Researchers develop prediction model for adverse cardiac events in mitochondrial diseases
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Researchers have developed the first prediction model for the prediction of HF- and arrhythmia-related major adverse cardiac events in patients with mitochondrial diseases.
Independent predictors of HF-related and/or arrhythmia-related major adverse cardiac events in patients with mitochondrial diseases included the m.3243A>G variant of the disease, conduction abnormalities, left ventricular hypertrophy, reduced LV ejection fraction, premature ventricular beats, and single, large-scale mitochondrial DNA deletions, according to data published in the Journal of the American College of Cardiology.
“Patients with mitochondrial diseases have a high risk of HF and arrhythmia-related major adverse cardiac events (MACE), which remains extremely challenging to estimate in the absence of specific prediction models,” Konstantinos Savvatis, MD, PhD, of the inherited cardiac conditions unit at Barts Heart Centre, St Bartholomew’s Hospital in London, and colleagues wrote. “In this international multicenter study, we sought to analyze the frequency of arrhythmia-related and HF complications in a large cohort of patients with genetically confirmed mitochondrial diseases and to identify risk factors for the development of these two events to guide the implementation of specific diagnostic and therapeutic measures.”
Mitochondrial diseases are characterized by dysfunctions of the mitochondrial respiratory chain and abnormal adenosine triphosphate (ATP) production, with the most common genetic changes being single, large-scale mitochondrial DNA deletions and the m.3243A>G point variant in mitochondrial DNA, according to the study.
Researchers found that the most common indications of cardiac involvement in mitochondrial diseases include LV hypertrophy, conduction disease, Wolff-Parkinson-White syndrome and dilated cardiomyopathy.
Using the data of 600 patients at nine international recruiting centers, Savvatis and colleagues developed prediction models to estimate risk for HF- and arrhythmia-related MACE in mitochondrial diseases.
During a median follow-up time of 6.67 years, 4.9% of participants experienced HF-related mortality, cardiac transplantation or HF hospitalization.
Overall, 5.1% experienced an arrhythmia-related MACE, including third-degree or type II second-degree atrioventricular blocks with sinus node dysfunction and sudden cardiac death.
Predictors of cardiac outcomes in mitochondrial diseases
Savvatis and colleagues observed the following to be the strongest predictors of HF in patients with mitochondrial diseases:
- identification of the m.3243A>G variant (HR = 4.3; 95% CI, 1.8-10.1);
- conduction defects (HR = 3; 95% CI, 1.3-6.9);
- LV hypertrophy (HR = 2.6; 95% CI, 1.1-5.8);
- LVEF less than 50% (HR = 10.2; 95% CI, 4.6-22.3); and
- premature ventricular beats (HR = 4.1; 95% CI, 1.7-9.9).
Additionally, independent predictors of arrhythmia-related major adverse events included single, large-scale mitochondrial DNA deletions (HR = 4.3; 95% CI, 1.7-10.4), conduction defects (HR = 6.8; 95% CI, 3-15.4) and LVEF less than 50% (HR = 2.7; 95% CI, 1.1-7.1).
The researchers reported C-indexes of models for HF of 0.91 (95% CI, 0.88-0.95) and 0.8 for arrhythmia-related MACE (95% CI, 0.7-0.9).
“We have developed the first model to date for HF risk stratification in mitochondrial diseases, which can be easily used after simple cardiac assessments even in nonexpert centers,” the researchers wrote. “Patients with HF MACE risk factors may benefit from closer follow-up or potentially advanced cardiovascular tests such as cardiac MRI, which may identify early myocardial changes. High-risk patients may also be eligible for early initiation of HF medication to delay myocardial disease progression or novel therapies such as mitochondrial DNA elimination or mitochondrial DNA gene therapy.”
Understanding of mitochondrial diseases ‘broadly useful’
In a related editorial, Stephanie M. Ware, MD, PhD, professor of pediatrics and medical and molecular genetics, vice chair of clinical affairs in medical and molecular genetics and program leader in cardiovascular genetics at the Herman B. Wells Center for Pediatric Research at Indiana University School of Medicine, discussed the significance of predictive models in this setting.
“Diagnostics for mitochondrial disorders have improved dramatically over the 20 years. ... The ability to perform molecular testing for nuclear and mitochondrial genome causes of cardiomyopathy should significantly enhance the discovery of these disorders and provide a better understanding of the spectrum of cardiac disease,” Ware wrote. “Because more common causes of end-stage HF and ischemia are characterized by mitochondrial dysfunction, understanding the pathogenesis and potential treatment of specific rare mitochondrial disorders may prove broadly useful.”
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