A Suspected Case of Left Dominant Arrhythmogenic Cardiomyopathy

Gaurav Surana MBBS MD, Arjun Susar MBBS MD, and  Nikhil Borikar MBBS MD
TNMC & BYL Nair Charitable Hospital, Mumbai Central, Mumbai, Maharashtra, India

CLINICAL HISTORY:

A 39 year old male with a history of chronic oral tobacco use presented to emergency department with palpitations lasting 30 minutes. He denied chest pain, breathlessness, syncope, fever, or similar prior symptoms. He is addicted to tobacco chewing, requiring 2 pouches per day since the past 15 years. His medical history was otherwise unremarkable. His family history did not reveal any heart disease or sudden cardiac death (SCD). ECG (Figure 1) revealed wide complex tachycardia with extreme axis deviation suggestive of ventricular tachycardia, which reverted to sinus rhythm after intravenous amiodarone 150 mg bolus. Echocardiography revealed hypokinesia of the mid to distal anterior and septal myocardium with left ventricular ejection fraction (LVEF) of 40%. Right ventricle (RV) was normal in size and function. In view of his acute presentation, tobacco chewing addiction and echocardiogram findings, coronary angiography was immediately performed and was normal. He was started on medical management in the form of aspirin 75 mg, rosuvastatin 20 mg, amiodarone 200 mg daily.  He declined further workup and was discharged to outpatient follow-up. After one month, he noted during clinic follow-up persistent symptoms of intermittent palpitations and dizziness. ECG was suggestive of multiple ventricular premature complexes and on echocardiogram LVEF remained mildly reduced. Therefore, his clinicians referred him for CMR to further evaluate the etiology of heart failure (HF) with mildly reduced LVEF and ventricular arrhythmia.

Figure 1.  Twelve lead ECG at presentation(top)and on follow-up(lower). Presentation (top) ECG shows ventricular tachycardia. Follow-up (lower) ECG shows normal sinus rhythm with multiple premature ventricular contractions.

 

CMR FINDINGS:

He underwent CMR with 3T Digital MRI (Mahajan Imaging, Nagar, New Dehli, India). Steady state free precision (SSFP) cine images showed normal LV chamber size (LV end-diastolic volume indexed was 91.6 ml/m2) with moderate global LV hypokinesia with LVEF of 35% (LV end-systolic volume indexed was 59 ml/m2). The RV was normal with RVEF 55%. On SSFP, areas of hyperintensity were noted in the mid-myocardium of the lateral and septal LV suggestive of fatty infiltration (Figure 2 andMovie 1).

Figure 2.  SSFP four chamber view (A), three chamber (B) and basal short axis (C) respectively shows areas of possible fibrofatty infiltration in the interventricular septum (IVS) and free wall (arrows).

 

Movie 1.  SSFP four chamber and three chamber show areas of possible fibrofatty infiltration in the interventricular septum (IVS) and free wall.

On late gadolinium enhancement (LGE), different views showed ring-like sub-epicardial enhancement in the LV wall and mid-myocardial LGE in the interventricular septum suggestive of fibrofatty infiltration. (Figure 3 and Movie 2).  Myocardial mass was normal (82.89 g) with LGE mass of 9.77 g (12% of myocardial mass).  The global native T1 was normal at 1233 ms (normal T1 range on local scanner is 1250 +/- 20 ms for males and 1280 +/- 18 ms for females) and T2 was slightly low at 38 ms (normal T2 value on local scanner is 50 +/-10 ms). First pass stress myocardial perfusion did not identify significant perfusion defects.

Figure 3. Late gadolinium enhancement LV two chamber (A), mid short axis (B), four chamber (C), and LV three chamber (D).  There is patchy epicardial LGE present in the basal to mid anterior walls and apical inferolateral wall (arrows) and mid-myocardial LGE of the basal to apical septal walls (arrows).

Movie 2. Late gadolinium enhancement stack LV three chamber, four chamber, and short axis.  There is patchy epicardial LGE present in the basal to mid anterior walls and apical inferolateral wall and mid-myocardial LGE of the basal to apical septal walls.

