Most cardiac studies focus on evaluating left ventricular (LV) systolic function. However, the assessment of diastolic cardiac function is becoming more appreciated, especially with the increasing prevalence of pathologies associated with diastolic dysfunction like heart failure with preserved ejection fraction (HFpEF). Diastolic dysfunction is an indication of abnormal mechanical properties of the myocardium, characterized by slow or delayed myocardial relaxation, abnormal LV distensibility, and/or impaired LV filling. Diastolic dysfunction has been shown to be associated with age and other cardiovascular risk factors such as hypertension and diabetes mellitus. In this context, cardiac magnetic resonance imaging (MRI) has the capability for differentiating between normal and abnormal myocardial relaxation patterns, and therefore offers the prospect of early detection of diastolic dysfunction. Although diastolic cardiac function can be assessed from the ratio between early and atrial filling peaks (E/A ratio), measuring different parameters of heart contractility during diastole allows for evaluating spatial and temporal patterns of cardiac function with the potential for illustrating subtle changes related to age, gender, or other differences among different patient populations. In this article, we review different MRI techniques for evaluating diastolic function along with clinical applications and findings in different heart diseases. The left ventricle (LV) of the heart fills via two separate mechanisms. In early-diastole, the LV fills passively through active relaxation. In late-diastole, the remaining blood contributing to the total end-diastolic volume enters the ventricle via active contraction of the left atrium (LA). During isovolumetric relaxation, LV volume increases due to alterations in principal strains and untwisting of the ventricles . CompletDiastolic dysfunction is an indication of abnormal mechanical properties of the myocardium, characterized by slow or delayed myocardial relaxation, abnormal LV distensibility, and/or impaired LV filling . DiastolHeart catheterization is the current gold standard for demonstrating the characteristics of diastolic heart failure, but due to the risks and costs involved with invasive hemodynamic evaluation, it is not practical for the diagnosis of diastolic dysfunction. Echocardiography, with significantly less risk compared to heart catheterization, is currently the method of choice for diagnosing diastolic dysfunction. Nevertheless, echocardiography has limitations related to poor acoustic windows, geometric assumptions, suboptimal spatial resolution, and high dependency on the operator’s skills. Some of these limitations restrict the technique’s ability to accurately measure annular velocities and assess diastolic function if regional dysfunction is present . Cardiac31P magnetic resonance spectroscopy (MRS) is another technique for non-invasively quantifying the energy required for active relaxation of the myocardial tissue through calculating the ratio of myocardial phosphocreatine to adenosine triphosphate (PCr/ATP).Different MRI techniques are currently available for evaluation of diastolic cardiac function, such as cine imaging for global function analysis, phase contrast (PC) imaging for flow analysis, and myocardial tagging for regional function analysis. Simple measurements, such as longitudinal fractional shortening, can be measured quickly and easily by MRI, which has reliably identified echocardiography-evidenced diastolic dysfunction in patients with preserved LV EF . AssessmGlobal diastolic function is assessed using time-volume curves generated by tracing the epicardial and endocardial borders of the myocardium in cine MRI images throughout the cardiac cycle or from 4D flow images across atrioventricular valves . StudiesThe heart function can also be studied using MRI tagging . MRI tagThe introduction of complementary spatial modulation of magnetization (CSPAMM) by Fischer et al.  helped rMRI feature-tracking (MRI-FT) is yet another technique for evaluating regional cardiac function directly from the cine images . Ng et aPhase-contrast (PC) MRI offers an alternative method to echocardiography for assessing vascular blood flow and myocardial tissue velocity. PC MRI has the potential to measure hemodynamic parameters that are important for assessing diastolic function in clinical routine  Figure , with inFour-dimensional flow (4D-Flow) MRI is superior to Doppler echocardiography for evaluating intracardiac velocity as it is not limited by flow direction or inconsistency in transducer alignment. Previous studies using 4D-Flow MRI demonstrated significant flow reduction and end-diastolic volume and kinetic energy increase in patients with moderate-to-severe dilated cardiomyopathy . The res, resulting in underestimation of the absolute volume change of respective indices . Ch. Ch97]. 31P-MRS predicted hypertrophic changes before they happen, possibly due to the lower myocardial phosphocreatine levels leading to calcium overload and impairment of cardiac cells [Li et al.  showed tac cells ; furtherac cells . Russel ac cells  showed tac cells  demonstrThe risk for diastolic dysfunction is known to increase with age, obesity, and hypertension in the general population , but theConstrictive pericarditis is another cause of diastolic dysfunction and is reflected by the abrupt displacement of the interventricular septum in the LV during diastole. Alternatively, aberrant septal systolic motion into the RV is a common finding following cardiac surgery in constrictive pericarditis . In theiCancer treatment is known to have adverse cardiac effects on both systolic and diastolic functions and tissue composition . DeleterThe precise mechanism leading to the development of cardiac allograft vasculopathy is still unclear. Some suggestions include stiffness of the transplanted heart due to hypertrophy of cardiac myocytes and endocardial fibrosis, immunologic mechanisms combined with other risk factors for vascular injury, and the combination of systemic hypertension and microvascular stenosis . Given tMRI is gaining ground as a routine clinical tool for the evaluation of diastolic HF. Multiple cardiac MRI techniques have demonstrated superiority over methods that are currently considered the gold standard or are most commonly used. Furthermore, new methods for applying these techniques are being developed to eliminate time-consuming post processing and burdensome image acquisition. Armed with these advances, MRI is becoming a feasible and convenient tool for the accurate prediction, diagnosis, and long-term monitoring of diastolic dysfunction. It should be noted that although cardiac MRI provides several parameters that allow for evaluating heart morphology and function, myocardial contractility and tissue characterization, and hemodynamic parameters, its clinical utility could be affected by its relatively high cost, long scan time, and the need for experienced operators. Nevertheless, recent advances in MRI hardware, pulse sequences, and artificial intelligence (AI) capabilities allow for mitigating these limitations. For example, phased-array coils allow for parallel imaging capabilities that reduce scan time . Further


To evaluate the ability of single heartbeat fast-strain encoded (SENC) cardiovascular magnetic resonance (CMR) derived myocardial strain to discriminate between different forms of left ventricular (LV) hypertrophy (LVH).314 patients (228 with hypertensive heart disease (HHD), 45 with hypertrophic cardiomyopathy (HCM), 41 with amyloidosis, 22 competitive athletes, and 33 healthy controls) were systematically analysed. LV ejection fraction (LVEF), LV mass index and interventricular septal (IVS) thickness, T1 mapping and atypical late gadolinium enhancement (LGE) were assessed. In addition, the percentage of LV myocardial segments with strain ≤ − 17%  was determined.2, p < 0.05 vs all others) and lower LVEF compared to controls . Analysing subjects with mild to moderate hypertrophy (IVS 11–15 mm), %normal myocardium exhibited excellent and high precision, respectively for the differentiation between athletes vs. HCM  and athletes vs. HHD . Combining %normal myocardial strain with atypical LGE provided high accuracy also for the differentiation of HHD vs. HCM  and HCM vs. amyloidosis .Patients with amyloidosis and HCM exhibited the highest IVS thickness , whereas patients with amyloidosis showed the highest LV mass index (95.1 ± 20.1 g/mFast-SENC derived myocardial strain is a valuable tool for differentiating between athletes vs. HCM and athletes vs. HHD. Combining strain and LGE data is useful for differentiating between HHD vs. HCM and HCM vs. cardiac amyloidosis.The online version contains supplementary material available at 10.1186/s12968-021-00775-8. Left ventricular (LV) hypertrophy (LVH) can be part of an adaptation process in athletes; due to increased afterload in patients with hypertensive heart disease (HHD); or an expression of myocyte hypertrophy and disarray in hypertrophic cardiomyopathy (HCM). In addition, systemic diseases affecting the heart, such as amyloidosis, also result in increased LV wall thickness (WT) . IdentifEchocardiography provides accurate measurement of the LV mass and WT and, if required, myocardial strain, which were shown to aid the differential diagnosis of patients with LVH . DespiteHerein we sought to evaluate to ability of fast-SENC derived LV strain to distinguish between different forms of LVH in competitive athletes, HHD, HCM and  cardiac amyloidosis. The ability of %normal myocardium by fast-SENC was compared to that of LV ejection fraction (LVEF), T1, LV mass index and to LGE.The study was performed between September 2017 and February 2019 at the Marien Hospital Hamburg, Hamburg, Germany and German Heart Center Berlin, Berlin, Germany). During this period 1566 CMR scans were performed. Patients were selected with a clinical indication for the CMR examination that was related to (1) further evaluation of LVH diagnosed by echocardiography (2) evaluation of an underlying cause for symptoms of heart failure (3) evaluation of the presence and extent of scar tissue in patients with