Abstract P233: Diabetic Cardiomyopathy is Reversed by Increased Mitochondrial Bioenergetics Due to PGC-1α Activation by EET Treatment of Obese Mice

Introduction: Obesity and diabetes are associated with progressive cardiac fibrosis that, sequentially, results in diastolic dysfunction, reduced contractility, and ultimately heart failure. Contributing factors include hyperglycemia, insulin resistance, mitochondrial dysfunction, and a reduction in AMPK signaling. PGC-1α activates mitochondrial biogenesis and oxidative phosphorylation and is decreased in patients with diabetes mellitus (DM). We hypothesize that an epoxyeicosatrienoic acids (EETs) agonist (EET-A) will increase PGC-1α levels in a db mouse model of DM attenuate cardiomyopathy, and prevent heart failure. Methods: Db mice (4-wks), were allowed to acclimatize for 16-wks and were then divided into 3 treatment groups for an additional 16 wks: A) control, B) EET-A 1.5mg/100g BW 2 weeks and C) EET-A-Ln-PGC-1α shRNA. Ln-PGC-1α shRNA suppressed PGC-1α protein in heart tissue by 40-50%. Oxygen consumption (VO 2 ), and blood glucose was determined. Heart tissues were harvested to measure PGC-1α, HO-1, pAMPK, PGC-1α, echocardiographic fractional shortening, mitochondrial oxidative phosphorylation (OXPHOS) and mitofusion protein markers. Results: All mice developed heart failure by the end of 16 weeks and were characterized by a decrease in myocardial contractility, an increase in insulin resistance and blood pressure, decreased VO 2 , the appearance of mitochondria dysfunction and a decrease in AMPK and downstream PGC-1α signaling. Mice treated with EET-A demonstrated an increase in PGC-1α levels, improved mitochondrial function and oxidative phosphorylation (p<0.01 vs control), increased NO bioavailability (p<0.05 vs control), and normalization of glucose metabolism, insulin levels, VO 2 and LV systolic function (p<0.05 vs control). All of these findings were suppressed by PGC-1α inhibition which was accompanied by the onset of even more severe LV dysfunction than in the control group. Conclusion: Increased EET levels result in activation of PGC-1α-HO-1 which reverses diabetes induced insulin resistance, mitochondrial dysfunction, and cardiomyopathy. EET may have potential as a powerful agent for therapeutic application in the treatment of diabetic cardiomyopathy.

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Abstract 16485: The Nitroxyl Donor 1-Nitrosocyclohexyl Acetate Limits Cardiac Superoxide Upregulation and Diastolic Dysfunction in a Mouse Model of Diabetic Cardiomyopathy

Circulation ◽

10.1161/circ.130.suppl_2.16485 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Rebecca H Ritchie ◽

Nga Cao ◽

Yung George Wong ◽

Sarah Rosli ◽

Helen Kiriazis ◽

...

Keyword(s):

Heart Failure ◽

Mouse Model ◽

Diastolic Dysfunction ◽

Diabetic Cardiomyopathy ◽

Ex Vivo ◽

Systolic Function ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Lv Diastolic Dysfunction ◽

The Impact

Nitroxyl (HNO), a redox congener of NO•, is a novel regulator of cardiovascular function combining vasodilator and positive inotropic properties. Our previous studies have demonstrated these properties occur concomitantly in the intact heart; HNO moreover also exhibits antihypertrophic and superoxide-suppressing actions. HNO donors may thus offer favorable actions in heart failure. The impact of chronic HNO donor administration has however yet to be reported in this context. We tested the hypothesis that the HNO donor 1-nitrosocyclohexyl acetate (1-NCA) limits cardiomyocyte hypertrophy and left ventricular (LV) diastolic dysfunction in a mouse model of diabetic cardiomyopathy in vivo. Male 6 week-old FVB/N mice received either streptozotocin (55 mg/kg/day i.p. for 5 days, n=17), to induce type 1 diabetes, or citrate vehicle (n=16). After 4 weeks of hyperglycemia, mice were allocated to 1-NCA therapy (83mg/kg/day i.p.) or vehicle, and followed for a further 4 weeks. As shown in the table, blood glucose was unaffected by 1-NCA. LV diastolic dysfunction was evident in diabetic mice, measured as echocardiography-derived A wave velocity, deceleration time and E:A ratio; LV systolic function was preserved. Diabetes-induced diastolic dysfunction was accompanied by increased LV cardiomyocyte size, hypertrophic and pro-fibrotic gene expression, and upregulation of LV superoxide. These characteristics of diabetic cardiomyopathy were largely prevented by 1-NCA treatment. Selectivity of 1-NCA as a donor of HNO versus NO• was demonstrated by the sensitivity of the coronary vasodilation response of 1-NCA to the HNO scavenger L-cysteine (4mM), but not to the NO• scavenger hydroxocobalamin (50μM), in the normal rat heart ex vivo (n=3-7). Collectively, our studies provide the first evidence that HNO donors may represent a promising new strategy for the treatment of diabetic cardiomyopathy, and implies their therapeutic efficacy in settings of chronic heart failure.

