Computational models of the heart are increasingly being used in the development of devices, patient diagnosis and therapy guidance. While software techniques have been developed for simulating single hearts, there remain significant challenges in simulating cohorts of virtual hearts from multiple patients. To facilitate the development of new simulation and model analysis techniques by groups without direct access to medical data, image analysis techniques and meshing tools, we have created the first publicly available virtual cohort of twenty-four four-chamber hearts. Our cohort was built from heart failure patients, age 67±14 years. We segmented four-chamber heart geometries from end-diastolic (ED) CT images and generated linear tetrahedral meshes with an average edge length of 1.1±0.2mm. Ventricular fibres were added in the ventricles with a rule-based method with an orientation of -60° and 80° at the epicardium and endocardium, respectively. We additionally refined the meshes to an average edge length of 0.39±0.10mm to show that all given meshes can be resampled to achieve an arbitrary desired resolution. We ran simulations for ventricular electrical activation and free mechanical contraction on all 1.1mm-resolution meshes to ensure that our meshes are suitable for electro-mechanical simulations. Simulations for electrical activation resulted in a total activation time of 149±16ms. Free mechanical contractions gave an average left ventricular (LV) and right ventricular (RV) ejection fraction (EF) of 35±1% and 30±2%, respectively, and a LV and RV stroke volume (SV) of 95±28mL and 65±11mL, respectively. By making the cohort publicly available, we hope to facilitate large cohort computational studies and to promote the development of cardiac computational electro-mechanics for clinical applications. In the last decades, computational models for cardiac electro-mechanics underwent a rapid development. The increased level of detail included in such models have made them more appealing to the clinical community. Significant progress has been made in the methods and software to simulate single hearts. However, simulating cardiac electro-mechanics on large cohorts still remains a challenge.Previous cohorts of personalised multi-scale models were focused on one or two cardiac chambers. One of the largest computational studies used forty-six biventricular meshes to simulate ventricular electrical activation and mechanical contraction . The resRecently, computational electro-mechanics started moving towards four-chamber models –14. SimuAs previously discussed, capturing patient anatomical variability is fundamental for computational electro-mechanics models intended for clinical applications. Representing variation in anatomy across a cohort of individuals is, however, a well-known challenge in medical imaging analysis. In the last decade, cardiac atlases were increasingly used to study variability in shape –23 and m10.5281/zenodo.3890034 [In this paper, we build the first publicly available cohort of four-chamber heart models generated from twenty-four heart failure (HF) patients. We develop a semi-automatic pipeline to build three-dimensional tetrahedral meshes of the whole heart from CT images. We test the usability of the meshes for cardiac electro-mechanics simulations by running electro-mechanical simulation tests on all twenty-four meshes. To facilitate the development of new simulations and model analysis techniques by groups without direct access to medical data, image analysis techniques and meshing tools we make the cohort of meshes available for download (DOI .3890034 ).We first describe the image acquisition protocol and the data available for each patient. The pipeline we built to generate four-chamber segmentation’s from high-resolution CT images is then presented, followed by the meshing process and ventricular fibres assignment. Finally, we describe the electro-mechanics simulation tests we used to demonstrate that our meshes are suitable for electro-mechanics simulations.Data were gathered as part of two clinical trials: clinical trial REC numbers 14/WM/1069 and 18/LO/0752 approved by the West Midlands Coventry & Warwick ethics committee and by the London-Harrow ethics committee, respectively. Data were analysed anonymously.Our models were based on twenty-four cardiac resynchronization therapy (CRT) patients recruited for CRT upgrade. Demographics of the cohort are shown in max and dP/dtmin. There data are shown in columns 6 to 9 of LV pressure was recorded invasively during the upgrade procedure. For each patient, we processed baseline pressure measurements  by averaging the acquired trace over five to ten heart beats. Ectopic beats were manually identified and discarded. We were therefore able to measure the baseline peak in systolic pressure, ED pressure, dP/dtWe segmented ED CT images with a semi-automatic pipeline shown in The pulmonary veins, the superior vena cava and the inferior vena cava were cut from the LA and the RA blood pool perpendicular to the vessel direction. Rings at each of the cut veins were generated to apply boundary conditions in the mechanics simulation. The left atrial appendage (LAA) was only partially covered by the CT image volume for some of the cases. For consistency throughout the cohort, we cropped the LAA from the LA blood pool as we did for the pulmonary veins. Labels representing a small portion of the pulmonary artery blood pool and wall thickness were generated by cutting the RV blood pool and myocardium at the ouflow tract, perpendicular to the vessel direction. The endocardial surface of atria and ventricles were closed with 2mm-thick valve planes at each inflow and outflow , 39. Altμm with a variational approach [In order to reduce the staircase effect due to image artifacts or small manual corrections, the resulting four-chamber segmentation was up-sampled and smoothed with an isotropic resolution of 150approach . Prior tAlthough LV and RV myocardium show intricate trabeculation, we did not include these structures in the segmentation we used to generate the final meshes. Some LV trabeculations and the papillary muscles were grossly segmented by the automatic segmentation tool, but the resolution of the CT images was not high enough to capture them completely. RV trabeculations were not visible in the CT images. Therefore, we excluded these structures from the segmentation and we meshed only the smooth myocardial wall.We used the multi-label segmentation to generate tetrahedral meshes with a target resolution of 1mm using CGAL . Fibre and sheet directions in the ventricles were assigned using a rule-based method . The basπ at the LV free wall, 0 at the septum and π back to the LV free wall; 3) a transmural coordinate, ranging from 0 at the endocardium to 1 at the epicardium; 4) an intraventricular coordinate, defined at -1 at the LV +1 at the RV. We assigned ventricular nodes of the meshes with a value for each of these four coordinates. Non-ventricular nodes were assigned with a value of -100.To have a common frame of reference for the twenty-four meshes, we applied a universal ventricular coordinate (UVC) algorithm to all the geometries . This remeshtool (https://bitbucket.org/aneic/meshtool/src/master/). These high resolution meshes will also be publicly available as part of the database, inclusive of element tags as described above , a much finer resolution is needed for more complex models (e.g. monodomain or bidomain). To show that it is possible to refine the given meshes, we resampled all twenty-four original 1mm-resolution meshes to achieve a 0.35mm resolution using ed above  and vent10.5281/zenodo.3890034 [case format, readable with paraview (https://www.paraview.org/). All binary files containing the meshes data (ens and geo formats) are provided within the zipped folder. Points coordinates are given in mm. Element tags are assigned to the elements of the mesh . Each fmesh see , as wellTo ensure that that our mehes are suitable for electro-mechanics simulations, we ran electro-mechanics simulation tests on all twenty-four 1mm-resolution meshes using linear tetrahedral elements. We simulated ventricular electrical activation and free mechanical contraction.−1 and 0.24 s−1, respectively, consistently with experimental measurements on human ventricular tissue [m, shown in orange in Ventricular electrical activation was simulated with a reaction-eikonal model . Ventricr tissue . To simur tissue , 44. Ther tissue . We simur tissue . The actC, bf, bfs and bss are the material parameters. The f, s and n in the Cauchy-Green strain tensor E represent the strain in the fibres, sheet and normal to sheet directions, while J indicates the Jacobian determinant of the deformation gradient tensor. Parameters for ventricular stiffness were set based on parameters estimated in HF patients [c is the only material parameter and I1 denotes the first invariant of the Cauchy-Green strain tensor. For atrial myocardium, wall of the aorta, pulmonary artery and veins, we ignored the effect of the fibres, and we set passive stiffness parameters using the following values from the literature. For the atria, we used the average of the parameter values of the anterior and posterior regions reported in the literature [κ = 1MPa.Large deformations of the heart throughout the cardiac cycle were modelled with the finite elasticity equations solved in a Lagrangian reference frame . Cardiacpatients  and are terature , resultiterature , 52. Rinterature , 54, witTa was computed as follows:peak is the peak in active tension, t is time and tact is the activation time computed with the eikonal model. Electro-mechanical delay temd, duration of the twitch tdur, rising time τr and decay time τd were set to 20ms, 550ms, 130ms and 100ms, respectively. Tpeak was set to 125.0kPa to achieve an LV EF of about 35% for all cases. This falls within the range of EF measured in our cohort (34±10%). The active tension transient is shown in Active tension transient of ventricular myocardium was simulated with a phenomenological model , 55, disf = 8.0, bfs = 4.0 and bt = 3.0. Parameters for electrical activation and active contraction were left unchanged.We wanted to verify that our meshes element quality was high enough to endure a more significant contraction, with a left ventricular ejection fraction falling within healthy ranges (48%-69%) . Since t−1. The effect of the pericardium on the ventricles was simulated by applying unidirectional springs to the epicardium to penalise displacement normal to the surface, using the ED state as the reference configuration for the springs [The mechanics simulation was constrained by applying omni-directional springs at the right superior and inferior pulmonary veins, and at the superior vena cava , 18, witWe did not account for ventricular preload or ventricular afterload. The initial configuration was assumed to be ventricular end-diastole, and we did not perform any unloading of the mesh. The ventricles were assumed to contract against zero pressure and zero resistance. Therefore, we did not include any representation of the aortic and pulmonary valves. The atria were passive, with no electrical excitation and active mechanical contraction. Our model did not include any representation of flow across the atrio-ventricular valves.All the electro-mechanical simulations were run with the Cardiac Arrhythmia Research Package (CARP) , 58, 59.For details of the finite element discretisation of the mechanics equations, we refer to Augustin et al. . The mecFirst, we present results for the general characteristics of the twenty-four meshes. Then, we present results for the electro-mechanics