Chemotherapeutic agents reduce mortality and can prevent morbidity in a wide range of malignancies. These agents are, however, associated with toxicities of their own, and the treating physician must remain ever vigilant against the risk outgrowing the benefit of therapy. Thus, pre-treatment evaluation and monitoring for toxicity during and following administration is a fundamental tenet of oncologic practice. Among the most insidious and deadly toxicities of anti-tumor agents is cardiac toxicity, which in some cases may be irreversible. Early detection of cardiotoxicity allows the treating oncologist to redirect therapy or dose modify, taking into account the cost of a reduction in therapy against the potential of further injury to the patient. In these instances, the role of the cardiologist is to assist and advise the oncologist by providing diagnostic and prognostic information regarding developing cardiotoxicity. This review discusses noninvasive diagnostic options to identify and characterize cardiotoxicity and their use in prognosis and guiding therapy. We also review established protocols for cardiac safety monitoring in the treatment of malignancy. Over the past decade a bonanza of new chemotherapeutic agents have matured, in many cases rendering cancer a chronic disease rather than a terminal one. As early detection of malignancy leads to a higher likelihood of cure, the treated population may survive to experience secondary toxicities of their cancer therapy, in spite of the initial benefit. Of paramount importance in both morbidity and mortality are the short and long term effects of cancer therapy on cardiac tissue and subsequent effects on cardiac function. Early detection of toxicity during therapy may allow for dose modification, alteration, or abandonment of regimens which may reduce or even eliminate long term complications associated with reduced left ventricular function. Further, there is mounting evidence that early therapeutic interventions with cardioprotective medications such as beta-blockers or angiotensin-renin-aldosterone system altering agents may improve cardiovascular outcomes in the population treated with chemotherapeutic agents , 2. Non-It is important to note that the demographics and exposure history of many oncologic patients is such that the incidence of cardiovascular disease is higher than in other populations. Oncologic patients frequently have one or more risk factors for coronary artery disease . Regarding clinical monitoring for cardiotoxicity in clinical trials of chemotherapeutic agents, the Cardiac Review and Evaluation Committee (CREC) reviewing cardiotoxicity in several trials of trastuzumab in the treatment of breast cancer formulated the following, which has become the de facto standard: cardiomyopathy is characterized by  a decreavia several mechanisms, including a) direct cellular toxicity involving cardiac myocytes, resulting in both systolic and diastolic dysfunction; b) induction of ischemia through vasoactive side effects, thrombogenesis, or vascular toxicities; c) arrhythmia either as a collateral effect to cellular toxicity or due to interference with cellular membrane channels; d) induction of myocardial and/or pericardial inflammation (myopericarditis) with associated direct dysfunction or mechanical sequelae due to a pericardial effusion. Survival can be markedly improved with intervention, both in the form of dose adjustment if cardiotoxicity is recognized early, or with medical therapy to allay the onset of heart failure and perhaps retard its progression. With many of the agents described below, when myocardial dysfunction is present in the chronic phase, it commonly represents permanent myocyte injury, and though the syndrome may be clinically treatable for a time the pathophysiology is most likely irreversible. This belies the importance of early detection of toxicity, in the hopes of preventing disease progression. The nature of the chemotherapeutic agent plays a central role in determining cardiotoxicity. Cardiotoxicity may occur Assessment of potential toxicity begins with physical examination and historical features, including an assessment of functional status. A thorough history and physical examination is paramount. Clinical predictors including age, prior hypertensive, vascular, or other cardiac disease are powerful predictors of subsequent toxicity. Other readily available clinical parameters such as biochemical markers, electrocardiographic studies, and finally noninvasive imaging, provide further diagnostic power in determining the presence, degree, and progression of cardiac toxicity. Intensive monitoring of cardiotoxicity in chemotherapeutic regimens may allow for early detection of cardiac dysfunction, and thereby allow clinical intervention, either by dose adjustment, pharmacologic intervention, regimen modification, or therapy aimed at treating subsequent heart failure as it develops. Further, regimens or agents administered prior to the infusion of anthracycline may induce myocardial dysfunction, which makes the patient more susceptible to a clinically significant decline in cardiac function. The protocol under which the anthracycline was infused also has an impact on the likelihood of subsequent development of cardiotoxicity; bolus protocols tend toward cardiotoxicity more than slow infusion protocols, perhaps unveiling a toxic threshold within the mechanism of anthracycline-induced cardiotoxicity , 5 The aThe nature of the chemotherapeutic agent in use is an important factor in determining the likelihood and natural history of cardiotoxicity, if it develops. Comprehensive discussion of the specific cardiotoxicities of the various chemotherapeutic agents are discussed elsewhere in this series. In summary, the mechanism of cardiotoxicity may result from direct injury to the cardiomyocyte, ischemia either due to native disease or vascular effects of the agents in question , 6-8. Thvia a central vein  across the tricuspid valve and into the right ventricle. There, several small biopsies are taken from various positions on the interventricular septum. Though uncommon, complications can occur and include perforation of the right ventricular free wall with subsequent hemopericardium and possible development of tamponade physiology requiring emergent drainage. Other complications include arrhythmia, injury to the tricuspid valve, fistula formation, bleeding and infection. The nature of cardiotoxicity in the setting of many chemotherapeutic agents often occurs in a patchy fashion, thus multiple (3-5) biopsies are required, and even in this setting the sensitivity of endomyocardial biopsy in diagnosing chemotherapy-induced cardiotoxicity is low. Specificity is, however, quite high and can confirm the diagnosis. Though not a noninvasive procedure, endomycardial biopsy does deserve some mention here. In patients with cardiac toxicity, electron microscopy of endomyocardial biopsy specimens reveal disruption of z-lines, mitochondrial disruption, myofibrillary bundles, myofibrillar lysis and vacuolization within the myocytes . Though Cardiac biomarkers generally refer to proteins released from cardiac myocytes under conditions of both mechanical and severe metabolic stress, up to and including cell death. Myocyte death, or severe metabolic stress, will lead to the release into the blood of intracellular proteins, including AST, ALT, creatine-kinase (CK) and the cardiac isoenzyme of CK (CK-MB), as well as cardiac isoforms of troponins I and T (cTnI and cTnT). While skeletal muscle may encode at least trace amounts of cardiac CK-MB, the exclusive translation of the cardiac troponins within the cardiac myocyte renders them more accurate for the detection of cardiac damage. Cardiac troponin T and I are released from cardiac myocytes under conditions of severe metabolic stress, but more commonly following cell death and eventual lysis. These markers reach the bloodstream where they may then be measured peripherally. Cardiac troponins are established as a sensitive and specific marker of cardiac injury. B-type naturetic peptide is a sensitive biochemical marker of myocardial stretch and strain, and has been validated as a diagnostic tool in identifying congestive heart failure as the source of dyspnea . MechaniElevations of cardiac biomarkers have been closely associated with acute toxicities attributable to chemotherapeutic agents, however evidence is lacking to support long term associations of toxicity as well as the prospective use of cardiac biomarkers in determining a course of therapy. Nonetheless, cardiac biomarkers may play a central role in the early identification of patients at high risk for cardiac toxicity in the setting of chemotherapy . Though During the administration of high-dose chemotherapeutic regimens, elevations in cardiac troponins correlate strongly with the development of cardiac dysfunction in patients treated with high dose chemotherapy  are that the procedure is inexpensive, widely available, and without risk to the patient. ECG is essential in the diagnosis of heart rhythm abnormalities. In addition, reduction in limb lead voltages by >30% may predict cardiotoxicity in patients receiving anthracyclines . HoweverEvaluation and surveillance of cardiac function is recommended before, during, and after administration of chemotherapeutic agents with associated cardiotoxicity. There are not, however, published consensus guidelines on the modality or frequency of cardiac assessment - nor on the most effective parameter or set of parameters to follow in a particular situation. Further, coronary artery disease is prominent among many populations of cancer patients, and non-invasive cardiovascular imaging may be used to assess for significant coronary artery disease in addition to assessing for toxicity. Comparison between imaging of both cardiac structure and of perfusion or perfusion surrogates during both rest and stress conditions is a widely utilized paradigm for assessment of injured or ischemic myocardium.via noninvasive imaging in this context is the left-ventricular ejection fraction (LVEF). Often interpreted as an aggregate of left ventricular systolic function, the ejection fraction represents the fraction of left ventricular blood volume at end diastole that is ejected during systole (often expressed as a percentage). Its assessment relies upon accurate evaluation of the left ventricular chamber volume at these two points in the cardiac cycle. Early data, particularly in patients treated with anthracyclines, demonstrated a fall in LVEF associated with the development of anthracycline associated persistent cardiomyopathy. A minor (≤4%) fall in LVEF early in the course of anthracycline based chemotherapy, below what is considered the standard cumulative toxic dose in adults, has also been demonstrated to predict later sustained fall in EF into the toxic threshold in treated patients [The most common parameter assessed patients . Thus, aAs cardiovascular disease, dominantly ischemic heart disease, remains the most common cause of death in the western world, much of what is known about the non-invasive imaging of cardiac structure, function, and dysfunction is derived from efforts to understand and noninvasively detect myocardial ischemia. As the decoupling of myosin from actin is an energy dependent process, the initial myocyte dysfunction in the ischemic heart induces a decline in diastolic function. This leads to an elevation in filling pressures and activation of stretch receptors within the ventricular  walls, subsequently activating the neuroendocrine axis and leading to a release of natriuretic peptides. Loss of systolic function may occur as ischemia progresses to infarction and myocardial necrosis; autopsy studies have in fact demonstrated patchy areas of myocyte necrosis in such patients. Assessment of other parameters of myocardial motion throughout the cardiac cycle, as well as visualization of myocardial tissue features, may provide clues to subclinical toxicity well before it is reflected by a fall in ejection fraction. The strengths and weaknesses of several methods of