To assess prognosis of pulmonary thromboembolism using tissue Doppler echocardiography and brain natriuretic peptide.Patients aged over 18 years were evaluated within 24 hours of confirmed diagnosis (chest tomography/pulmonary scintigraphy) of pulmonary embolism using two-dimensional echocardiography and tissue Doppler for right ventricular systolic (s') velocities, strain, tissue tracking and myocardial performance index. Plasma brain natriuretic peptide was also obtained within 24 hour. The influence of echocardiographic and clinical variables on mortality was examined (up to 12 months) using Cox regression analysis.Out of 118 patients, 100 patients were included in the study . Right ventricular dysfunction was observed in 28% using two-dimensional echocardiography. Tissue Doppler right ventricular variables  were decreased only for patients with right ventricular dysfunction, whereas myocardial performance index and systolic pulmonary artery pressure were increased. Mean brain natriuretic peptide value was 66±111pg/mL, also increased in patients with right ventricular dysfunction (136±146pg/mL). Mortality was 11% and related to age, malignancy and brain natriuretic peptide levels. The only echocardiographic variables capable of predicting events by univariate analysis were pulmonary pressure and right ventricular s' velocity. However, multivariate analysis showed only malignancy to predict mortality in this group.Lower tissue Doppler systolic velocities and elevated brain natriuretic peptide levels are associated with poorer prognosis in patients with pulmonary thromboembolism; but only malignancy emerged as an independent predictor of mortality. Two-dimensional echocardiogram emerges as the preferred test to assess right ventricular (RV) performance since it is non-invasive, devoid of radiation, portable and can be serially undertaken. However, echocardiographic evaluation presents limitations because of RV structural complexity. Alternatively, tissue Doppler (TD) can be used to complement the two-dimensional echocardiogram. This methodology relies on the analysis of myocardial velocities to increase the sensitivity of the examination to detect myocardial dysfunction. In addition, TD can be used for prognostic evaluation in certain situations, such as identification of higher mortality and cardiovascular events in patients with cardiomyopathy and RV involvement. However, there is no description of the influence of TD in the prognosis of patients with PE. On the other hand, in regard to the B-type atrial natriuretic peptide (BNP), although its importance for risk stratification is well-known for patients with heart failure, there is limited data regarding BNP and prognosis in PE,8. Patients with PE and increased BNP seem to present a higher morbidity and mortality, but with a lower cutoff value (BNP<50pg/mL) than that used for heart failure. However, there is no conclusive data about the contribution of this biomarker specifically in regard to mortality after PE,9.Mortality in pulmonary thromboembolism (PE) is essentially related to hemodynamic instability resulting from right ventricular dysfunctionTo prospectively evaluate right ventricular function using two-dimensional echocardiogram with tissue Doppler in patients with pulmonary thromboembolism, analyzing its relation with the B-type atrial natriuretic peptide and the prognosis.. Other exclusion criteria were: chronic obstructive pulmonary disease, arrhythmias , inadequate echocardiographic window and missing BNP measurements. All the patients were treated with anticoagulation ; patients with hemodynamic instability  received thrombolytic therapy . Patients were prospectively evaluated during hospital stay and followed after discharge via telephone calls up to 12 months to assess mortality. The study was approved by the institutional review board (CAAE: 0064.0.028.000-07) and all the patients signed a written informed consent form to participate in the study.From August 2007 to January 2010, all patients admitted to the Emergency Room Unit or inpatients with clinical suspicion of PE (pain/dyspnea of sudden onset in the previous week) were invited to participate in the study. PE was confirmed by chest multi-slice computed tomography showing a complete or partial filling defect in the pulmonary vessels or by a pulmonary scintigraphy with a high probability of PE. Patients with left ventricular dysfunction (ejection fraction <55% by echocardiogram) were not included in the study to avoid the influence on BNP. Pulsed and continuous Doppler and color flow mapping were used to evaluate the presence and grade of valve regurgitation. Additional measurements of the ventricular diastolic diameters were obtained from the apical four-chamber view to obtain the RV/LV ratio. Parasternal, apical and subcostal views were used to evaluate RV systolic contractility. The presence of RV hypokinesia associated with abnormal septum motility (flattening) and/or RV dilation (RV/LV ≥1) was regarded as RV dysfunction by two-dimensional echocardiogram. Pulmonary pressure measurements were obtained from the tricuspid regurgitation, and the RV-right atrial gradient was added to the right atrial pressure estimated by the collapsibility of the inferior vena cava. Transmitral Doppler measurements were obtained for evaluation of the diastolic function .Patients underwent a comprehensive echocardiogram  up to 24 hours after the event, including measurements of the left ventricular (LV) diameters and ejection fraction according to the recommendations of the American Society of Echocardiography. Patients were asked to breathe more slowly during the Doppler measurements. TD with color flow mapping was carried out from the apical 4-chamber view, with sector scan size and depth optimized to acquire images with a minimum frame rate of 100 fps, for adequate measurements of variables such as tissue tracking, strain and strain rate. Myocardial performance index (MPI) was obtained by TD of the RV and given as the ratio between isovolumetric contraction time (ICT) + isovolumetric relaxation time (IRT) divided by the ejection time (ET): MPIRV=(ICT+ IRT)/ET. The average of three Doppler measurements was used for analysis. The data were digitally stored and subsequently analysed.TD was obtained from the apical 4-chamber view of the septal, lateral and RV (tricuspid) anullus for measurements of systolic (s') and diastolic (e' and a') velocities, with the cursor parallel to the ventricular wall to minimize the influence of the angle on Doppler measurements . Estimat®, Siemens Heathcare Diagnostics, Bayswater, Australia).Plasma BNP levels were measured up to 24 hours after confirmed PE. Blood was collected in a tube containing ethylenediaminetetraacetic acid and separated by centrifugation. BNP was measured by radioimmunoassay , version 17.0 . Statistical significance was determined at the 0.05 level. Measurements of TD myocardial velocities, tissue tracking, strain and strain rate were repeated after 3 months to evaluate inter-observer and intra-observer variability and tested by the intra-class correlation coefficient.Continuous variables were expressed as mean±standard deviation (SD) while categorical variables were expressed in proportions. Univariate analysis was used to assess the influence of clinical and echocardiographic variables on mortality up to 12 months after PE; χFrom a total of 118 patients with confirmed diagnosis of PE by tomography (n=114) or ventilation/pulmonary perfusion scintigraphy (n=4), 7 had inadequate echocardiographic windows, 5 refused to participate in the study, 2 did not have their BNP measured, 2 had associated left ventricular dysfunction and 2 presented arrhythmia. Therefore, the group included 100 patients and none of them was lost to follow-up. Deep venous thrombosis (29%) was the most frequent predisposing factor, followed by malignancy (24%), surgery (22%) and long-distance flight (6%). Most patients underwent conventional treatment, with only 4 patients treated with thrombolysis. Male gender (60%) was more predominant, with a mean age of 55±17 years. The mean BNP value found was 66±111pg/mL. Tricuspid regurgitation was present in 66 patients, and pulmonary pressure was 41±13mmHg. Of the 100 patients studied, 28 showed RV dysfunction according to the pre-established criteria: measurements of RV TD variables  were decreased only for patients with RV dysfunction; MPI and pulmonary artery systolic pressure were also increased for these patients. BNP, in turn, was 30±39pg/mL (median=12pg/mL) for patients without RV dysfunction , and incDuring the follow-up period of 12 months there were 11 deaths; only 3 occurred within 1 month of PE. According to the univariate analysis, mortality was related to plasma BNP , age and the presence of malignancy. Of the echocardiographic variables, only TD RV s' velocity and pulmonary systolic pressure were correlated with mortality. No other variable derived from TD, or even MPI, showed significant influence on survival . MultivaIntraclass correlation coefficient was 0.98 (intra-observer) and 0.97 (inter-observer) for RV s' wave velocity; 0.98 (intra-observer) and 0.96 (inter-observer) for tissue tracking and 0.95 (intra-observer) and 0.94 (interobserver) for strain measurements. Measurements of strain rate were not used for the analysis because of their marked variability.,3. Our prevalence of RV dysfunction was relatively low (28%) compared to that in literature,3. Two factors may have contributed to this finding: first, since patients with left ventricular dysfunction were excluded, those patients with preexisting RV myocardial involvement associated with cardiomyopathy may have been equally eliminated. Additionally, in other reports, multiple echocardiographic criteria such as RV dilatation and hypokinesia, the presence of pulmonary hypertension, inferior vena cava dilatation and RV free wall hypertrophy have been used to evaluate the RV. These criteria, used either isolated or in combination might lead to a higher sensibility  of the method. To characterize RV dysfunction in our study we did not include the presence of pulmonary hypertension, dilation of inferior vena cava or hypertrophy of the chamber.Acute PE is a disease with high prevalence, frequently underdiagnosed, with resulting treatment failure and complications. Prognosis of PE is related to the preexisting cardiovascular disease, the degree of pulmonary hypertension and vascular obstruction, and mainly, to the presence of RV dysfunction. Two-dimensional echocardiogram is routinely used to evaluate RV performance in PE in order to identify patients with higher risk of morbimortality, with indication of a more aggressive treatment,2. In our population, consisting mostly of hemodynamically stable patients, mortality up to 1 year was 11%. Isolated RV dysfunction evaluated by the two-dimensional echocardiogram, however, was not able to identify a group of patients with higher mortality. Despite the established risk for patients with PTE and hemodynamic instability due to right ventricular involvement, a systematic review of the studies with PE in hemodynamically stable patients did not confirm the utility of two-dimensional echocardiogram to predict a higher risk of death. The power of echocardiographic RV dysfunction to predict inhospital mortality was low . This is important because, although there is consensus in regard to more aggressive treatment in the presence of hemodynamic instability, some institutions may turn the same treatment to RV echocardiographic dysfunction, increasing the risks of thrombolysis. On the other hand, differently from the two-dimensional echocardiogram, TD RV myocardial velocities were able to identify the patients with a higher risk of death up to 1 year after the event. TD has been shown to be a very useful technique for quantitative evaluation of LV diastolic and systolic functions, being more sensitive to detect earlier functional myocardial abnormalities,17. In recent studies involving other diseases (including heart failure and hypertension), myocardial systolic velocities were able to predict mortality or the presence of cardiovascular events. TD velocities have been proved to be a rapid and simple means to study RV function and prognosis in situations where this chamber is observed to be impaired,19, however, there are no studies relating TD with prognosis in PE. In our study though myocardial velocities were more sensitive to assess outcome, they were not able to independently predict death after PE. TD is influenced by age, with decreased velocities in elderly patients, which may have contributed to the lower accuracy of this method. Other variables derived from TD (strain and tissue tracking) were not able to predict events even in univariate analysis.When adequately treated, mortality in PE is low (<5%). Patients who are hemodynamically unstable present a higher risk because of RV dysfunction, with mortality higher than 25%In regard to the MPI, it was observed that this measurement was increased in patients with RV dysfunction; however, no midterm correlation with prognosis after PE was observed in this population. Increased pulmonary resistance, such as seen in PE, would lead to a prolonged RV isovolumetric time and, consequently, to an increased RV MPI. Measurements of PMI by TD can be technically difficult in patients with dysfunction, which may partially explain this finding.. Pulmonary vasoconstriction after PE results in increased right heart work to increase pulmonary pressure; depending on the pulmonary pressure increase, RV failure may ensue. Since BNP is secreted in response to increased atrial or ventricular stress, it reflects pressure or volume overload. Pieralli et al. studied patients with PE who were hemodynamically stable. A BNP value >50pg/mL, along with echocardiogram, identified a group of patients with a higher number of adverse complications . In the present study population, we assessed