simulations. Finally, we investigate the relationship between LV and RV anatomy and simulation outputs.To test mesh quality we computed the scaled Jacobian for each element of each mesh to have a measure of the distortion of the tetrahedra , 64. A sWe quantified anatomical differences within the cohort. π in UVCs. The point on the side of the septum was taken as the point with the rotational coordinate closest to 0 in UVCs. The LV diameter was computed as the distance between these two points. In addition, we show the variability of the LV wall thickness, and local curvature of the endocardial surface of the LV, RV, LA and RV, which are important quantities for the Laplace law and wall stress estimation in m (top row) and active tension (bottom row) over time on mesh 01 in Results for the electro-mechanics simulation tests are summarised in We ran additional simulations with healthy passive stiffness in cases with LV EDV within the plausible physiological healthy range to demonstrate that we could achieve a healthy LV EF. These simulations resulted in an average EF of 50% (range: 48%-53%) and 44% (range 42%-46%) for the LV and the RV, respectively. This shows that the element quality of our meshes is high enough to endure an active contraction with LV EF in healthy ranges when LV EDV falls within normal values.We generated the first publicly available cohort of twenty-four four-chamber meshes from HF patients with our semi-automatic pipeline. The elements of the resulting geometries have high quality. We showed that our meshes are suitable for electro-mechanical simulations by successfully running test simulations for electrical activation and free mechanical contraction. We proved that our meshes can be refined to a desired edge length, making our cohort potentially suitable for more complex electrophysiology problems. Both coarse (1.1mm average edge length) and fine (0.39mm average edge length) versions of all twenty-four meshes are publicly available to download, in order to promote the development of computational cardiac electro-mechanics.Solver convergence in electrophysiology simulations is highly dependent on mesh resolution depending on the model used to simulate electrical activation . The average edge length of our meshes was close to the target edge length of 1mm, see a-priori stability of cardiac mechanics simulations for a given mesh [As opposed to electrophysiology simulation, in which the most important mesh characteristic for solver convergence is mesh resolution while element distortion does not represent an issue, solver convergence in mechanics simulations is affected by (but not only) element quality. Mesh quality was identified in the past as a metric to determine the stability of the mechanics simulation for different types of elements , 64, 66.ven mesh . The useven mesh . TetraheThe size of the heart is used as a determinant of cardiac function, and is identified as an independent predictor of cardiac events in patients with cardiovascular diseases –71. LV Eex-vivo imaging data, as in-vivo imaging techniques still do not allow for an enough high resolution to visualise such fine structures. Our four-chamber geometries were generated from in-vivo human CT clinical datasets. Therefore we were not able to include endocardial structures in our ventricular geometries. Ventricular trabeculations were reported to affect ventricular haemodynamics [Our meshes do not account for intricate and complex microstructures of ventricular endocardium. Highly detailed models of the rabbit –88, dog dynamics , 92. Vendynamics  and arrhdynamics . Therefohttps://github.com/fsahli/fractal-tree) or by mapping a pre-existing tree using the UVCs [Our ventricular models also do not include a Purkinje network. The Purkinje tree plays an important role in ventricular fibrillation , 96 and the UVCs , also prOur geometries do not offer a detailed model of atrial structures. The LAA was not included in the geometries because the CT volume often did not cover it. Other structures such as crista terminalis, pectinate muscles and fossa ovalis were not identified as separate tags in the atrial meshes. However, these can be included based on previous studies offering more detailed representation of LA and RA anatomical regions , 103.Another limitation of our atrial model is that we did not include atrial fibres. Atrial fibers are more challenging to embed in three-dimensional geometries compared to ventricular fibres, due to complex atrial anatomy and scarcity of data about fibre orientation in atrial myocardium. It is however possible for the user to define atrial fibres using a rule-based method , 104 or The aim of our study was not to provide a fully detailed model of the heart. We instead provided a reference set of twenty-four four-chamber anatomies which external users can add features  to. We believe that our database constitutes a significant step forward for the computational modelling community, as it provides the first publicly available database of four-chamber heart models.We built a cohort of twenty-four four-chamber heart meshes from HF patients CT data. The elements of our meshes have high quality, making them suitable for electro-mechanics simulations. We verified this by running electro-mechanics simulation tests for ventricular electrical activation and free contraction. The twenty-four geometries can be refined and integrated with more purpose-specific features, and used for large cohort computational studies and as a data set for verification of numerical methods for cardiac electro-mechanics.S1 FigThe image shows the segmentation for the components included in the final tetrahedral mesh for cases 01 to 04 overlapped with the end-diastolic CT image. For each case, we show a four-chamber axial view, two sagittal and two coronal views. Abbreviations: left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA), aorta (Ao) and pulmonary artery (PA).(PDF)Click here for additional data file.S2 FigThe image shows the segmentation for the components included in the final tetrahedral mesh for cases 05 to 08 overlapped with the end-diastolic CT image. For each case, we show a four-chamber axial view, two sagittal and two coronal views. Abbreviations: left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA), aorta (Ao) and pulmonary artery (PA).(PDF)Click here for additional data file.S3 FigThe image shows the segmentation for the components included in the final tetrahedral mesh for cases 09 to 12 overlapped with the end-diastolic CT image. For each case, we show a four-chamber axial view, two sagittal and two coronal views. Abbreviations: left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA), aorta (Ao) and pulmonary artery (PA).(PDF)Click here for additional data file.S4 FigThe image shows the segmentation for the components included in the final tetrahedral mesh for cases 13 to 16 overlapped with the end-diastolic CT image. For each case, we show a four-chamber axial view, two sagittal and two coronal views. Abbreviations: left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA), aorta (Ao) and pulmonary artery (PA).(PDF)Click here for additional data file.S5 FigThe image shows the segmentation for the components included in the final tetrahedral mesh for cases 17 to 20 overlapped with the end-diastolic CT image. For each case, we show a four-chamber axial view, two sagittal and two coronal views. Abbreviations: left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA), aorta (Ao) and pulmonary artery (PA).(PDF)Click here for additional data file.S6 FigThe image shows the segmentation for the components included in the final tetrahedral mesh for cases 21 to 24 overlapped with the end-diastolic CT image. For each case, we show a four-chamber axial view, two sagittal and two coronal views. Abbreviations: left ventricle (LV), right ventricle (RV), left atrium (LA), right atrium (RA), aorta (Ao) and pulmonary artery (PA).(PDF)Click here for additional data file.S7 FigA The plot shows error bars (mean ± standard deviation) of the mesh quality over time for a free contraction simulation for mesh 03. The other plots show mesh quality variations over simulation time for different regions of the mesh: B LV, C RV, D LA and E RA. Average mesh quality decreases from 0.74 to a minimum of 0.63, reached at maximum ventricular contraction. Change in mesh quality is driven by the LV and the RV, for which the average quality decreases of 16% and 20% from ED to end-systole, respectively. LA and the RA mesh quality, which are not actively contracting in the simulation and are therefore passive, underwent small variations . The same applied to all the other labels of the mesh (results not shown).(PDF)Click here for additional data file.S1 Appendix(PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.


Although mitral regurgitation (MR) is the most common valvular heart disease, it should be regarded as a complex multifactorial disease that involves multiple entities. Optimal medical therapy alone does not hinder the progression of the disease, and in the 1980s it was already recognised that corrective surgery is indicated if MR is severe and patients are symptomatic (except for those with the most severe left ventricle dysfunction). Later on, asymptomatic patients with deterioration of the left ventricular ejection fraction were also operated on to avoid irreversible left ventricular dysfunction, heart failure and eventually death. However, a major drawback remains the fact that a significant group of patients is considered to have a high perioperative risk due to their advanced age or severe comorbidities. Since less invasive, percutaneous interventions have been developed and recently thoroughly investigated in the MITRA-FR and the COAPT studies, the type of intervention and also the timing have become more crucial. In this critical review of the literature, we describe what we should have learned from the past and which (haemodynamic) parameters can best predict the outcome in patients with MR. Until the 1980s, mitral regurgitation (MR) was mainly diagnosed by right heart catheterisation in combination with left ventricular cine-angiography. Increased right-sided pressures, such as pulmonary artery and pulmonary wedge pressure, and in particular the presence of an early and/or high V wave, suggested the presence of MR. Moreover, an enlarged left ventricle as well as left atrium could be seen during left ventricular (LV) angiography. The grade of MR was mainly estimated from the shape and volume of contrast fluid in the left atrium. All of these values were used as criteria for surgery. The advancement of echocardiographic techniques, such as Doppler measurements, offered additional diagnostic possibilities and eventually largely replaced invasive and angiographic methods in daily clinical practice.2).Although considerations were made carefully with the aforementioned entities in the past, the postoperative results were sometimes disappointing. In order to search for criteria that could predict surgical success, several studies on the haemodynamics of MR have been published –3. CurreNot only are the criteria for MV surgery changing continuously, but the introduction of novel percutaneous edge-to-edge transcatheter MV repair techniques  also warrants comprehensive knowledge on the part of the treating physicians. Lessons learned from the past in haemodynamics and MV surgery could be essential for further improvements in patient selection and timing of the procedure.The Frank-Starling curve shows the relation between LV stroke volume (LVSV) and LV end-diastolic volume (LVEDV) Fig. . The essThus, increased LVEDV and LV end-diastolic pressure (LVEDP) will