Heart failure (HF) has been a hot topic in diabetology in the last few years, mainly due to the central role of sodium-glucose cotransporter 2 inhibitors (iSGLT2) in the prevention and treatment of cardiovascular disease and heart failure. It is well known that HF is a common complication in diabetes. However, most of the knowledge about it and the evidence of cardiovascular safety trials with antidiabetic drugs refer to type 2 diabetes (T2D). The epidemiology, etiology, and pathophysiology of HF in type 1 diabetes (T1D) is still not well studied, though there are emerging data about it since life expectancy for T1D has increased in the last decades and there are more elderly patients with T1D. The association of T1D and HF confers a worse prognosis than in T2D, thus it is important to investigate the characteristics, risk factors, and pathophysiology of this disease in order to effectively design prevention strategies and therapeutic tools. Heart failure (HF) is one of the most frequent causes of hospital admission and has a poor prognosis in most cases, despite great pharmacological advances developed in recent decades for heart failure with reduced ejection fraction  . In addiAlthough due to the development of sodium-glucose cotransporter 2 inhibitors (iSGLT2) and glucagon-like peptide 1 analogues (aGLP1), the evidence on heart failure in T2D is growing and extensive, in T1D there is a paucity of data. In this review, we will focus on the evidence about HF in T1D with a special interest in the epidemiology, risk factors, and pathophysiology of this complication.Until a few years ago, most epidemiological and long-term follow-up studies on diabetes were focused on classic cardiovascular complications with an atherosclerotic profile. However, thanks to the data from the cardiovascular safety studies of new antidiabetic drugs, more and more studies with epidemiological data are being published also on T1D, though its incidence and prevalence are not well established. In a 10-year retrospective study performed by McAllister et al. of over 3.25 million people without DM and with T2D and T1D, there were 1313 events of HF among patients with T1D. The crude incidence rate of hospitalization for HF in the T1D group was 5.6 per 1000 person-years compared to 2.4 in patients without diabetes and 12.4 in patients with T2D. However, the case-fatality rate was higher in patients with T1D than people without diabetes mellitus; the difference was larger for men  than for women  ) and coronary artery calcification (OR 60.1 [95% CI 8.4–410.0]) . The samFinally, regarding risk factors, there is an interesting study carried out by Khedr et al. on 78 adolescents with T1D of at least 6 years of duration, in whom they analyzed some lipid biomarkers as predictors of diastolic dysfunction. They found diastolic failure to occur in 50% of the females and 66.6% of the males, and described that lower high-density lipoproteins (HDL)  and a higher total cholesterol/HDL ratio  and triglycerides/HDL ratio  were associated with diastolic failure .Considering that classical risk factors seem to be important, but it also seems that HF in T1D has differential characteristics, it is necessary to continue investigating the most important risk factors for the development of this complication .The mechanisms responsible for the association between diabetes and heart failure are not entirely clear, although a great variety of them have been proposed, such as endothelial dysfunction, alterations in glucose and fatty acid metabolism at the myocardial level, myocardial fibrosis, the increase in oxidative stress, or the activation of local neuro-hormonal systems, such as the renin-angiotensin-aldosterone system, endothelin, or the sympathetic nervous system  Figure . It has Diabetic cardiomyopathy pathophysiology is widely studied in T2D, while its mechanisms in T1D are less clear. Hyperglycemia and chronic inflammation present in both types, promoting cardiac hypertrophy and fibrosis, increasing myocardial stiffness, and resulting in diastolic and systolic dysfunction. Increased levels of glucose lead to a higher production of advanced glycation end products (AGEs), which have been suggested to trigger deleterious effects on ventricular function through the formation of crosslinks between collagen molecules in the extracellular matrix, impairing its degradation and leading to myocardial stiffness and diastolic dysfunction . ActivatDue to the insulinopenia in T1DM, fatty acid β-oxidation is increased to maintain adenosine triphosphate (ATP) producti; however, this process becomes ineffective during diabetes evolution, resulting in intracellular lipid accumulation and lipotoxicity . IncreasMitochondrial dysfunction is usually found in cardiac tissue in T1D patients. Decreased mitochondrial oxidative capacity is caused by altered mitochondrial ultrastructure, proteomic remodeling, and oxidative damage to proteins and mitochondrial DNA .Concerning cardiac inflammation, the infiltration of macrophages and lymphocytes is usual in DM. These inflammatory cells secrete cytokines, such as tumor necrosis factor (TNF), interleukin 6 (IL-6), interleukin 1β (IL-1β), interferon-γ, and transforming growth factor β (TGFβ) that can produce profibrotic responses, leading to further adverse remodeling. Studies in mice have detected higher T-cell infiltration in the myocardium in T1D  and some2+ due to lower sarcoplasmic reticulum Ca2+ pump activity because of the decreased glucose transporter type 4 (GLUT 4) recruitment to the plasma membrane, mediating this disturbance in contractile dysfunction and arrhythmia . The latest guidelines for the diagnosis and treatment of HF recommend the use of these natriuretic peptides both in acute and non-acute settings to rule out HF, given its high negative predictive value, but not to establish its diagnosis. Thus, the diagnosis in diabetic patients in the non-acute setting should follow the diagnostic algorithm that emphasizes that patients with a high probability of HF may have an echocardiogram to confirm or rule out the diagnosis [However, in the population with T1D, it is important to diagnose diastolic dysfunction and subclinical systolic dysfunction, to do an early diagnosis of the disease using sensitive cardiac markers that are easy to incorporate in routine clinical practice. Type B natriuretic peptides  are plasmatic biomarkers, which are released in response to ventricular stretching and volume overload within the cardiac chambers, and can be affected by parameters such as age, sex, BMI, or renal function. These markers are a useful tool to guide the diagnosis of HF in the acute setting, in either diabetic or non-diabetic patients. Data from the multinational Breathing Not Properly trial suggest that diabetes is not a confounding variable in the interpretation of BNP levels in this situation . A receniagnosis . Echocariagnosis .n = 53) compared to non-diabetic controls (n = 