However, in multivariable analysis, diabetes mellitus (p = 0.001), atrial fibrillation (p = 0.001), malignancy (p = 0.006), and physical triggers (p = 0.006) outperformed measures of myocardial strain and emerged as the strongest, independent predictors of long-term mortality in TS. In conclusion, CMR-based longitudinal strain provides valuable prognostic information in patients with TS, regardless of the utilized technique of assessment. Long-term mortality, however, is mainly determined by comorbidities.Cardiac magnetic resonance (CMR)-derived left ventricular (LV) global longitudinal strain (GLS) provides incremental prognostic information on various cardiovascular diseases but has not yet been investigated comprehensively in patients with Takotsubo syndrome (TS). This study evaluated the prognostic value of feature tracking (FT) GLS, tissue tracking (TT) GLS, and fast manual long axis strain (LAS) in 147 patients with TS, who underwent CMR at a median of 2 days after admission. Long-term mortality was assessed 3 years after the acute event. In contrast to LV ejection fraction and tissue characteristics, impaired FT-GLS, TT-GLS and fast manual LAS were associated with adverse outcome. The best cutoff points for the prediction of long-term mortality were similar with all three approaches: FT-GLS −11.28%, TT-GLS −11.45%, and fast manual LAS −10.86%. Long-term mortality rates were significantly higher in patients with FT-GLS > −11.28% (25.0% versus 9.8%;  Takotsubo syndrome (TS) is an increasingly recognized form of acute heart failure and important differential diagnosis in patients presenting with suspected acute coronary syndrome. A characteristic and unique feature of TS is the distinctive contraction pattern of the left ventricle during the acute phase of the disease . The regThe aim of this study was, therefore, to investigate different approaches for the assessment of longitudinal strain using standard steady-state free precession (SSFP) CMR images and determine their value for the prediction of adverse outcome following TS.n = 125) and the University Heart Center Luebeck (n = 22). All patients underwent CMR imaging during the acute phase of the disease and met the recommended clinical and CMR criteria for the diagnosis of TS including the absence of a culprit lesion in coronary angiography and complete recovery of LV systolic function [The population of this cohort study consisted of 147 patients with TS prospectively enrolled at the Heart Center Leipzig n = 12 and the function ,17. TrigThe study was conducted according to the principles of the Declaration of Helsinki and approved by the local ethical committees. All patients gave written informed consent.CMR scans were performed on clinical 1.5- or 3.0-T magnetic resonance scanners. The standardized protocol included ECG-gated balanced SSFP sequences of 2- and 4-chamber long-axis views as well as short axis stacks for functional analysis. The presence of myocardial edema was assessed in T2-weighted triple short-tau inversion recovery images and T1-weighted inversion-recovery-gradient echo sequences were acquired 10 to 15 min after administration of a gadolinium bolus  to determine the presence of myocardial scar/fibrosis. LV ejection fraction, presence of myocardial edema, and myocardial fibrosis were assessed in short axis stacks from base to apex. Analyses were performed offline by blinded investigators at the CMR core-laboratory at University Heart Center Luebeck using certified evaluation software . T2 signal intensity ratios were calculated by comparing the mean signal intensity of the myocardium with that of the skeletal muscle in the same slice. A T2 signal intensity ratio ≥1.9 was the predefined threshold to identify myocardial edema. Significant late gadolinium enhancement was defined as >5 standard deviations above normal myocardium.Central core-laboratory masked analyses included 3 different approaches for the assessment of LV longitudinal strain: (a) global longitudinal strain (GLS) assessed with feature tracking (FT-GLS); (b) GLS assessed with tissue tracking (TT-GLS); and (c) fast manual long-axis strain (LAS). Examples are provided in CMR feature tracking was performed in an experienced core-laboratory at the University Medical Center Goettingen using dedicated evaluation software that has been validated and previously used in numerous studies  ,13,18. LAll analyses were performed by experienced and fully blinded operators at core laboratories with low inter- and intra-observer variabilities, as previously demonstrated ,13.p < 0.05). Furthermore, strain values and their prognostic implications were also assessed regarding confirmed or presumed cardiovascular causes of death.Categorical variables are presented as frequencies (percentages) and were compared with the Chi-square test. Continuous variables were mainly non-normally distributed in Shapiro–Wilk test and are therefore presented as medians with corresponding interquartile ranges (IQR). Between group differences were assessed with the Mann–Whitney U test. Baseline characteristics and CMR findings are reported for the entire study population and were compared between survivors and non-survivors. Correlations were assessed between LV ejection fraction and the different approaches to determine myocardial strain using the Spearman’s rank correlation coefficient. Intra- and inter-observer reproducibility in the core laboratories was tested in 10 randomly selected patients with TS. Calculations included Bland–Altman analysis, intraclass correlation coefficients (ICC), and coefficients of variation (CoV) using the root mean square method. The level of agreement was considered excellent in case of an ICC > 0.74. After application of receiver-operating characteristic curves, the Youden index was calculated to dichotomize myocardial strain and determine the best cutoff values for the prediction of outcome. These thresholds were used to stratify the study population and assess the impact of myocardial strain values on long-term mortality with the Kaplan–Meier method and log-rank testing. Predictors of mortality were identified in univariate and stepwise multivariable Cox regression analysis. Hazard ratios (HR) with corresponding 95% confidence intervals (CI) are reported. All baseline characteristics and CMR findings were considered for univariate analysis. Multivariable testing included only significant predictors of mortality in univariate analysis  and MedCalc version 19.2.1. . A 2-tailed The study population consisted of 147 consecutive patients with TS who underwent CMR imaging at a median of 2 days (IQR 2 to 4 days) after hospitalization. Clinical follow-up data after 3 years (IQR 1.6 to 5.3 years) were available in 138 patients (94%) and showed an all-cause mortality of 16% .The investigated cohort reflected a typical TS population of predominantly postmenopausal women with a stressful trigger in two-thirds of patients .Apical ballooning was the most prevalent contraction pattern resulting in a moderately reduced LV ejection fraction of 47% (IQR 41 to 53%) at acute presentation. CMR imaging performed a few days after admission still demonstrated a comparable impairment of LV performance .Furthermore, CMR revealed myocardial edema in 80% of patients and excluded significant scar/fibrosis. Complete recovery of LV function was documented in all participants.p = 0.006), more frequently male (p = 0.040), had more physical triggers (p = 0.002) and a higher prevalence of diabetes mellitus (p = 0.011) and malignancies  and consequently oral anticoagulation (p = 0.034) was significantly higher among non-survivors. Discharge medication differed also regarding the use of diuretics, which was higher in deceased TS patients (p = 0.030). Routine CMR findings including LV ejection were similar among survivors and non-survivors .The different CMR-based approaches to assess LV myocardial deformation resulted in the following strain values: FT-GLS −14.2% (IQR −11.3 to −18.2%), TT-GLS −10.4% (−8.6% to −12.8%), and fast manual LAS −11.2% (−9.1 to −14.2%). All strain parameters demonstrated excellent intra- and inter-observer reproducibility  and a mor = 0.750; FT-GLS and LAS: r = 0.602; TT-GLS and LAS: r = 0.675; p < 0.001 for all). TT-GLS (p = 0.032) and fast manual LAS (p = 0.014) were significantly impaired in non-survivors, and FT-GLS showed a trend towards higher values in survivors . However, when also including clinical markers in a multivariable model, myocardial strain was no longer independently associated with adverse outcome and diabetes mellitus (p = 0.001), atrial fibrillation (p = 0.001), malignancy (p = 0.006), and physical triggers (p = 0.006) emerged as the strongest, independent predictors of mortality in patients with TS , TT-GLS (−8.6% (IQR −6.7% to −10.0%) versus −10.9% (IQR −8.9% to −13.2%); p = 0.013), and LAS (−9.5% (IQR −6.5% to −10.8%) versus −12.0% (IQR −9.4% to −14.5%); p = 0.006) in patients with documented or presumed cardiovascular death. Univariate regression analysis confirmed the association of all strain parameters with cardiovascular outcome (FT-GLS: HR 1.13 (95% CI 1.02 to 1.27) p = 0.026; TT-GLS: HR 1.26 (95% CI 1.03 to 1.53), p = 0.023; LAS: HR 1.29 (95% CI 1.08 to 1.54), p = 0.005) and TT-GLS remained an independent predictor of cardiovascular death  in addition to age (p = 0.055) and atrial fibrillation (p = 0.032) in multivariable testing.An additional analysis, which excluded non-cardiovascular causes of death, revealed impaired FT-GLS (−11.2% (IQR −9.1% to –15.6%) versus −14.5% (IQR −11.5% to −18.5%); The present study is the first to comprehensively investigate different CMR-based approaches for the assessment of LV longitudinal strain in patients with acute TS regarding their value for long-term risk stratification. The main results can be summarized as follows: (a) in patients with TS, LV longitudinal strain is a superior marker of clinical outcome compared to LV ejection fraction; (b) FT-GLS, TT-GLS, and fast manual LAS provide similar prognostic information with a cutoff at approximately −11% to identify high-risk patients; and (c) long-term mortality in TS is mainly determined by comorbidities, which outperformed measures of myocardial strain in multivariable analysis.Despite the transient character of TS, patients face a substantial risk of life-threatening complications during the acute phase of the disease and the reported long-term mortality rates are at least comparable to patients with acute myocardial infarction ,20,21. TLimitations of the current study refer to the rather small and low-risk study population. CMR could not be performed in patients with contraindications  and unstable patients. The time from diagnosing TS to CMR was, at median, 2 days and hence after the critical period of the first 24 to 48 h. Therefore, there is an unavoidable selection bias for stable patients without severe complications during the acute phase of the disease. The primary study endpoint was all-cause mortality with a considerable number of patients with unknown causes of death. The impact of longitudinal strain on early adverse events or cardiovascular mortality could not be assessed in detail. Furthermore, the effect of confounding factors  on myocardial strain was not assessed in our study. However, our study reports CMR data from one of the largest cohorts of patients with TS with long-term outcome data and we were able to show a prognostic value even in this low-risk population. Follow-up CMR was not performed routinely in our study. Data regarding persistently impaired cardiac deformation indices after TS are available from previous investigations .This CMR study shows that different approaches to assess LV longitudinal strain, including a simple technique like fast manual LAS, are consistently associated with long-term mortality in patients with TS. Therefore, these findings support the use of longitudinal cardiac deformation as a marker for risk stratification, albeit clinical parameters outperformed myocardial strain in multivariable analysis. Additional data are required to determine the prognostic value regarding early and delayed cardiovascular complications and to assess management strategies based on LV longitudinal strain.


