Due to pressure overload of the right ventricle (RV) in precapillary pulmonary hypertension (PH) patients, the interventricular insertion regions showed Late Gadolinium Enhancement (LGE), representing fibrosis :1993-9). Another promising technique to characterize myocardium is native T1-mapping. Native T1-mapping can be assessed without contrast agents and the myocardial T1 can be quantified without the need of a reference area. Therefore, the aim of this study was to characterize the interventricular insertion regions in precapillary PH patients using native T1-mapping.70 precapillary PH patients (mean pulmonary artery pressure = 47±13mmHg) were included. Native T1-mapping was acquired on a Siemens 1.5 T Avanto scanner. A modified Look-Locker inversion-recovery (MOLLI) pulse sequence was used on a mid-ventricular short axis imaging plane. Three, three, and five non-segmented images were acquired at end-diastole of consecutive heart beats to sample the recovery of longitudinal magnetization after the inversion pulse. Minimal inversion time was 100 ms . Motion compensation was applied. Native T1-values were assessed using regions of interest (ROIs) at the interventricular insertion regions, the RV free wall and left ventricular (LV) free wall.Native T1-values of the RV were significantly higher than native T1-values of the LV . Native T1-values at the interventricular insertion regions were significantly higher compared to the RV free wall (p<0.001) and LV free wall (p<0.001) (Figure Native T1-values at the interventricular insertion regions are significantly increased in precapillary PH and are related to disease severity. This finding is in line with previous PH studies using LGE where contrast-enhancement was observed in the same region. Our results show that native T1-mapping can be an alternative for the characterization of the interventricular insertion regions without the use of contrast agents.N/A.


Ventricular noncompaction (VNC) of the myocardium is a rare genetic cardiomyopathy caused by a disorder during endocardial morphogenesis and could be accompanied by life-threatening complications. The major clinical manifestations of VNC are heart failure, arrhythmias, and embolic events. The left ventricle is the most commonly reported affected site, but a few cases of right ventricular involvement have also been reported. We report a case of biventricular noncompaction cardiomyopathy in a 31-year-old woman presenting with a new onset seizure. On the second day of her telemetry-monitored hospitalization, she suffered a witnessed ventricular fibrillation arrest requiring emergency direct-current cardioversion and induced hypothermia. Transthoracic echocardiography (TTE) showed isolated left ventricular (LV) noncompaction and depressed LV systolic function. Subsequent cardiac magnetic resonance imaging (MRI) revealed both left and right ventricular noncompaction. This unusual presentation highlights the importance of a complete and thorough evaluation of patients even when presenting with apparently noncardiac symptom(s). Ventricular noncompaction (VNC) of the myocardium is a rare genetic cardiomyopathy that is believed to arise from arrested endomyocardial development during embryogenesis . It is aA 31-year-old woman presented with a witnessed loss of consciousness while driving. The episode lasted for about five-to-ten minutes and was associated with tonic-clonic seizure-like movement. There was no urinary or bowel incontinence. She had no history of seizures, arrhythmias, or family history of sudden cardiac death.Physical exam was remarkable only for a 2/6 systolic ejection murmur loudest at the left midsternal border on cardiac auscultation. The laboratory results were within normal limits. Electrocardiogram (ECG) showed sinus rhythm with occasional premature ventricular complexes. An electroencephalogram (EEG) and a head-computed tomography (CT) scan were unrevealing.In the course of the workup, the patient suffered a ventricular fibrillation cardiac arrest requiring defibrillation and induced hypothermia for resuscitation. She recovered without neurologic deficits. Cardiac evaluation with echocardiogram  showed dVNC of the myocardium is a rare genetic cardiomyopathy. The left ventricle is more frequently involved, but biventricular involvement, as in this case, is rarely encountered , 11. WhaAlthough tonic-clonic seizure-like activity was the only presenting symptom given the extensive structural heart disease, it is plausible that this patient likely had a ventricular arrhythmic event  leading to generalized cerebral hypoxia, and thus the tonic-clonic seizure activity. The resulting motor activity has been attributed to a decreased cerebral blood flow , which rAlthough left ventricular noncompaction is more common, the improved imaging capabilities of cardiac MRI provide opportunity for better characterization of right ventricular involvement. Echocardiography has a crucial role in the diagnosis of VNC, but cardiac MRI, contrast ventriculography, and computed tomography could also be utilized during assessment, especially in patients with poor image quality on echocardiography , 22, in In conclusion, VNC is an uncommon disorder accompanied by life-threatening complications. Its unusual presentation highlights the importance of a complete and thorough workup of patients presenting with apparently noncardiac symptom(s). Data is limited on specific therapy for VNC, but it is recommended that medical management be tailored towards the clinical manifestations, and standard guidelines should be applied for patients with reduced LVEF, and heart failure with preserved systolic function , in the


A previously-introduced framework for creating multi-scale patient-specific cardiac models has been applied on all these patients. Novel parameters, such as global stiffness factor and maximum left ventricular active stress, representing cardiac active and passive tissue properties have been computed for all patients. Invasive pressure measurements from heart catheterization were then used to evaluate ventricular relaxation using the time constant of isovolumic relaxation Tau (τ). Parameters from heart catheterization and the multi-scale model have been evaluated and compared to patient clinical presentation. The model parameter global stiffness factor, representing diastolic passive tissue properties, is correlated significantly across the patient population with τ. This study shows that multi-modal cardiac models can successfully capture diastolic (dys) function, a prerequisite for future clinical trials on HF-pEF.The search for a parameter representing left ventricular relaxation from non-invasive and invasive diagnostic tools has been extensive, since heart failure (HF) with preserved ejection fraction (HF-pEF) is a global health problem. We explore here the feasibility using patient-specific cardiac computer modeling to capture diastolic parameters in patients suffering from different degrees of systolic HF. Fifty eight patients with idiopathic  The surge of interest has been driven by the prospect of being able to control all the variables to open up new possibilities toward better health care in a risk-free and ethically acceptable setting for the patient. The exponential growth of computational imaging capacities has also broadened the possibilities toward such models. From simplistic models based on geometric shapes as early as the 1960s to multi-scale multi-physics models, the transformation in this field has been tremendous The application of computational modeling to different organ systems has been gathering increasing interest from the research community. The possibility of performing Heart failure (HF) remains the leading cause of death in developed countries A chronological retrospective analysis of HF therapy in patients with dilated cardiomyopathy (DCM) in the last century sheds light on difficulties in treating this disease. Expert guidelines currently outline HF therapy based on patients’ clinical presentation, cardiac systolic function, and specific biomarkers, but oversee, to some extent, the pathophysiology and etiology that lead to reduced cardiac function The role of left ventricular (LV) systolic dysfunction has attracted broad attention from both clinical and experimental researchers ex vivo human and animal hearts, could be observed, capturing a more accurate representation of cardiac anatomy The progress in the field of cardiac simulation has been on a rise in the last decade Progress in other fields of science, especially in physics and mathematics, and advancements in computer technology opened up new possibilities toward improving existing computer simulations. The application of the finite element method in diverse sectors of engineering represented one of the major turning points in cardiac computational modeling and simulation. The conception and refinement of this method enabled the analysis of complex structural and mathematical problems The radical advances in cardiac imaging modalities and the implementation of non-invasive imaging sequences into the diagnostic algorithms marked the shift toward image-based models and allowed faster transition toward patient-specific cardiac models We have proposed previously a patient-specific cardiac model that captures the biomechanical, hemodynamic, and electrophysiological cardiac functions in patients with DCM τ) across the study population ranged 28–89 ms as shown in Figure 1A. Taking together the elevated pressure measured from the right circulation, approximately 40% of the patients proved to have a lengthened τ  τ), the time constant of isovolumic relaxation, is acknowledged as the time period needed for the ventricular pressure to fall to approximately 37% (or 1/e) of the pressure at the start of the isovolumic relaxation phase τ in this study, as a measure for the cardiac diastolic function, because τ remains a widely-accepted, less load-dependent surrogate for left ventricular relaxation and pressure decline From early animal experiments investigating the maximal rate of pressure fall  between the global stiffness factor and τ, whereas no significant correlation was found between left ventricular maximum active stress and τ. N-terminal pro-brain natriuretic peptide (NT-proBNP) is accepted as a prognostic biomarker in both systolic and diastolic HF τ was not only preserved but enhanced in the subpopulation with elevated NT-proBNP (125 ng/l) as shown in Figure 3B. The correlation between these two parameters was also preserved , with a higher cut-off level of 325 ng/l for NT-proBNP. At the same time, the correlation between LV maximum active stress, which represents the active and systolic component of myocardial contraction in the model, and τ remained non-significant. This observation underlines the potential benefit of combining molecular biomarkers with computational models.To assess the ability of the personalized cardiac model in capturing left ventricular relaxation, we correlated the model parameter of left ventricular global stiffness with τ of −0.33, 0.34, and −0.24, respectively τ appears modest, it remains at least on the same level as those between τ and the echocardiographic parameters mentioned above.Doppler echocardiography remains the current reference method for non-invasive assessment of diastolic LV function. Kasner et al. performed a clinical study evaluating the correlation between conventional or TDI echocardiographic