Focal Atrial Tachycardia During Central Gemcitabine Administration

Abstract

Background

Gemcitabine is not usually regarded as a cardiotoxic or significantly arrhythmogenic chemotherapeutic agent.

Case Summary

A 66-year-old woman developed narrow complex tachycardia immediately after gemcitabine administration via peripherally inserted central cannula. Electrophysiological study diagnosed a focal atrial tachycardia arising from the right atrium adjacent to the tip of the central cannula line abutting the atrial wall. The arrhythmia was successfully ablated with no symptom recurrence.

Discussion

This case suggests that gemcitabine can be arrhythmogenic in combination with improper central line sites. The patient had received gemcitabine previously via a different line without sequalae.

Take-Home Messages

Gemcitabine has the capability to be directly arrhythmogenic. Centrally placed lines can abut the endocardium or vascular endothelial surface, which may counteract the intention to dilute therapeutic agents in large volumes of blood. A clear temporal relationship between symptom and medication should prompt consideration of the therapeutic as the causative agent.

Graphical Abstract

Case Summary

A 66-year-old woman presented with weekly episodes of rapid palpitations with sudden onset and offset. The initial episode occurred at rest immediately after administration of gemcitabine chemotherapy prescribed for a relapse of metastatic pancreatic adenocarcinoma. Electrocardiogram demonstrated a narrow complex tachycardia (Figure 1), which was successfully managed with Valsalva maneuver. Chemotherapy had been delivered over 30 minutes as an intravenous infusion via a peripherally inserted central cannula (PICC), which had been inserted 2 weeks prior. Results of 24 hour ambulatory monitoring and echocardiography were unremarkable.

Take-Home Messages

• •Gemcitabine has the capability to be directly arrhythmogenic.
• •Centrally placed lines can abut the endocardium or vascular endothelial surface, which may counteract the intention to dilute therapeutic agents in large volumes of blood.
• •A clear temporal relationship between symptom and medication should prompt consideration of the therapeutic as the causative agent.

Figure 1.

Initial 12-Lead Electrocardiograms

ECGs demonstrating (Top) normal sinus rhythm without evidence of overt accessory pathway and (Bottom) narrow complex tachycardia at a rate of 155 beats/min. P waves are seen in leads I, II, and aVF. There is limb lead reversal in the ECG taken during tachycardia. ECG = electrocardiogram.

Before her presentation, the patient had no cardiac symptoms or cardiac history. She had been diagnosed with pancreatic adenocarcinoma in 2017, which was treated with pancreatosplenectomy and neoadjuvant gemcitabine and nab-paclitaxel intravenously. Local recurrence in 2018 was treated surgically, and lung metastases in 2020 were treated with radiotherapy and chemotherapy. Surveillance computed tomography performed 4 weeks before presentation had demonstrated spread to mesenteric nodes and the lungs, prompting initiation of further gemcitabine chemotherapy. Concomitantly, she was being considered for an early-phase clinical trial involving a novel agent directed against E-type prostanoid receptor 4 for advanced solid malignancies.

Atrioventricular (AV) nodal re-entrant tachycardia was suspected, and an invasive management strategy providing definitive treatment was preferred, as regular arrhythmia episodes excluded participation in the clinical trial. The patient underwent an urgent elective invasive electrophysiology study under conscious sedation. A 4-wire study (decapolar catheter in the coronary sinus, quadripolar catheters to the right ventricular apex and high right atrium, and a CRD-2 catheter across the AV junction) was undertaken. Baseline intervals were unremarkable. There was no ventriculoatrial (VA) conduction at baseline. Decremental antegrade AV conduction without evidence of dual AV node physiology was documented. Antegrade extrastimulus pacing comprising a drive train of 8 beats at 600 ms with an extrastimulus at 440 ms induced a narrow complex tachycardia with a cycle length of 320 ms. The tachycardia had a 1:1 VA relationship, and the coronary sinus catheter demonstrated proximal-to-distal activation. The earliest atrial signal was on the high right atrial catheter (Figure 2). Isoproterenol infusion was commenced, after which VA conduction was present. Overdrive entrainment pacing from the right ventricular apical catheter during tachycardia successfully accelerated the atrial activation and after cessation of pacing yielded a VAAHV response, after which a diagnosis of atrial tachycardia (AT) was made.

Figure 2.

Intracardiac Electrograms Showing Ventricular Overdrive Pacing During Tachycardia of Cycle Length 380 ms

The atrial rate is accelerated to the paced cycle length of 360 ms, and on cessation of right ventricular pacing, a VAAHV response is observed along with resumption of the tachycardia (cycle length: 380 ms). Observation of first ventricular signal, then atrial signals on the high right atrial and the His catheters, followed by His signal and further ventricular signal, is the VAAHV response seen here that is indicative of atrial tachycardia. During tachycardia (on the right of the image), high right atrial signals are leading, followed by His-proximal and CS-proximal signals. CS activation is concentric, with proximal (CS 9-10)–to–distal (CS 1-2) activation. CS = coronary sinus.

