Abstract 5307: Cardiomyocyte Sodium Accumulation Promotes Diastolic Dysfunction in Serca2 Knockout Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
William Louch ◽  
Karina Hougen ◽  
Magnus Aronsen ◽  
Halvor K Mork ◽  
Ivar Sjaastad ◽  
...  
Keyword(s):  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Gene Deletion ◽  
Diastolic Heart Failure ◽  
Functional Decline ◽  
Western Blots ◽  
Sodium Accumulation ◽  
Time Points ◽  
Rate Of Decline

Terminal decompensation during heart failure involves deterioration of diastolic function. We investigated the mechanisms underlying this functional decline in mice with cardiomyocyte-specific, conditional excision of the Serca2 gene (KO). At 4 weeks following gene deletion, SERCA levels in KO cardiomyocytes were reduced by more than 95% from flox-flox (FF) controls. Surprisingly, echocardiographic measurements indicated only moderate impairment of in vivo function, as systolic and diastolic tissue velocities were 62% and 72% of FF values, respectively. Diastolic heart failure developed in KO between 6 and 7 weeks, as diastolic tissue velocity rapidly declined to 51% of FF values. We compared cardiomyocyte contractions and Ca 2+ cycling at the 4 and 7 week time points. In KO cells, contractions were reduced between 4 and 7 weeks (from 40% to 14% of FF values), and the rate of relaxation was slowed (from 11% to 3% of FF values). Similar alterations were observed in Ca 2+ transients. Sarcoplasmic reticulum (SR) Ca 2+ content was markedly reduced in 4-week KO, although a minute thapsigargin-sensitive SR Ca 2+ release could be induced. SR content was further decreased in 7-week KO and SR Ca 2+ release was not detectable, although Western blots showed no difference in SERCA levels between 4 and 7 week KO. Ca 2+ influx via Ca 2+ channels was enhanced in KO (integrated current ≈200% of FF) at both time points. However, greater NCX-mediated Ca 2+ extrusion in 4-week KO was partially reversed in 7-week KO due to elevation in cytosolic [Na + ] (34 mM vs 25 mM in FF). Normalizing cytosolic [Na + ] using patch clamp increased the rate of decline of the Ca 2+ transient in 7-week KO to 4-week KO values. Thus, KO mice compensate for loss of SR function by increasing trans-sarcolemmal Ca 2+ flux. However, in the longer term, cytosolic Na + accumulation impairs NCX-mediated Ca 2+ extrusion, which promotes development of diastolic heart failure.

Abstract 361: Loss of Cardiac Retinoic Acid Receptor Alpha Promotes Diastolic Heart Failure With Preserved Ejection Fraction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sen Zhu ◽  
Rakeshwar Guleria ◽  
Candice Thomas ◽  
Fnu Gerilechaogetu ◽  
Amanda Roth ◽  
...  
Keyword(s):  
Heart Failure ◽  
Retinoic Acid ◽  
Ejection Fraction ◽  
Gene Deletion ◽  
Retinoic Acid Receptor ◽  
Diastolic Heart Failure ◽  
Left Ventricular ◽  
Heart Weight ◽  
Preserved Ejection Fraction ◽  
Acid Receptor

Objectives: We have previously demonstrated that the expression/activation of retinoic acid receptor (RAR) is inhibited in diabetic hearts, and that activation of RARα prevents diabetes-induced diastolic heart failure, suggesting that impairment of RARα signaling may be a critical mechanism in heart failure. Methods and Results: Cardiac RARα gene deletion (KO) was achieved by tamoxifen injection at 6-weeks old RARαfl/fl α-MHC-MerCreMer mice, RARαfl/fl mice were used as control (WT). Heart function was monitored by echocardiograph for 64 wks. Mice were sacrificed at 20 or 64 wks post gene deletion, respectively. A significant decrease in E/A ratio and TDI E’ and increase in IVRT (isovolumic relaxation time) and DT (deceleration time) suggested diastolic dysfunction after 16 wks of gene deletion in KO mice, which was confirmed by cardiac catheterization (decreased dP/dtmin and increased tau). Concentric hypertrophy developed in KO mice after 56 wks of gene deletion, as confirmed by increased thickness of left ventricular wall and interventricular septum and elevated heart weight/tibia length ratio. However, no significant difference was observed in LVEF (LV ejection fraction), FS (fraction shortening) and dP/dtmax between KO and WT mice. Significantly increased gene expression of NOX2 (NADPH oxidase 2) and NOX4, decreased SOD1 and SOD2 levels and increased intracellular reactive oxygen species (ROS) were observed in KO mouse hearts, along with a significantly decreased protein expression of SERCA2a and CaMKIIδ, decreased phosphorylation of PLB, Akt and CaMKIIδ. Overexpression of RARα in cardiomyocytes rescued RARα deletion-induced changes in SERCA2a, PLB, Akt and CaMKIIδ. Deletion of RARα in cardiomyocytes impaired intracellular calcium reuptake into SR and cardiomyocyte relaxation. Inhibition of ROS by N-acetyl cysteine abolished RARα deletion-induced calcium mishandling and cardiomyocyte relaxation. Conclusion: Cardiac specific deletion of RARα induces diastolic heart failure with preserved ejection fraction (HFpEF), by promoting intracellular ROS and disrupting SERCA2a-mediated calcium reuptake and cardiomyocyte relaxation. Our study suggests that deficiency in RARα signaling is a novel mechanism leading to HFpEF.

