Neurohumoral treatment for cardiac disease in dystrophinopathies and mitochondrial disorders

We read with interest the review article by Aimo et al. about neurohumoral modulation as a treatment of cardiac involvement in dystrophinopathies and mitochondrial disorders (MIDs).1 We have the following comments and concerns. When talking about neurohumoral treatment of cardiac disease in dystrophinopathies and MIDs it is important to mention that the rationale for this type of treatment is overactivation of the sympathetic arm of the autonomous nervous system (ANS). In this respect, causes of sympathetic overstimulation should be discussed. Sympathetic overactivity may not only be due to involvement of the central nervous system but also to involvement of the peripheral nervous system. As MIDs in particular may not only go along with central nervous system disease but also with involvement of the peripheral nerves (mitochondrial neuropathy), it is conceivable that the ANS is also involved and is thus responsible for the autonomic dysbalance. The cause of sympathetic overactivity in dystrophinopathies so far remains speculative. The authors do not mention left ventricular hypertrabeculation/non-compaction (LVHT) as a cardiac manifestation of dystrophinopathies and MIDs.2,3 When systematically screening patients with LVHT for neuromuscular disorders (NMDs), up to 80% of these patients have a NMD.4 Among the various NMDs, LVHT occurs most frequently in MIDs.5 Considering LVHT is important because it is complicated by heart failure, ventricular arrhythmias, cardiac embolism and sudden cardiac death.6 LVHT has a strong impact on the prognosis and outcome of NMD patients, which is why NMD patients should undergo a thorough cardiological examination. Cardiac involvement in MIDs not only includes LVHT, heart failure and arrhythmias, but also pulmonary hypertension, aortic root ectasia, coronary heart disease, ANS involvement and congenital heart defects.7 It should be addressed that some of these cardiac abnormalities may also be accessible to neurohumoral treatment. We do not agree with the statement that ‘little evidence is available regarding heart failure management in other genetic skeletal myopathies, mostly because heart failure is not a common finding in these conditions’. Heart failure also occurs frequently in laminopathies, desminopathies, nemaline myopathy, myotonias, Danon disease, or Barth syndrome and responds favourably to established heart failure therapy.8 As patients with dystrophinopathies and MIDs may experience arrhythmias and as ventricular arrhythmias in particular may go along with acute heart failure, these patients require thorough diagnostic work-up for arrhythmias and adequate anti-arrhythmic treatment, including device therapy by pacemaker implantation, implantable cardioverter defibrillator implantation, or cardiac resynchronization therapy implantation, if indicated. Sufficient anti-arrhythmic treatment may significantly reduce the risk of acute heart failure. The authors do not mention oral anticoagulation as an essential treatment for MID or dystrophinopathy patients with atrial fibrillation, dilative cardiomyopathy with severe heart failure, or LVHT and a history of cardioembolism. It should also be mentioned that the I(f) blocker ivabradine has been shown to exhibit a beneficial effect on left ventricular systolic dysfunction in patients with Becker muscular dystrophy.9 Ivabradine may be effective even if angiotensin-converting enzyme inhibitors or angiotensin II blockers fail to be effective.9 Overall, this interesting review could be more meaningful if any type of cardiomyopathy occurring in NMDs was considered, if arrhythmias were mentioned as a cause of systolic dysfunction, and if neurohumoral treatment is expanded by ivabradine. JF: design, literature search, discussion, first draft; SK: literature search, discussion, critical comments. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.