assessing left ventricular function are therefore described below. Early studies of doxorubicin cardiotoxicity relied upon radionucleotide ventriculography to risk stratify patients pre-therapy, and to follow patients serially during therapy in hopes of identifying early signs of cardiotoxicity. via equilibrium gated techniques to provide an accurate estimate of left ventricular volumes at end-diastole and end-systole, thus providing a surrogate metric of left ventricular function. A radiolabel (commonly technetium 99m) is attached to red blood cells or serum albumin from a patient blood sample and re-injected. In the multiple-gated acquisition technique (MUGA), the summation of counts from 800-1000 ECG-gated cardiac cycles is performed, producing an average cardiac cycle with good resolution of LV chamber dimensions. These dimensions are acquired in 3 standard projections - anterior, left anterior oblique, and left lateral. Each projection requires roughly 5 minutes of imaging time to acquire. Attempts to compare radionucleotide ventriculography (RVG) to standard 2D and M-mode echocardiography techniques have demonstrated inexact correlation [Radionucleotide ventriculography (RVG) is often performed relation . Serial relation . Unlike relation .99mTechnetium-labelled tracers as well as 201Thallium chloride. This group of myocardial perfusion studies rely on differences in regional myocardial blood flow to identify hemodynamically significant coronary stenosis, as well as uptake of the tracer by metabolically active tissue to assess myocardial viability. Radiation dose estimates with these modalities range from 9.4-12.8 mSv for a 99mTechnetium-sestamibi myocardial perfusion scan to as high as 40.1 mSv for a 201Thallium viability study [Other nuclear medicine modalities may be used to evaluate myocardial perfusion and estimate ischemic burden due to coronary artery disease. These include ty study .To put radiation exposure in context, medical workers and individuals in other occupations which expect repeated exposure to low-dose ionizing radiation typically limit radiation doses to 100 mSv every five years, with a limit of no more than 50 mSv in any given year period. The estimated average annual exposure to ionizing radiation worldwide is 2.4 mSv. Thus, a single study carries perhaps less concern in regard to long-term risk of ill effect, however repeated exposures, for example as part of a surveillance protocol, may be more concerning. The BEIR VII Phase 2 committee estimated an increased lifetime risk of 800 solid malignancies and 100 leukemias per 100,000 persons would result from a single exposure to 100 mSv . The risEchocardiography is the most commonly utilized non-invasive modality for assessing cardiac structure and function. The advantages of echocardiography over other methods of cardiovascular imaging include availability, lesser cost, lack of ionizing radiation and lack of exposure to potentially toxic contrast agents. In addition to accurate assessment of left ventricular function, echocardiography provides information about valvular function, presence of pericardial fluid, pulmonary arterial pressures, left ventricular filling pressures, and intravascular volume status. These additional parameters, while they may or may not be related to chemotherapeutic administration, provide useful clinical information. Like other modalities, body habitus and anatomic variation (such as rib location) affect image quality, and there can be inter-observer differences in study interpretation. Newer techniques, such as 3D echocardiography and tissue Doppler velocity assessments are becoming more widely used and will improve the accuracy and reproducibility of cardiac ultrasound. For example, with 3D echocardiography, volume assessment can be performed without relying on geometric assumptions (which is the case with standard 2D echocardiography) and provides an accurate, quantitative means of assessing left ventricular function. Dobutamine or treadmill stress echocardiography may also have a role in identifying patients with cardiomyopathy, as these studies allow assessment of contractile reserve and response to increased workloads. via the modified Simpson method . This method improves accuracy over M-mode estimates, and reduces inter- and intra-observer variability. These method does suffers from error in estimation of cavity size due to geometric assumptions which may not hold up from patient to patient, under different loading conditions, or when myocardial wall motion abnormalities have developed. Tissue velocity Doppler imaging (DTI) relies upon high-amplitude, low frequency Doppler shifts to measure velocity of various cardiac structures, including the left ventricular endocardium. Tissue velocities at different locations during various phases of the cardiac cycle are measured with this technique, and correlations to outcomes have been found in a number of disease states [endo) at various locations is observed and can be used as a surrogate for left ventricular function. In murine models of anthracycline-induced cardiotoxicity, Vendo allows earlier recognition of LV dysfunction when compared to standard 2D echocardiographic techniques  - as early as 1 day vs 4-5 days, respectively. Further, DTI produces lower rates of inter and intra-observer variability [via a speckle tracking technique were also significantly decreased early in this study [Standard methods of 2D echocardiography can be used to assess left ventricular function. M-mode echocardiography refers to an evaluation of structures along a single dimensional line, followed over time. This mode allows for tremendous temporal resolution, thus allowing for evaluation of motion of various cardiac structures - in particular the left ventricular endocardium. By convention, the LV cavity dimensions are measured at the level of the mitral leaflet tips or papillary muscle using 2D-guided M-mode. From these measurements, the fractional shortening can be calculated as well as an estimate of the fraction of blood volume ejected with each cardiac cycle, the ejection fraction. Using 2D echocardiography, the endocardial border can be traced by the interpreting clinician in two orthogonal planes . From these traced areas, the LV cavity volume may be estimated e states . The veliability . In patiis study . DTI mayis study . 3D echois study . With 3DEchocardiography is a safe imaging modality. The acoustic power of echocardiographic equipment is kept well below levels at which adverse effects of ultrasound energy may be observed. These effects include heating of target and intervening tissues, as well as induction of electrical dysfunction, often observed as frequent premature ventricular contractions (PVCs). Microbubble contrast agents can be administered in patients with difficult echo windows and make it possible to obtain diagnostic quality images in virtually all patients. Of the imaging techniques described here, echocardiography is the least expensive. Overall, echocardiography provides is an excellent method for serially evaluating left ventricular function and provides a significant amount of ancillary information, including valvular assessment, pericardial effusion detection, etc. There are no known long-term sequela from ultrasound evaluation, and the technology is relatively inexpensive and widely available.2010 Cardiac CT Appropriateness Criteria advocate that CCTA is appropriate in any patient with low or intermediate CAD risk with CAD symptoms. It is also appropriate in patients without symptoms but with new-onset or newly diagnosed heart failure with low or intermediate CAD risk [Coronary artery disease (CAD) is pervasive in our society, and is an important consideration in the differential diagnosis of any patient with decreased left ventricular function. CAD is the leading cause of death in the United States for both men and women. Given the high prevalence of CAD, and the fact that patients receiving chemotherapy often have multiple CAD risk factors, it is frequently necessary to exclude ischemia as a cause of cardiomyopathy, even in situations where a temporal correlation exists between onset of the cardiomyopathy and administration of the potentially cardiotoxic agent. Stress imaging studies can help identify potential ischemia; however, interpretation of these studies can be complicated in the setting of decreased left ventricular function. New technology in CT scanning enables direct visualization of coronary arteries and unequivocal determination of presence or absence of coronary artery disease . CoronarCAD risk . In addivia spatial and temporal modulation of the amount of x-ray radiation used during the study have reduced the doses of ionizing radiation in coronary CT substantially [While CCTA enables sensitive detection of coronary artery disease, there are several practical considerations that limit its use in patients with cardiomyopathy. Protocols commonly employed with current generation multi-detector row CT scanners require low heart rates (50-60 bpm) in order to obtain diagnostic images. This frequently requires aggressive pre-study beta blockade. In patients with reduced LVEF and a compensatory tachycardia to maintain cardiac output, beta blockade can be a difficult proposition. Patients with cardiomyopathy and reduced LVEF frequently have co-exiting arrhythmias, such as atrial fibrillation or premature ventricular contractions. Such heart rate irregularity also limits the ability to obtain diagnostic CCTA images. CCTA requires administration of iodinated contrast, which comes with increased risk of contrast nephropathy in patients with decreased renal function. Another consideration is the need for ionizing radiation with coronary CT angiography . Strategies to reduce the radiation dose antially . FinanciCardiac magnetic resonance imaging (CMR) is considered the gold standard for noninvasive estimation of cardiac volumes and assessment of left ventricular function . MultiplMRI has become the de facto standard for measuring cardiac chamber volumes, in particular those of the left ventricle. CMR is particularly useful in visualizing the right sided heart structures, which are often difficult to image using echocardiography and difficult to image with nuclear medicine studies due to overwhelming signal from the much thicker left ventricle. CMR has been validated in women receiving traztuzumab as part of a chemotherapeutic regimen, against both 2D and 3D echocardiography . Those pOne of the tremendous strengths of MRI is the ability to detect even minor myocardial injury with late gadolinium enhancement. Gadolinium contrast agents are typically not protein bound and diffuse freely into the interstitial space where interaction can occur with interstitial structures. This results in compartmentalization and differential washout kinetics. Gadolinium contrast agent remains in fibrosed, or scarred tissues, for a longer period of time than in healthy tissues. Gadolinium shortens T1 relaxation of surrounding tissue and enables identification and characterization of this tissue utilizing a variety of imaging pulse sequences. Late MR imaging (10-20 minutes following gadolinium administration) utilizing an inversion recovery sequence timed to null healthy myocardium produces bright, easily identifiable areas where myocardial scar is present. This late gadolinium enhancement produces different patterns of enhancement in various disease states that affect the myocardium. For example, cardiac MRI is a powerful imaging modality for the non-invasive diagnosis of myocarditis – an entity in which other imaging modalities often fail , 33. CarWithout exception, prognosis in chemotherapy-associated cardiotoxicity is determined by the presence and degree of cardiac dysfunction at presentation. Efficacy of specific therapy for heart failure associated with chemotherapy is not established, nor is the efficacy of prophylactic regimens. Treatment therefore falls to standard heart failure therapies, including beta adrenergic receptor blockade, modification of the renin-angiotensin-aldosterone pathway with angiotensin converting