Tumour biopsies specimens were collected after imaging and cellularity was measured from histology. Total 23Na-MRI scan time for each patient was approximately 11 min. At an isotropic resolution of 5.6 mm, signal-to-noise ratios (SNRs) of 82.2 ± 15.3 and 15.1 ± 7.1 (mean ± standard deviation) were achieved for imaging of tumour tissue sodium concentration (TSC) and intracellular weighted sodium concentration (IWS) respectively. Tumour TSC and IWS concentrations were: 56.8 ± 19.1 mM and 30.8 ± 9.2 mM respectively and skeletal muscle TSC and IWS concentrations were 33.2 ± 16.3 mM and 20.5 ± 9.9 mM respectively. There were significant sodium concentration differences between cancer and skeletal muscle, Wilcoxon signed-rank test, P <  0.001 for TSC and P =  0.01 for IWS imaging. Tumour cellularity displayed a strong negative correlation with TSC, Spearman’s rho = -0.92, P <  0.001, but did not correlate with IWS. This study demonstrates that 23Na-MRI using 3D-cones can rapidly assess sodium concentration in peritoneal deposits of HGSOC and that TSC may serve as a biomarker of tumour cellularity.The aim of this study was to assess the feasibility of rapid sodium MRI ( HGSOC oHGSOC lesions demonstrate significant intra- and intertumoural heterogeneity that can affect progression and survival . Multi-r+IC] is usually around 5–15 mM and extracellular sodium concentration [Na+EC] ranges from 135 to 155 mM. Overall tissue sodium concentration (TSC) is a weighted average of the intracellular sodium concentration and the extracellular sodium concentration. The weighting in this average is related to the cellularity of the tissue as higher cellularity corresponds to a greater fraction of intracellular space and consequently a lower TSC. Measurements of TSC could therefore potentially be used to probe cellularity and changes in cellularity such as with cell death in response to chemotherapy.In human tissue the sodium ion concentration is approximately ten times higher in the extracellular compartment compared to the intracellular space. Intracellular sodium concentration [Na+/K+-ATPase pump, also known as the sodium pump. Cell membrane porosity increases occurs early on in the process of cell death, allowing greater sodium movement into the cell down the electrical and concentration gradients that exist across the membrane. This intracellular influx of sodium is associated with an osmotic movement of water that contributes to cell swelling prior to death [23Na-MRI) can measure TSC and the ability of 23Na-MRI to assess tissue viability in the brain after acute stroke has already been demonstrated in several studies [23Na-MRI has also successfully detected the response of tumour to chemotherapy [23Na-MRI can detect cell viability and cellularity in HGSOC, then 23Na-MRI may be of clinical value for monitoring both the early and late tissue changes following successful chemotherapy treatment, as responding cells first undergo an increase in sodium and swelling before death, followed by a decrease in tumour cellularity and intracellular volume fraction as the process of death completes.The free movement of sodium between the intracellular and extracellular compartments is normally restricted by the phospholipid bilayer of the cell membrane which is poorly permeable to sodium. The majority of sodium ions that cross the cell membrane do so through specialized ion transporters like the Nato death . An incrto death ,6. Sodiu studies ,8. In muotherapy ,10. In Hotherapy . If TSC 23Na-MRI, the intracellular weighted sodium (IWS) signal can also be separated from the overall tissue sodium signal using an inversion recovery pulse sequence that exploits a difference in the T1 relaxation times of free and bound sodium. Increased TSC and IWS concentrations compared to normal tissue have been found using 23Na-MRI in several cancers including brain, breast and prostate [23Na-MRI has proved technically challenging. 23Na-MRI generates a signal which is 22,000-fold smaller than conventional proton MRI (1H-MRI) [In prostate . In the (1H-MRI)  and the 23Na-MRI signal. Previous studies of the abdomen have reported scan times of 16–25 min for the generation of quantitative sodium maps [23Na-MRI in the brain however was recently shown to improve acquisition times compared to the more widely used 3D-radial k-space sampling methods, without any compromise in image quality [23Na-MRI using 3D-cones to the imaging of peritoneal cancer deposits in HGSOC and explore the relationship of histologically measured tumour cellularity with the imaging.Longer scan times that permit signal averaging can compensate for the low ium maps . Such lo quality . Here we22.1This was a single centre prospective observational study  with institutional review board (IBR) approval (South Cambridge Research Ethics Committee reference number 15/EE/0378). All study related procedures were performed with the written informed consent of participants and in accordance with the ethical guidelines outlined in the Declaration of Helsinki. Consecutive HGSOC patients presenting from August 2016 to August 2017 with no contraindications to MRI and no previous treatment for their cancer were invited to participate.2.223Na-MRI and 1H-MRI were carried out on all patients using a 3 T MR system . The 23Na-MRI was performed with a custom made single-channel transmit/receive surface coil using a 3D-cones readout [2-weighted 1H-MRI was performed with a fast spin echo pulse sequence and a 32-channel cardiac array. Patients were not moved or repositioned during the coil change. The radiofrequency (RF) power used for the 23Na-MRI was adjusted for each patient to achieve penetration up to a maximum depth of 12 cm which was sufficient to image the peritoneal lesions in all cases. Detailed scan parameters for sodium and proton imaging are given in  readout  and an aSodium calibration phantoms were included in the field of view (FoV) to enable calculation of sodium concentration maps. Phantoms consisted of 50 mL tubes of diameter 6 cm containing sodium chloride (NaCl) with 4% agar at two sodium concentrations: 20 mM and 80 mM.Image processing and noise correctionSodium image reconstruction and post-processing were performed with in-house software written in MATLAB v9.2 . The method described by Miller et al. was applied for noise correction : this coRadiofrequency field inhomogeneity correction1 correction was applied to the sodium images. A dual flip angle gradient echo method [1 mapping to create an RF map (B1 map) of the true flip angle 1 maps which had very low effective flip angles (<10°) or high flip angles (>140°) where dual angle mapping is inaccurate [To compensate for RF inhomogeneity in the FoV, a Bo method  with imaaccurate  were exc1 of a surface coil [1, causing the overall relationship of the combined receive and transmit signal to reduce to approximately:A correction formula was derived to use ace coil . For the2.32-weighted images by a single observer using OsiriX  around the complete peritoneal deposits and around the adjacent areas of right gluteal muscle as a normal reference tissue for comparison with the tumour. ROIs were reviewed by a radiologist with eight years of experience as an attending physician and co-registered with the sodium maps to which the ROIs were imported for analysis. For patients with multiple peritoneal deposits, ROIs were combined into a single tumour volume.Sodium maps (TSC and IWS) were calculated from a linear calibration curve created with the sodium in agar phantoms based on the method described by Christensen JD et al. . ROIs we2.42 as follows:Tissue samples were collected from the peritoneal deposits of patients 1–14 days (median 7 days) after imaging either by ultrasound guided biopsy or at surgery. Samples were fixed in paraffin blocks for storage and cut into 3 μm sections that were retrieved with sodium citrate. Sections were stained with haematoxylin and a cell count and tissue area quantification were performed on the sections using automated histology image analysis software . Cellularity (cell density), 2.5t-test or Wilcoxon test was then applied to evaluate significance. Cellularity was compared to sodium concentrations from 23Na-MRI (TSC and IWS) using Spearman’s correlation.All statistical analysis was performed in R . For comparison of means, the Shapiro-Wilk test was used to assess data for normality and the Student’s 33.1Twelve high grade serous ovarian cancer patients were recruited: median age 69 (range 52–81) years. 3.223Na-MRI imaging time for each patient was under 11 min . Signal-to-noise ratios of 82.2 ± 15.3 and 15.1 ± 7.1 were achieved for tumour TSC and IWS imaging respectively. High signal intensity artefacts appeared at the edges of images after RF field inhomogeneity corrections because of small mismatches in alignment between B1 maps and sodium signal images at the interfaces of high sodium signal changes such as between air and tissue. These mismatches were due to patient movement and were found exclusively at imaging borders and therefore were not present in ROIs derived from peritoneal deposits or muscle. Examples of the 23Na-MRI images and changes with post-processing are shown in The total 3.3P <  0.001. IWS values for peritoneal cancer and muscle were 30.8 ± 9.2 mM and 20.5 ± 9.9 mM respectively; Wilcoxon signed-rank test, P =  0.01. These results are summarised in the boxplots of medians and interquartile ranges shown in The TSC for peritoneal cancer deposits and gluteal skeletal muscle were 56.8 ± 19.1 mM and 33.2 ± 16.3 mM respectively (mean ± standard deviation); Wilcoxon signed-rank test, P <  0.001. There was no significant correlation found between IWS concentration and cellularity, P =  0.44.An example of the typical histological appearances for a 73-year old HGSOC patient are shown in 423Na-MRI to image peritoneal lesions in high grade serous ovarian cancer patients for the first time. The completion of sodium imaging in approximately eleven minutes was achieved with a combination of a 3D-cones readout, a surface transmit/receive coil and a post-processing analysis method to correct for RF field non-uniformity. Short acquisition times are important for the clinical translation of 23Na-MRI and these results represent a moderate improvement to previously reported scan times in the abdomen [23Na-MRI is an effective biomarker for tumour cellularity.This study demonstrated the feasibility of using  abdomen . The comCellularity has already been shown to relate to the outcome of cytoreduction in HGSOC  and to b23Na-MRI demonstrated here provides information on tumour composition and can be employed to monitor the evolution of tumour cellularity over time and following treatment. This could additionally have implications for patient management in other malignancies where the detection of cell death and the monitoring of cellularity changes are of clinical relevance like in breast cancer.With the emergence of new therapies in heterogeneous cancers like HGSOC, there is an associated need for imaging to provide greater detail on tumour structure and function so that patients can be better stratified to the optimal treatment for their particular subtype of disease. The availability of alternative therapies also provides the opportunity for non-responsive patients to switch to more effective drugs and imaging tests that can assess response are therefore similarly required. The measurement of cellularity with 23Na-MRI also reflects the activity of transporters such as the Na+/K+-ATPase pump, and possibly by extension ATP levels, which may be altered earlier than cellularity in some physiological processes like cell death. 23Na-MRI could therefore potentially report on response to treatment earlier than other imaging methods like diffusion weighted MRI, which primarily also detects cellularity and probe processes like metabolism and transporter activity which diffusion cannot.Apart from cellularity, +/H+ antiporter activity which allows sodium to enter the cell in exchange for H+ efflux, and creates an acidic extracellular environment that facilitates tumour invasion [Despite the strong significance of the relationship between TSC and cellularity found here, no correlation between cellularity and IWS could be detected. IWS concentration in cancer is influenced by a large number of biological processes that may have a greater relative effect on the small IWS concentration and imaging signal than cellularity. For example, the IWS signal may be affected by the energy status of tumours due to the ATP and oxygen requirements of the sodium pump . In cancinvasion .TSC signal is dominated by the high concentration of sodium in the extracellular space and is less susceptible to the transmembrane movement of sodium as it is a measure of the total tissue sodium in each voxel, including signal from sodium in both the intracellular and extracellular environments. By comparison, the IWS pulse sequence nulls the large extracellular sodium pool with its inversion recovery, resulting in a much lower SNR and greater susceptibility of IWS measurements to noise.The conclusions that can be drawn from the findings in this study are limited by the possibility of errors introduced through patient movement during the sodium/proton coil change and the creation of edge artefacts in post-processing. The optimisation of RF power to image superficial peritoneal lesions also meant that muscle sodium measurements could not include deeper muscle regions. Reasonable measures were taken to minimise the effects of these limitations by masking possible inaccurate sodium map areas and the application of an RF inhomogeneity correction.523Na-MRI using 3D-cones was successfully performed in a technically challenging area of the body. This study shows for the first time that 23Na-MRI can assess peritoneal deposits of HGSOC patients and that the TSC measured by 23Na-MRI correlates strongly with tumour cellularity. The non-invasive quantification of sodium using MRI has the potential to provide information on cell viability, sodium transporters, metabolic activity, cell membrane integrity and tumour response to therapy. The rapid scanning method shown here demonstrates that larger human studies to evaluate 23Na-MRI in the abdomen are feasible and should be supported. Further work is needed to investigate other clinical applications of sodium MRI, to explore the utility of TSC in monitoring cellularity changes in response to specific cancer treatments and to validate the cellular changes that can be measured with 23Na-MRI.In conclusion, rapid Cancer Research UK grant (Grant reference C19212/A16628).To provide funding for the costs of this research. Funding was obtained from a The authors have no conflicts of interest to declare.


