Accumulating evidence indicates that myocardial fibrosis contributes to the pathogenesis of diastolic dysfunction. However, investigating this issue has long been hampered by lack of suitable methodology. We aimed to define the effect of fibrosis on left ventricular diastolic function, using cardiac magnetic resonance (CMR) and Doppler echocardiography.Ninety one eligible subjects undergoing cardiac structural and functional assessment with LGE-CMR and Doppler echocardiography were investigated. Left ventricular function, volumes, myocardial thickness, left atrial volume, wall motion score index (WMSI) and the extent of LGE were assessed using CMR. Mitral early diastolic peak (Ewave) and late peak (A-wave) velocities, E/A ratio, deceleration time (DT) of mitral early velocity, early diastolic mitral annulus peak velocity was measured by echocardiography, and ratio of transmitral diastolic peak velocity to the mitral annular diastolic peak velocity (E/E’) was calculated. Classification of diastolic function as normal, mild dysfunction (impaired relaxation), moderate dysfunction , and severe dysfunction (restrictive filling pattern) was performed according to standard criteria. The E/E ratio was used to estimate LV filling pressures.The majority (90%) of subjects with normal diastolic function exhibited no or minimal fibrosis . The prevalence of LGE positivity by diastolic filling pattern was 11.8% in impaired relaxation, 100% in pseudonormal, and 75% in restrictive filling (P<0.001). LGE score significantly and progressively increased with increasing severity of filling impairment, reaching 5  in patients with restrictive filling pattern (P<0.001). LGE was observed in 80% of patients with ischemic cardiomyopathy and 26.3% of patients with nonischemic cardiomyopathy, but only in 3.6% of patients with repaired tetralogy of Fallot and none of patients with simple congenital heart disease (P<0.001). LGE score progressively increased with increasing left ventricular filling pressure estimated by tissue Doppler imaging-derived E/E . However it did not have any significant correlation with other echocardiographic diastolic function indices, such as E velocity, A velocity, and DT. Multiple linear regression showed LGE score  and WMSI  to be positively predictive for E/E value.Severity of myocardial fibrosis by LGE significantly correlates with the degree of diastolic dysfunction in a broad range of cardiac conditions, and among diastolic echocardiographic indices E/E may provide more valuable insight to this severity. Noninvasive assessment of myocardial fibrosis may provide valuable insights into the pathophysiology of left ventricular diastolic function and therapeutic response.This project was not funded.


The survival rate of cancer patients has greatly increased over the last 20 years. However, to achieve this result, a considerable price has been paid in terms of the side effects associated with the intensive anticancer treatment. The most common adverse effect is cardiotoxicity which may compromise the clinical effectiveness of chemotherapy, affecting the patient's survival and quality of life independently of the oncological prognosis. There are 2 types of cardiac toxicities, type I which is more serious and result in permanent damage to the myocardium and type II which is usually reversible. Chemotherapies varies in their incidence of inducing cardiomyopathy, and the onset which may occur acutely (during or shortly after treatment), sub-acutely (within days or weeks after completion of chemotherapy) or chronically (weeks to months after drug administration). Cardiac events associated with chemotherapy may consist of mild blood pressure changes, thrombosis, Electrocardiographic (ECG) changes, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, cardiac failure (left ventricular failure), and congestive heart failure (CHF). The risk for such effects depends upon: cumulative dose, rate of drug administration, mediastinal radiation, advanced age, younger age, female gender, pre-existing heart disease and hypertension. Serial measurements of LVEF and fractional shortening are the most common indices monitored to assess left ventricular systolic function and cardiotoxicity. This can be achieved by 2-dimensional, M-mode and color Doppler echocardiographic examination; also Cardiac troponins as a biological marker for myocardial damage can be used for monitoring in patients received anthracyclines. Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) have been shown to slow the progression of left ventricular dysfunction in several different clinical settings, including anthracycline-induced cardiomyopathy. Carvedilol and probably with anti-oxidants like Probucol and vitamin E benefits also.Anthracyclines; Cardiomyopathy; Chemotherapy Chemothearpies are highly effective in treating most cancers, their use is limited by the potential for cardiotoxicity. All these drugs have a wide range of adverse effects the most serious one is cardiotoxicity, these severity of these effects are related to the chemotherapy regimens, patient populations and duration. The occurrence of clinical heart failure seems to be in the range of 1% to 5%, and asymptomatic decrease in left ventricular function is in the range of 5% to 20%. Toxicity can occur early (within 1 year) or late .Many trials address the role of ACE inhibitors and beta-blockers, effective therapies for established LVSD, in preventing chemotherapy-induced cardiotoxicity. In this article we discuss the types of the cardiomyopathy, diagnosis, prognosis, prevention and managements.The survival rate of cancer patients has greatly increased over the last 20 years. However, to achieve this result, a considerable price has been paid in terms of the side effects associated with the intensive anticancer treatment. Cardiotoxicity may compromise the clinical effectiveness of chemotherapy, affecting the patient's survival and quality of life independently of the oncological prognosis. As a result of the increasing number of long-term cancer survivors and of the tendency to use higher doses of cytotoxics and combined treatments with synergistic cardiotoxic effects, the magnitude of this problem is growing. Accordingly the onset of cardiac dysfunction, even if it is asymptomatic, not only negatively affects cancer patients' cardiac outcomes, but also seriously limits their therapeutic opportunities. There are 2 types of cardiac toxicities, type I which is more serious and result in permanent damage to the myocardium and type II which is usually reversible. Features and risk factors of both types summarised in As early as 1967, there were reports of heart failure in children treated with doxorubicin for leukemia; from that time concerns regarding chemotherapy starts. Aggressive and combination chemotherapy has achieved remission in most types of cancers. However, concerns for, or manifestations of, cardiac adverse events may result in discontinuation of or reluctance to use a particular agent at an effective dose. Cytostatic antibiotics of the anthracycline class have been clearly associated with cardiotoxicity. However, there are a number of other chemotherapy agents that cause cardiotoxicity and yet are not well recognized Cardiac events associated with chemotherapy vary in incidence and may occur acutely (during or shortly after treatment), sub-acutely (within days or weeks after completion of chemotherapy) or chronically (weeks to months after drug administration). They may also occur as late squeal, many years after the end of treatment. Cardiac events associated with chemotherapy may consist of mild blood pressure changes, thrombosis, Electrocardiographic (ECG) changes, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, cardiac failure (left ventricular failure), and congestive heart failure (CHF). The substantial limitations of using only changes in LVEF are compromised further by our knowledge that approximately half of all heart failure occurs in patients who maintain a normal LVEF; their overall cardiac outcomes are similar to those who exhibit a low LVEF [Cardiotoxicity may depend on the dose administered during each course or on the total cumulative dose, or may be completely independent of the dose like Anthracycline-induced cardiotoxicity which has been recognized for more than 20 years. It has been described as 3 distinct types of cardiotoxicity. Acute or sub-acute injury is a rare form of cardiotoxicity that may occur immediately after a single dose or a course of anthracycline therapy, with clinical manifestations occurring within a week of treatment. These may be in the form of transient electrophysiological abnormalities, a pericarditis, myocarditis syndrome or acute left ventricular failure. The electrophysiological abnormalities may present as nonspecific ST and T wave changes, T wave flattening, decreased QRS voltage and prolongation of QT interval. Sinus tachycardia is the most common rhythm disturbance. ECG changes may be seen in 20 to 30% of the patients [2 have shown to increase after-load or decrease contractility, or both, in 65% of patients with leukaemia up to 15 years after treatment with anthracyclines [Early onset chronic progressive cardiotoxicity: anthracyclines can also induce early onset progressive chronic cardiotoxicity resulting in cardiomyopathy. This is a more common and clinically important type of cardiotoxicity .Chronic cyclines . Late oncyclines . This cocyclines  or cardiThe cause of anthracycline-induced cardiotoxicity is probably multi-factorial. Free radicalmediated myocyte damage is one of the most thoroughly studied mechanisms by which anthracyclines have been proposed to cause cardiotoxicity . The myo2 body surface area, the incidence of CHF was found to be 0.14%. This increased to 7% at a dose of 550 mg/m2 and to 18% at a dose of 700 mg/m2 [2/a, Y is the likelihood of developing congestive heart failure, X equals to number of cycles of anthracycline-containg regimen administered, a equals to correction constant determined by cycle dose and the duration between the cycles, so if a patient receives 9 cycle of anthracycline in a dose of 50 mg/m2 every 21 days, so it will be Y= 81/16 X100, the Y will be equal to 5%, this is the risk of developing congestive heart failure [Some of the risk factors relating to early and late (but not acute) cardiotoxicity have been reported. These include cumulative dose, rate of drug administration, mediastinal radiation, advanced age, younger age, female gender, pre-existing heart disease and hypertension. A multivariate analysis of these factors based on histological evidence of anthracycline-induced cardiac damage concluded that higher rates of administration and previous cardiac irradiation were independent risk factors. At a cumulative total dose of < 400 mg/m2 and thereafter at 450 mg/m2 if they have no risk factors. If patients have known cardiovascular disease, prior radiation treatment to the chest, abnormal ECG changes or concomitant cardiotoxic chemotherapy, LVEF measurement should be repeated at 400 mg/m2 instead of 450 mg/m2. It should be monitored with each dose thereafter. Doxorubicin therapy should be stopped if there is a ≥ 10% absolute drop in the ejection fraction associated with a decrease in LVEF to ≤ 50% in patients with baseline LVEF ≥ 50%, and to ≤ 30% in patients with baseline LVEF < 50% but > 30% [Serial and post-therapy cardiac monitoring is necessary to reduce morbidity due to anthracycline-induced cardiotoxicity. Patients should be monitored for clinical signs of cardiomyopathy by physical examination, chest x-rays, ECG, echocardiogram, endomyocardial biopsy if feasible and radionuclide angiography before initiation of treatment and at periodic intervals during therapy. Physical examination alone may miss over 50% of cases of early and reversible chemotherapy-induced CHF . Acute Eut > 30% .Biomarkers such as B-type natriuretic peptide and troponins (I and T) are increasingly being used to stratify patients into higher and lower risk categories. This process is well established in the cardiology literature and recently has been reported in oncology patients. In fact, an elevated troponin during chemotherapy seems to correlate with increased risk for the development of cardiac toxicity . CardiacSome cardio-protective agents is used which associated with a decrease in cardiotoxicity and facilitates the use of higher cumulative doses of anthracyclines but it is beyond our article. Also Cardiotoxicity of anthracyclines can be minimized by using analogues that may be less cardiotoxic. Compounds such as epirubicin and idarubicin exhibited decreased cardiotoxicity in preclinical trials.The use of anti-oxidant agents or iron chelators finds their way in the prevention for cardiac toxicities. Probucol, vitamin E (as anti-oxidants) and carvedilol have shown promise in animal studies.Angiotensin-converting enzyme (ACE) inhibitors (ACEIs) have been shown to slow the progression of left ventricular dysfunction in several different clinical settings, including anthracycline-induced cardiomyopathy . FurtherAt the end, frequent monitoring and follow up for patients took anthracyclines with troponins and echocardiograms with early administration of carvedilol, enalapril and probably with anti-oxidants like Probucol and vitamin E will benefit.