enzyme inhibitors or angiotensin receptor blocking agents, aldosterone antagonists and diuretics as appropriate . Managem3)). Prior to initiation of chemotherapy, baseline cardiovascular health examination should be undertaken, including assessment and management of hypertension, hyperlipidemia, coronary disease and optimization of the patient’s health status for primary prevention of cardiovascular disease. In patients who have known significant cardiovascular disease, such as coronary artery disease associated with left ventricular dysfunction (ischemic cardiomyopathy), valvular heart disease, congenital or other structural heart disease, or arrhythmia, we recommend evaluation by a board certified cardiologist prior to initiation of therapy. When planned chemotherapy is likely to involve an agent associated with significant cardiotoxicity, baseline assessment of left ventricular function and cardiac structure is warranted  should be considered . We would extend this recommendation to all chemotherapeutic agents known to cause long-term cardiac dysfunction. No concrete guideline has been published for many of the chemotherapeutic agents regarding a quantum of change in LV systolic function. For example, a reduction in LVEF to an absolute level <55% or a 10% decline in LVEF indicates deterioration of cardiac function as defined by the CREC . It is rWhen high dose chemotherapy is administered, we recommend evaluation with serial serum troponins immediately following and at 12, 24, 36 and 72h after the end of a each cycle of chemotherapy when feasible . A positive troponin assay (troponin I > 0.08 ng/dL) should trigger a referral to a cardiovascular specialist, as this may serve as a marker for future cardiac dysfunction and consideration should be given to dose reduction, change in regimen, or addition of cardioprotective agents. Follow up one month later with a second troponin assay is also warranted in those patients with early elevations in serum troponin, to further risk stratify those patients at risk for more severe long term LV dysfunction. Of course, after each dose of chemotherapy a clinical assessment is paramount to detect any clinical signs or symptoms resulting from underlying cardiovascular dysfunction. Presence of chest pain not easily attributable to a non-cardiac cause, dyspnea, edema, or other evidence of ischemia or congestive heart failure would trigger immediate re-evaluation by the cardiologist. As patient survival continues to improve in treatment of malignancy, long term toxicity becomes a larger issue. With accumulating evidence behind successful therapy of some cardiac toxicities following chemotherapy, early identification takes on increasing importance. Presently, no evidenced based guidelines exist to guide monitoring for cardiovascular toxicity both during and following the administration of chemotherapeutic agents. It is further important to avoid toxicity secondary to a monitoring strategy, which could itself have long term consequences, either in the form of organ dysfunction or induction of secondary malignancies. In this review we have presented several techniques for detection and monitoring for cardiotoxicity during and following chemotherapuetic administration, and suggest an algorithm to assist the clinician in early detection of cardiac toxicity.


Objective. There is a paucity of a biological large animal model of myocardial infarction (MI). We hypothesized that, using autologous-aggregated platelets, we could create an ovine model that was reproducible and more closely mimicked the pathophysiology of MI. Methods. Mepacrine stained autologous platelets from male sheep (n = 7) were used to create a myocardial infarction via catheter injection into the mid-left anterior descending (LAD) coronary artery. Serial daily serum troponin measurements were taken and tissue harvested on post-embolization day three. Immunofluorescence microscopy was used to detect the mepacrine-stained platelet-induced thrombus, and histology performed to identify three distinct myocardial  zones. Results. Serial serum troponin levels (μg/mL) measured 0.0 ± 0.0 at baseline and peaked at 297.4 ± 58.0 on post-embolization day 1, followed by 153.0 ± 38.8 on day 2 and 76.7 ± 19.8 on day 3. Staining confirmed distinct myocardial regions of inflammation and fibrosis as well as mepacrine-stained platelets as the cause of intravascular thrombosis. Conclusion. We report a reproducible, unique model of a biological myocardial infarction in a large animal model. This technique can be used to study acute, regional myocardial changes following a thrombotic injury. Myocardial infarction (MI) resulting from coronary arterial disease is the number one cause for mortality in the United States. It is estimated that roughly 785,000 people in the United States will have a new MI in 2012 with an additional 470,000 having a recurrent MI .Currently, there are several large animal models used to study myocardial infarction; however, they deviate significantly from the biological pathophysiology of human MI –6. In oun = 7). Strict adherence was kept to the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.All studies were conducted with approval by the Institutional Animal Care and Use Committee (IACUC) at Ohio State University (Study number: 2012A00000040). Adult male Dorsett sheep weighing between 50–70 kg were used for this study  consisting of 6.85 mM citric acid, trisodium salt in saline [μg/mL) at each time point .Serum was collected daily at baseline and at postprocedure day 1, 2, and 3 for troponin level assessment . A volumAll animals were sedated, and all attempts were made to minimize animal discomfort as previously described . A rightTo minimize potentially fatal arrhythmias and provide hemodynamic support during the peri-infarct period, intravenous inotropic (epinephrine at 0.25 mcg/kg/hr) and antiarrhythmic (lidocaine at 2 mg/hr) medications were used .The left carotid artery was surgically exposed, and an introducer sheath  was placed. Subsequently, under fluoroscopic guidance  a Wiseguide 8 French AL-1 guide catheter  was placed into the left main coronary artery. Five-20 cc of Omnipaque (iohexol) Injection Contrast  was used for preembolization verification of the coronary anatomy, and all images were digitally stored. A Bard, Tru-Trac 4 mm × 2 cm balloon catheter  was positioned in the mid-left anterior descending (LAD) coronary artery. A balloon catheter was inflated to 2–4 atmospheres using an Encore 26 inflation device  to temporarily occlude the LAD and to prevent reflux during the infusion. Aggregated platelets (1.5 mL) were infused through the balloon catheter guide wire lumen to infarct the LAD. Subsequently, 5 mL of nonheparanized saline was used to flush the catheter, and then the balloon was deflated after 30 seconds.Continuous electrocardiograms and arterial line hemodynamic monitoring was carried out with a postembolization angiogram verifying occlusion of the mid-LAD. The epinephrine and lidocaine drips were weaned over a period of twenty minutes. The incision was then closed, and the animal was allowed to recover.On post-embolization day 3, the sheep underwent a 5th intercostal space left thoracotomy, and a cardiectomy was performed . StandarAll measurements are expressed as mean ± standard error of the mean. A repeated measures analysis of variance (ANOVA) was used to compare the serial daily intragroup troponin-level trends following embolization. A retrospective power analysis was performed to evaluate the power of the study and verify the sample size. Calculations were performed by using IBM SPSS Statistics for Windows, Version 19.0 .μg/mL  noninfarcted zone (>3 cm from the region of infarct), (b) peri-ischemic border zone (defined as within 0.5–2.0 cm of the gross edge of ischemic tissue), and (c) the infarct zone are illustrated in Large animal models make it more challenging to provide a direct ischemic event in the myocardium without either a thoracotomy with direct ligation or embolization using synthetic, nonbiological beads . Indeed,Although the direct coronary artery ligation model is widely used in large animals, MI in humans is due to a thromboembolic event and not a direction ligation of a coronary artery with an accompanying surgical trauma. Other less invasive animal models  have more closely mimicked the human pathophysiologic process; however, the use of foreign materials, such as the polystyrene beads, can potentially stimulate an exaggerated inflammatory response making it a less than ideal model for study . Recent Our current, nonthoracotomy strategy of accomplishing myocardial infarction should enable us to more closely explore the cellular and molecular pathways underlying an acute MI. It is essential to improve our current preclinical models to gain a better understanding of the human pathophysiology. This approach is important in order to accurately develop a relevant pathophysiologic model for clinical therapeutic evaluations. Unfortunately, there currently is a paucity of a biologic large animal model of an acute MI. Mice models of myocardial ischemia and heart failure are most commonly employed due to cost efficiency and availability; however, these models do not necessarily translate into the human condition.Various different species of large animals  have been used to explore myocardial disease. Amongst the large animal models, the ovine model has been shown to more closely mimic human coronary arterial anatomy , 13. TheSheep, however, do have some significant variability in the distribution of their left circumflex artery, leading to significant variation in infarct sizes . Our groVarious studies have been performed to evaluate the importance of how different regions of the heart are affected by a myocardial infarction. After a localized infarction, there is an increase in regional remodeling strain as a result of increased myocardial apoptosis and regional contractile dysfunction . MultiplClinically, various studies have shown the importance of not only regional but also global cardiac changes that occur after a localized myocardial infarction, governed by local changes in blood flow as well as global changes in adjacent myocardium . The heaThere are limitations to this study. The ovine left coronary anatomy does have some variation; the different anatomical configurations include (1) origin of where left circumflex branches result in a short left main coronary artery, (2) complex angles amongst the left main coronary artery requiring longer procedure duration, and (3) high bifurcation to an LAD diagonal branch that provides significant blood flow to the left anteroseptal area of the heart . Our goal was to place the embolization catheter/balloon past the last prominent diagonal branch of the LAD to prevent occlusion of the branch and better localize the area of ischemia. However, the LAD diagonal variability results in a variation of the amount of myocardial ischemia resulted from the embolization. The previous model  used theThe ideal embolization model should address variations of LAD anatomy to provide consistent areas of occlusion following embolization. Thus, future studies should analyze regional versus global mRNA/protein expression amongst the different myocardial zones following an infraction. Possible therapeutic interventions, including regionally targeted anti-inflammatory, proangiogenic, and antiapoptotic measures, can be tested using this model without the added variability of surgical and/or nonbiological inflammatory insult. As we further test the hypotheses with this model, we move the field closer to an ideal model to study acute human myocardial infarction.Our unique, nonthoracotomy surgical model platform will enable investigators to identify regional as well as global changes that occur after an acute heart attack. These targeted myocardial zones will enable the identification of genetic and protein targets to prevent infarct expansion following an MI. It is our hope that this approach will help to mitigate maladaptive cardiac remodeling and stop the development of ischemic heart failure in future studies.


