Myocardial fibrosis and left ventricular (LV) longitudinal strain are independently associated with adverse clinical outcomes. However, the relationship between tissue properties and strain indices as well as their collective impact on outcomes are yet to be fully elucidated. We aim to investigate the relationship between LV global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS) with extracellular volume (ECV) and their collective impact.Consecutive patients referred for clinical cardiovascular magnetic resonance (CMR) due to cardiomyopathy were prospectively enrolled. All patients underwent CMR with T1 mapping. ECV was calculated incorporating native and post-contrast T1 as well as hematocrit. LV GLS, GCS, and GRS were assessed by feature tracking. Hazard ratios and Kaplan–Meier curves were produced to assess the association between strains and T1 mapping indices with a composite outcome of all-cause mortality and hospitalized heart failure.The study consisted of 259 patients with mixed referring diagnoses of non-ischemic/ischemic cardiomyopathy and 21 normal controls. Decreased GLS, GCS and GRS were associated with increased ECV, increased native T1, and reduced post-contrast T1 in a dose dependent manner when T1 or ECV was in the abnormal range. After a mean follow-up of 31 ± 23 months, 41 events occurred including 37 heart failure admissions and 4 deaths. Kaplan–Meier plots demonstrated that reduced strains were associated with reduced event-free survival predominantly in patients with increased ECV (≥ 28.3%). The worst outcome was among those with both reduced strains and increased ECV. In the multivariable models, increased ECV, reduced post-contrast T1 and reduced strains in all 3 directions remained predictors of outcome risk, respectively.Our findings highlight the intrinsic link between altered CMR tissue properties and impaired myocardial mechanical performance and additionally demonstrate improved risk stratification by characterizing tissue property among patients with reduced strain. Increased extracellular volume fraction (ECV), assessed by cardiovascular magnetic resonance imaging (CMR), is a valuable surrogate of myocardial fibrosis burden and is associated with adverse clinical outcomes –3. Left 2, significant arrhythmia, claustrophobia and metallic hazards. Normal controls were recruited among subjects without cardiovascular history or risk factors and had a normal electrocardiogram (ECG), transthoracic echocardiogram and CMR.This was a prospective study approved by the institutional review board. Informed consent was obtained from all participants who were recruited from patients referred for clinical CMR due to a referring diagnosis of cardiomyopathy at our institution between January 2012 and December 2018. All participants completed a questionnaire for demographic information and medical history. The clinical charts were reviewed to confirm cardiovascular history. Exclusion criteria included implanted pacemaker or defibrillator, renal insufficiency with estimated glomerular filtration rate < 45 ml/min/1.73 m2. T1 mapping was performed with a modified Look Locker inversion recovery sequence with a 3(3)5-scheme before and 15 min after contrast administration [All subjects underwent scans in a 1.5 T CMR scanner  with an 8-element phased array surface coil. No adenosine or regadenoson stress was administered. Cardiac volumes and systolic function were assessed using balanced steady-state free precession cine images with retrospective ECG gating during a breath-hold. Average temporal resolution was 50 ms. A stack of short axis planes  and 3 long axis planes  were obtained using the following imaging parameter: echo time (TE) 1.3 ms, repetition time (TR) 3.1 ms, flip angle 70°, and average in-plane resolution 1.3 × 1.3 mmstration . Native Biventricular volumes and ejection fraction (EF) were analyzed based on a consecutive short axis stack of cine images using commercially available QMASS software . LV volume and mass were normalized to body surface area.T1 values of the myocardium and blood pool were assessed in the pre- and post-contrast T1 mapping images. We averaged T1 values of the basal, mid and apical slices. Hematocrit was drawn on the day of CMR. ECV was calculated using the formula: where R1 = 1/T1 time .LV strains, including GLS, global circumferential strain (GCS) and global radial strain (GRS) were analyzed using feature tracking on cine images. The feature tracking contours of the LV endocardium and epicardium were drawn manually at end diastole which were propagated automatically to all phases . Contourt-test. Categorical variables were compared using chi-square or Fisher’s exact test as appropriate. The Jonckheere–Terpstra test was applied to test the linear trend for non-parametric data. The primary outcome of interest was a composite endpoint which included all-cause mortality  and inpatient heart failure admissions obtained from electronic medical records in our six-hospital health care system. A receiver operating characteristic (ROC) curve analysis was performed to create optimal cut points by using the maximum of Youden’s Index (as sensitivity + specificity – 1). Unadjusted survival functions were produced using Kaplan Meier curves stratified by LV strain as well as ECV. Multivariable Cox proportional hazards models were performed to estimate the average hazard ratio (HR) and 95% confidence interval (CI) across the follow-up period. Important clinical confounders included in the models were age, gender, hypertension, diabetes and presence of an infarct pattern on LGE. An alpha of 0.05 was considered statistically significant for confidence intervals and p-values. Inter-class correlation coefficients (ICC) were calculated for reproducibility of T1 mapping. SAS   was used for analysis.Continuous variables were described as mean ± standard deviation (SD). Categorical variables were presented as frequency and percentage. Continuous variables were compared between groups using Student’s Our study consisted of 21 normal controls and 259 patients with mixed diagnoses including non-ischemic/ischemic cardiomyopathy. The categories of cardiomyopathy and baseline characteristics are listed in Table The relationship between strains and the T1 parameters are shown in Fig. After a mean follow-up period of 31 ± 23 months, 41 patients reached the composite outcome, including 37 heart failure admissions and 4 deaths. Kaplan–Meier curves stratified by strain cutoff values demonstrated worsening event-free survival associated with worsening strain  for ECV, 0.990 (0.977 to 0.996) for native T1 and 0.993 (0.985 to 0.997) for post-contrast T1. The inter-observer reliability measured by ICC was 0.961 (0.759 to 0.988) for ECV, 0.976 (0.940 to 0.990) for native T1, and 0.968 (0.854 to 0.990) for post T1. All data are presented as the averaged ICC of each component variable.In this clinical cohort, we demonstrated that decreased GLS, GCS and GRS are all associated with increased ECV, increased native T1 and decreased post-contrast T1 in a dose-dependent manner. But the dose-dependent change only occurs when T1 parameters are above the normal range. Reduced strains are all associated with hazards of worsening outcomes, largely dominated by heart failure admissions. In addition, increased ECV and decreased post-contrast T1 are associated with outcome hazards but not native T1. However, the association of lower probability of heart failure free survival with reduced strain is present only when ECV is increased and not when ECV is normal. Nonetheless, those with both increased ECV and reduced strains have the worst event-free survival.There have been investigations to uncover the tissue characteristics that lead to change in myocardial mechanical performance. Surgical specimens from a septal myectomy of patients with hypertrophic cardiomyopathy  and fromAt present, GLS has been widely adopted in clinical research in the investigation of myocardial mechanical performance, which is largely credited to its high reproducibility. In contrast, GCS and GRS are less reproducible by echocardiography . As for Among strain indices, GLS has also been most consistently associated with risk of cardiovascular outcomes , 2, 4, 5There are several limitations to our study. First, optimal sampling for ECV calculation is debatable. We chose basal, mid and apical representative slices to aim for better coverage while some published reports favor not including the apical slice due to concerns over the partial volume effect in apical region . Our appThere is a dose–response relationship between tissue abnormalities assessed by T1 parameters and impairment  of GLS, GCS and GRS. Reduced strains are associated with reduced event-free survival predominantly in patients with increased ECV. Those with both increased ECV and reduced strains have the worst outcome. Our findings highlight the intrinsic link between the tissue property alteration and the myocardial mechanical impairment in the pathophysiology of heart failure and additionally demonstrate an essential role of tissue characterization in risk stratification among patients with reduced strain.