Objectives: Masked hypertension (MH) is not uncommon in the youth and may increase risks of long-term cardiovascular impairment. However, little is known about the subclinical heart damage in this group of patients. Currently, 3-layer speckle tracking imaging based on two-dimensional echocardiography is feasible to detect the early signs of myocardial damage. We therefore aimed to investigate whether subtle changes of cardiac function occurred in the young MH patients by using advanced quantification with layer-specific speckle tracking.Methods: A total of 40 adolescents with MH  and 40 age-, gender-, race-, and height-matched normotensive volunteers were enrolled in our study. MH was defined as one or more of the ambulatory blood pressure (BP) parameters  higher than ≥ 95th percentile for gender and height according to the local reference. Both comprehensive two-dimensional echocardiography with layer-specific strain analysis and 24-h ambulatory BP monitoring were performed. Longitudinal strain and circumferential strain in endocardial, mid-myocardial, and epicardial layers were determined accordingly with the dedicated software .Results: Compared with normotensive controls, youths with MH had higher ambulatory pulse rate and left ventricular mass index, and were more obese. Interestingly, similar ventricular volumes and ejection fraction were observed in the study groups, but further analysis with layer-specific strains revealed that endocardial and mid-myocardial longitudinal and circumferential mechanical function were decreased in the young MH subjects when compared to normotensive individuals . However, there were no difference regarding radial strain and apical rotation derived from traditional speckle tracking analysis.Conclusion: Subclinical change of LV mechanic function assessed by layer-specific speckle tracking is present in youth with MH despite considered as normal with conventional ways.Thus, MH in youth should be monitored closely instead of labeling as an entirely benign entity. Masked hypertension (MH) has recently become a topic of interest in youths; it refers to a condition in which office blood pressure (BP) is normal but being elevated during ambulatory BP monitoring . ActuallTwo-dimensional (2D) speckle-tracking echocardiography (STE), capable of obtaining quantitative measurements of whole-layer longitudinal, circumferential, and radial directional deformation without the angle dependency of one-dimensional techniques, has been well recognized to allow easily early detection of myocardial damage while left ventricular (LV) ejection fraction (LVEF) is still preserved in various pathologies –9. RecenThus, this study for the first time provided the new insight to LV mechanical function in youths with MH, and assessed the occurrence of early echocardiographic signs of subclinical left ventricular dysfunction in this young group, using advanced quantification with layer-specific 2D speckle tracking.This was a community-based cohort study, which initially enrolled 1445 ethnic Chinese students for surveying 24-h ambulatory BP in Hong Kong during 2011/2012. The presented local reference was used for the definition of MH in Chinese adolescents as one or more of the ambulatory BP parameters  were higher than 95th percentile for age, gender and height, and the office BPs were normal . TotallyAnthropometric measurements  and laboratory analyses  were obtained from all the subjects included in the study. Body mass index (BMI) and body surface area (BSA) were calculated for each subject. The study was approved by the Joint the Chinese University of Hong Kong and New Territories East Cluster Clinical Research Ethics Committee and the Ethics Committee of the Department of Health of the Hong Kong Government (CRE-2013.563). Informed consent was obtained from the participants and their parents before commencement of the monitoring.Conventional BP measurements were obtained by measuring the average value of the 3 consecutive measurements in the sitting position, at least 1 min apart and after 5 min of rest, using the Datascope Accutorr Plus , which has been validated in our local Chinese children and adolescents , 18. AppAll the participants underwent a 24-h BP monitoring. The non-invasive 24-h ambulatory BP monitoring was performed on the non-dominant arm during a weekday with typical activities, using a portable non-invasive oscillometric recorder . The ABP readings will be obtained every 30 min over a 24-h period. Only ABP profiles with at least 40 recordings, including at least eight readings during sleep, will be accepted. Individual mean systolic, diastolic and mean arterial BP will be calculated for wake and sleep periods. All readings taken during 24 hours will be used to calculated mean 24-h, mean daytime and mean night-time SBP and DBP, in accordance with the method proposed by Soergel et al. . Local r2.7 , within 2–3 days after 24-h BP monitoring. Routine 2D cine loops of three consecutive cardiac cycles were obtained at end-expiratory apnea from parasternal long-axis and short-axis views and the standard three apical views  by the same operator. Grayscale recordings were optimized for LV evaluation at a frame rate between 50 and 70 fbp and saved for subsequent strain analyses. LV volume and LVEF were calculated with biplane Simpson method. Left ventricular mass index was determined according to the corrected method of the American Society of Echocardiography (ASE) and indexed to body height2.7 .All data of 2D speckle tracking were analyzed off-line using the dedicated EchoPAC V201 software . The advanced software automatically tracked the contour of endocardium to cover the myocardial thickness of the entire LV wall at an end-diastolic frame, similarly to traditional 2D-STE method, but allowing investigation of three myocardial layers for longitudinal and circumferential strain: endocardial, mid-myocardial and epicardial level. Adequate tracking could be verified in real time and corrected by manual to ensure optimal tracking of endocardium and epicardium and inclusion of the entire LV thickness including endocardial, mid-myocardial and epicardial layers in all observed echocardiographic views .t-tests for continuous variables, as well as the chi-square test and Fisher's exact test for categorical variables. The P < 0.05 was considered statistically significant.Collected data were computerized and analyzed using the IBM SPSS Statistics, version 20 (IBM) software. Continuous variables are expressed as mean ± SD and nominal variables as percentages. Data were compared between 2 groups using the independent sample None of subjects was found to be primary or secondary hypertensive. Patient characteristics are presented in Table 2.7 was significantly higher in cases than in normotensive individuals. There was no significant difference in the LV wall thickness, ventricular volumes and LVEF between the observed groups. Interestingly, young subjects with MH had lower mitral E/A ratio and mitral annulus e′ when compared with normotensive individuals , but no difference in E/e′.Routine echocardiographic features of the study population were shown in Table 2D-STE derived LV global LS and CS were significantly lower in youth with MH than in controls. Moreover, comparing with true normotensives, LV systolic and early diastolic longitudinal strain rates in MH subjects were significantly decreased, while late diastolic strain rates tended to increase in MH, although without statistically significance Table . Howeverp < 0.05)  to validate the layer-specific strain determined by 2D-STE. However, Altiok E et al. reported that the layer-specific strain using cardiac MRI demonstrated good correlations with the layer-specific strain using 2D echocardiography . Of noteWith layer-specific 2D-STE, subclinical impairment of LV mechanical function in different myocardial layers is present in youth with MH, despite considered as normal with conventional ways. Thus, periodic follow-up and early detection of LV functional deterioration in young MH patients may help to prevent the natural progression of the disease.M-CY, H-KS, and FF conceived and designed the experiments. X-XL, H-KS, and YZ organized the database. X-XL and YS performed the echocardiographic images analysis and statistical analysis. X-XL wrote the first draft of the manuscript. X-XL, YS, QG, and JS wrote sections of the manuscript. All authors have read and revised the manuscript, which was coordinated by FF and YZ, who also produced the final draft for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We have read with interest the Korean Society of Hypertension guidelines for the management of hypertension and congratulate the Society for an extensive review of literature while drafting the guidelines. The guidelines indicate preferring ACE-I and CCB over diuretics in patients with left ventricle hypertrophy. However, in landmark head-to-head comparison trials, the thiazide-like diuretic chlorthalidone has been shown to be superior to ACE-I and CCB in decreasing left ventricle mass and preventing heart failure in hypertensive patients. Also, we put forth the paradoxical finding that mere regression of LVH may not always translate into reduction in risk of HF; and that the pleiotropic effects of chlorthalidone may be the explanation behind its beneficial action in HF. Dear EditorIt is well established that chronically increased LV workload in hypertensive patients triggers cardiac remodelling, development of