suspected or known history of cardiomyopathy. A total of 314 met criteria. In addition, 22 competitive athletes and 33 healthy subjects were included. All healthy subjects were free of any history of medical conditions, were on no medication at the time of the CMR, had a normal electrocardiogram (ECG), and a normal physical examination.LVH was defined in patients with HHD, HCM, cardiac amyloidosis and in athletes according to current recommendations –9. Thus,All CMR examinations and protocols were performed by clinical indication and conformed with the declaration of Helsinki. The use of patient data for research purposes was approved by the local ethics committees and all patients gave written informed consent. For conventional and LGE acquisitions, a standard CMR protocol was used, as described elsewhere . The anaT1 mapping acquisitions were performed using a standard modified Look-Locker inversion recovery (MOLLI) 5 s (3 s) 3 s T1 native sequence in standard mid-ventricular short axis views. Phase sensitive LGE images are acquired 10 min after intravenous injection of 0.1 mmol/kg of gadoterate meglumine. For the LGE analysis, three long axis and multiple short axes covering the entire LV were acquired. Of note, LV mass was measured without including the papillary muscles. Care was taken when measuring septal WT to exclude trabeculations arising from the right ventricle (RV) .Each myocardial segment was analysed for the presence or absence of atypical LGE. In addition, different atypical LGE patterns were considered, including (1) diffuse or patchy LGE, (2) focal intramyocardial LGE and (3) focal epicardial LGE. For the calculation of a semiquantitative LGE score, segments with atypical LGE were summed up in each patient, and the resultant number was then divided by the total number of segments (n = 17). For the determination of the LGE pattern by patients, the most frequent pattern of LGE number in the affected segments was considered. Thus, if a patient for example with HCM had 2 segments with diffuse LGE and 3 additional segments with focal intramyocardial LGE pattern, the latter was considered for analysis, regarding the atypical LGE pattern on a patient-by-patient analysis. Patients with the same number of segments of 2 or 3 different LGE patterns were excluded from analysis.2, slice thickness = 10 mm, voxel size = 4 × 4 × 10 mm3, reconstructed resolution = 1 × 1 × 10 mm3, single-shot spiral readout with flip angle = 30°, effective echo time (TE) = 0.7 ms, repetition time (TR) = 12 ms, temporal resolution = 36 ms, typical number of acquired heart phases = 22, spectrally selective fat suppression (SPIR), total acquisition time per slice < 1 s [The protocol for this sequence is described elsewhere , 13. By ce < 1 s , 5. The The fast-SENC method uses out-of-plane phase encoding gradients along the slice-selected direction and thus longitudinal strain was extracted from the three short axes acquisitions using a 16-segment model, whereas circumferential strain was measured from three long axes views using a 21-segment model . The gloIn concordance with previous studies, we considered a value for either longitudinal or circumferential strain in any segment ≤ −17% as normal , 16. We The number of segments with diagnostic image quality, enabling the assessment of myocardial strain by fast-SENC was assessed in 80 randomly selected patients (n = 2960 segments).In addition, we calculated a relative regional ratio of the average of the apical segmental strain divided by the sum of the average basal and mid-ventricular segmental strain, to differentiate between amyloidosis and HCM, as previously described .To avoid confusion and in keeping with most of the literature on the subject, the strain parameters will be interpreted in their absolute values .Values are presented as mean ± standard deviation (SD) when normally distributed or as median and inter-quartile range for intervals without a normal distribution. A paired t-test was used to compare two groups of normally distributed values. The ANOVA test was used for comparing three or more normally distributed groups with the Scheffé test for post-hoc analysis . The anaData were available for 369 individuals, including 41 pts with amyloidosis, 45 pts with HCM, 228 with HHD, 22 athletes and 33 healthy subjects. All individuals included in the study were Caucasian and all studies exhibited diagnostic image quality, enabling the assessment of myocardial strain. Thus, using fast-SENC, 0.39% (5 of 1280) segments were excluded from analysis for the assessment of longitudinal and 0.48% (8 of 1680) for the assessment of circumferential strain, respectively.Table Poor correlations were observed between LV longitudinal, LV circumferential strain and %normal myocardium with LVEF, whereas moderate correlations were depicted between %normal myocardium and LV mass, T1 values and atypical LGE score index , there were no differences between the other groups. Patients with HCM and cardiac amyloidosis exhibited the highest LV mass index. Patients with cardiac amyloidosis exhibited the highest values for T1, followed by HCM patients . There were no significant differences in T1 however, between athletes, healthy controls and HHD patients. Atypical LGE score index was significantly higher in HHD and HCM and even higher with amyloidosis. GLS and %normal myocardium were similar between healthy subjects and athletes, decreased with HHD and further decreased with HCM and amyloidosis Fig. .Fig. 2ApSubgroup analysis was conducted in patients with mild to moderate LVH with a septal thickness between 11 and 15 mm . For the differentiation between athletes and HHD, %normal myocardium exhibited higher accuracy than atypical LGE . For the differentiation between HHD and HCM atypical LGE exhibited wither accuracy than %normal myocardium , whereas a trend was noted for wither accuracy of atypical LGE compared to %normal myocardium for the differentiation between HCM and cardiac amyloidosis, without reaching statistical significance , , % normal myocardium offers excellent accuracy for the differentiation of athletes vs. HCM and of athletes vs. HHD.IV.Combining atypical LGE score and patterns and % normal myocardium offers high precision for the differentiation between all studied underlying pathologies by a clustered multivariable approach. Specifically, good accuracies are provided for the differentiation between HCM vs. HHD and HCM vs. amyloidosis.In this analysis of over 300 patients, we found that:Increase in LV WT is common in clinical practice and can be caused by either a change in the loading conditions, namely increased afterload, or through alterations of the myocardial structure itself, secondary to genetic defects (HCM) or infiltrative diseases (cardiac amyloidosis). Echocardiography is usually the first imaging tool used in patients with suspected LVH. It can readily identify other causes of LVH  and provides assessment of LV mass and LVEF. However, the latter has little use in differentiating LVH, as most forms of LVH show preserved LVEF until very late stages of the diseases . This waThe athlete’s heart is characterised by a combination of LV dilatation and mild LVH . HoweverSENC was developed in 2001 . Since t%normal myocardium offered excellent precision for the differentiation between the athletes’ heart and HCM and high accuracy for the differentiation between HHD and HCM, clearly surpassing the value of LVEF, mass index, T1 values and atypical LGE score. This is in line with our previous findings in patients with different stages of heart failure, where %normal myocardium identified all-comer patients with subclinical disease . InteresBecause the differentiation between athletes and HCM or between athletes and HHD is often clinically challenging, especially in mild to moderate hypertrophy forms, the high precision of %normal myocardium in this setting, bears promising clinical implications. Furthermore, in both these clinical scenarios (athletes vs. HCM and athletes vs. HHD), %normal myocardium performed significantly better than T1 mapping. Although both sequences do not require the administration of contrast agents, fast-SENC acquisitions can be performed during free breathing within < 1 s and thus do not require long breath holds over ~ 10 heart beats as most current T1 mapping sequences. It should be noted however, that extracellular volumes (ECV) were not available in our study, and may have been superior to native T1, especially for the differentiation between amyloidosis and other forms of hypertrophy. For the differentiation between HCM and HHD and between HCM and amyloidosis with mild-moderate LVH, on the other hand, combining atypical LGE and %normal myocardium offered high accuracy rates, which surpassed that provided by other conventional CMR variables, such as T1, LVEF and LV mass index. In addition, for the differentiation between HCM and amyloidosis, a base-to-apex segmental strain gradient further aided the differentiation between the 2 clinical entities, in agreement with previous reports . The disOur cohort was extremely heterogenous in respect to demographic data. In addition, ECG data were not systematically analysed, whereas age and sex matching were not performed, which is a possible limitation due to possible variations of strain with age and gender . FurtherFast-SENC derived myocardial strain is a valuable tool for the characterisation of patients exhibiting LVH and can be used together with atypical LGE to help establishing an etiological diagnosis in forms of mild-moderate hypertrophy of unclear aetiology.Additional file 1: Figure S1. Poor correlations were observed between global longitudinal strain (GLS), global circumferential strain (GCS) and %normal myocardium with LVEF (A–C). Moderate correlations on the other hand, were depicted between %normal myocardium and LV mass (D), %normal myocardium and T1 values (E) and between %normal myocardium and atypical LGE score index (F).Additional file 2: Figure S2. The base-to-apex segmental strain gradient was significantly higher in patients with amyloidosis vs. HCM and helped differentiating the 2 entities with acceptable sensitivity and specificity in patients with mild-to-moderate LVH .