diastolic indexes and pressure volume measurements from heart catheterization. E′ (early diastolic peak of the annular TDI measurements), E/E′ , E′/A′ (ratio of early and late annular velocity) showed very modest correlations with in silico 3D computational cardiac models is promising, which strengthens the predilection toward its utilization in search of novel perspectives in risk stratification, therapy, and prognosis in other fields of cardiology The clinical applicability of using More and more accurate and detailed models of cardiac function in both humans and animals have been abundantly reported, including biomechanical models that specifically investigate cardiac diastolic function in vivo virtual models nowadays. The importance of fiber orientation in simulating cardiac electrophysiology and biomechanics has been abundantly described in previous studies in vivo virtual models in silico simulation of the individual heart.Our goal is the constant progression of the implementation of virtual cardiac models in a clinical setting to provide the patients with the optimal individualized medical care. Further advancement of computational modeling at different levels is anticipated in the near future. One of the first steps forward is validating the predictive prognostic power of such virtual models in a clinical setting. Secondly, capturing patient-specific cardiac fiber architecture remains one of the challenges and a limiting factor of advanced Patients with HF symptoms were enrolled in this study after having given their written informed consent. Only patients receiving heart catheterization due to clinical necessity were included. To reflect broad representation of potential HF phenotypes, cases with slightly to severely reduced systolic function were included. Clinical evaluation, diagnostics, and follow-up were performed in adherence to hospital guidelines.n = 58 patients were investigated in this study.The enrolled patients underwent comprehensive clinical assessment constituting a detailed clinical history, physical examination, 12 lead electrocardiogram, echocardiography, 6 Minute Walk Test, spiroergometry, and comprehensive laboratory tests including NT-proBNP. For the clinical diagnostic process, patients underwent also procedures to ensure exclusion of secondary causes of DCM . Acute myocarditis, significant coronary artery disease (CAD), history of chemotherapy with cardio-toxic agents or chest radiation, valvular heart diseases, and probable secondary causes for DCM were exclusion criteria. A total number of dP/dt) was calculated during the procedure. Maximum values for (−) (+) dP/dt were identified and output for each cardiac cycle. The calculation of τ (time constant of isovolumic relaxation) was based on the approach described by Weiss and colleagues P(t) = P(t = 0) x e−t/τ and τ = −P/(dP/dt).Hemodynamic assessment was performed using left and right heart catheterization. All pressure curves were checked for calibration errors. The customary femoral access was used in all patients receiving simultaneous left and right circulation evaluation. Pressure measurements of the left ventricle and aorta were performed over repeated cardiac cycles prior to application of the contrast agent. Hemodynamic pressure analysis was performed using the computer-assisted software Metek . The intraventricular rate of change in pressure ((−) (+) To further evaluate the clinical phenotype, all patients underwent cardiac MRI analyses . Standard multi-slice 2D steady-state free precession sequences (SSFP), late gadolinium enhancement (LGE) multi-slice inversion recovery sequence, and feature tracking imaging were included in the procedure protocols. Comprehensive 2D echocardiographic assessment of systolic and diastolic function according to current guidelines and hospital standards was also performed in all patients.The computational workflow and process of simulating the personalized multi-scale multi-physics model based on the acquired clinical data has been thoroughly described previously The myocyte contraction is modeled following the approach presented by Sermesant and colleagues, for which the contraction is related to the action potential through a bi-exponential law τ, global stiffness factor, and LV active force are continuous and show an approximate normal distribution. Therefore, a linear correlation analysis using Pearson’s correlation coefficient through the “cor” and the “cor.test” function was applied. The parametric P value, with a significance level of 0.05, was computed for all performed correlations. To account for a possible non-linear relationship between τ and global stiffness factor, a logarithmic analysis of both parameters is also presented . The parameters resented . A possiBM, AA, EK, FS, and TM designed the study; AA, FS, HK, EK, BM, DM, EZ, and SB carried out patient data acquisition; TM, TP, VM, DN, BG, AEP and MW performed the computational analysis, and AL, AA, BM, FS, and EK carried out statistical analysis. AA, EK, BM, TM, TP, DM, and HK were involved in manuscript drafting and revision. All authors read and approved the final manuscript.This work was in part conducted within an industry supported project . TP, VM, DN, BG, AEP, MW, and TM are employees of Siemens Healthcare. There are no further conflicts of interest. The features mentioned herein are based on research, and are not commercially available. Its future availability cannot be guaranteed due to regulatory reasons.


Aortic Coarctation requires a long term follow-up in order to detect late sequelae such as re-stenosis, aneurysms or arterial hypertension.The aim of this CMR study was to measure the myocardial extracellular volume fraction (ECV) as a surrogate marker of diffuse myocardial fibrosis in patients with aortic coarctation after surgical repair in infancy.As a part of comprehensive CMR examination myocardial extracellular volume fraction (ECV) was calculated from pre-and post- gadolinium contrast T1 measurements of blood and myocardium (Look-Locker technique) in 25 asymptomatic patients (age:18.9±7.6) with aortic coarctation after surgical repair and 10 age-matched controls. Parameters of ventricular volumes were obtained from cine CMR. All patients had normal parameters of systolic and diastolic function by echocardiography.Patients with aortic coarctation after surgical repair had an increased ECV compared to the control subjects 0.30±0.05; range 0.24-0.47 vs. 0.26±0.15 (range 0.28-0.23), p < 0.05. LV ejection fraction was 64±5.4% vs 60±4.2% (p=ns); indexed left ventricle end-diastolic volume was 80.7±21.4 ml/m2 vs 78.7±11.8 ml/m2 (p=ns); indexed left ventricle end-systolic volume was 32.1±2.1 ml/m2 vs 31.2±5.5 ml/m2 (p=ns); LV mass/BSA was 55.6±16.1 g/m2 vs 51.8±11.6 g/m2 (p=ns). LV mass/volume was 0.69±0.2 g/ml vs 0.67±0.2 g/ml (p=ns). Mild re-coarctation (ΔP≤10 mmHg) was present in four patients. One of them developed arterial hypertension which was controlled medically. None of the 25 patients had to undergo a reoperation in the past.Two decades after surgical repair of aortic coarctation at infancy asymptomatic patients show an increased myocardial extracellular volume fraction (ECV) indicative of adverse tissue remodeling. Our results suggest that these patients may have a higher lifetime risk for diastolic dysfunction and arrhythmias despite optimal surgical results.N/A.


P)−dP/dt relation. The study endpoint of this retrospective outcome-observational study was combined subsequent acute decompensated heart failure (ADHF) and all-cause mortality. During the follow-up period (median 6.1 years), seven unscheduled hospitalizations for ADHF and nine all-cause deaths were observed. The event-free survival rate was significantly higher among patients with IS than among patients without IS . On a multivariate Cox regression analysis, lack of IS was a prime predictor of the endpoint during follow-up . An LVEF ≥ 58 % was a surrogate indicator for the presence of IS, and patients with LVEF ≥ 58 % had fewer incidences of the endpoint than patients with LVEF < 58 %. In conclusion, lack of IS or LVEF < 58 % should be a predictor of future ADHF and all-cause mortality.Based on our previous observation, inertia stress (IS) of late systolic aortic flow was often observed in left ventricles with relatively higher left ventricular (LV) ejection fraction (EF). Most left ventricles with relatively lower LVEF did not have IS. Accordingly, lack of IS may correlate with LV diastolic dysfunction through the loss of LV elastic recoil and may contribute to the pathogenesis of heart failure (HF) and reduced survival. We enrolled 144 consecutive patients that underwent cardiac catheterization for the diagnosis of coronary artery disease. Left ventricular ejection fraction (LVEF) was obtained from left ventriculography. The IS was calculated from the LV pressure (The online version of this article (doi:10.1007/s00380-015-0657-1) contains supplementary material, which is available to authorized users. P) decay augmented by the effect of the inertia of blood flowing out of the left ventricle on a phase plot of P (dP/dt vs. P) during late systole and early diastole. Thus, lack of IS of late systolic aortic flow is associated with abnormal LV relaxation in patients with coronary artery disease (CAD) and atypical chest pain [The blood in the aorta, once set in motion, will continue in motion because of inertia until the heart stops it . In lateest pain . LV diasest pain –11. IS iest pain . LVEF ≥ est pain . Althougest pain , 12, somest pain , 14. On est pain . AccordiThe study patients consisted of 144 consecutive patients that underwent diagnostic cardiac catheterization to evaluate CAD using a catheter-tipped micromanometer from January 2004 to June 2006. All patients had symptoms suggestive of angina pectoris and/or clinical signs of CAD, including positive electrocardiographic changes during exercise, abnormal myocardial perfusion scintigraphic findings, and a previous history of myocardial infarction (MI) or coronary revascularization. Patients with renal insufficiency (serum creatinine ≥ 1.5 mg/dL), atrial fibrillation or flutter, artificial pacemaker, hemodynamically significant valvular disease, a post-prosthetic valve replacement condition, idiopathic dilated or hypertrophic cardiomyopathy, ADHF, or acute coronary syndrome were excluded. According to the findings of coronary angiography and left ventriculography, 126 patients had CAD: 36 without prior MI and 90 with prior MI. CAD was defined as at least 50 % narrowing of the luminal diameter of one or more of the major coronary arteries, as determined by selective coronary angiography. Prior MI was diagnosed on the finding of localized LV wall motion abnormality using biplane contrast left ventriculography with related electrocardiographic changes. Of the 90 MI patients, 46 had anterior-wall MI, 26 had inferior-wall MI, and 18 had combined anterior- and inferior-wall MI. The remaining 18 patients (those not identified as having CAD) had neither significant coronary stenosis nor LV wall motion abnormality, but had atypical chest pain.All studies were performed while patients were receiving cardiac medications. In describing patient characteristics, hypertension was defined as systolic blood pressure of at least 140 mmHg and/or diastolic blood pressure of at least 90 mmHg or being treated with antihypertensive drugs. Diabetes mellitus was diagnosed when the fasting blood glucose