result in an increased LV end-diastolic wall stress . Also anNot only the left ventricle, but also the left atrium shows enlargement due to volume overload, which reflects the severity and duration of the MR. There is a close relationship between LA diameter and mortality, with a more than 3‑fold increase in mortality when the LA diameter ≥55 mm . In cont2, LVESD of more than 2.6 cm/m2 and LV end-systolic wall stress of more than 195 mm Hg (260 kdyn/cm2) remained symptomatic postoperatively, despite continued medical therapy. These observations led to the understanding that earlier intervention could lead to better outcome in these patients. More than 20 years later, Gaasch and Meyer proposed the use of three stages of chronic MR. Stage 1 consisted of a chronic compensated state with LV enlargement, eccentric hypertrophy and normal systolic function. Subsequently, there was a transitional phase (stage 2) with mild LV dysfunction that is reversible after surgical correction of the regurgitant lesion. Finally, stage 3 was a decompensated MR with progressive and irreversible structural and functional changes in the ventricle [In 1984, Zile et al. investigated the effect of several preoperative LV echocardiographic parameters on clinical symptoms after MV replacement in 20 patients with chronic MR . They coIn 1998, Maisano et al. published an operative technique by means of which they approximated the mitral leaflets, creating a double-orifice MV, in order to diminish MR . The tecp = 0.003), and better LV unloading manifested by a decrease in LVEDP  and subsequently significantly lower systemic vascular resistance . Moreover, none of the patients had developed an acute postprocedural low cardiac output state, which occurred occasionally after surgical MV repair.A decade ago, Siegel et al. studied the acute haemodynamic effects of MitraClip implantation by right heart catheterisation and echocardiography under general anaesthesia . SignifiMore recently, two important studies (MITRA-FR and COAPT studies) investigating transcatheter MV repair found conflicting results , 14. TheFurthermore, a more aggressive strategy for correction of MR was applied in COAPT, as suggested by the larger number of clips implanted per patient in COAPT than in MITRA-FR. Moreover, the rate of sustained reduction of MR was higher in COAPT than in MITRA-FR. The lower sustained efficacy of the MitraClip procedure may also have contributed to the lack of benefit of the intervention in MITRA-FR. Both trials required that patients remained symptomatic (New York Heart Association (NYHA) class ≥ II) despite the use of guideline-directed medical therapy (GDMT) for chronic systolic heart failure. However, COAPT imposed more demanding criteria for the inclusion of patients, namely the use of maximal tolerated doses of GDMT, and treatment with cardiac resynchronisation therapy, defibrillators and revascularisation, if appropriate. Hence, in COAPT, medical treatment was optimised prior to randomisation and only a few major adjustments in treatment occurred during follow-up. On the other hand, in MITRA-FR medical therapy was not optimised in all patients at baseline and multiple adjustments in medical treatment were allowed in each arm during follow-up. This issue may also have decreased the ability to reveal a beneficial effect of the intervention in MITRA-FR.2 and/or regurgitant volume >45 ml.≥moderate-to-severe (grade 3+) secondary MR defined as effective regurgitant orifice area ≥30 mmLVEF between 20% and 50% and LVESD <70 mm.Persistent heart failure symptoms (NYHA ≥ II) despite optimal  tolerated GDMT with cardiac resynchronisation and coronary revascularisation if appropriate.In view of these findings, Pibarot et al. concluded that, to achieve a reduction in heart failure hospitalisation and mortality by the MitraClip procedure, patients had to meet the following three criteria :≥moderatBased on all these historical data, it can be expected that the benefit of treatment depends on the degree of MV disease. It is hypothesised that selection of patients, based on the criteria above, could be further improved by also measuring haemodynamic parameters as performed in the past , 16. Fro


Subclinical hypothyroidism (SH) may influence both ventricular functions. The aim of this study was to evaluation the findings of Tissue Doppler Imaging (TDI) and other echocardiography modalities in children with SH. We compared left ventricular mass index (LVMI) and TDI parameters of patients with SH and children with euthyroidism. Subclinical hypothyroidism was diagnosed when thyroid stimulating hormone level was higher than the reference value of the laboratory (> 4.2 mIU/L) and free thyroxine level was in normal range. The study included a group of 35 patients with SH and a control group of 38 children with euthyroidism . LVMI was significantly higher in the patient group (p = 0.005). TDI parameters including mitral septal ejection time was lower (p = 0.003) and mitral septal myocardial performance index was higher (p = 0.009) in the patient group. Right ventricular TDI revealed that tricuspid lateral E/Ea and tricuspid septal E/Ea were higher  and tricuspid septal Ea/Aa and ejection time were lower  in the patient group. SH may lead to increase LVMI. Left ventricular systolic and diastolic TDI parameters  as well as right ventricular systolic  and diastolic  functions may be also impaired in children with subclinical hypothyroidism. TDI is a useful method used for the assessment of the effect of SH on cardiac functions. Subclinical hypothyroidism has a prevalence of 3–18% of in adults2. Although, the prevalence of subclinical hypothyroidism in children remains unknown, it is reported that subclinical hypothyroidism is less frequent in children compared to adults4. Although numerous factors have been blamed in the etiology of subclinical hypothyroidism, autoimmune disorders of the thyroid gland are considered to be the most common cause of subclinical hypothyroidism both in children and adults5.Subclinical hypothyroidism is diagnosed when serum thyroid stimulating hormone level is increased and free thyroxine level is within normal reference8. Nevertheless, subclinical hypothyroidism mainly attacks the cardiovascular system, mostly leading to left and right ventricular systolic and diastolic dysfunction, heart failure, coronary heart disease, vascular dysfunction with increased vascular stiffness and endothelial dysfunction, and increased left ventricular mass13.Most studies investing the effects of subclinical hypothyroidism have mostly been conducted in adults and there is a paucity of data regarding subclinical hypothyroidism in children. Subclinical hypothyroidism has been shown to influence the neuromuscular system, carbohydrate mechanism, and cognitive functions16. The aim of this study was to compare the findings of Tissue Doppler Imaging and other echocardiography modalities  in children with subclinical hypothyroidism and control groups.Tissue Doppler imaging findings have been shown to be important in the subclinical hypothyroidism; however, most of these findings have been reported in adult studiesThe study included 35 children diagnosed with subclinical hypothyroidism at Dicle University Medical School Department of Pediatric Endocrinology between September 2016 and February 2017 and 38 healthy euthyroid children with normal thyroid functions. Normal reference values of our laboratory where the study was conducted were as follows: thyroid stimulating hormone 0.27–4.2 mIU/L, serum-free triiodothyronine 3.69–9.85 pmol/L, and free thyroxine 12–22.8 pmol/L. The diagnosis of subclinical hypothyroidism was established based on an increased thyroid stimulating hormone level (4.2–20 mIU/L) and normal serum-free triiodothyronine and free thyroxine levels measured in two morning fasting blood samples that were obtained at a minimum of a 15-day interval. Measurement of serum thyroid stimulating hormone, serum-free triiodothyronine and free thyroxine levels was performed by electrochemiluminescence immunoassay (ECLIA) method with a Cobos e601 analyzer .The children with SH were referred to pediatric endocrinology clinic by their physicians because of elevated serum TSH concentrations detected during check-up. No signs of hypertension, liver and kidney dysfunctions, lung disease, systemic infection, or chronic diseases were detected in any subject in both groups. Moreover, no subject was using medication during the study. The study excluded patients with obesity, low birth weight, diabetes mellitus, and a history of drug use. Electrocardiogram indicated normal sinus rhythm in all the subjects. In both groups’ Transthoracic Echocardiographic examinations, the subjects that were detected with any pathology that could affect Tissue Doppler Imaging, such as valvular heart disease and congenital heart defect, were excluded from the study.All the echocardiographic examinations were performed by an experienced pediatric cardiologist who was blinded to the clinical and biochemical characteristics of the patients. A written consent was received from the parents of each subject. The study was approved by the local ethics committee.14. Using conventional Doppler transthoracic echocardiographic examinations, mitral and tricuspid early diastolic E wave (m/s), late diastolic A wave (m/s), and E/A ratio were determined and evaluated in accordance with the American Society of Echocardiography guidelines17.Transthorasic echocardiographic examinations was performed using a 2–4 MHz phased-array transducer . Transducers of 2.5 or 3.5 MHz were used. Color flow and 2D Doppler echocardiography were performed at the apical four chamber, parasternal long axis, parasternal short axis, subcostal and at the suprasternal positions. M-mode echocardiography was performed at the parasternal long axis for the measurement of left ventricle end-diastolic diameter and left ventricle end-systolic diameter, fractional shortening, and ejection fraction. Left ventricle mass index was calculated by using the formula proposed by Devereux’s et al.a, m/s), late diastolic velocity , systolic velocity , acceleration time (ms), myocardial performance index, isovolumic contraction time , deceleration time (ms), ejection time  of the mitral valve, isovolumic relaxation time , tricuspid valve, and interventricular septum.For the measurement of tissue Doppler, the pulse wave sample was positioned on the mitral lateral, mitral septal, tricuspid lateral and at the junction of the septal cusp of the tricuspid valve with the ventricle. For the measurement of interventricular septum, the pulse wave sample was placed parallel to the septum and was positioned at its upper 1/3 part. Tissue Doppler Imaging was used to determine early diastolic velocity . Quantitative variables were expressed as mean ± standard deviation (SD) and categorical variables as count and percentage (%). Comparison of binary variables was performed by using independent samples The authors assert that all procedures contributing to this study comply with the ethical standards of the relevant national guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the institutional committees of Dicle University.Informed consent was given by the participants or by their legal guardians.This study was presented at “52nd Annual Meeting of the Association for European Paediatric and Congenital Cardiology ” as a poster presentation.p < 0.001) and serum-free triiodothyronine and free thyroxine levels were similar compared to the control group. Of the 35 patients, 31 of them had a thyroid stimulating hormone of 5–10 mIU/L and 4 had a thyroid stimulating hormone of ≥ 10 mIU/L. Table The study