In cardiac research, a major goal of prevention of catastrophic events by risk-factor management and earlier detection has, in recent years, led to a proliferation of imaging modalities, moving us from old-fashioned chest X-ray through increasingly sophisticated approaches such as magnetic resonance imaging (MRI) and multi-slice fast computer-aided tomography (CT) scanning. Today, we have the option of using a vast array of invasive and non-invasive approaches, with diverse technical underpinnings, to assess various, and often overlapping aspects of cardiac function.Tissue Doppler imaging (TDI) and the related applications of strain and strain rate imaging are new technologies that are now being evaluated in the realm of practical patient care, and the underlying principles remind us that cardiac contractility is a reflection of the integration of muscle fibre architecture, mechanics and metabolism. TDI is the first technology that allowed imaging of motion within the myocardial wall rather than that of the blood pool, and permits analysis of velocities and accelerations from ultrasonic scatterers in muscle. The efficiency of the cardiac pump depends on the effective contraction and relaxation (contractility) of the muscle walls and the topology and geometry of the cardiac chambers. It is not a homogeneous muscle mass, but its molecular constitution varies; this includes both normal variation and variation arising from disease states, which presumably affects contractility. These differences in constitution and architecture are seen between the endocardium, mesocardium and epicardium, between the left and the right ventricle as well as within different localities in these chambers, between young and older individuals, between normotensive and hypertensive states, and between diseases such as ischaemic heart disease and cardiomyopathies.Our perceptions of cardiac contractility have to a great extent been shaped by isolated heart muscle fibre experiments . For the whole heart, this is extrapolated to consider the geometry of the heart, so that velocity and power of contraction are generally correlated with ventricular volume or diameter at the end of diastole.● During contraction in single-fibre experiments, the increasing tension is taken up by in-line elastic components and possibly by elastic components operating in parallel. Force is generated by contractile elements called sarcomeres, and involves thickening in some places and thinning in others. There is an isometric phase during which there is no fibre shortening, and is equivalent to the isovolumic phase, while the shortening phase correlates with the ejection phase of systole. Similar equivalents exist for early and late diastole.● The tension and velocities generated in either single fibres or the whole heart can be manipulated by physical parameters such as starting length or load, and pharmacological and metabolic means.Terminology from such single-fibre experiments has led, at the level of the whole heart, to concepts of the rate of pressure development (dP/dt), wall tension, preload, afterload, end-systolic pressure–volume relationship (elastance), inotropic state, etc. Measurement of fractional shortening and ejection fraction became a ‘surrogate’ for pump function in the absence of direct information regarding pressure development from all the noninvasive diagnostic methods.Furthermore, anatomical and histological studies have taught us that the muscle of the heart is layered in a spiral fashion. While subendocardial fibres, which have a mostly lengthwise orientation, are mainly responsible for longitudinal shortening of the heart, subepicardial fibres, with a more circumferential orientation are mainly responsible for radial (short-axis) contraction. Ejection is therefore not just the result of inward pressure mounted from concentric forces when these muscle layers start to tense, but, very importantly, longitudinal shortening of the muscle fibres combined with these concentric forces results in a twisting effect, like a wet cloth being wrung out. Of course, the reverse happens in diastole. During cardiac contraction, the apex remains fixed, while the base of the heart ‘screws down’ onto the apex, with, as we have learnt from TDI, a velocity gradient running from base to apex.Reasoning from an anthropological principle, this whole sequence is purposeful, and in aspiring to assess myocardial function, we should strive to take account of these known facts. The ideal approach to assessing cardiac function would offer non-invasive measurement of the velocity and rate of acceleration of myocardial regions, as well as the moment-to-moment changes in chamber pressures. Currently no imaging modality can offer these features, but TDI, strain and strain rate imaging do at least address the issue of velocity and rate of acceleration of myocardial regions, and can give an indirect indication of tension and force development derived from measurements of conformational changes within muscle.The normal myocardial fibre architecture described earlier gives rise to differences in velocities of contraction in distinct myocardial regions, which can be detected by TDI. In contrast to conventional Doppler echocardiography, which produces blood flow data dependent on velocities of elements within the blood, TDI quantitatively measures velocities of elements (‘scatterers’) within the myocardium itself. Relative to blood flow, muscle movement 0.06–0.24 ms) is 10 times slower and returns high-intensity echoes (40 decibels higher than blood). ms is 10As with blood-flow Doppler, TDI accuracy depends on alignment of the probe with the elements generating the velocity, ie, with the direction of wall motion. However, in contrast to conventional grey-scale echocardiography, velocity data does not depend on the amplitude of the reflected signal, but rather on shifts in frequency. Therefore, because it is not absolutely dependent on a clearly defined border, and because data on myocardial movement can be obtained from an extremely small segment , even suboptimal echocardiographic images can be assessed with TDI.4Two types of TDI are currently available, pulse-wave and colour TDI. The first allows immediate analysis of muscle movement, which displays peak velocities at single locations , but does not allow comparison across myocardial regions. On the other hand, colour TDI can be used to detect velocity differences between the endo- and epicardium, from which the myocardial velocity gradient can be derived.An important limitation in interpreting such TDI results is that the velocities measured are determined not only by contraction and relaxation of the fibres themselves, but also by movement of the heart within the chest and the twisting motion of the heart when it contracts . Newer applications of colour TDI make use of deformation measurements (strain and strain rate) where particular myocardial velocities are correlated with other local velocities, making them relatively independent of translational effects and facilitating functional evaluations across myocardial regions. With colour TDI, strain and strain rate, a mass of imaging data are collected reasonably fast in a formulated manner. These images are then analysed off-line, which, although time consuming, has advantages and disadvantages.5In strain and strain rate imaging, myocardial strain is defined as the deformation of a section of myocardium in comparison with its original size and form. In a sense, shortening fraction and ejection fraction represent a gross form of strain; similarly, myocardial strain is dimensionless and usually shown as a percentage. Strain rate refers to the deformation of the region of muscle over time.Strain rate can currently be measured in only one dimension, which implies that the sonar beam must be parallel or perpendicular to the direction of deformation. If it were possible, three-dimensional strain imaging would be able to measure deformation in nine directions, which would then include the effect of shearing forces, namely, forces operating in directions not aligned with the main force.Currently, this is not possible with any echocardiography techniques, but is feasible with MRI. However, MRI is time consuming, acquisition of data takes longer and facilities are less readily available.Strain and strain rate imaging are new developments and the technology is currently being further refined. TDI-based strain and strain rate are extremely sensitive to the direction of the transducer. This drawback has been overcome by another new and related technique, namely, speckle-tracking imaging (STI), which is used to measure tissue velocity, strain and strain rate. In STI, speckles that are constant features within the myocardial image are tracked frame by frame, and yield information about muscle deformation in two orthogonal directions, both longitudinal and radial dimensions.7If strain and strain rate imaging could be extended to three-dimensional analysis, it would make this modality as informative as MRI, but with the added advantage of easier data collection. The applications of strain and strain rate imaging in day-to-day patient care are still being explored. While strain correlates with changes in stroke volume, and therefore with global contractility, strain rate seems to carry the same information as rate of pressure development in the ventricles (dP/dt).Performance of any new technology should be compared with existing gold standards before its practical utility and its ability to improve on or replace existing technologies can be interpreted, and, accordingly, the application of TDI to measure numerous aspects of systolic and diastolic function has been assessed over the past decade or so.Longitudinal shortening of the subendocardial fibres of entire cardiac walls, which is the primary event in cardiac contraction, is reflected in the displacement of mitral and tricuspid valve annuli, and this displacement is therefore considered a good surrogate for global left or right ventricular function. It is typically assessed by averaging mitral or tricuspid annular displacement velocity measured by pulse-wave TDI at two or more of the corners of valve annuli  during systole and diastole. This value derived from mitral annular displacement in systole (Sa) has been shown to correlate well with left ventricular ejection fraction (LVEF) determined by two-dimensional echocardiography (Sa < 7 cm/s indicates LVEF < 45%).9Diastolic function has conventionally been assessed by blood flow through the mitral valve in conventional Doppler echocardiography. However, these Doppler flow variables are highly load and volume dependent, making them inaccurate measures of diastolic function for some patients, such as those with hypertrophic cardiomyopathy (HCM) or mitral valve disease. By contrast, early diastolic mitral annular displacement velocity (Ea) may be less dependent on preload.13Another TDI parameter, namely tissue Doppler (TD) MPI, which is related to the myocardial performance index (MPI) or TeiThe interrelationship of velocities generated from the distinct myocardial regions is often perturbed due to cardiac disease states well before manifesting via the conventional clinical or Doppler echocardiography parameters. Therefore, TDI measurement of systolic and diastolic function of both ventricles and atria can be used for earlier diagnosis, prognosis and risk stratification in increasing numbers of cardiac disorders, in some respects adding, although incrementally, to conventional parameters, and in other respects, facilitating non-invasively, measurements which otherwise would have required invasive approaches. Some of these are discussed briefly below.In addition to facilitating non-invasive estimation of filling pressures during assessment of left ventricular diastolic dysfunction, TDI may provide a more accessible and less invasive approach for measurement of right ventricular as well as atrial function.Right ventricular function: To date, estimation of right ventricular function, which has prognostic and clinical value for heart failure and post-MI patients, has not been accurately assessable by conventional echocardiographic approaches. This is mainly due to imaging difficulties ensuing from right ventricular anatomy, so that cardiac MRI or CT imaging, which are generally less widely available, and introduce additional limitations, have had to be relied on. TDI may offer a fast, noninvasive approach for assessing right ventricular function, as peak systolic tricuspid annular velocity (Sa) < 11.5 cm/s has been shown to correlate well with right ventricular EF < 45%, and has been used in prognostication of heart failure patients.17Atrial function: Atrial electrical function can only be precisely measured by invasive electrophysiological means, while atrial mechanical function is usually determined from atrial volume-derived indices, which are load and observer dependent. However, lately, a number of studies have demonstrated that TDI is a non-invasive, reliable and easy approach to estimate total atrial electrical activation time22Preclinical genetic disease: Early identification of individuals at risk of genetically mediated cardiac disease is often desirable to facilitate implementation of preventive or remedial measures, however, variability in the age of onset and subtlety of preclinical features, as measured conventionally, may make clinical identification difficult. In addition, genetic identification can be complicated by heterogeneity of the causal genes and mutations. Because TDI can identify subtle signs of systolic and diastolic dysfunction, which cannot be detected by conventional twodimensional or blood-flow Doppler echocardiography, it can be used to identify cardiac involvement in sufferers of inherited disorders with a myocardial component, such as Friedreich’s ataxia, various muscular dystrophies and myotonic dystrophy, at an early stage of the disease.23For example, the variability in the extent of left ventricular wall thickening and the age of onset of hypertrophy makes clinical identification of individuals at risk of developing HCM problematical. In HCM mutation carriers, both systolic and early diastolic velocities are markedly lower than in non-carriers (Ea < 13.5 cm/s), even before the development of hypertrophy. These reductions in velocities can be used to predict mutation carriers in HCM families, allowing cost-effective follow-up and intervention .27Another example is Fabry’s disease, which often presents with exclusively cardiac manifestations in female carriers and in male carriers of particular genetic mutations.30On the other hand, when compared to non-carriers, Fabry’s mutation carriers demonstrate marked reduction in TDI systolic and early diastolic mitral annular velocity, measured at lateral and septal corners of the mitral annulus, irrespective of the extent of left ventricular hypertrophy or other systemic manifestations. 