For accurate interpretation of echocardiographic measurements normative data are required, which are provided by guidelines. For this article, the hypothesis was that these cannot be extrapolated to the Dutch population, since in Dutch clinical practice often higher values are found, which may not be pathological but physiological. Therefore this study aimed to 1) obtain and propose normative values for cardiac chamber quantification in a healthy Dutch population and 2) determine influences of baseline characteristics on these measurements.Prospectively recruited healthy subjects, aged 20–72 years  underwent physical examination and 2D and 3D echocardiography. Both ventricles and atria were assessed and volumes were calculated.147 subjects were included . Overall, feasibility was good for both linear and volumetric measurements. Linear and volumetric parameters were consistently higher than current guidelines recommend, while functional parameters were in line with the guidelines. This was more so in the older population. 3D volumes were higher than 2D volumes. Gender dependency was seen in all body surface area (BSA) corrected volumes and with increasing age, ejection fractions decreased.This study provides 2D and 3D echocardiographic reference ranges for both ventricles and atria derived from a healthy Dutch population. BSA indexed volumes are gender-dependent, age did not influence ventricular volumes and a rise in blood pressure was independently associated with increased right ventricular volumes. The higher volumes found may be indicative for the Dutch population being the tallest in the world. Echocardiography is indispensable in clinical practice. It is the most widely used non-invasive imaging tool to assess and quantify cardiac structural and functional parameters, mainly because of its versatility: it is widely available, relatively cost-effective and mobile. To interpret the performed measurements, solid normative data are essential. The recently revised guideline for cardiac chamber quantification provides guidance for echocardiographic assessment , 2. For In the literature, there are four studies that show an influence of gender and age on left ventricular (LV) and right ventricular (RV) volumes . HoweverTherefore, this study aims to provide 1) age-specific reference values for echocardiographic chamber measurements specifically in a Dutch population and 2) identify the influence of age, gender, body mass index (BMI), BSA and blood pressure on the echocardiographic measurements.2), pregnant women and women with breast implants were excluded. This study was carried out according to the principles of the Declaration of Helsinki and approved by the local ethics committee. Written informed consent was obtained from all patients.Healthy volunteers, aged 20–72 years, were enrolled in 2014–2015 for this prospective cross-sectional study and were stratified into five groups: 20–29, 30–39, 40–49, 50–59 and 60–72 years . Details have been published earlier [The study consisted of a questionnaire on medical history and health status, physical examination, venous blood sampling, 12-lead electrocardiogram and an echocardiogram.Echocardiographic studies were carried out by one of two experienced sonographers. Two-dimensional greyscale harmonic images were obtained in the left lateral decubitus position using an i33 or EPIQ7 ultrasound system  equipped with a transthoracic broadband X5-1 matrix transducer . Dedicated views were taken for assessment of both atria and ventricles. The studies were stored in Digital Imaging and Communications in Medicine (DICOM) format.The current recommendations for chamber quantification were used . LV end-The left atrial (LA) area was measured in dedicated atrial four- and two-chamber views to avoid foreshortening. Biplane volumes were measured using the method-of-disk summation technique.For the right ventricle, end-diastolic and -systolic areas (EDA and ESA) were measured in order to calculate the fractional area change:For the right atrium, the single plane volume was measured in the apical four-chamber view using the method-of-disk summation technique and the area length method.LV volumetric measurements were performed with TomTec 4D LV function suite  using a semi-automated endocardial border trace, after the apex and the middle of the mitral valve annulus are determined by the operator. The end systolic and diastolic frame are automatically detected in order to start contour detection. Corrections to the endocardial trace were manually applied by the operator if needed. For the right ventricle, a similar routine was used .2-test or Fisher’s exact test was used when appropriate. Correlations were measured using the Pearson correlation test. For correlations between echocardiographic parameters and age, linear regression analysis was applied. Variables that reached significance and did not show collinearity with other variables were included in a multivariable model. When collinearity did occur, the variable with the highest correlation coefficient was included. A p ≤ 0.05 was considered statistically significant. Statistical analysis was done using the Statistical Package for Social Science version 21 .Normal distribution was checked using Shapiro-Wilks tests and histograms. Depending on data distribution, continuous data are presented as mean ± standard deviation (SD) or median with first-third quartile (Q1-Q3). Categorical data are presented as frequencies and percentages. Student’s t‑test, the Mann-Whitney-U test, χOf the 155 subjects eligible, 147 were included  Fig. . Tab. 1 2 and end-systolic volume (ESV) 34 ± 6 ml/m2. For the right ventricle, values were 58 ± 12 ml/m2 and 24 ± 6 ml/m2. LV and RV volumes were not age-dependent; this was true for both 2D and 3D echocardiography. Age was inversely correlated with LVEF ). RVEF was 58 ± 4 ml/m2 and was not correlated with age. Importantly, volumetric measurements acquired with 2D echocardiography all exceeded the ULN as recommended in the guideline. This was also true for 3D LV volumes, but not for the 3D RV volumes.Tab. 2, with 25% of the study population having LA dilatation (>34 ml/m2) according to the guideline. In this study, the ULN was 43.2 ml/m2.Tab. Fig. BSA correlated strongest with echocardiographic parameters compared with height, weight or BMI. Ventricular volumes were not correlated with age, and LVEF and RVEF showed a decrease with age. RV volumes showed a linear increase with higher blood pressure and heart rate, also after correcting for heart rate, QRS duration and gender.r: 0.643, p < 0.001, and LV ESV r: 0.583, p < 0.001, respectively. For the RV correlations between 2D volumes and 3D areas were weak: 3D EDV vs 2D EDA r: 0.295, p: 0.004 and ESV r: 0.295, p: 0.005 respectively.Agreement between 2D and 3D for the LV measurements was moderate: LV EDV: This prospective study presents normative data for echocardiographic chamber quantification, age- and gender-specific, in a healthy Dutch population. Overall, linear and volumetric parameters exceeded the ULN as stated in the guideline, while functional parameters agreed with them. BSA remains the best variable for indexation.Feasibility of LV measurements in this study is in line with previous studies , 10, 11.2. This was due to both a higher weight (65 ± 12 vs 75 ± 13 kg) and height (169.8 ± 9.6 vs 175 ± 9 cm), meaning that these higher values are not due to leaner subjects.Comparing the results from this study to the ULN as stated in the guideline, we founGiven that the Dutch population is the tallest worldwide , the quer 0.240, p < 0.01) [Multiple studies reported on the negative relation between age and echocardiographic LV volumes, 11, 13,Hypertension was a reason for exclusion, but it is worth mentioning that some volunteers had a higher blood pressure but when checked again by a general practitioner were found to be normal. These volunteers were not excluded. Analysis showed that higher blood pressure led to higher RV volumes. This could imply that sufficient blood pressure regulation could influence the right ventricle.The reference values in this study could lead to some changes in clinical decision-making. Though most guidelines use functional parameters, there are situations where volumes or linear dimensions are being used. For instance, when diagnosing LV diastolic dysfunction, LA dilatation plays an important role . With thRV size is of particular importance for patients with adult congenital heart disease. In patients with an atrial septal defect, if the right ventricle is enlarged intervention is warranted; this is also true for patients with ventricular septal defect .The impact is smaller regarding valvular disease; LV linear dimensions are still used as opposed to volumes , and valConsidering the size and Dutch ethnicity of the study population, conclusions drawn should be interpreted with caution.This study presents age- and gender-specific normative data specifically for the native Dutch population, and reveals that linear and volumetric parameters exceed the ULN while functional parameters agree with the guideline. The higher linear and volumetric parameters found may be indicative to native Dutch people being the tallest people worldwide. The authors suggest specific normative values for echocardiographic assessment in the Dutch population.


