With hypertension, the cardiovascular system changes to adapt to the varying neuro-humoral and hemodynamic changes and this may lead to the development of different left ventricular geometric patterns, each carrying a different risk profile for major adverse cardiovascular events.Using a consecutive sampling technique, a cross-sectional, prospective, hospital based study was done and two hundred and twenty seven (227) hypertensive patients were studied.2.7 than to body surface area (70.0% vs. 52.9%). Duration of hypertension markedly influenced the type of LV geometry with normal LV geometry predominating in early hypertension and abnormal geometrical patterns predominating in late hypertension. The left ventricular fractional shortening decreased with duration of hypertension and was common in patients with eccentric hypertrophy. Age of the patient, systolic blood pressure, duration of hypertension and body mass index were found to be independent predictors left ventricular hypertrophy.The distribution of different abnormal LV geometrical patterns was 19.8%, 28.2%, 22% for concentric remodelling, concentric hypertrophy and eccentric hypertrophy respectively. With echocardiographic criteria, the proportion of patients with left ventricular hypertrophy (LVH) was higher when left ventricular mass (LVM) was indexed to heightAbout 70% of hypertensive patients had abnormal geometry existing in different patterns. Eccentric hypertrophy had more of clinical and echocardiographic features suggestive of reduced left ventricular systolic function. Hypertensive patients should be recognized as a heterogeneous population and therefore stratifying them into their respective LV geometrical patterns is useful as way of assessing their risk profile as well as instituting appropriate management. The World Health Organization (WHO) reported that non-communicable diseases accounted for 60% of the world's total deaths, and about 80% of these are occurring in the developing countries . In AfriThere are many conditions that are known to increase risk of cardiovascular diseases but hypertension has long been known explicitly to be a strong and independent risk factor for the development of major adverse cardiovascular events, whereby the cardiovascular system adopts different abnormal changes as a result of long standing hypertension . The heaWorld Health Organization (WHO) defines hypertension as a chronic medical condition in which the arterial blood pressure is elevated ≥140 mmHg systolic and/or ≥90 mmHg diastolic on two readings taken apart or a reported diagnosis of hypertension and treatment with recognized anti- hypertensive within 2 weeks before the visit. In a cross-sectional study involving three Sub-Saharan African countries , together, the prevalence of hypertension and pre-hypertension was found to be 22 and 44% respectively .The definition and criteria of left ventricular hypertrophy (LVH) are variable in many studies . The diaThe study population included adult patients firmly diagnosed to have essential arterial hypertension with or without treatment. A consecutive sampling method was used. We excluded patients who had poor quality of echocardiography imaging due to various reasons including obesity and lung problems. Patients noted to have impaired global or segmental wall motion and valvular lesions during echocardiography examination were excluded. Also patients with suspected or established secondary hypertension were also excluded.During recruitment, the principal investigator (PI) filled in a standardized structured questionnaire for each patient included in the study. A detailed history was obtained from the patient or from a close relative and recorded in the patient case-note and in the structured questionnaire. Physical examination findings, electrocardiogram and echocardiogram results were recorded in the data collection sheet.A thorough and detailed history was taken and in particular the history focused on presence or absence of overt heart-related symptoms. Duration of hypertension was also noted.Socio-demographic data, anthropometric and biometric measurements were taken: – Height (in meters) was taken using a commercially available stadiometer and the patient was required to stand upright away from but body and head touching the meter ruler (m). Weight (in kilograms) was taken using a standard weighing scale to the nearest rounded value while the patient is in light clothing and shoes taken off.A thorough general examination was conducted to each patient and vital signs obtained. Blood pressure measurement using standard well calibrated mercury sphygnomanometer based was taken.0.425 × Height0.725) × 0.007184.The body mass index (BMI) was derived by dividing the weight (kg) by the square of the height (m) and classification of obesity was done according to WHO criteria. The body surface area (BSA) was calculated using the formula derived by Du Bois and Du Bois (1929) as: BSA =  recommendations. The M- mode derived parasternal view was used to assess for the chamber and wall dimensions of the left ventricle and left atrium, including the derived systolic indices such as fractional shortening.The ASE recommended formula-leading edge to leading edge measurements-for estimation of Left Ventricular mass (LV mass) from left ventricular linear dimensions  was usedWhereby,1. LVPWd – posterior wall thickness at end diastole.2. IVSd – septal wall thickness at end diastole.3. LVIDd – dimensions of the left ventricle at end-diastole2 and >95g/m2 for men and women respectively when LVM was indexed to body surface area (BSA) and >49.2g/m2.7 and 46.9 g/m2.7 for men and women respectively, when LVM was indexed to allometric growth rate of 2.7. The relative wall thickness (RWT) was calculated using the formula 2 × LVPWd/LVIDd. Increased RWT was present when this ratio was >0.42 [Gender-specific and indexation of left ventricular mas (LVM) was used to diagnose LVH using the following defining criteria: >115g/mLeft ventricular (LV) geometry was divided into four patterns based on left ventricular mass index (LVMI) and relative wall thickness (RWT) values. These are:1. Normal geometry (NG) – normal LVMI and RWT ≤ 0.42,2. Concentric hypertrophy (CLVH) – increased LVMI and RWT > 0.42,3. Eccentric hypertrophy (ELVH) – increased LVMI and RWT ≤ 0.42,4. Concentric remodelling (CR) – normal LVMI and RWT > 0.42.SPSS version 17.0 software  was used in the analysis of the data. Continuous variables were expressed as mean ± SD while categorical variables were expressed as counts (percentages). Chi-square (χ2) analysis was done to compare proportions. Logistic regression was run to determine predictors of LVH. A 2-tailed p-value of 0.05 was taken as statistically significant.This study was ethically approved by the Kilimanjaro Christian Medical University College (KCMUCo) Research Ethics Committee after meeting the required ethical standards.The principal investigator fully explained to every prospective participant the purpose of the research and was requested to participate freely. A consent form containing details of the study regarding main purpose, role of participants, and benefits associated with participating in the study (if any) was given to each prospective participant. Those who agreed to participate in the study gave a verbal consent as well as signing a written consent form written both in English and Swahili language. Swahili language is a lingua franca in Eastern Africa.Patients who did not agree to participate in the study were not denied any services or treated with partiality and even those who agreed to be recruited in the study were not treated differently from those who did not agree to participate in the study.As shown in Table As shown in Table LV normal geometry was detected in 68 (30.0%) of the 227 hypertensive patients, concentric hypertrophy in 64 (28.2%), concentric remodelling in 45 (19.8%) and eccentric hypertrophy in 50 (22.0%).In Table In Table Normal geometry is more frequent in male than female (42.9% vs. 22.4%) while concentric remodelling and concentric hypertrophy is more frequent in female than male (23.1% vs. 14.3% and 33.6% vs. 19.0% respectively). Eccentric hypertrophy did not differ much between male and female (23.8% vs. 21.0%). The difference in presentation of LV geometrical patterns with sex is statistically significant (p=0.003).2 respectively).Abnormal LV geometrical pattern presentation with body mass index was present in patients who are at least overweight (BMI >25kg/m2). Concentric hypertrophy was present in patients who have higher mean BMI compared to patients with concentric remodeling and eccentric hypertrophy (29.72 vs. 27.20 and 27.60kg/m2) compared to other geometrical patterns. The difference in body mass index and LV geometrical pattern presentation was significant (p=0.001).Normal geometrical pattern was present in patients who have relatively smaller BMI .LV geometrical patterns presentation change with duration of hypertension significantly (p<0.001), being lower in normal geometry and highest in eccentric hypertrophy .2.7 dimension presentation in different LV geometrical patterns, increasing from normal through concentric hypertrophy and then declining in eccentric hypertrophy (p<0.001).There was a significant difference regarding the interventricular septal wall thickness at end-diastole, left ventricular posterior wall thickness at end diastole, relative wall thickness, left ventricular mass indexed to body surface are and heightThe left ventricular internal diameters during diastole and systole were relatively higher in patients with normal geometrical than with concentric remodelling patterns but increased from patients with concentric remodeling to eccentric hypertrophy patterns. This difference was statistically significant (p<0.001).The left ventricular fractional shortening was normal for normal geometrical, concentric remodeling and concentric hypertrophy geometrical patterns and was mildly lower for patients with eccentric hypertrophy.As shown in Table As is shown in Table In this study abnormal LV geometry was detected in 70% of patients while Aje  found 72Duration of hypertension markedly influenced the type of LV geometry with normal LV geometry predominating in early hypertension and abnormal geometrical patterns predominating in late hypertension, as is found also by Akintunde . During With regard to LVH, age of the patient, systolic blood pressure, duration of hypertension and body mass index were strong independent determinants of LVH. This was also shown in a Russian study .2.7 increased significantly from normal through concentric hypertrophy and then declining in eccentric hypertrophy.Regarding blood pressure and duration of hypertension, there was significant change characterized by progressive increase in mean systolic, mean diastolic and mean arterial blood pressure from patients with normal geometry to patients with concentric hypertrophy, followed by decline in patients with eccentric hypertrophy overtime ,13. The This is because in patients with concentric remodeling or concentric hypertrophy usually the pressure overload predominates rather than