Despite the clinical importance of this method, it has rarely been applied in small animal models of cardiac disease. In order to identify perfusion delays in the infarcted rat heart, here we present a method in which a TIn vivo measurements of myocardial morphology, function, perfusion and viability were made at 2 and 8 days after infarction. Morphology and function were further assessed using cine-MRI at 42 days. The perfusion delay was larger in rat hearts that went on to develop greater functional impairment, demonstrating that first-pass CMR can be used as an early indicator of infarct severity. First-pass CMR at 2 and 8 days following infarction better predicted outcome than cardiac ejection fraction, end diastolic volume or end systolic volume.In isolated perfused rat hearts, contrast agent infusion gave uniform signal enhancement throughout the myocardium. Occlusion of the left anterior descending coronary artery significantly reduced the rate of signal enhancement in anterior regions of the heart, demonstrating that the first-pass method was sensitive to perfusion deficits. First-pass CMR provides a predictive measure of the severity of myocardial impairment caused by infarction in a rodent model of heart failure. In co disease -5. CMR o disease ,5-8. MR  disease -14.Scaling down imaging techniques to study the ever increasing number of small animal disease models has been a formidable challenge . The rat1 mapping [Small animal cine-MRI has identified increased left ventricular mass, end diastolic and end systolic volumes in the infarcted heart during progressive cardiac remodeling . Pharmoc mapping -23, but  mapping ,25, prob mapping .1 weighted MR image every cardiac cycle, both in the isolated perfused heart and in vivo. Perfusion delay and myocardial viability, morphology and function were measured in vivo at 2 and 8 days after infarction to compare with cardiac function measured in the same animals at 42 days.Here, we have developed a method to identify perfusion deficits in infarcted rat hearts during bolus infusion by acquiring a TFor ex vivo MRI studies of isolated, perfused hearts, control female Wistar rat hearts (n = 12) were isolated, perfused and imaged as described below. Hearts were then removed from the magnet, the coronary artery occluded, the heart repositioned and re-imaged (n = 8).in vivo MRI studies, baseline cine-MRI was performed prior to surgery. Female Wistar rats (n = 34) underwent myocardial infarction followed by in vivo first-pass imaging, cine- and LGE-CMR at 2 and 8 days. Problems with i.v. infusions, owing to unsuccessful tail vein cannulation, movement of cannulae during positioning of rats within the magnet and blood clots or air bubbles in the drug line, meant that first-pass imaging could not be performed on all 34 rats at each time point . After 9 days, 7 of the rats that were imaged at 2 and 8 days were sacrificed; hearts were isolated, perfused and imaged ex vivo. The remaining 27 rats (14 and 20 of which had had first-pass imaging at 2 and 8 days respectively) underwent cine-MRI at 42 days. The University of Oxford Animal Ethics Review Committees and the Home Office  approved all procedures.For 2/5% CO2 and not re-circulated, to avoid contrast agent accumulation. A balloon connected to a pressure transducer was placed in the left ventricular (LV) cavity, inflated to an end diastolic pressure of 4 mmHg and used to measure cardiac function. The heart was placed in a 20 mm NMR tube and lowered into the centre of a vertical-bore, 11.7 T MR magnet  with a 20 mm 1H birdcage coil  and a Bruker console  running Paravision 2.1.1. Perfusion was then switched to a constant flow of 15-20 ml/min, based on each heart's coronary flow at 85 mmHg.Hearts were excised from control (n = 12) or infarcted (n = 7) rats, arrested in ice-cold Krebs-Henseleit buffer and attached to a cannula by the ascending aorta. Hearts were perfused at 85 mmHg with filtered Krebs-Henseleit buffer containing 11 mM glucose and 1.8 mM pyruvate. Buffer was maintained at 37°C and pH 7.4, aerated with 95% O1 weighted fast gradient echo sequence that acquired one image every 128 ms . It was determined that rapid image acquisition was preferential to greater spatial resolution as this allowed more images to be acquired during the first pass of contrast agent, gave greater signal to noise and reduced motion artifacts. A bolus of 25 μl of 0.5 mmol/ml Gd-DTPA-BMA  was rapidly infused after approximately 10 of the 128 images were acquired. First-pass imaging was repeated during multiple bolus infusions to cover the entire LV. Control hearts were then removed from the magnet, the LAD was permanently occluded using a 5-0 silk suture (successful in 8 hearts) and first-pass imaging was repeated during multiple bolus infusions to cover the entire LV. Saturated gradient echo images were also acquired to determine whether LGE could be detected in the infarcted, perfused heart.First-pass perfusion imaging was performed to cover the entire LV with repeated acquisitions using a T2, intubated, and a thoracotomy was performed. The pericardium was removed and the heart was infarcted by ligation of the left anterior descending coronary artery (LAD), approximately 2 mm from the origin, using a 5-0 proline suture [Rats (n = 34) were anesthetized with 2.5% isoflurane in Oe suture .2 and positioned supine in a purpose-built cradle. ECG electrodes were inserted into the forepaws, a respiration loop was taped across the chest and heart and respiration signals were monitored using a custom-built physiological motion gating device [Rats were anesthetized with 2.5% isoflurane in Og device . The craex vivo data, was ten times greater than that used in ex vivo experiments as in vivo cardiac output (75-100 ml/min) was 5 times greater than ex vivo perfusion rate (15 - 20 ml/min) and infusion time was 2 seconds in vivo and less than 1 second ex vivoFirst-pass CMR was performed on a single short axis slice, which encompassed the papillary muscles, using a fast gradient echo sequence that acquired one image per heart beat . The flip angle was adjusted to null signal in the myocardium before bolus infusion. A bolus of 0.5 mg/kg Gd in 200-270 μl saline was infused via the tail vein in 2 seconds during image acquisition. This volume, derived from et al [in vivo imaging protocol was performed in approximately 60 minutes.Cardiac cine-MRI was performed 10 to 25 min after Gd infusion as described . A stacket al . The entex vivo perfusion measurements, it was possible to measure the rate of contrast inflow and efflux from the gradient of the signal intensity/time curve. The area of reduced perfusion on the stack of ex vivo images was identified as myocardium with signal intensity greater than two standard deviations below that of remote myocardium.Image analysis was performed by an operator blinded to the surgical procedure performed on the rats using ImageJ . Left ventricular volumes and ejection fractions were calculated from the stack of cine images as described . To deteIn vivo LGE-MR images were thresholded to two standard deviations above the mean signal intensity from remote tissue. The volume and perimeter  of the hyperenhanced region was traced manually and expressed as a percentage of total LV volume or perimeter.P < 0.05 using unpaired Student t-tests or ANOVAs for repeated measures. Dependence between two measures was assessed using Pearson's Correlations.Results are shown as means ± standard errors. Differences were considered significant at Repeated imaging of bolus injections of Gd were performed to determine the contrast agent infusion volume and duration that resulted in maximal contrast within perfused control rat hearts. At a buffer flow rate of 15 ml/min, a rapid (approximately 1 second) injection of 25 μl of 0.5 mmol/ml Gd, directly proximal to the aorta, led to uniform enhancement throughout the myocardium Figure , with tiPerfused hearts were then removed from the magnet and the LAD occluded (successful occlusion in 8 of 12 hearts). Areas of low perfusion were identified below the occluded LAD as non-enhanced regions on MR images acquired during the Gd bolus infusion Figure . PerfusiCine-MRI measurements of cardiac morphology and function were made serially on rats prior to and at 2, 8 and 42 days after infarction Table . Left veInfusion of Gd initially reduced signal in the LV cavity owing to T1 and T2 shortening of blood from the high concentration of contrast agent Figure . This maLGE-CMR was performed 10-25 min after first-pass imaging. Hyperenhancement was present in 18 ± 2% of the LV volume and 19 ± 2% of LV endocardial perimeter at 2 days post infarction, and 11 ± 1% of the LV volume and 16 ± 2% of LV endocardial perimeter at 8 days post infarction Figure .p < 0.01; Figure p < 0.01).For the sub-group of infarcted rats (n = 14) in which tail vein canulation was successful at both time points, first-pass CMR and LGE-CMR were performed at both 2 and 8 days post infarction. Perfusion delay (measured using first-pass CMR) and LGE-CMR endocardial scar perimeter were unchanged from 2 to 8 days  and ejection fractions  measured at 42 days  and ejection fractions  measured at 42 days  and EF  at 42 days. Again, these correlations were stronger than those between LGE-CMR, ESV and EF at 8 days and the resulting ejection fractions and end systolic volumes measured at 42 days (data not shown).Perfusion delays measured at 2 days post infarction correlated with left ventricular end systolic volumes . The gradient of signal intensity increase was significantly lower in the infarcted and peri infarcted regions compared with remote tissue , while the rate of Gd clearance was significantly lower in infarcted regions compared with remote . These experiments also indicated that the volume of reduced perfusion measured ex vivo matched the volume of LGE measured in vivo  having