Cytosolic H2O2 mediates hypertrophy, apoptosis, and decreased SERCA activity in mice with chronic hemodynamic overload

Oxidative stress in the myocardium plays an important role in the pathophysiology of hemodynamic overload. The mechanism by which reactive oxygen species (ROS) in the cardiac myocyte mediate myocardial failure in hemodynamic overload is not known. Accordingly, our goals were to test whether myocyte-specific overexpression of peroxisomal catalase (pCAT) that localizes in the sarcoplasm protects mice from hemodynamic overload-induced failure and prevents oxidation and inhibition of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA), an important sarcoplasmic protein. Chronic hemodynamic overload was caused by ascending aortic constriction (AAC) for 12 wk in mice with myocyte-specific transgenic expression of pCAT. AAC caused left ventricular hypertrophy and failure associated with a generalized increase in myocardial oxidative stress and specific oxidative modifications of SERCA at cysteine 674 and tyrosine 294/5. pCAT overexpression ameliorated myocardial hypertrophy and apoptosis, decreased pathological remodeling, and prevented the progression to heart failure. Likewise, pCAT prevented oxidative modifications of SERCA and increased SERCA activity without changing SERCA expression. Thus cardiac myocyte-restricted expression of pCAT effectively ameliorated the structural and functional consequences of chronic hemodynamic overload and increased SERCA activity via a post-translational mechanism, most likely by decreasing inhibitory oxidative modifications. In pressure overload-induced heart failure cardiac myocyte cytosolic ROS play a pivotal role in mediating key pathophysiologic events including hypertrophy, apoptosis, and decreased SERCA activity.

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Abstract 1582: Adenosine A3 Receptor Deficiency Exerts Unanticipated Protective Effects on Pressure Overloaded-Induced Left Ventricular Hypertrophy and Dysfunction in Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_351 ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Zhongbing Lu ◽

John Fassett ◽

Xin Xu ◽

Xinli Hu ◽

Guangshuo Zhu ◽

...

Keyword(s):

Oxidative Stress ◽

Ventricular Hypertrophy ◽

Pressure Overload ◽

Heart Association ◽

Left Ventricular ◽

Neonatal Rat ◽

Protective Effects ◽

Rat Cardiomyocytes ◽

Extracellular Adenosine ◽

Myocardial Oxidative Stress

Endogenous adenosine can protect the overloaded heart against the development of hypertrophy and heart failure, but the contribution of A 1 receptors (A 1 R) and A 3 receptors(A 3 R) is not known. To test the hypothesis A 1 R and A 3 R can protect the heart against systolic overload, we exposed A 3 R gene deficient (A 3 R KO) mice and A 1 R KO mice to transverse aortic constriction (TAC). Contrary to our hypothesis, A 3 R KO attenuated 5 weeks TAC-induced left ventricular (LV) hypertrophy (ratio of ventricular mass/body weight increased to 7.6 ±0.3 mg/g in wild type (Wt) mice as compared with 6.3±0.4 mg/g in KO), fibrosis and dysfunction (LV ejection fraction decreased to 43±2.5% and 55±4.2% in Wt and KO mice, respectively). A 3 R KO also attenuated the TAC-induced increases of myocardial ANP and the oxidative stress markers 3-nitrotyrosine(3-NT ) and 4-hydroxynonenal. In addition, A 3 R KO significantly attenuated TAC-induced activation of multiple MAP kinase pathways, and the activation of Akt-GSK signaling pathway. In contrast, A 1 R-KO increased TAC-induced mortality, but did not alter ventricular hypertrophy or dysfunction compared to Wt mice. In mice in which extracellular adenosine production was impaired by CD73 KO, TAC caused greater hypertrophy and dysfunction, and increased myocardial 3-NT, indicates that extracellular adenosine protects heart against TAC-induced ventricular oxidative stress and hypertrophy. In neonatal rat cardiomyocytes induced to hypertrophy with phenylephrine, the adenosine analogue 2-chloroadenosine (CADO) reduced cell area, protein synthesis, ANP and 3-NT. Antagonism of A3R significantly potentiated the anti-hypertrophic effects of CADO. Our data demonstrated that extracellular adenosine exerts protective effects on the overloaded heart, but A 3 R act counter to the protective effect of adenosine. The data suggest that selective attenuation of A 3 R activity might be a novel approach to attenuate pressure overload-induced myocardial oxidative stress, LV hypertrophy and dysfunction. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