level was greater than 126 mg/dL or when the patient was treated with blood glucose-lowering medicine. Hypercholesterolemia was defined as a low-density lipoprotein cholesterol level exceeding 140 mg/dL or being treated with cholesterol-lowering medicine. This study was performed in a retrospective manner, and data were collected from our database. The Ethical Guidelines Committee of Nagoya City University Graduate School of Medical Sciences approved the study protocol. Written informed consent for future data analysis regarding the cardiac catheterization data was obtained from all patients at the time of cardiac catheterization.P) waves were obtained with a catheter-tipped micromanometer  and recorded on a polygraph system  as analog P signals. The P signals were sent to a digital data recorder  at a sampling interval of 2 ms, as we have reported elsewhere [P/dt was obtained by differentiating digitally the LV P with respect to time, and peak (−dP/dt) was defined as the maximum negative value of dP/dt. The time constant Tw was computed by applying a monoexponential fitting with zero asymptote to the LV P decay [P decay, Tp, was defined as the negative inverse slope of the relation between dP/dt and P on a phase loop. The intermediate data points between peak (−dP/dt) and the minimum pressure in the phase plane were fitted to a rectilinear line using the method of least squares, dP/dt_linear = −kP + C (k > 0),Before contrast material was injected into the left ventricle or coronary arteries, LV pressure  and those before the minimum P, because these data points deviated considerably from the linear fitting. We conducted this exclusion as follows. We took approximately 20 data points on the intercorporate P−dP/dt data starting from peak (−dP/dt). dP/dt was obtained at regular sampling intervals of P. From these points, we chose approximately 10 successive points, fitted a straight line to this set of points using the method of least squares, and calculated the standard error of the estimate. We repeated this procedure for all possible sets of the same number of successive points, and selected the set that yielded the minimum standard error of the estimate. From this set, we calculated the least squares values of k and C. The time constant Tp was given by Tp = 1/k [k was computed as the negative inverse slope of the best linear-fitting line (dP/dt_linear) between points a and b ∧P(c)(dP/dt − dP/dt_linear)dPA = integral_P(a) is the pressure at point a and P(c) is the pressure at point c which is defined as the intersection of P–dP/dt curve and dP/dt_linear.where d was determined as the crossing point of the vertical line that passes the points  and peak (−dP/dt), and the extended dP/dt_linear that passes the points a and b. The area divided by the vertical distance between  and point d is equal to the amount of pressure decay augmented by the effect of the inertia of blood flowing out of the left ventricle, and is defined as the IS of late systolic aortic flow [The point tic flow , 4.P0, 0) and point dIS (mmHg) = A/distance between (P/dt). The consensus we reached by reviewing the phase loops in our previous study was that we were able to confirm the existence of the bump in phase loops from patients with computed IS ≥ 0.5 mmHg (66.65 Pa) [The theoretical background to calculating IS in the phase plane was proposed by Sugawara et al. . A littl6.65 Pa) . Thus, i6.65 Pa)  was emplPressure measurements using a catheter-tipped micromanometer in left-sided cardiac catheterization are essential in order to measure IS. Obtaining these pressure measurements is difficult in daily clinical practice, because the procedure is invasive and using a catheter-tipped micromanometer is considerably expensive. As reported, IS is observed in left ventricles with relatively good systolic function , 4. LVEFt test or the Mann–Whitney U test, as appropriate. A difference in incidence was compared using the Chi-squared test. For event-free survival analysis, Kaplan–Meier curves were generated and compared by use of the log-rank test. We calculated hazard ratios (HRs) derived from the Cox proportional hazard model to identify predictors of combined subsequent HF and all-cause mortality. The variables entered into the model were sex, age ≥65 years, prior MI, LVEF <50 %, Tw ≥ 48 ms, and with or without IS. Differences with p < 0.05 were considered statistically significant.SPSS statistical software  was used for statistical analysis. Triglyceride level was summarized as median and interquartile range (IQR) (25th to 75th percentiles). Other data are presented as mean ± standard deviation or frequency (%). Relationships between two parameters were evaluated using Spearman’s correlation coefficients by ranks. Differences in parameters between two groups were compared using Student’s unpaired A total of 144 patients were enrolled . Clinical characteristics for all patients and subgroup demographics are shown in Tables p = 0.001; Fig. During the follow-up period (median 6.1 years), seven unscheduled hospitalizations due to ADHF and nine all-cause deaths were observed Table . The comp = 0.011; Fig. p = 0.016; Fig. p = 0.01), the combined endpoint of subsequent ADHF and cardiac death , and subsequent ADHF  during the follow-up period . The occurrence of such an endpoint was significantly lower in patients with IS than in patients without IS . From the receiver ROC curve analysis, an LVEF value of 58 % had 87 % sensitivity and 83 % specificity for predicting an absence of IS  for LVEF to predict an absence of IS of late systolic aortic flow was 0.94 , and higher prevalence of lack of IS than patients without these events during the follow-up period. The IS is produced by left ventricles with good systolic function . Thus, lLV diastolic dysfunction is reportedly an independent predictor of mortality in patients with acute MI  and in pIn addition, LVEF is another powerful predictor of prognosis in patients with MI and in patients with HF , 27, 28.Because the measurement of IS requires left-sided cardiac catheterization using a catheter-tipped micromanometer, we tried to identify a surrogate for the presence or absence of IS by measuring LVEF, a standard clinical parameter of LV systolic function. The ROC curve analysis indicated that LVEF had significant potential for identifying the presence or absence of IS. The LVEF value of 58 % should be a surrogate for whether or not left ventricles have significant values of IS in patients with CAD and atypical chest pain. Furthermore, patients with LVEF ≥58 % had fewer incidents of subsequent ADHF and good prognosis. In contrast, LVEF ≥50 % did not correlate significantly with the endpoints. Although the low LVEF values are the prognostic indicator, we found that the relatively high LVEF value of 58 % also has prognostic power in our patients. Thus, the presence of IS might be one reason why patients with higher LVEF have fewer incidents of ADHF. In the I-PRESERVE study, which investigated the effect of irbesartan on cardiovascular events in patients with HF with preserved ejection fraction (EF), a significant relationship between LVEF and poor outcome was only observed in patient with LVEF <60 % . The LVEAlthough HF with preserved EF accounts for more than one-half of all HF cases –14, effeThere are several limitations in this study. First, we used contrast enhanced left ventriculography for the measurement of LVEF. This methodology has potential sources of inaccuracy in the measurements of LV volumes, which are caused by irregularities of the surface of LV chamber with trabeculae, papillary muscles, and chordae tendineae. In addition, rapid injection of contrast material and/or specific effects of contrast material during left ventriculography may have affected the LV volume measurements. LV volume quantification using cardiac magnetic resonance imaging is more precise method; however, in the viewpoint of a simultaneous measurement of LV volume and LV pressure, we thought that left ventriculography using a catheter-tipped micromanometer was inevitable way. Second, this was a retrospective outcome-observational study conducted at a single institution with a limited number of patients. Therefore, a prospective study with a large number of patients should be conducted to confirm the present findings; however, we believe that the obtained findings are important for understanding the pathophysiology of patients with HF with preserved EF.Lack of IS is a predictor of future ADHF and all-cause mortality. An LVEF value ≥58 % could be used as a surrogate indicator that left ventricles have IS. Patients with LVEF ≥58 % may experience lower incidences of future ADHF and mortality, and they should have good prognosis.Supplementary material 1 (PDF 335 kb)Below is the link to the electronic supplementary material.


Trypanosoma cruzi that istransmitted to humans by blood-sucking triatomine bugs, known as "Kissing Bug", and viablood transfusion, mother-to-baby or organ transplant. This protozoan causes an acutesystemic inflammatory illness that usually progresses to chronic myocarditis and autonomicdisease leading to electrical and/or severe dilated cardiomyopathy. Myocardial damage isdisseminated throughout the heart. The outcome may present cardiac arrhythmias,life-threatening heart failure, thromboembolism, stroke and sudden death. The latter issometimes the first manifestation of the disease, even in the structurally normal heart(latent phase). In many patients, a chronic immunologic process may feed the inflammatoryphenomenon even without the parasite. As a rule, extensive involvement of the autonomicnervous system and the cardiac conduction system results in a huge variety ofsupraventricular and ventricular cardiac arrhythmias. As a corollary, in approximately 60%of cases, the sinus node is injured, developing a more or less extensive sick sinussyndrome. Additionally, many patients have to be treated for heart failure and cardiacarrhythmias. Thanks to a coordinated multi-country program in the Southern Cone countries,the transmission of Chagas disease by vectors and via blood transfusion was interrupted inUruguay in 1997, in Chile in 1999 and Brazil in 2006. For this reason, the incidence of newinfections by T. cruzi across the South American continent has decreasedby 70%. The natural course of the disease and the very common pharmacological requirementfor treating numerous arrhythmias cause a high sick sinus node syndrome prevalence. Onefrequent expression of this condition is the "Chronotropic Incompetence" (CI).Chagas disease or American trypanosomiasis is a chronic parasitosis affecting most LatinAmerican countries where an estimated 8 million people are infected. Current assessmentshave shown that even in the United States there is a total of 300,000 infected individuals,essentially all of whom are immigrants from the endemic countries. It is a tropicalparasitic disease caused by the protozoan READ ARTICLE ON PAGE 3112). During maximal aerobic exercise in a healthy person, VO2increases approximately 4-fold, that may be composed of 2.2-fold increase in heart rate,0.3-fold increase in stroke volume and a 1.5-fold increase in the arteriovenous oxygendifference. These data indicate that the heart rate increase is the most importantcontributor to the ability to perform sustained aerobic exercise. Therefore, it is wellknown that CI can be one important cause of a symptomatic exercise intolerance.Increasing heart rate