Diastolic dysfunction, commonly evaluated by echocardiography, is an important early finding in many cardiomyopathies. Cardiac magnetic resonance (CMR) often requires specialized sequences that extends the test time. Recently, feature-tracking imaging has been made available, but still requires expensive software and lacks clinical validation.To assess diastolic function in patients with aortic valve disease (AVD) and compare it with normal controls by evaluating left ventricular (LV) longitudinal displacement by CMR.We compared 26 AVD patients with 19 normal controls. Diastolic function was evaluated as LV longitudinal displacement in 4-chamber view cine-CMR images using steady state free precession (SSFP) sequence during the entire cardiac cycle with temporal resolution < 50 ms. The resulting plot of atrioventricular junction (AVJ) position versus time generated variables of AVJ motion. Significance level of p < 0.05 was used.-1), slope of the best-fit line of displacement in diastasis , and VDS/MVED ratio (0.35 vs. 0.02) were significantly reduced in AVD patients compared with controls, respectively. Aortic regurgitation showed significantly worse longitudinal LV shortening compared with aortic stenosis. Higher LV mass indicated worse diastolic dysfunction.Maximum longitudinal displacement (0.12 vs. 0.17 cm), maximum velocity during early diastole (MVED, 0.6 vs. 1.4sA simple linear measurement detected significant differences on LV diastolic function between AVD patients and controls. LV mass was the only independent predictor of diastolic dysfunction in these patients. This method can help in the evaluation of diastolic dysfunction, improving cardiomyopathy detection by CMR, without prolonging exam time or depending on expensive software. Diastolic dysfunction has an increasing incidence with age and is associated with diabetes mellitus, atrial fibrillation, coronary artery disease, pulmonary hypertension,6 and congenital heart diseases. Left ventricular (LV) hypertrophy has been associated with impaired diastolic function, which is commonly described in systemic hypertension, aortic valve diseases and hypertrophic cardiomyopathy.9Diastolic dysfunction is an early marker of cardiac disease and precedes systolic dysfunction. It can occur in the presence or absence of symptoms and with normal or abnormal systolic function.9 However, CMR is less used for evaluating diastolic function despite the development of several relevant techniques,10 including the use of volumetric filling curves,11 phase-contrast imaging,12 myocardial tissue tagging,13 and strain-encoded imaging.14 The reasons for the limited utilization of these techniques in clinical practice are the time-consuming processes for additional image acquisition and post-processing. For instance, obtaining LV volume curves over the entire cardiac cycle, with the mandatory tracking of endocardial and epicardial contours for all cardiac phases in a cine-CMR series takes a long time and requires a specialized software with automated contour detection. Additionally, other specialized techniques of diastolic dysfunction evaluation require additional sequences of images, such as phase-contrast images, which mean longer CMR exam time. In two recent publications by Saba et al.9 and Dusch et al.,7 CMR longitudinal LV shortening has been shown to be useful for diastolic dysfunction assessment.Echocardiography is the most used technique for diastolic dysfunction evaluation in daily clinical routine. Cardiovascular magnetic resonance (CMR) has been widely used for the evaluation of LV morphology and systolic function due to its excellent image quality and lack of geometric assumptions.In the current study, we hypothesized that patients with severe aortic valve stenosis or regurgitation and preserved ejection fraction have diastolic LV dysfunction defined by motion of the atrioventricular junction (AVJ) at CMR.We retrospectively identified 26 patients with severe aortic valve disease (AVD) and normal ejection fraction, who underwent CMR and were scheduled for aortic valve replacement surgery, and 19 normal control subjects. Eleven of AVD patients (42.3%) had predominantly aortic insufficiency, and 15 of them (57.7%) had predominantly aortic stenosis. This sample size was based on the number of patients with confirmed diagnosis, available for analysis.The patients were clinically followed up at valve disease outpatient clinic of our institution. The exclusion criteria were: age under 18 and over 85 years old, diabetes mellitus, systemic arterial hypertension, dyslipidemia or concomitant significant coronary artery disease. All patients over 40 years old had a coronary angiography, and those with significant coronary artery disease  were excluded. Patients with concomitant mitral valve disease were also excluded, as well as the ones with previous cardiac surgery and contraindications for CMR such as pacemaker use, metal clips or other ferromagnetic structures and claustrophobia.Healthy volunteers with no significant past medical history had been recruited to establish baseline AVJ motion values. In addition, 19 healthy volunteers (10 men), aged between 24 and 58 years old, without hypertension, diabetes mellitus, coronary artery disease or other significant past medical history, and all with normal CMR examinations were used for comparison with the 26 AVD patients.The CMR tests were performed with a 1.5 Tesla clinical scanner  and dedicated cardiac surface phased-array coil. After localization of the heart, eight to 12 contiguous short-axis slices (8.0 mm slice thickness and 2mm gap between the slices), encompassing the entire LV and 4 long-axis slices were selected. The analysis was performed in a four-chamber view. Cine images were acquired with a steady-state free precession pulse sequence (SSFP) with temporal resolution of less than 50 ms and standard parameters: TR 3.9 ms, TE 1.8 ms, flip angle 45°, receiver bandwidth ± 125 kHz, field of view (FOV) of 34 x 34 cm, 256x160 matrix, voxel size 1.3 x 2.1 x 8.0mm.9 as we aimed to find the septal and lateral AVJ precisely; we also simplified the measure when we traced a unique line with well-defined landmarks. A simple straight line was traced between basal and apical landmarks using the Webpax software tool   and the inferior limit (hypointense line) of the coronary sinus running through the AV groove, immediately lateral to AVJ. These specific landmarks showed clear visualization on the cine-MR SSFP images and allowed for a robust tracking throughout the cardiac phases, with minimal blurring or loss of image definition. We did not use the midpoint of the mitral annulusNC, USA) . This liLV longitudinal lengths were divided by the longitudinal length at end diastole (maximum length) to provide a percent reduction of longitudinal length, corrected for individual heart sizes. Based on the plots of AVJ position versus time in the cardiac cycle , four moContinuous variables of the AVJ motion are presented as means and standard deviation. Normality distribution was assessed by Shapiro-Wilk test. Data obtained in AVD patients were compared to normal control subjects using the unpaired Student t-test. The categorical variables are presented in percentage.Bland-Altman plots were used to compare LV displacement parameters between patients and controls obtained by two independent blinded observers.The SAS System and SPSS statistical software packages were used for data analysis with a significance level of p < 0.05.Patients’ age ranged between 26 and 72 years old, with 19 men and seven women. The mean age of AVD patients and healthy volunteers in the study was 46.8 ± 13.7 and 43.1± 11.8 years, respectively. All patients were symptomatic, complaining of exertional dyspnea, angina, and syncope . Indexes-1) in early diastole compared with healthy volunteers. Conversely, during diastasis, AVJ motion occurred at significantly faster normalized velocities in patients with AVD. We found a 17-fold higher VDS/MVED ratio in AVD compared with healthy volunteers  of AVD patients and normal control subjects. AVJ data were compared between patients and controls. We found statistically significant differences in MD and the three CMR correlates of diastolic LV function  in patients with AVD compared to normal controls, as noted in lunteers , Table 3The Bland-Altman analysis  for MD rComparison of diastolic function based on AVJ parameters between patients with predominant stenosis and predominant regurgitation did show significant differences in all diastolic function at CMR . ImpairmResults of univariate and multiple linear regression analysis including LV mass, volumes and function as well as patient characteristics such as age, gender, heart rate and blood pressure are shown in In a univariate analysis, MD and MVED correlated significantly with LV volume, left ventricular ejection fraction (LVEF) and LV mass. MVED also correlated to systolic blood pressure (SBP). VDS/MVED correlated with LV mass, LVEF and heart rate (HR). VDS showed correlation only with LV mass and HR . In a muIn summary, these results indicate that LV mass maintains a significant correlation across the four measured diastolic parameters in the univariate and forward stepwise multiple linear regression. Additionally, gender maintained a significant correlation with VDS and LVEF with VDS/MVED ratio. The remaining variables were not independently correlated with diastolic function parameters derived from linear measurements. Thus, body size (body mass index), HR and blood pressure did not influence significantly linear diastolic parameters measured by CMR.Novel correlates of diastolic LV function measured by CMR originally investigated in this study were markedly abnormal in patients with AVD. Measured at the AVJ, patients with AVD had significantly lower maximum displacement, slower velocity during early diastolic filling, and higher velocity during diastasis compared to normal control subjects.9 reported diastolic LV function alterations evaluated through the AVJ motion by CMR in patients with hypertrophic cardiomyopathy compared to normal control patients. Results from our control group were very similar to those reported by these authors, although with slightly greater values mainly because we used a more lateral anatomical landmark. Also, we used only one measurement instead of two of AVJ displacement, hence adopting one well-defined reference point of the AVJ lateral wall, in a more simplified method.Saba et al.15 and is associated with systolic and/or diastolic function disturbances.18 In patients with AVD, diastolic and systolic function disturbances have important implications for morbidity and mortality, before and after aortic valve replacement.21 In the study by Lamb et al.,22 the ejection fraction was largely unaffected in the group of patients with severe AVD, suggesting that a deterioration of the ejection fraction should be considered as a sign of severe and advanced disease,22 which was corroborated by other authors.22 After aortic valve replacement, LV diastolic function improves, as indicated by parameters of transmitral flow.22 In our results, we not only detect diastolic dysfunction in AVD patients compared to normal controls, but also demonstrated a worse diastolic dysfunction in patients with aortic regurgitation. LV mass was significantly and independently correlated with all linear measurements of diastolic function evaluated by CMR.LV hypertrophy is a recognized risk factor for cardiac morbidity and mortality7 In this sense, in a recently published study by Dusch at al.,7 similar to our study, the authors used a horizontal-long axis SSFP sequence, which they called midwall longitudinal fractional shortening. They verified the percentage of shortening of the distance from the anterior leaflet mitral valve basis to apical endocardium in diastole in relation to systole, comparing these measures to the echocardiogram of 80 patients with varied cardiomyopathies and different degrees of diastolic function.24 Using a simpler method than the one used in the present study, Dusch at al.7 were able to detect that the midwall longitudinal fractional shortening of grade II/III was significantly lower than that of grade 0/I.Phase contrast magnetic resonance imaging allows measurement of flow velocity as well as flow volumes across the mitral valve orifice, providing a new means of diastolic function assessment that may be even more sensitive than Doppler echocardiography. Although it is a well-established tool to assess systolic dysfunction, it is rarely used clinically to assess LV diastolic function, which may require additional dedicated sequences and extensive post-processing.Our study shows many advantages of using this new and accurate method for evaluation of LV diastolic function. It does not require the development of an acquisition sequence or post-processing software, and LV diastolic function can be easily evaluated by existing equipment. LV diastolic function can be retrospectively evaluated if prior cine image datasets were stored.Nonetheless, our study has several limitations. One of the most significant ones in terms of practicality is the need to perform manually 20 linear measurements in each phase of one cardiac cycle. However, the use of more automated software would help in a faster measurement. Another significant limitation was that AVJ motion and echocardiography variables were not directly correlated. It is possible that LV longitudinal displacement and the velocity of this displacement might suffer influence from LV geometric morphology. However, the LV dimensions measured as LV end-diastolic volume and diameter did not have significant effect on diastolic parameters. Additionally, LV longitudinal displacements are, by definition, normalized by the LV longitudinal dimension, and the other dimensions are incorporated to volume measurements. Despite the practical advantages of using this new method for LV diastolic function evaluation, it would be important, in future studies, to evaluate its accuracy compared to other existing methods in general evaluation of cardiac diseases that cause LV diastolic dysfunction, verifying the sensitivity and specificity in classifying different diastolic dysfunction degrees. Another limitation of the present study was the relatively small number of AVD patients.Finally, we have demonstrated that diastolic function evaluation can be performed by the SSFP cine sequences routinely acquired by conventional CMR tests, with no need for additional specific sequences or specific software. The incorporation of this technique to clinical routine would improve the CMR ability to analyze diastolic function, even retrospectively using previously acquired CMR images.In conclusion, LV longitudinal shortening is a quick and reliable technique for assessment of diastolic dysfunction in AVD patients that can be performed in routine CMR studies without the use of specific or sophisticated software.The AJV curve showed significant differences in all diastolic parameters analyzed between AVD patients and normal controls. Further studies should confirm that this method is valuable for other cardiac diseases.