We aimed to investigate the comparative prognostic value of left ventricular ejection fraction (LVEF), mitral annular plane systolic excursion (MAPSE), fast manual long-axis strain (LAS) and global longitudinal strain (GLS) determined by cardiac magnetic resonance (CMR) in patients after ST-segment elevation myocardial infarction (STEMI).p = 0.023), MAPSE (p < 0.001), LAS (p < 0.001) and GLS (p < 0.001) were significantly related to MACE. According to receiver operating characteristic analyses, only the area under the curve (AUC) of GLS was significantly higher compared to LVEF  0.64–0.73; p < 0.001 vs. 0.60, 95% CI 0.55–0.65; p = 0.031. AUC difference: 0.09, p = 0.020). After multivariable analysis, GLS emerged as independent predictor of MACE even after adjustment for LV function, infarct size and microvascular obstruction (hazard ratio (HR): 1.13, 95% CI 1.01–1.27; p = 0.030), as well as angiographical  and clinical parameters .This observational cohort study included 445 acute STEMI patients treated with primary percutaneous coronary intervention (pPCI). Comprehensive CMR examinations were performed 3 [interquartile range (IQR): 2–4] days after pPCI for the determination of left ventricular (LV) functional parameters and infarct characteristics. Primary endpoint was the occurrence of major adverse cardiac events (MACE) defined as composite of death, re-infarction and congestive heart failure. During a follow-up of 16 [IQR: 12–49] months, 48 (11%) patients experienced a MACE. LVEF (GLS emerged as independent predictor of MACE after adjustment for parameters of LV function and myocardial damage as well as angiographical and clinical characteristics with superior prognostic validity compared to LVEF. Despite remarkable advances in the management of patients suffering from ST-segment elevation myocardial infarction (STEMI), the risk of subsequent cardiovascular complications and mortality post-STEMI still remains considerable . TherefoRemnant left ventricular (LV) function is a key determinant in decision-making after acute myocardial infarction and has a strong impact on short- and long-term prognosis . LV funcAlternative approaches for the determination of LV function with a more subtle depiction of longitudinal shortening in the course of ischemia are mitral annular plane systolic excursion (MAPSE) and fast manual long-axis strain (LAS) –9. MAPSEIn the context of acute STEMI, GLS has been shown to independently predict major adverse cardiac events (MACE) after revascularized STEMI compared with conventional LVEF , 15. BesWe, therefore, aimed to investigate the comparative prognostic value of LVEF, MAPSE, LAS and GLS by CMR in the acute stage post-STEMI for the occurrence of MACE.Prior to study inclusion, written informed consent was given by all participants. The study was designed and conducted in compliance with the Declaration of Helsinki and received approval by the research ethics committee of the Medical University of Innsbruck.2 and any other contraindication to CMR examination   years and 67 patients 15%) were female. Total ischemia time was in median 197 [IQR: 126-344] minutes. Baseline patient characteristics are provided in detail in Table 5% were fp = 0.333). Table CMR scans were performed at a median of 3 IQR: 2–4] days after pPCI. Time to CMR did not differ between patients with and without MACE (–4 days an = 228) of the overall cohort.LVEF of the overall population was 53 [IQR: 45–59]%, MAPSE 9.0 [IQR: 7.4–10.9] mm, LAS − 14.4 [IQR: − 19.6 to − 10.0]% and GLS − 12.0 [IQR: − 14.0 to − 10.0]%. Infarct characteristics were as follows: IS 14.0 [IQR: 7.3–23.7]% and MVO 0.1 [0.0–1.9]% of LVMM. MVO occurred in 51% (p = 0.023) and presented more often with cardiovascular risk factors (diabetes p = 0.012 and hypertension p < 0.001). The number of diseased vessels was higher (p = 0.002) and thrombolysis in myocardial infarction flow post-pPCI was lower in the group with MACE (p = 0.002). Furthermore, peak hs-cTnT values were higher in patients with MACE (p < 0.001).During a median follow-up time of 16 [IQR: 12–49] months, 48 patients (11%) suffered from MACE . Patients with MACE were significantly older (p = 0.023). All three LV myocardial strain parameters  were significantly related to MACE . Accordingly, GLS was higher in the MACE group . MAPSE was significantly lower in patients with MACE , whereas LAS was higher in the MACE group . Among parameters of myocardial damage, the presence (p = 0.024) and the extent of MVO (p = 0.031) were associated with MACE (Table LVEF was significantly lower in patients with MACE p = 0.03. All thp < 0.001).As illustrated by the Kaplan–Meier curves Fig. , GLS > −p < 0.001). In comparison to all investigated LV functional parameters, only the AUC of GLS was significantly higher than the AUC of LVEF , LAS to LVEF  and MAPSE to LVEF  led to a significant improvement in risk classification.In reclassification analysis, the addition of GLS to LVEF (continuous net reclassification improvement (NRI): 0.60 [95% CI: 0.31–0.88], p = 0.030) and LAS  significantly predicted MACE. As demonstrated by the clinical model (Table p = 0.003) after adjustment for clinical determinants of MACE . All variables included in multivariable analysis showed a VIF of < 3 .In a multivariable CMR model Table  includinTo the best of our knowledge, this is the first comprehensive study investigating the comparative prognostic value of all currently available functional CMR parameters including LVEF, MAPSE, GLS and LAS in acute STEMI patients revascularized by pPCI. The major findings can be summarized as follows: LVEF, MAPSE, GLS and LAS were significantly associated with MACE. The prognostic value of MAPSE, GLS and LAS was incremental to LVEF. GLS emerged as independent predictor of MACE after adjustment for measures of LV function , myocardial injury (IS and MVO) angiographical  and clinical parameters  with superior prognostic validity compared to LVEF. Taken together, feature tracking of GLS using CMR independently enables risk assessment after STEMI and expands the prognostic significance of LVEF.As recommended by the current guidelines, myocardial function should be determined in all patients with acute STEMI before hospital discharge . Due to In a previous work, we revealed CMR assessed MAPSE to independently predict the occurrence of hard clinical events with superior prognostic validity than LVEF following acute STEMI . HoweverLAS is another parameter of global systolic function which can be easily assessed from standard cine CMR images  without Feature tracking CMR is a high-resolution investigation of global and regional myocardial deformation by tracking the actual myocardial borders and following them subsequently , 28. DepAs emphasized previously, the optimal timing for measurement of myocardial deformation is unclear . In accoWe could demonstrate that GLS as a single marker independently improved personalized risk stratification after STEMI with superior prognostic validity compared to LVEF. On the other hand, we demonstrated that the predictive value of LAS or MAPSE in addition to LVEF was higher than that of LVEF alone. These combinations might serve as good alternatives for LV-based risk assessment after STEMI, if GLS is not available. As advantages, LAS and MAPSE are faster to measure and require no proprietary software compared to GLS . HoweverIn this observational CMR study, only stable patients (Killip class < 3) with acute and first-time STEMI were included; hence, our findings may not be transferable to hemodynamically less stable patients or to patients with previous myocardial infarction. Notably, the vast majority of STEMI patients presents with Killip class < 3 . AlthougGLS by feature tracking CMR emerged as independent predictor of MACE with superior prognostic validity compared to LVEF. The combination of LAS or MAPSE with LVEF revealed a significantly better prognostic value than LVEF alone and could be used as alternatives for risk stratification after STEMI.


Treatment of ST-elevation myocardial infarction (STEMI) has improved over the years. Current challenges in the management of STEMI are achievement of early reperfusion and the prevention of microvascular injury. Sonothrombolysis has emerged as a potential treatment for acute myocardial infarction, both for epicardial recanalisation as well as improving microvascular perfusion. This study aims to determine safety and feasibility of sonothrombolysis application in STEMI patients in the ambulance.Ten patients with STEMI will be included and treated with sonothrombolysis in the ambulance during transfer to the PCI centre. Safety will be assessed by the occurrence of ventricular arrhythmias and shock during sonothrombolysis intervention. Feasibility will be assessed by the extent of protocol completion and myocardial visibility. Efficacy will be determined by angiographic patency rate, ST-elevation resolution, infarct size and left ventricular volumes, and function measured with cardiovascular magnetic resonance imaging, and contrast and strain echocardiography. A comparison will be made with matched controls using an existing STEMI database.Sonothrombolysis is a novel technique for the treatment of cardiovascular thromboembolic disease. The first clinical trials on its use for STEMI have demonstrated promising results. This study will be the first to examine the feasibility of in-ambulance sonothrombolysis for STEMI.EU Clinical Trials Register (identifier: 2019-001883-31), registered 2020-02-25. ST-segment elevation on the electrocardiogram (ECG) indicates the occlusion of an epicardial coronary artery, most commonly due to thrombus formation at the site of a ruptured atherosclerotic plaque. The optimal treatment strategy for ST-elevation myocardial infarction (STEMI) is immediate restoration of epicardial coronary blood flow. Currently, primary percutaneous coronary intervention (PCI) with concomitant dual antiplatelet therapy and periprocedural anticoagulation constitutes the treatment of choice in STEMI patients . While sThe primary objective is to study safety and feasibility of sonothrombolysis application in the ambulance. The secondary objective is to evaluate the efficacy of in-ambulance sonothrombolysis as assessed by ST-elevation resolution, initial angiographic patency, infarct characteristics and left ventricular dimensions, function, perfusion and remodelling.The main endpoints are safety and practical feasibility. Safety will be assessed by the occurrence of ventricular arrhythmias defined as sustained ventricular tachycardia and/or ventricular fibrillation and the occurrence of shock defined as a systolic blood pressure <100 mm Hg in combination with tachycardia (heart rate >100/min), after initiation of sonothrombolysis and before PCI.These endpoints will provide relevant information regarding the safety of sonothrombolysis in the ambulance. Two forms of shock are relevant for the present study: anaphylactic shock  and cardiogenic shock. The incidence of cardiogenic shock in STEMI patients is around 7% . The incPractical feasibility will be assessed by the extent of sonothrombolysis completion during ambulance transfer. The ultrasound images will be saved for offline review; sonothrombolysis completion will be measured by counting the number of high mechanical index impulses applied in each view and the quality of the acquired apical views will be scored.Secondary endpoints are ST-elevation resolution, initial TIMI flow, infarct characteristics and left ventricular dimensions and function at baseline (3–5 days) and follow-up (6–8 weeks) with cardiovascular magnetic resonance imaging (CMR). Myocardial perfusion and left ventricular remodelling parameters will be assessed on follow-up contrast-enhanced echocardiography (3–4 months). Six-month event-free survival will be calculated from treatment initiation to 6 months afterwards, where events include death, congestive heart failure, life-threatening arrhythmias, recurrence of acute coronary syndrome and need for prophylactic defibrillator.This study will be conducted in accordance with the standards for Good Clinical Practice and the Declaration of Helsinki. Ethics approval was obtained on 3 February 2020 from the Medical Ethics Review Committee VUmc (reference: 2019.556—NL69980.029.19). Given the logistical challenge of the study and the primary aim to assess feasibility, a total of ten patients will be included. Due to the urgent setting and need for rapid initiation of the study protocol, only brief oral consent will be obtained. The written informed consent procedure will be deferred until after coronary angiography. Inclusion and exclusion criteria are listed in Tab. The study will be conducted by the Amsterdam University Medical Center—location VUmc in collaboration with the emergency medical services (EMS) in Zaandam, the Netherlands. In the ambulance, ECGs of patients with signs of STEMI will be faxed to the PCI centre via the Lifenet system . When STAt least three ECGs will be performed: before and after sonothrombolysis and after primary PCI. Absolute and relative cumulative ST-elevation resolution will be measured. Creatine kinase (CK), creatine kinase MB (CK-MB) and troponin levels will be obtained through standard care venous blood sampling in the hospital. Maximum biomarker levels will be reported.All patients will undergo invasive coronary angiography. Primary PCI will be performed according to the guidelines and at the discretion of the interventional cardiologist. TIMI flow grade before and after PCI, myocardial blush grade and thrombus burden will be reported.CMR imaging will be performed at baseline (3–5 days after presentation) and 6 to 8 weeks later. A clinical 1.5 or 3.0 T scanner with phased-array cardiac receiver coils will be used. Cine images are obtained using a steady state free precession sequence in three long-axis views and multiple short-axis views to examine left ventricular mass, function and volumes and to quantify left ventricular ejection fraction. T2-weighted