Vascular endothelial cell alignment in the direction of flow is an adaptive response that protects against aortic diseases such as atherosclerosis. The RhoGTPases are known to regulate this alignment. We have shown previously that ARHGAP18 in endothelial cells is a negative regulator of RhoC and its expression is essential in flow-mediated alignment. Depletion of ARHGAP18 inhibits alignment and results in the induction of a pro-inflammatory phenotype. In embryogenesis, ARHGAP18 was identified as a downstream effector of the Yes-associated protein, YAP, which regulates cell shape and size.We have used siRNA technology to deplete either ARHGAP18 or YAP in human endothelial cells. The in vitro studies were performed under athero-protective, laminar flow conditions. The analysis of YAP activity was also investigated, using high performance confocal imaging, in our ARHGAP18 knockout mutant mice.We show here that loss of ARHGAP18, although decreasing the expression of YAP results in its nuclear localisation consistent with activation. We further show that depletion of YAP itself results in its activation as defined by an in increase in its nuclear localisation and an increase in the YAP target gene, CyR61. Depletion of YAP, similar to that observed for ARHGAP18 depletion, results in loss of endothelial cell alignment under high shear stress mediated flow and also in the activation of NFkB, as determined by p65 nuclear localisation. In contrast, ARHGAP18 overexpression results in upregulation of YAP, its phosphorylation, and a decrease in the YAP target gene Cyr61, consistent with YAP inactivation. Finally, in ARHGAP18 deleted mice, in regions where there is a loss of endothelial cell alignment, a situation associated with a priming of the cells to a pro-inflammatory phenotype, YAP shows nuclear localisation.Our results show that YAP is downstream of ARHGAP18 in mature endothelial cells and that this pathway is involved in the athero-protective alignment of endothelial cells under laminar shear stress. ARHGAP18 depletion leads to a disruption of the junctions as seen by loss of VE-Cadherin localisation to these regions and a concomitant localisation of YAP to the nucleus. The alignment of endothelial cells  in the dSENEX) promotes ECs senescence and the senescence is unique in showing a predominantly anti-inflammatory phenotype [The activity of the GTPases are regulated by three mediators, guanine nucleotide exchange factors  which achenotype , 10 medihenotype , 11. In henotype . TherefoThe Yes-associated protein (YAP), a transcriptional coactivator of the HIPPO family, is a mechanotransduction protein that controls proliferation, cell shape and organ size –15. Rece2 incubator according to the established method [2) or oscillating/disturbed (2dyne/cm2/1 Hz) flow.Human umbilical vein endothelial cells (HUVEC) were isolated and maintained in 5% COd method . HUVEC wMeasurement of active RhoA and RhoC levels was determined using the GLISA assays (Cytoskeleton) as previously described . BrieflyFor immunofluorescence staining of IBIDI slides or EZ cell (Merck), slides were fixed for 15 min with 4% paraformaldehyde, permeabilised for 10 min with 0.1%Triton X-100 in PBS followed by 2 h blocking with 2% BSA before probing with various antibodies. Primary antibodies and concentrations used were: Mouse Monoclonal anti-ARHGAP18 , Rhodamine Phalloidin , Rabbit Monoclonal anti-NF-κB p65 , Rat Polyclonal anti-VE-cadherin  and Rabbit Monoclonal anti- YAP .Eight to 10 weeks old male mice were euthanized and pressure perfused with saline through the left ventricle followed by perfusion with 5 ml of chilled 4% paraformaldehyde  solutionTotal YAP expression and nuclear localization in the aortic laminar region were examined using confocal microscopy (Leica SP5 model x) and magnification of 630x. A total of 6 fields of view were taken for each mouse per group and analysed using the ImageJ software (version 1.49 m). For the analysis, each z-stacked image was split into 3 channels of VE-Cadherin, YAP and DAPI. As total YAP was reduced in the KO mice, the threshold values for YAP in the WT and ARHGAP18 KO were set to a range of 34 to 40 with dark background. The image calculator with the function “multiply” between DAPI and YAP channels from each field of view was used to isolate nuclear areas that were YAP positive. Total number of endothelial cells per view was calculated using VE-Cadherin expression as reference. The percentage of nuclear positive YAP cells per field was calculated using number of nuclear YAP/total EC number.For ARHGAP18 knockdown, HUVECs were transfected with either stealth siRNA control (low GC content), 5 nM) or two stealth siRNAs  using Lipofectamine RNAiMAX (Life Technologies) as previously described . ReagentTotal cell lysates were prepared from HUVECs exposed to various experimental conditions. Equal amount of total proteins (8 μg) were loaded and separated on 4–12% NuPAGE gradient gel (Life Technologies), transferred to PVDF membrane and detect with Enhanced Chemiluminescence substrate (Pierce) as per the manufacturer’s instructions. Primary antibodies for YAP , YAP-PhosphoSer127 , VCAM1 , eNOS , Rabbit anti-CYR61  and ARHGAP18 clone 2A3-F3 (in-house), were used at 1:500–1000 and Actin-HRP (Abcam) was used at 1:10,000 dilution in PBS/Tween20 containing 1% BSA.t-test was used in some instances to compare means. Mean differences with p value of < 0.05 was considered statistically significance.All calculated values represent means ± SD. Statistical significances was determined by two way ANOVA with poshoc analysis or Unpaired two tailed Student In embryonic development ARHGAP18 has been shown to be a downstream effector of YAP . TherefoWe have recently shown that ARHGAP18 is essential for EC alignment under high shear stress laminar flow  and giveThe lack of alignment under high shear stress laminar flow in both ARHGAP18 and YAP-depleted ECs is similar to that described for EC in disturbed flow . FurtherDepletion of YAP itself also resulted in its activation. YAP depletion with siRNA, resulted in the loss of total YAP particularly evident from the cytoplasmic portion. However, nuclear YAP was evident at least in some cells, suggesting activation Fig. a. This wARHGAP18 shows both GAP dependent and GAP independent functions , 29. TheWe have previously shown that ARHGAP18 has activity against RhoC in ECs and that depletion of RhoC rescues the effect of ARHGAP18 knockdown on junctional disruption [−/− mice. The EC layer was identified by the expression of VE-cadherin, and imaging for YAP was performed on this same plane  [Cell alignment in the direction of flow is a major protective response of ECs to shear stress. The alignment and remodelling are mediated through the dynamic regulation of the family of RhoGTPases . We haveSENEX) , a negatSENEX) , is flowSENEX) . We show−/− mice and ARHGAP18 and YAP regulate the mechanotransduction activity in EC. Most interestingly we show that loss of YAP, through either ARHGAP18 depletion or through siRNA depletion of YAP itself, resulted in activation of YAP, defined by a decrease in cytoplasmic YAP levels, nuclear localisation of YAP and through an increase in the YAP target gene, CyR61. This was unexpected as it is in contrast to that previously seen where knockdown of YAP phenocopied the protective effect of laminar flow at least on the cell cycle inhibitor p21 and on the pro-inflammatory cytokine, CCL2 [−/− mice where there was a decrease in overall expression of YAP but a nuclear enrichment of YAP in the ECs in the descending region of the aorta. The activation of YAP in these regions in the ARHGAP18−/− mice, is consistent with the lack of alignment under flow and the priming of this region towards a more pro-inflammatory phenotype which we have recently reported [The transcriptional co-activator YAP has been linked to control of organ shape, size and alignment by regulation of tissue tension , 32 . YAne, CCL2 , 17. Thene, CCL2 . One posne, CCL2 . Indeed,ne, CCL2 . Furtherne, CCL2 , in our ne, CCL2 . Thus, ereported . Indeed,ARHGAP18 has both GAP dependent and GAP independent activity , 29. OurWe have shown that ARHGAP18 and YAP promote the shape change and athero-protective alignment of ECs in the direction of laminar shear stress. In conjunction with our previous studies we suggest ARHGAP18 is an essential inhibitor of the development of inflammation in the endothelium.