Diabetes mellitus is a major factor contributing to the development of cardiovascular disease. As morbidity and mortality rates rise dramatically, when target organ damage develops pre-symptomatic assessment is critical for the management of diabetic patients. Echocardiography is a noninvasive and reproducible method that may aid in risk stratification and in evaluation of treatment effects. The aim of this review is to analyze the echocardiographic techniques which can detect early alteration in cardiac function in patients with diabetes. Diabetes mellitus (DM) enhances coronary atherosclerosis and impairs microcirculation leading to left ventricular (LV) dysfunction. Ramifications of DM in the coronary circulation are quite broad. DM causes development of atheromatic plaques in coronary arteries, which leads to a narrowing of intravascular lumen and to thrombus formation. On the other hand, microcirculatory impairment is caused by the toxic effect of free radicals that are formulated due to persistent hyperglycemia and might provoke arteriolar thickening, perivascular myocardial fibrosis, capillary obstruction and finally endothelial dysfunction .Insulin resistance and glycemic dysregulation have detrimental effects on the systolic and diastolic function of left ventricle. Cardiac alterations in patients suffering from DM, without overt coronary artery disease, are referred as diabetic cardiomyopathy. Development of diabetic cardiomyopathy is a gradual process, which consists of the following alterations. Initially, thickness of left ventricular walls increases and left ventricular compliance declines. As a result, diastolic function is impaired and left ventricular end-diastolic pressure rises. Progressively, left ventricular volumes increase and left ventricular deformation deteriorates. Finally, heart failure syndrome occurs. As a result, diabetes has an important clinical impact in the development of cardiovascular adverse events .Rubler et al. defined diabetic cardiomyopathy in 1972 , after sEchocardiography is a time-sparing and cost-effective method that provides accurate and reproducible diagnostic and prognostic information in patients with DM . The appRecent data show that deterioration of LV diastolic function is quite usual among patients with DM, regardless of clinical status . This meEchocardiographic abnormalities are present in diabetics, despite the fact that symptoms or clinical characteristics do not mandate echocardiographic assessment. Joergensen et al. studied 1030 patients with DM type 2 and revealed remarkable abnormalities through echocardiographic assessment. More precisely, in half of these patients, researchers unveiled diastolic dysfunction with normal or elevated end-diastolic pressure, left atrial dilatation or LV hypertrophy. These findings were not associated with patient’s clinical profile and, as a result, clinical details could not discriminate subjects with deteriorated diastolic function, as assessed by echocardiography. Thus, it is implied that echocardiographic assessment should be an essential screening tool for diabetic patients, regardless of their clinical characteristics .Moreover, diastolic dysfunction can occur even in young individuals in the short term after DM manifestation. According to recent research, deterioration of LV diastolic properties is more common in diabetics compared to control subjects. In fact, they noticed that the higher the HbA1c and the longer the span of diabetes, the greater the probability that markers of diastolic function will be impaired . Older sFurthermore, it is claimed that LV diastolic function abnormality may be detected by echocardiography even in the first five years after the diagnosis of diabetes. According to previous studies referring to diabetics, diastolic dysfunction is associated with defective glucose regulation. Metabolic parameters, such as high glucose plasma levels, might also enhance oxidative stress, intoxicate the myocardial cell, and promote the development of diabetic cardiomyopathy . SimilarAnother research group assessed 1134 patients with diabetes heart failure via preserved ejection fraction. Diabetics displayed bigger volumes of cardiac chambers and increased mass of left ventricle. Moreover, markers of diastolic function, such as trans-mitral E/A ratio, Isovolumic Relaxation Time (IVRT), Deceleration Time (DT), pulmonary vein doppler, and e’ derived from Tissue Doppler unveiled deteriorated ventricular compliance with elevated left ventricular end-diastolic pressure. These findings were in concordance with increased levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP), which were detected in patients with diabetes mellitus, participating in an I-Preserve trial . Moreover, by studying diabetics with coronary artery disease with Doppler echocardiography and intracoronary ultrasound in order to qualify left ventricular diastolic properties, to assess epicardial plaque burden and microcirculation and to determine coronary flow reserve (CFR), it was concluded that there is a relationship between diastolic function deterioration and devastation of microcirculation .Apart from patients with DM type 2, in patients with DM type 1, despite being younger and manifesting less comorbidities, echocardiographic evaluation plays a critical role in risk stratification and has an incremental value on clinical risk scores. In a recent trial, 1093 individuals with DM type 1 were studied during a period of 7.5 years. Echocardiographic parameters, such as Left Ventricular Ejection Fraction (LVEF), impaired global longitudinal strain (GLS) and E/e’ ratio were the main determinants of prognosis. Consequently, assessment of these markers improved the early detection of individuals in jeopardy beyond conventional clinical risk factors .Moreover, left atrial evaluation is feasible by means of speckle tracking echocardiography. In accordance with a recent study, left atrial enlargement in patients with DM is not related to the presence of hypertension or diastolic dysfunction. Actually, left atrial dilatation is combined with deteriorated atrial longitudinal strain. More precisely, DM is likely to affect left atrial function and this abnormality leads gradually to left atrial enlargement . In summary, echocardiography is likely to detect diastolic abnormality and subtle myocardial dysfunction in asymptomatic diabetics before symptoms occur. In such cases, medical treatment should be optimized, in order to prevent further devastation of heart function.Diabetic cardiomyopathy is characterized by myocyte hypertrophy and fibrosis development, which may affect myocardial contractility .Speckle tracking echocardiography is a contemporary tool that analyzes myocardial deformation. It is feasible to detect subtle myocardial impairment in diabetics, before symptoms arise and before conventional echocardiography detects malfunction. Longitudinal deformation of the left ventricle is the most scrutinized mode, but also radial and circumferential deformation have been thoroughly studied . ImportaGlobal longitudinal strain (GLS), assessed by speckle tracking echocardiography (STE), was used to detect preclinical diabetic cardiomyopathy. GLS was impaired in patients with DM1 compared to controls. The recruited subjects had no history of cardiovascular disease and no additive risk factors. Nevertheless, they manifested subtle myocardial deterioration, which could not be detected by conventional markers of cardiac function, such as ejection fraction or tissue doppler systolic velocity .Similarly, the aim of another trial was to see if patients with DM type 1 develop preclinical, subtle biventricular functional deterioration. They examined asymptomatic subjects without either documented diabetic complications or known cardiovascular ramifications. After investigating thoroughly left and right ventricular longitudinal mechanics, they claimed that longitudinal deformation is abnormal in subjects with DM type 1. Additionally, they reported that the deformation impairment was associated with how long the disease lasted and how well the disease was controlled .Asymptomatic subjects with DM type 1 were studied thoroughly with exercise echocardiography. Parameters assessed were longitudinal and circumferential strain and strain rate, by STE, at rest and at peak exercise. Subjects were compared with healthy controls. Despite that asymptomatic subjects with DM type 1 and a short duration of the disease have good adaptation to exercise, as was implied by rising GLS and Global Circumferential Strain (GCS), poor compliance with treatment and improper diabetes regulation enhanced myocardial dysfunction .It is also claimed that obesity is an additive hazard factor for devastating myocardium in diabetics. After studying diabetic patients with a free history of cardiovascular disease and with preserved ejection fraction, researchers concluded that increased body weight induced subclinical alteration in longitudinal deformation, precisely detected by STE. As a result, we notice that while DM causes a subtle and global deterioration in cardiac function before symptoms occur, obesity further hampers proper systolic and diastolic function . Moreover, researchers hypothesized that Galectin-3, an established biomarker for monitoring patients with heart failure with reduced ejection fraction, might be in concordance with GLS deterioration and might identify subtle abnormality in left ventricular systolic properties of diabetics with preserved ejection fraction. Actually, they searched for an association between a potent rise in galectin levels and development of subclinical diabetic cardiomyopathy. According to their results, galectin-3 was increased in the study population, consisting of diabetics with preserved ejection fractions, and indeed patients with impaired longitudinal deformation, assessed by Speckle Tracking Echocardiography, had higher serum levels of galectin-3. Rising galectin-3 and reduced GLS in diabetics with preserved ejection fraction imply left ventricular remodeling and development of diabetic cardiomyopathy .On the other hand, another research group aimed to investigate whether subtle myocardial dysfunction, assessed by GLS, is a trait of uncomplicated DM or whether it is a complication of diabetes that occurs in later stages of the disease, when multisystem complications have been induced. With that purpose they compared normal controls, uncomplicated subjects with DM type 1 and subjects with DM type 1 and albuminuria. All subjects were free of cardiovascular disease. In concordance with previous trials, subtle abnormality in myocardial contractility, detected by deteriorated longitudinal deformation, was noticed in diabetics. Nevertheless, it was further claimed that the occurrence of diabetic cardiomyopathy was related to the detection of systematic diabetic complications, such as albuminuria, and not just with subclinical deterioration in GLS .So far, evidence supports that STE provides a diagnostic tool in order for preclinical myocardial dysfunction to be detected. The prognostic impact of this information was further validated by studying 247 patients with DM type 2 without a history of cardiovascular events. In this group of patients, abnormal GLS had additive value over conventional risk factors in hazard assessment .Beyond risk assessment, response to treatment can efficiently be monitored through estimating longitudinal deformation. Subjects with DM type 2 were upgraded to optimal medical treatment with regard to conventional risk factors and in accordance with contemporary guidelines. GLS, and early diastolic velocity by tissue doppler (e’) were measured, in order for left ventricular systolic and diastolic properties respectively to be evaluated. Optimal medical treatment for 12 months contributed to amelioration of GLS and e’, thus myocardial function was protected by the intensification of treatment .Furthermore, a study group tried to determine the echocardiographic features of diabetes in patients without a history of cardiovascular disease. Study population included healthy controls and asymptomatic, uncomplicated, diabetic subjects with preserved ejection fraction, normal left ventricular mass index, normal diastolic function parameters and BNP in normal range. They investigated longitudinal, radial, and circumferential deformation globally and afterwards separately for endocardium, midcardium and epicardium. They concluded that uncomplicated diabetes, in patients without comorbidities and without additional risk factors, formulates a specific pattern in the left ventricle, assessed by STE, which is characterized by impaired GLS and deteriorated subendocardial radial deformation .In a similar manner, in 52 