Novel mutation associated with non‐compaction ventricular myocardium: A case report

Left ventricular non-compaction (LVNC) is a rare structural cardiomyopathy characterized by persistent embryonic trabeculations within the left ventricle. This phenotype results from arrested compaction of the bilayered myocardium during fetal development, though the precise mechanisms driving excessive trabeculation remain incompletely elucidated.1 Consequently, a thin, compacted epicardial layer is juxtaposed with a thicker, spongy endocardial layer, which may or may not be accompanied by left ventricular dysfunction. LVNC exhibits substantial heterogeneity among patients. It can present asymptomatically or, in severe cases, with life-threatening arrhythmias, heart failure, thromboembolism and sudden cardiac death complications.2 Echocardiography and cardiovascular magnetic resonance (CMR) images are considered the reference standard for the diagnosis of LVNC. The diagnosis of cardiac ultrasound is based on the Jenni diagnostic criteria: typical two-layered structure of the myocardium with a thin, compacted outer (epicardial) band and a much thicker, non-compacted inner (endocardial) layer consisting of trabecular meshwork with deep endocardial spaces (the maximum end systolic ratio of the non-compacted endocardial layer to the compacted myocardium of >2 is characteristic).3 The diagnostic criteria for CMR imaging are the Petersen criteria: the ratio of the non-compacted to compacted myocardium (NC/C) layers of the myocardium as measured by CMR in diastole >2.3.4 LVNC is familial and is predominantly inherited in an autosomal dominant mode of inheritance, with other rare modes of inheritance being concomitant X-linked inheritance and autosomal recessive inheritance. To date, mutations in about 30 different genes have been identified in patients with LVNC. The most frequently implicated genes include TTN, HCN4, MYH7 and RYR2. Here we report a case of LVNC associated with a mutation in MYL2. A 57 year-old female presented to the emergency department with sudden chest pain for 1 h, presenting with persistent chest pain combined with profuse sweating and limb weakness. Her past medical history was negative for hypertension, diabetes mellitus and coronary heart disease. In the significant family history, her mother had hypertrophic cardiomyopathy (HCM). However, no detailed information regarding her mother's HCM was provided. Physical examination revealed a blood pressure of 102/57 mmHg, a heart rate of 69 beats per minute and no additional cardiac murmurs on auscultation. Upon admission, the electrocardiogram (ECG) indicated sinus rhythm, ST segment changes in leads V5–V6 and T wave change in I, aVL (Figure 1). Laboratory tests showed high-sensitivity troponin T at 0.196 ng/ml (normal range: <0.014), troponin I at 0.719 ng/mL (normal range: <0.034), N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1266 pg/mL (normal range: <300), uric acid at 569 μmol/L (normal range:149–506), haemoglobin at 132 g/L (normal range:115–150), and creatinine at 77 μmol/L (normal range:46–92). The white blood cell count and high-sensitivity C-reactive protein levels are within the normal range. The patient underwent a bedside two-dimensional echocardiogram, which revealed segmental hypokinesis of the left ventricular wall, with normal left ventricular systolic function, mild mitral regurgitation and a left ventricular ejection fraction of 58%. Doppler ultrasound of both lower limbs (femoral, popliteal and tibial veins) showed no evidence of deep vein thrombosis. Chest radiograph (posteroanterior view) demonstrated absence of pulmonary oedema (e.g., Kerley lines, peribronchial cuffing), pneumonic consolidation or pleural effusion; however, cardiomegaly was present with a cardiothoracic ratio of 0.64. (Figure S1). While inflammatory markers were unremarkable, myocarditis cannot be definitively excluded given its documented occurrence in serologically quiescent cases. Comprehensive assessment (including CMR tissue characterization) was prioritized over biomarker reliance. Considering the symptoms, ECG and myocardial marker results, it conformed to the diagnostic criteria of myocardial infarction by the European Society of Cardiology (ESC). Non-ST-segment elevation myocardial infarction was considered for diagnosis. The patient was treated with aspirin 0.1 g qd, ticagrelor 90 mg bid, atorvastatin 20 mg qn and fondaparinux sodium 2.5 mg qd. During hospitalization, the changes in high-sensitivity troponin, troponin I and NT-proBNP on reexamination were also consistent with the manifestations of myocardial infarction (Figure 2). The patient repeatedly refused coronary angiography. After repeated communication with the patient, coronary angiography was performed on the fourth day of admission. Coronary angiography revealed 30% stenotic lesion in the proximal left anterior descending artery, while no significant stenosis was observed in the circumflex artery and the right coronary artery. (Figure 3A–C and Video