In DMD subject groups, we showed that FWHM of the T2 histogram rose progressively with age and decreasing EF indicating that functional impairments could be associated with pre-existing abnormalities in tissue structure in young DMD patients. In this study we assessed the T2 distribution in DMD patients at two time points. We hypothesized that serial FWHM changes can be detected in individual DMD patients during a time when left ventricular ejection fraction (EF) changes are insignificant.Duchenne Muscular Dystrophy (DMD), a lethal X-linked skeletal and cardiac myopathy, affects 1/3500 males[1-2]. MRI studies have shown occult ventricular dysfunction and myocardial fibrosis in DMD patients. Previously we used the Full Width of Half Maximum 1 = 6 ms, TE2 = 34ms. A histogram of LV T2 distribution with bin size equal to 1 ms was constructed for each subject. The Full Width at Half Maximum (FWHM) was calculated after applying box car averaging. The FWHM was defined as the width of the histogram at half the maximum height.MRI Data of eighteen DMD patients obtained at two time points were analyzed  with a mean time of 2.3 years between the studies. Spin echo images of the left ventricle in the short axis plane were acquired using a black blood dual spin echo method. Imaging parameters were: Slice thickness = 5mm, in plane resolution = 1.4mm×1.4mm, echo train length = 5, Echo times: TEFHWM increased in all but two patients (89%). The average increase in FWHM was 6.8 ± 3.9 ms. The mean T2 increased in 5 patients while it declined in 13 patients. In a previous study we showed that FWHM did not change with age in normal subjects. Thus increase in T2 heterogeneity quantified by FWHM indicates progression of disease over a relatively short period.In the interval between studies the


Surgical procedures in small animal models of heart disease might evoke alterations in cardiac morphology and function. The aim of this study was to reveal and quantify such potential artificial early or long term effects in vivo, which might account for a significant bias in basic cardiovascular research, and, therefore, could potentially question the meaning of respective studies.Female Wistar rats (n = 6 per group) were matched for weight and assorted for sham left coronary artery ligation or control. Cardiac morphology and function was then investigated in vivo by cine magnetic resonance imaging at 7 Tesla 1 and 8 weeks after the surgical procedure. The time course of metabolic and inflammatory blood parameters was determined in addition.Compared to healthy controls, rats after sham surgery showed a lower body weight both 1 week  and 8 weeks  after the intervention. Left and right ventricular morphology and function were not different in absolute measures in both groups 1 week after surgery. However, there was a confined difference in several cardiac parameters normalized to the body weight (bw), such as myocardial mass , or enddiastolic ventricular volume . Vice versa, after 8 weeks, cardiac masses, volumes, and output showed a trend for lower values in sham operated rats compared to controls in absolute measures , but not normalized to body weight. Matching these findings, blood testing revealed only minor inflammatory but prolonged metabolic changes after surgery not related to cardiac disease.Cardio-thoracic surgical procedures in experimental myocardial infarction cause distinct alterations upon the global integrity of the organism, which in the long term also induce circumscribed repercussions on cardiac morphology and function. This impact has to be considered when analyzing data from respective animal studies and transferring these findings to conditions in patients. Surgical cardiovascular procedures, such as artificial ligation of the left anterior descendent artery (LAD) for induction of experimental myocardial infarction Even though a reference group undergoing surgical sham procedure is usually used in animal studies to possibly rule out a potential bias as good as possible - meaning that these animals undergo the same surgical procedure as those from the infarction study group besides the final step of coronary artery ligation The aim of the current study was to reveal potential side-effects of artificial thoracotomy and pericardiotomy on cardiac integrity, using cardiac magnetic resonance imaging (MRI) to characterize both left and right ventricular morphology and function in rats in vivo. In addition, the time course of metabolic and inflammatory blood markers was to be investigated. The findings of this study are intended to further validate the appropriateness of this model in cardiovascular research, potentially revealing limitations to past or future studies by experimental proof - and preferably even quantification - of possible side-effects.Examinations were performed in adult female Wistar rats  with an average age of 12 weeks. The animals were divided into two groups , which were matched for body weight and followed up over time. Rats in the sham group received surgery as follows : Left inMagnetic resonance investigations started one week after the sham operation for detection of potential early side effects, and were repeated eight weeks after sham surgery to reveal potential late appearing side effects. The untreated rats were used as controls at equivalent time points.All animal work was conducted according to the relevant national and international guidelines. The experimental protocol was approved by the local ethics committee of the University of Wuerzburg and the governmental animal care and use committee (Regierung von Unterfranken).Experiments were performed on a Bruker Biospec 70/21 using a whole body birdcage coil  for transmission and a circular polarized surface coil as receiver on intubated animals under inhalation anesthesia with isoflurane.An ECG-triggered fast gradient echo (FLASH) cine sequence was used Both ventricles were equally investigated; we chose standard short axis ventricular multi slice image stacks for quantification of cardiac morphological and functional parameters as most MRI studies are left ventricular optimized.In addition to the MRI investigations, serial blood analyses were performed in control and sham operated rats, investigating the time course of several metabolic and inflammatory blood markers. To this end, blood was extracted via the tail vein from the animals at baseline and 1, 4, 7, and 14 days after sham surgery. Quantitative analyses were then performed using enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's protocol. Metabolic testing included determination of the following blood serum parameters: glucose, urea, triglycerides, and leptin. Inflammatory testing included determination of the following blood serum parameters: c-reactive protein (CRP), tumor necrosis factor alpha (TNF), and interleukin 2 (IL-2).After completion of the experiments, the rats were euthanized. The hearts were excised, sliced, fixated, and stained using Picrosirius Red. Histology of the whole hearts was then performed to rule out inadvertent small myocardial infarction, which might have escaped detection in MRI and could potentially tamper the morphological and functional findings.3). For comparison of sham operated vs. untreated control animals the following cardiac parameters were included in the analysis: Left and right ventricular myocardial masses (LVM and RVM), enddiastolic and endsystolic wall thickness (EDWT and ESWT), enddiastolic and endsystolic volumes (EDV and ESV), absolute and percental systolic wall thickening , stroke volume (SV), ejection fraction (EF), and cardiac output (CO).Data analysis was done using an operator-interactive threshold technique (IDL 5.2 Software). Visual analysis was used to determine the endsystolic and enddiastolic frame for every slice. Ventricular slice areas were then manually encircled in the respective frames, and ventricular volumes per slice then calculated by multiplication of determined area and slice thickness . FinallyStroke volume was calculated as the difference between end-diastolic and end-systolic volumes after summing all slice volumes. For calculation of cardiac output, stroke volume was multiplied by heart rate. Ejection fraction was calculated by division of stroke volume and enddiastolic volume. Comparison of endsystolic and enddiastolic ventricular masses was used as a parameter to validate the preciseness of the measurements and postprocessing. Wall thickness and systolic wall thickening were examined as follows: Three representative midventricular slices were chosen and left and right ventricular wall thickness then measured manually in enddiastolic and endsystolic frames. The right ventricular wall thickness and thickening was measured only in the lateral part of the wall, while the left ventricular myocardial thickness was measured in an anterior, lateral, posterior, and septal segment for each slice. Mean wall thickening  was calculated for each slice, then overall mean wall thickening was calculated over the three slices. In addition to the SWT determination, the cine loops were visually analyzed to detect not only wall thinning and akinesia, but also potential dyskinesia.Data analysis was performed by two persons and identical equipment throughout the whole study to reduce intraobserver and interobserver variability. To follow convention, papillary muscles were not included in myocardial masses.SPSS Statistics 19  was used for statistical analyses. All data are given in mean ± standard deviation (SD). In calculated data, error was computed by Gaussian propagation of uncertainty and taken as the random error if it was larger than standard deviation. A two-tailed students t-test for paired group comparison was applied. P<0.05 was considered statistically significant.Six animals were included in each group. Mean body weight at baseline was 296±7.4 (sham) and 301±6.3 g (control). Sham surgery was performed successfully in all animals for the sham group without apparent acute complications.One week after sham surgery, rats in the sham group showed a marked decrease in body weight  accounting for a weight loss of −28.2±7.4 g, compared to an increase in body weight of +16.3±7.9 g in the control group . Heart rEight weeks after sham surgery, rats in both groups showed a (further) increase in body weight compared to week 1 with a trend for a higher increase in the sham animals , even though the resulting mean body weight still remained significantly lower in the sham operated group compared to the control group  . CompareHistology after completion of the MR measurements showed no significant areas of myocardial infarction (defined as scar areas covering >10% of the left ventricular myocardium) in any of the sham operated animals.Blood analyses using ELISA did not show any significant alterations in CRP, TNF, or IL-2 in the short or long term after sham surgery. Analyses of metabolic blood parameters showed normal glucose, but a significant decrease in urea and triglycerides 1 and 4 days after sham surgery, recovering to normal levels 7 days after surgery . Along wSmall