patients with DM type 1, investigators performed layer analysis of left ventricular walls by STE. While longitudinal strain was affected globally in the left ventricle, circumferential strain was impaired segmentally. The pattern included impaired circumferential strain at the external layers of the ventricular base and was more overt as the disease was in progress for a longer time period .Moreover, another study group recruited patients with heart failure and preserved ejection fraction and examined diastolic function parameters and left atrial deformation. The aim of the study was to investigate whether presence of diabetes has an incremental role in affecting these parameters. Indeed, in diabetics left atrial strain was significantly impaired in comparison with the other patients and this implies that left atrial function is much more deteriorated in diabetics. As a result, left atrial deformation has incremental predictive value in patients suffering from heart failure with preserved ejection fraction .With regard to another research group, left atrial volume does not accurately reflect atrial function. To support this hypothesis, they examined subjects with diabetes, subjects with hypertension and subjects with both diabetes and hypertension. According to their results, left atrial strain was abnormal in these patients, despite the fact that left atrial dimensions were in normal range. Additionally, they showed that deterioration of left atrial performance was more severe when subjects suffered concomitantly from both risk factors. Thus, investigation of left atrial deformation may reveal subtle atrial dysfunction early in the process of a disease, while left atrial volume remains normal .Furthermore, apart from DM, it seems that acute hyperglycemia may also adversely affect left ventricular performance. More specifically, left ventricular deformation was impaired in asymptomatic subjects with diabetes after an episode of acute hyperglycemia. Circumferential and longitudinal parameters, derived from STE, were mainly detected to be affected. An assessment after three months showed that affected parameters were still deteriorated .Acute hyperglycemia postprandially also seems to impair cardiac function. After studying first degree relatives of diabetics type 2 with normal oral glucose tolerance test (OGTT) and patients with abnormal OGTT, it was concluded that the OGTT had an impact on deformation parameters. Investigators claimed that both global and subendocardial longitudinal strain were deteriorated after the test, while left ventricular twisting and untwisting became more intense. According to the authors, this is explained by the fact that hyperglycemia deteriorates endocardial deformation and has neutral effect on epicardial deformation which gains a dominant role .Last but not least, according to another study, speckle tracking echocardiography could be used as a method to evaluate treatment’s effect in cardiac function. Actually, researchers recruited patients with DM type 2, with or without coronary artery disease and treated them according to contemporary guidelines. Subjects formed four groups with regard to treatment with insulin, glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) or GLP-1RA and SGLT-2i combination. After 12 months, GLP-1RA and SGLT-2i improved markers such as effective cardiac work and myocardial deformation compared with insulin treatment. The combined therapy (GLP-1RA and SGLT-2i) had even better effects on studied parameters ,37.In summary, speckle tracking echocardiography might detect subtle impairment in myocardial function, which has an incremental value in risk stratification and in response to therapy of diabetic patients with or without coronary artery disease.Stress echocardiography is a validated technique for the detection and risk stratification of coronary artery disease. By adding wall motion assessment during exercise and coronary flow reserve to clinical features, electrocardiographic changes and blood pressure adaptation to exercise, the efficiency of exercise to diagnose CAD is remarkably enhanced. Stress echocardiography is an affordable, cost-effective, radiation-free method and its detective and predictive capacity are similar to other noninvasive imaging techniques, such as magnetic resonance imaging and nuclear cardiology. Important studies referring to stress echocardiography in diabetics are mentioned in In fact, stress echo is safe for diabetic patients. Detection of segmental wall motion abnormalities during the test is a risk factor for the development of major adverse cardiovascular events. A normal or a pathologic response to stress echo obtains a different meaning with regard to pre-test probability. Despite normal response to stress, patients with reduced ejection fraction at rest or diabetics are still at higher risk compared with subjects with normal ejection fraction or non-diabetics, respectively. The diabetics in jeopardy for adverse cardiovascular events, regardless of a quite good response to stress test, are mainly older, with impaired ejection fraction, and unable to exercise efficiently. Moreover, subjects with DM, in whom a stress echo detected ischemia, are at bigger peril for developing major adverse cardiac events, compared to subjects without DM. Reduced ejection fraction at rest and an increased number of ischemic segments further increase cardiac risk . As a result, stress echo is an efficient method for risk stratification that adds significant information. Nevertheless, it is proven that stress echo is not a screening tool for the general population and consequently assessment without an indication does not provide any predictive evidence . This was also the aim of a recent study to assess whether compliance with pharmaceutical stress echo indications further enhances the impact of the method. The result was more or less obvious, as the method was proved to be effective when practitioners adhered to established indications and official guidelines. Diabetes per se is not an indication for performing a stress echo and therefore the method has no incremental predictive role in diabetics unless specific criteria are met. Therefore, clinicians should not refer inappropriate patients for stress echo evaluation even if they are diabetics . This isScreening all diabetics for coronary artery disease is improper, since it has been shown that a low rate of 5–10% of asymptomatic individuals with diabetes have significant lesions in coronary arteries. Only patients with specific traits may be eligible for being screened with stress echo, such as those needing pancreas or renal transplantation  or underMoreover, a research group tried to examine the role of stress echocardiography in determining prognosis of subjects with DM. Indeed, they reported that, after evaluating clinical features, baseline echo and stress echo information, they created a predictive model. By using this, they managed to distinguish 2349 individuals with DM in three different levels of risk for adverse cardiovascular events .Similarly, another study claimed that stress echocardiography is an elaborative method to evaluate potency for adverse cardiac outcome in diabetics with speculated coronary artery disease. Actually, they assessed the predictive value of dobutamine stress echo in 325 such individuals during a period of 34 months. Despite the fact that univariate analysis showed high cardiac mortality after a positive response in the stress test, finally only older age and peak ejection fraction <40% were independently associated with cardiac death. Furthermore, when the study subjects were distinguished according to baseline EF in two groups, it was shown that positive response in stress test and EF at high level of stress <40% were independently correlated with cardiac mortality .Due to the fact that CAD is the primary reason of cardiac mortality in subjects with DM, scientists search for methods to further determine cardiovascular risk. Thus, 193 diabetics were recruited and studied for two and a half years. Diabetics with findings of ischemia on Exercise Echocardiography (EE) had worse cardiac outcomes compared to general population. Thereafter, EE could indeed be a tool for the prediction of adverse outcomes in diabetics with cardiovascular disease .While ischemia at stress echo is an important indicator of mortality in both groups of patients with and without diabetes, it seems that antianginal medication alters the negative predictive value of the method only in subjects without DM but not in subjects with DM .According to the results of a recent study, stress echo seems to be important for risk assessment of individuals with DM. A negative for ischemia stress test is associated with good prognosis, regardless of the method used. However, the risk in diabetics is definitely higher. Nevertheless, detection of ischemia in a stress test is independently related with adverse events and the grade of peril is associated with the extent of ischemia detected . It has been shown that stress echocardiography in diabetics is less sensitive than perfusion imaging due to concomitant diabetic cardiomyopathy. On the other hand, it is more specific compared to myocardial perfusion imaging. This may be explained by the fact that in these patients both microcirculation and coronary vessels are affected. In comparison with normal subjects, in patients with diabetes a normal response to stress is followed by a worse outcome .On the other hand, a recent study reported that, in diabetic individuals who are unlikely to complete an exercise test, the pharmaceutic test has a reduced capability of foreseeing future adverse events. It was also suggested that there is a period of up to seven years after the test in which optimal risk stratification is provided . Finally, according to a trial which compared 44 diabetics with 35 healthy nondiabetics, it was claimed that dobutamine stress echo might detect subtle alterations in left ventricular deformation properties, which were not overt before the stress test. In particular, left ventricular stimulation by low dose dobutamine led to deterioration of left ventricular longitudinal deformation, circumferential strain, rotation and twist .In summary, it is obvious that when clinicians comply with the appropriateness criteria of stress echocardiography, the method is likely to contribute to the optimal management of individuals with diabetes. Actually, stress echocardiography can unveil the existence of CAD and may evaluate the risk for major adverse cardiovascular events in individuals with DM. Echocardiography, apart from unveiling preclinical myocardial dysfunction in subjects with DM, might further contribute to risk stratification in this group of patients. Innovative and state-of-the art methods, such as Coronary Flow Reserve Assessment by Doppler Echocardiography, may detect endothelial dysfunction and deterioration of both epicardial and microvascular circulation that are proportional with the severity of diabetes. Important studies referring to coronary flow reserve in diabetics are mentioned in The value of CFR in risk assessment of asymptomatic individuals with DM is crucial. Researchers investigated asymptomatic subjects with DM type 2 without established CAD and validated the prognostic role of CFR in this population. After excluding subjects with CFR < 2, because of increased probability of having a severe coronary lesion, they reported that CFR ≥ 2.5 was related to fewer adverse cardiovascular events. On the other hand, patients with 2 < CFR < 2.5 had a poorer prognosis. Thus, CFR helps us in achieving a more precise risk assessment of patients with DM . Other investigators studied patients admitted to hospital due to chest pain and with speculated coronary artery disease. Among them, diabetic patients had more significant aortic atherosclerosis and lower CFR, while significant CAD was more common in diabetics. CFR and diabetes were independent predictors of cardiovascular survival. Among subjects recruited, diabetics with decreased CFR, which implied devastated microcirculation, were at bigger peril for developing cardiovascular complications .Another group of researchers attempted to explore coronary microcirculation of patients with insulin resistance in comparison with diabetic patients and normal population. While CFR was reduced in patients with DM, patients with insulin resistance  and normal controls had similar CFR. With regard to this study, it is claimed that microcirculatory dysfunction is detected after the outbreak of DM .On the contrary, it was reported by another research group that first-degree relatives of diabetics with normal OGTT and subjects with abnormal OGTT had comparable resistance to