S1A–D). During the procedure, weakened left ventricular motion was noted, and further left ventricular angiography was performed. Left ventricular angiography demonstrated significantly weakened motion of the anterior wall and apex of the left ventricle; both diastolic and systolic functions declined; Suspected non-compact myocardium was observable; the thickness of the suspected non-compact myocardium on the anterior wall during diastole was approximately 7–8 mm, and the thickness during systole was approximately 11 mm (Figure 3D and Video S2). Subsequent CMR (3.0 T) demonstrated no myocardial perfusion defects in the left ventricular myocardium, as analysed visually on first-pass perfusion images by two experienced readers. Late gadolinium enhancement (LGE) imaging revealed prominent subendocardial and midmyocardial hyperenhancement in the mid-ventricular and apical septum, extending into the apical anterior wall and subendocardial region of the septum, with focal transmural involvement. Additionally, a reduction in left ventricular systolic function was observed, with a left ventricular ejection fraction of only 35.21% (See Table 1 for detailed data). This result is consistent with the abnormal wall motion observed in left ventriculography. Left ventricular non-compaction was identified, characterized by a non-compaction to compaction (NC/C) ratio of 3.04 at end-diastole (Figure 4 and Video S3A–F), which aligns with the diagnostic criteria for LVNC. Moreover, we conducted sequencing tests for genes related to hereditary cardiomyopathy in the patient. The test results indicated a mutation in the MYL2 gene, with the chromosomal location at chr12:111348933 and the zygote type being heterozygous. The transcript for MYL2 is NM_000432. A novel missense mutation in the encoding region of the MYL2 (c.449T>G: p.Leu150Trp) was identified in the patient. Therefore, the medication was adjusted to aspirin 0.1 g once daily and metoprolol sustained-release tablets 23.75 mg once daily. The patient was discharged after significant improvement of symptoms. In this case report, a 57 year-old female patient presenting with chest pain was initially suspected of having a myocardial infarction, but was ultimately diagnosed with left ventricular non-compaction. Upon admission, the patient was found to have elevated troponin levels, yet coronary angiography showed no vascular stenosis, suggesting ischaemic cardiomyopathy damage leading to type 2 myocardial infarction due to an imbalance between oxygen supply and demand. As the patient did not have atrial fibrillation and no deep vein thrombosis was detected by lower extremity vascular ultrasound, it is speculated that the myocardial infarction episode might be related to coronary artery spasm.5 LVNC is recognized for its highly heterogeneous clinical presentation, previous studies suggesting that systemic embolism occurs in less than 10% of patients.6 The definitive diagnosis of LVNC was established through CMR, emphasizing the importance of a comprehensive and sequential diagnostic strategy in cases presenting with atypical cardiac symptoms. This case provides valuable insights into the clinical manifestations, diagnostic procedures and genetics of this rare condition. LVNC is a primary hereditary cardiomyopathy. Besides abnormal embryonic development, the pathogenesis of LVNC includes gene mutations encoding sarcomeric proteins (such as MYH7, MYBPC3, TTN, ACTC1, TNNC1, TNNT2, TNNI3, TPM1 and ACTN2),7 mitochondrial gene mutations (such as SCO2, SDHA and TAZ), gene mutations related to neuromuscular diseases and DSG2 gene mutations.8 Acquired factors in the future include athletes, chronic anaemia, pregnancy and renal failure, which may affect the occurrence of LVNC. Genetic identification of this patient revealed a missense mutation (c.449T>G: p.Leu150Trp) in the coding region of MYL2, which has not been reported in other literature or cases. MYL2 is a gene encoding the regulatory light chain of cardiac myosin phosphorylation, which helps to regulate force production through phosphorylation and calcium binding,9 and is part of the slow skeletal muscle myosin complex as well as the beta-cardiac complex. Although limited, several variants in MYL2, including R58Q mutation,10 c.64G>A [p.(Glu22Lys)] mutation,11 c485G>A[p.Gly162Glu] mutation,12 D94A mutation and some compound heterozygous variant, have been reported as the cause of HCM, dilated cardiomyopathy and LVNC, and its variable phenotype may depend on the respective mutations located in different functional regions (Table S1). In the context of extant literature and investigative studies, a discernible pattern emerges: individuals harbouring compound mutations within the MYL2 gene manifest a spectrum of cardiomyopathic phenotypes, with a subset demonstrating a propensity for disease subtype evolution over time. Considering the patient's maternal history of HCM, there is a heightened risk for the emergence of alternative cardiomyopathy variants, including HCM and dilated cardiomyopathy. Consequently, it