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Alleviation of Inflammation and Oxidative Stress in Pressure Overload-Induced Cardiac Remodeling and Heart Failure via IL-6/STAT3 Inhibition by Raloxifene

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6699054 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Shengqi Huo ◽

Wei Shi ◽

Haiyan Ma ◽

Dan Yan ◽

Pengcheng Luo ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Protein Expression ◽

Cardiac Remodeling ◽

Pressure Overload ◽

Left Ventricular ◽

Stat3 Signaling ◽

H9c2 Myoblasts ◽

And Oxidative Stress ◽

Stat3 Inhibition

Background. Inflammation and oxidative stress are involved in the initiation and progress of heart failure (HF). However, the role of the IL6/STAT3 pathway in the pressure overload-induced HF remains controversial. Methods and Results. Transverse aortic constriction (TAC) was used to induce pressure overload-HF in C57BL/6J mice. 18 mice were randomized into three groups (Sham, TAC, and TAC+raloxifene, n = 6 , respectively). Echocardiographic and histological results showed that cardiac hypertrophy, fibrosis, and left ventricular dysfunction were manifested in mice after TAC treatment of eight weeks, with aggravation of macrophage infiltration and interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) expression in the myocardium. TAC (four and eight weeks) elevated the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) and prohibitin2 (PHB2) protein expression. Importantly, IL-6/gp130/STAT3 inhibition by raloxifene alleviated TAC-induced myocardial inflammation, cardiac remodeling, and dysfunction. In vitro, we demonstrated cellular hypertrophy with STAT3 activation and oxidative stress exacerbation could be elicited by IL-6 (25 ng/mL, 48 h) in H9c2 myoblasts. Sustained IL-6 stimulation increased intracellular reactive oxygen species, repressed mitochondrial membrane potential (MMP), decreased intracellular content of ATP, and led to decreased SOD activity, an increase in iNOS protein expression, and increased protein expression of Pink1, Parkin, and Bnip3 involving in mitophagy, all of which were reversed by raloxifene. Conclusion. Inflammation and IL-6/STAT3 signaling were activated in TAC-induced HF in mice, while sustained IL-6 incubation elicited oxidative stress and mitophagy-related protein increase in H9c2 myoblasts, all of which were inhibited by raloxifene. These indicated IL-6/STAT3 signaling might be involved in the pathogenesis of myocardial hypertrophy and HF.

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Abstract 1271: IKKβ/NF-κB Pathway Protects Hearts from Hemodynamic Stress Mediated through Regulating MnSOD Expression

Circulation ◽

10.1161/circ.116.suppl_16.ii_259-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Shungo Hikoso ◽

Kinya Otsu ◽

Osamu Yamaguchi ◽

Toshihiro Takeda ◽

Masayuki Taniike ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Remodeling ◽

