Conclusions: In patients with TTS, myocardial edema associated with increased LV mass still remained in the subacute phase despite functional recovery of the LV. Electrocardiogram may be useful to assess the degree of myocardial edema in the subacute phase. Our study suggests that myocardial ischemia might have a central role in developing TTS.Background: The wall motion abnormalities of the left ventricle (LV) in takotsubo syndrome (TTS) are known to be transient and completely recover within a few weeks. However, there is little information about the relationship between functional recovery and tissue characteristics. The aim of this study was to investigate the recovery process of TTS using cardiovascular magnetic resonance (CMR). Methods: Consecutive patients with TTS were prospectively enrolled. We performed serial CMR in the acute phase (<72 h after admission), the subacute phase (7–10 days after admission) and the chronic phase (3 months later). To assess the degree of myocardial edema quantitatively, we evaluated the signal intensity of myocardium on T2-weighted images and calculated the signal intensity ratio compared with the skeletal muscle. Results: Fifteen patients with TTS were enrolled. CMR demonstrated reduced LV ejection fraction in the acute phase, and it recovered almost completely by the subacute phase. On the other hand, severe myocardial edema was still observed in the subacute phase, associated with increased LV mass. The highest signal intensity ratio in the subacute phase was correlated with the maximum voltage of negative T wave on electrocardiogram (r = 0.57,  Takotsubo syndrome (TTS) is characterized by transient systolic dysfunction of the left ventricle (LV) and has been increasingly recognized since its first description in 1990 in Japan , but theCardiovascular magnetic resonance (CMR) has been used often in clinical studies regarding TTS because of its benefit in providing both functional information and tissue characterization of myocardium . PreviouThus, the aim of the present study was to explore the changes of LV systolic function and myocardial tissue characteristics by serial CMR during the recovery process in TTS patients.A total of 15 consecutive TTS patients without contraindication of CMR who were admitted to Chiba University Hospital and Chiba Emergency Medical Center from October 2013 to March 2016 were enrolled. TTS was diagnosed according to the following criteria ,11: (1) CMR was performed using a standardized protocol on 1.5-T magnetic resonance scanner with a 5-channel phased-array coil . Imaging consisted of cine (steady-state free precession images), T2-weighted (short-tau inversion recovery images) and LGE images , and we obtained a LV 4-chamber view, a 2-chamber view, and a stack of short-axis views in each series during breath-holds gated to the electrocardiogram. Short-axis views were acquired from the atrioventricular ring through the LV at intervals of 8 mm thickness with 0 to 2 mm gap in cine images and 8–10 mm thickness with −5 to 2 mm gap in LGE images, and by three slices  in T2-weighted images. The LGE images were acquired 10 to 15 min after intravenous administration of a gadolinium-based contrast agent  in patients without contraindications of LGE.max. For assessment of LGE, a region of interest was selected in an apparently normal myocardium in the 4-chamber images, and automated detection to 5 standard deviations above the mean signal intensity of normal myocardium was performed to identify fibrosis [Offline analysis was performed using commercially available software . LV functional analysis was performed by tracing endocardial and epicardial borders in short-axis cine CMR images throughout the cardiac cycle to calculate LV volume, ejection fraction, and LV mass. For quantitative assessment of myocardial edema, we traced myocardium manually with caution to exclude bright artifacts due to slow blood flow on basal, mid, and apical slices of short-axis T2-weighted images. We evaluated the mean signal intensity of myocardium on respective slices and compared that with the signal intensity of skeletal muscle on the same slices to calculate the signal intensity ratio (SIR) ,12. The t-test/Wilcoxon signed-rank test with Bonferroni correction as appropriate. Statistical analysis was performed using JMP Pro 13 . A p value of <0.05 was considered statistically significant.Continuous variables are listed as mean ± standard deviation (SD) or as median and interquartile range (IQR). Categorical variables are presented as counts and percentages. One-way factorial analysis of variance, repeated measures analysis of variance, or Friedman test were performed for comparisons of multiple variables as appropriate. Post hoc analysis was performed using Tukey’s test or paired Baseline characteristics are presented in p < 0.01, p < 0.01, CMR was performed in the acute phase , the subacute phase , and the chronic phase . Serial CMR findings were summarized in max in the acute phase was maintained in the subacute phase despite recovery of systolic function. After that, it decreased significantly in the chronic phase in parallel with LV mass reduction .Increased SIReduction C. SIRmaxmax in the subacute phase .The LGE images were obtained only from patients with normal renal function at each time. Myocardial fibrosis was identified in 21% (3/14) of patients in the acute phase, 25% (3/12) in the subacute phase, and 42% (5/12) in the chronic phase. All detected LGE showed patchy distribution, while transmural or subendocardial LGE, often observed in myocardial infarction or in myocarditis respectively, was not detected in this study cohort. Patients who had LGE in the chronic phase tended to show higher SIRThe main results of this study were: (1) LV systolic function recovered almost completely by the subacute phase; (2) myocardial edema and increased LV mass remained in the subacute phase despite recovery of systolic function; (3) both were resolved in the chronic phase. To the best of our knowledge, this is the first prospective study to evaluate changes of LV systolic function and tissue characterization during the recovery process of TTS using a serial CMR three times.max had already been higher than the normal range, and increased SIRmax remained in the subacute phase despite recovery of systolic function. After that, it was depressed significantly in the chronic phase. These trends of myocardial edema during the recovery process were similar to those of LV mass, which suggests that the cause of TAWT is myocardial edema.Previous studies reported that wall motion abnormality recovered completely within a few weeks in almost all TTS cases ,14. HoweShin et al. reported that TAWT was associated with worse in-hospital outcome . Thus, sFrom the pathophysiological perspective, it is of great interest why severe myocardial edema was shown in the subacute phase even after recovery of systolic function. The definitive pathophysiology of TTS is still unclear, although several hypotheses, such as multivessel coronary spasm, catecholamine-mediated myocardial stunning, excessive transient ventricular afterload, and microcirculatory dysfunction have been postulated . FurtherAlthough the absence of LGE was classically considered as one of the typical features of TTS, recent studies revealed that LGE was observed in TTS patients. Eitel et al. demonstrated that focal or patchy LGE was observed in 9% of TTS patients in the acute phase . HoweverSeveral limitations of this study should be acknowledged. First, the long-term outcomes of this study’s cohort were not assessed. The sample size was too small to evaluate association between CMR findings and long-term prognosis. Second, atypical variants of TTS were included in this study. However, this limitation did not affect our results because we could assess functional and pathological findings of the whole heart in detail using CMR. Third, we could not perform an endomyocardial biopsy to confirm histological findings because of its invasive nature.In patients with TTS, the wall motion abnormality of the LV recovers almost completely by the subacute phase, whereas myocardial edema associated with increased LV mass still remains despite functional recovery of the LV. The degree of myocardial edema is correlated with the maximum amplitude of negative T wave on electrocardiogram in the subacute phase. Thus, serial electrocardiogram may be useful as surrogate information for myocardial edema. In addition, our study provides important insights into the pathophysiology of TTS, suggesting myocardial ischemia might have a central role in developing TTS. To confirm our hypothesis, further studies with a large number of patients will be needed.


