Phosphatidylserine Supplementation as a Novel Strategy for Reducing Myocardial Infarct Size and Preventing Adverse Left Ventricular Remodeling

Phosphatidylserines are known to sustain skeletal muscle activity during intense activity or hypoxic conditions, as well as preserve neurocognitive function in older patients. Our previous studies pointed out a potential cardioprotective role of phosphatidylserine in heart ischemia. Therefore, we investigated the effects of phosphatidylserine oral supplementation in a mouse model of acute myocardial infarction (AMI). We found out that phosphatidylserine increases, significantly, the cardiomyocyte survival by 50% in an acute model of myocardial ischemia-reperfusion. Similar, phosphatidylserine reduced significantly the infarcted size by 30% and improved heart function by 25% in a chronic model of AMI. The main responsible mechanism seems to be up-regulation of protein kinase C epsilon (PKC-ε), the main player of cardio-protection during pre-conditioning. Interestingly, if the phosphatidylserine supplementation is started before induction of AMI, but not after, it selectively inhibits neutrophil’s activation, such as Interleukin 1 beta (IL-1β) expression, without affecting the healing and fibrosis. Thus, phosphatidylserine supplementation may represent a simple way to activate a pre-conditioning mechanism and may be a promising novel strategy to reduce infarct size following AMI and to prevent myocardial injury during myocardial infarction or cardiac surgery. Due to the minimal adverse effects, further investigation in large animals or in human are soon possible to establish the exact role of phosphatidylserine in cardiac diseases.

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Abstract 17348: Necrostatin 7 Limits Myocardial Infarct Size and Reduces Cardiac Remodeling After Permanent Coronary Occlusion in Rats

Circulation ◽

10.1161/circ.130.suppl_2.17348 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Yuri Dmitriev ◽

Sarkis Minasian ◽

Anna Dracheva ◽

Andrey Karpov ◽

Svetlana Chefu ◽

...

Keyword(s):

Infarct Size ◽

Rat Model ◽

Coronary Occlusion ◽

Ventricular Remodeling ◽

Ischemia Reperfusion Injury ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Morphological Characteristics ◽

Left Ventricular ◽

Myocardial Infarct Size

Background: Reduction of irreversible myocardial ischemia-reperfusion injury (IRI) remains important. One of the promising strategies aimed at myocardial IRI alleviation is modulation of programmed cell death (PCD) pathways. PCD mode displaying morphological characteristics of necrosis, and amenable to pharmacological manipulation is referred to as necroptosis. Necroptosis inhibitor necrostatin-1 has been shown to exert cardio- and neuroprotective effects. In the present work, the effect of necrostatin-7 (Nec-7) on myocardial injury in the rat model of permanent coronary occlusion was studied. Methods: Male Wistar rats (n = 19) were anesthetized with pentobarbital. The animals were subjected to permanent coronary occlusion (PCO) and intraperitoneal (i.p.) Nec-7 administration 1 h prior to PCO at a dose of 14.5 mg/kg in dimethyl sulfoxide (DMSO) or DMSO alone at a dose of 3.1 g/kg. Control rats were treated with saline. Three weeks after PCO, serum levels of NT-proBNP were measured, and histological outcomes were assessed. The infarct size (IS, %) and infarct length (IL, mm) were analyzed morphometrically. Results: DMSO caused significant reduction in serum NT-proBNP level vs. Control (0.3 ± 0.19 vs. 0.5 ± 0.22 ng/ml, p = 0.001), while Nec-7 further decreased NT-proBNP level in comparison with DMSO (0.2 ± 0.14 ng/ml, p = 0.008 vs. DMSO). Compared with Control, DMSO reduced adverse left ventricular remodeling, as evidenced by reduction in IS (16.0 ± 2.92 and 12.9 ± 1.72%, p = 0.015) and IL (6.2 ± 0.89 and 3.8 ± 0.35 mm, p = 0.008). Nec-7 treatment resulted in additional reduction of both IS and IL vs. DMSO group (9.0 ± 4.91 % and 2.9 ± 1.62 mm, respectively; p = 0.013 and p = 0.011 vs. DMSO, respectively). Conclusion: Nec-7 has cardioprotective properties, reducing myocardial wall stress and myocardial remodeling in the rat model of myocardial infarction.