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Reduced myocardial reserve in cirrhotic patients: an evaluation by dobutamine stress speckle tracking and tissue Doppler imaging (TDI) echocardiography

Journal of Cardiovascular and Thoracic Research ◽

10.15171/jcvtr.2019.22 ◽

2019 ◽

Vol 11 (2) ◽

pp. 127-131 ◽

Cited By ~ 4

Author(s):

Mahmood Zamirian ◽

Forough Afsharizadeh ◽

Alireza Moaref ◽

Firoozeh Abtahi ◽

Fatemeh Amirmoezi ◽

...

Keyword(s):

Heart Failure ◽

Strain Rate ◽

Speckle Tracking ◽

Systolic Function ◽

Peak Stress ◽

Tissue Doppler ◽

Doppler Imaging ◽

Control Group ◽

Basal Segment ◽

Cirrhotic Patients

Introduction: Despite the normal systolic function at rest, cirrhotic patients often suffer from volume overload and symptoms of heart failure as they face stressful situations. This study investigated the myocardial reserve in cirrhotic patients at resting condition and peak stress by dobutamine speckle tracking echocardiography (STE) and tissue Doppler imaging (TDI). Methods: Twenty cirrhotic patients and 10 normal individuals aged 30-50 were selected randomly. For all of the participants, complete echocardiographic study of 2D, STE and TDI was done at rest and peak stress status with dobutamine. The following parameters were assessed: ejection fraction (EF), global longitudinal LV strain (GLS), strain rate in the septal basal segment and lateral wall and E’ in the septal basal segment by color-coded method. Results: At baseline, EF was higher than 55% in both groups. GLS was higher (-22.6±2.4%) in the case group than the control group (-19.2±1.9%) at resting condition. After stress, it showed a greater increase (-22.5±1.7%) in the controls compared to cirrhotic patients (-22.6±3.3%; mean difference = 2.6 ± 2.03, P = 0.02). In cirrhotic patients, the average strain rate in the basal septal segment decreased after stress (-1.2 ± 0.3/s to-1.1 ± 0.3/s), but it increased in the control group (-1.1 ± 0.2/s to -1.8 ± 0.2/s). Conclusion: Despite the presence of normal resting systolic function in cirrhotic patients, there was insufficient increase or even a decrease in myocardial function with stress; this may indicate the absence of sufficient myocardial reserve in cirrhotic patients. These findings would help to explain the reason for occurrence of heart failure or hemodynamic changes in cirrhotic patients.

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Contractile protein phosphorylation predicts human heart disease phenotypes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00957.2012 ◽

2013 ◽

Vol 304 (12) ◽

pp. H1644-H1650 ◽

Cited By ~ 12

Author(s):

Lori A. Walker ◽

David A. Fullerton ◽

Peter M. Buttrick

Keyword(s):