the association of BNP with mortality, not with complications, and statistical significance was not maintained after the multivariate analysis. BNP relation with RV pressures is not linear, and several factors influence secretion and elimination of this biomarker, including left ventricular systolic dysfunction with increased filling pressures. To avoid this influence on BNP, patients with systolic ventricular dysfunction were excluded. Previous studies where BNP was presented as an independent factor for higher risk of events in PE, either lack reference to left ventricular function or include patients with heart failure, which would certainly have an influence on BNP levels. In the absence of left ventricular dysfunction, the association of BNP with mortality in PE is probably limited, and its importance should be carefully evaluated. Diastolic dysfunction is only modestly correlated with BNP, with better correlations in cases of marked diastolic dysfunction or in the setting of associated systolic dysfunction,22. In this study, since it would not be possible to exclude patients with diastolic dysfunction, LV filling pressures were estimated. The low E/e' values found suggest the absence of marked diastolic dysfunction; we believe that the influence of diastolic dysfunction on BNP values can thus be minimized.In regard to BNP, it was elevated in patients with RV dysfunction, and the association with mortality in the univariate analysis confirmed the literature findings. Older age is an additional factor for higher comorbidity by other diseases.Other factors associated with higher mortality were increased pulmonary pressures and older age. Persistently elevated pulmonary pressures are associated with a higher prevalence of chronic PE and RV dysfunction,26. Patients with PE and malignancy more frequently have advanced disease and have a worse prognosis. In our population, a large number of patients with PE presented with malignancy (24% of the studied population), with an inevitable influence on mortality, especially due to the low prevalence of hypotension or shock in the group: only one death was directly attributed to massive PE with hemodynamic instability and right ventricular failure. Of the 11 deaths, 10 patients had cancer. Mortality was related to the baseline disease in all the patients, except for one patient (infection). In the midterm follow-up, PE was most likely an important contributor to mortality than the cause of death itseft. However, it is important to emphasize that, differently from other studies, most patients were hemodynamically stable and that patients with heart failure were excluded.Regarding PE association with malignancy, venous and arterial thromboembolism are frequently found in patients with cancer; they can be potential causes of morbimortality and are predictors of a higher risk in this population, thus allowing adequate analysis by TD. Additionally, in regard to the technique, TD depends on image quality, requiring a high frame rate for an adequate tracings. Although pulsed TD has shown to be of excellent quality, probably as a result of interference related to the respiratory pattern, other TD measurements (strain rate) may have suffered more influence from image quality.Some limitations to the study should be pointed out: only the basal segment of RV was analyzed by TD. However, it is known that RV involvement in PE affects the entire free wall, occasionally sparing the apexThe presence of malignancy is related to higher mortality in patients with acute pulmonary thromboembolism. In the studied population, tissue Doppler and B-type atrial natriuretic peptide did not correlate independently with a worse prognosis.


Although many electrocardiographic abnormalities have been reported previously, prolonged QTC interval represented as the most important ECG finding in patients with liver cirrhosis. Echocardiography can detect structural cardiac abnormalities in cirrhotic patients.The present study aimed to determine the correlation between QTC prolongation and echocardiographic findings in end stage liver cirrhosis.The present study was conducted on 100 patients selected through convenient sampling. We recruited 80 cirrhotic patients with CHILD score > B or MELD score > 15 from the transplantation ward of Nemazee educational hospital. A complete echocardiographic study, including chamber quantification, a complete flow Doppler, and tissue Doppler analysis, was performed for each patient using a GE vivid 3 system equipped with Tissue Doppler Imaging (TDI). Then, twelve-lead ECG was carried out and QTc interval was calculated in all patients. The data were analyzed using the SPSS statistical software (v. 13) and Pearson’s correlation coefficient. P value < 0.05 was considered statistically significant.The patients’ age ranged from 20 to 60 years old and 62.5% of them were male. According to the results, the only parameter which was significantly associated with prolonged QTc interval was Left Ventricular End Diastolic Dimension (LVEDD). Additionally, a linear direct relationship was found between corrected QT interval and LVEDD .The current study showed a positive correlation between QTC prolongation as an electerocardiographic finding and LVEDD in echocardiography of the cirrhotic patients. This may indicate a direct relationship between the electrophysiological problems and the severity of volume overload in cirrhotic patients. Despite the frequent abnormalities in cardiac structure and function in the patients with end-stage liver disease, decreased afterload because of vasodilatation makes the diagnosis of myocardial dysfunction difficult. The patients with cirrhosis have a large spectrum of circulatory disturbances, including increased Cardiac Output (CO), reduced systemic vascular resistance, and increased vascular compliance , 2. In tThe present study aims to evaluate the correlation between echocardiographic and electrophysiological abnormalities in cirrhotic patients.All the subjects were selected from the transplantation ward of Nemazee educational hospital, a referral center for liver transplantation in the Middle East. This study was approved by the Review Board and Ethics Committee of Shiraz University of Medical Sciences, and written informed consents were obtained from all the participants. At first, 100 patients were selected through convenient sampling and after considering the exclusion criteria, 80 patients  with liver cirrhosis of various etiologies were entered into the study. Liver cirrhosis was determined on the basis of liver biopsy, presence of various laboratory data, or image studies including ultrasonography, Computed Tomography (CT) scan, and endoscopic findings which had been performed several months prior to the final enrollment.The patients were 20 to 60 years old with documented cirrhosis and CHILD class > B or Model for End-stage Liver Disease score (MELD score) > 15.On the other hand, the patients with coronary artery disease, significant vavular heart disease (moderate to severe), any history of arrhythmia or taking antiarrhythmic drugs, electrolyte imbalances, and history of taking any medication that could prolong QTc interval were excluded from the study.Surveillance consisted of a clinical examination performed by an experienced physician, imaging studies, and biopsy performed within one month of surveillance of all enrolled patient by an experienced radiologist or gastroenterologist. In addition, all the necessary lab data including a full panel of blood biochemistry, including blood count, liver function, kidney function, and coagulation, were collected. The imaging studies consisted of Ultrasonography and CT scan which were performed by a professional radiologist. Besides, endoscopic procedures and liver biopsy were carried out by an experienced gastroenterologist. Then, the biopsy specimens were observed and diagnosed by a skilled pathologist. Afterwards, another expert pathologist reviewed all the biopsy specimens that formed the basis for diagnosis of cirrhosis. Whenever possible, all the investigations were performed within the same month by the same specialist. All the investigations were documented and scored.A complete echocardiographic study, including chamber quantification, a complete flow Doppler, and tissue Doppler analysis, was performed using a vivid 3 system  equipped with Tissue Doppler Imaging (TDI). The frequency of the transducer was 2.5 MHz.In lateral decubitus, Para sternal M-mode images were used to measure Left Ventricular (LV) and Left Atrial (LA) size. In the 4 chamber view, mitral inflow velocity was measured by positioning the sample volume on the tip of the mitral valve and peak early diastolic velocity (E), peak late diastolic velocity (A wave), and E / A ratio were measured.In the apical 4-chamber view, the TDI cursor was placed near the septal border of the mitral annulus, where the mitral annulus moved along the sample volume and early diastolic velocity (E’), late diastolic velocity (A’), systolic velocity, Isovolumic Contraction Time (IVCT), Isovolumuc Relaxation Times (IVRT), and E / E’ were measured by pulse wave Doppler. Ejection Fraction (EF), Tricuspid Annular Plane Systolic Excursion (TAPSE), and peak tricuspid regurgitation velocity were also measured at the apical 4 chamber view. Besides, TR velocity was used to calculate the Pulmonary Artery Pressure (PAP) using the simplified Bernouii equation. Diastolic dysfunction was defined by E’ < 8 m / sec, while systolic dysfunction was defined by EF < 55 or IVCT > 65 msec. Recording and calculation of different cardiac chambers dimensions were performed according to the recommendation of American Society of Echocardiography guidelines.Twelve-lead ECG was carried out in all the patients with paper speed of 25 mm / s by electrocardiography . The QT interval duration was manually calculated from the beginning of the q wave to the end of the T wave in all 12 leads. Moreover, the maximal QT interval duration was measured among these 12 leads. QT intervals were corrected in accordance with the rate using the BAZET formula: QTC = QT / √RR. Accordingly, the adjusted QT of 460 milliseconds or more in women and 440 milliseconds or more in men was considered as prolonged QT interval.All the statistical analyses were performed using the SPSS statistical software (v. 13). Pearson’s correlation coefficient test was employed to determine the strength of linear relationships between the variables. The data were presented as mean ± SD. Besides, P value < 0.05 was considered as statistically significant.All the patients were between 20 and 60 years old with the mean age of 41.01 ± 14 years. Besides, the mean QTc interval was 490.02 ± 51 msec. All patients had a normal resting or high normal Left Ventricular (LV) Ejection Fraction (EF). In addition, Pulmonary Acceleration Time (PAT) was greater than 100 msec in all the patients that showed normal pulmonary arterial pressure. Moreover, systolic myocardial velocities at the septal angle of mitral annulus were greater than 0.0 6 m / s in all the patients with the mean value of 0.08 ± 0.01 m / s. Yet, nineteen patients had E’ < 8 cm / s that showed diastolic dysfunction. Also, the mean IVCT was 63.63 ± 7.82 msec and 67% of the patients had IVCT > 65 msec that showed subclinical systolic dysfunction. The mean IVRT was 74.95 ± 9 msec. Moreover, 50% of the patients had E / E’ > 8 that showed increased LV end diastolic pressure at rest. Tricuspid Annular Plane Systolic Excursion (TAPSE) was greater than 20 mm and systolic myocardial velocity at the lateral side of tricuspid annulus was greater than 11 cm / s in all the patients indicating normal RV Function at rest. QTC was prolonged in 65% of the females and 96% of the males. Bivariate analysis showed that the only echocardiographic variable which had a significant relationship with prolonged QTc was LV End Diastolic Dimension (LVEDD) . Additionally, a direct linear relationship was found between QTc interval and LVEDD as a marker of volume overload; such a way that the QTc intervals were more prolonged in larger ventricles . In contDespite the increased basal CO, systemic vascular resistance, arterial pressure, and cardiac response to physiologic or pharmacologic stimuli are decreased in cirrhotic patients. Existence of these components together is the basis of a phenomenon called Cirrhotic Cardiomyopathy (CCM) -9. CCM dElectrophysiological abnormalities, including prolonged repolarization time and impaired excitation-contraction coupling, have been found in cirrhotic patients , 17. ProThe present study aimed to determine any relationship between echocardiographic findings and QTC prolongation. The mean QTc interval was 490.02 ± 51 msec. Besides, QTc interval was prolonged in 65% of females and 96% of males, supporting the previous studies . AlthougLeft Ventricular Ejection Fraction (LVEF) was normal or supernormal in all the patients in the resting state, which indicates normal or high CO. PAT was also normal in all the patients PAT > 100 msec), showing normal pulmonary arterial pressure. Besides, TAPSE was greater than 20 mm and systolic myocardial velocity at the lateral side of tricuspid annulus was greater than 0.11 m / s in all the patients. These items showed normal RV systolic function in the resting state. The normal CO in the presence of many cardiac problems may be due to the decreased peripheral vascular resistance (00 msec, Considering the relationship between QTc prolongation and overloaded heart, based on the findings of our study, tight volume control in the cirrhotic patients with prolonged QTc is strongly recommended due to the possibility of decompensation after each procedure.In conclusion, our study showed a positive correlation between QTc prolongation, as an EKG finding, and LVEDD in echocardiography of cirrhotic patients. This may indicate a relationship between the electrophysiological problems and overloaded heart in these patients.


