MELAS and POLG exhibit high rates of hypertension with differential resistance to anti‐hypertensive drugs suggesting divergent pathogenic mechanisms

Background We previously reported elevated hypertension (HT) rates in adults with the m.3243A>G mitochondrial encephalomyopathy, lactic acidosis, and stroke‐like episodes (MELAS) mutation. The cause of HT in MELAS is not known but could be linked to dysautonomia and endothelial dysfunction. Hypertension is also reported in transgenic mice that have an error‐prone gamma DNA polymerase (POLG) that increases mtDNA mutation rate. In contrast to MELAS, HT in POLG−/− mice appears to be due to hypertrophy of the tunica media . It is not known if humans with pathogenic POLG mutations similarly exhibit HT, and whether the hemodynamic basis of HT in MELAS and POLG are consistent with common or distinct pathogenic mechanisms. Purpose We aimed to examine whether POLG patients have an increased risk of HT, and whether the hemodynamics and therapeutic sensitivity of such HT resembles that of HT in MELAS patients. Specifically, we hypothesized that POLG patients would be prone to isolated systolic HT, while MELAS patients should exhibit remodeling of resistance vessels. Methods We conducted a chart review at the Adult Metabolic Disease Clinic, Vancouver General Hospital of 35 MELAS and 26 POLG patients in accordance with institutional human research ethics guidelines. Demographic factors, including age, weight, BMI, sex, smoking status and diabetes status were collected. Patients were scored as hypertensive if they were on anti‐hypertensive drugs or had consistently elevated blood pressure measurements in accordance with the Canadian Hypertension Education Program Guidelines. Results MELAS and POLG patients showed increased prevalence of HT (20–39 yr age group: 30% MELAS, 14% POLG; 40–59 yr: 71%, 57%; 60–79 yr: 83%, 81%) compared to the Canadian population. Hypertension was not associated with sex, smoking or BMI, and exceeded expected levels given 50% of MELAS patients were diabetic. In the 40–59 and 60–79 yr age groups, antihypertensive drugs controlled systolic blood pressure in MELAS but not in POLG patients (40–59 yr: POLG 145 ± 21 mmHg n = 8 vs MELAS 122 ± 23 n = 12; 60–79 yr: POLG 157 ± 6 n=4 vs MELAS 134 ± 21 n=5), while diastolic blood pressure did not differ between MELAS and POLG. Preliminary analyses suggest that MELAS, but not POLG, patients exhibit elevated peripheral resistance despite therapeutic correction of blood pressure. Conclusions MELAS and POLG increase the risk of HT, which can increase the propensity for cardiac hypertrophy and cerebrovascular problems. Signs of vascular remodeling as a contributor to HT suggest that early therapeutic treatment at the onset of pre‐hypertension may be warranted to prevent and control HT in these diseases, especially POLG. These findings warrant detailed hemodynamic assessments in larger populations.

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