ObjectiveTo assess the effect of the COVID-19 pandemic on the cardiothoracic and vascular surgery procedures volume at a tertiary care hospital.Materials & MethodsThis cross-sectional retrospective study was carried out at a tertiary care hospital's Cardiothoracic and Vascular Surgery department. All the four-year surgical procedures data were reviewed from August 2017 to August 2021. After extracting data from the hospital database software, a databank was generated in SPSS version 24.0. Average cases per month were calculated, and the data were stratified into three groups, Pre-COVID, COVID, and Post-COVID. Tables and charts were generated for the representation of data.ResultsThe total number of patients that underwent cardiovascular and thoracic procedures during the years 2017-2021 were 3,624, with male predominance (71.5%). Procedures were divided into Pre-COVID (68.5%), COVID (15.2%) and Post-COVID (16.3%) groups. Coronary Artery Bypass Grafting (CABG) was the most common procedure throughout the study duration (56.8%) and during the COVID-19 pandemic (29 procedures/month). Congenital Heart Surgeries (16.6%) and Valvular surgeries (11.5%) were next on the list. However, congenital heart surgeries were most affected during the pandemic (16 to 5 procedures/month). The average number of surgeries per month peaked at 2017 (135 procedures/month) and after that declined to its low of 46/month during the COVID-19 pandemic (The year 2020).ConclusionCardiothoracic and Vascular Surgeries have significantly decreased during the COVID-19 pandemic, especially the Coronary Artery Bypass (CABG) and Congenital Heart Surgeries. CABG procedures, however, remained the highest performed surgery even during the pandemic due to their emergent nature. Thoracic, vascular, and combined surgeries have stayed almost constant. The year 2020 (COVID-19 year) saw the lowest number of surgeries performed per month. An uprising trend in the number of surgical procedures is seen in the post-pandemic time (2021).  Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. They account for a staggering approximation of 17.5 million annual deaths globally. Most of these deaths (80%) occur in low- and middle-income countries .According to a report by the society of thoracic surgeons, 2,24,724 adult cardiac surgeries were performed in 2018 alone . In PakiThe heart is a dynamic organ with a challenging role in keeping us alive, so it is no surprise that many types of diseases affect different parts of the organ in diverse ways. Common cardiac surgical procedures include Coronary Artery Bypass Graft (CABG), Heart Valves Surgery, Congenital Cardiac Surgeries , among others. The overall mortality from cardiovascular diseases has dropped dramatically in developed countries due to these surgical interventions .Before World Warr II, a leading cause of valvular heart disease was rheumatic heart disease (RHD) worldwide. With improvement in health care accessibility and antibiotic use, a significant decline has been observed in RHD incidence in developed countries -9. HowevA structural anomaly of the heart or the great vessels of the heart, present at birth, is defined as congenital heart disease (CHD). CHD's are one of the most commonly diagnosed pediatric disorders worldwide, with an incidence of approximately 0.8-1.2% in alive newborns. Many investigations have been conducted to find out the attributable factors; however, only about 15% of CHD can be attributed to a known etiology. CHD was once a fatal disease. With the advancement in cardiac surgical procedures and the invention of cardiopulmonary bypass, the disease is now curable .At a private tertiary care hospital with state-of-the-art facilities for cardiothoracic and vascular support, we had the opportunity to retrieve data of the last four years. The objective of this medical record review was to assess the effect of the COVID-19 pandemic on the cardiothoracic and vascular surgical procedures performed during the study period at this tertiary care hospital. A literature review has shown that little to no data exists on these statistics in Pakistan; hence providing a baseline can start a discussion on these important statistics.This retrospective cross-sectional study was carried out at a tertiary care hospital's Cardiothoracic and Vascular Surgery department. The data for this study was obtained after departmental and institutional ethical board approval  from the cardiothoracic and vascular surgery department database. This database is used for storing data of all patients operated on in this department. Data were initially acquired on a proforma, which included information related to the patient's demographics, date of admission, discharge, type of procedure, pre-and post-operative labs, radiology results, any complications during the hospital stay, and outcome at discharge. These data were then entered into the departmental database and stored in a password-protected database.All pre-operative patients assessment was done according to the American College of Cardiology and the American Heart Association (AHA/ACC) guidelines, followed by a multidisciplinary team that decided to carry out the surgery. The multidisciplinary team included cardiologists, echocardiographers, general physicians, and cardiac surgeons. Post-operatively, almost all patients were shifted to the cardiac intensive care unit (CICU) and subsequently shifted to the ward after 48 hours.Congenital heart surgeries included surgeries related to the atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA), coarctation of the aorta (CoA), and tetralogy of Fallot (TOF). Valvular surgeries included aortic, tricuspid, and mitral valves repair or replacement surgeries. Thoracic surgeries included pneumonectomies, decortication, chest wall tumor excisions, thoracic, abdominal aneurysm repair, esophagectomy, pleurectomy, thoracotomies, etc. Vascular surgeries included mainly embolectomies and thrombectomies, along with arteriovenous fistulas and fasciotomies. All in-patients' records that stated that the patient had undergone the cardiovascular or thoracic surgical procedure at this tertiary care hospital during the study duration were included without any data exclusion. The study duration was from August 2017 to August 2021.Data recorded from August 2017 to December 2019 was labeled as Pre-COVID. Data from January 2020 till December 2020 was classified as COVID, while January 2021 to August 2021 was defined as Post-COVID. This is in line with the data provided by the COVID-19 dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) and local trends.A databank was generated in SPSS version 24.0 after extracting data from the hospital database software. An average number of procedures done per month per year and an average number of cases per month pre, during, and post-COVID pandemic was calculated and presented in charts. Trend lines were generated.The total number of patients that underwent cardiovascular and thoracic procedures during the years 2017-2021 were 3,624, with male predominance (71.5%). The male to female ratio was 2.51:1. Overall Coronary Artery Bypass Grafting (CABG) was the most common procedure throughout the study duration (56.8%). Congenital Heart Surgeries (16.6%) and Valvular surgeries (11.5%) were next on the list. CABG was also combined with other procedures such as endarterectomy (5.1%), Valvular Surgeries (1.8%), and Congenital Heart Surgeries (0.9%). Combined valvular and congenital heart surgeries were the least common procedures done (0.5%). This is shown in table Figure Figure Heart disease has no socio-demographic, identity, or terrestrial boundaries. At least 20 million people suffer from heart attacks each year, and 12 million dies because of an adverse cardiac event or stroke. Although non-cardiac diseases carry the highest burden of diseases globally, CVD remains the global leader in deaths. In 2011-12, an estimated 17.4 million deaths per annum were due to CVD. A figure is expected to rise by >6.0 million deaths per year by 2030 . By the In our hospital, 603 congenital heart surgeries alone and 52 additional cardiac procedures were performed over the study duration. National Institute of Cardiovascular Diseases (NICVD) in Karachi, the largest cardiac facility in Sindh, performed a slightly lower number (537) of procedures in 6 months. Previously this same hospital had reported 1,004 surgeries in two years (October 2013 to September 2015) [As shown in figure Combined CABG plus valvular surgeries (1.8%) or CABG plus congenital heart surgeries (0.9%) did not share the major burden of procedures at this tertiary care hospital. These procedures have remained less than 2.0% throughout the study duration. Thoracic and vascular surgeries also remained just below 3.0% in total during the study. Most of the vascular surgeries in our setting were for limb-threatening diagnoses, and the trend of procedures per month has also stayed the same. A total of 5,34,067 cardiac surgical procedures were performed between 2002 and 2016 in England. This data was extracted from the UK National Adult Cardiac Surgery Audit database. According to the study, most of the procedures were CABG initially, which had steadily declined; however, the valvular procedures had increased [A study conducted by Abbas S et al. found the burden of ischemic heart disease (IHD) significantly higher in males, corresponding to our study . AlthougIn developing countries, Valvular heart diseases are becoming a growing problem. It was estimated by a study conducted in Pakistan that 5.7 per 1,000 children have echocardiographic findings of rheumatic heart disease . The aveFigure Cardiothoracic and Vascular Surgeries have significantly decreased due to the COVID-19 pandemic, especially the Coronary Artery Bypass (CABG) and Congenital Heart Surgeries. However, CABG procedures remained the highest even during the pandemic due to their emergent nature. Thoracic, vascular, and combined surgeries have stayed almost constant. The year 2020 (COVID-19 year) saw the lowest number of surgeries performed per month. An uprising trend in the number of surgical procedures is seen in the post-pandemic time (2021).


To the EditorGiven recent improvements in medical management, risk models for acute myocardial infarction are required to be updated. Wang et al. proposed a novel scoring method to predict short‐term mortality in patients with acute myocardial infarction.In their study, the GRACE score was used as a comparator.Several parameters such as blood glucose and pulmonary artery systolic pressure included in their risk score are modifiable.The prognostic impact of several parameters such as blood glucose might be “U‐shape” instead of linear, unlike their hypothesis.