53) and assert that it could constitute an early and sensitive marker of diastolic dysfunction in T1D. The E/e′ ratio is frequently used as a marker of diastolic dysfunction . Bradley TJ et al. [p = 0.0003) increased in patients with T1D (n = 199) compared to non-diabetic subjects (n = 178). However, not all the findings are consistent in this regard [For the study of diastolic dysfunction in young people with T1D , it is rJ et al.  observeds regard .p = 0.001), mid-lateral LV ( 21.43 ± 4.27 vs. 23.17 ± 1.92 p = 0.02), basal septum , and mid septum  compared to non-diabetic controls (n = 25), despite the absence of manifest heart failure and normal ejection fraction. In addition, greater endothelial dysfunction was detected by flow-mediated dilatation (FMD) in subjects with T1D compared to non-diabetic patients . These myocardial alteration parameters correlated with HbA1c levels . These findings reinforce the hypothesis of the possible early effect of the diabetic metabolic environment on myocardial function.Kaushik A et al. , in a reSome studies that evaluate systolic function in T1D with HFrEF expose a parallel reduction in ultrasound parameters such as longitudinal tension and global ventricular circumference, as well as a reduction in the systolic strain rate using speckle-tracking echocardiography , althougThese basic and central examinations based on clinical, analytical, and mainly ultrasound parameters can be completed with other modalities such as cardiac magnetic resonance imaging. Cardiac MRI allows for calculating improved rates of myocardial deformation of diastolic incoordination, including biventricular desynchrony and incoordination. The EMERALD study, carried out in a young population with T1D, reports alterations in the diastolic pressure of the ventricular septum and the diastolic relaxation fraction, which reflects an uncoordinated and energetically less favorable myocardial relaxation compared to non-diabetic subjects .Although the identification of this underlying heart problem in T1D can be very important to delay or prevent the development of manifest HF, it is necessary follow-up with these patients, through longitudinal studies, to accurately determine the clinical importance of the preclinical myocardial changes detected in this population.According to the latest European guidelines for the treatment and diagnosis of HF , in patiThe identification of asymptomatic T1D patients with cardiac dysfunction may favor the development of useful therapeutic strategies in diabetic cardiomyopathy, to optimize the treatment of these patients and improve the prognosis of the disease. As we mentioned before, McAllister et al.  and KrisThe gold-standard treatment in T1D is the use of basal-bolus insulin therapy and the early intensive therapy is a fundamental aspect to reduce HF risk in the long-term . Current2 [Certain drugs approved for the treatment of T2D such as metformin, aGLP1, and iSGLT2 are being evaluated as potential complementary drugs to insulin therapy in T1D . Reflect2 . It also2  as well 2 . However2 .In recent years, the development of these hypoglycemic molecules such as aGLP1 or iSGLT2 and the performance of cardiovascular safety studies for their commercialization have shown that they are not only beneficial in glycemic control, but also have cardioprotective effects in both T2D and non-diabetic patients. This opens the door to a clinical entity with important clinical repercussions, highly prevalent as we have seen in the general diabetic population and T1D. Furthermore, in certain stages, the lack of therapeutic options stands out, and although the studies show promising results, there are no specific data on the use of these drugs in the T1D population.Metformin is the first-line treatment in T2D. In recent years, cohort studies and systematic reviews have analyzed its role in cardiovascular disease, finding that metformin seems to be associated with a reduction in mortality from all causes in T2D patients with HF, as well as with a reduction in readmissions by HF ,76, so iRelative to iSGLT2, in the DECLARE-TIMI 58 trial, dapagliflozin treatment was associated with a lower rate of HF-related death and hospitalization than the placebo . Likewisn = 241), it was found that the use of liraglutide did not affect left ventricular systolic function (LVEF) compared to the placebo in patients with stable HF, although it was associated with an increase in heart rate and serious adverse cardiac events, such as sustained ventricular tachycardia, atrial fibrillation, or worsening ischemic heart disease . A meta-analysis published in recent years showed encouraging results regarding cardiovascular safety with the use of aGLP1, suggesting that they can reduce major adverse cardiovascular events, cardiovascular mortality, and all-cause mortality risk; no significant effect was identified in relation to hospitalization for HF [n = 49) showed that treatment for 26 weeks with liraglutide versus a placebo reduced early diastolic LV filling and LV filling pressure to normal levels, pathogenic characteristics of HFpEF. However, future studies are needed to investigate these potential effects of aGLP1 in HF in its early stages and its benefits in other populations such as non-diabetic, obese, or T1D subjects.Regarding aGLP1, trials have shown heterogeneous information with favorable results in the reduction of cardiovascular mortality events for some molecules : LEADER n for HF  or even n for HF . A doubln for HF  performeRegarding the position of the different international cardiology and endocrinology societies in the use of iSGLT-2 and aGLP1, both are the recommended therapies in cases of T2D with cardiovascular disease, preferably leaning towards the use of the former in HF cases without ruling out the use of aGLP1 ,100,101.HF is a complication of increasing concern in diabetes, and given the high incidence of HF and the risk of hospitalization for HF in the population with T1D, more studies should be developed in this regard to clarify pathophysiological aspects, determine specific risk factors to control, and develop standardized protocols to establish specific precision biomarkers for the diagnosis of this entity in T1D patients from early stages.The relationship between classic cardiovascular risk factors—such as hyperglycemia, hypertension, or dyslipidemia—and the cardiac and vascular abnormalities seen in people with T1D is not fully understood, so further research is required to identify potential treatment targets allowing for the development of therapeutic agents in this field. Some therapeutic groups, such as iSLGT2 and aGLP1, have shown a clear benefit in preventing cardiovascular complications in T2D. In particular, iSGLT2 have shown to be very effective in reducing HF-related deaths and hospitalization for HF in both T2D and non-diabetic patients. However, it remains to be determined if they are useful and safe in patients with HF and T1D.