poor prognosis . MR imag1 mapping can provide quantitative measurement of blood flow post infarction in rats and mice [82Rb or H215O, limit the application of this technology, especially when applied to small animals [Several methods have been used to assess myocardial perfusion in small animal models. Arterial spin labelling and Tand mice -23. Howe animals -13,30,31We initially developed and optimised the first-pass method using isolated perfused rat hearts. This preparation permitted repeated contrast infusions in the same heart so that Gd bolus volume, concentration and infusion time could be optimised in a controlled environment. Repeated infusions indicated good reproducibility and uniform enhancement in anterior, lateral and inferior myocardial regions. To determine the sensitivity of the first-pass technique to regional perfusion deficits the LAD coronary artery was occluded and first-pass imaging was repeated. Signal intensity was measured in regions of interest placed in infarcted, peri-infarcted and remote tissue of all 128 images acquired during bolus infusion. Two methods were used to quantify regional perfusion changes. Firstly, perfusion delay was calculated as the time delay, in seconds, between 90% max enhancement in infarcted regions compared with remote regions. Secondly, in ex vivo perfused hearts it was possible to assess contrast influx rate from the linear portion of the positive gradient of the signal intensity/time curve and contrast efflux rate from the signal intensity/time curve 10-15 seconds after infusion. As both of these analysis methods relate changes in infarcted regions with those of remote regions of the same infusion any effects of slight differences in bolus transit time and volume can be reduced, providing more reproducible data.1 weighting and temporal and spatial resolution to permit in vivo measurement of contrast inflow into the myocardium. The requirement for a rapid imaging sequence that could acquire an image every heart beat favoured a fast gradient echo acquisition rather than the more traditional inversion recovery sequence. The fast gradient echo acquisition resulted in signal saturation within the myocardium prior to contrast arrival, but did not null signal in the blood pool due to the rapid influx. Contrast transit through the ventricular cavities reduced signal intensity owing to the susceptibility effects of high Gd concentration at 11.7 T. Importantly the Gd bolus resulted in signal enhancement within the perfused myocardial tissue. As with the isolated perfused heart experiments, signal intensity was measured in regions of interest placed in infarcted, peri-infarcted and remote tissue of all 128 images acquired during bolus infusion and perfusion delay was calculated as the time delay in seconds between 90% max enhancement in infarcted regions compared with remote regions. Perfusion delay in the infarcted regions was significantly longer than in remote tissue. Owing to the need for acquisition of high temporally resolved images, the in vivo spatial resolution of the first-pass technique is limited. Although regions of interest could be selected within the infarct territory, it was not possible to accurately assess the area of the perfusion deficit. This is augmented in the thinned scar tissue of the chronically infarcted heart and can make delineation of the endocardial border problematic. A further limitation of the method is that it cannot be performed at multiple slice positions during a single Gd bolus, while repeated bolus imaging is complicated by LGE in infarcted regions.The first-pass imaging method had sufficient TThe severity of perfusion delay and extent of delayed enhancement measured at 2 and 8 days strongly correlated with cardiac function measured in the same rats 42 days after infarction. These correlations were stronger than those between ejection fraction and end systolic volume measured at 2 or 8 days and ejection fraction or end systolic volume at 42 days. Acutely after infarction, myocardial stunning, edema, and elevated catecholamine levels can strongly influence EF and ESV, masking the extent of systolic dysfunction. A combination of these factors, coupled with the variability of infarct size typically induced by experimental myocardial infarction, makes acute measurement of EF and ESV a poor early predictor of outcome and suggests that the common practice of dividing infarcted animals into experimental groups based on EF measured made principle by echocardiography in the first week post infarction can lead to wide variability in extent of functional impairment between groups. The first-pass and LGE-CMR techniques presented here gave better predictors of outcome cine-MRI, provided a more accurate assessment of myocardial viability acutely after infarction and may offer a useful baseline measure of infarct severity prior to administration of the therapeutic agent.x vivo first-pass imaging was performed on isolated, perfused infarcted rat hearts that had undergone in vivo imaging at 2 and 8 days post infarction. In vivo and ex vivo measurements of perfusion delay correlated, as did in vivo LGE-CMR volume and ex vivo low perfusion volume and Gd clearance time. This supports the hypothesis that LGE-CMR is due to reduced washout and hence greater retention of Gd in infarcted regions [E regions .The volume of LGE significantly decreased from 2 days to 8 days post infarction, and was unquantifiable at 42 days. Similar results were reported in canine models  and in tin vivo whether the graft is incorporated into the host's vasculature. First-pass CMR may be able to detect contrast agent inflow into the engineered tissue and determine successful integration.The resolution of the first-pass method may be improved through parallel imaging using multi channel phase array coils and accelerated image acquisitions. Schneider et al recently demonstrated the feasibility of using parallel imaging to achieve threefold acceleration of cine image acquisition in mice . By usinIn summary, we have presented a novel, simple and useful MR method for identification of under-perfused tissue in the infarcted rat heart and demonstrate the high prognostic value of the technique compared with other non-invasive measures of cardiac function and viability. This method is a useful tool for assessing the severity of myocardial ischemia acutely after infarction and could provide important data on treatment strategies designed to revascularise and regenerate the infarcted heart.LGE-CMR: late gadolinium enhancement cardiac magnetic resonance; EF: ejection fraction; EDV: end diastolic volume; ESV: end systolic volume; FLASH: fast low angle shot; Gd-DTPA: gadolinium diethylenetriaminepentaacetate; LAD: left anterior descending coronary artery; LV: left ventricle; MVO: microvascular obstruction; PD: pefusion delay.The authors declare that they have no competing interests.DJS conceived and designed the study, performed all MRI and analysis, and drafted the manuscript; CAC performed all surgical procedures and assisted with MRI; SJM and MAC assisted with perfused heart experiments, DJT assisted with MRI; KC assisted with study design, manuscript preparation and funding. All authors read and approved the final manuscripta) Plot showing similarity in percent volume of LGE-MRI in slices from base to apex measured in vivo 8 days post infarction, and percent volume of myocardium with low perfusion measured from base to apex measured using first-pass MRI of isolated, perfused rat hearts 9 days post infarction: (b) Correlation between LGE-MRI volumes measured in vivo and low perfusion volumes measured using first-pass MRI in the same slice in isolated, perfused hearts (R = 0.80. P < 0.01)(.Click here for file


Several strategies can be applied for the prevention and management of anesthesia-related hypoxemia. The aim of our study was to investigate the cardiovascular effects of a specific recruitment maneuver (RM) used for the management of intraoperative hypoxemia.2/FiO2 <200), were enrolled in our study. For the management of hypoxemia a total of 67 RMs have been applied, which consisted of a manual increase of the airway pressure to 40 cmH2O. This rise has been maintained for 10 seconds and was followed by an increase of positive end-expiratory pressure from 5 to 10 cmH2O. Before RM application an oesophageal Doppler monitor probe was inserted into the patients for measuring stroke volume (SV), cardiac output (CO), peak velocity (PV) and flow corrected time (FTc). Standard monitoring also included ECG, IBP, ETCO2 and SpO2. Heart rate (HR), systemic arterial pressure (SAP), SV, CO, PV and FTc were recorded directly before, during, right after and 5 minutes after RM application (T1 to T4). Kolmogorov-Smirnoff was used to test normal distribution of data and ANOVA was used for the statistical analysis. P <0.05 was considered statistically significant.Forty-nine patients  of mean age 57.4 ± 9.9 years, mean weight 80.2 ± 13.6 kg and ASA-PS classification I to IV , undergoing general surgery procedures, who developed intraoperative hypoxemia (PaOHR, SAP, SV, CO, PV and FTc showed a statistically significant decrease during and right after RM compared with the baseline values but they were gradually restored to control values after RM discontinuation Table .According to our results, RM application causes a profound impairment of the cardiovascular system. This can be attributed to the increase of the airway pressures, which results in preload decrease and afterload increase of the right ventricle and cardiac contractility attenuation. Nevertheless, these effects are transient and reversible and RM application is a safe technique for the management of intraoperative hypoxemia, provided that adequate cardiac preload is ensured and the anesthesiologist is alert to discontinue the RM if it exceeds cardiovascular reserves.