insulin, similarly defective arterial elastic properties and diminished CFR compared to controls. According to these results, it was concluded that resistance to insulin is a contributing factor to the development of subtle deterioration of vascular, microvascular and myocardial function .Moreover, researchers tried to evaluate whether CFR decline in diabetics is associated with insulin resistance or affected by acute hyperglycemia. On that purpose, they investigated individuals with DM2 and controls. Despite that CFR declined in diabetics compared with controls, it was reported that proper glucose regulation, as assessed by fasting glucose and HbA1c levels, was correlated with less diminished CFR. Insulin resistance was not correlated with CFR. Thus, in type 2 diabetics, glucose regulation is most likely to be associated with the decline in CFR .Finally, questions had been raised as to whether CFR is similar among diabetic patients with complications and without complications. As a result, researchers studied diabetic patients with or without diabetic retinopathy. It was concluded that coronary flow reserve was remarkably diminished in diabetics complicated with diabetic retinopathy. Despite that CFR is generally decreased in diabetics, the presence of a complication such as retinopathy, which implies a more advanced stage of diabetes, is also associated with a more intense deterioration of microcirculation. Consequently, the more advanced the development of retinopathy, the more exaggerated the impairment in microvascular function, as assessed by coronary flow reserve .In summary, CFR plays a major role in the diagnosis of microvascular dysfunction in diabetics. Additionally, when CFR is combined with stress echocardiography, it has incremental role in the diagnosis of coronary artery disease and risk stratification in patients with DM.Echocardiography is an efficient tool for the management of diabetics . In factProper assessment of diabetic patients is critical, in order to hamper the development of vascular and microvascular complications. Echocardiography is a feasible and safe method that provides diagnostic and predictive information in individuals with diabetes mellitus. A diversity of applications, such as Doppler echocardiography, Speckle Tracking Echocardiography and Stress Echocardiography, could be useful for the management of diabetics and the optimization of medical treatment. Contemporary standard of care in diabetics should include echocardiography for clinical assessment.


Maximum oxygen uptake is an established measurement of diagnosing chronic heart failure and underlies various central and peripheral factors. However, central and peripheral factors are little investigated, because they are usually measured invasively. The aim of this study was to compare non-invasively measured central and peripheral factors of oxygen uptake between patients with chronic heart failure and healthy controls.2; ejection fraction: 30 ± 4%) and ten male healthy controls  were tested for blood pressure, heart rate, stroke volume, cardiac output, and cardiac power output  as well as muscle oxygen saturation of the vastus lateralis and biceps brachii muscle  during an incremental cycling test. Stroke volume and muscle oxygen saturation were non-invasively measured by a bioreactance analysis and near-infrared spectroscopy, respectively. Additionally, a maximum isometric strength test of the knee extensors was conducted. Magnitude-based inferences were computed for statistical analyses.Ten male patients with heart failure with reduced ejection fraction (62 ± 4 years; body mass index: 27.7 ± 1.8 kg/mPatients had a likely to most likely lower oxygen uptake, mean arterial pressure, and heart rate at maximum load as well as very likely lower isometric peak torque. Contrary, patients had a possibly to likely higher stroke volume and muscle oxygen saturation of the vastus lateralis muscle at maximum load. Differences in cardiac output, cardiac power output, and muscle oxygen saturation of the biceps brachii muscle at maximum load were unclear.Non-invasively measured central and peripheral factors of oxygen uptake differ between patients with chronic heart failure and healthy controls. Therefore, it is promising to measure both types of factors in patients with chronic heart failure to optimize the diagnosis and therapy. Chronic heart failure is a clinical syndrome “caused by structural and/or functional cardiac abnormality, resulting in a reduced cardiac output” . Based oFor the treatment of chronic heart failure, it is essential to accomplish valid diagnostic and therapeutic methods. Considering diagnostic methods, blood, electrocardiography, echocardiography, and maximum oxygen uptake are established measures , 6. HoweIn this context, previous studies investigating patients with chronic heart failure have focused on stroke volume , cardiacTo our knowledge, there is only one study that has compared the cardiac output between patients with chronic heart failure and healthy controls . In thisThe aim of this study was to compare non-invasively measured central and peripheral factors of oxygen uptake between patients with chronic heart failure and healthy controls. Based on previous research , 25, we Ten male patients with chronic heart failure (62 ± 4 years) and ten male healthy controls (59 ± 3 years) participated. The patients were recruited from a local medical practice for cardiology, whereas the healthy controls were acquired of the investigators’ circle of acquaintances. Out of the ten patients, six were classified New York Heart Association (NYHA) class II, three NYHA class III, and one NYHA class IV. The mean ejection fraction and mean duration of the QRS complex of the patients were 30 ± 4% and 124 ± 28 ms, respectively. The relative medication was as follows: beta-blockers (100%); diuretics (80%); ACE inhibitors (80%); aldosterone antagonists (70%); AT1-antagnoists (20%); and Marcumar (30%). Besides their heart failure, the patients suffered from different comorbidities, namely arterial hypertension (40%), hypercholesterolemia (40%), bronchial asthma (20%), diabetes mellitus (10%), fatty liver disease (10%), chronic obstructive pulmonary disease (10%), renal failure (10%), allergies (10%), stroke (10%), and depression (10%). To describe the impact of chronic heart failure on daily situations, the Kansas City Cardiomyopathy Questionnaire was used. The maximum score is 100, whereas a higher score indicates a better condition . The corA cross-sectional design under laboratory conditions was applied. The following tests were conducted in the mentioned order: (a) anthropometric measurements, (b) incremental test until exhaustion on a cycling ergometer, and (c) maximum isometric strength test of the knee extensors on an isokinetic device. Between the incremental cycling and isometric strength test the participants were given a 30-min break. During all tests, a cardiologist was present and monitored all procedures.r = 0.98–0.99 [Body fat and fat-free mass were determined by using a 4-point bioelectric impedance analysis  in supine position. For later muscle oxygen saturation measures by near-infrared spectroscopy, skinfold thickness of vastus lateralis and biceps brachii muscle was determined using a caliper . The validity of the 4-point bioelectric impedance analysis is .98–0.99 .The incremental test was performed on a cycling ergometer . Testing consisted of a ramp-like protocol. For reaching a comparable time to exhaustion, the load started and increased per minute by 5 and 10 W for patients with chronic heart failure and healthy controls, respectively. The test was ended, when the required pedalling frequency of 75–80 rpm could no longer be maintained. Finally, patients and healthy controls performed a 5-min cool-down at 15 and 30 W, respectively. To clarify exhaustion, the healthy controls had to reach three out of five criteria: (a) heart rate ≥ 200 bpm – age; (b) blood lactate ≥8 mmol/l; (c) respiratory exchange ratio ≥ 1.1; (d) rating of perceived exertion ≥18; and (e) visual analogue scale ≥60% of total exertion . However) = 8.2% , intracl) = 8.2% , and CV ) = 8.2% , respectThroughout the incremental cycling test, stroke volume (SV) and heart rate (HR) were recorded non-invasively by a bioreactance analysis . The measurement principle is described in detail elsewhere . BrieflyCardiac output (CO) was estimated afterwards as follows:The validity and reliability of the used bioreactance analysis are regression coefficient (R) = 0.82  and ICC Muscle oxygen saturation of the right vastus lateralis muscle was measured using a near-infrared spectroscopy . The measurement principle is also explained in detail elsewhere . BrieflyTo obtain additional insights into peripheral differences, strength differences between patients with chronic heart failure and healthy controls were examined by a maximum isometric strength test of the knee extensors using an isokinetic device . The dominant leg was tested at a hip angle of 90° and a knee angle of 60° flexion and lasted 6 s. The test was performed twice, separated by a 2-min rest period, and the highest peak torque was used for statistical analyses. As body weight was similar in both groups, the data were not relativized for later statistical analyses. The reliability of the used isometric device is ICC = 0.90–0.98 .http://www.sportsci.org/. Since hemodynamic responses with the same clinical status may diverge and to emphasize intra- and interindividual variabilities of the participants, individual responses of the underlying factors of maximum oxygen uptake are also shown.To investigate differences between both groups, Magnitude-based inferences were computed. This alternative statistical approach is well suited for small sample sizes with high intra- and interindividual variabilities and aims to increase the transfer of findings into practice . The approach is described in detail elsewhere . FirstlyTable Figure Figure Figure For the first time, we investigated non-invasively measured central and peripheral factors of oxygen uptake between patients with chronic heart failure and healthy controls by the same standardized research design. Our main findings were: patients with chronic heart failure had (a) a lower maximum oxygen uptake, (b) a similar cardiac output and cardiac power output at maximum oxygen uptake, and (c) lower values in muscle oxygen saturation of vastus lateralis muscle at rest and higher values at maximum load as well as lower values in isometric peak torque values.Regarding our first main finding, patients with chronic heart failure had a most likely lower maximum oxygen uptake than healthy controls Table . The maxConcerning our second main finding, patients with chronic heart failure had a similar cardiac output and cardiac power output at maximum load compared to healthy controls Fig. . Our resRegarding our last major finding, patients with chronic heart failure had lower values in muscle oxygen saturation of the vastus lateralis muscle at rest and higher values at maximum load as well as lower isometric peak torque values compared to healthy controls Fig. . Our resTaken together, central and peripheral factors may affect the maximum oxygen uptake in patients with chronic heart failure. Thus, it is promising to measure both types of factors in clinical settings to allow more effective and individually adjusted therapies. The cardiac power output should be gaining increasing importance in diagnosis, follow-ups, and prognosis of heart failure, because of its possible superior prognostic impact compared to maximum oxygen uptake –11. AddiWhile our study increased the knowledge concerning non-invasively measured central and peripheral factors of oxygen uptake in patients with chronic heart failure, some limitations should be acknowledged. Firstly, we investigated a relatively small sample size, which caused large confidence intervals and unclear differences between the groups. A larger sample size would allow a better generalization. Additionally, a crucial point of our statistical approach is the definition of the smallest worthwhile difference. Compared to sport science, the definition is less approved in sport medical settings . MoreoveIn conclusion, our study shows that non-invasively measured central and peripheral factors of oxygen uptake differ between patients with chronic heart failure and healthy controls. Therefore, it is promising to measure both types of factors in patients with chronic heart failure to optimize the diagnosis and therapy. Especially, peripheral factors can reveal new insights into the pathophysiology of chronic heart failure and should therefore be more investigated in combination with central factors in future studies.