32Early graft rejection: Cardiac transplant rejection is difficult to detect non-invasively at an early stage because of the non-specificity of conventional echocardiographic findings. However, in children with orthotopic heart transplants, TDI demonstrated a dramatic decrease in tricuspid  systolic and early diastolic velocities at three to six months before terminal graft failure. This has lead to the suggestion that bi- or tri-annual TDI examinations rather than annual invasive catheterisation and angiography may be a more efficient approach to survey for graft impairment.34Although most conditions that affect myocardial function manifest with reduced myocardial velocities, a number of studies have demonstrated that various TDI indices, sometimes in conjunction with conventional clinical criteria, can provide discriminatory information for making differential diagnoses.Constrictive physiology: For instance, in both restrictive cardiomyopathy and constrictive pericarditis, the heart manifests with abnormal left ventricular filling patterns; however, differentiating the two conditions is crucial for appropriate treatment. Respiratory variation in mitral and pulmonary flow on conventional Doppler echocardiography can differentiate constrictive pericarditis patients from those with restrictive cardiomyopathy in some but not all cases. However, when also using a peak TDI Ea of ≥ 8.0 cm/s, accuracy of diagnosis can be increased.35Hypertrophic states: Similarly, differentiation of physiological hypertrophy, such as that seen in athlete’s heart, from pathological hypertrophy seen in disease states such as hypertension or hypertrophic cardiomyopathy, has implications for patient management and therapy. However, distinguishing these states by morphological information derived from conventional echocardiography is not clear-cut. TDI reveals that the long-axis systolic and early diastolic velocities are decreased in cases of pathological hypertrophy, but not in physiological hypertrophy.The best differentiation of pathological hypertrophy  from physiological hypertrophy (athlete’s heart) was provided by a mean systolic annular velocity < 9 cm/s.38Because TDI mitral annular velocities predominantly measure the long-axis contraction of the ventricle, they reflect the functionality of the subendocardial myofibres, which are particularly prone to disturbance by disease conditions. The extent of these disturbances, as reflected by altered velocities, is often predictive of the extent of the underlying condition, and therefore TDI myocardial velocities are useful predictors of outcome, adding incremental value to conventional prognostic indicators in a variety of cardiac conditions.42Predicting responders to cardiac resynchronisation therapy: Biventricular pacing is considered a promising technique for the treatment of congestive heart failure and dilated cardiomyopathy. Patients are selected for this treatment predominantly on the basis of a wide QRS. However, the therapy succeeds because it improves left ventricular mechanical synchrony, and therefore selection of patients on the basis of mechanical function of the myocardium may be more rational. Prepacing colour TDI assessment of 12 left ventricular segments is used to assign a dyssynchrony index for systolic function, which has proven very useful for predicting responders and non-responders to cardiac resynchronisation therapy (CRT).46Prediction of preserved contractile function in MI patients: Defining the degree of preserved myocardial function is clinically important after acute myocardial infarction. A TDI-derived peak systolic velocity at the mitral annulus of > 7.5 cm/s can be used to predict preserved global left ventricular systolic function with 79% sensitivity and 88% specificity in individuals who have suffered acute myocardial infarction.47-1] and nontransmural infarcts.50Furthermore, although the extent of the infarct can be defined by delayed-enhancement cMRI, such facilities are not always accessible. The absence of a TDI-measured positive pre-ejection velocity wave, which originates between ventricular activation and aortic valve openingIn addition, quantitative pulsed-wave TDI assessment during a low-dose dobutamine challenge can differentiate between stunned, hibernating and irreversibly dysfunctional regions by the degree of reduction in regional myocardial wall velocities.52TDI and the related applications of strain and strain rate imaging allow excellent quantitative assessment, specifically of focal myocardial function and are therefore second to none for estimation of diastolic function, optimal identification of individuals for cardiac resynchronisation therapy and early identification of sufferers of certain inherited cardiac disorders in the absence of genetic testing. TDI-related approaches have also turned out to be on a par with existing techniques for the non-invasive, indirect (by proxy) estimation of parameters pertaining to tension and force development, and only time will tell whether TDI will replace existing approaches for measuring these parameters. Certainly, for myocardial disease, colour TDI, strain and strain rate imaging are invaluable for opening up new possibilities to understanding disease pathology, and further technological development of these modalities, including STI, should be watched with interest.


Myocardial dysfunction is recognized in sepsis. We hypothesized that mechanical left (LV) and right (RV) ventricular function analysed using 2-dimensional speckle-tracking echocardiography in a cohort of early severe sepsis or septic shock patients, would be different to that of a group of critically ill, non-septic patients.n = 48) and major trauma patients with no sepsis (n = 24) were included retrospectively, as well as healthy controls (n = 16). Standard echocardiographic examinations, including right (RV) left (LV) volumes and mitral, aortic and pulmonary vein Doppler flow profiles, were retrospectively identified and the studies were then reanalysed for assessment of myocardial strain using speckle-tracking echocardiography. Endocardial tracing of the LV was performed in apical four-chamber (4-Ch), two-chamber (2-Ch), apical long-axis (3-Ch) and apical views of RV determining the longitudinal LV and RV free wall strain in each subject.Critically ill adult patients with early, severe sepsis/septic shock (p = 0.009) and systolic (p < 0.001) and mean arterial pressures (p < 0.001), as well as systemic vascular resistance (p < 0.001) were significantly lower when compared to the non-septic trauma group. Ninety-three per cent of the septic patients and 50 % of the trauma patients were treated with norepinephrine (p < 0.001). LV ejection fraction (LVEF) was lower in the septic patients (p = 0.019). In septic patients with preserved LVEF , seventeen patients (50 %) had a depressed LV global longitudinal function, defined as a LV global strain > −15 %, compared to two patients (8.7 %) in the non-septic group (p = 0.0014). In septic patients with preserved LVEF, LV global and RV free wall strain were 14 % (p = 0.014) and 17 % lower (p = 0.008), respectively, compared to the non-septic group with preserved LVEF. There were no significant differences between groups with respect to LV end-diastolic or end-systolic volumes, stroke volume, or cardiac output. There were no signs of diastolic dysfunction from the mitral or pulmonary vein Doppler profiles in the septic patients.In septic patients, heart rate was significantly higher  contains supplementary material, which is available to authorized users. Patients with severe sepsis or septic shock often have significant myocardial dysfunction. A common and often reversible pattern of ventricular dilation, depressed systolic function, though with maintained or increased cardiac output has been described –4. On thIn more recent years, 2-dimensional (2D) echocardiography has been used to study myocardial dysfunction in severe sepsis, demonstrating impaired LV function in septic shock and a high incidence of global LV hypokinesia with LV dilatation as well as, in some patients, isolated impairment of LV relaxation –8. MyocaMyocardial deformation during systole or diastole may provide a more specific indication of global myocardial dysfunction . In a reThe aim of the present study was to evaluate myocardial function in patients with early severe sepsis or septic shock using 2D speckle tracking strain echocardiography. Another cohort of critically ill patients (major trauma) with no sepsis, served as a control group, to see if there are early strain indicators of LV dysfunction related to sepsis. We tested the hypothesis that 2D speckle tracking imaging may detect LV systolic dysfunction not diagnosed by conventional echocardiography in early clinical severe sepsis and that these findings were not present in critically ill non-septic patients.n = 16) were matched by gender and age to the septic patients.This study was approved by the Gothenburg Regional Human Ethics Committee (Dnr: 580–14), which waived the need for informed consent, because of the retrospective analysis of anonymised patients. From the first of January 2011 to the 10th of December 2014, conventional echocardiograms were retrospectively reviewed in adult (>18 years) septic and critically ill major trauma patients with no sepsis. The septic patients met American College of Chest Physicians/Society of Critical Care Medicine criteria for severe sepsis or septic shock . The ind2O). The inspired oxygen fraction (FiO2) was adjusted to obtain an arterial oxygen saturation of > 90 %. Peak inspiratory pressure, tidal volume, respiratory rate, arterial oxygen saturation (SaO2), fraction of O2 in inspired air (FiO2) and end-tidal carbon dioxide were recorded. During mechanical ventilation, the patients were sedated with propofol and fentanyl infusions.Blood pressures were obtained from arterial and central venous direct measurements. According to the institutional protocol, norepinephrine was used to treat hypotension  in volume-resuscitated patients. Milrinone or epinephrine was used for inotropic support at the discretion of the attending physician. Mechanical ventilation was performed with a tidal volume of 6–7 ml/kg body weight minute ventilation to obtain normocarbia and positive end-expiratory pressure (PEEP) level set by the attending physician  pressures and central venous pressures (CVP), Systemic vascular resistance (SVR) was calculated as (MAP-CVP)/cardiac output. The simplified acute physiology score was recorded in all patients on arrival to the ICU and injury severity score was recorded in the trauma patients. ICU mortality, 30-days mortality, ICU length of stay, cause of sepsis and the results of blood or local site cultures were recorded in all patients.2 x TVI-LVOT) [Echocardiograms were obtained using one of three different ultrasound machines . Standard measurements of LV systolic and RV systolic function in all subjects included LV volumes, ejection fraction (modified Simpson’s rule), LV and RV fractional area change , time velocity integral in the LV outflow tract (TVI-LVOT) and stroke volume (π x LVOT radiusVI-LVOT)  were cal0) and end-systole (L) and calculated as: (L-L0)/L or ∆L/L0. Strain is presented as percent change (%). Negative values of strain indicate myocardial contraction. A frame rate of 52 ± 3 frames/s and 50 ± 3 were obtained for the LV and RV, respectively.Echocardiograms were stored in a digital format (DICOM) in the hospitals PAX system. The investigations were retrieved in DICOM format with preserved frame rate and transferred to and analysed in an offline system . Myocardial strain is defined as a fractional change in length between 2 time points, end-diastole  and the trauma group , were analysed separately.A subgroup of patients with a preserved LV ejection fraction (PEF), that is an EF > 50 %) in the sepsis group  between the sepsis and the trauma groups . Including at least 20 patients in each group gave us a power of 0.89 to detect a 20 % difference in global systolic strain between groups at a α = 0.05 and a standard deviation of 3.0. Differences between septic and trauma patients were compared using independent Student’s t-test. Categorical baseline data were compared using Fisher’s exact test. A linear regression analysis was applied to quantify the strength of the relationship between global LV systolic strain and LV ejection fraction for septic and trauma patients. A multivariate analysis was performed to identify variables that were independent predictors of global LV systolic strain. The following independent variables were included in the model: end-diastolic volume, (preload), systolic arterial pressure (afterload) and heart rate or the diagnosis (sepsis or trauma). The coefficients of variation for intra-observer agreement for paired observations of LV systolic strain