volume overload stimuli. With pressure overload the wall tension is high trying to counteract the high peripheral resistance and usually the cardiac myocyte hypertrophy typical of concentric hypertrophy. With time, the hypertrophied cardiac muscle becomes maladapative and fatigues for reasons not known and so to overcome the volume overload the chambers dilate and cardiac output is decreased and resultant reduced systolic and diastolic pressure in eccentric hypertrophy.About 70% of hypertensive patients at KCMC which is a tertiary hospital in northern Tanzania had abnormal LV geometry, whereby 19.8% had concentric remodelling, 28.2% concentric hypertrophy and 22% eccentric hypertrophy.The left ventricular systolic function by fractional shortening was worse in patients with eccentric hypertrophy who were also more likely to have clinical features of heart failure than patients with other types of geometrical patterns.Hypertensive patients are not a homogenous population and characterization into different left ventricular phenotypes is important to stage an appropriate management and monitor prognosis.The authors declare that they have no any competing interests.LSK: first author of this work, involved in the early conception of the idea, proposal development, data analysis, manuscript writing and submitting to the publishing journal. VPM: highly contributed to the study concept, design, global and direct supervision of data collection and report writing. HD: was the focal person responsible for doing echocardiograms. HM: was involved in teaching basics hands-on technique on echocardiography to the main author GK: was involved in statistical analysis. MD: involved in proposal writing. BH: was involved in supervisory role in study concept, manuscript writing and critical review of the work at all stages. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/12/109/prepub


Many case reports have been published of reversible left ventricular dysfunction precipitated by sudden emotional stress. We have evaluated 10 women hospitalized for acute chest pain and dyspnea, mimicking an acute coronary syndrome, after a severe emotional trigger. Those patients, postmenopausal women, presented ST segment alterations on the EKG, minor elevations of cardiac enzymes, and biomarkers levels. At the coronarography there was not coronary thrombosis or severe stenosis, but the ventriculography showed wall motion abnormalities involving the left ventricular apex and midventricle, in the absence of significant obstructive coronary disease. The course was benign without complication, with a full recovery of left ventricular function in some weeks. These observations, like other reports, demonstrate the impact of emotional stress on left ventricular function and the risk of cardiovascular disease. The cause of this cardiomyopathy is still unknown, and several mechanisms have been proposed: catecholamine myocardial damage, microvascular spasm, or neural mediated myocardial stunning. Broken heart syndrome or transient stress induced cardiomyopathy is characterized by left reversible systolic dysfunction which appears to be triggered by an intense psychologic stress in the absence of myocardial infarction.The syndrome is also known under several names, including “Ampulla cardiomyopathy, Takotsubo cardiomyopathy, Left Apical Ballooning Syndrome.” First reported by SATO et al. in the Japanese population in 1980, Takotsubo is a pot with a round bottom and a narrow neck used for trapping octopuses in Japan –4.Ten previously healthy patients were admitted to the Coronary Care Unit of the Academic Hospital Center of Rangueil in Toulouse or in the General Hospitals of Midi Pyrénées Area.Their median age was 52 years (range 48–65 years). Those patients, ten postmenopausal women, were hospitalized for a severe chest pain and acute dyspnea in emergency in the Coronary care Unit. All were evaluated by means of serial electrocardiograms and serial measurements of cardiac isoenzymes, including creatine kinase, creatine kinase MB fraction, and cardiac troponins I and T. All these patients underwent in emergency, coronary angiography and left ventriculography. A two-dimensional trans thoracic echocardiography was realized within the 24 hours after the onset of symptoms.The two oldest women had been treated for hypertension and dyslipidemia, and the eight others had not vascular risks factors. The causal emotional stress was an acute emotional distress after their sudden accidental son's death in two cases, an armed robbery for two patients, financial loss for two others patients, car accident for one patient, and dramatic explosion of a factory in Toulouse causing severe acute pain for two patients. Acute dyspnea and pulmonary sub-oedema with severe left ventricular dysfunction were associated to chest pain in six cases. The cardiac markers were slightly elevated suggestive of mild cardiac injury with a mean peak of troponins of 1,20 ng/mL. The peak creatine kinase level was 150 mL/L/(range from 104 to 283), and the mean peak cKMB level was 8 ng/mL.At the coronarography, seven women had absolute normal coronary arteries, three mild luminal irregularities in the proximal left anterior descending artery. No patient had angiographic evidence of coronary spasm or thrombosis. The contrast left ventriculography revealed apical and mild ventricular akinesis, apical dilatation, with normal contractility of the basis of the heart. Mean ventricular ejection fraction value was 0,35 . Initial echocardiogram showed a similar contractile pattern with preserved basal function and apical dyskinesia. For only 3 patients it was possible, on hospital days 2 and 3, to measure plasma level of catecholamines: mean value of epinephrine, 1340 pg/mL and norepinephrine, 1570 pg/mL. During the outpatients followup, the left ventricular ejection fraction had completely recuperated, and all segments of left ventricle had normal contractility.Four patients underwent magnetic resonance imaging confirming left ventricular dysfunction in acute phase. This examination demonstrated the absence of myocardial necrosis or late gadolinium-enhanced image.The prognosis was favourable for all these women, without major complication during the hospital stay and without mortality. All the patients had a good evolution with a treatment by furosemide, betablockers, heparin, and ACE inhibitors. Dyspnea and the signs of pulmonary congestion disappeared after the diuretic treatment, conversely the T wave inversion on EKG resolved very slowly, in mean after 3 months. By a median of 6 days after presentation in the hospital, the left ventricular ejection fraction had improved to 0,50. A full recovery of left ventricular function was recuperated to echocardiography within 4 to 6 weeks from the onset of symptoms. None recurrence or other complication were observed during the two years of followup.After the introduction of the term Takotsubo and the description of this syndrome in Japan many cases were reported worldwide. The characteristic feature of this syndrome is the peculiar and transient end-systolic ventricular shape that inspired the name. The prevalence of this disease is unknown. In Japan it is estimated to be as high as 2% of hospital admissions for chest pain and acute ST changes. A strict predilection for female gender and for postmenopausal women is one of the hallmark of Takotsubo cardiomyopathy –5.Postmenopausal women reported to make up over 90% of the cases in most series. The reason for the female predominance remains unknown although a lack of oestrogen in the postmenopausal phase seems to play a pathogenic role. Patients suffering from broken heart syndrome have a clinical presentation very similar to that of an acute coronary syndrome. Most reported patients with this cardiomyopathy were hospitalised after an episode of an important psychological or emotional stress. The acute chest pain or left ventricular dysfunction follows an acute mental trigger: unexpected loss of a close relative, dispute with another person, devastating financial loss, or a physical stress, sepsis, trauma, or cerebrovascular accident. But the lack of preceeding trigger does not exclude the diagnosis of Takotsubo cardiomyopathy. Chest pain is often accompanied by an acute dyspnea, palpitations arrhythmias, collapses and syndrome of heart failure. A true cardiogenic shock requiring circulatory assistance was reported , 5. The syndrome mimics acute myocardial infarction in the absence of obstructive epicardic coronary atherothrombosis. Sharkley et al. studied the EKG of 59 patients with this diagnosis. On admission 56% had ST elevation, 27% T-wave inversion, 10% new Q waves or abnormal R-wave progression [ Plasma levels of catecholamines and their metabolites are elevated in the acute phase in 74% of patients when these concentrations are measured. Wittstein et al. compared plasma catecholamines in 13 patients with Takotsubo cardiomyopathy with seven controls hospitalized for acute myocardial infarction with left ventricular dysfunction. They found that catecholamines levels were two or three times higher in patients with left ventricular ballooning syndrome –8. RecenThe typical and important finding is the absence of obstructive coronary disease. Nevertheless, Ibanez et al. were able to describe the presence of ruptured atherosclerotic plaques in some patients with the use of intravascular ultrasound .cardiogenic shock 8%,congestive heart failure 8%,ventricular tachycardia 3%,subite death 3,5%, andothers rare complications have been reported: left ventricular rupture, apical thrombus formation, distal or cerebral emboli (5-7-10).Based on their experience a team of the Mayo Clinic proposed some criteria for this diagnosis . In the  A microvascular dysfunction or a multivessel acute epicardial coronary spasm with transient impaired coronary blood flow has been evocated by some authors , 3, 5.Elesber et al. have reported an abnormal TIMI myocardial perfusion grade  in 69% of their patients . Structural and ultrastructural myocardial changes are rather suggestive of direct catecholamines toxicity, and myocardial sudden stunning.Since the first report by Kume et al. about increased catecholamines plasma levels in patients with Takotsubo cardiomyopathy, other studies have confirmed these author's finding reporting increased local release assessed by blood sampling from the aortic root and coronary sinus . The inc According to Akashi et al., “a number of important questions remain.” “Experimental approaches to mimic the clinical manifestations may provide new insights into the pathogenesis of this syndrome. The development of animal models began to address this issue. The adrenal stimulation given by immobilization in rats mimics the clinical condition of takotsubo cardiomyopathy. Immobilization induces upregulation of immediate early genes, such as c-fos and c-jun in endothelial, myocardial, and coronary muscle cells. The expression of these genes suggests coronary spastic changes and consequent microvascular dysfunction.” . Akashi et al. have hypothesized that the reduced estrogen levels after menopause explain the predisposition of elderly women to this cardiomyopathy and induced vulnerability to stress. Estrogen supplementation attenuated the immobilization-induced cardiac dysfunction, sympatho adrenal activation, and vagal inhibition.  “Treatment with estrogen attenuated the immobilization-induced increase in c-fos mRNA expression in the lateral septum, medial amygdaloid nucleus, paraventricular and dorsomedial hypothalamic nucleus, laterodorsal tegmental nucleus, regions that are parts of the central autonomic network and possess immunoreactive estrogen receptors.” These data suggest that reduced estrogen levels play a role in the pathogenesis of this cardiomyopathy .  “But the estrogen hypothesis does not seem sufficient to explain the occurrence—albeit uncommon—of this cardiomyopathy in men.” The hypothesis that catecholamine surge may play an important role in the pathogenesis of the syndrome is supported by many authors.  The development of transient severe left ventricular outflow obstruction is another mechanism that has been implicated in the pathogenesis of the Takotsubo syndrome. In the setting of massive catecholamine surge, elderly women, who frequently had a sigmoid interventricular septum, could potentially develop severe obstruction, outflow tract leading to apical ischemia as a result of increased wall stress. However, if this was the case, one would expect to document an intraventricular gradient more often than it has been reported in the literature . NeverthThe pathogenetic mechanisms underlying the development of this transient ventricular dysfunction remain largely unknown. Several theories have been proposed.The optimal treatment of broken heart syndrome remains unknown. Initial management should be definitely directed towards the treatment of myocardial ischemia with continuous EKG monitoring, heparin, oral and intravenous nitrates, and betablockers. Cardiogenic shock due to pump failure is treated with standard therapies and in some severe cases, intra-aortic ballon counter pulsation. Anticoagulation should be considered during initial presentation and the acute phase if severe left ventricular dysfunction is present, like the prescription of ACE Inhibitors or angiotensin blockers therapy, before discharge. In our practice in the absence of contraindications, it is possible to recommend prolonged beta blockers therapy with the aim of reducing the likelihood of recurrent episodes. Annual clinical followup is advisable because the natural history of apical left ventricular ballooning syndrome remains unknown. In conclusion, stress or Takotsubo cardiomyopathy is an increasingly recognized type of acquired cardiomyopathy occurring commonly after a recent stressful event, in peculiar emotional stress. It is typically characterized by transient myocardial systolic dysfunction that is mainly confined to the apical region of the left ventricle. The clinical presentation closely resembles that of an acute coronary syndrome, with chest pain, ischemic type ST changes, or T-wave inversion and minimal cardiac enzyme elevation. Coronary angiography and echocardiography are necessary to establish the diagnosis. The pathogenetic mechanism remains unknown although catecholamine surge plays probably a primary role. A relative deficiency of estrogen after menopause may predispose women to developing this Takotsubo syndrome. Microvascular disease and dysfunction in women may lead to myocardial ischemia in response to mental stress . The mos


Heart failure is seen as a complex disease caused by a combination of a mechanical disorder, cardiac remodeling and neurohormonal activation. To define heart failure the systems biology approach integrates genes and molecules, interprets the relationship of the molecular networks with modular functional units, and explains the interaction between mechanical dysfunction and cardiac remodeling. The biomechanical model of heart failure explains satisfactorily the progression of myocardial dysfunction and the development of clinical phenotypes. The earliest mechanical changes and stresses applied in myocardial cells and/or myocardial loss or dysfunction activate left ventricular cavity remodeling and other neurohormonal regulatory mechanisms such as early release of natriuretic peptides followed by SAS and RAAS mobilization. Eventually the neurohormonal activation and the left ventricular remodeling process are leading to clinical deterioration of heart failure towards a multi-organic damage. It is hypothesized that approaching heart failure with the methodology of systems biology we promote the elucidation of its complex pathophysiology and most probably we can invent new therapeutic strategies. Systems biology is a term selected for the study of the vast amount of experimental data advanced from current technologies in genomics and proteomics . It is aThe explanation given to the clinical syndrome of heart failure is limited if only the pathophysiological mechanisms are described. Also the specific clinical models developed to interpret the variety of clinical phenotypes are not sufficiently coherent to explain the progressive deterioration of heart failure and some of the successful aspects of the new therapeutic agents. Targeting the involved molecular mechanisms, only the biomechanical model predicts that the novel therapeutic strategies interrupt the viscous cycle of myocardial dysfunction and cardiac remodeling .The present paper debates the biomechanical model of heart failure under the current concept of systems biology methodology exploring the connection of the complex metabolic and regulatory networks with the clinical phenotypes of heart failure. It is accepted that early  mechanical stresses applied in the myocytes and/or mechanical changes in the left ventricular cavity comprise the primary initiating causes for cardiac remodeling and neurohormonal activation.It is hypothesized that only through systems biology methodology can we explain the complex phenomenon of heart failure and defend the concept of the biomechanical model. This approach will increase the knowledge of the pathogenesis of heart failure and eventually will enable the development of effective drug therapy.The nature and the biological world constitute a complex system compiled of many interacting components that produce complex physical and biological phenomena. The research on complex phenomena extends from physics to biological and the medical world . The phyA network of interactions is considered modular if it is made of autonomous interconnected components that act together in performing some discrete physiological function  , 5. The Systems biology integrates diverse areas of science targeting the underlying principles of hierarchical metabolic and regulatory systems from the cell to an organismal level . It enta1). The heart should be considered as a multifunctional organ that participates in the homeostatic regulation of the body and is an essential element of a complex and integrated network of organs and systems. Human heart failure from the point of view of systems biology is considered as a syndrome with different causes that involves many clinical appearances or clinical phenotypes. Each clinical phenotype involves many biochemical pathways, pathophysiological changes and physiological regulatory systems. These regulatory systems are important in upgrading or inhibiting the cardiac cavity remodeling process that delineates the syndrome. Two of the most important regulatory systems in heart failure, the natriuretic peptide axis and the renin-angiotensin-aldosterone system (RAAS), are considered examples of critical functional modules . In the aAtrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and their prohormones (proANP and proBNP) are secreted by cardiomyocytes. Under normal circumstances the ANP and BNP are released after increase of the atrial and myocardial stretch or after excessive sodium intake. In patients with heart failure the natriuretic peptides release is considered the earliest regulatory mechanism that is motivated in contrast to later sympatho-adrenal system (SAS) and RAAS activation. It is accepted that the ANP is produced mainly from atria and BNP from ventricles, and they are differently regulated in the two cavities. Therefore two cardiac endocrine systems are working in parallel, one in the atria producing ANP and the other in the ventricles secreting BNP . In chroThe BNP is considered both as a biomarker of heart failure diagnosis and as a prognostic factor in various cardiovascular diseases. In clinical practice the BNP sensitivity and specificity for increased filling pressure detection are lower than the echocardiographic estimation criteria for filling pressure. In a recent article doppler echocardiography methodology increased the accuracy of heart failure diagnosis in the presence of intermediate BNP or amino-terminal proBNP (NT-proBNP) and improved the stratification of risk across all periods of heart failure . NeverthThe natriuretic peptides possess vasodilator, natriuretic and diuretic effects, and an inhibitory action on immunological and inflammatory systems, and on growth factors , 13. TheSystems biology approach to the natriuretic peptide axis is revealed from genomic and proteomic studies which identified many locations that were responsible for heart failure exacerbation. Genomic studies recognized multiple polymorphic structural variants of the BNP gene, which were responsible for the blood levels of BNP and NT-proBNP in normal subjects and in patients with heart failure , 16. Alsa diagnostic and prognostic point of view. Recent proteomic studies define some aspects of the functional importance of the natriuretic peptide axis in comprehending the heart failure syndrome. The BNP-32 is considered to represent the main biologically active form of BNP and predictably is increased in patients with heart failure. However, using a novel method of mass spectrometry, new high molecular weight forms of BNP have recently been discovered that are less biologically active than BNP-32, but with the current assays were erroneously identified as BNP-32 or NT-Pro BNP . The aboThe increased BNP in patients with heart failure is inadequate to delay the disease progression and its beneficial physiological effects are reduced partly because of the up-regulation of the phosphodiesterase type-5 enzyme (PDE5) . The PDEThe levels of natriuretic peptides in patients with chronic heart failure are increased compared with healthy individuals. Excessively high circulating levels of natriuretic peptides are confirmed in patients with chronic heart failure presented with fluid retention and vasoconstriction. The defective biological activity of the natriuretic peptides system suggests a kind of peripheral resistance to the biological effect of natriuretic peptides . This peThe above data support the hypothesis that the natriuretic peptides are elements of an integrated network that includes the cardiac muscular, endocrine, immune, and nervous system.bThe depressed left ventricular function generates a variety of physiological reactions in an endeavor to remedy the diseased