Post Infarction Research Articles

Incidental finding of cor triatriatum sinister in an adult post-myocardial infarction

We report a case of a 51-year-old man who was transferred from a community hospital to our institution in cardiogenic shock after thrombolytic therapy for myocardial infarction. At autopsy, a cor triatriatum sinister was found. This may have contributed to his poor outcome post infarction.

Transplantation of embryonic cardiomyocytes reduces post infarct arrhythmias in mice post infarction

Transplantation of embryonic cardiomyocytes reduces post infarct arrhythmias in mice post infarction

Gene therapy with hypoxia-inducible factor 1 alpha in skeletal muscle is cardioprotective in vivo

Aims Gene therapy of a peripheral organ to protect the heart is clinically attractive. The transcription factor hypoxia-inducible factor 1 alpha (HIF-1α) transactivates cardioprotective genes. We investigated if remote delivery of DNA encoding for HIF-1α is protective against myocardial ischemia–reperfusion injury in vivo. Main methods DNA encoding for human HIF-1α was delivered to quadriceps muscles of mice. One week later myocardial infarction was induced and four weeks later its size was measured. Echocardiography and in vivo pressure–volume analysis was performed. Coronary vascularization was evaluated through plastic casting. HL-1 cells, transfected with either HIF-1α or HMOX-1 or administered bilirubin or the carbon monoxide (CO) donor CORM-2, were subjected to lipopolysacharide (LPS)-induced cell death to compare the efficacy of treatments. Key findings After four weeks of reperfusion post infarction, animals pretreated with HIF-1α showed reduced infarct size and left ventricular remodeling (p < 0.05, respectively). Fractional shortening was preserved in mice pretreated with HIF-1α (p < 0.05). Invasive hemodynamic parameters indicated preserved left ventricular function after HIF-1α (p < 0.05), which also induced coronary vascularization (p < 0.05). HIF-1α downstream target heme oxygenase 1 (HMOX-1) was upregulated in skeletal muscle, while serum bilirubin was increased. Transfection of HL-1 cells with HIF-1α or HMOX-1 and administration of bilirubin or CORM-2 comparably salvaged cells from lipopolysacharide (LPS)-induced cell death (all p < 0.05). Significance HIF-1α gene delivery to skeletal muscle preceding myocardial ischemia reduced infarct size and postischemic remodeling accompanied by an improved cardiac function and vascularization. Similar to HIF-1α, HMOX-1, bilirubin and CO were protective against LPS-induced injury. This observation may have clinical potential.

Do Implantable Cardioverter Defibrillators (ICD) Cause Tricuspid Regurgitation? A Retrospective Study

Background: ICDs are an important treatment option in the management of arrhythmias post myocardial infarction. One complication of having an ICD is tricuspid regurgitation (TR), attributed to the passage of the transvenous lead across the tricuspid valve (TV). There is conflicting evidence regarding the effect of the ventricular lead on the TV with some evidence suggesting that the function is significantly compromised. Aim: To examine the impact of ICD leads on the TV by assessing the severity of TR in both acute (<6 months) and chronic (>12 months) phases after insertion. Methods: A retrospective review of patients who underwent percutaneous coronary intervention for an acute STEMI in a tertiary referral teaching hospital (2004–10), with left ventricular ejection fraction <40% at day 3 post infarct as determined by a gated heart pool scan or transthoracic echocardiography (TTE). Of the 299, 59 had an ICD inserted following detection of spontaneous or induced ventricular tachycardia on electrophysiological study within seven days of the infarct vs 241 who did not have ICD. Only subjects who had a TTE pre- and post-implantation of AICD TTE were considered. Results: In the case group 19 had TTEs at all three time points, 24 had TTES pre implant and within six months and the remaining 29 had echos pre implant and >12 months after implantation. The odds ratio of worsening TR at long term follow up compared to short term follow up was 1.6 (95% CI 0.7–3.6, p = 0.28 NS). Conclusion: The presence of an ICD does not appear to worsen tricuspid regurgitation with an odds ratio of 1.6 which was not statistically significant.