Background: Epicardial adipose tissue (EAT) has been linked with the pathogenesis of heart failure (HF). Limited data have been reported about the clinical value of EAT for cardiac resynchronization therapy (CRT) in non-ischemic systolic HF. We aimed to explore the values of EAT measured from CT to predict the response to CRT in patients with non-ischemic systolic HF.Methods: Forty-one patients with CRT were consecutively recruited for our study. All patients received both gated resting Single Photon Emission CT (SPECT) myocardial perfusion imaging (MPI) and dual-source multi-detector row CT scans. EAT thickness was assessed on both the parasternal short and horizontal long-axis views. The area of EAT was calculated at the left main coronary artery level. Left ventricular systolic mechanical dyssynchrony (LVMD) was measured by phase standard deviation (PSD) and phase histogram bandwidth (PBW). The definition of CRT response was an improvement of 5% in left ventricular ejection fraction (LVEF) at 6 months after CRT implantation.Results: After 6 months of follow-up, 58.5% (24 of 41) of patients responded to CRT. A greater total perfusion deficit (TPD) was observed in the left ventricle, and a narrower QRS complex was observed in the nonresponse group than in the response group (p < 0.05). Meanwhile, the systolic PSD and systolic PBW were statistically greater in the CRT group with no response than in the response group (p < 0.05). Meanwhile, the baseline QRS duration, TPD, systolic PSD, systolic PBW, EAT thicknesses of the left ventricular (LV) apex, right atrioventricular (AV) groove, and left AV groove were all significantly related to the CRT response in the univariate logistic regression analysis. Furthermore, the QRS duration and EAT thicknesses of the right AV groove and left AV groove were independent predictors of CRT response in the multivariate logistic regression analysis.Conclusions: The EAT thickness of the left AV groove in patients with non-ischemic systolic HF is associated with the TPD of LV and LV systolic dyssynchrony. The EAT thickness of the AV groove has a good predictive value for the CRT response in patients with non-ischemic systolic HF. Cardiac resynchronization therapy (CRT) is an effective option for patients with medically refractory heart failure (HF). However, one-third of patients with HF treated with CRT have a suboptimal response in clinical practice . As the Epicardial adipose tissue (EAT) is speculated to be linked with microvascular dysfunction, impairment of functional myocardium, and cardiac fibrosis independent of traditional risk factors . PreviouHowever, little data have been obtained about the clinical value of EAT for CRT in patients with non-ischemic systolic HF. We aimed to explore the values of EAT measured from CT to predict the CRT response in patients with non-ischemic systolic HF.Forty-one patients with CRT with non-ischemic systolic HF  were conAn electrocardiogram (ECG) was acquired by researchers during hospitalization. The QRS duration in 12-lead ECG was analyzed from the widest QRS complex.Left ventricular diameter parameters and diastolic function were measured by two experienced imaging-specialized experts according to standard transthoracic echocardiography. LV parameters included left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), and LVEF. The diastolic function included mitral inflow E velocity to tissue Doppler e' velocity ratio (E/e') and mitral inflow E velocity to mitral inflow A velocity ratio (E/A). Both experts were blinded to the other clinical data during the research. The biplane-modified Simpson method was used to record the LVEF.The resting ECG-gated SPECT MPI scan was completed in patients before implantation. Approximately 20–30 mCi of Tc-99m sestamibi was injected, and the MPI scan was continued 60 min after injection. The MPI images were assessed by a dual-headed camera using a routine protocol . Reconstruction and reorientation to MPI images were performed using the Emory Toolbox .The resulting short-axis MPI images were performed to evaluate the LV contour parameters by inputting them into an interactive tool. These results in each cardiac frame were then put into an automatic myocardial sampling algorithm for maximal count circumferential profiles. Subsequently, the onset contraction of the left ventricle was acquired from a first-harmonic Fourier approximation . Global All heart CT scans were acquired from a dual-source multi-detector-row scanner . CT scan data were as follows: detector collimation, 64 × 0.6 mm; gantry rotation time, 330 ms; pitch, 0.2–0.43 (adapted to the heartbeat); temporal resolution, 83 ms; tube current, 380–420 mAs per rotation; and tube potential, 100–120 kV depending on the body mass index (BMI). To minimize motion artifacts, all patients were requested to hold their breath during detection. We synchronized the data reconstruction by a retrospective gating technique according to the ECG signal in all cardiac phases at 40% of the left atrial volume max at a total slice thickness of 0.75 mm and a reconstruction increment of 0.4 mm. All EAT data were measured by one experienced radiologist, and the best diastolic phase images of all the patients were selected for analysis. The adipose tissue between the surface of the myocardium and epicardium was defined as EAT, and the EAT volume was automatically acquired by applying cardiac risk assessment software to the cardiac image . The EATAll enrolled individuals underwent CRT in standard procedures. The LV lead was steadily placed in one branch vein, and the right ventricular (RV) lead was positioned in the RV apex as determined by trained electrophysiologists following standard implantation guidelines. The final position was determined based on three factors: no phrenic nerve capture, good stability, and an acceptable pacing threshold. Finally, fluoroscopic venograms were used to assess the LV lead position implantation in the left anterior oblique 45° and right anterior oblique 30° regions.Follow-up data of all the patients were collected from telephone interviews, hospital discharge summaries, and government records. The primary end point was the CRT response at 6 months after CRT implantation, which was defined as an improvement of 5% in the LVEF. All-cause mortality was the secondary end point in the whole study. Atrial arrhythmias and ventricular pacing rate during follow-up were detected and extracted from the device system. According to the follow-up data, patients were divided into two groups: the CRT response group and the CRT non-response group.p < 0.10 in the univariate logistic regression analysis were included in the multivariate logistic regression analysis. A receiver operating characteristic (ROC) curve analysis was performed for the EAT variables to predict the probability value for CRT. A Kaplan-Meier analysis was performed between two groups to compare the all-cause mortality by a log-rank test. A two-sided p < 0.05 was considered statistically significant.Data were analyzed with SPSS 21 . Categorical variables were summarized as counts or percentages. Continuous variables are presented as the mean ± SD. The Pearson linear correlation coefficient was used to determine whether two variables were linearly related. Baseline clinical variables associated with the CRT response were used in univariate and multivariate logistic regression analyses. All variables with p > 0.05). However, in the non-response group, there was a narrower QRS duration and more total perfusion deficit (TPD) in the left ventricle than in the response group (p < 0.05). Meanwhile, the systolic PSD and systolic PBW were statistically greater in the CRT group with no response than in the response group .p > 0.05 for all). Notably, EAT thickness values in the right AV groove, LV apex, and left AV groove were lower in the CRT response group than the CRT group with no response . r = 0.371, p = 0.017). Meanwhile, a positive relationship was observed between the TPD and systolic SD levels . The EAT thickness of the left AV groove was positively correlated with systolic SD and systolic BW values .In addition to the total EAT thickness values, the EAT thickness over the LV lateral wall, LV anterior wall, LV inferior wall, and the right lateral wall did not differ between subjects with and without a CRT response (p = 0.039); meanwhile, in the ROC analysis of the EAT thickness of the left AV groove, the AUC, optimal cut off value, specificity, and sensitivity were 0.687, 1.375, 0.792, and 0.529, respectively (p = 0.043). According to the ROC analysis of the EAT thickness of the LV apex, the AUC, optimal cut off value, specificity, and sensitivity were 0.695, 0.415, 0.708, and 0.647, respectively  were CRT responders. LV leads were implanted in lateral, anterolateral, posterior, or posterolateral coronary veins according to the anatomic characteristics of coronary veins. In the univariate logistic regression analysis, the CRT response was significantly associated with the TPD, systolic PSD, systolic PBW, QRS duration, EAT thicknesses of LV apex, right AV groove, and left AV groove . When mup = 0.089). There was no significant difference in the number of new AF during follow-up in the response group and the no response group . Meanwhile, the ventricular pacing rates were 94.5 and 91.6% in the response group and the no response group (p = 0.061), respectively. Meanwhile, the LVEF was significantly increased compared with the baseline . In the Kaplan-Meier survival analysis, the CRT response group had a better prognosis in the long term than the non-response group , three (7.3%) patients died of all-cause mortality, and they were all were included in the CRT non-response group (The main findings of our study are as follows: (1) the EAT thickness of the left AV groove is associated with total defect perfusion of the left ventricle and LV systolic synchrony in patients with non-ischemic systolic HF; and (2) the EAT thickness of the AV groove is predictive of CRT response at 6 months in patients with non-ischemic systolic HF.The CRT value has been widely evaluated in patients with HF in a large number of clinical trials. Despite moderate improvement over the past two decades, the CRT response is still rather mixed, and approximately one-third of patients with HF do not show benefits from CRT implantation. Therefore, it is imperative to enhance CRT benefits by patient selection, LV lead placement optimization, post-implantation device programs, and patient management. Numerous attempts have already been made to find reliable parameters to improve the CRT response. Different studies have reported the significance of LV myocardial scars in CRT non-response , 13. In In accordance with previous results, our study also confirmed that a wider QRS complex was a strong predictor of CRT response . When thThe use of