A noninvasive left ventricular (LV) pressure-strain loop (PSL) provides a new method to quantify myocardial work (MW) by combining global longitudinal strain (GLS) and LV pressure, which exerts potential advantages over traditional GLS. We studied the LV PSL and MW in patients with type 2 diabetes mellitus (T2DM).This cross-sectional study included 201 subjects  who underwent complete two-dimensional echocardiography (2DE), including 2D speckle-tracking echocardiography (STE), as well as brachial artery pulse pressure measurement. The PSL was used to determine the global myocardial work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE) of all study participants. The association between T2DM and LV function was evaluated according to these MW indices.P < 0.001), indicating that the LV myocardium had been damaged, although the LV ejection fraction (LVEF) was still normal. The GWI and GWE were decreased (P = 0.022) and the GWW was increased (P < 0.001) in diabetic patients compared with controls, but the GCW was comparable in the two groups (P = 0.160). In all diabetic patients, age, body mass index, systolic blood pressure, smoking history, and LVEF were correlated with GWI, GWW and GWE.The GLS was significantly lower in the T2DM group than in the control group (The use of LV PSL is a novel noninvasive technique that could help to depict the relationship between LV myocardial damage and MW in patients with T2DM. Type 2 diabetes mellitus (T2DM) is a global epidemic. The global prevalence of diabetes in 2019 was estimated to be 9.3% (463 million) and is expected to increase to 10.2% (578 million) by 2030 and 10.9% (700 million) by 2045. T2DM accounts for approximately 90% of the total, with an estimated number of cases of approximately 520 million by 2030 and 630 million by 2045 . T2DM was diagnosed according to current clinical guidelines. Data related to drug use were obtained from all participants in the study. The study was approved by the local ethics committee of our hospital, and written informed consent was obtained from all participants.BP measurement for each patient was performed in a quiet 25 °C room after a 10-min supine rest. We measured the brachial artery BP and heart rate in the right arm with an automatic digital sphygmomanometer . BP was measured before and immediately after echocardiography, and the mean value was used for statistical analysis.Echocardiography was performed with a model E95 ultrasound machine . All parameters were the average of three consecutive cardiac cycles. The left atrial dimension (LAD), LV end-diastolic dimension (LVEDD), LV end-systolic dimension (LVESD), LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), interventricular septum (IVS) thickness, posterior wall thickness (PWT), and LV stroke volume (LVSV) were obtained according to the guidelines of the American Society of Echocardiography . The LVEThree consecutive cardiac cycles were collected for two-dimensional (2D) strain analysis . Q-analyMW was evaluated using the same software. After calculating the GLS of the left ventricle, the brachial artery BP was entered, and the valve opening and closing time was determined by echocardiography , 20. TheP < 0.05 was considered statistically significant.Continuous variables are represented as the means ± standard deviations and were compared using independent sample t-tests. Age, BMI and systolic BP (SBP) were used as covariates, and multivariate correlation analysis was used to evaluate the relationship of basic, laboratory and echocardiographic parameters with MW parameters. Interobserver and intragroup correlation coefficients (ICCs) were used to assess repeatability. P < 0.05). In terms of laboratory parameters, there were significant differences in fasting blood glucose, HDL, LDL, triglycerides, and HbA1c between the groups; the differences in fasting blood glucose, HDL, triglycerides and HbA1c were all significant with P < 0.01.This study population consisted of 201 individuals: 147 patients with T2DM  and 54 healthy controls . The clinical characteristics of the patients in the two groups are shown in Table P < 0.001), and the IVS thickness and PWT were greater . There was a significant difference in the E/A ratio and E/e' ratio between the control and T2DM groups . Although the LV volume of diabetic patients was slightly lower and LV diastolic function was more impaired, there was no significant difference in the LVEDD, LVESD, LVEDV, LVESV, or LVEF between the diabetic patients and controls.Table P < 0.001). The GWI in the control and T2DM groups was 1692.86 ± 349.63 vs. 1814.50 ± 270.50 mmHg% (P < 0.05). There was no significant difference in the GCW between the control and T2DM groups , and the GWW was significantly greater in the T2DM group than in the control group . This condition led to a decrease in GWE; the GWE in the T2DM group was 92.26% ± 28% (IQR: 91.56–92.69%), while that in the control group was 96.07% ± 1.52% (IQR: 95.66–96.49%) (P < 0.001).Table P < 0.05), sex , age , BMI , smoking history , SBP , fasting blood glucose , HDL , and LVEF , smoking history , LVESV , age , SBP , DBP , LAD , IVS thickness , LV PWT , E/A ratio , E/e' ratio , LV PWT , and LVEF .GWW was correlated with BMI , creatinine , BMI , age , smoking history , SBP , DBP , fasting blood glucose , HDL , LAD , LVESD , IVS thickness , PWT , LVESV , LVEF , E/A ratio , E/e' ratio , and LVEF . Age, BMI, and SBP were used as covariates after correction, and there were still significant differences.GWE was correlated with LVEDV , E/e' ratio , LV diastolic function , GWI  and GCW . Moreover, there were no correlations with other echocardiographic parameters.T2DM duration was associated with E/A ratio ; GWI, 0.95 ; GCW, 0.93 ; GWW, 0.82 ; and GWE, 0.88 .The interclass correlation coefficients (ICCs) for interobserver variability were as follows: GLS, 0.97 ; GWI, 0.94 ; GCW, 0.91 ; GWW, 0.82 ; and GWE, 0.88 .The ICCs for intraobserver variability were as follows: GLS, 0.98  The GLS was lower in the T2DM group than in the control group, indicating that the myocardial contractile function of diabetic patients had changed while the LVEF was preserved. (2) Compared with the control group, the GWI was significantly reduced in the T2DM group, but the GCW showed no significant difference, and the GWW was significantly greater in the T2DM group, which led to a decrease in the GWE in diabetic patients. (3) Age, BMI, SBP, smoking history, and LVEF were associated with GWI, GWW, and GWE in patients with diabetes.Cardiovascular disease is the main cause of death in T2DM . DiabeteLV GLS is still dependent on load, which may be a limitation in the event of changes in hemodynamic conditions. Myocardial function has been introduced as a new LV function parameter that takes into account LV deformation and LV afterload. Based on noninvasive LV pressure (BP) measurement, the LV PSL was constructed. Compared with the traditional GLS method, this approach combines measurement of the myocardial deformation and stress load and has advantages , 26, 27.The GWI, GCW, GWW, and GWE in the