Reduced myocardial expression of calcium handling protein in patients with severe chronic mitral regurgitation☆☆☆

Leszek, Przemysław; Korewicki, J; Klisiewicz, Anna; Janas, Jadwiga; Biederman, Andrzej; Browarek, A.; Charlemagne, D.; Trouvé, Pascal

doi:10.1016/j.ejcts.2006.07.008

Cited by 13 publications

(10 citation statements)

References 26 publications

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“…Nevertheless, the marked lipofuscin accumulation and myofibrillar degeneration in LV endomyocardial biopsies are indeed markers of heart failure that were present in patients with otherwise normal LV strain rates and LVEF prior to surgery. This underscores the unreliability of ejection phase indices in reflecting underlying LV myocardial damage on ours and other studies (8–10). These findings may be of use in defining the optimal timing of mitral valve surgery.…”

Section: Discussionsupporting

confidence: 66%

“…Previous studies in patients with isolated MR and LVEF > 55% have demonstrated decreases in the force-frequency effect in isolated LV muscle strips (9) and in LV calcium handling proteins (8), indicative of mechanical and biochemical markers of heart failure. In another study, LV TNF-α was increased in patients with isolated MR and well preserved LVEF (13).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, it is well accepted that LVEF may belie the degree of dysfunction in the setting of MR. Indeed, some studies have reported myocardial dysfunction from LV muscle strips, derangement of calcium handling proteins, and increased cytokines in patients with isolated MR despite LVEF > 55% (8–10)—all of which can be associated with and/or attributed to increased oxidative stress. Xanthine oxidase (XO) is well characterized as a major contributor to free radical generation and oxidative stress in the cardiovascular system (11).…”

Section: Introductionmentioning

confidence: 99%

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

Ahmed

Gladden

Litovsky

et al. 2010

Journal of the American College of Cardiology

129

123

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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.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Ahmed

Gladden

Litovsky

et al. 2010

Journal of the American College of Cardiology

129

123

View full text Add to dashboard Cite

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“…It is of interest that previous studies report that in patients with isolated MR, who largely present in Class III to IV heart failure, there is a down regulation of SERCA2a LV protein levels and a negative correlation between SERCA2a protein levels and LV end-diastolic diameter. 10,11 Thus, as with the failing heart, the decompensated MR heart has decreased SERCA2a expression, whereas in our patients who largely presented in Class I and II symptoms, β-adrenergic signaling is increased and SERCA2a mRNA and protein expression is unchanged at this earlier stage in isolated MR.…”

Section: Discussionmentioning

confidence: 49%

Increased Sarcolipin Expression and Adrenergic Drive in Humans With Preserved Left Ventricular Ejection Fraction and Chronic Isolated Mitral Regurgitation

Zheng

Yancey

Ahmed

et al. 2014

Circ: Heart Failure

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Background There is currently no therapy proven to attenuate left ventricular (LV) dilatation and dysfunction in the volume overload induced by isolated mitral regurgitation (MR). To better understand molecular signatures underlying isolated MR, we performed LV gene expression analyses and overlaid regulated genes into Ingenuity Pathway Analysis in patients with isolated MR. Methods and Results Gene arrays from LV tissue of 35 patients, taken at the time of surgical repair for isolated MR, were compared to 13 normal controls. Cine-magnetic resonance imaging (MRI) was performed in 31 patients before surgery to measure LV function and volume from serial short axis summation. LV end-diastolic volume was 2-fold (p=0.005) higher than normals and LV ejection fraction (EF) was 64±7% (50-79%) in MR patients. Ingenuity pathway analysis identified significant activation of pathways involved in β-adrenergic, cyclic AMP, and G-protein coupled signaling; while there was downregulation of pathways associated with complement activation and acute phase response. SERCA2a and phospholamban protein were unchanged in MR vs. control LVs. However, mRNA and protein levels of the sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) regulatory protein sarcolipin, which is predominantly expressed in normal atria, were increased 12- and 6-fold respectively. Immunofluorescence analysis confirmed the absence of sarcolipin in normal LVs and its marked upregulation in MR LVs. Conclusions These results demonstrate alterations in multiple pathways associated with β-adrenergic signaling and sarcolipin in the LVs of patients with isolated MR and LVEF > 50%,suggesting a beneficial role for β-adrenergic blockade in isolated MR.

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“…To quantify the expression of the KA1 subunit and GAPDH, the PCR products were analyzed using the density-metric program (Multi Gauge) of a Las-3000 image analyzer (Fuji, Japan) after gel scanning with Gel-Doc 1000 (Bio-Rad, Italy). The expression density of the KA1 subunit PCR products was normalized against GAPDH [9,21,43]. The normalized data of each group (juvenile KA1/GAPDH, prepubescent KA1/GAPDH and adult KA1/GAPDH) were renormalized according to the juvenile density of each group.…”

Section: Methodsmentioning

confidence: 99%

Expression of KA1 kainate receptor subunit in the substantia gelatinosa of the trigeminal subnucleus caudalis in mice

Park

Han

2010

J Vet Sci

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The KA1 kainate receptor (KAR) subunit in the substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) has been implicated in the processing of nociceptive information from the orofacial region. This study compared the expression of the KA1 KAR subunit in the SG of the Vc in juvenile, prepubescent and adult mice. RT-PCR, Western blot and immunohistochemistry analyses were used to examine the expression level in SG area. The expression levels of the KA1 KAR subunit mRNA and protein were higher in juvenile mice than in prepubescent or adult mice. Quantitative data revealed that the KA1 KAR subunit mRNA and protein were expressed at levels approximately two and three times higher, respectively, in juvenile mice than in adult mice. A similar expression pattern of the KA1 KAR subunit was observed in an immunohistochemical study that showed higher expression in the juvenile (59%) than those of adult (35%) mice. These results show that the KA1 KAR subunits are expressed in the SG of the Vc in mice and that the expression level of the KA1 KAR subunit decreases gradually with postnatal development. These findings suggest that age-dependent KA1 KAR subunit expression can be a potential mechanism of age-dependent pain perception.

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Reduced myocardial expression of calcium handling protein in patients with severe chronic mitral regurgitation☆☆☆

Abstract: In chronic volume overload the down-regulation of SERCA2a and 2b at the mRNA and SERCA2 protein levels exist. Moreover, protein levels of SERCA2 tend to correlate to the grade of left ventricular diastolic dilatation and suggest an important role LV remodeling.

Cited by 13 publications

References 26 publications

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

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

Increased Sarcolipin Expression and Adrenergic Drive in Humans With Preserved Left Ventricular Ejection Fraction and Chronic Isolated Mitral Regurgitation

Expression of KA1 kainate receptor subunit in the substantia gelatinosa of the trigeminal subnucleus caudalis in mice

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