LVH, increased risk of heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) and, ultimately, death , 3. ThusTable 11 in the Guidelines   . Further 0.032)] –17.An interesting recent analysis of the ALLHAT data-set looked at the extent to which the effect of an anti-hypertensive on incident HF is mediated by evolving LVH. The researchers found that the beneficial effects of CTD in reduction of HF were entirely independent of evolving LVH, leading them to postulate that that the mechanisms by which chlorthalidone prevented HF were not restricted to prevention of LVH . In contThe ACC-AHA 2017 Guidelines  state thThe ESC-ESH 2018 Guidelines while discussing left ventricular hypertrophy and heart failure observe that “Treating hypertension has a major impact on reducing the risk of incident heart failure and heart failure hospitalization, especially in old and very old patients. This has been observed using diuretics, beta-blockers, ACE inhibitors, or ARBs, with CCBs being less effective in comparative trials. Reducing BP can also lead to the regression of LVH, which has been shown to be accompanied by a reduction of CV events and mortality. The magnitude of LVH regression is associated with baseline LV mass, duration of therapy, the SBP reduction, and the drugs used, with ARBs, ACE inhibitors, and CBBs causing more effective LVH regression than beta-blockers or diuretics” [Canada Hypertension Guidelines 2018 recommend that in treatment of HT in association with LVH “Initial therapy can be drug treatment using ACE inhibitors, ARBs, long-acting CCBs, or thiazide/thiazide-like diuretics. Antihypertensive treatment should include an agent from one of the five major classes in patients with LVH, with care given to the inferiority of β-blockers in patients with LVH” .The 2016 National Heart Foundation of Australia Guidelines  state thOther hypertension guidelines: Finally, it is important to discuss similar recommendations from other recent hypertension guidelines.We have read with interest the Korean Society of Hypertension guidelines for the management of hypertension: part II-diagnosis and treatment of hypertension by Lee HY, et al.  and congTo summarize, we wish to highlight that data from head-to-head landmark studies suggests that CTD has superior effects than ACE-I and CCBs in reduction of LV mass and risk of HF amongst hypertensive patients. We have raised similar concerns about CCBs in diabetic hypertensive patients with diastolic dysfunction - thiazide-like diuretics should be preferred ahead of CCBs for blood pressure control in such patients to prevent HF . Similar


Photoacoustic imaging (PAI) has many interesting advantages, such as deep imaging depth, high image resolution, and high contrast to intrinsic and extrinsic chromophores, enabling morphological, functional, and molecular imaging of living subjects. Photoacoustic microscopy (PAM) is one form of the PAI inheriting its characteristics and is useful in both preclinical and clinical research. Over the years, PAM systems have been evolved in several forms and each form has its relative advantages and disadvantages. Thus, to maximize the benefits of PAM for a specific application, it is important to configure the PAM system optimally by targeting a specific application. In this review, we provide practical methods for implementing a PAM system to improve the resolution, signal-to-noise ratio (SNR), and imaging speed. In addition, we review the preclinical and the clinical applications of PAM and discuss the current challenges and the scope for future developments. W. W50]. WWang et al. developed Grueneisen relaxation PAM (GR-PAM) to improve the spatial resolution by exploiting the nonlinearity in PA signal generation b 52]. I. I52]. IDual-view OR-PAM, developed by Cai et al. in 2018, can also improve the spatial resolution c 54]. C. C54]. C4in vivo imaging, especially when compared to other microscopy techniques. Using near-infrared (NIR) light can extend the maximum imaging depth because biological tissues pose relatively less optical attenuation in this wavelength range . Th5.4in vivo imaging. For that reason, Li et al. developed a reflection-mode multifocus OR-PAM in which a microlens array is embedded underneath an array transducer : Fabry-Perot (FP) sensor and remote sensor.6.1In 2008, Zhang et al. developed AOPAM using a FP interferometer . The FP in vivo all-optical imaging of blood vessels in human palms, mouse skin [Thus, by detecting reflected interrogation beam power, the acoustic pressure can be detected. This approach uses a purely optical scanning method. Hence, it can avoid the slow mechanical scanning or the complex optical design to bypass the transducer in existing PAM systems. In addition, FP sensors have a wide bandwidth, especially at a DC frequency, compared to conventional transducers. Therefore, the FP sensor can sensitively detect the PA signal even from large absorbers. They have successfully demonstrated use skin , and mouuse skin  using th× 10 mm using a 200-Hz pulsed laser.However, there was a slow scanning speed problem. As described, FP interferometer-based PAM illuminates a wide field, requiring a high-power excitation laser source. However, many commercial high-power lasers have a slow PRF, and this slow PRF (50 Hz in ) resultsThis all-optical PAM method has been also developed as a handheld probe type. In 2017, Ansari et al. introduced an all-optical forward-viewing PA endoscopic probe . They de6.2In addition to the problems associated with the use of the ultrasound transducer described above, there has been a problem that PAM requires coupling media, such as water or ultrasound gels. This problem can be a barrier to many clinical and preclinical applications. For this reason, many non-contact PAM techniques have been actively studied. Initially, the main approach for remote sensing was to use an optical interferometer . If a PAin vivo remote PAM imaging of the mouse ear with a high SNR of ˜40 dB using excitation laser energy of ˜ 40 nJ/pulse and 4-mW interrogation laser power. The lateral and the axial resolution were measured as 2.7 μm and 43 μm, respectively. In 2018, they developed a new remote PAM technique with a deeper imaging depth, called deep PARS (dPARS) microscopy [in vivo mouse ear imaging with an imaging depth of 1.2 mm and an SNR of ˜ 50 dB using excitation laser power of ˜60 nJ/pulse and interrogation laser power of 5 mW.In 2017, Hajireza et al. introduced non-interferometric PA remote sensing (PARS) microscopy  , two-photon microscopy, wide-field optical microscopy are widely used for the brain hemodynamic studies. However, these methods suffer from several disadvantages including poor spatial resolution, shallow imaging depth, and the use of external contrast agents. In contrast, PAM addresses these problems and measures multiple functional parameters such as sO2, cerebral blood flow (CBF), flow speed, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen  (Sentinel lymph node (SLN) imaging could also become an important application of PAM. SNL biopsy (SLNB) is an essential diagnostic procedure for staging cancer. For effective SLNB, first, identifying the target SLNs is very important. The existing SLN imaging methods have several issues including ionizing radiation and low spatial resolution of the Geiger counter. Thus, many PA SLN imaging studies have been conducted to take advantages of the PA features to identify SLNs ,117. In PAM can also be used to identify or treat the cancer cell using exogenous contrast agents ,121. Zho7.3The goal of breast-conserving surgery (BCS) is to minimize the risk of recurrence and cosmetic side effects. Intraoperative frozen section analysis (FSA) is known to be effective in achieving this goal because it allows immediate resection of residual disease . However7.4Dermatology is another potential clinical application for PAM. Conventionally, dermoscopy and human vision are used to diagnose skin diseases such as skin tumors, warts, or fungal infections. However, such inspection methods have disadvantages of shallow imaging depth and low optical contrast. PAM has deep imaging depth and high optical contrast to image skin chromophores . Moreover, the high sensitivity to hemoglobin is a great advantage in dermatology since the skin vasculature is a hallmark of the skin condition. For these reasons, recently, PAM is emerging as a new dermoscopy system.In 2015, Zabihian et al. demonstrated PA imaging of human skin . The mic8In this review, we introduced recent technical advances and the clinical and preclinical applicability of PAM. PAM has been developed over the years to have a better spatial resolution, higher SNR, faster imaging speed, and smaller size. In addition, PAM can be combined with other modalities  to obserHowever, PAM still faces several challenges. First, it is still difficult to display wide-field images in real time because most PAM systems acquire one dimensional depth-resolved PA signals per one laser pulse and reconstruct PA images from multiple scans. This disadvantage not only limits research throughput but also increases diagnosing time in clinical applications. The second problem is the SNR degradation at deep depth due to the optical and acoustic attenuation. The low SNR at deep depth can hinder full understanding of the underlying conditions of the relatively large tissue. Third, most PAMs require a coupling medium such as water or US gel, which can limit many intraoperative applications . Many reNone.


