Upregulation of Nrf2 in myocardial infarction and ischemia-reperfusion injury of the heart.

Myocardial infarction (MI) is a leading cause of morbidity and mortality in the world and is characterized by ischemic necrosis of an area of the myocardium permanently devoid of blood supply. During reperfusion, reactive oxygen species are released and this causes further insult to the myocardium, resulting in ischemia-reperfusion (IR) injury. Since Nrf2 is a key regulator of redox balance, it is essential to determine its contribution to these two disease processes. Conventionally Nrf2 levels have been shown to rise immediately after ischemia and reperfusion but its contribution to disease process a week after the injury remains uncertain. Mice were divided into MI, IR injury, and sham surgery groups and were sacrificed 1 week after surgery. Infarct was visualized using H&E and trichrome staining and expression of Nrf2 was assessed using immunohistochemistry, Western blot, and ELISA. MI displayed a higher infarct size than the IR group (MI: 31.02 ± 1.45%, IR: 13.03 ± 2.57%; p < 0.01). We observed a significantly higher expression of Nrf2 in the MI group compared to the IR model using immunohistochemistry, spot densitometry of Western blot (MI: 2.22 ± 0.16, IR: 1.81 ± 0.10, Sham: 1.52 ± 0.13; p = 0.001) and ELISA (MI: 80.78 ± 27.08, IR: 31.97 ± 4.35; p < 0.01). There is a significantly higher expression of Nrf2 in MI compared to the IR injury group. Modulation of Nrf2 could be a potential target for therapeutics in the future, and its role in cardioprotection can be further investigated.

Integrating basic sciences into clerkship rotation utilizing Kern's six-step model of instructional design: lessons learned.

BACKGROUND: It is generally agreed that basic and clinical sciences should be integrated throughout the undergraduate medical education, however, there is still need for continued formal integration of basic sciences into clinical clerkship in many medical schools across the globe. METHODS: Utilizing Kern's Six-Step Model of Instructional Design, we aimed to develop an intervention that would facilitate cognitive integration of basic and clinical sciences. After problem identification and targeted needs assessment through focused group discussion with the students and faculty, objectives were devised with an implementation plan of using flipped class approach to develop a content-focused and learner-centered teaching strategy. This intervention was piloted in the 2-week cardiology clerkship in Year 5. Evaluation of the content, integration, student and faculty experiences were recorded through in-depth interviews, FGDs and a formative MCQ test. RESULTS: Flipped classroom based integrated sessions were successfully developed. The implementation phase was met with challenges that primarily stemmed from the diverse teaching styles among faculty members, hesitance to deviate from conventional practices, variations in clinic timings, and demanding schedules. Noteworthy observations were in terms of ownership of the project, the need for faculty development in modern student-centered teaching pedagogies, opportunities for content improvement, scheduling of sessions, and suggestion of revisiting fundamental concepts in basic sciences through a brief boot camp-style session at the onset of the clerkship. The role of flipped case model and clinical cases in integrating basic sciences into clinical sciences were appreciated by the students. Standardization in teaching practices was identified as the major challenge by the faculty. CONCLUSIONS: A functional, learner-centered framework of cognitive integration of basic sciences in clinical sciences curriculum of cardiology rotation was developed with a potential to be implemented in other clerkship rotations.

MRAS in coronary artery disease-Unchartered territory.

Genome-wide association studies (GWAS) have identified coronary artery disease (CAD) susceptibility locus on chromosome 3q22.3. This locus contains a cluster of several genes that includes muscle rat sarcoma virus (MRAS). Common MRAS variants are also associated with CAD causing risk factors such as hypertension, dyslipidemia, obesity, and type II diabetes. The MRAS gene is an oncogene that encodes a membrane-bound small GTPase. It is involved in a variety of signaling pathways, regulating cell differentiation and cell survival (mitogen-activated protein kinase [MAPK]/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase) as well as acute phase response signaling (tumor necrosis factor [TNF] and interleukin 6 [IL6] signaling). In this review, we will summarize the role of genetic MRAS variants in the etiology of CAD and its comorbidities with the focus on tissue distribution of MRAS isoforms, cell type/tissue specificity, and mode of action of single nucleotide variants in MRAS associated complex traits. Finally, we postulate that CAD risk variants in the MRAS locus are specific to smooth muscle cells and lead to higher levels of MRAS, particularly in arterial and cardiac tissue, resulting in MAPK-dependent tissue hypertrophy or hyperplasia.