animal models of cardiac diseases have been extensively used in basic cardiovascular research to investigate the pathophysiology of various medical conditions and subsequent potential therapeutic approaches. Artificial myocardial infarction by surgical ligation of the left descending coronary artery is a particularly popular disease model The current study aimed at a deeper understanding of the artificially induced pathophysiological aspects and/or side-effects in the above mentioned small animal model of myocardial infarction induced by surgical ligation of a coronary artery excluding the specific effects of coronary artery occlusion itself. Execution of this particular procedure not only means a disturbance of global integrity of the organism e.g. by blood loss or development of a subsequent inflammatory response due to the surgery. Because the surgical procedure includes a direct, mechanical intervention at the (epi-)myocardium, the heart's integrity might be distinctly disturbed, e.g. by intramyocardial bleeding or the secondary effects of pericardiotomy/pericardectomy. It might be reasonable to suggest that the latter might substantially alter cardiac hemodynamics particularly regarding filling of the right ventricle. In order to investigate and quantify such potential effects we used high field MRI to characterize development of cardiac morphology and function in vivo over time after the surgical procedure.MRI offers exceptional options for exact characterization not only of the left, but also the right ventricle, and therefore is suitable to detect even small alterations which might remain undetected by other imaging modalities like e.g. echocardiography Based on the results of the current study, a main effect of the sham operation was an acute slight decrease of the animals' body weight, presumably as a direct consequence of the surgical procedure. Following the acute phase, weight gain in these rats was apparently not further diminished, but these rats rather caught up part of this decrease in body weight loss compared to the control animals. However, at week 8, there was still a significant remaining difference comparing the total body weight in both groups. According to the current findings from blood analyses, it is unlikely that inflammatory processes account for significant alterations in the short or long term: quantitative ELISA showed only minor, non-significant alterations in CRP, TNF, or IL-2 after sham surgery. Metabolic blood parameters, however, confirmed distinct metabolic alterations due to sham surgery, including a significant drop in urea and triglycerides from 1 till 4 days post-surgery. In addition, serum leptin levels - which are suggested to play a major role in regulation of food intake, but have also been shown to be reversely influenced by behavioral and metabolic changes in food intake It can also be concluded from the results of the study that the acute, direct side-effects of the surgical procedure on cardiac morphology and function are negligible one week after the intervention. There was no acute substantial alteration in myocardial mass, wall thickness, ventricular volumes, or function in comparison to the control animals, neither for the left nor right ventricle. In addition to the global functional cardiac parameters, visual analysis of the cine cycles also showed no regional impairment of cardiac function in the sham operated animals. It can be concluded from the results of the study, that the integrity of the pericardium has only a small effect on both left and right ventricular morphology and function. Right ventricular function was impaired neither at week 1 nor at week 8 after surgery. The only apparent effect seen in the rats after the intervention was a tendency for higher right ventricular wall thickness at least in some of the animals, even though not statistically significant comparing the entire groups. This increase in the myocardial wall thickness might in fact be an incorrect labeling, as even using MRI it is not always possible to discriminate the right ventricular myocardium from the pericardium. Therefore, rather than effects on the myocardium itself, pericardial swelling or hemorrhage might be primarily responsible for this (limited) effect seen in the MRI, which was less pronounced 8 weeks after surgery.In contrast to the acute phase after sham surgery, which led to no significant alterations in cardiac morphology or function in absolute measures, but some measureable differences of cardiac parameters in relation to the respective body weight, there were some differences in cardiac parameters between both groups in absolute measures at week 8 after sham surgery, but no longer normalized to the animal body weight. This implicates physiological secondary long term customization of the cardiac morphology and function on the aroused alterations in body weight, rather than suggesting a pathological cause. A marked difference between both groups in the long term was a substantially higher heart rate in the control animals compared to the sham animals, and also compared to both groups at the early time point. From the results of the study, the reasons for this increase in heart rate in the respective group compared to all other groups are unclear. It could be speculated though, that the main reason for this increase might simply be the higher body weight, which might imply less cooling of the animal under anesthesia and subsequently lead to a higher body temperature with higher heart rate during the MR investigation. The accompanying trend for an increased cardiac index in these animals might be explained equivalently as a direct result of the higher heart rate, since stroke volume index normalized to the body weight was identical in both groups at week 8.Surgical procedures undertaken to evoke artificial myocardial infarction by ligation of a branch of the coronary arteries induce a transient general impairment of the body integrity, apart from the local effects on the connective tissue mainly apparent by a slight decrease in body weight in the short term. Despite pericardiotomy and circumscribed intramural wounding through the procedure for coronary ligation, there are only minimal acute effects on left and right ventricular morphology and function. Correlation of many cardiac parameters with body weight can, however, show alterations compared to healthy controls. In the long term, the transient impairment in body weight is partly regained, with cardiac morphology gradually adapting according to the development of the organism similar to healthy individuals. These findings should be taken into account when evaluating results from basic cardiovascular research in small animal models of cardiac disease, particularly if the results from studies including thoracic surgery are directly compared to those from studies that do not include thoracic surgery.


Chagas disease is a highly prevalent zoonosis in Mexico, Central, and South America. Early cardiac involvement is one of the most serious complications of this disease, and conduction disturbances may occur at an early age. We describe a young pregnant woman with Chagas disease and a high degree atrioventricular block, who required implantation of a permanent dual chamber pacemaker. Using an electroanatomic navigation EnSite NavX® system the pacemaker was successfully implanted with minimal fluoroscopic exposure. This case demonstrates the safety and feasibility of using an electroanatomic navigation system to guide permanent pacemaker implantation minimizing x-ray exposure in pregnant patients. Chagas Disease is a highly prevalent endemic zoonosis in most of Mexico, Central, and South America. It is caused by a parasite transmitted to humans by insects, blood transfusions, oral secretions, or across the placenta. Cardiac involvement is one of the most serious complications of chronic infection by Chagas disease, leading to a chronic dilated cardiomyopathy, which can present with multiple conduction disorders including atrioventricular (AV) blocks. Cardiomyopathy develops approximately 20 years after acute infection, putting fertile women at risk of having cardiac rhythm disturbances during pregnancy if infected at an early age . There aA 33 -year-old pregnant woman was referred with the diagnosis of bradycardia. She presented with a 2 months history of fatigue; during that time she was found to have positive antibodies for Chagas disease. At the time of admission she had a 31 weeks gestation. Her past medical history was only remarkable for a previous cesarean section. At physical exam a resting heart rate of 33 bpm was noted, and her ECG showed a third degree AV block . By UltrWe decided to implant a dual chamber permanent pacemaker. To minimize the X-ray exposure, we used an electroanatomic navigation system ENSITE NavX® System  during pacemaker implantation. A written informed consent was obtained from the patient. Three pairs of adhesive electrodes were placed on the patient chest to create the electrical field needed to create the navigation field. Under local anesthesia, two left subclavian punctures were performed, and a quadripolar steerable catheter was advanced through the sheath . Contours of the superior vena cava, right atrium, tricuspid annulus, right ventricular apex and right ventricular outflow tract were created with the quadripolar catheter. The quadripolar catheter was then withdrawn, and an 8 Fr. replaced the 7 Fr. introducer. To visualize the atrial and ventricular leads, two cables were used with alligator clips attached to the pacemaker leads and a 2 mm pin end attached to the Ensite NavX® polygraph box. By being attached to the polygraph box, the leads were visualized as catheters within the electroanatomic contour. An active fixation ventricular lead  was advanced using the electroanatomic images as a reference and was placed in the right ventricular outflow tract. An R wave of 4.8 mV, a threshold of 0.5 V, and an impedance of 357 ohms in bipolar mode were documented after implantation. A second introducer was advanced, and an active fixation atrial lead  was positioned guided by the electroanatomic map. A P wave of 6.5 mV, a threshold of 1.2 V, and an impedance of 481 ohms in bipolar mode were obtained. Three-dimensional map documenting the final position of both leads is shown . The posSix months after the procedure the pacemaker was functioning correctly . The baby was uneventfully delivered at term by a cesarean section. The position of the leads was confirmed after delivery with a chest x-ray . The newA permanent pacemaker is the treatment of choice in symptomatic pregnant patients with high degree AV block . HoweverThis case of a pregnant woman with complete heart block secondary to Chagas cardiomyopathy demonstrates the feasibility of using the NavX® mapping system to guide the insertion of a permanent dual chamber pacemaker and reduce the risk of X-Ray exposure to the fetus. This approach seems safe, feasible and can be considered as first line option in pregnant patients when permanent pacemaker implantation is needed.