Urocortin 2 and urocortin 3 may play a role in the pathophysiology of heart failure and are emerging therapeutic targets. We aimed to examine the local and systemic cardiovascular effects of urocortin 2 and urocortin 3 in healthy subjects and patients with heart failure.n = 8) and age and gender‐matched healthy subjects (n = 8) underwent bilateral forearm arterial blood flow measurement using forearm venous occlusion plethysmography during intra‐arterial infusions of urocortin 2 (3.6–36 pmol min−1), urocortin 3 (360–3600 pmol min−1) and substance P (2–8 pmol min−1). Heart failure patients (n = 9) and healthy subjects (n = 7) underwent non‐invasive impedance cardiography during incremental intravenous infusions of sodium nitroprusside (573–5730 pmol kg−1 min−1 ), urocortin 2 (36–360 pmol min−1 ), urocortin 3 (1.2–12 nmol min−1) and saline placebo.Patients with heart failure (P < 0.05 for both) with no difference in magnitude of vasodilatation between patients and healthy subjects. During systemic intravenous infusions, urocortin 3 increased heart rate and cardiac index and reduced mean arterial pressure and peripheral vascular resistance index in both groups . Urocortin 2 produced similar responses to urocortin 3, although increases in cardiac index and heart rate were only significant in heart failure (P < 0.05) and healthy subjects (P < 0.001), respectively.Urocortin 2, urocortin 3 and substance P induced dose‐dependent forearm arterial vasodilatation in both groups (Urocortins 2 and 3 cause vasodilatation, reduce peripheral vascular resistance and increase cardiac output in both health and disease. These data provide further evidence to suggest that urocortins 2 and 3 continue to hold promise for the treatment of heart failure. Urocortins 2 and 3 are emerging therapies for treating heart failure.Urocortins 2 and 3 reduce peripheral vascular resistance and increase cardiac output in both health and disease.This is the first direct head‐to‐head comparison of urocortin 2 and urocortin 3 in man.These data provide further evidence that urocortin 2 and urocortin 3 hold major potential for the treatment of heart failure.There are almost six million people living with heart failure in the USA. This comes at an annual cost to the US economy of over $30 billion The urocortins are an endogenous peptidic hormone group comprising urocortin 1, urocortin 2 and urocortin 3 with vasodilator, inotropic and lusitropic effects A recombinant acetate salt of urocortin 3 (JNJ‐39 588 146 [recombinant stresscopin]), improved cardiac output whilst reducing vascular resistance in a multicentre study of patients with chronic stable heart failure We aimed to evaluate and compare the local and systemic cardiovascular effects of urocortins 2 and 3 in patients with heart failure and healthy subjects by assessing (i) local forearm arterial blood flow using venous occlusion plethysmography and (ii) cardiac output and vascular resistance using thoracic bioimpedance cardiography. We hypothesized that urocortins 2 and 3 would cause vasodilatation, reduced peripheral vascular resistance and increased cardiac output in both healthy subjects and patients with heart failure.Both studies were approved by the local research ethics committee (South East Scotland REC 01) and carried out in accordance with the Declaration of Helsinki. The registered clinical trials on UKCRN were ID 10749 and 13002.Written informed consent was obtained from all participants prior to the study.Patients with heart failure were eligible if they were aged 18–80 years, New York Heart Association (NYHA) symptom class II–III and had echocardiographically confirmed left ventricular ejection fraction <35% with left ventricular end diastolic diameter > 5.5 cm. Patients were required to be receiving maximally tolerated doses of angiotensin‐converting enzyme inhibitor and β‐adrenoceptor blocker therapies for at least 3 months. Healthy subjects had no significant previous medical history and were on no regular medications. Exclusion criteria for both groups included systolic blood pressure > 190 mmHg or <90 mmHg, haemodynamically significant valvular heart disease and other severe or significant co‐morbidities including bleeding diathesis, renal or hepatic failure, anaemia or recent infective/inflammatory conditions. Women of child bearing potential were also excluded.−1, molecular weight 4450.3 g mol−1), urocortin 3  and substance P  for 6 min at each dose with a 30 min washout period between agents.This was a randomized study Figure A of eighForearm venous occlusion plethysmography studies were performed with the subject lying supine, in a quiet, temperature‐controlled room (22–25°C). Participants fasted for 4 h prior to the study and refrained from alcohol and caffeine for 24 h prior to the study. Venous cannulae (17G) were inserted into large subcutaneous veins in the antecubital fossae of both arms at the start of the study to facilitate periodic venous sampling. Heart rate and blood pressure were monitored at regular intervals throughout the study with a semi‐automated oscillometric sphygmomanometer (Omron 705IT). Participants underwent brachial artery cannulation of the non‐dominant forearm with a 27 standard wire‐gauge steel needle for agent infusion. Forearm blood flow was measured in the infused and non‐infused forearms using bilateral venous occlusion plethysmography as described previously n = 9) and healthy subjects (n = 7) were recruited. Participants had venous cannulae inserted into both antecubital fossae and attended on two occasions, receiving intravenous infusions of saline (placebo) or SNP  followed by either urocortin 2  or urocortin 3 . On the second visit, participants received the two remaining agents not administered on visit 1. Each agent was given in three ascending doses for 10 min at each dose. A 1 h saline washout was given between agents and a further 30 min of saline washout was administered after the cessation of the second agent.This was a randomized, double‐blind, placebo controlled crossover study Figure B. Three Haemodynamic measurements were recorded throughout the study. Cardiac output, blood pressure and stroke volume were recorded using non‐invasive thoracic impedance cardiography  and oscillometric sphygmomanometry . Values were indexed to body surface area where appropriate and peripheral vascular resistance index was calculated using recorded measurements (PVRI = MAP/CI).−1 or rise above 120 beats min−1, at the request of the participant, attending nurse or the attending physician.Study stopping criteria were in place to ensure participant safety. Criteria included a drop in diastolic blood pressure of >25 mmHg, fall in heart rate below 50 beats minBaseline blood samples were drawn for assessment of full blood count, renal function, glucose and cholesterol concentrations at the start of each study. The local clinical biochemistry and haematology reference laboratories performed analysis.P < 0.05.Data were collected in a double‐blind fashion for both studies. Data were analyzed, where appropriate, by analysis of variance . All results in figures are expressed as mean ± SEM. All statistical analysis was performed with GraphPad Prism, version 6 . Statistical significance was taken as two‐sided Patients with heart failure and healthy subjects recruited were predominantly male and middle‐aged. Heart failure patients had greater BMI compared with healthy subjects. Participant characteristics are shown in Table The intra‐brachial infusion of all three drugs was well tolerated with no adverse effects. Intra‐brachial infusion of urocortin 2 and 3 produced localized, self‐limiting forearm flushing and some facial flushing in both groups of participants as noted in previous studies P < 0.05, +72% [21–123] P < 0.01; urocortin 3 +167% [100–237] P < 0.0001, +151% [82–219] P < 0.0001; substance P +227% [130–326] P < 0.0001, +155% [57–253] P < 0.001 for healthy controls and heart failure patients, respectively; Figure P = 0.84, urocortin 3 −18% [−86 to +50%], P = 0.80; substance P −72% [−170 − +26%] P + 0.19).Urocortin 2, urocortin 3 and substance P all evoked dose‐dependent forearm arterial vasodilatation in both participant groups  that was accompanied by a drop in systolic  and diastolic blood pressure in patients with heart failure  and a drop in diastolic blood pressure alone in healthy subjects , frequently reaching study stopping criteria. A dose reduction to SNP (maximum dose of 5730 pmol kg−1 min−1) was made after two healthy subjects completed the study. For the urocortins, hypotension reaching study stopping criteria was met in one heart failure patient for urocortin 2 and two heart failure patients and one healthy subject for urocortin 3. Participants described dose‐dependent symptoms of tachycardia and a warm sensation with both urocortins, but there were no significant adverse events attributable to either urocortin 2 or urocortin 3. Full blood count and serum biochemistry was unchanged between the two study visits . There was no effect of either urocortin 2 or urocortin 3 on stroke volume (P > 0.05 for both).Urocortin 2 had no significant effect on cardiac index in healthy subjects and heart rate in heart failure patients when compared with saline placebo (P < 0.01) and heart rate  and greater mean reductions in mean arterial pressure  and peripheral vascular resistance index  in patients with heart failure. No such haemodynamic differences existed between urocortin 2 and urocortin 3 in healthy subjects. No haemodynamic differences existed between participant groups for both urocortin 2 and urocortin 3 . Following cessation of the intravenous infusions, haemodynamic variables returned to baseline after 40–60 min  than urocortin 2 in patients with heart failure but not in healthy subjects (P = 0.48).At the doses used, urocortin 3 caused greater mean increases than urocortin 2 in cardiac index . Surprisingly two recent studies did not detect a statistically significant reduction in PCWP in patients with heart failure with either urocortin 2/stresscopin In conclusion, we demonstrate that both urocortin 2 and urocortin 3 increase cardiac index and reduce peripheral vascular resistance. Their parenteral administration was feasible, safe and well tolerated. We conclude that these data provide further evidence suggesting urocortin 2 and urocortin 3 continue to hold promise for the treatment of heart failure.www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.All authors have completed the Unified Competing Interest form at


Chronotropic incompetence has prognostic value of all-cause and cardiovascular mortality in both patients with asymptomatic and symptomatic ischemic heart disease (IHD), regardless of traditional risk factors. The aim of this study was to investigate the relationship between chronotropic response during exercise test and the development of ventricular arrhythmias.153 patients with stable ischemic heart disease were screened and observed during the 24 months since October 2014 in a university hospital in Astana Kazakhstan. They underwent bedside electrocardiography, 24h heart rate Holter monitoring, echocardiography, exercise stress test (treadmill) for assessment of chronotropic index calculating at first contact. Holter- electrocardiography was repeated three times  to reveal life-threatening ventricular arrhythmias.The quantity of the ventricular extrasystoles was higher in the group with low chronotropic index. Low chronotropic index increased the risk of high grade ventricular extrasystoles more than two times (P=0.015); episodes of non-sustained VT more than three times (p<0.001); and episodes of sustained VT more than nine times (p<0.001).Chronotropic index less than 35.6 increases the risk for life-threatening ventricular arrhythmias in patients with stable chronicle ischemic heart disease irrespectively of severe left ventricle systolic dysfunction. According to World Health Organization data in 2012, 17.5 million people died of cardiovascular diseases as 31% of all causes of death in the world. From this number, 7.4 million people died of ischemic heart disease. Proceeding results of regional statistical reports, mortality of cardiovascular diseases in the Central Asian countries remains one of the highest in the world, making nearly 140 cases of 100 000 population.  