images will be taken in short-axis planes identical to the cine images. T1 mapping in three parallel short-axis views positioned at the basal, mid and apical levels will be done using a Shortened Modified Look-Locker Inversion recovery sequence. First-pass perfusion will be performed in the same three short-axis views as T1 mapping using saturation recovery imaging. Early and late gadolinium enhanced (LGE) images are acquired 2 and 10 min, respectively, post-injection using a segmented gradient echo sequence. LGE images will be used to assess infarct size, the presence and extent of microvascular injury and to measure the area at risk. Short-axis T2-weighted images will be used for the detection of intramyocardial haemorrhage and infarct-related oedema. All CMR analyses will be performed in a core laboratory by blinded observers.Contrast-enhanced echocardiography will be performed 3–4 months after initial presentation. Left ventricular function and volumes will be measured. Left ventricular remodelling will be defined as a 20% increase in end-diastolic volume at the 3 month follow-up biplane contrast-enhanced echocardiogram compared with the pre-discharge echocardiogram.Follow-up will take place at 6 months by telephone contact and electronic patient records will be consulted.n (%) and mean with interquartile range (IQR). Secondary outcomes will be compared between patients included in this study and historical control patients. All these analyses will be considered exploratory. Categorical variables will be compared between groups using a chi-square test or Fisher’s exact test. Continuous variables will be compared using an independent sample t‑test  or the Mann-Whitney test (otherwise). The study and the trial conduct will be audited by an independent monitor from the Amsterdam UMC.Statistical analyses for the primary endpoints will be purely descriptive. Baseline characteristics will be presented, continuous variables will be given as Although multiple studies on new therapeutic strategies for STEMI have been performed in the pre-hospital setting Tab. , incorpoIt requires preparation of all materials and processes, briefing of EMS nurses and staff of the emergency control room as well as the presence of a trained physician to perform sonothrombolysis. The aim is to complete the entire process—from oral informed consent and microbubble preparation to ultrasound imaging and sonothrombolysis—during patient transfer. Obtaining oral consent, preparing the microbubble solution and obtaining appropriate ultrasound views is estimated to take 4 min. The ultrasound regimen consists of 30–60 high MI impulses and can be completed within 8 min, considering a 4–8 sec microbubble replenishment time in between the high MI impulses. To prevent any delay in patient transfer, the study treatment needs to be completed within 10–15 min, which approximates the mean duration of the ambulance ride to the PCI centre. A custom-built holder has been developed to keep the ultrasound machine in place Fig. . FurtherThrombolysis and PCI have significantly improved the prognosis of STEMI patients. However, two major clinical problems remain. Firstly, early reperfusion is restricted by patient factors, delays in transfer to PCI capable centres and delays in PCI initiation . The lonnot have epicardial recanalisation [In recent years, sonothrombolysis has emerged as a potential adjunctive therapy in cardiovascular ischaemic disease. The technique is based on the lytic and flow-inducing properties of the ultrasound-induced cavitation of contrast microspheres. Once high MI ultrasound impulses are administered during simultaneous infusion of ultrasound contrast agents, the contrast microspheres compress and expand and eventually collapse, inducing local microstreaming capable of thrombus dissolution (Fig. lisation . Improvelisation . The firlisation . As preclisation , a smalllisation . While flisation . TreatmeSince contrast ultrasound is portable, readily available and non-invasive, this technique can be provided at the point-of-care to the STEMI patient. To prevent system delay, sonothrombolysis in the ambulance may offer a convenient solution to achieve early myocardial reperfusion and concomitantly treat microvascular injury in the setting of a STEMI. This study will be the first study in the ambulance setting to examine feasibility of pre-hospital therapeutic contrast ultrasound in STEMI patients.Recruitment is expected to start in September 2020, completion of recruitment is expected in December 2020. The date and version of the study protocol approved by the ethical review board are: version 3, January 2020.


As the paucity of data focusing on evaluating cardiac structure and function in patients with or without gene mutation, this study was sought to investigate the correlation between genotype and cardiac magnetic resonance (CMR) phenotype in patients with left ventricular non-compaction cardiomyopathy (LVNC) and to explore prognostic relevance in this cohort if possible.Patients with LVNC who underwent CMR and targeted gene sequencing between 2006 and 2016 were retrospectively evaluated. Demographic data, clinical presentation, genetic analysis, CMR data and follow-up data of all participants were collected.p < 0.05). LA volume was able to discriminate patients with G + , as well as those with multiple genetic mutation . During a median follow-up of 5.1 years, Kaplan–Meier survival analysis revealed worse primary endpoint-free survival among carriers of multiple variants compared to G− group.Compared to negative genotype (G−) group, patients with positive genotype (G+) had larger left atrial volume (LAV), and carriers of multiple variants had lower left ventricular (LV) ejection fraction and cardiac index, increased LV fibrosis, larger LA volume, reduced LV global circumferential strain, LA reservoir strain and booster pump strain (all CMR feature tracking is a remarkable tool to evaluate implication, genetics cascade screen and predict outcome in LVNC population. LA volume is a sensitive and robust indicator for genetic mutational condition, of which facilities to guide clinical management and intensity of follow-up for patients and their relatives.The online version contains supplementary material available at 10.1186/s13244-021-01130-2. CMR characteristics are associated with genetics, especially influenced by multiple genetic mutations interacting.LA volume is a sensitive and robust indicator of genetic mutational condition.CMR-FT is a remarkable tool to evaluate implication, genetics cascade screen and prognosis in LVNC population.Left ventricular non-compaction cardiomyopathy (LVNC) is a genetically and clinically heterogeneous cardiomyopathy that can occur in isolation or in correlation with other congenital and acquired cardiac pathologies . It is cThe American Heart Association classified LVNC as a genetic cardiomyopathy, and gene mutations are associated with those encoding sarcomere, Z disk, cytoskeletal, ion channel proteins, or mitochondrial, and those involved in cellular energy metabolism . HoweverCurrently, echocardiography is considered to be the first line image modality for diagnosing LVNC with three different diagnostic criteria , 13, andPatients with LVNC who underwent CMR at our Hospital between April 2006 and July 2016 were enrolled in the study. Diagnosis of LVNC was referred to consensus of re-evaluated echocardiography and CMR imaging, according to the Jenni and Petersen criteria by experienced cardiologist and radiologist , 15. TheGenomic DNA was extracted from peripheral venous blood of each subject. The coding exons and their adjacent 10-bp intronic sequences of 72 cardiomyopathy-related genes were enriched referring to a custom-designed library  and were screened on an Illumina next-generation sequencing platform. The mean depths of all samples were > 4009, with coverage of > 99.7%. Related details are described in Additional file Variants were explained in the guidelines for mutation nomenclature of the Human Genome Variation Society. Variants were defined as polymorphisms and excluded once their minor allele frequency was ≥ 0.05% among East Asians in the Genome Aggregation Database . The patCMR images were performed at 1.5T MR  with retrospective electrocardiogram gating and 8-channel cardiac coil. For morphologic, functional and subsequent feature tracking analysis, bSSFP breath-held cine images were acquired in the following planes: one 2-chamber view, one 3-chamber, one 4-chamber view, and 8 equidistant short-axis planes covering entire left ventricle. Conventional imaging parameters included the following: repetition time 2.9–3.4 ms, echo time 1.1–1.5 ms, field of view 320 × 320 mm ~ 380 × 380 mm, temporal resolution: 30–55 ms, slice thickness 8 mm, matrix size 192 × 162 [LV volumes , LV cardiac index, LV ejection fraction (LVEF) and LV compacted mass index were measured using a workstation  based on the short-axis cine images. The normalized reference values of LV function metrics referred to Maceira AM criterion . The nonLeft ventricular and atrial (LA) strain analysis were performed offline using a commercially available software  based on 2-, 3- and 4-chamber and short axis cine images  curve was performed to identify the parameters with the highest sensitivity and specificity for discriminating genotype status. Univariable Cox regression models were computed to evaluate the unadjusted hazard of primary endpoint. Hazard ratios (HRs) with corresponding 95% confidence intervals were generated assessed with Durbin–Watson test. Moreover, the differences in event-free survival according to genotype status were evaluated by Kaplan–Meier survival analysis. Statistical analysis was performed by using IBM SPSS . Statistical significance was defined as TTN was the most commonly involved gene (30%), followed by MYBPC3 (11.8%), KCNE1 (11.8%), DMD (11.8%), and DSP (11.8%) , of 20 (71.4%) of them were male. 17 pathogenic variants were found in 11 (39.3%) of patients, of which 10 (58.8%) of variants were located in sarcomere genes  as well as greater LV end-diastolic volume index (133.4 ml/m2 ± 52.3) and LV end-systolic volume index (93.7 ml/m2 ± 56.5)  (Table p < 0.001). LV global deformations were associated with CMR parameters regarding the non-compacted areas, such as LV non-compacted thickness, LV indexed non-compacted mass. There were fair correlations between LV strain and the thickness and mass index of compacted myocardial. There was nonsignificant trend toward LA parameters derived from CMR-FT and parameters of compacted and non-compacted areas.As shown in Table n = 7, 70.0% vs. n = 12, 66.7%, p > 0.99) and percentage of LGE  which only 7 patients involved in LGE > 15%. Lower LVEF, LV cardiac index and larger percentage of LGE were observed in carriers of multiple variants compared to noncarriers  , and strongly predicted carriers of multiple variants in this cohort   Fig. .Fig. 3CoDuring a median follow-up of 5.1 years , 7 (23.3%) patients were documented cardiovascular death and 3 (10%) patients underwent from heart transplantation. Of those, 5 (50%) were G+ and 4 (40%) were carriers of multiple variants. No patients lost follow-up. Patients presented with adverse events were associated with lower EF, larger volume index and more impaired deformation in left ventricle and atria as well as LV indexed mass and fibrosis. Using univariate Cox analysis, variables as previously mentioned emerged as predictors of primary endpoint as well as LV regional strain . In our study, LA volumetric and deformation measurements were evaluated by CMR-FT for the first time. Compared to G−, patients with G+ had significantly larger LA volume, whereas not of myocardial strain parameters. And patients with multiple mutation had more severe LA reservoir  and booster pump (active strain) dysfunction. There is a subtype, restrictive LVNC, characterized by LA or biatrial dilation and diastolic dysfunction [Moreover, it has been demonstrated that impaired LA function is an independently predictor of new-onset atrial fibrillation. During hemodynamic stress or exertion, LA serves as the modulation of LV diastolic filling and cardiac performance by reservoir, conduit, and booster pump function . In 339 function . This maIt is well recognized that 15–30% of patients with LVNC could suffer from premature death, and approximately 10% could develop severe HF that may eventually lead to HT . One morThere were several limitations in this study. First, this was an observational study, which might have been associated with an intrinsic bias. Second, this is a single-center study with relatively small sample size, which might limit the generalizability of the findings and need larger populations to confirm these finding, especially in prognostic result. Third, differences of strain measurements caused by various CMR-FT vendors cannot be excluded. So standardized postprocessing methods would be desirable to facilitate comparative analysis of LV deformation and reduce inter-vendor variability.Cardiac involvement, assessed by CMR presentation, is associated with genetic status in patients with LVNC, especially influenced by multiple genetic mutations interacting. LA volume is a sensitive and robust indicator of genetic mutational condition, of which facilities to guide clinical management and intensity of follow-up for patients and their relatives. CMR-FT is a remarkable tool to evaluate implication, genetics cascade screen and provide prognostic information in LVNC population.Additional file 1. Data S1. Gene panel. Table S1. Criteria for classifying pathogenic variants according to ACMG guideline. Table S2. Rules for combining criteria for pathogenic and likely pathogenic variants. Table S3. Primers for Sanger sequencing confirmation. Table S4. Pathogenic and likely pathogenic variants detected in the cohort. Table S5. Left ventricular segmental strain data assessed by CMR feature tracking. Table S6. Univariate Cox analysis of LV segmental strain for predicting primary endpoint.


