Analysis of mitochondrial DNA deletions in four chambers of failing human heart: hemodynamic stress, age, and disease are important factors

Abstract

Mitochondrial DNA (mtDNA) mutations are not only responsible for organ dysfunction due to inefficient energy production but also indicators of metabolic and functional stresses in the organ. To analyze the significance of deletion mutation in human myocardium, we screened the presence of two common deletions (7.4 kb from 8637–16084 nt, 5.0kb from 8470–13477 nt) in four chambers using long PCR, and using serial-dilution PCR, measured the amount of deleted mtDNA in normal heart (NL) of brain-dead victims of road accidents (n = 9, age = 10–59) and failing hearts (CHF) of patients who underwent heart transplantation (n = 24, age = 17–63). Frequency of both deletions was higher in ventricles (Vt) than in atria (At) (Vt: At = 25/33 : 12/33 for 7.4 kb, 19/33 : 6/33 for 5 kb) (p < 0.05), whereas it was the same in the right and left chambers. In ventricles, both deletions were more frequent among older persons (> 35 yrs) than in younger persons /≤ 35 yrs) (older : younger = 16/20 : 9/13 for 7.4 kb, 15/20 : 4/13 for 5 kb) (p < 0.05). In ventricles of failing heart, the 5-kb deletion was more frequent than in those of normal heart (CHF : NL = 17/24 : 2/9) (p < 0.05), whereas the 7.4-kb deletion was frequent both in failing and normal hearts (CHF : NL = 19/24 : 6/9). The association of mutation with aging or disease process observed in ventricles was not found in the atria. Although the amount of mutant mtDNA in the left ventricle tended to increase according to a disease process, it was small, at most 1.56% or 0.012% of total mtDNA for a 7.4- or 5-kb deletion, respectively. No deletion was found, however, in lymphocytes from any patient who underwent transplantation. In conclusion, deletion mutation of mtDNA is frequently, but in a small amount, found in the ventricle of older failing heart than in the atrium of younger normal heart. This suggests that hemodynamic stress, age, and disease are factors to induce mtDNA mutation that represents the indicator of stresses on the heart and might turn into a contributor of progressive heart failure under extreme conditions.