Possible mechanism of increasing resistance of the myocardium during combination of post infarction remodeling and diabetes mellitus

It was shown that the energy metabolism of the heart mitochondria of experimental animals and patients is more resistant to damage at combined postinfarction cardiosclerosis and diabetes in comparison with the individual pathology. We found that the changes of free fatty acid content and conjugation of the processes of oxidation and phosphorylation in heart mitochondria are components of the metabolic stability of myocardium at the combined development of postinfarction cardiosclerosis and diabetes mellitus. Our data demonstrate a direct link between the violations of the processes of oxidative phosphorylation and accumulation of free fatty acids owing to change in activity of endogenous phospholipases, in particularly, mi- tochondrial phospholipase A2. Similar results were obtained for intraoperative biopsy specimens of patients’ hearts, and of adult Wistar rats’ hearts. We hypothesized that the preservation of energy metabolism is a manifestation of summing up of compensatory processes at de- velopment of nonspecific response of cells to damage at the early stages of pathological pro- cess.

Purkinje-related Arrhythmias

The Purkinje system has been found to be responsible for the mechanism of some ventricular tachyarrhythmias. These ventricular tachyarrhythmias can be called Purkinjerelated arrhythmias, and are manifested as monomorphic ventricular tachycardia (VT) and polymorphic VT, including ventricular fibrillation (VF). In monomorphic VTs, 4 distinct tachycardias have been found to be related to the Purkinje system: (1) verapamil-sensitive left fascicular VT, (2) Purkinje fiber-mediated VT post infarction, (3) bundle branch reentry (BBR) and interfascicular reentry VTs, and (4) focal Purkinje VT. In polymorphic VT and VF, the Purkinje system may also play an important role. The Purkinje network plays a pivotal role in both the initiation and perpetuation of VF. A triggering ventricular premature beat could arise from either the right or left Purkinje system, and the catheter ablation of the trigger results in a very high cure rate for VF. In patients with an electrical storm, catheter ablation of the triggering VPBs from the Purkinje system should be used as an electrical bailout therapy.

Revisit the Purkinje Related VT

Purkinje-related VT includes idiopathic LV VT (ILVT), some post infarction VT, bundle branch reentry, and focal Purkinje VT. Among them, ILVT is the most common one. In 1983, Lin et al. designated ILVT as an unique clinical entity with specific properties: patients having no structural heart disease, tachycardia showing RBBB/superior axis pattern, a reentry mechanism, verapamil responsive, slow-response tissues related. Subsequently, Ohe et al. reported this VT may also having right axis deviation in 1988. Catheter ablation was demonstrated in eliminating this VT at exit site by Nakagawa and Wen et al. in 1994. The underlying substrate was suggested as LV false tendons by Suwa et al., but Lin or Tharkur et al. did not have a conclusive answer on this. In 1997, we firstly demonstrated this tachycardia can be ablated at least 2–3 cm away from the tachycardia exit site. We found it is macroreentry along the LV septum. Subsequently, Tsuchiya et al. recorded the late diastolic potential preceding the Purkinje potential. Nogami et al. described the relationship between the late potential and presystolic Purkinje potential within the circuit revealing diastolic potential is another ablation target. This reentry circuit was further defined by Lai and Aiba et al. Now LVVT can be classified by QRS morphology: common type, uncommon type, and upper septal type. The success rate in catheter ablation is 90–95%. But the etiology of ILVT is still need to be determined.