ROC analyses identified the optimal CFVR cut-off value ≤ 2.1 obtained during high-dose dobutamine (>20 µg/kg/min) for the identification of MB associated with stress-induced WMA, with a sensitivity, specificity, positive and negative predictive value of 96%, 95%, 88%, and 98%, respectively . Multivariate logistic regression analysis revealed that MLD and percent DS, both at end-diastole, were the only independent predictors of ischemic CFVR values ≤2.1 . Conclusions: Noninvasive CFVR during dobutamine provocation appears to be an additional and important noninvasive tool to determine the functional severity of isolated-MB. A transthoracic CFVR cut-off ≤2.1 measured at a high-dobutamine dose may be adequate for detecting myocardial ischemia in patients with isolated-MB.Background: It has been shown that coronary flow velocity reserve (CFVR) measurement by transthoracic Doppler echocardiography (TTDE) during dobutamine (DOB) provocation provides a more accurate functional evaluation of myocardial bridging (MB) compared to adenosine. However; the cut-off value of CFVR during DOB for identification of MB associated with myocardial ischemia has not been fully clarified. Purpose: This prospective study aimed to determine the cut-off value of TTDE-CFVR during DOB in patients with isolated-MB, as compared with stress-induced wall motion abnormalities (VMA) during exercise stress-echocardiography (SE) as reference. Methods: Eighty-one symptomatic patients  with the existence of isolated-MB on the left anterior descending artery (LAD) and systolic MB-compression ≥50% diameter stenosis (DS) were eligible to participate in the study. Each patient underwent treadmill exercise-SE, invasive coronary angiography, and TTDE-CFVR measurements in the distal segment of LAD during DOB infusion (DOB: 10–40 μg/kg/min). Using quantitative coronary angiography, both minimal luminal diameter (MLD) and percent DS at MB-site at end-systole and end-diastole were determined. Results: Stress-induced myocardial ischemia with the occurrence of WMA was found in 23 patients (28%). CFVR during peak DOB was significantly lower in the SE-positive group compared with the SE-negative group (1.94 ± 0.16 vs. 2.78 ± 0.53;  Coronary flow velocity reserve (CFVR) measured by transthoracic Doppler echocardiography (TTDE) is a clinically useful and feasible noninvasive diagnostic index for the assessment of fixed coronary stenosis severity ,5,6,7,8.Eighty-one symptomatic patients  undergoing coronary angiography due to recurrent typical or atypical chest pain were eligible to participate in this prospective study. Key inclusion criteria, in addition to chest pain, was the existence of isolated-MB on the left anterior descending artery (LAD) and systolic MB-compression ≥50% diameter stenosis (DS), after intracoronary administration of 200 µg of nitroglycerin (NTG), as measured by quantitative coronary angiography (QCA). Exclusion criteria were: (1) patients aged ≤18 years old; (2) presence of coronary artery disease in the LAD and/or other coronary arteries; (3) acute coronary syndrome with or without ST elevation; (4) any previous myocardial infarction; (5) any previous percutaneous or surgical myocardial revascularization; (6) left ventricular ejection fraction (LVEF) <40%; (7) left ventricular (LV) hypertrophy; (8) hypertrophic, dilated, or restrictive cardiomyopathies; (9) any valvular heart disease; (10) uncontrolled arterial hypertension; (11) atrial fibrillation ; and (12) renal failure (acute or chronic).Each patient underwent standard two-dimensional echocardiography, treadmill-exercise stress echocardiography (SE), computed-tomography coronary angiography (CTCA), invasive coronary angiography, and TTDE-CFVR measurements during dobutamine provocation which was performed within 1 month after the invasive procedure. Study patients without objective signs of myocardial ischemia on exercise-SE were referred to CTCA in order to rule-out the presence of coronary lesion/s  as a possible cause of chest pain. If CTCA showed the presence of intramyocardial LAD segment penetrating the interventricular septum at a depth of at least 1.0 mm from the anterior interventricular groove surface (deep type of MB) and no fixed stenosis on any epicardial coronary artery, then invasive coronary angiography was performed. Antianginal drugs  and xanthine-containing foods or beverages , were discontinued 24 to 48 h before exercise-SE, invasive coronary angiography and TTDE-CFVR measurements, separately. The study protocol was approved by the Ethical Committees of University Clinical Center of Serbia and Faculty of Medicine University of Belgrade . Informed consent was obtained from all patients.Following a standard two-dimensional echocardiography examination, all patients underwent treadmill exercise-SE according to the maximal Bruce protocol, as previously described ,27,28. BInvasive coronary angiography and detailed frame-by-frame QCA analysis of the interpolated reference diameter, minimal luminal diameter (MLD), and percent DS, at the most severe MB-site, were performed as previously described in detail elsewhere ,30. BrieThe same ultrasound unit was used to assess CFVR during dobutamine provocation, as had been described in detail previously . To adeqMaximal (peak) diastolic coronary flow velocities (CFVs) under basal conditions and during maximal hyperemia induced by peak dobutamine infusion (30 or 40 µg/kg/min) were measured in the distal segment of LAD, by a senior investigator who was blinded for the patient’s clinical and functional status . CFVR wat-test (paired or unpaired) as appropriate. A Pearson correlation coefficient, along with a linear regression model, is used to estimate the correlation between continuous variables. ANOVA for repeated measures was used to determine differences in hemodynamic parameters measured under basal conditions and during peak dobutamine infusion. To assess the most appropriate cut-off value of CFVR during peak dobutamine infusion for stratifying MB-patients with and without stress-induced myocardial ischemia, receiver operating characteristic (ROC) curve with 95% confidence intervals (CI) and the highest Youden’s index (sensitivity + specificity-1) was used. Cohen’s kappa coefficient was applied to evaluate the agreement between two dichotomous variables: exercise stress-induced myocardial ischemia , and TTDE-CFVR . Univariate binary logistic regression was used to identify whether different variables are significantly associated with established ischemic CFVR values. To establish variables independently associated with ischemic CFVR values in MB-patients, univariate predictors with a value of p < 0.2 were included in a multivariate regression model using a backward method. Statistical significance was defined as a two-sided value of p < 0.05.Statistical analysis of the data was performed using IBM SPSS Statistics for Windows, version 26.0 . Categorical variables are presented as counts with percentages and continuous variables as means ± standard deviations (SD). Kolmogorov–Smirnov and Levene tests were used to verify the normal distribution of continuous variables. Differences between categorical variables were analyzed using a Chi-squared or Fischer’s exact test, depending on group size, whereas those between continuous variables were analyzed using a Student’s Mean systolic compression of the intramyocardial LAD segment was 62 ± 10% (range: 51–95% DS). At peak dobutamine dose, the HR ≥50 bpm from baseline was achieved in all patients (100%), whereas the HR ≥75% of maximum age-predicted HR was achieved in 73 patients (90%). However, due to the onset of chest pain and/or ischemic ECG changes, the remaining 8 patients (10%) were not able to reach HR ≥75% of maximum age-predicted HR during dobutamine provocation, requiring an earlier termination of the test. There were no major complications. Dobutamine provocation caused ventricular bigeminy in one patient, which was resolved after its cessation and concomitantly administering metoprolol (2.5–5.0 mg).p < 0.001). Exercise-induced chest pain was experienced by 11 of 23 patients with VMA and 11 of 58 patients without VMA .Stress-induced myocardial ischemia with the occurrence of WMA in medial and distal segments of the anterior septum was found in 23 patients (28%). Thirteen of 23 patients with WMA and 1 of 58 patients without WMA had ST depressions ≥1.0 mm during exercise , but not at end-systole .p < 0.001; 1.93 ± 0.16 vs. 2.78 ± 0.54%, p < 0.001, respectively) (ctively) .p < 0.001) (p < 0.001).ROC analyses identified the optimal CFVR cut-off value ≤ 2.1 obtained during high-dose dobutamine (>20 µg/kg/min) for the identification of MB associated with stress-induced ischemia, with a sensitivity, specificity, positive and negative predictive value of 96%, 95%, 88%, and 98%, respectively  . The ovep = 0.009; r= −0.295, p = 0.024, respectively), and a borderline