control group were consistent with the normal values obtained in the European Association of Cardiovascular Imaging (EACVI) Normal Reference Ranges for Echocardiography (NORRE) study. Our study also confirms the results of other previous studies . In thisIn this study, there was a significant difference in smoking among the baseline data between the control and T2DM groups. After multivariate regression analysis, smoking was significantly correlated with the GWI, GWW and GWE, indicating that smoking impairs myocardial function. There is evidence that nicotine can cause direct damage to the structure and function of the heart even in patients without atherosclerosis or other chronic diseases related to the risk of cardiovascular disease , and theIn our study, SBP was significantly correlated with GWI, GWW and GWE, and DBP was significantly correlated with GWW and GWE, indicating that hypertension is associated with impaired myocardial function. Essential hypertension and T2DM are two common chronic diseases. T2DM can aggravate LV diastolic dysfunction in patients with essential hypertension , 39.A recent study showed that subclinical myocardial dysfunction can be detected by real-time three-dimensional echocardiography (RT-3DE) in T2DM patients with poor glycemic control and that myocardial dysfunction is related to the duration of diabetes and level of HbA1c . HoweverGulsin GS et al. found that in asymptomatic working-age adults with T2DM, after weight loss, blood glucose control improved LV diastolic function, concentric LV remodeling and aortic stiffness, which provides the possibility that LV function in T2DM patients may be improved once metabolic control is obtained .P = 0.041 and P < 0.001, respectively). All patients had an increase of MW index after 12 months of treatment [Recent data on diabetic patients showed that the use of either a glucagon-like peptide-1 receptor agonist (liraglutide) alone or in combination with a sodium-glucose cotransporter-2 inhibitor (empagliflozin) increased a number of cardiac work indicators in patients after 4 months of treatment and reduced cardiac failure compared to baseline (reatment . It is sis of particular importance in diabetic patients, as cardiovascular disease may change with the course of diabetes, use of medication, and level of blood glucose control. This approach could serve as a better tool for clinicians to improve the follow-up of LV function in these patients and assess the potential effects of different treatments. In addition, it may represent a new risk stratification tool for assessing the prognosis of patients with T2DM.The introduction of cardiac parameters in the routine assessment of T2DM may improve the detection rate of early-stage heart disease in these patients. This There are several limitations to this study.First, the sample size was relatively small. In addition, the average age of the subjects was approximately 50 years. Thus, the generalization of our findings to other populations may require further confirmation. Second, we excluded some elderly patients upon speckle-tracking analysis failure, which may contribute to the risk of reporting bias. Third, we selected only patients with poorly controlled plasma glucose levels, leading to an increased risk of selection bias in this study. Finally, the study followed a cross-sectional design. Future studies with larger sample sizes following a cohort or randomized controlled trial design are needed to confirm our findings.This study shows that the LV PSL method could be used to evaluate myocardial dysfunction in T2DM patients in the early stage. The GWW of the patients was significantly increased, and the GWI and GWE were decreased, indicating that myocardial contractile function was damaged even while the LVEF was preserved. Age, BMI, SBP, smoking history and LVEF were all independently related to MW. Future studies with larger sample sizes evaluating the prognostic impact of MW on cardiovascular outcomes in diabetes are needed.


Thoracic irradiation is one of the cornerstones of Hodgkin lymphoma (HL) treatment, which contributes to high rates of long-term survivorship, but begets a life-long increased risk of heart disease including heart failure. At the cardio-oncology (CO) clinic, persistent sinus tachycardia or elevated resting heart rate (RHR) is frequently observed in these patients. The aim of this study was to evaluate the relation between RHR and left ventricular (LV) dysfunction.In 75 HL survivors visiting our CO-clinic echocardiographic evaluation of LV systolic and diastolic function including global longitudinal strain (GLS) was performed to assess subclinical LV dysfunction.. 54.8 ± 6.6; p = 0.543), patients with elevated RHR had abnormal GLS  and higher prevalence of diastolic dysfunction . GLS, E/e’ ratio and presence of diastolic dysfunction were independently associated with RHR when correcting for age, sex and mantle field irradiation. A significant improvement was observed of the RHR-association model with solely extracardiac confounders when LV-function parameters were added to the model .Median age of HL diagnosis was 24 [25th-75th percentile: This study indicates RHR as a possible marker for subclinical LV-dysfunction in HL survivors. All patients underwent transthoracic echocardiographic examination according to clinical protocol. Patients were eligible for inclusion in the study if they (i) were diagnosed with a histologically confirmed HL, and (ii) received thoracic radiotherapy at least ten years prior to referral to the CO-clinic. For the purpose of this study patients with a history of myocardial infarction or cardiac surgery prior to echocardiographic examination were excluded. Furthermore, patients were excluded in case of incomplete HL diagnosis- and treatment history or incomplete echocardiographic examination. Also patients with persistent atrial fibrillation, atrial flutter or supraventricular tachycardia during echocardiographic examination were excluded from this study. The local Medical Ethical Committee approved this study. All patients gave informed consent to participate in the study. This study complies with the Declaration of Helsinki.A retrospective cohort study among HL survivors treated with mediastinal irradiation referred to the cardio-oncology outpatient clinic at the Leiden University Medical Centre was performed. Patients are referred to the CO-clinic through the national HL survivorship care pathway, where all HL survivors between 15 and 60 years of age are eligible for routine cardiovascular screening. Between 2012 and 2019 88 unique HL survivors were identified . All patWhen patients were eligible for inclusion, medical records were reviewed to acquire detailed HL diagnosis and treatment data including Ann Arbor stage, radiotherapy treatment plan, cumulative mediastinal radiation dose, chemotherapy regimen and cumulative dose of anthracyclines. Additionally, demographic characteristics, traditional cardiovascular risk factors and medications at time of index clinic visit were collected from the departmental Cardiology