NWR) of the upper limb at rest and after injection of Botulinum toxin type A (BoNT‐A) in poststroke subacute hemiparetic patients.The aims of this study were to evaluate the pattern of the nociceptive withdrawal reflex  were performed at T0, one month (T1), and three months (T2) after the BoNT‐A injection, as were Modified Ashworth Scale (MAS) and Functional Independence Measure (FIM) scores.Fourteen patients with poststroke subacute hemiparesis underwent clinical and instrumental evaluation and BoMAS score for the elbow (p < 0.001) and wrist joints (p < 0.001) and in the FIM score at T0 and T2. BoNT‐A injection had a significant effect on both NWR amplitude and baseline EMG activity in the posterior deltoid (PD) and flexor carpi radialis (FCR) muscles as well as in all averaged muscles. Analysis of elbow kinematics before and after treatment revealed that the reflex probability rates were significantly higher at T1 and T2 than at T0.Comparison of results at T0, T1, and T2 revealed significant changes in the NT‐A in the subacute phase of stroke can modify both the baseline EMG activity and the NWR‐related EMG responses in the upper limb muscles irrespective of the site of injection; furthermore, the reflex‐mediated defensive mechanical responses, that is, shoulder extension and abduction and elbow flexion, increased after treatment. BoNT‐A injection may be a useful treatment in poststroke spasticity with a potential indirect effect on spinal neurons.Injection of Bo The exclusion criteria were: (a) previous stroke; (b) cerebrovascular encephalopathy; (c) concurrent sensory deficits; (d) neglect; (e) apraxia; (f) cognitive deficit ; (g) muscle or joint pain; (h) concomitant orthopedic disorders of the affected arm; (i) aphasia.All patients were evaluated by two experienced neurologists .Muscle tone was evaluated using the 6‐point  Modified Ashworth Scale (MAS)  met the inclusion criteria and were included in the study. The patients’ clinical characteristics are reported in Table All patients were hospitalized in the Neurorehabilitation Unit of the Department of Neurology, C. Mondino National Neurological Institute, Pavia, Italy. During their hospital stay, the patients underwent a daily physiotherapy program conducted according to European stroke rehabilitation guidelines Gillen, .The research was approved by the local ethics committee and complied with the Helsinki Declaration. All the subjects gave their written informed consent to participate.2.2The muscles to be treated were chosen on the basis of: the long experience of the injecting neurophysiologist (EA), data from the literature RCP,  and the 2.3Voluntary movement of the shoulder and the elbow joints was recorded using a 6‐camera optoelectronic system  with a sampling rate of 100 Hz.Ten markers were placed on anatomical landmarks in accordance with a validated upper limb and trunk biomechanical model .The surface EMG (sEMG) signals were recorded with a sampling rate of 1,000 Hz using a 16‐bit acquisition board, and amplified using a 16‐channel Wi‐Fi transmission surface electromyograph . The common mode rejection ratio was 100 dB. After skin preparation, bipolar circular Ag/AgCl surface electrodes , prepared with electroconductive gel , were placed in single differential configuration over the long head of the anterior and posterior deltoid (AD and PD), biceps brachii (BB), triceps brachii (TB), flexor carpi radialis (FCR), and extensor carpi radialis (ECR), according to standard anatomical landmarks.Electrodes were placed on the center of each muscle belly, in the direction of the muscle fibers, according to European recommendations on sEMG . The subjects rested their arm on the table in a semiflexed position to encourage maximum muscle relaxation. In this position, the shoulder was abducted to 50° and anteflexed to 25°, the elbow was flexed to 100° with the forearm fully pronated, the wrist was in line with the forearm, and the fingers were spontaneously flexed. Electric shocks with an intensity of 2xPT were delivered to the patients in this position. Ten trials were recorded in each subject.All patients were evaluated before (T0) and after one month (T1) and three months (T2) BoNT‐A injection. All BoNT‐A injections were performed by an experienced neurologist after careful evaluation of the muscles to be treated.Nociceptive withdrawal reflex recordings (EMG and kinematic response) were performed at T0, T1 and T2. The MAS was administered at T0, T1 and T2, while the FIM was administered at T0 and T2.2.6The data were processed using 3D data processing software . A validated biomechanical model was used to measure shoulder and elbow joint angles  in order to reduce slow transient noise and instrumentation noise. The sEMG signals recorded were processed using the following procedure: digital filtering (low pass Hamming filter with a cutoff frequency of 100 Hz), followed by rectification and smoothing using a root mean square with a mobile window of 10 ms.SD, calculated in the prestimulus interval, was used as a threshold to determine the presence  or absence  of the NWR in the poststimulus interval in each trial. The NWR‐related EMG responses were measured as the difference between the EMG areas in the post‐ versus the prestimulus intervals for each examined muscle  and for the 60–200 ms interval after the stimulus . The mean of the EMG area plus 2 2.7All the analyses were performed using SPSS statistics software (version 17).One‐way ANOVA for repeated measures was performed to evaluate the effect of BoNT‐A injections on: baseline EMG activity and NWR‐related responses (EMG activity and kinematic reflex amplitudes), and Modified Ashworth Scale scores (three‐level within‐subject factors). We used Greenhouse–Geisser correction when appropriate to avoid violations of sphericity  = 71.401, p < 0.001) and wrist joints  = 23.735, p < 0.001), while no significant differences were found for the shoulder joint. Post hoc analysis revealed lower levels of spasticity at both T1 (1.1 ± 0.2) (p < 0.001) and T2 (1.1 ± 0.4) compared to T0 (2.0 ± 0.4) (p < 0.001) for the elbow joint; lower values at both T1 (1.2 ± 0.3 p < 0.001) and T2 (1.8 ± 0.5 p < 0.001) as compared to T0 (2.2 ± 0.8) was also found for the wrist joint. Furthermore, at the wrist joint we recorded a significant increase in spasticity at T2 (1.8 ± 0.5) as compared to T1 (1.2 ± 0.3) (p < 0.05).A significant effect of BoNT‐A injections on MAS scores was found for the elbow .Significant differences in both FIM total score and FIM upper limb subscore were found between T0  and T2   = 5.627, p = 0.009). Post hoc analysis revealed lower values at T1 versus both T0 and T2, whereas no differences were found between T0 and T2  = 8.849, p = 0.005). Post hoc analysis revealed lower values at T1 compared to T0, whereas no significant differences were found between T0 and T2 or T1 and T2 , although a trend toward NWR‐related EMG amplitude reduction was evident for all these muscles  = 22.643, p = 0.001). Post hoc analysis revealed significantly lower values at T1 and T2 compared with T0 =4.934, p = 0.015). Post hoc analysis revealed significantly lower values at T1 compared with T0 .A significant correlation was found between the averaged NWR‐related EMG responses and the total dosage of BoNT‐A (3.3p < 0.05). Although a trend toward recovery of the baseline conditions at T2, no significant differences were found between T1 and T2 , shoulder abduction (probability rate > 74%) and elbow flexion (probability rate > 81%) Table .F = 5.760, p = 0.008) and elbow flexion  = 7.841, p = 0.002), whereas no effect was found for shoulder extension  = 1.418, p = 0.260). Post hoc analysis revealed significantly higher shoulder abduction and elbow flexion angle values at T2 compared to T0  after BoNT‐A injection in a representative patient are reported in Figures 4In the current study, the upper limb NWR was used as a tool to evaluate the effect of BoNT‐A administration on the excitability of spinal cord neurons in the subacute phase of stroke. In particular, our aim was first to characterize abnormal patterns of the multijoint, multimuscle NWR, and then to evaluate the changes in this reflex induced by injection of BoNT‐A. Our assumption was that this investigation may help to shed light both on the plastic rearrangement occurring at the level of the NWR‐mediating neurons, and on the changes induced by BoNT‐A injection that may, potentially, prevent the development of spasticity and promote a better motor recovery.The main results can be summarized as follows: (a) the spasticity, as measured by MAS scores, was significantly reduced at both elbow and wrist joints level after BoNT‐A injection at one (T1) and three (T2) months, with a trend toward recovery of the baseline condition at three months (T2) in the wrist joint; (a) baseline EMG activity was significantly reduced in all muscles, when considered as both single and averaged values, at one (T1) and/or three (T2) months after BoNT‐A injection with a trend toward recovery of the baseline condition at three months (T2) only for PD and FCR muscles; (b) reflex‐related EMG responses were significantly reduced in the PD and FCR muscles, as well as in all the muscles  at one month (T1) after BoNT‐A injection, after which there was a trend toward recovery of the baseline condition at three months (T2); (c) oppositely to reflex‐related EMG responses, the shoulder and elbow reflex‐related kinematic responses were significantly increased at both one (T1) and three (T2) months after BoNT‐A injection, with a trend toward recovery of the baseline condition at three months (T2).Only a few studies have investigated changes in NWR excitability in poststroke hemiparetic patients with spasticity in the lower . A similar decrease was observed also for the baseline EMG activity. Both NWR‐related EMG amplitude and baseline EMG activity changes were likely induced by BoNT‐A and reflect the fact that their maximal clinical effect occurs about one month after the injection  after BoNT‐A injection, but instead tended to increase in terms of both reflex probability rate and amplitude Table . This inMost of the studies on botulinum toxin injection for poststroke spasticity have been performed in chronic stroke patients. However, early use of botulinum toxin (in acute‐to‐subacute stroke) has been shown to reduce spasticity, preventing disabling stiffness and contractures  with physiotherapy might modify the reflex responses and improve the motor recovery. Furthermore, how much the rehabilitation program may have affected the patient cohort remains speculative here. Hence, a nonintervention cohort (Rehab program only) vs BTX with or without Rehab will be an ideal approach.None of the authors have potential conflict of interests to be disclosed.