included a group of 35  patients with subclinical hypothyroidism and a control group of 38 healthy  children with euthyroidism. Mean age was 7.6 ± 3.5 years in the patient group and 9.0 ± 2.4 years in the control group. No significant difference was found between the groups in terms of age, gender, body weight, and body mass index. Thyroid stimulating hormone was significantly higher (p = 0.005). However, left ventricle end-diastolic diameter, fractional shortening, and ejection fraction established no significant difference between the groups. Left ventricular end-systolic diameter was lower in the patient group compared to the control group (p = 0.023). Table Left ventricular mass index was significantly higher in the patient group compared to the control group (p p = 0.03. Table p = 0.020). Table Mitral flow E wave velocity was significantly higher in the patient group compared to the control group  and myocardial performance index was higher (p = 0.009) in the patient group compared to the control group. Evaluation of the right ventricular Tissue Doppler Imaging revealed that tricuspid lateral E/Ea and tricuspid septal E/Ea were higher  and tricuspid septal Ea/Aa and ejection time were lower  in the patient group compared to the control group. Intraventricular septal Aa was higher (p = 0.022) and Ea/Aa was lower (p = 0.032) in the patient group compared to the control group. Table The comparison of Tissue Doppler Imaging parameters between the two groups indicated that mitral septal ejection time and deceleration time were lower  and a negative correlation was established with mitral flow ejection time .18. Hypothyroidism could trigger cardiac remodeling in 3 manners. First, hypothyroidism reduces activity of several enzymes involved in intracellular calcium handling, thereby leading to alteration in the expression of contractile protein. Second, cardiac dysfunction may be caused by the chronic inflammation and tissue changes induced by subclinical hypothyroidism. Third, subclinical hypothyroidism is responsible for the hemodynamic alterations associated with cardiac impairment20. As a result of these, hypothyroidism leads to numerous changes in cardiac contractile, myocardial oxygen use, stroke volume, blood pressure, and systemic vascular resistance21. The effects of subclinical hypothyroidism on cardiac functions and Tissue Doppler Imaging parameters have mostly been reported in adult studies24. Although the number of studies reporting on the cardiac effects of subclinical hypothyroidism have been growing recently, particularly in children, there is still scarcity in the number of studies conducted in children25.Myocardial tissue is highly sensitive to thyroid hormones due to its excess of thyroid hormone receptors18. Rodonti et al.12 reported that left ventricular mass might increase in patients with thyroid stimulating hormone > 10 mU/l during long-term follow-up although no increase might be seen at baseline measurements. A review of the English-language literature showed that there have been only two studies reporting on increased left ventricular mass in children with subclinical hypothyroidism26. Of these, the study by Catli et al.9 evaluated 31 children with subclinical hypothyroidism and found a significant increase in left ventricular mass index and interventricular septal thickness. The other study was conducted by Sert et al.26 which evaluated obese children with subclinical hypothyroidism and found increased left ventricular mass index in children with thyroid stimulating hormone > 4 mIU/L compared to children with thyroid stimulating hormone < 4 mIU/L. Therefore, the present study is of prime value since it is one of the few studies in the literature showing that left ventricular mass index significantly increases in children with subclinical hypothyroidism.Left ventricle mass has been shown to increase in adults with subclinical hypothyroidism25 found that mitral E-wave velocity and E/A ratio were lower and mitral A-wave and IVRT were higher in children with subclinical hypothyroidism compared to healthy controls. Another study showed that no differences were found in mitral flow diastolic parameters  between patients with subclinical hypothyroidism and healthy controls9. Some adult studies have also indicated that left ventricular systolic, in particular, and diastolic dysfunction may occur in patients with subclinical hypothyroidism24. In our study, mitral flow E velocity was higher in children with subclinical hypothyroidism compared to healthy controls, which contradicted with the findings of other studies that found lower mitral flow E velocity in children with subclinical hypothyroidism compared to controls25. However, a previous study that evaluated adults with subclinical hypothyroidism reported that peak E velocity was markedly higher in patients with thyroid stimulating hormone > 10 mU/L and that this finding represented left atrial pressure and was also associated with heart failure in patients with thyroid stimulating hormone > 10 mU/L11.Studies investigating mitral and tricuspid flow pulsed-wave Doppler have indicated that diastolic dysfunction may develop in children with subclinical hypothyroidism. Irdem et al.23. However, this association has been scarcely reported in pediatric studies25. Catli et al.9 reported that subclinical hypothyroidism was associated with left ventricular diastolic  and systolic (lower IVCT) dysfunctions in children with subclinical hypothyroidism. In addition, the study also found that lateral mitral myocardial performance index was higher, systolic IVCT was higher and ejection time was lower, and diastolic IVRT and myocardial performance index were higher. In contrast, Irdem et al.25 revealed that left ventricular septal Em velocity and Em/Am ratio were markedly decreased and Am velocity was markedly increased in children with subclinical hypothyroidism compared to healthy controls. The authors also reported that left ventricular lateral Em velocity and Em/Am ratio were lower and E/Em ratio was higher in the patient group.Subclinical hypothyroidism has been commonly associated with Tissue Doppler Imaging in adult studies27. In the present study, increased mitral septal myocardial performance index and ejection time indicated impaired diastolic and global ventricular function. Catli et al.9 found increased mitral lateral myocardial performance index in children with subclinical hypothyroidism, whereas we found increased mitral septal myocardial performance index. These two findings suggest that global ventricular function may be impaired in children with subclinical hypothyroidism.Myocardial performance index is a simple method used in the evaluation of systolic and diastolic cardiac functions. Moreover, increased myocardial performance index is an indicator of impaired systolic and diastolic functions18. In our study, of the right ventricular Tissue Doppler Imaging diastolic parameters analyzed, tricuspid septal and lateral E/Ea ratio were higher in children with subclinical hypothyroidism compared to controls, which indicated right ventricular diastolic dysfunction (impaired ventricular filling). Catli et al.9 reported that mitral annulus E/Aa ratio was higher in children with subclinical hypothyroidism compared to controls; however, we found no study in the literature reporting on increased tricuspid annulus E/Aa ratio in children with subclinical hypothyroidism. On the other hand, in our study, we found that tricuspid septal Ea/Aa was lower in children with subclinical hypothyroidism compared to controls. A similar finding was reported by Kosar et al.16, who suggested that this finding was another indicator of right ventricular diastolic dysfunction. The same study also revealed that both mitral annular Ea/Aa ratio and tricuspid annular Ea/Aa ratio were lower and a negative correlation was found between thyroid stimulating hormone and Ea velocity and Ea/Aa ratio. The findings reported by Kosar et al.16 suggest that not only left ventricular diastolic functions but also right ventricular diastolic functions may be impaired in patients with subclinical hypothyroidism. Similarly, we also found that tricuspid septal ejection time was lower in children with subclinical hypothyroidism compared to controls, which indicated impairment in right ventricular systolic functions. In this regard, our study is the first study in the literature showing that left ventricular dysfunction as well as right ventricular systolic and diastolic dysfunction may occur in children with subclinical hypothyroidism.Besides left ventricular functions, right ventricular functions may also be impaired in patients with subclinical hypothyroidisma wave and decreased Ea/Aa ratio at interventricular septum may indicate impaired global ventricular diastolic functions. Catli et al.9 also investigated interventricular septum Tissue Doppler Imaging and suggested that systolic , diastolic (higher IVRT), and global  functions may be impaired in children with subclinical hypothyroidism.Increased A18. Our study revealed that as thyroid stimulating hormone level increases, mitral flow ejection time decreases (related to left ventricular systolic dysfunction) and mitral septal Aa increases (related to left ventricular diastolic dysfunction). This correlation indicates the importance of the effect of increased thyroid stimulating hormone level on the development of left ventricular systolic and diastolic dysfunction in children with subclinical hypothyroidism. To our knowledge, this correlation has never been reported in any study in the literature. In our study, thyroid stimulating hormone levels were significantly different between the subclinical hypothyroidism and the control group; however, sT4 and sT3 levels were similar, and no significant correlation was found between sT4 and sT3 levels and myocardial dysfunction indicators as in TSH. For these reasons, we think that the main cause of myocardial dysfunction is thyroid stimulating hormone.There are adult studies showing that some myocardial dysfunction indicators measured by Tissue Doppler Imaging and conventional echocardiography have significant correlations with serum thyroid stimulating hormone levels in subclinical hypothyroidisma, lower tricuspid septal Ea/Ea) functions may be impaired in children with subclinical hypothyroidism. Although left and right ventricular dysfunctions have been commonly reported in adults with subclinical hypothyroidism in echocardiographic studies, our study is the first study in the literature showing that left ventricular dysfunction as well as right ventricular systolic and diastolic dysfunction may occur in children with subclinical hypothyroidism.Subclinical hypothyroidism may lead to increased left ventricular mass index. Our study is one of the few studies in the literature showing that left ventricular mass index may be increased in children with subclinical hypothyroidism. Although the present study showed that increased left ventricular mass index may have adverse effects on ventricular functions in children with subclinical hypothyroidism, further studies with longer periods are needed to investigate these effects. Our study also indicated that left ventricular systolic and diastolic Tissue Doppler Imaging parameters  as well as right ventricular systolic  and diastolic (higher tricuspid septal and lateral E/EThis study has several limitations. Firstly, the study evaluates cardiac functions in children with SH. However, long-term follow-up of patients and cardiac functions have not been performed. For this reason, longer-term studies are needed. The small number of patients may also act as another limitation of our study.