Precision medicine is a new frontier in healthcare that uses scientific methods to customize medical treatment to the individual genes, anatomy, physiology, and lifestyle of each person. In cardiovascular health, precision medicine has emerged as a promising paradigm to enable cost-effective solutions that improve quality of life and reduce mortality rates. However, the exact role in precision medicine for human heart modeling has not yet been fully explored. Here, we discuss the challenges and opportunities for personalized human heart simulations, from diagnosis to device design, treatment planning, and prognosis. With a view toward personalization, we map out the history of anatomic, physical, and constitutive human heart models throughout the past three decades. We illustrate recent human heart modeling in electrophysiology, cardiac mechanics, and fluid dynamics and highlight clinically relevant applications of these models for drug development, pacing lead failure, heart failure, ventricular assist devices, edge-to-edge repair, and annuloplasty. With a view toward translational medicine, we provide a clinical perspective on virtual imaging trials and a regulatory perspective on medical device innovation. We show that precision medicine in human heart modeling does not necessarily require a fully personalized, high-resolution whole heart model with an entire personalized medical history. Instead, we advocate for creating personalized models out of population-based libraries with geometric, biological, physical, and clinical information by morphing between clinical data and medical histories from cohorts of patients using machine learning. We anticipate that this perspective will shape the path toward introducing human heart simulations into precision medicine with the ultimate goals to facilitate clinical decision making, guide treatment planning, and accelerate device design. The human heart beats 100,000 times a day, 40 million times a year, and three billion times throughout an average lifetime. Four centuries BC, Aristotle recognized the heart as the most important organ of our body and this observation still holds true today. In the early 17th century, William Harvey proved the function of the heart and the circulation of blood, a discovery that is considered the greatest medical achievement of all time. Throughout the past three decades, our understanding of the human heart has become much more quantitative, made possible by the close collaboration between medical scientists, biologists, and mathematical modelers. Today, we are at a critical turning point where we can confidently assume that, within the next decade, we will be able to model and simulate anybody’s individual personalized history of the heart. We take this opportunity to revisit what is possible to model and simulate today, what may become reality in the near future, and how mathematical modeling will guide medical device design and clinical decision making in the era of precision medicine.idealized cylindrical models that only focus on cross-sections of the left ventricle to rapidly develop and test constitutive models under physiological and pathological conditions (Guccione et al. elliptical left ventricular models with easy reproducibility and popular applications in benchmarking constitutive models (Nielsen et al. elliptical biventricular models, which can illustrate the effects of pulmonary and systemic hypertension, while still utilizing a generic geometry (Göktepe and Kuhl axisymmetric left ventricular models that can be constructed by rotationally sweeping a cross section of the left ventricular anterior free wall represented through a set of epi- and endocardial points with discrete fiber orientations (Guccione et al. anatomic left ventricular models from personalized geometries (Genet et al. anatomic bi-ventricular models (Sahli Costabal et al. anatomic whole heart models from real personalized geometries (Zygote The art of mathematical modeling is to reduce a problem to the simplest possible mathematical description that is still manageable and, at the same time, detailed enough to capture the relevant effects. Figure s Zygote  that becs Zygote .monodomain models (Aliev and Panfilov bidomain models become necessary (Pathmanathan et al. mechanical models characterized through the equations of motion or Newton’s second law (Nash and Hunter electro-mechanical models of excitation-contraction coupling (Cherubini et al. chemo-electro-mechanical models trace the origin of the electrical excitation back to ionic currents across individual cells, for example, to understand the effects of drugs on the heart Sahli (Costabal et al. computational fluid dynamics models that represent details of the fluid flow become necessary (Taylor et al. fluid-structure interaction models that capture not only the fluid flow within the contracting atria and ventricles, but also its interplay with the endocardium and the valves (Kaiser et al. Fortunately, not all simulations of the heart require complex whole heart modeling. The choice of the model depends strongly on the medical condition of interest, or, more precisely, on the relevant physics that govern this medical condition. Problems associated with the excitation of the heart, arrhythmias, or pacing, are represented through the integral equations of action potential propagation, in the simplest case through The beauty of most constitutive models of the heart is that they are hierarchical and modular in nature and easy to expand or combine with one another. For the electrical behavior, the simplest phenomenological model for excitable cells is the Fitz Hugh-Nagumo model FitzHugh  and its Clearly, the ultimate objective of human heart modeling is the individualized prediction of different treatment outcomes with the goal to virtually select the most promising strategy within the paradigm of precision medicine (Taylor et al. In the USA alone, over 850,000 people die as a result of cardiovascular disease and more than 370,000 sudden cardiac deaths are related to arrhythmias (American Heart Association We create the Purkinje network for rapid cardiac excitation as a random fractal tree (Sahli Costabal et al. Figure Drugs can induce changes in cardiac electrophysiology by interacting with specific ionic channels. Undesirable side effects of some of these compounds include cardiac arrhythmias. A particularly lethal type of arrhythmia is torsades de pointes (Dessertenne Multiscale modeling can help to characterize the effects of drugs in cardiac electrophysiology (Sahli Costabal et al. Figure The main function of the heart is to pump blood through the cardiovascular system to continuously supply all other organs with oxygen and nutrients while removing carbon dioxide and other waste products. Upon electrical depolarization, the muscle cells in the heart release calcium ions, which activate actin-myosin interaction, sarcomere shortening, and active muscle contraction. An in-depth biophysical insight into the ventricular mechanics through multi-scale computational modeling requires realistic constitutive models that characterize this nonlinear, anisotropic, passive, and active tissue behavior, as well as the in vivo geometry, microstructural architecture, hemodynamic loading, and kinematic constraints of the heart. With a view toward personalized simulations, we need to calibrate all model parameters, loads, initial conditions, and boundary conditions to accurately match the physiological response.Figure Figure For patients who suffer from arrhythmias, an irregular or abnormal beating of the heart, implantable cardioverter defibrillators and artificial pacemakers continue to be life-saving devices. While implantable cardioverter defibrillators treat fast or chaotic rhythm disorders (Luther et al. The pacemaker lead is a long flexible wire of a length on the order of 150 mm. In a finite element setting, we can represent it with beam elements. It has a cross sectional area of 3.0 mm, which is magnified in Fig. A pacemaker lead is a thin flexible wire. During the cardiac cycle, its main mode of mechanical deformation is bending. The pacemaker lead curvature is the primary kinematic quantity of interest to quantify this deformation mode. We can characterize the curvature through the section curvature, the curvature change about two orthogonal planes. Figure Heart failure is a progressive chronic condition in which the heart is unable to pump enough blood to meet the body’s oxygen demand. With a five-year mortality rate of 50%, heart failure remains–and will remain in the foreseeable future–one of the most common, costly, disabling, and deadly medical conditions worldwide (World Health Organization Cardiac growth models typically build on the theory of finite growth (Rodriguez et al. Our results in Fig. A ventricular assist device is a battery-operated, mechanical pump that is used for end-stage heart failure patients to help their left ventricle pump blood to the rest of the body (Rose et al. We previously created a model of a failing left ventricle supported with partial left ventricular assistance in a four-chamber generic heart model (Sack et al. s Abaqus . We simus Abaqus . The mods Abaqus . The lefComputational simulations provide a window into the effects of left ventricular assist devices on myocardial dynamics. The contour plots of the free wall and septal stresses illustrate the potential of computational modeling to quantitatively compare the myofiber stress in the ventricular wall for varying rotational speeds of the assist device. Specifically, we have created a geometrically and physically realistic model of an end-stage failing heart with representative systolic and diastolic myocardial material properties coupled to lumped parameter Windkessel-like models of the pulmonary and systemic circulations (Sack et al. Understanding the in vivo loading and boundary conditions for cardiovascular implants remains a major challenge for device design manufacturers. Characterizing these conditions is not only critical to guide the design specifications for cardiac implants but also to select the optimal device and device placement for each individual patient. Typically, device design and placement are studied using benchtop cadaveric tests, animal studies, and clinical imaging. The precise quantification of the forces between the device and the tissue is virtually impossible, especially in the beating heart. Mitral regurgitation is a chronic condition of the left heart during which the mitral valve does not close completely in the systole and allows leakage of blood back to the left atrium. Edge-to-edge mitral valve leaflet approximation, the so-called Alfieri procedure, is often performed for patients with ischemic mitral regurgitation (Fucci et al. We use the Living Heart Model (Baillargeon et al. l Abaqus . When plFigure In the healthy heart, the mitral valve manages unidirectional blood flow from the left atrium to the left ventricle by opening and closing in a precisely coordinated manner. Functional mitral regurgitation, a back flow of blood from the ventricle into the atrium, is a clinical condition that can occur in response to myocardial infarction (Glower et al. We induce functional mitral regurgitation through myocardial infarction in the Living Heart Model by modifying the active material properties in the infarcted region while leaving the passive material properties unchanged. By varying the size of the modified region, we can induce degrees levels of myocardial infarction causing different degrees of mitral regurgitation. Figure Our device design study indicates that, among the three design variables, the strongest effect is from changing the length, which is likely due to different chordae being engaged with various lengths. This highlights the importance of identifying the appropriate chordae that need to be included or excluded in the engagement with the ring to minimize mitral regurgitation. Based on the myocardial infarction model and the ring design in this study, the engagement of marginal chordae that attach to the P3 scallop seems to affect the A3-P3 coaptation segment while the basal posterior chordae are engaged to improve the A2-P2 coaptation. After the initial optimization study, we selected the best design with the smallest objective function as the new starting point for further design optimization using the downhill simplex method Isight . This seIn understanding physiological and pathological conditions of the human heart, high fidelity multi-physics models of hemodynamic phenomena are of critical importance. Depending on the type of application, it is often sufficient to represent the pump function of the heart through one-dimensional fluid network models that accurately capture the dynamic pressure-volume changes in the intra- and extra-cardiac circulation (Baillargeon et al. In the fluid structure interaction approach (Aksenov et al. To understand the