Hickam’s Dictum Rules When Chemotherapy and Premature Ventricular Contractions Prevail in a Patient with Chronic Lymphocytic Leukemia

CMR was performed on a 1.5T Philips Ingenia scanner with standard imaging protocol for cardiomyopathy. At the time of CMR, heart rate was 61 bpm, BMI 29 kg/m², and BSA 2.21 m². CMR revealed severely dilated LV (LV end-diastolic volume indexed (LVEDVi= 135 ml/m²), with moderately reduced systolic function (LVEF= 38%), global hypokinesis and intraventricular dyssynchrony (Movie 1). LV mass was normal (63 gm/m²), but hypertrabeculations were noted in the LV apex. The right ventricle (RV) was moderately dilated (RV end-diastolic volume indexed RVEDVi=135 ml/m²) with mildly reduced systolic function (RVEF= 38%) and hypertrabeculations in the apical RV.

Movie 1. Cine two chamber and four chamber views reveal biventricular dilatation, global hypokinesis and hyper-trabeculations in LV/RV apical cavity. There was mild mitral and tricuspid regurgitation and bi-atrial dilation.

On late gadolinium enhancement phase sensitive inversion recovery (LGE- PSIR) images, subendocardial late gadolinium enhancement (LGE) was noted in apical LV and RV (Figure 2, Movie 2).

On T1-mapping modified Look Locker Inversion recovery (MOLLI), the native T1 value was 1136 ms (abnormally elevated, normal value < 1050ms), extracellular volume (ECV) was elevated to 31% (normal ECV up to 29%) (Figures 3-5). On T2 weighted imaging there was evidence of myocardial edema. T2 mapping showed elevated T2 value of 65ms (normal T2 value < 60ms) (Figures 6,7). Strain Imaging with feature tracking revealed abnormal global longitudinal strain measuring -10.0% (normal cut off -13.9%, Movie 3 and 4).

Movie 2. LGE-PSIR images revealed subendocardial late gadolinium enhancement (LGE) in apical LV and RV. Figure 2: LGE-PSIR four chamber and mid short axis images show subendocardial LGE highlighted by arrows. Figure 3: Native T1 map with visual evaluation showing higher T1 values in septum, inferior and lateral wall. Figure 4: Segment-wise distribution of T1 values. Figure 5: Segment-wise distribution of extracellular volume (ECV) values. Figure 6: T2 Map showing edema in the septum and inferior wall.   Figure 7: Segment-wise distribution of elevated T2 values.     Movie 3 and 4. Two chamber and four chamber feature tracking CMR strain showing abnormal global longitudinal strain quantified as -10.0%.

 

Conclusion:

 

CMR suggested the development of cardiotoxicity related to zanubrutinib and venetoclax. Parametric mapping suggested presence of both interstitial fibrosis and myocardial inflammation as a result of drug toxicity. Biapical subendocardial LGE was likely related to subendocardial fibrosis from drug toxicity. This constellation of CMR findings favored dilated cardiomyopathy due to drug related cardiotoxicity. Both zabrutinib and venetoclax were stopped after the diagnosis on CMR and his CLL monitored off of therapy.

However, the patient was re-hospitalized a month later for heart failure decompensation when repeat ambulatory ECG monitoring showed episodes of sustained VT and increased PVC burden of 41%. This PVC burden was thought to be exacerbated from volume overload. He was treated with diuresis to his dry weight of 95 kg and his BNP improved to 364 pg/ml. Treatment was initiated with amiodarone loading followed by maintenance therapy. With treatment, his PVC burden improved, but remained significantly elevated at 18%.

Given the persistently high PVC burden despite metoprolol and amiodarone, the patient was offered catheter ablation of PVCs. On electroanatomic mapping two PVCs were identified.  PVC 1 was rare and mapped to the chordal insertion of the anterolateral papillary muscle. PVC 2 was common and mapped to the ventricular insertion of the posteromedial papillary muscle. Post-ablation, no recurrent PVCs were noted for 15min off of isoproterenol, and only multi-focal non-clinical PVCs were noted on isoproterenol (Figure 8). There were no procedural complications.  A repeat CMR after 2 years revealed persistent and similar extent of biventricular apical subendocardial fibrosis but overall improved cardiac function with LVEF of 50%. Overall patient was doing well without repeat hospitalizations.

Figure 8: PVC ablation map showing ablation of anterolateral and posteromedial papillary muscles.