 

CONCLUSION:

CMR findings were suggestive of left dominant arrhythmogenic cardiomyopathy (ACM). In view of his presentation with VT and extensive LGE on CMR, he was advised of class I indication for secondary prevention implantable cardioverter defibrillator (ICD) and promptly underwent implantation. He was started on guideline directed medical therapy (GDMT) for HF with reduced LVEF in the form of angiotensin receptor neprilysin inhibitor, metoprolol, eplerenone, and dapagliflozin. Genetic testing was advised but he declined.  In follow-up, he has symptomatically improved with slightly improved LVEF on echo and no evidence for recurrence of VT on ICD interrogation.

PERSPECTIVE:

The differential diagnosis of fibrofatty lesions within the LV myocardium with systolic dysfunction presenting with VT include dilated cardiomyopathy (DCM), myocarditis, sarcoidosis and duchenne muscular dystrophy (DMD).[4] The normal LV size with extensive subepicardial and midmyocardial LGE ruled out DCM. In myocarditis, LGE can be sub-epicardial and mid-myocardial with a focal and patchy distribution, but is not typically as extensive as in our case. Moreover, there was also no preceding acute febrile illness or viral prodrome, no signs and symptoms of connective tissue disease, and no prior vaccination history. In sarcoidosis, LGE is patchy and commonly located in basal septum and RV insertion points, which was not seen in our case. Systemic examination excluded DMD. Such CMR features narrowed our diagnosis to left dominant ACM after exclusion of other diseases.

Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease characterized by substitution of the ventricular myocardium by fibrofatty tissue.[1] The disease was originally termed ARVC, a condition which distinctively affected the RV and predisposed to fatal ventricular arrhythmias.[2] LV involvement by ACM may be present in advanced ARVC. However, left dominant ACM is rare (although with increasing reports coinciding with increased CMR utility) and unlike ARVC, it lacks the specific diagnostic criteria, making its diagnosis much more challenging.[3] The current classification of ACM includes predominant RV involvement and no LV abnormalities (‘dominant-right’ variant), equal involvement of both ventricles (‘biventricular’), or predominant LV involvement with no or minor RV abnormalities (‘dominant-left’).[4,5] According to the 2020 International Padua Criteria, the diagnosis of each phenotypic variant of ACM requires that at least one criterion from morpho-functional ventricular abnormalities or structural myocardial abnormalities, either major or minor, is met.[6]

PARAMETERS	CRITERIA FOR LV INVOLVEMENT
I. Morpho-functional ventricular abnormalities	By 2D echocardiogram, CMR or angiography: Minor • Global LV systolic dysfunction (depression of LV EF or reduction of echocardiographic global longitudinal strain), with or without LV dilatation (increase in LV EDV according to the imaging test specific nomograms for age, sex, and BSA) Minor • Regional LV hypokinesia or akinesia of LV free wall, septum or both
II. Structural myocardial abnormalities	By CECMR: Major • LV LGE (stria pattern) of ≥1 Bull’s Eye segment(s) (in 2 orthogonal views) of the free wall (subepicardial or midmyocardial), septum or both (excluding septal junctional LGE)

CMR is not only useful for the diagnosis but also for risk stratification and prediction of adverse outcomes of patients with ACM. The septum is involved in more than half of the left dominant ACM cases on CMR, in comparison to advanced stage ARVC with LV involvement in which the septum was usually spared.[7]  Recent imaging studies reported that left dominant ACM predicted a worse prognosis compared with isolated RV disease or normal CMR.[8] Myocardial LV fat infiltration is easily detected in left dominant ACM as the wall thickness is greater than the RV, and may exhibit a specific bite-like pattern in PKP2 mutations.[9] T2 sequences are generally not recommended, however, they can be useful in ACM patients with a myocarditis like presentation which is common in DSP gene mutation.[5, 10]