myocardium. These counteracting responses that include the increased activity of both the SAS and the RAAS, are considered deleterious for the myocardium, and therefore correctly their association with the cardiovascular and cardiorenal disease became a therapeutic target. The SAS is activated early (but after the activation of BNP) in the course of heart failure due to autonomic imbalance or to loss of the inhibitory effect of the baroreceptor reflexes. The RAAS is activated later in the course of heart failure with the possible mechanisms of the renal hypoperfusion due to low cardiac output and the increased renin release due to sympathetic stimulation of the kidney.1 receptor blockers (ARBs) ( antagonize angiotensin II binding to AT1 receptors). The above therapeutic agents to a degree could prevent or reverse heart failure deterioration and progression. These treatments cope with the overexpression of the biologically active neurohormonal molecules that exert deleterious effects on the heart and circulation [The most significant classes of drugs targeting the RAAS are the β-adrenergic antagonists (β blockers) (reduce renin), the angiotensin-converting enzyme inhibitors (ACEI) (reduce levels of angiotensin II) and the ATculation . The metculation . The comSystems biology approach supports the hypothesis that there are two integrated and opposing systems acting not only at the cardiac level but in the whole body. The first system is the RAAS with vasoconstrictive, sodium retaining, thrombophylic, prohypertrophic, and proinflammatory properties, while the second is the natriuretic peptide system that manifests opposing qualities such as natriuretic, vasodilating, anti-inflammatory, anti-thrombotic and anti-hypertrophic. In patients with heart failure the first system controls the hemodynamic homeostasis, initially as a counterbalancing mechanism but later induces a progressive and deleterious worsening of the cardiac function. The second opposing mechanism, the natriuretic peptide system, seems to be inadequate in delaying the heart failure progression.1).The goal of modern clinical cardiology is to obtain a reliable description and understanding of the human physiology in various states and diseases, to incorporate the different physiological and interrelated derangements presented in databases, and finally to use the available clinical variables constructing specific clinical models  mechanical stimulus responsible for cardiac remodeling and neurohormonal activation, and also the progressive mechanical remodeling changes responsible for the persistence and progression of clinical heart failure syndrome . The oveLAX) and early diastole (ELAX) which were lower in the patients with diastolic heart failure [M) and early diastolic (EM) velocities in patients with HFrEF, HFpEF and isolated diastolic dysfunction [’) is useful to assess left ventricular filling pressure while a persistent elevation of this ratio may be a prognostic factor of diastolic heart failure in patients with HFpEF independent of left ventricular hypertrophy [’ ratio after optimized medical therapy is predictive of cardiac events [’ greater than 15, ejection fraction less than 50%, and severe functional mitral regurgitation were independent echocardiographic predictors of cardiac events [’<3 cm/s was associated with a significantly excess mortality, and this measurement added incremental prognostic value to E/E’ >15 [In a recent paper, a mathematical model is introduced that predicts the dominant role of remodeling as a compensatory physiological response in chronic heart failure resulting in a normalization of stroke volume . In the  failure . Left ve failure . Systolifunction . The Dopertrophy . In patic events . In patic events . In patiE/E’ >15 .In the end-stage of heart failure the persistent mechanical remodeling changes are self-determined probably without neurohormonal dependence operating until the end of the disease. In this stage it is improbable for the neurohormonal activation to have a sustained and effective inotropic performance and therefore the only compensatory mechanism that remains is the left ventricular remodeling. The compensatory mechanisms of left ventricular remodeling and neurohormonal activation are not sufficient to counterbalance effectively the initial mechanical left ventricular changes while the progressive mechanical remodeling changes that occur during the end-stage of the left ventricular dysfunction are deleterious and unopposed by any other compensatory mechanisms. In a sense significant left ventricular dysfunction begets progressive ventricular remodeling, that in turn begets progressive left ventricular dysfunction. The end-staged left ventricle represents a terminally remodeled and noncompliant cavity with low contractility and function.The mechanosensation is an old biological process to be found in all forms of life. In mechanotransduction the mechanical effect is closely related and affects the transduction systems of vasopeptides, hormones, sensing receptors, ionic fluxes and other autocrine/paracrine mechanisms.The endothelium of arteries and veins is constantly exposed to hemodynamic forces due to the pulsatile nature of blood pressure and flow. Therefore the endothelium is permanently detecting various biomechanical forces , which are translated into intra- and extracellular signals . The bioThe Kruppel-like factor (KLF2) is a transcriptional inhibitor of endothelial mediated inflammation . The KLFThe biomechanical stress is speculated as an early and most significant stimulus for cardiac hypertrophy and heart failure. The gp130 cytokine receptor plays a significant role in myocyte survival pathway in the transition to heart failure. During aortic pressure overload, in mice with ventricular restricted knockout of the gp139 cytokine receptor, was described a rapid onset of dilated cardiomyopathy and massive myocyte apoptosis in contrast to control mice that showed compensatory hypertrophy . The actin vivo analyses of intracardiac flow forces in zebrafish embryos [It is hypothesized that in the adult the early hemodynamic cavity stresses of left ventricular dysfunction induce ventricular endothelial dysfunction and remodeling. Probably that follows the embryonic model of flow-structure interactions that influence the process of cardiac development . The int embryos . The rec embryos . The ana embryos . The β aMyocardial biomarkers like natriuretic peptides are considered useful biochemical substances in the diagnosis of patients with heart failure. The natriuretic peptides ANP and BNP are secreted in response to increasing cardiac wall tension and/or circulating neurohormones. The blood levels of ANP and BNP are increased in patients with left ventricular dysfunction as well in patients with preserved ejection fraction. In patients with systolic heart failure the BNP blood levels are directly related to wall stress, ejection fraction and functional failure classification . In wome1R), as it is well known that angiotensin II is proinflammatory and proatherosclerotic. This was demonstrated in an immunohistochemical analysis in the aortic arch of transgenic mice where a pronounced expression of AT1R was found in the inner atheroprone regions of the aortic arch, characterized by disturbed or oscillatory shear stress, but not in the outer aortic arch exposed to high shear stress [1R protein expression.Shear stress demonstrates an atheroprotective role through downregulation of angiotensin type 1 receptors (ATr stress . In the 2).How can the early mechanical effects be translated into clinical phenotypes? The impact of the early mechanical changes on clinical outcome in heart failure patients remains to be established in a future study comparing initial mechanical changes with the earliest neurohormonal activation. It is significant from a clinical perspective the design of a trial with sufficient power to discern meaningful interactions between early mechanical effects and neurohormonal activation in order to improve our understanding of the later clinical outcome  give several reasons supporting the wall-stress hypothesis: 1) Pure mechanical overload that is not accompanied by a neurohormonal reaction is a rather rare phenomenon and therefore the coexistence of the two processes obscures the significance of the mechanical initial factor. 2) The transgenic hypothesis is impossible to reproduce the entire cascade that follows the mechanical stress. 3) During cardiogenesis the different transcription factors operate synergistically in a combinatorial way that is not documented in cardiac hypertrophy. They support the hypothesis that cardiac hypertrophy results from an initial mechanical effect and a re-expression of the fetal program, and during clinical conditions in humans the effects of mechanics are modified by senescence, obesity, diabetes and ischemia [The transgenic technology queries the validity of the wall-stress hypothesis that both cardiac hypertrophy and fetal reprogramming were a necessary adaptive response to mechanical load. It is suggested that the progression of heart failure depends on different mechanisms triggered by new molecular rearrangements. The above position is not absolutely valid and it is not necessary to reconsider the wall-stress hypothesis . Swyngheet al  give sev2). Phenotype in biology is considered any observable characteristic of an organism that includes morphology, biochemical properties, physiological functions, and behaviors. As phenotypic data from systems biology perspective are examined network functional states such as fluxomic data that give information about the actual flux distributions in a network . The comHuman heart failure is a syndrome exhibiting multiple clinical phenotypes implicating a number of common pathophysiological, biochemical and molecular mechanisms. The clinical phenotypes are marked by multiorgan dysfunction due to the upregulation or downregulation of the above mechanisms. It is important from experimental and clinical perspective to define these phenotypes and to schedule a therapeutic strategy of multifaceted heart failure targeting to a more personalized therapy. The described heart failure models represent clinical phenotypes that can be studied using the current available data from the advanced fields of genomics, proteomics and experimental model systems . RecentlTherefore the neurohormonal dysfunction initially compensates cardiac hemodynamic changes and in a later stage becomes toxic to the myocardium reducing myocardial contractility and increasing the deleterious processes of cardiac remodeling.In conclusion the systems biology analysis of heart failure will increase our understanding of the biological and mechanical basis of the disorder. The progressive nature of the mechanical model of the heart failure from early mechanical changes to left ventricular remodeling and the modular analysis of the neurohormonal homeostatic regulation will produce a comprehensive analysis of the disease process. The elucidation of the complex heart failure disease will also provide the material for further development of new therapeutic strategies.