test today. This article is devoted to evaluate the prognostic value of chronotropic function of the heart. According to epidemiologic studies, the profile of changing heart rate in and after exercise test has prognostic value . The maxIn 1970’s Ellestad et al. in a retrospective study of 2700 people, who underwent exercise ECG test, showed the inability of increasing heart rate during the test which is related to a larger risk of fatal events in the next 5 years more than ischemic ST segment depression  and thenThis is a prospective one-center cohort research conducted from October 2014 to October 2016. The research included adult patients with inclusion criteria of chronic stable IHD,with preserved (more than 50%) or mildly reduced (40-50%) LV ejection fraction (LVEF). Among the 480 patients with stable IHD, 135 of them were selected according to the inclusion criteria (108 men and 27 women) with mean age of 63 years old. All patients were hospitalized in the Cardiology Department of a university hospital in Astana, Kazakhstan. Before the beginning of the study, all patients obtained an informed consent, research did not conflict with the principles of Helsinki declaration and was approved by the local Research Ethics Committee of Astana Medical University. The exclusion criteria were: myocardial infarction, coronary artery bypass graft surgery ,percutaneous coronary intervention, acute coronary syndrome in the previous 12 months; angina pectoris class IV (Canadian Cardiovascular Society); heart failure class IV New York Heart Association (NYHA); congenital heart disease; valvular heart disease; non-ischemic cardiomyopathy; sick sinus syndrome, chronic atrial fibrillation; history of sudden cardiac death (SCD) with resuscitation; documented ventricle tachycardia (VT) and ventricle fibrillation (VF) in history; permanent administration of antiarrhythmic drugs; the presence of implanted cardiac devices, anemia, and documented thyroid diseases. All patients underwent anthropometric measurements, laboratory tests, 6-minutes walk test, 12-lead resting ECG, 12-lead 24-hour Holter-ECG and echocardiography was carried out on the same day as baseline examination. All participants underwent Bruce treadmill stress test protocol with the subsequent calculation of chronotropic indexes. The treadmill stress test was carried out according to guideline  / [3/4×(220 – patient’s age) – resting heart rate] + (reached heart rate – resting heart rate) / [17.20×(220 – patient’s age) – resting heart rate]+ (reached heart rate – heart rate in the first minute of recovery period)+ (reached heart rate – heart rate in the second minute of recovery period).The reached heart rate means maximum heart rate reached during treadmill stress test (beat per minute); and the resting heart rate means the heart rate before beginning stress test (beat per minute). Chronotropic reserve, the first minute of recovery period was calculated as a difference between the reached heart rate and heart rate at the end of the first minute of recovery period (beat per minute) . Some hiStatistical analysis: Kolmogorov-Smirnov test was used to assess the normality of distribution. The results of the quantitative variables presented as mean ± standard deviation (M±SD), and with non-Gaussian distribution as median and interquartile range ). Qualitative variables are presented as absolute values and percentages. Comparison of the qualitative characteristics was performed using χ² Pearson, Fisher’s exact test. Quantitative indicators are compared with each other using the student’s t-test for independent samples, and with non-Gaussian distribution using Mann-Whitney U-test. To assess the risk of life-threatening VA relative risk was calculated using analysis of contingency tables with calculation of 95% confidence interval (95% CI) by D. Katz method (15). For all types of analysis, a p<0.05 was considered statistically significant. Statistical analysis was performed using IBM SPSS statistics 20 software .Out of the 153 patients, 135 enrolled the study. Their data were completed for the analysis. Among patients, dropout occurred in 18 patients, two people died , and 16 people withdrew from the study of their own volition due to different reasons. Depending on the chronotropic index, patients were divided into two groups: with normal ChI (n=79) and with low ChI (n=56). Among the 135 patients who completed the study, there were 108 (80%) males; the average age of participants was 63 [63±6] years, with average follow-up period of 14.9±1.5 months. In table 1, the baseline characteristics of groups are indicated depending on the chronotropic index. The group with the normal chronotropic response had larger number of participants, males prevailed in both groups. There were also no differences in socio-economic status, ethnicity or the place of residency. Patients with normal chronotropic index were younger. Among patients with normal chronotropic index, about one third of them suffered diabetes mellitus type II that is nearly 1.5 times less than patients with low chronotropic index.As findings in table 1, there was lack of relationship between groups with normal and low chronotropic index. On the other hand; sex, average age, nationality, smoking and even degree of acceptable load  did not differ in both groups. But the presence of type II diabetes mellitus and the previous myocardial infarction in group with abnormal chronotropic response considerably exceeded comparing patients with normal heart rate response during stress test.Pathological chronotropic index prevailed also among patients with symptomatic heart failure. Patients with NYHA I heart failure were more in group with normal chronotropic response whereas NYHA III – in group with low index. There was approximately the same number of patients with NYHA II heart failure in both groups. With Spearman’s rank test, we revealed direct strong correlation between chronotropic index and LVEF . Moderate decrease of LVEF correlated with low chronotropic index .Average blood pressure measured in hospital was higher in group of participants with low chronotropic index. The average resting heart rate in patients with abnormal ChI exceeded comparing to persons with normal chronotropic index. The analysis of transthoracic echocardiographic parameters confirmed the relationship between increased dimensions and decreased global contractility of left ventricle in patients with low chronotropic response, but LV myocardial mass index did not differ significantly in both groups. Baseline electrocardiographic abnormalities depending on chronotropic index were distributed as follows: LV hypertrophy on ECG was revealed in 52 (65%) patients in group with normal chronotropic index compared with 39 (69%) patients in group with low index (P=0.36). The average night heart rate on 24-hour Holter-ECG was not different; 64±9.8 beats/min in group with normal chronotropic index and 66±7.2 beats/min in patients with low chronotropic index (P=0.08). Significant differences in two groups were revealed only in average daily heart rate during 24-hour Holter-ECG; the average daily heart rate was 74±4.8 beats/min in group with normal chronotropic index, and 83±7.6 beats/min in group with low chronotropic index (P=0.02).Results of treadmill exercise stress tests were coordinated with data of several studies (16). Patients with low chronotropic index reached smaller METs during the test and had more rigid profile of heart rate during recovery period . The com arrhythmogenesis markers is important for the prevention of SCD in IHD patients. In practice, primary prevention of SCD for patients with IHD without previous life-threatening VA mainly focuses on LVEF. Previous studies also indicated a significant role of chronotropic function of heart rate in the prediction of sudden cardiac death. In the present research, the possibility of chronotropic response indexes and possible predictors of fatal arrhythmia among patients with IHD is considered. Among the 56 patients with low chronotropic index, the relationship with development of life-threatening VA was revealed. The fatal coronary events and increased cardiac mortality recorded in patients with low chronotropic response  are subjective and anamnestic without the possibility of objective verification. The present study did not include a stress test using pharmacological autonomic nerve blockades. The ECG and Holter-ECG were performed during patient admission in the hospital on drug-free background after at least two days of drug withdrawal on ambulatory basis therapy. A small number of patients with comorbidities were prescribed drugs in the follow-up period, indirectly affecting the electrophysiological properties of the myocardium including macrolide antibiotics and short-acting bronchodilators, which could be the cause of changes in the ECG and Holter-ECG. In conclusion, chronotropic index less than 35.6 increases the risk for life-threatening VA development in patients with chronic ischemic heart disease. It requires longer observational studies for better evaluation of clinical outcomes with precise study on chronotropic function during ECG stress test as the possible predictor of fatal arrhythmia.


Eighteen open chested pigs had conductance catheter RV pressure‐volume (PV)‐loops recorded during PA snare to determine Ees/Eamax sw. This was then applied to 10 patients with chronic thromboembolic pulmonary hypertension (CTEPH) and ten patients with CTED, also assessed by RV conductance catheter and cardiopulmonary exercise testing. All patients were then restratified by Ees/Ea. The animal model determined an Ees/Eamax sw = 0.68 ± 0.23 threshold, either side of which cardiac output and RV stroke work fell. Two patients with CTED were identified with an Ees/Ea well below 0.68 suggesting occult RV dysfunction whilst three patients with CTEPH demonstrated Ees/Ea ≥ 0.68 suggesting residual RV energetic reserve. Ees/Ea > 0.68 and Ees/Ea < 0.68 subgroups demonstrated constant RV stroke work but lower stroke volume  and higher end‐systolic pressure . Lower Ees/Ea in CTED also correlated with reduced exercise ventilatory efficiency. Low Ees/Ea aligns with features of RV maladaptation in CTED both at rest and on exercise. Characterization of Ees/Ea in CTED may allow for better identification of occult RV dysfunction.Chronic thromboembolic disease (CTED) is suboptimally defined by a mean pulmonary artery pressure (mPAP) <25 mmHg at rest in patients that remain symptomatic from chronic pulmonary artery thrombi. To improve identification of right ventricular (RV) pathology in patients with thromboembolic obstruction, we hypothesized that the RV ventriculo‐arterial (Ees/Ea) coupling ratio at maximal stroke work (Ees/Ea Chronic thromboembolic pulmonary hypertension (CTEPH) occurs when organized thrombi obstruct the pulmonary arteries (PA) increasing pulmonary vascular resistance (PVR) and in turn elevating the mean PA pressure (mPAP) .Pressure‐volume (PV)‐loop methodology allows for RV‐PA Ees/Ea coupling to be defined as the matching between RV contractility (End‐systolic elastance – Ees) and PA afterload   were studied.2O and positive end‐expiratory pressure of 5 cmH2O. Paralysis was induced with an IV injection of pancuronium (0.15 mg/kg). Anaesthesia was maintained using a constant infusion of fentanyl (0.2 mcg/kg/min) and propofol (0.2 mg/kg/min). Arterial and venous cannulas were located for measurement of arterial blood pressure and central venous pressure, respectively, using multi‐parameter anesthesia monitor. Prior to placing the conductance catheter into the RV an IV injection of lidocaine  was administered.Swine were fasted for 12 h leading up to the procedure. Water was allowed until one hour before premedication. Premedication was undertaken with intramuscular injection of midazolam (0.5 mg/kg), ketamine (15 mg/kg) and atropine (0.02 mg/kg). Induction of anesthesia was performed using intravenous (IV) injection of fentanyl (5.0 mcg/kg) over 5 min and propofol (2.0–4.0 mg/kg) administered to effect. Oral endotracheal intubation was established for institution of mechanical ventilation with a respiratory rate of 12–15 breaths per min and tidal volume 10 ml/kg. The ventilator was set with volume control with peak pressure <12 cmHTD). A midline sternotomy was performed and the pericardium was removed. A 7‐F, 8 electrode conductance catheter  was inserted through a puncher in the RV apex and placed along the long axis of the ventricle  in triplicate using 10 mL cool saline injection. A 7‐F, eight electrode conductance catheter was then inserted through the venous sheath, advanced across the tricuspid valve