Successful revascularization of chronic total occlusions has been associated with potential effects on left ventricular (LV) function. Strain and strain rate are more sensitive measures of LV mechanics than LV ejection fraction (LVEF). This study was conducted to investigate the impact of revascularization of chronic total occlusion (CTO) on LV function using tissue Doppler (TDI) strain echocardiography.p value < 0.01), the peak systolic strain improved from 6.54 ± 2.48 to 11.51 ± 3.33% , and the end systolic strain improved from 7.88 ± 2.77 to 10.51 ± 3.14% . There was no significant improvement in the mean LVEF ). In the OMT group, there was no improvement in all the strain parameters and there was no change in the mean LVEF. In the PCI group, there was a significant improvement in the angina class  while, in the OMT group, there was no significant improvement .This study included 60 patients divided into two main groups: the percutaneous coronary intervention (PCI) group including patients who had a successful PCI of CTO on left anterior descending (LAD) artery and was presented for elective PCI with symptomatic angina and/or positive functional ischemic study. They included 18 males with a mean age of 57 ± 5 years. The optimum medical treatment (OMT) group, including 30 patients, had non-revascularized CTO-LAD and was kept on OMT alone; 20 of them were males with a mean age of 58 ± 4 years. In the PCI group, there was a significant improvement in all the TDI strain parameters of the LAD territory segments. Six months after PCI, the peak systolic strain rate improved from − 0.65 ± 0.21 to 1.05 ± 0.31 1/s (Successful PCI for CTO improved regional LV myocardial function assessed by TDI strain echocardiography. This improvement was associated with improvement in the angina class. Coronary chronic total occlusions (CTOs) are defined as an occluded coronary segment with thrombolysis in myocardial infarction (TIMI) flow 0 for ≥ 3 months duration . ApproxiSuccessful percutaneous coronary interventions (PCIs) of CTOs have been shown to improve the left ventricular (LV) systolic function, reduce angina, increase exercise capacity, and reduce the need for bypass surgery .Two-dimensional (2D) echocardiography has been described as the ideal imaging modality for the assessment of global and regional ventricular function. However, conventional assessment of wall motion, on the basis of visual interpretation of endocardial excursion and myocardial thickening, has the limitations of being a qualitative method and is subjective and experience-dependent .Tissue Doppler (TDI) imaging has been introduced in an attempt to provide a more objective assessment of myocardial contractility but is subject to the confounding effects of cardiac translational motion and passive pathological tethering .These limitations may be overcome by the measurement of local myocardial deformation parameters with strain and strain rate echocardiography .The aim of this study was to evaluate the impact of PCI of CTO on clinical outcome and regional myocardial function using TDI strain echocardiography.Our study included 60 patients prospectively recruited from the period of December 2015 till January 2018. They were divided into two groups: The PCI group, including thirty patients, was presented for elective PCI of CTO on left anterior descending (LAD) artery with symptomatic angina and/or positive functional ischemic study, had successful PCI with final TIMI flow more than II, and was kept on optimum medical treatment (OMT). They included 18 males with a mean age of 57 ± 5 years. The OMT group, including thirty patients, had non-revascularized CTO and was kept on OMT alone. Twenty of them were males with a mean age of 58 ± 4 years.CTO was defined as the presence of TIMI flow grade 0 within the occluded artery with an estimated occlusion duration of ≥ 3 months, as suggested in the Euro CTO Club consensus document .We included patients having sinus rhythm and viable myocardium in the LAD artery territory artery using dobutamine stress echocardiography or myocardial perfusion imaging study.We excluded patients having poor echocardiographic windows, severe renal impairment (creatinine clearance < 30 ml/min), emergency PCI in acute coronary syndrome, and the presence of conduction defects in the electrocardiogram.All individuals were subjected to a full assessment of history, a thorough clinical examination, laboratory investigation, and resting 12-lead ECG.All participants gave written informed consent, and the study was approved by the local ethics committee.The echocardiography was done within 24 h before PCI and after 6 months in the PCI group, and at baseline and after 6 months in the OMT group.2D and TDI strain echocardiography were performed on the subjects at rest in the left lateral decubitus position with synchronized electrocardiography using a commercially available system  equipped with a broadband S3 transducer.The parasternal long-axis views were used to derive the M-Mode measurements of the LV end diastolic (LVEDD) and end systolic (LVESD) dimensions.The apical views were used to derive the LV end diastolic volume (LVEDV) and LV end systolic volume (LVESV). Ejection fraction was measured by endocardial tracing using the modified Simpson method.Cardiac TDI velocity data from the anterior, apical, and anteroseptal wall segments were recorded using apical 2-, 3-, and 4-chamber views with the wall in the middle of the sector. All datasets were acquired over three consecutive heartbeats at a high frame rate (180–200 frames/s), with an image depth of 11–14 cm. In all acquisitions, the 2D sector angle was minimized to obtain a high frame rate. The digital cine-loop raw datasets containing both gray-scale and tissue velocity imaging information were stored for off-line analysis.The data were analyzed off-line to obtain regional myocardial velocity, strain, and strain rate imaging profiles.Peak systolic strain (peakε) and strain rate (SR) were determined as the maximal negative strain and SR value during ejection ), but end systolic strain (εes) was measured at AVC.We analyzed only the segments in the territory of totally occluded LAD territory.Baseline angiography data included the CTO territory length of occlusion, collaterals, number of diseased vessels, and baseline SYNTAX score. PCI of the CTO was performed using available techniques, such as bilateral injections; specialized hydrophilic, tapered tip, and stiff wires; and parallel wires. Procedural success was defined as the successful recanalization of CTO with a residual stenosis of less than 20% and a TIMI flow of more than 2.Revascularization for all significant non-CTO lesions within a vessel diameter of ≥ 2.5 mm for patients with multivessel coronary artery disease was recommended.Patients were prescribed guideline-derived OMT, including aspirin, P2Y12 receptor inhibitors (> 12 months in case of PCI), beta-blocker, calcium channel blockers, nitrate, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, and a statin, and a follow-up for 6 months was done.χ2 test and an unpaired t-test, respectively. A value of p < 0.05 was considered statistically significant.The continuous variables are reported as the mean and standard deviations (SD), and the categorical variables are expressed as percentages. Comparisons of the categorical and continuous variables between the two groups were performed using the In the PCI group, only 28 patients completed the study (one patient died and one missed from the follow-up). In the OMT group, only 27 patients completed the study (two patients died and one missed from the follow-up).Baseline characteristics are shown in Table PCI of CTO on the LAD artery was attempted in 35 patients. It was successful in 30 patients with a success rate of 85%. Complications occurred in five patients (17%): 1 patient had post-procedural bleeding, 2 patients had a hematoma, and 2 patients had a coronary dissection.The angiographic characteristics of the CTO-PCI group are summarized in Table p value = 0.6).In the PCI group, mean LVEF before PCI was 60.70 ± 8.33 and after 6 months was 61.91 ± 8.16 with no significant improvement .In the OMT group, mean LVEF was 59.46 ± 7.78 and after 6 months was 59.15 ± 7.99 with no significant difference . Regarding angina, in the PCI group, there was a statistically significant improvement in the angina class (CCS) 6 months after PCI compared to the CCS before PCI .Global longitudinal strain was done with no significant statistical difference between both groups .In the OMT group, there was no improvement in CCS after 6 months compared to the baseline with no statistical significance  study revealed that the baseline LV dysfunction was an independent predictor for improvement in LVEF after revascularization of CTO .Another modality to assess the LV systolic dysfunction even with no regional wall motion abnormalities at rest is the strain imaging.In our study, we aimed to assess the effect of CTO-PCI on regional myocardial function using a strain imaging TDI technique.The regional strain parameters improved significantly in the PCI group, with no improvement in the OMT group; other studies assessed the global longitudinal strain as in Erdogan et al.  who enroHealth status and quality of life indices are increasingly used in cardiovascular studies and reflect the increasing importance of these patient-perspective endpoints as an indication for therapy.In our study, there was a significant improvement in CCS in the PCI group with no improvement in the OMT group, and this is in line with Olivari et al.  who enroThere are several limitations to this study. The main limitation is its observational nature and the fact that it was non-randomized. Besides, the use of a single modality for the assessment of regional myocardial function and the limitations of TDI strain echocardiography constitute other limitations.We conclude that successful PCI for CTO, with evidence of a viable myocardium, improves LV function assessed by TDI strain echocardiography. This improvement is associated with improvement in the CCS.


Regional higher T1‐w/T2‐w values were associated with higher CSF tau concentrations  and worse MMSE scores . These higher T1‐w/T2‐w values in AD seem to contradict previous pathological findings of demyelination and disconnectivity in AD. Future research should further investigate the biological processes reflected by increases in T1‐w/T2‐w values.Myelin determines the conduction of neuronal signals along axonal connections in networks of the brain. Loss of myelin integrity in neuronal circuits might result in cognitive decline in Alzheimer's disease (AD). Recently, the ratio of T1‐weighted by T2‐weighted MRI has been used as a proxy for myelin content in gray matter of the cortex. With this approach, we investigated whether AD dementia patients show lower cortical myelin content . We selected structural T1‐w and T2‐w MR images of 293 AD patients and 172 participants with normal cognition (NC). T1‐w/T2‐w ratios were computed for the whole brain and within 90 automated anatomical labeling atlas regions using SPM12, compared between groups and correlated with the neuronal injury marker tau in cerebrospinal fluid (CSF) and Mini Mental State Examination (MMSE). In contrast to our hypothesis, AD patients showed higher whole brain T1‐w/T2‐w ratios than NC, and regionally in 31 anatomical areas ( The cut‐off for abnormal drift‐corrected CSF Aβ1–42 was set at <813 ng/L  images, acquired in a sagittal plane, with TR 8,000 ms, TE 126.6 ms, FA 90°, voxel size 1 mm3, 5.48 min.Structural T1‐weighted and T2‐weighted images were acquired as part of routine patient care from a single scanner (3T GE MR750). The following parameters for T1 were used: 3D‐FSPGR, sagittal plane, TR 7.8 ms, TE 3 ms, FA 12°, voxel size 1 mm2.4T1‐w and T2‐w images were converted to Nifti format and analyzed using a similar method as proposed by Glasser and Van Essen . The ori2.5t tests for continuous data or chi‐square tests for categorical data. We used general linear models (GLM) to test whether AD patients had globally  significantly different T1‐w/T2‐w ratios compared to the NC group. This analysis was adjusted for sex and age as the T1‐w/T2‐w ratio has previously shown to vary as a function of age. This model was repeated for regional T1‐w/T2‐w values using