is imperative to schedule periodic assessments utilizing echocardiography or CMR. Such vigilant surveillance, facilitated by these non-invasive diagnostic modalities, is pivotal in optimizing patient outcomes and potentially augmenting their longevity. Although specific details of the mother's condition and the genetic identification results of the patient's immediate relatives are lacking, this emphasizes the necessity of thorough family screening and genetic counselling for such cases. In the diagnosis of LVNC, echocardiography and CMR are the most prevalently employed diagnostic modalities. In the present study, the CMR results demonstrated that NC/C > 2.3 was consistent with the Petersen criterion.4 The sensitivity, specificity, positive predictive value and negative predictive value of this criterion for diagnosing LVNC were 86%, 99%, 75% and 99%, respectively. According to previous research indications, due to the low prevalence of this disorder, the detection rate of LVNC in echocardiography was 0.01%–0.26%.13 The echocardiogram of this patient did not indicate overt left ventricular non-compaction, which we attribute to the suboptimal accuracy of the echocardiographic imaging. Given the patient's severe condition at admission, the bedside echocardiogram provided us with a general overview of the cardiac status to guide initial treatment strategies. Subsequently, after the patient underwent CMR, no additional three-dimensional echocardiogram was performed to avoid redundant examinations. Currently, there are no guidelines or consensus on the treatment of LVNC. Published case reports suggest adverse consequences of LVNC, including cardiac insufficiency, arrhythmias and thromboembolism, and therefore, treatment varies widely depending on the clinical complications.1The treatment of cardiac insufficiency refers to the existing guidelines for heart failure, including (1) pharmacological treatment: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor–neprilysin inhibitors, mineralocorticoid receptor antagonists and sodium–glucose co-transporter 2inhibitors; (2) cardiac resynchronization therapy; (3) heart transplantation. Arrhythmia is the most fatal complication in patients with LVNC. Conventional clinical treatment methods include the use of anti-arrhythmic drugs, pacemaker placement, implantation of implantable cardioverter defibrillators and radiofrequency ablation. Due to the complexity of the myocardial structure and mechanism of LVNC, the risk of thrombosis/embolism is very high, but there are currently no guidelines recommending anticoagulation therapy for LVNC. Previous literature14 suggests that LVNC itself is not associated with an increased incidence of thromboembolic events. When there are risk factors such as low left ventricular ejection fraction or atrial fibrillation, or when thrombosis in the left ventricle is identified through imaging, it is recommended to initiate anticoagulation therapy. The patient in this study did not have combined risk factors for thrombosis. Considering the relatively fast heart rate, metoprolol was administered based on the treatment plan for cardiac insufficiency, and the therapeutic drugs were adjusted according to the disease condition during the long-term follow-up. There are certain limitations to this case report. Concomitant type 2 myocardial infarction from coronary spasm could not be definitively excluded. Although intravascular imaging or provocative spasm testing could assess plaque erosion/coronary spasm, these procedures were not performed due to institutional constraints in conducting pharmacologic provocation and patient refusal of additional invasive procedures over safety/cost concerns. Comprehensive echocardiographic assessment was limited to emergent bedside 2D imaging given the patient's critical presentation at admission. This precluded detailed structural/functional evaluation and resulted in discordant left ventricular ejection fraction measurements compared to cardiac MRI. Genetic testing of first-degree relatives—particularly the patient's mother—was not pursued due to lack of informed consent, preventing analysis of MYL2 variant heritability patterns in LVNC. The absence of segregation analysis precludes definitive variant interpretation. Future efforts should establish protocols to facilitate family studies in such critical scenarios. These limitations do not diminish the novel association between the MYL2 mutation and LVNC pathogenesis or its therapeutic implications. The authors declare no conflicts of interest. Figure S1. Supporting Information. Table S1. Supporting Information. Video S1A. Supporting Information. Video S1B. Supporting Information. Video S1C. Supporting Information. Video S1D. Supporting Information. Video S2. Supporting Information. Video S3A. Supporting Information. Video S3B. Supporting Information. Video S3C. Supporting Information. Video S3D. Supporting Information. Video S3E. Supporting Information. Video S3F. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.