The variations in recovery time, complications, and survival among cardiac patients who have undergone coronary artery bypass graft (CABG) procedures are vast. Many formulas and theories are used to predict clinical outcome and recovery time, and current prognostic predictions are based on medical and family history, lifestyle, co-morbidities, and performance status. The identification of biomarkers that provide concrete evidence supporting clinical outcome has greatly affected the field of medicine, helping clinicians in many medicine sub-specialties to forecast clinical course. Recent studies have discovered biomarkers that may be used as predictors of cardiac patients’ status post-cardiothoracic surgery, and the applications are numerous. In this review, we assess currently available cardiac biomarkers as predictors of clinical outcome for post-operative CABG patients. Data were collected from various studies in which cardiac biomarkers were measured in pre-operative and post-operative CABG patients. Humans exist in an environment full of stress-inducing factors, such as microorganisms, poor dietary choices, family history, or emotional hardship, which can all impact human health. Our successful survival has depended on effective mechanisms that prevent or assist in adapting to such taxing events. These defense mechanisms include the immune system, which is comprised of multiple molecular pathways that respond to traumatic stress. However, the timing and intensity of the immune reaction varies between individuals, especially during cardiothoracic surgeries. Thus, not every patient will have a smooth recovery post-op, or a ten-day hospital course when battling hospital-acquired pneumonia. This diversity of response will be highlighted in this discussion.Each organ system of the human body has developed specific mechanisms for injury response. For example, stress to the skin may cause induration and erythema to an inflamed area, whereas the intestines often manifest inflammation by a change in bowel habits. This review will focus on the mechanisms of the heart and how the cardiac system responds to stress. Specifically, current data regarding biomarkers of inflammation will be examined to determine whether these markers can be used to predict clinical outcomes and overall patient survival.The cardiovascular system is intricately extensive, and takes the brunt of many stress-inducing factors. According the American Heart Association and American Stroke Association in 2006, cardiovascular disease was the leading cause of mortality in the United States. While not every individual will endure a myocardial infarction, develop cardiomyopathy, or suffer from coronary artery disease, each person reacts to cardiovascular strain differently, and it is this aspect that provides the unique pathophysiology of the cardiovascular system.One of the most common pathologies of the heart, coronary artery disease (CAD), is precipitated by the gradual deposition of fat and cholesterol to form atherosclerotic plaques in coronary vessels. The formation of these plaques reduces the diameter of the lumen of the vessels, thereby impairing antegrade myocardial blood flow. A stenotic coronary artery results in reduced coronary blood flow, and therefore decreased oxygen and nutrients delivered to the myocardium. When the heart is starved of oxygen and nutrients, it may become ischemic. This ischemia can be completely asymptomatic or manifest as angina. Prolonged ischemia may result in death of cardiac tissue, which is a permanent condition.Depending on the severity of the coronary artery damage, patients may develop a partial blockage that may only result in transient ischemia and angina, or a complete blockage resulting in a myocardial infarction (MI). MI is defined as myocardial cell death due to prolonged ischemia . MI is dNumerous procedures are currently used to treat coronary blockages, including the use of tissue plasminogen activator (TPA), cardiac catheterization and coronary artery bypass grafting (CABG). During a CABG, a healthy artery or vein, typically the saphenous vein from the medial side of either lower extremity or the internal mammary artery from the chest wall, is grafted to bypass the blocked coronary artery. The three most commonly affected vessels are the left anterior descending artery (LAD), commonly known as the widow maker, the left circumflex artery, and the right coronary artery (RCA).A CABG procedure usually takes 3 to 5 hours, and can include a single or multiple vessel bypass Table . During An alternative procedure, off-pump CABG is performed on a beating heart. It is indicated for high-risk patients who are not stable enough to use the cardiopulmonary bypass machine for prolonged periods of time. These patients often have a history of peripheral vascular disease, cerebral vascular accidents (CVA), or multiple transient ischemic attacks (TIAs).The CABG procedure is complex and does not come without risk. Cardiac surgery is a highly invasive procedure that can potentially lead to further myocardial insult. The degree of insult is dependent on multiple factors such as the type and extent of the surgical procedure, duration of cardiopulmonary bypass and aortic cross-clamping, pre-operative condition of the heart, length of anesthesia use and timing of post-operative revascularization .Cardiac surgery with the cardiac bypass machine causes an acute inflammatory response through activation of inflammatory cells, complement cascade, and secretion of cytokines and chemokines. Vascular endothelial cells are activated and increase leukocyte adhesion molecules, a marker for inflammation. This same response also occurs once the cross-clamp is released and the heart is re-perfused . It is uA major biomarker in the heart is serum cardio-specific troponin T. Troponin T is one of three proteins of the troponin regulatory complex found on tropomyosin, a protein involved in the contractile apparatus of cardiac muscle. Troponin T is integral to muscle contraction in skeletal and cardiac muscle. Although typically present at low levels in the heart, its levels rise after cardiac surgery, before returning to baseline levels. Troponin T levels have been shown to correlate with the duration of cardioplegia . RecentlIn addition to Troponin T and IL-6, cardiac troponin I (CTn1), myoglobin, creatine kinase (CK) and its isoenzyme creatine kinase-myocardial band (CK-MB), which is specific to the heart, are all involved in cardiac inflammation. Serum concentrations of these protein biochemical markers are increased during acute coronary syndrome (ACS), pericarditis, cardiac surgery and renal dysfunction -39. CTn1In addition to C-reactive protein, tetranectin is a plasma protein found in secretory cells such as monocytes. Upon stimulation from stress or trauma, tetranectin facilitates monocyte migration to the site of injury. High concentrations of tetranectin are found in areas of regenerating muscle and are associated with tissue remodeling .B-type natriuretic peptide (BNP), a protein commonly used to evaluate heart failure, is a polypeptide secreted by the ventricles of the heart in response to excessive stretching of cardiac myocytes. This molecule is responsible for decreasing systemic vascular resistance and central venous pressure as well as an increasing natriuresis. This adaptive response allows for the reduction of systemic blood pressure, decrease in afterload, and therefore increase in cardiac output. Measuring BNP is an indirect way to evaluate ventricular function and identify patients at risk that may be asymptomatic. Using this marker to stratify patients prior to CABG can help eliminate the need for additional testing. Although checking a patient’s BNP level is typically reserved for patients admitted for congestive heart failure exacerbation, with the current data indicating BNP as a marker for pre-op and post-op patient outcome, ordering a BNP for pre-op clearance may become more mainstream. Especially in patients with a history of CAD, increased BNP levels are associated with an increased rate of myocardial infarction and cardiovascular death during mid-term follow-up. BNP levels are a prognostic marker associated with higher mortality in patients with myocardial infarction, cardiogenic shock, and pulmonary embolism.NT-proBNP, another established marker for cardiac failure, is also present in other pathologies, such as exacerbated chronic obstructive pulmonary disease, acute coronary syndromes, atrial fibrillation, and myocarditis. In contrast to BNP, higher NT-proBNP levels are associated with female gender, impaired renal function, and older age. NT-pro-BNP is one of the biomarkers increased by myocardial ischemia or subsequent, burdened wall stress.Several adhesion molecules have also been identified to play essential roles as cardiac inflammation biomarkers.E-selectin, also known as CD62 antigen-like family member E (CD62E), is an endothelial-leukocyte adhesion molecule. It plays an important part in recruiting leukocytes to a site of injury. The local release of cytokines by damaged cells induces the overexpression of E-selectin on endothelial cells of nearby blood vessels. As the inflammatory response progresses, chemokines released by injured tissue enter the blood and activate rolling leukocytes, which then tightly bind to the endothelial surface and exit the blood vessels via diapedesis. Leukocytes migrate through the interstitium to the site of injury or infection guided by chemotactic signals. The levels of E-selectin were found to be the highest in the right atrium and the lowest in the left ventricle .th hour of the procedure. This indicates that patients with a higher amount of IL-6 at hour 6 might suffer from greater drops in cardiac contractility, thus a decrease in cardiac output and lower blood pressure and therefore insufficient circulation to the myocardium.Certain cytokines have been discovered to be closely related to the inflammatory cascade and also can be used as biomarkers to trend response to cardiac stress. While patients are on the CPB machine, pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukins (IL) 1, 6 and 8 are released and mediate the systemic inflammatory response syndrome (SIRS), which