Weight Ratio ◽

Pressure Overload ◽

Left Ventricular ◽

Negative Regulator ◽

Iκb Kinase ◽

Jnk Activation

Objectives: We have previously reported that NF-κB contributes to GPCR agonist-induced hypertrophy in cultured cardiomyocytes. However, the in vivo role of this pathway in the pathogenesis of cardiac remodeling remains to be elucidated. Although IκB kinase β (IKKβ)/NF-κB pathway is a major negative regulator of cell death, it can sensitize cells to death-inducing stimuli in some instances, thus it can be either anti- or pro-apoptotic. In this study, we aimed to clarify the role of IKKβ/NF-κB signaling in cardiac remodeling using cardiac-specific IKKβ deficient mice. Methods and Results: We crossed mice bearing an IKK β flox allele with mice expressing the Cre recombinase under the control of the myosin light chain 2v promoter ( MLC2v-Cre +/− ) to generate IKK β flox/flox ; MLC2v-Cre +/− mice (conditional knockout:CKO). Then, CKO mice (n=14) and control littermates bearing IKK β flox/flox (CTRL, n=14) were subjected to pressure overload by means of transverse aortic constriction (TAC). EMSA analysis revealed NF-κB DNA binding activity after TAC had attenuated in CKO hearts. One week after TAC, echocardiography showed significantly lower left ventricular fractional shortening (26.9±2.7% vs. 41.4±0.9%, p<0.01), and higher left ventricular end-diastolic dimension (4.02±0.14 mm vs. 3.47±0.08 mm, p<0.01) and lung weight/body weight ratio (11.1±1.4 vs. 5.5±0.1, p<0.01) in CKO mice compared with CTRL mice, indicating the development of heart failure in CKO mice. Number of apoptotic cells had increased in CKO hearts after TAC, suggesting that the enhanced apoptosis is a cause for heart failure. The expression levels of MnSOD mRNA and protein after TAC, which is one of NF-κB target genes, were significantly lower in CKO than those in CTRL mice. As a consequence, oxidative stress and JNK activation in CKO hearts after TAC had significantly increased compared with those in CTRL heart, suggesting that increased oxidative stress and enhanced JNK activity resulted in cardiomyocyte apoptosis in CKO hearts. Conclusion: These results show that IKKβ/NF-κB pathway in cardiomyocyte plays a protective role mediated through attenuation of oxidative stress and JNK activation in response to pressure overload.

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Abstract 069: Mitochondrial Mechanisms Of Reverse Remodeling In Heart Failure

Circulation Research ◽

10.1161/res.113.suppl_1.a069 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Preeti Ahuja ◽

William R MacLellan ◽

Yibin Wang

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Cardiac Myocyte ◽

Pressure Overload ◽

Left Ventricular ◽

Reverse Remodeling ◽

Ventricular Assist ◽

Hypertrophic Response ◽

Mtdna Deletions ◽

And Function

Enhancement of myocardial mitochondrial (mt) function resulting in efficient energy production by means of Left ventricular assist device (LVAD) has been suggested in heart failure (HF) which could have important clinical implications and may represent a novel therapeutic target. However, the basis for this improvement remains unknown. To characterize mt biogenesis, mt genomic integrity and mitophagy in reversing pathological remodeling, we investigated LV tissue from post-LVAD human hearts and after reversal of transaortic constriction (TAC) in mice. In Post-LVAD human hearts there was increased expression of mt fusion and biogenesis, mtDNA levels were normalized and deletion mutation rates were significantly reduced with reverse remodeling and these changes were associated with enhancement of mt ETC complex I and II activities and improved cardiac-myocyte morphology. To better understand the mechanisms underlying mt repair/remodeling with LVAD support, we developed a model of aortic banding (AB) and debanding (DB) in mice. C57BL/6 mice were subjected to 2 weeks of AB and subsequent DB for period of 1 to 20 days and cardiac function and hypertrophy were evaluated by echocardiography and real-time PCR, respectively. Compared with control animals, mice that had undergone banding had a robust hypertrophic response with decline in cardiac function. These parameters were reversed following removal of pressure overload by DB. Even 1 day of unloading led to significant increase in the expression of mt fusion and biogenesis genes. Hearts from AB (2 weeks) mice showed a 3.7-fold (P<0.05) increase in frequency of mtDNA deletions. However, mtDNA deletions were significantly reduced in frequency with DB when compared with AB hearts alone. Increase in expression of autophagy related genes could also be observed after hemodynamic unloading in mouse failing hearts. Removal of pressure overload by DB led to 2.58-fold (P<0.05) increase in expression of LC3B when compared to sham and AB mice. Thus, our data strongly suggest that protective effect of enhanced mt biogenesis, fusion/mtDNA repair and removal of damaged mitochondria by mitophagy could play an important role in maintaining mt integrity and function in the adult heart with reverse remodeling.

