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SEVERITY OF SYMPTOMS OF SYSTEMIC INFLAMMATORY RESPONSE SYNDROME ACCOMPANIED ISCHEMIC HEART DISEASE IN AGING ANIMALS. 

Sukoyan G.V.1, Galenko-Iaroshevsky P.A.2, Ionov D.Iu.2, Zelenskaya A.V.2, Golovach S.V.1
1International Centre of Introduction of New Biomedical Technology, Tbilisi, Georgia; 2Department of Pharmacology, Kuban State of Medical University, Krasnodar, Russian Federation  
Sukoyan G.V. �  HYPERLINK "mailto:galinasukoian@gmail.com" galinasukoian@gmail.com
Galenko-Iaroshevsky P.A. -  HYPERLINK "mailto:galenko.yaroshevsky@gmail.com" galenko.yaroshevsky@gmail.com
Ionov D.Iu. -  HYPERLINK "mailto:kybfarma@yahoo.com" kybfarma@yahoo.com
Zelenskaya A.V. -  HYPERLINK "mailto:kybfarma@yahoo.com" kybfarma@yahoo.com
Golovach S.V. �  HYPERLINK "mailto:icbiomedtech@" icbiomedtech@yahoo.com 

Correspondence author:  Galina V. Sukoyan , PhD, Department of Molecular and Clinical Pharmacology, International Centre of Introduction of New Biomedical Technology (assigned of NV Karsanov Scientific Centre of Introduction of New Biomedical Technology), Kairskaya str, 19, Tbilisi, 0137, Georgia. Tel.:+995595418030; E-mail:  HYPERLINK "mailto:galinasukoian@mail.com" galinasukoian@mail.com

ABSTRACT
Background
Systemic inflammatory response syndrome (SIRS) is one of the key accompanied states that worsening severity of chronic ischemic heart disease and leads to its refractory to the conventional therapy. 
Aims
This study aimed to determine whether the symptoms and signs of SIRS under chronic ischemic heart disease in age-related in experimental animals. 
Methods
40 rabbits � 20 adults and 20 aged were used to obtain age-associated differences in the severity of signs of SIRS and congestive heart failure caused by left descending coronary artery stenosis 3 month duration. All animals were euthanized after 14 days of the beginning of treatment. 
Results and Discussion
Long-term aortic stenosis leads to a simultaneously developing of congestive heart failure, diagnosed by developing cardiac hypertrophy, increased level of brain natriuretic peptide (BNP) and myocardial oedema and SIRS, confirmed by increased the markers and symptoms of endotoxemia, tissue hypoxia/ischemia and decreasing reserve ability of intrinsic defense systems. In aged animal�s cardiac hemodynamics disturbances, increased water content in myocardium and BNP in plasma, deterioration in the spectrograms of plasma and erythrocytes and levels of markers of inflammation were more pronounced in comparison with adults. Myocardium redox-potential and level of NAD under aged decreased in 1.3 fold in comparison with obtained in adult�s animals, which associated with the strengthening in severity of endotoxemia and disturbances in functioning of intrinsic defense systems (lysosomal dysfunction and free radical defense system). Redox-potential NAD/NADH modulated proinflammatory  tumor necrosis factor alpha (TNF-�) content and nuclear transcription factor kappa B (NF-kB/p65 subunit) activity in myocardium and its alteration is related to inflammatory states severities. 
Conclusion
Potential important link between cellular metabolism (hypoxia/ischemia), endotoxemia and disturbances in intrinsic defense system is the level of redox-potential, NAD/NADH in myocardium. The severity of symptoms of SIRS in animals under chronic coronary artery diseases are age-dependent and its correction could be a part of pharmacological interventions in preventing of age-related cardiovascular disease.
Key words: age, chronic ischemic heart disease, systemic inflammatory response syndrome, chronic heart failure, endotoxemia, antioxidant defense system, redox-potential