Microinfarction is common following coronary interventions (PCI and CABG) and acute coronary syndromes. Magnetic resonance imaging (MRI) has become the reference method for non-invasive quantification of: 1) left ventricular (LV) function using cine imaging and 2) myocardial perfusion deficits using first pass perfusion and 3) acute and chronic myocardial contiguous infarction using delayed contrast enhancement (DE) technique. Modern multidetector computed tomography (MDCT) has also been recently used in assessing the above parameters in contiguous infarction. To our knowledge both modalities have not been tested in the assessment of microinfarction caused by microembolic agents.This study aimed to examine the potential of 64-slice MDCT and MRI in assessing LV function, regional perfusion and viability in microinfarction.An XMR-suite was used to catheterize the LAD coronary artery under X-ray and to define the LAD-territory using first-pass MRI during intracoronary injection of 10% Gd-DOTA. The perfusion territory was selectively microembolized in six pigs using a microembolic agent . LV function (cine imaging), perfusion (first-pass imaging) and viability (DE imaging) were determined 7–8 weeks after microembolization using MRI followed by MDCT (5 days later). Histochemical staining (TTC) was used as golden standard for quantification of microinfarction. Figure P = ns for all segments, bias 0.3 ± 21.9%). MRI, but not MDCT, detected a perfusion deficit in the microembolized territory . Microinfarction size did not differ between MDCT (6.3 ± 0.8%LV), MRI (6.6 ± 0.5%LV) or TTC (7.0 ± 0.6%LV). Bias (Bland-Altman test) for quantifying microinfarction on MDCT was -0.6 ± 1.9%LV compared to TTC and for MRI -0.4 ± 1.3%LV compared to TTC.The LAD-territory was 32.4 ± 3.8% of the LV mass. There was no significant difference between MR and MDCT measurements of systolic wall thickening. Global LV function did not differ between MRI  and MDCT . Both MRI and MDCT showed a decrease in function in the microembolized territory and an increased contractility in remote myocardium. There was no difference in the quantification of systolic wall thickening  between the methods (Modern MDCT and MRI techniques have the sensitivity to: 1) visualize and quantify chronic microinfarction and 2) demonstrate regional LV dysfunction. MRI, but not MDCT, has the sensitivity for detecting small changes in regional perfusion of chronic microinfarction. Close agreements were found between MDCT and MRI in measuring regional and global LV function. The results of this study suggest that MDCT and MRI can be used for detecting the consequences of microinfarction following coronary interventions and evaluating the efficacy of new therapies and devices designed to prevent microembolization.


The interaction of ageing and exercise training status on left-ventricular (LV) peak strain is unclear. Additionally, strain analysis across the entire cardiac cycle facilitates a more detailed assessment of deformation, yet this has not been implemented to characterize the ageing LV and in association with training status. This study investigated healthy ageing and training status on LV systolic and diastolic strain utilizing novel echocardiographic applications.RA,n = 9; 28 ± 5 years), old recreationally active , young trained , and old trained  groups. Two-dimensional speckle-tracking echocardiography was performed to ascertain peak LV longitudinal and circumferential strain (base and apex) strain within each myocardial layer and at 5% increments across the cardiac cycle.Forty healthy males were included and allocated into four groups; young recreationally active (YP < 0.05). Whereas, strain throughout systole was similar between groups (P > 0.05). Longitudinal and circumferential (base and apex) peak and layer-specific strain did not differ between groups (P > 0.05).Older groups had lower diastolic longitudinal lengthening and circumferential expansion between 40–85% mid-diastole, regardless of training status  contains supplementary material, which is available to authorized users. The left ventricle (LV) is characterized by structural and functional modifications with advancing age, including increased wall thickness and reductions in diastolic function  males.This cross-sectional study required participants to visit the laboratory on two separate occasions having been asked to abstain from alcohol, caffeine (24 h), and vigorous exercise (48 h) prior to both visits. The study was granted ethical approval and all participants provided written, informed consent before being enrolled.RA), young trained (YT), old recreationally active (ORA), and old trained (OT). Individuals were approached at local sports clubs , via social media posts, through word-of-mouth, attendance at social clubs  and also at local community events, such as ‘Men’s Shed’ and ‘University of the Third Age (U3A)’.We aimed to recruit two adults with physiologically meaningful differences in age; therefore, we recruited young adults between the ages of 18–40 years  and old individuals 55–80 years  excluded based on treatment for cardiovascular diseases , type 2 diabetes mellitus, use of cardioactive medications for treatment  or blood pressure classified as ‘hypertensive crisis’ (≥ 180 systolic or 120 diastolic mmHg). Five individuals withdrew due to personal reasons , with two YRA participants excluded due to violations of requirements prior to or during data collection, with a further two YRA participants excluded due to being smokers. All remaining participants were not habitual smokers at the time of assessment.Medical questionnaires assessed suitability for healthy individuals, with 12 older individuals , all reported non-structured exercise habits and took part in < 2 h per week of continuous endurance exercise . Similarly, some ORA individuals performed recreational hill walking, golf, walking soccer, and gym-based exercise, albeit all ≤ 2 h per week of continuous endurance exercise.A self-reported questionnaire was used to ascertain the number of hours spent performing aerobic exercise, corresponding to high dynamic activities , cycling only (n = 3), or both modalities (n = 4). Similarly, OT individuals took part in running only (n = 5), cycling only, (n = 2) or both modalities (n = 4). Three OT previously competed internationally, including one a past half marathon world champion for their respective age group. See supplementary material 1 for YT and OT training durations, volumes, and dose. Twenty-eight individuals were excluded, resulting in 40 males included in the final analysis .Y:During visit 1, unshod stature and body mass were measured using a free-standing stadiometer,  and scales . Body mass index (BMI) was calculated asDuring visit 2, following 5 min’ supine rest, three blood pressure readings, using an automated sphygmomanometer , were recorded each separated by 2 min. A resting echocardiographic assessment was conducted with resting HR recorded offline from the three-lead electrocardiogram (ECG) inherent to the ultrasound machine, as the average of cardiac cycles used for LV outflow tract. Mean arterial pressure (MAP) was calculated as: 0.667), and sphericity index as the ratio between LVEDD and LV length  with a phased array transducer . Images were acquired and analyzed by a single sonographer (AB) in accordance with standard procedures (Maragiannis and Nagueh s′), early (e′) and late (a’) diastole were averaged, and then, their ratio (e′/a′) calculated. Doppler tissue velocities were then scaled to LV length  calculated. Longitudinal tissue velocities were established using pulsed waved Doppler in the apical four-chamber view from medial and lateral sites, and then averaged. Unidimensional velocities from the septal and lateral regions during systole . Aortic valve closure (AVC) was identified as end-systolic timing from the pulsed wave tracings obtained from apical 5-chamber LV outflow tract. The clearest cardiac cycle with most optimized myocardial layer delineation was selected, and then, the endocardial border was manually traced before an automated region of interest (ROI) was generated to encompass the entirety of the LV wall extending to the epicardial border. The operator manually adjusted the ROI paying attention to ensuring LV and RV trabeculations, moderator band, papillary muscles, and pericardium were not included within the ROI. The software automatically divided the myocardial wall into six segments and in the instance that two or more segments could not be tracked sufficiently, the image was excluded from analysis. Raw files were exported from the EchoPac software and imported into custom software . The custom software applied a 500-point cubic spline to each of the systolic and diastolic portions of the cardiac cycle (derived from AVC). The splined data were then used to identify systolic and diastolic peaks and relative timings, as well as identifying strain or strain rate values at 5% increments of the systolic and diastolic phases, respectively.S) was identified as the peak of the SR-time curve and for early diastolic SR (SRE), a filter of 50 ms from AVC was used to exclude peaks in isovolumic relaxation time. Using the ECG, P-wave timing was identified and the late diastolic SR (SRA) was determined after this detection point. Therefore, peak SRS, SRE, and SRA were determined in the longitudinal orientation and from the parasternal short-axis views for radial and circumferential strains at the basal and apical levels and their averages calculated.Systolic SR  was conducted in a subset of eight, young males. For peak indices relating to this study, the coefficients of variations are as follows: four-chamber longitudinal strain, 2.9%; basal circumferential strain, 10.8%; apical circumferential strain, 4.6%. See supplementary material 3 for extended reproducibility including normalized analysis across the cardiac cycle.P ≤ 0.050 and analyses performed using jamovi  was lower in older than younger cohorts, while late diastolic filling  was greater in older than younger cohorts. Together, E/A, e′/a′ were lower in older than younger, whereas estimated filling pressure (E/e′) was greater in the former. Lateral e′ was greater in trained than RA, with a significant interaction which revealed that YT had greater tissue velocity than the other groups. Average e′ (absolute and indexed) were greater in trained than RA without a significant interaction effect. Finally, e′/a′ was greater in trained than RA, yet the interaction effect identified that this was in the main due to being larger in YT.Conventional indices of functional systolic and diastolic dynamics are presented in Table S than younger cohorts, which was also lower in trained than RA. Whereas 2-chamber and averaged SRS were lower in trained than RA, but did not differ between ages. Four-chamber, 2-chamber, and averaged SRE were lower, with higher SRA in older than younger cohorts. No training effect was noted for SRE or SRA from 4-chamber; however, 2-chamber and averaged SRA were lower in trained than RA.Layer-specific longitudinal strain and SR are presented in Table T than YT. Basal SRS was lower in older than younger cohorts but not at the apex of when average. No differences between trained and RA were observed for SRS. Basal, apical, and global circumferential SRE were lower, whereas SRA were higher in older than younger cohorts. Diastolic SR were not different between trained and