S100B Protein in the Nervous System and Cardiovascular Apparatus in Normal and Pathological Conditions

Accumulating evidence suggests that S100B, a Ca2+-binding protein of the EF-hand type, functions as a regulator of intracellular activities and as an extracellular signal. Within cells, S100B interacts with a relatively large number of target proteins thereby regulating their functions (Figure 1). While most of these interactions are Ca2+ dependent, in some instances S100B/target protein interactions are not. S100B is also secreted by certain cell types and released by activated/damaged/necrotic cells. Secreted/released S100B can affect cellular functions with varying effects depending on its local concentration. Figure 1 Schematic representation of intracellular regulatory effects of S100B. S100B is not a ubiquitous protein, its expression being restricted to astrocytes, Schwann cells, ependymocytes, certain neuronal populations, adipocytes, chondrocytes, melanocytes, dendritic cells, muscle satellite cells, skeletal myofibers, arterial smooth muscle cells, and bronchial epithelium, in normal physiological conditions. However, the S100B cell expression pattern during prenatal and postnatal development might be different (there is limited information about this issue); S100B expression levels in certain cell types may be varied in response to extracellular factors; levels of S100B are high in several cancer cells; S100B expression may be induced in cardiomyocytes and arterial endothelium in response to norepinephrine. Serum levels of S100B in normal prepubescent and postpubescent human subjects are relatively high and low, respectively, and increases in S100B serum levels are found in physiological conditions (such as intense physical exercise) and in several pathological conditions (mostly, brain diseases, certain psychiatric disorders, melanoma, and heart infarction and insufficiency). The present special issue of “Cardiovascular Psychiatry and Neurology” focuses on the brain-heart role of S100B. In the adult brain, S100B amounts to ~0.5% of cytoplasmic protein content and is most abundant in astrocytes (with an estimated concentration of ~10 μM), where the protein is found diffusely in the cytoplasm and associated with microtubules, GFAP intermediate filaments, and intracellular membranes. Such a high concentration and its diffuse localization in the cytoplasm explain S100B's ability to interact with enzymes, enzyme substrates, scaffold/adaptor proteins, transcription factors, and cytoskeleton constituents thereby regulating energy metabolism, Ca2+ homeostasis, transcription, and cell shape, proliferation, differentiation, and motility (Figure 1). Besides, ~5% of S100B is being constitutively secreted by astrocytes; S100B secretion can be enhanced or reduced by a number of factors and/or conditions; in case of brain damage, large amounts of S100B are being passively released, with a fraction of the protein diffusing into the cerebrospinal fluid (CSF) and blood. Whereas increases in the CFS and/or serum S100B content are taken as an indication of brain damage (yet increases in serum S100B content might point to nonbrain damage as well), a large body of evidence indicates that brain extracellular S100B behaves as a neurotrophin in normal physiological conditions and as a damage-associated molecular pattern (DAMP) factor upon massive release consequent to astrocyte activation or necrosis. In this latter case, S100B participates in the amplification of the brain inflammatory response by activating microglia and astrocytes and exerting toxic effects on neurons. RAGE (receptor for advanced glycation end products) has been identified as the receptor transducing both trophic and toxic effects of S100B in the brain and might act as a coreceptor supporting certain S100B effects on microglia (Figure 2). Figure 2 Schematic representation of extracellular regulatory effects of S100B on neurons, microglia, and astrocytes. As an intracellular regulator, S100B also participates in myocardium remodeling post infarction inhibiting the hypertrophic response in cardiomyocytes surviving the insult, and once released from necrotic cardiomyocytes, it acts as a DAMP factor causing cell death again via RAGE engagement. Adipocytes also release S100B in response to catecholamines with unidentified effects, though. Lastly, as a DAMP factor, S100B also participates in the pathophysiology of atherosclerosis stimulating vascular smooth cell proliferation and activating monocytes/macrophages. The present issue of “Cardiovascular Psychiatry and Neurology” attempts to delineate the functional roles of S100B in the brain and the cardiovascular apparatus and to update the information about this multifaceted protein. We are confident that both cell biologists and clinicians will benefit by the reading of the papers presented therein. Rosario Donato Claus W. Heizmann

Alteration of Post Infarction Myocardial Strain with an Adjustable Pressure Device

Introduction: We hypothesize that placing an adjustable pressure device over the infarct region can alter the directional strain component and improve post infarction cardiac function. Method: A 20% posterolateral infarct was created in a swine and a custom device was placed over the infarct region. 1-week post infarction the animal was imaged using a 3T MRI (Siemens TIM Trio). 3D SPAMM tagged images were acquired at inflation volumes of 0 mL, 5 mL and 10 ml. Image analysis was performed using an optical flow method (OFM).