The differentiated assessment of functional parameters besides morphological changes is essential for the evaluation of prognosis in systemic immunoglobulin light chain (AL) amyloidosis.Seventy-four subjects with AL amyloidosis and presence of late gadolinium enhancement (LGE) pattern typical for cardiac amyloidosis were analyzed. Long axis strain (LAS) and myocardial contraction fraction (MCF), as well as morphological and functional markers, were measured. The primary endpoint was death, while death and heart transplantation served as a composite secondary endpoint.p <  0.001 for all). In unadjusted univariate analysis, LAS  and MCF  were associated with reduced transplant-free survival. Kaplan-Meier analyses showed a significantly lower event-free survival in patients with reduced MCF. MCF and LAS performed best to identify high risk patients for secondary endpoint (Log-rank test p <  0.001) in a combined model. Using sequential Cox regression analysis, the addition of LAS and MCF to LV ejection fraction led to a significant increase in the predictive power of the model (χ2 (df = 1) = 28.2, p <  0.001).After a median follow-up of 41 months, 29 out of 74 patients died and 10 received a heart transplant. Left ventricular (LV) functional parameters were reduced in patients, who met the composite endpoint  contains supplementary material, which is available to authorized users. Immunoglobulin light chain (AL) amyloidosis is the most common type of systemic amyloidois. The incidence in developed countries is described about 9–12 cases/million inhabitant per year and autopsy studies suggest that the incidence might even be higher . AL amylBeside development of heart failure symptoms, amyloidosis may initially lead to apparent left ventricular (LV) wall thickening mimicking left ventricular hypertrophy (LVH). Cardiovascular magnetic resonance (CMR) imaging is recommended as the diagnostic tool of choice in LVH as it can help differentiate cardiac amyloidosis from other potential causes of a cardiomyopathy Fig. a 15–17]–1715–17]Therefore, this study aims to assess the novel CMR-derived deriveparameters long axis strain (LAS) and myocardial contraction fraction (MCF) for risk stratification in patients with AL amyloidosis. Both parameters have several important advantages. First, they can be derived from every standard CMR examination without the need for a dedicated post processing software. Second, the assessment of LAS and MCF does not require gadolinium contrast, which is relatively contraindicated in patients with severe impaired renal function. Third, unlike biomarkers, LAS and MCF are not influenced by any organ dysfunction, which may exist in systemic amyloidosis.The goal of this study was to evaluate the prognostic value of novel imaging parameter in biopsy-proven and LGE-positive AL amyloidosis patients.The study population consisted of consecutive patients with AL amyloidosis, who received a CMR scan between June 2005 and October 2014 at the University of Heidelberg as part of a standard institutional protocol for the evaluation of cardiomyopathies. CMR was performed in all patients with AL amyloidosis in a clinically stable condition.2 were also excluded from the analysis.Only patients with biopsy-proven AL amyloidosis and LGE pattern characteristic for cardiac amyloidosis were included in the analysis. Exclusion criteria were contraindications for CMR including incompatible devices such as cardiac pacemakers or implantable cardioverter defibrillators (ICD) or other metallic implants, severe claustrophobia, severe obesity preventing patient entrance into the scanner bore, and pregnancy or lactation. Patients with renal failure and an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73mThis single center study was approved by the local Ethics Committee and in accordance with the Declaration of Helsinki. The study population signed a written informed consent for the retrospective post-hoc analysis of their clinical routine data.In all patients, the diagnosis of systemic AL amyloidosis was confirmed by biopsy and the cardiac involvement showed a characteristically LGE pattern and LV morphology.Diagnosis of AL amyloidosis was based on tissue deposition of amyloid, the presence of a monoclonal gammopathy by serum electrophoresis, immunofixation on serum and urine, with free light chains, and conformation by positive Congo red staining with birefringence under polarized light of any biopsy , positive immunohistology for kappa or lambda in the biopsy, and on the exclusion of hereditary forms of amyloidosis, if necessary.n = 34) the other hs cTNT (n = 40). The samples for NT-proBNP and cTNT were analyzed using the commercially available sandwich immunoassay on a fully automated analyzer . eGFR was calculated in each individual using the “Modified Diet in Renal Diseases” (MDRD) formula [Renal function, NT-proBNP, cTNT and the difference between pathologic and nonpathologic serologic free light chains (dFLC) were determined . Because formula .2, repetition time/echo time (TR/TE) = 2.8/1.4 ms, acquired voxel size = 2.2 × 2.2 × 8 mm3, flip angle (FA) = 60°, reconstructed voxel size = 1.3 × 1.2 × 8 mm3. Data were analyzed by a single examiner blinded to the patient’s clinical status. The analysis was performed on a commercially available clinical workstation  Version 7.0.1, Philips Healthcare). Results for LV volumes, LV ejection fraction (LVEF) and LV myocardial mass were derived from short axis slices by tracing endocardial and epicardial borders of the LV. Papillary muscles and trabeculations were excluded from LV mass. LGE imaging acquisitions were performed 10 min after the administration of 0.2 mmol Gd-DTPA/kg body weight . For selection of appropriate inversion time (TI) gradient echo sequences were used to null myocardial signal. The TI scout had the following parameters: TE 2.0 milliseconds, TR 3.4 milliseconds and flip angle 25°. Three-dimensional LGE sequences were carried out during breath-hold in expiration and using retrospective ECG gating. The pattern of LGE was described as transmural if LGE involved circumferential the complete subendocardium through to the epicardium. The presentation of subendocardial involvement was specified as subendocardial LGE. The term patchy and focal LGE was used for description of any other LGE distribution, for example a mid-wall, subepicardial or diffuse.All CMR scans were performed on a 1.5 T CMR system  using an institutional standard protocol. A 32-channel phased-array cardiac coil was used. Cine images were obtained using a breath-hold, segmented-k-space, balanced steady-state free precession sequence with retrospective electrocardiogram (ECG) gating in long axis views  as well as in contiguous short axis slices covering the entire LV and right ventricle (RV) from the annulus of the atrioventricular valves to the apex, with 35 phases per cardiac cycle. The CMR imaging parameters were: field-of-view (FOV) = 350 × 350 mmLAS is an image based functional marker that describes longitudinal function. LAS is defined as the percentage in longitudinal shortening of the LV between end-diastole and end-systole Fig. c. To calMCF was calculated by dividing LV stroke volume (LV end-diastolic volume - LV end-systolic volume) by LV myocardial volume:LV myocardial volume was defined as LV myocardial mass divided by the mean density of myocardium, which is 1.05 g/ml. To achieve the index the result was multiplied by 100.Both parameters have been validated for their diagnostic and prognostic value in previous studies –25.CMR myocardial global strain analyses were performed using dedicated 2D CPA CMR Feature tracking software . This software algorithm has been validated previously in experimental and clinical studies –28. The All-cause mortality was the primary study endpoint. The combination of all-cause mortality and heart transplantation (HTX) due to progressive disease was defined as the secondary endpoint. Follow-up was obtained by review of the patient’s hospital chart or telephone interview with the patient or relatives. All survivors completed the 2 years of follow-up. The median follow up of surviving patients was 55 months (43–66 months).p <  0.05. All statistics were calculated using MedCalc 15 .Categorical variables are given as number and percentage, continuous parametric variables as mean ± standard deviation (SD) and continuous non-parametric variables as median and interquartile range (IQR). For the comparison of means between groups two-tailed Student’s t-test was used and differences between nominal variables were assessed using the Fisher exact test. Group differences of continuous non-parametric variables were tested using the nonparametric Mann-Whitney U test. Proportions of categorical were compared using Chi-squared test. Correlations were analysed using Spearman’s rank correlation coefficient. Kaplan-Meier curves were used to estimate the distribution of survival as a function of the follow-up duration. Optimal cut-off values were defined by Receiver operating characteristics (ROC) and Youden’s J statistic. The association of clinical, imaging and serological parameters with outcome was evaluated by uni- and multivariate Cox proportional-hazards regression models. Differences were considered statistically significant at Initially 94 patients with systemic AL amyloidosis were included in the study. However, 20 patients, who received chemotherapy before CMR was performed, were excluded from the final analysis. Therefore, the total study consists of 74 subjects.Chemotherapy was administered 65 days (22–106 days) after CMR examination. 15 participants (20.3%) received melphalan and dexamethasone, 16 (21.6%) bortezomib and further 43 (58.1%) received other forms and combinations of chemotherapy. The amount of organ involvement was heterogenic .During the follow-up period of 2 years, 29 patients died, while 10 patients (13.5%) received a HTX. After the follow-up period, 35 patients were alive without HTX (47.3%), leaving 39 patients (52.7%), who reached the combined endpoint of death or HTX. Baseline characteristics including co-morbidities, laboratory data and CMR measurements are presented in Table n = 60, 81.1%) was higher than the one of kappa light chains . The values of dFLC  and NT-pro BNP were higher in patients, who reached the combined endpoint. In addition, a high proportion of the total study population presented positive values of cTNT (71.6%).The age of all study participants was 59 ± 11 years and 50 (68%) subjects were male. Cardiovascular disease risk factors were presented in both groups  without any significant difference (Table p = 0.011). In addition, the segmental longitudinal strain analysis demonstrated normal longitudinal strain of the apical segments, while basal segment strain segments were significantly reduced . However, the segmental analysis did not significantly differ between both groups . In addition, the correlations between the CMR-derived parameters (MCF and LAS) and cardiac biomarkers (NT-proBNP and cTNT) was weak to moderate .There was an intermediate correlation between MCF and LAS , GLS , LV mass index (LVMI) , LV ejection fraction (LVEF)  and MCF  were all associated with a reduced survival in patients with AL amyloidosis  based on the ROC curve analysis regarding the secondary endpoint. The AUC for LAS was 0.75 and for GLS was 0.65. A significant difference was found between the fields under the ROC curves for MCF and GLS p = 0.01, Fig. 2.p <  0.001, Fig. The Kaplan-Meier analyses for primary and for composite endpoint demonstrated a significantly reduced event-free survival in patients with a LAS value above − 7% and a MCF value below 56.6% (Log-rank test 2 (df = 1) = 16.3) led to a significant increase in the predictive power (χ2 (df = 1) = 22.6, p <  0.001). The addition of MCF to this model resulted in a further significant increase in the predictive power (χ2 (df = 1) = 28.2, p <  0.001)  Fig. .Fig. 5Inn = 26 (37.1%), group 2: transmural LGE, n = 25 (35.7%) and group 3: patchy and focal LGE, n = 19  LGE images were available for a reliable analysis. Our analysis demonstrated a trend of higher mortality rates in patients presenting transmural LGE. However, we found no significant difference between the LGE pattern and the endpoint  and MCF (≤ 52.6%) values were at greatest risk for death.sis in patients with cardiac involvement. Previous studies have shown a significant correlation between LGE extent on CMR and biomarkers of myocardial injury in patients with acute viral myocarditis [Cardiac involvement of AL amyloidosis is a major determinant of treatment options and prognosis. Early identification of high-risk patients may lead to begin of intensive therapeutic strategies with better survival. Cardiac serum biomarkers NT-proBNP and cTNT are currently used in clinical routine for estimation of the prognocarditis .CMR is currently the diagnostic tool of choice for identification of cardiac amyloidosis. Additionally, it has been shown, that presence of LGE in patients with systemic amyloidosis is associated with mortality , 32. HowPrevious studies have already shown that LV longitudinal function may be a marker for early diagnosis and outcome in cardiac diseases of various etiologies –35. EspeCMR-derived LAS has been shown to be a simple and rapidly assessable parameter representing global LV longitudinal function without the necessity of additional post-processing software tools . The majMCF is a quantitative parameter representing a volumetric index of fractional contraction of the myocardium. MCF is calculated as a ratio between LV stroke volume and the LV myocardial volume. In LVH independent of its etiology, a decrease in MCF indicates an abnormal myocardial function, although LVEF may remain normal even in advanced stages because of the progressive reduction in ventricular capacitance. Therefore, measurement of LVEF alone gives an incomplete representation of the complex process of dysfunction especially in hypertrophied hearts. In a previous study we could demonstrate that CMR-derived MCF has an excellent diagnostic accuracy discriminate between patients with AL amyloidosis from patients with other forms of LVH . We coulThe present study has some limitations. First, it is a retrospective analysis. Second, because of two different Troponin essays  in our institution during the study period, it was only possible to divide between troponin positive and negative participants. Therefore, an assessment regarding Troponin values and outcome was not possible. Finally, because of a long period of data collection beginning from 2005, this study does not provide any T1 mapping information.In conclusion, LAS and MCF are easily available and robust CMR-derived parameters which predict outcome in LGE-positive AL amyloidosis patients. Among these, patients with reduced LAS and MCF fraction are at highest risk for death and HTX.Additional file 1:Table S6. Late Gadolinium Enhancement (LGE) pattern analysis. Table S7. CMR data of patients with light-chain amyloidosis compared to different Late Gadolinium Enhancement (LGE) distribution groups (DOCX 31 kb)Additional file 2:Figure S6. Kaplan-Meier estimates of the time to events by late gadolinium enhancement (LGE) pattern. Presented for the composite endpoint (death and heart transplantation). (PNG 33 kb)