The purpose of the study was to evaluate a novel approach for the quantification of right ventricular sympathetic dysfunction in patients diagnosed with ARVC/D through state-of-the-art functional SPECT/CT hybrid imaging.123I-MIBG-SPECT/CT in 17 patients diagnosed with ARVC according to the modified task force criteria, and in 10 patients diagnosed with idiopathic ventricular fibrillation (IVF). The 123I-MIBG-uptake in the left (LV) and right ventricle (RV) was evaluated separately based on anatomic information derived from the CT scan, and compared to the uptake in the mediastinum (M).Sympathetic innervation of the heart was assessed using P = 0.014), with a cut-off value of 3.41 . There was a highly significant difference in the mean RV/M ratios between both groups , with optimal cut-off for discrimination at 1.86 .There was a significant difference in the LV/M ratio between the ARVC/D and the IVF groups  contains supplementary material, which is available to authorized users. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a mainly inherited disease of heart muscle, which is characterized by a progressive replacement of contractile heart muscle with fibrotic and fat tissues (fibrofatty degeneration), primarily in the right ventricle (RV).4The diagnosis of ARVC/D is especially hindered at early stages due to the absence or non-specific nature of clinical findings, and due to its multifactorial genesis, in conjunction with the anatomic complexity of RV function and failure. Therefore, there has been no single diagnostic gold standard for detection of ARVC/D, but rather a reliance on combining results from several diagnostic examinations. Currently the diagnosis of ARVC/D is based on the presence of major and minor criteria including ECG re- and depolarization abnormalities, ventricular arrhythmias, RV function and morphology, histopathology, and family history. The diagnosis is established when two major, one major plus two minor, or four minor criteria from different groups are fulfilled, as suggested by the modified Task Force Criteria.5123I-Metaiodobenzylguanidine (123I-MIBG) is an analogue of guanethidine, which is an established agent for visualizing the sympathetic innervation of myocardium and other tissues.8Molecular imaging with single photon computer tomography (SPECT) might provide improved sensitivity and specificity for the diagnosis of ARVC/D. 123I-MIBG-uptake in the LV myocardium is associated with higher risk of future recurrence of life-threatening ventricular tachyarrhythmia.123I-MIBG studies investigating ARVC/D patients was the restricted focus on the reduction in LV uptake, without considering changes in the RV uptake. Based on the understanding that the ARVC/D pathology first arises in the right ventricle, we hypothesized that the diagnosis should be better supported by quantitation of right ventricular 123I-MIBG uptake (RVU). Therefore, we prospectively evaluated the myocardial sympathetic function using 123I-MIBG SPECT/CT in patients diagnosed with ARVC/D and, as a reference, also in patients with idiopathic ventricular fibrillation (IVF).Initial cardiac imaging studies revealed abnormal sympathetic innervation patterns in the left ventricle in those patients which was first described by Wichter et al.Over the course of 46 months, 27 consecutive patients were investigated at our clinic. Of these, 17  met the ARVC/D diagnosis according to the modified task force criteria. The remaining 10 patients  were diagnosed with IVF, with exclusion of ARVC/D according to the modified task force criteria; this patient group served as our reference cohort for molecular imaging. This study was conducted with the approval of the local ethics committee, with provision of informed consent from all patients.123I-MIBG was applied over a span of 2 minutes. Planar images of the thorax were acquired at approximately 15 minutes and 4 hours after tracer injection . Following completion of the second planar acquisition, a SPECT/CT was acquired using a low energy, high-resolution collimator . Ancillary to the previously mentioned protocols an additional low-dose CT  for attenuation correction and morphological co-registration was performed. All scans were performed with a Symbia TruePoint SPECT/CT scanner .SPECT data acquisition was performed in accordance to previous published protocols, with fasting on the day of the scan.123I-MIBG images were analyzed using the Hermes Hybrid Viewer  by manually drawing regions of interest (ROIs), as previously described.Planar SPECT/CT images were reconstructed with attenuation and scatter correction , and analyzed using the Inveon Research Workplace . In this analysis, we imported and fused the SPECT and CT images, and manually drew volumes of interest (VOIs) around the left and right ventricle in the CT scan, which were then applied to the SPECT images .All variables are reported as mean ± standard deviation (SD). Variables were tested for normal distribution using the Kolmogorov–Smirnov test. The paired and unpaired Student’s t-test ; the WOR was non-significantly higher in the ARVC/D group   as well as to RV/M ratio .There was a moderate but significant positive correlation between the delayed (4 hours) planar H/M ratio and LV/M ratio  of 0.73 Figure A. The RO123I-MIBG imaging in a group of 27 patients, 17 of whom proved to have ARVC/D. Using the SPECT/CT fusion images, we were able to obtain separate assessment of the left and right ventricular sympathetic innervation. Whereas planar scintigraphy provided only limited information, the delayed RV/M ratio in SPECT/CT was significantly lower in patients with diagnosed ARVC/D and could distinguish with high sensitivity and specificity between ARVC/D patients and patients with other underlying cardiac heart diseases in our study cohort. To our knowledge, this is the first SPECT/CT study to demonstrate the feasibility of separate left and right ventricular in vivo evaluation of the sympathetic myocardial innervation.The objective of this study was to examine a novel hybrid SPECT/CT molecular imaging approach for detecting myocardial sympathetic dysfunction in patients with suspected or diagnosed ARVC/D by analyzing the left and right ventricular uptake separately. To this end, we performed early and delayed planar and delayed SPECT/CT 123I-MIBG uptake. The mean H/M ratio in our reference group was 1.7, indicating generally less severe heart disease than in the ARVC/D group. The small numerical difference did not differ significantly between groups, likely because the planar H/M ratio is weighted towards tracer uptake in the left ventricle, which is relatively spared in earlier stages of the disease.A number of different ROI-based methods to quantify the myocardial sympathetic innervation in planar images have been published,123I-MIBG study, Ogita et al.In a previous 123I-MIBG. As a 3D modality, SPECT/CT can bring additional valuable information about the distribution of tracer uptake in the heart. In our approach, we used the additional morphological information of the low-dose CT scan to define separate VOIs of the left and right ventricle.Planar scintigraphy is the established method in the clinical setting to quantify the sympathetic innervation with 123I-MIBG uptake by planar imaging as compared to SPECT, most likely arising from the somewhat higher mediastinal tracer uptake in planar imaging, also reported by Chen et al.123I-MIBG uptake in the LV myocardium, most notably in the posteroseptal basal segments.P = 0.014).Veen et al. demonstrated a high correlation between planar and left ventricular H/M ratios,123I-MIBG imaging, predicts poor prognosis in heart failure patients.123I-MIBG SPECT/CT for individual risk stratification and the possibility to detect the disease in the early phase. However, we contend that previous methods have been inadequate since they were restricted to consideration of LV, and provided no information regarding the RV sympathetic innervation.P = 0.001), and indeed proved to be the best method to distinguish between the two patient groups. Nonetheless, to establish the absolute magnitude of reduced RV innervation a comparison to individuals without heart disease will be mandatory.Previous studies demonstrated that a present sympathetic dysfunction, as visualized by 123I-MIBG uptake is hampered due to the damaging of sympathetic fibers.It is well known that ARVC/D is characterized by a fibrofatty infiltration of the heart muscle, which primarily affects the right ventricleROC-analysis revealed a threshold for the H/M ratio of (1.66) comparable to that previously published for patients with heart failure (1.60) by Jacobson et al.,123I-MIBG imaging in the revised McKenna criteria could be a future consideration. However, in order to establish this parameter for the diagnosis of ARVC/D, it would be essential to validate our findings in a larger cohort.In this context, it is of great interest to compare the sensitivities and specificities of our SPECT/CT results with those of the modified task force major criteria; parameters determined by echocardiography required 95% specificity, with sensitivity of the individual parameters ranging from 55% to 75%. Based on our findings yielding a high specificity and sensitivity for the RV/M ratio the inclusion of the In addition, the progressive fibro-fatty replacement of the RV with a subsequent enlargement of the ventricle leads to abnormalities in the regional wall motion. These changes can be assessed by cardiac magnetic resonance imaging.123I-MIBG uptake between individuals with heart disease.A major limitation of our study is the low number of patients and the heterogeneous clinical stage of the disease, both of which are due to rarity of ARVC/D. Furthermore, the lack of a healthy control group—due to the ethical requirements of radiation exposure to healthy subjects—is limiting the transfer of this results into the clinical routine, since the published thresholds were established to distinguish the cardiac 123I-MIBG uptake. We found significantly reduced 123I-MIBG accumulation in the RV of ARVC/D patients in comparison to our reference group, such that the RV/M ratio confirmed diagnosis of ARVC/D with a high sensitivity and specificity. Validation of this finding in a larger cohort could be helpful in the management of patients with suspected ARVC/D. Future studies might also investigate cohorts with other electrophysiological cardiac disorders, e.g., right ventricular outlet tract tachyarrhythmias that currently pose major diagnostic dilemmas.ARVC/D can be diagnosed reliably based on structural abnormalities of the RV, but definitive diagnosis is difficult at early disease stages. The present SPECT/CT method allows for non-invasive evaluation of cardiac sympathetic function, with separate evaluation of left and right ventricular 123I-MIBG uptake can be assessed using SPECT/CT imaging and used to distinguish between patients with suspected and proven ARVC/D. This might be helpful in the management of patients with suspected ARVC/D.Right ventricular cardiac Supplementary material 1 (DOCX 2071 kb)Supplementary material 2 (PPTX 356 kb)Below is the link to the electronic supplementary material.