correlation between CFVR and MLD at end-systole and end-diastole   (p < 0.001).There were a significant correlations between CFVR and both percent DS at end-systole and end-diastole after peak dobutamine infusion  . Howeverctively) . MLD andThe present study evaluated for the first time the best cut-off value of CFVR during dobutamine provocation to identify the presence of myocardial ischemia in patients with MB, as compared to the results of exercise-SE test. The major finding of this study is that CFVR during inotropic stimulation with high-doses of dobutamine is feasible, safe, reliable, and clinically useful noninvasive test for physiologic assessment of the MB severity. The optimal cut-off of ≤2.1 for CFVR at peak dobutamine dose, as determined by TTDE, has the best sensitivity, specificity, positive and negative predictive value, for identifying the MB concerning exercise stress-induced myocardial ischemia. The same cut-off of ≤2.1 for TTDE-CFVR during high-dose dobutamine provocation was suggested in the earlier study by Takeuchi et al. regarding functional evaluation of fixed coronary stenosis . This waThe present study showed a high negative predictive value for the CFVR threshold of 2.1 (98%) which is in agreement with previous studies that evaluated the value of CFVR measured either with adenosine or dobutamine provocation for the prediction of myocardial ischemia on noninvasive tests ,21,22,32Our study demonstrates that both percent DS and MLD at end-diastole, but not at end-systole, were independent predictors of ischemic CFVR values ≤ 2.1 during dobutamine provocation, suggesting that coronary blood flow in a coronary artery with MB mainly depends on the severity of residual MB-compression during diastole. Similarly, our previous study in MB-patients evaluating the role of invasive conventional and diastolic fractional flow reserve measurement during both adenosine and dobutamine provocation has also observed that percent DS at end-diastole and diastolic fractional flow reserve at peak dobutamine dose were the only independent predictors of stress-induced myocardial ischemia . The preEven though exercise-SE is a well-established diagnostic tool in detecting myocardial ischemia, due to its semi-quantitative nature and small areas of WMA, certain patients might be misdiagnosed regarding the presence of myocardial ischemia . HoweverAs the most simple and reproducible variable, CFVR, defined as the ratio of hyperemic to basal CFV during diastole, was used in our study since it correlates strongly with coronary perfusion reserve determined by PET . Since tNoninvasive CFVR during dobutamine provocation appears to be an additional and important noninvasive tool to determine the functional severity of isolated-MB. A transthoracic CFVR cut-off ≤2.1 measured at a high-dobutamine dose may be adequate for detecting myocardial ischemia in patients with isolated-MB.


Exercise stress electrocardiography (ExECG) is recommended as a first-line tool to assess ischemia, but standard ST-analysis has limited diagnostic accuracy. ST elevation in lead aVR has been associated with left main and LAD disease in the population undergoing coronary angiography but has not been studied in the general population undergoing stress testing for the initial evaluation of CAD without coronary angiography. We sought to determine the predictive value of lead aVR elevation for ischemia, early revascularization, and subsequent cardiac events in consecutive patients undergoing ExECG.The study cohort included 641 subjects referred for ExECG who were dichotomized by presence or absence of aVR elevation ≥1mm and compared for prevalence and predictors of ischemia and a composite of cardiac death, nonfatal myocardial infarction, and late revascularization. The cohort had a median age of 57 and 57% were male. The prevalence of aVR elevation was 11.5%. The prevalence of significant ischemia on patients who received imaging was significantly higher with aVR elevation . Early revascularization occurred in 10.9% with vs 0.2% without aVR elevation, p<0.001. No subjects without aVR elevation or ST-depression underwent early revascularization. However, cardiac event rates were similar over a median 4.0 years of follow-up with and without aVR elevation . aVR elevation did not predict long-term cardiac events by Kaplan-Meier survival analysis (p = 0.94) or Cox proportional hazards modeling (p = 0.35).aVR elevation during ExECG predicts ischemia on imaging and early revascularization but not long-term outcomes and could serve as a useful adjunct to standard ST-analysis and potentially reduce the need for concurrent imaging. Coronary artery disease (CAD) is a significant source of morbidity and mortality . ExercisLead aVR has shown promise in the diagnosis of CAD and as a prognostic marker for abnormal perfusion and cardiac events. It is uniquely positioned as a “pseudo-intracavitary” lead, allowing it to signal changes that may not be visible in other leads . Prior sAccordingly, we examined the prevalence of ≥1mm elevation of lead aVR during ExECG and assessed its diagnostic and prognostic impact and incremental value compared with clinical variables and stress myocardial perfusion imaging (MPI) or stress echocardiography in an unselected and consecutive cohort of outpatients referred for stress testing for their initial ischemia evaluation.We performed an analysis of a study cohort using previously-collected prospective data from the University of Virginia Stress Laboratory  to which outcomes data were subsequently collected and added.The derivation of the study cohort is illustrated in Clinical information collected at the time of ExECG included patient demographics, comorbidities, and physical examination and baseline ECG findings. The parameters of the exercise test as well as the stress imaging results (when applicable) were also collected . InformaFollow-up data on all-cause and cardiac mortality and nonfatal cardiac events were obtained through chart review by a clinician blinded to the stress results, with questionable events verified by a second blinded clinician. For those patients in whom appropriate follow-up data could not be ascertained, a phone call was made to the patient to verify their health status. Protocol and follow-up questionnaire approval and waiver of informed consent were obtained from the University of Virginia Institutional Review Board.ExECG was performed in accordance with the most recent ACC/AHA guidelines on exercise testing . A standA subset of the patients underwent subsequent imaging to assess for ischemia either with SPECT myocardial perfusion imaging (MPI) or stress echocardiography. Tc-99m Sestamibi rest-stress gated SPECT MPI was performed in accordance with the latest guidelines with standard dosages under a one-day protocol or over two days for those with a body mass index ≥36 . The isoNuclear cardiology specialists performed visual and quantitative image analysis . BorderlStress echocardiography was performed in accordance with guidelines from the American Society of Echocardiography . Left veIn patients referred, invasive coronary angiography was performed and interpreted by experienced operators with the assistance of computer-assisted quantitation . Stenoses of ≥70% or equivocal stenoses of 50–69% with a fractional flow reserve of <0.8 were considered significant. Operators had access to all clinical data during study interpretation and for revascularization consideration.The primary outcome for this study was a composite of cardiac death, nonfatal MI, and late revascularization. Each of these was separately assessed as a secondary outcome. Cardiac death was defined as death with any demonstrable cardiac cause or without a clear non-cardiac cause. Non-fatal MI was defined as presentation of the patient consistent with acute coronary syndrome and a troponin ≥ 2 times the upper limit of normal, with or without typical ischemic changes on an ECG, which we defined as ≥1mm horizontal or down-sloping depression of the ST segment. Invasive coronary angiography and revascularization were considered late events when performed >4 weeks after ExECG.th and 75th percentiles and were compared with t-tests. Categorical variables were given as percentages and were compared with chi-square or Fisher’s exact testing where appropriate. Univariable logistic regression was performed to assess predictors of early revascularization. Multivariable logistic regression was performed on the two variables with the highest univariable Chi-square values due to constraints in the number of events. Univariable Cox proportional hazards analysis was performed to assess predictors of cardiac events. These predictors were then entered into a stepwise multivariable Cox model. A p<0.10 was required to enter the model, <0.05 to remain in the model. aVR elevation was forced into this model. Incremental chi-square analysis