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New Interventional Therapies beyond Stenting to Treat ST-Segment Elevation Acute Myocardial Infarction

Journal of Cardiovascular Development and Disease ◽

10.3390/jcdd8090100 ◽

2021 ◽

Vol 8 (9) ◽

pp. 100

Author(s):

Pablo Vidal-Calés ◽

Pedro L. Cepas-Guillén ◽

Salvatore Brugaletta ◽

Manel Sabaté

Keyword(s):

Myocardial Infarction ◽

Infarct Size ◽

Ischemia Reperfusion Injury ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Myocardial Damage ◽

Left Ventricular ◽

Myocardial Infarct Size ◽

St Segment Elevation ◽

St Segment

Myocardial infarction remains the principal cause of death in Europe. In patients with ST-segment-elevation myocardial infarction (STEMI), a promptly revascularization with primary percutaneous intervention (PCI) has transformed prognosis in the last decades. However, despite increasing successful PCI procedures, mortality has remained unchanged in recent years. Also, due to an unsatisfactory reperfusion, some patients have significant myocardial damage and suffer left ventricular adverse remodeling with reduced function—all that resulting in the onset of heart failure with all its inherent clinical and socioeconomic burden. As a consequence of longer ischemic times, distal thrombotic embolization, ischemia-reperfusion injury and microvascular dysfunction, the resultant myocardial infarct size is the major prognostic determinant in STEMI patients. The improved understanding of all the pathophysiology underlying these events has derived to the development of several novel therapies aiming to reduce infarct size and to improve clinical outcomes in these patients. In this article, based on the mechanisms involved in myocardial infarction prognosis, we review the new interventional strategies beyond stenting that may solve the suboptimal results that STEMI patients still experience.

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High-resolution imaging of murine myocardial infarction with delayed-enhancement cine micro-CT

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01307.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. H3172-H3178 ◽

Cited By ~ 47

Author(s):

Matthias Nahrendorf ◽

Cristian Badea ◽

Laurence W. Hedlund ◽

Jose-Luiz Figueiredo ◽

David E. Sosnovik ◽

...

Keyword(s):

Myocardial Infarction ◽

Infarct Size ◽

Ventricular Remodeling ◽

Ex Vivo ◽

Myocardial Infarct ◽

Left Ventricular ◽

Delayed Enhancement ◽

Constant Infusion ◽

Mouse Heart ◽

Myocardial Infarct Size

The objective of this study was to determine the feasibility of delayed-enhancement micro-computed tomography (μCT) imaging to quantify myocardial infarct size in experimental mouse models. A total of 20 mice were imaged 5 or 35 days after surgical ligation of the left coronary artery or sham surgery ( n = 6 or 7 per group). We utilized a prototype μCT that covers a three-dimensional (3D) volume with an isotropic spatial resolution of 100 μm. A series of image acquisitions were started after a 200 μl bolus of a high-molecular-weight blood pool CT agent to outline the ventricles. CT imaging was continuously performed over 60 min, while an intravenous constant infusion with iopamidol 370 was started at a dosage of 1 ml/h. Thirty minutes after the initiation of this infusion, signal intensity in Hounsfield units was significantly higher in the infarct than in the remote, uninjured myocardium. Cardiac morphology and motion were visualized with excellent contrast and in fine detail. In vivo CT determination of infarct size at the midventricular level was in good agreement with ex vivo staining with triphenyltetrazolium chloride [5 days post-myocardial infarction (MI): r2 = 0.86, P < 0.01; 35 days post-MI: r2 = 0.92, P < 0.01]. In addition, we detected significant left ventricular remodeling consisting of left ventricular dilation and decreased ejection fraction. 3D cine μCT reliably and rapidly quantifies infarct size and assesses murine anatomy and physiology after coronary ligation, despite the small size and fast movement of the mouse heart. This efficient imaging tool is a valuable addition to the current phenotyping armamentarium and will allow rapid testing of novel drugs and cell-based interventions in murine models.

