In conclusion, significantly lower cardiovascular mortality rates were observed in CAD patients with intrinsic iron release shown during follow-up.Intrinsic iron release is discussed to have favorable effects in coronary artery disease (CAD). The aim of this study was to evaluate the prognostic relevance of intrinsic iron release in patients with CAD. Intrinsic iron release was based on a definition including hepcidin and soluble transferrin receptor (sTfR). In a cohort of 811 patients with angiographically documented CAD levels of hepcidin and sTfR were measured at baseline. Systemic body iron release was defined as low levels of hepcidin (<24 ng/mL) and high levels of sTfR (≥2 mg/L). A commercially available ELISA (DRG) was used for measurements of serum hepcidin. Serum sTfR was determined by using an automated immunoassay . Cardiovascular mortality was the main outcome measure. The criteria of intrinsic iron release were fulfilled in 32.6% of all patients. Significantly lower cardiovascular mortality rates were observed in CAD patients with systemic iron release. After adjustment for body mass index, smoking status, hypertension, diabetes, dyslipidemia, sex, and age, the hazard ratio for future cardiovascular death was 0.41. After an additional adjustment for surrogates of the size of myocardial necrosis (troponin I), anemia (hemoglobin), and cardiac function and heart failure severity , this association did not change ,  Iron is an essential component for the transport and utilization of oxygen and for appropriate mitochondrial function ,2. In isIntrinsic systemic body iron release is defined as concomitance of low hepcidin and high soluble transferrin levels (sTfR) levels and mirrors a state of maximum bioavailability of iron in the circulation (low hepcidin), as well as increased utilization and high turnover of iron by demanding cells (high sTfR) . Hepcidin is secreted by hepatocytes and orchestrates systemic iron metabolism . Humans,Here, we hypothesized that intrinsic iron release might be beneficial in coronary artery disease (CAD). We report (i) the prevalence of systemic iron release in patients with CAD, (ii) the rate of correlation of hepcidin and sTfR with various clinical and demographic factors, and (iii), its prognostic value in 811 patients with CAD beyond established and emerging cardiovascular risk factors.Between June 1999 and March 2004, 3800 patients who underwent coronary angiography were recruited in the AtheroGene Study at the Department of Medicine II of the Johannes Gutenberg-University Mainz and the Bundeswehr-Zentralkrankenhaus Koblenz ,11. SurgSubjects with acute coronary syndrome (ACS), missing information on the cause of death, or missing information on the clinical presentation were additionally ruled out. This resulted in 2022 patients with stable CAD. Subsequently, subjects with missing samples or low sample volume, and missing laboratory measurements, were additionally excluded. This resulted in 811 subjects to be analysed in the present work. Informed consent was obtained by all patients. AtheroGene is in accordance with the Declaration of Helsinki and obtained approval by the Ethics Board of the Johannes Gutenberg-University Mainz and of the Physicians’ chamber of the State Rhineland-Palatinate (Germany) under the number 837.057.99.Baseline information was obtained using standardized questionnaires and hospital charts. Regarding baseline medication, there was no difference between incident cases and noncases. Diagnosis of CAD was based on stenosis >30% in a major coronary artery revealed by cardiac catherization. Braunwald criteria were used in order to define unstable angina, while diagnosis of acute myocardial infarction (AMI) was based on cardiovascular guideline definitions . All patN = 3274; respective median values). C-Reactive protein (CRP), N-terminal pro B-type natriuretic peptide  troponin I, total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol measurements were done by routine methods in the participating hospitals [At baseline, blood was drawn before angiography in a fasting state under standardized conditions and stored at −80 °C until analysis. Levels of sTfR were measured using an automated immunoassay . The inter and intraassay coefficient of variation was 8.8% and 2.4%, respectively. Serum hepcidin was measured using a newly available immunoassay from DRG . The intospitals –17. All Patient population was described giving baseline characteristics, while the correlation of iron parameters with variables of interest is shown by calculating Spearman correlation coefficients. Hazard ratios for the outcome measure future cardiovascular mortality according to presence and absence of iron release were estimated by Cox regression models adjusted for potential confounders. Two adjusted models were constructed. Model 1 was adjusted for age (years), sex, hypertension, smoking status, diabetes, hyperlipidemia, body mass index (BMI), and model 2 additionally for hemoglobin, log(NT-proBNP), and log(troponin I). p-values below 0.05 were considered statistically significant.Statistics were calculated with R 3.2.3 . All p-vp < 0.001). Interestingly, both iron parameters showed no correlation with hemoglobin .In order to assess the correlation of sTfR and hepcidin with conventional and emerging cardiovascular risk factors, Spearman rank correlation coefficients (R) were calculated and yielded, if at all, moderate correlations . Both irp = 0.076). Remarkably, this association did not change (HR 0.37 (95% CI 0.14–0.99), p = 0.047) after additional adjustment for common confounders of cardiovascular disease as of ((log) troponin), surrogate of systolic heart function ((log) NT-pro BNP), and anaemia ((log) hemoglobin). During a median follow-up of 4.0 years, 27 patients (3.33%) experienced cardiovascular death. In order to assess whether systemic iron release is associated with lower rates of cardiovascular death during follow-up, Cox regression analyses were performed . Hazard In this study, we evaluated the prevalence of intrinsic iron release in patients with CAD and its prognostic relevance regarding future cardiovascular death in the midterm. To our best knowledge, this is the first study to evaluate the impact of intrinsic iron release in cardiovascular disease.We report three major findings: first, almost one third of patients with stable CAD, 32.6%, showed increased intrinsic iron release at baseline. p = 0.63; hepcidin: R = 0.01, p = 0.82). Secondly, correlation between both components of intrinsic iron release with conventional and emerging cardiovascular risk factors were negligible, if significant at all. Accordingly, both iron parameters showed no correlation with hemoglobin ).Thirdly, stable CAD patients with systemic iron release had significantly lower cardiovascular mortality rates, even after adjustment for surrogates of systolic heart function, size of myocardial necrosis, and anemia. Cardiovascular mortality rate over four years was 63% lower in those with intrinsic iron release , a significant decrease in left-ventricular end systolic volume , and in addition a significant decrease in both, endocardial extent, and prevalence of transmural infarctions. These findings were irrespective of an iron deficiency (ID) status.Secondly, the increased availability and turnover of iron, as mirrored by high sTfR levels, seems to be beneficial regarding the course of CAD. Iron is critically involved in the citric acid cycle . It incrOur data show that intrinsic iron release is a wide-spread phenomenon in stable CAD, which is strongly associated with favourable outcome in the mid-term, independent of systolic heart function, size of myocardial necrosis, and anemia. The potential clinical significance of this project is substantial, regarding the fact that CAD remains a leading cause of morbidity and mortality worldwide. Approximately 450,000 people in the United States die from coronary disease per year, and the 2013 overall rate of death attributable to CVD was 222.9 per 100,000 Americans . Based oWithin this multicenter trial, patients with AMI and concomitant ID will be enrolled and randomly assigned to receive intravenous iron  or saline (placebo). For the primary end point (change in left-ventricular ejection fraction from baseline to month 4), all patients will undergo cardiovascular magnetic resonance at baseline and at follow-up.l-type calcium channels. In this report, we assessed systemic iron body iron release which differs from myocardial iron metabolism. Furthermore, we used NT-proBNP as a surrogate for heart function, since routine echo was not applied within the protocol of this study. Moreover, like in most CAD populations, women are clearly underrepresented.The strengths of our study are the high standard of biobanking applied, and the fact that diagnosis of CAD was exclusively based on coronary angiography. Importantly, myocardial iron metabolism is a key component of the cardiac response to injury, especially in ischemic heart disease and involves ferroportin and CAD patients with intrinsic body iron release showed significantly lower cardiovascular mortality rates during midterm follow-up. Meanwhile, this report on the prospective relevance of intrinsic iron release paved the way to the first controlled multicenter trial, randomizing CAD patients for intravenous iron supplementation versus placebo .