 

Perspective:

A multi-modality diagnostic approach is often needed to diagnose the cause of a non-ischemic cardiomyopathy, particularly when it might be due to multiple etiologies. CMR can help delineate the etiology, and facilitates change in management when a specific etiology is identified. The principle of parsimony: “Occam’s razor” suggests that a single diagnosis is usually the explanation for complex presentations. However, in our patient, Hickam’s dictum (a patient can have as many diagnoses as they please) prevailed: We found two pertinent issues that contributed to this patient’s HFrEF. Both drug related cardiotoxicity and PVC induced cardiomyopathy were implicated.

Drug related cardiotoxicity:
Many anticancer drugs cause cardiotoxicity. Both zanubrutinib and venetoclax are used for treating CLL and can cause cardiotoxicity.  However, zanubrutinib, which is a highly selective BTK inhibitor can lead to fewer off-target cardiovascular adverse effects, such as atrial fibrosis and atrial fibrillation, than first generation BTK inhibitors.  In the ASPEN study, zanubrutinib had a 10-fold lower rate of atrial fibrillation or flutter than the first generation BTK inhibitor ibrutinib (p=0.0004).[1]  Atrial fibrillation (AF) -related tachycardia-induced cardiomyopathy can cause heart failure.[2] Current evidence to support a direct causal association between BTK inhibitors and ventricular arrhythmia and cardiomyopathy is only modest. Treatment-related cardiac arrhythmia was reported as a common cardiac adverse events in patients treated with zanubrutinib monotherapy (U.S. Food and Drug Administration, 2019b).[3] 

Our patient did not have AF or atrial scar on LGE imaging. He did, however, have VT. Venetoclax (VTX) targets the BH3 domain of Bcl-2 as a BH3 mimetic (Bcl-2 inhibitor) and induces the release of proapoptotic from Bcl-2 to restore apoptosis in malignant cells.  VTX treatment may cause cardiac injury with elevated cardiac enzymes. A increase in oxidative stress, as well as inflammatory and apoptotic markers are the main mechanisms that induce cardiac toxicity.[4]  Our CMR findings of dilated cardiomyopathy with elevated native T1 values likely from underlying interstitial fibrosis and elevated T2 value likely from myocardial inflammation and edema indicated VTX related cardiotoxicity. Thus, the decision to discontinue both these drugs in this patient.

PVC induced cardiomyopathy:
Premature ventricular complexes can cause LV dysfunction and heart failure. LVEF impairment can occur within 3 months of induced ventricular ectopy. Some of the explanations include increased repolarization heterogeneity, and ventricular dyssynchrony, analogous to that of left bundle branch block. Inefficient conduction leads to inefficient contraction and altered LV load distribution in the late-activated regions with altered myocardial blood flow.[5] PVC cardiomyopathy is a potentially reversible condition but requires the exclusion of other causes of cardiomyopathy. Predictors of PVC induced cardiomyopathy include consistency in PVC burden throughout the day, PVC burden >24 % and the presence of epicardial scar.[6]  The right ventricular outflow tract (RVOT) is the most frequent site of origin of idiopathic PVCs.[7] Other sites include myocardial extensions to the aortic and pulmonary cusps, interventricular septum, papillary muscles, free walls, or left ventricular fascicles. In a post-myocardial infarction population, frequent PVCs are associated with VT, ventricular fibrillation (VF), and predispose to sudden cardiac death. However, medical PVC suppression with certain anti-arrhythmic drugs can be pro-arrhythmic in the setting of LV scar, so should be undertaken cautiously.[8]  Improvement in LV function has been reported after suppressing PVCs with pharmacologic antiarrhythmic drugs or catheter ablation. The 2015 European Society of Cardiology guidelines state that, in patients with RVOT PVCs needing treatment, catheter ablation is recommended as first-line treatment, whereas in patients with left ventricular outflow tract (LVOT) PVCs, catheter ablation should be considered after failed AAD.[9]

The diagnosis of PVC induced cardiomyopathy includes the diagnosis of frequent and consistent PVCs, echocardiography with increased LV size, and impaired LV systolic function.[10] Cardiac MRI can evaluate for the presence of scar, rule out infiltrative diseases, detect arrhythmogenic cardiomyopathy with or without LV involvement.[11] A pre-procedural CMR guides in planning an ablation procedure by identifying the location and extent of scar to target for ablation.[12]

Our patient had a PVC burden of up to 40%. Elimination of cardiotoxic drugs, beta blockers, and amiodarone did adequately suppress PVCs. The PVCs in our patient may have been a symptom of the chemotherapy induced cardiotoxicity as PVC, VT and SCD are common with inflammatory cardiomyopathy as in this case with edema and abnormal T1/ECV). In our patient, CMR did not show epicardial scar or RVOT enhancement. Thus, a decision was taken to pursue endocardial ablation.  Electroanatomic mapping identified arrhythmogenic substrate, and ablation of PVCs lead to improvement in PVC burden.