Bonferroni correction for multiple comparisons , and for analysis of individual T1‐w and T2‐w images as well.Demographic and biomarker data of the diagnostic groups were compared using two‐sample To gain further insight into the biological underpinnings of the T1‐w/T2‐w ratio, we further studied the influence of factors known to be associated with AD, that is, WMH, tau, and Mini Mental State Examination (MMSE), on T1‐w/T2‐w values. We used GLM, adjusted for age and sex, to investigate whether WMH severity has an effect on the T1‐w/T2‐w ratio by comparing T1‐w/T2‐w ratio values between individuals with WMH, defined as having a Fazekas score 2–3, to individuals without pronounced WMH (Fazekas 0–1).Next, we computed a linear regression analysis of CSF total tau concentration and mean T1‐w/T2‐w ratio values for all AAL regions using all subjects and for each group separately. Previous studies have shown that total tau and p‐tau concentrations are highly correlated  = 8.33, d = 0.15, p < .01] ; Figure d = 0.21 to d = 0.48; p < .0005 to p < .00000001; Table Average whole cortex T1‐w/T2‐w values were higher in AD compared to NC . Next, the effect of the neuronal injury marker tau on the mean global T1‐w/T2‐w ratio was explored. The regression analysis indicated that T1‐w/T2‐w ratios across the whole cortex increased with higher tau concentrations in CSF  and located in mostly frontal and parietal regions with significant correlation values ranging from r = .16 to .22 . Which implies that worse global cognitive functioning correlated with higher T1‐w/T2‐w ratios at a trend level  in individuals with normal cognition  reflect myelin content. Currently the T1‐w/T2‐w ratio is used frequently across various populations to characterize myelin. Our results suggest that this measure should be interpreted with caution in particular in disease populations and further validation and characterization of the T1‐w/T2‐w ratio and its neurobiological origin in AD is necessary for correct interpretation.W. Pelkmans and E. Dicks report no disclosures. F. Barkhof is a consultant for Biogen‐Idec, Janssen Alzheimer Immunotherapy, Bayer‐Schering, Merck‐Serono, Roche, Novartis, Genzume, and Sanofi‐Aventis; has received sponsoring from European Commission–Horizon 2020, National Institute for Health Research–University College London Hospitals Biomedical Research Centre, Scottish Multiple Sclerosis Register, TEVA, Novartis, and Toshiba; is supported by the University College London Hospitals NHS Foundation Trust Biomedical Research Center; and serves on the editorial boards of Radiology, Brain, Neuroradiology, Multiple Sclerosis Journal, and Neurology. H. Vrenken reports no disclosures. P. Scheltens has acquired grant support (for the institution) from BiogenGE Healthcare, Danone Research, Piramal, and Merck. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Lilly, GE Healthcare, Novartis, Sanofi, Nutricia, Probiodrug, Biogen, Roche, Avraham, and EIP Pharma, Merck AG. W. M. van der Flier's research programs have been funded by ZonMW, the Netherlands Organization of Scientific Research, Seventh European Framework Programme, Alzheimer Nederland, Cardiovascular Onderzoek Nederland, Stichting Dioraphte, Gieskes‐Strijbis fonds, Boehringer Ingelheim, Piramal Imaging, Roche BV, Janssen Stellar, Biogen MA and Combinostics. All funding is paid to her institution. B. M. Tijms declares that she is supported by the ZonMW Memorabel “(Grant number #73305056).”Supplementary figure 1 Whole brain group average T1‐w/T2‐w ratio surfacemap of subjects with normal cognition. The signal strength distribution shows relatively high T1‐w/T2‐w values (myelin content) in sensory and motor regions and lower values in temporal and frontal areas corresponding with previous literature.Click here for additional data file.Supplementary figure 2 Scatterplot of global T1‐w/T2‐w ratios with CSF and WM volume using different GM probabilities. In the main analysis the T1‐w/T2‐w image was masked using a mask with a GM probability of >.3. In a subset of N = 50  subjects, data was reanalyzed using a GM mask probability of >.1 and > .9. These T1‐w/T2‐w values were correlated with CSF and WM volumes. The results of both images with different GM probabilities are very similar, and no increase in T1‐w/T2‐w ratios was seen with higher CSF or WM volume. Therefore, we think it is unlikely that our main results, that is, higher T1‐w/T2‐w ratios in AD, can be fully explained by partial volume effects.Click here for additional data file.Supplementary figure 3 Scatterplot of global T1‐w/T2‐w ratios masked with an eroded GM mask with CSF and WM volume. In a subset of N = 50 , the data was re‐run using an eroded GM mask to reduce possible partial volume effects from neighboring GM voxels. Using the erode function in fslmaths, the subject specific GM masks were eroded when zero voxels was found in kernel. The eroded GM mask actually resulted in more PVE, likely associated with atrophy and was therefore not applied in the main analysis.Click here for additional data file.Supplementary table 1 Table of mean T1‐w/T2‐w ratio values for all AAL brain regions compared between AD and NC subjects. Areas showing significantly higher T1‐w/T2‐w ratios in AD compared to CN subjects are displayed in bold.Supplementary Table 2. Table of mean T1‐w/T2‐w ratio values for all AAL brain regions compared between AD and NC subjects without image bias correction. Areas showing significantly higher T1‐w/T2‐w ratios in AD compared to CN subjects are displayed in bold.Supplementary Table 3. Table of mean T1‐w/T2‐w ratio values for all AAL brain regions compared between AD and NC subjects using age and sex matched individuals (n = 50). Areas showing significantly higher T1‐w/T2‐w ratios in AD compared to CN subjects are displayed in bold.Click here for additional data file.


In this work, we suggest volumetric optoacoustic tomography (VOT) for non-invasive assessment of heart function in response to chronic hypoxia. Mice exposed for 3 consecutive weeks to normoxia or chronic hypoxia were imaged in vivo with heart perfusion tracked by VOT using indocyanide green contrast agent at high temporal (100 Hz) and spatial (200 µm) resolutions in 3D. Unequivocal difference in the pulmonary transit time was revealed between the hypoxic and normoxic conditions concomitant with the presence of pulmonary vascular remodeling within hypoxic models. Furthermore, a beat-to-beat analysis of the volumetric image data enabled identifying and characterizing arrhythmic events in mice exposed to chronic hypoxia. The newly introduced non-invasive methodology for analysis of impaired pulmonary vasculature and heart function under chronic hypoxic exposure provides important inputs into development of early diagnosis and treatment strategies in pulmonary hypertension.Exposure to chronic hypoxia results in pulmonary hypertension characterized by increased vascular resistance and pulmonary vascular remodeling, changes in functional parameters of the pulmonary vasculature, and right ventricular hypertrophy, which can eventually lead to right heart failure. The underlying mechanisms of hypoxia-induced pulmonary hypertension have still not been fully elucidated while no curative treatment is currently available. Commonly employed pre-clinical analytic methods are largely limited to invasive studies interfering with cardiac tissue or otherwise  The latter include chronic obstructive pulmonary disease (COPD), interstitial lung diseases, sleep disordered breathing, but also chronic exposure to high altitude and some rare neonatal diseases3.Pulmonary hypertension (PH) is a disorder characterized by pulmonary vascular remodeling, right ventricular hypertrophy and increased pulmonary arterial pressure. PH has been associated with various disorders while, according to the recent WHO classification, it is regarded as a separate entity when associated with hypoxia or chronic diseases of the respiratory system4. The hypoxia-inducible factor (HIF) has been highly implicated in the development of PH5 where several preclinical studies focus on the molecular mechanisms of HIF and its role in PH9. However, there is a lack of direct functional studies of the heart in response to chronic hypoxia. Methods for assessing pulmonary and cardiac structural alterations in PH are usually limited to histopathological ex vivo analyses looking at right ventricular (RV) hypertrophy and pulmonary vasculature changes. RV catheterization is an invasive in vivo procedure to measure pressure differences as a surrogate parameter of increased pulmonary arterial pressure13. Yet, the majority of the analytical methods interfere with integrity of the heart, which calls for introduction of new methods for direct in vivo assessment of cardiopulmonary coupling in small animal models.Murine models have been widely used to gain deeper insight into lung-heart interactions under chronic hypoxic conditionsIn vivo imaging of the murine heart is challenging due to its small size and rapid motion14, which imposes hard requirements on the spatial and temporal resolution of non-invasive imaging modalities to accurately capture a heart volume of less than a cubic centimeter beating at a 400–600 cardiac cycles per minute. Even though cardio-respiratory gating in magnetic resonance imaging (MRI) and X-ray computed tomography (CT) may enable characterizing some of the in vivo functional cardiac parameters, those methods are generally ill-suited for cardiac imaging due to insufficient temporal resolution when performing true 3D whole-heart imaging at high spatial resolution16. To this end, ultrasound (US), and more recently ultrafast US, are arguably the most suitable modalities for cardiac imaging in murine models. US enables discerning anatomy and measuring important physiological parameters, such as blood flow17. Yet, it is generally not suitable for measuring some of the key functional parameters in the entire heart volume in 3D, in particular for analysis of right ventricular size within murine models. To our knowledge, very few methods generally exist for non- or minimally-invasive imaging and assessment of the effects of exposure to chronic hypoxia in pre-clinical models.in vivo cardiac imaging in murine models, for a number of reasons: (1) the high number of effective voxels rendered by state-of-the-art systems allows for imaging the whole murine heart with high spatial resolution using stationary matrix detection arrays; (2) optical contrast allows for blood perfusion monitoring18, and (3) the high temporal resolution in 3D facilitates analyzing functional parameters of the living murine heart on a beat to beat basis19. An important functional parameter that can be measured with OA via injection of a contrast agent is the pulmonary transit time (PTT). The latter has been shown to significantly decrease in infarct murine models and hence can serve as an important indicator of heart function19. Another key feature of volumetric optoacoustic tomography (VOT) is the ability of imaging the entire heart with a single laser pulse. This is crucial to characterize potential delays in cardiac activation across different regions, e.g. during arrhythmic events. In this work, we demonstrate the capabilities of a recently developed real-time three-dimensional OA imaging system for analyzing heart function in vivo and non-invasively in chronic hypoxic murine models.Optoacoustic (OA) imaging is becoming an increasingly powerful tool in pre-clinical research, in particular for in vivo murine heart imaging . This clear difference in PTT between hypoxia-treated and normoxic mice strongly suggests that chronic hypoxia affects cardiac function and/or pulmonary hemodynamics.The PTT was measured as the difference between the time points corresponding to the maximum signal peaks for the right (RV) and left ventricles (LV), corresponding to the time of appearance of the ICG bolus Fig. . BoxplotCharacteristically, exposure to chronic hypoxia results in a vasoconstrictor response as well as in muscularization of small pulmonary vessels indicative of pulmonary vascular remodeling leading to an increase in pulmonary vascular resistance and right ventricular hypertrophy. As evinced by staining for α-smooth muscle actin of lung sections Fig. , the numP < 0.001 . The irregular cycles are also clearly visible in the