The contractile response of patients with heart failure (HF) may be assessed by exercise stress echocardiography (ESE)-derived indexes. We sought to test whether ESE parameters are useful to identify the risk of adverse left ventricular (LV) remodeling in patients with chronic HF and reduced or mildly reduced LV ejection fraction (EF).2. All patients underwent a symptom-limited graded bicycle semi-supine ESE, with evaluation of peak stress LV EF, end-systolic pressure-volume relation  and cardiac power output to LV mass (CPOM). A complete echocardiographic study was performed at baseline and after 6 ± 3 months. Adverse LV remodeling was defined as the association of eccentric LV hypertrophy  with an increase in LV end-systolic volume index ≥10% at six months.We enrolled 155 stabilized patients  with chronic HF, LV EF ≤50% and LV end-diastolic volume index > 75 ml/mp < 0.0001) followed by ischemic aetiology .Adverse LV remodeling was detected in 34 (22%) patients. After adjustment for clinical, biochemical and echocardiographic data, peak ESPVR resulted in the most powerful independent predictor of adverse LV remodeling (OR: 12.5 [95% CI 4.5–33]; In patients with HF and reduced or mildly reduced EF, a compromised ESE-derived peak ESPVR, that reflects impaired LV contractility, resulted to be the most powerful predictor of adverse LV remodeling. In patients with left ventricular (LV) dysfunction and reduced ejection fraction (LVEF), transition to heart failure (HF) is often accompanied by progressive LV dilation and changes in ventricular architecture  and decline in wall thickness-to-cavity radius, which is referred to as relative wall thickness (RWT), resulting in eccentric LV hypertrophy (LVH) . LV remoStress echocardiography, including dobutamine stress and exercise stress echocardiography (ESE), may endow with additional insights for the evaluation of LV performance and the prediction of changes in LV volumes . Evaluat2. The exclusion criteria were: HF secondary to degenerative valvular heart disease, peripheral artery disease limiting the capability of performing exercise stress test and reduced exercise tolerance attributable to myocardial ischemia or advanced HF . Of the 168 patients initially selected for the study, 13 were subsequently excluded: six owing to inability to perform the exercise, six due to poor image quality during the exercise test and one due to the occurrence of a second-degree atrioventricular block during exercise. The study patients were clinically stable and under oral treatment. Beta blockers were withheld at least 48 h before the test.This study included a total of 155 outpatients with HF enrolled between 2013 and 2016 at the Cardiac, Thoracic and Vascular Department, University of Pisa, Pisa, Italy. The inclusion criteria comprised LVEF ≤50% and LV end-diastolic volume index (EDVi) > 75 ml/mAll patients underwent transthoracic two-dimensional and Doppler echocardiographic examination at baseline, during bicycle semi-supine exercise and after follow-up with commercial equipment using 2nd-harmonic imaging and a 3.5-MHz transducer: Acuson Sequoia C256  and iE33 X-matrix.2 (cm2). The LV stroke distance (cm) was measured tracing the outer edge of the densest (or brightest) portion of the spectral aortic tracing recorded from the apical 5-chamber view, with the PW Doppler sample volume positioned about 5 mm proximal to the aortic valve  ≥10% . These vSymptom-limited graded bicycle semi-supine exercise was performed at an initial workload of 20 watts; afterwords, the workload was increased stepwise by 10 watts every two minutes. A 12-lead electrocardiogram and blood pressure (BP) determination were performed at baseline and during the exercise.At baseline and during each exercise level, Doppler-derived cardiac output at LV outflow tract, heart rate and arterial systolic and diastolic BP (by cuff sphygmomanometer) were measured. Mean BP (MBP) was estimated as follows: diastolic BP + 1/3 (systolic BP – diastolic BP). Stroke volume was calculated as stroke distance times LV outflow tract area and cardiac output (CO) as stroke volume times heart rate.2) was measured as the ratio of the LV ESP to the LV ESV indexed for body surface area [The LV end-systolic pressure (ESP) was obtained as 0.9 x systolic BP (mmHg). The ESVPR or LV elastance (mmHg/ml/mace area .1 = 2.22 × 10^-3) with CO (l/min) and MBP (mm Hg). CPOM (W/100 g) was obtained by multiplying CPO by 100 divided by LV mass = K × CO (l/min) × MBP (mmHg) × M− 1 (g); K = 2.22 × 10− 1 [p < 0.0001).LV cardiac power output (CPO) was calculated as the product of a constant . The probability level was p < 0.05 for all the data examined. Data management and analyses were performed using the IBM SPSS Software Package version 17.0.1.Categorical variables were compared using the Chi-square or Fisher test, as appropriate. Logistic regression was used to explore the determinants of LV diastolic dysfunction. All variables showing a Baseline data of the overall patients’ population  and in patients categorised according to the presence of adverse remodeling at follow-up are summarized in Table p < 0.0001), LV ESV decreased from 140 ml (133–147) to 132 ml (123–142) (p = 0.01) and LV mass decreased from 146 (140–151) g/m2 to 139 (134–145) g/m2 (p = 0.006). A normal geometric pattern was observed in 8 patients at baseline and in 13 at follow-up, an eccentric non-hypertrophied pattern was reported in 5 at baseline and in 11 at follow-up, a non-eccentric LVH was apparent in 82 at baseline and in 79 at follow-up, while eccentric LVH was present in 60 at baseline and in 52 at follow-up.Adverse LV remodeling was reported in 34 (22%) of the study patients at follow-up. Figure Sixty-four of patients exhibited a > 10% reduction in ESVi. Among study patients, 6 underwent percutaneous or surgical correction of functional mitral regurgitation, 3 were submitted to cardiac resynchronization therapy, 2 underwent coronary percutaneous angioplasty and one was revascularized by coronary artery bypass grafting.Patients with adverse remodeling were prevalently male, presented more advanced NYHA functional class, higher rates of renal dysfunction and moderate to severe mitral regurgitation. Moreover, this group showed higher BNP levels, greater resting and exercise LV volumes, greater LV mass, increased E/e’ratio and more compromised resting and exercise LV EF, peak CPOM and ESPVR.p = < 0.0001), followed by ischemic etiology .Univariate and multivariate predictors of adverse LV remodeling are presented in Table In the present study, conducted in a population of 155 outpatients with HF and reduced or mildly reduced LV EF, we demonstrated that a compromised LV contractility, as reflected by a blunted ESPVR in response to ESE testing, independently predicted adverse LV remodeling as defined by an increased LV mass, RWT < 0.32 and a ≥ 10% increase in LV ESVi.LV remodeling is usually the result of a progressive process that starts with myocardial damage or excessive LV overload and is very often characterised by the slowly progressive increment of LV volume, increased LV mass and reduced RWT. Since LV overload is initially matched by an adequate growth of cardiac myocytes, the chamber radius is increased, and the wall thickness is increased moderately. To some extent, the initial remodeling may be considered beneficial as the stroke volume may be preserved by augmenting cavity size, but, when the left ventricle further dilates, this adaptive mechanism may progress toward maladaptive remodeling and maladaptive (high-stress) LVH –22.The concept that the occurrence of pathological LVH and LV remodeling in patients with LV overload forms a continuum from a compensatory phase to the stage in which exhaustion and myocardial failure prevail is consistent with the work of Meerson . The firThe importance of changes in LV shape and volume over time has been addressed in some studies. In 1987, White et al.  observedIn an attempt to provide a comprehensive classification, a new categorization capable of including virtually all LV remodeling patterns based on LV volume, mass index and RWT has been proposed , 28. TheThe combination of increased LV mass with the development of eccentric LVH is directly related to deterioration of LV performance. It has been demonstrated that the inability of hypertrophy to keep pace with an abnormally high ventricular wall stress may be responsible for depressed LV function . We hypoIn our study, the results of the ESE testing showed that LV contractility, that is the intrinsic ability of the myocardium to generate force and to shorten independently of changes in loading conditions (afterload and preload), as assessed by the evaluation of echo-derived ESPVR (LV elastance) in response to exercise, can predict subsequent development of adverse LV remodeling. The prognostic value of echo-derived ESVPR at increasing heart rate has been widely demonstrated with either ESE or pharmacological stress echo –32, but,The transition from a compensated stage of hypertrophy to adverse LV remodeling could be related to the mechanisms by which the inotropic reserve decreases from the initial compensatory phase, albeit the presence of LV dysfunction, to the final stage of exhaustion and progressive deterioration . This foThe most important study limitation was the reproducibility of LV metrics. As it has been recently pointed out , the magA compromised ESE-derived peak ESPVR, that reflects impaired LV contractility, resulted to be the most powerful predictor of adverse LV remodeling, defined on the basis of LV volumes and RWT, in patients with HF with reduced or mildly reduced LVEF.


The aim of this retrospective study was to evaluate the relationship between right ventricular function derived from cardiac magnetic resonance imaging (CMR), echocardiography and exercise stress test performance, NT-proBNP  level and NYHA class in patients with a systemic right ventricle.All patients with congenitally corrected transposition of the great arteries (ccTGA), or transposition of the great arteries after Mustard or Senning procedures, (TGA) followed at our centre who had undergone CMR, echocardiography, an exercise stress test and blood sampling, were included in the study.We examined 11 patients  who have a median age of 32 years (22-67 years). A significant correlation was observed between the systemic ventricular function, expressed as the CMR-derived right ventricular ejection fraction and the right ventricular global longitudinal strain .We have demonstrated that in patients with ccTGA or TGA right ventricular global longitudinal strain may be useful in the evaluation of the systemic right ventricular function. Before the arterial switch operation was introduced in 1975, patients with transposition of the great arteries (TGA) were treated with the Mustard or Senning procedure, also referred to as atrial switch operation . In congAssessment of the systemic right ventricular function by echocardiography is sometimes complicated, and cardiac magnetic resonance imaging (CMR) is the optimal method. However, it is not possible to use magnetic resonance imaging to examine patients who have a pacemaker, or who suffer from claustrophobia. CMR is also expensive, and availability may be limited. Assessment of the systemic right ventricular function using alternative methods is therefore of interest.Two-dimensional speckle tracking echocardiography has been used to assess systemic right ventricle function, although experience is limited. Previous studies have shown correlations between systemic right ventricular function and right ventricular global longitudinal strain (GLS), where GLS predicted adverse clinical outcome in patients with TGA –6 and ccThe records of all patients with TGA or ccTGA at Skåne University Hospital were obtained from a national registry, “SWEDish registry on CONgenital heart disease” (SWEDCON), which contains information on patients with congenital heart defects and who have undergone heart surgery. The study was approved by the Ethics Review Board in Lund. The selection criteria were: 1) patients with cardiac MRI data, 2) data from other parameters to be collected within the time span of one year, 3) adequate echocardiographic image quality, and 4) patients had reached their teens at time of data collection. Data on NT-proBNP level (ng/L), NYHA class (I-IV), exercise test performance, and the results of CMR and transthoracic echocardiographic loop examination were collected from the patients’ medical records and the SWEDCON database.All laboratory analysis was carried out at the laboratory of the University Hospital in Lund, using the commercial version of the NT-proBNP ElectroChemiLuminiscence Immunoassay (ECLIA). The lowest detection limit for NT-proBNP was 5 ng/L and the highest detection limit 35 000 ng/L. The coefficient of variability was 5% at 177 ng/L, and 4% at 2100 ng/L.http://segment.heiberg.se) [The parameters measured with echocardiographic loops were: 1) global longitudinal strain (GLS) (%), 2) tricuspid annular plane systolic excursion (TAPSE) (mm), 3) fractional area change (FAC) (%), 4) apical 4 chamber strain (AP4) (%) and 5) short-axis transection strain (SAX) (%). Echocardiographic loop analysis was performed by one cardiologist with experience in echocardiographic examination of grown-ups with congenital heart disease. The venous left ventricular function (LVEF) was measured with echocardiography. The systemic right ventricular function (RVEF) and venous LVEF were derived using CMR. The RVEF (%) was used for assessment of the ventricular function. All patients were examined with CMR in Lund at rest in supine position and during end-expiratory breath hold. A 1.5 T CMR scanner was used for all studies . Images were acquired using sequences with identical temporal and spatial resolution at both field strengths –13. All berg.se) .Performance during the exercise stress test was expressed as maximum heart rate , maximum working capacity (W) and expected maximum working capacity (%). Exercise testing was performed Monark 939E cycle ergometer and Oxygen Pro . Blood pressure and a 12 lead ECG were monitored during exercise. Continuous data are presented as the median and range. NT-proBNP were not normally distributed and therefore log transformed. The relationship between the systemic RVEF derived from CMR, and exercise test results, logNT-proBNP, and echocardiographic parameters  was evaluated using the Pearson correlation coefficient. The relationship between NYHA class and the systemic RVEF, exercise test results, logNT-proBNP, and echocardiographic parameters  was evaluated using the Spearman correlation coefficient. The statistical significance was set at p < 0.05. Analysis was performed using IBM SPSS Version 24.A total of 11 patients were eligible for inclusion: seven who had undergone atrial switch operation and four with ccTGA. The patient characteristics and measured parameters are given in Table none in the other classes. The venous LVEF derived from echocardiography was 41 % (34-47%) in patients who had undergone atrial switch operation and 40% (27-40%) in ccTGA patients. The RVEF derived from CMR was 44% (32-60%) in patients who had undergone atrial switch operation and 48% (23-60%) in ccTGA patients (Table The median age of the patients with ccTGA was 35 years (25-67 years), and that of the patients undergoing atrial switch operation was 30 years (13-37 years) . In contrast to the findings of Lipczynska et al., we did not find a significant correlation between systemic right ventricular systolic function and the right ventricular FAC. This could be due to our smaller study population. It has been suggested that systemic right ventricular GLS could be used instead of right ventricular FAC in patients with systemic right ventricular dysfunction as it has been found to have a higher predictive value, better measurement-remeasurement reproducibility, and can predict adverse clinical outcomes as morbidity and mortality [A correlation between CMR-derived right ventricular function and right ventricular GLS has been described previously by Lipczynska et al . In thei r= -0.62. In contThe relationship between right ventricular function and NT-proBNP has been reported in previous studies. Plymen et al. reported a statistically significant correlation between CMR-derived RVEF and NT-proBNP in patients after atrial switch operation  . KotaskaNo significant relationship was found between the CMR-derived RVEF and any of the exercise test parameters. Reduced exercise capacity in patients after atrial switch operation has been reported in several studies –19. PrevThis study is limited by the small study population. Also, the time between the dates of examination varied.This study has shown that right ventricular GLS measured with echocardiography may be useful in the evaluation of systemic right ventricular function.