P < 0.05 DM-Sed vs C-Sed and DM-Ex). Papillary muscle function was depressed in DM-Sed compared to C-Sed. Exercise attenuated this change in DM-Ex. Lipid hydroperoxide concentration was higher in DM-Sed than C-Sed and DM-Ex. Catalase and superoxide dismutase activities were lower in diabetics than controls and higher in DM-Ex than DM-Sed. Glutathione peroxidase activity was lower in DM-Sed than C-Sed and DM-Ex. Conclusion. Low intensity exercise attenuates left atrium dilation and myocardial oxidative stress and dysfunction in type 1 diabetic rats.We evaluated the effects of a low intensity aerobic exercise protocol on cardiac remodeling and myocardial function in diabetic rats. Wistar rats were assigned into four groups: sedentary control (C-Sed), exercised control (C-Ex), sedentary diabetes (DM-Sed), and exercised diabetes (DM-Ex). Diabetes was induced by intraperitoneal injection of streptozotocin. Rats exercised for 9 weeks in treadmill at 11 m/min, 18 min/day. Myocardial function was evaluated in left ventricular (LV) papillary muscles and oxidative stress in LV tissue. Statistical analysis was given by ANOVA or Kruskal-Wallis. Echocardiogram showed diabetic groups with higher LV diastolic diameter-to-body weight ratio and lower posterior wall shortening velocity than controls. Left atrium diameter was lower in DM-Ex than DM-Sed (C-Sed: 5.73 ± 0.49; C-Ex: 5.67 ± 0.53; DM-Sed: 6.41 ± 0.54; DM-Ex: 5.81 ± 0.50 mm;  Diabetes mellitus is an important public health issue due to its high prevalence and increased morbidity and mortality. Cardiovascular disease is a major cause of death in diabetic patients . CardiacThe pathophysiology of diabetic cardiomyopathy is not completely understood as several mechanisms can be involved; these include myocyte hypertrophy, myocardial fibrosis, contractile dysfunction, calcium handling and mitochondrial function changes, and nitric oxide signaling impairment –8. HyperRegular physical exercise is an established nonpharmacological strategy used as an adjuvant therapy in heart failure from different etiologies , 14. Cli In vivo evaluation of cardiac function is subjected to myocardial function modulation by hemodynamic and systemic metabolic abnormalities. Left ventricular isolated papillary muscle preparations allow us to properly control preload and afterload and analyze intrinsic myocardial function without the effects of systemic metabolic changes [ in vivo cardiac remodeling and in vitro myocardial function in rats with streptozotocin-induced diabetes mellitus. As oxidative stress is associated with diabetes cardiomyopathy and can be influenced by physical exercise, we also analyzed myocardial oxidative stress in diabetic rats.In diabetes, physical exercise reduces cardiovascular risk factors and improves glycemic control, functional capacity, and muscle strength –29. Howe changes –36. Furt changes , 38. The ad libitum. All experiments and procedures were approved by Botucatu Medical School Ethics Committee, UNESP, Botucatu, SP, Brazil.Male Wistar rats were purchased from the Central Animal House at Botucatu Medical School, UNESP. All animals were housed in a room under temperature control at 23°C and kept on a 12-hour light/dark cycle. Food and water were suppliedn = 14); exercised control ; sedentary diabetes ; and exercised diabetes . Diabetes was induced by intraperitoneal injection of streptozotocin  at the dose of 50 mg/kg diluted in 0.01 M citrate buffer pH 4.5 [The rats were assigned into four groups: sedentary control  as previously described . The proNarco Bio-System, model 709-0610, International Biomedical Inc., USA).Systolic blood pressure was measured at the end of experiment by the tail-cuff method  using anEchocardiographic evaluation was performed using a commercially available echocardiograph  equipped with a 5–11.5 MHz multifrequency probe. Rats were anesthetized by intraperitoneal injection of a mixture of ketamine (50 mg/kg) and xylazine (0.5 mg/kg). A two-dimensional parasternal short-axis view of the left ventricle (LV) was obtained at the level of the papillary muscles. M-mode tracings were obtained from short-axis views of the LV at or just below the tip of the mitral-valve leaflets and at the level of the aortic valve and left atrium –46. M-mo2 and 5% CO2 (pH 7.38). The composition of the Krebs-Henseleit solution in mM was as follows: 118.5 NaCl, 4.69 KCl, 1.25 CaCl2, 1.16 MgSO4, 1.18 KH2PO4, 5.50 glucose, and 25.88 NaHCO3. The spring clips were attached to a Kyowa model 120T-20B force transducer and a lever system which allowed for muscle length adjustment. Preparations were stimulated 12 times/min at a voltage 10% above threshold.Two days after the echocardiographic study, intrinsic myocardial contractile performance was evaluated in isolated LV papillary muscle preparation as previously described –50. RatsLmax). After a 5-minute period, during which preparations performed isotonic contractions, muscles were again placed under isometric conditions and length-tension curve apex was determined. A 15-minute period of stable isometric contraction was imposed prior to the experimental period. One isometric contraction was then recorded for later analysis.After a 60-minute period, during which the preparations were permitted to shorten whilst carrying light loads, muscles were loaded to contract isometrically and stretched to the apices of their length-tension curves (2), resting tension , time to peak of tension , maximum rate of tension development , and maximum rate of tension decline . To evaluate contractile reserve, mechanical papillary muscle performance was evaluated at basal condition and after the following inotropic stimulation: postrest contraction, extracellular Ca2+ concentration increase, and beta-adrenergic agonist isoproterenol addition to the nutrient solution [The following parameters were measured from isometric contraction: peak of developed tension  was calculated from muscle weight and length by assuming cylindrical uniformity and a specific gravity of 1.0. All force data were normalized for muscle CSA. Papillary muscles with CSA > 1.7 mmAfter dissecting papillary muscle, atria and ventricles were separated and weighed. Fragments of lung and left and right ventricles were weighed before and after drying sessions (65°C for 72 h) to evaluate the wet-to-dry weight ratio.Transverse LV sections were fixed in 10% buffered formalin and embedded in paraffin. Five-micrometer-thick sections were stained with hematoxylin and eosin. From each LV, the smallest transverse diameter was measured in at least 50 myocytes, in which the nucleus could be clearly identified . MeasureμL aliquot of the hydrolysate was dried in the SpeedVac Concentrator; 1 μL of deionized water was added; and the sample transferred to a Teflon tube. One milliliter of potassium borate buffer (pH 8.7) was added to maintain constant pH and the sample was oxidized with 0.3 mL of chloramine T solution at room temperature for 20 min. The addition of 1 mL of 3.6 M sodium thiosulfate and thorough mixing for 10 s stopped the oxidative process. The solution was saturated with 1.5 g KCl. The tubes were capped and heated in boiling water for 20 min. After cooling to room temperature, the aqueous layer was extracted with 2.5 mL of toluene; 1.5 mL of toluene extract was transferred to a tube; and 0.6 mL of Ehrlich's reagent was added. The color was allowed to develop for 30 min. Absorbance was read at 565 mm against a reagent blank. Deionized water and 20 μg/mL HOP were used as the blank and standard, respectively.To estimate myocardial collagen content, hydroxyproline concentration was measured in LV tissue as previously described , 52. Bri++ method using an enzymatic colorimetric method that incorporates polyethylene glycol-modified cholesterol ester oxidase.Biochemical parameters were measured in serum using a spectrophotometer from Pharmacia Biotech . Analyses were performed with a CELM kit . Glycemia was determined by enzymatic method using glucose oxidase and peroxidase. Total cholesterol levels were measured enzymatically using cholesterol ester/oxidase. High-density lipoprotein (HDL) concentration was measured after precipitation of VLDL and LDL by the sodium phosphotungstate/MgμM ammonium ferrous sulfate, 100 μM xylenol orange, 25 mM sulfuric acid, and 4 mM butylated hydroxytoluene. The solution was incubated for 30 min at room temperature and measured at 560 nm. Glutathione peroxidase was assayed in 15 μL using 0.15 M phosphate buffer, pH 7.0, containing 5 mM EDTA, 0.1 mL of 0.0084 M NADPH, 4 μg of glutathione-reductase, 1.125 M sodium azide, and 0.15 M glutathione reduced form (GSH) in a total volume of 0.3 mL. Superoxide dismutase (SOD) activity was determined using its ability to inhibit reduction of nitroblue tetrazolium, in medium containing 50 mM phosphate buffer pH 7.4, 0.1 mM EDTA, 50 μM NBT, 78 μM NADH, and 3.3 μM phenazine methosulfate. One unit of SOD was defined as the amount of protein needed to decrease the reference rate to 50% of maximum inhibition. Enzyme activities were analyzed at 25°C using a microplate reader system . Catalase activity was determined in a mixture containing 10 mM hydrogen peroxide and sodium phosphate buffer 50 mM, pH 7.0, in a final volume of 0.3 mL. Catalase unit was defined as the amount of enzyme related to μmol H2O2 decomposition in a first order rate constant during 15 s, at 240 nm. All reagents were purchased from Sigma .Oxidative stress was assessed as previously described , 53. MyoP < 0.05.Values were expressed as mean ± standard deviation or median and 25th and 75th percentiles, according to normal or nonnormal distribution, respectively. Parameters with normal distribution were compared by one way ANOVA followed by the Bonferroni post hoc test and nonnormal parameters were compared by Kruskal-Wallis and the Dunn post hoc test . Systat 12 for Windows software was used for analyses. Statistical significance was accepted at the level of P > 0.05), glycemia , and final systolic blood pressure  did not differ between groups. Final glycemia was higher in diabetic groups than controls and slightly lower in DM-Ex than DM-Sed  and LV myocyte diameter  did not differ between groups. Total cholesterol concentration was higher in both DM groups than controls and lower in DM-Ex than DM-Sed (C-Sed: 90.5 (86.5–100); C-Ex: 98 (86.5–121); DM-Sed: 188 (182–198); DM-Ex: 148 (136–165) mg/dL; P < 0.05). HDL-cholesterol was lower in DM-Sed than C-Sed and DM-Ex (C-Sed: 41.6 (37.8–49.0); C-Ex: 38.6 (37.1–45.3); DM-Sed: 21.5 (20.8–24.5); DM-Ex: 40.8 (30.4–43.8) mg/dL; P < 0.05).Myocardial hydroxyproline concentration (C-Sed: 2.06 ± 0.50; C-Ex: 1.96 ± 0.09; DM-Sed: 2.19 ± 0.40; DM-Ex: 2.29 ± 0.36 mg/g; Oxidative stress data are shown in In this study, we evaluated the effects of a low intensity physical exercise protocol on cardiac remodeling and myocardial oxidative stress and function in type 1 diabetic rats.We used a low intensity exercise protocol for nine weeks including one week of adaptation. Low intensity exercise protocols have been