was performed predicting events using Cox proportional hazards analysis. Survival curves were generated using the Kaplan-Meier method [Continuous variables were described as medians with 25r method . The alp2. There were no differences in gender, diabetes, tobacco use, history of MI, or prior revascularization between the groups.The clinical characteristics of the study cohort are provided in th percentile for patients without aVR elevation led to a significant difference. There were no differences in maximum heart rate, maximum systolic blood pressure or rate pressure product between the two groups. The cohort with aVR elevation had a >2-fold increase in the incidence of angina during testing and an 8-fold increase in ST-depression ≥1mm. When these data are combined with exercise workload, the median Duke Treadmill Score (DTS) was significantly lower in the group with ≥1mm aVR elevation with moderate risk at 2.0 versus a low-risk score of 9.0 for those without aVR elevation ≥1mm. There was also a higher percentage of patients with a moderate or high-risk DTS in the subgroup with aVR elevation , while echocardiography was performed in 184 (28.7%), and 353 (55.1%) had concomitant SPECT MPI. Ischemia in at least one segment was present in 63 of the 537 (11.7%) who had imaging. The prevalence of ischemia in patients with ≥1mm aVR elevation was 26.9% versus 9.6% in those without ≥1mm aVR elevation (p<0.0001). Of the patients who underwent SPECT MPI, the rate of ≥10% LV ischemia was 14.3% in those with ≥1mm aVR elevation versus 2.3% in patients without ≥1mm aVR elevation (p<0.0001). There were 3 patients with ≥20% LV ischemia, all of whom had ≥1mm aVR elevation (p = 0.003). The percentage of subjects with any ischemia subdivided by aVR elevation and ST-depression ≥1mm are provided in There were 14 patients with obstructive disease on invasive coronary angiography, 11 of whom (78.6%) had ≥1mm aVR elevation. Of the 8 patients who underwent early revascularization, 7 (87.5%) had aVR elevation ≥1mm. The rates of early revascularization in those with and without ≥1mm aVR elevation were 10.9% and 0.19%, respectively (p<0.001). We found the negative predictive value of ≥1mm aVR elevation for early revascularization to be 99.8%. The positive predictive value of ≥1mm aVR elevation for early revascularization was still low at 9.5%, given the low prevalence of this outcome. Sensitivity and specificity were 87.5% and 89.4%, respectively.Univariable predictors of early revascularization were METS achieved  1.4 , p = 0.019), Duke Treadmill Score , p<0.001) and ≥1mm aVR elevation , p<0.001). Both DTS (p = 0.006) and aVR elevation (p = 0.019) remained significant predictors in the multivariable logistic regression model, which was highly predictive of early revascularization with a C-statistic of 0.96. Lead aVR elevation had incremental diagnostic value over the Duke Treadmill Score (p = 0.008).th, 75th: 2.8, 4.4 years). A comparison of characteristics between those with and without follow-up available reveals a higher rate of hypertension (p<0.001) and CAD (p = 0.035) in those with follow-up available. There were no differences in age, gender, diabetes, hyperlipidemia, tobacco use, history of MI, or prior revascularization.Follow up data was available in 561 of the 641 patients (88%). The median follow-up time was 4.0 years , while the 412 subjects with a low-risk score had only 30 events (2.1%/year), p = 0.007. Only one subject had a high-risk score and did not have a subsequent event.2 values and provide similar information. aVR elevation did not predict cardiac events (p = 0.35).Cox proportional hazards univariable analysis for cardiac events identified the following significant predictors: age, hypertension, diabetes, known CAD, prior MI, prior revascularization, ischemia, and DTS. We entered these factors into a multivariable model with the results in 2 analysis of a Cox model for the prediction of cardiac events showed a significant improvement adding the DTS to clinical variables  with a X2 of 32.0, p = 0.032. Ischemia also brought incremental prognostic value . However, ≥1mm aVR elevation did not add incremental predictive value for the prediction of total cardiac events in models with (p = 0.91) or without (p = 0.40) ischemia.Incremental XMultiple prior studies have found a relationship between ST-elevation in lead aVR and the presence of obstructive CAD on invasive coronary angiography and adverse cardiac outcomes across a variety of patient subsets. In the setting of acute coronary syndrome, ST-segment elevation in lead aVR has been shown to be an indicator of left main or left anterior descending coronary artery disease , 20. A maVR elevation, alone and coupled with other ECG changes, has also been studied well in patients referred for coronary angiography after ExECG. The combination of aVR elevation and ST depression in V5 during ExECG has been highly correlated with obstructive CAD in patients referred for coronary angiography, occurring in 99% of the cohort studied by Michaelides et al. . The majHowever, there have been few published studies to date examining the rate of aVR elevation in the general population undergoing ExECG. Prior research has predominately been limited to patients who have undergone coronary angiography. Limiting analysis to this subset leads to selection bias and increases the likelihood of higher risk CAD. Multiple editorials have called for evaluation of “non-enriched populations” and thus identification of the “true specificity” of aVR elevation for significant CAD , 12. A kThe prevalence of aVR elevation in studies examining populations undergoing coronary angiography has been approximately 25% , 24. In In our analysis, aVR elevation predicted abnormal imaging results, with a 2.8-fold increased risk of ischemia. ST-depression did not significantly change the likelihood of ischemia when added to aVR elevation. The increased risk with aVR elevation was even more prominent for significant ischemia (≥10% of the LV), with a 6.2-fold increased likelihood. This is the level of ischemia shown to predict benefit with revascularization .In the setting of an increased risk of significant ischemia, aVR elevation is associated with a 57-fold increased risk of early revascularization. This finding has important implications for the diagnostic evaluation of chest pain. ExECG without imaging is recommended as the initial test of choice in patients at intermediate risk for CAD who are able to exercise, but imaging is typically performed due to the low diagnostic accuracy of stress ECG alone , 26. In A substantial concern with a diagnostic strategy that does not include imaging is the potential of missing obstructive CAD that could lead to downstream cardiac events if not revascularized. However, it is important to note that the recently published ISCHEMIA trial  did not show an association with the degree of myocardial ischemia and all-cause mortality . This stThe population selected for this study is more generalizable to the general population undergoing an evaluation for CAD, and thus the low prevalence of aVR elevation is more reflective of the true prevalence of disease. This study shows that while aVR elevation is a predictor of early revascularization in the population undergoing ExECG, it is not predictive of future cardiac events. Patients with aVR elevation were more likely to have ischemic ST changes in diagnostic leads, but more than 50% of patients with aVR elevation did not manifest these changes. Patients with aVR elevation tended to have more diagnostic signs on ECG suggestive of poor functional status, including angina. The nuclear and stress echo results are consistent with prior studies showing higher prevalence of ischemia in patients with aVR elevation. Finally, as has been demonstrated previously, patients with aVR elevation had a much higher rate of early revascularization. Additionally, the negative predictive value of aVR elevation for early revascularization was very high.A limitation of this study is that it was a single-center analysis using data collected predominately retrospectively with the typical limitations that result. Follow-up data was collected prospectively, though data were not available in 12% of subjects. The characteristics in this subgroup did not differ significantly from those with follow-up available. The lack of randomization to diagnostic strategies and angiography could result in referral bias, but the lack of increased events suggests high risk disease was not missed. Finally, it should be emphasized that our analysis only applies to those undergoing ExECG rather than pharmacologic stress. Furthermore, the low numbers of enrolled patients with aVR elevation limits our evaluation of long-term cardiac events.In contrast to the close linkage between lead aVR elevation and high-risk obstructive CAD in studies of populations referred to invasive coronary angiography after ExECG, our analysis of the general population undergoing ExECG found a low positive predictive value for early revascularization. Nevertheless, aVR elevation has incremental diagnostic value and a high negative predictive value of 99.8% for early revascularization. No subjects without ST-depression or aVR elevation underwent early revascularization. Moreover, there was no increased risk of events over 4 years with aVR elevation. These findings suggest that aVR analysis should be routinely added to ST-analysis to improve diagnostic accuracy and potentially to improve strategies avoiding imaging in appropriate lower risk subgroups.S1 Data(XLSX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