Magnetic resonance imaging (MRI) is an emerging tool for diagnosis and treatment monitoring of chronic thromboembolic pulmonary hypertension (CTEPH). The current study aims to identify central pulmonary arterial hemodynamic parameters that reflect clinical, cardiac and pulmonary changes after PEA. 31 CTEPH patients, who underwent PEA and received pre- and postoperative MRI, were analyzed retrospectively. Central pulmonary arterial blood flow, lung perfusion and right heart function data were derived from MRI. Mean pulmonary arterial pressure (mPAP) and 5-month follow-up six-minute walk-distance (6MWD) were assessed. After PEA, mPAP decreased significantly and patients achieved a higher 6MWD. Central pulmonary arterial blood flow velocities, pulmonary blood flow (PBF) and right ventricular function increased significantly. Two-dimensional (2D) phase-contrast (PC) MRI-derived average mean velocity, maximum mean velocity and deceleration volume changes after PEA correlated with changes of 6MWD and right heart ejection fraction (RVEF). Deceleration volume is a novel 2D PC MRI parameter showing further correlation with PBF changes. In conclusion, 2D PC MRI-derived main pulmonary hemodynamic changes reflect changes of RVEF, PBF and 5-month follow-up 6MWD and may be used for future CTEPH patient monitoring after PEA. Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, life-threatening disease. Its primary treatment promising cure is pulmonary endarterectomy (PEA) –5. ThreeFollowing the latest diagnostic algorithm proposed in the”2015 guidelines for the diagnosis and treatment of pulmonary hypertension” of the European Respiratory Society, CTEPH should be diagnosed in specialized centers [Magnetic resonance imaging (MRI) has been proposed for CTEPH assessment –9. RegarThus, the aim of the present study is to identify central pulmonary arterial hemodynamic parameters that reflect clinical, cardiac and pulmonary changes after PEA in CTEPH patients to provide a clinically useful compound marker using 2D PC MRI.This retrospective study was approved by the ethics committee of Hannover Medical School . Written informed consent was obtained from all patients. CTEPH patients undergoing PEA between September 2011 und June 2016 in our hospital were considered for this study. Only patients that completed clinical routine cardiopulmonary MRI before and after surgery were included. MRI is part of our clinical routine workup to evaluate i.a. perfusion defects and cardiac function. Mean pulmonary arterial pressure (mPAP) was documented preoperatively by right heart catheterization and during the postoperative intensive care unit stay before removal of the Swan-Ganz catheter. 6MWD (measured in meters) was obtained in the clinical workup routine before and after PEA. PEA was performed in general anesthesia using cardiopulmonary bypass and deep hypothermia as previously described , 13. A sCardiopulmonary MRI was performed at 1.5T . An eight-channel torso phased array coil was used for all sequences.Blood flow was evaluated by retrospectively electrocardiography-gated phase-contrast sequences during free breathing with slices set perpendicular to the main pulmonary artery about 1cm distal of the valve and the bifurcation respectively. The following sequence parameters were used: TR 20ms, TE 2.8ms, flip angle 30°, slice thickness 5mm, matrix 256 × 256, field of view 460mm × 460mm, 75 reconstructed phases, 3 averages, 2 segments, velocity encoding individually adjusted.Cardiac function was evaluated by retrospectively electrocardiography-gated cine balanced steady-state free precession sequences during short inspiratory breath-holds using short-axis views covering the whole heart with the following sequence parameters: TE 1ms, TR 2.9ms, flip angle 75°, slice thickness 8mm, field of view 290mm x 360mm, matrix size 208 x 256, temporal resolution 35ms, in-plane resolution 1.4mm x 1.4mm, bandwidth/pixel 540Hz/pixel, 30 reconstructed phases.Regional lung perfusion was evaluated by three-dimensional dynamic contrast enhanced (DCE) time-resolved angiography with stochastic trajectories (TWIST)  with thePhase-contrast and short axis cine MR images were analyzed with cvi42 version 5 . Semiautomatic contour detection with manual adjustment where necessary was applied, a strategy that has previously shown good interobserver agreement , 15. Pap2), minimum area (mm2), area change (mm2), average mean velocity (cm/s) and maximum mean velocity (cm/s) were determined with phase-contrast cine images. Acceleration time was defined as the time interval from the beginning of systolic antegrade flow up to the time point of maximum antegrade flow. The latter time point was defined as the beginning of deceleration time that ended at the next inflection point of the flow curve except a notch or at the end of antegrade flow. Acceleration volume and deceleration volume were calculated as the integral of flow over acceleration time and deceleration time respectively. Acceleration time (ms), acceleration volume (ml), deceleration time (ms), deceleration volume (ml), maximum area (mmRight ventricular (RV) ejection fraction , end-diastolic volume , end-systolic volume  and myocardial mass (g) were calculated from the short axis cine images.First-pass DCE MR images were used for calculating parenchymal microvascular pulmonary blood flow (PBF) maps by using pixel-by-pixel deconvolution analysis with PMI-MIKE 0.4  , 17. Theth and 75th percentile. Shapiro-Wilk test was applied for normality testing. Data before and after PEA were compared with paired two-sided Wilcoxon rank sum tests as being mainly not normally distributed. One-sided Spearman correlations were applied for rank correlations of parameter ratios before and after PEA.Data are shown as median values with 25via one-sided Spearman correlations. The latter 2D PC MRI parameters were restricted to those that showed significance in global (i.e. non-subgroup) analysis before.Subgroup analysis was applied to subjects who also received post PEA right-heart catheterization. Right-heart catheter mPAP, pulmonary vascular resistance and total peripheral resistance were analyzed with Wilcoxon signed-rank tests. Pre/post ratios of these parameters were than correlated to 2D PC MRI parameters p-values .Benjamini-Hochberg procedure was applied for control of false discovery rate at level α = 0.05 with adjustment of Between September 2011 und June 2016 we identified 83 CTEPH patients that underwent PEA in our hospital, of which 72 received MRI exams. In total 31 patients with a mean age of 57 years (age range: 20–82 years), 11 women and 20 men, had MRI scans before and after PEA. These were included in this study. Due to a technical error a single 2D PC MRI measurement of the main pulmonary artery before PEA had to be excluded. 6MWD values were available for 22 patients. p = <0.001). In turn 6MWD increased by 68 m (p = 0.002). Right heart ejection fraction improved  and pulmonary parenchymal perfusion increased .After PEA, mPAP decreased significantly by 22 mmHg (p = 0.005 and p = 0.001) while deceleration time and volume decreased (p<0.001 and p = 0.038). Maximum and average mean velocities significantly increased (p<0.001). The ejection phase of flow changed significantly after PEA: acceleration time and volume increased (p<0.001 and p = 0.017), as well as area change (p = 0.004). RV EDV (p<0.001), ESV (p<0.001) and mass (p<0.001) also decreased significantly.Significant postoperative decreases could be observed for maximum and minimum area of the main pulmonary artery . Right-heart catheter mPAP changed from 47.0  before to 42.0  mmHg after PEA (p = 0.12), pulmonary vascular resistance from 8.1  to 6.0  Wood units (p = 0.028) and total peripheral resistance 21.0  to 16.1  Wood units (p = 0.028). The results of the subgroup parameter ratio correlations are shown in A subgroup of six patients received post PEA right-heart catheterization 293  days after PEA. The subgroup consists of 3 men and 3 women with a mean age of 56 years  changes, but also with 6MWD and RVEF ratios. These three parameters represent key aspects of successful CTEPH surgery: restoration of lung perfusion with reduction of pulmonary vascular resistance, improvement of right ventricular function and clinical outcome. Thus, deceleration volume ratio represented a non-invasive surrogate compound parameter in this study.The main purpose of surgical CTEPH treatment is the restoration of lung perfusion through removal of thrombi and scars. As a consequence, we measured significantly increased PBF  and mainPEA reduced right heart strain in our patient cohort. We observed an RVEF increase and in turn RV mass, ESV and EDV decrease , 10. RVEvia Swan-Ganz catheter as limitation. Intensive care measurements are less accurate than those obtained from right heart catheterization, but were the only data available for all patients. We, however, do not assume a major impact on the results. We furthermore applied a subgroup analysis to six patients that underwent right-heart catherization after PEA. This subgroup analysis is limited by the small number and a selection bias, as these patients received right heart catheterization due to clinical worsening and suspected recurrent embolism, not as routine clinical follow-up. Despite these limitations, the subgroup analysis additionally showed a strong correlation of deceleration volume with right-heart catheter mPAP ratios.MRI has been proposed and continuously validated as perioperative monitoring tool for CTEPH , 18, 22.In conclusion, we showed that hemodynamic changes, assessed by 2D PC MRI in the main pulmonary artery after PEA, reflected changes of right heart function, pulmonary parenchymal perfusion and clinical outcome. We identified deceleration volume ratio as a new parameter and compound marker for perioperative CTEPH patient monitoring.S1 Data(XLSX)Click here for additional data file.


Pulmonary hypertension (PH) accounts for substantial morbidity and mortality. Advances in cardiac imaging have enabled the 3 Dimensional (3D) study of right ventricular (RV) geometry and functional parameters; however, their impact on patient outcomes in various groups of patients (pts) such as idiopathic pulmonary arterial hypertension  when compared to PH secondary to other causes  has not been fully studied.We propose that the RV volume and geometry in IPAH and SPH pt groups will correlate with a clinically important prognostic parameter such as 6-minute walk distance (6 MWD).Pts (n = 32) with severe PH were divided into 2 groups: 15 pts with IPAH and 17 pts with SPH. All pts underwent cardiac MRI (CMR)  and measurements of 3D RV end-diastolic and end-systolic volumes , ejection fraction (EF), mass and relative wall thickness (RWT), all indexed to BSA and were compared to 6 MWD.There were no differences in the RV geometry or function between the two groups. The mean RV mass index, RWT and RVEF were 34.8 ± 29, 0.19 ± 0.11 and 34 ± 14% in the IPAH group vs 27 ± 10, 0.20 ± 0.11 and 44 ± 15%, in the SPAH group (p = ns). The RWT and RV mass index demonstrated that the RV was eccentrically hypertrophied in both groups despite severe PH. The IPAH pts had slightly higher PA systolic pressure when compared to SPH  but had lower pulmonary wedge pressures . The mean 6 MWD was similar between the IPAH vs. SPH group . The RVEDVI, RVESVI and RVMI positively correlated with 6 MWD  of IPAH patients but did not demonstrate significant correlation for SPH pts. Furthermore, the 3D RVEF, 2D TAPSE and ratio of RVMI to RV volume did not demonstrate correlation with the 6 MWD.Although IPAH and SPH patients have very similar RV geometry, structure and function, noninvasive CMR metrics only predict 6 MWD for IPAH patients. Clinically important predictors of 6 MWD by CMR metrics for the SPH group, a potentially more heterogeneous group, is not beneficial. These observations highlight the key pathophysiologic differences in the compensatory response of the RV to vastly different pathophysiology despite a more homogeneous response at the level of the RV chamber. This finding may account for the observed differences in treatment response and clinical outcomes in these patients.