While mammalian heart size maintains constant proportion to whole body size, scaling of left ventricular (LV) function parameters shows a more complex scaling pattern. We used 2-D speckle tracking strain imaging to determine whether LV myocardial strains and strain rates scale to heart size.Long/SRLong, SCirc/SRCirc), and LV end-diastolic volume (EDV) or mass were assessed by the allometric (power-law) equation Y = kMβ.We studied 18 mice, 15 rats, 6 rabbits, 12 dogs and 20 human volunteers by 2-D echocardiography. Relationship between longitudinal or circumferential strains/strain rates  SCirc was unchanged (p = NS for both LV EDV or mass). Systolic and diastolic SRLong and SRCirc showed inverse correlations to LV EDV or mass . The ratio between SLong and SCirc increased with increasing values of LV EDV or mass .Mean LV mass in individual species varied from 0.038 to 134 g, LV EDV varied from 0.015 to 102 ml, while RR interval varied from 81 to 1090 ms. While SCirc is unchanged, SLong increases with increasing heart size, indicating that large mammals rely more on long axis contribution to systolic function. SRLong and SRCirc, both diastolic and systolic, show an expected decrease with increasing heart size.While S The structure of mammalian hearts is grossly invariant between the species. Heart size maintains constant proportion to whole body size, while left ventricular (LV) myocardial histology shows a stable pattern of distribution of fibers that are oriented obliquely in subendo- and subepicardium, and circumferentially in mid-myocardium in all species. long) reflecting long axis, and circumferential (Scirc) and radial (Srad) strains reflecting corresponding components of short-axis deformation. Liu et al. have shown that Scirc and Srad are decreased in mice and rats. long to Scirc) decreases with decreasing heart size. What is less understood is the impact of heart size on LV deformational mechanics, namely myocardial strain and strain rate. Normal myocardial strains quantify myocardial deformation occurring in the direction of the three principal axis of the heart, with longitudinal strain  normal myocardial strains show a small but significant decrease with decreasing heart size Out of our database of 117 healthy volunteers free of any known cardiovascular disease, with normal physical examination, normal electrocardiogram, and not taking any cardio-active medication, we randomly selected 20 subjects whose age was between 21 and 45 years.The studies in human subjects were performed in accordance with the Declaration of Helsinki. The Institutional Review Board of the Cleveland Clinic approved that study, and all participants gave written informed consent. The animal data were collected during echocardiographic evaluation of control  animals used in several different studies in the period of 2003–2011. The data collection in each of these studies was prospective and specified by the respective study protocols. Importantly, the evaluation of the reported echocardiographic data was performed in each study and animal by using compatible equipment and techniques. All the animal experiments reported in this article were approved by the Institutional Animal Care and Use Committee of Cleveland Clinic and were in compliance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.Subjects were studied in left lateral decubitus position. Due to the specificity of the animals’ behavior, the procedures differed slightly among the species. Twelve mongrel dogs were trained to lie down calmly for echocardiography. Six white New Zealand rabbits were lightly sedated with 35 mg/kg ketamine administered intramuscularly, with the handler keeping the head covered with soft cloth in a dark room. Echocardiography was performed using Vivid 7 echocardiography machine . M-mode echocardiography, two dimensional echocardiography, and two-dimensional color tissue Doppler echocardiography data were collected using a dual harmonic 1.7/3.4 MHz or 2.0/4.2 MHz sector transducer , 6 MHz or 11.5 MHz pediatric sector transducer  and 14 MHz epicardial linear transducer (mice). The minimal frame rates acquired during standard two-dimensional echocardiography in humans, dogs, rabbits, rats and mice were 30, 50, 70, 90 and 160 frames s−1, respectively. The minimal frame rates acquired during color tissue Doppler two-dimensional echocardiography in humans, dogs, rabbits, rats and mice were 125, 125, 189, 200 and 208 frames s−1, respectively. Data were digitized in a proprietary format for further analysis. Long axis views were obtained from parasternal window in mice, rats and rabbits, and from apical window in dogs and human.−1. LV end-diastolic and end-systolic volumes were measured from the long-axis view by the single-plane Simpson equation. LV mass was calculated from two-dimensional echocardiography data by the bullet equation:Data were analyzed using Echopac PC . LV ejection time was measured directly from the digital pulsed-wave Doppler tracing of the LV outflow tract with the sweep speed set to 200 mmsLV mass (g) = 1.05(5/6)[Aepi(L +√Aepi/π−√Aendo/π) − AendoL]where 1.05 is the specific gravity of muscle, Aepi and Aendo are the epi- and endocardial parasternal short-axis areas, respectively, and L is the parasternal long-axis LV length. LV mass was calculated using both end-systolic and end-diastolic data, and the two estimates were then averaged. Previous studies have validated LV mass measurement based on two-dimensional echocardiography in mice long) and strain rate (SRlong), circumferential strain (Scirc) and strain rate (SRcirc), and radial strain (Srad) and strain rate (SRrad) curves were then constructed and then averaged to obtain global segmental strain and strain rate curves. End-systolic strains were then obtained from the global strain curves, while peak systolic and diastolic strain rates were calculated from global strain rate curves. For the analysis of human, dog and rabbit data, at least three beats were measured. For small rodents, at least six beats (for rats) or nine beats (for mice) were averaged. The mean value was used for statistical analysis. Long – short axis strain ratio (L/C strain ratio) was calculated by dividing longitudinal strain by circumferential strain.We used a speckle-tracking algorithm incorporated into Echopac PC PC . The speckle-tracking analysis was performed by the same trained observer. The region of interest was overlaid across a cross section of the ventricular silhouette at the image corresponding to the minimal endocardial area. The software algorithm then automatically divided the LV long-axis view and LV short-axis view into six segments for speckle tracking throughout the cardiac cycle. The tracking quality was then visually inspected, and, if it was satisfactory for at least five segments, the tracing was accepted. In mice, since our experiments were done in conscious setting without the possibility of registering the electrocardiogram, we manually defined end- systole and end-diastole. long) were measured in mid interventricular septum using a strain rate length/region of interest of 0.6 mm/0.6 mm, 1.5 mm/1 mm, 3 mm/3 mm, 12 mm/6 mm and 15 mm/6 mm in mice, Tissue Doppler Imaging, while carrying higher noise and larger operator variability, has a higher sampling rate and therefore potentially better detection of short-duration, high frequency peaks. To estimate intraobserver variability, we used data obtained in 2 mice, 2 rats, 2 rabbits, 2 dogs, and 2 humans. The same observer applied speckle tracking software twice to the same cardiac cycle. Data are presented as means of the absolute and relative differences between measurements and by the correlation coefficient (r).We used proposed power-law function to predict the magnitude of the impact of LV size on strain and strain rate Basic morphometric and echocardiography parameters of different species are presented in long showed a small but significant increase with increasing LV EDV and LV mass, with power exponent of βEDV 0.047±0.006, and βLVmass 0.051±0.007, respectively (p<0.0001 vs. 0 for both). As expected, absolute strain rates decreased with increased heart size, with systolic SRlong scaling with exponent of βEDV −0.216±0.019, and βLVmass −0.236±0.020 (p<0.0001 vs. 0 for both), and diastolic SRlong scaling with exponent of βEDV −0.159±0.020, and βLVmass −0.175±0.021 (p<0.0001 vs. 0 for both) (Sor both) .long scaled to LV EDV and mass with exponent of βEDV −0.252±0.021 and of βLVmass −0.263±0.021 , while diastolic-TDI-SRlong scaled with exponent of βEDV −0.241±0.020 and of βLVmass −0.262±0.020   .circ was not affected with heart size . Again, systolic SRcirc decreased with increasing heart size with exponent of βEDV −0.261±0.021, and βLVmass −0.277±0.021 (p<0.0001 vs. 0 for both). Similarly, diastolic SRcirc scaled with exponent of βEDV −0.206±0.023, and βLVmass −0.228±0.023 (p<0.0001 vs. 0 for both) (Sor both) .rad scaled with exponent of βEDV 0.078±0.012, and βLVmass 0.086±0.014 (p<0.0001 vs. 0 for both). Systolic SRrad scaled with exponent of βEDV −0.193±0.012, and βLVmass −0.203±0.013 (p<0.0001 vs. 0 for both). Diastolic SRrad scaled with exponent of βEDV −0.130±0.018, and βLVmass −0.142±0.020 (p<0.0001 vs. 0 for both) (Sor both) .EDV 0.038±0.009 and βEDV 0.039±0.010, p = 0.0002 for both when compared with 0)  . These rlong = −0.07±0.02, p<0.0001; β for ratio between systolic and diastolic SRcirc = −0.06±0.01, p<0.0001; β for ratio between systolic and diastolic SRrad = −0.06±0.02, p<0.0001).During data review, we noted that diastolic strain rates have consistently lower absolute values of power exponent. To elucidate this, we assessed the way the ratio between systolic and diastolic strain rates scales with LV EDV. All three ratios showed highly significant power exponent β  function, with the power exponents similar to the ones a priori proposed by us.In this paper, we show that while SFrom a practical viewpoint, our findings are relevant for the accurate translation of research from bench to bedside. Additionally they are important in the context of evolutionary biology, as we describe the way cardiac structures adopt to size constraints by changing the way they operate.circ lower, but by a lesser degree (by 6%), than conscious humans circ that is 2% lower, but Slong, that is similar to humans; of note, this study reported markedly lower human Slong than the one reported in the largest clinical multi-center Slong study of healthy controls circ between species but Slong that was 5% lower in mice than in humans. A possible discrepancy between these studies may be due to differences in methods and/or the use of anesthetics/sedatives long/Scirc ratio with increasing animal size are in accordance with the previously shown increase of the ratio between long- and short-axis displacement with animal size increase, long of −24.6% but similar Scirc of −19.7%, again consistent with increase in Slong/Scirc ratio with increasing animal size.Myocardial deformation is a complex phenomenon that can best be represented as a 3×3 tensor, with diagonal elements representing three normal strains , and off-diagonal elements representing shear strains. LV myocardial deformation during systole leads to expulsion of blood, with this process most often quantified by ejection fraction, a measure of global systolic function. As ejection fraction is constant between the species. rad, which could represent a true physiologic phenomenon, or may be due to difficulties in accurately measuring radial strain rate. As a further support for our findings, Decloedt et al. have shown that trotter horses have mean values of all strain rate components lower by almost one order of magnitude when compared to the ones we obtained in mice We confirmed that strain rates scaled to the heart size with power exponents that were similar to the ones proposed in long by speckle tracking were 1.0−s and 1.5−s in humans, but 6.5−s and 4.3−s in mice. This issue is even more complex given relatively shorter diastolic filling time in small mammals. It is interesting that for all three components of global strain rates, diastolic strain rates showed lower values of the power exponent. This would indicate that decreasing heart size leads to a larger increase in systolic, rather than diastolic strain rate. For example, in our data, the average systolic and diastolic SRSeveral confounding factors, such as differences in heart rate to frame rate ratio, impact of sedation, or intrinsic differences in heart geometry) could have influenced the results. However, recent report showed that speckle-tracking LV strain efficiently detects discrete alterations in mice despite being obtained from images acquired at the frame rate identical to one used in this study. 2, i.e. within normal limits.In this study LV mass of our human subjects was lower than reported in our previous studies, which decreased the range of LV mass studied. The reason for this was that 14 out of 20 of our subjects were women with relatively small body size. The average indexed LV mass was 61±12 gm/mSpeckle-tracking derived strains obtained by method used in this study were validated only in humans and dogs, We have not assessed all strain components, and the significant impact of shear strains cannot be excluded. Also, strain rate measurements by speckle tracking echocardiography are less accurate than the strain measurements. Yet several authors showed that one can accurately measure strain rates in mice and rats, and that these measures correlate with relevant physiologic parameters. Furthermore, we tried to overcome this issue by averaging strain from multiple segments. Finally, the impact of sedation and the stress of performing echocardiography studies cannot be completely eliminated.Circ is unchanged, SLong and Srad increase with increasing heart size, indicating that large mammals rely more on long axis contribution to systolic function. While both diastolic and systolic SRLong, SRCirc, and SRRad increase with decreasing heart size, the increase is more substantial for systolic SR. Further studies are needed to develop species normal ranges for subsequent intervention studies.In conclusion, while SFigure S1Scaling of left ventricular (LV) length and systolic and diastolic mitral annulus (MA) long axis velocities to left ventricular mass derived from previous data long) (Panels C and D); Scaling of longitudinal and circumferential strains (Slong and Scirc) derived from data from Liu et al.  (Panels A and B); Predicted scaling of longitudinal systolic and diastolic strain rates (SR (Panel E).(TIF)Click here for additional data file.Appendix S1Study Background.(DOC)Click here for additional data file.