To measure T2 values for magnetic resonance neurography (MRN) of the healthy distal sciatic nerve and compare those to T2 changes in patients with nerve compression.Twenty-one healthy subjects and five patients with sciatica due to disc herniation underwent MRN using a T2-prepared turbo spin echo (TSE) sequence of the distal sciatic nerve bilaterally. Six and one of those healthy subjects further underwent a commonly used multi-echo spin-echo (MESE) sequence and magnetic resonance spectroscopy (MRS), respectively.T2 values derived from the T2-prepared TSE sequence were 44.6 ± 3.0 ms (left) and 44.5 ± 2.6 ms (right) in healthy subjects and showed good inter-reader reliability. In patients, T2 values of 61.5 ± 6.2 ms (affected side) versus 43.3 ± 2.4 ms (unaffected side) were obtained. T2 values of MRS were in good agreement with measurements from the T2-prepared TSE, but not with those of the MESE sequence.A T2-prepared TSE sequence enables precise determination of T2 values of the distal sciatic nerve in agreement with MRS. A MESE sequence tends to overestimate nerve T2 compared to T2 from MRS due to the influence of residual fat on T2 quantification. Our approach may enable to quantitatively assess direct nerve affection related to nerve compression. Magnetic resonance neurography (MRN) of the peripheral nervous system (PNS), the application of magnetic resonance imaging (MRI) for the depiction and study of peripheral nerves of the human body, is increasingly applied in vivo. Advances in protocols and MRI scanner techniques now allow depicting even small or highly oblique nerves originating from the brachial plexus or lumbosacral plexus (LSP) –3. A proUsing qualitative MRN and structural evaluations, the sciatic nerve has shown to be affected in various pathologies, such as hamstring injury due to different causes , injectiIn addition to such qualitative MRN, (semi-)quantitative approaches have been introduced recently. Diffusion parameters derived from diffusion tensor imaging (DTI) have been evaluated for the sciatic nerve in patients with muscular disorders such as myotonic dystrophy , radiculDespite being increasingly used and yielding promising results among patients with primarily neuropathic diseases, evidence is still lacking for even more common conditions such as sciatica occurring due to structural pathology such as degenerative disc disease with nerve compression , 30. QuaAgainst this background, the objective of the present study is (1) to provide T2 values for the healthy distal sciatic nerve and to evaluate reliability of quantitative MRN by T2 mapping in healthy subjects, (2) to compare our novel T2 mapping approach against T2 measurements in a commonly used MESE sequence (having nerve-water T2 from MRS as the reference standard), and (3) to evaluate potential alterations in T2 values of the distal sciatic nerve due to degenerative disc disease with nerve compression at the level of the LSP in patients suffering from unilateral sciatica. We hypothesize that T2 mapping using a T2-prepared turbo spin echo (TSE) sequence shows good agreement with nerve-water T2 from MRS, due to robust suppression of residual fat that can affect T2 quantification whilst being characterized by high precision. Furthermore, we propose that patients with nerve compression at the level of the LSP present with unilaterally elevated T2 values of the distal sciatic nerve when compared to the unaffected side or healthy subjects, probably due to edematous changes or swelling of nerves related to proximal compressive effects.The study protocol was approved by the local ethics commission (registration number 408/15S) and was followed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all included subjects.This prospective study enrolled twenty-one healthy volunteers  and five patients  with unilateral sciatica due to degenerative disc disease. Inclusion criteria were (1) written informed consent, (2) age above 18 years, (3) strict unilateral sciatica matching at least one dermatome with the presence of symptoms  for at least 4 weeks and not longer than 6 months (only for the patient group), and (4) previous anatomical MRI suggesting degenerative disc disease with disc herniation and unilateral nerve contact of degenerated disc material (only for the patient group). Exclusion criteria for both the healthy volunteers and patients were (1) pregnancy, (2) contraindications for MRI, and (3) previous surgery at the hip, thigh, or lumbar spine .The healthy volunteers and patients underwent MRN during a 1-day study visit. Furthermore, the patients underwent detailed clinical examinations that included assessments of coordination, sensory function, and muscle strength according to the British Medical Research Council (BMRC) scale. Additionally, the Oswestry Disability Index (ODI) was calculated , 33, and3, acquisition voxel size = 0.3 × 0.3 × 8 mm3, TE = 60 ms, repetition time (TR) = 2500 ms, scan time = 6 min 10 s, SENSE acceleration factor = 2.0.Two-dimensional (2D) high-resolution T2-weighted DIXON TSE sequence : field of view (FOV) = 140 × 150 × 104 mm3, acquisition voxel size = 0.7 × 0.7 × 8 mm3, TE = 30 ms, TR = 1600 ms, scan time = 3 min 30 s, fat suppression using Spectral Attenuated Inversion Recovery (SPAIR), SENSE acceleration factor = 2.5, T2 preparation applying a B1-insensitive rotation radiofrequency pulse as previously used . . 4]. EacIn healthy volunteers, the described approach of ROI positioning and extraction of T2 values from T2 maps of the 3D T2-prepared TSE sequence and 2D MESE sequence was performed by a medical doctor . Furthermore, to assess inter-reader reliability, ROI positioning and extraction of T2 values from T2 maps of the 3D T2-prepared TSE sequence was also performed by a second medical doctor . In patients, only R1 evaluated the imaging data of both sides using the T2 maps of the 3D T2-prepared TSE sequence. During analyses, readers were strictly blinded to the measurements of each other, and R1 was furthermore blinded to the side of sciatica in patients and to previous anatomical MRI that suggested degenerative disc disease with disc herniation.The processing of the MRS data was performed with in-house software and included zero-order phasing, Gaussian apodization, and frequency alignment of single acquisitions. Peak area quantification was achieved considering eight fat peaks and was considered separately for each TE. The T2 fitting was only performed on the water peak signal and was carried out twice, once considering all available TEs and once only considering the matched TEs with the 3D T2-prepared TSE sequence.p value < 0.05 was considered statistically significant.Statistics and generation of graphs were performed using GraphPad Prism  and SPSS . A In healthy volunteers, the measured T2 values of the ROIs of the three consecutive slices were averaged, which was achieved separately for both sides, the measurements of both readers, and for values of the T2 maps as derived from the 3D T2-prepared TSE sequence or 2D MESE sequence. Differences between sides were assessed using Wilcoxon matched-pairs signed rank tests, which was achieved separately for the measurements of both readers and measurements derived from the T2 maps of the 3D T2-prepared TSE sequence and the 2D MESE sequence. Moreover, Wilcoxon matched-pairs signed rank tests were conducted to compare T2 values of the 3D T2-prepared TSE sequence and the 2D MESE sequence. To assess inter-reader reliability for T2 mapping derived from the 3D T2-prepared TSE sequence, we calculated the root mean square error (RMSE) and the root mean square coefficient of variation (RMSCV) based on the values obtained from R1 and R2, again separately considering T2 values of the left and right sides . Since MIn patients, the measured T2 values by R1 derived from the ROIs of the three consecutive slices were averaged, which was achieved separately for the affected side and the contralateral side with respect to the side of disc herniation and unilateral nerve contact. The T2 values of the affected side were compared to the left-sided and right-sided values obtained from the healthy subjects derived from evaluations of R1 according to T2 mapping from the 3D T2-prepared TSE sequence using Mann–Whitney tests.MRN including T2 mapping of the distal sciatic nerve with the 3D T2-prepared TSE sequence was successfully achieved bilaterally in all enrolled healthy volunteers, with the distal sciatic nerve being clearly interpretable in all subjects. Thus, forty-two T2 values  derived from the 3D T2-prepared TSE sequence were available for analyses. Furthermore, six volunteers also underwent bilateral scanning of the distal sciatic nerve with the 2D MESE sequence, leading to twelve T2 values  derived from this sequence. One volunteer also underwent MRS bilaterally using STEAM.p = 0.87, R2 p = 0.92; Table The T2 values derived from the 3D T2-prepared TSE sequence were 44.6 ± 3.0 ms R1) and 45.7 ± 3.3 ms (R2) for the left and 44.5 ± 2.6 ms (R1) and 45.7 ± 3.0 ms (R2) for the right distal sciatic nerve  for the left and 43.6 ms (40.7 ms unmatched) for the right distal sciatic nerve for the volunteer examined (R1).Figure Five patients underwent MRN with T2 mapping of the distal sciatic nerve bilaterally using the 3D T2-prepared TSE sequence. These patients initially presented in the outpatient clinic with unilateral sciatica due to degenerative disc disease with disc herniation and unilateral nerve contact of degenerated disc material according to previous anatomical MRI Fig. . Neurofop < 0.0001 each).When discriminating between T2 values of the affected and non-affected side derived from the 3D T2-prepared TSE sequence for the distal sciatic nerve, patients showed T2 values of 61.5 ± 6.2 ms for the affected side and 43.3 ± 2.4 ms for the contralateral, unaffected side (R1). When comparing the T2 values of the affected side against the T2 values obtained in the healthy subjects, significant differences were observed for both the comparison against left-sided and right-sided normal T2 values quantitative MRN for evaluations of the sciatic nerve was on systemic diseases with components affecting also the PNS or rather rarely observed diseases , 23–25. As the study’s limitations, the size of the study cohort that was comparatively small has to be mentioned. Although forty-two T2 values derived from the 3D T2-prepared TSE sequence were obtained as a result of the segmentation of both the left-sided and right-sided distal sciatic nerves in healthy subjects, upcoming studies using data derived from larger cohorts are highly needed to provide normative data. Furthermore, factors such as sex, age, or body mass index should be considered in future studies as they may have an impact on T2 measurements. Moreover, we have only reported on a case series of patients, with upcoming studies having to confirm the results observed in the small number of patients of this investigation. However, the finding of differences in T2 values between sides in the patients and when comparing T2 values between healthy subjects and patients still points at the clinical relevance of quantitative MRN using T2 mapping. The multi-compartment signal decay of peripheral nerves should also be considered as a potential shortcoming regarding determination of T2 values, especially with respect to the desirable comparability of MRI sequences of different vendors or centers. In this study, a sequence with strong initial T2 weighting was employed that mitigates contributions of short T2 components on the signal decay curves. With the used 3D T2-prepared TSE sequence a very good agreement with MRS measurements was observed. This indicates that this sequence is well suited in the presented context but other sequences might have to be adapted to achieve a similar fat suppression and TE to deliver comparable results. Another limitation regarding the MRS measurements is the potential contribution of surrounding water-containing tissues. We tried to avoid muscle tissue surrounding the nerves when placing the VOI. However, contributions of the surrounding tissue due to partial volume averaging cannot be fully excluded but should be minor compared to the contribution of the nerves.In conclusion, this is one of the first studies to apply quantitative MRN and to present T2 values of the distal sciatic nerve in healthy subjects. Our results suggest that T2 mapping derived from a 3D T2-prepared TSE sequence is highly reliable and, importantly, shows lower values than a commonly used 2D MESE sequence whilst being in agreement with the nerve water T2 from MRS. The influence of residual fat on the T2 quantification that is not entirely suppressed in a commonly used 2D MESE sequence may account for this discrepancy and should be considered during T2 mapping of the PNS. Furthermore, T2 mapping using a 3D T2-prepared TSE sequence might allow for evaluations of quantitative alterations of the distal sciatic nerve in patients with unilateral sciatica due to degenerative disc disease with unilateral nerve contact of degenerated disc material, which may allow T2 values of the distal sciatic nerve to become biomarkers of direct nerve affection in patients with degenerative changes at the level of the LSP.