Abstract 12877: Magnesium Deficiency Causes Reversible Metabolic Diastolic and Systolic Cardiomyopathies

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Man Liu ◽  
Hong LIU ◽  
Feng Feng ◽  
An Xie ◽  
Cody R Hou ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dysfunction ◽  
Magnesium Deficiency ◽  
Diastolic Heart Failure ◽  
Cellular Level ◽  
Normal Diet ◽  
Ca Channel ◽  
Mg Deficiency ◽  
Mitochondrial Membrane Depolarization

Introduction: Low circulating magnesium (Mg) level is associated with increased cardiovascular mortality, and conversely, dietary Mg intake is associated with a decreased risk of developing heart failure. Hypothesis: We investigated whether Mg deficiency alone could cause cardiomyopathy. Methods: C57BL/6J mice were fed with a low-Mg diet (low-Mg, 15-30 mg/kg Mg) or a normal diet (nl-Mg, 600 mg/kg Mg) for 6 weeks. To test reversibility, half of the low-Mg mice were fed then with normal diet for another 6 weeks (low→nl-Mg group). Results: Mg deficiency increased mortality, especially in female mice. After 6 weeks of low-Mg diet, surviving mice showed significantly decreased serum Mg (0.9±0.1 vs. 2.8±0.1 mg/dL for nl-Mg) and a reciprocal increase in serum Ca, K, and Na. Low-Mg mice exhibited a decreased cardiac ejection fraction (EF%, 39.8±1.9% vs. 52.0±1.7% of nl-Mg) and impaired relaxation (E/e’: 21.1±1.1 vs. 15.4±0.4 of nl-Mg) in echocardiography. At the cellular level, ATP, Ca transient amplitude, sarcoplasmic reticulum (SR) Ca load, resting sarcomere length, and sarcomere shortening were all decreased significantly in low-Mg hearts and cardiomyocytes. These changes were accompanied by evidence of mitochondrial dysfunction with significantly increased mitochondrial ROS production and mitochondrial membrane depolarization. Mg repletion normalized electrolytes, contraction, relaxation, and cellular changes. The SR Ca pump (SERCA) was decreased, the SR Ca channel RyR2 oxidized, and cardiac myosin binding protein C S-glutathionylated in low-Mg mouse hearts. These changes were normalized with Mg repletion. In vivo , mitoTEMPO treatment during low Mg diet improved the cardiac relaxation and increased cellular ATP levels without improving contraction. Conclusions: Mg deficiency caused a reversible diastolic and systolic cardiomyopathy associated with mitochondrial dysfunction. This cardiomyopathy may explain the relationship of hypomagnesemia and worsening heart failure. Mg intake could reverse these changes, reinforcing the known correlation of increased Mg intake and reduced heart failure symptoms and mortality. In deficiency states, Mg supplementation may represent a novel treatment for systolic and diastolic heart failure.

Sarcoplasmic reticulum calcium leak contributes to arrhythmia but not to heart failure progression

2018 ◽  
Vol 10 (458) ◽  
pp. eaan0724 ◽  
Author(s):  
Belal A. Mohamed ◽  
Nico Hartmann ◽  
Petros Tirilomis ◽  
Karolina Sekeres ◽  
Wener Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Sarcoplasmic Reticulum ◽  
Ex Vivo ◽  
Pressure Overload ◽  
Volume Overload ◽  
Polymorphic Ventricular Tachycardia ◽  
Heart Failure Progression ◽  
Delayed Afterdepolarizations ◽  
Induced Pluripotent