and placed along the long axis of the ventricle in to the RV apex under fluoroscopic guidance , the RV and finally the PA (PA pressures were measured). Cardiac output was determined by thermodilution . Exercise testing was undertaken according to ATS protocols aiming for an optimal exercise test duration of 8–12 min.G(t), was calculated by measuring the sum of the conductance between the five remaining sensing electrode pairs. The conductance catheter was calibrated for parallel conductance G(p) using the hypertonic saline technique first described in the LV by Baan et al. (V(t), was calculated as follows: V(t) = 1/α × L2/σx[G(t) ‐ G(p)]; α the ratio of the conductance‐derived volume to the true volume calculated by COTD), L is the inter‐electrode distance, σ is the blood conductivity  and G(p) is the parallel conductance (conductance of fluids and tissues surrounding the RV).A 20‐kHz 30 μA current was applied to the outer most electrodes to generate an intra‐cavity electric field. The time varying conductance, n et al.  and has n et al. . The timThe conductance technique was used to measure the PV‐loop relationship during ventilation suspension to provide a beat‐to‐beat assessment of RV function at steady state for at least 5‐cardiac cycles Fig. . Two famThe conductance technique was used to measure the PV‐loop relationship during ventilation breath hold at end‐expiration to provide a beat‐to‐beat assessment of RV function at steady state for at least 5‐cardiac cycles Fig. . It was max). The diastolic parameters of ventricular function were end‐diastolic pressure (EDP), the maximum rate of isovolumic relaxation (dP/dtmin), the effective arterial elastance (Ea) . Five steady‐state PV‐loops were recorded to generate load‐dependent parameters of systolic and diastolic function. The systolic parameters of ventricular function were stroke work (SW), cardiac output (CO), stroke volume (SV), ejection fraction (EF), end‐systolic pressure (ESP) and the maximum rate of isovolumic contraction (dP/dtA family of PV‐loops recorded during an IVC snare were used to determine the Ees. Ees is the gradient of the slope of the end systolic pressure volume relationship (ESPVR) and is a load‐independent parameter of systolic contractility. Ees can be used with Ea to determine the ventriculoarterial‐coupling ratio (Ees/Ea). A family of PV‐loops was recorded during a PA snare to determine how systolic and diastolic parameters of RV function (as described above) vary in response to increasing afterload (Ea) and ventriculoarterial‐coupling (Ees/Ea).PV‐loop morphology was used to determine maximal RV efficiency from the SW/pressure volume area (PVA) relationship. Ventricular efficiency is defined as the ratio between SW and oxygen consumption (Burkhoff and Sagawa Pmax) from a nonlinear extrapolation of the dP/dtmax and dP/dtmin points on the RV pressure waveform  sinusoidal curve‐fitting algorithm to estimate the theoretical maximal isovolumic pressure  and compared with the Fisher Exact test. Linear regression analysis was used to determine Ees. A P < 0.05 was considered statistically significant. Analysis was performed using SigmaPlot 12.5  statistical analysis package. The primary outcome measure was Tau. The number of subjects required was informed from previous work . We decided to recruit 20 to account for possibly incomplete or poor quality datasets.Data are expressed as mean ± standard deviation and The animal study was approved by the Home Office (Project Licence 70/7967). All animals received humane care and the animal study adhered to the Code of practice for the housing and care of animals bred, supplied, or used for scientific purposes  Procedures Act, 1986, published 2014). The animal study was performed to conform to the guidelines from Directive 2010/63/EU of the European Parliament on the protection of animals used for scientific purposes.The clinical study was approved by the local research ethics committee (REC number 12/EE/0085), and complied with the guidelines set out in the Declaration of Helsinki. All participants gave written informed consent.P = 0.829) and Tau (P = 0.930) remained constant there was a significant increase in dP/dtmin (P < 0.001), explained by the load‐dependency of dP/dtmin and the significant rise in ESP (P < 0.001) whilst EDP remained constant (P = 0.626). Below the Ees/Eamax sw coupling ratio threshold of 0.68, RV SW, efficiency, and CO declined.Baseline hemodynamic data are shown in Table P < 0.001) and PVR (P < 0.001) were normal in the CTED group and elevated in the CTEPH group. Ea (P = 0.005) was elevated in the CTEPH group. While HR (P = 0.560) and Tau (P = 0.954) remained constant, there was a significant increase in dP/dtmax (P = 0.016) and dP/dtmin (P < 0.001) in those with CTEPH. This is explained by the load‐dependency of these measurements and the significant rise in ESP (P < 0.001) in those with CTEPH whilst EDP (P = 0.162) remained constant.Demographic human data from 10 patients with CTEPH and 10 patients with CTED are shown in Table max sw threshold established in the animal model (Table P = 0.006) and PVR (P = 0.003) were normal in the Ees/Ea ≥ 0.68 group and elevated in the Ees/Ea < 0.68 group. There was a significant increase in HR (P = 0.04) in the Ees/Ea < 0.68 group. While Tau (P = 0.418) remained constant, there was a significant increase in dP/dtmin (P = 0.003), again explained by the load‐dependency of this measurement and the significant rise in ESP (P < 0.001) whilst EDP (P = 0.103) remained constant. Although SW (P = 0.853) remained constant between the Ees/Ea subgroups, there was a significant reduction in CO (P = 0.024), SV (P = 0.006), ESV (P = 0.034) and EDV (P = 0.007) in the Ees/Ea < 0.68 group. The differences in heart rate and volumetric indices were not identified when patients were stratified by pressure.After reclassifying patients according to the Ees/Eael Table , we demo5).Two patients with CTED were identified with an Ees/Ea < 0.68 indicating occult RV pathology Fig.  and thre2 (%) was marginally higher in patients with CTED. Ees/Ea related to both VE/VCO2 slope and peak end‐tidal CO2 .Cardiopulmonary exercise test data for patients with CTED and CTEPH are displayed in Table CO2 Fig.  in patiemax sw was 0.68 ± 0.23, beyond which RV dysfunction ensued. Redefining patients with CTED and CTEPH using this Ees/Ea threshold revealed three patients with CTEPH who had an Ees/Ea ≥ 0.68, demonstrating RV energetic reserve and two patients with CTED who had Ees/Ea < 0.68. This suggests occult RV dysfunction that was not apparent on resting right heart catheterization. On exercise, CTED patients with lower Ees/Ea also developed greater exercise ventilatory inefficiency with an increased hyperventilatory response. This supports a possible link between resting RV dysfunction detected by conductance catheterization and unfavorable RV adaptation to exercise. These findings provide novel insight into RV energetics observed in CTED and CTEPH, potentially improving on the current disease definition in CTED and identifying those with RV maladaptation.This is the first study to use the conductance technique to first determine the interaction between the RV and PA in a large animal model to define an Ees/Ea threshold for maximal SW, and then applied it in a cohort of patients with CTED or CTEPH to help re‐characterize RV pathophysiology. The interaction between the RV and the PA determines the external work and metabolic efficiency of the ventricle. Animal model data have shown that the Ees/EaWe establish that while maximal efficiency is important from the perspective of understanding ideal energy transfer conditions between RV work and oxygen consumption, the threshold of maximal SW is the determinant factor in RV failure. We have demonstrated acute RV adaptation in response to acute changes in afterload. There is an immediate response where the RV systolic pressure rises to maintain ejection. Then, as the afterload continues to increase, there are only relatively small increases to EDP and EDV as the RV dilates and distends to accommodate the increasing systolic pressure required to attempt to facilitate ejection. As the systolic pressure rises beyond the threshold point of maximal SW, ESV increases and combined with the relatively small change in EDV, this results in a reduction in SV. This reduction in SV causes a decline in CO and SW, as the RV fails to maintain sufficient output against the increasing loading conditions. Therefore, in terms of efficiency and SW, as the afterload increases from baseline, RV output is adequately maintained through the arbitrary point of maximal efficiency until the loading conditions reach a threshold point of maximal SW at an Ees/Ea = 0.68. Beyond this threshold of maximal SW, SW and CO may continue to offer sufficient output to meet demand at rest. However, if the afterload loading conditions are increased further (as is observed during modest exercise), there is insufficient RV energetic reserve and the RV will fail to meet demand. Ees/Ea can be used as a surrogate load‐independent indicator for RV failure. Evaluating the Ees/Ea at maximal SW could better determine disease severity and guide management.We have established a threshold for RV‐PA ventriculoarterial uncoupling in an animal model, beyond which, there is insufficient energetic reserve to maintain adequate RV function. Theoretical models have predicted optimal mechanical coupling corresponded to an Ees/Ea = 1  in this condition. We used an animal model to define the Ees/Ea coupling ratio at maximal SW and, in one analysis, apply this threshold to re‐evaluate patients with CTED and CTEPH by assessing RV function. Previous studies have relied on single‐beat estimation methodologies to determine Ees from a real end‐systolic point on the baseline PV‐loop and a second theoretical point (Bellofiore and Chesler Applying an Ees/Ea coupling ratio threshold derived from our animal model suggested that in the majority of our CTED patients, the RV retained its energetic reserve whereas in only two patients, resting RV function appears to be compromised. Conversely whilst most patients with CTEPH have significant RV dysfunction, a few retain a RV energetic reserve. After reclassification, those patients with Ees/Ea uncoupling suffer a reduced SV, and therefore, HR and ESP is significantly increased to maintain adequate CO at rest. Reclassification was made in 25% of our cohort which may be clinically important. In those CTED patients that lack RV energetic reserve, endarterectomy or pulmonary vasodilator therapy may be indicated.2 slope gradients in patients with low Ees/Ea values. Higher end‐tidal CO2 values at anaerobic threshold also suggest preserved cardio‐ventilatory coupling with a lower hyperventilatory response to exercise in patients with preserved Ees/Ea values. A recent study of 42 patients with CTED undergoing pulmonary endarterectomy demonstrated an improvement in 6‐min walk distance of 49 m at 12 months post‐operatively (Taboada et al. An implication of reduced RV energetic reserve in CTED may be an impaired RV exercise response, giving rise to impaired exercise ventilation‐perfusion matching. This is supported by higher VE/VCOSome limitations of our study must be recognized. The porcine model of RV‐PA ventriculoarterial interaction has an open pericardium that reduces RV contractility and partly explains why porcine PVR is higher than in humans. However, this remains the best physiological model of assessing the response of normal RV function to changes in afterload, as LV‐RV interdependence is retained. Furthermore, fentanyl can adversely affect contractility and we inserted the conductance catheter apically in the animal model that may have further diminished RV contractility. Nevertheless, it remains the most commonly studied model (Kuehne et al. The Ees/Ea coupling ratio at maximal SW determined from an animal model defined an Ees/Ea threshold of 0.68, beyond which RV dysfunction occurs. Using this threshold we have detected occult RV pathology at rest in patients with otherwise normal pulmonary hemodynamics, and demonstrated RV energetic reserve in some cases of CTEPH. Detailed Ees/Ea coupling data may improve the diagnostic accuracy of patients with chronic pulmonary thromboemboli and usefully influence their management.None. There are no relationships with industry.Table S1. Cardiopulmonary exercise testing data when classifying patients by mPAP at rest.Click here for additional data file.