Cardiotoxicity is a well-recognised side effect of cancer-related therapies with a great impact on outcomes and quality of life in the cancer survivor population. The pathogenesis of chemotherapy-induced cardiotoxicity in patients with gastrointestinal cancers involves various molecular mechanisms, and the combined use of various chemotherapies augments the risk of each drug used alone. In terms of cardiotoxicity diagnosis, novel biomarkers, such as troponins, brain natriuretic peptide (BNP), myeloperoxidases and miRNAs have been recently assessed. Echocardiography is a noninvasive imaging method of choice for the primary assessment of chemotherapy-treated patients to generally evaluate the cardiovascular impact of these drugs. Novel echocardiography techniques, like three-dimensional and stress echocardiography, will improve diagnosis efficacy. Cardiac magnetic resonance (CMR) can evaluate cardiac morphology, function and wall structure. Corroborated data have shown the importance of CMR in the early evaluation of patients with gastrointestinal cancers, treated with anticancer drugs, but further studies are required to improve risk stratification in these patients. In this article, we review some important aspects concerning the cardiotoxicity of antineoplastic drugs used in gastrointestinal cancers. We also discuss the mechanism of cardiotoxicity, the role of biomarkers and the imaging methods used in its detection. Gastrointestinal (GI) cancer represents an important cause of cancer-related deaths being a major public health problem that encompasses cancers of the oesophagus, stomach, colon and rectum . ColorecAs overall cancer-related deaths decline, chemotherapy-associated cardiotoxicity increases and has a great impact on the outcome and life-quality of cancer survivor patients. They have an important cardiovascular (CV) risk , and shoChemotherapy-induced cardiotoxicity is defined as a reduction in left ventricle (LV) ejection fraction (LVEF) below 50%, a reduction from baseline with >10% or a Global Longitudinal Strain (GLS) reduction of >15% from baseline . It maniCardiotoxicity was initially divided in two categories based on its reversibility, but this classification is no longer available, due to several mismatches . MoreoveAnthracyclines may produce cardiotoxicity by interacting with both topoisomerase II (topoII) isoforms, topoIIα and topoII , and by Cardiac histopathological changes associated with anthracyclines are mainly represented by cytoplasmatic vacuolisation, myofibrillar and myocardial sarcomere disarray ,23.Late-onset cardiotoxicity is the most frequently encountered. Cardinale et al. have shown that 98% of cardiotoxicity cases occurred within the first year after treatment .Fluoropyrimidines may be cardiotoxic , even inBeing metabolised to 5-FU, capecitabine has similar cardiotoxicity as 5-FU . CoronarTherefore, fluoropyrimidines may cause chest pain, Takotsubo cardiomyopathy, Kounis syndrome, arrhythmias and cardiac arrest. The incidence of cardiac events in high-dose 5 FU treated patients may be as high as 7.6% ,33,34.Platinum-based compounds are important chemotherapies in gastrointestinal tumours, which is used in oesophageal cancer, colorectal cancer (FOLFOX). Cisplatin is another commonly used drug that is associated with significant toxicity , while cThe incidence of thromboembolic side effects was as high as 10 to 20% in different studies. Endothelial dysfunction can also play a role in cisplatin-associated cardiotoxicity, which is associated with increased levels of von Willebrand factor . StudiesTrastuzumab, a HER2 antagonist, has recently been proven beneficial in some HER2 positive gastric and colorectal cancers ,41. TrasNeuregulin, an ErbB receptor found in the CV system, may be involved in HER2 therapy-induced cardiotoxicity. Neuregulin, ErbB2 and ErbB4 receptor tyrosine kinases have been documented to play important roles in cellular cross-communication and stress-response . The disICI are a class of drugs that block the immune down-regulators, such as programmed cell death-1 (PD1), PD ligand-1 (PDL1), cytotoxic T-lymphocyte antigen 4 (CTLA-4) . NivolumAccording to recent data, ICI-related myocarditis may occur in 1.14% of patients when the drugs are used alone and in 2.4% of patients if the drugs are used in combination therapy. Nonetheless, the risk of developing myocarditis is shown to be lower with anti-PD1 drugs, when compared to anti-PDL1 and anti-CTLA4 drugs . StudiesVEGFs are involved in angiogenesis, endothelial cell survival, vasomotricity and cardiac contractile function, and their inhibitors have been associated with HF and arterial hypertension . BevacizIt has been shown that these drugs can increase the risk of both ischemic and haemorrhagic stroke, especially when bevacizumab is used. This risk is also higher in patients with colorectal cancers, and it doubles when a double dose is used . HF was VEGFs inhibitors associated cardiotoxicity is usually divided into two types: (1) On-target toxicity, which is due to the inhibition of CV-expressed kinases and it occurs mostly with imatinib treatment; and (2) off-target toxicity, encountered with sunitinib therapy, in which CV side effects are due to inhibition of non-targeted kinases .The evaluation of cardiotoxicity has an important role in patients treated with cancer therapies. Detecting subclinical changes in cardiac function represents the subject of interest of many studies. Echocardiography and cardiac magnetic resonance imaging (CMR) is the most used techniques. Cardiac biomarkers are used to increase the sensitivity of imaging methods in detecting cardiotoxicity, mainly in the early stages ,63.Biomarkers are considered to be a cost-effective alternative to other diagnostic techniques for screening subclinical changes in cardiac function. The most useful serum biomarkers used for the assessment of chemotherapy-based cardiotoxicity are represented by cardiac troponins (cTn) I/T, brain natriuretic peptide (BNP), C-reactive protein, myeloperoxidase (MPO), growth differentiation factor 15 (GDF-15), galectin-3, soluble interleukin 1 receptor-like 1 (ST2) and some microRNAs (miRNA). These can be used in the risk stratification and follow-up of cardiotoxicity and in evaluating cardio-protection. Current guidelines recommend using such biomarkers in patients treated with chemotherapy, by determining their value at baseline, during chemotherapy and after chemotherapy ,64.Cardiac troponins I and T are organ-specific biomarkers used to diagnose myocardial injury, which are also reliable in chemotherapy-based cardiotoxicity. In a recently published meta-analysis, the significant link between cardiac troponins and chemotherapy was proved. Studies have found that cTn was able to detect early cardiac injury more accurately than natriuretic peptides . IncreasFurthermore, elevations in serum cTn were observed with trastuzumab treatment and were associated with cardiac dysfunction . cTn hasBNP, another serum biomarker, having an important role to diagnose chemotherapy-induced cardiotoxicity, is associated with increased LV filling pressures . In patiMPO and GDF-15 are associated with impaired LV function and even with decreased LVEF . miRNAs Echocardiography is the main imaging method used in diagnosing cardiotoxicity, which comprehensively evaluates heart morphology and function ,78. LVEFDiastolic dysfunction was the first to occur in most of the chemotherapy-treated patients. In some studies, the E/A ratio was impaired, due to doxorubicin, along with changes in isovolumetric relaxation time (IVRT), even after the first dose ,88,89. I2, and a global longitudinal strain (GLS) <−17.5%, having comparable efficacy with CMR [3DE has comparable accuracy with CMR and multi-gated acquisition scan (MUGA) in terms of LVEF evaluation ,91. The with CMR . LV strawith CMR . A 6-monwith CMR .3DE speckle-tracking imaging (STI) overcomes the limitations of 2DE STI in terms of identifying early cardiac changes . Global During anthracycline therapy, changes in LV torsion, twisting and untwisting occurred earlier than an LVEF drop. Apical torsion, twisting and untwisting rates after chemotherapy, were