forces that act on heart valve leaflets, it is critical to not only study the fluid or the structure in complete isolation, but to understand how the blood flow modulates the shape of the leaflets and, in turn, how the motion of the leaflets modulates the flow conditions. A recent study that compared finite element analysis and fluid structure interaction found that, in agreement with in-vitro studies of artificial aortic heart valves, the fluid structure interaction approach predicts higher effective stresses in the leaflet belly and edge regions (Sodhani et al. Coronary artery disease is the number one cause of death for both men and women in the United States every year (Go et al. To create realistic, anatomically variable computational phantoms to conduct virtual imaging trials in cardiac imaging, we combine the Living Heart Model (Baillargeon et al. This study offers a major advance to enable realistic virtual imaging trials in cardiac imaging. Combining a prototype human heart model with extended cardiac-torso whole body models, we created a new series of realistic four dimensional computational phantoms. We have shown that different hearts can be integrated into different background anatomies to provide a diverse collection of phantoms capable of simulating a range of normal and abnormal cardiac anatomies and functions. To image the phantoms, we created an accurate computed tomography simulation package capable of simulating realistic cardiac computed tomography data from various manufacturers. This computational platform provides the essential tool to quantitatively optimize clinical cardiac technologies in terms of image quality and radiation dose for more precise and personalized imaging of the heart. As illustrated in Fig. Digital twins, virtual patients based on computational modeling and simulation, have advanced as an important technology to improve efficiency of clinical trials for new device designs (Madni et al. The ENRICHMENT trial, a new in silico clinical trial for cardiac device design, combines digital evidence from simulations with physical evidence from real patients and assesses model credibility in accordance with engineering standards. Figure e Abbott . To redue Abbott . The proe Abbott .The objective of the ENRICHMENT trial is to explore the merits of designing and virtually testing a medical device in its end-use environment before building and physically testing prototypes. At the same time, it studies the possibility of utilizing data generated in virtual patients as credible evidence in a regulatory device review. The trial uses physics-based computational models and simulations of the device, implanted within a cohort of beating heart models, constructed to represent the disease state and other inclusion criteria in a virtual patient population. To create and validate these virtual patient models, the trial uses clinical information from real patients. Statistical variations from the validation set will be used to represent the target patient population. Initially, for proof of concept, the ENRICHMENT trial focuses on the condition of functional mitral regurgitation and on a patient population that shows acute success: Patients with severe mitral regurgitation, small ventricles, good ejection fraction, and a history with optimized medical management of heart failure. To accurately simulate the clinical endpoints of these functional mitral regurgitation patients, their computational models include their annulus, their mitral valve, their papillary muscles, their chordae, and their left ventricle simulated through the complete cardiac cycle. The constitutive behavior, hemodynamic loading, initial and boundary conditions are similar to the baseline model in Sect. The general objective of this study is to raise awareness and capability for others to perform in silico clinical trials, agnostic to the software tools. In contrast to classical clinical trials that use simulation as a post-processing tool for data analysis, the ENRICHMENT trial uses silico testing early on in the workflow to put less patients at risk, save time and resources, and provide better designs with a faster turnaround time. The specific objective of the trial is to demonstrate how digital evidence, in the form of virtual patients, can be used to significantly reduce the time, cost, and risk with human clinical trial data collection. On a broader scale, this study demonstrates that a collaborative product lifecycle management platform can significantly improve the robustness, response time, and transparency of the medical device review process. It enables regulators with full digital access to all relevant information and people required to make science-based, informed regulatory decisions. Several limitations of the current study design point towards potential future improvements. An important missing link is the longitudinal assessment of chronic disease management. From an analysis point of view, this involves not only simulate and analyze the acute changes in the stretch and stress profiles in response to the intervention (Zhang et al. With the rapid developments in machine learning, data-driven modeling, and physics-based simulation, we can confidently assume that, within the next decade, we will be able to simulate each person’s individual heart. Within this perspectives article, we show what is already possible today, what will be possible in the near future, and what will probably never be possible. We have identified the missing pieces to create fully personalized, high-resolution whole heart models that encode a fully personalized medical history. While conceptually possible, this process is technically cumbersome, computationally expensive, and labor intensive. Instead, we propose to create personalized human heart models out of population-based libraries with geometric, biological, physical, and clinical information by morphing between a finite number of fully reconstructed four-dimensional human heart models using machine learning. We propose to analyze these personalized human heart models by combining physics-based multiscale modeling and machine learning. This allows us to learn the underlying physics, infer the model parameters, analyze parameter sensitivities, and quantify model uncertainties. We have outlined the challenges and opportunities for precision medicine in human heart modeling, not only as a purely academic exercise, but also as a translational path towards clinical decision making in full alignment with the regulatory agencies. Our examples highlight the potential for personalized human heart simulations in medical device design, clinical decision making, and personalizing treatment planning.


After traumatic brain injury (TBI), fever is frequent. Brain temperature (BT), which is directly linked to body temperature, may influence brain physiology. Increased body and/or BT may cause secondary brain damage, with deleterious effects on intracranial pressure (ICP), cerebral perfusion pressure (CPP), and outcome.Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI), a prospective multicenter longitudinal study on TBI in Europe and Israel, includes a high resolution cohort of patients with data sampled at a high frequency (from 100 to 500 Hz). In this study, simultaneous BT, ICP, and CPP recordings were investigated. A mixed-effects linear model was used to examine the association between different BT levels and ICP. We additionally focused on changes in ICP and CPP during the episodes of BT changes (Δ BT ≥ 0.5 °C lasting from 15 min to 3 h) up or downward. The significance of ICP and CPP variations was estimated with the paired samples Wilcoxon test .n = 79) ICP increased, whereas CPP was reduced; opposite ICP and CPP variations occurred during episodes of BT reduction (n = 70). All these changes were of moderate clinical relevance , even if statistically significant (p < 0.0001). It has to be noted, however, that a number of therapeutic interventions against intracranial hypertension was documented during those episodes.Twenty-one patients with 2,435 h of simultaneous BT and ICP monitoring were studied. All patients reached a BT of 38 °C and experienced at least one episode of ICP above 20 mm Hg. The linear mixed-effects model revealed an association between BT above 37.5 °C and higher ICP levels that was not confirmed for lower BT. We identified 149 episodes of BT changes. During BT elevations (Patients after TBI usually develop BT > 38 °C soon after the injury. BT may influence brain physiology, as reflected by ICP and CPP. An association between BT exceeding 37.5 °C and a higher ICP was identified but not confirmed for lower BT ranges. The relationship between BT, ICP, and CPP become clearer during rapid temperature changes. During episodes of temperature elevation, BT seems to have a significant impact on ICP and CPP. The injured brain is extremely sensitive and vulnerable to body temperature changes , 2. An iHigh body temperature can also worsen the cerebral ischemia. In experimental models of brain ischemia, hyperthermia increased the release of glutamate  and the Most patients with moderate and severe TBI experience hyperthermia during their intensive care unit (ICU) stay –11 and aA substantial proportion of experimental and clinical evidence on the interplay between hyperthermia and the brain is based on temperature measured outside the brain, either with sensors measuring temperature in the bladder –14, rectUnfortunately, temperatures measured outside the brain may markedly underestimate the BT, especially when it rises . The meaTo provide a general description of BT, ICP, and CPP in a limited sample of patients with TBI.To clarify the relationships between BT, ICP, and CPP during acute BT changes.We consulted a centralized data collection covering several centers in Europe  to obtaiOf the 2,138 patients in the ICU in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) data collection, a subgroup of 277 patients had high frequency digital signals from ICU monitoring  and was named High Resolution (HR) CENTER-TBI substudy (HR CENTER-TBI). These patients were enrolled in 21 centers from January 2015 to December 2017 and treated in accordance with current evidence-based guidelines for TBI , 25. In Data collection in the CENTER-TBI study adhered to ethical standards; medical ethical committees of all participating centers approved the study. Informed consent was obtained in accordance with local regulations .http://icmplus.neurosurg.cam.ac.uk), Moberg CNS Monitor , or both. Arterial blood pressure (ABP) was obtained through arterial lines connected to pressure transducers. ICP was acquired from an intraparenchymal strain gauge probe  or parenchymal fiber optic pressure sensor . BT was measured through invasive parenchymal monitoring , usually placed in the frontal lobe. Signal processing was done with ICM + software. Signal artifacts were removed partially automatically and partially manually. The whole process of HR CENTER-TBI signal acquisition and data processing is described in previous publications [Data were collected using ICM + software  and analyzed.Parallel to the digital HR monitoring, information on specific therapeutic interventions  was recorded and synchronized to the corresponding monitored variables using ICM + . Interventions and their timing were subsequently extracted using HDFView Software  developed by the International Neuroinformatics Coordinating Facility , vs. 2.1. Analysis was done using the files available from July 2019.CT was not recorded at high frequencies in the selected patient cohort, and thus the information on maximal daily CT  together with the epidemiological data were accessed using a bespoke data management tool, Neurobot (Data are summarized as mean and standard deviation or as median and interquartile range (IQR). For the general description of BT, ICP, and CPP, colored maps were plotted  for the first 7 days of HR monitoring. Only simultaneous recordings of ICP and BT were analyzed, and missing values were excluded from the analysis.CT was recorded daily by the investigators as the maximum and lowest temperature measured during a 24-h interval. To provide a comparison between BT and CT, maximum daily CT was compared with the highest BT recorded during the corresponding monitoring day.p values were extracted to determine the significance of differences between ICP and BT groups. The figure was plotted using BT < 36.4 as the reference group.To examine the relations between absolute values of six BT ranges  and ICP, we used a generalized mixed-effects linear model, with a random intercept per patient (that accounts for the repeated measurements in single patients). For the model, the per-minute values of BT and ICP were used. To correct for potential confounders, the mixed model was adjusted for TBI severity using poststabilization motor Glasgow Coma Scale ratings and pupil response . For eveTo assess the effects on ICP