Aims: Left ventricular ejection fraction is the conventional measure used to guide heart failure management, regardless of underlying etiology. Left ventricular global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE) is a more sensitive measure of intrinsic myocardial function. We aim to establish LV-GLS as a marker of replacement myocardial fibrosis on cardiovascular magnetic resonance (CMR) and validate the prognostic value of LV-GLS thresholds associated with fibrosis.Methods and results: LV-GLS thresholds of replacement fibrosis were established in the derivation cohort: 151 patients  with hypertension who underwent STE to measure LV-GLS and CMR. Prognostic value of the thresholds was validated in a separate outcome cohort: 261 patients with moderate-severe aortic stenosis  and preserved LVEF ≥50%. Primary outcome was a composite of cardiovascular mortality, heart failure hospitalization, and myocardial infarction. In the derivation cohort, LV-GLS demonstrated good discrimination  and calibration  for replacement fibrosis. In the outcome cohort, 47 events occurred over 16  months. Patients with LV-GLS > −15.0%  had the worst outcomes compared to patients with LV-GLS < −21.0%  and those between −21.0 and −15.0% (log-rank P < 0.001). LV-GLS offered independent prognostic value over clinical variables, AS severity and echocardiographic LV mass and E/e′.Conclusion: LV-GLS thresholds associated with replacement myocardial fibrosis is a novel approach to risk-stratify patients with AS and preserved LVEF. BioRender.com.Thresholds of echocardiographic left ventricular global longitudinal strain (GLS) that are associated with replacement myocardial fibrosis risk-stratify patients with aortic stenosis and preserved left ventricular ejection fraction. Some images in the figure were created with  Myocardial fibrosis is one of the hallmarks of a failing heart . In non-Regardless of etiology, impaired LV ejection fraction (LVEF) is commonly used as a measure of global LV systolic dysfunction to guide heart failure management. However, LVEF is a late marker of cardiac decompensation. Global longitudinal strain (GLS) using speckle tracking echocardiography is more sensitive in detecting early LV dysfunction and correlates with myocardial fibrosis on histology . DespiteIn Stage B heart failure , adverse myocardial remodeling in left ventricular hypertrophy (LVH) conditions such as hypertensive heart disease and aortic stenosis (AS) is accompanied by myocardial fibrosis that is mediated in part by myocardial injury/ischemia, neurohormones and the renin-angiotensin-aldosterone system , 11. In Independent of underlying etiology, LV GLS reflects the functional consequences of myocardial fibrosis. In this study, we aim to examine the mechanistic association between LV GLS and the myocardium; and establish optimal LV GLS thresholds associated with myocardial fibrosis on cardiovascular magnetic resonance (CMR) in a cohort of hypertensive patients who have undergone both CMR and echocardiography. Subsequently, we will validate the prognostic value of these LV GLS thresholds in a separate cohort of asymptomatic/minimally symptomatic  patients with moderate to severe AS and preserved LVEF.clinicaltrials.gov identifier: NCT02670031) at the National Heart Center Singapore (NHCS). The aim of the REMODEL trial was to examine the role of CMR in patients with hypertension. The inclusion and exclusion criteria were published previously  and LVEF ≥50% from a multicenter Singapore study coordinated by the National University Heart Center Singapore (NUHCS) as well as an ongoing AS registry at the Leiden University Medical Center (LUMC). Patients with regional wall motion abnormalities on echocardiography were excluded. Patients in the Singapore cohort were prospectively recruited in September 2010 and followed until March 2021. Patients in the Netherlands cohort were followed up until October 2018.The outcome cohort consisted of asymptomatic/minimally symptomatic  patients with moderate and severe AS . Balanced steady-state free precession cine images were acquired in the standard long-axis  and short-axis views . Myocardial fibrosis was assessed using two approaches: late gadolinium-enhanced (LGE) imaging for replacement myocardial fibrosis and myocardial T1 mapping for reactive interstitial myocardial fibrosis. LGE imaging was performed ~8 min after administration of 0.1 mmol/kg of gadobutrol . An inversion-recovery fast gradient echo sequence was used, and the inversion time was optimized to achieve appropriate nulling of the myocardium. Myocardial T1 mapping based on the Modified Look-Locker inversion-recovery sequence (heartbeat acquisition scheme of 5(3)3 and 4(1)3(1)2 for native and post-contrast myocardial T1, respectively). Replacement myocardial fibrosis on LGE was assessed qualitatively. Extracellular volume fraction (ECV) was estimated from the native and 15-min post-contrast T1 map, analyzed using the T1 mapping module  , 19. HemCardiac volumes, function and LV mass were analyzed using the CVI42 software  at the National Heart Research Institute of Singapore (NHRIS) CMR Core Laboratory. Image analyses were performed by trained individuals using standardized protocols .LV GLS assessment by two-dimensional speckle tracking echocardiography was performed at the individual centers. LV GLS was analyzed by post-processing triplicate apical LV images  using EchoPAC software . Myocardial tracking was carefully verified and manually adjusted, if needed. Width of the region of interest was adjusted to include the entire thickness of the LV myocardium.AS severity  in the outcome cohort was assessed according to the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines . The ratThe primary outcome was a composite of first major adverse cardiovascular events: cardiovascular mortality, heart failure hospitalization and myocardial infarction. Secondary outcome was a composite of heart failure hospitalization, myocardial infarction, aortic valve replacement (AVR), and death from any cause. Events were censored at the time of AVR or last patient contact if no events were experienced.t-test or non-parametric Kruskal–Wallis test were used to compare groups of continuous data. Categorial data were compared using the χ2 test. Statistical analyses were performed using SPSS version 23 . A two-sided P < 0.05 was considered statistically significant.Data were reported as percentages for categorical variables and mean ± standard deviation or median (interquartile range) for continuous variables as appropriate. The distribution of all continuous variables was assessed using the Shapiro–Wilk test. Depending on the normality of the distribution, parametric Student's c statistic for discrimination  and the Hosmer-Lemeshow goodness of fit for calibration. Optimal LV GLS thresholds defined as ≥95% specificity and ≥95% sensitivity for myocardial fibrosis on CMR were established from the AUC. These values would define the risk categories of patients in the outcome cohort.In the derivation cohort, multivariable logistic regression (forward step-wise selection method) was used to establish relevant determinants of myocardial fibrosis: age, sex, systolic blood pressure and LV GLS. The diagnostic performance of the model was assessed using the In the outcome cohort, LV GLS values less than the sensitive threshold defined a low-risk category. Conversely, LV GLS greater than the specific threshold for myocardial fibrosis was categorized as high-risk. LV GLS values between the sensitive and specific thresholds were considered as intermediate-risk. Time-to-first major event survival curves associated with the different risk categories were estimated using the Kaplan–Meier method and compared with the log-rank test. The Cox regression model was used to adjust for potential confounders .n = 55) had a higher systolic blood pressure compared to those without . These patients had higher indexed LV mass , and higher measures of reactive interstitial myocardial fibrosis . Patients with replacement myocardial fibrosis  but a weaker correlation with native T1  and ECV . Despite similar LVEF, patients with replacement myocardial fibrosis demonstrated impaired LV GLS on echocardiography  and replacement myocardial fibrosis  were independently associated with LV GLS, after adjusting for age, sex and systolic blood pressure.LV GLS demonstrated a moderately strong correlation with indexed LV mass (P < 0.001). Age, sex and systolic blood pressure were not retained in the regression model. LV GLS demonstrated high discrimination  and calibration  for the presence of replacement myocardial fibrosis. Based on the ROC analysis, a LV GLS threshold of −21.0% was associated with 95% sensitivity to rule out replacement myocardial fibrosis, while a LV GLS threshold of −15.0% was associated with 95% specificity to rule in replacement myocardial fibrosis.In the analysis to determine LV GLS thresholds of replacement myocardial fibrosis, LV GLS was the only variable associated with replacement myocardial fibrosis  and had the highest systolic blood pressure compared to the other risk groups  and were considered as low-risk. Conversely, 28 patients had LV GLS more than −15.0% (worse strain) and were classified as high-risk. The other patients with LV GLS values between −15.0 and −21.0% were considered at intermediate risk. High-risk patients were predominantly males  and hemodynamics . Using the LV GLS thresholds established in the derivation cohort, 11.9% (n = 31) of the patients were classified as low-risk and 46.4% (n = 121) were classified as high-risk. High-risk patients with AS had the most severe AS disease, highest E/e′ ratio and lowest LVEF compared to the other groups (P = 0.674).The outcome cohort consisted of 261 patients with moderate to severe AS with preserved LVEF  that occurred during 16  months of follow-up . Only 1 event occurred in low-risk patients. Conversely, 23 events occurred in those at high-risk and the remaining 23 events in those at intermediate-risk , AS severity, LV mass and E/e′ ratio .The current study demonstrates that LV mass and replacement myocardial fibrosis on CMR were independently associated with echocardiographic LV GLS; while CMR measures of reactive interstitial fibrosis had weaker correlations with LV GLS. LV GLS thresholds of replacement myocardial fibrosis risk-stratified patients with AS. Despite absent/minimal symptoms and preserved LVEF, patients with moderate or severe AS deemed at high risk (LV GLS > −15.0%) experienced increased cardiovascular events compared to those at intermediate- (LV GLS −15.0 to −21.0%) and low-risk (LV GLS < −21.0%) over medium term follow-up. LV GLS was independently associated with adverse cardiovascular outcomes after adjusting for the effects of potential confounders .myocardial fibers  is impaired in patients with aortic stenosis, even in the absence of epicardial coronary artery disease . AlthougRisk stratification in AS with either echocardiographic LV GLS, the clinical risk score or other approaches would need to be guided by local expertise and availability of resources. LV GLS, as a marker of replacement fibrosis, has incremental prognostic value over conventional prognostic markers such as LVEF, AS severity and E/e′. These observations may impact future management of AS. Potentially, asymptomatic patients with moderate to severe AS and preserved LVEF can be further risk-stratified using echocardiographic LV GLS. Patients at intermediate risk may benefit from further risk stratification with CMR , computed tomography aortic valve calcium score and/or exercise stress testing. Whether these patients identified to be at high-risk would benefit from early AVR would need to be guided by future trials.Myocardial deformation is affected by co-existing cardiac conditions. As this study attempts to validate LV GLS as a novel marker of replacement myocardial fibrosis, we have carefully excluded cardiac conditions that may confound the assessment of LV GLS in the derivation cohort. The prognostic value of these LV GLS thresholds on the individual endpoint would need to be verified in other more heterogeneous cohorts of asymptomatic patients with significant AS. These thresholds will also require further validation with different speckle tracking software, imaging modalities (such as CMR) and techniques of assessing GLS [such as the novel 3D speckle tracking ]. GLS waEchocardiographic LV GLS has an independent association with replacement myocardial fibrosis and LV mass on CMR. Asymptomatic patients with significant AS and LV GLS thresholds specific for myocardial fibrosis (GLS > −15.0%) are at high-risk of adverse cardiovascular outcomes. Conversely, those at low-risk (GLS < −21.0%) have very favorable prognosis. LV GLS thresholds of replacement fibrosis is a novel approach to risk-stratify patients with moderate to severe AS and preserved LVEF who may benefit from early AVR.