ST-elevation myocardial infarction is associated with high levels of cardiac sympathetic drive and release of the co-transmitter neuropeptide Y (NPY). We hypothesized that despite beta-blockade, NPY promotes arrhythmogenesis via ventricular myocyte receptors.P < 0.05) higher venous NPY levels despite the absence of classical risk factors including late presentation, larger infarct size, and beta-blocker usage. Receiver operating curve identified an NPY threshold of 27.3 pg/mL with a sensitivity of 0.83 and a specificity of 0.71. RT-qPCR demonstrated the presence of NPY mRNA in both human and rat stellate ganglia. In the isolated Langendorff perfused rat heart, prolonged  stimulation of the stellate ganglia caused significant NPY release. Despite maximal beta-blockade with metoprolol (10 μmol/L), optical mapping of ventricular voltage and calcium (using RH237 and Rhod2) demonstrated an increase in magnitude and shortening in duration of the calcium transient and a significant lowering of ventricular fibrillation threshold. These effects were prevented by the Y1 receptor antagonist BIBO3304 (1 μmol/L). Neuropeptide Y (250 nmol/L) significantly increased the incidence of VT/VF (60% vs. 10%) during experimental ST-elevation ischaemia and reperfusion compared to control, and this could also be prevented by BIBO3304.In 78 patients treated with primary percutaneous coronary intervention, sustained ventricular tachycardia (VT) or fibrillation (VF) occurred in 6 (7.7%) within 48 h. These patients had significantly (1 receptor work synergistically with beta-blockade as a new anti-arrhythmic therapy.The co-transmitter NPY is released during sympathetic stimulation and acts as a novel arrhythmic trigger. Drugs inhibiting the Y We also sought to ascertain whether patients undergoing PPCI for STEMI with high plasma NPY levels were therefore more likely to experience ventricular arrhythmias. To further investigate possible causation, we tested whether NPY promotes arrhythmias during experimental ST-elevation ischaemia/reperfusion in the rat and explored the receptor pathways involved to assess whether these may be applicable for human pharmacological intervention.See t-test was used to compare grouped data with two measures, whilst a one-way analysis of variance (ANOVA) was applied to grouped data with more than two measures, with post hoc analysis to determine significance (Neuman–Keuls). An unpaired t-test assuming unequal variance was used to determine significance between independent groups. Non-parametric data from two independent groups were compared using a Mann–Whitney U test and for more than two groups using a Kruskal–Wallis one-way ANOVA. Discrete data were analysed using χ2 or Fisher’s exact test in contingency tables. All significance tests are two-tailed and significance accepted at P < 0.05.Data are presented as mean ± standard deviation, or as median [interquartile range] if data did not pass a normality test (Shapiro–Wilk). A paired Table 1).A total of 78 patients with acute left coronary artery STEMI  were recruited and underwent peripheral venous blood sampling at the time of PPCI. Overall patients were 63 ± 12.4 years old and 61/78 (78.2%) were male. The mean pain to balloon time was 218 ± 159 min. Peripheral venous NPY concentration was 19.0 [11.7–31.7] pg/mL. For comparison, the venous NPY level measured during elective coronary angiography in 12 patients of a similar age and sex, with similar cardiovascular risk factors but with unobstructed coronary arteries was 7.8 [6.5–12.2] pg/mL . Ejection fraction, oedema, and late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (MRI) at 48 h were also similar. However, patients with VT/VF had significantly higher venous plasma NPY levels compared to the rest of the study group (31.9 [27.8–47.7] vs. 17.8 [10.6–30.2] pg/mL).Sustained VT/VF was observed in 7.7% (6/78) of the STEMI patients. The individual characteristics of these patients in terms of pain to balloon time, arrhythmia timing, and termination are detailed in Figure . A receiver operating characteristic curve was used to define an NPY threshold that best identifies those patients with sustained VT/VF as shown in Figure . A threshold NPY level of 27.3 pg/mL has a sensitivity of 0.83 and a specificity of 0.71 . The baseline characteristics of STEMI patients according to this threshold level are summarized in Table 3. Patients with high venous NPY levels were on average slightly older and a higher proportion were hypertensive. Usage of beta-blockers, angiotensin converting enzyme (ACE) inhibitors, and statins prior to presentation were similar in the two groups and both groups had similar pain to balloon times, left anterior descending artery infarctions, flow-limiting bystander disease, and haemodynamic parameters. There was no association between beta-blocker dose on admission  and NPY levels . There were no significant differences in ejection fraction or infarct size as assessed by LGE between patients with low and high venous NPY levels above as shown in Table 3. The occurrence of all ventricular arrhythmias according to NPY levels are summarized in Table 4. Patients with high venous NPY levels had similar coupling intervals of ventricular ectopics compared to those with low NPY levels .The NPY levels of patients experiencing sustained VT/VF in relation to the entire NPY distribution are illustrated in n = 4) and rat (n = 4) stellate ganglia tissue . Prolonged (2 min) high frequency (10 Hz) stimulation of either left or right stellate ganglia in the integrated sympathetic nerve rat heart model resulted in the release of NPY in the coronary perfusate , although release of NPY was greater with left stellate stimulation (n = 6) compared to right (n = 6). Stimulation of either stellate ganglia also resulted in a frequency-dependent increase in heart rate and left ventricular developed pressure, greater with left (n = 5) compared to right (n = 7) stellate stimulation, which could be abolished with the beta-blocker metoprolol  even during prolonged (2 min) high frequency (10 Hz) stimulation .Using quantitiative reverse transcription polymerase chain reaction (RT-qPCR) NPY mRNA was identified in human (n = 5) or activation time as shown in Figure . However, there was a significant increase in the amplitude of the intracellular calcium transient accompanied by a significant shortening of the calcium transient duration as demonstrated in and EFigure . The increase in calcium transient amplitude and shortening of the calcium transient duration could be prevented by a NPY Y1 receptor antagonist BIBO3304 .Optical mapping of voltage and intracellular calcium transients (using RH237 and Rhod2) at the anterior ventricular wall demonstrated that independent of heart rate (pacing at a cycle length of 140 ms), prolonged high-frequency stellate stimulation in the presence of metoprolol did not significantly change action potential duration  or left (n = 7) stellate stimulation in the presence of beta-blockade remained pro-arrhythmic with a significant reduction in VFT  and this could be prevented by the addition of the Y1 receptor antagonist BIBO3304  in combination with metoprolol . This suggests that the pro-arrhythmic effect seen following prolonged high-frequency stellate ganglia stimulation in the presence of beta-blockade was due to NPY.To determine whether the increase in the magnitude and shortening in duration of the calcium transient predisposed the heart to ventricular arrhythmias, we measured ventricular fibrillation threshold (VFT) in response to burst pacing before and after prolonged high-frequency stellate ganglia stimulation in the presence of metoprolol. Right (n = 4) as shown in Figure . Furthermore, metoprolol alone did not have a direct effect on VFT compared to control (n = 7) . We also demonstrated that combined beta and alpha-receptor blockade  also did not prevent the reduction in VFT to prolonged high-frequency stellate ganglia stimulation (n = 7) as shown in Figure .To further validate effective blockade of adrenergic receptor signalling, we demonstrated that metoprolol abolished the inotropic  and chronotropic response  to a maximal dose of norepinephrine (1 μmol/L) and also reversed a fall in VFT (n = 10) significantly increased the incidence of sustained VT and VF (60% vs. 10%) compared to control (n = 10) and this could be abolished with the Y1 receptor antagonists BIBO3304 (n = 10) as shown in Table 5.To directly assess whether NPY triggers ventricular arrhythmia, we assessed the incidence and severity of arrhythmia in the rat in the setting of ST-elevation ischaemia reperfusion. NPY  or delayed rectifier potassium current (Ik) activity have been demonstratedIto was reduced.ICaL have been shown to be species dependent with inhibition in guinea pigAlthough no animal model has identical electrophysiology and expresses the same combination of co-transmitters compared to human, the rat remains the best-studied model of NPY action at the single ventricular myocyte level in terms of electrophysiology and calcium handling, and NPY is the dominant sympathetic co-transmitterIK1) and the activity of the Na+/K+ ATPase. It also causes localized acidosis, uncoupling of gap junctions, and the generation of reactive oxygen species.+/H+ exchange leads to a rise in intracellular Na+ and subsequently Ca2+ via NCX.,,The pathophysiology of ventricular arrhythmias following ischaemia and reperfusion is complex. Ischaemia causes a reduction in cellular adenosine triphosphate (ATP), raises extracellular potassium through opening of ATP sensitive potassium channels, reduces inward rectifier potassium current  blood,,Historical studies undertaken in the 1980s before the advent of PPCI and modern medical treatment have shown that venous ‘NPY-like activity’ is elevated during ischaemic events and left ventricular failure and correlates with 1-year mortality.Ventricular arrhythmias causing out of hospital cardiac arrests have very low survival to discharge rates that are dependent on bystander recognition, adequate cardiopulmonary resuscitation, and early defibrillation.in vivo. However, our stimulation parameters produce physiological changes in heart rate and left ventricular developed pressure and increased NPY levels as observed in the STEMI population. Inducing ventricular arrhythmias through pacing protocols could also be considered unphysiological, and the same criticism can also be applied to clinical VT stimulation testing (e.g. using the Wellens protocol). Ventricular fibrillation threshold testing in animal models allows for paired measurements of susceptibility before and after complex multi-step experimental interventions and therefore remains useful. However, we were careful to also demonstrate the effects of NPY on reperfusion arrhythmias induced by experimental ST-elevation ischaemia reperfusion in the rat as proof of principle that our findings are applicable to arrhythmogenesis following PPCI for STEMI.Whilst constant frequency stimulation is used universally for experimental neural stimulation, this clearly does not reproduce spontaneous neuronal firing behaviour observed 1 receptor may offer a novel pharmacological strategy in patients with ventricular arrhythmias, working synergistically with beta-blockers, and other secondary prevention medications. There is the possibility of administering such drugs via an intracoronary route at the time of PPCI, given their potential to also improve microvascular resistance and reduce infarct size,Despite over half a century of research, the only primary prevention anti-arrhythmic drugs that reduce mortality following acute MI are beta-blockers. There is therefore an urgent need to identify new therapeutic targets and our data support the notion that blockers of the Y,It is also interesting to note that a variety of interventions aimed at reducing cardiac sympathetic drives such as cardiac sympathetic denervation, thoracic epidural anaesthesia, and renal denervationehz852_Supplementary_Table_1Click here for additional data file.