during exercise is necessary for Chagas disease patients not onlyto adjust cardiac output but also to blunt the excessive sympathetic tone increase. Theability to perform physical work is enabled by a growth in oxygen uptake + restingHR.Nevertheless, the lack of a consistent methodology and standardized criteria todetermine CI probably justifies the high range of prevalence described in theliterature, 9% to 89%, mainly in pacemaker patients.Technically, CI is considered when the heart rate fails to reach 85%, 80%, or, lesscommonly, 70% of the age-predicted maximum heart rate (APMHR), usually based on the 220- age, obtained during a controlled incremental exercise test. Despite being frequently underdiagnosed inclinical practice, this condition must deserve specific attention in Chagas diseasepatients with pacemakers, defibrillators or resynchronizators, each of one with very peculiarconsiderations.Despite being an exception as an isolated pacemaker indication, CI must be prevented andtreated in all pacemaker's patients by programming the biosensor. The European Societyof Cardiology pacemaker guidelines published in 2013 included CI as one isolated, veryspecific indication for pacemaker: "CI after heart transplantation: Cardiac pacingshould be considered for CI impairing the quality of life late in the post-transplantperiod" . In addition, they recommend that rate responsefeatures should be adopted in pacemaker patients with CI, especially if young andphysically active, .More recently, it has been shown that IgG fractions of sera from patients with chronicChagas disease can decrease the HR of isolated rabbit hearts. Patients in early stages  as well asthose with baseline LV segmental wall motion abnormalities exhibit blunted myocardialcontractile response to dobutamine infusion, CI and a biphasic inotropic response  to dobutamine despite the normalangiographic appearance of the coronary arteries.As the sinus node is usually involved in the pathological process, this condition isvery frequent in Chagas disease, even in the latent phase when the heart may beapparently normal. The inflammatory and fibrotic processes reduce the number of "P"cells, destroy the innervation and cause significant barriers to sinus node impulseprogression. In addition, sera of patients with Chagas disease contain autoantibodiesagainst both beta1 and beta2 adrenergic receptor subtypes with a theoretical gradualblockade of myocardial neurotransmitter receptors impairing both inotropic andchronotropic effectsWhen the sinus node is normal, it is the best sensor and the DDD pacemaker would notneed a biosensor. However, even in this situation the biosensor is necessary to informthe system about physical activity and to manage the heart rate above the upper-tracklimit. The sleep-rate, for example, must be turned-off in case walking is detected. Inaddition, this resource may contribute to discriminating pathological and functionaltachycardia in defibrillators.,13. This behavior strengthens the need for sensorprogramming and a good sensor tuning in Chagas disease patients, as the increasedsympathetic tone is an additional risk factor for severe ventricular arrhythmias andsudden death in this pathology. Indeed, coronary sinus norepinephrine is higher inpatients with VVI pacemaker during exercise. The increase in catecholamine on exerciseduring VVI pacing is likely to be related to the need for improving contractility and,consequently, cardiac output to compensate for the lack of rate response. This enhancedcardiac sympathetic activity may eventually produce an adverse effect on LV function,with the possible development of congestive heart failure and arrhythmias. On the otherhand, an adequate chronotropic response that provides an appropriate increase in cardiacoutput during physical activity will surely reduce the risk of these arrhythmias. Inaddition, preliminary data suggest that rate adaptive AAIR and DDDR modes may be moreefficacious in preventing atrial arrhythmias than their non-rate adaptive counterpartsin Sick Sinus Syndrome. DDDR pacemakers may prevent arrhythmias by eliminating therelative bradycardia noted during exercise in patients with non-adaptive devices, whenexcessive catecholamine release may increase the likelihood of atrial arrhythmias.When patients with complete AV block exercise, the sinus rate is significantly higherwith VVI pacing than during dual chamber or VVIR modes, a response possibly reflectingthe increased activity of the sympathetic nervous system when pacing is set to VVImodeThe most common are the sensor based on body mechanical vibration induced by movementand physical activity and the sensor that detects respiratory activity. Additionally,many other types of sensors have been tested and different parameters have beeninvestigated to control the pacemaker rate: central venous temperature, changes of theright ventricular inotropism that may change impedance during the cardiac cycle , QT interval, venous pH, oxygen saturation, stroke volume,minute ventilation, peak endocardial acceleration, gravitational sensor, etc.There is a great range of advantages and disadvantages in these systems with respect tospecificity and response proportionality, energy consumption, effort forecasting, easeof programming, auto-tuning, need for special leads, external interferencesusceptibility, influence of associated diseases and age limitation.The most used single sensor is based on a piezoelectric crystal or an accelerometer thatsenses mechanical activity. The first increases its electrical vibration in response tobody mechanical activity, and the second is inertial and responds to the movementdirection. Despite a quick response, it is not as specific as responding to vibrationsrelated or not to physical activity and it has an inadequate response to isometricefforts and intellectual activity. In addition, its post-exercise frequency decay is notproportional to the duration of the effort. Nevertheless, its major advantages aresimplicity and low power consumption.The QT interval biosensor is based on the fact that this parameter shortens with theincrease in metabolic activity, being almost always quite physiological. However, in thecase of low T wave amplitude, it may have a reading error, it cannot be used in theatrium and it suffers interference of drugs that prolong or shortens the QT interval, aswell as in pathological conditions such as ischemia and infarction, which can lead to anundesirable increase in heart rate.The central venous blood temperature sensor is grounded on the premise that there is atemperature increase during physical effort related to muscle heat production andaugmented circulation. However, in the early stages a drop in temperature of the centralvenous blood may occur, delaying the response. Moreover, it demands a particular leadthat reduces their use, especially in cases of generator exchange when the patient hasan implanted conventional lead.The respiratory sensor is based on measurements of changes in thoracic bioimpedance as aresult of changes in the quantity of air in the chest. It was improved by using theminute ventilation (MV) that takes into account both the respiratory rate and the tidalvolume. It holds the advantage of using a conventional bipolar lead that can beimplanted in the atrium or the ventricle. It is quite physiological given its highproportionality with the metabolic increase, independent of the quantity of mechanicalaction. Accordingly, it may change with mental activity and emotions. The post-exerciseheart rate decay keeps great proportion to the intensity and duration of the activityperformed. A disadvantage is the higher power consumption compared to the piezoelectriccrystal sensor and the impossibility of using it in patients with lung diseases andpediatric age.2 saturation, pH, PEA  have been less applied because of the complexity ofthe lead, the impossibility of using in generator exchange in patients with old leadsand the non-applicability in the atrial chambers.Several other sensors that rely on the need for special leads, such as those based onO.Because none of the currently available sensors allow a response equal to the sinusnode, there has been an effort of the cardiac pacing industry to associate twocomplementary sensors to yield a more physiological response. There are systemscommercially available with the following associations: activity sensor and respiratoryvolume minute sensor , activity sensor and QT sensor(Vitatron), activity and myocardial contractility sensor (Biotronik) and PEA withactivity (Sorin). The combination most commonly used is the activity or accelerometersensor with the respiratory volume minute sensor that brings the fast response of thefirst to the proportionality and specificity of the second resulting in a morephysiological heart rate modulation. The goal is to harness the advantages andcompensate for the shortcomings of each systemAs CI is highly prevalent in this pathology, it is very important to program thepacemaker with this resource. Similar to the long QT syndrome, it would always bedesirable that the sensor slightly anticipates the chronotropic needs of the patient byreducing sympathetic stimulation, since in these cases the catecholamines have anunwanted effect on the electrical stability of the myocardium. Especially in thiscondition, the well-adjusted sensor could have an effect enhancing the beta-blockersaction by causing a reflex reduction in sympathetic tone. It can therefore be concludedthat the dual sensor, allowing more fine-tuning and more physiologic heart rate, ishighly desirable in this pathology. It is also highly recommended that in such cases adetailed program of the sensor be carried out, through exercise testing and/or Holter,in order to obtain the maximum arrhythmia suppression with proper adjustment of theheart rate response, while on the other hand, it is crucial to avoid ventriculardyssynchrony caused by excessive ventricular pacing due to a high biosensor driven heartrate. However, there are very few scientific studies addressing this issue. In addition,there are rare randomized studies comparing different frequency response modes in thesepatients. In this sense, it is appropriate to consider the results of the DUSISLOGstudy.vs. Single Sensor comparison using patient activityLOGbook (DUSISLOG) study was designed to find if there is any benefit from usingdual-sensor for rate response in pacemaker patients. It is a two arms multicenter,prospective, randomized study enrolling 105 patients who received a rate-responsivepacemaker . After 1 month of DDD pacing at 60 ppm lower rate, asingle sensor  was activated for 3months at the manufacturer's nominal settings, followed by a 3-month period with dualsensors optimized for automatic response. During the last month of each period, thefollowing data concerning patient physical activity were retrieved from pacemakerdiagnostics Log: mean percentage of physical activity, mean intensity of activity.Quality of life (QoL) scores and 6-minute walk test (WT) were also recorded. A total of105 patients achieved the enrollment criteria and completed all the specified follow-upprogram. WT, QoL, and patient activity significantly improved after activation of asingle sensor and there was similar symptomatic benefit by using Activity or MinuteVentilation. However, no additional benefit was found using dual sensor. In spite ofthis, one important information came from the subgroup analysis. The patients weredivided into three subgroups according to the degree of atrial CI, based on theirpercentage of sensed intrinsic atrial activity, calculated as % of atrial sense (AS) at1 month follow-up . A significant increase in thedistance covered with the 6-mintue WT, QoL, and percentage of atrial pacing over 70 ppmwas observed for single sensor, with an additional advantage of dual sensor, only inpatients with major atrial chronotropic disease defined as the absence of intrinsicatrial activity over 60 bpm (0% AS%), which accounted for 17% of the enrolledpopulation. Patients with moderate CI (0-10% AS%) showed only a trend toward symptomaticbenefit from rate-responsive pacing, whereas those with mild or no CI (>10% AS%) hadless or no benefit. Based on these data, it is worth to conclude that the rateresponsive pacemaker with at least one sensor in Chagas disease is highly desirable,being the dual-sensor greatly recommended for the cases presenting severe CI.The Dual Sensor