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Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00720.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. H1146-H1153 ◽

Cited By ~ 66

Author(s):

Jo El J. Schultz ◽

Betty J. Glascock ◽

Sandra A. Witt ◽

Michelle L. Nieman ◽

Kalpana J. Nattamai ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Contractility ◽

Pressure Overload ◽

Left Ventricular ◽

Wild Type ◽

Human Heart Failure ◽

Protein Levels ◽

Plasmic Reticulum ◽

Lv Mass ◽

Pump Activity

We recently developed a mouse model with a single functional allele of Serca2 ( Serca2+/–) that shows impaired cardiac contractility and relaxation without overt heart disease. The goal of this study was to test the hypothesis that chronic reduction in sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2 levels in combination with an increased hemodynamic load will result in an accelerated pathway to heart failure. Age-matched wild-type and Serca2+/– mice were subjected to 10 wk of pressure overload via transverse aortic coarctation surgery. Cardiac hypertrophy and heart failure were assessed by echocardiography, gravimetry/histology, hemodynamics, and Western blotting analyses. Our results showed that ∼64% of coarcted Serca2+/– mice were in heart failure compared with 0% of coarcted wild-type mice ( P < 0.05). Overall, morbidity and mortality were greatly increased in Serca2+/– mice under pressure overload. Echocardiography assessment revealed a significant increase in left ventricular (LV) mass, and LV hypertrophy in coarcted Serca2+/– mice converted from a concentric to an eccentric pattern, similar to that seen in human heart failure. Coarcted Serca2+/– mice had decreased contractile/systolic and relaxation/diastolic performance and/or function compared with coarcted wild-type mice ( P < 0.05), despite a similar duration and degree of pressure overload. SERCA2a protein levels were significantly reduced (>50%) in coarcted Serca2+/– mice compared with noncoarcted and coarcted wild-type mice. Our findings suggest that reduction in SERCA2 levels in combination with an increased hemodynamic load results in an accelerated pathway to heart failure.

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Minoxidil accelerates heart failure development in rats with ascending aortic constriction

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y98-068 ◽

1998 ◽

Vol 76 (6) ◽

pp. 613-620 ◽

Cited By ~ 4

Author(s):

Marian Turcani ◽

Ruthard Jacob

Keyword(s):

Heart Failure ◽

Myocardial Contractility ◽

Pressure Overload ◽

Volume Overload ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Aortic Constriction ◽

Lung Weight ◽

Eccentric Hypertrophy ◽

Hemodynamic Overload

To test the ability of the heart to express characteristic geometric features of concentric and eccentric hypertrophy concurrently, constriction of the ascending aorta was performed in 4-week-old rats. Simultaneously, these rats were treated with an arteriolar dilator minoxidil. An examination 6 weeks after induction of the hemodynamic overload revealed no signs of congestion in systemic or pulmonary circulation in rats with aortic constriction or minoxidil-treated sham-operated rats. The magnitude of hemodynamic overload caused by aortic constriction or minoxidil treatment could be considered as equivalent, because the same enlargement of left ventricular pressure-volume area was necessary to compensate for either pressure or volume overload. Myocardial contractility decreased in rats with aortic constriction, and the compensation was achieved wholly by the marked concentric hypertrophy. Volume overload in minoxidil-treated rats was compensated partially by the eccentric hypertrophy and partially by the increased myocardial contractility. In contrast, increased lung weight and pleural effusion were found in all minoxidil-treated rats with aortic constriction. Unfavorable changes in left ventricular mass and geometry, relatively high chamber stiffness, and depressed ventricular and myocardial function were responsible for the massive pulmonary congestion.Key words: cardiac hypertrophy, heart failure, pressure overload, volume overload, minoxidil.