Heart Failure ◽

Heart Disease ◽

Protein Phosphorylation ◽

Protein Phosphatase ◽

Human Heart ◽

Troponin I ◽

Systolic Function ◽

Left Ventricular ◽

Control Group ◽

Lv Function

Human heart failure has been associated with a low level of thin-filament protein phosphorylation and an increase in calcium sensitivity of contraction relative to both “control” human heart tissue and tissue from small animal models. However, diverse strategies of human tissue procurement and the reliance on tissue obtained from subjects with end-stage heart failure suggest this may be an incomplete characterization. Therefore, we evaluated cardiac left ventricular (LV) biopsy samples from patients with aortic stenosis undergoing valve replacement who presented either with LV hypertrophy and preserved systolic function (Hyp) or with LV dilation and reduced ejection fraction (Dil). In Hyp, total troponin I (TnI) phosphorylation was markedly increased and myosin light chain 2 (MLC2) phosphorylation was unchanged relative to a control group of patients with normal LV function. Conversely, in Dil, total TnI phosphorylation was significantly reduced compared with control subjects and MLC2 phosphorylation was increased. Site-specific analysis of TnI phosphorylation revealed phenotype-specific differences such that Hyp samples demonstrated significant increases in phosphorylation at serine 22/23 and Dil samples had significant decreases at serine 43. The ratio of phosphorylation at the two sites was biased toward serine 22/23 in Hyp and toward serine 43/45 in Dil. Western blot analysis showed that protein phosphatase-1 was reduced in Hyp and protein phosphatase-2 was reduced in Dil. These data suggest that posttranslational modifications of sarcomeric proteins, both singly and in combination, are stage specific. Defining these changes in progressive heart disease may provide important diagnostic and treatment information.

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Protective Effects of Myrtus communis Linn Fruit and Leaf Extracts on Isoproterenol-Induced Heart Failure in Rat

Traditional and Integrative Medicine ◽

10.18502/tim.v6i2.6793 ◽

2021 ◽

Author(s):

Nahid Aboutaleb ◽

Fataneh Hashem-Dabaghian ◽

Azinmehr Elahian Boroujeni ◽

Asie Shojaii

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cardiac Fibrosis ◽

Experimental Period ◽

Stress Factors ◽

Control Group ◽

Alcoholic Extract ◽

Protective Effects ◽

Myrtus Communis ◽

Leaf Extracts

Myrtus communis Linn. (MC) is a cardiotonic plant in traditional Persian medicine. This study was conducted to evaluate the protective effect of MC on isoproterenol-induced heart failure (HF) in rats. Isoproterenol was injected subcutaneously in all groups except the control group for 4 consecutive days to induce myocardial injury in male Wistar rats. In the case of treatment groups, the animals were treated with different doses of the hydro-alcoholic extract of MC fruit or leaves (150, 300, and 700 mg/kg), and were compared with healthy and HF rats. In order to evaluate cardiac function, echocardiography was performed on day 28 after treatment. MC fruit and leaf extracts were administered to all groups except the healthy control group for 28 days by gavage. At the end of the experimental period, the animals were sacrificed and the left ventricle regions of tissue hearts were collected to measure the levels of oxidative stress factors (MDA, SOD, GSH) using ELISA methods. Cardiac fibrosis was evaluated by Mason’s trichrome staining. Hematoxylin-eosin staining was used to assess histopathological changes in cardiac structure. Our results showed that administration of MC fruit and leaf extracts significantly reduced the MDA level and increased SOD and GSH levels in treated HF rats compared to the HF group (P<0.05). In addition, MC mitigated fibrosis and improved cardiac histological changes compared to the HF group. Collectively, our findings show that MC can be considered as a good candidate to provide cardioprotective effects in HF rats through reduction of oxidative stress and myocardial fibrosis.

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Coronary microvascular dysfunction is only detectable in type 2 diabetes in the presence of obesity

European Heart Journal ◽

10.1093/eurheartj/ehab724.0237 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

A Chowdhary ◽

S Thirunavukarasu ◽

N Jex ◽

C Bowers ◽

R Cubbon ◽

...

Keyword(s):

Heart Failure ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Magnetic Resonance ◽