Increased sarcoplasmic reticulum (SR) Ca2+ leak via the cardiac ryanodine receptor (RyR2) has been suggested to play a mechanistic role in the development of heart failure (HF) and cardiac arrhythmia. Mice treated with a selective RyR2 stabilizer, rycal S36, showed normalization of SR Ca2+ leak and improved survival in pressure overload (PO) and myocardial infarction (MI) models. The development of HF, measured by echocardiography and molecular markers, showed no difference in rycal S36– versus placebo-treated mice. Reduction of SR Ca2+ leak in the PO model by the rycal-unrelated RyR2 stabilizer dantrolene did not mitigate HF progression. Development of HF was not aggravated by increased SR Ca2+ leak due to RyR2 mutation (R2474S) in volume overload, an SR Ca2+ leak–independent HF model. Arrhythmia episodes were reduced by rycal S36 treatment in PO and MI mice in vivo and ex vivo in Langendorff-perfused hearts. Isolated cardiomyocytes from murine failing hearts and human ventricular failing and atrial nonfailing myocardium showed reductions in delayed afterdepolarizations, in spontaneous and induced Ca2+ waves, and in triggered activity in rycal S36 versus placebo cells, whereas the Ca2+ transient, SR Ca2+ load, SR Ca2+ adenosine triphosphatase function, and action potential duration were not affected. Rycal S36 treatment of human induced pluripotent stem cells isolated from a patient with catecholaminergic polymorphic ventricular tachycardia could rescue the leaky RyR2 receptor. These results suggest that SR Ca2+ leak does not primarily influence contractile HF progression, whereas rycal S36 treatment markedly reduces ventricular arrhythmias, thereby improving survival in mice.

scholarly journals Interferon-γ ablation exacerbates myocardial hypertrophy in diastolic heart failure

2012 ◽  
Vol 303 (5) ◽  
pp. H587-H596 ◽  
Author(s):  
Anthony G. Garcia ◽  
Richard M. Wilson ◽  
Joline Heo ◽  
Namita R. Murthy ◽  
Simoni Baid ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Ventricular Myocytes ◽  
Salt Water ◽  
Diastolic Heart Failure ◽  
Velocity Ratio ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Left Ventricular

Diastolic heart failure (HF) accounts for up to 50% of all HF admissions, with hypertension being the major cause of diastolic HF. Hypertension is characterized by left ventricular (LV) hypertrophy (LVH). Proinflammatory cytokines are increased in LVH and hypertension, but it is unknown if they mediate the progression of hypertension-induced diastolic HF. We sought to determine if interferon-γ (IFNγ) plays a role in mediating the transition from hypertension-induced LVH to diastolic HF. Twelve-week old BALB/c (WT) and IFNγ-deficient (IFNγKO) mice underwent either saline ( n = 12) or aldosterone ( n = 16) infusion, uninephrectomy, and fed 1% salt water for 4 wk. Tail-cuff blood pressure, echocardiography, and gene/protein analyses were performed. Isolated adult rat ventricular myocytes were treated with IFNγ (250 U/ml) and/or aldosterone (1 μM). Hypertension was less marked in IFNγKO-aldosterone mice than in WT-aldosterone mice (127 ± 5 vs. 136 ± 4 mmHg; P < 0.01), despite more LVH (LV/body wt ratio: 4.9 ± 0.1 vs. 4.3 ± 0.1 mg/g) and worse diastolic dysfunction (peak early-to-late mitral inflow velocity ratio: 3.1 ± 0.1 vs. 2.8 ± 0.1). LV ejection fraction was no different between IFNγKO-aldosterone vs. WT-aldosterone mice. LV end systolic dimensions were decreased significantly in IFNγKO-aldosterone vs. WT-aldosterone hearts (1.12 ± 0.1 vs. 2.1 ± 0.3 mm). Myocardial fibrosis and collagen expression were increased in both IFNγKO-aldosterone and WT-aldosterone hearts. Myocardial autophagy was greater in IFNγKO-aldosterone than WT-aldosterone mice. Conversely, tumor necrosis factor-α and interleukin-10 expressions were increased only in WT-aldosterone hearts. Recombinant IFNγ attenuated cardiac hypertrophy in vivo and modulated aldosterone-induced hypertrophy and autophagy in cultured cardiomyocytes. Thus IFNγ is a regulator of cardiac hypertrophy in diastolic HF and modulates cardiomyocyte size possibly by regulating autophagy. These findings suggest that IFNγ may mediate adaptive downstream responses and challenge the concept that inflammatory cytokines mediate only adverse effects.

scholarly journals Author response: Age-dependent diastolic heart failure in an in vivo Drosophila model

2017 ◽  
Author(s):  
Matthew P Klassen ◽  
Christian J Peters ◽  
Shiwei Zhou ◽  
Hannah H Williams ◽  
Lily Yeh Jan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Heart Failure ◽  
Author Response ◽  
Drosophila Model ◽  
Age Dependent
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