Patients with single ventricle (SV) circulations are at risk for heart failure, frequently burdened by both systolic and diastolic cardiac dysfunction. The mechanisms of adverse remodeling of functionally univentricular hearts are incompletely understood. Diffuse myocardial fibrosis is one of the candidate morphological substrates, for which cardiac magnetic resonance (CMR) derived native T1 times and extracellular volume fraction (ECV) have been used as markers. The purpose of this pilot study was to explore whether there is evidence of accelerated myocardial fibrosis in young children after the Fontan operation using CMR.Consecutive pediatric SV patients after the Fontan operation who were referred for a clinical CMR examination underwent T1 mapping using a modified look-locker inversion recovery approach. Patients with two relatively balanced ventricles were excluded. Native T1 times and ECV in the free wall of the dominant ventricle were measured along with ventricular volumes and mass. Results were compared with those from healthy pediatric controls as well as between dominant left (LVs) and right ventricles (RVs).2 = 0.71, p = 0.001).Thirteen SV patients (7 with a dominant LV and 6 with a dominant RV), aged 8.8 ± 4.9 years and 28 healthy control children  were included. Despite the younger age native T1 times were longer in the dominant ventricles of SV patients than those in the LVs of the control group . ECV in SV patients with dominant LVs was similar to that of controls while ECV in dominant RVs was increased . Among univentricular hearts, there was a trend towards shorter native T1 times in dominant LVs (p = 0.07). ECV was significantly lower in LVs than those in dominant RVs (p = 0.01). Indexed ventricular volumes and mass, ejection fraction, cumulative cardiopulmonary bypass or cross-clamp times did not correlate with native T1 or ECV. Native T1 times positively correlated with the age at the bidirectional cavopulmonary connection (rPre- and post contrast T1 measurements are feasible in children with functionally SVs. Higher T1 times suggest an increased likelihood of myocardial fibrosis in Fontan patients, especially in patients with a dominant RV. Whether the known greater risk for long-term complications following the Fontan completion in non-dominant LVs is a function of their increased fibrosis burden remains to be investigated.


Pressure-volume loops (PVL) provide vital information regarding ventricular performance and pathophysiology in cardiac disease. Unfortunately, acquisition of PVL by conductance technology is not feasible in neonates and small children due to the available human catheter size and resulting invasiveness. The aim of the study was to validate the accuracy of PVL in small hearts using volume data obtained by real-time three-dimensional echocardiography (3DE) and simultaneously acquired pressure data.3D). PVL3D were compared to conductance catheter measurements (PVLCond) under various hemodynamic conditions . In order to validate the accuracy of 3D volumetric data, cardiac magnetic resonance imaging (CMR) was performed in another 8 piglets.In 17 piglets (weight range: 3.6–8.0 kg) left ventricular PVL were generated by 3DE and simultaneous recordings of ventricular pressure using a mini pressure wire . Hemodynamic changes under different conditions were well detected by both methods (ICC 0.82 to 0.98). Inter- and intra-observer coefficients of variation were below 5% for all parameters.Correlation between CMR- and 3DE-derived volumes was good (enddiastolic volume: mean bias -0.03ml ±1.34ml). Computation of PVL3D generated from 3DE combined with mini pressure wire represent a novel, feasible and reliable method to assess different hemodynamic conditions of cardiac function in hearts comparable to neonate and infant size. This methodology may be integrated into clinical practice and cardiac catheterization programs and has the capability to contribute to clinical decision making even in small hearts.PVL Cond) is considered the gold standard for the determination of PVL and has been widely applied in basic and clinical research  kg), the accuracy of 3D-volume calculations was compared to cardiac magnetic resonance imaging (CMR). Anesthesia, non-surgical and surgical procedures were identical in both animal groups.Validation studies comparing PVL3D were compared to PVLCond under various hemodynamic conditions. Moreover, the accuracy of left ventricular, 3D-dervived volume calculations was assessed by direct comparison to volume calculations in CMR. All studies were analyzed by independent investigators in a blinded fashion.In this preclinical prospective study left ventricular PVLAfter intramuscular injection of ketamine (20 mg/kg), midazolam (0.5 mg/kg), and atropine (0.02 mg/kg), a peripheral venous catheter was placed and animals were anesthetized by continuous intravenous anesthesia with fentanyl (10 μg/kg/h), ketamine (5 mg/kg/h) and midazolam (0.2 mg/kg/h) throughout the experiment. Sufficient depth of anesthesia was ensured by monitoring heart rate and blood pressure for pain induced increases, testing of eyelid reflexes and reaction to cold and pain stimuli. If necessary, anesthesia was deepened by additional administration of fentanyl (10μg/kg) and/or ketamine (5 mg/kg). Muscle relaxation was performed throughout the procedure with pancuronium (0.2 mg/kg/h). Ventilation of the animals was done in a pressure-controlled mode .2, transcutaneous saturations and ECG were monitored continuously. Arterial and venous blood gas analysis were performed before and after any change in hemodynamic conditions. At the end of the experiment the animals which were still in deep anesthesia were euthanized by intravenous injection of T61® .Prior to the insertion of the conductance catheter or the pressure wire, a 4F sheath  was introduced into the right carotid artery. For preload reduction, a 10 mm dilatation balloon  was inserted via a 5F sheath , placed in a femoral vein. An additional central venous catheter  was placed into the left jugular vein. For transpulmonary thermodilution measurements (TPTD) a 4F 8 cm thermistor tipped femoral artery catheter  was placed in the right femoral artery as previously described . FemoralFor the assessment of ventricular volume data, 3D datasets were obtained using a matrix transducer . For data acquisition and data analysis a standardized protocol was used ,18. Beca™, Radi, St. Jude Medical, St. Paul, MN, USA) and its introduction into the left ventricle by a retrograde arterial approach without fluoroscopy. Data were recorded using the Radi Analyzer  with a sampling rate of 200 Hz.Continuous pressure monitoring was performed after calibration of a 0.014 inch (0.36 mm) mini pressure wire (PressureWirePVL were obtained by combination of the synchronized volume-time curves derived by 3DE and the simultaneously acquired pressure-time curves using customized software  16]..16].Acquisition was performed three times under steady state in every hemodynamic condition examined. Systolic function was measured using end-systolic elastance (Ees), which was calculated by single-beat estimation method . The eff10) as a practically load-independent parameter of ventricular chamber stiffness, using a single-beat approach [max and dp/dtmin) were determined from continuous pressure measurement.For the assessment of diastolic function, the indexed EDV was calculated at an end-diastolic pressure of 10 mmHg  was placed into the left ventricle using fluoroscopic guidance. After determination of parallel conductance by injection of 3 ml of 10% saline, PVL were recorded during expiratory breath hold and during preload reduction in three subsequent measurements and averaged. Determination of parallel conductance was done using Baan's equation for parallel conduction [Immediately after obtaining PVLnduction ,14. For nduction ,23.max, dp/dtmin and tau were calculated from the mean of at least 3 consecutive cardiac cycles. Linear fits estimated from recordings during preload reduction were used to calculate load-independent end-systolic pressure-volume-relations (Ees). Correspondent to assessment of diastolic function with 3DE and pressure wire EDV10 was calculated at an end-diastolic pressure of 10 mmHg.ESP, end-diastolic pressure (EDP), dp/dt3D and PVLCond were performed under closed and open chest conditions. As poor 3DE image quality on a closed chest results in inappropriate volume calculations [max and Pmax of more than 20% as indicators for effectiveness of esmolol dose [3D and PVLCond were obtained successively. For 3DE acquisition the conductance catheter was removed to avoid artifacts that could impair left ventricular volume calculations.Baseline measurements of PVLulations , distal lol dose ,25. Duri3DE was performed on closed chests just before the CMR and was repeated on closed and open chests after CMR.CMR was performed on a 3 Tesla whole body scanner . Retrospectively gated balanced steady state free precision (SSFP) cine images  with 30 For each slice and heart phase, endocardial borders (including papillary muscles) were traced manually in a short axis data set, covering the whole left ventricle using a dedicated analysis software . Left ventricular EDV, ESV, EF and SV were calculated.All data were analyzed using Graph Pad Prism 6  and SPSS version 22 . For Bland-Altman-analyses for multiple observations per individual MedCalc for Windows, version 12.5  was used. We used a subset of 10 randomly selected animals to determine intra- and inter-observer variability of 3DE-derived data by two different observers who were blinded to the previous measurements. Time between intraobserver measurements was 4 weeks. Intra- and inter-observer variability was expressed by the coefficient of variation (standard deviation (SD)/mean), and Bland-Altman analysis.Cond and PVL3D as well as open and closed chest measurements were compared by Bland-Altman analysis or by Bland-Altman analysis for multiple observations per individual [Agreement of PVLdividual . CorrelaCMR and 3DE volume calculations were compared using Bland-Altman analysis.3D correlated well with those calculated from PVLCond. Bland-Altman plots were calculated for each hemodynamic condition  did not change significantly during phenylephrine administration. The esmolol-induced changes were comparable between PVL3D and PVLcond. Application of esmolol resulted in a decrease in ESP, dp/dtmax, Ees and EF.Both methods reflected the same changes induced by the pharmacologic agents . During urements . Diastol3D were less than 5%  than Cassidy et al. (2 μg/kg/min) [max, dp/dtmin, Ees and EF as well as an increase in ESV, EDV and EDP [Alpha-adrenergic stimulation by administration of phenylephrine notably affected systolic function while diastolic parameters did not change significantly. Phenylephrine, an alpha-1 agonist, causes peripheral vasoconstriction and thus increases afterload, which was directly reflected by a significant increase in Ea . Consequ/kg/min) , we obse/kg/min) ,25 and oTo achieve satisfactory temporal and spatial resolution in the fast-beating infant heart, 3D full-volume datasets have to be used and recorded over 4–7 cardiac cycles. In consequence, beat-to-beat variability cannot be assessed by 3D full-volume acquisition mode. The echocardiographic evaluation of beat-to-beat variability is only possible using the technique of single-beat acquisition of 3D datasets with low temporal and spatial resolution . Kutty eBesides conductance catheter technique, several alternative methods have been developed to assess PVL. CMR-derived PVL have been tested in pigs and humans ,32. In s3D in pediatric hearts.Fully non-invasive approaches based on 3DE and radial tonometry  are promFor 3D volume measurement, an adequate imaging window is essential. Underestimation of 3D volume calculations can be related to blurred imaging of ventricular borders and difficult contour detection on post-processing. We demonstrated in our pilot study  that lef3D and PVLCond could not be obtained simultaneously. In contrast to findings in adult pigs [3D and PVLCond and might have resulted in wider limits of agreement and confidence intervals. As stated in the work of Hapfelmeier et al. hemodynamics such as cardiac output change from assessment to assessment. So a scenario with real repetition of measurements is hardly possible. In these cases Bland-Altman plots are still the best way to interpret the data [For technical reasons, PVLult pigs , we obsethe data .3D and PVLCond regarding detection and tracing of hemodynamic changes. Basing the calibration of volumetric data on the same reference in the beginning enabled us to study the tracking of hemodynamic changes of the two methods without an additional bias of a third volumetric method like TPTD. We cannot rule out that this might have led to bias.For volume measurements, the conductance catheter has to be calibrated with a reference method. Often this reference method is a thermodilution method. We also measured SV with TPTD and found a high bias with wide limits of agreement compared to CMR. We also compared 3D-derived volume measurements with CMR data and found that 3DE correlated better with CMR data than TPTD measurements and showed a smaller bias and limits of agreement. Therefore we decided to calibrate the conductance catheter with volumes obtained by 3DE which were closer to the CMR data. Moreover, we sought to examine the agreement of PVL3D could easily be applied in adults, e.g. during TEE-guided transcatheter aortic valve implantation or mitral valve clip procedure [Accurate measurement of cardiac size and function is particularly important in neonates and infants because fundamental decisions concerning conservative, interventional or operative therapy have to be made. In patients with borderline ventricles  , or singrocedure .3D and PVLCond are lacking so far. Therefore we decided to first do a validation for PVL3D compared to the goldstandard conductance technique in normally shaped small hearts to avoid further bias by these mentioned limitations of the conductance technique.The calculation of ventricular volumes measured by conductance technology is based on Ohm´s law, based on the assumption that the ventricle can be regarded as several stacked cylindrical segments. However, ventricular shape in congenital heart disease does not always meet this ideal geometric assumption. Central positioning of the catheter along the ventricular axis is also required for exact measurement of volume changes. Therefore abnormal shape of the ventricle or incorrect placement of the catheter influences the measurements by conductance technique. 