correlated with prolonged IVRT, but didn’t predict LVEF decrease .Echocardiography is used in detecting wall motion abnormalities, due to ischemia or evaluation of LV wall hypertrophy secondary to arterial hypertension in patients treated with fluoropyrimidines, platinum-based chemotherapy and anti-VEGFs. Stress echocardiography (SE) may be used to reveal subclinical changes in LV function . In patiCMR is used in evaluating cardiac structure and function, and it is the gold standard for accurate assessment of ventricles’ functions and volumes. It may detect myocardial oedema and fibrosis, and early changes in cardiac function . Mild LV2 was associated with a higher risk of HF and CV deaths [Myocardial oedema, inflammation and interstitial fibrosis, occur early before LV dysfunction and LVEF impairment . MyocardV deaths . RV dysfV deaths ,112.Late-gadolinium enhancement (LGE) is used in evaluating myocardial fibrosis ,114, andT1 mapping is used to quantify extracellular volume fraction (ECV), which indicates interstitial fibrosis . On T1 wEarly gadolinium enhancement (EGE) detects myocardial injury in patients with myocarditis , is inclFurthermore, the myocardial consequences of arterial hypertension secondary to TKIs can be evaluated by CMR . VasculaAn important aspect in evaluating patients treated with chemotherapy is establishing their baseline cardiovascular risk and their risk of developing cardiotoxicity . This apAccording to the recently published position paper by the European Society of Cardiology (ESC), risk factors that should be considered are represented by previous cardiovascular diseases, co-existing medical disease, demographic traits and lifestyle factors that are accounted as cardiovascular risk factors, elevated serum biomarkers before initiation of chemotherapy and previous chemotherapy. High risk patients are considered those with one or more high risk factors or patients with medium risk factors with a sum of >5 points. Very high risk patients are considered those with one or more very high risk factors .Very high risk factors are represented by pre-existing heart failure or cardiomyopathy in patients treated with anthracycline, HER-2 targeted therapies and VEGF inhibitors.High risk factors are represented by ischemic cardiomyopathy , severe valvular heart disease, low LVEF at baseline (<50%), age >80 years, previous chemotherapy (anthracycline or HER-2 therapies) and radiotherapy to the left side of the chest or mediastinum .Serum biomarkers are used in surveillance during and after chemotherapy, and according to ESC position paper in high risk CV patients treated with anthracycline BNP/NT-proBNP, cTn should be measured at baseline, before cycles 2, 4 and 6 or before every cycle and at 3 and 6 months following chemotherapy or at 12 months after the final cycle. In low and medium CV risk patients, these biomarkers should be determined at baseline, before the fifth cycle and at 12 months after chemotherapy. In patients treated with HER-2 targeted therapies for gastric cancer, serum biomarkers should be measured at baseline, before every cycle for 3–6 months and then every 3 months for the remaining treatment in the first year. Following chemotherapy serum biomarkers are measured only if the patient is symptomatic .2. In patients treated with HER-2 targeted therapy, echocardiography should be done every two or three cycles for three months, then to every fourth cycle in the first year [According to the British Society of Echocardiography and British Society of Cardio-Oncology guidelines published recently regarding the frequency of echocardiography during chemotherapy, high risk patients treated with anthracycline, should be evaluated every two cycles or every cycle if the dose of doxorubicin is >240 mg/mrst year .There are still many uncertainties in evaluating patients undergoing cancer therapy, especially in detecting subclinical changes. Some new imaging techniques have been investigated to detect early cardiotoxicity, such as 3DE STI and new CMR techniques, which proved to have promising results. With the development of these new imaging techniques, there is a need for more clinical trials, for better cancer treated patients’ surveillance, to improve their outcome. Resorting to cardiac imaging methods and cardiac biomarkers may help to detect subclinical changes in cardiac function, while the damage is still reversible and cardio-protection methods are effective.


Background: Phase analysis is a technique used to assess left ventricular mechanical dyssynchrony (LVMD) in nuclear myocardial imaging. Previous studies have found an association between LVMD and myocardial ischemia. We aim to assess the potential diagnostic value of LVMD in terms of myocardial viability, and ability to predict major adverse cardiac events (MACE), using Nitrogen-13 ammonia ECG-gated positron emission tomography (gPET).Methods: Patients with coronary artery disease (CAD) who underwent Nitrogen-13 ammonia and Fluorine-18 FDG myocardial gPET were enrolled, and their gPET imaging data were retrospectively analyzed. Patients were followed up and major adverse cardiac events (MACE) were recorded. The Kruskal-Wallis test and Mann-Whitney U test were performed to compare LVMD parameters among the groups. Binary logistic regression analysis, receiver operating characteristic (ROC) curve analysis, and multiple stepwise analysis curves were applied to identify the relationship between LVMD parameters and myocardial viability. Kaplan–Meier survival curves and the log-rank test were used to look for differences in the incidence of MACE.Results: In total, 79 patients were enrolled and divided into three groups: Group 1 , Group 2 , and Group 3 . All LVMD parameters were significantly different among groups. The median values of systolic phase standard deviation (PSD), systolic phase histogram bandwidth (PHB), diastolic PSD, and diastolic PHB between Group 1 and Group 3, and Group 2 and Group 3 were significantly different. A diastolic PHB of 204.5° was the best cut-off value to predict the presence of myocardial scar. In multiple stepwise analysis models, diastolic PSD, ischemic extent, and New York Heart Association (NYHA) classification were independent predictive factors of viable myocardium and myocardial scar. The incidence of MACE in patients with diastolic PHB > 204.5° was 25.0%, higher than patients with diastolic PHB <204.5° (11.8%), but the difference was not significant.Conclusions: LVMD generated from Nitrogen-13 ammonia ECG-gated myocardial perfusion imaging had added diagnostic value for myocardial viability assessment in CAD patients. LVMD did not show a definite prognostic value. Evaluation of myocardial viability is important in patients with coronary artery disease (CAD) when planning revascularization  and predPhase analysis has emerged as an important technique to assess left ventricular mechanical dyssynchrony (LVMD) using nuclear imaging. Studies of the application of phase analysis have concentrated on the use of single-photon emission computed tomography (SPECT), in areas such as LVMD assessment in patients with left bundle branch block , optimizLimited studies have focused on gPET –18, espeThis study was approved by the Institutional Ethical Committee of the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Patients who underwent Nitrogen-13 ammonia gPET and Fluorine-18 FDG gPET for the myocardial viability assessment at the PET Center of Union Hospital from December 2015 to October 2019 were retrospectively enrolled. The inclusion criteria were adult patients with CAD as the main diagnosis confirmed by coronary angiography or coronary CT angiography. The exclusion criteria were: (1) severe valvular heart disease, (2) non-ischemic cardiomyopathy, and (3) severe arrhythmias such as left bundle branch block. Age, sex, history of myocardial infarction (MI) or old MI, risk factors for CAD, New York Heart Association (NYHA) functional classification were recorded. All the patients were followed up via medical records or telephone review to record the incidence of major adverse cardiac events (MACE), including unstable angina pectoris, myocardial infarction, heart failure, PCI, CABG, stroke, and cardiac death.