in apical four-chamber (4-Ch), two-chamber (3-Ch), apical long-axis (2-Ch) views were calculated. The data are presented as mean ± standard deviation (SD). A probability level  of less than 0.05 was considered to indicate statistical significance.Two-hundred and eighty-nine patients were treated at the ICU for severe sepsis/septic chock during the study period. A conventional echocardiogram examination was performed because of haemodynamic instability in 135 patients. Forty-eight patients fulfilled inclusion but not exclusion criteria and were evaluated together with 24 major trauma patients. Baseline patient characteristics are shown in Table Heart rate, was higher whereas systolic and mean arterial pressures, as well as SVR were significantly lower when compared to the non-septic trauma group. The CVP was significantly higher in the sepsis group  compared to the trauma group , while CVP did not differ significantly comparing sepsis-PEF to trauma-PEF groups. There was no difference in right ventricular systolic pressure between groups. The use of the vasopressor therapy (norepinephrine or epinephrine) was more frequent in the sepsis group.2 and a lower SaO2 were seen in the septic group compared to the trauma group. End-tidal carbon dioxide did not differ between groups.Peak inspiratory and positive end-expiratory pressures and respiratory rate were higher in the septic group, while there was no difference in tidal volumes between groups. A higher mean FiOp = 0.019) . There were no significant differences between the sepsis  and the trauma  group with respect to stroke volume, TVI-LVOT or cardiac output. The diastolic function variables did not differ between the septic and then trauma patients. There were no differences in any of the measured conventional echocardiographic variables comparing the sepsis-PEF with the trauma-PEF group, although there was a trend for a higher cardiac output in the sepsis-PEF group (p = 0.070).LV ejection fraction was slightly but significantly p = 0.09 . There were no differences in any of the measured conventional echocardiographic variables comparing the sepsis-PEF with the trauma-PEF groupThere was a trend for a lower RV fractional area change in the sepsis group  compared to the trauma group  , two-chamber (3-Ch), apical long-axis (2-Ch) and RV free wall views, were 9.0 %, 11.0 %, 14 % and 9.6 %, respectively. The corresponding data for inter-observer agreement were: 8.6 %, 9.5 %, 8.3 % and 8.8 %, respectively.p = 0.003) and 0.39 (p = 0.061) for the sepsis  and the trauma group , respectively. In the sepsis-PEF group, the LV strain was significantly lower in the 2-Ch and 3-Ch views and the LV global strain was 14 % lower compared to the trauma-PEF group .LV strain was significantly lower in all three apical views and the LV global longitudinal strain was 18 % lower in the septic  compared to the trauma group  Fig. . The corRV strain was 21 % lower in the septic  compared to the trauma group  and 17 % lower in the sepsis-PEF compared to the trauma-PEF Figs.  and 6.Fip = 0.009, ß = −0.056, 95 % CI: −0.09–(−0.02)), but not end-diastolic volume or systolic arterial pressure, was independently associated with global LV strain. Furthermore, the diagnosis (sepsis or trauma) could predict global LV strain .This analysis revealed that heart rate , were impaired to a greater extent in septic patients with preserved ejection fraction, when compared to critically ill, non-septic, trauma patients with preserved ejection fraction.For the clinical application of speckle tracking echocardiography, the definition of normal values of LV strain is of crucial importance. However, the results from speckle tracking are known to be vendor-dependent and the lower border of normality is not defined . In a reOur data are in line with a recent study on myocardial performance in children with septic shock using STI echocardiography . They foIn healthy subjects it was recently shown that free wall RV strain by STI is between −27 % and −30 % , 22. In Using mitral annular TDI, it has been suggested that diastolic function is impaired in septic shock , 11. WheWhen evaluating RV and LV function in critically ill septic patients, the choice of a control group is critical. In ICU patients, with on-going multimodal intensive care treatment including sedation, mechanical ventilation, fluid therapy, vasoactive and inotropic treatment as well as, renal replacement therapy, one must consider the possibility that these treatment modalities themselves may affect RV and LV function. It has been shown that positive pressure ventilation with PEEP causes a decrease in RV strain and cardiac chambers’ volume . In the In a recent study, Orde et al. performed speckle tracking echocardiography in adult patients with early severe sepsis/septic shock . The incThe LV loading conditions may influence myocardial deformation. Longitudinal LV strain is reduced when afterload is increased, and LV strain is increased when preload is increased , 32. FurThe major limitation of the present study is its retrospective nature and the relative small sample sizes. Another limitation is that three different ultrasound machines were used for the echocardiographic examinations. However, the same software for analysis of strain was used by an experienced operator, to perform all the primary end-point measurements. Furthermore, the observer was blinded to the diagnoses and the intra-observer coefficient of variation was acceptably low.Strain echocardiographic LV and RV systolic functions in patients with early severe sepsis and preserved LV ejection fraction were significantly impaired compared to critically ill, non-septic trauma patients. We conclude that strain imaging by speckle-tracking echocardiography may be useful for early detection of septic cardiomyopathy.


Autonomic nervous system balance can be significantly deteriorated during heart failure exacerbation. However, it is still unknown whether these changes are only the consequence of heart failure decompensation or can also predict development thereof. Objectives were to verify if simple, non-invasive autonomic parameters, such as baroreflex sensitivity and short-term heart rate variability can provide independent of other well-known clinical parameters information on the risk of heart failure decompensation in patients with left ventricular systolic dysfunction.In 142 stable patients with left ventricular ejection fraction ≤ 40%, baroreflex sensitivity and short-term heart rate variability, as well as other well-known clinical parameters, were analyzed. During 23 ± 9 months of follow-up 19 patients were hospitalized due to the heart failure decompensation (EVENT).2) were significantly associated with the EVENTs . EVENTs were also associated with other parameters, such as left ventricular ejection fraction, NYHA class, diuretic use, renal function, brain natriuretic peptide and hemoglobin level, left atrial size, left and right ventricular heart failure signs. After adjusting baroreflex sensitivity and low frequency power index for each of the abovementioned parameters, autonomic parameters were still significant predictors of hospitalization due to the heart failure decompensation.Pre-specified cut-off values of baroreflex sensitivity (≤2.4 ms/mmHg) and low frequency power index of heart rate variability (≤19 msSimple, noninvasive autonomic indices can be helpful in identifying individuals with increased risk of hospitalization due to the heart failure decompensation among clinically stable patients with left ventricular systolic dysfunction, even when adjusted for other well-known clinical parameters. According to literature, patients with heart failure are characterized by predominance of sympathetic activity and decreased vagal tone –3. Barorobjectives of the study were to verify if BRS and HRV indices can provide independent information on the risk of hospitalization due to heart failure decompensation in stable patients with LV systolic dysfunction, and whether this information is independent of other well-established clinical parameters.Therefore, exclusion criteria were: age <18 years, pacemaker rhythm including cardiac resynchronization therapy with successful resynchronization, NYHA functional class IV, permanent atrial fibrillation/flutter, permanent second- or third-degree atrioventricular block, type 1 diabetes mellitus, documented autonomic neuropathy (information based on patients records), poor general condition , and non-cardiologic comorbidities with potential unfavourable effect on survival.Between December 2009 and March 2012, 142 consecutive patients with chronic heart failure, presenting with typical clinical signs and symptoms of this condition  and LVEFMingograf 720C) and beat-to-beat non-invasive arterial blood pressure  were recorded continuously for 10 min during spontaneous breathing. The signals were acquired with a PC workstation, processed with a dedicated software ). In an event of potential drop-outs, the sample size was eventually set at 142 . The patients’ data were censored on the date of the end-point or last follow-up. Due to the lack of normal distributions, all the variables were expressed as medians , or numbers (n) and percentages (%). The quantitative characteristics of the EVENT_(+) and EVENT_(-) groups were compared with the Mann-Whitney U-test, and the qualitative data with the chi-square test or Yates’ chi-square test. The power and direction of relationships between pairs of selected variables were analyzed on the basis of the Pearson’s coefficients of linear correlation. The accuracy of ANS indices and other parameters as potential predictors of the study end-points was determined on the basis of area (AUC) under the receiver-operating characteristic (ROC) curve. An association between analyzed parameters and the end-point was assessed using the Cox univariate and multivariate proportional hazard models, after dichotomization of the measurements according to their cut-off values that maximized the hazard ratio (HR). For this purpose, we calculated HR for progressively increasing appropriate values comprised between the 20th and 50th percentiles (to have an adequate number of patients in each subgroup) and identified the point at which HR attained its maximum. The time course of the end-point, stratified according to the aforementioned cut-off values, was estimated using the Kaplan-Meier method, and the association between compared groups was estimated by the log-rank test. All the results were considered statistically significant at p≤0.05. The statistical analysis was conducted with STATISTICA 9.0  package and R 2.15.2 environment.The minimum sample size was estimated as Baseline clinical and demographic characteristics of the study group are presented in A total of 36 out of the 142 (25%) recordings used to calculate the BRS and HRV indices could not be analyzed due to large number of ectopic beats or presence of artifacts. As shown in R = 0.02, P = 0.81 and R = 0.07, P = 0.49 for EVENT_(+) and EVENT_(-), respectively). In turn, a significant linear correlation between BRS and LF values was observed ; on subgroup analysis this correlation turned out to be particularly strong in the case of the EVENT_(+) patients  group).We did not find significant linear correlations between BRS and LF values (i.e. the parameters that differed significantly between the EVENT_(+) and EVENT_(-) groups) and LVEF . BRS (AUC 66.5% [CI 45.8–87.2%]) and LF (AUC 64.0% [CI 43.8–84.2%]) were characterized by lower discriminatory powers.2, LVEF ≤ 25%, glomerular filtration rate (GFR) less than 60 ml/min, LA size > 45 mm and BNP ≥ 125 pg/ml. All these values, as well as NYHA class III, anemia, LV- and RV failure signs and diuretic use, turned out to be significantly associated with the incidence of the end-point on univariate Cox analysis  accurately identified the patients who were at increased risk of heart failure decompensation during nearly two-year follow-up. A significant association between mentioned above clinical markers  and the risk for heart failure decompensation was also confirmed.The observation that decreased BRS and LF may predict hospitalization due to heart failure decompensation in clinically stable patients with LV systolic dysfunction, even after adjusting for other well-known clinical parameters , is the principal finding of our study. The cut-off values determined in this study  could not be analyzed in 25% of included patients, which narrows even more the group of patients. This, unfortunately, is a known problem of ANS tests described in published documents in this field. Furthermore, we did not analyze neither invasive hemodynamic parameters or dynamics of the ANS indices before reaching the end-point, nor the ANS parameters at the moment of patients’ hospitalization due to the heart failure exacerbation. All these data would be useful for detailed understanding of pathophysiological mechanisms underlying the hereby reported phenomena. Unfortunately, so far, it has been difficult to unequivocally determine the pathophysiological mechanism linking ANS parameters and the factors leading to the decompensated phase of heart failure and hospital admission of patients.We are well aware of potential The results of our study suggest that simple noninvasively obtained parameters of ANS activity, such as BRS and short-term LF, can be helpful in identifying individuals at increased risk of hospitalization due to heart failure decompensation among clinically stable patients with LV systolic dysfunction, even when adjusted for other simple clinical parameters, such as LVEF and NYHA class. These findings substantiate further research during which patients with systolic LV dysfunction would be subjected to repeated BRS and HRV analyzes in order to study the dynamics of changes in ANS activity and to identify short- and long-term predictors of heart failure decompensation.