Myocardial Perfusion ◽

Diabetic Cardiomyopathy ◽

Microvascular Dysfunction ◽

Left Ventricular Ejection ◽

Coronary Microvascular Dysfunction

Abstract Background Heart failure (HF) is a leading cardiovascular complication of type 2 diabetes (T2D). Coronary microvascular dysfunction (CMD) precedes HF in diabetes and carries important prognostic information. CMD is also evident in metabolically healthy obese individuals without diabetes or hypertension. Whether diabetes causes CMD in the absence of obesity is uncertain. The interrelation among visceral adiposity and CMD has not been assessed previously. Objectives We sought to better understand the links between visceral and epicardial adipose tissue (VAT and EAT respectively) distribution, insulin resistance with myocardial perfusion, energetics and function in asymptomatic lean (LnT2D) and overweight/obese T2D patients (ObT2D) without cardiovascular disease. Methods 62 participants [27 Ob-T2D, 15 Ln-T2D, and 20 overweight controls] were recruited. Subjects underwent cardiac and abdominal magnetic resonance imaging and 31P-magnetic resonance spectroscopy, for measurements of EAT and VAT areas, rest and adenosine stress myocardial blood flow (MBF), cardiac function and phosphocreatine to ATP ratio (PCr/ATP). Fasting blood samples were taken for plasma homeostasis model assessment of insulin resistance (HOMA-IR) index calculations. Results The biochemical characteristics and multiparametric MR results are given in Table 1 and results of Pearson's regression analysis in the entire study population are given in Table 2. Stress MBF was lowest in ObT2D, while rest MBF was highest in LnT2D. Left ventricular ejection fraction (LVEF) and myocardial PCr/ATP were similarly reduced in diabetes groups. In the absence of obesity, there was no significant increase in VAT, EAT or HOMA-IR in T2D patients compared to controls. BMI and VAT, negatively correlated with LVEF, and strain parameters. PCr/ATP correlated with LVEF, but not HOMA-IR. BMI, EAT and VAT all correlated significantly with HOMA-IR, and HOMA-IR correlated with cardiac functional parameters. There was no association between HOMA-IR and myocardial perfusion. Conclusions In this study CMD was only evident in ObT2D patients, with normal rest and stress MBF in LnT2D patients. Despite normal perfusion and no significant increase in insulin resistance, LVEF and myocardial PCr/ATP were similarly reduced in LnT2D and ObT2D, and PCr/ATP correlated with LVEF. This suggests that alterations in cardiac energy metabolism are mechanistically more relevant for the pathophysiology of diabetic cardiomyopathy in LnT2D patients. In the absence of correlation between insulin resistance and myocardial perfusion, factors like inflammation and altered adipokine profile may play important roles for the pathophysiology of CMD in ObT2D patients. A better understanding of the underlying pathophysiological mechanisms of diabetic cardiomyopathy in LnT2D and ObT2D may help to develop contemporary tailored treatment and prevention strategies to tackle excess heart failure risk. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): BHFWellcome trust Table 1 Table 2

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The effect of sulodexide on placental mitochondria function in rats with experimental preeclampsia

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20166205572 ◽

2016 ◽

Vol 62 (5) ◽

pp. 572-576 ◽

Cited By ~ 5

Author(s):

T.A. Popova ◽

V.N. Perfilova ◽

G.A. Zhakupova ◽

V.E. Verovsky ◽

O.V. Ostrovskij ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Mitochondrial Dysfunction ◽

Respiratory Control ◽

Negative Control ◽

Urinary Protein ◽

Control Group ◽

Respiratory Control Ratio ◽

Pregnant Rats ◽

Pronounced Increase ◽

Uncoupling Of Oxidative Phosphorylation

Substitution of drinking water for 1.8% NaCl in pregnant rats caused a pronounced increase in arterial pressure by 24,3% and urinary protein by 117% to day 21 of pregnancy. State 4 respiration of isolated placental mitochondria in the group of negative control was 3- and 1.5-fold higher with malate/glutamate and succinate as substrates than in placental mitochondria isolated from uncomplicated pregnant animals. This led to a decrease of the respiratory control ratio. These results suggest that development of experimental preeclampsia is accompanied by mitochondrial dysfunction through uncoupling of oxidative phosphorylation. Daily administration of sulodexide to females with experimental preeclampsia (EP) per os at a dose of 30 LE during the whole period of gestation decreased manifestations of the disease as evidenced by a slight increase in blood pressure (by 8,6%) and less pronounces increase in urinary protein (by 58,9%). Sulodexide decreased development of mitochondrial dysfunction in EP rats as shown a decrease of non-stimulated ADP respiration with malate/glutamate and succinate (4.5- and 2.5-fold, respectively) as compared with the negative control group and the corresponding increase in the respiratory control ratio (2.5- and 1.5-fold, respectively). Thus, sulodexide reduces uncoupling of oxidative phosphorylation and enhances the functional activity of mitochondria in EP animals, possibly due to its antioxidant and endotelioprotective effects.