3DE has the potential to correctly assess volumes even in malformed ventricles . Studies3D requires smaller vascular access and does not need additional fluoroscopy. Insertion of the pressure wire and measurement is easier and faster than that of the conductance catheter whose correct placement along the axis of the ventricle can be cumbersome, time-consuming and requires repeated fluoroscopy. Therefore PVL3D can be included into routine catheterization programs with minimal additional effort and has the potential to provide correct PVL even in malformed hearts as often found in congenital heart defects. In future, totally noninvasive approaches based on noninvasive pressure measurements and 3D-derived volume-time curves may improve serial assessment of cardiac function in daily practice.Compared to the conductance technology, PVLWe have demonstrated that the combination of 3DE and mini pressure wire measurements provides a reliable assessment of PVL compared to conductance catheter technique. This novel method is sensitive and accurate in detecting hemodynamic changes in the juvenile, mammalian heart. Due to its severe limitations, conductance technology is unlikely to be used as routine procedure to assess ventricular function. Our 3DE-derived PVL measurement protocol is a promising new approach to determine cardiac function in clinical settings especially during cardiac catheterization programs.S1 Table(DOCX)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Chronic left ventricular (LV) pressure overload causes relative ischemia with resultant LV dysfunction. We have recently demonstrated that low-intensity pulsed ultrasound (LIPUS) improves myocardial ischemia in a pig model of chronic myocardial ischemia through enhanced myocardial angiogenesis. In the present study, we thus examined whether LIPUS also ameliorates contractile dysfunction in LV pressure-overloaded hearts.Chronic LV pressure overload was induced with transverse aortic constriction (TAC) in mice. LIPUS was applied to the whole heart three times in the first week after TAC and was repeated once a week for 7 weeks thereafter (n = 22). Animals in the control groups received the sham treatment without LIPUS (n = 23). At 8 weeks after TAC, LV fractional shortening was depressed in the TAC-Control group, which was significantly ameliorated in the TAC-LIPUS group . Capillary density was higher and perivascular fibrosis was less in the LV in the TAC-LIPUS group than in the TAC-Control group. Myocardial relative ischemia evaluated with hypoxyprobe was noted in the TAC-Control group, which was significantly attenuated in the TAC-LIPUS group. In the TAC-LIPUS group, as compared with the control group, mRNA expressions of BNP and collagen III were significantly lower (both P<0.05) and protein expressions of VEGF and eNOS were significantly up-regulated associated with Akt activation . No adverse effect related to the LIPUS therapy was noted.These results indicate that the LIPUS therapy ameliorates contractile dysfunction in chronically pressure-overloaded hearts through enhanced myocardial angiogenesis and attenuated perivascular fibrosis. Thus, the LIPUS therapy may be a promising, non-invasive treatment for cardiac dysfunction due to chronic pressure overload. Heart failure (HF) is one of the major health problems with a prevalence of approximately 6 million in the United States (US) and more than 23 million worldwide –5. In thUltrasound is an acoustic wave with frequency higher than 20 kHz, the upper audible limit of humans. Ultrasound is clinically used not only for diagnosis but also for therapeutic purposes, including tumor ablation, thrombolysis, bone regeneration, and drug delivery . Low-intAll animal experiments were performed conform the NIH guidelines  and were conducted in accordance with the protocols approved by the Institutional Committee for Use and Care of Laboratory Animals of Tohoku University (2013 Idou-547). Male C57BL/6 mice  underwent transverse aortic constriction (TAC) to induce chronic LV pressure overload. They were separated every three or six individuals in the cages where was kept the temperature (22°C) and humidity (60%), and were given the food and water in the cages, and could access ad libitum. TAC procedures were partly modified and were performed as we have previously reported .,29.28,29Echocardiographic study showed that LV wall thickness was significantly higher in the TAC-operated groups than in the Sham-operated groups, although there was no difference in LV wall thickness between the TAC-operated groups . Also, t2, P<0.005)  . There wP<0.005) . AlthougP<0.005) , which wP<0.005) . There rSince relative ischemia has been reported to be involved in the transition from compensated hypertrophy to decompensated HF , we eval1-integrin and caveolin-1 are the key molecules in the LIPUS-induced therapeutic angiogenesis, which play crucial roles in mechano-transduction and subsequent activation of angiogenic signal pathways such as VEGF and endothelial NO synthase (eNOS) [We have previously reported that βe (eNOS) . We thusAlthough there were no differences in the circulating levels of VEGF and other angiogenic factors between the TAC-LIPUS and TAC-Control groups , the proIn the present study, we were able to demonstrate that the LIPUS therapy ameliorates LV contractile dysfunction in TAC-induced pressure-overloaded hearts in mice in vivo, where enhanced myocardial angiogenesis and attenuated perivascular fibrosis in the LV may play a pivotal role in the beneficial effects of the LIPUS . To the In the present study, the LIPUS therapy ameliorated LV contractile dysfunction caused by chronic pressure overload, associated with enhanced myocardial angiogenesis and suppressed perivascular fibrosis in the LV. These beneficial effects were observed when the LIPUS was applied to the hearts three times in the first week after TAC and was repeated once a week for 7 weeks thereafter Figs  and 2. HWe have previously demonstrated that the LIPUS therapy enhances the expression of VEGF and phosphorylation of eNOS, induces angiogenesis, and ameliorates LV dysfunction in a porcine model of chronic myocardial ischemia . In the 1-integrin and caveolin-1 are the key molecules in the LIPUS-induced therapeutic angiogenesis [We have previously reported that βogenesis . To studogenesis , we did VEGF signaling has been reported to play a crucial role in promoting angiogenesis and restoring blood supply to ischemic tissues in various pathological conditions, including LV pressure overload-induced HF ,35,36. I-/- mice compared with wild-type mice [eNOS is known as an important regulator of cardiac function as LVH and contractile function in response to LV pressure overload are deteriorated in eNOSype mice ,41. In tAlthough collagen type I is ubiquitously expressed, collagen type III is expressed in a relatively tissue-specific manner, which is highly expressed in the skin, lungs, and blood vessels . In the Hypertension is one of the major risk factors for HF. Although we have previously demonstrated that the LIPUS therapy is effective to ameliorate HF in a pig model of chronic myocardial ischemia  and a moIn the present study, no complications were noted as the intensity of ultrasound used is below the upper limit of the regulation for diagnostic devices. Due to its non-invasive nature, the LIPUS therapy is feasible even for elderly patients or complicated patients. We are now conducting a clinical trial of the LIPUS therapy in patients with refractory angina pectoris. Hypertensive heart disease and aortic stenosis would be other possible indications for the LIPUS therapy.Several limitations should be mentioned for the present study. First, although we have demonstrated the beneficial effects of the LIPUS therapy in HF models, including chronic myocardial ischemia in pigs , AMI in In the present study, we were able to demonstrate that the LIPUS therapy preserves contractile function in chronically pressure-overloaded hearts, associated with enhanced myocardial angiogenesis and attenuated perivascular fibrosis in mice in vivo. Thus, the LIPUS therapy may be a promising, novel, non-invasive therapy for cardiac dysfunction due to chronic LV pressure overload in humans.S1 Fig(A) Study protocol. LIPUS was applied to the whole heart only three times in the first week after TAC, while animals in the control group underwent the same procedures but without the LIPUS therapy. (B) Peak flow velocity at TAC. Results are expressed as mean±SD.(TIF)Click here for additional data file.S2 Fig(A) Representative echocardiographic images at 8 weeks after TAC. (B~G) Graphs showing the time course of anterior wall thickness (AWT) and posterior wall thickness (PWT) of the LV, LV dimension at end-diastole (LVDd), LVD at end-systole (LVDs), LV fractional shortening (LVFS), and LV ejection fraction (LVEF). Statistical analysis was performed at 8 weeks after TAC. Results are expressed as mean±SD.(TIF)Click here for additional data file.S3 Fig(A) Heart weight/tibial length (HW/TL). (B) Lung weight/tibial length (LW/TL). (C) Systolic blood pressure during the therapy. Results are expressed as mean±SD.(TIF)Click here for additional data file.S4 Fig(A) Graphs showing the relationship between LVDd and LVDs in TAC-operated groups. (B) Graphs showing the relationship between LVDd and LVDs in Sham-operated groups.(TIF)Click here for additional data file.S5 FigThese images showing p-eNOS, t-eNOS, p-Akt, t-Akt, VEGF and α-tubulin. Left; Control group. Right; LIPUS group.(TIF)Click here for additional data file.S6 FigGraphs showing the levels of growth factors in the serum. bFGF, basic fibroblast growth factor; PDGF-BB, platelet-derived growth factor-BB; VEGF, vascular endothelial growth factor. Results are expressed as mean±SD.(TIF)Click here for additional data file.S7 Fig(A) Protein levels of HGF in the acute and chronic phases. (B) Protein levels of bFGF in the acute and chronic phases. Results are expressed as mean±SD.(TIF)Click here for additional data file.S8 Fig(A) Study protocol. LIPUS was applied to the whole heart three times in the first week after TAC and was thereafter repeated once a week for 7 weeks in the LIPUS group, while the control group underwent the same procedures but without the LIPUS therapy. (B) Study setup. (C) Peak flow velocity at TAC. (D) Heart weight/body weight (HW/BW). (E) Lung weight /body weight (LW/BW). Results are expressed as mean±SD.(TIF)Click here for additional data file.S9 Fig(A) Representative echocardiographic images in Cav-1-KO mice at 8 weeks after TAC. (B~G) Graphs showing the time course of anterior wall thickness (AWT) and posterior wall thickness (PWT) of the LV, LV dimension at end-diastole (LVDd), LVD at end-systole (LVDs), LV fractional shortening (LVFS), and LV ejection fraction (LVEF). Results are expressed as mean±SD. Statistical analysis was performed at 8 weeks after TAC.(TIF)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.