To investigate the association between unrecognized myocardial infarction (UMI) assessed with cardiac magnetic resonance (CMR) and coronary artery calcium (CAC) and cardiovascular risk prediction scores in asymptomatic Asian subjects.Total 872 asymptomatic subjects without prior cardiovascular event  who underwent both CMR and CAC scoring CT were included. UMI were accessed and framingham risk score (FRS) and ASCVD (atherosclerotic cardiovascular disease) risk score by ACC/AHA were calculated.p < .001, p = .011 and p = .024, respectively). The prevalence of UMI differed significantly according to the CAC scores as follows: 1% in CAC = 0 (4/403), 1% in 1 ≤ CAC <100 (2/293), 6.1% in 100 ≤ CAC < 400 (7/114) and 14.5% in CAC ≥ 400 (9/62), respectively (p < .001). Receiver operating characteristics (ROC) analysis by using CAC score demonstrated an area under the curve (AUC) of 0.816 , 0.780–0.848; p < .0001) for predicting UMI, which is superior to FRS  and ASCVD risk score .Late gadolinium enhancement indicating UMI was noted in 23 of 872 subjects (2.64%), but only three of them showed ECG abnormality (13.04%). Subjects with UMI showed higher CAC scores, FRS, and ASCVD scores than those without UMI (The prevalence of UMI increases with increasing burden of CAC and FRS. CAC score is a good discriminator for UMI, superior to FRS and ASCVD score, in asymptomatic population. Introduction of late gadolinium enhancement (LGE) images on cardiac magnetic resonance (CMR) allows accurate detection of myocardial infarctions (MIs) and other myocardial scars. With advances of LGE imaging technique, the detection rate of clinically unrecognized MIs (UMIs) has increased. Earlier studies demonstrated that CMR depicts significantly larger number of UMIs than has previously been estimated by electrocardiography (ECG).–3Until now, many researchers have sought for the clinical implication of UMIs detected on the CMR. Various population studies have been performed in Sweden, Iceland, Scotland and US to document the prevalence and clinical impact of myocardial scars and UMIs.,3–6 StudThe prevalence of UMIs has been described varying 7.8~25%.–3,8,9 HoThe institutional review board of Samsung medical center approved the study (IRB-2018-05-187), and informed consent was waived for the use of patients’ medical and imaging data.We identified 1270 asymptomatic subjects over 40 years of age who underwent both CMR and coronary artery calcium scoring CT for a health checkup at the Health Promotion Center of Samsung Medical Center between September 2009 and October 2016. Among them, 465 patients were excluded for the following reasons: 1) history of percutaneous transluminal coronary angioplasty due to obstructive CAD (n = 5), 2) nonischemic cardiomyopathy such as hypertrophic cardiomyopathy confirmed on CMR (n = 8), and 3) Interval between acquisition of CMR and CAC scoring CT longer than a year (n = 452). Through medical chart review, we confirmed that none of the study population had visited hospital or medicated for chest pain or chest discomfort in the past. In addition, none had previous history of cardiac operation or diagnosed with congenital heart disease or other nonischemic cardiomyopathy. Sixty-seven patients whose CAC score was 0, which was obtained more than a year after CMR acquisition, were additionally included, under the assumption that their CAC score was 0 at the time of CMR acquisition. Finally, a total of 872 self-referred asymptomatic subjects  were included in our study .The clinical information and laboratory results were obtained from chart review. Cardiovascular risk scores were calculated in 519 of 872 subjects, as full medication history of 353 subjects was not available due to insufficient medical records. Ten-year risk of cardiovascular event was calculated based on FRS, and subjects were classified into low risk (10% or less risk at 10 years), intermediate risk (10–20%) and high risk (20% or more). ASCVD riAll subjects underwent CMR in a 1.5-T scanner  with a 32-channel phased-array receiver coil. CMR scans consisted of localizing images , cine scans , and LGE scans. LGE imaging was acquired using a phase-sensitive inversion recovery (PSIR) technique 15 min after injection of 0.2 mmol/kg gadobutrol  at an injection rate of 3 ml/sec, followed by a 30-ml saline flush. Contiguous short-axis image acquisition of 10–12 slices at 6 mm thickness and a 4-mm interslice gap was used. Inversion delay times were typically 280–360 msec. Detailed CMR protocol has been described elsewhere.All CT scans were performed using a 64-slice scanner system  and a 40-slice scanner system . Tube voltage was 120 kVp and tube current was 125 mA. Step and shoot mode was used with prospectively ECG triggered to 75% of the R-R interval in subjects with a heart rate (HR) at most 65 beats per minute (bpm) and 45% of the R-R interval in subjects with a HR faster than 65 bpm. Imaging was reconstructed into a 2.5-mm slice thickness with a 512 X 512 matrix and a 25-cm field-of-view. No premedication with nitrate or beta-blocker was administered. CAC score analysis was performed using dedicated software  and CAC scores were subsequently calculated using the methods described by Agatston et al.. Then, suCMR data were analyzed using a commercially available dedicated software tool  by an experienced MR technician , who was blinded to the clinical information of the participants. Parameters such as left ventricular (LV) end-diastolic volume, LV end-systolic volume, LV ejection fraction, LV mass, and stroke volume (SV) were obtained by drawing LV contours at the end of diastole and systole. Papillary muscles and trabeculation were included in the LV cavity for volume and mass measurements. Cardiac output was calculated as the product of SV and HR. The LV mass index (LVMI) and cardiac index were calculated as LV mass and cardiac output divided by the body surface area, respectively.Analysis of the LGE sequences was performed by use of picture archiving and communication system . The presence of LGE was interpreted by the consensus of two observers  blinded to patient history. High signal-intensity lesion with subendocardial or transmural involvement, located in territories consistent of specific epicardial coronary arteries, on LGE images were considered to represent UMIs . The locp values less than 0.05 were considered statistically significant. The confidence level and cutoff value of each variable was analyzed with use of the receiver operating characteristic (ROC) method. Statistical analysis was executed using SAS version 9.4 .Continuous data were expressed as mean and standard deviation, and all categorical data were presented as proportions. Student’s t-test and one-way ANOVA were used to test for differences in normally distributed continuous variables, and the Wilcoxon rank sum test, Mann-whitney test, and Kruskal-Wallis test were used for comparison involving variables that were not normally distributed. The Jonckheere-Terpstra test was used to report the association of variables according to the groups classified with CAC score and FRS. Categorical variables were compared with the chi-square test or Fisher’s exact test, as appropriate. A two-tailed p = .006), and all three of them showed transmural extent of infarction of over 75%. The coronary territories of UMIs were as follows: 11 patients with left anterior descending artery (LAD)-territory, two patients with left circumflex coronary artery (LCX)-territory, five patients with right coronary artery (RCA)-territory, one patient with LAD+LCX-territories, two patients with LAD+RCA-territories, and two patients with LAD+LCx+RCA-territories.Among 872 subjects, LGE indicating UMI was noted in 23 patients (2.64%). In terms of elderly population, the prevalence of UMI was elevated to 3.74% (4/107) for subjects older than 60 and 4.55% (2/44) for those older than 65. Only three of 23 patients showed ECG abnormality , with a sensitivity of 13.04% for detecting MI. Among 23 patients with UMI, 15 showed focal MI involving only one segment, whereas remaining eight patients showed MI involving multiple segments, ranging from three to 10 segments. In terms of three patients who showed ECG abnormality, the infarcted myocardial territory was significantly larger than those without ECG abnormality , atypical pattern LGE, not typical for MI, showing nonspecific epicardial or mid-wall LGE without relation to a coronary territory on CMR was noted . The mosIn terms of CMR parameters such as LV function, reduced LVEF below 55% (asymptomatic mild LV dysfunction) was observed in 20 of 872 (2.3%) subjects, with a range from 45.7% to 54.8%. However, only one of them had UMI and none of them showed atypical LGE.p < .001 and p = .030, respectively). In addition, CAC score was significantly higher in subjects with UMI (p < .001). In terms of LV parameters on CMR, however, LV function and myocardial mass did not differ significantly between the two groups.The baseline characteristics and CMR parameters of the patients with and without UMI are summarized in p = .011]. However, there was no significant difference in CMR parameters such as LV function and LV mass. When we compared transmural (n = 4) and non-transmural (n = 19) infractions among UMI patients, LVEF was significantly reduced in those with transmural UMI . When we compared CAC scores of each coronary artery according to the presence or absence of UMI, significant difference in LAD calcium score was noted between those with (n = 16) and without (n = 7) LAD-territorial infarction. LAD calcium score of patients with LAD-territorial infarction was significantly higher than those without it . In terms of those with UMI of LCX and RCA territories, however, no significant difference in CAC scores of LCX  and RCA  was observed.In the comparison between one-segment (n = 15) and multi-segment UMI (n = 8), CAC score was significantly higher in multi-segment UMI group  with a cutoff value of 79, 0.712  with a cutoff value of 15.8 and 0.689  with a cutoff value of 17.2, respectively.The ROC curve by using CAC score in 872 subjects demonstrated an area under the ROC curve (AUC) of 0.795 , 0.766–0.821; p = .723) and 0.526  without statistical significance for predicting UMI. However, the AUC for CAC score was 0.780  with a cutoff value of 77, showing a sensitivity of 83.3% and a specificity of 75.3%.As CAC scoring CT is generally indicated for intermediate-risk subjects according to the 2010 guideline for the appropriate use of cardiac CT [In this study, we have demonstrated that CAC score is a good discriminator for UMI, superior to FRS and ASCVD risk scores, in asymptomatic Asian cohort. Furthermore, our ROC analyses suggest a potential role of CAC score as a predictor of UMI in those with intermediate risk of cardiovascular disease, as indicated in the 2010 guideline by ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR.,22 In adOne of unique result of our study is that subjects with UMI did not show any functional degradation, such as LVEF and cardiac index, compared with those without UMI. Many of prior studies, on the contrary, have stated a prognostic implication of UMI, demonstrating impaired LV function and increased myocardial mass in those with UMI compared with normal groups.,6,8,24 OCMR is a valuable modality in the detection of UMI. Prior studies have shown that CMR can detect UMIs with a higher sensitivity, specificity and reproducibility than ECG.,25 IndeeIn this study, the prevalence of UMIs in asymptomatic Asian subjects was 2.3%. This is far lower rate of UMI compared with Sweden and Iceland cohorts, described a prevalence of 30% and 16.8%, respectively.,26 Main Atypical LGE, not typical MI, was noted in 12 of 872 patients, and the most common finding