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Novel antisense therapy targeting microRNA-132 in patients with heart failure

European Heart Journal ◽

10.1093/eurheartj/ehab724.0920 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

J Taubel ◽

W Hauke ◽

S Rump ◽

J Viereck ◽

S Batkai ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Fibrosis ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Control Group ◽

Private Company ◽

Ventricular Ejection Fraction ◽

Pharmacodynamic Effects ◽

Amino Terminal ◽

Patients With Heart Failure

Abstract Background Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. Purpose The aim of the current clinical Phase 1b study was to assess safety, pharmacokinetics, target engagement, and exploratory pharmacodynamic effects of CDR132L in patients on standard-of-care therapy for chronic ischaemic HF in a randomized, placebo-controlled, double-blind, dose-escalation study. Methods Patients had left ventricular ejection fraction between ≥30% and <50% or amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) >125 ng/L at screening. Twenty-eight patients were randomized to receive CDR132L (0.32, 1, 3, and 10 mg/kg body weight) or placebo (0.9% saline) in two intravenous infusions, 4 weeks apart in four cohorts of seven (five verum and two placebo) patients each. Results CDR132L was safe and well tolerated, without apparent dose-limiting toxicity. A pharmacokinetic/pharmacodynamic dose modelling approach suggested an effective dose level at ≥1 mg/kg CDR132L. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma. Patients given CDR132L ≥1 mg/kg displayed median 23.3% NT-proBNP reduction, vs. 0.9% median increase in the control group. CDR132L treatment induced significant QRS narrowing and positive trends for cardiac fibrosis biomarkers. Conclusions This study is the first clinical trial of an antisense drug in HF patients. CDR132L was safe and well tolerated, confirmed linear plasma pharmacokinetics with no signs of accumulation, and suggests cardiac functional improvements. The indicative efficacy of this drug is very encouraging justifying additional clinical studies to confirm the beneficial CDR132L pharmacodynamic effects for the treatment of HF. FUNDunding Acknowledgement Type of funding sources: Private company. Main funding source(s): Cardior Pharmaceuticals GmbH

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The Effect of Acute Allergic Reactions on Diastolic Heart Function

Clinical & Investigative Medicine ◽

10.25011/cim.v37i2.21088 ◽

2014 ◽

Vol 37 (2) ◽

pp. 70

Author(s):

Oguz Kaan Kaya ◽

Necati Dagli ◽

Mustafa Yildiz ◽

Ilgin Karaca ◽

Bilal Ustundag ◽

...

Keyword(s):

Heart Failure ◽

Heart Function ◽

Systolic Function ◽

Diastolic Heart Failure ◽

Coronary Artery Spasm ◽

Laboratory Data ◽

Control Group ◽

Allergic Reactions ◽

Laboratory Findings ◽

Significant Difference

Purpose: Diastolic heart failure is characterized by the presence of heart failure symptoms despite preserved systolic function. Cytokines released during allergic reactions may impair diastolic heart function, either through their direct toxic effects or by inducing coronary artery spasm. The purpose of this study was to examine the effects of acute allergic reactions on diastolic heart function. Methods: Fifty patients, randomly selected from those who were admitted to the emergency room between May 2010 and December 2010 with the complaints of rash and itching, and who were subsequently diagnosed with allergic reactions based on the clinical and laboratory findings, were included in the study as the allergy group. Thirty healthy volunteers, in whom the diagnosis of allergy was ruled out based on the clinical and laboratory data, were use as the control group. Diastolic heart functions were evaluated in patients presenting with allergic reaction as well as in control subjects. Results: There was no significant difference between the two groups in terms of basal systolic functions, diameters of the cavities and wall thicknesses, and biochemical parameters. Color M mode flow progression velocities, E ratios, E/A ratios and mitral lateral annulus tissue Doppler velocities measured by echocardiography at Day 0 and Day 5 were significantly altered in the allergy group (p < 0.05). Conclusion: Impairment in diastolic functions was observed following acute allergic reactions. Acute allergic reactions could be a cause of mortality and morbidity if they lead to the development of diastolic heart failure.

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Abstract 177: Insulin Resistance and Mechanisms of Heart Failure

Circulation Research ◽

10.1161/res.113.suppl_1.a177 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Shaodong Guo ◽

Yajuan Qi ◽

Qinglei Zhu ◽

Zihui Xu ◽

Candice Thomas ◽

...