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Cardioprotection with esmolol-based cardioplegia for non-infarcted and infarcted rat hearts

European Journal of Cardio-Thoracic Surgery ◽

10.1093/ejcts/ezab117 ◽

2021 ◽

Author(s):

Alexander B Veitinger ◽

Audrey Komguem ◽

Lena Assling-Simon ◽

Martina Heep ◽

Julia Schipke ◽

...

Keyword(s):

Myocardial Infarction ◽

Cardiac Function ◽

Infarct Size ◽

Myocardial Infarct ◽

Lactate Production ◽

Left Ventricular ◽

Myocardial Infarct Size ◽

Cardioplegic Arrest ◽

Blood Cardioplegia ◽

Rat Hearts

Abstract OBJECTIVES Esmolol-based cardioplegic arrest offers better cardioprotection than crystalloid cardioplegia but has been compared experimentally with blood cardioplegia only once. We investigated the influence of esmolol crystalloid cardioplegia (ECCP), esmolol blood cardioplegia (EBCP) and Calafiore blood cardioplegia (Cala) on cardiac function, metabolism and infarct size in non-infarcted and infarcted isolated rat hearts. METHODS Two studies were performed: (i) the hearts were subjected to a 90-min cardioplegic arrest with ECCP, EBCP or Cala and (ii) a regional myocardial infarction was created 30 min before a 90-min cardioplegic arrest. Left ventricular peak developed pressure (LVpdP), velocity of contractility (dLVP/dtmax), velocity of relaxation over time (dLVP/dtmin), heart rate and coronary flow were recorded. In addition, the metabolic parameters were analysed. The infarct size was determined by planimetry, and the myocardial damage was determined by electron microscopy. RESULTS In non-infarcted hearts, cardiac function was better preserved with ECCP than with EBCP or Cala relative to baseline values (LVpdP: 100 ± 28% vs 86 ± 11% vs 57 ± 7%; P = 0.002). Infarcted hearts showed similar haemodynamic recovery for ECCP, EBCP and Cala (LVpdP: 85 ± 46% vs 89 ± 55% vs 56 ± 26%; P = 0.30). The lactate production with EBCP was lower than with ECCP (0.6 ± 0.7 vs 1.4 ± 0.5 μmol/min; P = 0.017). The myocardial infarct size and (ECCP vs EBCP vs Cala: 16 ± 7% vs 15 ± 9% vs 24 ± 13%; P = 0.21) the ultrastructural preservation was similar in all groups. CONCLUSIONS In non-infarcted rat hearts, esmolol-based cardioplegia, particularly ECCP, offers better myocardial protection than Calafiore. After an acute myocardial infarction, cardioprotection with esmolol-based cardioplegia is similar to that with Calafiore.

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Abstract 2894: Essential Role of ERK 1/2 in Sildenafil-Induced Early and Delayed Cardioprotection in Mice

Circulation ◽

10.1161/circ.118.suppl_18.s_794-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Anindita das ◽

Lei Xi ◽

Fadi N Salloum ◽

Yuan J Rao ◽

Rakesh C Kukreja

Keyword(s):

South Carolina ◽

Infarct Size ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Critical Role ◽