was linear mid-wall enhancement. These atypical LGE is known to be seen in infiltrative myocardial disease or myocarditis, however, there was no significant difference in baseline characteristics and CMR parameters between those with atypical LGE and normal group in our study. AlthoughThere are several limitations in our study. First, our study was limited inherently by its retrospective design. Second, our study was performed at a single health promotion center of tertiary referral hospital. All of the subjects in our study were self-referred for a routine health check-up, who were predominantly male, and therefore, selection bias may limit the generalizability to other populations. Third, cardiovascular risk scores such as FRS and ASCVD score were available only in 519 of 872 subjects due to lack of medication history of hypertension. Fourth, the prevalence of UMI was low, resulting in small sample size and limited power for analysis. However, we tried to identify the incidence of UMI among asymptomatic Asian population in this study. Fifth, tiny high signal intensity might be missed if placed in between two consecutive slices of LGE imaging, which can underestimated the prevalence of UMI.In conclusion, our study demonstrated that the prevalence of UMI increases with increasing burden of CAC and increasing risk of 10-year cardiovascular disease on FRS. CAC score is a good discriminator for UMI, superior to FRS and ASCVD risk scores, in asymptomatic Asian population, especially for those with intermediate risk of cardiovascular disease, as indicated in 2010 guideline for cardiac CT. Furthermore, subjects with UMI did not show any LV functional impairment compared with those without UMI in our study, thus, further study to figure out the final consequences of UMI in general population, regarding cardiac function and prognosis, can be a next step.


The technique was validated against conventional methods in phantom and 9 healthy subjects.The free‐running sequence is inversion recovery (IR)‐prepared followed by continuous 3D golden angle radial data acquisition. 1D respiratory motion signal is extracted from the k‐space center of all spokes and used to bin the k‐space data into different respiratory states, enabling estimation and correction of 3D translational respiratory motion, whereas cardiac motion is recorded using electrocardiography and synchronized with data acquisition. 3D translational respiratory motion compensated T2 = 0.99) of T1 estimation with reference method. Homogeneous systolic and diastolic 3D T1 maps were reconstructed from the proposed technique. Diastolic septal T1 estimated with the proposed method (1140 ± 36 ms) was comparable to the saturation recovery single‐shot acquisition (SASHA) sequence (1153 ± 49 ms), but was higher than the modified Look‐Locker inversion recovery (MOLLI) sequence (1037 ± 33 ms). Precision of the proposed method (42 ± 8 ms) was comparable to MOLLI (41 ± 7 ms) and improved with respect to SASHA (87 ± 19 ms).Phantom results demonstrated good agreement (R1 mapping method allows for reconstruction of isotropic resolution 3D T1 maps at different cardiac phases, serving as a promising tool for whole heart myocardial tissue characterization.The proposed free‐running whole heart T They acquire multiple images with different T1 contrasts and estimate pixel‐wise T1 by fitting the acquired signal to an exponential recovery model. Respiratory and cardiac motion may result in blurring artefacts in each T1‐weighted image and can cause misalignment between different images, influencing the T1 mapping accuracy.1 estimation.The modified Look‐Locker inversion recovery (MOLLI)1 and T2 imaging without breath‐holding or ECG triggering.1 mapping is technically challenging, because respiratory gating and ECG‐triggering together with the requirement of whole heart coverage, may lead to very long scan time. To cover the whole heart in an acceptable scan duration, current 3D T1 mapping techniquesRecently, the magnetic resonance multitasking technique using 2D radial acquisition has been proposed for motion‐resolved quantitative myocardial T1 mapping, we propose a free‐running  3D whole heart T1 mapping technique with high isotropic spatial resolution (1.5 mm3), which is able to provide images in any desired orientation. The proposed sequence consists of an inversion recovery (IR)‐prepulse, followed by an efficient 3D golden angle radial acquisition1 relaxation curve. The k‐space center is repeatedly sampled within each spoke and used to estimate 1D respiratory motion. ECG signal is recorded and synchronized with data acquisition. Respiratory binning is performed based on the estimated 1D respiratory signal, enabling estimation and correction of 3D translational respiratory motion. For the reconstruction, a recently proposed algorithm that combines dictionary‐based low‐rank inversion1 mapping at different cardiac phases. The feasibility, accuracy and precision of the proposed technique was validated against conventional T1 mapping methods in a standardized T1 phantom and 9 healthy subjects.To address the current technical challenges of myocardial T22.11 contrast, after which a spoiled gradient‐echo (SPGR) readout is performed with small flip angle (θ). Spatial‐spectral pulse for selective water excitation is adopted for fat suppression. To achieve pseudo‐uniform distribution of radial spokes for retrospective cardiac and respiratory binning, the continuously acquired radial spokes conform to the 3D golden angle distribution.ϕ1 = 0.4656, ϕ2 = 0.6823 are the 2D golden angle means.The proposed IR‐prepared 3D radial sequence is shown in Figure 2.21 mapping of a given cardiac phase is shown in Figure The flowchart of retrospective processing, including motion extraction, respiratory motion correction and data sorting for T1 mapping at a given cardiac phase.After retrospective respiratory binning and cardiac gating, 3D translational respiratory motion is estimated via registration from the intermediate reconstruction of low‐resolution respiratory bin images at diastolic cardiac phase by using central part of selected k‐space data. Representative diastolic bin images of 5 respiratory motion states and the difference images with the end‐expiratory bin are shown in Figure 2.32.3.11 mapping at a given cardiac phase, spokes for the corresponding cardiac delay and acquisition window are selected, which are then sorted into a time series of T1 contrasts according to TI and a given temporal window for each T1 frame. After data selection, the highly undersampled 3D radial data is reconstructed over multiple T1 contrasts by combining a dictionary‐based low‐rank inversion1 contrasts to be reconstructed with a recently proposed high‐dimensionality 3D patch‐based undersampled reconstruction (HD‐PROST), exploiting local (within a patch), non‐local (between similar patches), and contrast redundancies.F and ||·||* denote the Frobenius norm and nuclear norm respectively; I is the compressed T1 image series to be reconstructed; E=DAUrFS is the encoding operator, with S being sensitivity maps, F being Fourier transform, rU being the low‐rank operator obtained by truncating the singular value decomposition (SVD) of a dictionary generated by Bloch simulation,A being the convolutional gridding operator, transforming Cartesian data back to 3D radial, and D being the non‐Cartesian density compensation function; K is the undersampled data; pP(·) is the patch selection operator at pixel p of a 3D multi‐contrast image set. This operator selects patches on local (patch for a given pixel location and contrast), non‐local (similar patches within a neighborhood for a given contrast) and contrast  scales and Tp is a 3D tensor built by the selected patches centered at pixel p; T represents the denoised multi‐contrast images constructed by folding and aggregating the tensors Tp for each pixel p (see the step 2 below); Y is the Augmented Lagrangian multiplier; λ is the sparsity‐promoting regularization parameter and µ is the penalty parameter. Equation For 3D Tndancies.LI,T,Y=EIStep 1: joint reconstruction updateI by incorporating the denoised multi‐contrast images T obtained at the end of step 2 as prior informationThe first step is a joint reconstruction of the compressed TI image series  Step 2: high‐order singular value decomposition based denoisingThe above equation can be efficiently solved using the conjugate gradient (CG) algorithm.I and Y from step 1 and step 3 separately, the second step is to minimize the following equation regarding to the high order tensor TpWith obtained Tp is obtained by thresholding the singular values obtained via high‐order singular value decomposition of the 3D tensor built by the patches selected from the multi‐contrast images. The thresholding parameter is defined by λμ. The denoised Tp is then rearranged to form the denoised image patches. This process is repeated for all the pixels in the singular images, and aggregation is then performed to generate the final denoised singular images T.Step 3: Lagrangian multiplier updateThe details to solve the above equation can be found in Bustin et al.I and T from step 1 and step 2, the Lagrangian multiplier is updated by Y = Y + I − T. The above 3 steps are iteratively interleaved in the reconstruction process to improve the reconstructed image quality.Finally, with the optimized 2.3.23, spatial resolution = 1.5 × 1.5 × 1.5 mm3, TR/TE = 11.6 ms/5.1 ms, flip angle = 6°, IRTR = 2200 ms, number of readouts after IR = 175, gapT = 9.5 ms , exT = 160.5 ms, scan duration = 9.5 min.The sequence was implemented on a 1.5 T MRI scanner  for cardiac imaging. The following scan parameters were used for both phantom and in vivo experiments: FOV = 200 × 200 × 200 mm1 frame was also set to 186 ms, resulting in 10 T1 frames to be reconstructed. A dictionary‐based low‐rank compression1 contrast dimension to further reduce the number of T1 frames to be reconstructed  was set to 15, and the regularization parameter µ, balancing the contribution of the prior term, was empirically set to 0.01. Coil sensitivity maps were estimated by using spokes of TI larger than 1000 ms and reconstructed in low resolution by using only the central half of k‐space to reduce noise. The regularization parameter λ of HD‐PROST was optimized by visual inspection of the reconstruction quality on 1 subject and used for all other data set. For the patch‐based denoising step in HD‐PROST,2.41 mapping accuracy of the 3D T1 mapping sequence, a standardized T1 phantom1 values ranging from ~250–1600 ms was imaged using a 28‐channel cardiac coil. To obtain reference T1 values of the phantom for validation, a 2D inversion recovery spin echo (IR‐SE) sequence was performed with the following imaging parameters: FOV = 140 × 140 mm2, in‐plane spatial resolution = 1.5 × 1.5 mm2, slice thickness = 8 mm, TR/TE = 10,000/5.8 ms, 13 TIs = 50, 100, 200, 300, 400, 500, 700, 900, 1200, 1500, 2000, 2500, and 3000 ms. Standard T1 values were determined by a 3‐parameter non‐linear least square fitting algorithm.To test the T1 mapping sequence, the ECG signal used for the retrospective binning was generated by physiological simulation with heart rate varying between 50 bpm and 70 bpm during the acquisition. The acquired 3D radial data was retrospectively binned into 10 T1 contrasts for a simulated diastolic phase with cardiac delay of 650 ms. The phantom T1 map acquired with the 3D imaging sequence was generated using the HD‐PROST reconstruction as explained above.For the proposed 3D radial T2.51 mapping reference consisted of the clinically adopted breath‐hold 2D MOLLI (3‐3‐5)2, in‐plane resolution = 2 × 2 mm2, and slice thickness = 8.0 mm. The SASHA sequence was performed with TR/TE = 2.6/1.3 ms, flip angle = 70°, and the same FOV and spatial resolution as used for MOLLI. Parallel imaging with SENSE acceleration factor of 2 in the phase‐encoding direction was used in the 2D MOLLI and SASHA mapping acquisitions, resulting in a mid‐diastolic acquisition window of ~187 ms. MOLLI and SASHA images were acquired in the same short‐axis location as the cine scan and reconstructed to an in‐plane resolution of 1.5 × 1.5 mm2. The 2D T1 maps for MOLLI and SASHA were obtained by fitting the corresponding standard 3‐parameter models.The study was approved by the local institutional review board and 9 healthy subjects  were imaged using a 28‐channel cardiac coil. All volunteers provided written informed consent before inclusion into this study. First, standard breath‐hold 2D cine images were acquired in the mid ventricular short‐axis view with retrospective gating to 16 cardiac phases, based on which the cardiac delays for systole and diastole were determined. The T1 mapping sequence was also acquired in short‐axis orientation covering the entire heart and centered around the slice location of the 2D MOLLI and SASHA scans. Besides diastole, T1 mapping was also reconstructed for systole using the proposed framework, considering that systolic T1 maps may find applications in patients with thin myocardium or arrhythmias.The proposed free‐running 3D T2.61 values were calculated for each vial. The accuracy of the proposed 3D T1 mapping technique was evaluated by comparing the estimated T1 values to the 2D IR‐SE method using Pearson's linear correlation and Bland‐Altman analyses.For phantom data, circular region‐of‐interests (ROIs) were drawn for each vial and the mean and SD of T1 map in the mid short‐axis view that was most similar to the MOLLI and SASHA geometry was selected from the 3D T1 maps of the proposed approach for each subject. Septal ROIs with the same size were drawn for the 3 T1 mapping methods. The mean and SD of T1 values in the septum were measured and compared between the proposed 3D method and 2D MOLLI and SASHA separately using the Wilcoxon rank‐sum test with Bonferroni correction to evaluate the in vivo accuracy and precision.For the analysis of in vivo images, the diastolic T1 maps, 3 slices from base, mid to apex were selected from the diastolic and systolic T1 maps. T1 values of the myocardium were measured according to the myocardial segments model defined by the American Heart Association (AHA),1 values were calculated for all segments to evaluate the spatial T1 distribution of the proposed method. The T1 value in each segment was compared between diastole and systole using the paired t‐test. Then the diastolic and systolic T1 values for each segment were determined by averaging across all the volunteers and visualized with bull's‐eye plots.For the analysis of 3D in vivo TP‐value of <0.05 was considered statistically significant.All image reconstruction and analysis were performed using MATLAB  on a server with a dual 16‐core CPU and 256 GB RAM. Statistical analysis was carried out in GraphPad Prism 7 . A 33.11 maps with the proposed approach and 2D IR‐SE are shown in Figure 1 values of all vials are shown in Figure 1 estimations between the proposed 3D technique and the 2D IR‐SE reference (R = 0.99). Bland‐Altman plot demonstrates no correlation between the difference and average of T1 measurements of the 2 methods  (P = 0.68), but is higher than that of MOLLI (1037 ± 33 ms) ( P < 0.01). The SD, indicating the precision of septal T1 measurements, was 42 ± 8 ms with the proposed approach, which is much lower than the SD of SASHA (87 ± 19 ms) (P < 0.01) and similar to that of MOLLI (41 ± 7 ms) (P = 0.79).Diastolic T1 maps from 2 subjects are shown in Figure 1 maps also demonstrated a uniform T1 distribution with thicker myocardium compared with diastole. The diastolic and systolic T1 values of each AHA segment are shown in the bull's‐eye and box plots in Figure 1 values in diastole and systole for all myocardium segments are summarized in Table 1 values estimated with the proposed technique in most of the AHA segments, except for the inferior segments in the apical and mid ventricular slices, and the inferoseptal segment in the basal slice, with significantly longer T1 values in diastole than in systole.Representative systolic and diastolic T41 mapping with 1.5 mm3 isotropic spatial resolution has been successfully achieved with predictable 9.5 min scan time. The proposed sequence features free‐breathing, retrospective cardiac gating and continuous data acquisition, so T1 maps can be compensated for 3D translational respiratory motion and reconstructed at different cardiac phases by retrospective data binning. Using combined dictionary‐based low‐rank inversion1 mapping was demonstrated in vivo. Myocardial T1 measurements with the proposed 3D technique were comparable to conventional breath‐hold, cardiac‐gated 2D MOLLI and SASHA.In this study, free‐running 3D whole heart myocardial T1 values estimated with the proposed technique showed good accuracy for T1 ranging from 250–1600 ms as compared with the reference 2D IR‐SE. Septal T1 values at diastole with the proposed technique were comparable to SASHA and were significantly larger than those for MOLLI, which has been reported to underestimate T1.1 increment of 1%, resulting in 10–12 ms increments in the myocardial T1 range of 1000–1200 ms, which are small compared with the measured septal T1 SD (42 ± 8 ms). The precision of septal T1 was similar to MOLLI and significantly higher than SASHA. The results indicate that the proposed 3D T1 mapping technique improves accuracy compared to MOLLI and precision compared to SASHA. Therefore, the proposed technique may be a promising tool for myocardial T1 mapping with the advantages of both high accuracy and precision. In addition, with the proposed 3D high resolution T1 mapping technique, visualization of the right ventricle was improved, which may facilitate fibrosis quantification in the thin wall of the right ventricle. Nevertheless, T1 values of the thin right ventricle should be interpreted carefully, considering that there may be partial volume effects resulting from residual fat caused by the imperfection of the water selective excitation pulse.In the phantom study, T1 mapping.In this study, respiratory motion was addressed by correcting the phase of k‐space data using motion parameters estimated from 3D translational image registration of images acquired at different respiratory states. More sophisticated registration methods, such as affine and non‐linear transforms could be considered in future work to account for more complex respiratory‐induced cardiac movement. To extract reliable cardiac trigger signal to account for cardiac motion, ECG signal was logged and synchronized with data acquisition for retrospective data selection. Previous studies have proposed several approaches for cardiac self‐navigation using radial or spiral trajectories.1 mapping at systole has special diagnostic value when the diastolic T1 map cannot be reliably obtained, such as in patients with thin myocardium, where partial volume effects may corrupt myocardial T1 estimation, and in patients suffering from frequent arrhythmias, where the diastolic onset and duration are changing.1 maps were reconstructed along with diastolic T1 maps for each subject. The AHA segment analysis showed good spatial uniformity of the myocardial T1 values measured across the left ventricle in both diastole and systole. In general, the systolic myocardium T1 was comparable to the diastolic myocardium T1. The shorter T1 in the inferoseptal segment of the basal slice and inferior segments of the mid and apical slices may be explained by increased myocardial thickness and therefore reduced partial volume effects from blood during systole compared to diastole.1 mapping was set to ~186 ms, which was adequate for diastole, but may not be optimal for systole. In spite of this, radial data acquisition is less sensitive to motion than Cartesian sampling, and no obvious motion artefacts were observed in the systolic T1 maps.T1 maps were reconstructed for each subject separately in our experiments. Instead of separate reconstruction for each cardiac phase, cardiac‐resolved T1 maps can be reconstructed simultaneously, by which additional redundancy along cardiac phases can be exploited and improved reconstruction performance can be expected at the expenses of memory requirement and computational times. Furthermore, 3D cardiac cine reconstruction from the free‐running sequence should be also possible. This could be done by sorting the respiration motion compensated k‐space data with a small temporal window along the cardiac phase  and a large temporal window along contrast. After binning, the undersampled k‐space data of different cardiac phases could be reconstructed simultaneously, e.g., by adding a total variation constraint along the cardiac phase directionSystolic and diastolic T1 and B0 field inhomogeneities that will influence T1 estimation and may cause banding artefacts in the image. The proposed technique was investigated at 1.5 T in this study, but has potential to be extended to 3 T. Furthermore, benefits of higher SNR, and therefore shortened scan time or improved spatial resolution can be expected at 3 T.SPGR readout with low flip angle instead of balanced steady‐state free precession (bSSFP) readout was used in the proposed sequence. Although bSSFP readout may have SNR benefits, the low flip angle SPGR readout is less sensitive to B1 mapping technique cannot estimate T1 of flowing blood accurately. This is because the signal model used for T1 mapping assumes that the tissue of interest is static and experiences all the inversion and excitation pulses in the sequence, which may not be true for flowing blood. When measurement of myocardial extracellular volume is needed, estimation of blood T1 could be performed using a free‐breathing rapid low spatial resolution (enough to only define a region of interest within the blood pool) T1 mapping sequence acquired in a mid‐ventricular slice. Second, in this study the proposed technique was only tested for native myocardial T1 mapping. However, post‐contrast myocardial T1 mapping using this technique should be also feasible. Furthermore, considering the reduced T1 after contrast injection, shorter IRTR could be adopted and shorter scan duration can be expected. Third, in the free‐running sequence with retrospective binning, although inter‐bin respiratory and cardiac motion has been carefully addressed, compared with breath‐hold images, there may still be some remaining intra‐bin respiratory motion and cardiac motion that result in some blurring of the reconstructed images. Future studies will investigate the performance of the proposed sequence in a cohort of patients with cardiovascular disease. Last, the current implementation of HD‐PROST reconstruction is suboptimal and it takes ~3 h to reconstruct a whole heart 3D T1 map. GPU implementation will be investigated in the future for the non‐uniform Fourier TransformSeveral limitations of the proposed technique need to be mentioned. First, the proposed T51 mapping technique with whole heart coverage and high isotropic spatial resolution is proposed. 3D T1 mapping was shown to have good accuracy and precision in comparison to reference sequence in phantom and conventional T1 mapping methods in in vivo experiments. Based on retrospective data selection and combined dictionary‐based low‐rank inversion and patch‐based reconstruction, high resolution 3D T1 maps could be obtained for different cardiac phases. Future studies will investigate the clinical value of the proposed technique.In this study, a free‐running 3D myocardial T Click here for additional data file.