Congenital corneal opacities (CCOs) are the major causes of early visual deprivation in infants. Balloon ultrasound biomicroscopy (UBM) examination is an effective method to diagnose CCO. However, whether it is suitable for children examination is still unknown.  26 Peters' anomaly (PA) or Rieger's anomaly (RA) infants with congenital corneal opacities (CCO) (40 eyes) underwent UBM examinations to study their imaging features.  Based on the results, they were divided into UBM Dx-Type I: Descemet's membrane (DM) and endothelium have heterogenous or discontinuous echo accompanied with corneal stroma echo-enhanced or shallow anterior chamber. Type II: Type I alteration plus abnormal strand of iris extended to the border of the posterior corneal defect or iridocorneal adhesion. Type III: Type I or II combined with the abnormal hyperechoic lens, lens luxation, or keratolenticular adhesion. Type IV: echoes of the DM and the endothelium are continuous, corneal stroma echo is enhanced, and an abnormal strand of peripheral iris extends to the prominent Schwalbe line, accompanied by iris stroma or pupil heteromorphism and a shallow or flat anterior chamber.  UBM not only could accurately evaluate the anterior segment abnormalities in CCO infants but also would be a step forward for the management of PA- and RA-associated CCO. Congenital corneal opacities (CCOs) are uncommon, occurring in only 2.2–3.1 per 100,000 newborns each year. CCO interferes with vision, leading to early visual deprivation and a lifetime of severe amblyopia, which becomes the major causes of early visual deprivation in infants –6. PA anUltrasound biomicroscopy (UBM) is a noninvasive ultrahigh frequency ultrasound imaging system. It has been widely applied in the examination of disorders of the anterior segment of the eyeball, which provides ultra-high-frequency sound imaging to analyze the structure of the anterior segment and severe corneal opacities in living body . In the In this study, we prospectively studied the application of the high-resolution bag/balloon UBM technique as a routine examination for infant patients under sedation and surface anesthesia. This study will provide insight into the safety of UBM examination in infants, the value of UBM imaging, and the potential diagnostic capabilities of UBM in infants with PA and RA.This study was approved by the Guangzhou Women and Children's Medical Center Review and Ethics Board. All CCO infantile patients were recruited from the Guangzhou Women and Children's Medical Center in Guangdong, China, between November 2012 and November 2017. Corneal opacities were the first symptom in all cases. Patients with congenital glaucoma or posterior segment diseases, like retinopathy of prematurity, persistent fetal vasculature, or retinoblastoma were excluded from this study.All patients received slit-lamp microscopy and high-resolution bag/balloon UBM examination using the Aviso S instrument 50 MHz  to detect PA and RA under oral chloral hydrate sedation and tetracaine surface anesthesia in the supine position. Scans were performed by the same experienced technician, while a nurse fixed the head of patients. A sterile balloon was filled to the top of the flexible sealing collar with room temperature distilled water . A gel wAll data were analyzed using SPSS 23.0 .In total, 50 CCO eyes were preliminarily screened and 10 eyes were excluded due to congenital glaucoma. Finally, 40 eyes of the 26 CCO infants with PA or RA were enrolled in this study. Among them, 13 cases were male (22 eyes) and 13 patients were female (18 eyes). From these patients, 12 cases were unilateral  and 14 were bilateral (28 eyes). The average age at the first visit to the hospital was 344.7 days with a range of 7 days to 3 years .According to the degree of the anterior segment structure observed through the opacity cornea, the corneal opacity was divided into three clinical types. Mild: corneal haze, anterior segment structure could be observed. Medium: anterior segment structure is indistinctive. Severe: corneal leucoma, anterior segment structure could not be observed Figures . As showThe high-resolution bag/balloon UBM examination captured clear images of the CCO patients under sedation and surface anesthesia. The pathological alterations in the anterior segment structure of all the patients with PA and RA were observed and evaluated by UBM. According to the anatomical position of the anterior segment, we distinguished the variation of the anterior segment tissue structure . The detailed findings of the UBM for each CCO patients are summarized in Based on the alteration of the histological structure of the anterior segment and the imaging features from the UBM examination, the patients were classified into the following four types : UBM Dx-In this study, we reported the UBM findings in 40 eyes from 26 infants with PA- and RA-associated CCO. The high-resolution ball/balloon UBM technique was applied in patients with an age range of 7 days to 3 years . All infantile patients were successfully examined by UBM under sedation and surface anesthesia to obtain valuable images. All UBM images revealed the structural features of the cornea, anterior chamber, iris, and lens. To our knowledge, this is the most extensive study to apply the high-resolution ball/balloon UBM technique to diagnose PA- and RA-associated CCO in infants so far.UBM examination is a noninvasive, real-time, fast, and high-resolution detection method to observe the structure of the anterior segment from the living body. The images provide sectional visibility of anatomical sections, which show the structure of the anterior segment in high resolution. It is especially suitable for the patient whose cornea is opaque to clearly display the relationship between the cornea, iris, ciliary body, chamber angle, lens, and surrounding tissue in a noninvasive manner. Thus, it is valuable for the role of the histological examination of living tissue , 16. In Most ophthalmologists still use the traditional open-shell UBM technique. It is necessary to choose the appropriate eye cup according to the size of the palpebral fissure. Thus, it is only suitable for most adult patients. However, it is not ideal for the adults and infants whose palpebral fissures are small, as it may cause discomfort and non-cooperation during the examination, especially for children . During According to the UBM finding features, the cases were classified into four types (UBM Dx-Type I to IV). Waring et al. have classified PA and RA based on the characteristics of histological and anatomical alterations . Indeed,Although the UBM images of UBM Dx-Type I to III varied, they showed the heterogenous or discontinuous echo in the DM and endothelium, which histologically corresponds with the PA's alteration of specific local defects. UBM Dx-Type I only has the above image features, but its iris and lens were normal. UBM Dx-Type II accompanies with an iris anomaly, such as the abnormal strand of iris extending to the border of the posterior corneal defect or with iridocorneal adhesion. This image feature is consistent with the type of posterior corneal defect common with stromal edema and iridocorneal adhesion in PA. The images of UBM Types I andII are consistent with the PA Type I of Waring's classification. UBM Dx-Type III is on the fundamental alteration of UBM Dx-Type I or II, plus the abnormal hyperechoic lens, lens luxation, or keratolenticular adhesion. Its image feature is consistent with the type of posterior corneal defect with stromal edema, cataract formation, or keratolenticular in PA, also known as the PA type II.The UBM image of UBM Dx-Type IV  is consistent with the type of RA, including peripheral anterior adhesion that strands of iris tissue to the Schwalbe line and uplifts as a ring, iris hypoplasia, polycoria, and corectopia. In this observation of 26 cases (40 eyes), 22 eyes were divided as PA type I (55%), 12 eyes were diagnosed as PA type II (30%), and 6 eyes were assigned as RA (15%) by the Waring classification. Interestingly, 5 of the 15 bilateral cases were found to be inconsistent, among which, four cases were inconsistent with the degree of bilateral, and another one was in a different classification. According to the features of UBM images, cases 11 and 21 were both diagnosed as PA type II in the right eye and PA type I in the left eye; case 15 was diagnosed as PA type II in the right eye and PA type III in the left eye; case 23 was diagnosed as PA type III in the right eye and PA type II in the left eye; and case 26 was diagnosed as PA in the right eye and RA in the left eye.Previous reports have shown that the penetrating keratoplasty (PKP) had been performed on some PA patients to treat the corneal opacity , 25. In This study indicates that UBM not only could accurately evaluate the anterior segment abnormalities in CCO infants but also would be a step forward for the management of PA- and RA-associated CCO. Moreover, the classification may play a role in guiding treatment recommendations in the future.


The primary outcome was all-cause mortality, and the secondary outcome was a composite of coronary artery disease and cerebrovascular accidents. The following trajectory patterns were identified: stable, 61%; decreased, 5%; mildly increased, 32%; and markedly increased, 2%. During follow-up , 557 participants died and 217 experienced secondary outcomes. The adjusted hazard ratios of primary and secondary outcomes for participants with a markedly increased trajectory pattern were 1.80 (95% CI [1.18–2.76]) and 1.45 (95% CI [0.67–3.12]), respectively, compared to those for participants with a stable trajectory pattern. A markedly increased heart rate trajectory pattern may be associated with all-cause mortality risks. Heart rate trajectory patterns demonstrated the utility of repeated heart rate measurements for risk assessment.Heart rate trajectory patterns integrate information regarding multiple heart rate measurements and their changes with time. Different heart rate patterns may exist in one population, and these are associated with different outcomes. Our study investigated the association of adverse outcomes with heart rate trajectory patterns. This was a prospective cohort study based on the Chin-Shan Community Cardiovascular Cohort in Taiwan. A total of 3,015 Chinese community residents aged > 35 years were enrolled in a prospective investigation of cardiovascular risk factors and outcomes from 1990 to 2013. Resting heart rate is a straightforward and easily obtainable clinical variable. Epidemiologic studies have demonstrated that elevated heart rate is a sensitive indicator of short life expectancies and is associated with an increased risk of adverse outcomes, such as all-cause mortality, cardiovascular diseases, diabetes, cancer, and stroke . This asMost previous studies used a single-point heart rate measurement, such as the baseline heart rate, for analysis . The majTo the best of our knowledge, few studies have investigated repeated heart rate measurements through heart rate trajectories combined with time-dependent covariates. This study aimed to identify different heart rate trajectory patterns using longitudinal heart rate data and to study the risk of adverse outcomes among different heart rate trajectory patterns.n = 391); whose baseline and follow-up heart rate data were missing (n = 162); with key-in error (n = 1); whose heart rhythm demonstrated complete atrioventricular block or pacemaker rhythm (n = 5); and with atrial fibrillation (n = 28). After these exclusions, 3,015 participants were included in the study population. During the 1992–1993 follow-up period, 2,386 participants were available for heart rate analysis. Data were collected from 1,786 and 1,133 participants during the 1994–1995 and 2001–2002 follow-up periods, respectively. The flow diagram of cohort selection is shown in This prospective cohort study was based on the Chin-Shan Community Cardiovascular Cohort. The details of this cohort have been described previously . All patThe participants’ anthropometric and lifestyle data, medical history and current health conditions were assessed using interview questionnaires in 2-year cycles through the assistance of trained young faculty and medical students.A 12-lead electrocardiography was performed in each participant to obtain heart rates, and two cardiologists blindly evaluated the results. Participants were instructed to avoid alcohol, food or drink with caffeine, and smoking 8 h before examination. Four repeated heart rate measurements were obtained during 1990 and 2002. The first heart rate reading was obtained during 1990–1991, and the follow-up heart rate readings were obtained during 1992–1993, 1994–1995, and 2001–2002. Heart rate parameters were the baseline and final heart rates. Baseline heart rate was defined as the heart rate measured at the first examination, and the final heart rate was defined as the last available heart rate during follow-up. The change in heart rate was defined as the change in heart rates between examinations. When data were missing between examinations, we omitted the missing heart rate. For example, if