Introduction
Age-related changes in the cardiovascular and other organs systems are associated with the increasing prevalence of cardiovascular diseases at older age and characterized by a progressive deterioration in physiological functions, metabolic processes and a decrease in cardiac reserve [1-4]. With advancing age, the immune system undergoes a dynamic change characterized by the coexistence of a smaller immune response induces by profound �sterile� stimules or silent inflammation, which is different  type of internal inflammation, and has an insidious nature for many chronic diseases that are primarily caused by poor lifestyle habits and environmental pollutants [4-11]. As a result occurs the development of systemic inflammatory response syndrome (SIRS), activation of a wide range of interrelated pathways including endotoxemia mediators or endotoxin release; profound tissue dysoxia, hyperproduction of oxygen radicals, disintegrated of lysosomes; dysregulation of complement, coagulation, fibrinolytic and kallikrein systems. The progression of a SIRS divided into three stages. The first stage occurs in response to an insult, resulting in a local cytokine response primarily intended to evoke an inflammatory response to promote local cellular repair by recruiting cells from the reticuloendothelial and immune systems. The second stage involves release of small quantities of cytokines into the systemic circulation in order to enhance, or magnify, this local response. This acute-phase response is usually tightly controlled by endogenous proinflammatory antagonists, and cytokines and immunologic mediators are kept in check by specific downregulation and antagonism. At the beginning of SIRS toxins or product of metabolites enter the blood, lymph, interstitial fluid and spread of pathological focus (inflammation). If the protective system of the body is able to neutralize these substances, clinical symptoms may not occur, although any pathological conditions associated with the accumulation in tissues and body fluids of normal or perverted metabolism products or ketone response, there is a latent or transient SIRS. At third stage, when decompensation protective and regulatory systems - excretion, detoxification (microsomal oxidation, conjugation), mononuclear-macrophage, begin the accumulation of endogenous toxins in the body. 0 MB>9 AB0488 =0:>?;5=85 B>:A8G5A:8E ?@>4C:B>2 ?@>8AE>48B 2 >@30=0E 8 B:0=OE ;>:0;L=>, 2 ?5@28G=>< ?0B>;>38G5A:>< >G035 A 38?5@5@38G5- A:>9 2>A?0;8B5;L=>9 @50:F859. At this stage, the accumulation of toxic products occurs in organs and tissues locally, in the primary pathological focus with hyperergic inflammatory response and the rapid removal of the major mediators of inflammation. 4=0:>, MB> <>65B ?@82>48BL 8 : >4=>2@5<5==><C C40;5=8N 70I8B=KE <>;5:C;, =0?@8<5@, 70I8B=>3> F8B>:8=0<8 ?>2KH5=8N C@>2=O $ (D0:B>@0 =5:@>70 >?CE>;59) . "0:8< >1@07><, 8725AB=K5 A@54AB20, 8A?>;L7C5<K5 2 ;5G5=88 CCBO, >A;>6=ONI53> B5G5=85 @07;8G=KE 701>;520=89 =5 ?@54CA<0B@8205BAO MDD5:B82=KE <5B>4>2 2>7459AB28O =0 A>1AB25==K5 70I8B=K5, 45B>:A8F8@CNI85 A8AB5<K >@30=87<0. 
       The goal of our investigation was to compare the intensity of SIRS progression under chronic ischemic heart disease in adult and aged animals.
Methods
 Experimental protocol design
All experiments were carried out on the chinchilla rabbits weighing between 2,5-3,0 kg and reviewed in accordance with Principles of Laboratory Animal Care (�Guiding Principles in the Care and Use of Animals� of the American Physiology Society�, NIH Publication no. 86�23, revised in 1996) and approved by the Local Ethics Committee at International Centre of Introduction of New Biomedical Technology and Kuban State Medical University, Krasnodar, Russia. The rabbits were kept in a daylit environment and fed commercial laboratory rabbit food pellet, in specially designed housed (animal room) at a mean temperature 20oC, humidity 40-70%, lighting 12 hours per day) for at least 1 week before the experiments. 
         Chronic ischemic heart disease was reproduced by left descending coronary artery stenosis (banding (ligation) up to one third of the original size under sterile conditions [12]) 3-month duration (average ratio of heart to the body mass increased from the 1.52(0.09 to 1.96(0.14 (p>0,001) in adults and from the 1.27(0.11 to 2.3(0.2 (p>0,001) in aging (5,3�1,5 years, late middle aged) animals. In the sham operated groups cardiac hypertrophy in both groups did not observed and the survival is 100%. Average survival of animals after 3 month of coronary artery stenosis reproducing was about 82% (9 from 11 animals) in the adult and 67% (8 from 12) in aged. 
Deterioration  of cardiac hemodynamics and intensity of symptoms of cardiac hypertrophy 
Cardiac hemodynamics and SIRS were determined as described below [13-15]. The ventricles have been trimmed of atria and visible blood vessels. The left ventricular weight (LVW) and the ratio of LVW to body weight (LVW/BW) were obtained. The heart weight index was calculated by dividing the heart weight by the body weight in each group and as a cardiac wet-to-dry weight ratio. Wet-to-dry weight ratios were determined by drying tissue at 70�C. The brain natriuretic peptide (BNP) was measurement using MyBioSource ELISA assay.