Acute thrombotic events, such as heart attacks and strokes, are the leading causes of morbidity and mortality worldwide. The heart disease and stroke statistics - 2016 update from the American Heart Association stated that cardiovascular disease (CVD) accounted for 1 in 3 deaths in the United States [One of the major risk factors for developing CVD is aging itself. In most cases of acute heart attack and stroke, the rupture of a vulnerable plaque results in the activation of platelets and the coagulation cascade . PlateleThe activation of platelets causes the release of dense granules containing large amounts of adenosine triphosphate, serotonin, and the potent platelet agonist adenosine diphosphate (ADP) . This crNon-invasive anti-platelet and/or anti-thrombotic therapies are used to dissolve the blood clot or to prevent (further) growth of the thrombus, thereby preventing potentially deadly events. However, current anti-platelet drugs inhibit both resting and activated platelets and the use of these drugs have an inherent risk to cause bleeding complications, which hinders their use in the wider community, in particular of elderly patients –5. Even Our group has developed an alternative therapeutic strategy which blocks the activated GPIIb-IIIa, as well as degrades the potent platelet agonist ADP. By genetic coupling of the ecto-nucleoside triphosphate diphosphohydrolase CD39 to a single-chain antibody (scFv) against the active conformation of GPIIb/IIIa on activated platelets, we have designed a bifunctional molecule termed Targ-CD39 .Using Targ-CD39 in a murine model of myocardial ischemia/reperfusion, we have demonstrated improvement of cardiac function via conventional 2-dimension echocardiography using Brightness-mode, as well as reduced cardiac deformation using strain analysis . EchocarBy targeting CD39 to activated GPIIb/IIIa, we can control the amount of drugs required to be injected. This targeting effect homes the drugs to the area of thrombosis, resulting in a maximum therapeutic effect while eliminating the undesirable side effect of bleeding . While tThe ability to target activated GPIIb/IIIa is ideal for drug delivery . ScFvs aOverall, this proof-of-concept study justifies further development towards targeted drug delivery in thrombotic diseases after further extensive experimental testing. Targ-CD39 has the potential to be translated to clinical application and holds promise to be beneficial to many patients with cardiovascular diseases. In particular, elderly patients who have both an increased risk of a myocardial infarction and stroke as well as an increased risk of bleeding complications, may benefit substantially.


Introduction: Timing of atrial, right (RV), and left ventricular (LV) stimulation in cardiac resynchronization therapy (CRT) is known to affect electrical activation and pump function of the LV. In this study, we used computer simulations, with input from animal experiments, to investigate the effect of varying pacing delays on both LV and RV electrical dyssynchrony and contractile function.Methods: A pacing protocol was performed in dogs with atrioventricular block (N = 6), using 100 different combinations of atrial (A)-LV and A-RV pacing delays. Regional LV and RV electrical activation times were measured using 112 electrodes and LV and RV pressures were measured with catheter-tip micromanometers. Contractile response to a pacing delay was defined as relative change of the maximum rate of LV and RV pressure rise (dP/dtmax) compared to RV pacing with an A-RV delay of 125 ms. The pacing protocol was simulated in the CircAdapt model of cardiovascular system dynamics, using the experimentally acquired electrical mapping data as input.Results: Ventricular electrical activation changed with changes in the amount of LV or RV pre-excitation. The resulting changes in dP/dtmax differed markedly between the LV and RV. Pacing the LV 10–50 ms before the RV led to the largest increases in LV dP/dtmax. In contrast, RV dP/dtmax was highest with RV pre-excitation and decreased up to 33% with LV pre-excitation. These opposite patterns of changes in RV and LV dP/dtmax were reproduced by the simulations. The simulations extended these observations by showing that changes in steady-state biventricular cardiac output differed from changes in both LV and RV dP/dtmax. The model allowed to explain the discrepant changes in dP/dtmax and cardiac output by coupling between atria and ventricles as well as between the ventricles.Conclusion: The LV and the RV respond in a opposite manner to variation in the amount of LV or RV pre-excitation. Computer simulations capture LV and RV behavior during pacing delay variation and may be used in the design of new CRT optimization studies. Cardiac resynchronization therapy (CRT) is an established therapy for heart failure patients with a reduced left ventricular (LV) ejection fraction (EF), and left bundle branch block (LBBB) . Throughmax)  and ventriculoventricular (VV) pacing delays strongly influences the contractile response to CRT, as determined by both ultrasound and maximum rate of LV pressure rise (LV dP/dtmax) . Howevermax) . Suggestmax) . Two clix values .In recent years, computational models of cardiac electrophysiology, mechanics of the heart and cardiovascular system have increased our understanding of dyssynchronous heart failure and its treatment with CRT . Right vA vast majority of the studies on the heart, also our aforementioned studies, are related largely to the LV. In the present study, we aim to study the changes in both LV and RV contractile response to variations of pacing delay settings in CRT, and to evaluate whether the CircAdapt computer model reliably simulates LV and RV pump function during these interventions. Subsequently we aim to use the computer modeling results to investigate how cardiac output is affected by differences between LV and RV contractile changes.Animal handling was performed according to the Dutch Law on Animal Experimentation and the European Directive for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purpose. The protocol was approved by the Animal Experimental Committee of Maastricht University. The animal experiments have been conducted in 2010–2011 and the methodology used has partially been described in a previous publication , reportiMeasurements were performed 12–21 weeks after inducing the AV-block using an external custom-built pacing system. RV-only pacing with an A to RV (A-RV) pacing delay of 125 ms was used as the baseline pacing setting, mimicking the activation pattern as seen in LBBB. The A-RV and A to LV (A-LV) delays were then programmed individually, ranging from 50 to 230 ms in steps of 20 ms, resulting in 100 possible combinations Figure . Pacing Local electrical activation times were determined as the duration between the atrial pace and the timepoint of steepest negative deflection of the electrogram using custom software Figure .max compared to the baseline setting. We applied quadratic LOESS fitting to account for measurement variability within each dog  scripts to perform all simulations and analysis thereof are provided as an online supplement . Time of onset of activation was assigned based on the electrical activation times measured in the animal experiments. As previously stated, in the current MultiPatch module the segments were considered to be mechanically coupled in series, meaning that the order in which patches were placed was not significant . This almax values are compared with the experimental measurements. In addition, the simulations extended the animal experiments by providing quantitative insight in the beat-to-beat and steady-state changes of ventricular volumes and cardiac output.A representative baseline simulation was obtained by imposing the ventricular activation pattern measured during the experimental baseline condition, i.e., RV-only pacing with an A-RV delay of 125 ms. Systemic vascular resistance was adapted to obtain a MAP of 60 mmHg and heart rate was set to 80 bpm, both similar to the animal experiments. Furthermore, total circulating blood volume was adjusted so that cardiac output was maintained at 5.1 L/min. The resulting baseline simulation was used as the starting point for the pacing setting simulations. For each of the 100 pacing delay simulations, the pattern of ventricular activation was changed to the activation pattern measured in the canine experiments and the resulting beat-to-beat changes in ventricular mechanics and hemodynamics were stored until a new hemodynamic steady state was reached. During all pacing simulations, systemic vascular resistance and total circulating blood volume were kept constant in order to quantify the acute effect of pacing-induced changes of ventricular pump mechanics and cardiac hemodynamics. Simulated steady-state dP/dtBaseline characteristics for the AV-blocked dogs are described in Table Figure Figure max in response to changes in pacing delay settings are presented in Figure max in both measurements and simulations. The relative effect of changing VV delay  was largest in RV dP/dtmax. Changing pacing settings from RV to LV pre-excitation decreased RV dP/dtmax with more than 30% in the experiment. The decrease in RV dP/dtmax was less pronounced in the simulations but followed the same pattern. LV dP/dtmax was highest with LV pre-excitation and simultaneous pacing in both the experiment and simulations.The changes in LV and RV dP/dtmax are observed when changing the VV delay. The largest increase in LV dP/dtmax in the measurements was reached with a short A-LV (50 ms) and A-RV (90 ms). LV pre-excitation led to a larger increase in LV dP/dtmax than RV pre-excitation during all measurements and simulation, with an optimal LV pre-excitation range of 10–50 ms. For RV dP/dtmax, all LV pre-excitation pacing settings led to a decrease up to 33% in the experiment and 18% in the simulations, while RV pre-excitation caused little change compared to baseline (RV-only) pacing.The heat maps of both the animal experiments and computer simulations  was reached, with SV in both ventricles (and therefore cardiac output) increasing by about 3%. This example, representative for the other conditions, illustrates that dP/dtmax was largely independent of preload, whereas SV depended on it, most likely due to the length dependent activation, implemented in the CircAdapt model .In order to find an explanation for the differences in behavior between cardiac output and RV and LV dP/dtn Figure . In the Figure In this study we investigated the influence of LV and RV pacing delay settings on LV and RV electrical activation and contractility in animal studies and computer simulations. Both studies showed that LV TAT is smallest during synchronous RV and LV stimulation and increases when VV delays increase. RV TAT becomes larger in particular during LV pre-excitation. LV and RV contractility vary most, and in opposite direction, with changes in VV delay settings. After demonstrating the realistic simulations in the model, we used the model to calculate cardiac output changes and to explain why changes cardiac output differed from both RV and LV contractility. The latter findings demonstrate how a model like CircAdapt can extend mechanistic understanding of circulatory changes due to a device therapy.max change in opposite direction when changing the VV pacing delay. max identify different “optimal” VV delays in most of the patients included in their study. Furthermore, max than LV-only or simultaneous LV + RV pacing. In an experimental study in pigs, different VV delays were tested at different pacing locations , it was demonstrated that interventricular dyssynchrony during intrinsic rhythm is the dominant electrical substrate driving response to CRT  