To evaluate the role of diffuse myocardial fibrosis (DMF) in familial Dilated Cardiomyopathy (fDCM) using Equilibrium Contrast-CMR (EQ-CMR).Post mortem/biopsy studies have shown that DMF occurs in DCM, but its clinical significance remains largely unknown as its assessment requires invasive biopsy. EQ-CMR is a recently described technique that permits the non-invasive and accurate assessment of DMF by measuring the myocardial contrast volume of distribution (Vd(m)) at equilibrium contrast .Using international diagnostic guidelines we identified 28 patients with fDCM . This cohort excluded the most severe cases of fDCM due to the high prevalence of permanent pacemakers or ICDs.The Vd(m) (a measure of DMF) was compared to that obtained in healthy volunteers  and also to other indexed CMR parameters, including left atrial area and echocardiographic parameters of diastolic function (tissue doppler and strain imaging).fDCM patients had increased LV size , worse ejection fraction , increased indexed left atrial area (LAAi)  when compared to healthy volunteers. Significantly impaired diastolic function was detected in 14% of fDCM patients. No patients had worse than mild mitral regurgitation.The Vd(m) in patients was significantly greater than that of healthy volunteers  . Vd(m) correlated with LAAi (fig 2)  and EF , but was independent of indexed LV diastolic volume, mass and echocardiographic derived parameters of diastolic function.On univariate analysis, LAAi was predicted by both Vd(m) (r2= 0.44) and E/Ea (r2= 0.31), which on multivariate analysis were independent with Vd(m) being the strongest predictor.EQ-CMR can reliably and non-invasively measure increased Vd(m), reflecting DMF even in patients with mild fDCM. Diffuse myocardial fibrosis in this tightly defined fDCM cohort correlates with known prognostic variables, particularly LA size and EF. For LA size, DMF is independent of diastolic function and the most important predictor. As such, these data suggest EQ-CMR is measuring a key disease parameter. Further study is recommended.


Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by recurrent coma, ventricular tachycardias and the replacement of the myocardium with fatty and fibrous tissue. We described a 42-year-old female patient without clinical arrhythmias which was diagnosed as ARVC by magnetic resonance imaging (MRI), but the transvenous endomyocardial biopsy was not specific. The patient received heart transplantation due to her refractory heart failure and the pathology of explanted heart demonstrated typical replacement of fatty and fibrous tissue and piles of infiltrated lymphocytes in myocardial tissue. It is concluded that ARVC might not have any arrhythmias and inflammatory process may be involved in the mechanism of ARVC.http://www.diagnosticpathology.diagnomx.eu/vs/6573514507145351The virtual slide(s) for this article can be found here:  Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias . It invoA 42-year-old woman presented with severe abdominal distension and shortness of breath without syncope and chest pain. The patient had class IV right cardiac insufficiency by New York Heart Association (NYHA) classification. No previous similar medical history was found in her family. On physical examination, her blood pressure was 122/72 mmHg. The skin and mucosae was stained mildly yellow. She had obvious distention of jugular vein. Neither moist nor dry rale can be auscultated in her lungs. Heart rate was 98 ~ 100 bpm. 2/6 ~ 3/6 systolic cardiac murmurs can be auscultated at tricuspid valve. Her liver can be palpated 3.0 cm lower under right costal margin and 5.0 cm lower under the xiphoid process. She had positive signs of ascites with moderate to severe pitting edema at lower extremities. The total bilirubin level was 38.4umol/L. . The anti-myocardial antibody tests showed negative with ANT and β1 but positive with M2 and MHC. The anti-Cox-IgM and anti-CMV-IgM tests were negative but EVs-RNA was positive. Her chest X-ray showed mild increase of transverse cardiac diameter. The left cardiac border protruded left mildly (FigureARVC is a disease pathologically characterized by fibrofatty replacement of the RV myocardium. A broad range of symptoms and signs may occur including palpitations, fatigue, syncope, chest pain and all kinds of atrial and rapid ventricular arrhythmias, especially recurrent episodes of ventricular tachycardias. Few patients presented the chronic congestive cardiac failure as chief complaint which is often confused with symptoms of mildly dilated cardiomyopathy . The cliThe etiology of ARVC is still unclear. Bowles et al found that cardiotropic viruses are more frequently identified in patients with ARVC and have been claimed to support an infective etiology of this disease . But theTransplantation indications for ARVC have not been defined. In some refractory congestive heart failure, cardiac transplantation is the only therapeutic option -20. Our In conclusion, ARVC without arrhythmias is rare and easily misdiagnosed. Cardiac MRI has become a non-invasive imaging tool in diagnosis of ARVC with high sensitivity and specificity. Inflammatory process may be involved in the mechanism of ARVC.Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.JW collected the patient’s clinical information and wrote this manuscript. LX conducted the MRI interpretation and drafted the related parts in the article. XC conducted the pathology interpretation and drafted the related parts in the article. JT and DWW revised the article and were in charge of the patient. All authors read and approved the final manuscript.


Coarctation is a common cardiovascular lesion accounting for 5 - 7% of all congenital heart disease. Without appropriate treatment complications are common and up to 90% of patients with uncorrected coarctation die by the age of 60.After repair close follow-up of patients is recommended. Recognised complications may include residual or recurrent coarctation and aneurysm formation. Follow up of associated aortic valve disease is also required.MRI is the preferred imaging modality for coarctation repairs as it provides anatomical and functional information without radiation exposure. It may also aid planning for further intervention or surgical treatment where necessary.Available sequences;Cine images- Steady State Free Precession (SSFP) or Gradient Recalled Echo (GRE) sequences, providing anatomical and functional information.Black Blood Fast Spin Echo (FSE) provides good visualization of the vessel wall and is less susceptible to metal artefact and is therefore particularly useful following stenting.Magnetic Resonance Angiography (MRA) either Contrast Enhanced or Free- breathing ECG triggered, navigator-gated 3D segmented SSFP. Both provide a 3D volume of data. This may be reformatted to any plane.Phase Contrast imaging allows for assessment of blood flow and further physiological evaluation.In our dedicated Cardiac MR (CMR) unit, we have retrospectively evaluated studies from the past 6 years, where patients have had coarctation repair. With particular emphasis on the sequences used in relation to the type of repair. We have also looked at associated features of the aortic valve and left ventricle.We will present a comprehensive imaging guide, highlighting the benefits and deficiencies of the MR sequences used in coarctation repairs, including common complications.Key learning points;Black Blood (FSE) and GRE are less susceptible to metal artefact therefore improve visualization around the stent.CE-MRA or Navigator SSFP may be particularly useful in visualising aneurysm formation or extra cardiac conduits.Cardiac MR can provide excellent anatomical and functional information about coarctation repairs, providing imaging strategies are related to the type of repair done.No funding.


We measured extracellular volume fraction (Ve) from pre- and post-contrast T1 maps of the left ventricle in 13 patients with systemic sclerosis (SSc) and 13 age-matched controls. SSc patients and controls were similar with regard to LV and RV mass, volumes, and function. However, Ve was significantly higher in SSc patients than in controls, even when patients with visible late gadolinium enhancement were excluded. Ve correlated with SSc severity as measured by the modified Rodnan Skin Score. Ve may be valuable for detection of myocardial involvement in SSc, even when conventional CMR appears normal.Primary cardiac involvement is common in systemic sclerosis (SSc) and responsible for 25% of deaths. Myocardial extracellular volume fraction (Ve), derived from cardiac magnetic resonance (CMR) T1 mapping of the myocardium, has been shown to quantify diffuse myocardial fibrosis (DMF) - but its utility in SSc has not been studied. We hypothesized that subjects with SSc have a higher Ve compared to controls and that patients with worse SSc severity have higher Ve.CMR was performed in 13 SSc patients (5 diffuse and 8 limited cutaneous) and 13 age-matched controls. Cine, pre- and post- contrast T1 mapping, and late gadolinium enhanced (LGE) imaging was performed. LV mass index (LVMi), LV end-diastolic volume index (LVEDVi), LV ejection fraction (EF), RV mass index (RVMi), RV end-diastolic volume index (RVEDVi), RV ejection fraction (RVEF) and LGE as a percent of the LV (LGE%) were quantified (Medis QMass MR 7.2). Ve was calculated as Ve = [ΔR1myocardium/ΔR1bloodpool × p × (1 - hematocrit)] - Vp, where R1 = 1/ T1, ΔR1 is post-contrast - precontrast R1, p is myocardial specific density (1.05), and Vp is myocardial plasma volume fraction (0.045). Skin involvement was quantified in all SSc patients using the Modified Rodnan Skin Score (mRSS) by clinicians blinded to all CMR data.LGE was visible in 3/13 SSc and 0/13 controls. Ve was significantly higher in SSc than controls, even when patients with visible LGE were excluded (Table This is the first study to demonstrate the utility of CMR T1 mapping for identification of diffuse myocardial fibrosis in SSc. Extracellular volume fraction measured by CMR correlates with SSc severity measured by mRSS. Ve identifies diffuse myocardial fibrosis in SSc patients, even in the absence of LGE. Given the high mortality associated with clinically symptomatic myocardial involvement in SSc, this technique may be valuable for detection even when conventional CMR appears normal.None.


