Impact of cardiovascular involvement on the clinical course of paediatric mitochondrial disorders

Abstract

Background Primary mitochondrial disorders (PMD) are rare conditions resulting in progressive multi-organ failure. Cardiovascular involvement (CVI) has been reported in paediatric patients. However, its age-related prevalence, clinical presentation and prognostic impact are unresolved. We detailed CVI in a cohort of children diagnosed with PMD over two decades at a tertiary referral centre. Results We enrolled 86 PMD patients (M/F = 30/56; mean age 6.4 ± 8.58 years). CVI was detected in 31 patients (36%), with mean age at onset of 5.7 ± 7.8 years including the pre- and neonatal phase in 14, often representing the first sign of PMD (42% of those with CVI). Heart disease resulted more common in males and in children with specific aetiologies (Barth, TMEM70 and MELAS syndromes). Hypertrophic, non-compaction and dilated cardiomyopathies were the prevalent disorders, although pulmonary arterial hypertension was also found. Adverse cardiac events (heart failure, resuscitated cardiac arrest, ICD/PM implantation, sudden death) occurred in 19% of children with CVI over a follow-up period of 5.4 ± 4.3 years. All-cause mortality was higher in patients with CVI compared to those without CVI (45.1% vs 21.8%; p < 0.01); female sex, age at onset < 5 years, acute heart failure at presentation and diabetes also proved independent predictors of outcome. Conclusion Cardiovascular involvement occurred in over one-third of children diagnosed with PMD, often at a very early age, and was associated with adverse prognosis. Final outcome of PMD-related CVI was influenced by the specific underlying aetiology, suggesting the need for tailored management of heart failure and sudden death prevention.

Nutritional Approach in Selected Inherited Metabolic Cardiac Disorders—A Concise Summary of Available Scientific Evidence

“…Primary mitochondrial diseases (PMDs) are a heterogeneous group of afflictions caused by anomalies in the mitochondrial respiratory chain or in cellular oxidative phosphorylation [15][16][17]. Mitochondrial DNA (mtDNA) codes for part of the subunits forming the five complexes, and the remaining parts are synthesized from nuclear gene transcripts [18][19][20].…”

Mitochondrial Syndromes Revisited

“…Heart disease was observed to be more common in male children with specific mitochondrial conditions (Barth syndrome, TMEM70 mutations, and MELAS). Non-compaction, hypertrophic, and dilated cardiomyopathies were the prevalent conditions, while pulmonary arterial hypertension was less frequent [40].…”

Recent Advances in Modeling Mitochondrial Cardiomyopathy Using Human Induced Pluripotent Stem Cells

“…Mitochondrial diseases comprise a multisystemic group of metabolic disorders characterized by early- or late-onset progressive neurodegenerative and cardiac symptoms, likely associated with a psychomotor regression, encephalopathy, myopathy and cardiomyopathy ( DiMauro and Schon, 2013 ). Around 20–40% of children with a mitochondrial disease develop a kind of cardiac symptoms ( Brambilla et al, 2020 ; Mazzaccara et al, 2021 ). In such cases, severity is quite variable ranging from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death.…”

“…In fact, epidemiological studies demonstrated that mutations in mitochondria-related genes including single-nucleotide variants to large-scale deletions, affect 1 in 4,500 individuals ( Chinnery et al, 2000 ), and the risk to develop cardiac symptoms is significantly higher in this patient cohort. Furthermore, a clinical study showed that 36% of patients with mitochondrial disorders harboring mutations in nuclear DNA- or mtDNA-encoded genes developed a kind of cardiomyopathy ( Brambilla et al, 2020 ), probably due to the high bioenergetic demand required by the heart. At the same time, infants with cardiovascular compromise in mitochondrial deficiency display a worse late survival compared to patients without cardiac compromise and current therapies are unable to substantially mitigate the disease burden ( Wahbi et al, 2015 ; Brambilla et al, 2020 ).…”

“…Furthermore, a clinical study showed that 36% of patients with mitochondrial disorders harboring mutations in nuclear DNA- or mtDNA-encoded genes developed a kind of cardiomyopathy ( Brambilla et al, 2020 ), probably due to the high bioenergetic demand required by the heart. At the same time, infants with cardiovascular compromise in mitochondrial deficiency display a worse late survival compared to patients without cardiac compromise and current therapies are unable to substantially mitigate the disease burden ( Wahbi et al, 2015 ; Brambilla et al, 2020 ). The genotype-phenotype correlation in patients with mitochondrial cardiomyopathies as well as the underlying pathophysiological mechanisms associated to mitochondrial gene mutations are still poorly understood.…”