Heart Association ◽

Myocardial Infarct Size ◽

Western Blots ◽

Delayed Cardioprotection

Background: Sildenafil (SIL), a potent inhibitor of phosphodiesterase-5 induces powerful protection against myocardial ischemia-reperfusion (I-R) injury through activation of protein kinase G (PKG). However, the downstream targets of PKG in SIL-induced cardioprotection remain unclear. We hypothesized that PKG-dependent activation of survival kinase, ERK may play a critical role in SIL-induced cardioprotection in mice. Methods & Results: Ventricular myocytes were isolated from adult male ICR mice and exposed to 40 min of simulated ischemia (SI) with/without 1 hr pre-incubation of SIL (1 μM). Myocyte necrosis and apoptosis were determined after 1 hr or 18 hrs of reoxygenation (RO) using trypan blue or TUNEL assay, respectively. Pretreatment with SIL protected cardiomyocytes after SI-RO (necrosis 18.5±0.5% and apoptosis 6.6±0.7%; n=4, p<0.001) as compared with controls (necrosis 42.1±1.8% and apoptosis 23.3±0.9%). Co-incubation of PD98059 (20 μM), a selective ERK1/2 inhibitor blocked both anti-necrotic and anti-apoptotic protection in cardiomyocytes. Furthermore, intra-coronary infusion of SIL (1 μM) in Langendorff isolated mouse hearts 10 min prior to zero-flow global I (20 min) and R (30 min) significantly reduced myocardial infarct size (from 29.4±2.4% to 16.0±3.0%; p<0.05, n=6). Co-treatment of PD98059 abrogated SIL-induced protection (33.0±5.9; n=4). To evaluate the role of ERK1/2 in delayed cardioprotection, mice were treated with saline or SIL (0.7 mg/kg i.p.) 24 hours before global I-R in Langendorff mode. PD98059 (1 mg/kg) was administered (i.p.) 30 min before the treatment of SIL. Infarct size was reduced from 27.6±3.3% in saline-treated controls to 6.9±1.2% in SIL-treated mice (P<0.05, n=6). The delayed protective effect of SIL was also abolished by PD98059 (22.5±2.3%). Western Blots revealed that SIL significantly increased phosphorylation of ERK1/2 which was blocked by PKG inhibitor, KT5823 in the heart and adult myocytes. Selective knockdown of PKG in cardiomyocytes with short hairpin RNA of PKG also blocked the phosphorylation of ERK1/2. Conclusion: SIL-induced cardioprotection involves the activation and phosphorylation of ERK which appear to be intimately linked with a PKG-dependent survival pathway. This research has received full or partial funding support from the American Heart Association, AHA Mid-Atlantic Affiliate (Maryland, North Carolina, South Carolina, Virginia & Washington, DC).

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Abstract 16538: Circulating Ketone Levels are Associated With Myocardial Infarct Size and Left Ventricular Function in Patients Presenting With St-Elevation Myocardial Infarction

Circulation ◽

10.1161/circ.142.suppl_3.16538 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Marie Sophie L de Koning ◽

B. D Westenbrink ◽

Solmaz Assa ◽

Dirk J van Veldhuisen ◽

Robin P Dullaart ◽

...

Keyword(s):

Myocardial Infarction ◽

Ejection Fraction ◽

Left Ventricular Function ◽

Infarct Size ◽

Ventricular Function ◽

Myocardial Infarct ◽

Left Ventricular ◽

St Elevation Myocardial Infarction ◽

Myocardial Infarct Size ◽

St Elevation

Background: Circulating ketone bodies (KB) are increased in patients with heart failure, corresponding with increased utilization of KB as a cardiac fuel. Whether circulating KB are increased in patients presenting with ST-elevation myocardial infarction (STEMI) and whether this is associated with infarct size is unknown. Methods: KB were measured in 379 non-diabetic participants of the Glycometabolic Intervention as Adjunct to Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction (GIPS) III trial (Clinicaltrial.gov Identifier: NCT01217307). Non-fasting plasma concentrations of the KB beta-hydroxybutyrate, acetoacetate, acetone were measured at presentation, 24 hours and 4 months after STEMI presentation using nuclear magnetic resonance spectroscopy. Associations of circulating KB with myocardial infarct size and left ventricular ejection fraction (both detected with MRI at 4 months after STEMI) were determined using multivariable linear regression analyses. Results: Circulating KB were higher at baseline (total KB 520 [315-997](median [IQR], μmol/L), compared to 206 [174-246] at 24 hours and 166 [143-201] at 4 months ( P <0.001 for all)). KB at 24 hours were positively associated with enzymatic infarct size, HbA1C and beta-blocker use. KB at 24 hours were independently associated with MRI outcomes at 4 months. Higher KB was associated with larger myocardial infarct size (total KB: standardized β=0.17, 95%-confidence interval (CI) (0.04-0.31), P =0.012) and lower ejection fraction (standardized β=-0.15, 95%-CI (-0.29- -0.009), P =0.037). Conclusion: Circulating KB are increased in patients with STEMI and are independently associated with myocardial infarct size and left ventricular function after 4 months of follow-up. The increase in circulating KB may reflect maladaptive changes of myocardial metabolism during the acute phase.