Myocardial iron overload in patients with thalassemia major (TM) is one of the most important complications. The purpose of the study was to identify advanced echocardiography parameters for early identification of myocardial dysfunction during follow-up of patients with TM.Forty TM patients who were 41 ± 5 years old were included in the study and divided into two groups according to cardiac magnetic resonance T2* results . Liver T2* parameters were also measured. Conventional and deformational echocardiographic parameters were measured at baseline and approximately 2 years later.p = 0.64), and liver T2* was 4 ± 5 and 17 ± 21 ms (p = 0.01) in Groups 1 and 2, respectively. At baseline, Group 1 had better left ventricular global longitudinal strain (GLS)  and similar left ventricular ejection fraction (LVEF)  than Group 2. At the 28 ± 11-month follow-up, LVEF, GLS, and T2* values in Group 1  and Group 2  did not change significantly compared to their corresponding baseline values. In 8 patients from Group 1, a worsening (> 15%) in LS (p = 0.001) was detected during follow-up, with a marginal reduction in LVEF.Thirty-two patients had Τ2* = 34 ± 4 ms (Group 1), and 8 had Τ2* = 17 ± 9 ms (Group 2). Blood consumption was 185 ± 60 and 199 ± 37 ml/kg/yr  in a minority of patients, underscoring the multifactorial etiology of cardiomyopathy. Thalassemia major (TM) is one of the most common inherited hemoglobin disorders. Ineffective erythropoiesis results in hemolytic anemia, and the patient is in need of lifelong transfusion therapy that ultimately leads to iron overload. Despite advances in the field of iron chelator therapies for TM, iron continues to accumulate in heart tissue, and subsequent cardiomyopathy remains the leading cause of death for these patients –3.The pathophysiology of the cardiomyopathy that develops in the modern era of iron chelator therapies is more complicated. Even though iron overload is still considered the leading cause of the occurrence of heart failure in patients with TM, the production of free radical oxygen, immunogenetic mechanisms and viral infections are being increasingly recognized , 4, 5.The complex etiopathogenetic milieu of thalassemia cardiomyopathy requires identifying the dysfunctional myocardium at an early stage to make the most of the early implementation of medical therapies. While cardiac magnetic resonance imaging (MRI) provides the ability to directly and noninvasively measure cardiac iron , 7, echoThe purpose of our study was to evaluate the changes in left ventricular global longitudinal strain and circumferential strain in patients with thalassemia major with and without myocardial iron overload.We retrospectively studied 70 consecutive patients diagnosed with TM who were receiving blood transfusions and chelation therapy. Patients were eligible for enrollment when they fulfilled all the following criteria: (a) cardiac MRI for T2* measurement at the beginning of the study and during the follow-up period and (b) echocardiographic study at the initiation of the study and during the follow-up period. Patients were included in the study if their initial LVEF was more than 50%, (c) their transthoracic echocardiographic images for the measurement of left ventricular longitudinal and circumferential strain were of adequate quality, and (d) they had undergone a follow-up period between 12 and 36 months.Patients with heart failure, valvulopathy, or history of myocardial infarction were not included in the study.Patients were studied in the left lateral decubitus position with a commercially available system  coupled with a 3.5 MHz (M3S) transducer. Analysis was performed offline.Cardiac MRI was performed no later than 1 month after the echocardiography study. Echocardiographic studies included complete 2D and Doppler examinations. Assessment of LVEF was performed using apical 4- and 2-chamber views. Doppler evaluation included the assessment of mitral inflow velocities. The mitral inflow parameters evaluated were early mitral inflow velocity (E-wave) and late or atrial mitral inflow velocity (a-wave). Peak right ventricular systolic myocardial velocity (RVSm) was obtained by placing the sample volume of tissue Doppler imaging at the lateral tricuspid valve annulus. All measurements were performed by following the current European Society of Echocardiography guidelines , 10.For both global longitudinal strain (GLS) and circumferential strain (CS) measurements, analysis was performed with dedicated software .Grayscale two-dimensional apical images of the LV  were obtained, and global longitudinal strain (GLS) analysis of the LV was performed by speckle-tracking imaging , 10. ThrAdditionally, we separately studied non-iron–overloaded TM patients who demonstrated a relative percentage of worsening in the GLS > 15% during the follow-up period. We considered the relative percentage reduction in GLS > 15% to be a clinically meaningful reduction, similar to the cases of oncology patients where the changes in GLS are used for the early identification of myocardial damage following the administration of agents with potential cardiotoxic properties .Circumferential strain (CS) of the mid-LV was calculated using the short-axis view at the level of the papillary muscles. Peak CS was defined as the average CS of all 6 segments (generated as previously described) in the short-axis view.Magnetic resonance imaging examinations were performed with a 1.5-T scanner . The scans included measurements of the liver T2* and myocardial T2* values. The T2* of the heart was assessed by a cardiac-gated single breath-hold multiecho technique ; flip angle, 20; slice thickness, 10 mm; matrix, 192 × 75; number of averages, 1; bandwidth in Hz/pixel, 810).t-test was used for intragroup comparisons of the echocardiography measurements at baseline and during follow-up. Independent-sample t-tests were used to compare baseline parameters of the TMio and Group 2 patients. For values with a nonnormal distribution, the Mann–Whitney U test was used. The χ2 test was used to compare the noncontinuous characteristics between the 2 groups. Spearman’s correlation coefficient was used to assess correlations of the measured parameters. The statistical software package SPSS for Windows was used for the analysis . A p-value < 0.05 was considered statistically significant.Values are reported as the mean ± SD. The paired Out of the 70 patients with TM disease who we identified in our database, 40 fulfilled the criteria for inclusion in our study Fig. . SeventeThe age of the patients was 41 ± 5 years, and 22 were males. Chelation therapy consisted of desferrioxamine (n = 7), defersirox (n = 14), deferiprone (n = 4), desferrioxamine + defersirox (n = 2), and desferrioxamine + deferiprone (n = 13)  , 13. In Analysis of strain parameters was performed by one experienced operator. Group 1 had similar LVEF to Group 2 patients. Additionally, Group 1 had significantly better GLS values than Group 2. No differences in CS values were observed between the two study groups (Table The mean follow-up of TM patients was 29 ± 11 months (range 12–36 months). Patient chelation therapy was adjusted by the attending physicians. There was no significant change in either conventional or deformational parameters during the follow-up period for either group of patients. Interestingly, during the follow-up period, we detected no significant changes in serum ferritin or T2* signals for either group of patients 2).Table There was a good correlation between LVEF and T2* and between LS and T2* values Table . There wThe main findings of the present study suggest that in patients with TM, left ventricular longitudinal strain (GLS) can detect LV subclinical dysfunction due to high cardiac iron load better than LVEF. There was a good correlation of cardiac T2* with both LVEF and GLS, both at baseline and follow-up. At the mid-period of follow-up, we detected no changes in conventional or deformational echocardiographic parameters in either iron– or non-iron–overloaded TM patients. Interestingly, during the follow-up period, we detected a relative worsening in the left ventricular longitudinal strain by more than 15%, with a concomitant marginal reduction in their corresponding LVEF, in eight patients in the non-iron—overloaded patient group.Two-dimensional and three-dimensional LVEF measurement using echocardiography is the standard method for evaluating systolic function in TM patients. Serial studies have identified that a reduction in LVEF ≥ 7% is a strong predictive factor for cardiac death in TM populations , 15. OncEarly impairment of other indices of left ventricular systolic function using tissue Doppler imaging, before any remarkable reduction in left ventricular ejection fraction, has already been reported , 19, 20.During the follow-up period, iron load status according to cardiac T2* did not change in either iron– or non-iron–overloaded patients; accordingly, we did not find significant changes in conventional or deformational echocardiographic parameters, while a statistically significant correlation between T2* signal and GLS remained. This suggests that left ventricular deformational analysis can detect early myocardial systolic dysfunction and could be a sensitive tool for serial follow-up measurements of cardiac function. The absence of improvement in deformational parameters and T2* values during follow-up in iron–overloaded patients could be attributed to the patient’s compliance issues with chelation therapies, and irreversible myocardial damage secondary to repeated exposure of the myocardium to toxic factors related to thalassemia major may also play a role.In our study, circumferential strain (CS) was also measured as an additional index of myocardial deformation, but we identified no correlation between CS and CMR T2* signals. Previous studies have shown that GLS is a more sensitive parameter than CS in identifying early impairment of LV function , 27.Impairment of left ventricular longitudinal strain has been identified as an early marker of left ventricular dysfunction in patients undergoing chemotherapy . In our The pathogenesis of systolic dysfunction in TM is complex. Apart from the toxic effect of iron load, there is a significant contribution of the immunoinflammatory and inherited components –31. ChroThe small number of patients in our study indicates that our results need validation with a larger group. Additionally, longer and less variable follow-up periods could potentially detect subtle differences in the deformational mechanics in patients with thalassemia major myocardial iron overload. The cutoff point value of a 15% reduction in GLS  is arbitrary in patients with TM, and more studies are needed to define its clinical significance. Finally, late enhancement studies with gadolinium are not performed routinely during CMR to search for myocardial fibrosis. These studies could further characterize the myocardium in TM patients.The present study suggests an important role of echocardiography in TM patients, identifying early left ventricular dysfunction with the use of longitudinal strain parameters. TM patients with high iron cardiac load had low left ventricular longitudinal deformation, although LVEF values were normal. For a midterm follow-up period, there was no significant change in myocardial deformational parameters parallel to the absence of T2* value changes in patients with TM. Additionally, in a small subgroup of patients without myocardial iron overload, a deterioration in left ventricular deformational parameters was observed before a striking decrease in LVEF. These findings emphasize the significant contribution of serial GLS measurements on top of MRI follow-up, aiming to identify those patients with myocardial dysfunction at early stages, prompting potential therapies.