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Left Ventricular SGLT1 Protein Expression Correlates with the Extent of Myocardial Nitro-Oxidative Stress in Rats with Pressure and Volume Overload-Induced Heart Failure

Antioxidants ◽

10.3390/antiox10081190 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1190

Author(s):

Alex Ali Sayour ◽

Mihály Ruppert ◽

Attila Oláh ◽

Kálmán Benke ◽

Bálint András Barta ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Protein Expression ◽

Volume Overload ◽

Left Ventricular ◽

Diabetic Rat ◽

Strong Positive Correlation ◽

Sodium Glucose Cotransporter ◽

Hemodynamic Overload

Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to be upregulated in humans with heart failure (HF) with or without diabetes. In vitro studies have linked SGLT1 to increased nitro-oxidative stress in cardiomyocytes. We aimed to assess the relation between left ventricular (LV) SGLT1 expression and the extent of nitro-oxidative stress in two non-diabetic rat models of chronic heart failure (HF) evoked by either pressure (TAC, n = 12) or volume overload (ACF, n = 12). Sham-operated animals (Sham-T and Sham-A, both n = 12) served as controls. Both TAC and ACF induced characteristic LV structural and functional remodeling. Western blotting revealed that LV SGLT1 protein expression was significantly upregulated in both HF models (both p < 0.01), whereas the phosphorylation of ERK1/2 was decreased only in ACF; AMPKα activity was significantly reduced in both models. The protein expression of the Nox4 NADPH oxidase isoform was increased in both TAC and ACF compared with respective controls (both p < 0.01), showing a strong positive correlation with SGLT1 expression (r = 0.855, p < 0.001; and r = 0.798, p = 0.001, respectively). Furthermore, SGLT1 protein expression positively correlated with the extent of myocardial nitro-oxidative stress in failing hearts assessed by 3-nitrotyrosin (r = 0.818, p = 0.006) and 4-hydroxy-2-nonenal (r = 0.733, p = 0.020) immunostaining. Therefore, LV SGLT1 protein expression was upregulated irrespective of the nature of chronic hemodynamic overload, and correlated significantly with the expression of Nox4 and with the level of myocardial nitro-oxidative stress, suggesting a pathophysiological role of SGLT1 in HF.

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MitoQ regulates redox-related noncoding RNAs to preserve mitochondrial network integrity in pressure-overload heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00617.2019 ◽

2020 ◽

Vol 318 (3) ◽

pp. H682-H695 ◽

Cited By ~ 4

Author(s):

Seulhee Kim ◽

Jiajia Song ◽

Patrick Ernst ◽

Mary N. Latimer ◽

Chae-Myeong Ha ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Sarcoplasmic Reticulum ◽