RA. Similarly, radial SRA were higher in old than young, without difference based on training status. Radial SRE did not differ based on age or training, while trained had greater global radial SRS than RA without further differences noted.Layer-specific circumferential strain, SR, and radial strain and SR are presented in Table Longitudinal strain and SR throughout the cardiac cycle are illustrated in Fig. T than OT. Older cohorts had higher strain (more negative) than younger cohorts between 40 and 85% , regardless of training status. Between-group comparisons of apical circumferential strain during systole were unremarkable. In contrast, at 20% diastole, strain was lower in trained than RA. Moreover, between 25 and 85% diastole, older cohorts had more strain  than younger cohorts , regardless of training status.Basal and apical circumferential strain and SR are illustrated in Fig. Basal circumferential SR was lower in older than young cohorts from 25–60% systole. An interaction effect was observed at 90–100% systole; however, post hoc analysis did not identify significant between-group differences. During diastole, older cohorts had higher SR than young at 85–90%. Trained cohorts had higher SR than RA at 15% diastole, yet lower SR than RA at 25–30% and 60% diastole.T than ORA at 95%, yet not between-group differences at 100%. At 25–30% diastole, trained had lower SR than RA. Older cohorts had higher SR at 90% diastole than younger cohorts.A significant interaction effect was observed for apical circumferential SR at 95–100% systole. Post hoc analysis identified lower SR in OThe main findings from this study were: (1) diastolic lengthening  and expansion  were lower during mid-diastole in older than younger groups. (2) The age-associated reductions in mid-diastolic lengthening and expansion were not attenuated in chronically trained older exercisers. (3) There were only minor differences in peak systolic longitudinal and circumferential strain, within myocardial layers according to healthy ageing or training status. Thus, the influence of ageing and exercise on LV longitudinal and circumferential strain is not synonymous across the entire cardiac cycle, but appears to be dependent on systole and diastole. Importantly, using non-invasive STE derived techniques, this study presents novel characterization of strain mechanics and, subsequently, plasticity in both young and old RA and athletic hearts of men.Less lengthening  and expansion  were evident in the older than younger cohorts during mid-diastole (diastasis). We speculate that without temporally aligned LV pressure, these differences are a consequence of compromised compliance (increased stiffness and reduced distension) during diastasis with advancing age. Similar modifications are known to occur within the senescent human LV, including increased end-diastolic stiffness with reduced chamber compliance and distensibility through multiple reports of invasive pressure–volume curves  with ageing may reflect a stiffer LV following the active period of relaxation, yet prior to atrial systole. In turn, and in accordance with the strain profiles, the LV does not return to its baseline length until after atrial systole, which may represent a greater reliance on atrial systole to return LV fibers to their original length. Indeed, the atrial contribution to ventricular lengthening in strain may need to increase to normalize LVEDV, which is evidenced by faster A wave and SRThe implications of lower mid-diastolic lengthening and expansion in older cohorts at this moment are unclear; however, it would not appear to impair LV filling, since difference in LVEDV index was unremarkable between RA groups. Yet, further interpretation would be overly speculative due to the sample sizes in this study. Moreover, whether the reduced lengthening and expansion in the older cohorts represent altered intrinsic myocardial properties or elastic modifications of extracellular structures Smiseth  cannot bT are unclear, yet the lack of compensation with chronic exercise training does not seem to impair maximum diastolic filling. Although, these observations were made at rest and, thus, the functional reserve during physiological stress, such as exercise, for example, may provide further insights into the functionality between trained and RA older cohorts. Indeed, it would be of further interest to investigate the response of these novel measures from rest to exercise, up to the merging of early and late diastolic filling.An important and novel finding from this study was that the lower LV lengthening and expansion with ageing was not attenuated in chronically trained exercisers and, consequently, ageing rather than training status appears to be dominant in altering mid-diastolic strain profiles. The ramifications of this in OT had larger LVEDV than both YRA and ORA; therefore, alterations in diastolic strain and LVEDV may not be interdependent. Indeed, both trained groups had similar diastolic strain profiles but larger LVEDV than their age-matched counterparts. Larger LVEDV was evident in trained groups without heightened reliance on atrial systole  compared to their RA counterparts, suggesting that it is unlikely that atrial systole is responsible for their larger volumes. Indeed, trained groups did show greater averaged e’ than RA, which may have improved early diastolic filling. Also, trained groups had lower HR than RA which could have lengthened the filling time and, in turn, facilitated a larger LVEDV. Moreover, it is difficult to determine whether larger EDV in trained groups represents augmented end-diastolic distensibility, as has previously been suggested at similar filling pressures (PCWP) with increasing chronic exercise training doses  and its interaction with exercise training independently. In turn, the healthy status of our participants could provide some explanation for the maintained strain with advancing age. Indeed, reduced longitudinal strain is indicative of early LV dysfunction and commonly observed in pathological conditions and hypertensive populations  and previously meta-analysis (28 g m2)  engagement with exercise, which may act as a confounder. However, these sports and the participants’ involved were intermittent and the limitations of classifying team-based sports as highly dynamic given differences in playing position have been acknowledged  of older men were still excluded because of medications or medical conditions. Whilst exclusion of such conditions was intentional and limits generalizability, the primary aim of the study was to understand the cardio-physiology of exercise during ageing. Consequently, our use of ‘healthy ageing’ differs from the epidemiological definition by the World Health Organization Supplementary file2 (DOCX 422 kb)Supplementary file3 (DOCX 742 kb)Below is the link to the electronic supplementary material.


The incidence and pathophysiology of right ventricular failure in patientswith severe respiratory insufficiency has been largely investigated.However, there is a lack of early signs suggesting right ventricularsystolic and diastolic dysfunction prior to acute cor pulmonaledevelopment.We conducted a retrospective analytical cohort study of patients for acuterespiratory distress syndrome undertaking an echocardiography duringadmission in the cardiothoracic intensive care unit. Patients were dividedaccording to treatment: conventional protective ventilation ; interventional lung assist ; veno-venousextracorporeal membrane oxygenation . Systolic anddiastolic function was studied assessing, respectively: right ventricularsystolic longitudinal function (tricuspid annular plane systolic excursion)and systolic contraction duration (tricuspid annular plane systolicexcursion length); right ventricular diastolic filling time and rightventricular diastolic restrictive pattern . Correlation between the respiratory mechanicsand systo-diastolic parameters were analysed.P<0.0001;r −0.42). Tricuspid annular plane systolic excursionand tricuspid annular plane systolic excursion length correlated with rightventricular diastolic filling time . Pulmonary valve presystolic ejection wave wasassociated with tricuspid annular plane systolic excursion(P<0.0001), tricuspid annular plane systolicexcursion length (P<0.0001), right ventricular diastolicfilling time (P<0.0001), positive end-expiratorypressure (P<0.0001) and peak inspiratory pressure(P<0.0001).In 98 patients studied, systolic dysfunction (tricuspid annular planesystolic excursion <16 mm) was present in 33.6% while diastolicrestrictive pattern was present in 64%. A negative correlation was foundbetween tricuspid annular plane systolic excursion and tricuspid annularplane systolic excursion length (Diastolic restrictive pattern is present in a remarkable percentage ofpatients with respiratory distress syndrome. Bedside echocardiography allowsa mechanistic evaluation of systolic and diastolic interaction of the rightventricle. Lung-protective strategies, usinglower end-inspiratory (plateau) airway pressure, lower tidal volumes (Vt) and higherpositive end-expiratory pressure (PEEP)6 and, eventually, rescue withextracorporeal support remains the cornerstone.7Acute respiratory distress syndrome (ARDS) is associated with alveolar epithelial andmicrovascular endothelial injury, resulting in severe hypoxemia, decreased pulmonarycompliance and increased pulmonary vascular resistance.4 However, dataregarding incidence and outcome vary among the studies4 and, more importantly, thepublished data focused mainly on ACP, which represents the last stage of RVdysfunction.9The incidence and mechanisms of RV dysfunction in the severe acute respiratoryfailure patient population has previously been investigated.4 Quantitative assessment of RVfunction can be performed by several methods, of which tricuspid annular planesystolic excursion (TAPSE) can be obtained routinely in critically ill patients andcorrelates well with RV function.1013 However, there is a paucity ofdata regarding non-invasive indices that allow us to identify RV injury before theonset of failure.Aside from the literature regarding ACP, there are few studies quantifying the RVsystolic function in ARDS and no data are available regarding RV diastolic functionand systo-diastolic interrelation.14 It is detectedas the forward end-diastolic pulmonary blood flow coincident with atrial systole,representing a sign of ventricular diastolic restrictive compliance, occurring whenthe RV end-diastolic pressure equals or exceeds pulmonary arterial diastolicpressure.15The pulmonary valve pre-ejection wave (named PV a wave or pulmonary end-diastolicforward flow) is a sensitive index of diastolic restrictive pattern.We sought to determine the incidence of RV systolic and diastolic dysfunction, in acohort of patients with ARDS, no features of ACP, managed with mechanicalventilation or extracorporeal support.16 Patientswith no echocardiographic windows, or who did not undergo echocardiography wereexcluded (n=14). Patients12 with ACP, defined as RVdilation with interventricular paradoxical motion leading to decreased leftventricular (LV) diastolic compliance and stroke volume reduction with severehaemodynamic impairment,17 were excluded as the aim of our study was to analysefeatures of RV dysfunction before end-stage RV failure occurs.We conducted a retrospective analysis cohort study of 98 consecutive patientsadmitted for ARDS requiring echocardiography