Disruption of desmin-mitochondrial architecture in patients with regurgitant mitral valves and preserved ventricular function

Abstract

Objective-Recent studies have demonstrated improved outcomes in patients receiving early surgery for degenerative mitral valvular regurgitation (MR) rather than adhering to conventional guidelines for surgical intervention. However, studies providing a mechanistic basis for these findings are limited. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Central Message: Chronic cardiomyocyte oxidative stress and disruption of the desmin cytoskeleton may explain post-operative LV functional decline in patients with well preserved LV function and adherence to conventional guidelines.Perspective Statement: Recent studies report improved outcomes in patients receiving early surgery for degenerative mitral regurgitation. Severe cardiomyocyte oxidative stress and desmin and mitochondrial disruption in patients with isolated mitral regurgitation and LVEF>60% may underpin the decrement in LV systolic function post valve repair and further supports the move toward earlier surgical intervention. Central HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptMethods-Left ventricular (LV) myocardium from 22 patients undergoing mitral valve repair for Class I indications was evaluated for desmin, the voltage-dependent anion channel, αβ-crystallin, and α, β unsaturated aldehyde 4-hydroxynonelal by fluorescence microscopy and in 6 normal control LV autopsy specimens. Cardiomyocyte ultrastructure was examined by transmission electron microscopy. Magnetic resonance imaging with tissue tagging was performed in 55 normal subjects and 22 MR patients pre-and 6 months post-mitral valve repair.Results-LV end-diastolic volume was 1.5-fold (p<0.0001) higher and LV mass to volume ratio was lower in MR (p=0.004) vs. normal and improvement six months after mitral valve surgery. However, LV ejection fraction decreased from 65 ± 7 to 52 ± 9% (p<0.0001) and LV circumferential (p<0.0001) and longitudinal strain decreased significantly below normal values (p=0.002) post-surgery. MR hearts had a 53% decrease in desmin (p<0.0001) and a 2.6-fold increase in desmin aggregates (p<0.0001) vs. normal along with significant, intense perinuclear staining of α, β unsaturated aldehyde 4-hydroxynonelal in areas of mitochondrial breakdown and clustering. Transmission electron microscopy demonstrated numerous electron dense deposits, myofibrillar loss, Z-line abnormalities and extensive granulofilamentous debris identified as desmin positive by immunogold transmission electron microscopy.Conclusion-Despite well-preserved preoperative LV ejection fraction, severe oxidative stress an...

Chymase uptake by cardiomyocytes results in myosin degradation in cardiac volume overload

“…Myofibrillar breakdown has been reported in the human with chronic isolated MR [9, 23] and in the dog [18] with experimentally-induced chronic MR by hematoxylin and eosin staining and transmission electron microscopy. Fig.…”

“…In addition to an increase in mast cells in VO, we have demonstrated fibroblast production of chymase that results in intracellular autophagic breakdown of procollagen and fibronectin in the rat [6]. There is also a concomitant breakdown of cardiomyocyte myofibrils and the major intermediate filament desmin [7, 8, 9]. Thus, extracellular and intracellular structural protein breakdown is the underpinning of cardiomyocyte elongation and thinning that translates to LV spherical dilatation and wall thinning.…”

Bromine inhalation mimics ischemia-reperfusion cardiomyocyte injury and calpain activation in rats

“…Tissue analysis. Transmission electron microscopy (TEM) was performed as previously described in our laboratory (EMLabs, Birmingham, AL) (6,21). Immunoblots on cardiac tissues were performed according to previously described methods using previously validated antibodies (4).…”

Cardiovascular magnetic resonance imaging to assess myocardial fibrosis in valvular heart disease

“…Similarly, Mankad et al showed with CMR tagging abnormal regional strain patterns in patients with severe MR and preserved LV ejection fraction: while radial strain was increased (19 ± 9 vs. 16 ± 6%, p = 0.003), circumferential strain was reduced (12 ± 6 vs. 21 ± 6%, p ≤ 0.001) as compared to healthy controls [ 71 ]. Several authors have demonstrated a decrease in global longitudinal and circumferential strain parameters on CMR tagging in patients with severe degenerative MR after mitral valve repair, which might imply an ongoing myocardial fibrosis after surgery [ 72 – 74 ].…”