The mammalian ventricular myocardium forms a functional syncytium due to flow of electrical current mediated in part by gap junctions localized within intercalated disks. The connexin (Cx) subunit of gap junctions have direct and indirect roles in conduction of electrical impulse from the cardiac pacemaker via the cardiac conduction system (CCS) to working myocytes. Cx43 is the dominant isoform in these channels. We have studied the distribution of Cx43 junctions between the CCS and working myocytes in a transgenic mouse model, which had the His-Purkinje portion of the CCS labeled with green fluorescence protein. The highest number of such connections was found in a region about one-third of ventricular length above the apex, and it correlated with the peak proportion of Purkinje fibers (PFs) to the ventricular myocardium. At this location, on the septal surface of the left ventricle, the insulated left bundle branch split into the uninsulated network of PFs that continued to the free wall anteriorly and posteriorly. The second peak of PF abundance was present in the ventricular apex. Epicardial activation maps correspondingly placed the site of the first activation in the apical region, while some hearts presented more highly located breakthrough sites. Taken together, these results increase our understanding of the physiological pattern of ventricular activation and its morphological underpinning through detailed CCS anatomy and distribution of its gap junctional coupling to the working myocardium. The mammalian ventricular myocardium consists of cardiac myocytes, which are thought to form a functional syncytium due to gap junctional channels (GJC). Each GJC is comprised of connexins (Cxs), which are, in general, important for metabolic and electric communication between the adjacent cells (reviewed in ). In theIn the mammalian atrial and ventricular myocardium, Cx43 represents the dominant isoform. Its conduction properties could by modified by post-translational modifications, mostly by de/phosphorylation ,9,10. ToIn contrast to working myocardium, the Purkinje myocytes in the terminal part of the CCS express Cx40, as well as Cx43 ,24. In aThe existence of Purkinje-working myocardium coupling is traditionally described only in homoiotherms, as no evidence for the Purkinje fibers (PFs) was found in the poikilotherms ,35. The Studying the activation sequence of the ventricular myocardium in three dimensions is a challenge. From the electrocardiogram it is deduced that the transmural activation proceeds from the endocardium (containing the PFs) to the epicardium. Epicardial optical mapping shows apex-to-base activation with the first activated regions located near ventricular apices ,40,41, cMany cartoons representing the CCS do not respect the true anatomy of the ventricular conduction fascicles. First, the bundle branches are flat and especially the left one resembles little a cable-like structure ,47; secoThe overarching goal of our research is to improve our understanding through providing data on detailed conduction system structure and function in the mouse heart, which closely resembles the human one from the point of CCS anatomy. This paper focuses on the most peripheral CCS component, the PFs, and their terminations in (or connection with) the working ventricular myocardium. To elucidate the anatomy and physiology of the CCS components, we applied a combined morphological  and functional  approach to study the nature and frequency of Purkinje-myocyte junctions and epicardial pattern of ventricular activation. In parallel, we studied the morphological maturation of the PFs in relation to the working cardiomyocytes . We hypothesized that the amount of PFs and their connections with the working left ventricular myocardium would reflect the typical observed apex-to-base activation of the left ventricle.Serial sectioning of the hearts at postnatal day 1 (P1) showed still extensive GFP-positive  trabecular network, which, while expressing also abundantly Cx43, did not show any Cx43 connections with the compact myocardium (data not shown). It was impossible to distinguish the future PFs from the rest of the myocardial trabeculae based solely upon GFP expression in these Cx40-GFP mouse hearts. Similarly, no such connections were detected at P10, but the GFP expression was now clearly restricted to the subendocardial Purkinje network . A totalTo quantify the amount of PFs by normalization to the amount of the working myocardium, transverse serial sectioning and visible staining were used . It showThe distribution of PFs around the ventricular perimeter was also non-random. From the apex, there were two major ascending pathways on the left ventricular free wall, one located dorsally and one ventrally, ascending along the papillary muscles . This peThe Purkinje network was, with the exception of the apical luminal region, flat against the ventricular endocardial surface and thus possible to image in 3D  when theTo evaluate functional consequences of the observed patterns of PFs connections to the working myocardium, epicardial optical mapping was performed on 10 normal mouse hearts aged 12–15 months . In the Cell shape analysis was performed in whole mount hearts at embryonic day (ED) 14 (end of septation), P10 and adult . In the adult, there was a further increase in volume in both groups, due to both cell thickening and elongation, resulting in a length to width ratio of 6.7 and 5.1, respectively.While at P10 the working myocytes showed a clear increase in transverse diameter , the widThe analysis of cell nuclear count showed that all the myocytes were strictly mononucleated at ED14, while at P10, some working, as well as a few of the Purkinje myocytes showed two nuclei. In the adult, however, while around 40% of the working myocytes had more than one nucleus, all 87 Purkinje myocytes analyzed in 3D contained a single nucleus .In agreement with previous studies , Cx43 orThe highest density of Cx43 connections between the PFs and working myocytes was observed at 20–30% of the distance between the left ventricular apex and the base. At this distance, on the septal surface of the left ventricle, the insulated left bundle branch splits into the network of (uninsulated) PFs . This poAt the macroscopic (whole ventricle) level, imaging using the 2× objective showed the general pattern of distribution with numerous, highly GFP-positive bundles in the apex and ascending strands along the anterior and posterior papillary muscles . This unWe found the highest number of connections between PFs and cardiomyocytes in the periapical region, where the left bundle branch splits to form the Purkinje network, with a second peak of PF number in the apex. Most of the adult mouse left ventricles were indeed activated from the apex, but there were some higher activation sites, reminiscent of the earlier developmental stages. The differentiating Purkinje myocytes started to show Cx43 connections with the working myocytes after postnatal day 10 and increased their volume chiefly by elongation starting by day 10. Interestingly, they remained in the adulthood, in contrast to their working counterparts, mononucleated.Our study of the connections is based on serial sections, possibly missing some of the connections that could be detected in whole mount . Our metIt would be interesting to provide direct measurements of transmural activation during spontaneous rhythm at different locations and compare those with the patterns from animals with developed intramural Purkinje network, such as sheep . This woFinally, recent data suggest a role for ephaptic conduction of activation in mammalian working ventricular myocardium . InteresCx40:GFP mouse hearts  in heterThe hearts from heterozygous animals killed by cervical dislocation at P10 and six months of age  were treated in the same fashion, except that the ventricles had to be microdissected into smaller pieces  to enable mounting . Three hn = 6) after their dissection, pinning and clearing using CUBIC [Whole mount confocal imaging without nuclear counterstaining  was perfng CUBIC   , and P30For validation purposes, additional hearts (three per stage) were cut at 10 microns in the transverse plane and every fourth section was stained for anti-GFP detected with diaminobenzidine for quantification of the ratio of PFs to working myocardium . Quantifn = 10, 12–15 months) using either 2× objective (NA 0.14) on an Olympus BX51 FS upright microscope (12 months), or a BrainVision macroscope (www.scimedia.com (1 March 2021)) with Leica objectives (15 months). The isolated hearts were perfused in a horizontal Langendorff chamber  and bolus-stained with di-4-ANEPPS (Invitrogen #D1199) as described [Optical mapping of left ventricular epicardial activation pattern was performed with the Ultima L CMOS camera on normal adult mouse hearts (escribed . Activatescribed  (Figure


Background: Biventricular longitudinal strain has been recently demonstrated to be predictive of poor outcomes in various cardiovascular settings. Therefore, this study sought to investigate the prognostic implications of biventricular longitudinal strain in patients with coronavirus disease 2019 (COVID-19).Methods: We enrolled 132 consecutive patients with COVID-19. Left ventricular global longitudinal strain from the apical four-chamber views (LV GLS4CH) and right ventricular free wall longitudinal strain (RV FWLS) were obtained using two-dimensional speckle-tracking echocardiography.Results: Compared with patients without cardiac injury, those with cardiac injury had higher levels of coagulopathy and inflammatory biomarkers, higher incidence of complications, more mechanical ventilation therapy, and higher mortality. Patients with cardiac injury displayed decreased LV GLS4CH and RV FWLS, elevated pulmonary artery systolic pressure, and higher proportion of pericardial effusion. Higher biomarkers levels of inflammation and cardiac injury, and the presence of pericardial effusion were correlated with decreases in LV GLS4CH and RV FWLS. During hospitalization, 19 patients died. Compared with survivors, LV GLS4CH and RV FWLS were impaired in non-survivors. At a 3-month follow-up after discharge, significant improvements were observed in LV GLS4CH and RV FWLS. Multivariate Cox analysis revealed that LV GLS4CH : 1.08 to 1.84; P = 0.011] and RV FWLS  were independent predictors of higher mortality in patients with COVID-19.Conclusions: LV GLS4CH and RV FWLS are independent and strong predictors of higher mortality in COVID-19 patients and can track improvement during the convalescent phase of their illness. Therefore, biventricular longitudinal strain may be crucial for risk stratification and serial follow-up in patients with COVID-19. Coronavirus disease 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic health crisis. Although, there is increasing awareness of the cardiovascular involvement in COVID-19 disease and its adverse impact on prognosis –5. FurthThis single-center, prospective study was performed at the west branch of Union Hospital, Huazhong University of Science and Technology, China, which was a designated hospital to treat patients with COVID-19. We enrolled 169 consecutive adult patients who were diagnosed with COVID-19 according to interim guidance of World Health Organization, from February 11 to March 16, 2020. Considering the presence of cardiac involvement in COVID-19 patients, bedside echocardiography was performed in all patients from three wards managed by the investigators for evaluation of cardiac function. The median time from admission to echocardiographic assessment was 7 days [interquartile range [IQR] 3–11]. Among these patients, three had dilated cardiomyopathy, four had old myocardial infarction, and 30 did not have images of sufficient quality for STE analysis. Finally, 132 patients were recruited in our analysis.This study was approved by Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Ethics Committee (KY-2020-02.06). Written informed consent was waived for all participants with emerging infectious diseases. Patients or the public were not involved in the design, conduct, reporting or dissemination plans of our research.Demographic characteristics, comorbidities, laboratory findings, medical history, complications, and outcomes for patients during hospitalization were independently reviewed by a team of trained physicians from electronic medical records. The timing of laboratory measurements were within 3 days of echocardiographic examinations with a mean interval of 1 days (IQR: 1–2). Acute cardiac injury was defined as serum levels of cardiac high-sensitivity troponin I (hs-TNI) above the 99th-percentile upper reference limit. The outcome