Keyword(s):

Heart Failure ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Cardiac Dysfunction ◽

Cardiac Fibrosis ◽

Expression Patterns ◽

Primary Cultures ◽

Neonatal Rat ◽

Atp Content

A major cause of death in patients with type 2 diabetes is cardiac failure and the molecular mechanism that links diabetes to cardiomyopathy remains unclear. Insulin resistance is a hallmark of type 2 diabetes and intensive insulin therapy on the patients with type 2 diabetes increases the risks of cardiovascular dysfunction. Thus, understanding the mechanisms of insulin actions and resistance, related to cardiac dysfunction, will be critical for development of new strategies treating heart failure in type 2 diabetes. Insulin receptor substrate 1, & 2 (IRS1, IRS2) are major components in insulin signaling pathway regulating metabolism and survival. Here we hypothesized that (1) loss of IRS1 and IRS2 causes heart failure; (2) hyperinsulinemia contributes to loss of IRS1 and IRS2 in type 2 diabetes and promotes cardiac dysfunction; and (3) underlying mechanisms are involved in protein kinase activation. H-DKO mice (Heart Double IRS1 and IRS2 Knock-Out) and L(Liver)-DKO mice were generated using Cre/Loxp system. Cardiac function and ATP content were measured by echocardiograms and ATP assay kit. Protein and gene expressions were detected through western-blot and Q-PCR. Primary cultures of neonatal rat ventricular cardiomyocytes (NRVMs) were prepared from Sprague-Dawley rats with enzymatic method. H-DKO mice reduced ventricular mass, developed cardiac fibrosis and failure, and diminished Akt→Foxo1 signaling accompanied by impaired cardiac metabolic gene expression patterns and reduced ATP content. L-DKO mice decreased cardiac expression of IRS1 and IRS2 proteins with insulin resistance, disrupting cardiac energy metabolism, leading to heart failure and activation of p38α MAPK (p38). Using NRVMs, we demonstrated that hyperinsulinemia degraded IRS1 and IRS2, resulting in insulin resistance and impaired insulin action through activation of p38. In conclusion, myocardial loss of IRS1 and IRS2 causes heart failure and is controlled by p38 during Insulin resistance, revealing a fundamental mechanism of heart failure during insulin resistance and/or type 2 Diabetes Mellitus.

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Effects of Apelin on Left Ventricular-Arterial Coupling and Mechanical Efficiency in Rats with Ischemic Heart Failure

Disease Markers ◽

10.1155/2019/4823156 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Qiufang Ouyang ◽

Tao You ◽

Jinjian Guo ◽

Rong Xu ◽

Quehui Guo ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Fibrosis ◽

Diastolic Pressure ◽

Systolic Function ◽

Mechanical Efficiency ◽

Left Ventricular ◽

Mesenteric Arteries ◽

Stroke Work ◽

Reduced Ejection Fraction ◽

Left Ventricular Arterial Coupling

Apelin plays important roles in cardiovascular homeostasis. However, its effects on the mechanoenergetics of heart failure (HF) are unavailable. We attempted to investigate the effects of apelin on the left ventricular-arterial coupling (VAC) and mechanical efficiency in rats with HF. HF was induced in rats by the ligation of the left coronary artery. The ischemic HF rats were treated with apelin or saline for 12 weeks. The sham-operated animals served as the control. The left ventricular (LV) afterload and the systolic and diastolic functions, as well as the mechanoenergetic indices were estimated from the pressure-volume loops. Myocardial fibrosis by Masson’s trichrome staining, myocardial apoptosis by TUNEL, and collagen content in the aorta as well as media area in the aorta and the mesenteric arteries were determined. Our data indicated that HF rats manifested an increased arterial load (Ea), a declined systolic function (reduced ejection fraction, +dP/dtmax, end-systolic elastance, and stroke work), an abnormal diastolic function (elevated end-diastolic pressure, τ, and declined −dP/dtmax), and decreased mechanical efficiency. Apelin treatment improved those indices. Concomitantly, increased fibrosis in the LV myocardium and the aorta and enhanced apoptosis in the LV were partially restored by apelin treatment. A declined wall-to-lumen ratio in the mesenteric arteries of the untreated HF rats was further reduced in the apelin-treated group. We concluded that the rats with ischemic HF were characterized by deteriorated LV mechanoenergetics. Apelin improved mechanical efficiency, at least in part, due to the inhibiting cardiac fibrosis and apoptosis in the LV myocardium, reducing collagen deposition in the aorta and dilating the resistant artery.

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