used in diabetic rats as they may not tolerate more extensive or intense periods of exercise , 54, 55.As expected, diabetic animals presented heightened glycemia increase and reduced body weight and physical exercise slightly attenuated serum glucose increase in DM-Ex group. As blood pressure did not differ between groups, we can discard the influence of hemodynamic changes on exercise-induced cardiac changes. in vivo cardiac structures and left ventricular function. In the C-Ex group, physical exercise induced a slight reduction in absolute LV diastolic diameter values and an increase in LV relative wall thickness with unchanged systolic or diastolic function. These results suggest a change towards LV concentric remodeling.Transthoracic echocardiogram was performed to analyze in vivo evaluation.DM-Sed presented LV hypertrophy with dilated left cardiac chambers, characterized by increased LV mass index, LV diastolic diameter-to-body weight ratio, and left atrial diameter, with reduced systolic function, characterized by decreased LV posterior wall shortening velocity, compared to C-Sed. A similar echocardiographic pattern of dilated cardiomyopathy has often been observed in experimental diabetes mellitus –61. The The echocardiographic study revealed that left atrium diameter was lower in DM-Ex than DM-Sed. Left atrium dilation is often caused by an increase in LV diastolic pressure, which may result from alterations in LV diastolic and/or systolic function. In clinical studies, left atrium dimension plays an important role in LV diastolic function evaluation. In fact, an increase in left atrium diameter can be considered an early indicator of diastolic dysfunction . PhysicaIn diabetes, several myocardial changes can be involved in myocardial dysfunction. In this study, we evaluated myocyte hypertrophy, myocardial fibrosis, and oxidative stress as mechanisms potentially involved in the benefits of physical exercise.Myocardial fibrosis was assessed by measuring myocardial concentration of hydroxyproline, an amino acid, and the main component of the collagen molecule which can only be found in small concentrations in a limited number of other proteins. We observed no difference in hydroxyproline concentration between groups. Myocyte hypertrophy, assessed by measuring the lower transverse diameter, also did not differ between groups. We can therefore conclude that myocardial fibrosis and myocyte hypertrophy are not involved in the cardiac effects of physical exercise. Some authors have previously observed increased myocardial interstitial collagen in streptozotocin-induced diabetes rats , 64, 65 We next evaluated myocardial oxidative stress status. Diabetes increased oxidative stress as lipid hydroperoxide concentration was higher and the activity of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase was lower in DM-Sed than C-Sed. Increased myocardial oxidative stress has previously been reported in diabetic rats , 66. We Oxidative stress is a common underlying mechanism in many diseases including cardiovascular diseases. Current knowledge indicates that oxidative stress plays a role as a major determinant of the onset and progression of diabetes-associated cardiovascular alterations , 8, 10. Studies have shown that increased oxidative stress jeopardizes myocardial function through mechanisms such as microvascular damage, abnormalities in calcium homeostasis, and endothelial dysfunction . AlthougIn conclusion, low intensity physical exercise attenuates myocardial oxidative stress, lung congestion, left atrium dilation, and myocardial dysfunction in type 1 diabetic rats.


This study sought to characterize global and regional right ventricular (RV) myocardial function in patients with Takotsubo cardiomyopathy (TC) using 2D strain imaging.We compared various parameters of RV and left ventricular (LV) systolic function between 2 groups of consecutive patients with TC at initial presentation and upon follow-up. Group 1 had RV involvement and group 2 did not have RV involvement.At initial presentation, RV peak systolic longitudinal strain (RVPSS) and RV fractional area change (RVFAC) were significantly lower in group 1  and improved significantly upon follow-up. Tricuspid annular plane systolic excursion (TAPSE) did not differ significantly at initial presentation between both groups . Differences in regional systolic RV strain were only observed in the mid and apical segments. LV ejection fraction (LVEF) and LV global strain were significantly lower in group 1  at initial presentation. None of the parameters were significantly different between the 2 groups upon follow-up. A RVPSS cut-off value of >−19.1% had a sensitivity of 85% and a specificity of 71% to discriminate between the 2 groups.In TC, RVFAC, RVPSS, LVEF and LV global strain differed significantly between patients with and without RV dysfunction, whereas TAPSE did not. 2 D strain imaging was feasible for the assessment of RV dysfunction in TC and could discriminate between patients with and without RV involvement in a clinically meaningful way. In 1991 Dote et al. In a previous work we characterized global and regional LV function in patients with TC using 2D strain echocardiography Estimation of RV function is challenging due to the complex RV geometry To the best of our knowledge, detailed echocardiographic quantification of RV function in TC using 2D strain echocardiography has not been performed so far. Therefore, in this study we sought to analyse RV function by using this novel technique in addition to conventional parameters of RV function.Twenty-eight patients with the clinical diagnosis of TC undergoing clinically indicated echocardiography were recruited for this study. Diagnosis of TC was based on the following criteria: (i) acute onset of apical and/or mid-ventricular wall-motion abnormalities of the left ventricle not confined to the vascular territory of a single major coronary artery, (ii) absence of severe coronary obstruction (>70%) or angiographic evidence of plaque rupture, (iii) new ECG abnormalities (either ST-segment elevation and/or T-wave inversion) or elevated cardiac troponin in the absence of phaechromocytoma and myocarditis. Depending on the additional presence of visually observed RV wall-motion abnormalities, patients were divided into two groups: fourteen patients with RV involvement (group 1) and fourteen without RV involvement (group 2).Echocardiography of both groups was performed within 48 h of diagnosis and upon follow-up, using a Vivid 7 machine  with a 2,5 MHz phased-array transducer. Standard echocardiographic images were obtained at end-expiratory apnoea. 2D strain analysis was performed offline using custom 2D strain imaging software . The endocardial borders were traced at the end-systolic frame of the 2D images. The interactive software then automatically tracked myocardial motion and divided each image into six segments. For each of the six segments numerical and graphical displays of deformation parameters were generated, reflecting the average value for tracking all acoustic markers in each segment Continuous variables are expressed as mean ± standard deviation. Continuous variables were compared using the two-sided Mann-Whitney U-test. A p-value <0.05 was considered statistically significant. Receiver operating characteristic (ROC) curves and Kendall-tau-b correlation coefficients were computed to assess the ability of RVPSS, RVFAC, TAPSE and LVGLS to predict RV involvement. Inter- and intraobserver correlation coefficients for strain measurements in our laboratory were 0.82 and 0.98, respectively The clinical and echocardiographic features of patients at initial presentation are shown in Follow-up examinations were performed in group 1 after 40±45 days and in group 2 after 68±170 days. Longitudinal peak systolic strain could be obtained in group 1 in 34 of 42 segments (81%) at baseline and in 32 of 42 segments (76%) upon follow-up  at baseline and 30 of 42 segments (71%) upon follow-up). RVPSS and RVFAC were significantly lower in group 1 compared to group 2 at baseline, and improved significantly in group 1 but not in group 2 upon follow-up . TAPSE iThe dot plots in Assessment of RV function is one of the most challenging tasks in modern echocardiography. Subjective analysis is probably the most commonly used method for assessment of RV function. RV speckle tracking echocardiography (STE) is a novel method that allows quantitative assessment of RV function. Utility of RV STE both as a diagnostic and prognostic tool has been shown in various disease entities, including pulmonary hypertension (PH) RV involvement is a well-known feature of TC. Initial experience was confined to single cases Using cardiovascular magnetic resonance imaging Haghi et al. The current study examined the utility of STE in the assessment of regional and global LV and RV function in TC. The importance of measuring RV longitudinal function is underlined by the fact that longitudinal shortening accounts for the majority of RV contraction in normal subjects and patients with PH Previous studies in patients with heart failure We found that RVPSS >−19.1% indicates RV involvement in patients with TC with a sensitivity of 85% and specificity of 71%. Previous studies have shown that RVPSS is superior to conventional parameters of RV function in various disease entities. For example, Teske et al. All patients with RV involvement also had LV involvement. Cases of isolated RV TC have been published  or variant (mid-ventricular involvement) forms of TC. RV-involvement occurred in both forms of TC.It has been described that patients with RV involvement have higher degrees of LVEF reduction and longer hospitalization compared to patients without RV involvement The pathophysiological mechanism underlying TC has not been clearly established. The biventricular involvement confirms the notion that TC is not a consequence of coronary artery occlusion There are limitations to this study that must be acknowledged. Because of the small number of patients the results should be regarded with caution. Some of the myocardial segments were uninterpretable due to signal noise. This was not always caused by poor acoustic windows. Tracking problems were particularly common in the LV and RV base.We conclude that 1) RV function quantification can be performed in patients with TC using 2D strain echocardiography. 2) Patients with TC who have RV involvement have significant impairment of several parameters of regional and global RV function. This is predominantly caused by dysfunction of RV mid and apical segments. 3) Patients with RV involvement have significantly lower LVEF and lower LV global strain at baseline which might be caused by a more severe initial insult. 4) A RVPSS cut off value of >−19.1% can differentiate between patients with and without RV dysfunction in a clinically meaningful way. 5) Pleural effusion was only found in patients with RV involvement and a RVPSS value >−14.8% indicated the occurrence of PE with good sensitivity and specificity.