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Singhealth CIRB and National Healthcare Group DSRB. The patients/participants provided their written informed consent to participate in this study.T-TL, WH, L-HL, and CC conceived the study idea. T-TL and WH contributed in data analysis, manuscript drafting, and preparation. BA, JAB, and D-FT recruited the patients, collected study/imaging data, and curated the data in the Singapore derivation cohort. SE, HT, ET, JY, QY, EL, PY, SC, PG, LL, HO, AR, and L-HL recruited aortic stenosis patients in the multi-center study, collected and curated the study data in their respective sites in the Singapore validation cohort. WS, YO, LG, and JL assisted in the data/imaging analysis of patients in the Singapore validation cohort. GS, VD, and JJB collected, analyzed, and curated the clinical and imaging data in the Leiden validation cohort. L-HL and CC contributed in supervising the writing and interpretation of the data. All authors have made critical feedback and contributed to the final manuscript.This study was funded by the National Medical Research Council, Singapore , and the Charles Toh Cardiovascular Fellowship Fund.The department of Cardiology at Leiden University receives unrestricted research grants from Abbott Vascular, Bayer, Biotronik, BIoventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis and Medtronic. VD received speaker fees from Abbott Vascular, Edwards Lifesciences, GE Healthcare, MSD, Medtronic and Novartis. JJB received speaker fees from Abbott Vascular. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


CTRCD was detected after the 3rd cycle of anticancer therapy. CTRCD patients had impaired exercise capacity : 13.9 ± 3.1 vs. 17.0 ± 3.9 ml/kg/min, p = 0.02). More primary outcome events occurred in the CTRCD group . LV GLS could detect subtle but clinically significant cardiac dysfunction in lymphoma patients in the early stage of anticancer therapy. CTRCD may be associated with not only a reduced exercise capacity but also a worse prognosis.Left ventricular (LV) global peak systolic longitudinal strain (GLS) is a sensitive measurement for detecting subtle LV systolic dysfunction and a powerful prognostic predictor. However, the clinical implication of LV GLS in lymphoma patients receiving cancer therapy remains unknown. We prospectively enrolled 74 lymphoma patients . We performed echocardiographic studies after the 3rd and 6th cycles and 1 year after chemotherapy and a cardiopulmonary exercise test upon completion of 3 cycles of anticancer therapy. Cancer therapy-related cardiac dysfunction (CTRCD) was defined as a ≥ 15% relative reduction in GLS value from baseline. The primary outcome was a composite of all-cause mortality and heart failure events. Thirty-six patients (49%) had CTRCD (LV GLS: baseline vs. after 3rd cycle of therapy: 20.1 ± 2.6 vs. 17.5 ± 2.3%,  In the last decade, enormous advances in anti-neoplastic therapeutics have led to a marked reduction in cancer mortality, but an increasing number of unintended cardiovascular consequences have been reported in cancer survivors3. These cancer therapy-related cardiac dysfunctions (CTRCDs) include heart failure, conduction disorders, hypertension, thromboembolic events and ischemia6. Heart failure is one of the most notorious cancer therapy-related cardiotoxicities and significantly impacts the prognosis of cancer survivors8.Cardiovascular diseases and neoplasms are the leading causes of death worldwide14. It was reported that LV GLS could be used to identify CTRCD in breast cancer patients after they completed cancer therapy19. Although it is recommended to use LV GLS to assess heart function prior to, during, and after chemotherapy20, how to define subtle LV dysfunction according to LV GLS is not well clarified, and the prognostic impact of subtle LV systolic dysfunction in cancer survivors is not clearly illustrated. Moreover, the cardiopulmonary exercise test (CPET) is an important clinical modality for assessing integrative exercise responses involving the pulmonary, cardiovascular, hematopoietic, neuropsychological, and skeletal muscle systems22. Nevertheless, there are limited studies using CPET to investigate cardiotoxicity in lymphoma patients receiving standard chemotherapy. Therefore, we conducted this prospective cohort study to investigate the clinical application of LV GLS in evaluating the early impact of cancer therapy on cardiac function and the clinical implication of subtle LV dysfunction in lymphoma patients during cancer therapy.Traditional 2-dimensional echocardiography could only identify notably impaired left ventricular (LV) systolic contractility but failed to detect the early deterioration of LV systolic function. Compared to conventional echocardiographic parameters, such as LV ejection fraction, speckle-tracking echocardiography (STE) with myocardial deformation analysis, such as LV global peak systolic longitudinal strain (GLS), has been indicated to be a feasible, objective and more sensitive modality to detect subtle but clinically significant LV systolic dysfunction and is a powerful prognostic predictorWe prospectively enrolled patients with newly diagnosed lymphoma (age ≥ 20 years) at the National Cheng Kung University Hospital between April 2017 and March 2019. All patients received anthracycline-based anticancer therapy. The exclusion criteria were moderate or severe aortic or mitral valve disease, pregnancy, breastfeeding, a prior history of chemotherapy or radiotherapy, atrial fibrillation with very irregular ventricular response, poor image quality in the GLS analysis, and unwillingness to participate in the study. This study adhered to the Declaration of Helsinki, and study approval was obtained from the Human Research and Ethics Committee of the National Cheng Kung University Hospital (IRB numbers: A-ER-105-407 and B-ER-106-392). All enrolled patients provided written informed consent. The enrolled patients’ medical records during the follow-up period (February 2017 to December 2019) were carefully reviewed. Clinical data on age, sex, comorbidities, medical history, cancer pathology, cancer stage, concomitant chemotherapy comorbidities, medical history, and anticancer regimen were obtained through medical record review. None of the patients received other cardiotoxic agents or radiation therapy or underwent cardiac protective protocols during the procedure.The primary outcome was defined as a composite of all-cause mortality or worsening heart failure events. Heart failure events included pulmonary edema on chest X-ray, hospitalization for heart failure, or an emergency room visit for intravenous therapy of loop diuretics for heart failure.The secondary outcomes included the Common Terminology Criteria for Adverse Events Version 5 (CTCAE V5) score for heart failure evaluated at the following time points: after the 3rd and 6th cycle and 1 year after the initiation of anticancer therapy.23. LAVi was calculated as (A1 x A2/L) × 8/3π, where L is the average LA length in the apical four- and two-chamber views. Mitral inflow velocity measurements included early (E) and late (A) peak mitral inflow velocities and the E/A ratio. We acquired pulsed tissue Doppler imaging from the apical 4-chamber view and placed the sample volume on the LV septal and the lateral mitral annulus to obtain peak early diastolic velocity (e′). The ratio of early mitral inflow velocity to early diastolic mitral annular velocity (E/e′) was calculated from the average of the septal and lateral e′ /2]). All images were acquired in 3 consecutive cardiac cycles and stored digitally with a frame rate of 50–90 frames/s for subsequent offline analysis.All subjects underwent echocardiography prior to chemotherapy; after the 1st, 3rd, and 6th cycle; and 1 year later. Patients were examined in the left lateral decubitus position by well-trained echocardiographers using an ultrasound system with a 2–5 MHz probe . Based on the recommendations of the American Society of Echocardiography, quantifications of LV mass index, LV EF, and left atrium volume index (LAVi) were performed19, CTRCD was defined as a relative reduction in GLS from baseline ≥15%.Two cardiologists who were blinded to the clinical information used automated function imaging (AFI) software  to measure LV GLS from three standard apical views. Each apical view assessment produced six segmental values of peak systolic longitudinal strain. Thus, LV GLS was defined as the mean of the peak systolic longitudinal strain of all the LV segments from three apical views. Additionally, analysis of the different myocardial layers was performed offline using AFI software. For each apical view, the AFI software automatically separated the myocardium into the subendocardial and subepicardial layers. According to the European Society of Cardiology guidelines24. We recorded the minute oxygen consumption (VO2), carbon dioxide production (VCO2), minute ventilation (VE), end-tidal carbon dioxide (PETCO2), and heart rate. The heart rate reserve (HRR), for which less than 15 is defined as low, was the difference between the maximal heart rate during CPET and the subject’s maximal predicted value. The ventilatory reserve, for which greater than 85% is defined as low, was the ratio of the maximal minute ventilation during CPET to the maximal voluntary ventilation. The oxygen pulse (VO2/HR), VE/VO2, VE/VCO2, and respiratory quotient (VCO2/VO2) were averaged every 10 seconds. The peak oxygen consumption (peak VO2) was determined as the highest value of the 30-second average value of oxygen consumption. The anaerobic threshold was defined using the V-slope method25. All eligible patients underwent CPET upon completing 3 cycles of anticancer therapy.The enrolled patients underwent CPET using a cycle ergometer  in an upright position with a standardized protocol. Patients with a poor performance status or musculoskeletal disorder were excluded from undergoing CPETt-test or the Mann-Whitney U test for continuous variables that showed a normal or nonparametric distribution, respectively. Chi-square test or Fisher’s exact test was used for categorical variables where appropriate. Using the Bland-Altman analysis of agreement26 and the interclass correlation coefficient, 30 randomly selected patients’ LV GLS measurements were applied to assess the intra- and inter-rater reliability. GLS was independently measured by two independent observers. For intra-rater variability, we repeated the same measurement 1 month apart. A paired t-test was used to determine the significance between EF and the change in GLS according to time. The Kaplan-Meier method was used with a log-rank test to compare event-free rates between strata. A univariate Cox regression analysis was performed to evaluate factors associated with the primary endpoint. Factors with a value of p < 0.1 based on the univariate Cox regression