and CPP of BT changes over time, episodes of BT elevation and reduction were manually selected according to the following criteria: elevations or reductions of at least 0.5 °C lasting from 15 min to 3 h. A maximum of five episodes was identified in each patient. BT elevation and reduction episodes were analyzed separately.p value < 0.05 was considered significant. ICP more than 20 mm Hg was defined as high ICP (hICP), and CPP below 60 mm Hg was used as an indicator of low cerebral perfusion. To define potentially harmfully high BT level, we used a threshold of BT of 38 °C.To assess the significance of ICP and CPP changes in response to BT, the baseline and end episode ICP and CPP within an episode were compared using the paired samples Wilcoxon test . A https://www.R-project.org/).All statistical analysis was done using R , with the lowest value of 36.0 °C reached in five patients and the highest, 39.7 °C, reached in one. All patients reached a BT of 38 °C or higher during the monitoring. BT varied widely among the patients. Figure Median ICP was 13 mm Hg (IQR 11–20). During approximately a third of monitoring time (31%), ICP reached > 20 mm Hg. All patients experienced at least one episode of hICP . For lower BT ranges (< 36.4 °C and 36.5–36.9 °C), this association was not confirmed.The linear mixed-effects model examined the interplay between six ranges of BT and ICP Fig. . BT abovWe identified 149 episodes of BT changes (at least 0.5 °C): 79 elevations and 70 reductions . BT reached > 38 °C in 40 episodes (51%), and hICP was observed in 33 cases (42%). During these BT increases, mABP remained constant, and consequently CPP decreased, with a median difference of 7.5 mm Hg (IQR 0.9–13.6); this change was significant (p < 0.0001). During 44 episodes of BT elevation, 128 active therapeutic interventions were recorded   but not clinically relevant increase of CPP . During 41 episodes of BT reduction, 106 interventions were recorded (Table Starting from a median baseline BT of 38 °C (IQR 37.7–38.4) in the 70 episodes of BT reduction, there was a median decrease of 0.67 °C IQR 0.58–0.81). ICP decreased as well, with a median reduction of 1.7 mm Hg IQR − 1.22 to 6.03) . However, ICP fluctuated, so each patient suffered some hICP episodes and low CPP (< 60 mm Hg).The generalized linear mixed model gave a biphasic pattern, tending toward higher ICP with BT above 37.5 °C and the opposite below BT of 37.4 °C  but, more importantly, they were clinically relevant, with a median ICP increase of 4.5 mm Hg, that, in 40% of the episodes has crossed the threshold of 20 mm Hg by the end of BT elevation. During these episodes active treatment for intracranial hypertension was provided, including osmotherapy and sedative and vasoactive drugs, documented by the total of 128 interventions during 44 BT elevation episodes (Table The second aim of this study was to elucidate the impact of rapid BT changes (from 15 min to 3 h) on ICP and CPP. We explored 149 episodes of significant BT changes (more than 0.5 °C) and found that both ICP and CPP deteriorated when BT rose. ICP and CPP changes were significant . A general analysis indicates that BT exceeding 37.5 °C seems to involve a concomitant rise in ICP. The relationships between BT, ICP, and CPP become clearer during rapid temperature changes. During episodes of temperature increase, BT seems to have a significant impact on ICP and CPP despite active treatment to prevent intracranial hypertension. A similar but less severe impact is seen when temperature decreases.


In 2015, a 66-year-old previously healthy man established care in my clinic in rural Washington. He was not feeling well, exhibiting signs of heart failure. An echocardiogram showed a normal ejection fraction, but a quite hypertrophied left ventricle, which did not seemingly correlate with his history or other objective data. Knowing the reticence a patient might feel about clinical ambiguity, I treaded lightly: “Let’s get a cardiac MRI to look at the heart muscle thickness in a bit more detail.” As his diagnosis came to light, I sent him to the University of Washington, where under the thoughtful guidance of an incredible team of heart failure experts, this patient’s evaluation culminated in a heart transplantation for transthyretin amyloid cardiomyopathy (ATTR-CM). To me, this was a seminal moment, and I suspect this story rings true for many cardiologists. Treating heart failure with preserved ejection fraction (HFpEF) had always been a bit frustrating knowing there was little we could do, but the power of just 1 patient success story seemed to open the floodgates for me. I was looking for amyloidosis everywhere, in every patient with even a modicum of signs. I was finding a fair share of cases and sending them on for advanced care, although the patients were much older and more frail and there was little we could do to really help them turn the tide of their disease. Eventually, an exasperated colleague in Seattle sighed, “What’s in the water out there?”As I take in, with incredible awe and admiration, the wealth of data, diagnostics, and treatment for ATTR-CM, I try to frame it in the broader context of where we are in medicine. It really feels as though we’re on the cusp of an incredible movement in cardiology. More than 50% of patients with heart failure have HFpEF , yet theTaking a step backward, and looking at where we are in the approach to cardiac amyloidosis has been so instructive. For example, my initial cases just a few years ago were typically diagnosed with a highly technical, advanced 2-hour diagnostic test , which then led to an endomyocardial biopsy at a transplant center. Treatment involved doxycycline and a clinical trial, if they qualified. Remarkably, the past few years have leveled the playing field for diagnostics in ATTR-CM, allowing community cardiology programs like mine to leverage local expertise in our cardiovascular team members to start more focused diagnostics for amyloidosis in our clinic. Software updates for transthoracic echocardiography now allow advanced strain rate imaging in any echocardiography lab, which can be a helpful screen for amyloidosis and help to differentiate it from other infiltrative or hypertrophic cardiomyopathies. Technetium pyrophosphate (PYP) nuclear scanning can be done in 20 minutes following the injection of a standard tracer used in bone scans. The specificity of PYP scans  epidemic evolve from a stigmatized death sentence to a chronic disease with remarkable therapeutics. I often reflect back on how those medical pioneers in San Francisco and New York must have felt when they made the connection between the rare Kaposi sarcoma and thrush they were seeing in gay men with what would eventually be traced to the human immunodeficiency virus (HIV). The ability to connect those dots in a minority population not only revolutionized infectious diseases and immunology, but it advanced the cause of health equity. Although early antiretrovirals for HIV were often disappointing, they moved the needle and laid a foundation for how we approach the development of diagnostics and therapeutics today well beyond HIV. Similarly, our approach to ATTR-CM has the potential to revolutionize how we approach more than 50% of patients with heart failure and perhaps even those who do not yet have it. We have seen this condition for years, but could not always connect the dots to make an actual diagnosis. My initial experience with ATTR-CM was not typical—it’s rare to see these patients get a transplant. Many are frail, elderly, and with comorbidities that often make more testing and treatment unappealing. As with HIV, the story of ATTR-CM is not about a small minority too sick to treat. Understanding this disease sets us on a path to preventing and eventually curing heart failure. Whether we call it diastolic heart failure, diastolic dysfunction, or HFpEF, the emerging recognition of amyloidosis will change how we view a previously vexing condition.The ethical dilemmas of using the most expensive medications in the history of cardiovascular medicine to treat ATTR-CM is not lost on most of us, given the advanced age at which the diagnosis is often made. Transthyretin stabilizers are making a difference, and more therapeutics are in the pipeline. Although many patients can get these transformative medications at an affordable price or even free from the manufacturers, there are significant costs incurred to our stretched system. Engaging my pharmacy colleagues to dive into yet another expensive medication for a chronic condition as they grapple with authorizations for antiarrhythmics, novel diabetes agents, oral anticoagulants, antiplatelets, and vasodilators for many of our patients may feel like a bridge too far. Which battles are we going to fight? Ultimately, though, if we don’t keep advancing care for the sickest among us, we will lose the ability to treat or perhaps prevent HFpEF in the long term. It seems imperative to focus less on age and more on the disease itself, the prognosis, and what we can do to improve quality of life. Patients with HFpEF die of heart failure, and they grapple with life-limiting dyspnea, fatigue, and medication side-effects for decades. While most do not have amyloidosis, those that do are often relieved to know there is a reason. Just acknowledging there could be a cause to the symptoms, and doing basic tests to look for something previously unrecognized, gives hope. It allows us to overcome the clinical inertia we’ve had for a condition thought to be untreatable for decades. Notably, therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction , so earlAs a rural cardiologist caring for patients in a large geographic area, I don’t have the luxury of tailoring my practice to specific disease states. I travel throughout our region, see patients where they are, and find myself serving as both an internist and cardiologist. Our careers humble us daily, and seeing a bigger picture can be difficult when we’re navigating a full day of clinic or a busy inpatient service. What keeps me grounded is the recognition that smart people are thinking hard about the dilemmas I encounter daily, and they are using their expertise to create ways to help me care for all of my patients. The diagnosis and treatment of ATTR-CM did not just logically happen, although future guidelines will make it seem like a fait accompli. What we are seeing is the remarkable nexus of diagnostics and therapeutics coupled with a disease state that has always been there but never fully recognized. It feels like we should appreciate this moment, embrace what it means for our profession and our patients, and use it as a foundation to build a clinical care paradigm for a condition afflicting so many. It’s remarkable to me that as practicing clinicians in any location, we can leverage minimal local resources to diagnose and treat a form of HFpEF while learning new skills, elevating the careers of those around us, and, most importantly, helping our patients. Indeed, beyond the impact we have had on patients, the emergence of ATTR-CM in our local consciousness has allowed me an incredible opportunity to build a team of cardiovascular professionals equally dedicated to raising their game and making a difference.I recently saw the ATTR-CM patient who received the heart transplant. Under the thoughtful care of his transplant team, his progress has been remarkable. I relayed to him that in the 5 short years since he and I met, the world of cardiovascular medicine has coalesced around ATTR-CM and advances in the disease state have been astounding. What felt most inspiring was that his success is now transforming the lives of countless others in our rural community, and that we can be a part of this clinical evolution in real time. As a mid-career physician, I’m old enough to know that this really is a moment, and experienced enough to realize that what I know now will probably seem quaint in a few years. I am grateful to my cardio-oncology and heart failure colleagues who are devoting their careers to moving the field forward and giving so many of our patients new hope. I am also lucky to work with a team in my rural cardiology practice committed to bringing clinical innovation to our underserved population—if we can do it in north central Washington, it can be done anywhere. The recognition, diagnostics, and treatment for cardiac amyloidosis is a parable for what comes next in managing heart failure, although most patients with HFpEF are still waiting for an effective treatment. We’re seeing a revolution in cardiovascular medicine right now, and it’s not confined to the advanced quaternary care centers. Everyone should feel empowered, no matter where you practice. The converging stories of ATTR-CM and HFpEF are just beginning, and from what I can tell, it’s going to be incredible.The author has reported that he has no relationships relevant to the contents of this paper to disclose.