Beyond the Basics: Unraveling the Complexity of Coronary Artery Calcification.

Coronary artery calcification (CAC) is mainly associated with coronary atherosclerosis, which is an indicator of coronary artery disease (CAD). CAC refers to the accumulation of calcium phosphate deposits, classified as micro- or macrocalcifications, that lead to the hardening and narrowing of the coronary arteries. CAC is a strong predictor of future cardiovascular events, such as myocardial infarction and sudden death. Our narrative review focuses on the pathophysiology of CAC, exploring its link to plaque vulnerability, genetic factors, and how race and sex can affect the condition. We also examined the connection between the gut microbiome and CAC, and the impact of genetic variants on the cellular processes involved in vascular calcification and atherogenesis. We aimed to thoroughly analyze the existing literature to improve our understanding of CAC and its potential clinical and therapeutic implications.

Dysregulation of metalloproteins in ischemic heart disease patients with systolic dysfunction.

Ischemic heart disease (IHD) is the leading cause of mortality worldwide. Metalloproteins have been linked to human health and diseases. The molecular functions of metalloproteins in IHD is not well understood and require further exploration. The objective of this study was to find out the role of metalloproteins in the pericardial fluid of IHD patients having normal (EF > 45) and impaired (EF < 45) left ventricular ejection fraction (LVEF). IHD patients were grouped into two categories: LVEF<45 (n = 12) and LVEF >45 (n = 33). Pooled samples of pericardial fluid were fractionated by using ZOOM-isoelectric focusing (IEF) followed by further processing using one-dimensional gel electrophoresis (1D SDS-PAGE) and filter-aided sample preparation (FASP). Tryptic peptides of each fraction and differential bands were then analyzed by nano-LC-ESI-MS/MS. Protein identification was performed through a Mascot search engine using NCBI-Prot and SwissProt databases. A total of 1082 proteins including 154 metalloproteins were identified. In the differential bands, 60 metalloproteins were identified, while 115 metalloproteins were identified in all ZOOM-IEF fractions. Twelve differentially expressed metalloproteins were selected in the intense bands according to their molecular weight (MW) and isoelectric point (pI). The 12 differentially expressed metalloprotein includes ceruloplasmin, Prothrombin, Vitamin K-dependent protein, Fibulin-1, Ribosomal protein S6 kinase alpha-6, nidogen, partial, Serum albumin, Hemopexin, C-reactive protein, Serum amyloid P-component, and Intelectin-1 protein which were all up-regulated while serotransferrin is the only metalloprotein that was down-regulated in impaired (LVEF<45) group. Among the metalloproteins, Zn-binding proteins are 36.5 % followed by Ca-binging 32.2 %, and Fe-binging 12.2 %. KEGG, pathway analysis revealed the association of ceruloplasmin and serotransferrin with the ferroptosis pathway. In conclusion, 154 metalloproteins were identified of them the Zn-binding protein followed by Ca-binding and Fe-binding proteins were the most abundant metalloproteins. The two metalloproteins, the Cu-binding protein ceruloplasmin, and Fe-binding protein serotransferrin are involved in the ferroptosis pathway, an iron-dependent form of regulated cell death that has been linked to cardiac pathology, especially in IHD patients having impaired systolic (LVEF<45) dysfunction. However, further research is required to validate these findings.

Galectin-3 Mitigates Cardiomyocytes Injury through Modulation of Left Ventricular Cathepsins B, D, L and S at 24-Hour Post Myocardial Infarction.

BACKGROUND/AIMS: Galectin 3 (GAL-3) is a beta galactoside binding lectin that has different roles in normal and pathophysiological conditions. GAL-3 was found to be up regulated in animal models of myocardial infarction (MI). Cathepsins are intracellular lysosomal proteases that degrade proteins. The objective of his study is to investigate if high GAL-3 after myocardial infarction has a protective role on the heart through its modulation of lysosomal Cathepsins in ischemic myocardium. METHODS: Male C57B6/J mice and GAL-3 knockout (KO) mice were used for permanent ligation of the left anterior descending artery of the heart to create infarction in the anterior myocardium. Hearts and plasma samples were collected 24 hours after the induction of MI and were used for enzyme linked immunosorbent assay and immunofluorescent staining. RESULTS: Our results show that the significant increase in GAL-3 levels in the left ventricle at 24-hour following MI is associated with significant lower levels of cathepsins B, D, L and S in GAL-3 wild MI group than GAL-3 KO MI group. We also report a significant lower plasma level of Troponin I in GAL-3 wild MI group than GAL-3 KO MI group. CONCLUSION: The increased levels of GAL-3 at 24-hour following MI regulates the process of cardiomyocytes injury through modulation of lysosomal cathepsins B, D, L and S.