analysis were included in the multivariate Cox regression analysis to identify factors independently associated with anticancer therapy-related subtle LV dysfunction.IBM SPSS Statistics V21.0 software  was used for statistical analysis. Continuous data are presented as the mean ± standard deviation or as the median (interquartile range), depending on the distribution. Dichotomous data are presented as numbers and percentages. Comparisons were conducted using Student’s Ninety-one patients with lymphoma receiving anticancer therapy were prospectively screened. Owing to the following reasons, 17 patients were excluded: radiotherapy (n = 1), inadequate image to analyze (n = 3), loss to follow-up (n = 3), follow-up refusal (n = 4), and death after the 1st cycle of chemotherapy (n = 6). Seventy-four patients  who completed all the echocardiographic studies, i.e., at baseline (prior to anticancer therapy), after the 3rd and 6th cycles of anticancer therapy, and 1 year after anticancer therapy, were included in the final analyses. According to the change in LV GLS, the patients were stratified into two groups: the CTRCD group  and the non-CTRCD group . There was no significant difference in baseline demographic characteristics between these two groups, except for male sex and anemia (hemoglobin (Hb) < 11 g/dl). The CTRCD group included more male patients and had a higher rate of anemia , EF, or diastolic function  after the 3rd and 6th cycles and 1 year after anticancer therapy Table , Fig. 1Ap = 0.01, post-3rd cycle treatment; 16.3 ± 2.2% vs. 19.6 ± 2.7%, p < 0.001, post-6th cycle treatment) was noted in the CTRCD group despite their LV EF value not being decreased  and lower VO2/kg at the anaerobic threshold , indicating a reduced exercise capacity due to cardiac systolic dysfunction. Thus, this study showed that CPET confirmed the diagnostic definition of CTRCD in terms of cardiac systolic dysfunction.Because the patients had poor general physical status at enrollment and could not tolerate undergoing CPET, we did not conduct baseline CPET. However, after the 3rd cycle of anticancer therapy, only 48 patients were well enough to undergo CPET. Among these 48 patients, CTRCD patients had lower VOp = 0.03, Table The mean follow-up duration was 1.4 ± 0.6 years, and 16 22%) patients reached end points. The incidence of the primary composite outcome was higher in the CTRCD group than in the non-CTRCD group  and 0.925 (95% CI 0.843–0.965), respectively. The mean intra- and interrater differences [mean ± standard deviation (95% limits of agreement)] for GLS were 0.16±1.13 (− 2.05 to 2.37) and − 0.45±1.20 (− 2.80 to 1.90), respectively. The Bland-Altman analysis demonstrated no systemic bias in LV GLS between intra- and interrater agreements . It is worth noting that only one patient had LV dysfunction, which was defined as EF < 50%. Although most patients with CRTCD had only subtle LV dysfunction but not EF less than 50%, CTRCD truly affected the patients’ prognosis. Therefore, more research is warranted to determine how to prevent CTRCD and improve cardiac function in CTRCD patients.Mounting evidence has shown that LV GLS is a very powerful prognostic predictor, not only for patients with cardiac disease but also for those with systemic diseases, such as hypertension19. However, many studies have shown that male sex is a predictor of LV dysfunction after doxorubicin therapy as well as a risk factor for subclinical late cardiomyopathy in adult lymphoma patients receiving doxorubicin29. Moreover, men had a greater incidence of major adverse cardiac events than women after anthracycline therapy30. Additionally, the prevalence of anemia is higher in lymphoma patients and is considered an adverse prognostic factor for overall survival and progression-free survival. Furthermore, a retrospective analysis that examined anticancer therapy-associated heart failure demonstrated that anemic patients have a higher risk of LV dysfunction31.Female sex was recognized to be associated with the risk of cardiotoxicity following anthracycline treatment21. In our cohort, patients with subtle LV dysfunction had lower VO2 and VO2 at the anaerobic threshold according to the CPET results. Despite physical exhaustion, CPET can also be considered an adjuvant tool to detect subclinical cardiotoxicity in conjunction with STE. However, some patients with a poor performance status or musculoskeletal disorder refuse to undergo CPET because of the associated discomfort. Finally, only 61% of patients had received CPET in our study. Thus, echocardiography with GLS may be a better and more comfortable tool than CPET for screening chemotherapy-related cardiotoxicity. However, investigation assessment scores, such as the CTCAE heart failure score, did not reveal a significant difference in either group, suggesting that the traditional clinical score is not sensitive enough to detect chemotherapy-related subtle LV dysfunction.CPET can provide a thorough assessment of integrative exercise physiology involving the pulmonary, cardiovascular, muscular, and cellular oxidative systems. Furthermore, CPET plays an important role in cardiology in terms of including several forms of exercise intolerance, with a predominant focus on heart failure with reduced or preserved EF32. Cancer and cardiovascular disease share some risk factors, such as tobacco smoking, unhealthy diet, obesity, chronic inflammation, and increased oxidative stress. Moreover, exposure to radiation from diagnostic assessments, epigenesis, and regenerative signaling also have potential associations with both illnesses33. Notably, there is interpatient variability despite the established clinical and cardiovascular risk factors for anthracycline-related cardiotoxicity. Several studies disclosed cardiotoxicity-related pharmacogenetic variants after anthracycline treatment. The genotypes CBR3, CELF4, and HAS3 in pediatric cancer patients are associated with the dose-response relationship between anthracycline exposure and the risk of cardiomyopathy34. The results from the meta-analyses revealed that ABCC2 rs8187710, CYBA rs4673, and RAC2 rs13058338 genetic polymorphisms played an important role in anthracycline-induced cardiotoxicity35. The current evidence regarding the molecular foundations of early or delayed anticancer therapy-related cardiotoxicity remains unclear.The factors that influence the risk of developing cancer therapeutic-related cardiac dysfunction may be subdivided into three groups: patient-related clinical risk factors, treatment-related risk factors, and the individual genetic profile16.There are some limitations to this study. First, the sample size is small; however, this is the first prospective cohort study to demonstrate that subtle cancer therapy-related LV dysfunction in lymphoma patients detected by GLS has prognostic value. Second, 39% of patients did not undergo CPET. Third, the chemotherapy regimens varied. Thus, the correlation between subtle LV dysfunction and drug combination is uncertain. Finally, we did not measure the levels of cardiac biomarkers, such as high-sensitivity cardiac troponin and brain natriuretic peptide in this study. However, we have to recognize that as stated in the 2016 ESC Position Paper on cancer treatments, the role of routine cardiac biomarker measurement for detecting CTRCD is not clearly established and needs further investigationIt is well recognized that cancer therapy-related cardiotoxicity represents an emerging problem for cancer survivors. Nonetheless, neither conventional echocardiographic parameters nor the CTCAE heart failure score could detect subtle LV dysfunction after cancer therapy. LV GLS derived from STE is a feasible, noninvasive, and objective modality for detecting early cardiac dysfunction in lymphoma patients receiving anticancer therapy. Patients with subtle LV systolic dysfunction not only had a reduced exercise capacity, as shown by the CPET study, but also may have a higher risk of all-cause mortality and heart failure events.Supplementary Information


Data were processed using Corridor4DM software, twice by one operator and once by another operator. Results: The repeatability of the assessed values was quite good in the whole myocardium, LAD and LCX vascular territories, but was poor in the RCA territory. Conclusions: The poor repeatability of MBF and MFR in RCA vascular territory can be explained by poor automatic orientation of the heart axis during post-processing and a so-called “cardiac creep” phenomenon. Better automatic heart orientation and introduction of automatic motion correction is likely to drastically improve this repeatability. In the present state of the software, PET is better for patients requiring assessment of MFR in the RCA territory.Background: Myocardial blood flow (MBF) and flow reserve (MFR) examination, especially useful in the diagnosis of multivessel coronary artery disease (CAD), can be assessed with a cadmium-zinc-telluride (CZT) SPECT gamma camera, as an alternative to the expensive and less available PET. However, study processing is not free from subjective factors. Therefore, this paper aims to evaluate intra- and interobserver repeatability of MBF and MFR values obtained by the same operator and two independent operators. Methods: This study included 57 adult patients. MBF and MFR were assessed using a Discovery NM530c camera in a two-day, rest/dipyridamople protocol, using  Owing to a recent ASNC/SNMMI position statement [Assessment of the absolute myocardial blood flow (MBF) and calculation of the myocardial flow reserve (MFR) are among the newest diagnostic methods used in nuclear cardiology. In contrast to the determination of the fractional flow reserve (FFR) in coronary angiography, which allows the assessment of the hemodynamic significance of epicardial coronary artery stenosis, the MFR allows the assessment of the coronary reserve of the entire left ventricular myocardium and selected vascular territories. An additional advantage of this method is its non-invasive character. This broadens the diagnostic potential of myocardial perfusion imaging (MPI), particularly in the diagnosis of multivessel coronary artery disease (CAD), where standard perfusion study is less sensitive. MFR assessment with cadmium-zinc-telluride (CZT) semiconductor gamma cameras is an alternative to PET examinations using However, processing of the data obtained in this study (both in SPECT and PET) is not free from subjective factors and must be performed with the utmost care. For the correct calculation of MFR, it is necessary to align the heart images in the rest and stress studies in the appropriate axes. Moreover, as some authors emphasize, the quality of the study is influenced by artifacts resulting from the movement of the heart during the study  ,3. There99mTc-MIBI) using the SPECT CZT Discovery NM530c gamma camera, as a continuation of our earlier, preliminary report [The aim of this work is to assess the repeatability of MBF and MFR determination in studies carried out with technetium-99m-labeled sestamibi , who were planned for invasive coronary angiography, were enrolled in the study. Each patient underwent MPI with MFR assessment. Seven patients were excluded after quality control of the acquired dynamic images (due to artifacts caused by significant patient motion or irregular bolus time-activity curves). The remaining 57 patients were included in the study. Their basic demographic and clinical data are presented in All patients underwent invasive coronary angiography, which revealed critical stenosis of at least one coronary artery in 23 patients (including 8 patients with two-vessel disease and 2 patients with three-vessel disease). Critical stenosis affected the left anterior descending (LAD) artery in 14 cases, the left circumflex (LCX) artery in 11 cases and the right coronary artery (RCA) in 10 cases. There were no findings of