Apoptotic death of interstitial cells and myocytes is a detrimental effect of the interstitial inflammatory infiltrate accompanying heart transplant rejection. This inflammatory reaction is followed by both replacement fibrosis and interstitial fibrosis which in the long term can impair diastolic and systolic ventricular (LV) function. Cardiac magnetic resonance (CMR) with gadolinium quantifies replacement fibrosis and new sequences with T1 mapping are proposed for the quantification of more elusive interstitial fibrosis. We aimed at determining the optimal T1 mapping approach to assess characteristic tissue composition in these patients.We studied 60 patients who underwent orthotopic heart transplant (HTx) and were free of active rejection, mean time from Tx 79 ± 79 mo (range 6 ÷307) age 47 ± 13 and 10 Normals (N) 39 ± 11 p = ns. Standard volumes and LGE-CMR scans were carried out on a 1.5-T scanner , with full myocardial coverage. The IR LGE images were acquired after intravenous Gadobutrol (0.15 mmol/kg) in identical short-axis planes to cine. MOLLI T1 maps  were generated from 3 short axis slices at Base, Mid and Apex and acquired pre and 15 minutes post contrast, parameters were TR = 2.5 msec, TE = 1.1 msec, Flip Angle 35°, Voxel size 2.2×1.4×6 mm, GRAPPA = 2. Regions of interest (ROIs) were defined defined according to AHA avoiding areas with coarse LGE or artifacts. Extracellular volume (ECV) was derived from T1-maps acquired pre- and post-contrast calibrated by blood hematocrit. Data are mean ± SDSystolic function was similar in both groups HTx 64 ± 11 vs N 68 ± 5 p = 0.32, LV Mass Index was slightly higher in HTx 75 ± 14 vs 69 ± 16 N p = 0.2. In HTx native pre -contrast T1 was 1007 ± 75 vs (N) 957 ± 44 msec p < 0.001, T1 post-contrast was 400 ± 47 msec vs (N) 455 ± 35 msec p < 0.001, ECV was 39.4 ± 4% vs 33.3 ± 3%(N) p < 0.001. ECV had the best Sensitivity(Se) 84% and Specificity(Sp) 78% at ROC analysis (cut-off 35.4%), for identifying HTx patients from N Figure . WhereasHTx patients with no active rejection show a significant increase of ECV and T1 relaxation time, an indication of increased interstitial fibrosis. In this population ECV seems to better identify deposition of collagen, whereas non contrast T1 mapping is also influenced by the presence of tissue inflammation. These preliminary findings need further confirmation in large scale studies that will assess both the diagnostic and prognostic values of T1 mapping derived parametersCNR.


Cardiac involvement is a frequent finding in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies. With this study, we aimed at elucidating the relationship between the phenotypic expression of cardiac involvement and the occurrence of adverse cardiac events in DMD/BMD patients.Eighty-eight male DMD/BMD patients (age 29 ± 14 yrs) were prospectively enrolled. All patients underwent cardiovascular magnetic resonance (CMR) comprising cine- and late-gadolinium-enhancement (LGE)-CMR at study entry and were subsequently followed-up for adverse cardiac events. The primary endpoint was defined as all-cause/cardiac death or cardiac transplantation. Secondary endpoints were (1) hospitalization for heart failure and/or (2) occurrence of non-/sustained ventricular tachycardia (VT).During a mean follow-up time of 47 ± 18 months, the primary endpoint was observed in three (3%) and the secondary endpoint in 21 (24%) patients. On multivariable analysis, LV-EF  and the presence of “transmural” LGE  were the only independent predictors for secondary endpoints. A cut-off for LV-EF of 45% was associated with the highest hazard ratio  in a Cox regression survival analysis. In the group of patients with a LV-EF (>45%), those patients already showing “transmural” LGE had a significantly lower event-free-survival  compared to those without.An impaired LV systolic function (LV-EF ≤45%) and a “transmural” pattern of myocardial fibrosis independently predict the occurrence of adverse cardiac events in DMD/BMD patients. Even in DMD/BMD patients with relatively preserved LV-EF (>45%), the simple and visually assessable parameter “transmural LGE” is of additive prognostic value. Duchenne and Becker muscular dystrophies (DMD and BMD) are X-linked inherited disorders affecting the synthesis of dystrophin, a large sarcolemmal protein with an essential role in the interaction between cytoskeleton, cell membrane and extracellular matrix ,2. The mSince respiratory failure, the former major cause of death in this population, can be better managed by ventilatory support techniques today, cardiac involvement with a non-ischemic, myocarditis-like pattern of left ventricular (LV) myocardial fibrosis leading to non-ischemic dilated cardiomyopathy, progressive heart failure and arrhythmias has become an important cause of morbidity and mortality ,4,8–10. With this study, we aimed at elucidating the relationship between the phenotype of cardiac involvement (assessed by CMR) and the occurrence of death and adverse cardiac events in DMD/BMD patients.Ninety male patients with known muscular dystrophy (MD) were prospectively enrolled in two German centres  between 2006 and 2013. A diagnosis of muscular dystrophy was previously made in a specialized neurology centre based on skeletal muscle pathology with immunohistochemical dystrophin analyses and/or genetic testing [ECG-gated CMR studies were performed on 1.5-T scanners  using commercially available cardiac software, electrocardiographic triggering, and cardiac-dedicated surface coils. Cine-imaging was performed using a steady-state-free-precession (SSFP) sequence in three long-axis slices  and a stack of short-axis slices completely covering the LV. LGE-imaging was performed using a T1-weighted inversion recovery gradient-echo sequence 10-15 min after intravenous contrast administration (0.15 mmol/kg Magnevist®) in the same imaging planes as the cine-images.CMR analysis was performed off-line by two experienced readers (AF and AY) blinded to outcomes and clinical characteristics. Ventricular volumes, ejection fraction and LV mass were derived by contouring endo- and epicardial borders on the short-axis cine images and indexed to body surface area. LGE presence and pattern were first visually assessed on the short-and long-axis images by using a model dividing each short–axis slice into 12 sectors and each sector into 3 equal circumferential segments . A LV ejection fraction (EF) less than 55% and/or presence of LGE in at least one myocardial segment were considered signs of cardiac involvement. LGE pattern was globally assessed by two readers (AF and AY) and classified according to its location as: subepicardial, intramural, mixed . In addition to the three patterns, a fourth transmural pattern was considered whenever all three segments in at least one sector were LGE positive. Eventual discrepancies were resolved by common agreement. Second, LGE extent was planimetered on the short-axis contrast images with the use of ImageJ software  and an image intensity level ≥3 SD above the mean of remote myocardium was used to define LGE indicative of damaged myocardium as described previously and expressed as percentage of total LV mass .Patients were first categorised as presenting with either deletions, duplications, point mutations or other defects in the dystrophin gene. Thereafter, a subclassification of those patients having dystrophin gene deletions was performed based on previous data relating deletions in specific dystrophin gene domains with the presence and severity of skeletal muscle disease and cardiomyopathy as follows: (1) presence of deletions affecting the amino-terminal domain of dystrophin - known to be associated with DMD/severe skeletal BMD and early onset of cardiomyopathy, (2) presence of deletions affecting exons 45 to 49 preserving Hinge 3 (that encodes a protein sequence responsible for dystrophin flexibility and intrinsic folding) and (3) presence of deletions affecting exons 50 and/or 51 removing or disrupting Hinge 3 ,16,17.After enrolment and baseline CMR, the patients were followed-up for the occurrence of death and adverse cardiac events until November 2013. Primary endpoints were defined as: (1) all cause death including cardiac death (and particularly sudden cardiac death and death from heart failure) and (2) cardiac transplantation. Secondary endpoints were defined as follows: (1) hospitalization for heart failure and/or (2) non-/sustained ventricular tachycardia (VT) defined as five or more consecutive ventricular beats at a rate of greater than 100/min. In patients with more than one event, the time to the first event was taken into consideration. Follow-up was done by phone calls as well as by periodical (every six months to one year) ambulatory monitoring of potential arrhythmias during a five day period by means of an external event loop recorder . This device records electrocardiographic tracings in two different leads during and up to 15min after arrhythmia detection (auto-triggered) and/or patient activation. Subsequently, all ECG recordings were assessed for presence of ventricular arrhythmias. In the case of an event, all explanatory medical records were obtained and reviewed to ensure an appropriate classification.t-Student test was used for comparison of normally distributed characteristics between DMD and BMD patients as well as between patients with and without adverse events. Mann–Whitney U test was used for comparison of non-normally distributed variables. One-way ANOVA with Bonferroni post-hoc correction was used in case of multiple comparisons. Dunnett’s post-hoc was used in case of inequality of variances. The Chi-square test with Yate’s correction was used to compare non-continuous variables expressed as proportions. Pearson correlation (r) was used to assess the relationship between different normally distributed CMR measurements. Intra-observer (AF) and inter-observer (AY) variability for LGE extent was performed in 10 random LGE positive patients and evaluated using Bland-Altman. In order to find independent predictors for the occurrence of a secondary endpoint, a univariable Cox proportional hazards regression analysis was performed first. Second, the parameters with significant p-values were introduced into a Cox regression multivariable analysis. Additionally, a separate model including only three variables: age , LV-EF and LGE characteristics as either (1) dichotomous presence or (2) extent as % of LV mass or (3) pattern was tested in order to avoid the potential for overfitting. The independent predictors thus obtained were used to generate the cumulative event-free survival curves. Statistical analysis was performed using SPSS software for Windows . A p-value ≤ 0.05 was considered statistically significant.Continuous variables are expressed as mean ± SD. Skewed variables are expressed as median and interquartile range (IQR). Categorical variables are expressed as frequency with percentage. Table The CMR findings are shown in Table An exclusively