is believed to play an essential role in myocardial ischemia and reperfusion injury . Table 2While the coagulation cascade may not appear to be directly related to inflammation, the risk of coagulopathic events increases when inflammation is present, and this attribute can be used as a marker for stress. Anti-thrombin 3 is a substance in blood plasma that inactivates thrombin during the clotting cascade, and is elemental in preventing post-operative deep vein thrombosis (DVT) and pulmonary embolism (PE). Its levels fell significantly post-op , indicatThe Von Willebrand factor (vWF) protein is involved in the intrinsic pathway of the coagulation cascade. It is bound to factor VIII and activated by thrombin. This helps to induce the binding of platelets and eventually clot formation. Increased plasma levels of vWF in a large number of cardiovascular, neoplastic and connective tissue diseases are presumed to arise from adverse changes to the endothelium, and may contribute to an increased risk of thrombosis.While a variety of hematological markers are used to monitor pre-op and post-op status, less invasive techniques have also been utilized. An excellent study performed by Pabst et al. determined that oxidative and metabolic stress during cardiac surgery could be monitored by breath biomarkers. They assessed acetone, isoprene, and pentane, and found that acetone release was an indicator of stress and isoprene levels correlated with cardiac output. Acetone in the breath mirrors other metabolic stresses, such as diabetic ketoacidosis . The incPabst et al. also assessed reactive oxygen species (ROS) and the release of ethane and pentane during peroxidation of omega 3 and omega 6 fatty acids. During CABG, exhaled pentane levels decreased immediately after the sternotomy was performed. Exhaled pentane concentrations measured immediately after termination of extracorporeal circulation correlated with the CK:CKMB ratio measured a few hours later, suggesting that exhaled pentane might serve as a fast and direct biomarker for early recognition of oxidative stress and ischemic reperfusion injury. Together this suggests that pentane acts as a fast and direct biomarker .Numerous studies have investigated pre-operative and post-operative variables that influence the outcome of CABG patients. Evaluating factors such as co-morbidities, family history, and diet can help anticipate problems that may ensue during the procedure or obstacles that might impede recovery time. While these aspects are very influential with regard to determining patient outcome, asking patients about family history and diet does not always guarantee an accurate answer. The use of biomarkers to predict prognosis serves as a more concrete method and eliminates variables that could alter the data.Fernandez et al. demonstrated that patients with recent or ongoing ischemia exhibited higher preoperative cardiac troponin I, CK, CKMB, and myoglobin concentrations in pericardial fluid than in serum . PossiblEikvar et al. compared post-CABG levels of cardiac markers in groups of patients that suffered from post-operative MI and those that did not . The firBNP is secreted primarily by the muscle cells of the pumping chambers in the heart as a response to increased stress. Elevated levels of postoperative BNP during the first several days after CABG surgery is known to be associated with increased mortality. However, further research has analyzed whether BNP is also associated with poorer long-term physical function.A study performed by Morimoto et al. found that plasma levels of BNP are markedly elevated in the acute phase after cardiac surgery requiring bypass and reflect the left ventricular function at the same time. Furthermore, myocardial damage due to ischemia may participate in the mechanism of synthesis and secretion of BNP . The stuA study performed on CABG surgery patients at Brigham and Women’s Hospital in Boston and the Texas Heart Institute in Houston both pre- and post-operatively focused on levels of BNP and post-op outcome. Increased levels of postoperative BNP were found to be significantly associated with poor physical function six months to two years status post-CABG.Wazni et al. found that patients with atrial fibrillation following cardiac surgery exhibited higher BNP levels than patients who remained in sinus rhythm throughout the post-operative course . When coBoth BNP and its counterpart, the N terminal fragment of proBNP, are established markers for cardiac failure. Schachner et al. determined the influence of preoperative serum NT-proBNP on postoperative outcome and mid-term survival in patients undergoing coronary artery bypass grafting (CABG) . In genePreoperative measurement of NT-proBNP levels can be used to determine CABG patients with an increased risk as shown above. Patients with increased NT-proBNP should have close follow-up and periodic monitoring. Mayer et al. found that CABG patients with NT-proBNP levels > 862 pmol exhibited decreased long-term survival rates without clinical manifestation of heart failure. Therefore, elevated preoperative serum NT-proBNP levels are associated with a higher postoperative early and mid to long-term mortality, as well as morbidity, in patients undergoing isolated CABG .vWF is a protein found in the endothelium that plays an essential role in platelet adhesion, and functions as a biomarker for endothelial dysfunction and damage. vWF was shown to be a predictor of ischemic heart disease in healthy individuals and patients with angina or acute MI . CertainCPB has generally been associated with increased levels of plasma soluble adhesion molecules of the endothelium, which have been attributed to the activation and injury of endothelial cells. Thus, the availability of useful biochemical markers for evaluating the endothelial state post-operatively offers a useful, non-invasive means to assess return of the endothelium to the unperturbed state, which is important in improving patient outcome . Among tWhile it is useful to study a certain patient population before, during, or after a CABG procedure, it can also be very helpful to focus on the same population throughout the entire process. Panagiotopoulous et al. measured concentrations of E and P selectins, tetranectin, von Willebrand Factor, and angiotensin converting enzyme in patients undergoing CABG prior to and up to 3 days after their procedure . These mrd day post-operatively in the majority of patients, while other markers decreased [Panagiotopoulos et al. assessed persistence of elevated biomarker levels in the post-operative CABG period. The post-operative period begins in the first moments when the patient’s chest is closed, and the patient is extubated and taken to the cardiac surgical intensive care unit. This is a critical period, during which the patient’s vitals and overall clinical performance must be closely monitored to avoid complications. Panagiotopoulos et al. concluded that of all molecules exhibiting elevated levels, tetranectin (TN) remained elevated on the 3ecreased . This coThe purpose of using biomarkers to predict post-operative outcomes of cardiac patients is to improve survival and quality of life. Other methods have been developed that help prevent adverse outcomes, such as the use of heparin. Heparin is a highly sulfated glycosaminoglycan produced by endothelial cells that functions as an innate anticoagulant. It can be injected as an anticoagulant, administered intravenously, and used to form an inner anticoagulant surface on various experimental and medical devices, such as test tubes and dialysis machines.A study performed by Ljunghusen et al. assessed the level of inflammation between two groups of CABG patients, one for which the bypass machine was heparinized and one for which it was not . C3a, asAs mentioned above, the use of heparinized systems not only aids in a reduction of granulocytosis but also affects the expression of HLA-DR. The percentage of monocytes expressing HLA-DR inversely correlated with the risk of developing postoperative infections following major resectional surgery as well as survival after severe trauma. There was no difference in the expression of HLA-DR during or after bypass surgery, but HLA-DR expression was lower the morning after surgery in patients with heparinized than in non-heparinized CPB systems Table . L-selecThe use of modified ultrafiltration (MUF) has proven to be helpful in achieving electrolyte balance in fluid overloaded patients as well as in ridding inflammatory mediators associated with the use of the cardiopulmonary. MUF has been shown to decrease transfusion requirements and improve post-operative oxygenation and myocardial contractility in children after CPB . HoweverIn addition to MUF, sodium nitroprusside (SNP) has also been found to help in regaining homeostatis after using the CPB machine. SNP was discovered to reduce reperfusion injury in experimental studies. It has multiple physiological effects, such as blocking free radicals, inhibiting platelet aggregation, regulating membrane permeability, and decreasing the effects of leukocytes. During the reperfusion period of a CABG, the production of nitric oxide (NO) is decreased, and this induces the expression of adhesion molecules, such as the membrane attack complex. Elevated levels of the membrane attack complex result in increased neutrophil adhesion to the endothelium. SNP was found to be effective at controlling hypertension during CPB, and its use decreases the need for vasodilators in the early post-operative period . SNP hasA study was performed with two groups of patients undergoing CPB: the control group received a 5% dextrose solution after the release of the aortic cross-clamp, and the SNP group was given 0.5 μg/kg/min SNP . No signAdenosine was found to have a cardio-protective effect during open heart surgery. Adenosine could be used in ischemic preconditioning (IPC) as an adjunct to cross-clamping the aorta. Compared with simple cold blood cardioplegia in heart valve replacement patients, adenosine pretreatment  as an adjunct to 1 mM adenosine cold blood cardioplegia may reduce CTnI, IL-6, and IL-8 release, resulting in reduced myocardial injury after surgery . The leaBuyukates et al. found that the use