critical stenosis in the coronary arteries of the remaining 34 patients. The time span between MPI and coronary angiography did not exceed 3 months.Prior to the study, each patient followed the routine protocol of preparation for the MPI performed with the dipyridamole stress test. Treatment with drugs that may interfere with the MPI was suspended for an appropriate period prior to the study. Calcium antagonists and nitrates were discontinued 2 days prior to the studies, and trimetazidine and its derivatives were discontinued for 7 days. In addition, patients were recommended to discontinue medication and avoid beverages and foods containing methyloxnatines (such as caffeine or theophylline) for 2 days prior to the dipyridamole pharmacological test. Patients were also asked to eat a sandwich with cheese or a hard-boiled egg immediately prior to the study, to accelerate hepatic clearance of the radiopharmaceutical agent.99mTc-MIBI  followed by 550 MBq in a quick bolus injection, carried out at the same time as the start of image acquisition. Dynamic image acquisition continued for 8 min. The stress part of the study consisted of a pharmacological test with dipyridamole, administered intravenously (dose: 0.56 mg/kg), after positioning the patient on the camera. The radiopharmaceutical bolus was administered 3 min after the injection of dipyridamole.MFR was assessed using a CZT Discovery NM530c camera  in a two-day protocol—at rest and after the pharmacological test with dipyridamole. Each time the patient was first administered intravenously 37 MBq of Data acquired using the gamma camera included dynamic images in listmode format, without attenuation correction. The dynamic data were reframed into 23 frames  and reconstructed according to the standard protocols of the camera supplier. Before further evaluation, a quality control of the patient positioning on the camera was carried out, by making sure that the heart is in the center of the field of view of the detectors and in the same position in both parts of the study (stress and rest)—86Rb or 13N ammonia PET MBF as a reference standard [SPECT images reconstructed in this way were processed using Corridor 4DM software, ver. 2015.0.2.66 , validated on the Discovery NM530c camera using 4DM with Initial post-processing was done automatically. Then, if necessary, it was adjusted manually. At this stage, each rest and stress study was assigned a numerical value, depending on the quality of the automatic image orientation: 0—automatic processing, which required little to no modification , 1—the cIn the next step, MBF and MFR values were generated using the one-tissue-compartment model with empirical Renkin-Crone compensation for the low first-pass extraction of the radiopharmaceutical and absence of attenuation correction , applyinTo assess repeatability, processing of each study was performed twice by one operator  and once by another, less experienced operator.2 determination coefficient, as well as—for selected parameters—Bland–Altman plots. The F-test was used to assess the relationship between standard deviations used to draw Bland–Altman plots. In all analyses, statistical significance was considered to be achieved when p ≤ 0.05. The calculations were carried out using Statistica v13.1  and LibreOffice v7.2  software.Normality of the distributions was tested with a Shapiro–Wilk test. The repeatability of the examined parameters, some of which were not distributed normally, was assessed using the non-parametric Spearman’s rank correlation coefficient and the rThe repeatability of the MBF values obtained by the same operator with a two-week interval between assessments and by two different operators was assessed in the whole myocardium of the LV (TOT) and in the vascular territories of the major coronary arteries . Spearman’s rank correlation coefficients were used as a measure of repeatability .p = 0.075). In the whole myocardium as well as LAD and LCX territories, the differences between the correlations of the results obtained by the same and two different operators were statistically insignificant.MBF values in the RCA vascular territory consistently showed statistically significantly weaker correlations than in other territories, both in assessments carried out by one and two operators. Additionally, in the RCA territory, the correlations of MBF results obtained by the same operator were significantly stronger than for two independent operators  and two different operators (p = 0.0086), and in case of the LAD territory and the whole myocardium, only in assessments by the same operator . In the remaining assessments, the differences were not statistically significant.The repeatability of the MBF values obtained by the same and two independent operators in the rest and stress studies that did not require significant manual adjustments  was compared with studies that required corrections (marked as “1” or “2”) . In the Repeatability of MFR values was assessed similarly to MBF. Correlation coefficients of the results obtained by the same and two different operators are presented in p = 0.035), with insignificant differences in the whole myocardium and LAD and LCX territories.In the assessments by two independent operators, as in the case of MBF, the values of MFR in the RCA vascular territory showed a statistically significantly weaker correlation compared to the MFR values in the whole LV as well as LAD and LCX vascular territories. In the RCA territory, correlation of MFR values obtained by the same operator was also significantly stronger than for two independent operators  is not sufficient to perform a statistical analysis of repeatability of MFR values in this group.A Discovery NM530c CZT gamma camera allowed for the assessment of MFR, which is a valuable addition to non-invasive MPI studies and can address some of their weaknesses, namely their lower sensitivity in the diagnosis of multi-vessel CAD, especially in cases of three-vessel disease. However, this dynamic examination, both in SPECT and PET techniques, is prone to errors and must be performed with the utmost care. There are several potential sources of such errors, both at the image acquisition stage and during post-processing.Positioning of the patient on the camera, respiratory motion and patient movement can significantly affect the results of the study, both in terms of MFR values and the perfusion evaluation ,10,11,122 = 0.99, [During data post-processing, there are also two stages that are prone to error due to subjective factors. The first is manual reorientation of the images to match the long axis of LV. Corridor 4DM software automatically adjusts the position and angle of the image axis, which should minimize the need for manual corrections. However, in this study, automatic orientation required significant manual adjustments, both in terms of image alignment and positioning the center of the axis at the center of the LV cavity, in the majority of cases . In PET studies, such problems are not reported frequently—automatic orientation of the images in most cases does not require such significant corrections, which can be indirectly deduced from the excellent repeatability of MBF values reported in PET studies  compared to 82Rb or 13N [It should also be mentioned that the lower extraction coefficient of b or 13N  can be aThe above factors suggest that in the current version of the Corridor 4DM software, the MFR evaluation with the CZT Discovery NM530c camera with manual motion correction has a fairly high repeatability in case of the whole LV myocardium, as well as regional MFR of LAD and LCX vascular territories. However, in the RCA territory, the repeatability is significantly lower, especially in the case of assessments carried out by two independent operators.Automatic motion correction software has recently been developed and has shown promising results in PET studies . It is rMBF values in studies where automatic image orientation did not require significant manual corrections are characterized by good repeatability, both in assessments by the same and two independent operators.The repeatability of MBF values in case of incorrect automatic image orientation is significantly lower in the RCA vascular territory.The MFR values for the whole myocardium as well as LAD and LCX vascular territories, obtained by the same and two independent operators, are characterized by fairly good repeatability, although it is clearly lower than in PET studies.The repeatability of MFR values in RCA territory obtained by two operators processing studies in the current version of the software is unacceptably poor.Improving the reliability of automatic image orientation and introducing automatic motion correction is likely to significantly improve the repeatability of MFR values and is necessary for a reliable assessment of MFR in RCA territory. This will require further investigation with updated software.In the present situation, patients requiring the assessment of MFR in RCA territory should not undergo the MFR study using the CZT Discovery NM530c camera processed using the version of the Corridor 4DM software used in this paper. PET study results will be much more reliable for this group of patients.Our analysis of dynamic SPECT studies of myocardial blood flow and flow reserve, performed using the Discovery NM530c gamma camera and processed with Corridor 4DM software, allows the following conclusions to be drawn:


Recent reports linked acute COVID-19 infection in hospitalized patients to cardiac abnormalities. Studies have not evaluated presence of abnormal cardiac structure and function before scanning in setting of COVD-19 infection. We sought to examine cardiac abnormalities in consecutive group of patients with acute COVID-19 infection according to the presence or absence of cardiac disease based on review of health records and cardiovascular imaging studies. We looked at independent contribution of imaging findings to clinical outcomes. After excluding patients with previous left ventricular (LV) systolic dysfunction , 724 patients were included. Machine learning identified predictors of in-hospital mortality and in-hospital mortality + ECMO. In patients without previous cardiovascular disease, LV EF < 50% occurred in 3.4%, abnormal LV global longitudinal strain (< 16%) in 24%, and diastolic dysfunction in 20%. Right ventricular systolic dysfunction  was noted in 18%. Moderate and large pericardial effusion were uncommon with an incidence of 0.4% for each category. Forty patients received ECMO support, and 79 died (10.9%). A stepwise increase in AUC was observed with addition of vital signs and laboratory measurements to baseline clinical characteristics, and a further significant increase (AUC 0.91) was observed when echocardiographic measurements were added. The performance of an optimized prediction model was similar to the model including baseline characteristics + vital signs and laboratory results + echocardiographic measurements. The presence of worse right ventricular (RV) function was shown to be associated with worse outcomes, albeit likely related to hypoxemia and pulmonary vascular abnormalities as opposed to primary cardiac disease. Interestingly, there are data showing in early disease, cardiac index is increased and systemic vascular resistance is decreased with normal RV function24.Several recent reports linked COVID-19 infection to cardiac abnormalities as determined by echocardiography and CMRNotwithstanding the above findings, most studies have not evaluated the presence of abnormal cardiac structure and function before imaging in the setting of COVD-19 infection which could have led to an apparently higher incidence of cardiac abnormalities in the setting of COVID-19 infection. In some studies, data were based on a completed survey questionnaire, confounding the interpretation of the results. Further, it is important to study