This condition is recognized to be associated with cardiovascular disease. Several studies have shown the effects of OSA on both geometry and cardiac function, with conflicting results. We aimed to investigate the relationship between echocardiographic abnormalities and the severity of OSA.this is a cross-sectional single center study including patients, without any cardiovascular or pulmonary comorbidities, with polygraphy proven OSA. All participants underwent a detailed transthoracic echocardiography (TTE).a total of 93 patients were included in the study, with 62.2% (n=56) females. According to the apnea hypopnea index (AHI), patients were divided into two groups: mild to moderate OSA (5≤ AHI< 30/H) and severe OSA (AHI≥ 30/H). There were no differences in baseline characteristics between the two groups. The assessment of echocardiographic parameters demonstrated that severe OSA have a higher left ventricular end-systolic (LVES) (47.6±7.2 VS 46.2±4.7), left ventricular end-diastolic (LVED) (31.3±6.2 VS 28.9±4.5) diameters and interventricular septum (IVS) thickness (12.7±2.4 VS11.7±2.5) diameters rather than mild to moderate OSA without a significant difference between the two groups. Furthermore, severe OSA patients had lower mean value of left ventricular ejection fraction (LVEF) and fractional shortening (FS) equal to 62.1±9.7 and 32.5±6.3 respectively. The difference between the two groups was not statistically significant. However, a significant association was shown between severity of OSA and left ventricular (LV) diastolic dysfunction, right ventricular internal diameter (RVID) and systolic pulmonary artery pressure (sPAP), with p=0.05, p=0.05 and p= 0.03 respectively. The RVID was also independently associated to the severity of the OSA .using bidimensional echocardiography showed a relationship between severe OSA and right ventricular parameters (diastolic dysfunction and RVID) and sPAP. Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder estimated to affect between 5% and 14% . ObstrucStudy design and subjects: this is a cross-sectional analytical study conducted at the Pneumology Department of Taher Sfar University Hospital. We included patients aged over 18 years referred to our sleep laboratory for OSA screening, between 2005 and 2017. Patients, newly diagnosed with OSA, but free of obstructive and/or restrictive respiratory or cardiovascular comorbidities , were enrolled after obtaining detailed history and performing physical examination, routine blood examination, polygraphy and transthoracic echocardiography (TTE).Polygraphy: all patients underwent an overnight polygraphy in the sleep laboratory using standard techniques. Electrocardiogram, chest and abdominal respiratory movements were made during the entire sleep duration. Oro-nasal airflow and arterial oxygen saturation (SaO2) were measured continuously. Sleep apnea refers to a reduction of ≥ 90% or complete obliteration in the respiratory airflow lasting ≥10s during sleep. Hypopnea was defined as a reduction ≥ 30% in the respiratory airflow lasting ≥10s and accompanied by a decrease ≥ 4% in oxygen saturation during sleep [ng sleep . ObstrucGrouping: according to the AHI, OSA severity is classified into mild (5≤AHI<15), moderate (15≤AHI<30) and severe forms (AHI≥30 events/hour) [ts/hour) . PatientEchocardiography: all the patients, recently diagnosed with OSA, underwent a comprehensive transthoracic echography examination according to the American society of echography guidelines [idelines . The lefidelines . Transthidelines .Statistical analysis: statistical analysis was performed with the statistical package for social sciences (SPSS) V.23 for Windows. Categorical variables were expressed in absolute values and proportions. Continuous variables were expressed as mean ± standard deviation. The relation of OSA severity with various echocardiographic parameters was assessed by Student's t-test or chi square test as deemed appropriate. Significant variables at the 15% level were introduced into multivariable analysis, binary logistic regression, in order to determine factors associated with severe OSA. Results were expressed as odd ratios (OR) with 95% confidence intervals (CI). A P value ≤ 0.05 was considered significant.General information: a total of 93 patients fulfilled the eligibility criteria were included in the study. The mean age of the total sample was 48.5±9.7 years, with 62.2% (n=56) females. According to AHI, 29% (n=27) had mild OSA, 19.4% (n=18) moderate OSA and 51.6% (n=48) severe OSA. Mild and moderate OSA patients were comparable in terms of demographic and clinical parameters. The mean AHI was 9.67±3.01/h in mild group and 20.68±4.4/h in moderate group, with a statistically significant difference (p<10-3). Patients, enrolled in this study, were classified into 2 groups: mild/ moderate OSA group  and severe OSA group . The detailed demographic and clinical characteristics as well as polygraphic data of the 93 patients are presented in . At univariate analysis, LV diastolic dysfunction, the RVID and the sPAP were significantly associated with OSA severity, with p=0.03, p=0.05 and p=0.05 respectively. A multiple regression analysis demonstrated that the RVID was independently correlated to severe OSA  ( p=0.05) .et al. have also shown that theses diameters were higher in OSA patients with a difference statistically significant [et al. conclude that the LVEF was slightly lower in moderate to severe OSA patients than in mild subjects. Another recent report demonstrates that the severity of OSA is correlated with a reduction in LVEF [The present study sought to identify subclinical effects of severe OSA on cardiac structural and functional alterations using a two-dimensional echocardiography. The key findings of this research comprise: patients with severe OSA compared with those presenting mild and moderate OSA had a higher and significant incidence of LV diastolic dysfunction, pulmonary hypertension and a larger RVID and the RVID was independently correlated to severe OSA. Several studies revealed that OSA is associated with the presence of echocardiographic abnormalities compared with controls. Those echocardiographic remodeling are related to different physiopathological mechanisms triggered by hypoxia and sleep fragmentation, involving sympathetic hyperactivity, inflammation, endothelial disfunction and oxidative stress. Comparison of conventional echocardiographic parameters in OSA patients, without any cardiovascular comorbidities, disclosed differences according to the severity of the disease. In our study echocardiographic screening showed that LVEDD and LVESD were higher in the group of severe OSA patients compared to mild to moderate OSA. However, this difference was not statistically significant between the two groups. Several studies demonstrate changes in these parameters in OSA compared to controls ,12. Daninificant . Prior snificant . In factnificant ,15. Howe in LVEF . In our et al. in 2015. In fact, the authors reported that 44% of OSA patients with normal biventricular systolic function presented different degrees of diastolic function [Even the majority of the study population had a preserved systolic function, 79.6% presented a diastolic dysfunction. This finding is in agreement with those of a recent study conducted by Imai function . In anotfunction . The assfunction ,19 and afunction ,22.The prevalence of pulmonary hypertension in OSA patients ranges between 12 and 70%, according to the severity of OSA, the sPAP evaluation method and time of measurement. Pulmonary hypertension is often associated with chronic obstructive pulmonary disease and cardiac comorbidities including hypertension and left ventricular dysfunction . HoweverAn independent effect of OSA on RV structure and performance was observed also in a number of studies, showing a correlation between AHI and RV parameters, such as RVID , right vIn our study, the assessment of echocardiographic parameters highlights a higher incidence of LV diastolic dysfunction, higher RVID and sPAP among severe OSA patients. The RVID was shown independently associated to the severity of the OSA. Moreover, there is the need for further study regarding RV involvement, as current data yields conflicting results.Obstructive sleep apnea (OSA) is a common sleep-related disorder, implicated in many serious cardiovascular diseases including cardiac remodeling and dysfunction;Most of the investigations were focused on the left heart.Conflicting results concerning the effect of OSA on RV;Relationship between OSA severity and echocardiographic parameters.