Recent clinical, experimental and modeling studies link oscillations of ventricular repolarization in the low frequency (LF) (approx. 0.1 Hz) to arrhythmogenesis. Sympathetic provocation has been shown to enhance both LF oscillations of action potential duration (APD) and beat-to-beat variability (BVR) in humans. We hypothesized that beta-adrenergic blockade would reduce LF oscillations of APD and BVR of APD in humans and that the two processes might be linked.2 vs. 5.5 ± 3.5 ms2, p = 0.027). A significant correlation was present between the initial control values and reduction seen following beta-adrenergic blockade in LF ARI  such that when initial values are high the effect is greater. A similar relationship was also seen in the beat-to beat variability of ARI . There was a significant correlation between the beta-adrenergic blockade induced reduction in LF power of ARI and the witnessed reduction of beat-to-beat variability of ARI . These clinical results accord with recent computational modeling studies which provide mechanistic insight into the interactions of LF oscillations and beat-to-beat variability of APD at the cellular level.Twelve patients with normal ventricles were studied during routine electrophysiological procedures. Activation-recovery intervals (ARI) as a conventional surrogate for APD were recorded from 10 left and 10 right ventricular endocardial sites before and after acute beta-adrenergic adrenergic blockade. Cycle length was maintained constant with right ventricular pacing. Oscillatory behavior of ARI was quantified by spectral analysis and BVR as the short-term variability. Beta-adrenergic blockade reduced LF ARI oscillations  in humans  Factors which influence the stability of ventricular repolarization are important in arrhythmogenesis. Enhanced oscillation of ventricular repolarization in the low frequency range and increased beat-to-beat variability (BVR) of ventricular repolarization are two of the strongest predictors of arrhythmia and sudden cardiac death . Both arOscillations of ventricular repolarization measured from the ECG T-wave vector referred to as periodic repolarisation dynamics (PRD) have been attributed to oscillations in APD at the frequency of the sympathetic nerves (approx. 0.05–0.1 Hz). Ventricular action potential duration (APD) measured as activation-recovery intervals (ARI) has recently been shown to oscillate in this frequency range . The LF in vivo.Computational modeling has provided early insight into the mechanisms underlying these oscillations of APD, the effect of beta-adrenergic stimulation and their relationship to the initiation of ventricular arrhythmias , b. MoreWe have studied 12 patients during cardiac catheterization allowing us to measure ARIs as an approximation for APD at 10 right ventricular (RV) and 10 left ventricular (LV) endocardial sites in order to investigate the effect of acute beta-adrenergic blockade on LF oscillations of ventricular APD and on BVR of APD, and the possible interaction between the two. Cycle length was held constant with RV pacing to avoid confounding effects due to the cycle length dependency of APD.The study was approved by the Ethics Committee of Guy’s and Thomas’ Hospitals and conformed to the standards set by the Declaration of Helsinki . All patients gave written, informed consent.Studies were performed in 12 patients  during the course of routine clinical radiofrequency ablation procedures for atrial fibrillation. Four patients had paroxysmal atrial fibrillation, and eight patients had persistent atrial fibrillation. All subjects had normal biventricular systolic function. Utilizsing the routine transseptal puncture of an AF ablation, a decapolar catheter was placed in the left ventricle via the left atrium and mitral valve. The pacing catheter and second decapolar catheter were placed in the right ventricle. Routine AF ablation femoral venous access was utilized for placement of all catheters. The transseptal puncture was conducted under radiographic guidance. Continuous synchronous recordings of femoral arterial blood pressure and unipolar electrograms (UEGs) at 10 endocardial RV and 10 endocardial LV sites  were obtmax) as a measure of myocardial contractility. Measurement of dP/dtmax from the femoral artery has been shown to provide good tracking of left ventricular contractility  using the Wyatt method . This meactility .max measurements could not be determined were replaced by linear interpolation between the surrounding beats. Recordings were rejected from the analysis if these surrogate beats constituted more than 10% of any series.To establish evenly sampled series, any beats for which ARI, SBP or dP/dtThe low frequency (LF) power in each ARI series was estimated by calculating the bandpower in the low-frequency band (0.04–0.15 Hz) using the Thomson’s multitaper method with three Slepian tapers, which is known to be robust against noise . The samBeat-to-beat variability of ARI was assessed by computing the short term variability (STV) of ARIs for each endocardial recording site over the entire recording as per established STV measures . The STViARI is the ARI at the ith beat and N is the number of beats. For each pole, we computed the mean STV in time and then averaged these values across poles. The STV of SBP (STV-SBP) and dP/dtmax (STV-dP/dtmax) were computed using the same formula and number of beats as for ARI.where max was tested for statistical significance using the two-tailed paired Wilcoxon signed–rank test. To evaluate whether there were different responses in ARI STV between individual electrodes (n = 20), we used the non-parametric Kruskal–Wallis test. Results were considered significant at p < 0.05.Results were averaged across the two separate breathing cycles for both control recordings and following introduction of beta-adrenergic blockade. Results are presented as mean ± standard deviation for normally distributed variables and as median and interquartile range (IQR) for non-normally distributed variables. The effect of beta-adrenergic blockade on LF power for ARI, SBP and dP/dtmax time series of one patient breathing at 15 breaths/min (0.25 Hz) during control and following beta-adrenergic blockade are shown in Example ARI, SBP and dP/dt2 vs. 5.5 ± 3.5 ms2, p = 0.027)     and the = 0.027) . A trend= 0.129) .–3 ± 3 × 10–3 ms2 vs. 6.1 × 10–3 ± 3.4 × 10–3 ms2, p = 0.91), SBP , nor dP/dtmax .No effect of beta-adrenergic blockade was seen on the HF power of ARI (6.5 × 10p = 0.4) or the beat-to-beat variability . We also did not observe an effect on the beat-to-beat variability of SBP , but the STV dP/dtmax was significantly reduced .No immediate effect of beta-adrenergic blockade was seen on mean ARI for group data . We also tested the differences in STV baseline and reduction between RV and LV. Mean values of STV baseline and reduction were slightly higher in the LV, but the differences were not statistically significant: mean ARI STV baseline: 8.7 ± 8.1 vs. 9.3 ± 5.0 ms, p = 0.4; mean ARI STV reduction: −0.1 ± 1.8 vs. 0.3 ± 1.0, p = 0.1, for RV and LV, respectively. Finally, we also investigated whether the LF power and STV response to beta-adrenergic blockade was different in patients who had previously been treated with beta-blocker . Although medication was discontinued for 5 days before the study in all patients, we found that the average response in both ARI LF power and ARI STV was slightly higher in patients treated with beta-blockers, but the numbers were too small to allow robust statistical analysis .The ARI STV response to beta-adrenergic blockade was not different across breathing frequencies: mean ARI STV reduction −0.1 (±0.7) for 15 breaths/min versus 0.2 (±1.4) ms for 30 breaths/min, r n = 7,  comparedrs = 0.62, p = 0.037) (p = 0.008)   . A simil= 0.008) , and thectively) .p = 0.01) (p = 0.2) or dP/dtmax-STV . There was also no significant relationships between the reduction in HF power and STV for ARI, SBP, and dP/dtmax: .There was a strong relationship between the reduction in LF power of ARI and the reduction of STV-ARI in response to beta-adrenergic blockade  . No signmax; (2) beta-adrenergic blockade was associated with a significant reduction of LF power of ARI and SBP, (3) individually no clear impact of beta-adrenergic blockade on the beat-to-beat variability of ARI, SBP and dP/dtmax was demonstrated, however, (4) there was a strong correlation between the reduction seen in the LF power of ARI, SBP, and dP/dtmax following beta-adrenergic blockade, and the reduction in beat-to-beat variability.We studied the effect of acute beta-adrenergic blockade on LF oscillations of ventricular APD (approximated by ARI) and on beat-to-beat APD variability. LF power and STV ARI measurements were made from 10 RV and 10 LV sites and then averaged in patients with normal ventricles. Cycle length was maintained constant with right ventricular pacing to eliminate confounding effects of cycle length dependency and breathing was controlled throughout the protocol at 0.25 and 0.5 Hz. Our main findings were: (1) we observed a wide variation of control values of LF power and beat-to-beat variability of ARI, SBP and dP/dtWhereas oscillations in heart rate variability have long been recognized and the underlying mechanisms the subject of much debate , oscillaEnhanced beat-to-beat variability of repolarization, measured clinically as QT variability or experimentally as APD variability, is well known to predispose to malignant ventricular arrhythmias . BVR hasThe present work was conducted in patients with normal hearts and we cannot exclude the possibility that the relationships we observed may have been different in patients with arrhythmias. However, in this context the following observations in patients with arrhythmias are worth mention. In a recent study in heart failure patients ARI recordings as a measure of local action potential duration were obtained from the left ventricular epicardial lead of an implanted cardiac defibrillator device. 