the incremental prognostic value of new onset cardiac disease over clinical and laboratory data which are routinely available in the setting of acute COVID-19 infection to determine the clinical relevance of new onset cardiac abnormalities. We therefore sought to examine cardiac function in a consecutive group of patients hospitalized with acute COVID-19 infection according to the presence or absence of cardiac disease based on electronic health records review, including cardiovascular imaging studies. We also looked at the independent contribution of echocardiographic findings to clinical outcomes.in this retrospective study. No patients were excluded a priori for suboptimal echocardiographic imaging. Diagnostic testing and management were determined by the treating physicians based on clinical status. Medical records were reviewed to determine the presence of CAD (coronary artery disease), heart failure, comorbid conditions, laboratory measurements, and clinical outcomes. Data were obtained from Houston Methodist’s (HM) COVID-19 Surveillance and Outcomes Registry (CURATOR), after Houston Methodist Research Institute IRB approval was granted. CURATOR is an Institutional Review Board (IRB) approved registry of socio-demographic, clinical, and outcomes data abstracted from the electronic medical records of individuals with COVID-19-related encounters within the HM system. CURATOR, through a secure HIPAA-compliant server houses COVID-19-related data from March 2020. Clinical records dating back to June 2016 are included in the database review. These records include, among others, demographics, laboratories, procedures, and results of imaging tests. For individuals with multiple hospitalizations, only first-time hospitalization was included in the current analysis. All COVID-19 cases were confirmed by an antigen test, reverse transcriptase-polymerase chain reaction (RT-PCR) test, or SARS-CoV-2 serology.Consecutive patients between March 2020 and September 2020 who were hospitalized with COVID-19 diagnosis, and who underwent at least one echocardiogram were enrolled All methods were carried out in accordance with Houston Methodist Research Institute guidelines and regulations. Houston Methodist Research Institute IRB granted waiver of informed consent (45 CFR 46.116) when it approved the study. There were no experimental protocols examined in this study.25. The indications for echocardiography were shortness of breath, positive troponin assays, and chest pain. Image acquisition was carried out at a frame rate of 40–80 frames/s, and 3 cardiac cycles were acquired in cine loop format. Studies were analyzed offline. From the apical window, PW (pulse wave) Doppler was used to record mitral inflow for 3–5 cardiac cycles at the level of the mitral valve annulus and tips26. Pulmonary venous flow was acquired in the apical 4 chamber view with the aid of color Doppler. A 2–3 mm sample volume was placed > 0.5 cm from LA  junction into the pulmonary vein26. Tissue Doppler (TD) was applied to record mitral annular velocities at the septal and lateral sides of mitral annulus, and lateral side of the tricuspid annulus26. The resulting annular velocities by PW Doppler were recorded for 5 cardiac cycles at a sweep speed of 100 mm/s. The tricuspid regurgitation velocity was recorded by CW (continuous wave) Doppler from multiple windows, and the highest velocity was noted. Imaging of the inferior vena cava and hepatic venous flow was obtained. Depending on the image quality, an ultrasound enhancing agent (UAE) was injected intravenously, if needed.The echocardiographic study followed standard guidelines25. Mitral inflow from the tips level was analyzed for peak early (E), and late (A) diastolic velocities, E/A ratio, and deceleration time (DT) of mitral E velocity26. Mitral annulus early (eʹ) diastolic velocity was measured at septal and lateral mitral annulus, and septal, lateral and average E/eʹ ratios were computed26. If satisfactory acquisition was achieved, pulmonary venous flow was evaluated for systolic to diastolic velocity ratio , and atrial velocity as an indicator of LV end diastolic pressure. The tricuspid regurgitation velocity was used along with inferior vena cava size and collapse and hepatic venous flow to estimate pulmonary artery (PA) systolic pressure based on the modified Bernoulli equation26. Measurements were averaged over 3 cardiac cycles. Tricuspid annular plane systolic excursion (TAPSE) and tricuspid sʹ (systolic ejection) velocity were determined25. LV global longitudinal strain (GLS) from the 3 apical views, RV free wall strain, and LA strain in apical 4-chamber view were measured by an observer blinded to clinical data and all other echocardiographic measurements27.Echocardiographic measurements were performed by an observer without knowledge of clinical status. LV (left ventricular/left ventricle) volumes, mass, EF (ejection fraction), and left atrial volumes were measured per ASE (American Society of Echocardiography) guidelinesBiographic data  were obtained. Patient medical histories were queried for the presence of pre-existing conditions, including obesity, heart disease, diabetes, respiratory disease, and renal disease, via International Classification of Disease (ICD)-10 codes, Diagnosis-related group (DRG) codes, with verification by chart review. These variables were grouped into patients’ baseline characteristics set.2). These variables were grouped into laboratory and vital signs data set.For index hospitalization, vital signs at admission and during echocardiographic scanning, and laboratory parameters were tabulated. Vital signs obtained were heart rate, respiratory rate, arterial oxygen saturation, and systolic and diastolic blood pressure. Laboratory parameters included B-natriuretic peptide (BNP), troponin, C-reactive protein (CrP), interleukin-6 (IL-6), ferritin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), serum creatinine, venous pH, lactic acid, and partial pressure of oxygen in arterial blood  by M-mode imaging and tricuspid lateral annular systolic velocity (S’) using tissue Doppler imaging from the apical 4-chamber view were noted. Tricuspid (TR) and mitral regurgitation (MR) were categorized as none-trace, mild, mild-moderate, and moderate-severe lesions28. LV global longitudinal strain (GLS), RV free wall and total strain, and LA reservoir, conduit, and pump strain were also included in the echocardiographic variables data set.Left ventricular (LV) end-diastolic, end-systolic volumes, mass, and LA and RA  maximum volumes were included in statistical analysis after indexing to BSA. LV diastolic function was determined based on guidelinesOutcomes included in-hospital mortality, intensive care unit (ICU) admission, mechanical ventilation, and extracorporeal membrane oxygenation (ECMO) use. The primary outcome of interest was in-hospital death. Secondary outcome was in-hospital mortality and ECMO use.2-test or Fisher’s exact test for categorical variables, two-sample t-test or Mann–Whitney U test for continuous variables depending on the normality of their distributions.Analyses were done using Stata  and Python. All continuous variables were tested for normality of their distributions. The study sample’s characteristics were summarized using mean (± standard deviation), median (interquartile range) and proportions. Two-group comparisons of these characteristics were conducted using χMachine learning was used to identify predictors of in-hospital mortality. Mean replacement was applied for missing data. Continuous variables were standardized using mean and standard deviation of respective variables. Three multivariable logistic regression models were fitted using in-hospital mortality as the outcome variable. In the first model, independent variables in the patients’ characteristics set were entered. In the second one, patient baseline characteristics and laboratory and vital signs data sets were included. In the third model, patients’ baseline characteristics, laboratory and vital signs parameters, and echocardiographic measurements were included. The three models were compared with respect to the area under the receiver operator curve (AUC).Finally, an optimized prediction model for in-hospital mortality was developed by iteratively adding variables one-by-one into a logistic regression model regarding their influence in increasing the AUC in a hierarchical manner. In this process, at first, the AUCs for models fitted with one independent variable was evaluated. All variables in the three sets were tested. Then, the variable that showed the largest AUC was retained and added into the logistic model. Then, all remaining variables were added one by one to the model and the AUCs were computed. The variable with the largest AUC was selected and added to the logistic model. The procedure was repeated until the AUC augmented Initially, there were 768 patients for analysis. After excluding 44 patients with echocardiograms showing systolic dysfunction, and patients on mechanical circulatory support including LV assist devices prior to COVID diagnosis, 724 patients were included in the study. Table Table The average duration of hospitalization was 13 days  and 425 patients (59%) were admitted to the ICU. Patients admitted to ICU had a significantly higher incidence of diabetes mellitus, respiratory disease, and kidney disease . Likewise, serum levels of AST, LDH, CrP (C reactive protein), IL-6, and ferritin were significantly higher  in patients admitted to ICU compared to those who were not admitted to ICU. Troponin was borderline higher in patients admitted to ICU . There were no statistically significant differences in echocardiographic measurements between patients admitted to the ICU and those who were not admitted to ICU.There were 349 patients (48%) who needed mechanical ventilation. Patients who were placed on mechanical ventilation had a significantly higher incidence of diabetes mellitus, respiratory disease, and kidney disease . Likewise, serum levels of AST, LDH, CrP, IL-6, and ferritin were significantly higher  in patients on mechanical ventilation compared to those did not need mechanical ventilation. Forty patients were placed on ECMO support. There were 79 total deaths (10.9%).The optimized prediction model included age, body mass index, presence of respiratory disease, presence of renal disease, BNP, IL-6, C reactive protein, ferritin, stroke volume index, free-wall right ventricular strain, total right ventricular strain, left atrial pump strain, LV GLS, right atrial pressure, pulmonary artery systolic pressure, and average E/eʹ ratio. Figure In patients without previous cardiovascular disease, EF < 50% occurred in 3.4%, abnormal GLS (< 16%) was observed in 24%, and LV diastolic dysfunction in 20%. RV systolic dysfunction defined by RV free wall strain < 20% was noted in 16%. Moderate and large pericardial effusion were uncommon with an incidence of 0.4% for each category.13. The majority of patients without prior cardiac diagnosis had normal estimates of left atrial pressure but in 6%, findings were consistent with elevated left atrial pressure. Therefore, it appears most patients had shortness of breath due to non-cardiac etiologies. This information is of value in directing diuretic therapy to patients with evidence of increased left atrial pressure. The apparent higher incidence of reduced GLS than LV diastolic dysfunction may be accounted for by the 5% of patients where diastolic function status could not be ascertained based on the available data gathered. While acute viral infection and the host immune response can explain the abnormal LV function, there are competing reasons for the abnormal LV function aside from the acute COVID-19 illness as 52% were obese, 52% had diabetes, and 62% had kidney disease, all of which can cause abnormal myocardial function including diastolic dysfunction.Previous studies