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Desmin loss and mitochondrial damage precede left ventricular systolic failure in volume overload heart failure.

ABSTRACT: Heart failure due to chronic volume overload (VO) in rats and humans is characterized by disorganization of the cardiomyocyte desmin/mitochondrial network. Here, we tested the hypothesis that desmin breakdown is an early and continuous process throughout VO. Male Sprague-Dawley rats had aortocaval fistula (ACF) or sham surgery and were examined 24 h and 4 and 12 wk later. Desmin/mitochondrial ultrastructure was examined by transmission electron microscopy (TEM) and immunohistochemistry (IHC). Protein and kinome analysis were performed in isolated cardiomyocytes, and desmin cleavage was assessed by mass spectrometry in left ventricular (LV) tissue. Echocardiography demonstrated a 40% decrease in the LV mass-to-volume ratio with spherical remodeling at 4 wk with ACF and LV systolic dysfunction at 12 wk. Starting at 24 h and continuing to 4 and 12 wk, with ACF there is TEM evidence of extensive mitochondrial clustering, IHC evidence of disorganization associated with desmin breakdown, and desmin protein cleavage verified by Western blot analysis and mass spectrometry. IHC results revealed that ACF cardiomyocytes at 4 and 12 wk had perinuclear translocation of ?B-crystallin from the Z disk with increased ?, ?-unsaturated aldehyde 4-hydroxynonelal. Use of protein markers with verification by TUNEL staining and kinome analysis revealed an absence of cardiomyocyte apoptosis at 4 and 12 wk of ACF. Significant increases in protein indicators of mitophagy were countered by a sixfold increase in p62/sequestosome-1, which is indicative of an inability to complete autophagy. An early and continuous disruption of the desmin/mitochondrial architecture, accompanied by oxidative stress and inhibition of apoptosis and mitophagy, suggests its causal role in LV dilatation and systolic dysfunction in VO.NEW & NOTEWORTHY This study provides new evidence of early onset (24 h) and continuous (4-12 wk) desmin misarrangement and disruption of the normal sarcomeric and mitochondrial architecture throughout the progression of volume overload heart failure, suggesting a causal link between desmin cleavage and mitochondrial disorganization and damage.

SUBMITTER: Guichard JL

PROVIDER: S-EPMC5538858 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Desmin loss and mitochondrial damage precede left ventricular systolic failure in volume overload heart failure.

Guichard Jason L JL Rogowski Michael M Agnetti Giulio G Fu Lianwu L Powell Pamela P Wei Chih-Chang CC Collawn James J Dell'Italia Louis J LJ

American journal of physiology. Heart and circulatory physiology 20170428 1

Heart failure due to chronic volume overload (VO) in rats and humans is characterized by disorganization of the cardiomyocyte desmin/mitochondrial network. Here, we tested the hypothesis that desmin breakdown is an early and continuous process throughout VO. Male Sprague-Dawley rats had aortocaval fistula (ACF) or sham surgery and were examined 24 h and 4 and 12 wk later. Desmin/mitochondrial ultrastructure was examined by transmission electron microscopy (TEM) and immunohistochemistry (IHC). Pr ...[more]

PMID: 28455287

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Project description:Current surgical management of volume overload-induced heart failure (HF) leads to variable recovery of left ventricular (LV) function despite a return of LV geometry. The mechanisms that prevent restoration of function are unknown but may be related to the timing of intervention and the degree of LV contractile impairment. This study determined whether reduction of aortocaval fistula (ACF)-induced LV volume overload during the compensatory stage of HF results in beneficial LV structural remodeling and restoration of pump function. Rats were subjected to ACF for 4 wk; a subset then received a load-reversal procedure by closing the shunt using a custom-made stent graft approach. Echocardiography or in vivo pressure-volume analysis was used to assess LV morphology and function in sham rats; rats subjected to 4-, 8-, or 15-wk ACF; and rats subjected to 4-wk ACF followed by 4- or 11-wk reversal. Structural and functional changes were correlated to LV collagen content, extracellular matrix (ECM) proteins, and hypertrophic markers. ACF-induced volume overload led to progressive LV chamber dilation and contractile dysfunction. Rats subjected to short-term reversal (4-wk ACF + 4-wk reversal) exhibited improved chamber dimensions (LV diastolic dimension) and LV compliance that were associated with ECM remodeling and normalization of atrial and brain natriuretic peptides. Load-independent parameters indicated LV systolic (preload recruitable stroke work, Ees) and diastolic dysfunction (tau, arterial elastance). These changes were associated with an altered ?/?-myosin heavy chain ratio. However, these changes were normalized to sham levels in long-term reversal rats (4-wk ACF + 11-wk reversal). Acute hemodynamic changes following ACF reversal improve LV geometry, but LV dysfunction persists. Gradual restoration of function was related to normalization of eccentric hypertrophy, LV wall stress, and ECM remodeling. These results suggest that mild to moderate LV systolic dysfunction may be an important indicator of the ability of the myocardium to remodel following the reversal of hemodynamic overload.

Project description:PurposeTo determine whether left ventricular (LV) extracellular volume (ECV) expansion is associated with atrial fibrillation (AF) or AF-mediated LV systolic dysfunction (LVSD) while minimizing the influence of biologic and imaging methodologic confounders.Materials and methodsThis study examined the prevalence of LV ECV expansion in 137 patients with AF (mean age, 62 years ± 11 [standard deviation]; 92 male patients and 45 female patients; 83 paroxysmal and 54 persistent) who underwent preablation cardiovascular MRI. Biologic confounders were minimized by measuring the ECV fraction and excluding patients with severe LV hypertrophy, defined as wall thickness greater than 1.5 cm. Imaging confounders were minimized by using an arrhythmia-insensitive-rapid (AIR) cardiac T1 mapping pulse sequence. Other cardiac functional parameters, including LV ejection fraction (LVEF) and left atrial end-diastolic volume indexed to body surface area, were assessed using cine cardiovascular MRI. A substudy was conducted in 32 patients with no AF (mean age, 54 years ± 16) in sinus rhythm to establish control values and convert these values between the AIR sequence and literature-based modified Look-Locker inversion recovery (MOLLI) values.ResultsThe mean ECV was not significantly different (P > .05) between patients with AF with a normal LVEF (24.5% ± 2.8; n = 107), patients with AF with LVSD (24.5% ± 2.5; n = 30), and patients with no AF (24.4% ± 3.8; n = 32), but there was a significant interaction between ECV and CHA2DS2-VASc score (P = .045). Compared with the literature data obtained from healthy control patients scanned using MOLLI, 99.3% of patients with AF had ECV below the fibrosis cutoff point (32.8% when converted from MOLLI T1 mapping to AIR T1 mapping), including a subset of patients with AF (n = 28) with low CHA2DS2-VASc score (0/1 for men/women).ConclusionStudy results suggest that an LV ECV expansion is not associated with AF or AF-mediated LVSD. Supplemental material is available for this article. © RSNA, 2020See also the commentary by Stillman in this issue.

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Desmin loss and mitochondrial damage precede left ventricular systolic failure in volume overload heart failure.

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Desmin loss and mitochondrial damage precede left ventricular systolic failure in volume overload heart failure.

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