of warm priming solution in open heart surgery resulted in significant improvements in acute inflammatory markers . Levels When considering the markers discussed above, attempts made to lower these values peri-operatively by exercise, change in diet, medication or other mechanisms may prove to be beneficial in improving patients’ post-op course. We discovered that using heparinized machines, modified ultrafiltration and warm priming solution in anticipation of possible adverse events has aided in more positive post-op courses. If modifying pre-op factors would help reduce unfavorable outcomes, then further evaluating the markers of inflammation may prove to be beneficial. In conjunction with these methods to prevent inflammation or adverse effects, measurements of BNP, troponin and CRP levels, for example, several months prior to CABG would provide helpful information and the possibility of decreasing these markers and altering post-CABG outcomes.Previous studies have reported biomarkers that were elevated or depressed during the CABG procedure or post-operatively. However, the majority of these studies did not investigate correlations between levels of markers and patient outcome. While we know that a rise in certain markers indicates that the cardiac system has been stressed, it is not clear if high levels indicate and correlate with more stress, and therefore a worse recovery course. Our objective was to examine the literature on cardiac biomarkers and identify associations regarding outcome from the current published data. Expression of the monocyte marker, HLA DR, was found to be inversely proportionate to the risk for developing post-operative infections. HLA DR may prove to be useful if examined pre-operatively, and could possibly be used as an indicator of risk of post-operative infection. An important correlation was made between exhaled pentane concentrations measured after coming off the CPB machine. This non-invasive biomarker may aid with early recognition of oxidative stress and ischemic reperfusion injury. Early awareness and treatment of tissue damage can help prevent further injury. High levels of P and E selectins may also predict major cardiovascular events in patients with pre-existing PAD or CAD . This caACS: Acute coronary syndrome; ATIII: Anti-thrombin 3; C3a: Mcomplement component 3; CABG: Coronary artery bypass graft; CAD: Coronary artery disease; CD11b/CD18: Cluster of differentiation 11b/ cluster of differentiation 18; CD62E: E-selectin; CD62L: I-selectin; CK: Creatine kinase; CK-MB: Creatine kinase-myocardial band; CPB: Cardiopulmonary bypass; CPK: Creatine phosphokinase; CTn1: Cardiac troponin 1; DVT: Deep vein thrombosis; ENOS: Endothelial nitric oxide synthase; F1 + 2: Prothrombin fragment; HLA-DR: Human leukocyte antigen-d related; HSCRP: Highly-sensitive C-reactive protein; ICAM-1: Intercellular adhesion molecule-1; Il-6: Interleukin-6; IPC: Ischemia preconditioning; LAD: Left anterior descending (artery); MABP: Mean arterial blood pressure; MAC-1: Macrophage-1 antigen; MI: Myocardial infarction; NO: Nitrous oxide; PAD: Peripheral artery disease; PE: Pulmonary embolism; POMI: Postoperative myocardial infarction; RC: Right coronary (artery); ROS: Reactive oxygen species; SIRS: Systemic inflammatory response syndrome; SNP: Sodium nitroprusside; TIA: Transient ischemic attack; TN: Tetranectin; vWF: von Willebrand factor.The authors declare that they have no competing interests.IP, as the primary author, helped draft the main manuscript. RG performed writing, editing, organization, formatting, and literature review. KJ performed much of the research and literature search. AA, LL and EE reviewed the manuscript for errors and provided input related to cardiothoracic surgery. As the corresponding author, KS designed the review, supervised the data gathering and literature search, and participated in the editing of the manuscript. All authors read and approved the final manuscript.


The aim of the study was to investigate circulating markers of apoptosis in relation to infarct size, left ventricular dysfunction and remodeling in an ST-elevation myocardial infarction (STEMI) population undergoing primary percutaneous coronary intervention (PCI).Immediate re-opening of the acutely occluded infarct-related artery via primary PCI is the treatment of choice in STEMI to limit ischemia injury. However, the sudden re-initiation of blood flow can lead to a local acute inflammatory response with further endothelial and myocardial damage, so-called reperfusion injury. Apoptosis is suggested to be a key event in ischemia-reperfusion injury, resulting in LV-dysfunction, remodeling and heart failure.The present study is a prespecified substudy of the F.I.R.E. trial. We included 48 patients with STEMI undergoing primary PCI. Blood samples were collected prior to PCI and after 24 hours. Plasma was separated for later analysis of soluble tumor necrosis factor receptor (sTNFR) 1, sTNFR2, sFas and sFas ligand (sFasL) by ELISA. Infarct size, left ventricular (LV) dysfunction and remodeling were assessed by cardiac magnetic resonance imaging at five days and four months after STEMI.The levels of sTNFR1 at 24 h as well as the relative increases in sTNFR1 and sTNFR2 over 24 h showed consistent and significant correlations with infarct size and LV-dysfunction at four months. Moreover, both sTNFRs correlated strongly with Troponin I and matrix metalloproteinase (MMP)-2 measurements. Soluble Fas and sFasL did not overall correlate with measures of infarct size or LV-dysfunction. None of the apoptosis markers correlated significantly with measures of remodeling.In STEMI patients, circulating levels of sTNFR1 and sTNFR2 are associated with infarct size and LV dysfunction. This provides further evidence for the role of apoptosis in ischemia-reperfusion injury. Coronary artery disease (CAD) is the leading cause of death in the western world. In many patients the first clinical presentation of CAD is an acute myocardial infarction. Immediate re-opening of the acutely occluded infarct-related artery via primary percutaneous coronary intervention (PCI) is the treatment of choice to limit ischemic injury in the setting of ST-elevation myocardial infarction (STEMI) Ischemia and reperfusion associated myocardial injury (IR-injury) involves a wide range of pathological processes. Vascular leakage, activation of cell death programs, transcriptional reprogramming, no reflow phenomenon and innate and adaptive immune activation all contribute to tissue damage, thereby determining the infarct size There are two major pathways for apoptosis: the intrinsic mitochondrial pathway and the extrinsic pathway, involving the binding of soluble or cell membrane-bound ligands to cell surface receptors 15–42 (FX06) on reperfusion injury in patients undergoing primary PCI for STEMI This study is a pre-specified substudy of the F.I.R.E. trial, which studied the effects of the fibrin –derived peptide BβCardiac magnetic resonance imaging (CMR) has consistently been found to accurately determine the size of myocardial infarct as well as left ventricular volumes used to calculate measures of left ventricular dysfunction and remodelling The aim of this study was to analyze the circulating levels of apoptosis markers, sTNFR1, sTNFR2, sFas and sFasL, in STEMI patients prior to and 24 hours after primary PCI. Furthermore, we wanted to investigate potential correlations between these biomarkers and measures of infarct size, left ventricular dysfunction and remodelling as assessed by CMR. Lastly, we aimed to study the effect of FX-06 on soluble markers of apoptosis.http://clinicaltrials.gov, NCT00326976) have been published elsewhere This study is a pre-specified substudy of the F.I.R.E. trial. The study design and results of the F.I.R.E. trial  and myeloperoxidase (MPO) were collected in vacutainer tubes (using sodium heparin as anticoagulant) at baseline immediately before primary PCI and at 24 hours. Samples were centrifuged within 30 minutes to separate plasma, which then was stored immediately at −20°C and within a week at −70°C until analyzed. Soluble TNFR1, sTNFR2, sFAS and sFASL were analyzed using commercially available ELISA kit . The lower limits of detection were 0.8 pg/mL (sTNFR1), 0.6 pg/mL (sTNFR2), <20 pg/mL (sFAS), and 2.7 pg/mL (sFASL), respectively. The interassay CVs ranged from 0.6–5.1% for sTNFR 1, 5.7–10.4% for sTNFR2, 2.4–4.5% for sFAS, and 1.5–2.4% for sFASL. Plasma levels of MMPs, TIMPs and MPO were analyzed as previously described Based on previous data, we calculated that a sample size of 21 subjects in each treatment group  would be sufficient to give 80% power to detect an estimated 20% change in plasma levels of the biomarkers We included 46 patients of whom 24 received placebo and 22 FX06 treatment. There were no differences between the FX06 treated group and the placebo group in the levels of any of the biomarkers at any time point. Thus, for further analysis both treatment groups were analyzed as one group. Baseline characteristics of the 46 study participants are summarized in th percentile, 75th percentile) levels were 1280 pg/mL  for sTNFR1, 2160 pg/mL  for sTNFR2, 6758 pg/mL  for sFAS, and 46.7 pg/mL  for sFASL, respectively. These levels were very similar to and did not differ significantly from the plasma levels of STEMI patients at 0 hours (data not shown).Plasma levels of sTNFR1, sTNFR2, sFAS, sFASL, MMP-2, MMP-8, MMP-9, TIMP-1, TIMP-2 and MPO at 0 and 24 hours, as well as the change in plasma levels over time, are summarized in The infarct size, defined as the late gadolinium enhancement zone (LGE zone) on CMR examination, was assessed at five days and four months after STEMI and primary PCI. All study participants were included in the day five examination, whereas 9 of the 46 patients did not complete the MRI at four months. Correlations between sTNFR1, sTNFR2, sFAS, sFASL and LGE zone are summarized in Findings are summarized in Correlations with Troponin I and MMP-2 are summarized in The main finding of the study was the consistent and significant correlation between 24 hour levels of plasma sTNFR1 and outcome measures of infarct size and LV-dysfunction. Individuals with the highest levels of sTNFR1 ended up with the