11 of 43 patients received appropriate shock treatment for sustained ventricular tachycardia or fibrillation, and ARI variability was significantly higher in these patients compared to patients who did not develop arrhythmia . In the Clinical conditions associated with high arrhythmia risk are commonly accompanied by adverse ventricular remodeling with downregulation of ionic currents and dysregulation of Ca2+handling and reduced repolarization reserve . Beta-adWhile a number of studies have investigated the cellular mechanisms underlying modulation of BVR by beta-adrenergic stimulation and the consequent effect on arrhythmia initiation , only a Kr, ICaL, and IK1  action potential model   . For STVand IKs) .in vivo (Mechanoelectric feedback (MEF) has been suggested to contribute to the development of LF oscillations and BVR of APD in humans in vivo  and by cin vivo , in accoin vivo . The rolin vivo . The timin vivo .The importance of risk stratification for arrhythmia and sudden death to guide patient selection for ICD implantation has already been stressed. A number of non-invasive markers of risk have been proposed including amongst others heart rate variability, baroreflex sensitivity, microvolt T-wave alternans, heart rate turbulence, Tpeak-Tend as an index of dispersion of repolarization and QT interval variability, all of which are modulated by autonomic activity . Howeverin vivo human heart in order to complement laboratory studies, we have always considered it a priority to integrate the research protocol with the clinical protocol avoiding additional invasive procedures. We recognize that it would be ideal to have longer recordings when studying LF related parameters, but to comply with clinical studies we designed the study with view to limiting the duration of the study as much as possible.The study population were patients with ostensibly normal ventricles undergoing routine ablation procedures for supraventricular arrhythmias. Eight of the 12 patients had persistent atrial fibrillation and therefore the possibility of some ventricular remodeling cannot be excluded. However, the routine procedure for atrial fibrillation ablation involves transseptal puncture to allow access to the left atrium from the right atrium. This enables placement of an LV decapolar catheter for the research procedure  without the need for arterial puncture for retrograde access to the left ventricle. In many years experience of acquiring basic electrophysiological data from the Recordings were made from 20 localized right and left ventricular endocardial sites and then averaged. It is possible that other regions may have yielded different results. Furthermore, averaging may confound local beat-to-beat variabilities, although we did not find evidence for this when comparing the STV reduction across electrode sites and between left and right ventricle. In addition, breathing frequency may also play a role. In this work we report averaged data from two different breathing frequencies (15 and 30 breaths/min), but the reduction in ARI STV between the two breathing frequencies was not found to be significantly different.Understanding the mechanisms underlying the interaction between beta-adrenergic stimulation, the LF oscillatory behavior of APD and beat-to-beat APD variability is important for the development of therapeutic strategies for the prevention of arrhythmia and sudden cardiac death. Enhanced oscillations of ventricular repolarization in the LF range measured from the ECG T-wave vector and referred to as periodic repolarization dynamics (PRD) have emerged as one of the strongest predictors of arrhythmia and sudden cardiac death in cardiac patients and are the subject of ongoing clinical trials . The preIn patients with normal ventricles acute beta-adrenergic blockade modulated LF oscillatory behavior of ventricular APD (measured as ARIs) and beat-to-beat variability of APD in a manner that was dependent on baseline APD variability. A strong correlation was present between the effect of beta-adrenergic blockade on LF oscillation of APD and beat-to-beat variability of APD. These findings are discussed in relation to computational modeling which reproduced the clinical findings and investigated cellular mechanisms. These observations provide valuable insight into the strong association of LF oscillations of ventricular repolarization and arrhythmic and sudden cardiac death. Further work is warranted to improve our understanding in order to develop therapeutic strategies.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by the Ethics Committee of Guy’s and Thomas’ Hospitals. The patients/participants provided their written informed consent to participate in this study.BP, SV, JG, and PT conceived and designed the experiments. All authors took responsibility in analyzing and interpreting the data, contributed to drafting or revising the manuscript, and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


AHF): treatment with the myosin activator omecamtiv mecarbil (OM) or dobutamine and ivabradine (D+I). Left ventricular (LV) ischemia was induced in anesthetized pigs by coronary microembolization (n = 12). The animals then received OM  (n = 6) or D+I (5 μg/kg per min + 0.29 ± 0.16 mg/kg) (n = 6), respectively. Ischemia reduced the stroke volume (SV), despite the increased left atrial pressure associated with impaired LV early relaxation, systolic dilatation, and LV late diastolic stiffness. Both treatments improved systolic ejection, but only D+I increased the SV from 26 ± 5 to 33 ± 5 mL. D+I enhanced LV early relaxation  and prolonged the diastolic time (DT) from 338 ± 60 to 352 ± 40 msec. In contrast, OM prolonged Tau (42 ± 5 to 62 ± 10 msec) and shortened the DT (from 326 ± 68 to 248 ± 84 msec). Our data suggest that enhanced early relaxation by D+I improves LV pump function in postischemic acute heart failure. In contrast, OM worsened lusitropy in this model.Acute ischemic cardiogenic shock is associated with poor prognosis, and the impact of inotropic support on diastolic function in this context is unclear. We assessed two suggested new inotropic strategies in a clinically relevant pig model of ischemic acute heart failure ( However, tachycardia is only beneficial when it results in a significant increase in cardiac output (CO). Shortening of diastole requires an enhanced filling rate to maintain stroke volume (SV). During physiological tachycardia , the filling rate is increased as the ventricle pulls blood from the atrium, that is “diastolic suction”. The suction forces are generated during the preceding systole when the myocardium is compressed below the resting equilibrium shape. This compression generates diastolic restoring forces when the ventricle recoils and regains its passive shape and subsequently actively draws blood into the cavity . Thus, a treatment principle that selectively restores impaired contractility with a limited chronotropic response would be theoretically advantageous.Left ventricular (LV) acute heart failure (AHF) following myocardial infarction is a serious and life‐threatening situation requiring urgent treatment  to treat AHF is well tolerated in patients . This drug has recently been evaluated in a phase 2 trial for the treatment of patients with AHF  were adapted to the new environment for 5–7 days. The animals were fasted overnight and were provided water ad libitum prior to the experiments.The pigs were premedicated with intramuscular injections of 20 mg/kg ketamine , 1 mg/kg midazolam  and 1 mg atropine . Anesthesia was induced by inhalation of isoflurane . After endotracheal intubation, intravenous injections of 10 mg/kg pentobarbital sodium , and 0.01 mg/kg fentanyl  were administered. The animals were ventilated on positive‐pressure ventilation at 60% oxygen. An introducer sheath catheter was placed into the left internal jugular vein, and anesthesia was maintained throughout the experiment by continuous infusion of 4 mg/kg per h pentobarbital sodium, 0.02 mg/kg per h fentanyl, and 0.3 mg/kg per h midazolam. The circulating volume was maintained by 20 mL/kg per h continuous infusion of 0.9% NaCl supplemented with 1.25 g/L glucose. In addition, the animals received 2500 IU heparin  and 5 mg/kg amiodarone  to prevent blood clotting of catheters and cardiac arrhythmia, respectively. The urinary bladder was catheterized and drained by cystotomy. To enable analysis of the hemodynamic effects with minimal influence of the sympathetic nervous system, hexamethonium chloride  was administered as an intravenous bolus of 20 mg/kg.A 7 Fr multisegment Millar MPVS Ultra pressure‐volume catheter  was placed into the left ventricle via the common carotid artery. Arterial pressure was measured via a vascular catheter in the abdominal aorta. A 7 Fr balloon catheter  was introduced into the inferior vena cava for preload reduction. After median sternotomy, the pericardium was removed, and the pulmonary truncus was dissected to enable the placement of a transit time flow probe  for CO measurements. Three sonomicrometry crystals  were placed in the myocardium to measure the long‐ and short‐axis myocardial dimensions. A 6 Fr introducer  was inserted through the thoracic wall into the left atrium, through which a 3.5 Fr pressure catheter  was placed. A pacemaker electrode was sutured onto the right atrium. Epicardial echocardiography  was used to calibrate the crystal dimensions to the LV volumes at baseline.A full data set was obtained at three time points during the experiments: (1) pre‐ischemia, (2) ischemia, and (3) postischemic treatment. Data were obtained at intrinsic HR and during pacing‐induced tachycardia. The pacing protocol was performed in successive steps at 120 and 160 bpm, with at least 1 min between each step to allow for pressure stabilization. Measurements were performed at steady state and during an abrupt reduction in preload induced by vena cava occlusion (VCO) at each time point. Ventilation was halted in expiration during the recordings to minimize the effects of respirator‐induced alterations.μm polystyrene microspheres (2.4 mg/mL)  into the left main coronary artery. The injections were repeated until the left atrial pressure (LAP) approached 20 mmHg. An average of 11.9 ± 3.9 mL was administered over 53 ± 15 min to achieve this level of heart failure. The ischemic recordings were performed at 30 min after the last coronary injection. The animals were then split into two groups to receive either OM or D+I.Following baseline recordings, LV ischemia was induced by repeated, fluoroscopic‐guided injections of 2–5 mL boluses of 50‐OM  was formulated as a 1 mg/mL solution containing 50 mmol/L citrate in sterile water, and the pH was adjusted to 5.0 with NaOH  was achieved or until the overall dose of ivabradine reached 0.5 mg/kg (average dose 0.29 ± 0.16 mg/kg)  was calculated from the endocardial short axis (Sendo) at a ratio of 1.37 2/6*Lendo  was defined as the remaining fraction of the cardiac cycle. The isovolumetric relaxation constant (Tau) was calculated by Weiss’ method. To obtain the preload recruitable stroke work (PRSW), we performed transient VCO at spontaneous HR, whereas the end‐diastolic and end‐systolic pressure–volume relationships  were calculated as the linear slopes of the steady state measurements. The maximum atrial‐ventricular gradient (L A‐V MAX) is the peak pressure difference between the left atrium and left ventricle during diastole, and the atrial‐ventricular pressure–time integral (L A‐V INTG) is the area under the curve during diastole. The maximum myocardial systolic deformation rate (s′) was measured as the peak negative derivative of the long‐axis sonomicrometry crystal, whereas e′ was measured as the peak positive derivative during diastole.LV pressure, transit time blood flow, sonomicrometric dimensions and vascular pressure signals were recorded, digitized, and analyzed using ADI LabChart Pro software . Cardiac dimensions were measured at baseline and after the interventions from the short‐ and long‐axis sonomicrometry crystals, and the measurements were corrected by the epicardial short‐axis ultrasound data at baseline. The echocardiographic endocardial long axis .Values are presented as the mean and standard deviation. To assess the impact of microembolization and treatment at intrinsic heart rate, the data were analyzed using paired Student's min, and dP/dtmin) and late diastole , resulting in diastolic dysfunction. Interestingly, both the L A‐V MAX and L A‐V INTG were maintained despite impaired early relaxation of the ischemic heart. Despite a twofold increase in the LV preload, the impaired systolic and diastolic function led to reductions in the SV, cardiac output, and mean arterial pressure.Global LV ischemia impaired early  and thus increased the L A‐V MAX during diastole. However, OM had no impact on these indices. OM biased the cardiac cycle towards systole, while D+I biased it towards diastole. The enhanced early relaxation and prolongation of diastole by D+I resulted in an increased L A‐V INTG beyond the pre‐ischemia levels. This was associated by increases in the SV (27%), mean arterial pressure (18%) and ejection fraction (from 24% to 32%). In contrast, the reduction in the DT and the impaired relaxation (Tau) observed with OM administration resulted in a leftward shift of the pressure–volume loop . Thus, OM failed to restore general pump indices, such as the SV, CO, mean arterial pressure, and ejection fraction. At elevated heart rate by atrial pacing the opposite effects of OM versus D+I treatment was reinforced  improved systolic unloading of the ischemic ventricle. The two treatments differed in three principal aspects: 1) the speed of contraction; 2) the speed of relaxation; and 3) the relationship between the systolic and diastolic times during the cardiac cycle. D+I reversed the ischemia‐induced impairments in inotropy and lusitropy, as demonstrated by a 77% increase in d the spee the spee the relaThis study shows that catecholamine‐induced inotropy (D+I) and direct myosin activation (OM) had opposite effects on diastolic function in the ischemic heart. Improved diastole by D+I was attributed to enhanced early relaxation and a prolonged DT that increased the driving force across the mitral valve. In contrast, OM unloaded the heart by prolonging systole at the expense of the DT. Together with impaired early relaxation, this reduced the driving force across the mitral valve. These diastolic impairments with OM were indicated by the leftward shift of the pressure–volume loop  and reduced tolerance to HR elevation Fig. .Restoring compromised SV is thought to be an important treatment target in postischemic CS. Data from the SHOCK trial  and increase the rate of sarcoplasmic reticulum Ca2+ reuptake (lusitropy)  Bers . The intion Fig. . The conion Fig. .Our data demonstrated that controlling tachycardia with ivabradine optimizes the lusitropic effect of dobutamine in ischemic acute heart failure. In contrast, inotropic support with omecamtiv mecarbil is limited by the impairment in diastolic function that is reinforced at elevated heart rates.The authors have no conflicts of interest to declare.