Axonal degeneration, regeneration and ganglion cell death in a rodent model of anterior ischemic optic neuropathy (rAION)

Using laser-induced photoactivation of intravenously administered rose Bengal in rats, we generated an ischemic infarction of the intrascleral portion of the optic nerve (ON) comparable to that which occurs in humans to investigate optic nerve axon degenerative events following optic nerve infarct and the potential for axon re-growth. Animals were euthanized at different times post infarct. Axon degeneration was evaluated with SMI312 immunolabeling, and GAP-43 immunostaining was used to identify axon regeneration. Terminal dUTP nick end labeling (TUNEL) was used to evaluate retinal ganglion cell (RGC) death. There was significant axon structural disruptinot ion at the anterior intrascleral portion of the ON by 3d post-infarct, extending to the posterior ON by 7d post-stroke. Destruction of normal axon structure and massive loss of axon fibers occurred by 2 weeks. GAP-43 immunoreactivity occurred in the anterior ON by 7d post-infarct, lasting 3-4 weeks, without extension past the primary ischemic lesion. TUNEL-positive cells in the RGC layer appeared by 7d post-insult. These results indicate that following induction of ischemic optic neuropathy, significant axon damage occurs by 3d post-infarct, with later neuronal death. Post-stroke adult rat retinal ganglion cells attempt to regenerate their axons, but this effort is restricted to the unmyelinated region of the anterior ON. These responses are important in understanding pathologic process that underlies human non-arteritic anterior ischemic optic neuropathy (NAION) and may guide both the appropriate treatment of NAION and the window of opportunity for such treatment.

The Correlation of 3D DT-MRI Fiber Disruption with Structural and Mechanical Degeneration in Porcine Myocardium

Evaluation of structural parameters following a myocardial infarction (MI) is important to assess left ventricular function and remodeling. In this study, we assessed the capability of 3D diffusion tensor magnetic resonance imaging (DT-MRI) to assess tissue degeneration shortly after an MI using a porcine model of infarction. Two days after an induced infarction, hearts were explanted and immediately scanned by a 3T MRI scanner with a diffusion tensor imaging protocol. 3D fiber tracks and clustering models were generated from the diffusion-weighted imaging data. We found in a normal explanted heart that DT-MRI fibers showed a multilayered helical structure, with fiber architecture and fiber density reflecting the integrity of muscle fibers. For infarcted heart explants, we observed either a lack of fibers or disruption of fibers in the infarcted regions. Contours of the disrupted DT-MRI fibers were found to be consistent with the infarcted regions. Both histological and mechanical analysis of the infarcted hearts suggested DT-MRI fiber disruption correlated with altered microstructure and tissue mechanics. The ability of 3D DT-MRI to accurately distinguish viable myocardium from dead myocardium only 2days post infarct without the use of radioisotopes or ionotropic agents makes it a promising approach to evaluate cardiac damage early post-MI.