Although the release of cardiac biomarkers after percutaneous (PCI) or surgical revascularization (CABG) is common, its prognostic significance is not known. Questions remain about the mechanisms and degree of correlation between the release, the volume of myocardial tissue loss, and the long-term significance. Delayed-enhancement of cardiac magnetic resonance (CMR) consistently quantifies areas of irreversible myocardial injury. To investigate the quantitative relationship between irreversible injury and cardiac biomarkers, we will evaluate the extent of irreversible injury in patients undergoing PCI and CABG and relate it to postprocedural modifications in cardiac biomarkers and long-term prognosis.The study will include 150 patients with multivessel coronary artery disease (CAD) with left ventricle ejection fraction (LVEF) and a formal indication for CABG; 50 patients will undergo CABG with cardiopulmonary bypass (CPB); 50 patients with the same arterial and ventricular condition indicated for myocardial revascularization will undergo CABG without CPB; and another 50 patients with CAD and preserved ventricular function will undergo PCI using stents. All patients will undergo CMR before and after surgery or PCI. We will also evaluate the release of cardiac markers of necrosis immediately before and after each procedure. Primary outcome considered is overall death in a 5-year follow-up. Secondary outcomes are levels of CK-MB isoenzyme and I-Troponin in association with presence of myocardial fibrosis and systolic left ventricle dysfunction assessed by CMR.The MASS-V Trial aims to establish reliable values for parameters of enzyme markers of myocardial necrosis in the absence of manifest myocardial infarction after mechanical interventions. The establishments of these indices have diagnostic value and clinical prognosis and therefore require relevant and different therapeutic measures. In daily practice, the inappropriate use of these necrosis markers has led to misdiagnosis and therefore wrong treatment. The appearance of a more sensitive tool such as CMR provides an unprecedented diagnostic accuracy of myocardial damage when correlated with necrosis enzyme markers. We aim to correlate laboratory data with imaging, thereby establishing more refined data on the presence or absence of irreversible myocardial injury after the procedure, either percutaneous or surgical, and this, with or without the use of cardiopulmonary bypass. The release of creatine phosphokinase enzymes (CPK), CK-MB isoenzyme (CK-MB), cardiac troponin, or both, in the absence of ECG waves indicating necrosis during percutaneous or surgical procedures has occurred in 10 to 35 % of cardiac patients. These indices are considered diagnostic for acute myocardial infarction (AMI) . Such reHowever, both invasive and noninvasive investigations during the period after the intervention have limitations related to the poor the sensitivity and specificity of the ECG and biomarkers. Although cardiac-specific biomarkers potentially have the greatest role in simple detection of myocyte necrosis, their independent utility in this setting remains inaccurate.To increase the diagnosis, the accuracy of delayed enhancement CMR imaging (DE-CMR) can quantify reversible and irreversible myocyte necrosis.In fact in recent studies, Pegg et al.  reportedMoreover, these authors evaluated the efficacy of cardiac enzymes for determination of cardiomyocyte necrosis after CABG and compared this with the efficacy of CMR .In the MASS-V study, we will prospectively examine the incidence and extent of new DE-CMR-defined irreversible injury in patients undergoing PCI or CABG and correlate it with postprocedural changes in TnI and CK-MB. Our hypothesis is that the releasing of biomarkers does not necessarily leads to myocardial fibrosis or left ventricular dysfunction; and the cut-off levels to define periprocedural AMI would be different from the ones established in current guidelines.The MASS-V Trial is an institutional project that the Heart Institute (InCor), Hospital das Clinicas, University of São Paulo designed to prospectively investigate 150 patients with multivessel coronary artery disease (CAD) with normal left ventricle ejection fraction (LVEF) and with a formal indication for CABG or PCI. Fifty patients will be operated on with cardiopulmonary bypass (CPB) and another 50 patients with the same arterial and ventricular conditions and also with a proper indication for myocardial revascularization will be operated on without the help of the CPB circuit. Another 50 patients with CAD and preserved ventricular function with a formal indication for percutaneous coronary intervention (PCI) with the use of intracoronary "stents” will be analyzed.The inclusion criteria will determine which patients are eligible for which of the three procedures. Anginal symptoms must be stable and the LVEF preserved. The main steps of the procedures are shown in Figure All patients will undergo CMR before and after surgical or percutaneous interventions to determine the presence or absence of myocardial necrosis complications after the procedure.In addition, we will be evaluating the release of cardiac necrosis markers immediately before and after each procedure. The measurement of necrosis markers in the series will be conducted 6, 12, 24, and 36 hours after the percutaneous intervention. For the surgical procedures, dosage series will expand from 48 to 72 hours.The patients will be studied in a 1.5-T clinical MR scanner (Philips Achieva), and steady-state free-procession cine images will be acquired in 2 long-axis (2 and 4 chambers view) and 8 to 10 short-axis views of the left ventricle. A gadolinium-based contrast agent  will then be injected intravenously (0.1 mmol per kilogram of body weight), and contrast-enhanced images will be acquired after a 5- to 10-minute delay with the use of an inversion-recovery segmented sequence. Contrast-enhanced images will be acquired in long- and short-axis planes identical to the cine images. Typical voxel size will be 1.6x2.1x8mm, with a reconstruction matrix of 528 and a reconstructed voxel size of 0.6 mm. The method for acquiring and analyzing CMR is standardized in our service and is reproduced according to conventional techniques [o) following a 5-min time delay after the administration of 0.1 mmol/kg contrast agent . Images will be acquired in two long-axis planes and in a short-axis stack covering the entire left ventricle. The inversion time will be meticulously adjusted throughout the acquisition to obtain optimal nulling of remote normal myocardium. The slice thickness at the apex will be reduced to 5 mm to avoid a partial volume effect [Delayed enhancement of cardiac magnetic resonance will be performed with a phase-sensitive inversion recovery (PSIR) sequence  and interpreted by two experienced observers blinded to the interventional technique and biochemical data. When measurements are different, a third observer will perform a review and a consensus will be obtained.Hyperenhanced pixels are defined as those with image intensities >2 SDs above the mean of image intensities in a remote myocardial region in the same image. Furthermore, we prospectively identified the site of any new hyperenhancement in relation to the implanted stent. Areas of new hyperenhancement that occur in the same short-axis image as the stent will be classified as adjacent to stent injury, whereas new hyperenhancement that occurs in the myocardium distal to the stent is deemed downstream injury.Just as with a percutaneous intervention, hyperenhanced pixels will be defined as image intensities greater than two standard deviations above the mean intensities in a remote myocardial region in the same image. Preintervention and postintervention scans will be read side by side in both surgical techniques, with and without extracorporeal circulation.Blood samples will be collected from each patient for measurement of troponin I (TnI) and CK-MB mass immediately before PCI and 6, 12, 24, and 36 hours after the procedure. For patients undergoing coronary artery bypass surgery, on-pump or off-pump, these cardiac markers will be measured immediately before surgery and 6, 12, 24, 36, 48, and 72 hours after surgery.The surgeon and clinical team will be blinded to the CK-MB or TnI data.All the samples will be centrifuged at 3000 rpm for 20 minutes and analyzed within 2 hours after specimen collection. TnI and CK-MB analysis will be performed in an immunoassay analyzer . According to the manufacturer, the lower limit of detection of TnI using a high-sensitivity kit, the Ultra kit, is 0.006 ng/mL, and the 99th percentile and MI reference limits are respectively 0.04 and 0.76 ng/mL. The assay precision, represented by the percentage coefficient of variation (%CV) is ≤ 10 % at 0.03 ng/mL.The detection limit of the CK-MB mass kit is 0.18 ng/mL, and the cut off values at the 99th percentile, established by our laboratory, are 3.8 ng/mL for women and 4.4 ng/mL for men. The CVs for CK-MB mass, as specified by the manufacturer, are 3.91 % at 3.55 ng/mL and 3.61 % at 80.16 ng/Ml.t test and the unpaired-sample t test will be used to compare means within the study group or between subgroups. χ2 statistics with Fisher’s exact test will be used for comparison of discrete variables. Continuous variables that were not distributed normally will be compared with the Mann–Whitney U test, and correlation between such variables will be made with the Spearman rank test. Binary logistic regression will be performed to determine which clinical and angiographic parameters predict the likelihood of myocardial hyperenhancement. Multivariate logistical regression will be used to assess the relative contribution of various clinical and angiographic variables to the presence of new hyperenhancement after PCI or CABG. A probability value of <0.05 is considered statistically significant.Values will be expressed as mean (±SD) or median (interquartile range) as appropriate. The paired-sample Primary outcome considered is overall death in a 5-year follow-up. Secondary outcomes are levels of CK-MB isoenzyme and I-Troponin in association with presence of myocardial fibrosis and left ventricle ejection dysfunction assessed by CMR.The release of biomarkers of myocardial necrosis occurs in most patients who undergo mechanical interventions of the heart, both CABG and PCI. Among the causes of this release are the trauma caused by the handling organ, contact of blood with the bypass circuit, aortic cross clamping, and reperfusion injury. On the other hand, periprocedural myocardial injury during PCI can result from procedural complications, such as distal embolization, side-branch occlusion, coronary dissection, and disruption of collateral flow.The clinical significance