The accuracy of 2D and 3D strain analyses was evaluated by comparing strain and cardiac function parameters in Fontan repair patients and normal child volunteers.We retrospectively enrolled 32 patients with Fontan circulation and 32 child volunteers who had undergone clinical cardiac magnetic resonance (CMR) assessment of the dominant ventricle with a 1.5-Tesla MRI scanner. Global and regional strain (2D and 3D) of the dominant ventricle in both groups was assessed using CMR feature-tracking. Correlations between cardiac function and strain data were assessed using Pearson’s correlation coefficient values. The intraclass correlation coefficient (ICC) and coefficient of variation (CoV) were determined to evaluate repeatability and agreement.p = 0.002). The 2D GRS and 2D GCS showed no significant differences between two groups. 2D GRS: 38.96 ± 14.48 vs. 37.46 ± 7.77; 2D GCS: − 17.64 ± 5.00 vs. -16.89 ± 2.96, respectively; p > 0.05). The 3D global radial strain (GRS), global circumferential strain (GCS), and global longitudinal strain (GLS) showed significant differences between the Fontan repair patients and volunteers . The ejection fraction (EF) and 3D GCS were significantly associated . The 3D GCS showed correlations with the indexed end-diastolic volume (EDV)  and indexed end-systolic volume (ESV) . 3D strain showed good reproducibility, with GCS showing the best inter-observer agreement (ICC = 0.87 and CoV = 5.15), followed by GLS (ICC = 0.84 and CoV = 5.36).The 2D GLS showed significant differences between the Fontan repair patients and volunteers (− 16.49 ± 5.00 vs. -19.49 ± 2.03; 3D GCS is feasible, highly reproducible, and strongly correlated with conventional cardiac function measures. 3D GCS assessments may be useful for monitoring abnormal myocardial motion in patients with Fontan circulation. Functional single ventricle (FSV) is a type of severe congenital heart disease (CHD) . The firCardiac magnetic resonance (CMR) has recently become the gold standard for measurement of ventricular function and myocardial motion . CMR feaOur study was approved by the ethics committee of our hospital  and was conducted in accordance with the Declaration of Helsinki. Thirty-two Fontan repair patients  were retrospectively enrolled from June 2015 through August 2017. Databases were reviewed to identify patients who had undergone the Fontan procedure in infancy or early childhood  with an 8-element cardiac phased array coil. Ventricular function and strain were assessed in the serial contiguous cardiac short-axis and long-axis planes (in 2- and 4-chamber views) by using a standard balanced steady-state free precession (b-SSFP) cine sequence. The parameters were as follows: repetition time (ms)/echo time (ms), 3.5/1.7; voxel size, 1.3 × 1.6 × 6–8 mm; flip angle, 60°; SENSE acceleration factor, 2.0; bandwidth, 130.8 kHz/pixel; and 20–28 phases per cardiac cycle.Cine image analysis was performed using Circle Cardiovascular Imaging software  by two individuals with more than 10 years of experience in cardiac functional analysis who were blinded to patient demographic data. The endocardial and epicardial borders of the dominant ventricle were manually traced on short-axis cine images at end-systole and end-diastole. Papillary muscles, trabeculae, and the rudimentary ventricle  were notThe FT module was used to perform strain analysis in the patient and control groups using cvi42 software. The semi-manually defined endocardial and epicardial borders’ contour at the end-diastole served as the starting point from which the software tracked displacement of spatial features in successive sequence images Fig. .Fig. 22t test for normally distributed variables and the Wilcoxon test for non-normally distributed variables. Correlations were assessed with Pearson’s correlation coefficient between cardiac function and strain data. Bland Altman analysis, intraclass correlation coefficient (ICC) and coefficient of variation (CoV) were obtained to evaluate the repeatability and agreement. A p-value of < 0.05 was considered statistically significant. Statistical analyses were performed with SPSS version 22.0 software package .All data were presented as means ± standard deviations or numbers (percentage) and ranges. Comparison of cardiac function and strain data between Fontan repair patients and volunteers was performed using the A single observer reviewed all CMR-FT studies and performed the image analyses. To assess intra-observer variability, the same investigator re-analyzed 10 random studies continuously 2 weeks after the first analysis. To evaluate inter-observer reproducibility, the same cases were then evaluated by a second observer who was blinded to the results recorded by the first observer. Intra-observer and inter-observer agreement for 2D/3D global radial, circumferential and longitudinal strain were measured using Bland Altman method by CMR with 10 random studies.2), and ventricle mass (47.77 ± 28.81 vs. 90.40 ± 25.83 g). However, there were no statistically significant CMR volumetric differences between the groups  values for the two groups are presented in Table D and 3D r = − 0.612, p < 0.001, EDVi: r = 0.471, p = 0.006, ESVi: r = 0.556, p = 0.001, Table r = 0.641, p < 0.001, EDVi: r = − 0.455, p = 0.008, ESVi: r = − 0.533, p = 0.002, Table r = − 0.491, p = 0.004, Table r = 0.523, p = 0.002, r = 0.602, p < 0.001, Table p = 0.001, Table p = 0.06, Table p < 0.001, Table The 2D GCS were highly correlated with cardiac function in Fontan repair patients , followed by GLS (ICC 0.84 and CoV = 5.36) and GRS (ICC 0.80 and CoV = 10.29) . it could be related to abnormal cardiac looping, which leads to hearts that lack helical fiber patterns. However, this theory needs further study.CMR-FT is a non-invasive modality for evaluating ventricular function in Fontan repair patients. It has been used to analyze ventricular function in CHD, particularly in cases of coarctation of the aorta  and repaThe 2D strain algorithm fits a 2D incompressible deformable cylindrical model of the myocardium to individual image slices over the entire cardiac cycle. This model is assumed to be completely determined by control points placed on the middle curve of the endo and epi-boundaries of the myocardial wall. The model is based on the feature-tracked boundaries and the incompressibility constraint of the model. In contrast, the 3D strain algorithm uses a 3D deformable model generated by interpolating the tracked boundaries from the 2D algorithm. The surface interpolation is performed using both long- and short-axis image information . The remBerganza et al. reported that the 3D GCS was associated with the indexed right ventricular EDV in patients with repaired tetralogy of Fallot . We founOur study was limited by its single-center design. The retrospective nature of the study also limited its population to those clinically referred for CMR, allowing for a potential selection bias. Due to the limitations of acquisition time, we collected SSFP cine images in the four-chamber, two-chamber, and short-axis views, and the three-chamber view was not included. Result had been affected on the 2D and 3D strain analysis without three-chamber view, this is also the limitation of retrospective study. There was evidence from previous studies that the problem of twisting motion and out of plane motion could affected using 3D strain compared with 2D algorithms. In addition, 3D images presented a substantially lower spatial and temporal resolution than their 2D counterpart. We inferred that these findings might be the reason why 3D GRS results are less stable and effective . Further3D GCS is feasible, highly reproducible, and strongly correlated with conventional cardiac function measures. 3D GCS assessments may be useful for monitoring abnormal myocardial motion in patients with Fontan circulation.