Gp130 cytokines stimulate proteasomal degradation of tyrosine hydroxylase in sympathetic neurons by ERK‐dependent pathway

Heterogeneity of sympathetic transmission in the heart after myocardial infarction contributes to ventricular arrhythmias and sudden cardiac death. Tyrosine hydroxylase (TH), the rate‐limiting enzyme in norepinephrine synthesis, is depleted in the left ventricle after myocardial infarction, but elevated in other parts of heart. Inflammatory cytokines acting through gp130 cause local depletion of TH in cardiac sympathetic nerves post infarction. However, the mechanism of cytokine‐induced TH loss remains unknown. We used cultured sympathetic neurons to investigate the mechanism of gp130 cytokine suppression of TH protein. Cytokines stimulate TH ubiquitination, and cytokine‐induced TH loss was prevented by MG‐132, suggesting that the proteasomal degradation pathway was involved. Cytokine activation of gp130 stimulates Janus kinase (JAK) which leads to activation of STAT3, ERK1/2, and PI3K/AKT. Blocking ERK activation by U0126 prevented cytokine‐induced TH ubiquitination, while inhibiting STAT3 phosphorylation with STAT3 inhibitor V enhanced cytokine‐induced TH ubiquitination. Inhibiting STAT3 enhanced ERK1/2 phosphorylation, suggesting that ERK was a major regulator of TH ubiquitination. Blocking JAK activity inhibited all downstream signaling and prevented cytokine‐induced ubiquitination of TH. Preliminary data implicate SOCS3 as a mediator of ERK‐STAT3 crosstalk.

Leukocyte count as a risk factor for coronary adverse events among patients admitted for an acute coronary syndrome

Leukocytosis occurs as a response to a variety of inflammatory processes. To determine if white blood cell count (WBCC) at admission among patients who suffer an acute coronary syndrome (ACS) has an independent prognostic value for the occurrence of new cardiovascular adverse events (CAE). Prospective study of 558 patients aged 68 +/- 13 years (122 women) admitted to the hospital for an acute coronary syndrome. WBCC was measured at admission. A logistic regression model was used to assess the association of WBCC with the occurrence of CAE during the next six months after admission (post infarction angina, re-infarction, cardiac failure and mortality). An univariate analysis showed that patients with a WBCC > 15.000 cell/mm(3) had a significantly higher mortality and occurrence of CAE. The multivariate analysis showed that subjects with WBCC < 10.000 cell/mm(3) experienced fewer CAE than subjects with a WBCC > 15.000 cell/mm(3), with an odds ratio of 0.46 (95% confidence intervals = 0.21-0.97, p = 0,042). An elevated WBCC at admission among patients with an ACS is associated with a higher incidence of CAE in the ensuing six months.

Recuento leucocitario y riesgo cardiovascular tras un síndrome coronario agudo

Leukocytosis occurs as a response to a variety of inflammatory processes.To determine if white blood cell count (WBCC) at admission among patients who suffer an acute coronary syndrome (ACS) has an independent prognostic value for the occurrence of new cardiovascular adverse events (CAE).Prospective study of 558 patients aged 68 +/- 13 years (122 women) admitted to the hospital for an acute coronary syndrome. WBCC was measured at admission. A logistic regression model was used to assess the association of WBCC with the occurrence of CAE during the next six months after admission (post infarction angina, re-infarction, cardiac failure and mortality).An univariate analysis showed that patients with a WBCC > 15.000 cell/mm(3) had a significantly higher mortality and occurrence of CAE. The multivariate analysis showed that subjects with WBCC < 10.000 cell/mm(3) experienced fewer CAE than subjects with a WBCC > 15.000 cell/mm(3), with an odds ratio of 0.46 (95% confidence intervals = 0.21-0.97, p = 0,042).An elevated WBCC at admission among patients with an ACS is associated with a higher incidence of CAE in the ensuing six months.

Whole-heart T2-weighted (T2w) sequence for imaging post-infarct edematous area at risk (AR) in mice

Introduction T2w cardiac magnetic resonance (CMR) defines the area at risk (AR) in large mammals by imaging post myocardial infarct (MI) edema. Here, we expand the T2w CMR to cover the entire left ventricle (LV) in mice and jointly applied late gadolinium enhanced (LGE) CMR to noninvasively define MI size as percent AR. Fast murine heart rate, flow and motion present challenges to T2w CMR success. The typical 60 ms echo time for edema contrast occupies a large portion of the murine cardiac cycle which prohibits traditional T2w methods.