Information System .2 using the CKD-EPI formula.Hypercholesteremia included any history of hypercholesteremia or statin use at index clinic visit. Family history of heart disease was defined as one or more first-degree relatives with myocardial infarction, cardiac surgery or sudden cardiac death before 60 years of age. Chronic renal insufficiency was defined as an estimated glomerular filtration rate below 60 mL/min/1.73 mRHR was determined during echocardiographic examination after at least ten minutes of supine rest when a stable RHR was established. An elevated RHR was defined as sinus rhythm equal or >80 beats per minute (bpm). The latter cut-off was chosen in line with previous publications regarding elevated RHR and excess mortality risk Patients were imaged in the left lateral decubitus position using the Vivid 7, E9 and E95 systems . Data acquisition was performed with 3.5 MHz or M5S transducers. Standard 2D, color, pulsed wave and continues wave Doppler images were acquired and stored for offline analysis .LV end-systolic, end-diastolic volume indexes  were quantified from the apical two- and four-chamber view using the modified Simpson rule, and subsequently the LV ejection fraction (LVEF) was derived LV diastolic function was quantified using mitral inflow Doppler E- and A-wave velocities, E/A ratio and E-wave deceleration time measurement. Tissue Doppler imaging was performed to measure peak early diastolic tissue velocity from the septal and lateral mitral annulus (e’-wave) and to calculate E/e’ ratio. Diastolic function was graded by American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI) recommendations Two-dimensional speckle-tracking strain echocardiography was applied to evaluate LV global longitudinal strain (GLS) using commercially available software (EchoPAC version 203). This technique quantifies myocardial deformation by tracking myocardial acoustic markers in every frame within the cardiac cycle. The LV endocardial border was traced in apical three-, four- and two-chamber views and the region of interest encompassing the LV myocardial wall was adjusted manually where needed. Calculation of the LV GLS is performed by the software as the average of the longitudinal strain values of each apical view and a color-coded 17-segment bulls-eye plot is provided. GLS is expressed as a negative value reflecting the shortening of the LV myocardium, thus more negative value represents better deformation. Systolic dysfunction was defined as LVEF < 50% or GLS > -16% Continuous variables are presented as mean ± SD, or median with 25th and 75th percentile depending on variable-distribution. Normality of distribution was assessed graphically and by Kolmogorov-Smirnov test. Categorical data are presented as frequencies and percentages.t-test, Mann-Whitney U test, Chi-square or Fisher’s exact test, where appropriate.Differences in baseline characteristics and echocardiographic parameters between patients with- and without elevated RHR were evaluated using unpaired Student’s Both simple- and explanatory multilinear regression modeling was performed to evaluate the association of echocardiographic parameters to RHR as a continuous variable. Possible confounders were identified by literature review added to the multilinear model: age, sex, mantle field irradiation.Furthermore, an F-test for nested regression model comparison was used to compare a model restricted to extracardiac confounders (age + sex + mantle field irradiation) - and an unrestricted model with both extracardiac confounders and markers of cardiac function in relation to RHR.Missing data was accounted for using complete-case analysis. Imputation methods for missing echocardiographic measurements were not contemplated, because they were assumed to be Missing Not At Random.All statistical analyses were performed in R version 3.6.3 .3A total of 75 patients were enrolled in the study. The selection process is shown in p=<0.001) . There were no significant differences in baseline characteristics between patients with and without elevated RHR. Furthermore, patients with concomitant anthracycline-containing chemotherapy did not have a significantly increased RHR compared to patients whom received only thoracic irradiation .The average RHR in the study population was 77 ± 14 bpm with 30 patients (40%) having an elevated RHR .A summary of echocardiographic parameters of systolic and diastolic function is presented in p = 0.022). This is emphasized by a significantly decreased e’ wave velocity (Asymp. p = 0.038), and increased E/e’ ratio - which has been well correlated with LV filling pressure (Asymp. p = 0.034) in patients with elevated RHR seep < 0.001).Furthermore, presence of diastolic dysfunction was more prevalent among patients with elevated RHR as compared to patients without an elevated RHR: 73.3% vs. 46.7%  and in case of diastolic dysfunction RHR increased with 8.38 bpm .In multilinear regression analysis GLS (per %), E/e’ ratio (per point) and presence of diastolic dysfunction were independently associated with RHR when controlling for age, sex and mantle field irradiation: see p = 0.003)]. This further supports our hypothesis that LV function is associated with RHR.When we compared an extracardiac confounder model (age + sex + mantle field irradiation) with an unrestricted model that included the before-mentioned confounders  systolic- and diastolic dysfunction are more prevalent among patients with an elevated RHR, and (ii) both GLS and diastolic dysfunction are independently associated with RHR. To our knowledge this is the first study to demonstrate an association between RHR and subclinical LV dysfunction in cancer survivors. The results confirm earlier studies showing high prevalence of both systolic and diastolic dysfunction in patients treated with thoracic irradiation and/or anthracyclines RHR is the product of a balance between vagal and sympathetic stimulation of the sino-atrial node. Increased adrenergic drive with positive chronotropic effects is one of the key mechanism in early stages of heart failure Izzo et al. demonstrated the inverse correlation with stroke volume changes and plasma norepinephrine (NE) concentrations in 68 mild hypertensive patients Grassi et al. displayed that elevated RHR can be considered a marker of sympathetic hyperactivity in both the general population and patients with cardiovascular disease. However, its value for this purpose is limited and the relation was most evident in heart failure and obese patients. In contrast, patients with essential hypertension did not show a correlation between elevated RHR and indices of sympathetic hyperactivity. While the HL survivors in this study do not have clinical heart failure, their background is also different from that of the general population or patients with cardiovascular disease because they have chemotherapy- and/or radiation induced myocardial fibrosis and impaired diastolic function Moreover, while LVESVi remained similar between both strata of RHR, there was a trend towards smaller LVEDVi in patients with an elevated