®, GE Healthcare, Milwaukee WI, USA) using a 1-day protocol. Aminophylline and caffeinated beverages were avoided for 48 h before the PET examination. All patients fasted for 6 h. After connection of electrocardiographic (ECG) gating, and immediately after intravenous injection of 370–740 MBq (10-20 mCi) Nitrogen-13 ammonia, rest Nitrogen-13 ammonia static PET images were acquired for 10 min. Subsequently, oral glucose-loading with 25–50 g was performed, with supplemental insulin administered as needed   to measuThe ischemic extent was assessed on Nitrogen-13 ammonia MPI, obtained from ECTb software by using the default threshold of 50% . The algx-axis representing the phase (time), and the y-axis representing the percentage of myocardium that starts contracting at the corresponding time on the x-axis. Phase standard deviation (PSD) and phase histogram bandwidth (PHB) were the most common parameters to describe systolic LVMD, as the standard deviation and 95% width of phase distribution, respectively . Normally distributed continuous variables are expressed as mean ± standard deviation, non-normally distributed continuous variables as median and interquartile range , and categorical variables as numbers or percentages. Either analysis of variance or the Kruskal–Wallis test was used to compare LV functional and LVMD parameters among groups. Mann-Whitney U test was performed for pairwise comparisons. Binary logistic and multiple stepwise regression analyses were performed to screen for parameters predictive of myocardial viability. A receiver operating characteristic (ROC) curve was generated. The cut-off value was determined by the Youden index. Kaplan–Meier survival curve and log-rank test were generated to assess for differences in the incidence of MACE. A total of 104 patients underwent both Nitrogen-13 ammonia and Fluorine-18 FDG myocardial gPET imaging; 86 patients were diagnosed with CAD. After excluding two cases of non-ischemic cardiomyopathy, three cases of severe valvular disease, and two cases with severe arrhythmia, a total of 79 patients were included in this study . Age, seThere were 7 patients in Group 1, 33 in Group 2, and 39 in Group 3 . The numP-value of systolic PSD, systolic PHB, diastolic PSD, and diastolic PHB was 0.007, 0.001, 0.001, and 0.001, respectively. In pairwise comparison after Bonferroni's correction, the median values were significantly different between Group 1 and Group 3, P = 0.044, 0.017, 0.019, and 0.012 for systolic PSD, systolic PHB, diastolic PSD, and diastolic PHB, respectively. They were also significantly different between Group 2 and Group 3 . No significant difference was found between Group 1 and Group 2. Examples of LVMD analysis were shown in The comparisons of LVMD parameters, including systolic PSD, systolic PHB, diastolic PSD, and diastolic PHB among groups were shown in P = 0.004. The cut-off value for diastolic PHB to discriminate between patients with and without myocardial scar was 204.5°, the Youden index = 0.548  = 1.015 (1.005–1.025),  = 0.548 . The senR2] = 0.329) and myocardial scar (R2 = 0.373), as shown in Age, sex, BMI, cardiac risk factors, NYHA functional classification, LV functional parameters, ischemic extent, wall thickening score, and LVMD parameters were included in the multiple regression stepwise model to predict viable myocardium and myocardial scar. Ischemic extent, diastolic PSD, and NYHA functional classification were identified as the independent factors to predict viable myocardium (coefficient of determination [P = 0.340).The mean follow-up time was 17.9 ± 12.9 months. Of the 79 patients, 65 had follow-up results, in which MACE occurred in 14 (17.7%), 44 did not have MACE, seven died of unknown causes. Kaplan-Meier survival curves of patients with diastolic PHB > 204.5° and PHB <204.5°were shown in This study focused on whether LVMD contributed to the diagnosis of viable myocardium and myocardial scar by Nitrogen-13 ammonia ECG-gated MPI. LVMD parameters differed among groups, which suggests the usefulness of LVMD to distinguish patients with different proportions of myocardial scar, which confirmed our hypothesis. Diastolic PHB contributed to predicting the presence of myocardial scar by the binary logistic regression model, and the cut-off value was 204.5°. Diastolic PSD, ischemic extent, and NYHA classification were identified in a multiple regression stepwise model to predict the degree of viable myocardium and myocardial scar. LVMD from phase analysis of Nitrogen-13 ammonia ECG-gated MPI was likely beneficial to the diagnosis of myocardial viability in CAD patients with LV systolic dysfunction. However, the value of LVMD as a predictor of MACE of CAD patients still needs further study.The application of LVMD for CAD diagnosis was focused on the relationship between LVMD with coronary artery stenosis and myocardial perfusion defects in previous studies , 24, 25.R2 values (0.329 and 0.373) of viable myocardium and myocardial scar indicated that ECG-gated MPI combined with phase analysis and NYHA classification were not completely equivalent to myocardial viability quantification assessed by myocardial perfusion/metabolism imaging.All the LVMD parameter values were larger in patients with a higher proportion of myocardial scar (Group 3) than in patients with a lower proportion (Group 2) and without myocardial scar (Group 1). A diastolic PHB cut-off of 204.5° predicted the presence of myocardial scar. The results suggested that combining LVMD with ischemic extent may provide clinicians with an intuitive impression on which patient has more proportion of viable myocardium. Previously, it was difficult to have a view of the degree of myocardial scar and viable myocardium on rest MPI alone. In the multiple stepwise regression analysis for the prediction of myocardial viability, we noticed the degree of myocardial scar increased and viable myocardium decreased with increasing diastolic PSD, indicating that diastolic PSD has diagnostic value in terms of myocardial viability in Nitrogen-13 ammonia ECG-gated MPI. There are several possible explanations. First, myocardial scar is one of the main features in the progression of CAD. It decreases regional myocardial electromechanical coupling efficiency and further reduces myocardial contraction or dilation coordination . Noise dPrevious studies of phase analysis were focused on the application of systolic LVMD in SPECT; little attention was paid to either diastolic LVMD or the application of LVMD in PET, especially in Nitrogen-13 ammonia gated MPI. To date, the pathophysiology and clinical value of diastolic LVMD had not been studied extensively. Similar to systolic LVMD, diastolic LVMD could assess the phase and amplitude of regional myocardial relaxation by multiple Fourier transforms to quantify myocardial discoordination in diastole  and appeIn a cohort of 489 patients with ischemic cardiomyopathy , worse LThere were several limitations of our study. First, it is a retrospective study with limited number of patients. There were only seven patients in Group 1, which may influence detecting statistically significant differences in LVMD parameters between Group 1 and Group 2. There were reduced number of female patients, which may affect the evaluation of sex. Second, this study was a preliminary attempt to analyze the prognostic value of diastolic LVMD. Larger sample-sized study and longer follow-up time are needed to further confirm the prognostic value of diastolic LVMD.LVMD from Nitrogen-13 ammonia gated MPI had added diagnostic value for viable myocardium and myocardial scar. Increased LVMD did not reach a statistically significant predictive value. Further studies are needed.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by Human Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. The patients/participants provided their written informed consent to participate in this study.DZ conducted the analyses and was a major contributor in writing the manuscript. YL analyzed the images. LZ collected clinical information of all patients. FH and XT acquired GPET images. DJ contributed to revision. WZ provided suggestions about the idea. XL and CQ conceived the idea and contributed to analysis and revision. All authors read and approved the final manuscript.This work was supported by the National Natural Science Foundation of China (Nos. 81873906 and 81401444).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