The appropriate management strategy for left dominant ACM is not completely established.[11] Restriction of sports activity and prophylactic β-blocker therapy are indicated to prevent ‘adrenergic dependent’ ventricular arrhythmias. Only the implantation of an ICD has been proven to successfully prevent sudden cardiac death (SCD) by interrupting potentially lethal ventricular arrhythmias.[12] Patients with advanced left dominant ACM and severe systolic dysfunction are treated with the traditional heart failure therapy. Heart transplantation is the final therapeutic option for those patients with end stage and unresponsive congestive heart failure or VT/ventricular fibrillation storms refractory to ablation and/or ICD therapy.[12]

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REFERENCES

1. Corrado D, Basso C, Judge DP. Arrhythmogenic cardiomyopathy. Circ Res 2017; 121: 784–802.
2. Corrado D, Link MS, Calkins H. Arrhythmogenic right ventricular cardiomyopathy. N Engl J Med 2017;376:61–72.
3. Norman M, Simpson M, Mogensen J, Shaw A, Hughes S, Syrris P, et al. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation 2005; 112: 636–42. doi: https://doi.org/10. 1161/CIRCULATIONAHA.104.532234
4. Corrado D, van Tintelen PJ, McKenna WJ, et al. Arrhythmogenic right ventricular cardiomyopathy: evaluation of the current diagnostic criteria and differential diagnosis. Eur Heart J 2020;41:1414–29
5. He J, Xu J, Li G, Zhou D, Li S, Zhuang B, Chen X, Duan X, Li L, Fan X, Huang J, Yin G, Jiang Y, Wang Y, Zhao S, Lu M. Arrhythmogenic Left Ventricular Cardiomyopathy: A Clinical and CMR Study. Sci Rep. 2020 Jan 17; 10(1):533
6. Corrado D, Basso C. Arrhythmogenic left ventricular cardiomyopathy. Heart 2022;108:733–743
7. Sen-Chowdhry S, Syrris P, Prasad SK, Hughes SE, Merrifield R, Ward D, et al. Leftdominant arrhythmogenic cardiomyopathy: an under-recognized clinical entity. J Am Coll Cardiol 2008; 52: 2175–87
8. Lie Øyvind H, Rootwelt-Norberg C, Dejgaard LA, et al. Prediction of life-threatening ventricular arrhythmia in patients with arrhythmogenic cardiomyopathy: a primary prevention cohort study. JACC Cardiovasc Imaging 2018;11:1377–86
9. Zghaib, T.; Te Riele, A.S.J.M.; James, C.A.; Rastegar, N.; Murray, B.; Tichnell, C.; Halushka, M.K.; Bluemke, D.A.; Tandri, H.; Calkins, H.; et al. Left ventricular fibro-fatty replacement in arrhythmogenic right ventricular dysplasia/cardiomyopathy: Prevalence, patterns, and association with arrhythmias. J. Cardiovasc. Magn. Reson. 2021, 23, 58
10. Bourfiss, M.; Prakken, N.H.J.; van der Heijden, J.F.; Kamel, I.; Zimmerman, S.L.; Asselbergs, F.W.; Leiner, T.; Velthuis, B.K.; Te Riele, A.S.J.M. Diagnostic Value of Native T1 Mapping in Arrhythmogenic Right Ventricular Cardiomyopathy. JACC Cardiovasc. Imaging 2019, 12, 1580–1582
11. Corrado D, Wichter T, Link MS, et al. Treatment of arrhythmogenic right ventricular cardiomyopathy/dysplasia: an international Task force consensus statement. Eur Heart J 2015;36:3227–37
12. Gilljam T, Haugaa KH, Jensen HK, et al. Heart transplantation in arrhythmogenic right ventricular cardiomyopathy – Experience from the Nordic ARVC Registry. Int J Cardiol 2018; 250:201–6

Case prepared by:
Eddie Hulten, MD, MPH, FACC, FACP, FSCMR, FSCCT, FASNC
Lifespan Cardiovascular Institute, Rhode Island, the Miriam and Newport Hospitals
Warren Alpert Medical School, Brown University