Tissue Doppler Imaging (TDI) is a sensible and feasible method to detect longitudinal left ventricular (LV) systolic dysfunction (LVSD) in patients with diabetes mellitus, hypertension or ischemic heart disease. In this study, we hypothesized that longitudinal LVSD assessed by TDI predicted inducible myocardial ischemia independently of other echocardiographic variables  in patients at increased cardiovascular (CV) risk.Two hundred one patients at high CV risk defined according to the ESC Guidelines 2012 underwent exercise stress echocardiography (ExSEcho) for primary prevention. Echocardiographic parameters were measured at rest and peak exercise.p = 0.001). The factors independently related to myocardial ischemia at multivariate logistic analysis were: lower peak S’, higher LV circumferential end-systolic stress and LASF.ExSEcho classified 168 (83.6 %) patients as non-ischemic and 33  as ischemic. Baseline clinical characteristics were similar between the groups, but ischemic had higher blood pressure, received more frequently beta-blockers and antiplatelet agents than non-ischemic patients. The former had greater LV size, lower relative wall thickness and higher left atrial systolic force (LASF) than the latter. LV systolic longitudinal function (measure as peak S’) was significantly lower in ischemic than non-ischemic patients (8.7 ± 2.1 vs 9.7 ± 2.7 cm/sec, In asymptomatic patients at increased risk for adverse CV events baseline longitudinal LVSD together with higher LV circumferential end-systolic stress and LASF were the factors associated with myocardial ischemia induced by ExSEcho. The assessment of these factors at standard echocardiography might help the physicians for improving the risk stratification among these patients for ExSEcho. Tissue Doppler Imaging (TDI) echocardiography is a sensible and feasible tool to detect subclinical left ventricular (LV) systolic dysfunction (LVSD). In particular, the assessment of mitral annular peak systolic velocity (peak S’) by Tissue-Doppler pulsed wave spectral analysis, reveals the longitudinal LVSD in several settings of patients at increased risk for cardiovascular (CV) adverse events such as those with type 2 diabetes mellitus, arterial hypertension, ischemic heart disease and/or heart failure with preserved LV ejection fraction (LVEF) –7. As a We prospectively studied a large cohort of patients at increased CV risk without history of cardiac disease to test the hypothesis that longitudinal LVSD measured as lower peak S’ at baseline echocardiographic evaluation can predict inducible myocardial ischemia during exercise stress echocardiography (ExSEcho) in these patients. Furthermore, we verified whether other echocardiographic parameters were prognosticators of inducible myocardial ischemia measured at baseline evaluation preceding ExSEcho.st January 2012 to the 31st June 2013 by 2 Italian referral centers (Trieste and Trento) into a prospective evaluation and their data collected in the same database. We selected outpatients aged >18 years without a history/symptoms of cardiac disease who had an increased (high or very high) risk of CV events according to the European Guidelines on Cardiovascular Disease prevention [The study patients were consecutively recruited from the 12.7 for men and > 46.7 g/m 2.7 for women [th percentile in a normal population) [Standard transthoracic Doppler echocardiographic studies were performed using a Megas Esaote Biomedica machine  at Trento, and a GE Vivid 9 machine (at Trieste) both equipped with a 2.5–3.5 MHz annular array transducer by two experienced cardiologists  who followed a standardized protocol. Images were stored on CD or MO disks and forwarded for final interpretation at the Echocardiography Core Laboratory at Villa Bianca Hospital of Trento, Italy. Sonographer (GC) was blinded to clinical data. LV chamber dimensions and wall thicknesses were measured by the ASE guidelines . LV massor women . Relativulation) . LV end-ulation) .th percentile distribution of S’ in the reference healthy population previously analyzed in our center) [TDI pulsed wave spectral analysis was used to measure peak S’ , as an estimate of longitudinal LV function . Peak S’ center) , 6 was cTransmitral and pulmonary vein pulsed wave Doppler curves and early diastolic TDI velocity of mitral annulus (E’) were assessed according to the ASE recommendations. Early diastolic velocity of transmitral flow (E) was divided by E’ and used to classify LV diastolic function together with other diastolic parameters in 4 degrees as proposed by Redfield et al. : normal,All patients underwent symptom-limited ExSEcho (semi-supine position on tilting cycloergometer) with protocol of 25 Watts for 2 minutes workload: heart rate, blood pressure and 12 lead ECG were recorded at rest and every 2 minutes of exercise. Echocardiographic data including LV volumes, LVEF, mitral Doppler and TDI parameters were measured at baseline and at the peak exercise. ExSEcho was considered positive or negative based on symptoms, electrocardiographic and echocardiographic criteria, following the indications of the international guidelines . Accordi2 statistics were used for descriptive statistics. Between-group comparisons of categorical and continuous variables were performed by χ2 test and analysis of variance (ANOVA) with comparison between each group by Scheffè test for unequal sample, as appropriate. The study population was stratified in patients with or without inducible myocardial ischemia. A multivariable logistic regression analysis was performed to identify the variables measured at baseline evaluation independently related to the development of myocardial ischemia during ExSEcho. Variables  significantly related to inducible myocardial ischemia at univariate tests (p ≤ 0.01) were included in the multivariate model; age and gender were forced into the statistical model. Receiver operating characteristic (ROC) curve analyses were performed to identify the best cut-off points as the best values for each variable independently associated with the development of inducible myocardial ischemia. To build a predictive score for inducible myocardial ischemia, point = 1 was assigned for each variable outside the predictive cut-off value. The score ranged from 0 (very low risk) to 3 points (very high risk) for inducible myocardial ischemia. All analyses were performed using statistical package SPSS 19.0 (SPSS Inc. Chicago. Illinois) and statistical significance was identified by two-tailed p <0.05.Data are reported as mean values ±1 standard deviation  or percentages. Unpaired Student’s test and χEchocardiographic reproducibility of peak S’ was tested on 50 patients of the study cohort and randomly selected. An expert cardiologist skilled in echocardiography (GC) twice per each patient analyzed data at baseline, 50 Watts and peak exercise. The mean difference between two measurements was ± 4 %. SD of this difference was ± 2 %. Bland-Altman plot showed that in none of these 50 patients the deviation of values of peak S’ measured twice at two different times exceeded the two SD of the mean of peak S’ between the two measures. Inter-observer variability for peak S’ was tested by comparing these measures with those acquired by a second sonographer: the mean difference between two measurements was ± 5 %. SD of this difference was ± 3 %. Intra and inter-observer variability was excellent and did not significantly change when peak S’ was measured at baseline and at peak exercise. Similar data resulted by the comparison between the two different echo machines used for this study (Megas Esaote Biomedica and GE Vivid 9 models). Regarding to the feasibility of peak S’ assessment, no patient had inadequate image quality and the variable could be assessed in all participants.The baseline clinical and echocardiographic characteristics of the 201 participants are shown in the Tables The mean duration of ExSEcho in the total study population was 8’55” corresponding to a mean workload of 111 ± 40 watts. According to the results of ExSEcho, patients were divided into two groups: 168 (84 %) non-ischemic and 33 (16 %) ischemic patients. During ExSEcho, among the 33 patients belonging to the ischemic group, 13 (39 %) suffered from typical chest pain, 24 (73 %) had typical electrocardiographic ischemic changes, 28 (85 %) developed changes in LV wall motion (ipokinesia or akinesia in 17 patients in the territory of the right coronary artery and 11 in the left coronary artery). Inducible myocardial ischemia was diagnosed after a mean time from the beginning of exercise of 6’50” corresponding to a mean workload of 84 ± 30 watts. The threshold of the myocardial ischemia was low in 10 patients (30 %), high in 7 patients (21 %), and intermediate in the remaining 16 patients. The baseline clinical and laboratory characteristics of ischemic and non-ischemic patients were similar, but systolic blood pressure was significantly higher in the former, who were treated more frequently with beta-blockers and antiplatelet agents, but less frequently with calcium channel blockers than the latter . Three patients (9 %) had no or minor lesions (less than 30 % diameter stenosis), 2 (6 %) had intermediate lesions (with 30–69 % diameter stenosis) and 27 (84 %) had significant coronary lesions (≥70 % diameter stenosis). Among these 27 patients, 20 (74 %) underwent percutaneous transcateter coronary angioplasty + stent implantation and 7 (26 %) underwent elective coronary artery by-pass graft surgery.The variables measured at baseline evaluation associated with the inducible myocardial ischemia at univariate analysis were higher systolic blood pressure, larger LV end-diastolic diameter and end-systolic volume, lower LV relative wall thickness, higher CESS, lower peak S’ and higher LASF. At multivariate logistic regression analysis, higher CESS, lower peak S’ and higher LASF emerged as the independent conditions associated with inducible ischemia in the study population Table .Table 3M2 = 0 point). The identification of the best cut-off points as the best values for each variable independently associated with the development of inducible myocardial ischemia was executed by ROC curve analyses and the results are shown in the Table According to the results of the multivariate regression analysis, a simple echo score was generated after the categorization of the 3 echocardiographic predictors of inducible myocardial ischemia (see “p < 0.001)  Fig. .Fig. 2BaThe main result emerged by the present study was that in patients at increased risk for CV events, without history of cardiac disease, a reduced longitudinal LV systolic function measured at baseline evaluation was closely associated with inducible myocardial ischemia during ExSEcho, independent of the traditional confounding factors. Furthermore, the coexistence of high CESS and high LASF with a reduced longitudinal LV systolic function predicted the development of inducible myocardial ischemia during ExSEcho in a substantial portion (one third) of the ischemic patients. This is what does our study finding add beyond current day ExSEcho. Unexpectedly, no clinical or laboratory variable including diabetes mellitus, hypertension or renal dysfunction was associated with inducible ischemia in our population.Peak S’ reduction was already identified as an early marker of longitudinal LV systolic dysfunction in different conditions . SeveralIn our study population, diabetes, hypertension and obesity were widely present. Thus, as predictable, these pathological conditions could not emerge as prognosticators