and electrical remodeling (QT-time prolongation), but normal contractility . On the A major difference between this animal experiment and patients in day-to-day life is that the animals were anesthetized. To allow comparison between the experiments and simulations, the model’s LV afterload in the baseline situation was adapted to fit the measured mean arterial pressure in the dogs. After the change in activation delays regulation was disabled, which is likely similar to the anesthetic condition were regulation is slow. Caution should, however, be taken when translating results of this study toward the clinical setting considering that loading conditions potentially affect the effect of pacing delay changes . Future max, aortic outflow integral, and LV systolic (or aortic) pressure. This study demonstrates that improving LV function can reduce RV function. Furthermore, cardiac output is not necessarily increasing when LV dP/dtmax increases. Hence, An exclusive focus on the LV might not lead to the best overall outcome. Therefore, future studies on optimization of therapy should not exclusively focus on the LV but also include measures of RV and/or whole heart function. In our analysis of cardiac output we also demonstrated that the moment of measurement affects what physiological phenomenon is actually observed. Contractile function alone might better be observed in the first beats while longer lasting measurements, that allow reaching a steady state, will provide more information about the loading of the heart and its interaction with homeostatic regulation. Insights acquired in the present opens the way for designing better optimization protocols, possibly even including computer modeling.The results of this study raise the question what outcome measure is best to use for optimization of pacing delay. Current clinical practice focusses almost exclusively on the LV, using parameters like LV dP/dtin silico platform for further optimization studies for device therapy.The LV and the RV respond in an opposite manner to LV or RV pre-excitation. LV pre-excitation improved LV contractility and decreased RV contractility, while RV pre-excitation had the opposite effects. The CircAdapt computer model realistically captures these opposite responses of LV and RV contractile function. Computer simulations extend animal experimental findings by revealing that improving ventricular contractility does not necessarily lead to an improvement of cardiac output. This study demonstrates the potential of CircAdapt to provide a valuable and efficient EW, PH, MS, JW, FP, and JL conceived and designed the experiments. EW, RS, and MS performed the experiments. EW, RS, PH, MS, GP, EV, FP, and JL analyzed and interpreted the data. MS, JW, FP, and JL contributed to materials and analysis tools. EW, RS, PH, MS, GP, EV, JW, KV, TD, FP, and JL wrote or provided the critical revision on the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Though echocardiographic evaluation assesses the right ventricular systolic function, which of the existing parameters best reflects the right ventricular ejection fraction (RVEF) in the critically ill patients is still uncertain. We aimed to determine the relationship between echocardiographic indices of right ventricular systolic function and RVEF.Prospective observational study was conducted in a mixed Surgical Intensive Care Unit  from November 2017 to November 2018. All critically ill patients monitored with a pulmonary artery catheter were assessed. We collected echocardiographic indices of right ventricular function  and compared them with the RVEF obtained from continuous volumetric pulmonary artery catheter.p < 0.001). S′ was also correlated to RVEF  whereas FAC, RIMP, IVA, and EDDr did not. TAPSE lower than 16 mm, S′ lower than 11 cm/s, and EDDr higher than 1 were always associated with a reduced RVEF.Twenty-five patients were analyzed. Admission diagnosis was acute heart failure in 11 patients and septic shock in 14 patients. Median age was 70 years [57–80], norepinephrine median dose was 0.29 μg/kg/min [0.14–0.50], median Sequential Organ Failure Assessment score was 12 [10–14], and mortality at day 28 was 56%. When compared to RVEF, TAPSE had the highest correlation coefficient  contains supplementary material, which is available to authorized users. Right ventricular (RV) dysfunction is frequently encountered in intensive care unit (ICU) and has been associated with poor outcome in many acute clinical situations such as respiratory failure, septic shock, acute heart failure, pulmonary embolism, myocardial infarction, and acute decompensated pulmonary hypertension –3. It ocAccording to international consensus, transthoracic echocardiography (TTE) is the first-line recommended exam when investigating the hemodynamic failure of ICU patients . InternaTo investigate this question, we compared echocardiographic indices of RV systolic function to RVEF measured by continuous volumetric pulmonary artery catheter (PAC). This method is not the gold standard for RVEF measurement and was chosen as the best bedside method available that is not based on echocardiography.Comité d’éthique de la Société Française d’Anesthésie-Réanimation, IRB 00010254-2016-034) which waived the need of signed informed consent.This is a prospective observational study aiming to compare TTE indices of RV systolic function to RVEF measured by continuous volumetric PAC. This study was approved by an institutional ethics committee . Our ICU has a long experience of PAC use. In our ICU protocol, PAC is indicated as according to international consensus, i.e., in case of refractory shock not responding to initial therapy and suspicion of RV failure . PostopeInclusion criteria were all consecutive patients in whom a PAC had been used for hemodynamic monitoring for less than 24 h.Exclusion criteria were age < 18 years old, insufficient TTE quality to allow the measurements of indices of RV systolic function , cardiac dysrhythmias responsible of irregular echocardiographic patterns, and parameters known to interfere with continuous volumetric PAC performance: hypothermia , intracardiac shunt, and tricuspid regurgitation (TR) evaluated after PAC insertion classified as severe according to recommendations  , current vasopressor and inotrope treatment, settings of mechanical ventilation, Simplified Acute Physiology Score (SAPS II) at admission, current Sequential Organ Failure Assessment (SOFA), comorbidities, Charlson comorbidity index, and mortality at day 28 were collected.PAC with continuous cardiac output and volumetric measurement  was connected to the bedside monitor for pressure measurement . Position was checked on the post-insertion chest X-ray or any other more recent X-ray. Zeroing at the phlebostatic level was performed, and waveform of pulmonary artery pressure (PAP) and right atrial pressure (RAP) checked to ensure good positioning. Quality of the arterial pressure signal was assessed with a fast-flush test ensuring no abnormal signal damping. Criteria for the adequate wedge position of the tip of the catheter were as follows: (1) change of the pulmonary artery waveform to atrial waveform during occlusion, (2) a mean end-expiratory pulmonary capillary wedge pressure (PCWP) lower than the diastolic pulmonary arterial pressure (dPAP), and in case of mechanical ventilation, (3) a ratio of induced variations of PCWP to induced variations of systolic pulmonary arterial pressure (sPAP) lower than 1.5 , 12.Continuous volumetric PAC was also connected to the Vigilance II monitor  for continuous cardiac output monitoring and computation of the RVEF. Briefly, the continuous PAC is supplied with a heating filament located in the right ventricle and a distal thermistor located in the pulmonary artery. The above criteria ensure the correct position of the catheter. A pseudorandom binary heating pattern delivered to the filament and the temperature variation registered by the thermistor are combined by a cross-correlation algorithm to compute the thermodilution curve every 54 s , 14. TheTo ensure concomitant evaluation of both echocardiographic and PAC indices, the following parameters were collected just before the TTE was performed: systolic pulmonary arterial pressure (sPAP), diastolic pulmonary arterial pressure (dPAP), mean pulmonary arterial pressure (mPAP), pulmonary capillary wedge pressure (PCWP), right atrial pressure (RAP), cardiac output (CO), stroke volume (SV), right ventricle end-diastolic volume (RVEDV), right ventricle end-systolic volume (RVESV), and RVEF. Coronary perfusion pressure (CPP) was secondarily calculated as DAP minus RAP.Echocardiographic data were obtained from a 1.5–3.6-MHz cardiac probe connected to a Vivid i echograph . To ensure consistency in the measurements of the echocardiographic indices, all TTE were performed by a limited number of physicians with advanced expertise in critical care echocardiography . Before the beginning of the inclusions, they all studied the latest recommendations of the American Society of Echocardiography endorsed by the European Association of Echocardiography [The following RV systolic function parameters were measured as recommended by international guidelines : fractioOther RV parameters not directly related to systolic function were also recorded: RV to left ventricle (LV) end-diastolic diameter ratio (EDDr) and peak TR velocity by continuous waved Doppler . EDDr isp value less than 0.05 was considered as significant.The results are expressed as median [interquartile range] for continuous variables and number (percentage) for categorical variables. Spearman’s correlations and 95% confident intervals (CI) were performed amongst all indices. Missing data were handled by pairwise deletion. Results of correlations are presented in a graphical correlation matrix. Tested variables were ordered using a hierarchical clustering method. A Specificity (Sp), sensitivity (Se), positive predictive value (PPV), and negative predictive value (NPV) to detect a reduced RVEF were determined for all indices at the recommended thresholds . 