RHR. As previously described, this reduction in stroke volume could be the consequence of myocardial fibrosis and LVEDVi shrinkage associated with cardiotoxic cancer treatment. Accordingly, several studies focused on whether RHR could serve as a therapeutic target to reduce cardiovascular events and mortality aside of patients heart failure with reduced ejection fraction, where heart rate reduction is a cornerstone of therapy. In cancer biology, sympathetic nervous system activation has been known to promote tumour growth and metastasis, and consequently a multitude of observational epidemiological studies have been conducted to assess the favourable effect of betablockers in a variety of solid tumours Both systolic and diastolic dysfunction were more prevalent among patients with an elevated RHR and importantly abnormal GLS, increased E/e’-ratio and any grade of diastolic dysfunction were independently associated with RHR. The relation between RHR and LV function was underlined by a significant improvement of the association model between RHR and extracardiac determinants – age, sex and use of mantle field irradiation – when echocardiographic parameters of LV function were included (e.g. GLS and presence of diastolic dysfunction). These findings suggest that an elevated RHR in these patients might not be a harmless sign, but a potential marker for underlying LV dysfunction as a result of anti-cancer treatment. It must be noted, while GLS and E/e’ were significantly more abnormal in patients with an elevated RHR, the observed systolic and diastolic dysfunction was subtle and the clinical implication of this subtle dysfunction needs to be further investigated. However, these findings were observed during the first echocardiographic examination ten years after mediastinal irradiation in an overall young population. It is likely that systolic and diastolic dysfunction will become increasingly more important during longer follow-up as several publications have shown that compared to the general population, HL patients have a significantly increased risk of cardiovascular disease Another notable finding is that in patients with diastolic dysfunction left atrial volume was low. Increase in left atrial size is usually one of the first signs of increased LV filling pressure and is therefore incorporated in classification algorithms of diastolic function Thoracic irradiation leads to a broad range of cardiac complications - including coronary artery disease, radiation valvulopathy, pericarditis and heart failure - through damaging both cancer- and healthy cells by creating reactive oxygen species that induce local inflammation and tissue fibrosis In our study a cut-off value of 80 bpm was used to define elevated RHR. Over the years both higher and lower thresholds have been utilized. While dichotomization of RHR - as being elevated or not - is helpful for conceptualization purposes, a “true” RHR is substantially influenced by testing circumstances, measuring method and medication. For instance, some patients used betablockers or non-dihydropyridine calcium channel blockers which have negative chronotropic properties and could lower RHR. While in regression analysis betablocker use and RHR were not independently associated, our study population was too small to study the effect of these medications on RHR. Furthermore, while RHR was determined when a stable heart rate had established, it is possible that some misclassification in RHR strata can occur as a result of physical discomfort by the ultrasound probe.To objectively assess LV function, patients with acute coronary syndrome or cardiac surgery have been excluded from our study populations, therefore the implication of these results cannot be extrapolated to all HL survivors. Furthermore, there is little spread in cumulative mediastinal irradiation dose in the study population and for this reason it is not possible to draw conclusions on dose-dependent occurrence of subclinical LV dysfunction or presence of an elevated RHR, but earlier studies have already supported this principle 5The results of our study indicate that elevated RHR is a common finding in HL survivors treated with thoracic irradiation. Importantly, elevated RHR was associated with LV diastolic dysfunction and subclinical systolic dysfunction as assessed by GLS.The department of Cardiology received research grants from Biotronik, Medtronic and Boston Scientific.


Cardiac resynchronization therapy (CRT) produces acute changes in electric resynchronization that can be measured noninvasively with electrocardiographic body surface mapping (ECGi). The relation between baseline acute electrophysiology metrics and their manipulation with CRT and reverse remodeling is unclear.To test (ECGi) derived parameters of electrical activation as predictors of volumetric response to CRT.ECGi was performed in 21 patients directly following CRT implant. Activation parameters  were measured at baseline and following echocardiographically optimized CRT. Remodeling response (>15% reduction left ventricular end-systolic volume) was assessed 6 months post CRT.P = .227). Remaining activation parameters were similar between responders and nonresponders . In volumetric responders activation parameters were significantly improved with CRT compared to nonresponders: VV sync , VVtat , LVtat , and LVdisp .Patients were aged 68.9 ± 12.1 years, 81% were male, and 57% were ischemic. Baseline measures of dyssynchrony were more pronounced in left bundle branch block (LBBB) vs non-LBBB. ECGi demonstrated a trend of greater interventricular dyssynchrony between responders and nonresponders that did not reach statistical significance (VVsync: -45.7 ± 22.4 ms vs -25.1 ± 29.3 ms, Baseline ECGi activation times did not predict CRT volumetric response. Volumetric responders exhibited significant improvements in ECGi-derived metrics with CRT. ECGi does not select CRT candidates but may be a useful adjunct to guide left ventricle lead implants and to perform postimplant CRT optimization.  