supplementary videos of the reconstructed VOT image sequences available in the on-line version of the journal. Figure Due to the excellent temporal resolution of the VOT system, it was possible to characterize the heart motion on a beat-by-beat basis. Heart rate variability was clearly identified within the hypoxic models (n = 3 (3 of 4)) in VOT image sequences of 500 frames (100 frames per second), whereas only periodic cycles were recorded in normoxic models Fig. . The irr001 Fig. . The rea001 Fig. . The proex vivo or invasive procedures that interfere with the integrity of the heart tissue, hampering an accurate assessment of heart function within an intact living organism. Development of new imaging approaches is thus crucial for comprehensive understanding of the scope of PH in an in vivo environment.Pre-clinical animal models are commonly used to investigate the pathophysiology of pulmonary hypertension and potential therapeutic interventions. Exposure to chronic hypoxia over 3 weeks characteristically leads to pulmonary hypertension in mice. To this end, pre-clinical assessment of PH has been largely limited to in vivo heart function in murine models of chronic-hypoxia-induced PH. The high temporal resolution of the imaging system enables tracking fast perfusion of contrast agents and estimation of the pulmonary transit time (PTT), a valuable capacity for functional assessment of the heart and pulmonary circuit dynamics. PTT has previously been shown to serve as an accurate indicator of heart performance, specifically left ventricular performance under pathophysiological conditions in the murine heart19. In this study, we have shown that the PTT in murine models exposed to chronic hypoxia was considerably longer than in normoxic models. As the PTT is determined by cardiac function and pulmonary hemodynamics, these findings point to deteriorated cardio-pulmonary function in response to chronic hypoxic conditions. In fact, as indicated in this study, chronic hypoxia results in pulmonary vascular remodeling and right ventricular hypertrophy. This has not only been associated with an increase in pulmonary vascular resistance and right ventricular pressure due to increased afterload in chronic hypoxic mice22, but has also been associated with a decreased ability of conductance vessels to store and deliver the entire stroke volume of the right ventricle and ultimately resulting in a loss of pulmonary flow during diastole23. PTT values (or CPTT - Cardiopulmonary Transit Times) have been previously studied in humans by using the first pass radionuclide cardiography technique24. In support of our studies on hypoxia-induced PH in mice, longer PTT values were shown in patients with pulmonary hypertension26. PTT is becoming increasingly recognized as an important marker for cardiopulmonary function, where very recent studies have been evaluating the PTT in patients using MRI and US27. At present, pulmonary hypertension in mice is mostly characterized by invasive measurement of right ventricular pressure, and ex vivo histopathological analysis of pulmonary and cardiac tissues. Very recently, MRI and US has been applied to evaluate pulmonary hypertension in the more severe hypoxia/Sugen5416 murine model by measuring right ventricular ejection fraction28 However, in mice PTT was only determined invasively using microangiography29. VOT enables measuring the PTT in vivo in mice, thus offering a new efficient and non-invasive tool to monitor heart remodeling and pulmonary circuit dynamics in models of pulmonary hypertension.In this study, we have examined the potential of VOT for assessing 30. However, heart rate or arrhythmia have not been well documented in the adult chronic hypoxia murine model. Here we show that irregular heart cycles were present in mice exposed to chronic hypoxia as detected in the time profiles of the VOT data that represented mechanical motion of the heart in three dimensions. Although actual blood pressure values cannot be extracted from the VOT data, the non-invasively recorded OA signal intensity changes extracted at given spatial locations, plotted similar patterns to pressure waveforms usually extracted via catheterization31. This is expected considering that pressure changes in the heart chambers induce a displacement or strain in the heart walls, which are easily detectable in the OA signal intensity profiles. In catheterization procedures, pressure waveforms can only be measured at a specific location of the heart, which generally hinders measuring the delays between mechanical activation across different heart regions. With the suggested VOT approach, the OA signal intensity changes can be simultaneously obtained from multiple locations in the heart, which enables readily identifying such delays and could serve as an alternative method to strain imaging which also maps mechanical activation across the heart. The preliminary results presented here on cycle variability have promoted future studies on this topic using VOT in order to fully understand the effect of chronic hypoxia on the electromechanical activity of the heart, where ECG and VOT data would be directly compared.Arrhythmic events, in particular atrial fibrillation or flutter have been frequently observed in patients with pulmonary hypertension or COPDin vivo simultaneous detection of two impaired heart functions have been demonstrated with VOT in the murine model of chronic-hypoxia-induced pulmonary hypertension. The PTT and heart rate were both altered in hypoxic hearts compared to normoxic hearts. Overall, VOT has been suggested as a method offering new capabilities for in vivo volumetric beat-by-beat characterization of cardio-pulmonary function in murine models of pulmonary hypertension, not attainable with existing approaches.In conclusion, 21.All animal procedures were approved by the local legislation on protection of animals  and conducted in accordance with the European directive 86/609/EEC and internal regulations of the Technical University of Munich and Helmholtz Centre Munich. Mice (129S/Sv/C57BL6 mixed background) were maintained for 21 days either under normoxic conditions (n = 3) or under hypoxic conditions  in a custom-built normobaric chamber, as described previouslyin vivo imaging of the heart. The fur covering the region of interest was initially clipped and then completely removed with hair removal cream. During imaging, the anesthetized mice were placed on top of a solid agar matrix filling the volume enclosed by the spherical array  for ray Fig. . Warmed 32. The imaging system consists of a spherical array transducer  composed of 512 piezoelectric elements with 5 MHz central frequency and >80% detection bandwidth. The array provides 140° solid angular coverage with 40 mm radius. The large angular coverage of the array reduces limited-view effects and further enables an improved sensitivity and deeper penetration. In the experiments, the spherical array was held pointing upwards . All processing steps were performed in MATLAB .High-frame-rate images of the beating murine heart were acquired with a VOT system specifically designed for high performance pre-clinical cardiac imaging Fig. 18,32. Thrds Fig. . The sph18. In short, the PTT was measured as the difference between the time points corresponding to the maximum signal peaks for the right (RV) and left ventricles (LV), corresponding to the time of appearance of the ICG bolus  of the signals. The STFT was used to resolve the frequency content at specific time points and track it over time. Abnormal beating events are expected to result in a lower frequency distribution in the STFT as opposed to the normal beating rhythm.21. Briefly, lung tissue samples were immersed in 10% buffered formalin solution for 48 h and subsequently embedded in paraffin (FFPE). FFPE lung sections were stained with an antibody against α-smooth muscle actin . The slides were heated at 60 °C for 1 h before rehydration in a series of alcohol solutions of decreasing alcohol concentration. The endogenous peroxidase activity was quenched in 1% hydrogen peroxide solution in methanol. The hydration process was completed by rinsing in DAKO wash buffer. Sections were heated in a water bath at 90 °C while submerged in antigen retrieval pH 9 epitope retrieval solution (DAKO) for 30 min. They were subsequently blocked in blocking reagent for 1 h, and then incubated with the antibody 1:100 diluted in M*O*M diluent (Vector M*O*M kit)  for 1 h at room temperature in a humidity chamber. The sections were washed in DAKO wash buffer and the secondary antibody was applied (anti-mouse IgG in dilution 1:250). The avidin–biotin complex  was applied to the slides for 30 min at room temperature. The chromogenic reaction was performed with diaminobenzidine  for 5 min at room temperature. Slides were counterstained with Mayer’s hematoxylin for 30 s , dehydrated in an ascending alcohol concentration, and mounted with Entelan (Merck). Positive and negative controls were included with each run. For evaluation of each lung, small α-smooth muscle actin positive vessels less than 30 µm were identified in three randomly selected regions of interest covering an area of 1 mm2 each22.Hypoxia-induced pulmonary vascular remodeling was validated by immunohistochemistry, as described previouslyTo determine the Fulton index as a measure of right ventricular hypertrophy, the right ventricle was separated from the left ventricle and septum, and masses were determined.Video 1


Vigorous physical activity (PA) in highly trained athletes has been associated with heightened left ventricular (LV) trabeculation extent. It has therefore been hypothesised that LV trabeculation extent may participate in exercise-induced physiological cardiac remodelling. Our cross-sectional observational study aimed to ascertain whether there is a ‘dose–response’ relationship between PA and LV trabeculation extent and whether this could be identified at opposite PA extremes.In a cohort of 1030 individuals from the community-based UK Biobank study , PA was measured via total metabolic equivalent of task (MET) min/week and 7-day average acceleration, and trabeculation extent via maximal non-compaction/compaction ratio (NC/C) in long-axis images of cardiovascular magnetic resonance studies. The relationship between PA and NC/C was assessed by multivariate regression  as well as between demographic, anthropometric and LV phenotypic parameters and NC/C.There was no significant linear relationship between PA and NC/C , or between extreme PA quintiles , across all adjustment levels. A negative relationship was identified between left ventricular ejection fraction and NC/C, significantly modified by PA .In a community-based general population cohort, there was no relationship at, or between, extremes, between PA and NC/C, suggesting that at typical general population PA levels, trabeculation extent is not influenced by PA changes. The degree of left ventricular (LV) trabeculation varies among individuals. The most documented pathological consequence of excessive trabeculation as a diagnostic phenotype is left ventricular non-compaction (LVNC), recognised as a genetic cardiomyopathy by the American Heart Association More recently, there is growing interest in the role of physiological influence on cardiac trabeculation. It has been shown that postnatal changes in cardiac loading conditions affect trabeculation extent using models of pregnancy and extreme physical activity (PA).Our study thus aimed to determine for the first time, in a community-based population cohort, whether the amount of PA undertaken by an individual resembled a relationship of a ‘dose–response’ nature, as well as at high and low extremes of PA, with the degree of LV trabeculation extent observed, quantified by high-resolution (CMR) imaging.The UK Biobank has collected a wealth of phenotypic and genotypic information about its population of over 500 000 enrolled individuals, including data collection from questionnaires, physical measures, accelerometry, imaging, genome-wide genotyping with subsequent longitudinal follow-up for health-related outcomes. The sample size of 500 000 was theoretically calculated for reliable detection of the effects of different exposures on a wide variety of conditions in nested case–control studies with sufficient statistical power. The