was defined as in-hospital death. The final date of follow-up outcome were April 9, 2020.Bedside transthoracic echocardiographic examinations were performed using an EPIQ7C machine  at the designated COVID-19 isolation wards or intensive care units (ICU). Forty-six survivors underwent follow-up echocardiographic examinations at 3 months after discharge. All scans were conducted by trained individuals in full personal protective equipment. All echocardiographic images were stored in digital format and analyzed by two independent observers (C.M. and Y.Z.) who were blinded to epidemiological and clinical characteristics, laboratory findings, treatment, and outcomes.Left ventricular (LV) and right ventricular (RV) structural and functional parameters were measured based on the guidelines of the American Society of Echocardiography . LV massTricuspid annular plane systolic excursion (TAPSE) was measured on M-mode echocardiography. RV fractional area change (RVFAC) was calculate as (RV end-diastolic area -RV end-systolic area)/end-diastolic area × 100%. Tricuspid lateral annular systolic velocity (S′) was assessed by tissue Doppler imaging from the apical 4-chamber view. Pulmonary artery systolic pressure (PASP) was evaluated using the simplified Bernoulli equation and right atrial pressure assessed on the basis of the size and collapsibility of the inferior vena cava.4CH was defined as the mean of the strain values in the six segments of left ventricle from the apical 4-chamber view. LV GLS and GLS4CH were obtained from the standard two-dimensional gray-scale image with a frame rate of 50~70 frames/s. The LV endocardial border was automatically traced at end diastole. Subsequently, the software tracked the endocardial layer throughout the cardiac cycle. The operator could manually adjust the endocardial border if necessary. Right ventricular free wall longitudinal strain (RV FWLS) was obtained from the standard two-dimensional gray-scale image of the RV-focused apical four-chamber view with a frame rate of 50~70 frames/s. The RV endocardial border was automatically traced at end diastole. The software tracked automatically the endocardial layer throughout the cardiac cycle and the observer may manually adjust the endocardial border if necessary. RV FWLS was calculated as the average of the basal, mid and apical RV free wall segments. Left atrial (LA) endocardial contours were drawn in the apical 4-chamber view with a frame rate of 50~70 frames/s at end systole. The appendage and pulmonary veins were not included. The endocardial border was automatically tracked by software throughout the cardiac cycle. Manual adjustments were performed when tracking was suboptimal. Peak left atrial strain (LAS-peak) was automatically generated from the software. Patients with two or more inadequately tracked segments were removed from analysis. Representative images with LV GLS4CH, RV FWLS and LAS-peak are shown in 4CH and RV FWLS were presented in this study for a simpler interpretation, as LV GLS, GLS4CH and RV FWLS were negative values.STE analyses were performed using commercially available AutoStrain software . LV global longitudinal strain (GLS) was calculated by averaging the values obtained in the apical 4-chamber, 3-chamber and 2-chamber views. LV GLS4CH, RV FWLS and LAS-peak were estimated in 20 randomly selected subjects and evaluated by intra-class correlation coefficient (ICC) and Bland-Altman analysis. Intraobserver variability was evaluated by having one observer remeasure after 4 weeks. Interobserver variability was assessed by a second observer who was blinded to the first observer's measurements.Intraobserver and interobserver variability of LV GLSt-test and one-way analysis of variance for normally distributed data, or Mann-Whitney test and Kruskal-Wallis test for non-normally distributed data. Categorical variables were expressed as frequency (percentage), and compared using the χ2 test or Fisher's exact test. Spearman's correlation coefficient were used to evaluate the association between biventricular strain and laboratory findings. Univariate and multivariate Cox regression models were used to assess the predictors of higher mortality. All potential predictors of higher mortality were included into univariate analyses: age, gender, comorbidities, complications, laboratory findings and echocardiographic parameters. Variables with P < 0.05 at univariate analysis were entered into multivariate Cox regression models. Owing to smaller patients with endpoints, there may exist an over-fitting issue. Therefore, to avoid problems of overfitting the data, a separate Cox proportional hazard model including clinical variables and each of biventricular function parameters , was used to determine the independent predictors of higher mortality. The model performance was assessed by Akaike Information Criterion (AIC). Receiver operator characteristic (ROC) curves were used to determine the optimal cutoff value of LA, LV and RV function parameters for detecting poor outcomes. Kaplan-Meier survival curves were plotted and compared using the log-rank test. All statistical analyses were performed using a SPSS version 20.0 , and a two-sided value of P < 0.05 was considered as statistically significant.Continuous numeric variables were expressed as mean ± SD or medians (IQR) and compared using a two-sample Student's Clinical characteristics of patients with COVID-19 are presented in 4CH measurements were obtained in all patients. LV GLS measurements were feasible in 99 patients. LV GLS4CH was strongly correlated with LV GLS . Furthermore, No significant difference between LV GLS4CH and LV GLS was observed in our study  , whereas LAS-peak did not differ between patients with ARDS and without .LV GLS= 0.885) . Therefo4CH, RV FWLS, and TAPSE, elevated PASP, higher proportion of moderate-severe TR, and higher mortality compared with moderate and severe groups. There was no significant difference in LVEF, LAS-peak, RVFAC and S′ among the moderate, severe, and critical groups  patients were in oxygen therapy. 72 (55.0%) patients were treated with high-flow oxygen. Compared with patients who did not require mechanical ventilation, those who required mechanical ventilation had impaired LV GLSo groups .4CH, higher proportion of moderate–severe MR and TR, and higher PASP. In contrast, left heart chamber dimension, LAS-peak, LV wall thickness, mass and diastolic function, and LVEF were similar between survivors and non-survivors .Forty-six survivors were followed up at 3 months after discharge . We obseLAS-peak , and a d4CH weakly correlated with decreased lymphocyte count , and elevated levels of CRP , PCT , IL-6 , CK-MB , hs-TNI , D-dimer  and APTT  (P = 0.001), PCT , CK-MB , hs-TNI , APTT , and PT  . In contrast, LAS-peak and LVEF had no significant correlation with biomarkers levels of inflammation, coagulopathy, and cardiac injury .A decrease in LV GLS= 0.003) . A reduc= 0.001) . Additio4CH, RV FWLS, TAPSE, and RVFAC were associated with higher risk of mortality , TAPSE , and RVFAC  were independent predictive of higher risk of death. The Cox models using LV GLS4CH (AIC = 131) or RV FWLS (AIC = 122) were observed to predict higher mortality more accurately than that with TAPSE (AIC = 134), RVFAC (AIC = 134) or traditional risk model (AIC = 138)  .4CH, RV FWLS, conventional RV function parameters and LVEF were entered into ROC analysis to estimate probability of in-hospital death. Impaired LV GLS4CH and RV FWLS were associated with higher mortality .LAS-peak, LV GLSortality . Areas u4CH lower than 17.9 % or RV FWLS lower than 22.9% were associated with higher mortality (P < 0.001)  . Patient RV FWLS . To detef hs-TNI .4CH, RV FWLS and LAS-peak are summarized in 4CH, RV FWLS, and LAS-peak were high.The intraobserver and interobserver reproducibility of LV GLS4CH and RV FWLS than those without cardiac injury. Compared with survivors, non-survivors displayed reduced biventricular longitudinal strain, and comparable LVEF. At a 3-month follow-up after discharge, we identify that biventricular longitudinal strain can track clinical improvement in the convalescent phase. Importantly, LV GLS4CH and RV FWLS are powerful predictors of higher mortality in patients with COVID-19. Therefore, biventricular longitudinal strain may be essential for risk stratification and serial follow-up in patients with COVID-19.To the best of our knowledge, our study is the first to systematically assess cardiac structure and function in COVID-19 patients using both conventional echocardiography and 2D-STE. This study demonstrates that patients with cardiac injury had higher levels of coagulopathy and inflammatory biomarkers, higher incidence of complications, more treatment with mechanical ventilation, higher mortality, and lower LV GLSSARS-CoV-2 are known to result in the acute and chronic damage of the cardiovascular system , 12. Alt4CH in patients with COVID-19. In the present study, we identified that COVID-19 patients exhibited significantly impaired LV GLS4CH and RV FWLS, while no difference was found in LVEF. Moreover, impaired biventricular longitudinal strain appeared to be worse in critically ill patients or those who required mechanical ventilation therapy. These findings are in agreement with the study of SARS, which revealed that the diminished LV performance was worse in patients who needed treatment with mechanical ventilation (4CH and RV FWLS with elevated biomarkers levels of inflammation, coagulopathy, and cardiac injury were observed in our study. Besides, we found that patients with cardiac injury displayed higher proportion of pericardial effusion than those without cardiac injury. Moreover, decreased LV GLS4CH and RV FWLS were also correlated with the presence of pericardial effusion, suggesting that the presence of pericardial effusion or pericarditis have a major influence on the biventricualr strain values.Despite the importance and extensive use of LVEF in routine clinical practice, there are several limitations of its application. First, it depends on geometric assumptions and loading conditions. Moreover, it could not reflect myocardial contractility . Finallytilation . Recentltilation –24. The tilation . Consist4CH and RV FWLS are important in COVID-19 patients, as owing to overlapping symptoms of dyspnea, the diagnosis of myocardial involvement may be challenging. These findings are also particularly significant to the majority of COVID-19 patients with a normal LVEF.In addition to myocardial injury, RV function was predisposed to impairment owing to increased RV afterload from ARDS, hypoxic pulmonary vasoconstriction, pulmonary microthrombi, and endothelial and microvascular injury . RV dilaAt 3-month follow-up after discharge, significant improvements in biventricular longitudinal strain were identified in our study, indicating that depressed LV and RV performance may be reversible on disease recovery when the acute inflammatory response waned. Consistent with our results, Li et al. showed that impaired LV function appeared to be reversible at 30-day follow-up study in 46 patients with SARS . In anot4CH and RV FWLS were at higher risk of death. Our findings reveal that biventricular longitudinal strain serve as novel imaging biomarkers that predicts higher mortality in patients with COVID-19. Consistent with these results, our study previously revealed that RV FWLS was an independent predictor of poor outcomes in COVID-19 patients (To the best of our knowledge, this may be the first study to investigate whether biventricular longitudinal strain were associated with fatal outcomes in COVID-19 patients. Indeed, in the present study, patients with diminished LV GLSpatients . Similarpatients  Another patients , which d4CH in COVID-19 patients remained unknown. Our findings showed that LV GLS4CH was predictive of higher mortality in COVID-19 patients, whereas LVEF was not. This is in contradistinction to a recent study in patients with COVID-19 in Israel, which reported that lower LVEF was associated with mortality (4CH and RV FWLS are not only more sensitive markers of subclinical myocardial impairment, but also powerful and independent predictors of higher mortality. Therefore, biventricular longitudinal strain could help risk stratification of COVID-19 patients.In addition, LV GLS has presented additional prognostic significance over LVEF in a range of cardiovascular disorders , 29. Howortality . Howeverortality , patient4CH and RV FWLS, rather than LVEF, were strong predictors of higher risk of mortality. Furthermore, biventricular longitudinal strain can provide highly useful and clinically relevant information during the follow-up in patients with COVID-19. The present study revealed