We report the case of a 23-year-old male with thalassemia major who developed long QT and continuous ventricular tachycardia (VT). Electrocardiography, echocardiography, and cardiac magnetic resonance imaging (MRI) were used for diagnosis and risk stratification. VT causes and treatments are presented and discussed. Ventricular arrhythmia can be treated by normalizing QT interval with high-dose beta-blocker therapy. However, MRI-compatible internal cardiac defibrillator implantation was performed due to the high risk in this patient. Excess iron loading occurs in many organs, primarily the heart and liver, and in patients with thalassemia major. In a study using magnetic resonance imaging (MRI) on a large number of patients, serious heart involvement was reported to be 20%, while in 58% of patients, iron deposition was reported to be within normal limits . Malignath day of treatment, QT-QTc intervals were corrected and ventricular premature beats disappeared with maximum tolerable doses of beta-blocker therapy  showed VT ; thus, t therapy . He was ∗ value 8.67 milliseconds). However, right ventricle (RV) myocardium was normal, stained with MRI , left atrium was dilated (end-diastolic diameter 4.1 cm), and stage III diastolic dysfunction (restrictive filling pattern) was observed. A cardiac MRI was requested to screen the iron deposition in the heart of the patient. On MRI imaging, left ventricle (LV) was diffuse hypertrophic and hypointense (dark) (myocardial T2with MRI . MRI reswith MRI . As a reIn thalassemia major, due to ineffective erythropoiesis, regular blood transfusions are needed and this may lead to excess iron deposition in the liver and heart. These patients are lost due to cardiac failure and cardiac complications that occur as a result of iron deposition in the heart. In patients with thalassemia major, mortality rates reduced significantly due to intravenous and oral chelation therapy , 4. Our ∗ <10 milliseconds were considered serious and those with T2∗ >20 milliseconds were considered normal [∗ levels <20 milliseconds [∗ = 8.6 milliseconds and was evaluated in the group with severe iron overload.In patients with thalassemia major, MRI imaging is widely used to detect early onset and general iron overload . In addid normal . In studiseconds . Our patIn thalassemia major, due to iron overload and cardiac fibrosis, fatal arrhythmias such as continuous VT and ventricular fibrillation may occur . In variBecause the current guideline  considerIn conclusion, in patients with thalassemia major, long QT and subsequent VT may occur due to excess iron accumulation. In these patients, ventricular arrhythmia can be treated by normalizing the QT interval with high-dose beta-blocker therapy after acute condition treatment. Beta-blocker therapy must be considered in thalassemia major patients with excess iron deposition and associated ventricular arrhythmia, and ICD therapy should be considered in patients at high risk.


In recent years, the role of left ventricular ejection fraction (EF) as the gold standard parameter for the evaluation of systolic function has been questioned, and many efforts have been concentrated in the clinical validation of new noninvasive tools for the study of myocardial contractility. Improvement in the accuracy of speckle-tracking echocardiography has resulted in a large amount of research showing the ability of two-dimensional strain to overcome EF limitations in the majority of primary and secondary heart diseases. Currently, global longitudinal strain (GLS) is considered the most accurate and sensitive parameter for the assessment of early left ventricular dysfunction. This review summarizes the advantages that this measurement can provide in several clinical settings. Moreover, the important cautions that should be considered in making the choice to use GLS also are addressed. Finally, a special focus on bull's-eye polar maps for the assessment of regional changes of longitudinal function and the usefulness of these maps in the differential diagnosis of several diseases is provided. The value of ejection fraction (EF) for the assessment of left ventricular (LV) function has been widely questioned during the past 10 to 15 years [With the potential to overcome these concerns, two-dimensional 2D) speckle-tracking echocardiography (STE) longitudinal strain was introduced. Global longitudinal strain (GLS) has been shown to be more reproducible and more useful clinically than circumferential and radial strains D speckle. It has Moreover, the possibility of quantifying regional alterations of longitudinal strain (LS) through its polar projection, the so-called bull's-eye map, allows a further evaluation of both the site and extent of myocardial damage. This last analysis is particularly useful in visualizing regional inhomogeneities in function, in some cases providing the identification of typical pathological patterns with an incremental value for differential diagnosis .General concepts about strain and STE and technical details about the practical performance of STE have been satisfactorily discussed elsewhere ; thus thTherefore, the aim of this review is to offer a critical overview of 2D global and regional LS, underscoring the advantages and disadvantages of each for the early detection of myocardial dysfunction and whether strain should or should not be indicated in the clinical evaluation of the function , a correct setting of spatial and temporal smoothing, and a proper size of the region of interest significantly reduce strain variability. Thus, it is reasonable that strain analysis be performed by expert echocardiographers with specific training. In addition, variability increases in the regional distribution of LS, whereas the global estimation is less affected; thus, bull's-eye maps should be considered a valid tool for differential diagnosis only when image quality is optimal. Currently, it could be reasonable and more useful to consider regional longitudinal strain distribution to be a semiquantitative tool, focusing attention on the assessment of differences between segments in bull's-eye maps to find typical patterns that can help obtain the correct diagnosis, as opposed to evaluating the numerical segment-specific strain values, and comparing them in the follow-up. Finally, intervendor variability had been considered one of the most important technical limitations of strain analysis. However, important efforts have been made to reduce differences among vendors , and no These good results and the increased availability of strain technique determined an improved reproducibility of GLS, now reported to be analogous  or even LVH is perhaps the setting in which EF quantification fails most clearly in the detection of LV systolic function because LVH and volume changes allow depressed systolic function to go unnoticed when assessed by EF . On the Athlete's heart is a benign increase in cardiac mass that represents a physiological adaptation to systematic training. The most challenging clinical dilemma is the differentiation between this physiological LVH and hypertrophic cardiomyopathy (HCM), one of the common causes of sudden cardiac death in young athletes. EF is commonly normal in athletes ; howeverEF is often normal or supernormal in HCM patients as well, especially in the first stages of the disease . On the  et al. [Moreover, analysis of the regional changes in LS might be suggested for differential diagnosis, given that LS is normal  in athletes  but is o et al.  reportedIn recent years, there has been much discussion about the role of GLS in the assessment of LV systolic function in hypertensive patients. Hypertension causes an increase in LV afterload. Because it is well known that LS is affected by LV overload, both preload and afterload, it is not completely clear if the reduction in GLS is associated with increased afterload or with the subendocardial ischemia and increased myocardial fibrosis that derive from it. Several studies have shown a significant reduction of GLS in hypertensive patients, both when they showed concentric LV remodeling  and whenSome recent studies have reported a reduction of GLS in patients with diabetes mellitus , 25, insDiabetes and hypertension, which are often associated with the impairment of longitudinal function, are also common findings in patients with HFpEF , 28, 29,Sarcomeric and nonsarcomeric HCMs typically are characterized by heterogeneous echocardiographic patterns of LVH, often with a normal or supernormal EF. On the contrary, GLS provides an accurate estimation of LV contractility, and its reduction is associated with poor prognosis and increased risk of ventricular arrhythmias . The rolThe assessment of regional LS seems to be useful for the detection of some HCM phenocopies, such as Fabry disease and cardiac amyloidosis. In Fabry disease, regional systolic LS is typically decreased at the basal posterolateral wall , and a reduced LS in these segments indicates fibrosis, as confirmed by late gadolinium enhancement at MRI . Also, tThe equations of LVH .Of course, apical sparing pattern is not exclusive to cardiac amyloidosis and can be found in some other diseases, including LV noncompaction and AS. However, a careful standard echocardiographic examination would allow the physician to make a differential diagnosis with the help of other specific markers such as a typical appearance of the endocardium in LV noncompaction or valve calcifications in AS.LVEF is a key parameter for establishing when an asymptomatic patient with severe heart valve disease (HVD) should be referred to surgery , 42; howOn the contrary, the most robust findings with regard to the usefulness of GLS have been obtained in patients with AS. GLS gradually decreases while AS severity increases without any simultaneous change in LVEF . This fiMoreover, GLS measured during dobutamine stress echocardiography may provide incremental prognostic value beyond GLS measured at rest and be helpful in enhancing risk stratification in low-flow, low-gradient AS .Accordingly, the most recent multimodality imaging guidelines suggest GLS as a parameter for the assessment of risk in patients with asymptomatic severe AS, stating that surgery may be considered in patients with high risk (Class IIb) . In addiTherefore, in our opinion, GLS is indicated for an accurate management of patients with severe AS  or associated comorbidities . So far, typical patterns of regional distribution of LS alterations have not been reported. Thus, further studies need to be performed to evaluate the effective role of GLS analysis in the follow-up of systemic disorders. Nowadays, this tool can be considered very useful but not indispensable for patient management . Echocardiography is the current standard for monitoring LV systolic function in these patients, but it might not detect early systolic dysfunction. Significant decreases in longitudinal peak systolic strain/strain rate and early diastolic myocardial velocities previously were found in the LV inferolateral and anterolateral walls in patients with DMD  Supplem. More reInteresting data have been reported about the role of 2D STE GLS in the assessment of subtle LV systolic dysfunction in patients with Friedreich's ataxia myocardial involvement, too. Friedreich's ataxia patients' hearts are characterized by iron deposits, diffuse fibrosis, focal necrosis, and LV hypertrophy, but often they show a normal LVEF and mass in the first stages of the disease –79. HoweHowever, the clinical significance of the early detection of cardiac dysfunction in these diseases warrants further studies. et al. [The early recognition of myocardial damage in patients who undergo chemotherapy is crucial for their clinical management. Indeed, chemotherapy discontinuation is based on the assessment of myocardial dysfunction, thus far quantified by EF. The most recent position papers , 82 stat et al.  showed t et al. –86 (Tabl et al. . Moreove et al. , providi et al. , 86 statBull's-eye maps show a frequent involvement of the septum and, often, an apical impairment ; Table 3Finally, we agree with the current scientific documents that GLS with bull's-eye map evaluation is indicated for an early detection of cardiac toxicity and to monitor cardiac effects of cancer therapy in long-term surveillance programs as well.The growing evidence of the superiority of GLS as a marker of global function compared with conventional analysis for an early diagnosis of myocardial damage and for risk stratification is, in our opinion, the key role of this tool in each clinical setting. Additional information provided by bull's-eye maps suggests that regional LS has the potential to improve the accuracy of clinical diagnosis according to specific patterns. However, as with all echocardiographic parameters, GLS is only one piece of the puzzle; this should be kept uppermost in mind to avoid overstating its usefulness. Regional LS still suffers from some limitations, and thus, currently, it could be reasonable and more useful to consider regional LS distribution as a semiquantitative tool, focusing attention on the assessment of differences between segments in bull's-eye maps to find typical patterns that can help obtain the correct diagnosis rather than evaluating the numerical segment-specific strain values.In the near future, improvements in technology could allow wider use of longitudinal strain analysis in the everyday routine, offering a better diagnostic accuracy and reliability and, consequently, an increased role in patient management (Supplementary