non-ischemic pattern of LGE was detected in all LGE-positive patients (N = 56) showing the following LGE distribution: 34% (N = 19) subepicardial, 7% (N = 4) intramural, 23% (N = 13) mixed  and 36% (N = 20) transmural. Presence of LGE in the LV lateral free wall was observed in 96% (N = 54), while septal, inferior and anterior wall involvement was present in 55% (N = 31), 50% (N = 28) and 34% (N = 19), respectively.A good reproducibility was obtained for LGE extent measurements both for intra-  and for inter-observer variability .A high correlation was found between LV-EF and LGE extent  was additionally performed. In this model, LV-EF was the strongest independent predictor  of adverse events. While a transmural pattern of LGE  was also an independent predictor for secondary endpoints, neither the categorical presence of LGE per se (p = 0.93) nor the extent of LGE (p = 0.70) were independently associated with adverse events. Several cut-offs for LGE extent  were also included in the multivariable model (that was limited to three variables) along with age and LV-EF. None of these cut-offs was independently associated with secondary endpoint occurrence.A cut-off for LV-EF of 45% was associated with the highest hazard ratio in the Cox regression survival analysis for secondary endpoints Figure A. MoreovResults of a genetic analysis were available in 92% (N = 81) of patients. Table No significant relationship between MD type and secondary endpoints was found in the respective regression analysis, although a significantly larger percentage of BMD patients experienced adverse events as compared to DMD. Keeping the limited number of patients in each subgroup in mind, no significant difference in prevalence of different genetic defects in relation to the occurrence of adverse events was found Table .Table 7Regarding the interaction between the underlying genotype and the cardiac phenotype (as assessed by CMR), no significant differences in LV functional parameters, i.e. volume indexes  or LV-EF (p = 0.39) were observed among the respective groups with different types of dystrophin gene mutations.Interestingly, patients with dystrophin deletions affecting exons 50 and/or 51 demonstrated more frequently absence of LGE . In contrast, patients with dystrophin duplications showed more frequently presence of LGE  Figure . MoreoveTo the best of our knowledge, this is the first follow-up study including DMD and BMD patients that aimed to evaluate the cardiac phenotype (based on CMR studies) in relation to the underlying genotype and to identify independent predictors for adverse cardiac events in a mid- to long-term follow-up period of approximately four years. We could show that the degree of LV systolic dysfunction bears the strongest (independent) predictive value for adverse cardiac events in DMD/BMD patients. Moreover, the addition of the simple, visually assessable CMR parameter “presence of transmural LGE” showed important independent as well as additive value in the further risk stratification of DMD/BMD patients.The current study findings are in accordance with previously published reports, revealing cardiac involvement as defined by an impaired LV-EF and/or the presence of LGE in approximately 70% of DMD/BMD patients ,4,18. SiThe frequency of cardiac disease was similar for both DMD and BMD patients in our study group. However, BMD patients demonstrated a more advanced stage of cardiac disease compared to the DMD group. This finding is easily explained by the age-dependent occurrence and progression of cardiac disease in DMD/BMD and by the fact that DMD patients were significantly younger ,20. The During the median 4-year follow-up period, only 3% (N = 3) of the study patients had a primary endpoint (two deaths and one heart transplantation) and 24% (N = 21) experienced secondary endpoints . Due to the limited number of primary endpoints, a meaningful correlation analysis in order to identify predictors for adverse primary events was not possible. However, the occurrence of a secondary endpoint was associated with older age and advanced cardiac disease that was assessed by both functional (cine-CMR) and structural parameters .Not surprisingly, the functional parameter “LV-EF” proved to be the strongest independent predictor for adverse cardiac events – followed by the parameter “transmural pattern of LGE”. Recently, Diegoli et al. studied patients with genetically proven dystrophin gene defects and already established DCM and reported an event rate of 50% during a median follow-up of five years (comprising nine deaths and eight heart transplantations) . ObviousWhereas the association of a reduced LV-EF with the occurrence of adverse cardiac events was shown for ischemic as well as different non-ischemic cardiomyopathies, the unique finding of the present study was obtained when LGE characteristics  were carefully looked at: A second independent predictor for adverse cardiac events was the presence of a transmural pattern of LGE (assessed as a dichotomous parameter) - but not the categorical presence of LGE per se or the extent of LGE. At first view, this finding seems to be in disagreement with previously established data in other non-ischemic cardiomyopathies, e.g. DCM, myocarditis or hypertrophic cardiomyopathy; in these forms of cardiac disease the qualitative presence of any LGE (without further quantification or classification) was suggested to be of prognostic value –25. HoweFurthermore, when looking at biopsy proven viral myocarditis, patients frequently show subepicardial or intramural patterns of LGE (similar to DMD/BMD ones) and presence of LGE was suggested to be the best independent predictor of cardiac mortality ,27,28. HMoreover, in a recent publication from our group, we have already shown the diagnostic value of novel myocardial tissue characterization techniques such as the measurement of extracellular volume fraction (ECV) based on T1-mapping pre- and post-contrast agent administration in BMD patients . We coulThe present study findings underline the importance of looking beyond the simple presence of LGE. In addition to that, the pattern of occurrence and further progression of LGE have to be considered, since the pattern and development of LGE reflect different pathomechanisms in different disease forms, e.g. in genetically-driven versus acquired cardiac diseases: increased cell fragility and subsequent cell death with fibro-fatty myocardial replacement fibrosis in DMD/BMD vs. an inflammatory mediated process in myocarditis .In the present study, a LV-EF cut-off value of 45% resulted in the highest hazard ratio for identifying /discriminating patients with adverse cardiac events. Importantly, when we looked at those patients with a LV-EF >45% , the additive depiction of a transmural pattern of LGE  allowed to identify those patients in this subgroup with significantly increased risk for adverse cardiac events - despite a LV-EF >45%. We hypothesize that (slow and rather diffuse) LGE progression to new myocardial regions directly relates to the continuous decline in LV systolic function, while the regional occurrence of transmural LGE - despite preserved LV systolic function - bears an independent negative prognostic value already in the early stages of cardiomyopathy from a functional point of view. Obviously, the identification of DMD/BMD patients who are at increased risk for adverse cardiac events despite a preserved LV systolic function (LV-EF >45%) based on the detection of transmural LGE during CMR is not possible when cardiac work-up in these patients is limited to conventional echocardiography.In the present study, DMD/BMD patients having dystrophin gene deletions in exons 50 and/or 51 showed less LGE, while patients with dystrophin gene duplications demonstrated more LGE regarding both LGE prevalence and extent. However, no association between the underlying genotype and the severity of cardiomyopathy, i.e. the degree of LV systolic impairment or LV dilatation, was found. Several previous studies attempted to relate the underlying dystrophin gene defect to the cardiac phenotype . For exaMoreover, considering our preliminary observations that a) the severity of cardiomyopathy may tremendously differ between (unrelated) MD patients of the same age having exactly the same dystrophin gene deletion and b) a similar severity of cardiac disease is frequently detected in MD siblings of similar age (suffering from the same dystrophin gene mutation), the presence of additional genetic modifiers that determine cardiac disease severity is highly expected. Hence, future comprehensive genetic analyses such as whole-exome sequencing or comprehensive epigenetic analyses (OMICS) in MD patients may help to identify such cardiac disease-modifying elements/pathways. However, non-genetic factors such as preserved physical activity  - particularly in BMD patients with no or only minor skeletal myopathy - may also play an important role regarding the occurrence and severity of cardiomyopathy in these patients.Taken together, our current findings indicate that, in addition to its already acknowledged role in the early diagnosis of cardiac involvement in DMD/BMD patients, LGE-CMR plays also a prognostic role in risk stratification for adverse cardiac events and might also be of potential therapeutic value . For exaA first limitation of the current study is the limited number of deaths/heart transplantations which prevented us to perform a multivariable risk analysis for primary endpoints. In the light of the above discussion, this is primarily due to the inclusion of relatively young patients with rather preserved cardiac function (only 11% with severe LV systolic dysfunction). Second, no comprehensive and meaningful genotype-associated prognosis assessment could be presently made. Obviously, the main reason was the discrepancy between the large number of different genetic mutations and the limited number of secondary endpoints that narrow the possibility for a robust subgroup analysis. Third, no complete data regarding serum natriuretic peptides were available for analysis. These biomarkers have an established prognostic role in heart failure patients and should be also addressed in future studies .Finally, no myocardial strain data were available for the current analysis. Myocardial strain abnormalities have been shown to occur early in the disease course in DMD patients while LV-EF is still preserved and may have a role in the risk stratification of patients with LV-EF > 45% .Cardiac involvement is a frequent finding in DMD/BMD patients and can be accurately detected in its early stages by comprehensive CMR studies. An impaired LV systolic function (LV-EF ≤45%) and a “transmural” pattern of myocardial fibrosis independently predict the occurrence of adverse cardiac events in DMD/BMD patients. Even in DMD/BMD patients with relatively preserved LV-EF (>45%), the simple and visually assessable parameter “transmural LGE” is of additive prognostic value.