Although increased volume of pericardial fat has been associated with decreased cardiac function, it is unclear whether this association is mediated by systemic overall obesity or direct regional fat interactions. We hypothesized that if local effects dominate, left ventricular (LV) function would be most strongly associated with pericardial fat that surrounds the left rather than the right ventricle (RV).Female obese subjects (n = 60) had cardiovascular magnetic resonance (CMR) scans to obtain measures of LV function and pericardial fat volumes. LV function was obtained using the cine steady state free precession imaging in short axis orientation. The amount of pericardial fat was determined volumetrically by the cardiac gated T1 black blood imaging and normalized to body surface area.In this study cohort, LV fat correlated with several LV hemodynamic measurements including cardiac output  and stroke volume , as well as diastolic functional parameters including peak-early-filling rate , early late filling ratio , and time to peak-early-filling . These correlations remained significant even after adjusting for the body mass index and the blood pressure. However, similar correlations became weakened or even disappeared between RV fat and LV function. LV function was not correlated with systemic plasma factors, such as C-reactive protein (CRP), B-type natriuretic peptide (BNP), Interleukin-6 (IL-6), resistin and adiponectin .LV hemodynamic and diastolic function was associated more with LV fat as compared to RV or total pericardial fat, but not with systemic inflammatory markers or adipokines. The correlations between LV function and pericardial fat remained significant even after adjusting for systemic factors. These findings suggest a site-specific influence of pericardial fat on LV function, which could imply local secretion of molecules into the underlying tissue or an anatomic effect, both mechanisms meriting future evaluation. Recent studies of humans using a variety of approaches have suggested that regional fat distribution, rather than overall obesity plays an important role in cardiac modification -4. PericTo explore which effect dominates LV modifications, we segmented and quantified fat covering the LV and the right ventricle (RV) separately to examine relationships of these specific fat depots to LV function. We hypothesized that if local effects dominate, pericardial fat surrounding the left ventricle would be associated more with measures of structure and function from the same chamber as opposed to the adjacent one. Since cardiovascular magnetic resonance (CMR) provides high spatial resolution and has the ability to perform 3D measurements, while maintaining adequate temporal resolution, it was chosen as the preferred imaging modality.2, n = 60, age = 21-60 yrs) with no known cardiovascular disease were recruited from the Nutrition and Weight Management Center at Boston Medical Center with informed consent approved by the Intuitional Review Board of Boston University Medical Center. Subjects with atherosclerotic vascular disease, including those who have had stroke, myocardial infarctions, heart failure, prior percutaneous or surgical revascularization procedures, anginas, or peripheral arterial disease were excluded. In addition, subjects who weighed over 136 kg or had a waist circumference greater than 140 cm were excluded due to the size limitation of the scanner.Female obese subjects (BMI ≥ 30 kg/mIR = (fasting insulin (mU/l) × fasting glucose (mg/dl))/405 [2, reconstructed resolution = 0.75 × 0.75 mm2, slice thickness = 4 mm. In order to assess cardiac function, short axis cine CMR was performed using a steady state free precession (SSFP) sequence with 8-11 s breath holds and ECG gating. Contiguous slices were obtained from the artrio-ventricular groove to the apex of the heart. The acquisition parameters were: TR = 3.0 ms, TE =1.6 ms, NEX = 1, sense factor = 1.5, FOV = 400 × 400 mm, matrix = 256 × 256, with 26–28 heart phases acquired per slice, slice thickness = 10 mm.Subjects arrived for CMR in a fasting state (no food or liquid other than water consumed over the previous 8 hours). Height (to the nearest 0.1 cm), weight (to the nearest 0.1 kg), and waist circumference (in cm) were measured. BMI was calculated as body weight divided by height squared, and used as a marker of overall obesity. A fasting blood sample was collected by routine venipuncture, and the plasma levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, triglyceride (TG), free fatty acids (FFA), fasting glucose, insulin, Interleukin-6 (IL-6), B-type natriuretic peptide (BNP), C-reactive protein (CRP), resistin and adiponectin were measured. Insulin resistance was calculated using the homeostatic model assessment (HOMA): HOMAdl))/405 . The subdl))/405 : repetitLV fat = 0.94, ICC RV fat = 0.89, ICC total pericardial fat = 0.90).Cardiac function including left ventricular ejection fraction (EF), stroke volume (SV), and cardiac output (CO) were calculated using ViewForum . Analysis was performed on contiguous short axis slices and summed up by Simpson’s technique. Diastolic function was determined based on the volume-time curve obtained from the previous step and processed using an in-house software (Matlab). The first derivative of the volume-time curve was obtained . After images were corrected for inhomogeneity using a bias-field algorithm , pericard Figure . The firt-test. Associations between continuous variables were assessed using Pearson’s correlation. Multivariable adjusted linear regression was used to assess the significance of relation between the LV pericardial fat and LV function. Due to the limitation of our sample size, covariates included only BMI and the systolic blood pressure. A Two-tailed probability value p < 0.05 was defined as statistical significance.Data are presented as mean ± SD. Comparisons between groups were performed using the student Pericardial fat presented in the current study includes both epicardial fat (the lipid layer between the myocardium and the pericardium) and the fat external to the pericardium, as the two can generally not be separated in our measurements.2). Table 2, Figure 2, pericardial fat = 213 ml, Figure The study sample consisted of 60 obese females . To control for potential systemic confounders, the relations between LV fat and LV function was further accessed by the multiple linear regression. After adjusting for BMI and the systolic blood pressure, LV fat remained significantly correlated Table  to the dTo our knowledge, this is the first report indicating that the relations of LV function to LV fat are stronger than RV fat, and remain significant after the multivariable adjustment. Meanwhile, no association was observed between LV function and systemic factors including plasma inflammatory markers and adipokines. These findings suggest that pericardial fat may exert local endocrine or anatomic effects on LV function.2, has been well established as an independent risk factor for cardiovascular diseases [Obesity, defined as BMI > 30 kg/mdiseases ,15. Howediseases -21. Amondiseases  studied diseases  reporteddiseases  in 2009.diseases  did not diseases . Howeverdiseases  may actu2). Firstly, dissociation was observed between pericardial fat and BMI, indicating that regional fat accumulation can deviate from total body fat accumulation. In other words, it is possible to find obese subjects with “normal” amount of pericardial fat, which may not carry the pathologic influences from distal fat if local effects dominate. Secondly, LV function did not correlate with serum biomarkers, including IL-6, CRP, BNP, resistin and adiponectin. These biomarkers have been found elevated/decreased in obese people, and linked to the increased inflammatory stress, which in turn could be detrimental to cardiac function [To address this issue, we examined the relations between pericardial fat and LV function from different aspects and found novel results for our obese subjects (BMI: 30.0-46.5 kg/mfunction -27. The 2+levels, because of reduced activity of Na+/K+ ATP-ase in the plasma membrane or decreased reuptake of Ca2+ into the sarcoplasmic reticulum [In this study cohort, subjects with severe cardiac dysfunction were excluded, and late stage diastolic dysfunction with pseudonormal diastolic pattern is not likely to occur. Hence, it is reasonable to believe only linear relationship may exist between LV diastolic function and pericardial fat. In this study cohort, LV diastolic indices showed correlations with RV fat, but to a lesser extent as compared with LV fat. This observation may not necessarily suggest that RV fat has a direct influence on LV relaxation, as it could result from the strong correlation between the two fat depots in volume. This evidence implies that LV diastolic function may be impaired to a greater extent by the presence of the local adipose tissue. Various studies ,29 have eticulum ,32.The 3D volumetric assessment of pericardial fat and LV function provides an advantage over previous studies that used the fat thickness for similar assessments. Additionally, by considering left ventricular fat separately from the adjacent pericardial fat, we were able to more accurately describe the relationship between cardiac function and regional fat depots. Some limitations warrant discussion. In particular, epicardial fat is more proximal to the myocardium and has a different metabolic activity than the fat outside the pericardium , which tVariation in LV hemodynamics and diastolic function, independent of body size or blood pressure, was observed that related specifically to the volume of pericardial fat overlaying the LV. Variation did appeared to associated to a lesser degree with fat overlying the RV, but was independent of serum inflammatory markers or adipokines in this healthy but obese population. These findings provide insight into a possible mechanism by which metabolic disease, and pericardial fat accumulation, might negatively impact cardiac function.The authors declare that they have no competing interests.NH conceived the study, participated data acquisition, data analysis and drafted the manuscript; ZJC, QY and AP participated CMR data acquisition; TP participated in data analysis; MPL performed the statistical analysis; SJB, MRR cordinated the study and participated in biological data acquisition; CMA, FLR and JAH participated in the study design. All authors read and approved the final manuscript.


