A 53-year old woman consulted our department for a second opinion concerning ventricular tachycardias. Initial presentation was with palpitations and vomiting. Her ECG showed remarkable low-voltage, echocardiography revealed normal dimensions and function of the left and right ventricle. Pericardial effusion was absent. She was not obese. Exercise testing was characterized by non-sustained monomorphic VT mainly during recovery.
Coronary artery disease was excluded by angiography. Laboratory tests were normal; no sign of infection or systemic disease. MRI showed normal function and motion of both left and right ventricle, however, there was pathologic gadolinium uptake in the left ventricle during DHE series.
The patient’s mother experienced palpitations at a younger age, one uncle from the mother’s side had died suddenly at the age of 45 years.
Fig 1.ECG of the patient
Fig.2 NSVT during recovery phase in exercise test
1. What could be the differential diagnosis in this patient?
2. Would you perform genetic testing at this moment and if so, what genes?
3. What is the origin of the attenuated R-amplitude on the ECG in this case?
4. How would you treat the patient?
Question 1: What could be the differential diagnosis in this patient?
Answer: The ECG pattern with micro voltages can be concordant with several clinical circumstances. It is seen with extreme obesity, pericardial effusion, myocarditis, massive ischemia or myocardial infarction, but none of these conditions was present in this patient. It can also be seen in cardiac amyloidosis and other metabolic or storage disorders, however in this patient there are no laboratory anomalies, normal systolic function, no signs of restrictive CMP on echocardiography, and in the case of amyloidosis one would expect more widespread heterogeneous myocardial enhancement with other supporting features of infiltrative myocardial disease on MRI. Rare endocrine disorders that can cause micro voltage ECG like myxoedema are excluded by normal lab results.
Question 2: Would you perform genetic testing at this moment and if so, what genes?
Answer: Patient has clearly pathological ventricular tachycardias and a family history of sudden death. Having excluded all above-mentioned possibilities using standard medical examination to explain these tachycardias, there is the rationale to perform genetic testing. Mutations in the lamin A/C gene, SCN5A, genes associated with ARVC can be considered. In addition, sympathetic activity seems to trigger the nonsustained VTs. This could suggest mutations in cardiac ryanodine receptor and calsequestrin 2, that have been associated with exercise related ventricular tachycardias. However, the clear micro voltage ECG suggests a mutation in the phospholamban (PLN) gene (ref 1). Indeed, genetic testing revealed that our patient is heterozygous for a c.40_42del (pArg14del) mutation in the gene encoding PLN, a transmembrane protein that, in its dephosphorylated state, inhibits the sarcoplasmic reticulum calcium ATPase (SERCA2a). Deletion of PLN Arg-14 (PLN-R14Del) is associated with inherited human DCM and premature death. Some of the heterozygous individuals develop mild left ventricular dilation and dysfunction with frequent ventricular extra systolic beats and ventricular tachycardia episodes, leading to progressive left ventricular dilatation and heart failure.
Question 3: What is the origin of the attenuated R-amplitude on the ECG in this case?
Answer: The most striking phenotype among PLN-R14Del carriers is the attenuated R amplitude on ECG. The fact that these features are not observed in relatives negative for the mutation indicates a mutation-associated phenotype irrespective of the presence or absence of echocardiographic abnormalities. Significant QRS amplitude attenuations are related to left ventricular late gadolinium enhancement in cardiac magnetic resonance imaging study. Therefore, cardiac fibrosis may represent the electro-anatomic substrate for low R amplitudes. Cardiac fibrosis and scar tissue are common findings in patients with DCM and are mainly considered secondary phenomena. However, in this patient, there is preserved cardiac function together with significant late gadolinium enhancement. The early presence of cardiac fibrosis in the absence of cardiac dysfunction would make fibrosis as a secondary process in reaction to the loss of cardiomyocytes less likely. In contrast, PLN mutations seem to trigger primary cardiac fibrosis ultimately leading to heart failure or arrhythmias.
Question 4: How would you treat the patient?
Answer: The pathophysiology of mutations in PLN, as those in cardiac ryanodine receptor and calsequestrin 2 are most likely related to disturbed calcium homeostasis in the ventricular myocyte. The relation to exercise suggests disturbances that are under influence of sympathetic activity, which is known to modulate calcium trafficking in the cardiac myocyte. Therefore, beta-blockade seems quite rational. At the time of presentation at our department, the patient was already on beta blockers and indeed this was quite effective as there were no long NSVTs anymore. Holter monitoring now only showed solitary monomorphic PVB with LBBB configuration, originating from the RVOT (Fig.1). An ICD is not indicated as there is no syncope, preserved left ventricular ejection fraction, no more NSVTs under beta-blockade and normal left ventricular dimensions.
Genetic deletion of arginine 14 in phospholamban causes dilated cardiomyopathy with attenuated electrocardiographic R amplitudes. Posch MG, Perrot A, Geier C, Boldt LH, Schmidt G, Lehmkuhl HB, Hetzer R, Dietz R, Gutberlet M, Haverkamp W, Ozcelik C. Heart Rhythm. 2009 Apr;6(4):480-6. Epub 2009 Jan 18.
PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing. Am Heart J. Jan161(1):165-71Landstrom AP, Adekola BA, Bos JM, Ommen SR, Ackerman MJ. Am Heart J. 2011;161:165-71.
Focused : Update on the use of devices in heart failure 2010. European Society of Cardiology. http://spo.escardio.org/eslides/view.aspx?eevtid=40&fp=220.
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