reported a variable incidence of abnormal LV systolic function, based on the criteria used to define systolic dysfunction and whether patients with known cardiac disease were excluded. Expectedly, the incidence is higher if the more sensitive index of LV systolic function, GLS, is used to detect disease. An abnormal LV EF was much less common and was mostly due to global dysfunction with very few patients having stress induced cardiomyopathy, as noted in previous reports with adult patients23. In comparison with previous studies, the incidence of RV dysfunction was lower in our cohort but when present, it was still associated with worse outcome.RV function as assessed by echocardiographic indices is affected not only by intrinsic RV contractility but also by loading conditions. In the setting of pulmonary disease due to COVID-19 infection, hypoxemia can develop along with pulmonary vasoconstriction leading to RV systolic dysfunction in the absence of primary myocardial disease. Treatment of pulmonary parenchymal and vascular pathology would therefore be expected to have a favorable effect on RV function, to the extent that these treatments are effective. Notwithstanding the underlying mechanisms for RV dysfunction, RV systolic dysfunction is associated with worse clinical outcomesSeveral of COVID-19 patients who are hospitalized have an increased risk of adverse events. It is of value to identify those at higher risk so as to consider different management algorithms. In approaching the patients in this study sample, we looked at baseline demographics and clinical characteristics and used these data as the first level with which to compare the incremental value of other variables since they represent the initial set of data available to the treating physicians. Similar to previous findings, older patients with higher body mass index and those with respiratory or renal disease were at higher risk of death. With respect to the second group of laboratory findings, BNP, IL-6, C reactive protein, and ferritin added to the baseline risk as AUC significantly increased from 0.77 to 0.85. This by itself is useful to consider even in patients who have not undergone echocardiographic imaging. While routine imaging in all patients is not recommend, the incremental value of data on biventricular function when there is an appropriate echocardiographic indication is evident as AUC further increased with the addition of echocardiographic variables from 0.85 to 0.91. Further, the optimized prediction model with AUC at 0.91 included stroke volume index, RV free wall strain, total RV strain, left atrial pump strain, LV GLS, right atrial pressure, pulmonary artery systolic pressure, and average E/e’ ratio .31. Troponin elevation may be misleading with respect to drawing the conclusion of myocardial disease being due to COVID-10 infection, since coronary syndromes can also cause this finding. On the other hand, echocardiographic imaging can provide more specific evidence of coronary disease as well as a detailed look at the extent of cardiac pathology in the setting of acute COVID-19 infection.One of the 3 indications for obtaining an echocardiogram was the abnormal elevation in troponin levels. Troponin elevation is influenced by baseline characteristics including preexisting cardiac diseaseThe findings are applicable to hospitalized COVID-19 patients and may not apply to patients whose clinical status does not warrant admission. Echocardiography was not obtained in all hospitalized patients as only those who had a clinical indication were scanned. This could have led to an overestimation of the incidence of cardiac abnormalities. Notwithstanding, the study findings are applicable to the current practice as routine imaging is not obtained in all patients in the absence of an appropriate indication.15.There were no cardiac biopsies obtained, and thus it is difficult to determine if abnormal LV function is due to viral infection of cardiomyocytes, cytokines induced cardiac dysfunction, or is the consequence of adverse effects of hypoxemia in some patients. CMR (cardiac magnetic resonance) was not obtained in these patients in the acute setting based on judgement of the treating physicians but could have shed light about the possible presence of replacement fibrosis, increased extracellular volume, and tissue edema. While a large number of patients was included in this study, additional multicenter studies with many more patients can provide other insights. We did not include a control group of patients with similar baseline characteristics but without viral infection. However, the summary statistics for the echocardiographic measurements in this study are very similar to other studies which included a control group


Myocardial recovery associated with durable mechanical circulatory support represents an important potential treatment paradigm but is poorly understood.182.See Article page Durable left ventricular assist device (LVAD) therapy provides lifesaving benefit and improvement in quality of life for patients with advanced heart failure refractory to guideline-directed medical care. Although originally intended for bridge-to-transplant and later as permanent therapy , mechanical unloading with durable LVADs has been associated with improvement in myocardial function that has permitted device explant with long-term freedom from heart failure in a small cohort of patients; that is, a bridge to recovery. This observation has raised the possibility that mechanical unloading with durable LVADs can facilitate myocardial recovery and alter the clinical phenotype of advanced heart failure.heart failure remission rather than recovery reflects our uncertainty and the lack of a basic understanding of the recovery phenomenon. Second, the prevalence of myocardial recovery during support is generally believed to be low, but some important clinical characteristics such as young age, short duration of heart failure, nonischemic etiology of the heart failure, and smaller left ventricular volumes predict a higher prevalence of myocardial recovery. Aside from these factors, the ability to accurately predict with high probability those patients who might respond to mechanical unloading is lacking. Third, concomitant treatment with optimal medical therapy and use of guideline-directed heart failure therapies in addition to mechanical unloading is likely essential to the recovery paradigm. Fourth, we lack an understanding of how LVADs should be managed to promote myocardial recovery. Current LVADs are operated in a fix speed mode and unload the left ventricle during all phases of the cardiac cycle, conditions that may not optimize myocardial recovery. Further, the functional assessment of myocardial recovery and selection of patients for device explantation remains arbitrary, although some clinical weaning characteristics or criteria appear relevant to patient selection. Last, current device technology presents a formidable challenge to device removal in the setting of myocardial recovery. The complexity of device removal has some surgeons advocating for device decommissioning rather than device explantation. Whether device decommissioning and retention of the device in a young patient (most commonly the cohort likely to experience recovery), is safe over the long-term is not known.Faerber and colleaguesFaerber and colleagues provide a succinct summary of the state of using durable LVADs to promote myocardial recovery. This is an important area that needs continued investigation to bring to reality a potentially important treatment paradigm and option for patients with advanced heart failure.


Background: Impact of mechanical left ventricular (LV) unloading on myocardial tissue perfusion and its regulating factors remain unclear. This study was conducted to elucidate the predictors of regional blood flow (RBF) improvement by mechanical LV unloading.Materials and Methods: One to four weeks after percutaneous induction of myocardial infarction (MI), Yorkshire pigs (n = 15) underwent mechanical LV unloading using Impella CP. Hemodynamic parameters were collected prior to LV unloading. RBF in infarct, border and remote myocardium were measured by fluorescent microsphere injections before and 120 min after LV unloading.Results: RBF showed variable responses to mechanical LV unloading. While infarct RBF improved in general , there were a few pigs that showed little improvement. Meanwhile, there were no clear trends in the border  and remote myocardial RBF . In the simple linear regression analysis, cardiac output, mean pulmonary arterial wedge pressure, mean left atrial pressure, minimum LV pressure, end-diastolic LV pressure, maximum dP/dt, slope of end-diastolic pressure-volume relationship (EDPVR) and end-diastolic wall stress were significantly associated with % change of infarct RBF. In the multiple regression model, slope of EDPVR and maximum dP/dt remained as independent predictors of infarct RBF change.Conclusion: Steeper EDPVR and lower maximum dP/dt were associated with increased blood perfusion in the infarct area after LV unloading. Our data suggests mechanical LV unloading is more beneficial in post-MI patients with high diastolic pressure associated with increased LV stiffness and in those with worse cardiac contractility. In the modern era where catheter-based therapies have become routine treatment, acute mortality for myocardial infarction (MI) has dramatically reduced. However, there have been an increasing number of patients who develop ischemic heart failure due to markedly reduced contractility after MI . IschemiThe Impella  is a percutaneously implantable left ventricular (LV) assist device that can assist cardiac output by pumping blood from the LV to the aorta via an axial flow pump. In addition to the beneficial effect on systemic circulatory support, it has been shown that active withdrawal of blood from the LV reduces the ventricular wall stress in failing hearts . In animIn this study, we hypothesized that mechanical LV unloading is more effective in certain patient populations and that hemodynamics prior to mechanical LV unloading can predict the change in RBF. The purpose of this study was to determine factors that predict RBF improvement in the ischemic heart before and after the implementation of mechanical LV unloading.All animal procedures were approved by the Institutional Animal and Use Committee at the Icahn School of Medicine at Mount Sinai, and the care of all animals complied with the Guide for the Care and Use of Laboratory Animals . The animals were acclimatized at the animal facility for at least 72 h before being enrolled in experiments.n = 8), 2 weeks (n = 6), and 4 weeks (n = 1) after MI. For all procedures, pigs were intubated and ventilated with 100% oxygen under propofol (10 mg/kg per hour) anesthesia. After each mechanical LV unloading experiment, pigs were euthanized, the hearts were quickly excised, and the great vessels were dissected. The right and left atria  were carefully separated from the ventricular chambers. The right ventricular (RV) free wall was dissected from LV and each myocardial chamber was weighed separately. Intra-atrial and intraventricular septum were included in the LA and LV, respectively.A total of 15 Yorkshire pigs  that survived percutaneous MI induction were included in the study. Pigs were recovered and mechanical LV unloading experiments were conducted at 1 week  . LV voluA Swan-Ganz catheter  was advanced to the main pulmonary artery through femoral vein access. Cardiac output was measured in triplicate using the thermodilution method after confirmation of hemodynamic stability and during breath-hold. Left atrial pressure was obtained using the atrial septal puncture technique.via the right carotid artery to collect LV pressure-volume measurements during steady state and transient inferior vena cava occlusion with short