and long-term prognosis of this condition continues to be debated. Initial short-term follow-up found no increase in the incidence of cardiac events; however, further large prospective trials have suggested that elevation of biomarkers of myocardial necrosis after PCI or CABG is clinically relevant. In addition, outcomes after CABG or PCI with very high procedural TnI or CK-MB levels have prognostic implications considered similar to those of spontaneous acute myocardial infarction.Delayed enhancement CMR imaging can quantify irreversible myocyte necrosis for the identification of subedocardial infarction.However, uncertainties remain about the mechanisms and functional significance of the release of cardiac biomarkers and the direct relationship between procedure-related troponin and CK-MB increase and the degree of myocardial tissue loss.MASS-V trial will be conducted in accordance with the principles of the Declaration of Helsinki and with laws and regulations of our country. The Ethics Committee of the Heart Institute of the University of São Paulo, Brazil, approved the study protocol. The attending physician will obtain written informed consent from the all study participants.This is a proposed trial and the enrollment process has not started until the date of manuscript submission.AMI: Acute Myocardial Infarction; CABG: Coronary Artery Bypass Graft; CMR: Cardiac Magnetic Resonance; CPB: Cardiopulmonary Bypass; CPK: Creatine Phosphokinase Enzymes; CK- MB: Creatine Kinase Isoenzyme; CAD: Coronary Artery Disease; CPB: Cardiopulmonary Bypass; CV: Coefficient of Variation; DE-CMR: Delayed Enhancement CMR imaging; LVEF: Left Ventricle Ejection Fraction; MASS: Medicine, Angioplasty, or Surgery Study; PCI: Percutaneous Coronary Intervention; SD: Standard Deviation; TnI: Troponin I.None of the authors of the MASS-V Trial has a financial or any other relation that would pose a conflict of interest.Each of the authors has made substantial contributions to this manuscript, either in conception and design or in the drafting of the article and critical revision for important intellectual content. Specifically, study concept and design: WH, BJG, CLG, ACP, PCR, CN, CCS, JAFR, RKF. Acquisition of data: FTCO, RMVM, LMAC, ER, PL, NS, FJ, ACH, CN, CCS. Analysis and interpretation of data: WH, PCR, EGL, CLG. Drafting of manuscript: Critical revision of the manuscript for important intellectual content: CN, ACP, CCS, ER, NS, FJ. Statistical expertise: ACP, DF, PL, CVSJ. Study Supervision/Support and planned Ancillaries Studies: WH, ER, PL, NGS. All authors participated in drafting and revising the manuscript, and all authors have read and approved the final manuscript.Steering Committee Members, Whady Hueb, Bernard J Gersh, Eduardo Gomes Lima, Cibele Larrosa Garzillo, Rosa Maria Rhami Garcia, Paulo Cury Rezende, Pedro Lemos, Expedito Ribeiro, Célia Cassaro Strunz, Fabio B Jatene, Noedir A G Stolf, José A F Ramires, Roberto Kalil Filho. Cardiology Committee, Whady Hueb, Eduardo Gomes Lima, Cibele Larrosa Garzillo, Paulo Cury Rezende, Fernando Teiichi Costa Oikawa, Rodrigo Morel Vieira de Melo, Leandro Menezes Alves da Costa, José A F Ramires, Roberto Kalil Filho. Hematologic Disorders Committee, Dalton A F Chamone, Roberto Abi-Rached, Alexandre Costa Pereira. Endocrinologist Committee, Rosa Maria Rhami Garcia, Raul Maranhão, Célia Cassaro Strunz. Cardiac Imaging Techniques Committee, Cesar Nomura, José Rodrigues Parga Filho, Luiz Francisco Rodrigues de Ávila, Alexandre Volney Villa. Electrocardiography and exercise stress testing Committee, Willian Chalela, Augusto H Uchida. Interventional Committee, Expedito Ribeiro, Pedro Lemos, Marco A Perin Alexandre Ciappina Hueb. Cost-effectiveness and Quality of Life Committee, Myrthes E Takiuti, Priscyla Girardi, Marcela F Silva, Ana Luiza Oliveira Carvalho, Teryo Nakano. Ancillary Studies Committee, Cesar Nomura, Alexandre Costa Pereira, Célia Cassaro Strunz, Expedito Ribeiro, Noedir A G Stolf, Fabio B Jatene. Data and Safety Monitoring Board, Eliana Lima, Laura Caringe, Marcela F Silva. Source Information, The members of the writing group, Whady Hueb, Célia Cassaro Strunz, Alexandre Costa Pereira, Expedito Ribeiro, Pedro Lemos, Cesar Nomura, Fabio B Jatene, José A F Ramires, and Roberto Kalil Filho assume all responsibility for the overall content and integrity of this article.The MASS-V Trial is funded in part by the Zerbini Foundation and Fundação de Amparo á Pesquisa do Estado de São Paulo (FAPESP) Number 2011/20876-2 Sao Paulo, Brazil.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/12/65/prepub


Sarcoidosis is a multisystemic disorder of unknown aetiology characterised by the formation of noncaseating epithelioid cell granuloma involving various organ systems. Cardiac involvement has an important prognostic factor as it can present with life-threatening arrythmias and sudden death. Here, we present a case of cardiac sarcoidosis in a 46-year-old gentleman who presented with nonspecific signs and symptoms. We also discuss diagnostic difficulties especially when cardiac involvement is the only clinical sign. In this case, cardiac magnetic resonance (CMR) played an important role in the diagnosis and followup of our patient. Cardiac sarcoidosis is an important cause of death in patients with systemic sarcoidosis. Approximately 20–30% of patients with systemic sarcoidosis have evidence of granulomatous infiltration of the myocardium at autopsy . The preA previously well forty-six-year old Caucasian man presented with exertional dyspnoea and two cutaneous nodules on his left wrist which were biopsied and confirmed as sarcoid nodules. He was referred to the respiratory physicians for further investigations. Chest X-ray showed classical changes of pulmonary sarcoidosis, and serum ACE was mildly elevated at 92 U/L. He also described episodes of palpitation on exertion, ankle oedema, and progressively worsening breathlessness. However, the extent of his dyspnoea seemed disproportionate to that of his pulmonary involvement. An electrocardiogram (ECG) showed sinus rhythm with a prolonged PR interval (210 milliseconds), right bundle branch block, and left anterior fascicular block. Based on his clinical presentation and ECG abnormalities, heart failure secondary to cardiac sarcoidosis was suspected and he was referred to the cardiology department.Twenty-four-hour ambulatory monitoring showed sinus rhythm though out with short runs of sinus tachycardia. Serum brain-natriuretic peptide (BNP) level was unremarkable at 21.3 pg/mL . Percutaneous coronary angiography demonstrated normal coronary arteries, and endomyocardial biopsy showed “mild” and “nonspecific changes,” failing to confirm sarcoid infiltration. A CMR scan was subsequently performed to further examine the LV systolic function and assess for myocardial sarcoid infiltration. The left ventricle (LV) was nondilated and demonstrated moderate impairment of LV systolic function (ejection fraction 39%) associated with an akinetic but nonthinned interventricular septum. The right ventricular systolic function was also significantly impaired. Late gadolinium enhancement imaging showed several areas of myocardial hyperenhancement involving the anteroseptal subendocardium, subepicardium, and basal lateral epicardium.The patient was initially treated with high-dose oral prednisolone therapy (40 mg/day) and referred to the tertiary heart failure centre. Following treatment, twelve lead ECG abnormalities improved with the only residual abnormality being right bundle branch block.A second CMR scan was carried out 42 days after the initiation of his steroid therapy and showed marked improvement in right and left ventricular systolic function. Despite this, the areas of hyperenhancement seen in the first CMR scan remained. In addition, the RV surface of the inferior interventricular septum and RV free wall also appeared affected .Cardiac sarcoidosis is an important cause of death in patients with systemic sarcoidosis and should be considered in those who demonstrate cardiac symptoms and/or signs. Myocardial involvement is present in approximately 5 percent of patients with sarcoidosis although autopsy studies indicate subclinical cardiac involvement in 20 to 30 percent of cases . ClinicaSigns and symptoms of cardiac sarcoidosis are largely nonspecific, and, when cardiac involvement is the sole manifestation, diagnosis is often challenging. Previous attempts to identify sarcoid infiltration of the myocardium relied on transthoracic echocardiography, nuclear scintigraphy, and right ventricular endomyocardial biopsy . The feaCMR is a powerful noninvasive imaging modality which produces images with excellent spatial, soft tissue, and temporal resolution. Myocardial infiltration and scarring can be observed as late gadolinium hyperenhancement in the mid-wall and subepicardium. There seems to be a predilection for the lesions to affect the anterobasilar, anterolateral and lateral wall of the left ventricle. Furthermore, cardiac sarcoidosis is known to produce zones of thinning, segmental myocardial wall motion abnormalities, and subendocardial late gadolinium hyperenhancement similar to those seen in myocardial infarction but often in a noncoronary distribution –7. CMR cIn our patient, the first CMR scan demonstrated systolic dysfunction of both ventricles and both subepicardial and subendocardial late gadolinium hyperenhancement of the basal anteroseptal and basal anterolateral regions. This pattern appeared inconsistent with an ischaemic insult to the myocardium especially in the context of a normal coronary angiogram. Instead, supported by the normalisation of ventricular function following high-dose prednisolone, we felt it reflected myocardial infiltration and scarring secondary to sarcoidosis. This case highlights the importance of considering cardiac sarcoidosis in patients with systemic sarcoidosis when they present with symptoms such as heart failure. ECG may also be useful in indicating the possibility of myocardial infiltration. CMR offers a powerful noninvasive method of assessing myocardial fibrosis and infiltration, which can greatly assist in the diagnosis of sarcoid and in some cases eliminate the need for biopsy. In our patient, we demonstrated the role of CMR in diagnosing cardiac sarcoidosis especially when other investigations including endomyocardial biopsy failed to confirm sarcoid infiltration.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no conflict of interests.J. R. Payne identified the patient, analyzed the images and edited the paper. S. Prasher acquired the images and ECGs, performed the literature search, and drafted the paper. M. Dweck and P. T. Lee contributed to literature search, writing and editing of the paper. All authors read and approved the final paper.