Because LV function can be difficult to measure accurately by echocardiography in the context of very frequent PVCs, an echocardiogram immediately post-ablation or with adequate PVC suppression can clarify whether LV dysfunction is intrinsic or related to PVC related measurement issue. An immediate normalization of function suggests a PVC related measurement issue. However, persistent LV dysfunction after successful ablation that improves gradually over time (as was seen in our patient) indicates PVC-induced cardiomyopathy.[13] Our patient on short term follow-up showed improvement in symptoms. A follow up CMR after 2 years helped in characterization of scar evolution after ablation. Thus, this case highlights the strength of multidisciplinary approach with consideration to Hickam’s dictum in treating patients with non-ischemic cardiomyopathy.

Click here to view entire initial CMR on CloudCMR. Click here to view entire repeat CMR on CloudCMR.

 

References:

1. Tam CS, Opat S, D’Sa S, Jurczak W, Lee H-P, Cull G, et al. A randomized phase 3 trial of zanubrutinib versus ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136:2038–50.
2. Slamon D. J., Neven P., Chia S., Fasching P. A., De Laurentiis M., Im S.-A., et al. (2018). Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J. Clin. Oncol. 2018:20;36(24):2465-2472.
3. Jin Y, Xu Z, Yan H, He Q, Yang X, Luo P. A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors. Front Pharmacol. 2020;11:891.
4. AlAsmari AF, Alghamdi A, Ali N, Almeaikl MA, Hakami HM, Alyousef MK, AlSwayyed M, Alharbi M, Alqahtani F, Alasmari F, Alsaleh N. Venetoclax Induces Cardiotoxicity through Modulation of Oxidative-Stress-Mediated Cardiac Inflammation and Apoptosis via NF-κB and BCL-2 Pathway. Int J Mol Sci. 2022 Jun 2;23(11):6260.
5. Wang Y, Eltit JM, Kaszala K et al. Cellular mechanism of premature ventricular contraction-induced cardiomyopathy. Heart Rhythm. 2014;11:2064–72.
6. Baman TS, Lange DC, Ilg KJ et al. Relationship between burden of premature ventricular complexes and left ventricular function. Heart Rhythm. 2010;7:865–9.
7. Del Carpio Munoz F, Syed FF, Noheria A et al. Characteristics of premature ventricular complexes as correlates of reduced left ventricular systolic function: study of the burden, duration, couplinginterval, morphology and site of origin of PVCs. J Cardiovasc Electrophysiol. 2011;22:791–8.
8. Anderson JL, Rlatia EV, Hallstrom A et al. Interaction of baseline characteristics with the hazard of encainide, flecainide, and moricizine therapy in patients with myocardial infarction. A possible explanation for increased mortality in the Cardiac Arrhythmia Suppression Trial (CAST). Circulation. 1994;90:2843–52.
9. Priori SG, Blomstrom-Lundqvist C, Mazzanti A et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Ratients with Ventricular Arrhythmias and the Rrevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Eur Heart J. 2015;36:2793–867.
10. Delgado V, Ypenburg C, van Bommel RJ et al. Assessment of left ventricular dyssynchrony by speckle tracking strain imaging comparison between longitudinal, circumferential, and radial strain in cardiac resynchronization therapy. J Am Coil Cardiol. 2008;51:1944–52.
11. Latchamsetty RY, Yokokawa M, Morady F et al. Multicenter outcomes for catheter ablation of idiopathic premature ventricular complexes. JACC Clin Electrophysiol. 2015;1:116–23.
12. El Kadri M, Yokokawa M, Labounty T et al. Effect of ablation of frequent premature ventricular complexes on left ventricular function in patients with nonischemic cardiomyopathy. Heart Rhythm. 2015;12:706–13.
13. Panizo JG, Barra S, Mellor G, Heck P, Agarwal S. Premature Ventricular Complex-induced Cardiomyopathy. Arrhythm Electrophysiol Rev. 2018;7(2):128-134.

 

Case prepared by:
Avanti Gulhane, MD FSCMR
University of Washington