of ExSEcho-induced myocardial ischemia in this setting of patients. No difference, indeed, existed in clinical characteristics between the two study groups. Some difference in drug therapy was present at baseline evaluation but no medication significantly influenced the development of ischemia during ExSEcho.Together with longitudinal LVSD, another condition independently associated with the inducible myocardial ischemia was the higher LASF. With increased LV stiffness and reduced LV compliance, LASF increases to preserve LV filling and has to be considered as a sensible marker of LV diastolic function , 26. FurAlso an increased LV CESS, row index of LV afterload, was independently associated with inducible myocardial ischemia in our patients. CESS was studied in patients at high CV risk, where it was found increased in presence of hypertension and LV hypertrophy . In our Taking one by one the three echocardiographic parameters emerged at multivariate regression analysis as prognosticators of inducible myocardial ischemia , the sensibility and specificity for the event prediction was around 60 %, slightly better for peak S’. Furthermore, there is significant overlap between the S’ values between the two study groups, resulting in a relatively high number of both false positive and false negative results where S’ value would be considered as continuous variable. But combining the three variables together, on the basis of the cut-off got from ROC analysis, we could better predict inducible myocardial ischemia during ExSEcho at baseline echocardiography. The echocardiographic methods for the assessment of these variables are easy and feasible using standard echocardiography, so that the proposed evaluation can be performed in every echo-Lab without high technology.Lacking follow-up data, no prognostic inference in regards to the detection of longitudinal LVSD in patients candidate to ExSEcho can be made. Although our statistical models were extensive, some confounders explaining the observed relations could be left out. The tissue Doppler S’ is an angle dependent measure, so that we cannot exclude that this aspect may have influenced at least in part our results. Finally, the analyses did not consider any parameter of vascular function. Strengths of our study include the large number of participants prospectively enrolled, the reliable, appropriate and validated methods for the assessment of longitudinal LVSD, LASF and CESS as well as the other numerous echocardiographic variables considered in this investigation, the comprehensive nature of the dataset and the capability to correct for the most clinically relevant CV risk factors.In asymptomatic patients at increased risk for adverse CV events baseline longitudinal LVSD together with higher LV circumferential end-systolic stress and LASF are the factors associated with myocardial ischemia induced by ExSEcho. The assessment of these factors at standard echocardiography might help the physicians for improving the risk stratification among these patients for ExSEcho. This approach could lead to save substantial human and economic resources. The present findings might have an extensive clinical applicability mostly because ExSEcho has the advantages of its wide availability, safety, low cost and versatility for the assessment of inducible myocardial ischemia.ACE, Angiotensin-converting enzyme; ARB, Angiotensin receptor blockers; ASE, American Society of Echocardiography; CAD, Coronary artery disease; CESS, Circumferential end-systolic stress; CV, Cardiovascular; ExSEcho, Exercise stress echocardiography; LASF, Left atrial systolic force; LV, Left ventricular; LVEF, Left ventricular ejection fraction; LVSD, Left ventricular systolic dysfunction; ROC, Receiver operating characteristic; S’, Mitral annular peak systolic velocity; TDI, Tissue Doppler Imaging.


Cardiac MRI has become the reference imaging modality used to assess left ventricular (LV) remodelling. Ventricles are generally characterised by bulk metrics such as cavity volume, mass or wall thickness. We introduce a workflow that aims to improve the stratification power of conventional analysis by providing 3D shape metrics through the construction of computational cardiac atlases.http://www.vph-share.eu). Its use is illustrated by the analysis of a cohort of 224 subjects. Specifically, we report how the shape of the LV in adulthood  can predict gestational age (either premature or term-birth), comparing the performance of traditional metrics  to the first three atlas-derived descriptors.Computational 3D meshes of the LV are personalised to MRI images, capturing and encoding shape information. The method requires the provision of segmented myocardial images, and a parameter to choose the relative importance between minimise noise and artefacts and maximise accuracy in the personalisation of meshes. Subsequently, the principal modes of anatomical variation are extracted from the set of 3D meshes that constitute the atlas. These principal modes represent how ventricular shape changes within the population under study. The anatomy of each subject is then described by a set of shape indexes that are used for further stratification and analysis. This fully automatic procedure has been made available through an online cloud infrastructure (Ventricular meshes were fully automatically reconstructed from the end diastolic frame of cine-SSFP sequences, with average fitting error of 1.25mm. Gestational age was predicted with 85% specificity and 88% sensitivity based on traditional metrics, improving to 93% and 98% respectively with atlas-derived shape descriptors.Shape of the left ventricle described by a computational atlas has the potential to improve the stratification of disease processes. Researchers are invited and encouraged to use this tool that has been made available to the community.This work was partly supported by the FP7 VPH-Share project under Grant agreement n.269978. P.L. holds a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society, grant n.099973/Z/12/Z.


Early postoperative ventricular tachyarrhythmia (PoVT) after left ventricular assist device (LVAD) implantation are common and associated with higher mortality-rates. At present, there is no data on initiation of these PoVT and the role of alterations in cardiac hemodynamics. A LVAD was implanted in a patient with end-stage heart failure due to a ischemic cardiomyopathy. Alterations in cardiac rhythm and hemodynamics preceding PoVT-episodes during the first five postoperative days were examined by using continuous recordings of cardiac rhythm and various hemodynamic parameters. All PoVT (N=120) were monomorphic, most often preceded by short-long-short-sequences or regular SR and initiated by ventricular runs. Prior to PoVT, mean arterial pressure decreased; heart rate and ST-segments deviations increased. PoVT are caused by different underlying electrophysiological mechanisms. Yet, they are all monomorphic and preceded by hemodynamic deterioration due to myocardial ischemia. Early postoperative ventricular tachyarrhythmia (PoVT) after implantation of left ventricular assist devices (LVAD) are common, despite the unloading of the left ventricle, and are associated with higher mortality-rates due to eventually failure of the right ventricle –4. The aThis case report is part of the Rotterdam Rhythm Monitoring Project (AMOR) ). Written informed consent was not applicable. Continuous postoperative rhythm recordings were semi-automatically analysed for the first five days after Heartmate II implantation. PoVT-episodes (series of ventricular beats lasting ≥30 s) were classified as either monomorphic or polymorphic; CL of every PoVT-episode was assessed separately. Using 5 beats preceding a PoVT-episode, rhythms were subdivided into 1)sinus rhythm (SR), 2)SR with ventricular-run (V-run) or 3)SLS-sequences. PoVT-episodes were initiated by either a VPB, ventricular-couplet (V-couplet) or -run, or it started with a SO. In the latter case, the morphology of the first PoVT beat was similar to the remainder of the PoVT beats and the prematurity index (PI) of the first beat had to be <110 % . The PI T-test was used to demonstrate differences between continuous variables. Mann-Whitney U-test was applied for continuous skewed data. A P-value of <0.05 was considered statistically significant.Continuous normally distributed variables were expressed as mean ± SD. The unpaired, two tailed Student’s N = 55, 46 %), SLS-sequences  or V-run  and started either suddenly , with a VPB , V-couplet  or V-run  as is depicted in Table P > 0.05)). In case of regular SR preceding PoVT, the averaged CL of the beats preceding PoVT were significantly shorter compared to the averaged CL of the beats in the reference time periods . The left lower panel of Fig. N = 8) and 52 % (N = 29)), whereas PoVT with VPBs or V-couplets at the onset are mostly preceded by SLS-sequences (respectively 44 % (N = 15) and 56 % (N = 10)). For every type of PoVT-onset, there was a large variation in the PI, but there were no significant differences in median PI between the various onset categories , as demonstrated in the middle lower panel of Fig. P > 0.05)).A 47-year-old male with end-stage heart failure due to ischemic heart disease received a Heartmate II (a rotary continuous flow device) which served as a bridge-to-heart transplantation . Prior t-run N = 3, 11 % aP = 0.008 and P < 0.001, and d-ST and HR were higher; both time intervals 1.0 mm versus 0.5 mm (P < 0.001); 133/bpm and 134/bpm both versus 80/bpm (P < 0.001). RAP did not alter prior to development of PoVT-episodes. The patient finally died 13 days after Heartmate II implantation due to incessant VTs.Differences between hemodynamic parameters  30s and 1 min. prior to every PoVT-episode in comparison with similar reference-data are illustrated in Fig. The LVAD rotational speed during the postoperative period was around 9200 rpm with an mean flow rate of 5.2 L/min, which indicates no major suction events. Prior to death, both rotational speed and flow decreased.In our patient, all PoVT-episodes were monomorphic. The phenomenon of similar monomorphic episodes in one patient has previously also been defined as intra-individual reproducibility 80–88 %) [0–88 % 8. This obOf interest is that all PoVT-episodes in our patient are preceded by a significant decrease in MAP, an increase in d-ST and HR suggesting that decreased myocardial perfusion plays an important role in the pathophysiology of PoVT. The resulting myocardial ischemia in turn may induce heterogeneity in conduction, dispersion in refractoriness or enhance ventricular ectopy. In addition, ventricular ectopy is caused by e.g. triggered activity or enhanced automaticity due to on-going increased ventricular stretch in the postoperative period. In the presence of an extensive substrate due to myocardial scarring (rarely caused by the site of the inflow cannulation), VT may be initiated by a trigger . As descP < 0.01) [As VTs are the most common tachyarrhythmia occurring after implantation of LVADs (early- and late-postoperative VTs ranged from respectively 13–28 % and 11–66 %) , 18, 21 PoVT-episodes in a patient with ischemic cardiomyopathy after Heartmate II implantation are induced by different electrophysiological mechanisms though the resulting PoVT are monomorphic. All PoVT-episodes were preceded by hemodynamic deterioration indicating that myocardial ischemia is the major contributor to development of PoVT. Hence, optimization of cardiac hemodynamics is essential for prevention of PoVT-episodes.