Registration of SIRS development 
Level of endotoxemia. The severity of SIRS was evaluated by the increase in the content of medium-molecular-weight molecules in the plasma and erythrocytes and soluble vascular cellular adhesion molecule-1 (VCAM-1s) with ELISA-tests as described  [14-15]. Plasma and myocardium content of TNF-( and NF-kB in nuclear fraction of myocardium from left ventricle were determined by ELISA technique using standard kits (RayBiotech, Inc., USA). Frozen sections of hearts were mixed with 1.5 ml of physiological solution contained 0,5%NaN3 and homogenized. 
Level of tissue hypoxia-ischemia. The content of NAD and NADH, ratio of lactate/pyruvate in the myocardium homogenate were measurement as described below [12]
Level of the activity of intrinsic defense systems. The disturbances in the intrinsic defense system activities were measurement by the level of catepsin D activity (as a marker of lysosomal integrity of the myocardium [16-17]) with and without 0,1% triton X-100. Production of superoxide anion and hydrogen peroxide in mitochondrial fraction of LV myocardium as markers of deterioration in antioxidant defense system were described below [14-15]. 
Statistical analysis
The statistical significance assessed as the mean(standard deviation (SD) using the Statistical Sciences (SPSS, version 23) program.  Comparison of two means was performed using the Student t test for normally distributed variables and p<0.05 considered significant. Chi-square testing was used to analyze categorical data. 
Results and discussion.
Congestive heart failure (CHF) symptoms caused by chronic ischemic heart disease
        The cardiac hypertrophic index (CHI) in animals with chronic ischemic heart disease significantly increased above the control (sham operated animals) by 23% in adults and 81% in aged animals. Water concentration in LV of myocardium was also increase and exceeded the control level by 6% in adults (averaged 776�23 mg/g in control animals and 814�25 mg/g in chronic ischemic heart disease group) and by 7,5% in aged (averaged 789�29 mg/g in sham operated animals and 852�32 mg/g in chronic ischemic heart disease group). Moreover, the rates for +dp/dtmax, "dp/dtmax were markedly slower and left ventricle end diastolic pressure (LV EDP) higher in aging group (table 1).
The prolonged stenosis of coronary artery characterized by simultaneously developing of two syndromes: congestive heart failure, as was diagnosed by developing of cardiac hypertrophy, myocardial edema and increasing of level of BNP (table 1) and SIRS, as diagnosed by increased the markers and symptoms of endotoxemia, tissue dysoxia and decreasing reserve ability of intrinsic defense systems such as antioxidant and lysosomal (table 2). The severity of signs of both syndromes are more pronounced in aging group of animals.
Severity of SIRS and efficacy of therapy for its correction
        Despite advances in the treatment of cardiac arrest, the development of organ dysfunction following return of spontaneous circulation causes considerable morbidity and mortality. Our article is devoted to the definitions of �stress�, �systemic inflammatory response syndrome� and to their equivalence. 
Intensity of Endotoxemia under chronic ischemic heart disease and improvement after treatment
The SIRS caused by chronic coronary artery disease 3 month duration characterized by small leucocytosis e" 12x109 cells/L, stable temperature 37,2(2,2oC in adults and aging animals, tachycardia 168(12 beats/min in adults and 182(10 beats/min (p<0,05) in aged group.  Blood medium-mass molecules (MMM) concentration was revealed reflecting the condition severity, pattern, and manifestation of endogenous intoxication as a key part of SIRS under CHF (table 2). Changes in spectrograms of plasma and erythrocytes together with the more than 1,36-fold increase of VCAM-1s content in the blood confirmed the persistent release of ischemic-induced structural deterioration molecules from the myocardium and their absorption on the glycocalyx or in erythrocytes in adults.  In aged animals VCAMs content in blood increased only in 1,2-fold. This accompanied by elevated level of proinflammatory cytokine, TNF-� in 7-fold in plasma and in 4.8-fold in LV of myocardium in comparison to practically healthy rabbits in adults and  in  11- and 6.5-fold respectively in aged animals (table 2). NF-kB(p65) activity in LV also increases in 2.5 fold in nuclear fraction of LV myocardium in adults and in 3-fold in aging animals. 
Intensity of tissue dysoxia and efficacy of treatment