95% CI https://www.R-project.org). The visualization of the correlation matrix was drawn with the R package “corrplot” version 0.84 . The diagnostic accuracy statistics were performed with the R package “pROC” version 1.1.00 .All statistical analyses were performed using R statistical software version 3.4.3 . At the time of evaluation, 24/25 patients were ventilated, 22/25 received norepinephrine at a median dose of 0.29 μg/kg/min [0.14–0.50], and 4/25 received dobutamine at a median dose of 5 μg/kg/min [5–5]. The median Sequential Organ Failure Assessment score was 12 [10–14]. Mortality at day 28 was 56%. RV free-wall thickness could not be measured for 9 patients, FAC could not be obtained for 2 patients, and EDDr could not be obtained for one patient. Clinical and hemodynamic characteristics of patients are reported respectively in Tables Results of Spearman’s correlations between TTE and continuous volumetric PAC parameters of RV systolic function are shown in Figs. p < 0.001). S′ was also correlated to RVEF  whereas FAC, RIMP, IVA, and EDDr did not .When compared to RVEF, TAPSE had the highest correlation coefficient .When evaluating correlations amongst indices, we only found TAPSE and S′ to be significantly correlated  had a reduced RVEF. However, a decrease in RVEF can be missed by a simple measure of RV dilation. This is expected as dilation of the RV is one of the determinants of reduced RVEF, but not the only one.All other tested indices were neither correlated to RVEF nor efficient classifiers of reduced RVEF at the tested cutoffs. Thus, our study shows that amongst all the recommended indices of RV systolic function, TAPSE and S′ are those who have the most determinants in common with RVEF. However, our results do not imply that other indices of RV function should not be used since they bring additional information to RVEF that might help the clinician when assessing RV systolic function.The present study focuses on severe critically ill patients with a high mortality rate, high SAPS II and SOFA scores, elevated lactate level, and who required both vasopressors and mechanical ventilation while most of the available literature regarding validation of echocardiographic indices of RV systolic function with RVEF were performed on stable cardiology patients. The investigation of RV function in patients with refractory shock is clinically relevant because it is a subset of patient with poor outcome in which clinician should evoke the possibility of RV failure in the hemodynamic picture because it can modify the management of the supportive therapies  and potentially impact outcome –3, 44. IOur study has some limitations. It is a monocenter study with a limited number of patients. Thus, it is likely that we only identified the strongest correlations and cannot exclude that a larger study may reveal significant correlations between the other indices. We compared echocardiographic indices of RV systolic function to RVEF in patients with primary septic shock or acute heart failure in which poor response to initial therapy leads to the decision of PAC monitoring by the attending physician. These are already resuscitated patients who achieved standard hemodynamic targets but remain dependent on vasopressor and/or inotropes and do not recover from their organ failures or have persistent hyperlactatemia. None of our patients had myocardial infarction, and CPP did not appear to be limiting. It is a particular severe subtype of patients and represents a selection bias that prevents generalization of our results to all critically ill patients. These are preliminary data that advocate for a larger study to confirm our results. Another limitation is that these indices were not tested in patients with non-resuscitated shock or primary RV failure at ICU admission (pulmonary embolism with shock or RV infarction with shock). Our results should not be extrapolated to these clinical scenarios.We found that amongst indices of right ventricular systolic function, TAPSE and S′ were well correlated with thermodilution-derived RVEF in critically ill patients.Additional file 1:Criteria for severe tricuspid regurgitation and Figure of Doppler tissue velocities and time intervals obtained at lateral tricuspid valve annulus (DOCX 218 kb)Additional file 2:Flow chart of the study (PDF 14 kb)Additional file 3:Correlation matrix of continuous volumetric pulmonary arterial catheter and echocardiographic parameters of right ventricular function (DOCX 596 kb)Additional file 4:Receiver operating characteristic curves of echocardiographic indices for diagnosis of reduced right ventricular ejection fraction (DOCX 160 kb)Additional file 5:Diagnostic accuracy of reduced right ventricular ejection fraction (< 25%) with echocardiographic indices (DOCX 17 kb)


To assess NT-proBNP as a biomarker for hyperdynamic circulation in decompensated cirrhosis.Hyperdynamic circulation is common in decompensated cirrhosis. The previous studies reveal that N-terminal-proBNP (NT-proBNP) is elevated in cirrhosis. A prospective study involved 47 patients with decompensated cirrhosis. All of them underwent echocardiography with simultaneous measurement of blood pressure and heart rate. Cardiac output and systemic vascular resistance were calculated. The concentration of NT-proBNP in blood was measured with enzyme-linked immunosorbent assay. In patients with decompensated cirrhosis, the concentration of NT-proBNP in blood directly correlated with end-diastolic volume , stroke volume , cardiac output , volume of the left atrium , and inversely correlated with systemic vascular resistance . There was no significant correlation between NT-proBNP and ejection fraction (p=0.083). Patients with hyperdynamic circulation have higher concentration of NT-proBNP  regardless of the presence of diastolic dysfunction (p=0.222). According to ROC analysis, the best cut-off values for detection of hyperdynamic circulation in decompensated cirrhosis are considered to be 170.0 pg/ml of blood NT-proBNP, showing sensitivity and specificity of 72.0 and 86.4%, respectively. The positive and negative predictive value are 86.4% and 73.1%, AUC = 0.829 (0.709-0.949). NT-proBNP may serve as a non-invasive biomarker for hyperdynamic circulation in decompensated cirrhosis. Hemodynamic changes in cirrhosis were first described more than 60 years ago ,2 and inNon-selective beta-blockers remain the cornerstone of medical treatment of portal hypertension. However, the effect of non-selective beta-blockers depend on the severity of the hyperdynamic circulation and splanchnic vasodilation . No biomThe endocrine function of the heart was first described in 1981, when the researchers injected the extract from the atria to rats and observed a significant increase in sodium and water excretion with urine . MyocardHowever, as it was revealed later that despite its name most of the BNP of blood is formed by the myocardium of the heart ventricles -9. AfterIt was found that the stretching of cardiomyocytes, which is observed in the dilatation of the left ventricle in heart failure, leads to an increase in the release of BNP into the blood . Since hThe aim of this study is to assess NT-proBNP as a biomarker for hyperdynamic circulation in decompensated cirrhosis. In this cross-sectional prospective study, 140 consecutive patients with cirrhosis admitted to the Department of Hepatology’s Clinic for Internal Diseases, Gastroenterology and Hepatology (the Clinic), at Sechenov University, Moscow, were screened for inclusion. Study procedures were explained to potential participants and written informed consent was obtained before enrollment. The study had been performed in accordance with the ethical standards laid down in an appropriate version of the Declaration of Helsinki. The study protocol was approved by the Ethical Committee of Sechenov University.Inclusion criteria were: diagnosis of decompensated cirrhosis verified by histology, clinical, biochemical, and ultrasound findings; age between 18 and 70 years. Severity of liver disease was determined using the Child–Turcotte–Pugh (CTP) scoring system, in which class A was defined as compensated cirrhosis and classes B and C were defined as decompensated cirrhosis.Exclusion criteria included: cardiac disease, cancer or any other severe disease. Of the original 140 patients screened for inclusion, 47 met criteria and were enrolled in the study. The other patients had compensated cirrhosis (n=61), cancer (n=4), other severe disease (n=9), and 19 patients declined to participate.The concentration of NT-proBNP in blood was measured with enzyme-linked immunosorbent assay.Echocardiography was performed at rest according to guidelines published by The American Society of Echocardiography . End-diaStatistical analysis was performed with STATISTICA 10 software  and SPSS . The differences between continuous variables were assessed with the Mann-Whitney test. Correlations between variables were computed using Spearman's rank correlation. Fisher's exact test was used to assess the difference between categorical variables. Data were represented as mean ± SD, except for NT-proBNP concentration, which was represented as interquartile range. P-value < 0.05 was considered statistically significant. The main parameters of participants are presented in Systolic heart dysfunction (ejection fraction < 50% (10)) was revealed in 2 patients but they had a NT-proBNP level in the blood of less than 125 (cut-off for heart failure (10)). It was interesting that the decrease in the ejection fraction was not accompanied by an increase in the level of NT-proBNP in the blood, as it takes place in heart failure. In patients with elevated blood NT-proBNP (>125 pg/ml (10)), end-diastolic volume, stroke volume, cardiac output, the volume of the left atrium were higher, systemic vascular resistance was lower, ejection fraction, blood pressure, and heart rate were not significantly differ, hyperdynamic circulation, dilatation left atrium, and diastolic dysfunction Grade II were more often revealed . In patiDiastolic dysfunction Grade I was not accompanied by a significant increase in blood NT-proBNP, in contrast to diastolic dysfunction Grade II .Based on our previous study, we determined that for our population, the upper value of the normal range of cardiac output is 5.5 l/min . CardiacIn patients with hyperdynamic circulation, blood NT-proBNP was higher, regardless of the presence of diastolic dysfunction, but in ones with diastolic dysfunction there was a tendency for higher NT-proBNP values .According to ROC analysis, the best cut-off values for detection of hyperdynamic circulation in decompensated cirrhosis are considered to be 170 pg/ml of blood NT-proBNP, showing sensitivity and specificity of 72.0 and 86.4%, respectively. The positive and negative predictive values were 86.4% and 73.1%. AUC = 0.829 (0.709-0.949), which correspond to a good biomarker characteristic .An analysis of the results shows that an increase in blood NT-proBNP in decompensated cirrhosis is associated with an increase in the size of the left chambers of the heart as in heart failure. However, unlike the latter, in cirrhosis an increase in blood NT-proBNP are accompanied by an increase in stroke volume and cardiac output and a decrease in systemic vascular resistance without a significant change in ejection fraction. In decompensated cirrhosis, blood NT-proBNP directly correlates with end-diastolic volume, stroke volume, cardiac output, volume of the left atrium, inversely correlates with systemic vascular resistance, and does not correlate with ejection fraction, whereas in heart failure, a negative correlation with ejection fraction is shown . In contThe findings allow suggesting that the pathogenesis of the increase in blood NT-proBNP in decompensated cirrhosis and systolic heart failure is different, but in both cases is associated with stretching of left ventricular cardiomyocytes.In systolic heart failure, ejection fraction decreases which leads to decrease in stroke volume and, consequently, cardiac output. As a compensatory reaction in accordance with Starling's law, end-diastolic volume increases to increase stroke volume and cardiac output, but this is not always sufficient to normalize these. Therefore, an increase in NT-proBNP in systolic cardiac dysfunction is accompanied by a decrease in stroke volume and cardiac output and a compensatory increase in systemic vascular resistance to maintain blood pressure. In decompensated cirrhosis, reverse changes are observed. Endotoxemia leads to arterial vasodilation which leads to a decrease in systemic vascular resistance and blood pressure . In respThus, we showed that blood NT-proBNP in decompensated cirrhosis is a biomarker for hyperdynamic circulation, but not a biomarker for systolic cardiac dysfunction. As a result of the ROC analysis, we proposed a cut-off point for the value of this biomarker (170.0 pg/ml), which allows to identify patients with hyperdynamic circulation with high analytical reliability.In one of the previous studies , there wIn another study , it was The use of NT-proBNP as a simple serum biomarker for hyperdynamic circulation may provide differential management with beta-blockers and control for their use, which may increase the effectiveness of therapy and reduce the incidence of side effects. Further searches are required to test this hypothesis.The authors declare that they have no conflict of interest.