In a cohort of type 2 diabetic (T2D) patients who underwent baseline cardiac magnetic resonance (CMR) and biomarker testing, during a median follow-up of 6 years, we aimed to determine longitudinal changes in the phenotypic expression of heart disease in diabetes, report clinical outcomes, and compare baseline clinical characteristics and CMR findings of patients who experienced major adverse cardiovascular events (MACE) to those remaining MACE free.  T2D increases the risk of heart failure (HF) and cardiovascular mortality. The long-term impact of T2D on cardiac phenotype in the absence of cardiovascular disease and other clinical events is unknown. n = 100) with no history of cardiovascular disease or hypertension were recruited at baseline. Biventricular volumes, function, and myocardial extracellular volume fraction (ECV) were assessed by CMR, and blood biomarkers were taken. Follow-up CMR was repeated in those without interim clinical events after 6 years.  Patients with T2D . Of the remaining 59, 32 patients who experienced no events received follow-up CMR. In this cohort, despite no significant changes in blood pressure, weight, or glycated hemoglobin, significant reductions in biventricular end-diastolic volumes and ejection fractions occurred over time. The mean ECV was unchanged. Baseline plasma high-sensitivity cardiac troponin T (hs-cTnT) was significantly associated with a change in left ventricular (LV) ejection fraction. Patients who experienced MACE had higher LV mass and greater LV concentricity than those who remained event free.  T2D results in reductions in biventricular size and systolic function over time even in the absence of cardiovascular/clinical events. Cardiovascular disease represents the primary cause of death in type 2 diabetic patients (T2D) . AlthougCardiac magnetic resonance imaging (CMR) is the reference standard for the assessment of cardiac volumes, mass, and function . Using CIn this longitudinal observational study, we tested the hypothesis that T2D would be associated with a progressive decline in biventricular systolic function even in a cohort of diabetic patients with no prior cardiovascular disease or interim major adverse cardiovascular events (MACE) during the follow-up period. We also sought to report clinical outcomes and compare demographic, clinical, and biochemical variables, and CMR and plasma biomarkers measured at baseline between those patients who experienced MACE and those who remained free of MACE during the follow-up period.Using CMR at two time points baseline visit and end of the study, we performed a prospective longitudinal study in a cohort of ethnically diverse, asymptomatic patients with T2D with no history or evidence on examination of cardiovascular disease. Participants who remained asymptomatic and free of MACE or any other new clinical comorbidity were invited for a second CMR scan after 6 years.Recruitment was performed from primary care health centers in Leeds, the United Kingdom. One hundred participants with T2D were recruited at baseline . The res2), or if they were using insulin. After 6 years, surviving participants who remained asymptomatic, with no MACE, other diabetic complications, or important comorbidity  were invited for a second CMR study.Asymptomatic adult patients with a diagnosis of T2D   with theAt baseline and at the follow-up visit, height and weight were recorded and body mass index (BMI) was calculated. A fasting blood sample was taken from each participant at baseline for assessments of full blood count (FBC), eGFR, fasting glucose, glycated hemoglobin (HbA1c), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) levels. All participants underwent resting ECG, and all had 24-hour BP monitoring at baseline to exclude undiagnosed hypertension . At the Imaging was performed on a 3.0 Tesla magnetic resonance system both at baseline and at year 6 CMR study visit. The baseline CMR protocol has been previously described . Follow-Images for biventricular and left atrial (LA) volumes and function were acquired using a steady-state free precession (SSFP) sequence with breath holding at end expiration in multiple orientations . AdenosiAll image analyses were performed off-line by AC (with 2 years of CMR experience) in a blinded fashion, and all scan contours were subsequently reviewed by EL using cvi42 software . Baseline and follow-up images were analyzed in a random order after the second visit by investigators blinded to any other data. Biventricular volumes and ejection fraction (EF) were obtained from contouring the endocardial and epicardial borders in diastole and systole on the SSFP short-axis stacks. The LA volume and EF were calculated using the biplane area-length method in the horizontal and vertical long axes as previously described . Using ct-test. Bivariate correlations were performed using Pearson's correlation coefficient. The relationships of change in left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF)  with age, BMI, HBA1c, fasting glucose, resting BP and heart rate (HR), NT-proBNP, and hs-cTnT were analyzed using multiple logistic regression. A p-value of ≤0.05 was considered statistically significant.Statistical analysis was performed using SPSS . Categorical data were compared with Pearson's chi-square test. Continuous variables were checked for normality using the Shapiro-Wilk test and are presented as mean ± SD. Comparisons of CMR data between baseline and follow-up were performed with a two-tailed paired The study was approved by the National Research Ethics Committee (Ref: 13/YH/0098), and informed written consent was obtained from each participant. The follow-up assessment was given additional ethical approval (Ref: 18/YH/0168). Participants were asked to sign a second consent form for the follow-up scan.Clinical outcomes of the baseline cohort were determined after a median follow-up of 6.3 years (interquartile range (IQR): 6.05–6.53 years) using electronic health records systems, and symptom status was determined by phone assessments . Demograp=0.01), the proportion taking a sodium-glucose cotransporter-2 (SGLT2) inhibitor increased from none to 12% (p=0.03). The number of participants on sulfonylureas, thiazolidinediones, gliptins, aspirin, or statins did not significantly change during the follow-up period.In the 32 patients comprising this study cohort, 29 were men, the mean age was 64 ± 9 years, and median diabetic duration was 11.9 years (IQR: 11.8–12.3 years). There were no significant differences in resting HR and BP, glycemic control, or BMI between the baseline and follow-up measurements . GlucoseNone of the patients were on an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB) therapy at baseline as per recruitment criteria of the initial study , whereasp=0.0001; mean RVEF 55 ± 5% vs. 51 ± 7%, p=0.003) . There was no change in LV PEDSR over time .The presence of new mid-wall fibrosis in a nonischemic pattern was detected in only one patient at follow-up. There were no changes in mean ECV between baseline and follow-up  compared to those who did not . HoweverR = −0.44, p=0.01). There was no such association for change in RVEF.There were no associations between changes in cardiac function and the baseline clinical variables. Although there were also no associations between laboratory variables of glucose management or NT-proBNP, there was a significant correlation between the change in LVEF and baseline plasma hs-cTnT  despite the asymptomatic status of these patients . SupportThere were no changes in mean HbA1c, systolic and diastolic BP, resting HR, or BMI at follow-up. Moreover, we detected no relationship between the baseline systolic or diastolic BP, HR, BMI, HBA1c, and glucose levels with the change in LVEF and RVEF over time . This lack of association between glycemic control and cardiac functional decline supports the notion that there are more central mechanisms to HF pathophysiology in diabetes than glycemic control. While a few studies demonstrated a positive impact of metabolic control on ventricular function , 25, mosHigh-sensitivity cardiac troponin isoforms are unique to the cardiac myocyte and are objective, quantifiable, and sensitive biomarkers for detecting cardiac injury . They arOur study does not suggest a similar role for NT-proBNP in asymptomatic patients with T2D with no known cardiovascular disease. A previous diabetic study did, however, demonstrate an independent correlation of NT-proBNP with the short-term prognosis of cardiovascular events . The disLV mass is a strong and independent predictor of subsequent cardiovascular events, including myocardial infarction, HF, and mortality . While tThe present data are in a modest number of patients, recruited to a single study site. The study was not powered to assess the potential association of the treatments and the CMR findings with regression analysis. However, the longitudinal nature of the study allowed paired analysis of images that, to minimize bias, were randomized in time and by subject. Moreover, the image data of a random sample of subjects were evaluated by two investigators to demonstrate good inter- and intraobserver reproducibility.Another limitation is the small number of female participants as only a smaller proportion agreed to return for a second scan. While diabetes has been consistently found to be a stronger risk factor for heart disease in women compared to men , in thisEven in the absence of overt clinical CAD, significant valvular disease, uncontrolled hypertension, or change in BMI, T2D resulted in a significant reduction in cardiac size and biventricular systolic function over time. Plasma hs-cTnT measured at baseline was associated with the magnitude of change in LV systolic function suggesting that hs-cTnT could play a role in identifying patients with T2D at higher risk for heart failure. Patients who experienced MACE during the follow-up exhibited higher LV mass and greater LV concentric remodeling at baseline compared to those who remained asymptomatic and event free.