The use of brief screening tools to identify inactive patients is essential to improve the efficiency of primary care-based physical activity (PA) programs. However, the current employment of short PA questionnaires within the Spanish primary care pathway is unclear. This study evaluated the validity of the Spanish version of a Brief Physical Activity Assessment Tool (SBPAAT).A validation study was carried out within the EVIDENT project. A convenience sample of patients  completed the SBPAAT and the 7-day Physical Activity Recall (7DPAR) and, in addition, wore an accelerometer (ActiGraph GT3X) for seven consecutive days. Validity was evaluated by measuring agreement, Kappa correlation coefficients, sensitivity and specificity in achieving current PA recommendations with the 7DPAR. Pearson correlation coefficients with the number of daily minutes engaged in moderate and vigorous intensity PA according to the accelerometer were also assessed. Comparison with accelerometer counts, daily minutes engaged in sedentary, light, moderate, and vigorous intensity PA, total daily kilocalories, and total PA and leisure time expenditure (METs-hour-week) between the sufficiently and insufficiently active groups identified by SBPAAT were reported.The SBPAAT identified 41.3% sufficiently active (n = 489) and 58.7% insufficiently active (n = 695) patients; it showed moderate validity  and a specificity and sensitivity of 74.3% and 74.6%, respectively. Validity was fair for identifying daily minutes engaged in moderate  and vigorous PA . Insufficiently active patients according to the SBPAAT significantly reported fewer counts/minute (-22%), fewer minutes/day of moderate (-11.38) and vigorous PA (-2.69), spent fewer total kilocalories/day (-753), and reported a lower energy cost (METs-hour-week) of physical activities globally (-26.82) and during leisure time (-19.62).The SBPAAT is a valid tool to identify Spanish-speaking patients who are insufficiently active to achieve health benefits. Encouraging adults to reach the healthy recommendations for moderate and vigorous physical activity (PA) (150 minutes of moderate or 75 minutes of vigorous intensity PA throughout the week) is a public health priority for chronic disease prevention and management . PrimaryThe delivery of PA promotion in family medical practice is influenced by many issues such as work overload and shortage of time ,5. ConseBrief PA questionnaires have shown moderate correlation with longer ones and weaker correlations with objective PA measures . Only a A preliminary study linguistically adapted and validated two brief PA questionnaires ,8 againsThis validation study was carried out within the EVIDENT project. Methods and study population of the EVIDENT study have been previously described in detail . BrieflyFrom 2011–2012, sixty general practitioners from 6 primary care centers recruited patients aged 20–80 years old . Exclusion criteria were known coronary or cerebrovascular atherosclerotic disease, heart failure, moderate or severe chronic obstructive pulmonary disease, walking-limiting musculoskeletal disease, advanced respiratory, renal or hepatic disease, severe mental diseases , treated oncological disease, pregnancy, terminal illness, and having relative or absolute contraindications for PA practice. Of the 1,553 subjects, three hundred and sixty-nine patients (23.7%) were excluded for not reporting complete information on PA measurements. The final sample size was 1,184 subjects. No statistically significant differences regarding age (p = 0.788), sex (p = 0.842) nor body mass index (p = 0.524) were observed between the 1184 subjects of the present study and the whole sample of the Evident study. The study was approved by an independent ethics committee of Salamanca University Hospital (Spain). All patients signed written informed consent before taking part in the study.Validity of the SBPAAT was evaluated by measuring agreement with the 7 day Physical Activity Recall (7DPAR) in achieving current PA recommendations for health (sufficiently active or meeting PA recommendations). Scores on the SBPAAT were classified into sufficiently and insufficiently active patients by gender and different age groups  . Both quValidity of the SBPAAT was also evaluated by comparison with accelerometer activity. Accelerometer measurements were used to (i) assess how well the SBPAAT discriminated on counts per minute, daily minutes engaged in sedentary, light, moderate, and vigorous intensity PA, total daily kilocalories, and total PA expenditure (METs-hour-week) and PA at leisure time (METs-hour-week) between the sufficiently and insufficiently active; (ii) correlate SBPAAT scores evaluating daily minutes of moderate and vigorous PA with the objective measurements of moderate and vigorous PA provided by accelerometers. Accelerometry data was collected within two months following the initial individual interview. The average daily time engaged (minutes) in PA at different intensities was considered an appropriate measure to test the criterion validity of the SBPAAT .A detailed description of variables and measurements has been published elsewhere . BrieflyPhysical activity was measured by the 7DPAR, the SBPAAT, and accelerometers (ActiGraph GT3X). The 7DPAR is a common measure of PA, it has been recognized as a valid and reliable tool and is widely used in epidemiological, clinical, and behavioral change studies . The 7DPThe Brief Physical Activity Assessment Tool (BPAAT) is a two-item questionnaire administered by health care professionals which measures the frequency and duration of moderate and vigorous PA in an individual’s usual week . By comb-2, the acceleration of gravity). Activity “counts” are recorded to the internal memory of accelerometers by converting acceleration units over a given epoch [ActiGraph GT3X accelerometers  were used to measure PA objectively, which have been previously validated –20. Actien epoch . Individen epoch . Light, Height, weight, body fat percentage , age, seData on key outcome variables were described using frequencies (percentage) and means (standard deviation). Chi square and Student T statistical tests were used to test differences between the sufficiently and insufficiently active groups identified by the SBPAAT in demographic, lifestyle, and health status variables. Validity of the SBPAAT was evaluated by measuring (i) the percentage of agreement for classifying sufficiently/insufficiently active patients with the 7DPAR, (ii) Kappa coefficient to evaluate how well the SBPAAT discriminated sufficiently and insufficiently active patients as compared to the 7DPAR, and (iii) the ability of the SBPAAT to correctly identify sufficiently active patients  and insufficiently active ones .Validity was also evaluated with (i) Pearson correlation coefficient (r) to assess how well time spent (minutes/day) in moderate (question n° 2) and vigorous PA intensity (question n° 2), as measured by the SBPAAT, correlated with the accelerometer-determined activities of time spent in moderate PA and heavy or very heavy PA , and (ii) Mann-Whitney Test to compare differences between the sufficiently and insufficiently active groups on accelerometer daily counts, daily minutes engaged in sedentary, light, moderate, and vigorous intensity PA, total daily kilocalories, total PA expenditure (METs-hour-week), and PA dose at leisure time (METs-hour-week). Data were analyzed using the Statistical Package for the Social Sciences version 15 . A value of p < 0.05 was considered statistically significant.A total of 1,184 subjects were included in the study . Mean body mass index (BMI) and a percentage of body fat were 27.1 ±4.6 kg/m2 and 34.7±7.6, respectively. Twenty-one percent (n = 252) were current smokers (11.16±9.5 cigarettes/day) and the average weekly alcohol consumption was 4.5±7.8 basic units of alcohol. The most frequent cardiovascular diseases were hypercholesterolemia (30.1%) and diabetes (7.7%). More than 30% followed the Mediterranean Diet and they spent an average of 20.0 ±14.9 hours per week watching television .p<0.001), current smokers (p<0.001), and those with a greater tobacco consumption (p = 0.020) were identified as insufficiently active (66% vs. 52.6%). The mean BMI (p = 0.009), percentage of body fat (<0.001), and weekly hours watching television (p<0.001) were all higher among insufficiently active individuals (The SBPAAT identified 41.3% sufficiently active (n = 489) and 58.7% insufficiently active patients (n = 695). No differences between groups were found regarding age, alcohol consumption, and presence of cardiovascular pathology (ischaemic cardiopathy and heart failure), cerebrovascular diseases and chronic conditions (Type 2 diabetes and hypercholesterolemia) . In contividuals .p<0.001). Light PA did not show significant differences between groups. A similar pattern was identified for different age groups   in a divThe main result of this study highlighted the fact that the SBPAAT had moderate concurrent validity to determine sufficiently and insufficiently active patients, showing an acceptable kappa correlation coefficient in terms of self-reported PA assessment (kappa coefficient = 0.454) . These rOur results suggest that validity of the SBPAAT is as good as longer self-reported PA questionnaires . A totalOnly a few studies have assessed the validity properties of brief PA questionnaires by gender and age groups. In a similar manner to SBPAAT, Wanner et al (2014) reported that a single item PA questionnaire performed better at identifying sufficiently/insufficiently active patients in women and younger people (<40 years old) . In patiRecently, two brief PA questionnaires  were validated for Spanish-speaking Mexicans residing in the United States  (n = 34)The SBPAAT showed fair validity in measuring time spent (minutes/day) doing moderate or vigorous PA against accelerometry. Other short PA questionnaires (RAPA) have reported higher correlation coefficients between questionnaire scores and accelerometry measures of minutes/day doing moderate and vigorous PA  . HoweverThere are several limitations to the present study. First, this is a cross-sectional study that has not been able to detect changes in PA over time. Second, participation was voluntary and it is well known that subjects who agree to participate tend to undertake healthier lifestyle behaviors. Third, despite the valuable information gathered by the accelerometer, this device does not record all physical activities such as aquatic or muscular activities. Finally, accelerometry measurements were taken within 2 months after completing the SBPAAT, which means it measured PA levels at different time points.In summary, the SBPAAT is a valid tool to identify Spanish-speaking patients who are not active enough to gain health benefits and shows acceptable validity across age groups and gender. Using the SBPAAT as a screening tool for PA in the Spanish primary care system could contribute to increasing the efficiency of primary care-based PA programs by providing reliable records on patient´s PA information and identifying those to whom PA promotion programs should be offered.S1 Dataset(ZIP)Click here for additional data file.