LV dyssynchrony to predict benefits from CRT in patients with HF has been discussed in recent studies. Several recent studies found that LV mechanical dyssynchrony could predict CRT response during follow-up , 21. HowA novel finding of our work is that the EAT thickness of the AV groove has predictive value for CRT implementation in patients with non-ischemic systolic HF. This study is the first to relate the volumes and distribution of EAT to CRT response. In a previous study, EAT was found to be a directly adjacent tissue to the cardiac myocardium, which is a vital regulator of the energy needs of the heart myocardium in lipid fluxes . HoweverNevertheless, the potential mechanisms between EAT and CRT response remain to be elucidated, which might partly be attributed to mechanical and paracrine processes. The physical boundary in anatomy between the EAT and ventricular myocardium is not obvious and shares the same coronary microcirculation. Therefore, factors contributed by EAT could have direct vasocrine and paracrine effects on the ventricular myocardium, which worsen myocardial fibrosis by localized EAT accumulation . PreviouFirst, the samples in our retrospective study were relatively small, which was a disadvantage for identifying the predictive factors for CRT response in HF. While, the present retrospective study included patients with non-ischemic systolic HF, undergoing CRT therapy, and receiving ECT and contrast-enhanced cardiac CT scans. So far, there was limited data about the association between EATs and CRT response. Second, the definition of CRT non-response was based on echocardiographic results of LVEF to measure the primary end point. We did not investigate other clinical factors, such as the 6-min walking test or quality of life. Third, the follow-up period was rather short for post-CRT implantation in the current research. Fourth, EAT parameters were limited in all patients with CRT, and our sample was not compared with an adequate control group. Finally, this study was still preliminary, and further research should be undertaken in a larger population.The EAT thickness of the left AV groove is associated with total defect perfusion of the left ventricle and LV systolic synchrony in patients with non-ischemic systolic HF. The EAT thickness of the AV groove has predictive value for CRT response in patients with non-ischemic systolic HF.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Institutional Ethical Committee of the First Affiliated Hospital of Nanjing Medical University. The patients/participants provided their written informed consent to participate in this study.H-yQ and CW performed the clinical study and drafted the original manuscript. H-yQ and D-dQ enrolled the patients and analyzed all of the clinical data. CC and M-lC reviewed and edited the manuscript. All authors contributed to the whole article and approved the final version of this manuscript.This research was supported by grants from the National Nature Science Foundation of China (81900295 and 82100338) and the Natural Science Foundation of Jiangsu Province (BK 20191071).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We enrolled 112 infants (median age 1 (0.5–3) months; 62% males) hospitalized with acute bronchiolitis. Increased values of the pulmonary variables  showed moderate correlations with NT-proBNP and all echocardiographic parameters indicative of pulmonary hypertension and myocardial dysfunction (Tei index). Up to 36 (32%) infants required respiratory support during the hospitalization. This group presented with higher lung ultrasound score (p < 0.001) and increased values of NT-proBNP (p < 0.001), the Tei index (p < 0.001) and pulmonary artery pressures (p < 0.001). All the analyzed respiratory and cardiac variables showed moderate-to-strong correlations with the LOS of hospitalization and the time of respiratory support. Lung ultrasound and echocardiography showed a moderate-to-strong predictive accuracy for the need of respiratory support in the ROC analysis, with the AUC varying from 0.74 to 0.87. Those cases of bronchiolitis with a worse pulmonary status presented with a more impaired cardiac status. Cardiopulmonary ultrasonography could be a useful tool to easily identify high-risk populations for complicated acute bronchiolitis hospitalization.We aimed to delineate cardiopulmonary interactions in acute bronchiolitis and to evaluate the capacity of a combined cardiopulmonary ultrasonography to predict the need for respiratory support. This was a prospective observational single-center study that includes infants <12 month of age admitted to a hospital due to acute bronchiolitis. All the included patients underwent clinical, laboratory and cardiopulmonary ultrasonographic evaluation at the same time point within 24 h of hospital admission. The existence of significant correlation between cardiac and respiratory parameters was the primary outcome. The association of different cardiopulmonary variables with the need of respiratory support higher than O Bronchiolitis is the viral lower respiratory infection that most often affects children under 2 years of age, with a peak of incidence and morbidity in young infants (under 3 months of age) ,2. It isThe existence of a physiological interdependence between the cardiovascular and respiratory systems has long been recognized. The heart and lungs are anatomically coupled through the pulmonary circulation and coexist within the sealed thoracic cavity, making the function of these systems highly interdependent. During ARF, these interactions are magnified, with a striking effect on the pulmonary vasculature and myocardial function ,4. An unClinical scores have proven to be inaccurate in predicting a prognosis in acute bronchiolitis, with weak interobserver reliability and limited construct validity . Thus, lThe primary objective of this study was to explore the influence of the respiratory state over the heart and pulmonary circulation using CPU in infants with bronchiolitis at early stages of the disease. The secondary objective was to evaluate the prognostic implications of adverse CPI and the predictive values of different CPU measurements in this setting.We conducted a single center, prospective and observational study from October 2018 to March 2020 at the Pediatric Department of a tertiary university hospital in Cadiz, Spain. We included infants hospitalized with acute bronchiolitis. The diagnosis and management were made by the attending pediatrician following the current international recommendations . The memAfter the enrolment of patients, the attending pediatrician and nursery and the sonographers coordinated to perform a clinical evaluation, blood extraction for laboratory analysis and CPU at the same time point within the first 24 h of hospitalization.2, pulmonary auscultation and costal retractions. It ranges from 0 to 14 points. A score greater than 10 points is defined as severe bronchiolitis. The venous pH and pCO2 levels were used as laboratory markers of the respiratory state. A significant hypercarbia was defined as pCO2 > 55 cmH2O independently of the pH levels. Lung ultrasound (LU) was performed by 3 intensive care pediatricians with at least 2 years of experience in LU in routine practice, according to the recommendations for point of care lung ultrasound by Volpicelli et al. [The respiratory state was clinically evaluated by the attending pediatrician using the bronchiolitis of Sant Joan de Déu (BROSJOD) score . This sci et al. . Sonograi et al. . Each ari et al. ,17.NT-proBNP was used as a laboratory parameter of myocardial strain. The serum NT-proBNP levels were determined within 2 h of the venous blood samples collection using the electrochemical luminescence immunoassay Elecsys proBNP II . We used the previously reported 99th percentile for infants aged less than 1 year old (1121 pg/mL) as the limit to establish that NT-proBNP was elevated .One experienced pediatric cardiologist performed all echocardiographic studies following the methodology recommended in the guidelines for pediatric echocardiography ,21,22,23The follow-up started at the research intervention time and finished at hospital discharge. At the end of the study period, an independent observer collected the participant data through our institution’s electronic medical records and included in a relational database. The baseline information included demographic, clinical, laboratory and ultrasound data.2, the length of respiratory support and the length of stay (LOS) hospitalization.The existence of a significant correlation between the cardiac and respiratory parameters was the primary outcome in this investigation. The secondary endpoint was the association of different cardiopulmonary variables with PICU admission, PICU stay, the need of respiratory support higher than Ot-test or Wilcoxon Mann–Whitney test were used to compare the mean and medians as appropriate. Proportions were compared using the chi-square test or exact methods as necessary. Spearman’s and Pearson’s coefficient tests were used to verify correlations between variables. Due to the exploratory nature of our study, significance threshold adjustments for multiple testing were not performed. Logistic regression and the receiver operator curve (ROC) analysis were used to explore the predictive accuracy of each marker for respiratory support. Odds ratio (OR), sensitivity, specificity and predictive values with 95% confidence intervals were estimated for the cut-off value at which they were considered abnormal. A significance level of 0.05 was used for all the statistical tests. Statistical analyses were performed with the use of Stata 16.0 .Data are presented as the median (range) or mean (standard deviation) after testing the normality with the Shapiro–Wilk test for the continuous variables and as the frequencies and percentage for the categorical variables. A Student’s We enrolled 112 infants (median age 1 (0.5–3) months; 62% males) hospitalized with acute bronchiolitis. 