cohort’s characteristics make it well-suited to study exposure–disease relationships due to its large size and heterogeneity of exposure measures. The baseline summary characteristics of the cohort can be viewed on the UK Biobank website, in the data showcase section.For each individual, PA was measured subjectively by both total metabolic equivalent of task (MET) min per week using information gathered from a self-reported International Physical Activity Questionnaire10.1136/heartjnl-2018-314155.supp1Supplementary dataThe 7-day average acceleration measurement was acquired by an Axivity AX3 accelerometer worn continuously on the wrist of the participant’s dominant hand for seven consecutive days, detecting movement in all three axes. The raw data obtained from the device captured at 100 Hz was calibrated to adjust for acceleration due to local gravity using the van Hees method.42  was used for scan analysis. LV mass, LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF) were manually measured from balanced steady-state free precession cine short-axis and long-axis images.For all participants, all CMR studies were acquired with a wide bore 1.5 Tesla scanner  and the postprocessing software cviThese long-axis images were also used to measure trabeculation extent, using the maximal non-compaction/compaction (NC/C) ratio. There was an initial qualitative assessment for the presence of trabeculation in each of the three LV regions  in the end-diastolic phase, defined as the visual identification of two myocardial layers represented by a difference in signal intensity between the two layers. If a trabeculated layer was visualised, the point at which the highest NC/C ratio could be obtained was measured for each region.All continuous variables were assessed for normality using histograms and quantile–quantile plots. Descriptive statistics for continuous variables were presented as mean±SD or median±IQR, while categorical variables were presented as a frequency (percentage). Missing data, if encountered, was addressed using multiple imputation by chained equation technique to create statistically valid imputed data based on variables from the original observed dataset to form 20 differently imputed datasets. The estimates and SEs from each imputed dataset were then pooled with Rubin’s rules.We constructed multiple nested linear regression models to identify any potential ‘dose–response’ relationship between the NC/C ratio and each PA measurement variable. We scaled both PA variables by their IQR before entering into the models to enable sensible comparison of effect estimates between the two methods of PA measurement; the effect estimates therefore indicate the change in relevant dependent variable per IQR increment in PA. In the unadjusted models, the bivariate association between PA and maximal NC/C ratio was tested. In limited models, adjustments were made for demographics and anthropometrics: age, sex, ethnicity and height. In fully adjusted models, the remaining covariates were added: body mass index (BMI), systolic blood pressure, diastolic blood pressure, heart rate (HR), smoking status, regular alcohol use, degree level education, diabetes, cardiovascular disease, hypertension, income, Townsend deprivation index, antihypertensive use, statin use, LVEDV, LV mass and LVEF.2=0.05). Online 2 values and effect sizes.We performed the following secondary analyses: (1) an investigation of the association between NC/C ratio and high and low PA quintiles (for each PA measurement method) using multivariate linear regression, following the same levels of adjustment, to form the extreme groups analysis, (2) an analysis of effect modification by age, sex, BMI, LVEDV, LV mass and LVEF by introducing cross-product terms to the dose–response linear regression analysis, (3) an investigation of the fully adjusted models of multivariate regression analysis between PA and maximal NC/C ratio to observe any significant associations between the outcome and the included covariates, (4) an investigation of the relationship between PA and clinical cardiac parameters  to clarify whether typical physiological changes that occur in exercise-induced cardiac remodelling were exhibited in our cohort and (5) an investigation of ‘dose–response’ relationships (using the same method of model construction) between PA in MET-min and maximal NC/C ratio at walking, moderate and vigorous PA intensities and between categorical predefined PA intensity levels and maximal NC/C ratio  and maximal NC/C ratio. LVEF was the only covariate to produce a significant effect modification when PA was measured in total MET-min/week. There was an overall negative relationship between LVEF and NC/C ratio, where one SD increment in LVEF was associated with a decrease of 0.04 units of maximal NC/C ratio. Incorporating PA  with LVEF as a cross-product significantly modified this relationship by augmenting the negative relationship between LVEF and NC/C ratio (p=0.03).Across all levels of adjustment, there was no significant relationship between PA and LVEF with both methods of PA measurement. However, with full adjustment, there was a significant positive relationship between PA (in both measurement methods) and LV mass, with a similar significant relationship also observed at limited adjustment when PA was measured in 7-day average acceleration. The analysis of these relationships is shown in In our study, the first to examine the relationship between PA and LV trabeculation extent in a community-based cohort using CMR imaging, the following observations were made. First, there was no linear relationship between PA and maximal NC/C ratio for both PA measurement methods. Second, there was no significant difference in maximal NC/C ratio between the lowest and highest PA extreme groups for both PA measurement methods. Third, PA  augmented the negative relationship between LVEF and maximal NC/C ratio. Finally, age and LVEDV exhibited a significantly positive linear relationship with maximal NC/C ratio, while male sex, BMI, LV mass and LVEF exhibited a significantly negative linear relationship with maximal NC/C ratio.Studies that previously hypothesised that LV trabeculation extent may participate in the exercise-induced cardiac remodelling process using models of pregnancy and extreme athletically trained PA levels found increased trabeculation extent in tandem with other phenotypical LV changes expected under these preload increasing conditions, such as increased LV mass, LVEDV and LV cavity size.It could therefore be suggested that there exists a PA threshold that must be exceeded for increased trabeculation extent to manifest as a phenotypical change in response to increased PA. As Gati’s study selected athletes ‘competing at regional or national levels’ that were aged between 14 years and 35 years, it was more likely to select for elite athletes compared with that of our cohort, with an older age range and more reflective of a general community-based population. It is therefore possible that the PA levels reached by the cohort in our study were not high enough to produce trabeculation changes of sufficient magnitude to be detected despite our large sample size.Effect size modification by covariates was also investigated. In the fully adjusted model, including LVEF as a cross-product produced a significant effect size modification in the relationship between PA  and maximal NC/C ratio. Given the significant negative relationship found in our study between LVEF and maximal NC/C ratio, the effect modification analysis suggests that PA may have some degree of further negative influence on this relationship.Our study also echoed previous research within another community-based cohort—the Multi-Ethnic Study of Atherosclerosis (MESA), where higher PA levels resulted in both an increased LVEDV and a decreased resting HR.Evidence from another recent study has further validated our finding of an association between LVEDV and trabeculation extent. This was undertaken in a healthy Singaporean Chinese cohort, which found LVEDV to also be positively concordant with LV trabeculation extent, measured by fractal dimension (FD) analysis.There were some limitations of the data relevant to our study. The total MET-min/week measurement of PA was self-reported, reducing the consistency of recordings due to differing interpretations of the questionnaire by each participant. The calculation process in the questionnaire also did not take into account more precise measures of the amount of each exact type of PA undertaken, instead grouping activities into three relative MET intensities for calculation. Seven-day average acceleration was a more objective alternate measurement gained from the wrist-worn accelerometer, but the 1 week sample period may not have produced average estimates as accurate as those from a longer sample period. Also, the values produced by average measurements may not have been large enough to reflect a potential ‘threshold dose’ of PA, above which an effect on maximal NC/C ratio may have been observed.Our study was also limited in the trabeculation measurement method used. As the maximal NC/C ratio was taken for the LV globally, regional distribution of LV trabeculation was therefore not considered, meaning that more detailed region-specific analysis could not be performed, such as the impact of PA purely on apical trabeculation extent. Also, much previous analysis of LV trabeculation has been performed using echocardiographic data,While our study used well-known measures of both trabeculation and PA, it would be valuable to additionally explore this relationship using different approaches to these measurements.Increasing the time over which the average acceleration is measured would increase its validity by accounting further for the variation that exists between individuals’ activity patterns. In addition, using the accelerometer to gain a measurement of direct activity intensity may better differentiate those that indeed undergo the most athletic activity in the cohort, which would introduce a more robust analysis of the relationship at low and high PA extremes.Trabeculation extent could alternatively be measured by FD. This is a more automated measurement than the NC/C ratio, which is based on the fractal biology in which trabeculation is structured to measure the complexity of the trabeculation in short-axis CMR slices. While removing the possibility of analysis of compacted myocardial thickness , FD takes trabeculation measurement into account across the whole LV, allowing for region-specific analysis as well as demonstrating marginally higher intraobserver reproducibility than NC/C ratio measurements.In the first study to investigate the relationship between PA and LV trabeculation extent within a community-based sample population using CMR imaging, our results showed no significant relationship between PA and maximal NC/C ratio in a cohort that demonstrated characteristics of exercise-induced cardiac remodelling. At the levels of activity recorded, there was no evidence to suggest that trabeculation changes occur as an epiphenomenon to other processes in this remodelling. The possibility of whether exercise-related changes in trabeculation extent occur above a certain threshold of PA, and where this threshold lies, remains to be investigated.It has been shown that postnatal changes that affect cardiac loading conditions affect left ventricular (LV) trabeculation extent, such as in pregnancy and during extreme athletic-level physical activity (PA). Excessive levels of LV trabeculation form a diagnostic phenotype in left ventricular non-compaction cardiomyopathy.This study provides insight into the relationship between PA and LV trabeculation extent, at levels of PA typical of a non-athletic community-based middle-aged population cohort analysed using cardiovascular magnetic resonance (CMR) imaging. We observed no relationship at or between extremes of PA within our cohort of 1030 individuals, despite evidence to suggest exercise-induced cardiac remodelling in other parameters such as left ventricular end-diastolic volume and LV mass.At the PA levels typical of a community-based population, there is no evidence to suggest that excessive trabeculation, if observed, occurs as an epiphenomenon to other exercise induced cardiac remodelling processes.