Aims. The correspondence between the localization and morphology of ischemic scars and the infarct related artery (IRA) by use of cardiac magnetic resonance imaging and a novel automatic postprocessing method. Methods and Results. Thirty-four patients with one-year-old single IRA myocardial infarction were examined. Endocardium, epicardium, and the point where right and left ventricles are coinciding were manually marked. All measurements were automatically assessed by the method. The following are results with manual assessments of scar properties in parenthesis: mean scar size (FWHM criterion): 7.8 ± 5.5 as %LV (17.4 ± 8.6%); mean endocardial extent of infarction: 44 ± 26° (124 ± 47°); mean endocardial extent of infarction as %LV circumference: 9.7 ± 7.0% (34.6 ± 13.0%); and mean transmurality: 52 ± 20% of LV wall thickness (77 ± 23%). Scars located in segments 1, 2, 7, 8, 13, and 14 by use of the automatic method were 96–100% specific for LAD occlusion. The highest specificities of RCA and LCX occlusions were segment 4 with 93% and segment 6 with 64%, respectively. The scar localization assessed automatically or manually was without major differences. Conclusion. The automatic method is applicable and able to assess localization, size, transmurality, and endocardial extent of ischemic scars. The 17-segment model of the American Heart Association (AHA) is important for assessing regional function and pathology in many imaging modalities of the heart .The assignment of myocardial scar to coronary artery territories has also been investigated in other studies during percutaneous coronary occlusion and use of technetium-99m sestamibi , 4. TherThe aim of this study is to demonstrate the clinical applicability of a new automatic method by assessment of the correspondence between the infarct related artery (IRA) and the segmental localization of the scar and compare the results with the AHA proposal and other studies that show the relationship between the IRA and the location of scars.We evaluated 41 consecutive patients with healed myocardial infarction (MI) caused by 1 vessel disease and acute ST-segment elevation myocardial infarction (STEMI) successfully revascularized with primary percutaneous coronary intervention (pPCI) one year prior to LGE-CMR examination . After rThe LGE-CMR protocol has been described previously . CMR was2, covering the whole ventricle with short-axis slices of 10 mm thickness, without interslice gaps . Inversion time was individually adapted aiming to null normal myocardium . Mean heart rate was 57.7 bpm (range 52–68).After assessments of volumes and LVEF were performed, a gadolinium-based contrast agent, Omniscan, was administered intravenously at a dosage of 0.25 mmol/kg . The seq12 = 4096 values of signal intensity (SI), but most of our patients had 256–1024 different SI values. The image analysis was done using in-house-developed software programs written in MATLAB. As a first step in assessing the localization parameters of the myocardial scar, the endocardial and epicardial borders must be found, illustrated with box 1, The images were retrieved in DICOM  format with 512 × 512 pixels and a bit depth of 12, which represents DICOM format with up to 2ϕ = 0 axis and the angle was defined from 0 to 360° in a counterclockwise direction [ 3DmaxSI and this value is used to identify scar tissue in all slices [ 3DmaxSI and that is the Full-Width-Half-Max (FHWM) criterion. Thereafter, a scar segment is defined as a group of at least two connected pixels labelled as a scar, knowing that this small hyperenhancement could also be artefact, vessel, muscular cleft, or similar structures. For every pixel (x) between the endocardial and epicardial border, ϕ(x) is the angle between the heart axis and a radial line from the center of the myocardium through the pixel. The circumferential involvement of any scar is called the endocardial extent of infarction (Δϕ) and it is defined as the smallest angle (sector) containing all the pixels defined as scar segment (ϕ) from the endocardial extent of infarction as %LV circumference, which is the sum of all Δϕ divided by 360∗number of slices with one scar [In accordance with the recommendation by AHA, only transverse slices containing myocardium in all 360° were selected for the assessment of the myocardium. This is due to the complex mixing of myocardium and connective tissue at the base of the heart, especially the septum . The nexirection . After vl slices . Scar or segment . It is ione scar , 16.x) between the endocardial and epicardial border, we also define λ(x) to be a value between 0 and 1, indicating if the pixel is close to the endocardial border (close to 0) or close to the epicardial border (close to 1). In short, this is done by again using the radial line from the center of the myocardium through the pixel (x). The pixels inside the myocardium along this line  are given a value from 0 to 1 so that even if the thickness of the myocardium is not fixed, the λ(x) value will always give an interpretation of how close that specific pixel is to the endocardium (or epicardium) wall (λ(x) and minimum λ(x) is called the transmurality of the scar, Δλ. For every patient, the sum of scar areas was divided by the sum of sectors surrounding the scars and presented as the scarring % [For every pixel (um) wall . The difarring % .λ = 0 were set as the border of endocardium, and values with minimum λ > 0 are scars without connection to endocardium.All scars with minimum ϕ(x). Note that a contiguous scar area can be split into several of the AHA model segments. Each individual pixel of the scar is assigned to the corresponding AHA model segment. The demarcation of the myocardial border and the marking of the point of the heart axis were done manually as previously described.The left ventricle is divided into equal thirds perpendicular to the long axis of the heart. This generates three circular sections of the left ventricle named basal, mid-, and apical regions . The basSegment 17 is the area of myocardium beyond the end of the left ventricular cavity and it is not included in our automatic analyses. However, the localization of scars in this segment was visually assessed by use of the 2-chamber long-axis views, and a scar was present if LGE was present in more than 50% (>180°) of the circumferential extent of that segment. Except for segment 17, all calculations involving allocation of scar pixels to the AHA segments and the size, transmurality, and endocardial extent of the infarction are done entirely automatically .In order to compare the results found by this new automatic method, a manual method was employed. One representative slice from the apical, mid-, and basal cavity of all patients was selected and scars were manually allocated to the coronary artery territories according to the 17-AHA proposal. First the heart center was visually marked . The stap value of ≤0.050 was considered significant.Statistical analyses were performed using SPSS version 21. Continuous data are reported as means and standard deviations, and categorical data are reported as counts and proportions. Differences in the distribution of continuous variables between all three patient groups were tested by the Kruskal-Wallis test. For categorical data, the Chi-square test was used. All tests were two-tailed and a 2).A total of 34 patients were included in this analysis . All patλ = 0 were used for the assessment of scar localization in order to include only ischemic scars attached to the endocardium. A total of 257  slices were analysed in addition to the long-axis views of all patients. There were no significant differences of baseline characteristics in patients with LAD, RCA, or LCX as IRA, except the use of aldosterone antagonists, Only scars with minimum ϕ and endocardial extent of infarction as %LV circumference in patients with LAD and RCA as IRA.Cardiac magnetic resonance characteristics assessed by automatic and manual methods are shown in Automatic assessments of scars according to the AHA segmentation of LGE-CMR images in relation to the IRA are presented in By LGE-CMR imaging of myocardial scars one year after successful revascularization of single-vessel occlusion by use of PCI, only 4 segments were 100% specific for LAD occlusion and none for RCA or LCX occlusion.ϕ, endocardial extent of infarction as %LV circumference, and mean Δλ are bigger when the manual method is used.The scar or infarct size assessed with the automatic method used the FHWM criterion, and the size is much smaller than the size assessed with manual marking . We usedIt has been demonstrated that the degree of hyperenhancement caused by LGE-CMR portrays the damage caused by the IRA . The 17-ϕ), and endocardial extent of infarction as %LV circumference, although the differences are not statistically significant in this small study. When the manual method is used, LAD as IRA causes significantly larger mean Δϕ and endocardial extent of infarction as %LV circumference compared with RCA as IRA. These findings are in accordance with the study by Ortiz-Pérez et al. [LAD or RCA supplies segment 9 . In our z et al. , where tOur data of RCA territory is in agreement with the proposed AHA locations for segments 3, 4, and 10 with a specificity of 63, 93, and 67%, respectively , Table 3Our automated method provides fast and reliable measurements of myocardium at risk or endocardial extent of infarction, scar size, transmurality, and localization of each scar. These data may have a potential clinical role in the assessment or treatment of ventricular arrhythmias and cardiac failure. Combined with coronary angiography, localization of scars may be used for clinical planning of surgical revascularization and potentially alter the specific placement and number of bypass grafts and used for planning of lead placement in patients with ICD and cardiac resynchronization devices .It is a limitation that the LCX territory is assessed with only 4 patients. Scars adherent to the endocardium were included in the current study in order to ensure that only ischemic scars were assessed. Areas of LGE between endo- and epicardium without a subendocardial origin are therefore excluded. This selection of LGE reduces the risk of the erroneous inclusion of artifacts, but we cannot exclude the possibility that some parts of the LGE areas were due to nonischemic myocardial pathology adherent to endocardium or that some ischemic scars not adherent to endocardium were excluded. The images are hampered by partial volume effects, but the use of relative values compensates to some degree for this drawback.It is also a limitation that only slices containing myocardium in all 360° have been selected because of the complex mixing of myocardium and connective tissue at the base of the heart, especially the septum . It is aThis study demonstrates the applicability by use of an automatic method to assess the localization, size, transmurality, and endocardial extent of ischemic scars of LGE-CMR images.