Validation of a Simple Screening Tool for Assessment of Nutritional Status in Coronary Patients

Background: In 2008, the Heart Foundation published a minor position statement and supporting documents to recommend marine n-3 omega fatty acids (EPA), (DHA) in all patients with coronary disease and set targets of intake for asymptomatic individuals. Since thepublication new relevant trials have been published and other groups around the world have made recommendations. Methods:Reviewofpublishedarticles regardingmarine n-3 fatty acids and review of guidelines of other national bodies such as the National Institute of Health and Clinical Excellence (NICE) and the European Society of Cardiology. Results: Since the Heart Foundation review, two major outcome trials have been published. First, an underpowered post infarction trial from Germany involved 1000 i t w v p e t s t

Bipolar Ablation of the Interventricular Septum is More Efficient at Creating a Transmural Line than Sequential Unipolar Ablation

Post infarct ventricular tachycardia (VT) often involves the interventricular septum (IVS) and requires transmural septal ablation. The purpose of this study was to compare the efficacy of bipolar ablation (BIA) versus sequential unipolar ablation (SUA) in creating a transmural ablation line along the IVS scar border. Both ablation strategies were compared in a phantom agar model first and then in 10 post infarct sheep. In the phantom agar model BIA lesions were larger, transmural, and less dependent on catheter alignment and contact compared with SUA. Noncontact mapping was used in the animals to identify the septal scar border and create a 30-mm ablation line. In five animals BIA (50 W) was performed between two irrigated catheters on either side of the IVS, and in five control animals SUA (50 W) was performed, first on the left ventricle (LV) septal scar border and then on the opposing right ventricle (RV) septal surface. Electrical block along ablation lines was confirmed with noncontact mapping. BIA required significantly less ablations (12 + or - 1 vs 29 + or - 7, P = 0.001), ablation time (22 + or - 3 vs 48 + or - 6 minutes, P < 0.001), and energy (58 + or - 7 vs 124 + or - 21 kJ, P < 0.001). At pathological examination all ablation lines in both groups were transmural at the IVS border. BIA endocardial ablation lines (LV + RV) were significantly longer than SUA lines (76 + or - 10 vs 49 + or - 11 mm, P = 0.003). BIA of the IVS is highly effective at creating a transmural ablation line, requiring less ablation and creating longer lesions than SUA. BIA ablation may have a role for post infarct VT involving the IVS.

Abstract 5212: Resolution of Pathological Q-waves is Associated With Improved Outcomes After Primary PCI for Acute Myocardial Infarction

Background: The presence of pathological Q-waves in patients presenting with ST-elevation myocardial infarction (STEMI) independently predicts 30-day mortality. A question that remains is whether new Q-waves which resolve within 30 days are predictive of an improved prognosis. Methods: 3,189 patients with STEMI enrolled in the prospective, randomized Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial were evaluated for the presence of new and persistent Q-waves by serial electrocardiography. ECGs were performed at baseline, 60 minutes post PCI, at hospital discharge and at 30 days, and were interpreted by independent cardiologists at an academic ECG core laboratory. Net Adverse Clinical Events (NACE) was defined as Major Adverse Cardiovascular Events (MACE (death, reinfarction, stroke or repeat revascularization) or major bleeding unrelated to CABG. Results: There were 2358 patients with new Q-waves either at baseline or which developed during hospitalization. Patients were classified for the presence of Q-wave resolution within 30 days (n=225) (Group A) or presence of persistent Q-waves (n=2133) (Group B). Group B patients were more likely to have a lower baseline left ventricular ejection fraction and a longer duration of symptom to balloon inflation time, and were less likely to have successful reperfusion as measured by post PCI infarct artery epicardial TIMI flow. Group B also had a significantly higher rate of NACE at 30-days (Table ). Conclusions: In patients with STEMI undergoing primary PCI, resolution of new Q-waves present during hospitalization is associated with a higher baseline left ventricular ejection fraction, faster and more effective reperfusion, and an improved short-term prognosis. TABLE