We investigated the validity of ECGi to characterize baseline activation measures in CRT recipients and to assess acute changes in activation parameters following CRT in relation to volumetric remodeling response.ClinicalTrials.gov Identifier: NCT01831518). Consecutive patients at St Thomas’ Hospital with guideline-indicated criteria for CRT  were prospectively included in the study.The local ethics authority approved the study and all patients provided written informed consent; the study complies with the Declaration of Helsinki (Transvenous biventricular pacing was undertaken using standard techniques. Positioning of the left ventricular (LV) and right ventricular (RV) leads were at the operators’ discretion and dependent upon target vessels and optimal electrical parameters with empirical placement of the LV lead targeted to a posterolateral vein. Biventricular pacing was not activated directly after implantation. ECGi was undertaken the following day prior to discharge. The device was turned on as part of the ECGi protocol and echocardiographic optimization of the atrioventricular and ventriculo-ventricular delays was performed using the iterative mitral valve inflow and LV outflow tract velocity time integral methods to achieve standardized optimal biventricular pacing.The raw epicardial mapping data of intrinsic activation and echo-optimized biventricular pacing activation was analyzed with ecSYNC software ((1)Global biventricular total activation time (VVtat), defined as the maximum of (mean of maximum 10% of LV activation times and mean of maximum 10% of RV activation times) minus the minimum of (mean of minimum 10% of LV activation times and mean of minimum 10% of RV activation times);(2)LV total activation time (LVtat), defined as the average of the maximum 10% of activation times in the left ventricle minus the average of the minimum 10% of activation times;(3)Global left/right ventricular electrical synchrony (VVsync), defined as the mean activation time in the right ventricle minus the mean activation time in the left ventricle;(4)Global LV dispersion of activation (LVdisp) calculated as the standard deviation of the activation times in the left ventricle, defined as the standard deviation of activation times in the LV region of interest.Four ventricular activation metrics were calculated:These metrics were assessed at baseline and following acute CRT. Remodeling response was assessed at 6 months and changes in electrical parameters were compared on the basis of volumetric response.t test or a paired-samples t test for normally distributed data. Nonparametric data were compared using the Mann-Whitney U test. Categorical variables were compared using the Fisher exact test or the χ2 test dependent on number. Receiver operator characteristic (ROC) curve analysis was used to define potential cut-offs for predictors of response. Values of P < .05 were considered statistically significant.Statistical analysis was performed with PASW Statistics version 24 software . Group comparisons were performed using an independent-samples Twenty-one consecutive patients were prospectively studied, with a mean age of 68.9 ± 12.1 years; 17 (81%) were male. The predominant etiology was ischemic , and the majority of patients were NYHA class III (86%). Mean preimplant LV ejection fraction was 25.1% ± 8.2%. Mean QRS duration was 165 ± 21 ms. QRS morphology was LBBB in 10 (48%), with 9 of these patients having strict LBBBP = .79). Despite this, ECGi demonstrated a greater degree of LV/RV dyssynchrony with LBBB , reflecting a greater degree of ventricular electrical uncoupling despite a similar QRS duration. Comparison between strict LBBB, nonspecific interventricular conduction delay, and RV pacing exaggerated this difference between VVsync .The mean baseline activation parameters  for the P = .021) (P = .897). ECGi demonstrated a trend to a greater degree of interventricular dyssynchrony between responders and nonresponders that did not reach statistical significance . The other baseline activation parameters were similar between responders and nonresponders  (P = .640) .In total there were 9 (43%) patients who remodeled with CRT, including all 4 female patients ( = .021) . Baselin = .726) . ROC cur = .640) . There wP < .001) and VVtat was significantly shortened with CRT . When patients were dichotomized into volumetric responders and nonresponders there was a difference in the magnitude of acute activation time changes with CRT. In volumetric responders all activation parameters were significantly reduced with CRT: VV sync , VVtat , LVtat , and LVdisp . In nonresponders only VVsync improved, whereas the rest of the parameters were not improved with CRT: VV sync , VVtat , LVtat , and LVdisp  (P = .061). All responders had improvement with VVtat and LVtat with CRT and all but 1 responder had improvements in LVdisp; these improvements were not seen in all nonresponders  . Relativsponders . ROC anasponders .Table 3CWe assessed the baseline values and acute changes following CRT of 4 ventricular activation metrics derived from ECGi.The main findings are as follows: (1) Baseline activation metrics demonstrated greater interventricular dyssynchrony  in LBBB patients compared to other intrinsic QRS morphologies despite similar QRS duration, suggesting ECGi provides useful information regarding ventricular activation in addition to surface ECG–derived QRS duration and morphology. (2) Baseline activation metrics did not reliably predict CRT volumetric response. There was a signal for greater interventricular dyssynchrony, which did not reach statistical significance, but no reliable correlation between the degree of interventricular dyssynchrony and the magnitude of volumetric response. (3) There were significant improvements in ECGi-measured activation timings with optimized biventricular pacing compared to baseline in volumetric CRT responders, which were not apparent in nonresponders.clinical response to biventricular pacing in 33 consecutive CRT patients from a single center , with a 50 ms cut-off for VEU having 90% sensitivity and 82% specificity.max , an acute hemodynamic response parameter recognized as a predictor for ventricular remodeling.P = .0359). Another explanation is that this metric may not be robust when tested in a different center; this is a similar effect as seen with echo-based dyssynchrony parameters and response to CRT.P = .983). The lack of correlation between the VVsync and reverse remodeling is also not supportive of the use of baseline metrics of activation being able to predict volumetric response.Longer ventricular activation derived from the 12-lead ECG is known to predict a greater degree of response to CRTmax and, furthermore, the concept of iatrogenic electrical dyssynchrony with worsening (prolongation) of activation times associated with a deterioration in acute hemodynamic response. Our current findings are in keeping with this, with significant improvement in activation times with CRT in patients that exhibited favorable volumetric remodeling and all patients who had acute worsening in activation times with CRT not responding; this supports the hypothesis that acute electrical resynchronization translates into favorable chronic ventricular remodeling. A non–statistically significant improvement in VVtat was associated with reverse remodeling, raising the potential of this metric in determining LV lead placement, guiding postimplant optimization, and predicting CRT response.QRS shortening after biventricular pacing is associated with volumetric response to CRTClinicaltrials.gov number NCT03504020), and we have previously shown that ECGi can characterize acute changes in activation metrics with different programming of multipolar LV electrodes, suggesting that vector optimization may play a role in CRT optimization.Our results suggest that although intrinsic activation times are important for patient selection, they are not the only factor to deliver response. In our cohort the degree of electrical improvement with CRT from baseline appears to have more consequence than the baseline parameters themselves. Therefore, CRT