We have previously reported strain dyssynchrony index assessed by two-dimensional speckle tracking strain, and a marker of both dyssynchrony and residual myocardial contractility, can predict response to cardiac resynchronization therapy (CRT). A newly developed three-dimensional (3-D) speckle tracking system can quantify endocardial area change ratio (area strain), which coupled with the factors of both longitudinal and circumferential strain, from all 16 standard left ventricular (LV) segments using complete 3-D pyramidal datasets. Our objective was to test the hypothesis that strain dyssynchrony index using area tracking (ASDI) can quantify dyssynchrony and predict response to CRT.We studied 14 heart failure patients with ejection fraction of 27 ± 7%  and QRS duration of 172 ± 30 ms  who underwent CRT. Echocardiography was performed before and 6-month after CRT. ASDI was calculated as the average difference between peak and end-systolic area strain of LV endocardium obtained from 3-D speckle tracking imaging using 16 segments. Conventional dyssynchrony measures were assessed by interventricular mechanical delay, Yu Index, and two-dimensional radial dyssynchrony by speckle-tracking strain. Response was defined as a ≥15% decrease in LV end-systolic volume 6-month after CRT.ASDI ≥ 3.8% was the best predictor of response to CRT with a sensitivity of 78%, specificity of 100% and area under the curve (AUC) of 0.93 (p < 0.001). Two-dimensional radial dyssynchrony determined by speckle-tracking strain was also predictive of response to CRT with an AUC of 0.82 (p < 0.005). Interestingly, ASDI ≥ 3.8% was associated with the highest incidence of echocardiographic improvement after CRT with a response rate of 100% (7/7), and baseline ASDI correlated with reduction of LV end-systolic volume following CRT .ASDI can predict responders and LV reverse remodeling following CRT. This novel index using the 3-D speckle tracking system, which shows circumferential and longitudinal LV dyssynchrony and residual endocardial contractility, may thus have clinical significance for CRT patients. Cardiac resynchronization therapy (CRT) is an established therapy for advanced heart failure (HF) patients with wide QRS duration-8. HowevA newly developed three-dimensional (3-D) speckle tracking system using complete 3-D pyramidal datasets can quantify LV dyssynchrony,12. MoreThe study included 15 consecutive HF patients with New York Heart Association functional class III or IV, ejection fraction ≤ 35%, and QRS duration ≥ 120 msec, who underwent CRT. One of these patients was excluded from all subsequent analyses because of poor echocardiographic image quality, so that eventually 14 patients were enrolled in this study . Patients were studied before and 6 ± 1 months after CRT. We acquired digital LV 3-D volume data from the apical view with 4- or 6-beat electrocardiogram-gated acquisition. Routine digital grayscale 2-D and tissue Doppler cine loops were obtained, including mid-LV short axis views at the level of the papillary muscle and standard apical views . Sector width was optimized to allow for complete myocardial visualization while maximizing the frame rate. Mean volume rates were 22 ± 3 volumes/s in the apical views for gray scale imaging used for 3-D speckle tracking analysis, 45 ± 4 frames/s in the short axis view for gray scale imaging used for 2-D speckle tracking analysis, and 44 ± 3 frames/s in the apical axis view for tissue Doppler imaging used for tissue Doppler velocity analysis. LV end-diastolic volume, end-systolic volume (ESV), and ejection fraction were obtained with the modified biplane Simpson's method. A respoOur relatively simple version of the strain dyssynchrony index with 2-D speckle tracking strains represents the average of the wasted energy due to LV dyssynchrony as previously described in detail. In the Routine pulsed-Doppler was used to determine interventricular dyssynchrony as previously described,15. InteLongitudinal dyssynchrony was determined by using tissue Doppler cine loops from three consecutive beats which were obtained in three standard apical views as previously described in detail,16. RegiFor dyssynchrony analysis by 2-D speckle tracking radial strain, routine gray scale mid-LV short-axis images were used as previously described in detail,17. BrieA biventricular pacing system was implanted with an RV apical lead and an LV lead through the coronary sinus in all patients. The LV lead was placed in the lateral vein of seven patients, the posterolateral vein of four patients, and the anterolateral vein of three patients. Device implantation was successful for all patients without any major complications. The AV interval was adjusted for optimal diastolic filling by Doppler echocardiographic assessment of mitral inflow, and theThe interobserver and intraobserver reproducibility of the measurements of ASDI for randomly selected 10 patients was evaluated by two independent observers. To assess the interobserver reproducibility, measurements for all patients were analyzed by the second observer blinded to the values obtained by the first observer. For assessment of the intraobserver reproducibility, measurements of all patients were analyzed on 2 consecutive days by an observer blinded to the results of the previous measurements. The intraclass correlation coefficient was used to evaluate interobserver and intraobserver reproducibility.t test was used to compare group data obtained before and 6 months after CRT, and the unpaired Student's t test for comparison of group data for responders and non-responders. The diagnostic performance of LV dyssynchrony indexes for predicting response to CRT was evaluated by means of receiver operating characteristic curve analysis. Univariate linear correlation analysis was used for a comparison of baseline ASDI and reduction in ESV after CRT. For all tests, p value < 0.05 was considered statistically significant. All the analyses were performed with commercially available software .Continuous variables were expressed as mean ± SD. The paired The baseline clinical and echocardiographic characteristics of the 14 patients are summarized in Table Of the individual parameters including ASDI and conventional dyssynchrony measures, ASDI ≥ 3.8% proved to be the best predictor of response to CRT with a sensitivity of 78%, specificity of 100% and area under the curve (AUC) of 0.93 . On the other hand, pre-defined cut-off values of the conventional dyssynchrony parameters showed that CRT response rates were 67% (6/9), 62% (8/13), and 82% (9/11), respectively Figure . FurtherThe intraclass correlation coefficient for interobserver reproducibility was 0.961 , and the intraclass correlation coefficient for intraobserver reproducibility was 0.966 .The findings of our study demonstrate that ASDI as determined by means of 3-D speckle area tracking imaging can predict response to CRT, and baseline ASDI may be capable of predicting LV reverse remodeling following CRT. This is the first study to assess the utility of novel 3-D speckle area tracking strain for predicting response to CRT and LV reverse remodeling.CRT is an established therapeutic option for HF patients with severe symptoms and a wide QRS complex-8. AlthoThe LV myocardial function represents three different patterns of myocardial deformation, including radial direction , circumferential direction , and longitudinal direction . Because LV dyssynchrony is also a 3-D phenomenon, these three types of deformation do not provide the same information about the failing heart. STAR (the Speckle Tracking and Resynchronization) study, which is the recently conducted first prospective multi-centre study to assess the utility of radial, circumferential, transverse and longitudinal speckle tracking strain for predicting response to CRT and important long-term outcome events after CRT, verified the utility of multidirectional analysis for the quantification of LV dyssynchrony. This stIn this study, we found that baseline ASDI, as determined by means of novel 3-D speckle area tracking strain can predict response to CRT as well as predict LV reverse remodeling following CRT. 3-D area strain may provide new and more predictive endocardial information, because 3-D area strain coupled with both 3-D longitudinal and circumferential factors pertaining to the endocardium is considered to be the most sensitive to changes in myocardial function, especially in the failing heart or as a result of ischemia. 3-D area strain thus appears to be the ideal parameter to express LV dyssynchorny. Further3-D speckle tracking strain method was a novel developed technology and used in a few human studies. The potential advantages of 3-D speckle strain method were expression of myocardial/endocardial function of the whole heart, independency of tomographic imaging planes, and being able to analyze regional ventricular function using 3 different 3-D strains  from the same heart beat acquisition. On the contrary, the potential disadvantages were relatively low volume rate of 25-30 volume/sec and relatively low spatial resolution. However, these disadvantages will be improved with technical development in the future.3-D speckle tracking is a simple, feasible, and reproducible method for quantifying LV dyssynchrony,12, and Because the area tracking by means of 3-D speckle tracking system was developed only recently, this study covered a very small number of patients in a single-center study. Future studies of larger patient populations are therefore needed to test the accuracy of ASDI for predicting response to CRT and LV reverse remodeling. Moreover, the problem of the small number of the patients may be enhanced by the heterogeneous study population including 3 patients with ischemic cardiomyopathy and 4 patients with previously undergone implantation of a permanent RV pacing device. However, previous investigators have demonstrated that HF patients with RV pacing had similar dyssynchronous patterns and similar EF response and long-term outcome compared to those with left bundle branch block. A limitASDI can predict responders and LV reverse remodeling following CRT. This novel index using the 3-D speckle area tracking system, which shows circumferential and longitudinal LV dyssynchrony and residual endocardial contractility, thus have clinical significance for CRT patients.CRT: cardiac resynchronization therapy; 3-D: three-dimensional; AV: atrioventricular; VV: venoventricular; LV: left ventricular; RV: right ventricular; ASDI: strain dyssynchrony index using area tracking; AUC: area under the curve; ESV: end-systolic volume; IVMD: interventricular mechanical delay.The authors declare that they have no competing interests.KT designed the study, carried out subject recruitment, performed echocardiography, analysed the data, and wrote the manuscript. AY performed biventricular pacemaker implantation. TT, AK, KY, KR, AO, YF, KN, KM, and TO assisted recruitment and manuscript revision. HT, HK, and KH assisted in study design, data interpretation and manuscript revision.All authors read and approved the final manuscript.


The aim of this analysis was to look at the impact of gender on LV geometry and the predictors of myocardial perfusion reserve (MPR) in severe aortic stenosis (AS).It is well recognised that cardiac size is different between the two genders, even when corrected for body size. In AS echocardiographic studies suggest women have higher relative wall thickness and better preserved left ventricular (LV) ejection fraction (EF). There are little cardiac magnetic resonance (CMR) data on gender differences in severe AS, in particular MPR.Forty-one patients with isolated severe AS without obstructive coronary artery disease underwent adenosine stress perfusion CMR in a 1.5T scanner (Siemens Avanto); MPR was calculated from absolute myocardial blood flow during adenosine hyperaemia and rest determined by model-independent deconvolution of signal intensity curves with an arterial input function. Transthoracic echocardiography was used to assess AS severity, tissue Doppler derived diastolic function, LVRPP (LV rate pressure product=[systolic blood pressure(SBP) + peak aortic valve gradient]*heart rate) an estimate of myocardial work, and diastolic perfusion time .Females were older with significantly lower body surface area (BSA) and higher SBP. Despite equivalent AS severity females had significantly lower LV mass index (LVMI), LV volumes and wall thickness (relative and absolute), less late gadolinium enhancement (LGE) and higher EF. Resting and hyperaemic myocardial blood flow (MBF) were higher in females although MPR remained the same. Results are summarised in Tables These findings confirm the gender differences in LV geometry in response to pressure overload. The factors contributing to microvascular dysfunction also appear to be different. In males increased LV mass and relative wall thickness with associated diastolic dysfunction appear to be important determinants of microvascular dysfunction, in contrast to females where pressure gradients and diastolic perfusion time play a larger role. Paradoxically LVRPP was positively correlated with MPR in females. These differences may have implications for the treatment of microvascular dysfunction in females compared with males.