Background: Quantification of cardiac structure and function is essential for diagnostic interpretation and clinical decision making. We sought to establish cardiovascular magnetic resonance (CMR) reference values of left and right ventricular (LV and RV) morphology and function based on a large sample of healthy Chinese adults.Methods: Five hundred fifty validated healthy Chinese adults  free of hypertension, diabetes, and obesity were included in this study. All the subjects were stratified by gender (men and women) and age decades. On cine CMR, measurements of biventricular end-diastolic, end-systolic, and stroke volumes , ejection fraction (EF), and end-diastolic LV wall thickness (LVWT) and mass (LVM) were obtained.Results: Men had greater LVEDV (111.6 ± 19.8 vs. 94.6 ± 15.6 ml), LVESV (36.5 ± 9.8 vs. 28.2 ± 7.9 ml), LVM (121.1 ± 19.9 vs. 86.1 ± 14.5 g), global end-diastolic LVWT (8.1 ± 1.1 vs. 6.7 ± 1.0 mm), RVEDV (128.0 ± 23.6 vs. 101.7 ± 17.0 ml), and RVESV (53.5 ± 13.7 vs. 36.8 ± 8.9 ml), while women had greater LVEF (67.5 ± 5.4 vs. 70.4 ± 5.7%) and RVEF (58.5 ± 5.2 vs. 64.0 ± 5.3%) . For both men and women, age was negatively correlated with LVEDV (r = −0.31 and r = −0.32), LVESV (r = −0.37 and r = −0.47), RVEDV (r = −0.31 and r = −0.29), and RVESV (r = −0.33 and r = −0.44), while it was positively correlated with LVEF (r = 0.28 and r = 0.43) and RVEF (r = 0.28 and r = 0.41) . Aging was associated with increasing global end-diastolic LVWT and LVM/LVEDV in both sexes . Older age was associated with increasing LVM only in women , not in men .Conclusions: We systematically provide age-, sex-, and body size-specific CMR reference values for biventricular morphology and function based on a large sample of healthy Chinese adults. Biventricular structure and function are significantly associated with age and sex. The evaluation of left and right ventricular (LV and RV) morphology and function is one of the routine tasks due to its great predicting values in multiple cardiovascular diseases including heart failure, coronary heart disease, cardiomyopathy, and pulmonary diseases –5. As a Normative cardiac reference values are essential to distinguish between healthy and abnormal states in cardiology. Previous studies have confirmed pronounced racial differences in cardiac volumes and function –10, emphOur study population came from the local medical imaging and health screening institution, which aimed at the early detection of various diseases through systemic examinations, with cardiovascular disease screening being one of the key programs. The main screening items included (i) baseline characteristics: age, sex, height, weight, exercise intensity, occupation, and personal and family history, etc., (ii) comprehensive physical examination and electrocardiogram, (iii) laboratory and biochemical tests: routine blood, urine, stool, fasting blood glucose, insulin, lipid, sex hormone, thyroid, liver, kidney function tests, etc., (iv) imaging examination: CMR, echocardiography, chest X-ray film or chest CT, and magnetic resonance examination of the brain, spine, and abdomen. All the examinations for individuals were completed within the same day, and the diagnosis was performed by physicians with more than 10 years of experience. The authors were authorized with full access to all the subject information.2 for the Chinese population  subjects with chief complaint or cardiovascular symptoms, abnormal electrocardiogram , abnormal cardiac biomarkers including troponin T, pro-brain natriuretic peptide, and C-reactive protein ; (ii) subjects with abnormal CMR findings of cardiovascular diseases, including ischemic heart diseases , hypertrophic cardiomyopathy [defined as end-diastolic left ventricular wall thickness ≥15 mm in any LV segment ], congenCMR studies were performed on 1.5T magnetic resonance scanners  with a 16-channel phased-array surface coil. The subjects were in the supine position, and balanced steady-state free precession (SSFP) sequences were used to acquire cine images in held end expiration. Electrocardiogram-triggered continuos short-axis stack, parallel to the atrioventricular groove, covering the whole left and right ventricle (10–15 slices) was acquired at one slice per breath hold. In addition, long-axis cines  were also obtained. All the individuals were examined under the sinus rhythm. The scanning time for each individual is about 20–35 min.The parameters of sequence for Signa HDxt, General Electric Medical Systems are as follows: repetition time = 4 ms, echo time = 1.75 ms, flip angle = 60°, field of view = 310 × 310 mm, matrix size = 224 × 224, slice thickness = 8 mm, slice gap = 1 mm, and 30 phases per cardiac cycle. The scanning parameters for Magnetom Essenza, Siemens, are as follows: repetition time = 4.38 ms, echo time = 1.37 ms, flip angle = 60°, field of view = 275 × 340 mm, matrix size = 224 × 256, slice thickness = 8 mm, slice gap = 0 mm, and 30 phases per cardiac cycle.Image analysis was performed using commercial software . Images were magnified to 250%. All the measurements were completed by an experienced reviewer  blinded to all the personal information .The frames with the smallest blood pool by visual assessment in the middle of the ventricular cavity were defined as the end systole and the largest as the end diastole. As for the LV, the most basal section with at least 50% surrounding myocardium was regarded as the base. The most apical section with visible cavity was considered as the apex. On the short-axis cine imaging, the LV endocardial borders were traced by semi-automatic threshold-based segmentation method with manual correction if necessary. The LV epicardial borders were manually traced using the point-and-click method. Trabeculae and papillary muscles (TPM) were excluded from the LV blood pool and included in the myocardium. For the RV, the phases of end diastole and end systole were consistent with the definition of the LV. From the inflow tract, the slice in which the surrounding muscle was thin and not trabeculated, suggestive of the right atrium, were excluded from the RV volumes. In order to improve reproducibility, TPM was included in the RV blood pool according to the recent standards for image interpretation and post-processing . The out2) = 1/2. The LVM/LVEDV ratio was calculated to assess LV concentricity.Biventricular end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), and ejection fraction (EF) were obtained. The LV mass (LVM) was obtained from the end-diastolic frames. Segmental LVWTs at the end diastole according to the AHA 17-segment model  were obtained automatically by software on short-axis images. Global end-diastolic LVWT was defined as the average of the segmental wall thickness at end diastole. The mean end-diastolic LVWT at the base, mid-cavity, and apex of the left ventricle were calculated according to the AHA model. Heart rate (HR) was measured at the time of the CMR scan. Cardiac output (CO) was obtained by multiplying SV and HR. Parameters of biventricular structure and function were indexed to body surface area (BSA). BSA was calculated using the Mosteller formula: BSA , 50 datasets were randomly selected from the subjects and were measured by two independent observers (both have more than 5 years of experience). To assess the intra-observer reliability, the datasets were measured by an observer for the second time using the same method with a time interval of more than a month.t-test. Associations of age with biventricular parameters , global end-diastolic LVWT, and LVM were assessed using simple linear regressions. Intra- and inter-observer variability were analyzed using Bland–Altman analysis.All statistical analyses were performed with SPSS  and GraphPad Prism . All the data were tested by the Shapiro–Wilk-test and were confirmed as normal distribution. The demographic parameters, as well as the measurements of biventricular structure and function, are presented as “mean ± standard deviation.” The gender differences in the demographic characteristics and biventricular measurements were examined using Student's p < 0.05. All p-values were two-sided.Differences were regarded as statistically significant at p = 0.660) and HR (p = 0.077). Height, body weight, BMI, BSA, SBP, DBP, and FBG were all greater in men . There was no significant gender difference in age (p < 0.001). After normalized by BSA, all the LV and RV volume parameters were still greater in men than those in women , except for LVEDV, LVSV, and RVSV . Besides, both absolute and indexed LVM and global end-diastolic LVWT were all greater in men .The reference values of biventricular structural and functional parameters for both sexes are shown in r = −0.31 and r = −0.32, both p < 0.001), LVESV , RVEDV , and RVESV . In men and women, age was positively correlated with LVEF  and RVEF  , while it was associated with increasing LVM only in women , not in men . Compared with men, there was a greater age-associated increase in LVM/LVEDV ratio in women   . Moreove< 0.001) .Intra- and inter-observer variability for LV and RV measurements are shown in In this CMR study, we systematically established age-, sex-, and body size-specific normal values of biventricular morphology  and systolic function  based on a large sample of validated healthy Chinese adults over a wide age range. In addition, we further confirmed that biventricular structure and function were significantly associated with age and sex.n = 90), Le et al. (n = 180), and Lei et al. (n = 120). Finally, the subjects included are of a wide age range (21–70 years) and were further stratified by sex and age deciles, so the obtained reference values have good clinical practicality. In comparison, the study of Li et al. (Several multi-ethnic studies confirmed that East Asians have a smaller ventricular chamber size than Westerners , 10. Sime et al.  (n = 180i et al.  (n = 120i et al.  includedi et al.  had a laIt has been confirmed that the measurements of the LV volumes and systolic function could be significantly affected by the management of TPM , 24. HowIn accordance with most previous studies –13, 28, We confirmed that aging was associated with decreasing biventricular volumes and increasing end-diastolic LVWT, which was parallel to most previous reports , 21, 35.Some limitations should be acknowledged in this study. First, although we included a large sample of subjects with a broad age range, normative biventricular values of adults over 70 years old were still not covered due to the small number of the elderly population. Second, reference values of other cardiac functional parameters such as strain and strain rate were not included in the present study. Third, although we have tried to exclude subjects with cardiovascular diseases through strict exclusion criteria, techniques for diagnosing ischemic heart diseases such as late gadolinium enhancement imaging or coronary angiography were not performed in the present study. Finally, the associations of age with ventricular structure and function are based on the cross-sectional study, and follow-up studies are necessary in the future.In conclusion, we systematically provide age-, sex-, and body size-specific CMR reference values of biventricular morphology and function derived from a large sample of healthy Chinese adults. Biventricular structure and function are significantly associated with age and sex. The present study may be used as a reference standard for the diagnosis, risk stratification, and prognosis evaluation of cardiovascular disease in clinical research and practice.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Chinese Ethics Committee. The Ethics Committee waived the requirement of written informed consent for participation.ZZhan contributed to imaging analysis, study design, and drafting of manuscript. QM and YG contributed to imaging analysis and statistical analysis. LC and CZ contributed to study supervision. ZZhao, JZ, and LZ organized the database. ML, GP, and KL contributed to study design and manuscript revision. All authors approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.