Use of simulation based technology in pre-clinical years improves confidence and satisfaction among medical students.

OBJECTIVE: To determine perception of medical students about learning from integrated simulated clinical skill sessions as part of the undergraduate curriculum. METHODS: The cross-sectional study was conducted at the Centre for Innovation in Medical Education, Aga Khan University (AKU), Karachi, from July 2018 to February 2019, and comprised first year medical students undertaking the Respiration and Circulation module of the curriculum. Quantitative data was collected using a questionnaire and the responses were assessed on a five-point Likert scale. Data was analysed using SPSS 21. Qualitative data was gathered through focused group discussion with students and an in-depth interview with the facilitator conducting the sessions. The data was subjected to thematic analyses. RESULTS: Of the 161 subjects, 71(44%) participated in the session I and 90(56%) in the session II. Altogether 68(96%) students in session I and 81(90%) in session II believed integrated sessions to be effective in achieving learning objectives, and 65(92%) in session I and 79(88 %) in session II found them motivating, while 61(86%) in session I and 76(84%) in session II expressed the confidence that they had accomplished learning objectives and felt they had learned practical clinical skills; session I, 59(84%), session II, 73(81%). Qualitative analysis revealed that these sessions enhanced understanding of the subject matter and student engagement. CONCLUSIONS: Integrated clinical skills sessions improved students' interest, engagement and confidence. It should be implemented in undergraduate medical teaching curriculum.

Understanding of metals dysregulation in patients with systolic and diastolic dysfunction in ischemic heart disease.

Ischemic heart disease (IHD) is the leading cause of death and chronic disability in the world. IHD affects both the systolic and diastolic function of the heart which progressively leads to heart failure; a structural and functional impairment of filling or ejection of blood from the heart. In this study, the progression of systolic and diastolic dysfunction characterized according to their echocardiographic parameters including left ventricular ejection fraction (EF), grades of diastolic dysfunction and ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e'), were correlated with differential regulation of various metals in patients sera samples (n = 62) using inductive coupled plasma-mass spectrometry (ICP-MS). Chromium, nickel and selenium were found significant (p < 0.05) in patients having EF < 45% compared with EF > 45%. In patients with systolic dysfunction (EF < 45%), the level of selenium was decreased while the level of chromium and nickel was increased compared to patients with EF > 45%. Selenium level was also decreased significantly (p < 0.05) in grade 1A and 2 patients that are considered as higher grades of diastole dysfunction in comparison to grade 0-1. Overall, selenium deficiency was identified in both systolic and diastolic dysfunctions of IHD patients corresponding to the progression of disease that could be related to many metabolic and translational pathways specifically which involve selenoproteins.

Galectin-3: A Cardiomyocyte Antiapoptotic Mediator at 24-Hour Post Myocardial Infarction.

BACKGROUND/AIMS: Galectin 3 (GAL-3) is a beta galactoside binding lectin that has different roles in normal and pathophysiological conditions. GAL-3 has been associated with heart failure and was linked to increased risk of death in a number of studies. GAL-3 was found to be up regulated in animal models of heart failure as well as myocardial infarction (MI). The objective of his study is to test if high GAL-3 after myocardial infarction has a protective role on the heart through its anti-apoptotic and anti-necrotic functions. METHODS: Male C57B6/J mice and GAL-3 knockout (KO) mice were used for permanent ligation of the left anterior descending artery of the heart to create infarction in the anterior myocardium. Heart and plasma samples were collected 24 hours after the induction of MI and were used for immunohistochemistry, Tunnel procedure, electron microscopy and enzyme linked immunosorbent assay (ELISA). RESULTS: Our results show that the significant increase in GAL-3 levels in the left ventricle at 24-hour following MI is associated with significant lower levels of pro-apoptotic proteins; cytochrome c, Bax, annexin V, cleaved caspase-3 and a higher levels of anti-apoptotic protein Bcl2 in GAL-3 wild MI group than GAL-3 KO group. We also have identified the anti-apoptotic activity of GAL-3 is mediated through a significant increase in Akt-1, NF kappa-B and beta- catenin proteins. In addition, we have identified the antiapoptotic activity is mediated through a significant lower levels of cathepsin-D protein. CONCLUSION: We conclude that the increased levels of GAL-3 at 24-hour following MI regulate antiapoptotic mechanisms in the myocardium that will shape the future course of the disease. We also identified that the anti-apoptotic mechanisms are likely mediated through interaction of GAL-3 with Akt-1, NF kappa-B, beta- catenin and cathepsin D proteins.