the important clinical implication of biventricular longitudinal strain, as measurements of LV GLS4CH and RV FWLS are fast and non-invasive methods that can be easily obtained from bedside echocardiography. More importantly, they can identify subclinical myocardial impairment, help detect in higher risk of COVID-19 patients and serially follow patients.LVEF is a key determinant in clinical decision-making in various diseases. However, it is relatively indiscriminant within the normal range. Novel biventricular longitudinal strain may be of particular clinical significance in COVID-19 patients with relatively normal LVEF. Our data showed LV GLS4CH rather than the LV GLS to estimate LV myocardial longitudinal function during the epidemic of COVID-19 to allow rapid image acquisition and reduce contagion exposure duration to healthcare worker. Another limitation was that only a small proportion of COVID-19 patients had follow-up echocardiographic data, though improvement in biventricular longitudinal strain was noted. Finally, the study was a single-center study with a relatively limited sample size. Therefore, further large multi-center studies are needed to confirm the results in the present study.Our study has several limitations that should be mentioned. First, as 2D-STE depends on image quality, severe and critically ill patients with inadequate echocardiographic images might have been underrepresented. Furthermore, 2D-STE analysis was performed using Qlab software in our study, so the results in the present study may not be apply to other software algorithms because 2D-STE parameters are hampered by inter-vendor variability. Although our study exclude dilated cardiomyopathy and old myocardial infarction that may significant lead to impaired biventricular longitudinal strain, patients had hypertension or coronary artery diseases, who had underlying medical condition that could have affected strain values. In addition, our study used the LV GLS4CH and RV FWLS are independently predicative of higher mortality, providing incremental prognostic implications over conventional echocardiographic parameters in patients with COVID-19. We also identify that biventricular longitudinal strain provide highly relevant information regarding the recovery of cardiac function when the acute inflammatory response subsided. Therefore, biventricular longitudinal strain are valuable non-invasive parameters in risk stratification and serial follow-up of patients with COVID-19.Our study demonstrates that LV GLSThe original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by Medical Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Left atrial (LA) volume (LAV) is one of the recommended key variables for evaluating left ventricular (LV) diastolic function. However, only LA anteroposterior diameter (LAAP) is available in numerous large-scale existing databases. Therefore, this study aimed to validate whether LV diastolic function could be evaluated with estimated LAV from LAAP.F-value were chosen in the first 276 subjects (derivation set), and concordance for evaluating LV diastolic function between using estimated and observed LAVI was verified in the remaining 276 subjects .A total of 552 inpatients with sinus rhythm were consecutively enrolled. LAV was measured by biplane Simpson’s disk summation method. LV diastolic function was evaluated according to the 2016 proposed recommendations. Best-fitting regression models of LAAP index (LAAPI)–LAV index (LAVI) were developed and equations with the highest F-value in all subjects and in the subjects with normal or depressed LV ejection fraction. In the validation set, using the linear equation (LAVI = 2.05 × LAAPI − 13.86), the higher area under curve and narrower range of difference were shown between estimated LAVI and observed LAVI, respectively. Further, concordance for diagnosis  and grading  of LV diastolic dysfunction was substantial between using estimated and observed LAVI.In the derivation set, the linear model has the highest LV diastolic function can be evaluated with estimated LAVI from LAAPI, which might provide a surrogate method when the direct measurement of LAV is not available. Left ventricular (LV) diastolic dysfunction (DD) is associated with an increase in all-cause mortality in the general population, even in the preclinical stage . The preRecently, the proposed recommendations by the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) in 2016 integrated two-dimensional echocardiographic and Doppler echocardiographic parameters and provided a practical and reliable algorithm for diagnosing and grading LVDD irrespective of LVEF . Among tAlthough the LAV measured using the biplane disk summation algorithm is more accurate and recommended to describe LA size in routine clinical practice and research , 11, LA In view of the foregoing considerations, we conducted this study to develop the best-fitting regression models and seek the optimum equations for estimating LAVI from LAAPI, and validate whether LVDF could be evaluated with estimated LAVI, which might provide a surrogate method to evaluate LVDF when the direct measurement of LAV is not available or the LAV values are highly variable.We prospectively and consecutively enrolled the inpatients in sinus rhythm from the Cardiology Department of our hospital from January 2019 to October 2019.In accordance with the 2016 recommendations for the evaluation of LVDF from the ASE and EACVI , patientA total of 552 subjects  met the eligibility criteria during the study period. These subjects were randomly divided into two groups: (1) derivation set , in which best-fitting regression models and equations of LAVI–LAAPI were developed; and (2) validation set , in which concordance for evaluating LVDF between using estimated and observed LAVI was verified.Written informed consent was obtained from all patients before enrollment. The study protocol was approved by the China Medical University Ethics Committee and was conducted in line with the ethical guidelines of the 1975 Declaration of Helsinki.All subjects were examined at rest using a Vivid E9 ultrasound system  equipped with M5S phased-array probe. Standard two-dimensional cine loops, including at least 3 consecutive cardiac cycles, and Doppler spectrum during normal respiration (< 20 breaths/min) were recorded for offline analysis using an EchoPAC workstation . Both image acquisition and quantitative analysis were performed according to the recommendations of transthoracic echocardiographic examination and cardiac chamber quantification from ASE by two experienced cardiologists who were blinded to any clinical data , 16.LVEF was measured using the biplane Simpson’s disk summation method from both the apical two- and four-chamber views during LV end-diastole. LVEF < 52% in males or < 54% in females was considered depressed . LAAP wa2, TR velocity > 2.8 m/s). Patients were diagnosed with normal DF if none or only one variable met the cutoff values, DD if more than two of the variables met the cutoff values, and indeterminate if just two variables met the cutoff values. In patients with normal LVEF and myocardial disease or DD, and in those with depressed LVEF, grade I DD was diagnosed if E/A ratio ≤ 0.8 and E ≤ 50 cm/s and grade III DD if E/A ratio ≥ 2. If E/A ≤ 0.8 and E > 50 cm/s, or 0.8 < E/A < 2, additional variables are needed . Grade I DD was diagnosed if only one of the variables met the cutoff values, and grade II DD if more than two of the variables met the cutoff values. However, if only one variable is available, or only two variables are available but discrepant, LV diastolic dysfunction grade could not be determined.The diagnosis and grading of LVDD was performed according to 2016 ASE/EACVI recommendations . For patInter- and intra-observer agreement of LAAP and LAV measurements were examined in 10 randomly selected patients. To assess intra-observer variability, the same doctor repeated the measurements after > 4 weeks. In addition, to assess inter-observer variability, the two doctors independently repeated the measurements twice.F-values, which express the statistical significance of the different models, of these models were compared. The regression equations with the highest F-values were chosen to calculate the estimated LAVI in the validation set. The comparison between the observed LAVI with estimated LAVI by each equation was performed by paired samples t-test or Wilcoxon test, where appropriate. The variability of estimated and observed LAVI was assessed by calculating the intra-class correlation coefficient and 95% confidence interval (CI) using a two-way random-effects model. Receiver operating characteristic (ROC) curve analysis and area under curve (AUC) were used to evaluate the performance for identifying observed LAVI > 34 mL/m2. Bland–Altman analyses were used for assessing the bias and limits of agreement (LOA) between the observed and estimated LAVI, and estimating the inter-observer and intra-observer reproducibility of LAAP and LAV. The concordance for evaluating LV diastolic function between using estimated and observed LAVI were tested by calculating the κ coefficient and the overall proportion of agreement . The calculated κ coefficient was judged as follows: 0 ≤ κ < 0.2 slight; 0.2 ≤ κ < 0.4 fair; 0.4 ≤ κ < 0.6 moderate; 0.6 ≤ κ < 0.8 substantial, and 0.8 ≤ κ < 1 perfect , and the concordance between LAAPI > 23 mm/m2 with LAVI > 34 mL/m2 .Before estimating LAVI, we first analyzed the identifying performance of LAAPI for LAVI > 34 mL/m2] and estimated LAVI by the first equation [30.79 (26.88–35.42) mL/m2] and the second equation [29.98 (27.23–33.98) mL/m2]  mL/m2, and concordance between estimated and observed LAVI > 34 mL/m2, respectively. The estimated LAVI using the first equation showed the similar intra-class correlations coefficient  and overall proportion of agreement (78.98%) with observed LAVI, but the slightly higher AUC  for identifying observed LAVI > 34 mL/m2. In Bland–Altman analysis, the estimated LAVI using the first equation showed the slightly narrower range of difference compared with observed LAVI  and grading  of LVDD was substantial between using estimated and observed LAVI , and 0.6 mL , respectively. The intra-observer reproducibility for LAAP and LAV had a bias of − 0.1 mm , and 0.6 mL , respectively.In the present study, we developed the best-fitting regression models for estimating LAVI from LAAPI and established the optimum linear regression equations in the subjects with normal LVEF and depressed LVEF in the derivation set, respectively. We also validated that LVDF could be evaluated with estimated LAVI from LAAPI in the validation set when the direct measurement of LAV is not available or the LAV values are highly variable.Normal LVDF plays a significant role in ensuring normal LV filling and adequate cardiac output. LVDD has been recognized to be associated with incident heart failure and resultant poor outcomes , 19, andLA size is one of the recommended indispensable elements for evaluating LVDF by echocardiography as per recommendations from ASE and EACVI because it can reflect the chronicity and severity of LVDD . To desc2 could be directly substituted as a variable for LAVI > 34 mL/m2 to assess LV DF when directly measured LAV is not available. However, our study revealed that the concordance between LAAPI > 23 mm/m2 with LAVI > 34 mL/m2 were lower than the estimated LAVI obtained by the proposed regression equation in our study. Therefore, our results indicated that this optimistic idea was not recommended when directly measured LAV is unavailable.Maybe, it was an optimistic thinking that LAAPI > 23 mm/mRecently, Canciello et al.  developeThe major limitation of our study was related to the exclusion of the patients with several specific cardiovascular diseases, such as atrial fibrillation, mitral valve dysfunction, left bundle branch block, hypertrophic cardiomyopathy, and so on, in which the evaluation of LVDF required the determination of additional specific parameters according to the 2016 recommendations . This maAnother study limitation was the relatively low percentage of patients with depressed LVEF and limited range of LAVI, which was mainly attributable to the unselected and consecutively recruited population for reducing selection bias in the present study, and a multicenter study with a larger number of patients with depressed LVEF and a wide range of LAVI should be designed to verify the findings.LVDF can be evaluated with estimated LAVI from LAAPI, which might provide a surrogate method when the direct measurement of LAV is not available or the LAV values are highly variable. It is necessary to verify these results in future practice.