Over the past two decades it has become evident that more than 50 % of all heart failure patients suffer of heart failure with preserved left ventricular (LV) ejection fraction (HFpEF), previously called diastolic heart failure because of important involvement of diastolic LV dysfunction. The advances and current status of HFpEF research are described in this special focus issue of the Netherlands Heart Journal. HFpEF is the most common heart failure phenotype in ageing societies, highly prevalent in elderly women and frequently accompanied by comorbidities which result from a detrimental lifestyle, such as obesity, metabolic syndrome, type 2 diabetes mellitus and salt-sensitive arterial hypertension . DespiteA targeted strategy is needed to prevent the progression from obesity and type 2 diabetes towards diastolic LV dysfunction and HFpEF. Available heart failure therapies might exert beneficial effects at an early stage of HFpEF, which is, however, poorly recognised with many patients initially presenting with an advanced form of heart failure. Recognition of an early stage of diastolic dysfunction and initiation of heart failure therapy should be done in primary care, and novel staged therapeutic strategies should be tested to prevent or retard the progression from diastolic LV dysfunction to end-stage heart failure. To battle this life-threatening chronic disease, specialists from different areas of expertise need to join forces.Based on recent findings in cardiac tissue samples from HFpEF patients, a novel paradigm on HFpEF pathogenesis was formulated . This pa


Major advances in chronic heart failure (cHF) therapy have been achieved and documented in adult patients, while research regarding the mechanisms and therapy of cHF in children has lagged behind. Based on receptor physiological studies and pharmacological knowledge, treatment with specific ß1-adrenergic receptor blocker (ARB), tissue angiotensin-converting enzyme inhibitor (ACE-I), and mineralocorticoid antagonists have to be recommended in children despite lack of sufficient data derived from prospective randomized studies. At our institution, bisoprolol, lisinopril, and spironolactone have been firmly established to treat systolic cHF, hypoplastic left heart syndrome (HLHS) following hybrid approach and congenital left-right shunt diseases, latest in patients where surgery has to be delayed. Chronic therapy with long-acting diuretics and fluid restriction are not advocated because short-term effects are achieved at the expense of further neuro-humoral stimulation. It remains unclear why diuretics are recommended although evidence-based studies, documenting long-term benefit, are missing. However, that is true for all currently used drugs for pediatric cHF.Conclusion: This review focuses on the prevailing “nihilism” of cHF therapy in children with the goal to encourage physicians to treat pediatric cHF with a rationally designed therapy, which combines available agents that have been shown to improve survival in adult patients with cHF. Because of the lack of clinical trials, which generate the needed evidence, surrogate variables like heart and respiratory rate, weight gain, image-derived data, and biomarkers should be monitored and used instead. The recommended pharmacological therapy for systolic heart failure is also provided as the basis for utilizing reversible pulmonary arterial banding (PAB) as a novel strategy in young children with dilative cardiomyopathy (DCM) with preserved right ventricular function.The online version of this article (doi:10.1007/s00431-016-2700-3) contains supplementary material, which is available to authorized users. Heart failure is the final stage of a wide variety of cardiac diseases. Symptoms of HF develop, once the heart becomes unable to meet the metabolic demands of the body.In adults, heart failure is frequently called the new epidemic of the twenty-first century . Causes Hsu and Pearson summarized the various causes of pediatric heart failure  as well Considering that cardiac output (flow) is based on heart rate, myocardial contractility, preload, afterload, synchrony, and ventricular-ventricular interaction (VVI), a low cardiac output might be associated with heart failure due to one or all of these variables Fig. .Fig. 1PaIf there is no successful strategy to remove the root cause, the aims of chronic congestive heart failure (CHF) therapy are to modify the neuroendocrine responses that worsen CHF and their pathophysiological consequences and to stimulate endogenous repair mechanisms.Established therapies in adults aim at reducing preload, afterload, and neuro-humoral activation and to halt the ongoing loss of cardiomyocytes, which gives way to replacement fibrosis . In TablIn this context, tachy- and brady-arrhythmias need to be prevented and if present effectively treated; sinus rhythm heart rate needs to be adjusted to the lowest effective level in order to reduce myocardial oxygen demand and to optimize the diastolic ventricular filling time. Chronic stimulation of a dysfunctional myocardium is counterproductive; all exogenous therapeutic strategies that stimulate the neuro-humoral system have been repeatedly analyzed and ought to be, whenever possible, omitted (for example: chronic treatment with loop-diuretics); if inotropic agents and vasoconstrictors become necessary, they should be used as short as possible or as a bridge towards heart transplant, if cardiac assist devices are not the better option.Considering the balance of oxygen delivery and consumption, positive inotrope vasodilators  ought to be preferentially used as long as myocardial perfusion pressures are not compromised. During catecholamine infusion therapy, strategies designed to protect the myocardium should be considered, for example: a combination of epinephrine or norepinephrine infusion with ß1-receptor blockers. In decompensated systolic heart failure, which often occurs in infants and children with dilated cardiomyopathy, short-term epinephrine infusion combined with intravenous or oral ß1-receptor blocking agents  is not a contradiction, but an actually used and recommended strategy . In addiBridging to heart transplantation (HTX), with or without the use of assist devices, or transiting the patient from an acute to a chronic heart failure status might be the therapeutically strategy of choice, if no satisfactory return to normal function can be achieved .Age- and perhaps mechanism-independent chronic HF is associated with neuro-humoral activation and increased levels of circulating neuro-hormones , which lead to vasoconstriction, sodium, and water retention. Continuous endogenous neuro-humoral activation leads to myocardiocyte apoptosis, necrosis, and cardiac fibrosis, the main causes of chamber dilatation and progressive dysfunction, culminating in a vicious cycle of ever worse quality of myocardium and heart function .Medical treatment recommendations for chronic HF in adults have been based on controlled, randomized studies . Large cIn adults with chronic HF, new therapeutic strategies like angiotensin-neprilysin inhibition have been lauded as a paradigm shift in HF therapy , while iThe third thrust of HF therapy should decrease the endogenous neuro-hormonal response by mineralocorticoid antagonism. In the RALES trial , treatmeIn conclusion: HF drugs need a clearly defined indication and a convincing rationale. Simply, a randomized, placebo controlled study design—which is highly desirable—however, lacking a crisp definition of the clinical target and the underlying disease mechanism does not allow us to generate the needed outcome information. One wonders also why the effectiveness of a chronic HF drug is not reported, as it is customary for the drugs targeting pulmonary arterial hypertension ; i.e., i2 measurements. Follow-up laboratory and imaging data should be acquired.The incidence of childhood cardiomyopathy is in the range of 1.13–1.24 per 100,000 children according to the data collected by two population-based registries, where dilated cardiomyopathy accounts for more than half of the primary causes , 27. DilTaking into account-specific exclusion criteria, at our institution, the chronic, age-independent heart failure therapy consists of specific long-acting ß1-adrenoreceptor blocker (bisoprolol), long-acting tissue angiotensin-converting enzyme inhibitor (lisinopril), and mineralocorticoid-receptor blocker (spironolactone) and applying a goal-oriented drug dosage . DigoxinConsidering the (patho-)physiology of the ß-adrenergic receptors (ß-AR) in pediatric DCM, highly selective ß1-AR blockers are recommended in children to treat chronic HF caused by LV-DCM , 43, 50.Combined with ß1-adrenoreceptor blockers, long-acting tissue angiotensin-converting enzyme inhibitors  like lisIn order to improve systemic blood flow, these drugs have not only been recommended in HF patients with stable hemodynamics , but alsAdditional questions arise: why is captopril typically recommended as the first choice for HF treatment in infants and enalapril an appropriate choice for those older than the age of 2 years ? In infaSurgical or transcatheter closure of a hemodynamically relevant ventricle septum defect (VSD) is the treatment of choice. However, there may be several reasons why such a curative approach cannot be performed or need to be delayed. Diuretics, digoxin, and fluid restriction are usually recommended to treat chronic HF based on a left-right shunt, although there is no data that document efficacy , 42, 55.The right ventricle as the systemic heart chamber is usually found in congenital malformations like congenital corrected transposition of the great arteries (ccTGA) and also in the hypoplastic left heart syndrome (HLHS) and in the HLH-complex; in HLHC, the right ventricle works in parallel with an obstructed or borderline left ventricle. There is growing evidence that RV dysfunction develops in many of those patients and accounts for the considerable morbidity and mortality. Therefore, systemic RV function needs close surveillance and sufficient timing of an appropriate intervention to optimize outcome. Almost dogmatically, HF medications, which have been pronounced to be effective for the treatment of a failing left ventricle, are judged to be ineffective for treating a failing systemic right ventricle , 25. HowAt our institution, neonates born with HLHS and some patients with HLHC are palliated using the Giessen Hybrid approach which consists of bilateral pulmonary banding, duct stenting, and, if necessary, atrial septum manipulation Fig. . This apVideo 1With permission of the mother shown here with her premature baby treated with the “Giessen Hybrid” method (see text), the video demonstrates how the parents are advised to monitor her babies that have a high risk of acute clinical deterioration. If the age-dependent respiratory rate at rest is normal the baby is stable; if the respiratory rate becomes fast, for example: double the normal rate, the parents have been advised to contact an experienced doctor or the responsible institution (MOV 2982 kb)Our clinical practice and institutional experience in chronic HF treatment in infants and children with left ventricular systolic heart failure, high-output failure due to significant left-right shunting congenital heart diseases, as well as HLHS and HLH-complex after hybrid stage I, are in clear contrast to the official guidelines for chronic HF therapy in infants and children. We acknowledge as a substantial weakness that we are missing randomized study results; however, in the absence of such trials, observational studies should receive credit as a first step. In addition, the here illustrated chronic HF therapy can lay the ground for a randomized multicenter studies designed to analyze the efficacy of other endogenous repair mechanisms supporting therapies as we advocated by pulmonary arterial banding in selected young patients with DCM and preserved right ventricular function.Below is the link to the electronic supplementary material.