Cardiac MRI (CMR) is increasingly being used clinically to assess the regional thickness of the compacted and trabeculated layers of the left ventricle (LV) in patients with suspected non-compaction. However, there is no consensus on whether the short or longitudinal axis view is preferred. We sought to assess the compacted and trabeculated layers in a young ventricular dysrhythmia population with age matched controls and to compare the measurements derived from both the short axis and longitudinal views.The study consisted of 91 patients aged 20 to 49 years with ventricular dysrhythmia (VT) and 23 age-matched normal subjects. Regional wall thickness was assessed in short axis CMR cine views using a basal, mid and apical slice as well as in longitudinal views using the 2, 3, and 4 chamber view. The images were analyzed at end-diastole where the compacted layer was measured following the standardized 16-segment model. The apical segments were chosen 2 cm from the most apical portion of the LV for both short and longitudinal views. Within each wall segment, the most prominent trabeculation was measured, and the ratio of the trabeculated to compacted layer was compared between the VT group and controls in both views.The mean age was 38 years and 48 (42%) were men. In the VT group, 31 had premature ventricular contractions and 60 had ventricular tachycardia. VT patients were associated with larger LV end-diastolic volumes , larger LV mass (58 g/m2 vs. 49.9 g/m2 p=0.001), and lower LV ejection fraction (50% vs. 60% p=0.015) as compared to the control group, respectively. Using the short axis view, the prevalence of trabeculated to compacted layer ratios ≥ 2.0, ≥ 2.1, ≥ 2.2 and ≥ 2.3 were 18.4%, 15.2%, 9.2% and 8.7% in the VT group, respectively while the prevalence in the control group was 13% for a ratio ≥ 2.0 with no segments ≥ 2.1. Using the same ratio cut points for the longitudinal view, the prevalence was 39.1%, 32.6%, 27.2% and 16.3% in the VT group and 43%, 39.1%, 21.7%, and 13% in controls, respectively.In this young cohort, the trabeculated to compacted ratio ≥ 2.1 is only present in patients with ventricular dysrhythmias and not seen in normal controls using short axis planes, suggesting that increased thickness of the trabeculated layer in young subjects may be associated with the risk of ventricular dysrhythmia. However, the ratio ≥ 2.3 is equally prevalent in both groups using longitudinal planes. Our findings suggest that the short axis view may be more discriminatory then the longitudinal view in identifying normal subjects. More importantly, there is a clear need to standardize the assessment of the trabeculated to compacted layer ratio in clinical practice.None


Non-contrast T1-mapping using the novel ShMOLLI (Shortened Modified Look-Locker Inversion Recovery) sequence detects acute myocardial edema with high diagnostic accuracy.T2-weighted cardiovascular magnetic resonance (CMR) is commonly used to detect myocardial edema. T1-mapping is also sensitive to changes in free water content and is quantitative, obviating the need for a presumed normal reference region to detect changes within affected myocardium. We hypothesized that T1-mapping using the novel sequence Shortened Modified Look-Locker Inversion Recovery (ShMOLLI) would have a higher diagnostic performance in detecting acute myocardial edema than dark-blood (STIR) and bright-blood (ACUT2E) T2-weighted CMR.We investigated 18 healthy controls (age 53 ± 14 years) and 19 patients (age 61 ± 10 years) presenting with acute myocardial stunning without infarction. Stunning was defined as acute cardiac symptoms associated with positive biomarkers for injury and acute wall motion abnormalities, but without late gadolinium enhancement (LGE). CMR performed within 9 days included cine, ShMOLLI T1-mapping, STIR, ACUT2E and LGE imaging. We analyzed wall motion, absolute T1 values and T2 signal intensity (SI) relative to both skeletal muscle  and remote myocardium (T2 SI myo:remote).Ten patients had Takotsubo cardiomyopathy and 9 had regional stunning as a final diagnosis by CMR. All had positive troponin levels . No patients had significant LGE. There was good correlation between mean T1 values and mean T2 SI using skeletal muscle as a reference: r=0.79 for STIR  and the University of Oxford Clarendon Fund Scholarship. Dr. Robin Choudhury is a Wellcome Trust Senior Research Fellow in Clinical Science. Stefan Neubauer and Robin Choudhury acknowledge support from the British Heart Foundation Centre of Research Excellence, Oxford.


Over the last decade noninvasive ventilation (NIV) gained the dignity of first-line intervention for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) in the ICU. Its great interest is based on a lower complications rate compared with traditional invasive ventilation. However, the NIV application, although less invasive, cannot ignore its hemodynamic effect over the patient. This study evaluates the NIV effects on the left ventricle in terms of systolic and diastolic function through trans-thoracic echocardiography (TTE). We also try to obtain a preload value index equivalent of flow time corrected (FTc).2O of PEEP and 5 to 7 cmH2O of pressure support ventilation. During NIV for a better patient compliance a continuous i.v. infusion of remifentanil was used (range 0.03 to 0.05 μg/kg/minute). At baseline (T0 = before NIV) and after 30 minutes of NIV (T1), the following data were recorded: respiratory - RR, SaO2%, PaO2, PaCO2, pH, BE, and HCO3-; and cardiac - heart rate (HR), arterial blood pressure , diastolic and systolic volume , ejection fraction (EF), stroke volume (SV), velocity time integral (VTI), FTc, E wave, deceleration time (Dt), A wave, ventricular flow propagation velocity (Vp).Thirteen patients admitted to our ICU with ALI/ARDS underwent TTE before and during NIV. NIV was set as a 1 hour cycle with 5 to 7 cmHP < 0.05*). PaO2 (94 to 123 mmHg*), SaO2 (87 to 97%*) and PaO2/FiO2, RR (37 to 28/minute*). At T0, EF was >55% in seven patients and <55% in six patients. In the group with EF <55% (T0) the EF increased at T1 (42 to 52%*). Dt significantly increased from T0 to T1 (182 to 198 cm/second*). No significant changes were observed in VTI, E/A ratio, Vp, and E/Vp ratio, from T0 to T1.From T0 to T1 the following changes with Wilcoxon matched pairs test were statistically significant (Our study suggests that NIV improves cardiac function in patients with reduced EF, positioning the patients to a more favorable point of the Frank Starling curve. In these patients we also showed an increase in FTc that seems to be affected by either preload or afterload reduction.