 The ratio of lactate/pyruvate in myocardium of animals with chronic coronary artery disease increases in 2.8-fold in adults and in 3.3-fold in aging that strongly confirm that metabolism shift to an anaerobic processes and energy supply deterioration. The decreasing of redox-potential at this stage of CHF has not coupled with reduced of total pool of pyridine nucleotide (including NADP(H) pool our unpublished dates) in adults animals.  In aging animals pseudonormalization of redox-potential accompanied with the decreasing of sum of reduced and oxidized from pyridine nucleotides by 25% (table 2). Early it was shown that changes in the level of NAD, and we suggested redox-potential with total pool of pyridine nucleotide, in each subcellular, cellular and tissues compartment can directly regulate sirtuin activity and is critical, contributing to the maintenance of physiological robustness [18] and cardiac hypertrophy [19].  The strong negative correlation between increasing level of TNF-� production and NF-kB (p65) activity and redox-potential NAD/NADH (r=-0,73, p<0,001 and r=-0,67, p<0,01 respectively) was established.  Statistically significant negative correlation was shown between the level of redox-potential and the activity of NF-kB in LV myocardium, along with negative correlation between the level of NAD/NADH and TNF-� in LV myocardium and plasma in peripheral blood. Obtained dates correlated with the hypothesis that intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner [20]. Inflammatory processes underlie many diseases and syndromes associated with injury of the heart muscle, and acutely, subacutely, and chronically cause structural, functional, and molecular deficits and defects. Although this subset of stimuli is structurally very diverse and might appear to be unrelated, there is accumulating evidence that the innate immune system may recognize them in similar ways and stimulate the sterile inflammatory response via common pathways. 
Intensity of tissue intrinsic defense systems reserve ability 
       Under prolonged ischemic heart damage the decreasing the redox-potential NAD/NADH by 30% as a marker of the mitochondrial complex 1 functioning disturbances is occurred which leads to an increasing of generation of superoxide anion. Superoxide anion production in the ischemic injuring myocardium significantly increases (P<0.001). Hyperproduction of hydrogen peroxide  in ischemic genesis CHF myocardium increased in 1.36-fold in adults and in 1.48 in aging animals (table 2). 
          The total catepsin D activities increased in hypertrophied myocardium by 20% in adults and did not changed in aging animals. The free catepsin D activities increased in hypertrophied myocardium by 189% (p<0.001) and 180% (p<0.01) in adults and aging animals, respectively as a result, the ratio of total activity/free activity of catepsin D decreased by 37% in CHF myocardium in adults and by 43% in aging groups.  In aging animals lysosomal integrity decreased in comparison with adults by 18% in practically healthy (sham operated) and in 27% in animals with chronic coronary artery diseases. 
Conclusion. Cardioinflammation is currently a hot topic, primarily due to its association with chronic ischemic heart disease has become a highly significant therapeutic target in aged patients. Obtained results demonstrated that aging strengthening the progression of cardiac hypertrophy, myocardial edema and intensity of all signs and symptoms of SIRS with aging. Redox-potental, NAD/NADH could be the intrinisic regulator of the control of pathways of TNF-( synthesis, level of the hypoxic/ischemic and free radical-induced damage in myocardium. Thus, alteration in myocardial NAD homeostasis and redox potential have an aged-dependent effect and indicates that drug with redox-potential regulation ability may have therapeutic potential in the prevention and treatment of CHF and SIRS in aged patients and the subject of personalized medicine.  
Author Contributions 
Participated in research design: Sukoyan G.V., Galenko-Yaroshevsky P.A. Conducted experiments: Zelenskaya A.V., Ionov D.Iu., Golovach S.V. Contributed new reagents or analytical tools: Sukoyan G, Galenko-Yaroshevsky P.A., Ionov D.Iu. Performed data analysis: Sukoyan G, Zelenskaya A.V. Wrote or contributed to the writing of the manuscript: Sukoyan G.V., Galenko-Yaroshevsky P.A., Ionov D.Iu.
Compliance with ethical standards
Acknowledgments
We thank the Chief Kamkamudze R. and his staff for animal housing.
Conflict interests
The authors declare that they have no conflict of interests regarding the publication of this paper. 
Ethical approval   The study was approved by the local ethics committee.

Informed consent


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Table 1. Cardiac  remodeling and congestive symptoms formation in rabbits with chronic coronary artery diseases
ParametersSham operated animalsChronic  coronary artery diseasesControl I, n=11Control  II, n=12Main I, 
n=9Main, II,
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Table 2. Changes in cytokines profile, NF-kB and redox-potential in left ventricle myocardium of rabbits with chronic ischemic heart disease.

Parameters/GroupControl ICHFControl II+Traditional Therapy+Adenocin�IL-1�, pg/mg protein3.4(0.8 24.5(1.8***20.3(1.7***#5.8(1.4##xxIL-6, pg/mg protein6.5(1.638.2(1.9***21.0(1.9***#7.9(0.9##xxIL-10, pg/mg protein2.8(0.92.9(0.5**2.7(0.4**5.2(0.6##xxTNF-(, pg/mg protein0.7(0.3 9.5(0.8***8.0(0.9**1.8(0.7##xx(IL-1�+IL-6+ TNF-():IL-103.8(0.624.9(1.6***18.3(1.5***#3.0(0.9###xxxNF-kB (@65) activity at 450 nm (od)0,10(0,020,24(0,04***0,20(0,03***0,12(
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