Activation mapping during tachycardia with a multipolar catheter referenced to the coronary sinus signals was performed. The earliest activation of the tachycardia was localized to the lateral right atrium, adjacent to the tip of the PICC via which gemcitabine had been delivered (Figures 3 and 4). Fluoroscopically, the tip of the PICC line appeared to be lying against the atrial border on both anteroposterior and right anterior oblique views. In this region, bipolar voltage was reduced both in tachycardia and in sinus rhythm. Complex and fractionated atrial signals were seen surrounding the area of earliest activation. The total surface area of reduced bipolar voltage was 0.8 cm² (<0.05 mV). At the point of earliest activation, pure negative deflections were seen on the unipolar electrograms.

Figure 3.

Three-Dimensional Electroanatomical Images Showing Activation Timing Map and Voltage Map on Right Atrial Geometry

(Top) Right lateral view with activation timing with a pin at the point of earliest activation, with the corresponding electrograms shown to the right. (Bottom Left) Modified right lateral view with activation timing color overlay showing the location of ablation lesions colored as per ablation index. (Bottom Right) Bipolar voltage map (0.05-0.5 mV) with a focus of low voltage (<0.05 mV; in red) in the right lateral atrium that corresponded to the tip of the PICC line on fluoroscopy (blue arrow). PICC = peripherally inserted central cannula.

Figure 4.

Fluoroscopic and Electroanatomical Images Showing the Ablation Catheter Relative to the Tip of the PICC Line

(Top) Fluoroscopic RAO and AP projections with quadripolar high right atrial, decapolar coronary sinus, multipolar mapping catheter in the mid cavity, and ablation catheter at the tip of the PICC catheter, where the first ablation lesion was delivered. The blue arrows indicate the PICC line, which appears to be abutting the atrial wall. (Bottom) Electroanatomical RAO and AP views in “glass mode” showing the ablation lesion locations mirroring the position of the catheters in the fluoroscopic images above. AP = anteroposterior; PICC = peripherally inserted central cannula; RAO = right anterior oblique.

Power-controlled, temperature-limited ablation was delivered with a ThermoCool SmartTouch SF D,F curve-irrigated catheter (Biosense Webster) at a power of 40 W, targeting a contact force of 10 to 20 g and an ablation index of 450. The tachycardia terminated within the first second of the first ablation lesion. Further consolidation lesions were delivered to the adjacent low-voltage tissue with complex fractionated signals. After delivery of ablation and a 15-minute waiting period, aggressive stimulation with burst pacing, incremental atrial pacing, and atrial extrastimulus pacing both with and without isoproterenol provocation did not induce any further arrhythmias.

On re-review of the patient's original transthoracic echocardiogram, which was performed after PICC line insertion, there appeared to be an artifact in the lateral right atrium that could be representative of the PICC line tip (Figure 5, Video 1).

Figure 5.

Transthoracic Echocardiography With Artifact

Transthoracic echocardiography 4-chamber view with artifact in the lateral right atrium (arrows), which may represent the PICC line against the lateral right atrial wall. The artifact is more easily appreciated in Video 1.

During follow-up, the patient experienced complete resolution of her palpitations, and repeat ambulatory cardiac monitoring did not reveal any arrhythmias. Gemcitabine was discontinued in preparation for initiation of the trial therapy. However, in the intervening period, the patient developed biliary sepsis with obstruction, requiring hospital admission and biliary stent placement. The patient's course was further complicated by COVID-19 infection delaying initiation of trial therapy. Repeat cross-sectional imaging demonstrated advancement of the disease. Coupled with deterioration in the patient's functional capacity, she was unfortunately no longer eligible for clinical trial participation. A palliative approach was adopted, and the patient succumbed to the malignancy 6 months after the ablation procedure.

Discussion

Gemcitabine is a cytidine analog that inhibits elongation of DNA and is used in the treatment of multiple solid cancers. It is not typically regarded as a cardiotoxic chemotherapeutic agent, though can cause side effects of interstitial pneumonitis, hepatic injury, and pancytopenia, in addition to more generalized bowel and systemic symptoms.

