allopurinol and Mitral-Valve-Insufficiency

Mechanisms of left ventricular (LV) dysfunction in isolated mitral regurgitation (MR) are not well understood. Vasodilator therapy in other forms of LV dysfunction reduces LV wall stress and improves LV function; however, studies in isolated MR show no beneficial effect on LV remodeling using vasodilator drugs or renin-angiotensin system blockade. Therefore, the search for new therapies that improve LV remodeling and function in isolated MR is clinically significant. Recent work in the authors' laboratory has demonstrated increased oxidants from a number of sources including the enzyme xanthine oxidase (XO) in the LV of patients with isolated MR. In addition to being a major source of reactive oxygen species, XO is linked to bioenergetic dysfunction because its substrates derive from adenosine triphosphate catabolism. Correspondingly, there was also evidence of aggregates of small mitochondria in cardiomyocytes, which is generally considered a response to bioenergetic deficit in cells. Future studies are required to determine whether XO and persistent oxidative stress are causative in maladaptive LV remodeling and offer potential therapeutic targets in ameliorating LV damage in patients with isolated MR.

Topics: Animals; Heart Failure; Humans; Mitochondria, Heart; Mitral Valve Insufficiency; Myocytes, Cardiac; Oxidative Stress; Reactive Oxygen Species; Vasodilator Agents; Ventricular Remodeling; Xanthine Oxidase

This study assessed myocardial damage in patients with chronic isolated mitral regurgitation (MR) and left ventricular ejection fraction (LVEF) >60%.. Typically, MR patients have decreased LVEF after mitral valve (MV) repair despite normal pre-operative LVEF.. Twenty-seven patients with isolated MR had left ventricular (LV) biopsies taken at time of MV repair. Magnetic resonance imaging with tissue tagging was performed in 40 normal subjects and in MR patients before and 6 months after MV repair.. LVEF (66 +/- 5% to 54 +/- 9%, p < 0.0001) and LV end-diastolic volume index (108 +/- 28 ml/m(2) to 78 +/- 24 ml/m(2), p < 0.0001) decreased, whereas left ventricular end-systolic (LVES) volume index was 60% above normal pre- and post-MV repair (p < 0.05). The LV circumferential and longitudinal strain rates decreased below normal following MV repair (6.38 +/- 1.38 vs. 5.11 +/- 1.28, p = 0.0009, and 7.51 +/- 2.58 vs. 5.31 +/- 1.61, percentage of R to R interval, p < 0.0001), as LVES stress/LVES volume index ratio was depressed at baseline and following MV repair versus normal subjects (0.25 +/- 0.10 and 0.28 +/- 0.05 vs. 0.33 +/- 0.12, p < 0.01). LV biopsies demonstrated cardiomyocyte myofibrillar degeneration versus normal subjects (p = 0.035). Immunostaining and immunoblotting demonstrated increased xanthine oxidase in MR versus normal subjects (p < 0.05). Lipofuscin deposition was increased in cardiomyocytes of MR versus normal subjects (0.62 +/- 0.20 vs. 0.33 +/- 0.11, percentage of area: p < 0.01).. Decreased LV strain rates and LVES wall stress/LVES volume index following 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.

Topics: Adult; Aged; Biopsy; Blotting, Western; Case-Control Studies; Female; Humans; Immunohistochemistry; Lipofuscin; Magnetic Resonance Imaging, Cine; Male; Microscopy, Electron, Transmission; Middle Aged; Mitral Valve Insufficiency; Myocardium; Myocytes, Cardiac; Oxidative Stress; Postoperative Period; Preoperative Period; Stroke Volume; Tyrosine; Ventricular Dysfunction, Left; Xanthine Dehydrogenase; Xanthine Oxidase