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Cardiac manifestations of mitochondrial disorders: reply

With interest we read the article by Limongelli et al. about cardiac involvement (CI) in 32 patients with mitochondrial disorders (MIDs). The study raises concerns. Exercise limitation was found in 24 patients and was exclusively regarded as a cardiovascular symptom. Since 14 patients had exercise intolerance and progressive muscle weakness, since 17 developed muscle fatigue during a metabolic exercise test, and since easy fatigability is generally a dominant phenotypic feature of MIDs, it is conceivable that exercise limitation was at least in part or exclusively attributable to the oxidative defect or weakness of the striated muscles and not exclusively to CI. Although dyspnoea is a frequent manifestation of cardiac disease it can also be a manifestation of affected respiratory muscles. Since eight patients had mitochondrial myopathy, 12 mitochondrial myopathy with ophthalmoplegia, two Kearns–Sayre-syndrome and seven MELAS-syndrome, it cannot be excluded that the respiratory muscles were also affected. Did all patients undergo spirometry to assess the muscular component of dyspnoea? Left ventricular non-compaction, also known as left-ventricular hypertrabeculation, is frequently found in patients with neuromuscular disorders and MIDs. The definition of non-compaction, however, is under debate. According to which criteria was noncompaction diagnosed, and did the patient develop ventricular tachycardia or cardiac embolism, frequent complications of non-compaction? Phenotypic expression of mtDNAmutations largely depends on the relation between the amount of mutated and wildtype mtDNA. What were the mutation rates of the A3243G, A8344G, G9952A, 12294-tRNA, 11232-tRNA, and mtDNAdeletions? Which nucleotide-exchange was associated with the 12294and 11232tRNA-mutations? The A8344G mtDNA-mutation has not been described as the cause of a neuropathy, ataxia, and retitintis pigmentosa (NARP)phenotype. Was this patient also tested for the T8993G/C mutations, which usually cause NARP? Although mitochondrial tRNAmutations may cause chronic progressive ophthalmoplegia it has not been reported together with the 11232 tRNA-mutation. Were these mutations also found in other family members? What was the mutation rate? Did the NARP-patient also develop features of MERRF-syndrome, which is most frequently due to the A8344G mutation? To conclude that life-threatening cardiovascular complications occur rarely is not justified with regard to the number of investigated patients, the duration of follow-up, previous reports about death from CI in MIDs, and the few studies available which address this question. Overall, patients with MIDs need to be closely followed-up for CI, since the rate and frequency of progression is largely unknown and it is unclear if patients profit from preventive measures (CRT/ICD-devices) at an early stage of CI.