This study evaluated the feasibility of using two-dimensional speckle tracking echocardiography (2D-STE) to monitor left ventricular (LV) and overall function after percutaneous recanalization.LV function after percutaneous recanalization was monitored by 2D-STE and conventional echocardiography in 43 patients with coronary chronic total occlusion (CTO) who underwent primary percutaneous coronary intervention (PCI). Follow-ups were carried out 1 day as well as 3 and 6 months after CTO-PCI. At each time point, LV ejection fraction (LVEF) was examined by echocardiography, and LV global longitudinal strain (GLS) was measured by 2D-STE.It was found that the global longitudinal strain assessed with 2D-STE was improved as early as 1 day after CTO-PCI, whereas LVEF tended to improve up to 3 and 6 months after CTO-PCI.PCI can effectively improve LV function in patients with CTO. 2D-STE is a superior technique for objectively quantifying the functional change earlier. Chronic total occlusion (CTO) is defined as an occluded coronary artery presenting as thrombolysis in myocardial infarction (TIMI) with grade 0 or 1 flow in a recent myocardial infarction (MI) . The myoIn this study, the LV systolic function of CTO patients with dysfunctional myocardium was evaluated at 1 day as well as 3 and 6 months after percutaneous revascularization using 2D-STE. It was found that 2D-STE was superior in detecting subclinical LV systolic dysfunction in CTO patients after percutaneous revascularization.A single-center prospective observational study was performed from July 2012 to March 2016. Patients with CTO with an estimated duration of less than 3 months or an MI during the previous 30 days were excluded, but no other predefined clinical inclusion or exclusion criteria were applied. The indication for PCI was determined by individual investigators at the participating center. In all, 43 patients (mean age: 66.09 ± 10.99 years) scheduled to undergo PCI for CTO in a native coronary artery were eligible for enrollment. Among them, there were 40 males and three females. The CTO of ten patients was located in the left anterior descending artery in ten patients, in the right coronary artery in 25 patients, and in the circumflex artery in eight patients. A follow-up visit or telephone interview was scheduled at 1 day as well as 3 and 6 months after percutaneous revascularization. Prior written and informed consent was obtained from every patient. This study was approved by the Ethics Review Board of Capital Medical University.Percutaneous revascularization was performed by operators highly experienced in the treatment of CTO according to their standard practices with the femoral or brachial approach. The operation was considered successful when the residual stenosis was ≤30% of the intraluminal diameter, with TIMI grade 3 flow and no in-hospital complications . Clopidogrel (75 mg daily) was prescribed to all patients for at least 1 year after stent implantations, and aspirin was given indefinitely.Echocardiography was performed using a Philips IE33 ultrasound machine  with an M4S transducer according to the recommendations of the American Society of Echocardiography . The perThe 2D echocardiography images (transmit/receive 1.9/4.0 MHz) were obtained from several views with frame rates of 30–90 frames/s. Digital data were stored and analyzed off-line. LV endocardial surface was traced manually, and the speckle tracking width was modified to cover the whole LV wall thickness so as to obtain curves for the peak longitudinal strain of: (a) the inferior septum and lateral wall in the apical four-chamber view (4C-PLS); (b) the inferior and anterior walls in the apical two-chamber view (2C-PLS); and (c) the inferior lateral and anterior septum in the apical three-chamber view (3C-PLS). LV global longitudinal systolic strain (GLS) was calculated by averaging the peak systolic values of the six LV walls. All the echocardiographic studies were performed by one echocardiographer. In terms of intraobserver variability, a sample of 2D strain was randomly selected and examined by the same observer in 2 days and the intraclass correlation coefficients were also calculated. All data were analyzed using Philips QLAB Advanced ultrasound quantification software (release 8.1).t test or chi-square analysis. Statistical significance was defined as a p value of less than 0.05.The collected data were analyzed using the Statistical Package for Social Science . Differences among groups were compared using the two-tailed Student’s All the images of the 43 patients were suitable for analysis. Improvement of LVEF by CTO-PCI was observed at up to 3 and 6 months. The clinical characteristics of the 43 patients are listed in Table The 2D-STE revealed that GLS Fig a, b was These results indicated that 2D-STE could detect early subclinical LV systolic dysfunction in CTO patients after percutaneous revascularization.This study found that the LVEF tended to improve at approximately 3 and 6 months after percutaneous revascularization in patients with CTO. Using 2D-STE, GLS was observed to be restored as early as 1 day after CTO-PCI. These results demonstrate that 2D-STE is a reliable way to monitor early subclinical LV changes.Myocardium in the perfusion territory of a CTO can be functional, dysfunctional but viable, or dysfunctional and nonviable –16. The In this research, improvement of LVEF was observed for up to 3 and 6 months. However, by 2D-STE, the GLS improvement was observed as early as 1 day after CTO-PCI. 2D-STE is an automated and quantitative technique for the measurement of cardiac mechanics, which is based on the speckle interference of ultrasound beams within tissues. Speckles are tracked on a frame-by-frame basis throughout the cardiac cycle , which hSystolic dysfunction might initially appear in the longitudinal direction, as the longitudinally oriented subendocardial fibers are more vulnerable to myocardial ischemia and fibrosis. GLS correlates well with EF measured by echocardiography, and GLS is a superior predictor of outcome compared with LVEF . The EF There are several limitations in this study. There was a lack of control patients without intervention. Drug and other treatments may synergize the effects of revascularization on LV function. Only three time points were used in the follow-ups. More time points should be included to describe continuous improvement of heart function.PCI treatment can effectively improve LV function in patients with CTO. The results of this study provide evidence to support the clinical use of 2D-STE to monitor the early changes of LV function.


Gelsolin (AGel) amyloidosis is a hereditary condition with common neurological effects. Myocardial involvement, especially strain, T1, or extracellular volume (ECV), in this disease has not been investigated before. Local myocardial effects and possible amyloid accumulation were the targets of interest in this study. Fifty patients with AGel amyloidosis were enrolled in the study. All patients underwent cardiovascular magnetic resonance imaging, including cine imaging, T1 mapping, tagging, and late gadolinium enhancement (LGE) imaging at 1.5 T. Results for volumetry, myocardial feature-tracking strain, rotation, torsion, native T1, ECV, and LGE were investigated. The population mean native T1 values in different segments of the left ventricle (LV) varied between 1003 and 1080 ms. Myocardial mean T1 was 1031 ± 37 ms. T1 was highest in the basal plane of the LV (1055 ± 40 ms), similarly to ECV (30.0% ± 4.4%). ECV correlated with native T1 in all LV segments (p < 0.005). Basal LGE was detected in 76% of patients, and mid-ventricular LGE in 32%. LV longitudinal strain was impaired (− 17.4% ± 2.6%), significantly decreasing apical rotation (p = 0.018) and concurrently myocardial torsion (p = 0.005). LV longitudinal strain correlated with mean T1 and ECV of different LV planes . Myocardial involvement in AGel amyloidosis is significant, but the effects are local, focusing on the basal plane of the LV. Hereditary gelsolin (AGel) amyloidosis is a Finnish dominantly inherited systemic amyloidosis. Neurological characteristics of the disease include cranial and peripheral neuropathy, corneal dystrophy, and skin disease , 2. SeveCardiovascular magnetic resonance (CMR) imaging is a valuable clinical tool in diagnosis of myocardial diseases. Unlike other imaging modalities, CMR enables characterization of tissue composition using fundamental magnetic properties. Combining this capability with the possibility for regional motion analysis makes CMR the top choice for repeatable, investigational use.CMR facilitates non-invasive and repeatable quantitative tissue characterization through relaxation time mapping, myocardial strain analysis, and late gadolinium enhancement (LGE). The present study was designed to evaluate and characterize cardiac involvement in patients with AGel amyloidosis. We used novel and conventional CMR methods, including T1 mapping, extracellular volume (ECV) analysis, LGE imaging, tagging, and feature tracking (FT).Fifty patients with Finnish hereditary AGel amyloidosis were included in this prospective study. Patients were selected from the patient registry of Finnish Gelsolin amyloidosis (FIN-GAR). Patients selected from the registry had a biopsy and genetic testing. All Finnish patients to date have been confirmed to carry gelsolin gene mutation G654A. The disease penetrance is 100%, meaning all patients show symptoms of the condition. Mean age of the patients was 66 ± 7 years. Exclusion criteria for the study population were (1) age below 50 years, (2) implanted cardiac pacemaker, (3) claustrophobia, and (4) implanted metal objects that could interfere with CMR. Patients selected were older than 50 years due to disease progression beginning at an older age [fit system . The scans were performed using a 32-channel cardiac receiver coil with retrospective electrocardiographic gating. Images were acquired in breath-hold to minimize breathing artifacts. The scan protocol included stacks of balanced steady-state free precession (bSSFP) cine images with 30 temporal phases in short-axis direction and a 4-chamber stack in long-axis direction. Pre-contrast and post-contrast shortened modified look-locker inversion recovery  T1 mapping, tagging, and inversion recovery spoiled gradient echo LGE images were acquired in the same basal, mid-ventricular, and apical planes. Gadolinium-based contrast agent  of 0.2 mmol/kg was used as a contrast agent. BSSFP-cine images, pre-contrast T1 mapping, and spatial modulation of magnetization (SPAMM) tagging were acquired prior to contrast agent administration. LGE images were acquired 5 min and post-contrast T1 mapping 12 min after the contrast agent administration. Cine images were analyzed for volumetric data and strain data. The volumetric analysis was performed using QMass MR software v7.6 . FT strain, tagging, T1, and ECV analysis were performed with Segment v2.2 R6190  [All patients underwent CMR scan using a 1.5 T AvantoBasal, mid-ventricular, and apical short-axis and 4-chamber long-axis cine images were selected for FT analysis at end-diastole according to Taylor et al. . EpicardTagging images were used to derive peak apical and basal rotation and peak LV myocardial torsion. Torsion is defined as the difference between apical and basal rotation, normalized with the long-axis distance between the slices and mean radius of the slices. Tagging images were acquired in addition to cine images since myocardial rotation is best recorded with the tagging grid pattern. In the normal cine images, the myocardial wall is homogeneous and rotational analysis is unreliable; rotation results have been shown to have no acceptable agreement between tagging and FT . TaggingThe T1 images were used to derive pre-contrast and post-contrast T1 maps. The motion corrected pre-contrast ShMOLLI images were first loaded into Segment. Then, epicardial and endocardial borders were imported from the FT analysis to the T1 images, the segmentation was verified visually, and corrected manually if needed. The software was used to generate pre-contrast