Background. We investigated the cardiac effects of TSH (thyroid-stimulating hormone) oversuppression in women with thyroidectomized differentiated thyroid cancer (DTC) during levothyroxine suppression therapy. Methods. Fourteen young female patients with DTC were enrolled. The duration of TSH-suppressive therapy was 5 to 9 years. They satisfied the following criteria: (1) a serum level of TSH < 0.1 mU/L in the intermediate-risk or TSH < 0.3 mU/L in the low-recurrence-risk group and (2) having been receiving a fixed dose of LT4 before the study. Controls matched for age, sex, and body mass index (BMI) were compared in terms of the levels of serum free T4, free T3, TSH, plasma N-terminal pro-brain natriuretic peptide (NT-pro-BNP), and cardiac functions and structures. Results. DTC patients and control subjects were well matched in heart rate and blood pressure. There were marked differences in serum TSH (P = 0.001) and free T4 (P = 0.002). However, there were no differences between the groups in serum free T3 and plasma NT-pro-BNP. Furthermore, there were nonsignificant differences in cardiac functions and structures between the groups. Conclusions. This study shows that TSH suppression therapy in women with DTC may be safe with respect to cardiac functions and structures despite intermittent oversuppression of TSH during long-term suppressive therapy. Trial Registration. This trial is registered with clinicaltrials.gov identifier NCT02645786. After total or near-total thyroidectomy in differentiated thyroid cancer, long-term thyrotropin  suppression therapy with levothyroxine (LT4) should be carried out to prevent hypothyroidism and to minimize potential TSH stimulation of tumor growth in patients 3}) + 0.6, where LVID is LV end-diastolic dimension, PWT is posterior wall thickness, IVS is interventricular septal wall thickness, and d is diastole. Systolic function was evaluated by measurements of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) of the LV. The following parameters of diastolic function were measured by tissue Doppler-derived imaging: early diastolic flow of mitral valve velocity (E), late diastolic flow of mitral valve velocity (A), early diastolic mitral annular velocity (e′), late diastolic mitral annular velocity (a′), and isovolumetric relaxation time (IVRT) were measured from the septal corner of the mitral annulus in the apical 4-chamber view. To evaluate the GLS of the left ventricle, echocardiographic images were obtained at the apical 4-chamber view and the strain was analyzed based on routine DICOM  data sets using software . A region of interest was manually placed on the endocardial and epicardial borders. The echocardiographic data were gathered and analyzed by 2 experienced echocardiographers who were unaware of any corresponding clinical data.Comprehensive transthoracic echocardiography was performed using commercially available equipment . Standard 2-dimensional measurements were obtained as recommended by the American Society of Echocardiography (ASE) in the left lateral position . Left atn = 14 for each group). All P values calculated are two-tailed and considered significant at P < 0.05. All statistical analysis was performed using SPSS 20.0 software .Data were reported as means and standard deviation (SD). For the comparison of means between groups, we used the Mann-Whitney test because the sample size was small (μg/kg (ranging from 1.67 to 3.82 μg/kg). The baseline characteristics of cancer patients are summarized in P = 0.001) and free T4 (P = 0.002). However, there were no differences between groups in the mean quantities of serum free T3 and plasma NT-pro-BNP . There were no significant differences in diastolic echocardiographic parameters, such as E, A, e′, a′, IVRT, and E/e′. The GLS of the left ventricle was also not different between the groups  during less-than-10-year TSH-suppressive therapy.Thyrotoxicosis can influence cardiac function and structure and clinical symptoms . TetraioIn conclusion, the present study shows that TSH-suppressive therapy with LT4 in asymptomatic athyreotic women with DTC, especially in the low- or intermediate-risk-of-recurrence categories, may be safe for cardiac function and structure despite intermittent oversuppression during long-term (less than 10 years) TSH-suppressive therapy. Also, this study suggests that if no cardiac symptoms are present in overly suppressed DTC patients, additional cardiac evaluation for cardiac function and structure is not necessary.


Pituitary apoplexy (PA) is a rare and potentially fatal clinical condition presenting acute headache, vomiting, visual impairment, ophthalmoplegia, altered mental state and possible panhypopituitarism. It mostly occurs in patients with haemorrhagic infarction of the pituitary gland due to a pre-existing macroadenoma. Although there are pathological and physiological conditions that may share similar imaging characteristics, both clinical and imaging features can guide the radiologist towards the correct diagnosis, especially using magnetic resonance imaging (MRI). In this review, we will describe the main clinical and epidemiological features of PA, illustrating CT and MRI findings and discussing the role of imaging in the differential diagnosis, prognosis and follow-up.Teaching pointsHeadache, ophtalmoplegia and visual impairment are frequent symptoms of pituitary apoplexy.• CT is often the first imaging tool in PA, showing areas of hyperdensity within the sellar region.• MRI could confirm haemorrhage within the pituitary gland and compression on the optic chiasm.• Frequent simulating conditions are aneurysms, Rathke cleft cysts, craniopharingioma and mucocele.• The role of imaging is still debated and needs more studies.•  Pituitary apoplexy (PA) was first described by Pearce Bailey in 1898 . It is aThe diagnosis of PA can be made only when haemorrhagic infarction of the pituitary gland leads to the previously described clinical syndrome; the use of the term PA should be avoided in asymptomatic patients. In fact, huge haemorrhages can be a common finding in patients with macroadenomas without PA symptoms , 15.Many clinical series of patients with PA have been reported, while its imaging features are less frequently described. Because of the potential severe prognosis of PA, radiologists should be aware of its imaging characteristics on both computed tomography (CT) and magnetic resonance imaging (MRI), being able to recognise the main conditions that may mimic PA, from a clinical and radiological perspective.Based on the above-mentioned clinical definition, PA is a rare event and occurs in 1.6 to 2.8 % of patients with macroadenomas; it is more frequent in males, with a gender ratio of 2:1 and a mean age of onset of 57 years –18. AbouPituitary apoplexy has a wide spectrum of clinical manifestations; based on many reports, the most common symptom is headache, with an incidence of 90–97 % –5, 19. TThe second most frequent symptom is the visual deficit, ranging from 50 to 82 % of cases , 20–25, Many authors described that PA is strictly associated with a sudden enlargement of a pre-existing pituitary adenoma, resulting in a disturbance of the residual pituitary function and local mass effect on surrounding structures or, less frequently, in a sudden increase of intracranial pressure , 26–28. Many known factors predispose patients to symptomatic infarction of the pituitary, amongst which the most important are hypertension , 20, diaMost of the patients with symptoms related to PA will undergo computed tomography (CT) in an emergency setting. It is likely that, in most of them, the clinical suspicion might something other than PA. CT is effective in visualising pituitary expansive lesions leading to sellar enlargement (up to 94 % of cases) , 20, 25.Magnetic resonance imaging (MRI) is the most important tool in the diagnosis of PA, being able to identify the presence of an adenoma and its haemorrhagic degeneration. MRI is definitely superior to CT in the diagnosis of PA with a sensitivity ranging from 88 % to 90 % , 41. RecIt is well known that the signal of blood clots in MRI changes over time. In the acute phase (0–7 days), deoxyhaemoglobin leads to shortening of the T2 relaxation time due to the susceptibility effect and the MRI signal is hypointense on T2-weighted imaging (T2W1) with isointensity or slight hypointensity on T1-weighted imaging (T1WI) Fig.  and 4. IFirst, Poitin et al. and, more recently, Dubuisson et al. described the MRI features in a group of patients with PA , 45. MRIMany authors , 14, 45 Another important MRI finding that is highly indicative of PA is the thickening of sphenoid sinus mucosa Fig.  14, 46,,46, 48. Less is known about the MRI appearance of pituitary apoplexy without haemorrhagic infarction. Ostrov et al. found that this condition may appear as low signal intensity on both T1WI and T2WI, without contrast enhancement inside the lesion but with a peripheral rim of enhancement . It has The use of T2*-weighted gradient-echo (GE) MR imaging is currently the most sensitive neuroimaging technique for the identification of brain haemorrhage. T2*-weighted images are highly sensitive to the paramagnetic effects of deoxy-HB and meta-HB and show bleeding products and haemosiderin deposits as areas of strongly hypointense signal. Tosaka et al. recently demonstrated that this statement could be applied even to PA . GE MR cMRI is a useful tool in the differential diagnosis of pituitary apoplexy. Many conditions can present with hyperintensity  on T1WI in the sellar region, the most frequent MRI feature of PA . Thus, iThe posterior lobe of the pituitary gland usually appears as a hyperintense spot on T1WI because of storage of vasopressin –53; thisIn the case of anterior pituitary lobe hyperactivity, the gland may be hyperintense , 55. In Another condition to consider for the differential diagnosis is the presence of an aneurysm Fig. . AneurysRathke cleft cysts (RCCs) occur with T1 hyperintensity because of the variable protein content  Fig. 6)6). RCC, Craniopharingioma is another pathology that can be difficult to distinguish from PA. It is usually an intra-/suprasellar lesion with variable solid, cystic and calcified components , 58. TheOther conditions that can simulate PA on imaging are lipoma, dermoid cysts and postoperative changes. Lipoma and dermoid cysts contain fat and can be confirmed with fat-suppressed images. Anyway, these pathologies do not usually appear with the clinical syndrome of PA.In clinical practice, many endocrinologists and pituitary surgeons believe that patients presenting with ophthalmoplegia  without visual field loss may safely be monitored conservatively—typically with spontaneous full recovery of the ophthalmoplegia after several weeks and very often with substantial shrinkage of the pituitary mass on the follow-up scan some months later.The role of imaging, in particular of MRI, in the decision-making process for a proper therapy is still debated and probably needs more study. Some authors reported that MRI findings in patients with PA do not correlate with the severity of its clinical presentation, in terms of both visual loss and cranial nerve palsies , 45, 50,Although no study demonstrated that chiasm compression may represent the most relevant MRI feature, it is likely that this observation has a clinical impact in the decision-making process Fig. .For the above-mentioned reasons, even though the most important features for treatment decisions  are related to the severity of the clinical condition , MRI canThe recent UK guidelines for the management of PA indicate an urgent MRI in patients with suspected PA as IIIB evidence class, since more randomised clinical trials are required. If MRI is contraindicated, a dedicated pituitary multidetector CT is advisable .Radiological follow up with MRI in patients affected by PA is important. The pre-existing adenoma might grow after bleeding and eventually re-bleed Fig.  20]. In. In20]. PA is a severe clinical syndrome and imaging is important to rule out other pathologies showing similar symptoms.Currently, CT is the most commonly used imaging modality during the acute onset of symptoms consistent with PA. Despite this, CT lacks sensitivity and MRI should always be performed if PA is suspected. MRI can evaluate pituitary infarct and haemorrhage, mass effect and differentiate PA from other pathologies such as a Rathke cleft cyst or craniopharingioma. Other MR techniques such as MRA, DWI and T2*-weighted GE images can increase its diagnostic capabilities.Although more studies will be necessary to define the role of MRI in treatment choices and prognostic information, this modality is a fundamental step in the diagnosis of PA in the acute phase and is mandatory in the follow-up of these patients.