Teaching "Shock Pathophysiology" by Flipped Classroom: Views and Perspectives.

Flipped classroom (FCR) is an active learning pedagogical method in which the students prepare prior to class using different modalities, for example, reading materials and videos, and afterward spend the time in class discussing the content and reinforcing the concepts. We chose to replace one problem-based case on "Shock" with flipped-style teaching in the respiration circulation module of a private medical university. Our objective was to use the clinical presentation of "Shock" to open a window to interrelate basic science concepts of cardiovascular physiology and pathology. It aimed to merge the case-based discussion with small-group discussions in the form of FCR activity. The qualitative study gives an overview of comments of facilitators, observers, and leadership of the Department and University obtained during focus group discussions and in-depth interviews. Thematic analysis of responses emphasized the importance of FCR as an effective teaching learning modality, which can be made more effective by careful selection of topic and provision of facilities to support technology-enhanced learning. The discussions with facilitators, observers, and leadership revealed its usefulness through student's engagement and increased participation to build learning of the key concepts. Student satisfaction in these activities can be enhanced by construction of knowledge acquired in non-face-to-face component with substantial pre-reading materials, videos, peer discussions, quizzes, and prompt feedback.

Pericardial fluid proteomic label-free quantification of differentially expressed proteins in ischemic heart disease patients with systolic dysfunction by nano-LC-ESI-MS/MS analysis.

Left ventricular systolic dysfunction (LVSD) is common in patients with pre-existing ischemic heart disease (IHD) and myocardial infarction. An untargeted proteomic approach is used to improve the understanding of the molecular mechanisms associated with LVSD and to find out potential proteomic signatures in pericardial fluid. The pericardial fluid of IHD (n = 45) patients was grouped into two categories according to the left ventricular ejection fraction, LVEF ≥45 (n = 33) and LVEF <45 (n = 12), and analyzed by using nano-liquid chromatography-mass spectrometry (nano-LC-MS/MS) technique. The nano-LC-MS/MS analysis resulted in the identification of 709 pericardial fluid (PF) proteins in both normal and impaired systolic functional groups (LVEF ≥45 vs. LVEF <45). Sixteen proteins were found to be differentially expressed (p < 0.05, fold change >2) including 12 down-regulated and 4 up-regulated in the impaired systolic functional group (LVEF <45) compared to the normal group (LVEF ≥45). Among the differentially expressed proteins the inflammatory marker albumin, atherosclerosis marker apolipoprotein A-IV and hedgehog-interacting protein marker of angiogenesis were predominantly associated with the impaired LVEF <45 group. KEGG pathway analysis revealed that the hedgehog (Hh) signalling pathway is up-regulated in LVSD reflecting the underlying molecular and pathophysiological processes.

Ionomic profiling of pericardial fluid in ischemic heart disease.

Metals are essential cofactors that play a crucial role in heart function at the cell and tissue level. Information regarding the role of metals in the pericardial fluid and its ionome in ischemic heart disease (IHD) is limited. We aimed to determine the association of elements in pericardial fluid and serum samples of IHD patients and their correlation with systolic and diastolic function. IHD patients have been studied with systolic and diastolic dysfunction categorized on the basis of echocardiographic parameters. We measured concentrations of sixteen elements in the pericardial fluid and serum of 46 patients obtained during open heart surgery with IHD by ICP-MS. The levels of chromium and nickel in pericardial fluid were significantly higher as compared with serum samples of IHD patients (p < 0.05). The chromium, nickel and manganese levels in pericardial fluid were lower in patients with ejection fraction (EF) < 45% as compared to EF > 45% (p < 0.05). There was no significant difference in pericardial concentrations of elements in diastolic dysfunction grade 0-1 with 2 in IHD patients. We also found that decreased concentration of these elements in pericardial fluid is associated with decreased systolic function. These results suggest that pericardial fluid concentrations of these metals may reflect the extent of ischemic heart disease. These findings are hypothesis generating with regards to a role in the pathogenesis of the disorder.

Teaching "Shock Pathophysiology" by Flipped Classroom.

