Researchers have developed a model to predict adverse cardiac events in mitochondrial diseases

October 03, 2022

3 minutes to read

Savvatis has not made any relevant financial disclosures. Please see the study for all relevant financial disclosures by other authors. Weir reports that she receives funding from the American Heart Association and serves as a consultant for Metis Genetics.

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Researchers have developed the first prediction model to predict adverse cardiac events associated with HF and arrhythmias in patients with mitochondrial disease.

Independent indicators of major adverse cardiac events associated with HF and/or arrhythmias in patients with mitochondrial disease included the m. Single-stranded DNA deletion is widespread in mitochondria, according to data published in Journal of the American College of Cardiology.

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“Patients with mitochondrial disease have a high risk of HCV and adverse cardiac events associated with arrhythmias (MACE), which remain very difficult to estimate in the absence of specific prediction models,” Konstantinos Savatis, MD, PhD, from the Inherited Cardiology Unit at Barts Heart Center and St Bartholomew’s Hospital in London, colleagues wrote. “In this international, multicenter study, we sought to analyze the frequency of complications associated with arrhythmias and hepatitis C in a large cohort of patients with genetically confirmed mitochondrial disease and to identify risk factors for the development of these two events to guide implementation of specific diagnosis and therapeutic measures.”

Mitochondrial diseases are characterized by disruption of the mitochondrial respiratory chain and abnormal production of adenosine triphosphate (ATP), with the most common genetic alterations being deletions of single large-scale mitochondrial DNA and the m.3243A>G point variant in mitochondrial DNA, according to the study.

The researchers found that the most common indications of cardiac involvement in mitochondrial disease include LV hypertrophy, conduction disease, Wolff-Parkinson-White syndrome, and dilated cardiomyopathy.

Using data from 600 patients at nine international recruitment centers, Savvatis and colleagues developed prediction models to estimate the risk of MACE-associated HF and arrhythmias in mitochondrial diseases.

During a median follow-up period of 6.67 years, 4.9% of participants experienced HF-related deaths, heart transplantation, or HF hospitalization.

Overall, 5.1% experienced MACE associated with arrhythmias, including grade 3 or type II atrioventricular blocks with sinus node dysfunction and sudden cardiac death.

Predictors of cardiac outcome in mitochondrial disease

Savvatis and colleagues note that the following are 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% (heart rate = 10.2; 95% CI, 4.6-22.3); And the
  • Early ventricular beat (heart rate = 4.1; 95% confidence interval, 1.7-9.9).

In addition, independent indicators of major arrhythmia-related adverse events included extensive single 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% (heart rate = 2.7, 95% CI, 1.1-7.1).

The investigators reported C-indices for HF models of 0.91 (95% CI, 0.88-0.95) and 0.8 for MACE related to arrhythmia (95% CI, 0.7-0.9).

“We have developed the first model to date to classify HF risk in mitochondrial diseases, which can be readily used after simple cardiac assessments even in non-expert centers,” the researchers wrote. Patients with HF MACE risk factors may benefit from close follow-up or potentially advanced cardiovascular tests such as cardiac magnetic resonance imaging, which may identify early changes in the myocardium. Patients at high risk may also be eligible for early initiation of HF medications to delay progression of myocardial disease or new treatments such as mitochondrial DNA removal or mitochondrial DNA gene therapy.”

Understanding mitochondrial diseases ‘widely useful’

In a related editorial, Stephanie M. Weir, MD, Ph.D., Professor of Pediatrics and Medical and Molecular Genetics, Vice President for Clinical Affairs in Medical and Molecular Genetics and Chair of the Cardiovascular Genetics Program at the Hermann B. Wells Research Pediatrics at Indiana University School of Medicine, discuss the importance of predictive models in this setting.

The diagnosis of mitochondrial disorders has improved dramatically over the past 20 years. “The ability to perform molecular testing of the nuclear and mitochondrial genetic causes of cardiomyopathy should greatly enhance the detection of these disorders and provide a better understanding of the heart disease spectrum,” Weir wrote. “Since the most 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 be of broad interest.”


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