Systematic review and meta-analysis of cardiac involvement in mitochondrial myopathy

Discussion

Overall, patients with MM have a high prevalence of cardiac abnormalities, although the data indicate that MELAS has a higher prevalence of ECG abnormalities compared with other clinical syndromes, and the m.3243A>G mutation is associated with a higher prevalence of ECG abnormalities than other genetic defects. Abnormalities detected by echo are more prevalent in MELAS and myoclonic epilepsy with ragged red fibres (MERRF) compared with other syndromes, and when analyzed by genetic category, the m.3243A>G and m.8344A>G mutations were associated with a higher prevalence than other mutations. Comparing children to adult patients, we report the descriptive finding of a higher prevalence of ECG abnormalities in children compared with adults with MM, supporting the concept that MM has a more severe cardiac phenotype in childhood compared with adult patients. However, this difference was not significant (p = 0.07), perhaps relating to the small number of participants in pediatric studies.

The majority of the available data are from ECG and echo and both modalities demonstrated a high prevalence of detected abnormalities. We expected that a higher prevalence of abnormalities would be detected with CMRI, given that CMRI is recognized as a structural imaging test with higher sensitivity and reproducibility.^13,14 The available evidence shows similar diagnostic yield of CMRI in comparison with echo; however, the data are very heterogeneous and from a limited number of patients. In studies including m.3243A>G and/or MELAS patients, 2 studies^15,16 reported no CMRI abnormalities, and 1 study¹⁷ reported CMRI abnormalities in nearly all patients. This discrepancy can hopefully be addressed in future research. One study of CMRI in 14 participants showed no structural abnormalities, but an overall reduction of myocardial glucose uptake, which may be a biomarker of interest for future study.¹⁶ Only a single study included CMRI data from a pediatric participant.¹⁰ Overall, CMRI has thus far had very limited study in MM, and further investigation will be required to understand the advantages and limitations of this modality in patients with MM.

Pediatric patients may characteristically be considered to have a more severe phenotype than adult patients with MM. Based on this, it was expected that pediatric patients would have a higher prevalence of abnormalities, which was suggested by our data comparing ECG abnormalities in children and adults. This suggests that pediatric patients with MM should be more closely monitored for cardiac conduction abnormalities. However, we cannot exclude the possibility that the prevalence of abnormalities for pediatric MM could have been inflated by the incidental inclusion of patients with KSS.

We observed that most studies of children included patients with nonspecific MM syndromes.^18,–,20 Only 2 studies reported m.8344A>G patients,^5,10 in which all patients had no abnormalities on ECG, but 1 patient had abnormalities detected by echo.¹⁰ Further investigation into pediatric MM patients, with better described clinical syndromes and molecular defects, should be conducted to determine the severity of the cardiac phenotype in these patients. In our analysis, Holter monitoring was a very low-yield investigation in adult and child patients with MM, and its use as a routine screening procedure should perhaps be reassessed.

In our study, 10 articles described patients with MM with diabetes.^{9,11,12,15,–,17,21,–,24} Of the 122 patients with diabetes, 47 of them were diagnosed with MELAS. Given that diabetes is a major risk factor for cardiac dysfunction, it might be expected that patients with MELAS have greater cardiac risk as a consequence. This elevated risk was borne out by the data, and the interaction of diabetes on cardiac dysfunction in patients with MM is worthy of future study.

The goal of this study was to systematically review the prevalence of cardiac abnormalities in MM syndromes; it was not a goal of this work to characterize the natural history, symptoms, sudden-death occurrence, or therapies. However, these might be areas for future study, and in the course of this review, some of the included articles contained data regarding symptoms, sudden cardiac death, and natural history. We found 8 articles reporting symptoms of cardiac dysfunction in patients before diagnosis, including chest pain,^4,11,17 various degrees of dyspnea,^{4,10,11,17,22} syncope,¹¹ palpitation^10,11 and exercise limitations.¹¹ Although 1 article found all patients to be asymptomatic,³ 5 articles reported cardiac symptoms occurring before investigation for MM.^{9,11,17,21,25,26} One article⁹ reported 7 patients with a history of major adverse cardiac events including heart failure and third-degree atrioventricular block, whereas another study²⁵ reported a patient who had previously underwent cardiac transplantation. Two studies^21,26 presented patients with cardiomyopathy preceding their diagnosis of MM. Of interest, 1 study concluded that 31% of their patients with MM were previously diagnosed with cardiac conditions, particularly arrhythmia, impaired left ventricular systolic function, LVH, coronary artery disease, and left bundle branch block.¹⁷ However, it is unclear in 1 study whether indicators of cardiac abnormalities were present before or after the diagnosis of MM.²²