the second examination was missed, then we calculated differences in the heart rates of the third and first examinations. Group-based trajectory models (GBTMs) of heart rates were based on statistical analyses, and individuals with similar patterns of changes in heart rate were grouped together. The heart rate coefficient of variation (CV) was defined as the ratio of the standard deviation to the average heart rate.The primary outcome was all-cause mortality, and the secondary outcome was a composite of coronary artery disease and cerebrovascular accidents (CVAs). Coronary artery disease was defined as nonfatal myocardial infarction, fatal coronary artery disease, or hospitalization for percutaneous coronary intervention or coronary artery bypass surgery, including hospitalization for angina, and coronary angiography showing >50% luminal stenosis. Fatal coronary artery disease was considered to have occurred if hospital records confirmed fatal myocardial infarction or if coronary heart disease was listed on the death certificate as the underlying and most plausible cause of death. CVAs were defined as sudden neurological deficits of the vascular origin that lasted for more than 24 h. Primary and secondary outcomes identified during follow-up visits were reviewed by physicians on the Committee of Mortality and Morbidity within the study team. Four cardiologists reviewed the completed interview questionnaires, medical records, and laboratory reports to determine whether each event met the protocol established by the project steering committee. The study team invited all participants to have biennial follow-up visits and examinations. Relatives of non-respondents were contacted to obtain information on the health status of non-responsive individuals. Medical students were responsible for administering the questionnaires and interviewing participants. We reviewed the hospitalization and outpatient service records corresponding to the questionnaires. Moreover, we regularly collected death certificate documents from the local health station and performed oral interviews with relatives and family members about death events to confirm the causes of death.Baseline characteristics of participants, including personal medical history, smoking habits, alcohol habits, lifestyle choices, exercise frequency, socioeconomic status, and family history, were collected through questionnaires. Physical examinations were conducted by trained physicians. Laboratory tests were conducted after a 12-hour fasting period. Blood pressure was measured after 10 min of rest using a mercury sphygmomanometer. This measurement was obtained with participants in a comfortable seated position, with their arms supported and positioned at the level of the heart. Blood pressure was measured twice in the right arm. If the readings varied by more than 10 mmHg, then an additional reading was performed. The average of these blood pressure measurements was used as the final blood pressure.2 (m2). Diabetes mellitus (DM) was defined as fasting glucose ≥126 mg/dL or as the use of oral hypoglycemic or insulin medication. The estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft–Gault formula  was calculated as weight (kg)/height formula . An eGFRFor descriptive analyses, continuous variables are described as mean (± standard deviation), and categorical variables as numbers and percentages. Characteristics of demographic data across groups were compared using an analysis of variance for continuous variables and using chi-square test for categorical variables of sex, history of hypertension, DM, atrial fibrillation, smoking, and sports.The GBTM analysis was performed using SAS software  with the Traj package to identify trajectory patterns of long-term changes in heart rate. We adopted the censored normal model because heart rate is a continuous variable. We initially assumed the trajectory patterns to be cubic and treated heart rate as a dependent variable and time as an independent variable. A repeated trajectory analysis was performed by changing the number of groups from two to five. The Bayesian information criterion was used to estimate the number of trajectory patterns. The number of groups with the highest Bayesian information criterion was considered the appropriate one. After the number of groups was decided, we further tested each group of trajectories as linear, quadratic, or cubic to confirm the accurate graphical shape of change in heart rate by selecting the highest polynomial order to best characterize each trajectory group . To testBaseline and final heart rates were treated as both categorical and continuous variables in this study. To analyze the baseline and final heart rates as categorical variables, they were evaluated according to quartile. The change in heart rate was considered a continuous variable by calculating differences in heart rates between the first follow-up examination and baseline, between the second and first follow-up examinations, and between the third and second follow-up examinations. The heart rate CV was considered a continuous variable.2. The time-dependent covariates were age, BMI, cholesterol, diabetes status, SBP, and DBP .A survival curve was calculated using the Kaplan–Meier method. For Cox regression analyses, adjusted hazard ratios were reported with models 1 and 2. Model 1 was adjusted with age and sex only. Model 2 was adjusted with all covariates. We used baseline covariates to adjust for the baseline heart rate, GBTM of the heart rate, and CV of the heart rate, and we used time-dependent covariates to adjust for the final heart rate and change in heart rate. These covariates are established predictors of outcomes. Baseline covariates included age, sex, systolic blood pressure (SBP), diastolic blood pressure (DBP), diabetes status, smoking, cholesterol, BMI, and eGFR <60 mL/min/1.73 m and DBP . Statistn = 1,828; 61%), decreased , mildly increased , and markedly increased . Participants with stable, mildly increased, and markedly increased heart rate patterns started with lower baseline heart rates, whereas those with a decreased pattern started with higher baseline heart rates, but the trend decreased later. The trend of an increased heart rate was the highest for the markedly increased pattern and the lowest for the stable pattern. p = 0.011). For the composite outcome of coronary artery disease and CVA, no significant differences were found among the four heart rate trajectory patterns (p = 0.77). The adjusted hazard ratios of primary and secondary outcomes for participants with markedly increased trajectory pattern were 1.80  and 1.45 , respectively, compared with those with the stable trajectory pattern (p = 0.015) and 0.87   , respectThe study demonstrated an association between heart rate trajectories and all-cause mortality, but no association was evident between heart rate trajectories and cardiovascular events. Our study was primarily based on the analysis of heart rate in sinus rhythm. Participants with atrial fibrillation were excluded because previous literature showed that the impact of heart rate on adverse outcomes differed among patients with sinus rhythm and those with atrial fibrillation . We alsoHeart rate trajectories with time-dependent covariates adjustment will predict outcomes better in this situation. Participants with a decreased trajectory pattern started with the highest baseline heart rate among the groups. The risk of all-cause mortality in patients with a decreased trajectory pattern was not higher than that in patients with a stable trajectory pattern. Although participants with a decreased trajectory pattern started with higher baseline heart rates, the heart rate trajectory of the decreased pattern continued to decrease over time. The detrimental effect of a high baseline heart rate was diminished by the decrease in heart rate over time. However, participants with a stable trajectory pattern and those with markedly increased trajectory pattern started with similar baseline heart rates, but the heart rate trajectory of the markedly increased pattern increased over time. An approximate 50% increase in heart rate was found from the baseline in 2 years. The risk of all-cause mortality for those with markedly increased trajectory pattern was significantly higher than for those with stable trajectory pattern. The faster the heart rate increases, the higher the all-cause mortality rate. This finding confirmed that the heart rate trajectory could be a more sensitive predictor of adverse outcomes than a single heart rate measurement.In our study, there was a gap between the last heart rate measurement and final outcomes. This temporal relationship demonstrates that the observed associations were not due to reverse causation. Further, we compared the results of GBTM for heart rate with three and four repeated heart rate measurements and found that the trajectories were very close and that the markedly increased trajectory pattern was associated with a significantly higher risk of all-cause mortality than the stable pattern in both models. This finding confirmed the reliability of our heart rate group classification and showed the possibility to predict long-term heart rate trajectory patterns with earlier repeated heart rate measurements.Compared with the GBTM for heart rate, the change in heart rate did not correlate well with adverse outcomes. This finding may have been caused by the change in heart rate being considered as a continuous variable because it was difficult to predict a complex and non-linear trend for the risk of heart rate outcomes. The heart rate CV showed the extent of variability in relation to the mean heart rate but lacked information regarding how the heart rate changed with time; therefore, it correlated poorly with outcomes.For the secondary outcomes, there are several possible reasons for the insignificant results. First, a low events rate for secondary outcomes was responsible for the low statistical power in our population. Second, considering the effect size of trajectories on secondary outcomes, our sample size may have been too small for the analysis.Previous literature emphasized the role of resting heart rate as a predictor of adverse outcomes, and resting heart rate was regarded as an indicator of general health . In one Some studies reported that heart rate achieved during follow-up examinations was a better predictor of risk than the baseline heart rate . Other sParticipants in the markedly increased heart rate pattern group were likely to have higher BMI, DBP, and cholesterol. Several studies showed the association of these risk factors with heart rate. Lower BMI is associated with cardiorespiratory fitness. Regular exercise can improve cardiorespiratory fitness, which was proven by some studies to decrease resting heart rate . RestingOur study was based on a community cohort, and most participants were healthy individuals. Although the external validity of our study was not tested, our results highlighted the possibility of investigating the heart rate not only using a single measurement but also using trajectory patterns. In addition, our study demonstrated the utility of repeated heart rate measurements for risk assessment.Heart rate, as a component of vital signs, is underrated in the long term. The most widely accepted “normal heart rate” ranges from 60 to 100 bpm . In the This study had three major strengths. First, our study was based on a large sample size and included a long-term follow-up cohort study, both of which could have reduced the possibility of selection bias. Second, this study used several heart rate parameters, including the GBTM of heart rate, to estimate the effects of changes in heart rate on adverse outcomes. Third, our heart rate measurements were based on the ECG not the pulse rate. Participants would rest for 10 min before the heart rate was measured. This type of standardization enhanced the accuracy of heart rate measurements. This study also had limitations. Our results were based on the GBTM, and group identifications were not certain. The GBTM may identify additional groups to accommodate non-normality in the data rather than true latent groups. Other limitations include a large attrition between the follow-up visits, lack of medication information collected at the follow-up visits, oversimplified grading of physical activity, lack of updated information about smoking status and kidney function, and lack of specific cause of death. In addition, some residual confounders, such as inflammation, infection, weight gain, pregnancy, thyroid function, and other metabolic factors, were not well adjusted in the study.This study demonstrated the importance of identifying specific heart rate trajectory patterns and elucidating their associations with all-cause mortality, coronary artery disease, and CVA in a community-based population. The markedly increased trajectory pattern was associated with a much higher risk of all-cause mortality than the stable trajectory pattern, even when the heart rate was in the normal range.10.7717/peerj.8987/supp-1Supplemental Information 1Click here for additional data file.