Abstract 5115: Purified Human Muscle-Derived Pericytes Support Formation of Vascular Structures and Promote Angiogenesis After Myocardial Infarction

We have recently shown that perivascular cells isolated from multiple human tissues represent stem cells endowed with mesodermal lineage potentials, and the injection of multipotent muscle-derived pericytes repair damaged skeletal muscle in vivo . Our current study further demonstrated that transplantation of human muscle-derived pericytes (3.0×10 5 cells/heart) into the ischemic myocardium of NOD/SCID mice sustains the cardiac function of the infarcted hearts. Here, we tested the hypothesis that purified CD34 − /45 − /56 − /146 high pericytes support formation of structures of blood vessels and promote angiogenesis post infarction. To illustrate the potential vessel-forming properties of purified pericytes, pericytes and endothelial cells were co-cultured in Matrigel in vitro, and co-formation of capillary-like structures was observed. To evaluate the angiogenic effect of pericytes in vivo , histological examination was performed two weeks after transplantation. Capillary density was measured by anti-CD31 staining on tissue sections. Capillary density within peri-infarct areas was 43% higher in the pericyte-injected group than in the saline-injected group ( P &lt;0.05). Myocardial fibrosis estimated by Masson’s trichrome staining revealed a 38% reduction of the scar area in pericyte-injected hearts when compared to saline-injected hearts. These findings indicated that transplantation of pericytes sustains the cardiac function of the infarcted left ventricle presumably through enhancement of angiogenesis and reduction of myocardial fibrosis. We further examined potential mediators of pericyte-induced cardiac repair in the ischemic micro-environment by culturing pericytes under hypoxic conditions (2.5% oxygen) in vitro for 24 hours. Real-time quantitative PCR analysis showed that vascular endothelial growth factor (VEGF)-related genes, including VEGF 165 and VEGF receptor 1 and 2, were significantly up-regulated in the pericyte population. Overall, the data suggested a role of VEGF-regulated angiogenesis on pericyte-mediated cardiac repair. Experiments are being performed to elucidate the potential of pericytes to differentiate into cardiac cell lineages and explore the regulatory mechanisms involved in vivo .

Molecular Imaging of Apoptosis In Vivo with Scintigraphic and Optical Biomarkers – A Status Report

The balance between proliferation and programmed cell death--apoptosis--is essential for multicellular organisms which use apoptosis to regulate and maintain the number and type of their cells during embryogenesis, growth and homeostasis. Increased cell proliferation or enhanced cell loss can be caused by dysregulated apoptosis and are observed in various diseases: in clinical scenarios such as neurodegenerative disorders, myocardial infarction and stroke the rate of apoptosis is upregulated compared to the physiological situation, while in clinical scenarios such as cancer or autoimmune diseases which are connected with pathological proliferation, apoptosis is often downregulated. Therefore, non-invasive imaging of apoptosis is of great clinical interest as patients would clearly benefit from the diagnosis of cell loss post infarction or from monitoring apoptosis triggered by chemotherapy or radiation therapy of tumours. Several biochemical transformations occur in apoptotic cells offering different biological targets for the development of specific molecular biomarkers of apoptosis. Key steps that occur during apoptosis have already been evaluated; among these are the externalisation of phospholipid phosphatidylserine to the outer leaflet of the cell membrane, which can be visualized by labeled annexin A5 and the activation of caspases, especially effector caspase-3, which can be addressed by labeled enzyme substrates or synthetic caspase inhibitors. Here, recent advances in tracer development for the molecular imaging techniques PET, SPECT and optical imaging are presented, the discussion of breakthroughs is involved, drawbacks and methodological issues of apoptosis imaging are highlighted.