Posttranscriptional Regulation ◽

Noncoding Rnas ◽

Pressure Overload ◽

Left Ventricular ◽

Mouse Heart ◽

Mitochondrial Network ◽

Mitofusin 2

Evidence suggests that mitochondrial network integrity is impaired in cardiomyocytes from failing hearts. While oxidative stress has been implicated in heart failure (HF)-associated mitochondrial remodeling, the effect of mitochondrial-targeted antioxidants, such as mitoquinone (MitoQ), on the mitochondrial network in a model of HF (e.g., pressure overload) has not been demonstrated. Furthermore, the mechanism of this regulation is not completely understood with an emerging role for posttranscriptional regulation via long noncoding RNAs (lncRNAs). We hypothesized that MitoQ preserves mitochondrial fusion proteins (i.e., mitofusin), likely through redox-sensitive lncRNAs, leading to improved mitochondrial network integrity in failing hearts. To test this hypothesis, 8-wk-old C57BL/6J mice were subjected to ascending aortic constriction (AAC), which caused substantial left ventricular (LV) chamber remodeling and remarkable contractile dysfunction in 1 wk. Transmission electron microscopy and immunostaining revealed defective intermitochondrial and mitochondrial-sarcoplasmic reticulum ultrastructure in AAC mice compared with sham-operated animals, which was accompanied by elevated oxidative stress and suppressed mitofusin (i.e., Mfn1 and Mfn2) expression. MitoQ (1.36 mg·day−1·mouse−1, 7 consecutive days) significantly ameliorated LV dysfunction, attenuated Mfn2 downregulation, improved interorganellar contact, and increased metabolism-related gene expression. Moreover, our data revealed that MitoQ alleviated the dysregulation of an Mfn2-associated lncRNA (i.e., Plscr4). In summary, the present study supports a unique mechanism by which MitoQ improves myocardial intermitochondrial and mitochondrial-sarcoplasmic reticulum (SR) ultrastructural remodeling in HF by maintaining Mfn2 expression via regulation by an lncRNA. These findings underscore the important role of lncRNAs in the pathogenesis of HF and the potential of targeting them for effective HF treatment. NEW & NOTEWORTHY We have shown that MitoQ improves cardiac mitochondrial network integrity and mitochondrial-SR alignment in a pressure-overload mouse heart-failure model. This may be occurring partly through preventing the dysregulation of a redox-sensitive lncRNA-microRNA pair (i.e., Plscr4-miR-214) that results in an increase in mitofusin-2 expression.

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Myocardial work index better reflects contractility than longitudinal strain in rat models of pressure- and volume overload-induced heart failure

European Heart Journal - Cardiovascular Imaging ◽

10.1093/ehjci/jeaa356.171 ◽

2021 ◽

Vol 22 (Supplement_1) ◽

Author(s):

BK Lakatos ◽

M Ruppert ◽

M Tokodi ◽

A Olah ◽

S Braun ◽

...

Keyword(s):

Heart Failure ◽

Longitudinal Strain ◽

Pressure Overload ◽

Volume Overload ◽

Left Ventricular ◽

Stroke Work ◽

Loading Conditions ◽

Rat Models ◽

Work Index ◽

Hemodynamic Overload

Abstract Funding Acknowledgements Type of funding sources: None. Speckle-tracking echocardiography (STE)-derived global longitudinal strain (GLS) is considered to be a sensitive marker of left ventricular (LV) function in a wide variety of cardiovascular diseases. Still, evidence suggests that GLS is significantly influenced by loading conditions. Myocardial work index (MWI) evaluates myocardial deformation in the context of afterload through the interpretation of strain in relation to instantaneous LV pressure. MWI may potentially overcome the limitations of mere strain calculation, and may better reflect cardiac contractility in hemodynamic overload states. Accordingly, our aim was to examine the relationship of GLS and MWI with load-independent markers of LV contractility in rat models of pressure- and volume overload-induced heart failure. Male Wistar rats underwent transverse aortic constriction (TAC; n = 12) to generate LV pressure overload, or aortocaval fistula (ACF; n = 12) was established to induce severe LV volume overload. In case of the control groups, sham procedures were performed (n = 12/12). Echocardiography loops were obtained to determine STE-derived GLS and global MWI. Pressure-volume analysis with transient occlusion of the inferior vena cava was carried out to calculate preload recruitable stroke work (PRSW), as a load-independent „gold-standard" parameter of LV contractility. GLS was mildly reduced in the ACF group (-13.2 ± 2.4 vs. -15.4 ± 2.0%, p < 0.05), while it was significantly lower in TAC group compared to controls (-7.0 ± 2.8 vs. -14.5 ± 2.5%; p < 0.001). In contrast with these findings, PRSW and also MWI were significantly reduced in ACF (58 ± 14 vs. 111 ± 40 mmHg; 1328 ± 411 vs. 1934 ± 308 mmHg%, both p < 0.01), however, they were comparable between TAC and the corresponding sham group (110 ± 26 vs. 116 ± 68 mmHg; 1687 ± 275 Hgmm% vs. 1537 ± 662 Hgmm%; both p = NS). In the pooled population, GLS did not show relationship with PRSW (r=-0.23; p = 0.12), while MWI showed significant correlation with it (r = 0.70; p < 0.001). GLS is significantly influenced by loading conditions, therefore, in case of severe pressure- or volume overload it may not be a reliable marker of LV contractility. In our rat model of pressure overload induced heart failure, contractility was maintained despite decreased GLS, while in the model of volume overload induced heart failure, GLS was maintained despite decreased contractility. MWI reflects contractility in hemodynamic overload states, therefore, it may be a more suitable marker of systolic function. Abstract Figure. Pressure-strain loops of the groups