The first line of treatment for most cervical intradural tumors is surgical resection through laminotomy or laminectomy. This may cause a loss of posterior pulling force leading to kyphosis, which is associated with decreased functional outcome. However, the incidence and predictors of kyphosis in these patients are poorly understood.To assess the incidence of posterior fixation (PF), as well as predictors of radiological kyphosis, following resection of cervical intradural tumors in adults.A population-based cohort study was conducted on adult patients who underwent intradural tumor resection via cervical laminectomy with or without laminoplasty between 2005 and 2017. Primary outcome was kyphosis requiring PF. Secondary outcome was radiological kyphotic increase, measured by the change in the C2–C7 Cobb angle between pre- and postoperative magnetic resonance images.Eighty-four patients were included. Twenty-four percent of the tumors were intramedullary, and the most common diagnosis was meningioma. The mean laminectomy range was 2.4 levels, and laminoplasty was performed in 40% of cases. No prophylactic PF was performed. During a mean follow-up of 4.4 years, two patients (2.4%) required delayed PF. The mean radiological kyphotic increase after surgery was 3.0°, which was significantly associated with laminectomy of C2 and C3. Of these, C3 laminectomy demonstrated independent risk association.There was a low incidence of delayed PF following cervical intradural tumor resection, supporting the practice of not performing prophylactic PF. Kyphotic increase was associated with C2 and C3 laminectomy, which could help identify at-risk patients were targeted follow-up is indicated.The online version of this article (10.1007/s00701-020-04416-4) contains supplementary material, which is available to authorized users. Spinal intradural tumors are benign or malignant growths that arise in or around the spinal cord. They account for 2–4% of all primary central nervous system tumors  and can The aim of this study was to assess the incidence and predictors of long-term kyphosis following resection of cervical intradural tumors, evaluating the need for delayed posterior fixation surgery and describing situations where prophylactic stabilization may be indicated.All adult patients (≥ 15 years) who underwent cervical laminectomy (where lamina was removed and not reinstated) or laminectomy with laminoplasty (where lamina was removed but reinstated using microplates and screws) and intradural tumor resection between 2005 and 2017 were eligible for inclusion. Exclusion criteria were previous cervical laminectomy and simultaneous laminectomy of the thoracic spine; the latter was to avoid potential confounding effects of laminectomy at the cervicothoracic junction in accordance with previous literature . The stuThe operations were performed by either of three senior consultant neurosurgeons as the primary attending. With the patient in prone position, a posterior midline approach was performed. Laminectomy was then conducted using an ultrasonic bone scalpel (from 2012 to 2017)  or a high-speed diamond bit drill and Kerrison rongeur (between 2005 and 2011). Under the microscope, the dura was incised, and the arachnoid was dissected sharply, allowing exposure of the tumor. For extramedullary tumors, the cranial and caudal poles were identified, and the tumor was dissected from surrounding structures. For intramedullary tumors, a midline myelotomy was performed using a diamond knife, and the tumor was then dissected sharply or removed using an ultrasonic aspirator . When visual gross total resection was achieved, the myelotomy was closed and sutured [Calculation of cervical lordosis and kyphotic increase was performed on midline sagittal views of supine magnetic resonance images (MRI) using PACS . Cervical lordosis was measured with the C2–C7 Cobb angle , which mp < 0.1) were then entered into a step-down multivariable linear regression analysis to determine independent risk factors. In the step-down model, the least significant variable was sequentially eliminated until only significant variables remained. Listwise deletion was used to handle missing data. The statistical significance level was set to p < 0.05. All statistical analyses were conducted using SPSS .For descriptive purposes, continuous data are presented as mean (standard deviation), and categorical data, as numbers (proportion). Shapiro-Wilk test was used to test for normality of distribution. Two statistical models were used. First, McNemar’s test (dichotomized data) and Wilcoxon signed-rank test (continuous data) were used to test for consistent differences between pre- and postoperative functional status. Secondly, a univariate linear regression was conducted to assess predictors of radiological kyphotic increase. For this, delta-cobb was used as the continuous dependent variable where an increase correlated to a larger degree of kyphotic increase. Factors that showed a trend toward significance in the univariate analysis  and sensory deficit . Six patients (7%) had neurofibromatosis  of the patients were male, and the mean age was 52 years. The mean preoperative C2–C7 Cobb angle was 14 ± 15° lordosis. The mean preoperative modified McCormick scale was 1.8 ± 0.7, and the most common symptoms were pain , followed by schwannoma  and ependymoma   were dumbbell shaped. Twenty (24%) of the tumors were intramedullary. The mean laminectomy range was 2.4 ± 1.0 levels. Laminoplasty was performed in 34 cases (40%), and facet joint resection, in 5 (6.0%). Prophylactic posterior fixation was not performed in any patient  underwent delayed posterior fixation due to kyphosis. Tumor growth or recurrence occurred in eight 10%) patients, of whom two underwent renewed tumor resection (both schwannomas) and one received adjuvant radiotherapy  (Table 0% patienp = 0.003), motor deficit (p < 0.001), and pain (p < 0.001)  was 3.0 ± 12°  and laminectomy of C3  were identified as significant risk factors (Table p = 0.004). Laminectomy, as opposed to laminoplasty, was not significantly associated with an increased risk for postoperative kyphosis  of 65°  of 3.0° and that 56% of patients showed some form of kyphotic increase (delta-cobb > 0°). Generally, we found that our cohort showed a normal distribution around zero with a few outliers where there was a large kyphotic increase Fig. . We belin = 15) of C2 laminectomies were combined with a C3 laminectomy. Furthermore, while the spinous process and muscle attachments of C3 in itself are usually small, surgical access to the C3 lamina often requires detaching at least the inferior parts of the muscle insertions on C2. Several studies have emphasized the importance of the extensor muscle force on sagittal balance and that their detachment from C2 causes instability [While both C2 and C3 were identified as predictors of postoperative kyphosis in the univariate analysis, C3 was the only one that showed independent risk association in our multivariable analysis. A possible explanation for this may be a bias where C2 laminectomy is avoided if not centered over the tumor and therefore essential to the surgery. In these cases, the adjacent C3 lamina will most often also be removed resulting in a material with very few cases of C2 laminectomy without C3. In our cohort with 25 C2 laminectomies, only 1 was an isolated C2 laminectomy, and 9 were C1–C2 laminectomies. Thus, the remaining 60%  for intramedullary tumors was 4.4° as compared to 2.6° for the remaining tumors. Moreover, intramedullary tumors underwent a mean laminectomy range of 3.2 levels as compared to 2.2 levels in the remaining cohort. Thus, it is possible that the regression analysis was underpowered to show a statistically significant difference between intra- and extramedullary tumors.We did not find that laminoplasty decreased the risk for kyphosis. While there may be a theorized decreased risk for iatrogenic deformity, the literature has yet to establish conclusive efficacy of laminoplasty over laminectomy in preventing spinal deformity following intradural tumor resection as well as degenerative spinal disorders , 18, 24.There is no golden standard for measuring cervical sagittal malalignment. We, and many others , used thThe need for delayed posterior fixation in patients who underwent cervical intradural tumor resection was low, supporting the practice of not performing prophylactic posterior fixation. We found that kyphotic increase was associated with C2 and C3 laminectomy, which could help identify a subset of at-risk patients were targeted radiological and clinical follow-up is indicated.ESM 1(DOCX 33 kb)