breath-holds. All pressure-volume data were analyzed using an iox2 application . Alpha value and parallel conductance were calibrated using cardiac output derived from thermodilution method using a Swan–Ganz catheter and bolus injections of hypertonic saline.A high-fidelity pressure-volume loop catheter  was inserted into the LV 7 polystyrene fluorescent microspheres  were injected into the left atrium through trans-septal access via the femoral vein. Reference blood was withdrawn from a femoral artery sheath using a specialized pump  for 2 min at a rate of 2.9 mL/min. Microspheres with different wave lengths were used for measurements before and 2 h after LV unloading. The number of fluorescent microspheres trapped in the infarct , infarct border , and remote regions  were quantified by flow cytometric analysis. Regional blood flow (RBF) was calculated using the following formula:Regional myocardial blood flow was quantified using fluorescently colored microspheres as previously described . Brieflywhere R is blood reference withdrawal rate (2.9 mL/min); lt and Ibr are fluorescent counts in the tissue and the blood reference sample, respectively; and Wt is the weight of the tissue sample (g).t-test was used to compare the differences between before and after LV unloading. The Pearson's correlation test was used for all correlation analyses. To determine the independent contributing factors for infarct RBF change after mechanical LV unloading, a multivariable linear regression analysis was performed, adjusted by the significant factors in simple linear regression analyses. All analyses were conducted with JMP version 12.0 , and p < 0.05 was the criterion for statistical significance.Continuous variables are expressed as mean ± SD. A paired Student's A total of 15 pigs successfully completed the LV unloading experiment. Echocardiographic and hemodynamic results before mechanical LV unloading are shown in p = 0.06; Border RBF 1.06 ± 0.46 to 1.02 ± 0.65 mL/min/g, p = 0.73; Remote RBF 1.25 ± 0.52 to 1.23 ± 0.67 mL/min/g, p = 0.85).To determine the predictive factors associated with the RBF change in the infarct area, simple linear regression analysis was conducted on hemodynamic parameters before mechanical LV unloading. To determine the independent predictive factors of % RBF change in the infarct area, multivariable linear regression analysis was conducted using the factors derived from simple linear regression analysis. Considering the collinearity, covariates which had strong correlation with other parameters (r > 0.8) were excluded and exchanged. To create the regression model, the forward stepwise method was applied on the following covariates: cardiac output, maximum dP/dt, mean pulmonary arterial wedge pressure, either of minimum or end-diastolic LV pressure, and slope of EDPVR. The model revealed maximum dP/dt and the slope of EDPVR before mechanical LV unloading as independent predictors of % RBF change in the infarct area. Both covariates were significant, and EDPVR was the strongest predictor . These pp = 0.002; Border area p = 0.43, Remote area p = 0.35).The cutoff value of EDPVR slope for infarct RBF improvement, calculated from the ROC curve, was 0.49 . When pigs were divided into two groups according to the EDPVR slope prior to mechanical LV unloading , signifip = 0.99; RV: 45.8 ± 8.0 g, r = 0.20, p = 0.45; LA: 23.1 ± 5.4 g, r = 0.58, p = 0.01; LV: 128.3 ± 20.4 g, r = 0.20, p = 0.44).The main findings of the current study is that mechanical LV unloading improves myocardial tissue perfusion in the ischemic tissue and this improvement is most pronounced in animals with high EDPVR slope and low maximum dP/dt prior to unloading. High EDPVR slope indicates stiff heart whereas low maximum dP/dt is a sign of decreased cardiac contractility. These are commonly found in severe MI and our data suggest that mechanical LV unloading is more effective in improving ischemic tissue flow in those with severe heart failure.Reduction of LV work has been highlighted as a mechanism of beneficial effect in mechanical LV unloading, whereas few studies examined how it influences tissue perfusion. We have previously shown that mechanical LV unloading improves ischemic myocardial tissue flow by reducing end-diastolic wall stress . This isper se contributes to low infarct RBF independent of reduced cardiac output needs further studies.In this study, not only diastolic distension but also impaired systolic contraction seemed to be a significant predictor of improved infarct RBF after Impella. This is likely associated with reduced cardiac output in those with low cardiac contractility, which can be augmented by Impella support. In fact, cardiac output was one of the predictive factors in univariate regression analysis although it's correlation to infarct RBF was less than that of maximum dP/dt. Whether reduced myocardial contractility Even though LV pressure is equally applied to the infarct and non-infarct (remote) areas, the RBF change showed different patterns in each area. In the infarct area, higher slope of EDPVR and lower maximum dP/dt prior to mechanical LV unloading were associated with improved RBF, whereas RBF in the remote area did not show any clear relationship to these parameters. One possible explanation is the loss of auto-regulation in infarcted vessels due to endothelial dysfunction. Endothelial injury occurs in myocardial ischemia and subsequent ischemia-reperfusion injury –16. The In acute and severe ischemic heart failure, inotropic therapy is often required for circulatory support. However, auto-regulation systems of coronary flow do not function effectively in the infarcted heart, and the mechanism of vasodilation that offsets the vasoconstriction of coronary microcirculation by inotropic agents does not work . This fuThe microspheres technique allows sensitive quantitation of tissue perfusion, but lacks temporal information. LV pressure becomes the lowest just after aortic valve closing and rises gradually along with LV filling, thus the coronary flow is maximal at the early diastolic phase , 27. In Higher slope of EDPVR and lower maximum dP/dt before mechanical LV unloading predicted increased blood perfusion in the infarct myocardium. Our data suggests mechanical LV unloading is more beneficial in post-MI patients with high diastolic pressure due to increased LV stiffness and in those with worse cardiac contractility. Understanding the profiles of patients who would benefit more from mechanical LV unloading is essential for using this therapy in clinical ischemic coronary disease.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The animal study was reviewed and approved by Institutional Animal and Use Committee at the Icahn School of Medicine at Mount Sinai.TS and KI: conceived and designed research and interpreted results of experiments. TS: analyzed data, prepared figures, and drafted manuscript. KI: edited and revised manuscript. All authors performed experiments and approved final version of manuscript.This work was supported by National Institutes of Health R01 HL139963 (to KI), Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad (to TS), and ABIOMED Inc. A-CURE Research Fellowship (to TS).KI serves as a PI of a research grant to the institution from Abiomed Inc. TS received a research fellowship award from Abiomed Inc. RM received a research award from Abiomed. Inc. not related to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: This systematic review and meta-analysis aimed to assess whether tricuspid annular plane systolic excursion (TAPSE) could be used as a prognostic tool in patients with coronavirus disease 19 (COVID-19).Studies on the relationship between TAPSE and COVID-19 since February 2021. Standardized mean difference (SMD) and 95% confidence intervals were used to assess the effect size. The potential for publication bias was assessed using a contour-enhanced funnel plot and Egger test. A meta-regression was performed to assess if the difference in TAPSE between survivors and nonsurvivors was affected by age, sex, hypertension or diabetes.P < .00001; I2 = 71%), and a subgroup analysis indicated that TAPSE was also lower in critically ill patients , P < .00001; I2 = 46%). Heterogeneity was also significantly reduced, I2 < 50%. Pooled results showed that patients who developed right ventricular dysfunction had lower TAPSE , P = .004; I2 = 82%). There was no statistically significant difference in the TAPSE of patients who sustained a cardiac injury vs those who did not , P = .31; I2 = 88%). No significant publication bias was detected (P = .8147) but the heterogeneity of the included studies was significant. A meta-regression showed that heterogeneity was significantly greater when the incidence of hypertension was <50% (I2 = 91%) and that of diabetes was <30% (I2 = 85%).Sixteen studies comprising 1579 patients were included in this meta-analysis. TAPSE was lower in nonsurvivors , Low TAPSE levels are associated with poor COVID-19 disease outcomes. TAPSE levels are modulated by disease severity, and their prognostic utility may be skewed by pre-existing patient comorbidities.PROSPERO CRD42021236731 On August 5, 2021, the cumulative number of COVID-19 cases globally surpassed 200 million, just 6 months after reaching 100 million. As a result, the understanding of the disease and its risk factors are key factors for implementing public health policies at present.Coronavirus disease 19 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), thereby creating an inflammatory state that can lead to cardiopulmonary injury.–10 Endothelial dysfunction induced by shear stress, hypoxia, autoimmune phenomena, viral infections may initiate the process of excess vasoconstriction, inflammation, and uncontrolled cellular growth,–15 and lead to pulmonary hypertension.,15 In response to an increase in pulmonary vascular resistance by a factor of 5 to 10, the right ventricle (RV) undergoes hypertrophy, chamber dilatation, fat deposition, fibrosis, and metabolic shifts as pulmonary hypertension progresses.–17 Right ventricular function (RVEF) is the major determinant of clinical outcomes and survival among patients with pulmonary hypertension.COVID-19 induces cytokine release, Hugues et al proved in their study that tricuspid annular plane systolic excursion (TAPSE) was significantly correlated with RVEF results measured by magnetic resonance imaging . TAPSE has also proven to be easy to perform, accurate, reproducible and with little variation between observers. And the American Society of Echocardiography currently recommends using TAPSE measurement as one of the tools to assess RV function. However, diagnostic use of echocardiography during the COVID-19 pandemic is largely based on expert recommendations and lacks data from large samples of evidence-based scientific results . The protocol for this study was registered in PROSPERO (CRD42021236731).2.1Eligible articles were identified in the process illustrated in Figure Inclusion criteria: Studies with primary data on patients with COVID-19 with TAPSE measurements that were used as a prognostic metric. The primary outcome of the work was a “poor outcome,” defined by the authors of the study using some composite of death, disposition to a long-term acute care facility (LTAC), cardiac injury, and right ventricular dysfunction (RVD).Exclusion criteria: Preprints, review articles, nonresearch letters, commentaries, case reports, and articles not written in English. Preprints were excluded due to inconsistent credibility.2.2; TAPSE was measured using guidelines set forth by the American Society of Echocardiography. In short, TAPSE was assessed by placing an M-mode cursor through the lateral tricuspid valve annulus in the apical 4-chamber view and measuring the total systolic excursion distance of the tricuspid annulus; Mortality was defined as clinically validated death/nonsurvival; LTAC centers are