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Longitudinal strain reflects the interaction of myocardial contractility to afterload in rat models of hemodynamic overload-induced heart failure

European Heart Journal ◽

10.1093/ehjci/ehaa946.0124 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Ruppert ◽

B.K Lakatos ◽

M Tokodi ◽

C Karime ◽

I Hizoh ◽

...

Keyword(s):

Heart Failure ◽

Strong Correlation ◽

Longitudinal Strain ◽

Pressure Overload ◽

Volume Overload ◽

Left Ventricular ◽

Funding Source ◽

Entire Study ◽

Rat Models ◽

Hemodynamic Overload

Abstract Background Two-dimensional (2D) speckle tracking echocardiography (STE)-derived myocardial strain parameters are sensitive markers of left ventricular (LV) systolic function. Novel findings suggest that the contractile state of the myocardium, afterload and preload are major determinants of STE measurements. However, the hypothesis that longitudinal strain expresses the interaction between contractility and loading conditions rather than contractility alone in hemodynamic overload-induced heart failure (HF) has not been tested. Purpose This study aimed to explore the connection between longitudinal strain and contractility, afterload and preload in rat models of pressure overload (PO)- and volume overload (VO)-induced heart failure (HF). Methods Pressure overload (PO)-induced HF was evoked by transverse aortic constriction ([TAC], n=14). Volume overload (VO)-induced HF was established by an aortocaval fistula ([ACF], n=12). Age-matched sham operated animals served as controls. Pressure-volume analysis was carried out to compute cardiac contractility (slope of end-systolic pressure-volume relationship [ESPVR]), afterload (arterial elastance [Ea]) and ventriculo-arterial coupling ([VAC] = Ea/ESPVR). Preload was evaluated by meridional end-diastolic wall stress (σend-diastolic). STE was performed to assess global longitudinal strain (GLS). Results GLS was impaired in both PO-induced HF (−5.9±0.6 vs. −12.9±0.5%, TAC vs Sham, P<0.001) and VO-evoked HF (−11.7±0.7 vs. −13.5±0.4%, ACF vs Sham, P=0.048). Hemodynamic measurements indicated that the TAC group presented with maintained ESPVR, increased Ea and enhanced σend-diastolic. In contrast, the ACF group was characterized by reduced ESPVR, decreased Ea and enhanced σend-diastolic. Ordinary least squares non-linear regression revealed that GLS was predominantly determined by afterload (Ea) in the TAC model and by contractility (ESPVR) in the ACF model. In accordance, GLS showed a strong correlation with Ea in case of PO-induced HF (R= 0.848, P<0.001) and with ESPVR in case of VO-evoked HF (R=−0.526; P=0.008), respectively. Furthermore, GLS also demonstrated strong correlation with VAC in both the TAC and the ACF models. Of particular interest, a robust correlation between VAC and GLS could also be detected in the entire study population (R= 0.654, P<0.001). Conclusion Both afterload and contractility define GLS. Hence, under conditions when both factors become altered, GLS reflects VAC. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

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