Mechanisms of Arrhythmogenesis

There are 3 putative mechanisms of arrhythmogenesis. The first is mechanical interaction between the right atrium and the tip of the PICC, and this is a recognized complication of centrally placed lines, occurring almost universally at the time of line placement.1, 2, 3, 4 In the current case, it would be very coincidental that the tachycardia would initiate only at the time of medication administration, rather than during line placement. When examining the literature, there is only a single report in which tachycardia was also invasively mapped to the central venous catheter tip, and symptomatic response was refractory to ablation and was only achieved after re-siting the central venous catheter.⁴ This contrasts with the successful ablation seen in this case. Overall, these make purely mechanical effects of the line less likely.

The second explanation is that the AT is unrelated to either the PICC line or the gemcitabine. The absence of previous cardiac symptoms or arrhythmias, timing with gemcitabine administration, and origin at the PICC line tip make this implausible.

The third explanation is that gemcitabine via PICC line administration was the driving factor behind the AT in this case. The origin at the PICC tip and timing of the tachycardia link both the gemcitabine and the line to the arrhythmia. The intention with PICC lines is to dilute the therapeutic agent in a larger volume and flow of blood than would be achievable with peripheral administration. From the fluoroscopic images (Figure 4) and the transthoracic echocardiography (Figure 5, Video 1), the tip of the PICC line appears to lie directly against the lateral atrial wall, with the suspicion that the distal lumen of the line is partially occluded by myocardial tissue. Such a configuration would result in slower gemcitabine transit and dilution, and as a result this localized tissue may have been exposed to higher than intended concentrations of gemcitabine, accounting for the reduced atrial bipolar voltage amplitude and emergence of focal AT from the region. This could explain why a chemotherapeutic agent that has only a weak association with arrhythmogenesis, and indeed one that the patient had received previously without any complication, had direct association with the initiation of AT in this instance.

Overall, although it is not possible to definitively identify the cause, there is a balance of probabilities that should be considered. Given the timing of events (Figure 6), purely mechanical action of the PICC or spontaneous tachycardia are less likely. The arrhythmia origin at the tip of the line provides a logical explanation that the combination of the gemcitabine via its delivery in the PICC line resulted in the clinical scenario. This hypothesis connects together the patient's background and presentation with the procedural findings. With Occam's razor in mind, the explanation proposed provides the fewest assumptions and the simplest explanation of the case summary and clinical findings.

Figure 6.

Timeline Demonstrating the Events in the Case Described

The timeline highlighted in red indicates when the patient experienced paroxysmal episodes of palpitations (after gemcitabine was administered in this cycle until successful ablation of the tachycardia). PICC = peripherally inserted central cannula; SVT = supraventricular tachycardia.

Management of the Atrial Tachycardia

In the current case, the AT was ablated, although an alternative management option could have been to reposition the PICC line. In this case the driving factor behind ablation was patient and physician preference for a more definitive solution to facilitate recruitment into the clinical trial. Mobilization of the line and monitoring for further symptoms may have resulted in delays in the patient's ongoing oncological therapy. The desire to avoid a repeat procedure, which was poorly tolerated, further contributed to the decision to ablate the AT.

Gemcitabine and Arrhythmogenesis

Literature reviews have indicated that there may be an otherwise under-appreciated increase in cardiovascular mortality associated with gemcitabine.^5,6 Hilmi et al⁶ have described a possible increased incidence of atrial arrhythmias, occurring most commonly within 30 days of administration. The incidence of supraventricular arrhythmia (SVT) was 0.65%, with the majority being atrial fibrillation rather than organized arrhythmias.⁶

There is a single case report describing gemcitabine causing SVT.⁷ As in the current case, the SVT occurred immediately after central administration of gemcitabine. It was managed conservatively with beta-blockers, and so a formal diagnosis of the mechanism of tachycardia was not reached, although it did not recur after cessation of gemcitabine.⁷

Gemcitabine has been shown to facilitate hERG channel downregulation, which is responsible for the plateau phase of the cardiac action potential. However, this process takes days to weeks and would not explain the concomitant administration and arrhythmia as seen in this case.⁸ An alternative explanation is that gemcitabine has caused direct myocardial damage via its antineoplastic mechanism of masked chain termination of DNA, thereby causing apoptosis and scar formation and providing substrate for micro-re-entry.

Conclusions

This case demonstrates a clear association between gemcitabine, the PICC line, and the patient's arrhythmia. Despite only a weak association with arrhythmogenesis, gemcitabine delivery via the PICC line is the likely culprit for the tachycardia described.

Funding Support and Author Disclosures

Support was received from the Wellcome Engineering and Physical Sciences Research Council (EPSRC) Center for Medical Engineering at King's College London (WT 203148/Z/16/Z). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Video 1

Transthoracic Echocardiography 4-Chamber View With Artifact

The artifact in the lateral right atrium may represent the PICC line against the lateral right atrial wall.