2 and LUS) showed moderate correlations with NT-proBNP and all the echocardiographic parameters indicative of pulmonary hypertension  and global myocardial dysfunction (LVTX and RVTX) but not with the parameters of systolic myocardial dysfunction (LVEF or TAPSE)  .p < 0.001), pCO2 (<0.001), LUS (p < 0.001) and lower pH levels (p < 0.001). With respect to the cardiac assessment, this group showed higher levels of NT-proBNP (p < 0.001); increased values of LVTX (p < 0.001), RVTX (p < 0.001), TRJG (p < 0.001), LVEI (p < 0.001) and RVLV (p < 0.001) and lower values of ATET (p < 0.001). All the analyzed respiratory variables and all the cardiac variables, except for LVEF and TAPSE, showed moderate-to-strong correlations with the LOS hospitalization and the time of respiratory support. None of the studied variables analyzed the presented association with the PICU stay (Of the 112 (%) participants, up to 36 (32%) required respiratory support during hospitalization . RegardiICU stay . All theICU stay .In this prospective study, we employed an integrative cardiopulmonary approach to comprehensively assess the pulmonary and cardiac conditions of previously healthy infants with acute bronchiolitis at the time of hospitalization. Under normal conditions, CPI are inconsequential; however, they may become exaggerated and of great importance in certain acute pulmonary diseases. Through simultaneous clinical, laboratory and CPU assessments, we showed that a more severe respiratory state with hypoxia, respiratory acidosis and increased respiratory effort resulted in increased rates of raised pulmonary pressures and declined myocardial dysfunction, even in the absence of underlying heart disease. Of note, the presence of adverse CPI at early stages of the disease were associated with a severe course of the disease, with higher rates of respiratory support, PICU admission and prolonged hospitalizations. Therefore, the early recognition of cardiopulmonary impairment could be crucial to identifying high-risk populations for complicated acute bronchiolitis.The viral-induced inflammatory response causes peri-bronchial inflammatory infiltrate, interstitial edema and epithelial desquamation, leading to small airway obstruction, air trapping and compromise of the lung parenchyma (consolidations and atelectasis). Almost all studies in bronchiolitis describe elevated inspiratory and expiratory resistance, reduced tidal volume, increased auto-PEEP, lung hyperinflation, increased FRC and, finally, decreased respiratory compliance ,25. Clin2. These results remark the potential utility of early point of care echocardiographic evaluation in infants hospitalized with acute bronchiolitis as a noninvasive tool to assess the severity and guide the management in a similar way to LU.Although these infants are usually admitted to the hospital for the management of respiratory distress and hypoxia, the relevance of the cardiovascular involvement in these patients is increasingly documented. Cardiovascular complications are described in up to 9% of hospitalized patients . SignifiTo detect myocardial dysfunction in bronchiolitis, echocardiographic study by tissue Doppler imaging (TDI) and speckle tackle echocardiography has proven to be a more sensitive method than conventional echocardiography. Tissue Doppler and STE imaging has provided more load-independent methods to assess myocardial function, with the additional advantage that high-quality two-dimensional images are no longer essential for reproducible recordings. Consistently, we observed that the TDI-derived Tei index was significantly impaired in those patients with a more compromised respiratory state. In addition, a combined systolic and diastolic measurement, such as the Tei index, may be more reflective of the overall myocardial dysfunction than those conventional methods for assessing only systolic function. Regarding the estimation of pulmonary pressures, we did not detect any differences in the pulmonary arterial pressure based on the standard TRJG findings between groups of severity. TRJG jet can be difficult to detect, and alternative semiquantitative parameters could be useful in this setting. Remarkably, the ATET, LVEI and RVLV could be measured in all infants, unlike tricuspid regurgitation, which was detectable in approximately half of them in our study. As previously reported, the inclusion of these parameters in the echocardiographic evaluation of these patients could improve the detection of PHT in this setting .Our major finding was that the echocardiographic parameters assessing myocardial function and pulmonary pressures and the biomarker of myocardial strain NT-proBNP showed a moderate correlation with the respiratory clinical score that includes the respiratory rate and hypoxemia with respiratory acidosis and with our LUS. Therefore, our study documented those factors such as lung edema, consolidations and airway obstruction, leading to hypoxia, respiratory acidosis and increased respiratory effort, cause a deleterious effect in the cardiac performance in bronchiolitis. Of note, this is the first clinical study to apply a homogeneous prospective methodology investigating cardiopulmonary interactions by a combined and integrative cardiopulmonary approach in this clinically relevant setting.The most likely underlying mechanism explaining our findings might be an increase in pulmonary vascular resistance and right heart afterload and subsequent reduced right and left ventricular functions ,30. PulmWith the increased pulmonary vascular resistance, the RV structure and function will be impaired by the increased afterload and, because of ventricular interdependence, can also cause LV myocardial dysfunction due to an abnormal pattern of relaxation and contraction secondary to geometric changes occurring in the LV . In addiLU is increasingly used to assess the respiratory state and even to predict the evolution and guide the treatment of bronchiolitis, with promising results ,12. In tEchocardiography is emerging as another useful tool to assess the severity in bronchiolitis. The use of echocardiography was first applied to assess the cardiac state in children with underlying heart disease . HoweverBoth echocardiography and LU have been well-described as having utility for guiding the diagnosis and management of critically ill patient ,41. Both2 and pH) also performed strongly as standalone tests. The significance in distinction between the correlation coefficients of all these variables was modest (0.55 to 0.60), while the expertise required to get CPU measures varied significantly. Notwithstanding the limitation of interobserver scoring, it would likely be easier to train emergency/pediatric doctors to accurately quantify BROSJOD or to order blood test analyses as opposed to the steep learning curve and technical proficiency required for accurate CPU. Consistent with this hypothesis, we recently tested the predictive accuracy of a model including NT-proBNP, the age and the BROSJOD score with excellent results (AUC 0.945), improving the traditional assessment (age and BROSJOD score) alone [2 would be strongly predictive and would require little technical up-skilling for front-line clinicians. Therefore, adding blood test analyses to the current recommendations for clinical evaluations alone seems to be an adequate approach to assess the severity in bronchiolitis pending cost efficiency studies. However, the increasing relevance and availability of point of care ultrasound in the pediatric emergency care setting joined with reluctance  to perform invasive/painful blood tests in infants with bronchiolitis led us to explore a noninvasive tool such as CPU in this setting, demonstrating also a strong predictive capacity for this purpose.Although our results suggest that CPU would be a promising tool for the severity of acute bronchiolitis, we must acknowledge that some of our findings hint that less technically complex tools may perform just as well, if not better than, CPU. In this study, CPU good-quality images could be obtained from all patients who accepted to be included, but this could be due to the expertise of the investigators. Thus, one of the main limitations of the application of our results to clinical practice is the need for training to obtain adequate images in a relatively short time in infants usually irritable and with a poor acoustic window. We mentioned that clinical scores are usually limited by a high inter-observer variability. Additionally, there are many different clinical scores, making challenging the universalization of the clinical assessment of bronchiolitis in institutions. Of note, the clinical score used in this study (BROSJOD) demonstrated a correlation with the outcomes that was strongly competitive with the best ultrasonographic measures. In addition, the blood tests  alone . Due to All the discussions mentioned above point out that the answer to the question of what could be the best strategy for determining the severity and outcomes in bronchiolitis is complex. As all the tools analyzed present relevant limitations, maybe different combinations of them according to availability at different centers and cost efficiency issues would be the correct answer to this question. Until the best predictive model in terms of accuracy and cost efficiency is elucidated in future studies, our investigations provide evidence that there are different accurate tools available for this purpose, and each clinician/institution will choose those that best suit their local clinical practice.This was a single-center study with relatively few patients, so for stronger conclusions, a larger study is needed. Additionally, it may not be possible to extrapolate our findings to clinical practice in other hospitals. CPU is highly operator-dependent, and this is an inherent limitation. Echocardiographic measures and the BROSJOD score are observer-dependent but were not analyzed for intrareader or inter-reader variability in this study. All the echocardiographic parameters analyzed were already described to have high inter-reader and intrareader agreement in previous studies. There is no validated LUS in bronchiolitis, and the classification of the ultrasound findings employed in the study was developed specifically for use in this study. The NT-proBNP values are assay-dependent, and therefore, our results would not be comparable with those of centers using a different laboratory kit. Another limitation of our study was the lack of gold standard diagnostic tests for myocardial dysfunction and PHT, mainly cardiac magnetic resonance imaging and right heart catheterism. Finally, the BROSJOD score is used as a criterion for PICU admission and the initiation of respiratory support in our institution, and it could influence our results regarding its predictive accuracy for severity.Our study documented that pulmonary and cardiac functions are closely connected in children hospitalized with bronchiolitis. Those patients with a worse pulmonary status presented with a more impaired cardiac status. As those patients with adverse CPI developed more severe bronchiolitis, the current findings demonstrated that CPU examination could be a useful tool with an added value to easily identify high-risk populations for complicated bronchiolitis hospitalization. Rather than compartmentalizing the two techniques, we favor the integration of echocardiography with LU in this setting, Finally, this work provided exploratory evidence about the accuracy of different tools  for this purpose, and each clinician/institution will choose those that best suit their personal/local availability. Future studies are warranted to clarify the best strategy in terms of cost efficiency.