for a period of 2 years. The studywas performed at adult intensive care, Royal Brompton Hospital, London, UK. Thestudy was approved by the local ethics committee at the Royal Brompton andHarefield NHS Foundation Trust. All selected patients were older than18 yearsand had a diagnosis of ARDS as defined by the Berlin definition.Patients were managed at the discretion of the treating physician withconventional protective ventilation , interventional lungassistance  and veno-venous extracorporeal membrane oxygenation. The demographic data, clinical profiles, laboratoryinvestigations and therapeutic regimens of the patients were extracted from theintensive care unit (ICU) patient data managing system . Patient characteristics are summarised in 18 ventricular dimensions andvolume and flow velocities were obtained using pulsed and continuous waveDoppler techniques according to the ASE and European Association ofEchocardiography guidelines.20Patients underwent transthoracic or transesophageal echocardiography asclinically indicated. All echocardiographic studies were performed within 48hours of intensive care admission. Studies were clinically indicated by thetreating physician and performed by two board-certified ICU physicians usingtransthoracic or transesophageal echocardiography .Echocardiographic data were retrospectively analysed offline, blinded to patientdemographic and clinical characteristics. All measurements were acquired atend-expiration, and averaged on at least 3 beats when in sinus rhythm and 5–10beats when in supraventricular arrhythmias; all the recordings were done at apaper speed of 100 mm/s with superimposed ECG trace (lead II). RV systolic anddiastolic parameters were evaluated according to American Society ofEchocardiography (ASE) guidelines;Echocardiographic data analysis was performed offline by a EACVI certifiedoperator (GT).20 Moreover,TAPSE length with respect to the ECG, was also assessed and regarded aspost-ejectional shortening when annular displacement peaked after the T wave onthe ECG, meaning a pathological systolic contraction elongating during theproto-diastolic period.21 The pulmonary artery systolic diameter was measured inmodified parasternal long axis and parasternal short axis views. Pulmonaryartery flow was measured by placing the pulsed-wave Doppler sample volume at thecentre of the transpulmonary valve flow. Presystolic A wave (PV a wave orpulmonary end-diastolic forward flow) is seen, when present, as an anterogradeflow through the pulmonary valve in correspondence to the atrial systole (P waveat the superimposed ECG) preceding the ventricular contraction  from the end of diastole to end systole. As perguidelines, a TAPSE less than 1.6 cm was considered pathological.traction .23 Pulmonaryarterial systolic pressure was determined from the tricuspid regurgitation jetvelocity using the simplified Bernoulli equation adding the right atrialpressure measured directly from the central venous pressure at endexpiration.18Right ventricular filling time (RVFT) was measured as the interval between theonset of the E wave to the end of the A wave using pulse wave Doppler with thecursor placed at the RV inflow in apical four-chamber view. As filling timesdepend on heart rate, RVFT was adjusted accordingly. RV ejection time wasquantified as the interval between the onset of forward pulmonary flow and theonset of the pulmonary valve closure artefact. Furthermore, pulmonary valveacceleration time (PV ACC time), calculated as the interval between the onset ofejection and the peak flow velocity, was measured as it is a Dopplerechocardiographic parameter strongly correlated with right heartcatheterisation- based measures of pulmonary vascular resistance.P values less than 0.05 were considered significant.Statistical analyses were performed using SPSS . The normality of the data was assessed using the Shapiro–Wilk testalong with inspection of histograms and QQ plots. The Kruskal–Wallis test wasused for assessing differences between the three groups of patients while theMann–Whitney test assessed differences between groups dichotomised by thepresence of PV A wave. Associations between continuous variables were assessedusing Spearman correlations. Intra-observer and inter-observer reliabilitieswere assessed by the intraclass correlation coefficient. For all tests,The patient characteristics are summarised in For the parameters measured , theoperator intra-observer variability was 0.996  see .P<0.001;r=−0.42), meaning that the reduction in longitudinal excursionentailed a prolongation of systolic contraction (post-systolic shortening).Furthermore, an inverse correlation resulted between TAPSE and an increase inintrathoracic pressure (PEEP and peak inspiratory pressure (PIP)P<0.001). A positive correlation between RVFT and TAPSEwas found (P<0.001) whereas RVFT was inversely related toTAPSE length (P<0.001), meaning that the reduction in thelongitudinal excursion entailed a prolongation of the contraction and areduction in diastolic filling time.Systolic dysfunction was present in 33.6% of the patients overall in thepopulation: nine patients (23%) in CV; two patients in iLA and 23 patients (86%)in VV-ECMO. A negative correlation was found between the reduction of TAPSEexcursion and TAPSE length . PV a wave was associatedwith signs of impaired RV performance (TAPSE and shortened filling time) andincreased afterload  P<0.0001), TAPSE length(P<0.0001), RVFT (P<0.0001), PV ACCtime (P<0.0001), PEEP (P<0.0001), PIP(P<0.0001) and Vt/kg (P<0.02) P<0.001), TAPSE length (P=0.03), RVFT(P<0.001), PV ACC time (P<0.001),PEEP and PIP (P<0.001). PV a wave was shown to be related toRVFT (P=0.03), PEEP (P<0.001) and PIP(P<0.001) in the iLA group.Presystolic a wave was present in 63 (64%) patients , PV ACC time (P<0.001), PEEPand PIP (P<0.001) The difference of echocardiographic andventilation variables splitting the population between patients with (presence)or without (absence) PV a wave are shown in Supplementary Table 1.In the VV-ECMO group correlations were found between PV a wave and TAPSE, pulmonary vascularresistances (PV ACC time) and diastolic performance (RVFT and PV a wave). Ourresults show …that:1) RV systolic dysfunciton is present in one third of patients;2) diastolic restrictive pattern is recognisibel in more than 60% of patients;3) it shows the close interaction between the systolic and diastolic function.24 although the occurrence of ACP is not negligible in ARDSpatients ventilated with airway pressure limitation.25 Our patients were ventilatedaccording to the protective ventilation strategy in term of Vt/kg, as shown in ACP has been largely investigated, and ….. The introduction of more protectiveventilation and the other strategies have been demonstrated to have a beneficialimpact on haemodynamics,2527 Multiple studies havepreviously focused on the incidence, predictors and outcome of RV function in ARDS,identifying respiratory acidosis, plateau pressure, driving pressure and otherrespiratory variables as predictors and causal factors leading to ACP.2527 However, ACP may be arelatively late phenomenon in RV dysfunction.9Our results confirm the relation previously determined on the influence of increasedintrathoracic pressure on RV haemodynamics.10 because itevaluates the excursion of the longitudinal fibres, revealing the contribution ofthe RV itself to systolic contraction.29 However, there are no dataregarding post-ejectional shortening, a phenomenon related to the perfusion mismatchof the longitudinal fibres that may lead to both a reduction of longitudinalshortening and an increase in the duration of longitudinal myocardial contraction(annular displacement peaking after the T wave on the ECG).20 Thisphenomenon results in a decline of the effective proto-diastolic filling period,leading to a reduction in stroke volume and demonstrating a severe systo-diastolicinteraction impairment.3032 This mechanismis largely demonstrated in patients with LV dysfunction while it has never beendescribed in the RV. We hereby report the existence of post-ejectional shortening onRV and its correlation with both reductions of TAPSE excursion and with theimpairment of diastolic filling time (RVFT).TAPSE has been the most common parameter to define RV systolic dysfunction33 Simultaneous catheter pressure monitoring has previouslydemonstrated that this flow occurs when the RV end-diastolic pressure equals orexceeds the pulmonary arterial diastolic pressure.15 In our population, the PV awave was present in a consistent percentage of patients and was significantlyassociated with ventilation established factors that increase intrathoracicpressures and pulmonary vascular resistance (Supplementary Table 1). Interestingly,the patients in the iLA groups had minor haemodynamic impairment. One possibleexplanation is that those who did not exhibit hypoxic issues had less severeparenchymal impairment, with a less severe V/Q mismatch and lower pulmonary vascularresistance. Previous studies on RV dysfunction and pulmonary hypertensionpathophysiology have shown that for the right ventricle to fail needs thecoexistence of two conditions: an increase in afterload and a reduction of coronaryperfusion.3538 The increased afterload leadsto significant change in RV pulmonary valve loop inducing a significant alterationin diastolic compliance.29 An impairment of systolic performance, besides thereduction in the longitudinal excursion, could imply a prolongation of systoliccontraction reducing the effective proto-diastolic filling time, furthercontributing to the diastolic function impairment.31 The pathophysiologicalmechanism is demonstrated by the correlation found between the alteration of TAPSEand TAPSE duration (systolic impairment), the reduction of RVFT (effective diastolicfilling) and the presence of PV a wave (diastolic compliance). This studyillustrates, for the first time, the systolic and diastolic interrelation studiedwith echocardiography, in patients with ARDS without ACP, treated with differentstrategies and showing reproducible indices potentially preceding the RV failure.The recognition of early signs of RV dysfunction may have important implications inthe clinical setting in terms of patient management.38The PV A wave represents an anterograde diastolic pulmonary arterial flow, coincidentwith premature opening of the pulmonary valve during right atrial systole,reflecting reduced RV diastolic compliance and RV restrictive pattern at enddiastole.The first limitation of this study is the nature of retrospective analysis ofprospectively acquired data, which limited the kind of mechanical ventilationdata to be analysed. Indeed, we were unable to obtain the plateau pressure andthe driving pressure at the time of the analysis as the data were retrieved fromthe hospital electronic data system. The second limitation is the sample size: aheterogeneous population divided into three relatively small groups without anyintervention. Some of the echocardiographic parameters (RVFT) of patientstreated with VV-ECMO were not analysed due to the suboptimal quality of theimages acquired. The third limitation is the non-interventional nature of thestudy.Systolic and diastolic dysfunction is relatively common in patients with ARDS withoutACP. TAPSE excursion and length, the study of RVFT and PV a wave allows theevaluation of RV systolic and diastolic performance and their interrelationelucidating the mechanism of RV impairment.


