing and stimulation threshold, although given the complex time course and uncertainty about the details of the tissue response to cSABR, these are difficult to predict. In addition, a direct effect of radiation on CIED hardware integrity is a possibility.¹⁰ The combination of any or all of these effects will result in the clinically observed impact on CIED parameters following irradiation. In this patient it is not possible to draw definitive conclusions regarding the mechanism of the observed increase in stimulation threshold; however, the time-course suggests an effect prior to when myocardial fibrosis occurs. The observed change in RV threshold may reflect the complex evolution of myocardial tissue changes in response to cSABR at the lead tip–myocardium interface or a direct effect on CIED hardware. No change in LV lead threshold was seen in this case, despite a similar radiation dose exposure. The reason for this is unclear. Different lead manufacturers and different lead tip–heart interfaces may be contributory, as the LV lead has an epicardial rather than myocardial interface.

The effect of radiotherapy on CIED performance is of great clinical importance, as SABR is a common treatment modality for prevalent conditions such as lung and breast cancer, and in CIED patients treated for these conditions a significant radiation dose may overlap with the device leads.

CIED malfunctions in the context of irradiation may result from the cumulative dose received, neutron-induced upsets, dose-rate effects, magnetic effects, and electromagnetic interference.¹¹ Device malfunction may be the result of any of these mechanisms and include transient device interference during treatment, such as inhibition of pacing or initiation of tachycardia therapies; device software malfunction, such as loss of diagnostic data or electronic reset; or permanent damage, such as loss of generator function. The most often reported impact of irradiation on CIED malfunction refers to cumulative dose effects.¹¹ Mouton and colleagues¹² demonstrated in an in vitro study that pacemaker malfunctions occurred at a wide range of doses. However, changes in CIED function seen with the lowest observed in their study, being at a cumulative dose of 0.15 Gy,¹² may be more likely the result of single event upset induced by photoneutrons, the risks of which are stochastic in nature and therefore not a reflection of total cumulative dose.¹² In line with observations such as this, neither Abbott nor Boston Scientific provides safe maximal doses that their devices can receive,¹³ nor does the Heart Rhythm Society consensus statement on radiation exposure in CIEDs.¹⁴ Medtronic has recommended maintaining the cumulative dose to their devices of <5 Gy. In the absence of a consensus on the maximum tolerated dose, a pragmatic cut-off of 2 Gy is usually recommended based on guidance from the American Association of Physicists in Medicine.¹¹ No guideline currently refers to the maximum dose that would be tolerated by device lead tip, an issue that may need addressing as cSABR become more a common treatment modality.

In this patient, the received dose of 6.77 Gy may be associated with an increase in lead threshold. Further information, likely in the form of registry data, is necessary to elucidate the strength of this association and whether other risk factors may contribute to post-treatment device function.

The importance of potential lead performance issues will be determined in due course as the prevalence of these complications becomes clearer with increasing patient numbers. The management of this risk will be dependent on the efficacy of cSABR for VT judged in larger clinical trials. This treatment involves balancing several risks and benefits. On a technical level, this includes the risk of potential adverse effects of radiotherapy to nontarget sites, including CIED complications, to ensure that the p is not compromised. From a wider perspective, the risk-benefit profile of SABR for the treatment of VT may be very different from other, more conventional uses, such as in lung cancer, where SABR efficacy is more well established. The appropriate functionality of ICDs is always of vital importance in this particular patient cohort, given the high VT burden. As such, adding to the body of evidence concerning CIED performance post cSABR is crucial as this intervention becomes more widespread. Of note, in this case, cSABR was offered as a potential alternative to escalated pharmacological therapy in a patient in whom medication side effects were impacting quality of life. Currently, cSABR efficacy has only been tested in observational trials as an adjunct to antiarrhythmic drug therapy rather than a replacement. During the shared decision-making process, it is vital that patients be appropriately counseled regarding the uncertainty of cSABR efficacy, given current sparsity of the evidence base, and are aware of the treatment risks, including the potential for rare events that have not yet been uncovered in the early development stages of this field. In its current form, cSABR is being used as a palliative procedure to reduce frequency of ICD therapy, with the understanding that it is likely to be safer than catheter ablation in this patient cohort, or as an alternative option where catheter ablation is not possible. A full appreciation of the risk profile, both common and rare, that will be gathered as treatment numbers increase will better inform our ability to effectively counsel our patients in this regard.