OBJECTIVE: To assess usefulness of flipped style of teaching conducted as small-group format in Cardiovascular and Respiration module for Year-I undergraduate medical students at Aga Khan University. METHODS: The study was planned and conducted over a period of eight months from March to October 2017 including the time taken for planning, mock run, execution followed by analysis and dissemination. It was carried out at the Aga Khan University Medical College, Karachi. Pre and post test scores of students after flipped class room sessions was compared. Moreover, perception of students was assessed on Likert scale (0-4) by a pretested validated questionnaire. RESULTS: The mean pre-test scores of the students was 4.86 ± 0.91 which improved to 6.09 ± 0.81 (p = 0.021) after attending the flipped class session. Students approved that the frame work helped to promote their learning motivation and engagement with improvement in understanding of the course materials and enhancement of learning during Face to Face activity. CONCLUSIONS: The flipped classroom approach showed promise in teaching and learning of 'Pathophysiology of Shock' by clinical scenarios in small group discussions. Implementation of flipped class room activity on a wider scale however needs careful selection of course objectives and logistics.

Changes in ventricular depolarisation vectors during exercise caused by regional myocardial ischaemia.

Research at the Aga Khan University for several years has been directed to find a reliable, low-cost, portable, non-invasive method for identification of coronary artery disease, its location and extent. A new method has been devised to measure the magnitude and direction of cardiac electrical vectors in three perpendicular planes during physical exercise to identify reduction in myocardial excitability as the electrophysiological marker of hypoxia. This report shows that changes in electrical forces due to exercise-induced regional hypoxia serve as indicators of reversible myocardial ischaemia. Changes in the magnitude and direction of vectors at stages of the Bruce protocol were measured in healthy volunteers, and patients undergoing the same exercise protocol for distribution of a radioactive tracer injected intravenously at peak exercise and after recovery (myocardial perfusion scan). Alterations in the magnitude and direction of resultant vectors during exercise were scored to enable analysis. Analysis identified slow progression of myocardial depolarisation as the electrophysiological marker of regional hypoxia relative to physical work. Compared with myocardial perfusion scan the sensitivity and specificity of electrical vectors for identification of ischaemia were 88% and 71%, respectively. Accuracy of ischaemia shown by electrical vectors is being assessed in patients undergoing elective coronary angiography.

Molecular switch model for cardiomyocyte proliferation.

This review deals with the human adult cardiomyocyte proliferation as a potential source for heart repair after injury. The mechanism to regain the proliferative capacity of adult cardiomyocytes is a challenge. However, recent studies are promising in showing that the 'locked' cell cycle of adult cardiomyocytes could be released through modulation of cell cycle checkpoints. In support of this are the signaling pathways of Notch, Hippo, Wnt, Akt and Jak/Stat that facilitate or inhibit the transition at cell cycle checkpoints. Cyclins and cyclin dependant kinases (CDKs) facilitate this transition which in turn is regulated by inhibitory action of pocket protein e.g. p21, p27 and p57. Transcription factors e.g. E2F, GATA4, TBx20 up regulate Cyclin A, A2, D, E, and CDK4 as promoters of cell cycle and Meis-1 and HIF-1 alpha down regulate cyclin D and E to inhibit the cell cycle. Paracrine factors like Neuregulin-1, IGF-1 and Oncostatin M and Extracellular Matrix proteins like Agrin have been involved in cardiomyocyte proliferation and dedifferentiation processes. A molecular switch model is proposed that transforms the post mitotic cell into an actively dividing cell. This model shows how the cell cycle is regulated through on- and off switch mechanisms through interaction of transcription factors and signaling pathways with proteins of the cell cycle checkpoints. Signals triggered by injury may activate the right combination of the various pathways that can 'switch on' the proliferation signals leading to myocardial regeneration.

Untargeted metabolomic analysis of coronary artery disease patients with diastolic dysfunction show disturbed oxidative pathway.