The pathophysiology of this entity is multifactorial; systemic, cellular,and extracellular mechanisms have been described, including maldistribution of coronaryblood flow, myocardial injury, complement-triggered (C5a) myocyte contractile failure,cytokine-induced neutrophil activation , dysregulation of calcium handling, and cytopathic hypoxia due tomitochondrial dysfunction.,4 whereas otherforms of myocardial dysfunction have been often overlooked. These variants include leftventricular diastolic dysfunction-8 and right ventriculardysfunction,,10 which have different treatment options and prognosticimplications. Interestingly, all types of myocardial dysfunction can be present inisolation or in combination and can be fully reversible with resolution of criticalillness.,11Cardiovascular compromise is a central component of multiple organ dysfunction syndrome,an often fatal consequence of severe sepsis and septic shock. There is a sizable body ofwork on left ventricular systolic dysfunction in sepsis, TDI is anechocardiographic technique based on measurements of myocardial velocities, which are low frequency,high-amplitude signals filtered from conventional Doppler imaging.It is particularly useful as a measureof ventricular relaxation and ventricular filling pressures. The significance of diastolic dysfunction wasrecently highlighted by studies that demonstrated that TDI might be prognosticallyuseful in the general intensive care unit (ICU) population.,16-22With the use of tissue Doppler imaging (TDI), a technique that has gained acceptanceamongst cardiologists and intensivists for the evaluation of diastolic function, it hasbecome evident that diastolic dysfunction is indeed common in critically illpatients.Revista Brasileira de Terapia Intensiva, aninteresting, single-center prospective cohort study confirmed the importance ofdiastolic dysfunction in patients with severe sepsis and septic shock. The authorsstudied 53 patients with the aim of assessing the prevalence of myocardial dysfunctionboth at ICU admission and one week later and also of evaluating the impact of leftventricular systolic and diastolic dysfunction on ICU mortality.In this issue of the A detailed echocardiographic examination was performed within 48 hours of ICU admissionand 7-10 days later, which included M-mode, two-dimension, and Doppler echocardiography.Systolic and diastolic function, including TDI, as well as right ventricular assessmentwith tricuspid annular plane systolic excursion, were carefully evaluated by a singlecardiologist specialized in echocardiography.The authors found an alarmingly high prevalence of diastolic dysfunction of 84% in thegroup of septic patients, a finding that remained unaltered in the follow-upechocardiography performed one week later. This high prevalence might be related to theage range (74 ± 13 years) of patients included. However, we cannot exclude thepossibility of overestimation due to selection bias because only 25% of eligiblepatients entered the study with a comparable number of patients being lost to follow-up.Additionally, although tempting, we cannot ascribe all the echocardiographic findings toseptic cardiomyopathy. Diastolic dysfunction could as well be a premorbid condition inthe sample of elderly patients studied, a hypothesis supported by the lack of resolutionof echocardiographic findings in the follow-up exam. the importanceof this previously overlooked variant of myocardial compromise. The E/e' ratio, one ofthe TDI measures used to define diastolic dysfunction, was the only echocardiographicmeasurement independently associated with death even after adjusting for age and diseaseseverity. Interestingly, systolic dysfunction was not a predictor of death. Thesefindings highlight the need to perform thorough echocardiographic evaluations inpatients with sepsis and septic shock.Another relevant finding was the association of diastolic dysfunction with mortality,confirmingThe Unbearable Lightness of Being, Milan Kundera wasright to acknowledge the powerful predictive ability of the heart: "When the heartspeaks, the mind finds it indecent to object".In his famous work


Mitral regurgitation (MR) is common in patients with ischemic cardiomyopathy (ICM) and independently associated with worse mortality. We sought to determine the impact of adverse LV remodeling, total myocardial infarct (MI) size, location and extent of regional MI, and mitral valve geometry on the severity of mitral regurgitation.A total of 494 patients with LVEF ≤ 40% and ≥ 70% stenosis in ≥ 1 epicardial coronary artery and prior history of CABG or PCI were screened. Patients with transthoracic echocardiogram and CMR studies within 7 days were selected. Forty-two patients (9%) were excluded either due to prior mitral valve surgery, unavailable studies or organic mitral valve disease. Other 42 patients were excluded because of no mitral regurgitation noted on their study. Mitral regurgitation was assessed using semi-quantitative vena contracta method from a parasternal long axis zoomed view obtained of the mitral valve. LV volumes and EF were calculated from cine short axis CMR images. Mitral valve geometry was measured on end-systolic 2, 3, and 4 chamber cine views. LV scar was measured 10-15 minutes after gadolinium injection and using phase-sensitive inversion recovery sequence.The mean age of the cohort n = 410) was 63 ± 11 years and males represented 75%. LVEF, LV end-systolic volume index, mean total infarct size, MV annulus index, MV tenting area index, and MV displacement index were: 23 ± 0.5%, 115 ± 2 ml/m2, 31 ± 17%, 1.7 ± 0.5 cm2/m2, 0.88 ± 0.48 cm2/m2, respectively. Mean inferior, lateral, anterior infarct size were: 27 ± 21%, 25 ± 20%, 37 ± 23%. MR was classified as: mild (63%), moderate (22%) or severe (15%). The mean vena contracta was 0.33 ± 0.24 cm. Multiple variable linear regression (R2 = 0.23) revealed that male gender, worsening GFR, increase extent of inferior LV scar, LV ESVi and MV tenting area index were independent predictors of MR severity, whereas overall scar extent, anterior or lateral location were not. (Figure 0 was 63 Global LV remodeling, regional inferior myocardial scarring, and mitral valve geometry are more important predictors of worsening MR than total infarct size in patients with advanced ischemic cardiomyopathy.None.


In the setting of acute myocardial infarction (AMI), therapeutic and spontaneous reperfusion of ischemic myocardium can lead to interstitial intramyocardial hemorrhage (IMH) which is associated with microvascular obstruction (MVO) and subsequent adverse clinical outcomes. Imaging without contrast agents (native imaging) can be used in AMI patients for additional myocardial tissue characterization. Native T1 and T2 weighted imaging and quantitative measurements have been reported to detect myocardial edema and depict the myocardial area at risk. IMH affects T1, T2 and T2* relaxation as well as susceptibility and the feasibility of several MR image contrasts  has been demonstrated for the depiction of IMH. Susceptibility weighted imaging (SWI) uses a type of image contrast different from traditional spin density, T1 or T2 weighted MR imaging.In the present work, we report our experience with myocardial SWI imaging (combined gradient-echo magnitude and phase imaging) for the detection of IMH. We propose TE image averaging and gray-scale inversion as a means of providing a single image with good image SNR and excellent contrast for the detection of IMH.Eleven AMI subjects were studied at 1.5T before contrast agent administration with a dark blood double inversion recovery multiple spoiled gradient-echo sequence  and conventional CINE and late gadolinium-enhanced (LGE) imaging. Magnitude, susceptibility weighted and TE-averaged images were reconstructed from raw data k-space data. Contrast and signal-difference-to-noise were measured and compared between SWI methods for IMH detection. Volumes of LGE, IMH and MVO were measured and reported as a percentage of LV myocardial volume.There were six patients with microvascular obstruction (MVO) and four patients with IMH detected by TE-averaged SWI imaging. TE-averaged SWI images from a representative AMI subject with IMH are given in Figure TE-averaged SWI imaging is a promising method for myocardial tissue characterization in the setting of AMI for the detection of IMH. Along with gray-scale colormap inversion, it combines not only magnitude and phase information, but also images across TEs to provide a single image sensitive to IMH with characteristics similar to LGE imaging.American Heart Association scientist development grant (0635029N).


Copeptin is the C-terminal end of pre-provasopressin released equimolar to vasopressin into circulation and recently discussed as promising cardiovascular biomarker amendatory to established markers such as troponins. Vasopressin is a cytokine synthesized in the hypothalamus. A direct release of copeptin from the heart into the circulation is implied by data from a rat model showing a cardiac origin in hearts put under cardiovascular wall stress. Therefore, evaluation of a potential release of copeptin from the human heart in acute myocardial infarction (AMI) has been done. Copeptin is the small C-terminal portion of the antidiuretic pre-proprotein of arginine vasopressin (proAVP). AVP is generally released in response to stress on the circulatory system such as an increase in plasma osmolality resulting in an antidiuretic effect245Elevation of AVP and copeptin can be observed in a variety of pathophysiological conditions e.g. type 2 diabetes71012141516141516AVP is usually synthesized in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei and released from the neurohypophysis into the circulationTherefore, we analyzed a potential release from the heart by measuring the concentration of copeptin using a transcoronary gradient model (TCG) in patients with AMI.Patients who underwent a coronary angiography at the University Hospital Frankfurt between October 2009 and September 2010 were enrolled as described earlier in detailBlood was simultaneously collected from the aortic bulb (AO) and the coronary venous sinus (CVS) during a standard cardiac catheterization procedure before heparin or any contrast agent was administered and before any interventional procedure was started as described previouslyAfter centrifugation, plasma and serum samples were transferred to RNase/DNase-free tubes and stored at −80 °C within 1–2 hours.Copeptin levels were measured in CVS and AO blood samples in 50 μl serum using the copeptin US assay on a KRYPTOR compact PLUS (BRAHMS Thermo Scientific) in accordance with the manufactures instructions. Measurements were carried out by experienced staff blinded to patient characteristics.th percentile cut-off is available for cTnT measurements using CVS blood, a concentration of 100 pg/ml was used as discriminatory threshold.CTnT was measured using a commercially available highly sensitive assay (Roche diagnostics) at the central laboratory of the recruiting institution. As no established 99The p-values in the baseline table refer to the exact Fisher’s test, t- and Wilcoxon tests for categorical, symmetric and skewed distributions, respectively. A possible association between chest pain onset time, and copeptin TCG levels were analyzed by calculation of the Spearman correlation coefficients. All analyses were carried out using the R software package version 3.1 .To determine whether the heart contributes to the release of copeptin into the bloodstream in humans, we measured copeptin levels in patients suffering an AMI and in patients without AMI. A detailed characteristic of the study cohort is provided in Levels of cTnT, as established biomarker representing myocardial ischemia, as well as copeptin were determined in samples from the aorta (AO) and the coronary venous sinus (CVS) in patients with (n = 15) and without (n = 14) the diagnosis AMI. Of those, 5 suffered a non-ST elevation myocardial infarction whereas 10 showed significant ST elevation in the electrocardiogram.In the patient group without an AMI we found a mean cTnT concentration of 4.15 pg/ml (±0.66) in AO samples, while 5.59 pg/ml (±0.74) was detected in the CVS . This reIn the non-AMI group we found mean AO copeptin levels of 8.73 pmol/l (±1.67) and of 8.54 pmol/l (±1.64) in the CVS . In line14However, no relevant release or uptake of copeptin during the transcoronary blood passage could be detected when comparing the mean TCG of patients with or without the diagnosis AMI with −0.07 and −0.18 pmol/l (P = 0.78), respectively . ConsideAdditionally, the potential association of a transcoronary copeptin gradient and time between symptom onset and time of blood sampling was evaluated. This time interval did not show a relevant correlation with the TCG of copeptin . Furthermore, AMI patients presenting early, within 4 hours after onset of symptoms (n = 7), showed no difference in TCG of copeptin with mean of –0.185 pmol/l compared to 0.021 pmol/l (p = 0.91) as determined in patients presenting later than 4 h.Timely diagnosis and especially a valid early rule-out of an AMI are crucial already in the emergency department. Amendatory to the established biomarkers, which are released mainly from the heart due to myocardial injury, like cardiac troponins, copeptin has shown diagnostic value. Copeptin is increased by several disease processes besides the cardiovascular system and is therefore a more universal biomarker for severe patients’ physiology22Aside from the fact that AVP and copeptin are usually synthesized in the hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei and released from the neurohypophysis into the circulationth percentile reference limit of 9.8 pmol/l as potential diagnostic threshold in evaluation of suspected AMIWithin the present study, we measured copeptin levels before the transcoronary blood passage in the AO and after the heart in the CVS draining the myocardium. In the patients that did not suffer an AMI we determined copeptin with a mean 8.72 pmol/l (±1.66) in blood taken form the AO and with 8.54 pmol/l (±1.64) in CVS blood resembling non-diseased levels in the same magnitude as published in healthy individuals found with median of 4.3 pmol/l and of 3.2 pmol/l in females and males respectivelyIn line with several recent publications we demonstrate a clear increase of copeptin in patients with AMI1417th percentile 2.5 h, 75th percentile 9 h), quite comparable to the published results, and furthermore no relevant association of copeptin TCG with chest pain onset time was observed in our cohort, this seems not very likely. Moreover, in a human model for myocardial infarction in patients undergoing transcoronary ablation of septal hypertrophy, a significant increase of copeptin was seen as early as 30 min after induction of myocardial infarction lasting for 240–480 minHowever, copeptin and cTnT have different release kinetics after onset of chest pain. Patients with myocardial infarction might even have highest copeptin levels already at the time of admission to the emergency department14One has to acknowledge the aspect, that we measured copeptin as surrogate marker for AVP. Still, given the assumed equimolar release of AVP and copeptin and the preferable preanalytics of copeptin this should not limit the general information on transcoronary release as reported.To conclude, in line with previous reports we found a significant increase of copeptin in patients suffering an AMI supporting the use as diagnostic biomarker. Using a TCG model we could not detect a relevant direct cardiac release of copeptin into the coronary circulation in AMI patients. In summary even if there is an expression of AVP and copeptin in the human heart, the present study indicates that a direct release of copeptin is not detectable from the human heart in acute myocardial infarction.How to cite this article: Boeckel, J.-N. et al. Analyzing the Release of Copeptin from the Heart in Acute Myocardial Infarction Using a Transcoronary Gradient Model. Sci. Rep.6, 20812; doi: 10.1038/srep20812 (2016).