The aim of our study was to investigate whether remote preconditioning (RPC) improves myocardial function after ischemia/reperfusion injury in both normal and hypertrophic isolated rat hearts. This is the first time in world literature that cardioprotection by RPC in hypertrophic myocardium is investigated.Four groups of 7 male Wistar rats each, were used: Normal control, normal preconditioned, hypertrophic control and hypertrophic preconditioned groups. Moderate cardiac hypertrophy was induced by fludrocortisone acetate and salt administration for 30 days. Remote preconditioning of the rat heart was achieved by 20 minutes transient right hind limb ischemia and 10 minutes reperfusion of the anaesthetized animal. Isolated Langendorff-perfused animal hearts were then subjected to 30 minutes of global ischemia and reperfusion for 60 minutes. Contractile function and heart rhythm were monitored. Preconditioned groups were compared to control groups.Left ventricular developed pressure (LVDP) and the product LVDP × heart rate (HR) were significantly higher in the hypertrophic preconditioned group than the hypertrophic control group while left ventricular end diastolic pressure (LVEDP) and severe arrhythmia episodes did not differ. Variances between the normal heart groups were not significantly different except for the values of the LVEDP in the beginning of reperfusion.Remote preconditioning seems to protect myocardial contractile function in hypertrophic myocardium, while it has no beneficial effect in normal myocardium. The heart can be protected from an episode of acute lethal ischemia/reperfusion injury by applying brief non-lethal episodes of ischemia and reperfusion either to the heart itself (ischemic preconditioning = IP) or to an organ or tissue that is remote from the heart (remote preconditioning = RPC) -3.Initial enthusiasm for the beneficial effects of ischemic preconditioning of the heart in animal or human studies has given place to skepticism, since there has not yet been broad application of the method in clinical practice . ControvLarger multicenter trials would be required to confirm the results and novel methods should be employed to accurately estimate the influence of ischemic preconditioning in cardioprotection.Moreover, remote preconditioning of the hypertrophic heart has never been studied before. Moderate cardiac hypertrophy is a common state of many physiological and pathological conditions in humans: exercise, pregnancy, hypertension, heart valve disease or myocardial infarction. We have to note that RPC may refer to the same organ and to a distant organ or tissue. Remote preconditioning of the heart regarding transient ischemia caused to another organ or tissue far from the heart, has advantage over classic ischemic preconditioning or RPC regarding transient ischemia of a region of the heart other than the region examined for sustained ischemia, since it does not compromise the myocardium ,12.This study was designed to investigate if remote preconditioning at a distant organ improves myocardial function after ischemia/reperfusion injury in normal rat hearts and - for the first time in world literature - to examine the action of RPC in hypertrophic rat myocardium.Twenty eight male Wistar rats were used for this study. They were randomly divided into 4 groups of 7 animals each to form normal control , normal preconditioned (NP), hypertrophic control (HC) and hypertrophic preconditioned (HP) group.All animals were treated according to the Guidelines for the Care and Use of Laboratory Animals stated in the Greek law (160/1991) based on European Union regulations (European Commission Directive 86/609/EEC). Furthermore, the experimental protocol was approved by our Institutional Ethical Committee.Hypertensive myocardial hypertrophy was established to 14 animals  by concurrent administration of a synthetic mineralocorticoid  and saline for 30 days ,14. Cort++, 0.002 mg % fludrocortisone acetate) to drink in place of water for the first half of every day and a free quantity of a salt solution  for the rest of the day, in order to ensure a standard corticoid intake of 0.00025 mg per animal per day. Per os corticoid administration was adopted instead of subcutaneous injection [The animals intended for myocardial hypertrophy were given 12.5 cc of a salt solution with fludrocortisone acetate . Heparin was delivered intravenously (300 IU/kg) through the femoral vein. The right common femoral artery  of the animals that were scheduled to receive remote preconditioning was exposed and temporarily occluded for 20 minutes. Occlusion was achieved by a silicon loop tightened by a tourniquet. Then, circulation to the hind limb was restored for 10 minutes.2O during the entire duration of the experiment. The perfusion medium was a non-recirculating oxygenated  normothermic (37°C) Krebs-Henseleit bicarbonate (KHB) buffer. KHB buffer had the following ion concentrations in mmol/L: 25 NaHCO3, 4.7 KCl, 118.5 NaCl, 1.2 MgSO4, 1.2 KH2 PO4, 2.5 CaCl2 and 10 glucose (pH 7.4). The perfusion apparatus was water-jacketed to maintain a constant perfusion temperature of 37°C.Next steps of the procedure were common for all the groups. The hearts were rapidly excised and placed immediately in ice-cold perfusion buffer (0°C) before being mounted on a Langendorff apparatus. The ischemic time between excision and mounting was less than 1 min. The pericardium, the pleural cavities and the peritoneal cavity were at the same time explored for effusions; the liver weights as well as the lung weights of the rats were measured in order to calculate liver weight/body weight (LiW/BW) as well as lung weight/body weight (LW/BW) ratio; the aim was to investigate heart failure. Hearts were retrogradely perfused in an isovolumetric Langendorff mode at a constant hydrostatic pressure of 100 cm HTo determine left ventricular pressure, a catheter with a latex balloon on its tip was inserted into the left ventricle through an incision in the left atrial appendage. The balloon was tied securely into place and filled with water to give an end diastolic pressure between 6 and 10 mmHg. The adjusted volume remained constant throughout the experiment. This allowed continuous measurement of left ventricular pressures and recording of their alterations on a fixed preload. The balloon was connected to a pressure transducer via water-filled polyethylene tubing. Three stainless steel electrodes were inserted into the epicardium of both of the atria and of the right ventricle for three leads bipolar electrocardiogram recording. Left ventricular pressure and heart rhythm were monitored continuously and recorded on a computer. All hearts were allowed to stabilize for 10 min after being mounted. Baseline measurements were recorded during this period. Hearts were allowed to beat spontaneously throughout the experiment. Lethal or threatening arrhythmias  at the reperfusion period following the sustained ischemic insult were converted to normal rhythm by tapping the ventricle.Left ventricular function was assessed by left ventricular developed pressure (LVDP), end diastolic pressure (LVEDP) and the product HR (heart rate) × LVDP. Developed pressure is defined as peak systolic minus end diastolic pressure. In this experimental model, LVDP represents the heart's contractile ability which is not influenced by preload and afterload.th minute after reperfusion) were committed to paper.Zero flow ischemia was induced by clamping of the arterial line. Sustained ischemia lasted 30 min for all series. The reperfusion time was 60 min. The experiment protocol is concisely presented in table NC group was compared to NP group and respectively HC group was opposed to HP group. Values were expressed as the mean ± SEM. Two-tailed unpaired t test was used to compare BW, HW/BW ratio, LW/BW ratio, LiW/BW ratio, arrhythmia incidents and baseline hemodynamic data. Regular (not matching) two way ANOVA was performed to test for any differences between hemodynamic values  measured at various time points and examine if time point of reperfusion affected the result. Data in every separate group passed normality test and differences between SEMs in compared groups (raw data) were due to random sampling. A difference was considered statistically significant if p < 0.05.Body weight (BW) was similar between normal and hypertrophic heart rats, but heart weight to body weight (HW/BW) ratio markedly differed (hypertrophic approximately 46% in excess) as shown in table Baseline (stabilization period) values for LVDP, LVEDP and LVDPxHR did not significantly differ when control groups were compared to preconditioned groups as shown in table All hearts started beating within a few seconds at the onset of reflow. Thirty-minute sustained myocardial ischemia markedly affected myocardial function during reperfusion period in all groups: LVDP was lessened, LVEDP was elevated and the product LVDPxHR was reduced in every single group and at any time point of reperfusion, in comparison to baseline measurements figures , 2, 3. TMyocardial ischemia and infarction alter not only the contractile systolic properties of the heart but also its diastolic properties. Elevation of LVEDP against fixed preload is an indication of enhanced wall stiffness of the heart. In crystalloid perfused hearts, this enhanced stiffness is attributed to the increase of myofibrillar tone and the so-called erectile or garden hose effect whose relative magnitude is dependent on the severity of myocardial damage induced by ischemia ,17.Preconditioning did not significantly affect the LVDP between the normal groups p = 0.1314). However, time significantly influenced the values measured (p = 0.0011). As time passed, during reperfusion period, the preconditioned group retrieved from lower level; mean LVDP of the preconditioned group exceeded the normal group mean value after time point 45' (figure . HoweverLVEDP significantly differed between the two groups p = 0.0004) and in addition time point affected the result (p < 0.0001): non preconditioned myocardium was markedly "stiffer" than preconditioned at the early phase of reperfusion; however, thirty five minutes later and till the end of reperfusion period both groups behaved in a similar way  at any time point of reperfusion (p = 0.3931) for both normal groups  throughout all reperfusion time  figure . HypertrThe product LVDPxHR was markedly higher in preconditioned group (p < 0.0001) owned especially to LVDP factor . However, for the first 15 min of reperfusion difference was not significant , although the preconditioned group was superior all the time (time affection p = 0.01680) figure .In conclusion, RPC apparently improved post-ischemic left ventricular contractility of the hypertrophic heart according to this study, while it did not affect diastolic dysfunction.In laboratory studies, pressure overload induced cardiac hypertrophy has been shown to be associated with a greater susceptibility to ischemic/reperfusion injury in comparison to normal hearts. A number of morphologic, metabolic, and physiologic adaptive changes in the hypertrophic myocardium contribute to this phenomenon  -23. ThisIschemic preconditioning of hypertrophic myocardium has not been studied as extensively as preconditioning of normal myocardium. Unlikeness among the results of reported investigations might be due to different protocols -10,24-28Episodes of ventricular arrhythmia were rare in all groups. Conversion to normal rhythm was done automatically or by tapping the ventricles. Differences between the groups being compared were only due to chance table .Evidence exists for a heart in failure to be prone to arrhythmia when exposed to ischemia/reperfusion, but not for a hypertrophic myocardium. Very few laboratory researches deal with remote preconditioning and arrhythmia in normal hearts, thus, forming an opinion from the literature is not safe ,30.Several strategies of protection against ischemia/reperfusion injury by preconditioning the heart have been designed. A variety of experiment animals, duration of sustained ischemia and models of brief non-lethal ischemia  have been tried. The final aim of all these investigations is application to mankind and prevention or restriction of ischemia/reperfusion induced myocardial damage. In contrast to classic ischemic preconditioning, remote preconditioning is an intervention that does not expose myocardium to danger. Furthermore, myocardial hypertrophy is a common clinical situation. It is important to ascertain whether RPC is expected to improve the functional recovery of the heart .The contribution of this study is that remote preconditioning using transient limb ischemia as the remote stimulus can advantageously be applied to hypertrophic myocardium in rats, while it has no beneficial effect in normal hearts.RPC: remote preconditioning; IP: ischemic preconditioning; LVDP: left ventricular developed pressure; LVEDP: left ventricular end diastolic pressure; HR: heart rate; NC: normal control; NP: normal preconditioned; HC: hypertrophic control; HP: hypertrophic preconditioned; HW: heart weight; BW: body weight; LW: lung weight; LiW: liver weight; SEM: standard error of median; KHB: Krebs-Henseleit bicarbonate;The authors declare that they have no competing interests.All authors have read and approved the final manuscript.CV: conceived of the study, performed the study design and the experiment procedures, collected and analyzed data, wrote manuscript.AL, FT, and NT: designed study, collected and analyzed data, wrote manuscript.