An important limitation encountered in the literature is that few studies presented long-term follow-up data. Only 6 of the 21 included articles reported follow-up data regarding the evolution of cardiac dysfunction over time.^{3,5,9,11,27,28} Five of these reported detailed follow-up data^3,9,11,27,28 are as follows:

One study examined the occurrence of major cardiac events in a population of 260 patients, retrospectively followed for a median of 7 years.⁹ Twenty-seven of the patients died of cardiac events during the follow-up period, and the likelihood of death was associated with the presence of abnormalities on cardiac screening tests (42% in patients with 2 or more abnormalities on ECG/echo compared with 10% in the total study population). Patients with large-scale single mtDNA deletions and the m.3243A>G mutation had the most severe cardiac phenotype (although this former category may have incidentally included patients with KSS).

Another publication presented follow-up data on 15 patients diagnosed with adult-onset CPEO for a mean of 6.5 years with ECG and echo.³ A total of 5 patients developed new abnormalities, but in 4 of these cases, the abnormalities were unrelated to MM; only one patient developed a mild cardiomyopathy attributed to MM.

A previous investigation followed 32 patients for an average of 4.1 years, undergoing serial echocardiograms and clinical assessment.¹¹ Two patients with initially normal ECG developed hypertrophic cardiomyopathy during follow-up. Serial echocardiography in a patient with CPEO and a patient with MM showed LVH development, whereas 1 patient with MELAS developed systolic impairment.

A study reported 6 pediatric m.3243A>G patients, of which 2 died at an early stage of disease.²⁸ One patient had died because of multiorgan failure, whereas the other had died because of cardiorespiratory failure. One patient had developed mild LVH and tricuspid regurgitation without pulmonary hypertension in the first year of follow-up. One patient had developed stroke-like episodes in adulthood. The remaining patients did not develop clinical symptoms of cardiac dysfunction over 3 years of follow-up.

Last, one study examined the development of cardiac dysfunction in adult and pediatric patients with MELAS (10 of 11 harbored the m.3243A>G mutation) during subsequent follow-up.²⁷ They observed 11 patients, 4 adults, and 7 children, over an average time span of 6.9 years, whereas 6 patients were followed up for more than 5 years. Three patients showed a worsening ejection fraction, whereas 2 patients died, a child and an adult, one from causes unrelated to MM and the other due to congestive heart failure, respectively.

There are other works that did not meet our criteria for inclusion in this systematic analysis that have also provided important contributions to our understanding of the natural history of cardiac dysfunction in MM. A previous study of 228 patients with single mtDNA deletion syndromes presented data from initial presentation and after an average of 18.7 years of follow-up.²⁹ Over this time interval, the prevalence of cardiac conduction abnormalities increased from 1.3% to 5.3%, and the prevalence of cardiomyopathy increased from 0% to 2.6%. This demonstrates a lower prevalence of cardiac dysfunction than seen in our systematic analysis, which is a surprising finding given the inclusion of numerous KSS patients (which prevented it from being included in our systematic analysis). In contrast, another study of patients with MELAS and the m.3243A>G mutation had a mean follow-up of 3.8 years and identified death due to cardiac causes in 4 of 55 patients, which appears to be a more severe phenotype than expected for this short duration of follow-up.³⁰ This high level of variability between publications emphasizes the need for further study of natural history after extended follow-up.