To identify predictors of left ventricular remodelling (LVR) post-myocardial infarction (MI) and related molecular signatures, a porcine model of closed-chest balloon MI was used along with serial cardiac magnetic resonance imaging (CMRI) up to 5–6 weeks post-MI. Changes in myocardial strain and strain rates were derived from CMRI data. Tissue proteomics was compared between infarcted and non-infarcted territories. Peak values of left ventricular (LV) apical circumferential strain (ACS) changed over time together with peak global circumferential strain (GCS) while peak GLS epicardial strains or strain rates did not change over time. Early LVR post-MI enhanced abundance of 39 proteins in infarcted LV territories, 21 of which correlated with LV equatorial circumferential strain rate. The strongest associations were observed for D-3-phosphoglycerate dehydrogenase (D-3PGDH), cysteine and glycine-rich protein-2, and secreted frizzled-related protein 1 (sFRP1). This study shows that early changes in regional peak ACS persist at 5–6 weeks post-MI, when early LVR is observed along with increased tissue levels of D-3PGDH and sFRP1. More studies are needed to ascertain if the observed increase in tissue levels of D-3PGDH and sFRP1 might be casually involved in the pathogenesis of adverse LV remodelling. Identifying early predictors of LVR may benefit patients.Myocardial infarction (MI) leads to left ventricular remodelling (LVR), fibrosis, heart failure (HF), and death2. It is suggested that changes in LV myocardial strain (MS) may predict LVR3, tracking contractility both globally and regionally. Studying global and regional changes in MS post-MI in a relevant experimental model may help with predicting early LVR.Changes in LVEF are not reliable in predicting LVR due to confounding factors and do not represent regional changes4, with 2D speckle-tracking echocardiography featuring comparable spatial resolution to CMRI. However, 3D speckle-tracking echocardiography has a lower spatial and temporal resolution. CMRI is considered the reference method for analysis of LV function and mass. It provides superior image quality with less interference from anatomical structures5, and higher reproducibility, especially for circumferential parameters of strain6.The most effective imaging to measure changes in MS is still debated. Speckle-tracking echocardiography is more common than cardiac magnetic resonance imaging (CMRI)8; cardiac amyloidosis and hypertrophic cardiomyopathy. A meta-analysis, pooling 16 studies on HF, acute MI and valvular heart disease, has shown global longitudinal strain (GLS) to be a better predictor of mortality than LVEF, with its prognostic ability surpassing that of radial strain or circumferential strain (CS)10. Yet, MS remains largely a research tool. Longitudinal comparisons of MS between healthy and diseased myocardial territories could predict LVR more effectively, but little has been done in this area, partially due to a lack of relevant pre-clinical models11. Consequently, the use of GLS as predictor of late LVR post-MI remains controversial12. Global strain measures, calculated as averaged values, may result in loss of sensitivity due to missing key information on regional LV areas, a factor also applicable to measurements of LVEF. However, they can reduce the errors that can be associated with regional measures, with the associated improved reproducibility and ease of explaining their popularity5. A regional approach to MS, dividing the myocardium into sections and layers (endocardium vs epicardium), has the potential to be a superior predictor of LVR15. However, there are neither established values for healthy or cardiac disease-specific myocardial strains16 nor is there evidence of molecular signatures linked with LVR. Proteomics analysis of the myocardium has made the evaluation of cellular and cardiac extra-cellular matrix more approachable and reproducible allowing to study molecular signatures in health and disease including LVR17.The efficacy of MS has been investigated in HF with normal or recovered LVEFThe aim of this study was to identify changes in MS 1–2 days after acute MI and persisting at 5–6 weeks as signs of early LVR. We also set out to undertake tissue-based proteomics analysis to identify molecular signatures associated with MS and LVR.The animal regulated procedures were in line with UK Home Office regulations . The procedures were undertaken under a Project License (No 7008975) granted by the Home Office after formal review and approval by the University of Bristol Animal Welfare and Ethics Review Body (AWERB).c. 5–6 weeks (early chronic) post-MI. Previous studies have shown that the immune response post MI can be temporally divided into the early pro-inflammatory phase and the late inflammatory resolution/reparative phase, involving components of both the innate and adaptive immune systems18. Left ventricular remodelling was defined as 10% or more changes in left ventricular end-systolic and end-diastolic volumes based on evidence provided by others20. The additional methods and results for the MI protocol can be found in the Online Supplement.Ten Yorkshire female pigs represented the overall cohort of analysis. MI was induced by percutaneous balloon occlusion (60 min) of the mid portion of either the proximal left anterior descending  or the circumflex (Cx) artery (n = 2), according to operator preference. The coronary occlusion was conducted at the mid portion of the targeted coronary arteries, after the first diagonal or the first obtuse marginal branches. Global and regional morphology, function, LV volumes and scar size were assessed by CMRI in all 10 cases at: a. baseline; b. 12–48 h (acute); and 21. The methodology is summarised on the LV schematic in Fig. The strain-based metric used in this study was formulated to be robust and reproducible across sites/users/software, use a transparent, non-proprietary algorithm, and be sufficiently sensitive to characterise local ventricular function in a layer-wise manner, as recently reported by our group0, was the endocardial perimeter length at end-diastole, and this was then compared to the endocardial perimeter length, L, throughout the cardiac cycle for a given CMRI slice. Between seven and nine short-axis slices were contoured depending on the specimen and time point; for example, the degree of eccentric hypertrophy and specimen growth could increase the number of slices for a given specimen over time. Strain rate, The reference length, Lentclass1pt{minima22 . Accordingly, the global CS defined here is the average of 7–9 regional slices, rather than of only 3 slices reported by others22.The same short-axis slices were also divided into three ‘vertical regions’: apex, equator/mid, and base with two or three slices per region, and regional circumferential strains and strain rates were calculated. Similar analyses were conducted for the epicardium. To assess statistically significant changes through time, peak strain and strain rate values were measured. The strain values were averaged over 2–3 slices per region rather than from only one slice as reported by others23.Four-chamber long-axis data were used to investigate LV longitudinal strains and strain rates in both the endocardium and epicardium. Serial volumes were calculated for LV end-systole (LVESV) and end-diastole (LVEDV) by multiplying the area within the endocardial contour for a given slice by the slice thickness, and then all slice volumes were summed to give the ventricle blood pool volume. In addition, serial LV end-systolic volumes indexed to weight (LVESVi) were also calculated by dividing the end-systolic volume by the body surface area (BSA) of the animal. BSA was found through the relation suggested by Kelley et al. shown in Eq. 23.3\docuThe endocardial and epicardial contours were manually traced on all short and long axis images in the commercially available software package OsiriX , by one experienced user, and checked by another. Contours were analysed and strain & strain rate values were calculated using an in-house MATLAB script .24. Tissue homogenization was obtained with ceramic beads with Ripa Buffer and a protease and phosphatase inhibitors cocktail. The BCA method was used to quantify the protein concentration and samples were prepared at 2 mg/ml for the mass spectroscopic analysis (MSA). Serial troponin release was measured at baseline, reperfusion, 10, 20, 30 min, 1, 4, and 24 h after reperfusion, and before termination. Additional details are available in the Online Supplement.Proteomics analysis of infarcted versus remote viable myocardium was performed in five animals in keeping with established methodsp value of < 0.05 was considered statistically significant, but due to the high number of hypotheses tested, Bonferroni corrections were performed which suggested a p < 0.0024 as statistical significance. One-way ANOVA was used for initial assessment with Gabriel’s test to find differences between pairs of means. Linear regression and correlation analyses were performed to assess relationships between the scar weight and other mechanical properties, and between biomarker expression and strain. In the latter case, we elected to focus only on identified proteins showing an R2 ≥ 0.95. Statistical analyses were performed in IBM SPSS (IBM Corp. Released 2015).Non-parametric analysis was performed. Variables are presented as medians and confidence intervals. LVEF, peak values of global LS, global and regional CS, and peak values of corresponding strain rates measured at acute and chronic time-points post-MI were compared with the baseline data using a Kruskall–Wallis test. Observed significant differences were analysed further by using Mann–Whitney U tests. A https://www.R-project.org/). For western blotting analysis quantification of band intensity was performed using AlphaEase v5.5 software  followed by background subtraction and correction for protein loading. For evaluation of the differences between the protein expression in the non-ischaemic and ischaemic myocardium, the two-tailed unpaired Student's t-test was used.For each protein, an abundance ratio between infarcted and non-infarcted samples was calculated. Proteins found to be at least twofold more expressed in the infarcted myocardium were correlated with the endocardial strain data