To evaluate diffusion-weighted MR neurography (DW-MRN) for visualizing the brachial plexus and for the assessment of brachial plexopathy.40 oncological patients with symptoms of brachial plexopathy underwent 1.5 T MRI using conventional MR sequences and unidirectional DW-MRN. The images were independently reviewed by two radiologists. Anatomic visualization of the brachial plexus was scored using a 5 point scale on conventional MR sequences and then combined with DW-MRN. A brachial plexus abnormality was also scored using a 5 point scale and inter-observer agreement determined by kappa statistics. Diagnostic accuracy for brachial plexopathy assessed by conventional MRI alone versus conventional MRI combined with DW-MRN was compared by ROC analysis using reference standards.P < 0.001). When assessing brachial plexopathy, inter-observer agreement was moderate for conventional MRI (kappa = 0.48) but good for conventional MRI with DW-MRN (kappa = 0.62). DW-MRN combined with conventional MRI significantly improved diagnostic accuracy in one observer (P < 0.05) but was similar in the other observer.DW-MRN significantly improved visualization of the brachial plexus compared with conventional MRI alone (DW-MRN improved visualization of the brachial plexus. Combining DW-MRN with conventional MRI can improve inter-observer agreement and detection of brachial plexopathy in symptomatic oncological patients. The brachial plexus is a network of nerves formed by the ventral branches of the spinal nerves C5 - T1 in the posterior triangle of the neck, which provides motor and sensory innervation to the upper extremity. The roots of the brachial plexus combine to form three trunks, which in turn divide to form anterior and posterior divisions. At the level of the lateral margin of the first rib, the divisions combine to form the three cords, which in the axilla give rise to the peripheral nerves of the upper limb.Secondary tumours involving the brachial plexus are more common than primary neurogenic tumours. Brachial plexopathy from malignant disease most frequently arises from breast or lung carcinoma ,2. In onConventional MRI has been applied to evaluate the brachial plexus. Most commonly, a combination of fat-suppressed T2-weighted (either frequency selective or short tau inversion recovery (STIR)) sequences and T1-weighted MR sequences are utilized ,5. Howev2) ensure the suppression of unwanted signals from free fluid, fat, muscle and blood vessels. Image acquisition is performed in free breathing, resulting in images with high signal-to-noise for the same acquisition time compared with breath-hold and respiratory triggered acquisitions. This in turn, allows thinner slice acquisitions and multiple-slice excitations for multiplanar reformatting and display [Diffusion-weighted MR neurography (DW-MRN) has emerged as a promising method to visualize the peripheral nerves. The addition of a diffusion-weighted MR sequence to conventional MRI protocol may allow us to overcome some of the inherent disadvantages of conventional MRI ,7. DW-MR display . AlthougIn our department, DW-MRN is used as part of the imaging protocol for the evaluation of brachial plexopathy in the patient with cancer. The purpose of this study was to evaluate DW-MRN for the visualization of the brachial plexus and the added value of DW-MRN to conventional MRI for the assessment of brachial plexopathy.The study was approved by the local research and ethics committee . Patient consent was waived because this was a retrospective review of prospectively acquired data.Forty consecutive patients  with a known history of malignancy and symptoms of a brachial plexopathy were prospectively examined using conventional MRI and DW MRN of the brachial plexus. The inclusion criteria were: a) pathologically proven diagnosis of malignancy  and b) symptoms of brachial plexopathy . The exclusion criteria were any patient with contraindications for MRI or claustrophobia.All patients were examined with a 1.5 tesla MR system  using both a two-channel cervical spine and 16-channel torso phased array body coils. Conventional 2D MR sequences included T1-weighted images in the coronal, axial and parasagittal planes  as well as STIR images in the coronal plane . Axial T2-weighted were also obtained in the axial plane .2). The choice of b-value is optimized for signal-to-noise when assessing white matter. Images were acquired from the level of C3 to T4 in all patients. Image acquisition was performed in the axial plane as direct coronal imaging tends to result in greater image artifacts because of the large field of view required and the difficulty in image shimming over this area. Unidirectional, antero-posterior motion probing gradients were applied as diffusion is relatively more impeded perpendicular to the long axis of the nerves, thus maximizing signal return. The following imaging parameters were applied: TR = 16,000 ms, TE = 69 ms, TI = 180 ms (STIR fat suppression), FOV = 300 cm, Matrix size = 150 × 150, NEX = 20, 2 mm isotropic voxel size, receiver bandwidth = 1450 Hz/pixel. A 40 mm coronal saturation slice was placed several cm anterior to the brachial plexus to suppress signal from soft tissues anterior to the brachial plexus as well as breathing and swallowing motion. The typical acquisition time was 5 minutes 40 seconds minutes.DW-MRN was performed using free-breathing single-shot echo-planar imaging with background body signal suppression, using a single b-value (700 sec/mmThe DW MRN data was post processed on a Siemen’s workstation (VB17 Leonardo). Multi-planar reformatted  and oblique  coronal maximum intensity projection (MIP) images were created and viewed using an inverted black-and-white grey scale. The reconstructed thickness of the MIP images was 40 mm.Images from the symptomatic side were independently reviewed by two radiologists (**BLINDED**) with one year and eight years’ experience in body diffusion MRI, blinded to clinical and other radiological findings.The brachial plexus C5 to T1) of the symptomatic side was systematically evaluated by assessing the: 1) ganglia, 2) roots, 3) trunks and 4) divisions and cords, on the conventional MR images and then again with the combination of conventional MR and DW-MRN .The presence of a brachial plexus abnormality at each of the anatomical region assessed as above was also scored on a 5 point scale , 4 = probably abnormal , 5 = definitely abnormal (diffuse nodular thickening or mass encircling/obscuring the nerves) , follow up CT and MRI imaging , 18 FDG PET-CT (n = 8) and biopsy (n = 3) as the reference standard. For all analyses, a P-value of <0.05 was deemed statistically significant.The inter-observer agreement for the detection of a brachial plexopathy on a per region basis was determined by kappa statistics. The diagnostic accuracy for the presence of a brachial plexopathy using conventional MRI alone versus the combination of conventional MRI and DW-MRN was compared by receiver operating curve characteristics (ROC) analysis using the variance z-test. The reference standard was defined using clinical assessment . This improvement in visualization was seen at all levels of the brachial plexus assessed: neural ganglia (mean score 4.6 vs 2.6), roots (4.7 vs 2.2), trunks (4.3 vs 3.0), divisions and cords (4.2 vs 3.0), with the greatest improvement in visualization of the neural ganglia and nerve roots. The mean scores for the anatomic visualization are summarized in Table The combination of conventional MRI and DW-MRN significantly improved the anatomic visualization of the brachial plexus, compared to conventional MRI alone P < 0.0. This imBy the reference standard, 12 out of the 40 patients had a brachial plexus abnormality . For the assessment of the presence of a brachial plexus abnormality, on a per region basis, the inter-observer agreement was moderate for conventional MRI alone (kappa = 0.48) but good for the combination of conventional MRI and DW-MRN (kappa = 0.62). These scores are summarized in Tables On a per patient basis, by ROC analysis, DW-MRN combined with conventional MRI, significantly improved the diagnostic accuracy for detecting a brachial plexus abnormality in observer one , but was similar for the second observer (AZ =0.96 vs 0.96), These results are summarized in Table Conventional MRI sequences used to evaluate the brachial plexus typically include T1-weighted and fat-suppressed T2-weighted imaging. A major disadvantage of such conventional MRI techniques is their inability to produce MIP images, which aids visualization of the entire course of the neural plexus, due to the relatively unsuppressed signal from adjacent soft tissues . FurtherThe addition of DW-MRN to a conventional MRI protocol can help us overcome these limitations. DW-MRN improves the neural visualization by maximizing the contrast between the nerves and the signal suppressed background tissues. This enables MIP evaluation of the brachial plexus to be performed, allowing the nerves to be appraised over longer trajectories. The inclusion of DW-MRN to a standard MRI protocol does not incur significant time penalty, as the typical acquisition time is approximately 5 to 6 minutes. However, it has been reported even with the use of DW-MRN, visualization of the pre-ganglionic segments of the brachial plexus can still be suboptimal due to the small diameter of these nerves and cerebrospinal fluid flow fluctuations. Furthermore, depiction of the cervical nerves above C5 may also be unreliable because of their smaller diameters .The technique of DW-MRN is adapted from body DW-MRI, which enhances the visualization of the spinal cord and peripheral nerves, due to their fibre orientation and tissue organization. In our study, unidirectional motion probing gradients were placed in the anterior-posterior direction, which is perpendicular to the trajectory of the brachial plexus nerves. This perpendicular positioning offers the highest signal return from the nerves, as diffusion is relatively more impeded perpendicular to the nerve . In a stAn accurate anatomic depiction of the brachial plexus is important for the detection and localization of disease. In this study we showed that the addition of DW-MRN to conventional MRI sequences, improved the anatomic visualization of the brachial plexus. The greatest improvement in neural visualization was in the proximal brachial plexus, including the ganglia and roots; a finding that was also observed by Takahara et al. . This maThe use of DW-MRN together with conventional MRI can improve the detection of brachial plexus abnormality. In our study, an improvement in diagnostic accuracy was seen in one out of the two observers, but was unchanged in the other. Nevertheless, it would appear that DW-MRI can aid the detection of disease along the brachial plexus. Furthermore, the inter-observer agreement for the presence of a brachial plexopathy on a per-region basis was improved when DW-MRN was combined with conventional imaging.There are limitations to our current study. First, only oncological patients were evaluated. Further research should be performed to assess the diagnostic performance of DW-MRN in the detection of other conditions involving the brachial plexus, such as post-traumatic injury and neurogenic tumours. However, similar depiction of the brachial plexus using DW-MRN has been reported in studies involving small numbers of healthy volunteers and in non oncological patients by Yamashita et al. and Takahara et al. ,7. SeconDW-MRN improves the anatomic visualization of the brachial plexus. Using this technique, the conspicuity of the nerves was improved, which enabled MIP evaluation to be performed. Using DW-MRN in conjunction with conventional MRI improved inter-observer agreement for the detection of brachial plexus abnormality and can also improve the diagnostic accuracy in symptomatic oncological patients.