largest infarcts and developed a more pronounced LV-dysfunction, which are both markers of a poor prognosis. Similar but weaker and non-significant trends were found for 24 hour levels of sTNFR2. However, the relative increases in sTNFR1 and sTNFR2 over 24 hours were both significantly correlated with infarct size and LV-dysfunction. Notably, plasma soluble FAS and FAS ligand did not consistently correlate with any of the outcome measures.Several experimental studies have demonstrated the role of TNF signaling in myocardial cell apoptosis leading to IR-injury, LV dysfunction and congestive heart failure In the present study, we choose to measure sTNFRs instead of TNF in plasma. Data indicate that sTNFRs correlate well with circulating TNF, which due to short half-life in plasma is a less reliable marker In a previous study on acute myocardial infarction patients, sFAS and sFASL showed no correlation with infarct size, as measured by plasma levels of creatine phosphokinase and of myosin light chain type I Experimental data have demonstrated that intracellular MMP-2 activation in response to oxidative stress might be an important mechanism of triggering cardiomyocyte apoptosis Left ventricular remodeling was assessed by calculating changes in endsystolic and enddiastolic left ventricular volume indices (dESVI and dEDVI) from day 5 to 4 months after STEMI. None of the soluble markers of apoptosis showed significant correlation with these measures of remodeling. The lack of association between sTNFRs and remodeling, despite correlation with infarct size and left ventricular dysfunction (LVEF), have several possible explanations. The process of remodeling, occurring over a longer period of time, might involve pathways not dependent of TNF signaling or might not be determined by the early increase in TNFR activation following STEMI. Furthermore, in this homogenous STEMI population of patients arriving at the PCI lab within 6 hours of symptom onset and receiving state of the art treatment both in the acute phase and during follow up, infarct sizes were overall rather small and the process of remodeling might have been inhibited to a large degree.The present study was designed and sized to analyze the effect of FX-06 on soluble markers of apoptosis. No significant differences or trends to differences were found between the treatment groups. Also, the F.I.R.E-study had an overall negative result with no effect of FX-06 on primary or secondary outcomes The present study has some limitations. First, there were no prior studies available on soluble markers of apoptosis and cardiac MR measurements to use for power calculations. Therefore, we calculated power based on previous data of biomarkers , suggesting a sample size of 42 individuals would be adequate. The same power calculation was used in a previously published substudy of the F.I.R.E. trial, where we could detect differences in infarct size and LV-dysfunction in relation to biomarker levels To summarize, in a homogenous STEMI population we find that 24 hour levels of sTNFR1 as well as the relative changes in sTNFR1 and sTNFR2 from 0 to 24 hours are associated with myocardial infarct size as well as left ventricular dysfunction at follow-up. This indicates that apoptosis might be a determinant of the extent of IR-injury. The relative importance of apoptosis versus necrosis during IR-injury needs to be further investigated.


J) without overt clinical signs of heart failure.Two-dimensional speckle tracking echocardiography (STE) is a relatively new method to detect regional myocardial dysfunction. To assess left ventricular (LV) regional myocardial dysfunction using STE in Duchenne muscular dystrophy model dogs , and strain indices using STE, were assessed and compared among the 3 groups.Six affected dogs, 8 carrier dogs with CXMDSignificant differences were seen in body weight, transmitral E wave and E' wave derived from TDI among the 3 groups. Although no significant difference was observed in any global strain indices, in segmental analysis, the peak radial strain rate during early diastole in posterior segment at chordae the tendineae level showed significant differences among the 3 groups.J without any obvious LV dilation or clinical signs. The radial strain rate may be a useful parameter to detect early myocardial impairment in CXMDJ.The myocardial strain rate by STE served to detect the impaired cardiac diastolic function in CXMD Duchenne progressive muscular dystrophy (DMD) is characterized by progressive degeneration of skeletal and cardiac muscles with fibrotic tissue replacement and fatty infiltration. ResultiEchocardiography is one of the useful noninvasive methods used to assess cardiac function in patients and animals with Duchenne's cardiomyopathy-9. It isTwo-dimensional speckle tracking echocardiography (STE) is a new approach designed to assess left ventricular function in humans and animals,22. STE J) is a Beagle-based dog colony established by artificially inseminating frozen semen from spontaneous Golden retriever muscular dystrophy. CXMDJ has been reported to be comparable to human patients and dogs with DMD and LV ejection time [ET]) were measured using an aortic flow velocity curve. TransmiJ was reported to be localized in free wall at basal level of LV[a). The principal of speckle tracking analysis has been described in several previous studies[Right parasternal short-axis views at Ct level were used to measure all STE indices below, because myocardial lesion of dogs with CXMDvel of LV. Images s studies,22,34-37S, SrRE, SrCS and SrCE) were measured at the level of the Ct , and peak radial and circumferential strain rates during systole and early diastole  and buprenorphine , and then compared.For the assessment of reproducibility, intraobsever variability of STE analysis was assessed by use of images from 6 normal dogs. Using same cine loops, each STE value was determined again 3 weeks after the primary analysis.t-test. When the normality test failed, the Wilcoxon signed-rank test was applied. Intraobserver variability was express as mean of absolute difference as the percentage of the mean of two absolute measurements. A value of P < 0.05 was considered statistically significant.Comparisons among the 3 groups were performed using one-way ANOVA. A post hoc testing for the difference among the groups was performed by the Steel method. The assessment of the influence of sedation was performed using the paired The characteristics of affected, carrier and normal dogs in the present study are shown in Table A significant difference between pre- and post-sedation values was seen in HR and ESVI. In addition, a significant difference was also seen in the A wave of TMF Table .No significant difference among the 3 groups was noted in any parameters  among the 3 groups.P = 0.21). Intraobserver variability of measurements was 3.6 to 13.2%. Table E had significant differences between normal and carrier dogs.The frame rate used for this study to analyze STE indices ranged from 72 to 93 frames per second. Frames per cardiac cycle were 57.38 ± 6.53, 49.36 ± 10.70 and 49.44 ± 12.16 frames, in normal, carrier and affected dogs, respectively, and there was no significant difference among the 3 groups , which may suggest diastolic dysfunction. However with DMD.E between normal and carrier female dogs as well as affected dogs. Since our carrier females were young to middle-aged, it is possible that follow-up evaluation would reveal myocardial impairment.Duchenne's cardiomyopathy in a carrier female was previously reported, though it was found to be mild compared with that in an affected male,46. In tIn the present study, low dose of acepromazine was used for sedation. The influence of sedation was seen in EDVI, and A wave velocity of TMF. Schaefer et al. demonstrated increased A waves of TMF and myocardial velocity using TDI under anesthesia in normal mice, while increased heart rates were observed at the same time. They spJs. Second, body weight in affected dogs was significantly lower than in normal dogs. However, we consider that this difference would be less likely to affect our results. Third, one carrier dog had mild MR. A report described mitral valve prolapse in DMD patients, and MR was considered to be responsible for LV dilation[There were several limitations in the present study. First, the number of dogs available for each group was limited and age distribution was relatively wide in all groups because of the difficulty in maintaining a sufficient number of CXMD dilation. In the  dilation). This m dilation. Finally dilation, the resJ without any obvious LV dilation or clinical signs. The radial strain rate may be a useful parameter to detect early myocardial impairment in CXMDJ.The myocardial strain rate by STE served to detect the impaired cardiac diastolic function in CXMDS: peak radial strain rate during systole; SrRE: peak radial strain rate during early diastole; SrCS: peak circumferential strain rate during systole; SrCE: peak circumferential strain rate during early diastole; MR: mitral regurgitationLV: left ventricular; STE: speckle tracking echocardiography; CXMDJ: canine X-linked muscular dystrophy; TDI: tissue Doppler imaging; DMD: Duchenne's muscular dystrophy; Ct: chordae tendineae; LVIDd: left ventricular end-diastolic internal diameter; LVIDs: left ventricular end-systolic internal diameter; FS: fractional shortening; EF: ejection fraction; EDVI: end-diastolic volume index; ESVI: end-systolic volume index; EDV: end-diastolic volume; ESV: end-systolic volume; BSA: body surface area; LAD: left atrial diameter; AoD: aortic root diameter; LA/Ao: left atrium to aorta ratio; PEP: pre-ejection period; ET: ejection time; TMF: transmitral flow; DcT: deceleration time; IVRT: isovolumic relaxation time; MAV: mitral annulus velocity; SR: peak systolic radial strain; SC: peak systolic circumferential strain; SrRThe authors declare that they have no competing interests.HT performed echocardiographic examinations for all dogs and statistical analysis. NY and ST contributed to hold this genetic colony of CXMDJ, and carried out genetic examinations to determine each dog's genetic status. YF and YW conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/11/23/prepub