of the acute phase; a series of univariate linear regression models were performed to correlate each identified protein to each mechanical variable. This statistical analysis was conducted using R version 3.4.4  Act, 1986 (Home Office Project Licence No 7008975) and the European Union Directive 2010/63/EU. Female Yorkshire pigs  were used in the study. Regulated procedures were in line with Home Office  as described in approved PPL 7008975.This research was done without patient involvement. Patients were not invited to comment on the study design and were not consulted to develop patient relevant outcomes or interpret the results. Patients were not invited to contribute to the writing or editing of this document for readability or accuracy.Animals were 5–6 months old. Weight range was 55–70 kg, median 62.5 kg at the time of MI and 72–92 kg, median 84 kg at termination.CMRI outcome is shown in Table Myocardial strains were calculated from all 10 MI experiments (n = 8 LAD territory and n = 2 CX territory). The occurrence of MI in these two different coronary territories caused tissue damage in the apical and lateral LV wall regions respectively. For the majority of the analysis focusing on LV global metrics, such as LVEF, GCS and GLS, myocardial strains from all 10 experiments were included as these indices should be able to characterise the severity of an infarct & the subsequent LV remodelling regardless of the affected coronary territory. LV remodelling, occurring due to myocardial tissue’s response to the imposed occlusion, encompasses changes in ventricular shape, volume, and function throughout the cardiac cycle. Similarly, MRI data from all baseline, pre-MI scans were retained in the analysis. Nevertheless, for, the statistical analysis of myocardial strain changes in ACS at acute and chronic timepoints only data from the 8 LAD experiments were included, as only these cases were expected to determine an MI affecting the apical region i.e. that covered by the ACS metric. The same approach was taken for the other regional strains ECS and BCS. An evaluation of the regional strains for the CX territory was not performed, because with only n = 2 experiments in this sub-group such an evaluation would not have been meaningful.Changes in myocardial strains over time for all animals are shown in Table p = 0.002) point compared to baseline (− 37.5%), whereas the change at the acute time point did not reach statistical significance  (Table p = 0.002) vs. baseline (− 34.9%), whereas the change observed at the chronic time-point did not reach statistical significance . The endocardial equatorial CS (ECS) and basal CS (BCS) strains showed no statistical changes across the two time-points, with all p > 0.01  and apical CS (ACS) are shown in Fig. 03 Table . Endocarp = 0.0023)  and GLS versus LVEF  indicated strong and moderate correlations respectively  were measured by established CMRI methods Table . LVEF drely Fig. . LV volu2 ≥ 0.95) with the ECSR were: D-3-phosphoglycerate dehydrogenase , cysteine and glycine-rich protein-2 , and secreted frizzled-related protein 1 . Western blotting for D-3PGDH and sFRP1 confirmed that the level of D-3PGDH and sFRP1 protein in the infarcted myocardium was significantly increased compared to the non-infarcted myocardium  was observed 1–2 days after MI, which persisted 5–6 weeks later predicting early LVR. Additionally, early LVR post-MI was associated with an hyperexpression of 39 myocardial proteins, of which 21 correlated specifically with ECSR, with D-3PGDH and sFRP1 exhibiting the strongest correlation with ECSR.Our findings also show that the changes in regional strain (ACS) observed 1–2 days post MI accurately reflect the affected myocardial territories.10 and in an open-chest coronary ligation porcine MI model11. It is argued that GLS may predict LVR as the LV apical region affected by ischemia contains more longitudinal fibres, which contributes more to the local contractile performance and are less affected by ischemia12. However, the distribution of the circumferential fibres across the LV might reflect changes to longitudinal and circumferential deformations12, therefore suggesting that CS metric might add significantly to gauge predictive information on myocardial deformation25.GLS has been suggested as a predictor of late LVR in STEMI patients27. These findings, if confirmed, might affect the type and timing of pharmacological and/or mechanical LV unloading approaches post-MI to prevent heart failure28.Our data suggests that regional CS might be more sensitive than GLS in predicting late LVR and quantifying LV function. Averaging strains over few slices within a specific LV region, instead of assessing individual slices or global metrics, might boost the reproducibility and robustness of the method. In addition, this approach ensures that small differences in image location (from patient movement or from scans at different times or different patients) determine less bias when comparing longitudinal data. Also, performing strain over smaller volume/regions is associated with less variation, hence with higher potential of identifying smaller changes. Accordingly, CS has been shown to be an effective indicator of MI, marker of LV function, and infarct transmurality28.Correlations were also found between GCS and LVEF as well as between GLS and LVEF. Both GCS and LVEF were calculated using the same short-axis data, and so a strong correlation was expected based on geometrical considerations. Long-axis data was used for GLS, so the correlation found between these parameters suggests that GLS might be able to detect MI and changes to LV function in keeping with findings by others29. Farah and colleagues20 defined LV remodelling as an increase of 10% in ventricular end-systolic or end-diastolic diameter, and found a 58% incidence of LV remodelling after an anterior MI compared with other studies. In the Acute Myocardial Infarction Contrast Imaging (AMICI) trial, the term ’reverse REM’ was employed to denote a > 10% reduction in LVESV found at 6 months in 39% of patients following PPCI30, being the only independent predictor of 2-year event-free survival. Based on this definition we found that 75% of our experiments had an LV remodeling > 10% at both LVEDV and LVESV at 5–6 weeks at serial CMR.The occurrence of MI and related ischemia/reperfusion injury trigger a storm of molecular signalling, cellular remodelling, inflammatory reaction and fibrosis leading to scar formation and LVR31. Proteomics analysis in this study showed 39 hyper expressed proteins, 21 of these being strongly correlated with early changes in regional ECSR. The western blotting analysis showed that D-3PGDH and sFRP1 are significantly expressed within the infarcted myocardium. This finding might indicate their involvement in the early changes in ECSR as well as in determining LVR post-MI. D-3PGDH is the key enzyme for the L-Serine biosynthesis pathway that branches from glycolysis. It participates in a metabolic network interlinking folate and methionine cycles to support cell proliferation and an amplification of function has been associated with a pro-oncogenic role32. sFRP1 acts as an inhibitor of the Wnt signalling pathway by binding to Wnt proteins and preventing their association with Frizzled receptors34. Interestingly, sFRP1 protein has been associated with reduced scar size, improved cardiac function and decreased neutrophil infiltration in a mice model of coronary ligation, indicating a protective role of this protein via reduction of post-MI inflammation34. This anti-inflammatory role has been suggested by others in rodents but not in pigs. sFRP1 to suppress the Wnt pathway has potential clinical translation for novel therapies aiming to reduce scar size post-MI and warrants further investigation.Binek et al. found that ischaemia triggers changes in the levels of many myocardial proteins, some of which are linked to contractile function or systolic wall thickness31. Finally, while our study indicates that early changes in ACS post MI persist at 5–6 weeks along with early signs of LVR, further studies are needed to confirm the association with late chronic LVR.There are limitations to this study. The animals did not have atherosclerotic disease, which might have determined a different proteomic profile and a different pattern of LVR. However, the MI size and other CMRI measures were in keeping with what is observed in humans. In addition, we used a model of ischemia/reperfusion injury with an occlusion time of 60 min. It might be possible that in models with permanent coronary ligation, or with much longer ischemic time, the observed results might differ. Furthermore, the animals gained a substantial amount of weight over the study period with a possible confounding effect on scar size, LV volumes and proteomics. However, it has been suggested that the use of CMRI parameters indexed to the weight of the animal can minimise this effect, although this approach is not in keeping with what is done in humans. However, a marked increase in LVESV was observed as early as 1–2 days post MI suggesting that LVR starts soon after MI and that this early change cannot be biased by weight. Another limitation is the lack of troponin I measurement at 6 and 12 h post MI due to these time-points occurring overnight. A relatively small number of animals (n = 10) was used, with strain analyses and proteomics undertaken on sub-groups: non-parametric statistical tests were used to compensate. Another limitation is related to the lack of information on the dynamic proteomics changes that occur after MI: our study design precluded the possibility of also collecting myocardial specimens 1–2 days post MI in the same animals to characterise the dynamic proteomic processes as previously described by other authorsIn conclusion, this study shows that early changes in regional peak ACS persist at 5–6 weeks post-MI, when early signs of LVR are also observed along with increased tissue levels of D-3PGDH and sFRP1. New studies are warranted to ascertain if early changes in ACS post MI could predict late LVR and if the observed increase in tissue levels of D-3PGDH and sFRP1 might be casually involved in the pathogenesis of adverse LV remodelling.Supplementary Information 1.Supplementary Video 1.Supplementary Video 2.Supplementary Video 3.