This review highlights the importance of neural mechanisms capable of protecting the heart against lethal ischemia/reperfusion injury. Increased parasympathetic  activity limits myocardial infarction, and recent data suggest that activation of autonomic reflex pathways contributes to powerful innate mechanisms of cardioprotection underlying the remote ischemic conditioning phenomena. Ischemic heart disease remains the most common cause of morbidity and mortality in Western societies, although the relative mortality attributable to it has decreased significantly in the last decade. The heart is highly vulnerable to oxygen deprivation, and occlusion of a major coronary artery is followed by myocardial metabolic and functional changes that develop rapidly after cessation of the blood flow. Restitution of the blood supply to an ischemic area is crucial for tissue survival; however, it also results in a cascade of harmful events that lead to what is known as the myocardial reperfusion injury. Its manifestations include arrhythmias, contractile dysfunction, endothelial dysfunction, and lethal reperfusion damage of cardiomyocytes. Since the size of the myocardial infarction is the major determinant of the subsequent development of the congestive heart failure, novel therapeutic treatments are focusing on limiting the extent of myocardial ischemia/reperfusion injury. Animal experimentations demonstrated that the reduction of infarct size can be achieved either pharmacologically or via the recruitment of powerful innate mechanisms, which are highly effective in protecting myocardial tissue against lethal ischemia/reperfusion injury and include ischemic and remote ischemic pre- and postconditioning. Although none of the identified pharmacological strategies have been successfully translated to the clinical setting, promising results of recent trials in patients with acute myocardial infarction  give hopCardiac performance is controlled by the parasympathetic (inhibitory) and sympathetic (facilitatory) limbs of the autonomic nervous system. Sympathetic nerves innervate the sinoatrial and atrioventicular nodes, the atria, the ventricles, and the conducting tissue. Parasympathetic  efferent nerves are well known to control nodal tissues and atria, whereas the role of the parasympathetic innervation of the ventricles remains controversial. The majority of physiology textbooks teach that the vagal innervation of the ventricular system is sparse and that parasympathetic control of the ventricular contractility is insignificant. This view persists in both the scientific and educational literature, despite significant evidence obtained in various species (from rat to man) demonstrating the presence of choline acetyltransferase-positive nerve fibers, acetylcholinesterase enzyme, and muscarinic receptors in both the right and the left ventricles , 7230, 7The sensory innervation of the heart is provided by afferent neurones located in the nodose and the dorsal root ganglia. These neurones are responsible for sending information to the CNS, including brain stem areas involved in autonomic control, and their activation can trigger reflex changes in sympathetic and parasympathetic efferent outflows to the heart. Sensory neurones innervating the heart also have been identified in intrathoracic extracardiac ganglia and intrinsic cardiac ganglia  FIGURE . These sUnder resting conditions, the heart receives tonic influences from both sympathetic and parasympathetic efferent cardiac nerves, and it is generally believed that the control of the sympathetic and parasympathetic outflows to the heart is reciprocal in nature. The prevailing concept (conveyed by the physiology textbooks) of an autonomic balance postulates that activation of sympathetic or parasympathetic efferent limb is normally accompanied by inhibition of the other limb. This is certainly true for the operation of the baroreceptor reflex; however, there is evidence that some physiological responses may involve parallel co-activation of both sympathetic and parasympathetic drives to the heart . The importance of prompt reperfusion is defined by the axiom, “time is muscle and muscle is life” . HoweverMajor autonomic and sensory (afferent) innervations of the heart receive their own rich blood supply arising from extracardiac sources . HoweverActivation of cardiac afferents during ischemia/reperfusion leads to reflex changes in parasympathetic and sympathetic outflows to the heart. Observations in dogs revealed that “sympathetic” afferents are mainly distributed throughout the anterior and inferoposterior walls of the left ventricle and that their activation during ischemia in both locations leads to an increase in sympathetic drive, as evidenced by increases in renal sympathetic nerve discharge . In anotHuman data support the view that excitation of ventricular afferents is the predominant cause of general sympathetic activation, with similar increases in plasma norepinephrine observed in patients developing either anterior or inferior myocardial infarctions . In uncoAfferent fibers that when activated trigger vagally mediated responses appear to be located primarily in the inferoposterior walls of the left ventricle . Vagal e1a-adrenoceptor agonist methoxamine limits the infarct size in dogs subjected to regional ischemia and reperfusion  and acetylcholine released within the myocardium from sympathetic and parasympathetic efferent terminals may protect the myocytes against lethal ischemia/reperfusion injury. Stimulation of α-adrenoceptors under certain circumstances can result in cardioprotection. Intracoronary administration of αerfusion . Stimulait model .Potent cardioprotection could be established by a prototypical effector molecule of the parasympathetic nervous system: acetylcholine (ACh). In several studies, ACh was shown to be as potent as adenosine in protecting the myocardium against lethal ischemia/reperfusion injury , 64, 80.A number of studies have determined the extent of myocardial ischemia/reperfusion injury in conditions when neural control of the heart is experimentally altered. Electrical stimulation of the vagus nerve was found to be highly effective in limiting myocardial ischemia/reperfusion injury , 33. In 1-adrenoceptor blockade with prazosin and significantly reduced by β-adrenoceptor blockade with timolol  reduces the baseline activity of intrinsic sensory cardiac neurones and suppresses their activation triggered by ventricular ischemia and reperfusion . In a ra timolol . A more  timolol . Cardiop timolol .Paradoxically, if the myocardium is exposed to short, nonlethal ischemia-reperfusion episodes, it becomes “preconditioned.” After such ischemic preconditioning (IPc), the myocardium becomes more tolerant to subsequent, much longer periods of ischemia. In a landmark study using anesthetized dogs, Murry et al.  demonstrFurther experimental work has suggested that protective effects of IPc occur due to modulation of reperfusion injury, and consequently the idea suggesting that the preconditioning stimulus could only be effective when applied before ischemia was challenged . In the Importantly, the myocardium can also be protected by remote ischemic preconditioning (RPc), the phenomenon in which cycles of brief ischemia and reperfusion of an organ or tissue protect a remote organ or tissue against ischemia/reperfusion injury. Przyklenk et al.  first deThere is an ongoing debate on the mechanisms of how a “preconditioning stimulus” is relayed from the remote ischemic tissue/organ to the heart. Relay pathways of RPc-induced cardioprotection were suggested to involve humoral factor(s) produced during ischemia/reperfusion of the remote tissue and released into the systemic circulation , 68, 76,Gho et al.  demonstrIndeed, plasma dialysate obtained from patients receiving RPc stimulus protects the rabbit heart (Langendorff preparation) against ischemia/reperfusion injury . InteresIn an attempt to identify humoral factor(s) that mediate remote ischemic preconditioning, Lang et al.  performeThe results of our studies using a rat model of myocardial ischemia/reperfusion injury confirmed that RPc stimulus applied to the limbs  significantly reduces myocardial ischemia/reperfusion injury . It was Interestingly, strong cardioprotection is elicited when capsaicin is applied topically to stimulate sensory neurones innervating remote organ/tissue , 31, 61.Failure of remote ischemia/reperfusion to establish cardioprotection in conditions of bilateral cervical vagotomy or systemic muscarinic receptor blockade with atropine , 16, 48 Drosophila allatostatin receptor  was achieved by transducing them with a viral vector to express an inhibitory receptor . RPc carreceptor . These dreceptor , and thareceptor . These rIn conclusion, in this account, we have attempted to highlight the importance of neural mechanisms in protecting the heart against lethal myocardial ischemia/reperfusion injury. A large body of evidence demonstrates that the extent of myocardial infarction can be significantly reduced by experimentally induced changes in the activities of parasympathetic and sympathetic efferent fibers innervating the heart. Myocardial ischemia/reperfusion (via activation of cardiac afferents) and ischemia/reperfusion of tissues located remote from the heart (via activation of C-fiber afferents) can trigger distinct patterns of parasympathetic and sympathetic responses. The strength of these responses may be sufficient to establish cardioprotection, and it is conceivable that activation of these reflex pathways contribute to powerful innate mechanisms of cardioprotection underlying the (pre)conditioning phenomena. Promising results of clinical trials in patients with acute myocardial infarction  may lead


MYBPC3 encoding cardiac myosin binding protein C are common genetic cause of hereditary cardiac myopathies. An intronic 25-bp deletion in MYBPC3 at 3′ region is associated with dilated (DCM) and hypertrophic (HCM) cardiomyopathies in Southeast Asia. However, the frequency of MYBPC3 25 bp deletion and associated clinical presentation has not been established in an unrelated cohort of left ventricular dysfunction (LVD) secondary to coronary artery disease (CAD) patients.Mutations in MYBPC3 25 bp polymorphism on LVD in two cohorts of CAD patients.We sought to determine the role of MYBPC3 25 bp polymorphism was determined by polymerase chain reaction. Our results showed that carrier status of MYBPC3 25 bp deletion was associated with significant compromised left ventricle ejection fraction (LVEF ≤45) in CAD patients . To validate our results, we performed a replication study in additional 140 cases with similar clinical characteristics and results again confirmed consistent findings . Also, presence of the gene deletion did not have significant association in CAD patients with preserved ejection fraction (LVEF>45) .The study included 265 consecutive patients with angiographically confirmed CAD and 220 controls. MYBPC3 DW genotype and D allele was associated with compromised LVEF implying that genetic variants of MYBPC3 encoding mutant structural sarcomere protein could increase susceptibility to left ventricular dysfunction. Therefore, 25 bp deletion in MYBPC3 may represent a genetic marker for cardiac failure in CAD patients from Southeast Asia.The frequency of  Coronary artery disease (CAD) is defined as atherosclerotic blockageTNNI3),MYBPC3)Earlier genetic studies have correlated LVD with dilated cardiomyopathy (DCM).MYBPC3 result in disorganized sarcomeric structure, thus MYBPC3 has emerged as an important gene for increased risk of heart failure through cardiomyopathies (DCM and HCM).Myosin-binding protein C (MyBP-C) is a key constituent of cardiac muscle thick filaments, which by interacting with myosin,MYBPC3 at the 3′ region of the gene MYBPC3 has any role in LV dysfunction. To the best of our knowledge, it is the first study to report the association of 25 bp polymorphism of MYBPC3 with low left ventricular ejection fraction in CAD patients.A common polymorphic intronic deletion of 25-base- pair in Demographic and lipid profile of healthy subjects is shown in MYBPC3 gene deletion in controls were in accordance with Hardy-Weinberg equilibrium (p = 0.98). Considering the low allelic frequency allele, we also applied fisher exact test for conditional probability of heterozygous variants which was found to be p = 0.97.Distributions of genotypes of MYBPC3 25 bp polymorphism between CAD patients (both stages) and healthy controls. Our results suggested significant association of MYBPC3 gene deletion with CAD ; D allele p value  =  <0.001 [9.8 (3.5–27.6)] while no risk of DW genotype was observed in CAD patients with preserved ejection fraction : 403 bp and mutant [DW]: 378 bp) were analysed on 6% polyacrylamide gel. Ten percent of samples from patients and controls were sequenced to evaluate the quality of genotyping, which showed 100% concordance.Genomic DNA was isolated from peripheral blood leukocytes according to a standard salting out method. MYBPC3 25 bp deletion and significant risk factors of CAD were analyzed using binary logistic regression. Student t test was applied to find the significance for plasma cholesterol. Differences between groups stratified on the basis of genotypes were assessed using z proportional test. Overall we performed meta analysis by Stouffers method to combine the results of two cohorts (primary and replication) to calculate the overall z and p values. A two-tailed p-value of less than 0.05 was considered a statistical significant result. All statistical analyses were performed using SPSS software version 16.0 .Descriptive statistics were presented as mean and standard deviation (SD) for continuous measures while absolute value and percentages were used for categorical measures. The chi-square goodness of fit test was used for any deviation from Hardy Weinberg Equilibrium in controls and fisher exact test was applied as given by Emigh