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Abstract 145: Apelin Reduces Myocardial Infarction Size and Promotes Angiogenesis by Increasing SDF-1/CXCR4 and AKT/eNOS/VEGF Pathways

Circulation Research ◽

10.1161/res.111.suppl_1.a145 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Lanfang Li ◽

Heng Zeng ◽

Jian-xiong Chen

Keyword(s):

Myocardial Infarction ◽

Myocardial Ischemia ◽

Molecular Mechanisms ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Border Zone ◽

Heart Weight ◽

Tunel Staining ◽

Myocardial Infarct Size

Background: Apelin is an endogenous ligand for the angiotensin-like 1 receptor (APJ) and is emerging as a key player in the regulation of angiogenesis as well as ischemia/reperfusion injury. So far, little is known about the functional role of apelin in myocardial ischemia. We investigated the potential intracellular molecular mechanisms and protective role of apelin during myocardial ischemic injury. Methods and Results: Myocardial ischemia was achieved by ligation of the left anterior descending coronary artery (LAD) for 24 hours and 14 days. Myocardial apoptosis was detected by TUNEL staining. Akt, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), SDF-1 and CXCR4 expression were measured by western blot. The CD133+/cKit+/Sca1+, CD133/SDF-1+ and cKit/CXCR4+ cells were determined by immunostaining. Myocardial capillary and arteriole densities were analyzed in the border zone of infarcted myocardium at 14 d of ischemia. Treatment of C57BL/6J mice with apelin-13 (1 mg/Kg.d) by i.p. injection for 3 days before surgery results in significant decreases in TUNEL positive cells and myocardial infarct size at 24 hours of ischemia. Treatment with apelin increases the phosphorylation of AKT and eNOS and upregulates VEGF expression in the ischemic heart. Furthermore, treatment with apelin leads to the expression of SDF-1 and CXCR4 and increases in the number of CD133+/cKit+/Sca1+, CD133/SDF-1+ and cKit/CXCR4+ cells in ischemic hearts. Treatment with apelin also significantly increases myocardial capillary densities and arteriole formation together with a significant decrease in the ratio of heart weight to body weight at 14 days of ischemia. This is accompanied by a significant improvement of cardiac function after 14 days of ischemia. Conclusions: Our data demonstrate that apelin contributes to the protection of myocardial infarction and angiogenesis by the mechanisms involving in upregulation of SDF-1/CXCR4 and AKT/eNOS/VEGF pathways.

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The Effect Of Fibrinolysis In The Early Stage Of Acute Myocardial Infarction

10.1055/s-0038-1652450 ◽

1981 ◽

Author(s):

K Genth ◽

J Frank ◽

J Schaefer ◽

V Korten ◽

D Heene

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Infarct Size ◽

Ventricular Function ◽

Early Stage ◽

Myocardial Infarct ◽

Interventricular Septum ◽

Left Ventricular ◽

Myocardial Infarct Size ◽

Time To Peak

The influence of streptokinase (SK) on myocardial infarct size and left ventricular function after acute myocardial infarction was investigated. 21 patients with myocardial infarction received SK (SK-group), 27 patients underwent conventional therapy (C-group). In both groups therapy started within 8 hours after onset of chest pain. In the SK-group initially 250 000 IU were administered intravenously, followed by a maintenance dose of 100 000 IU/h, lasting 15 hours. Blood samples at 8 hours intervals were collected for 3 days for serial CPK-analysis to calculate infarct size (I=∫f(t)×dt×K×bw). M-mode echocardiography was taken before start of t her a py and after 15, 24, 48 and 72 hours. AOP and heart rate were recorded continuously. Infarct size was 47±12g in the SK-group and 84±25g in the C-group (p<0.05). The average time to peak blood CPK-activity was 24 hours in the SK-group and 40 hours in the C-group. Peak CPK-level was significantly higher (p<0.5) in the SK-group (841±160U/l) than in the C-group (532±13 8 U / l ) . In 16 patients of the SK-group short periods of ventricular tachycardia were recorded during the period of fibrinolysis. Before therapy all patients showed abnormal motion of the posterior left ventricular wall and/or the interventricular septum, detected by echocardiography. 14 patients showed after fibrinolysis an improved or normalized motion.The results indicate that early fibrinolysis may reopen the occluded coronary artery. Reperfusion of the ischemic perfusion area may salvage jeo pardized myocardium, therefore infarct size was reduced and ventricular function improved.

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