Diastolic dysfunction promotes atrial fibrillation (AF) inducing left atrial (LA) remodeling, with chamber dilation and fibrosis. Predominance of LA phasic conduit (LAC) function should reflect not only chamber alterations but also underlying left ventricular (LV) filling impairment. Thus, LAC was tested as possible predictor of early AF relapse after electrical cardioversion (EC).96 consecutive patients, who underwent EC for persistent non-valvular AF, were prospectively enrolled. Immediately after successful EC (3 h ± 15 min), an echocardiographic apical four-chamber view was acquired with transmitral velocities, annular tissue Doppler and simultaneous LV and LA three-dimensional full-volume datasets. Then, from LA–LV volumetric curves we computed LAC as: [(LV maximum − LV minimum) − (LA maximum − LA minimum) volume], expressed as % LV stroke volume. LA pump, immediately post-EC, was assumed and verified as being negligible. Sinus rhythm persistence at 1 month was checked with ECG-Holter monitoring.E/é values (p = 0.012), no major LA volume differences (p = NS), but a stiffer LV cavity (p = 0.012) for a comparable LV capacitance (p = 0.461). Conduit contributed more (p < 0.001) to LV stroke volume in AF subpopulation. Multiple regression revealed LAC as the most significant AF predictor (p = 0.013), even after correction for biometric characteristics and pharmacotherapy (p = 0.008).At 1 month 62 patients were in sinus rhythm and 34 in AF. AF patients presented pre-EC higher Our data suggest that LAC larger contribution to LV filling soon after EC reflects LA–LV stiffening, which skews atrioventricular interaction leading to AF perpetuation and makes conduit dominance a powerful predictor of early AF recurrence.The online version of this article (10.1007/s00392-017-1188-9) contains supplementary material, which is available to authorized users. Atrial fibrillation (AF) is one of the most frequent arrhythmias and one of the major causes of stroke, heart failure and cardiovascular morbidity worldwide .It develops in 1 out of 4 middle-age adults in Europe and its prevalence continues to grow , 3. EvenUntil nowadays there have been no strong predictors that allow physicians to identify the AF patient in whom to attempt EC with an acceptable probability of subsequent sinus rhythm maintenance. On this topic, a lot of various data among ECG measurements, echocardiographic parameters and biomarkers have been proposed, but no method has demonstrated good predictability so far , 7.Some authors have suggested that atrial phasic function assessment can stratify the risk of AF post-EC . This isIn this study, we demonstrate the existence of a strong association between the conduit contribution to LV filling volume, as computed with 3D echocardiography, and the arrhythmia recurrence in a group of patients with persistent AF and recent EC.After appropriate informed consent in agreement with institutional human review studies committee guidelines and local IRB approval, we enrolled prospectively 96 consecutive patients who underwent EC for persistent non-valvular AF. Patients younger than 18 years, with mitral prosthesis or severe mitral regurgitation and patients who did not respond to EC were, per protocol, excluded. To minimize possible bias related to various cycle duration differences during AF, patients were imaged few hours after successful EC, in regular sinus rhythm. During subsequent clinical follow-up all patients underwent clinical survey and a 24-h Holter ECG recording at 1 month, with AF recurrence defined as symptomatic or asymptomatic episode of atrial arrhythmia  causing cardiology consultation. The characteristics of the patients’ population (subdivided according to AF recurrence within 1 month) are reported in Table Transthoracic echocardiography data were acquired after successful EC (3 h ± 15 min) using a Vivid E9  system with both a 2D probe (average frame rate 65 frame/s) and a 4V probe for 3D acquisition (average 30 frame/s). We used apical four-chamber and two-chamber gray-scale and color views, with pulsed and continuous mitral flow velocity tracings. An apical four-chamber tissue Doppler acquisition was also obtained, together with a triplane apical LV volumetric view using the 4V transducer.At the end of the standard examination, a multi-beat (at least five consecutive cardiac cycles) pyramidal 3D echocardiographic full-volume dataset was acquired from the apex in each patient. The volume data was displayed in real-time, two orthogonal apical views and three cross-sectional slices, with optional volume rendering techniques for visualization of valves and structures. Full-volume acquisition was obtained during held respiration, with dataset sector (frame rate ranging between 20 and 40 frames/s) dimensions and depth set to include both the ventricle and the atrium, assuring volume sampling rates between 15 and 25/s .Subsequently, using a commercially available software package , each view was aligned to the standard apical views, using the positions of the mitral annulus plane and of the apex as markers. Initialization was done at end-diastole (ED), using two clicks in each view , with contouring and 3D surface detection automatically drawn. Once completed for ED, the same procedure was used for ES, with LV endocardial border tracked throughout the entire cardiac cycle. Surface 3D detection was automatically triggered, and if necessary, the detected 3D surface was edited manually by adding landmark points. After both ED and ES images were finalized, full 4D surface detection was performed. The same procedure was followed for LA chamber using the mitral annular plane and the roof of the cavity as reference markers , 12, 13.LA longitudinal strain was assessed using a 2D speckle-tracking technique from standard gray-scale loops. Regional deformation of six LA segments located along the perimeter of the LA cavity was assessed in the apical four-chamber view starting from the QRS complex, with an average of six equally spaced wall segments, generally peaking in late systole, as LA peak strain. Longitudinal LV strain was also assessed from the same images which were used to evaluate LA strain and it was averaged over six segments along the ventricular septum, apex, and lateral wall . An examWe, then, performed an off-line analysis using a commercially available spreadsheet program to transfer data and synchronize the LA and LV volume curves as a function of time. Early after EC, patients presented regular sinus rhythm at ECG surface but with echo characteristics of atrial mechanical stunning, as could be assumed from the null or very little lateral a’ peak wave at mitral tissue Doppler imaging [4 (3–5) cm/s)]. At this stage, we assumed that atrial phasic functions could be computed asmax− LAVmin),reservoir: maximum LAV − minimum LAV / LAVmax, as already described with cardiac magnetic imaging  if data were not normally distributed. Differences between means were assessed by unpaired t tests. A Mann–Whitney rank sum test was used if data were not normally distributed. A multiple logistic regression model was used to test the relationship between LA phasic conduit function, on top of other echocardiographic and biometric measurements, and early AF recurrences. Least square regression analysis was used as necessary. To find a diagnostic cut-off value of conduit for identification of short-term AF recurrence after EC, nonparametric receiver-operating characteristics (ROC) curve analyses were performed and the area under the curve showing the discriminatory ability of the cut-off variable reported. Sensitivity and specificity values of the best cut-off variable were also calculated. A p = 0.002) and E/é (p = 0.012), for non-dissimilar LA volumes (maximum: p = 0.383 and minimum: p = 0.07), but a stiffer LV cavity, as documented by a higher β value (p = 0.012) for a comparable capacitance , as obviously did reservoir function (Table p = 0.0136), thus modulating a larger E/A ratio, whose difference between the two sub-populations, however, did not reach statistical significance (p = 0.063).Results for the entire patients’ population and after they have been subdivided according to AF recurrence within 1 month are reported in Table E/é ratio.Parameters significantly different at baseline between the 1 month AF versus sinus rhythm groups were used in the multiple logistic regression to test the existence of an independent predictor of AF recurrence short-term after EC. To minimize the problem of collinearity peak E wave value was not included, being already represented within the p < 0.001) with optimal sensitivity (90%) and specificity (85%).Results of the multiple logistic regression are shown in Table Interobserver reproducibility for conduit has already been reported .In the present study, we observed a strong relationship between the conduit atrial phasic function and arrhythmia recurrence early after EC in patients with persistent AF. This association suggests that information obtainable from the LAC computation does provide additional insight into the mechanical characteristics of the cavity and potentially stroke risk stratifies patients post-EC .It is well known that LA modulates LV filling and function in three distinct phases: as a reservoir for pulmonary venous return during ventricular systole, as a conduit from pulmonary veins directly into the LV chamber during early ventricular diastole, and as a pump that seals ventricular filling at the end of the cardiac cycle . In patiThe absence of any significant relationship, in the multivariate analysis, between the LV β stiffness coefficient and the recurrence of the arrhythmia points, but not exclusively, in favor of the second interpretation. Previous nuclear magnetic imaging data are indeed available that associate the reservoir function to the LA enhancement in AF patients, suggesting that those with AF have more structural changes as compared with healthy volunteers . Furtherr = 0.35 p < 0.001 and r = 0.23 p < 0.03, respectively). No relation, instead, could be demonstrated between conduit and AF duration pre-EC (r = 0.13 p = 0.53). However, this can be in part due to the limited number of patients for whom the arrhythmia duration was known (27/96). For this reason, besides the unavailability of echo data post-EC, we cannot confirm or exclude a potential modification of conduit in the first few weeks after EC due to the influence of a positive chamber remodeling that may take place in that same period.It must also be considered that the duration of the AF episode may affect LA conduit function post-EC through its influence on chamber remodeling pre-EC. In this regard, we could demonstrate a significant direct linear relationship between conduit (expressed in ml) and LA minimal and maximal cavity volume . While recognizing the shortness of such interval we must underline the fact that most of the recurrences take place shortly after EC . In any We have chosen the time immediately after EC to acquire all the echocardiographic data, thus obviously limiting the clinical implications of our findings on the everyday clinical practice, when patients are imaged generally before EC. This was done to obtain data in regular sinus rhythm, minimizing the problem that could derive from the irregular R–R intervals that characterize the AF condition preceding EC in these patients. This consideration, however, does not exclude, for the future, the idea of imaging patients before EC. As the focus of the pathophysiological reasoning relies on the atrio-ventricular coupling process, we are convinced that the variations in the R-R intervals, which characterize AF, cannot substantially obscure the information on which the prediction is based.This is a single-center, small-sized cohort study that needs to be reproduced and verified in a larger population possibly studied across different centers.Conduit phasic function is a good descriptor of diastolic derangement relating both LA and LV volumes in particular during AF, when the pump is lost. The increment in conduit, expressed relative to LV stroke volume, and the consequent reduction in reservoir function due to the reciprocation of the two phases in our model reflects a context of increased atrioventricular stiffness, a condition prone to be a strong predictor of AF early recurrence after EC. Whether this analysis can also provide potential better stroke risk stratification in patients’ post-EC will be the object of a future study.Below is the link to the electronic supplementary material.Supplementary material 1 (DOCX 14 KB)