INTRODUCTION: Left ventricular diastolic dysfunction (LVDD) is common in patients with coronary artery disease (CAD) with prevalence estimates of 34% and constitutes a predictor of all-cause mortality. Although diastolic dysfunction is induced by myocardial ischemia and has been shown to alter the clinical course, the role of coronary artery disease in the diastolic dysfunction and its progression into heart failure has not been completely elucidated. OBJECTIVE: The present study was conducted to identify possible metabolites in coronary artery disease patients that are differentially regulated in patients with diastolic dysfunction. METHODS: The serum of CAD (n = 75) patients and young healthy volunteers (n = 43) were analysed by using gas chromatography mass spectrometry (GC-MS) technique. Pre-processing of data results in 1547 features; among them 1064 features were annotated using NIST library. RESULTS AND CONCLUSION: Fifteen metabolites were found to be statistically different between cases and control. Variation in metabolites were identified and correlated with several clinically important echocardiography parameters i.e. LVDD grades, ejection fraction (EF) and E/e' values. The results suggested that metabolic products of fatty acid oxidation and glucose oxidation pathways such as oleic acid, stearic acid, palmitic acid, linoleic acid, galactose, pyruvic and lactic acids are predominantly up regulated in patients with coronary artery disease and severity of diastolic dysfunction appears to be linked to increase in fatty acid oxidation and inflammation. The metabolic fingerprints of these patients give us an insight into the pathophysiological mechanism of diastolic dysfunction in coronary artery disease patients although it did not identify validated novel markers.

Myocardial Ischemia Reperfusion Injury: Apoptotic, Inflammatory and Oxidative Stress Role of Galectin-3.

BACKGROUND/AIMS: Myocardial reperfusion has the potential to salvage the ischemic myocardium after a period of coronary occlusion. Reperfusion, however, can cause a wide spectrum of deleterious effects. Galectin-3 (GAL-3), a beta galactoside binding lectin, is closely associated with myocardial infarction (MI), myocardial fibrosis and heart failure. In our study, we investigated its role in ischemia-reperfusion injuries (IR) as this phenomenon is extremely relevant to the early intervention after acute MI. METHODS: C57B6/J wild type (WT) mice and GAL-3 knockout (KO) mice were used for murine model of IR injury in the heart where a period of 30 minutes ischemia was followed by 24 hours of reperfusion. Heart samples were processed for immunohistochemical and immunofluorescent labeling, morphometric analysis, western blot and enzyme-linked immunosorbent assay to identify the apoptotic, inflammatory and oxidative stress role of GAL-3. RESULTS: Our results show that there was a significant increase in GAL-3 levels in the heart which shows GAL-3 is playing a role in the ischemia reperfusion injury. Troponin I was also significantly higher in GAL-3-KO group than wild type. Our study shows that GAL-3 is associated with an increase in the antioxidant activity in the IR injured myocardium. Antioxidant enzymes superoxide dismutase, glutathione and catalase were found to be significantly raised in the GAL-3 wild type IR as compared to the GAL-3 KO IR group. A significant increase in apoptotic activity is seen in GAL-3 KO IR group as compared with GAL-3 wild IR group. CONCLUSION: Our study shows that GAL-3 can affect the redox pathways, controlling cell survival and death, and plays a protective role on the myocardium following IR injury.

Ventricular depolarisation vectors in exercise induced myocardial ischaemia.

Ischaemia reduces membrane excitability and conduction of myocardial depolarisation. This would alter the synergy of electromotive forces that contribute to a resultant force at any instant. Changes in magnitude and direction of resultant forces are reflected in electrocardiographic signals. Here we show a method for obtaining the coordinates of resultant electrical forces during exercise derived from a bipolar orthogonal lead system for calculation of electrical vectors in three planes. In a trial, analysis of changes in vectors indicated that the extent of reduction in magnitude with exercise was significantly greater in groups of patients categorized by impaired effort tolerance and signs of ischaemia. Measurement of changes in the spectrum of depolarisation vectors during exercise has the potential for non-invasive assessment of myocardial ischaemia. This could be the basis of a portable, low-cost tool for investigation of patients with symptoms suggestive of coronary artery disease.

Is biological repair of heart on the horizon?

The stem cells keep us young by endogenously repairing us upon need. They do so bysmartly one step forward towards differentiation while another step backward to nurturethe undifferentiated stem cells. They are building blocks for every organ witha differential rate of repair of worn out tissues. Since stem cells can be cultured with a normal karyo type, they could be the ideal source for heart repair after myocardial infarction. As opposed to lower vertebrates and neonatal mice, cardiac regeneration in adult mammalian heart seems to be difficult to assess with a solid evidence of cytokinesis. It becomes more difficult to quantify the level of regeneration after myocardial infarction injury against a background of a large invasion of proliferating inflammatory cells. The question to beraised is how the renewal of a piece of myocardium follows the time line of picking upcell types in series: cardiomyocytes, endothelial cells, smooth muscle cells, fibroblast, pacemaker cells, conducting and Purkinje cells to bring the orchestration of rhythmically contracting and relaxing heart. This review focuses on where we are onthe status of heart repair and cardiac regeneration.