High rate of hypertension in patients with m.3243A>G MELAS mutations and POLG variants

Area of Science:

• Genetics
• Cardiovascular Medicine
• Mitochondrial Biology

Background:

• Decreased vascular mitochondrial DNA copy number is implicated in hypertension in animal models.
• Mitochondrial disorders, such as MELAS and POLG variants, affect cellular energy production and may impact cardiovascular health.

Purpose of the Study:

• To investigate the association between mitochondrial disorders (MELAS and POLG variants) and hypertension in human patients.
• To explore the role of POLG gene variants, including pathogenic and VUS, in the development of hypertension.

Main Methods:

• A retrospective chart review was conducted on patients with MELAS (n=36) and POLG variants (n=26).
• Blood pressure, hemodynamics, and clinical data were analyzed.
• Hypertension rates were compared to Canadian population norms.

Main Results:

• Hypertension prevalence was elevated in MELAS (50%) and POLG (50%) patient groups compared to age-matched Canadian norms.
• Hypertensive patients exhibited higher peripheral resistance, suggesting microvascular disease.
• Systolic blood pressure remained elevated in POLG patients despite treatment, compared to MELAS patients.
• Hypertension risk was not linked to MELAS heteroplasmy or the presence of chronic progressive external ophthalmoplegia (CPEO) in POLG patients.
• Hypertension was associated with POLG variants across all three functional domains, irrespective of pathogenicity (pathogenic vs. VUS).

Conclusions:

• Both pathogenic POLG variants and several variants of unknown significance (VUS) may contribute to human hypertension.
• The findings support a link between MELAS and an increased risk of hypertension.
• Mitochondrial dysfunction, particularly involving POLG, is implicated in the pathogenesis of hypertension.