Antiphospholipid syndrome (APS) is characterized by the combination of recurrent arterial and venous thrombotic events and detection of persistently elevated antiphospholipid antibody titers in the serum or plasma. APS clinical manifestations also include non-thrombotic complications from various organ systems, mainly the CNS, kidneys, and heart. Cardiac manifestations of APS include valvulopathy, myocardial infarction and angina . A previously published case series of cardiac magnetic resonance (CMR) in patients with APS has revealed a high rate of asymptomatic myocardial necrosis and scarring, but the prevalence of myocardial ischemia identified as CMR perfusion defects prior to development of necrosis is unknown.To detect CMR imaging markers of myocardial ischemia in APS patients without symptoms of cardiovascular disease (CVD).We will scan fifty APS patients without symptoms of CVD stress-perfusion CMR in a 1.5 Tesla tomographer, after intravenous infusion of adenosine and gadolinium. In addition to markers of cardiac anatomy and function, we will record imaging markers of ischemia and scarring, namely perfusion defects (PDs), and late gadolinium enhancement (LGE). We will perform parametrics using dedicated software in order to derive each patient’s myocardial perfusion reserve index (MPRI). Scans will be reviewed independently by two experienced reviewers, with evaluation of inter- and intra-observer reliability. Statistical hypotheses will be examined using Student’s test and Pearson’s correlation coefficient, or non-parametric equivalents  for continuous variables, and Fisher’s exact test for binary variables. Linear or logistic regression analyses will be used to investigate APS-related determinants of subclinical myocardial ischemia.We expect to identify CMR imaging patterns characteristic of APS, which will allow proactive therapeutic interventions for primary prevention of CVD and guide further research into the pathogenesis of APS cardiac manifestations. The 5-year mortality in APS is 5.3%, with up to 40% of deaths related to serious thromboembolic events such as stroke, pulmonary embolism and acute myocardial infarction.2Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by venous, arterial, and/or small vessel thrombosis, pregnancy morbidity, and elevated levels of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LAC), anticardiolipin antibodies (aCL), and/or anti-beta2-glycoprotein I antibodies.4 characterized by thickening and/or vegetation of the cardiac valves, as initially described by Libman and Sacks in patients with SLE.6 The coexistence of antiphospholipid antibodies (aPL) with SLE is associated with a 3-fold greater risk of HVD. Valvulopathy tends to progress overtime, with a corresponding increase in the risk of stroke.The most common type of cardiac involvement in APS is heart valve disease (HVD),2 Additionally, coronary vasospasm, has been described as a cause of myocardial ischemia without thrombosis  in patients with APS.8 Furthermore, myocardial ischemia can be caused by thrombotic cardiac microangiopathy, with the ischemic subendocardium acting as a triggering factor for clot formation, especially in the presence of left ventricular dysfunction.9 Finally, endomyocardial fibrosis (EMF) has been reported as a cardiac complication of APS, possibly related to primary lesions of the coronary microcirculation.10 Although the pathogenesis of EMF remains uncertain, the detection of antibodies in myocardial proteins of patients with this type of pathology suggests that the autoimmune response may be implicated in its etiology.Non-valvular heart disease manifesting as myocardial infarction (MI) has been diagnosed in 5.5% of APS and was the presenting manifestation in 2.8% of APS.13 The CE-MARC study established the diagnostic accuracy of Stress-CMR for the detection of myocardial ischemia or scarring and confirmed its superiority over the single photon emission computed tomography (SPECT) and positron emission tomography (PET) scans.16Cardiac magnetic resonance (CMR) is a reliable, non-invasive, radiation-free technique used in the evaluation of cardiac morphology, function, perfusion, and fibrosis. Contrast-enhanced stress perfusion-fibrosis CMR using adenosine (Stress-CMR) has demonstrated very high sensitivity in the detection on subendocardial perfusion defects over conventional imaging techniques in patients with coronary disease, cardiac syndrome X, and mincroangiopathy.18 The optimal time for scar detection is between 10 and 20 minutes of contrast administration, when characterization of scar, normal myocardium and blood pooling is most accurate, based on differences in contrast enhancement. This method is termed “late gadolinium enhancement” (LGE), and it is the gold standard for the evaluation of myocardial scarring in vivo.19 One previous study of CMR in patients with APS has shown high rates of asymptomatic myocardial ischemia detection,20 introducing CMR as an emerging technique for the evaluation of indolent cardiac disease in this population.Stress-CMR is the technique of choice when quantification of scar or fibrotic tissue is needed (viability study).1 Patients will be considered to have the secondary form of APS, if they have concurrent SLE, as defined by the American College of Rheumatology classification criteria.21 Patients with renal insufficiency, pregnancy and contraindications to CMR testing or to intravenous contrast administration, will be excluded. Informed consent will be obtained from all patients, following the protocol’s institutional review board by the local committee. Demographic, clinical and laboratory characteristics of patients will be recorded. Patients will undergo CMR on a 1.5 Tesla scanner  using ECG-triggered steady-state, free precession breath-hold cines (echo time (TE)/repetition time (TR) 1.6/3.2 ms, flip angle 60) in long-axis planes and sequential 8 mm short-axis slices (3 mm gap) from the atrioventricular ring to the apex. Stress perfusion CMR will be performed using 140 mg/kg/min adenosine for 4 minutes  and 0.1 mmol/kg Gd-DTPA will be given during the first-pass perfusion sequence . A rest perfusion will be performed using the same protocol. Finally, late gadolinium enhancement (LGE) images will be acquired 10 min after intravenous gadolinium-DTPA  in identical short-axis planes using an inversion-recovery gradient echo sequence for fibrosis detection . Inversion times will be adjusted to null normal myocardium .Fifty patients meeting the updated Sapporo criteria for APS (2006) and followed in Rheumatology Unit of the First Propaedeutic Internal Medicine Department (Director: Professor P. Sfikakis) at Laikon Hospital, Athens, Greece, will be included in the study.CMR scans will be analyzed independently by two experienced cardiologists at Onassis Cardiac Surgery Center, Athens, Greece, blinded to clinical data . A consensus will be used for discordant grades, and the intra and inter-observer variability will be calculated with a goal of 0.85. Ventricular volumes, anatomy, and function will be measured for both ventricles using standard techniques and analysed using specialized software. Perfusion defects (PDs) will be assessed by both visual and parametric analysis. Quantification will be performed using delineation of endo- and epicardial LV borders throughout first-pass perfusion . Stress and rest perfusion slopes will be derived using Fermi-fitting of signal intensity vs time and normalized to LV blood pool slope. A Myocardial Perfusion eserve Index (MPRI) will be calculated for each patient, defined as the ratio of stress to rest. Finally, LGE images will be assessed for midwall or subepicardial enhancement, compatible with myocarditis, with subendocardial or transmural enhancement in the distribution of a coronary artery, compatible with myocardial infarction, and for diffuse subendocardial fibrosis, compatible with vasculitis in this cohort.There is a high prevalence of asymptomatic cardiac involvement in patients with APS, which can be readily detected using CMR. Specifically, we expect to find high rates of silent myocardial ischemia and fibrosis, manifested as subendocardial PDs, low MPRI, and abnormal LGE.Distinct patterns of abnormal CMR findings will be found in PAPS and SLE/APS patients.Additional hypotheses include:Possible correlation of PDs, MPRI, and LGE abnormalities with double and triple antiphospholipid antibody positivity, a history of arterial, venous, or dual thrombosis, the number of prior thrombotic events, a history of a history of thrombotic versus obstetric-only APS, and exposure to corticosteroids, biologic agents, or other immunosuppressants.Detection of Stress-CMR abnormalities even in APS patients without traditional cardiovascular risk factor comorbidities.Our main investigative hypotheses are the following:TM, Texas, USA) will be used for all analyses.Investigational hypotheses of correlation between measured variables will be carried out using Student’s test or Pearson’s correlation coefficient, or non-parametric alternatives as appropriate  for continuous variables. For binary categorical variables, Fisher’s exact test will be used. Multiple linear or logistic regression analyses will be used to investigate associations of continuous or binary CMR outcome measures, respectively, with recorded demographic and clinical parameters. The pre-specified statistical significance level is set at a=0.05. STATA software version 12.0 (College StationThe present study will be the first provide high-quality epidemiologic data on the prevalence of CMR-detected cardiac involvement in a representative sample of patients with APS. We will estimate the prevalence of significant lesions indicative of valvulopathy, myocardial dysfunction, microangiopathy, ischemia, or fibrosis in PAPS and SLE/APS patients, and determine the frequency of clinically silent cardiac disease in this population. We will provide detailed results on the prevalence of PDs, MPRI, and LGE abnormalities. We will perform statistical analyses to examine potential correlations of abnormal imaging findings with disease-related clinical characteristics and comorbidities. Based on the coexistence of different abnormalities in individual patients, we will describe CMR imaging patterns of cardiac involvement in APS, and detect pattern differences between PAPS and SLE/APS patients.The present study will contribute valuable epidemiologic data on the prevalence and the patterns of asymptomatic cardiac complications in APS. This will be the first description of CMR-detected myocardial ischemia in Greek APS patients, and is expected to further our knowledge on the rarer cardiac manifestations of APS, such as microangiopathy and endomyocardial fibrosis. Finally, this will be an ideal screening for indolent cardiovascular disease in our high-risk APS population, allowing appropriate treatment and prevention of future complications.