unique institutions that provide a full range of medical services for medically complex patients who require an extended stay in an acute care facility; Cardiac injury was defined as an increase in high-sensitivity troponin T or troponin I levels above the 99th percentile upper reference limit in the setting of a newly abnormal electrocardiograph and/or transthoracic echocardiography; and RVD was defined by impairment of both TAPSE and S′ so as to reduce false positive classification.The following definitions were used for this analysis: COVID-19 was diagnosed with a positive RT-PCR for SARS CoV-2 with a throat swab, sputum or endotracheal suction sample2.3Articles published as of February 2021 in the PubMed, Cochrane Library, Embase, and Web of Science databases were included. The search strategy used across all databases combined medical subject headings and free words with “AND” and “OR” as the 2 logical operators. Key search terms included “(coronavirus or corona virus) AND Wuhan”, “2019 nCoV”, “2019nCoV”, “2019-nCoV”, “2019 novel coronavirus”, “COVID19”, “COVID 19”, “COVID-19”, “new coronavirus”, “novel coronavirus”, “novel corona virus”, “SARS CoV-2”, or “severe acute respiratory syndrome coronavirus 2” combined with “(cardiac or heart or right) AND ventric∗”, “RV”, “tricuspid annular plane systolic excursion”, or “TAPSE”. Only studies published in English with an available full text were included. When several publications involved the same patient group, the most recent or most complete (largest sample size) study was chosen. Potentially relevant articles were then assessed using our inclusion and exclusion criteria.2.4Two independent authors extracted data from eligible studies with the help of a standardized data form that included fields for first author, year of publication, country of publication, study design, sample size, age, male sex, hypertension, diabetes, chronic obstructive pulmonary disease, current smoker, outcome , LTAC disposition, cardiac injury, and RVD.The quality of each cohort study was evaluated with the Newcastle–Ottawa Scale, and cross-sectional studies were evaluated with the Agency for Healthcare Research and Quality scale. Quality assessments were performed by 2 independent authors. Discrepancies at the end of the assessment were addressed through the inclusion of a third party.2.5Z-test, and a P-value of <.05 was considered significant. In light of possible sources of heterogeneity, studies were stratified by disease severity. The potential for publication bias was assessed using a contour-enhanced funnel plot and Egger test. A meta-regression was performed to assess if the difference in TAPSE between survivors and nonsurvivors was affected by age, male sex, hypertension or diabetes.The meta-analysis of extracted data was performed using Review Manager 5.4  and STATA 16 . Standardized mean difference (SMD) and corresponding 95% confidence intervals were estimated with a random-effect meta-analysis. The significance of pooled SMD was evaluated with a 33.1,24,26–39 Baseline characteristics of the included studies are displayed in Table The initial search identified 1190 studies. Excluding duplicates, 577 articles were screened with a title and abstract review. The entire manuscript body of 63 relevant articles was assessed, of which 16 met the inclusion criteria for data analysis Fig. . This yi3.2P < .00001; I2 = 71%) , P < .00001; I2 = 46%) , 3.32 (I2 = 82% > 50%) and chi-square test P-values (P < .05), we chose a random effects model to analyze differences in TAPSE. Pooled results showed that patients with RVD had lower TAPSE , P = .004; I2 = 82%)  , 3.5P = .8147) and suggestive of a lack of publication bias. The included studies were therefore deemed comprehensive and yielded statistically reliable results.A contour-enhanced funnel plot was symmetric Fig. , which w3.6P = .047) and diabetes (P = .006), but not age (P = .398) or male sex (P = .925). A subgroup analysis showed that heterogeneity was significantly greater when the incidence of hypertension was ≥50% (I2 = 61%) and that of diabetes was ≥30% (I2 = 0%) , whereas our subgroup analysis of critically ill patients indicated that TAPSE (I2 = 46%) was equivalent, accompanied by significantly reduced heterogeneity. It may be more applicable in critically ill patients.Significant heterogeneity was a limitation of the analysis of the cohort and cross-sectional studies included in this study. The first reason for the observed heterogeneity was clinical severity. Our meta-analysis of TAPSE showed that nonsurvivors had lower TAPSE (IP = .047) and diabetes (P = .006), and a subgroup analysis showed that heterogeneity was significantly reduced when the incidence of hypertension was ≥50% or the incidence of diabetes was ≥30%. The fourth reason is that TAPSE may be angle-dependent when the image is off-center due to the enlargement of the RV, and may also be affected by cardiac displacement. Hsiao et al also found the correlation between severe tricuspid regurgitation affecting TAPSE and RVEF in their study, and the effect of severe tricuspid regurgitation should be considered comprehensively when applying TAPSE to evaluate RVEF.The second reason for the observed heterogeneity was that different research centers did not have a standardized protocol for treating patients but rather relied on their respective training and experience. The third reason was that the results of the present work were based on unadjusted estimates. A more precise analysis could be conducted if individual patient data were made available, thereby permitting the assessment of COVID-19 disease severity by age, sex, past medical history, and personal history. A meta-regression demonstrated that differences in TAPSE were affected by hypertension ( With the increase of pulmonary artery (PA) pressure (right cardiac afterload), stroke volume decreased nonlinearly. TAPSE, which can be used to evaluate RV function, has been proved as an independent prognostic marker of specific pathologies including ARDS. Fauvel et al also reported TAPSE as a good marker of RV contractility, with relative load-independence in the setting of pulmonary hypertension. However, the use of TAPSE as a prognostic marker remains controversial. Shadi et al did not find a correlation between severe sepsis or septic shock and TAPSE. This may have been owing to various factors such as patient comorbidities.COVID-19-induced systemic inflammation can lead to ARDS, pulmonary hypertension, myocardial injury, and ultimately RV failure. Studies have found that among hospitalized non-Intensive Care Unit patients with COVID-19, pulmonary hypertension was associated with signs of more severe COVID-19 and with worse inhospital clinical outcome. And some measurement methods are good, such as strains or 3D-derived measures, but they need better image quality and special software. On the other hand, most TAPSE measurements take less than 30 seconds, with high operability and repeatability, TAPSE seems to be more attractive to critically ill patients or primary hospitals.The important role of the RV in the management of the critically ill is increasingly acknowledged, and many novel measures of RV function have been developed. For example, RV free wall longitudinal strain overcomes some of the limitations of conventional diagnosis of RV systolic function parameters, but both lack standardized data and consensus. With developing pulmonary hypertension, the RV responds to a significantly elevated afterload by increasing its contractility. This response may be accompanied by an increased TAPSE. However, with persistent and progressive pulmonary hypertension, TAPSE may not correspond to an increase in PA pressure. Schmeisser et al also reported that combining TAPSE with PASP did not improve the noninvasive right ventricular (RV) to PA coupling information. Therefore, it seems more meaningful to evaluate RV and PASP separately.It has also been suggested that the ratio of TAPSE to PA systolic pressure (PASP) has a stronger association with outcome in COVID-19 patients than TAPSE. Studies by Zhou et al found that patients with cardiac injury had lower lymphocyte counts and higher levels of inflammatory biomarkers compared with those without cardiac injury. Studies by D’Alto et al,34,47,48 also found significant differences in myocardial enzyme levels in nonsurvivors compared with survivors, suggesting that these enzyme levels may have prognostic potential and affect pooled effect estimates. Therefore, the present work did not find a statistically significant difference; this may be related to the limited number of patients and the varying severity of the disease cases that were included in this meta-analysis.Prior studies have suggested that the cytokine profile of secondary hemophagocytic lymphohistiocytosis is related to COVID-19 severity. It has also been suggested that novel blood pressure and pulse pressure estimation based on pulse transit time and stroke volume approximation may better enable ubiquitous monitoring of blood pressure and management of cardiovascular risk indicators such as hypertension. Therefore, these indicators are likely to be used as part of a risk prediction model to predict the prognosis of COVID-19 patients.Furthermore, obese patients may suffer from obstructive sleep apnea hypopnea syndrome, in which the body is chronically deprived of oxygen for a long time, leading to cardiopulmonary damage. When these patients are infected with SARS-CoV-2, they are likely to develop heart and respiratory failure, which can lead to worsening of the illness and even death. Similarly, obesity is a risk factor for diabetes mellitus, which is reportedly associated with an increased risk of adverse outcome events in patients with COVID-19. However, our study analyzed TAPSE not only in relation to mortality, but also in relation to RVD and cardiac injury. At the same time, TAPSE is a good bedside method for judging right heart function, and also a good guide for treatment. We also concluded that the relationship between TAPSE and COVID-19 patients was affected by disease severity. Our results further complement previous findings of an impact of hypertension and diabetes on mortality. We also discuss why TAPSE was chosen as a predictor and what factors have the opportunity to be part of a predictive model.Previous meta-analyses have concluded that TAPSE is lower in nonsurvivors compared with survivors.5There were several limitations to this study. Only English-language sources were included, excluding potentially eligible studies that were not written in English. Since this index measured by different echocardiographers may lead to deviations in the results, echocardiographers should be trained to unify the measurement standards and a larger sample size is needed for research. In addition, because of the different factors and outcomes investigated in each study, we were not able to comprehensively analyze only 1 factor. Finally, although we performed a subgroup analysis of TAPSE, a robust risk prediction model is required to accurately predict the prognosis of patients with COVID-19.6Low TAPSE levels are associated with poor COVID-19 disease outcomes. TAPSE levels are modulated by disease severity, and their prognostic utility may be skewed by pre-existing patient comorbidities.Conceptualization: Ye Tian, Huaihai Lu, Pei Zhang.Data curation: Ye Tian, Huaihai Lu, Xuefang Liu, Yinlong Zhao.Formal analysis: Ye Tian, Huaihai Lu.Funding acquisition: Ye Tian, Huaihai Lu.Investigation: Ye Tian, Huaihai Lu, Pei Zhang.Methodology: Ye Tian, Huaihai Lu.Project administration: Ye Tian, Huaihai Lu.Resources: Ye Tian, Huaihai Lu.Software: Ye Tian, Huaihai Lu.Supervision: Ye Tian, Huaihai Lu, Pei Zhang.Validation: Ye Tian, Huaihai Lu.Visualization: Ye Tian, Huaihai Lu.Writing – original draft: Ye Tian, Huaihai Lu.Writing – review & editing: Ye Tian, Huaihai Lu, Pei Zhang.