After multivariable analysis, cardiac biomarkers remained the strongest predictors of LVMi, LVEDVi and LVESVi. NT-proBNP but none of the acute cardiac injury biomarkers were associated with remote LV wall thickness. Our analyses illustrate the value of cardiac specific biochemical biomarkers in predicting global LV remodeling after STEMI. We found no evidence for a hypertrophic response of the non-infarcted myocardium.Adverse left ventricular (LV) remodeling after acute ST-elevation myocardial infarction (STEMI) is associated with morbidity and mortality. We studied clinical, biochemical and angiographic determinants of LV end diastolic volume index (LVEDVi), end systolic volume index (LVESVi) and mass index (LVMi) as global LV remodeling parameters 4 months after STEMI, as well as end diastolic wall thickness (EDWT) and end systolic wall thickness (ESWT) of the non-infarcted myocardium, as compensatory remote LV remodeling parameters. Data was collected in 271 patients participating in the GIPS-III trial, presenting with a first STEMI. Laboratory measures were collected at baseline, 2 weeks, and 6–8 weeks. Cardiovascular magnetic resonance imaging (CMR) was performed 4 months after STEMI. Linear regression analyses were performed to determine predictors. At baseline, patients were 21% female, median age was 58 years. At 4 months, mean LV ejection fraction (LVEF) was 54 ± 9%, mean infarct size was 9.0 ± 7.9% of LVM. Strongest univariate predictors  were peak Troponin T for LVEDVi (R Myocardial injury caused by ST-elevation myocardial infarction (STEMI) leads to left ventricular (LV) remodeling, resulting in functional and structural LV changes . Over tiThe most widely investigated functional LV characteristic to predict patient outcome after STEMI is LV ejection fraction (LVEF) . SeveralThe objective of this study is to increase our understanding of the determinants of LV structural remodeling after STEMI. We performed a retrospective analysis of the GIPS-III trial, in which CMR was performed 4 months after STEMI. The primary endpoint of the GIPS-III trial on LVEF has been published previously . We studData was used from all patients included in the GIPS-III trial who underwent CMR assessment. The GIPS-III trial was a single-center, randomized, placebo-controlled trial, including STEMI patients treated with percutaneous coronary intervention (PCI) at the University Medical Center Groningen between January 1, 2011 and May 26, 2013, previously described in more detail , 11. PatCardiovascular magnetic resonance imaging (CMR) was performed 4 months after STEMI. LVEDV, LVESV, LVM, EDWT and ESWT were measured in addition to infarct size and LVEF, the primary outcome measure of the GIPS-III study . ImagingLaboratory analysis was performed at the laboratory department of the University Medical Center Groningen. Blood samples for assessment of myocardial injury with creatine kinase (CK), myocardial band of CK (CK-MB), and Troponin T were collected according to study protocol at baseline, and at 3, 6, 9, 12, 18, 24, and 36 h after PCI. Using the trapezoid method, area under the curve (AUC) values were determined over the first 36 h post-PCI from a median of seven blood samples . Other bβ) and significance level . Age, sex and variables with p-value ≤0.10 after correction for age and sex (and BSA in EDWT and ESWT), were included in multivariable analysis. Collinear variables were removed from multivariable analysis, based on the lowest R2 when combined with age and sex, until variance inflation factors were lower than ten. Multivariable linear regression analyses were performed using a forward stepwise algorithm, with cutoff for entry set at a significance level 0.05 to find independent predictors of LVMi, LVEDVi, LVESVi, EDWT and ESWT. To validate the models within the study cohort, a backward stepwise algorithm was used with cutoff for removal set at significance level 0.10, and significance level set at 0.05. Additionally, the bootstrap method was utilized, using 1000 repetitions for model selection, and the order of most prevalent variables was compared with the previous models. Significant variables in the multivariable model were reported with Std. β and p-value. The coefficient of determination (R2) was derived to assess the proportion of variance predicted by the multivariable linear regression model. Variables within the models were tested for significant interactions, in conjunction with age and sex. Analyses were performed with STATA/IC version 13.0 .Pearson product-moment correlation coefficient (Pearson’s rho) was derived to assess correlation between infarct size and the investigated structural LV characteristics. The percentage of deviating values of LVMi, LVEDVi and LVESVi was derived by comparison with 95th percentile (P95) values in a healthy reference population . UnivariCardiovascular magnetic resonance imaging (CMR) data was available for 271 (71%) patients participating in the GIPS-III trial. Baseline and follow-up clinical, biochemical, and angiographic characteristics are presented in Table Left ventricular (LV) structural characteristics in the study population are presented in addition to reference values of healthy adults of comparable age Table  18]. LV. LV18]. Univariate linear regression results are presented in Tables Multivariable linear regression models of LVEDVi, LVESVi, LVMi, EDWT and ESWT are presented in Table Delta values for NT-proBNP and eGFR between baseline and follow-up measures were tested in multivariable analysis but were not of additional value. Receiver operating characteristic (ROC) curves were made to analyze and visualize the performance of the multivariable models compared with the strongest univariate predictors in predicting LVEDVi, LVESVi and LVMi to be above P95 reference values Fig. . In addiWe studied the clinical, biochemical and angiographic predictors of LV remodeling characteristics 4 months after STEMI. Commonly used cardiac specific biomarkers for cardiac injury were the strongest predictors of the global structural LV remodeling response. We also considered the compensatory response of the remote non-infarcted LV wall thickness to STEMI. Interestingly, LV wall thickness of non-infarcted myocardium was not correlated with infarct size, biomarkers for cardiac injury, or other LV remodeling parameters, suggesting that the presumed compensatory response of remote myocardium is not related to cardiac injury caused by STEMI.Left ventricular (LV) volume indices after STEMI are affected by adverse remodeling, as emphasized by the strong correlations with infarct size. Predictors of LV dilatation after STEMI in previous studies include infarct zone, wall motion score index, peak CK, extent of coronary artery disease, LV dyssynchrony, and early mitral regurgitation , 20, 21.Within the multivariable model for LVEDVi, NT-proBNP was the strongest predictor, probably due to the relationship between LVEDV, wall stress and NT-proBNP. Heart rate during CMR assessment was an independent predictor of LVEDVi, which is a physiological effect resulting from increased LV filling times at lower heart rates.LVESVi increases and LVEF declines in post-infarction LV remodeling . In contLVMi was most strongly predicted by NT-proBNP, which was the only biochemical biomarker to remain significant in multivariable regression analysis adjusted for age, sex, hypertension, and blood pressure. NT-proBNP has been previously associated with LVM, and has been suggested to be used as a screening tool for LV hypertrophy –25. NT-pPrevious studies in humans have shown that LVMi is reduced in the first months after infarction due to the loss of infarcted myocardium, although baseline measurements were always acquired after STEMI , 28. We We observed that predictors of LV wall thickness in the remote myocardium generally correspond with predictors of LVMi. In addition, HbA1c appeared an independent predictor of both increased EDWT and ESWT. In the GIPS-III trial, patients with known diabetes were excluded, but one out of six patients were diagnosed with diabetes after randomization . In a prA previous study reports patients after STEMI to have significantly higher wall thickness in non-infarcted myocardium, compared to control patients . HoweverThere were several limitations to our study. We did not determine measures of myocardial edema, which might have influenced the relation of remote wall thickness with infarct size, and did not perform stress perfusion imaging to assess residual ischemia. CMR was performed at 4 months after STEMI, when LV remodeling might be ongoing. No additional CMR assessment was performed prior to, or after 4 months, to assess progression in remodeling. Mean infarct size (9% of LV mass) in our cohort was relatively small compared to other STEMI studies, possibly due to the inclusion criteria (first STEMI) and efficient management (median 155 min to treatment). Additional studies with a larger variability in infarct size might help to further investigate the relationship between remote myocardial remodeling after infarction. The use of in- and exclusion criteria of the GIPS-III trial has possibly affected our results. For example, known diabetes was an exclusion criteria and therefore the effect of prevalent diabetes on LV remodeling could not be studied.Our data underlines the strength of cardiac specific biomarkers in predicting global LV remodeling after STEMI. We found no evidence for the presumed hypertrophic response of remote non-infarcted myocardium at 4 months after STEMI.