Increased Oxidative Stress and Cardiomyocyte Myofibrillar Degeneration in Patients With Chronic Isolated Mitral Regurgitation and Ejection Fraction >60%

Abstract

Objectives We assessed myocardial damage in patients with chronic isolated mitral regurgitation (MR) and LV ejection fraction (EF) > 60%. Background MR patients typically have decreased LVEF after mitral valve (MV) repair despite normal pre-operative LVEF. Methods 27 patients with isolated MR had LV biopsies taken at time of MV repair. Magnetic resonance imaging with tissue tagging was performed in 40 normal subjects and in MR patients pre- and 6 months post-MV repair. Results LVEF (66 ± 1 to 54 ± 2% p<0.0001) and LV end-diastolic volume index (108 ± 5 to 78 ± 5 ml/m2 p<0.0001) decreased, while LV end-systolic volume index (ESVI) was 60% above normal pre- and post-MV repair (p<0.05). LV circumferential and longitudinal strain rates decreased below normal post-MV repair (6.38 ± 0.30 vs. 5.11 ± 0.25 p=0.0009, and 7.51 ± 0.50 vs. 5.31 ± 0.30, %RR, p<0.0001), as LVES stress (σ)/LVESVI ratio was depressed at baseline and post-MV repair vs. normals (0.25 ± 0.02 and 0.28 ± 0.01 vs. 0.33 ± 0.02, p < 0.01). LV biopsies demonstrated cardiomyocyte myofibrillar degeneration vs. normals (p=0.0016). Immunostaining and immunoblotting demonstrated increased xanthine oxidase (XO) in MR vs. normals (p<0.05). Lipofuscin deposition was increased in cardiomyocytes of MR vs. normals (0.62 ± 0.04 vs. 0.33 ± 0.04, % area, p <0.01). Conclusions Decreased LV strain rates and LVES σ/ESVI post-MV repair indicate contractile dysfunction, despite pre-surgical LVEF > 60%. Increased oxidative stress could cause myofibrillar degeneration and lipofuscin accumulation resulting in LV contractile dysfunction in MR.

Temporal pattern of left ventricular structural and functional remodeling following reversal of volume overload heart failure

“…These changes at short-term reversal were associated with increased cEDS, which is consistent with reported increased cEDS and reduced systolic function following mitral repair in canine hearts (36), adults (3,26), and children with congenital MR (22). The underlying mechanisms responsible for decreased systolic performance are unclear and may be attributed to changes in gene and protein expression, force generation, or Table 3.…”

The role of tenascin-C and oxidative stress in rheumatic and congenital heart valve diseases: an observational study

“…Another study reported normal plasma and tissue OSI levels in rheumatic HVD, in spite of low tissue TAC levels (17). On the other hand, increased oxidative stress levels were demonstrated in the tissue and serum of patients with degenerative MR (26,36). In the present study, the levels of serum TAC, TOS, and OSI were found to be statistically similar in both the rheumatic and the congenital HVD groups.…”

Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload

“…To gain further insight into the intracellular biochemical consequences of VO, we have shown that cyclical stretch of adult rat cardiomyocytes increases XO activity and results in mitochondrial swelling, disorganization, and myofibrillar degeneration that is similar to the changes identified in the human LV with isolated mitral regurgitation (1,18). Treatment of stretched cardiomyocytes with allopurinol or the mitochondria-targeted antioxidant drug MitoQ prevents myofibrillar degeneration, mitochondrial damage, and the increase in XO activity (18).…”

“…Recently, our laboratory has demonstrated increased cardiomyocyte oxidative stress in patients with VO of isolated chronic mitral regurgitation (1) and in rats with VO of aortocaval fistula (ACF) (18,39). Specifically, xanthine oxidase (XO) is elevated in cardiomyocytes along with myofibrillar degeneration and mitochondrial dysfunction and damage, despite a preserved LV ejection fraction (LVEF).…”