Previous studies evaluating the progression of the necrotic wave in relation to heart rate were carried out only in animal models of ST-elevated myocardial infarction (STEMI). Aim of the study was to investigate changes of myocardial salvage in relation to different heart rates at hospital admission in timely reperfused patients with STEMI by using cardiovascular magnetic resonance (CMR).One hundred-eighty-seven patients with STEMI successfully and timely treated with primary coronary angioplasty underwent CMR five days after hospital admission. According to the heart rate at presentation, patients were subcategorized into 5 quintiles: <55 bpm , 55–64 bpm , 65–74 bpm , 75–84 bpm , ≥85 bpm . Area at risk, infarct size, microvascular obstruction (MVO) and myocardium salvaged index (MSI) were assessed by CMR using standard sequences.Lower heart rates at presentation were associated with a bigger amount of myocardial salvage after reperfusion. MSI progressively decreased as the heart rates increased . Stepwise multivariable analysis showed heart rate, peak troponin and the presence of MVO were independent predictor of myocardial salvage. No changes related to heart rate were observed in relation to area at risk and infarct size.High heart rates registered before performing coronary angioplasty in timely reperfused patients with STEMI are associated with a reduction in salvaged myocardium. In particular, salvaged myocardium significantly reduced when heart rate at presentation is ≥85 bpm. In patients with ST-elevated myocardial infarction (STEMI), timely reperfusion is able to preserve part of the area at risk (AAR) from necrosis granting an amount of myocardial salvage resulting from the difference between AAR and final infarct size (IS). Myocardial salvage can be also modified by different factors, since for a same time of occlusion the quantity of myocardial salvage can be different. It is important to better understand the determinants of progression of necrotic wave  to develOne-hundred eighty seven consecutive patients with first STEMI undergoing PPCI within 6 hours after the onset of symptoms were prospectively enrolled in the study between January 2014 and February 2015. Heart rate was registered in the emergency room before any drug administration and before reperfusion by a caliper on the diagnostic electrocardiogram. Troponin I measurement was also systematically performed at hospital admission, every 3 h for the subsequent 24 h, and then every 12 h for the following 2 days. The CMR study was carried out on day 5 after PPCI. Exclusion criteria were: acute administration of beta-blockers before emergency room admission, atrial fibrillation, unsuccessful PPCI, rescue PCI, facilitated PCI, Killip class III-IV, previous myocardial infarction, previous coronary artery bypass grafting, and contraindications to CMR. Patients with hemodynamic instability at the time of CMR also were excluded. All participants gave written informed consent to the protocol, and the study was approved by the ethical committee of the Department of Cardiology, Policlinico Umberto I, Roma Italy.PPCI and stenting of infarct related artery was performed in all patients according to the clinical protocol used at our institution ,10. ThroCMR studies were performed with a 1.5-T unit Avanto Siemens, Erlangen, Germany. All studies were performed with the use of dedicated cardiac software, phased array surface receiver coil, and ECG triggering. In brief, after determination of cardiac axes with localizers, breath-hold steady state free-precession cine CMR was performed in cardiac vertical and horizontal long-axis orientation and in short-axis orientation. In cardiac short-axis orientation, both ventricles were completely encompassed by a stack of contiguous slices. Next, myocardial edema imaging was performed with the use of breath-hold black-blood T2-weighted, short-inversion time, inversion-recovery, fast spin-echo imaging (T2w imaging) in cardiac short-axis orientation. Finally, a breath-hold T1- weighted, 2-dimensional contrast-enhanced, inversion recovery, segmented gradient-echo sequence was used to depict the presence, location, and extent of IS (LGE imaging) and the concomitant presence of microvascular obstruction. An intravenous contrast agent dose of 0.1 mmol/kg gadolinium-BOPTA  was used. LGE imaging was performed between 10 and 20 minutes after contrast administration. Inversion time was individually adapted to nullify the signal of remote myocardium . Technical details of these sequences are described elsewhere , 14All CMR studies were analyzed off-line by the use of a dedicated workstation  by two experts (MF and IC) who had no knowledge of the patient identity. Conflicts in data interpretation were resolved by consensus. Left ventricular volumes, systolic function, and mass were calculated from the short-axis steady-state free precession cines. Infarcted myocardial mass and microvascular obstruction (MVO) were manually traced and calculated from the LGE short-axis images. As reported in Bondarenko et al. , myocardt test for independent groups was used to assess differences in continuous variables between anterior versus non-anterior infarction, these tests were made without correction for multiple comparisons. Differences were considered statistically significant at a 2-sided p value <0.05. A multivariable logistic regression analysis was conducted considering as dependent variable myocardial salvage index after reperfusion. The median value of MSI detected in our study patients (= 0.41) was used to divide the whole population in two groups (MSI < 0.41 and MSI > 0.41). All variables presenting a significant value >0.25 at univariate analysis were included in the model. The stepwise method with backward elimination was used, and odds ratios (ORs) with 95% CIs were calculated. The model was evaluated with Hosmer and Lemeshow test.Data were analyzed with SPSS software version 20.0 . Continuous variables were calculated as average values considering standard deviation, whereas categorical were calculated as percentages. Differences between means of continuous variables at different times to reperfusion were analyzed by 1-way analysis of variance by the use of a linear trend analysis; a post-hoc analysis with Bonferroni correction was made for differences between groups. The differences between categorical variables were analyzed with the chi-square test of Pearson. A Student S1 Minidataset. Clinical and angiographic data are summarized in The minimal dataset of this study may be found in An infarcted region on LGE images was visualized in 180 out of 187 patients, corresponded to the infarct related artery territory distribution. Mean IS among groups was 17±12% of LV mass. Not significant changes of IS over heart rate were found  ; Fig 1.  LAD infarcts were associated to higher heart rates and they were more frequently found in groups III, IV and V . Notably, when LAD was occluded a higher amount of edematous  and necrotic  myocardium was found. On the opposite, MSI did not significantly change in relation the occlusion site . (The relation between infarct location and heart rate was depicted in  0.672). .In the present study, we described, for the first time in human beings, benefits in terms of myocardial salvage associated with a lower heart rate in patients with successfully reperfused STEMI. Noninvasive myocardial tissue characterization provided by CMR enabled us to differentiate reversible and irreversible myocardial injury  and consequently to determine the presence and extent of salvaged myocardium. Major findings of this study are as follows: 1) Progressive reduction in myocardial salvage is present as heart rate increases during the occlusion-phase 2) Site of the lesion is associated with the extent of the area at risk and infarct size but not related to myocardial salvage. These results were observed irrespective of any other known factors influencing myocardial salvage, such us time to reperfusion , presencwavefront phenomenon”, Reimer and Jennings [Other than defining the “Jennings  were alsJennings . Maroko Jennings  observedJennings  demonstrJennings . On thisJennings  were alsJennings , 27. HeaJennings . Taken aCoherently with observations in animals, in our study we found a constant reduction of myocardial salvage as heart rate, registered at the admission before reperfusion, increased. At multivariate analysis, even when correcting for every known factors influencing myocardial salvage, heart rate remains an independent predictor of myocardial salvage. The result reinforces the hypothesis that high heart rate is able to accelerate the progression of the necrotic wave, facilitating necrosis in ischemic but still viable cells, by exposing them to a higher metabolic demand and to a lower perfusion through collateral circulation. We found no significant changes in IS between the groups. On the other hand, the final infarct extent is influenced by several factors other than the spreading of necrosis within the area at risk. In particular, the extent of the bed of perfusion of the culprit vessel is one of its major determinants, since AAR accounts for 70% of the variability in the extent of myocardial necrosis . AlthougFor the first time CMR allowed us to non-invasively verify in humans these results by measurement of both AAR and IS in vivo, and from their difference the amount of the salvaged myocardium. Notably, these measurements can be obtained in a single exam performed between one to five days after the infarction.Heart rate has been considered for years as an important prognostic factor, being able to predict both all-cause-mortality and cardiovascular mortality , either Even though the number of patients included in this study is quite large, our preliminary data needed to be confirmed by larger multicenter trails aiming to definitively demonstrate the independent role of heart rate on myocardial salvage extent. In particular, the absence of significant differences in MVO extent between groups should be confirmed in a larger population. Time to reperfusion is a stronger determinant of myocardial salvage and of the final extent of infarct size, however in a selected population treated according to the current guidelines (mean time from symptom onset to reperfusion was 152±149 min in our study population), also the basal heart rate has a strong importance. CMR studies were performed from day 4 to 5 after the infarction. A recent experimental study  showed tIn the present study we observed that high heart rates registered before performing coronary angioplasty in timely reperfused patients with STEMI are associated with a reduction in salvaged myocardium. In particular, salvaged myocardium significantly reduced when heart rate at presentation is ≥85 bpm. Possible benefits in therapy able to reduce heart rate in such a clinical setting should be hypothesized.S1 Minidataset(XLSX)Click here for additional data file.