Anti-mitochondrial antibody–mediated myopathy with cardiac involvement

We read with interest the article by Ishiguro et al. on a 59-year-old female who was diagnosed with anti-mitochondrial antibody (AMA)–associated myopathy complicated by cardiac involvement, manifesting as sick sinus syndrome and heart failure.¹ The patient benefited from implantation of a pacemaker and steroids, so that the serum creatine kinase levels fell.¹ The study is excellent but has limitations that are objectionable and should be discussed.

The major limitation of the study is that the index patient was not genetically tested. Because AMA can be a non-specific finding, according to a recent meta-analysis of 171 patients with idiopathic, inflammatory myopathy (IIM),² it is crucial that primary (hereditary) myopathy, particularly mitochondrial myopathy, is adequately ruled out. To rule out hereditary myopathy, it is essential not only to carry out whole-exome sequencing (WES) or a panel investigation for myopathy and cardiomyopathy but also to take a detailed family history. We should therefore know if any of the first-degree relatives had cardiac disease or some other non-cardiac or non-muscle disorder. Even if the family history is negative for myopathy and cardiomyopathy, this does not rule out a genetic cause. First, the index patient could carry a sporadic mutation, and second, the disorder could have remained subclinical in phenotypically unaffected first-degree relatives. Because myopathy can be part of a multisystem disease, such as in myotonic dystrophy,³ it is essential to know if the index patient also had manifestations in organs other than the muscle or heart.

Another limitation of the study is that the pathogenicity of the AMA has not been documented and their role in the development of myopathy and cardiomyopathy has not been elucidated. AMAs were not detected in serum until years after the first finding of elevated creatine kinase 1 year after implantation of the pacemaker, and they were not documented in either muscle or endo-myocardial biopsy. Although the specificity of AMA for cardiac involvement was 92% in a recent meta-analysis² and the I² value for these analyses was >50%, it was concluded that, according to diagnostic odds ratio (DOR) analysis, the overall pooled accuracy was not high enough to draw definitive conclusions on the pathogenicity of AMA in IIM-related cardiomyopathy.² Whether AMAs were already present in the index patient at initial presentation for arrhythmias remains speculative, as they were not determined. It is also not mentioned whether the index patient has been tested for myositis-specific antibodies (MSAs) or myositis auto-antibodies (MAAs) other than AMA, such as anti PL-7, anti-PL-12, SRP, TIF1-γ, anti-NXP2, anti-SAE, MDA5, ANA, HMGCR, or anti-Ro/SSA.

Interestingly, both echocardiography and cardiac magnetic resonance imaging (cMRI) were negative for suspected infiltrative or inflammatory cardiomyopathy. A fluor-deoxy-glucose–positron emission tomography (FDG-PET) was not performed at the initial presentation or when peripheral muscle symptoms occurred.¹ The FDG-PET could have helped to detect cardiac inflammation at first presentation. In addition, neither endo-myocardial nor muscle biopsy was evaluated by immunehistochemistry, electron microscopy, or biochemistry, to determine whether any of the respiratory chain complexes were dysfunctional or whether beta-oxidation or another metabolic pathway was defective. However, cMRI showed positive late gadolinium enhancement (LGE) and a slightly decreased left ventricular ejection fraction (EF) at the onset of peripheral muscle dysfunction, which were not observed at first presentation for arrhythmia. Late gadolinium enhancement is often associated with scarring, myocardial fibrosis, or inflammation.⁴

In summary, the interesting study has limitations that call the results and their interpretation into question. Addressing these issues would strengthen the conclusions and could improve the status of the study. The pathogenicity of AMA remained unproven in the index case, which is why differential diagnoses such as arrhythmogenic right ventricular cardiomyopathy (ARVC), sarcoidosis, amyloidosis, left ventricular hypertrabeculation (LVHT), and mitochondrial disorder should be considered and adequately ruled out.

 

Consent: Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images.

Funding: No funding was received.

Ethics approval: The study was approved by the institutional review board (responsible: J.F.) on 4 November 2022. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Data availability

Data that support the findings of the study are available from the corresponding author.