and post-contrast T1 maps. Regions of interests (ROIs) were placed on the T1 maps according to the AHA 17-segment model using the built-in tool to match the segments of the strain analysis. The ROIs were cropped 20%  from the epicardial and endocardial borders to avoid artifacts. ROIs placed in the pre-contrast T1 maps were copied to the post-contrast maps . Results are reported as mean ± standard deviation. Continuous variables were compared using independent samples Student’s t-test. No equal variances were assumed. Correlations were calculated using Pearson correlation coefficient. The tests used were two-sided, and p-values < 0.05 were considered significant.2). Apical rotation (8.6° ± 3.7°) was higher than basal rotation (− 3.5° ± 2.4°), as anticipated.Volumetric data and tagging results are presented in Table Strain and strain rate values for different LV segments and mean values are presented in Table In the mid-ventricular plane, peak CS and systolic and diastolic CSR were significantly decreased in the inferior and anterolateral segments (p < 0.025). RS or RSR was not significantly different in any segment relative to the others. In the apical imaging plane, there were no significant differences in the segments in any of the strain parameters.Mean CS values of different planes were similar at basal and mid-ventricular levels in both ventricles, the mean CS was the highest in the apical plane in both ventricles. Mean CSR, RS, and RSR were similar in all planes in both ventricles. The peak longitudinal strain (LS) and systolic and diastolic longitudinal strain rate (LSR) were higher in RV than in LV (p < 0.007).Native T1, ECV, and LGE values are presented in Table ECV was below 30% in all mid-ventricular and apical segments. At the basal level, ECV was over 30% in anteroseptal, inferoseptal, inferior, and inferolateral segments. ECV was the highest in the basal anteroseptal segment (32.0% ± 6.5%); in this segment, ECV of over 35% was detected in 19 patients (38%), and the highest single ECV in this segment was 53%. ECV values of different segments correlated significantly with corresponding T1 values (p < 0.005), as expected.LGE in the basal plane was detected in 38 patients (76% of the study population). LGE was mostly located in the basal septum or RV insertion point, and it was either patchy or subepicardial. Average LGE percentage (in relation to LV mass) was 6 ± 3%. Basal anteroseptal and basal inferior were the segments with the highest amount of LGE detected; 25 patients (50%) had LGE in these segments. At the mid-ventricular level, 14 patients (28%) had LGE in the inferior segment. In other mid-ventricular segments, only single patients had LGE. Only one patient had an apical LGE.Peak LV LS correlated with mean T1 and ECV values of the LV (p < 0.044). The correlations were especially significant in the basal plane (p < 0.01) Fig. . AdditioIn circumferential and radial directions, the only significant correlations were found in the basal plane, between LGE and peak diastolic CSR  and diastolic RSR . Increased LGE decreased peak diastolic CSR and RSR. Even though peak CS and RS were significantly decreased in some segments of the LV, no clear correlation in segmental values with T1, ECV, or LGE was found.This is the first study assessing myocardial motion, T1 relaxation, and ECV of AGel amyloidosis with CMR. We were specifically interested in amyloid accumulation in the myocardium since myocardial involvement is often a prognostic factor in amyloidosis . Our resIn cardiac amyloidosis, LV volumes and EF are commonly preserved, but LV wall thickness is increased . In our Peak strain values of different LV and RV short-axis planes and RV long-axis direction were within normal range , 15. NorNative myocardial mean T1 values were significantly increased (p < 0.0001) when compared with normal myocardial values acquired from a healthy reference population  using the same scanner and ShMOLLI pulse sequence. However, the native T1 values were lower than commonly observed in other types of cardiac amyloidosis . In prevIn addition to elevated ECV, LGE is a common finding in the main types of cardiac amyloidosis. LGE pattern in cardiac amyloidosis may vary and be nonspecific. In AL amyloidosis, global, subendocardial LGE is most common, whereas in ATTR amyloidosis the pattern of LGE is often more extensive and transmural . In our The study was limited to a relatively minor population for quantitative CMR analysis. Patients with cardiac pacing devices were excluded from the study. As AGel amyloidosis may require pacemaker systems to be implanted in patients during later phases of the disease, the results might have been different at more advanced stages of the disease. Pacemaker devices, however, may impair the image quality in CMR, affecting the reliability of analysis. Furthermore, the patient population selected in this study was over 50 years old and does not represent the entire population of AGel amyloidosis. The selection was made on prior knowledge of disease progression. Intra-observer and inter-observer variability of the results were not assessed. CMR FT has been shown to have inter-software variability in both feasibility and absolute strain values . HoweverContrary to the main types of cardiac amyloidosis, myocardial effects in patients with AGel amyloidosis are mainly local, focused on the basal plane of the left ventricle. Although majority of patients had LGE in this patient population, high increase in T1 or ECV was not detected.


Early detection and treatment of cardiotoxicity from cancer therapies is key to preventing a rise in adverse cardiovascular outcomes in cancer patients. Over-diagnosis of cardiotoxicity in this context is however equally hazardous, leading to patients receiving suboptimal cancer treatment, thereby impacting cancer outcomes. Accurate screening therefore depends on the widespread availability of sensitive and reproducible biomarkers of cardiotoxicity, which can clearly discriminate early disease. Blood biomarkers are limited in cardiovascular disease and clinicians generally still use generic screening with ejection fraction, based on historical local expertise and resources. Recently, however, there has been growing recognition that simple measurement of left ventricular ejection fraction using 2D echocardiography may not be optimal for screening: diagnostic accuracy, reproducibility and feasibility are limited. Modern cancer therapies affect many myocardial pathways: inflammatory, fibrotic, metabolic, vascular and myocyte function, meaning that multiple biomarkers may be needed to track myocardial cardiotoxicity. Advanced imaging modalities including cardiovascular magnetic resonance (CMR), computed tomography (CT) and positron emission tomography (PET) add improved sensitivity and insights into the underlying pathophysiology, as well as the ability to screen for other cardiotoxicities including coronary artery, valve and pericardial diseases resulting from cancer treatment. Delivering screening for cardiotoxicity using advanced imaging modalities will however require a significant change in current clinical pathways, with incorporation of machine learning algorithms into imaging analysis fundamental to improving efficiency and precision. In the future, we should aspire to personalized rather than generic screening, based on a patient’s individual risk factors and the pathophysiological mechanisms of the cancer treatment they are receiving. We should aspire that progress in cardiooncology is able to track progress in oncology, and to ensure that the current ‘one size fits all’ approach to screening be obsolete in the very near future. With more than 14 million new diagnoses of cancer in 2018 alone 48]. StreMore recently, CMR-derived GLS (using feature tracking) has been shown to detect LV dysfunction before LVEF falls  and to bLeft ventricular dysfunction is the most frequent final manifestation of cardiotoxicity, but may result from a variety of different, treatment-specific, pathophysiological mechanisms  includinCMR adds value because of its myocardial tissue characterisation capabilities with growing evidence within cardiooncology Fig. . GadolinCMR can also detect myocardial oedema and inflammation using T2-weighted imaging sequences, with higher T2 relaxation times seen with increasing myocardial water content. Parametric mapping techniques have been developed to quantify T2 relaxation times, and recent data from a pig model of doxorubicin-induced cardiotoxicity using serial multiparametric  mapping has shown that T2 values provide the earliest marker of myocardial damage •. Myocar18F-FDG uptake predicting a progressive increase in cardiac glucose consumption during and after chemotherapy, as well as a higher incidence of cardiotoxicity [PET imaging can detect alterations in myocardial metabolism and inflammation , offerintoxicity .Whilst cardiotoxicity related to cancer therapy generally focuses on left ventricular impairment , cancer Several cancer treatments have been implicated in the development of myocardial ischaemia and coronary events including myocardial infarction, including fluoropyrimidines, platinum compounds, VEGF inhibitors, certain bcr-abl tyrosine kinase inhibitors and radiotherapy •• Table. Pathoph. Importantly, surgical outcomes in these patients are worse than in a matched cohort of patients undergoing valve replacement [Valve disease is a rare complication of chemotherapy, however is well-recognized as a late consequence of high-dose radiotherapy to the mediastinum . There is a latent interval of 10–20 years between radiation exposure and development of clinically significant heart valve disease, with risk related both to radiation dose and interval from exposure, with reported prevalence rates of 5–32% in patients treated for Hodgkins lymphoma . Importalacement , meaninglacement .Echocardiography remains both the first-line and gold standard imaging modality for functional assessment of valvular heart disease, allowing qualitative and quantitative evaluation of both stenotic and regurgitant valves. Computed tomography and CMR  can alsoPericardial disease is a common finding with cancer therapy, and pericarditis, pericardial effusion and constrictive pericarditis are all seen associated with both chemotherapy agents , and mediastinal radiotherapy . PericarAlthough a rare complication of cancer therapy, development of pulmonary hypertension has been observed with dasanitib  is 5%), cyclophosphomide and other alkylating agents , 107. EcWhilst echocardiography is generally the initial modality to detect cardiac masses , assessing for tissue invasion and for differentiating mass aetiology generally requires advanced imaging techniques. CT has the spatial resolution to accurately determine the location, size and relationship of the mass to tissue planes, but CMR plays a key role , 109 in 99mTc-PYP and 99mTc-DPD) can help differentiate light chain (AL) from transthyretin amyloidosis and a novel PET radiotracer (18F-florbetapir) [Patients with myeloma and other haematological malignancies rarely develop light chain amyloidosis, which may present with cardiac amyloidosis—an infiltrative cardiomyopathy, often presenting as heart failure with preserved ejection fraction (HFPEF). The diagnosis is often suspected from the characteristic echocardiographic appearances of left ventricular hypertrophy, preserved LV function, impaired RV function and profound apical sparing on strain maps . Endomyobetapir)  has receImproved outcomes in oncology mean that it is increasingly important to prevent, detect and treat any early signs of treatment-related cardiotoxicity so patients can receive optimal cancer treatment but minimize subsequent cardiovascular morbidity and mortality. Advanced cardiac imaging techniques offer more sensitive and reproducible screening options than conventional 2D echocardiography or MUGA, and may provide novel insights into the underlying pathophysiology of CTRCD. The development of novel cancer treatments is currently rapid, and often cardiotoxicity is not detected until after initial phase 1 and 2 safety trials , with th