Based on the above data, the following observations are possible: (1) cardiac abnormalities are very common across various MM syndromes, (2) analysis of clinical syndromes indicates that MELAS and MERRF appear to have the most severe cardiac phenotype in adult patients, and (3) analysis of genetic subtypes reveals a more severe cardiac phenotype for the m.3243A>G and m.8344A>G mutations compared with other MM genetic defects. Cardiac screening investigations should be made on a case-by-case basis, but the following suggestions based on the evidence may be helpful and are summarized in table 2. ECG and echo are the best-established screening tests for MM; the role for CMRI requires further investigation. Generally, patients with MELAS and MERRF are considered to be at a higher risk of cardiac complications, and annual screening has been recommended.³¹ A common and well-described cardiac complication is Wolff-Parkinson-White syndrome (WPW), which is overrepresented in MELAS.³² In contrast, adult-onset CPEO is generally considered to have a milder phenotype, and a previous study has suggested a screening interval as long as 3–5 years.³ The results of our analysis appear to be consistent with these recommendations, but it should be emphasized that the data are based on a small number of studies, and the prevalence of abnormalities is high for most syndromes.

Some cardiac findings that have been associated with MM were rarely or not identified in this systematic analysis. Left ventricular noncompaction has been associated with several mtDNA point mutations,^31,33 and we identified a single case with a mtDNA point mutation at position m.11232.¹¹ Restrictive or histiocytoid cardiomyopathies have also been associated with MM,³⁴ but these were also not identified as part of this analysis. This was likely due to the inclusion criteria for this review, which excluded individual case reports and small case series.

Limitations of this review relate to the heterogeneity in study design, ascertainment methods, cardiac investigations, and outcome reporting. The majority of included publications were case series focused on cardiologic issues, which may have biased the reported cases toward a higher prevalence of cardiac involvement. The majority of the data pertain to patients with mtDNA-related diseases, and patients with nuclear mitochondrial disorders were not well represented. Details regarding the genetic investigations, which were performed (specific assays, their sensitivity, and other negative genetic investigations), were not generally reported. Details regarding muscle pathology interpretation were not generally reported, but our assumption was that a statement regarding diagnostic muscle pathology would be reliable in the reported literature. In 2 studies,^4,17 data from patients with CPEO were aggregated with data from a few patients with Kearns-Sayre Syndrome (KSS), so it is possible that the prevalence of cardiac abnormalities was inflated by the incidental inclusion of some patients with KSS to the CPEO group (given that patients with KSS necessarily have cardiac conduction defects as part of their syndrome). In some of the studies including patients with the m.3243A>G mutation, data from mutation carriers who were asymptomatic or paucisymptomatic were included, which could also have affected the results.^9,12,15,24 This illustrates another limitation of our study that patients with the m.3243A>G mutation included aggregate data from patients with MELAS syndrome or other phenotypes, which does not provide an accurate picture of the cardiac findings in phenotypic subgroups with the m.3243A>G mutation. A similar limitation is present for patients with the m.8344A>G mutation, in which only a subset would have had MERRF syndrome. There may also have been some overlap in the groups (for example, CPEO could overlap with single large-scale mtDNA deletions, mtDNA point mutations, and nuclear gene mutation groups); based on the available information, the groups were assigned based on how they had been designated in their respective publications. Based on this classification, it is also possible that differences in the definition of each syndrome existed between the included publications, which is also a limitation of this study. In 1 article, it was necessary to assume which abnormalities were from ECG (BBB and WPW) compared with Holter monitor (ventricular dysrhythmias).¹⁰ In 1 article studying CMRI, only aggregate data were presented, but as this was in the normal range, we assumed a normal result for all patients.¹⁵ Finally, our analysis could not assess the severity of individual reported results, so even if the prevalence of results was similar between syndromes, we cannot rule out the possibility that some of the abnormalities may have been more severe in some syndromes than others.

This systematic analysis provides evidence to support a more aggressive cardiac screening for subsets of patients with MM, based on a more severe cardiac phenotype for MELAS and MERRF among clinical syndromes and a more severe phenotype for m.3243A>G and m.8344A>G mutations among genetic defects. We also report a descriptive finding of more prevalent ECG abnormalities in pediatric MM compared with adult MM. The prevalence of abnormalities with Holter monitoring is low and suggests that it may not be necessary for routine screening. More research is needed to determine how CMRI compares with echo as a modality for structural cardiac imaging. There are overall limited data on natural history and treatment response, and further longitudinal study of these conditions will be of benefit to the field. Further study including pediatric participants would also be of benefit, given the small numbers of studies and participants identified in this review.