Therefore, we considered that myocardial perfusion may be superior to standard metrics of LV synchrony in selecting appropriate candidates for CRT. In addition, CRT can improve myocardial perfusion in addition to cardiac synchrony, especially in the setting of ischemic cardiomyopathy.Evidence-based criteria for applying cardiac resynchronization therapy (CRT) in patients with ischemic cardiomyopathy are still scarce. The aim of the present study was to evaluate the predictive value of real-time myocardial contrast echocardiography (RT-MCE) in a preclinical canine model of ischemic cardiomyopathy who received CRT. Ischemic cardiomyopathy was produced by ligating the first diagonal branch in 20 beagles. Dogs were subsequently divided into two groups that were either treated with bi-ventricular pacing (CRT group) or left untreated (control group). RT-MCE was performed at baseline, before CRT, and 4 weeks after CRT. Two-dimensional speckle tracking imaging was used to evaluate the standard deviation of circumferential (Cir12SD), radial (R12SD), and longitudinal (L12SD) strains of left ventricular segments at basal as well as middle levels. Four weeks later, the Cir12SD, R12SD, and myocardial blood flow (MBF) of the treated group were significantly improved compared to their non-CRT counterparts. Furthermore, MBF values measured before CRT were significantly higher in responders than in non-responders to bi-ventricular pacing. Meanwhile, no significant differences were observed between the responder and non-responder groups in terms of Cir12SD, R12SD, and L12SD. A high degree of correlation was found between MBF values before CRT and LVEF after CRT. When MBF value>24.9 dB/s was defined as a cut-off point before CRT, the sensitivity and specificity of RT-MCE in predicting the response to CRT were 83.3% and 100%, respectively. Besides, MBF values increased significantly in the CRT group compared with the control group after 4 weeks of pacing (49.8±15.5 dB/s vs. 28.5±4.6 dB/s,  Heart failure, a complex clinical syndrome that encompasses a host of abnormalities in cardiac structure and function, is a major public health epidemic that accounts for a high degree of mortality and morbidity worldwide in vivo for decades to quantitatively assess myocardial perfusion by calculating myocardial blood flow (MBF). Accordingly, the aim of the present animal study was twofold: (1) to validate that changes in myocardial perfusion may be key factors in predicting the outcome of CRT in the setting of ischemic cardiomyopathy and (2) to explore that CRT can improve myocardial perfusion in this common disease etiology.Two-dimensional speckle tracking imaging (2D-STI) is a novel technique for evaluating cardiac motion after CRT All protocols were approved by the Animal Care and Use Committee of Zhongshan Hospital of Fudan University. All surgery was performed under sodium pentobarbital anesthesia, and all efforts were made to minimize suffering.Totally 20 adult female beagles were divided into two groups that either underwent bi-ventricular pacing  or did not . All the animals were anesthetized  and intubated. Their chests were opened allowing ligation of their first diagonal branch, resulting in myocardial infarction (MI). An epicardial lead  was sutured to the surface of the marginal area of the MI. All beagles were followed for 2 weeks to document the presence and severity of heart failure after the MI procedure. Right atrial  and ventricular leads  were subsequently implanted along with the pacemaker unit ; meanwhile, the epicardial lead was connected to the pacemaker. Pacing was initiated in the CRT group only. After 4 weeks of pacing, animals receiving CRT were further divided into two subgroups on the basis of their response to CRT. The left ventricular ejection fraction (LVEF) of dogs in the control group was spontaneously improved after MI and peaked at 45% by 4 weeks after the intervention. Thus, LVEF ≥45% was considered a positive response to CRT after 4 weeks of resynchronization therapy in the CRT group. Animals in CRT group were then classified as “responders” or “non-responders” to the bi-ventricular treatment depending on their hemodynamic function after 4 weeks.The commercially available echocardiographic systems  was used, equipped with a 1–5 MHz transducer (S5-1) and a 1–3 MHz transducer (X3-1), by two experienced cardiologists. At baseline, 2 weeks after MI (before CRT), and 4 weeks after CRT was initiated, all beagles underwent two-dimensional, three-dimensional echocardiography as well as RT-MCE measurements. The data were stored in DICOM format. Furthermore, all the images were analyzed using Philips Q-Lab 8.1 work station .The LVEF, left ventricular end diastolic volume (LVEDV), and left ventricular end systolic volume (LVESV) were obtained from three-dimensional images of apical four-chamber views. Left ventricular synchrony was quantified with 2D-STI, which were traced and analyzed automatically from apical 4-, 3-, and 2-chamber views , as well as the parasternal short axis views . The standard deviations of the time-to-peak of the transmural regional circumferential strain (Cir12SD), radial strain (R12SD), and longitudinal strain (L12SD) for 12 segments of basal as well as middle level of left ventricle were determined.For RT-MCE, the contrast agent applied was the commercially available SonoVue . The contrast agent 59 mg SonoVue was diluted in 5 ml saline and injected via anterior auricular veins slowly (2.5 mL per 1 mL/min). When imaging performed, the focus was initially set at two-thirds of the depth of the image and then moved at the level of myocardial segment to be examined. Mechanical index was set at 1.7 for flash images and 0.1 for real-time images. The definitive setting of the echocardiographic images was optimized after initial infusion, kept constant throughout the study, and matched at follow-up MCE study. At least 15 consecutive heart beats of every destruction-replenishment sequence of basal and middle views at short-axis of left ventricle were captured in disc for subsequent off-line analysis. The MBF value, a reliable measure of myocardial perfusion, was calculated from the product of the plateau video intensity (A) and the rate constant rise of the plateau video intensity (β), as previously reported t test was used for comparing results of the CRT and control groups. The paired Student’s t test was used for comparing changes within each group. A Pearson correlation coefficient was used in testing the relationship between MBF and LVEF after CRT. Results were considered statistically significant for two-sided p<0.05. All data were analyzed using SPSS 16.0 software .All results were summarized as mean ± SD. The independent Student’s Two dogs of CRT group and one dog of control group died for ventricular fibrillation following the surgical procedure. All other canine successfully completed the study . Since the LVEF of dogs in the control group was spontaneously improved after MI and peaked at 45% by 4 weeks after the intervention, we defined LVEF ≥45% was a positive response to CRT for the beagles in the bi-ventricular pacing group. Then, animals in CRT group were classified as “responders” or “non-responders” depending on their hemodynamic function after 4 weeks of resynchronization treatment. Accordingly, 2 of 8 dogs in the CRT group showed no significant response to CRT and were therefore classified as non-responders, whereas the other 6 dogs exhibited significant benefits.As compared, there was no significant difference in LVEF, LVEDV, LVESV, MBF, Cir12SD, R12SD, or L12SD between the CRT and control groups at baseline and following MI . Similarly, animals in the CRT group exhibited a significantly greater reduction in LVEDV than those in the control group (p<0.05). As shown in p<0.05), thereby explaining the selective improvement in LVEF.LVEF showed a greater significant increase in the CRT group (from 31.9% to 53.3%) than in the control group by 4 weeks after the initiation of bi-ventricular pacing in the CRT group (p<0.05). Furthermore, both Cir12SD and R12SD were more significantly improved in the CRT group compared to the control group  or at 2 weeks after MI and before CRT (25.9±5.9 dB/s vs. 23.6±5.7 dB/s). However, MBF values increased significantly in the CRT group compared with the control group after 4 weeks of pacing , whereas no significant differences in LVEDV, Cir12SD, R12SD, or L12SD were observed  in the CRT group were found to be effectively treated by the therapy, the other 2 canine were sorted to as unsuccessful models. Obviously, LVESV and MBF differed significantly between the responders and non-responders before CRT . When MBF>24.9 dB/s was defined as a cut-off value before CRT, the sensitivity and the specificity of predicting the response to CRT were found to be 83.3% and 100%, respectively.On the other hand, while the myocardial perfusion was analyzed, the correlation coefficient between MBF before CRT and LVEF in responders after 4 weeks of CRT was 0.917  in patients with heart failure in vivo canine model of ischemic cardiomyopathy, in which we demonstrated significant improvement of MBF by CRT. We uncovered important differences in basal (pre-CRT) MBF values between responders and non-responders. The significance of MBF as a predictor of CRT outcome is further highlighted by the fact that no significant differences were observed for the other measured indices of cardiac function, including LVEF, LVEDV, Cir12SD, R12SD, and L12SD. The high degree of correlation between MBF measured before CRT and LVEF measured in the responder subgroup after 4 weeks of CRT is agreed with the notion that MBF may be mechanistically related to CRT success in ischemic cardiomyopathy. In other words, our findings indicate that assessment of myocardial perfusion may be more important than LV dyssynchrony  in selecting appropriate individuals for CRT.In brief, we established an 2+ homeostasis, and regional heterogeneity of action potential duration induced by the dyssynchronous mechanical activation of the failing LV in a canine model of left bundle branch block coupled with tachypacing induced heart failure Besides, our findings may also explain the high sensitivity of MBF in detecting hibernating myocardium which has been reported by Fernandes et al. already The present study has some important limitations that require mention. First of all, we relied on a clinically relevant large animal model. Therefore, the number of subjects per group  was by necessity limited when compared to rodent studies. In the next place, our study focused on the global dyssynchrony of the left ventricle, was not designed to uncover potentially important differences in intraventricular properties between various segments within the LV. Thirdly, despite its clinical relevance, our model of MI involved ligation of the first diagonal branch, and therefore, future studies in which the severity of MI can be modulated by ligating additional coronary arteries are warranted. Fourthly, as we mentioned, the pathophysiological process of CRT remains unclear. Varies studies are required to determine the cellular and molecular mechanisms that underlie the observations of the present study. Finally, as with any other animal study, our preclinical findings will require validation in humans before they can be appropriately translated to clinical applications.The MBF value is positively correlated with the responsiveness to CRT and, therefore, should be considered an important predictor of CRT outcome in the setting of ischemic cardiomyopathy. Meanwhile, we’re pretty sure that CRT can improve both cardiac synchrony and myocardial perfusion in this clinically relevant large animal model of ischemic cardiomyopathy.