optimized to improve electrical dyssynchrony, either during implant with necessary revision of the ECGi data acquisition process, at optimization, or using preprocedural simulations,This is a small mechanistic and hypothesis-generating study and is therefore open to bias secondary to the sample size; however, the small sample size is in keeping with routine clinical work and therefore questions the utility of body surface mapping for selection and monitoring of CRT patients in the clinical setting. In order to analyze the maps from the cardiac CT–derived epicardial shell, the border of the left ventricle is defined by annotating the left anterior descending artery as it travels down the anterior interventricular groove from base to apex. This impacts LVtat measurements and does not take into account variability in septal anatomy and inferior RV insertion lines. In this cohort LVtat estimation does not predict volumetric response and this value seems very similar between responders and nonresponders; therefore it is difficult to see how refinement in the anatomical processing will impact these predictive rates. One consideration for both LVtat and VVtat is that these measures are without direction; CRT manipulates activation wavefronts between 2 (or more) points in space, and therefore if there is a delay in intrinsic activation from apex to base where the leads are in a septal-to-inferolateral orientation then this is unlikely to impact total activation times, with corresponding low impact on remodeling response. LVdisp can be impacted by how the left ventricle is defined in postprocessing, as with LVtat, including not taking into account septal activation. The lack of difference between responders and nonresponders in LVdisp may be affected by this lack of inclusion of the septum, which is likely to be a critical shortcoming of this metric in the full assessment of LV electrical dyssynchrony.Baseline activation times from ECGi in particular electrical delays between mean RV and mean LV activation (VVsync) did not predict CRT volumetric response. This questions the clinical utility of ECGi in selection of CRT candidates. CRT volumetric responders exhibit significant improvements in ECGi-derived activation times from baseline with biventricular pacing whereas nonresponders do not, although there was no significant difference between degree of improvement between responders and nonresponders. This questions whether intraprocedural ECGi may be a useful adjunct to guide LV lead implants and to perform postimplant CRT optimization, as acute worsening in ECGi parameters indicates that a modification of CRT activation or intensification of other therapies will be needed to convert a nonresponder into a responder.CardioInsight Inc and by the Wellcome/EPSRC Centre for Medical Engineering [WT203148/Z/16/Z].This study was supported by CY was an employee of CardioInsight. All other authors declare no conflict of interest.All authors attest they meet the current ICMJE criteria for authorship.All patients provided written informed consent.The study complies with the guidelines set forth in the Declaration of Helsinki. The local ethics authority approved the study.


ESL), and the time to PSS (TPSS) were analyzed in all LAD segments, and the incremental values of the TESL and TPSS in detecting LAD stenosis and the diagnostic accuracy were evaluated. In the apical anterior segment, the peak systolic strain was significantly lower and TESL and TPSS were significantly longer in the single-vessel group than in the no stenosis group. In the single-vessel group, the addition of TESL and TPSS to the peak systolic strain significantly increased the model power in detecting stenosis, and the integrated analysis improved diagnostic accuracy compared with the peak systolic strain alone. In contrast, this incremental value was not demonstrated in the multivessel group. The integrated analysis of the peak systolic strain, ESL, and PSS may allow better screening of single-vessel LAD stenosis using nonstress speckle-tracking echocardiography.The diagnosis of coronary artery disease (CAD) with nonstress echocardiography remains challenging. Although the assessment of either early systolic lengthening (ESL) or postsystolic shortening (PSS) allows the sensitive detection of CAD, it is unclear whether the integrated analysis of ESL and PSS in addition to the peak systolic strain can improve the diagnostic accuracy. We investigated the incremental value of ESL and PSS in detecting left anterior descending artery (LAD) stenosis using nonstress speckle-tracking echocardiography. Fifty-nine patients with significant LAD stenosis but without visual wall motion abnormalities on echocardiography at rest  and 43 patients without significant stenosis of any vessel were enrolled. The peak systolic strain, the time to ESL (T Stress echocardiography is used to reveal ischemic myocardium in patients with coronary artery disease (CAD). However, the diagnosis of CAD using nonstress echocardiography is still challenging because myocardial ischemia may not occur at rest even in the presence of significant coronary stenosis.Myocardial ischemia is a pathophysiological state that occurs when myocardial blood flow cannot supply sufficient oxygen for myocardial demands; the imbalance between myocardial oxygen supply and demand is followed by left ventricular (LV) wall motion abnormalities3. Although the assessment of PSS provides the sensitive detection of CAD in stress echocardiography5 and can offer diagnostic information in nonstress echocardiography7, the incremental value of PSS over the peak systolic strain in detecting CAD is unclear. Similarly, the assessment of ESL appears to be useful for detecting CAD9; however, its incremental value is also unknown.Myocardial strain analysis with tissue Doppler and speckle-tracking echocardiography can evaluate regional myocardial wall motion quantitatively and is useful for identifying subtle abnormal deformations, such as the early systolic lengthening (ESL) and postsystolic shortening (PSS) observed in myocardium with contractile dysfunctionWe hypothesized that these subtle deformation abnormalities could emerge even at rest in some patients with significant CAD but without visual wall motion abnormalities and that the analysis of ESL and PSS in addition to the peak systolic strain could allow better screening of CAD in nonstress echocardiography. In this study, we sought to investigate whether the integrated analysis of peak systolic strain, ESL, and PSS could improve the diagnostic accuracy of single-vessel and multivessel left anterior descending artery (LAD) stenosis by using nonstress speckle-tracking echocardiography.10. For this reason, right coronary artery (RCA) stenosis and circumflex artery (LCX) stenosis were not evaluated in this study to avoid the influence of complicated regional heterogeneity. After excluding patients with single-vessel RCA stenosis, single-vessel LCX stenosis, and two-vessel RCA and LCX stenoses, the remaining patients were divided into three groups: single-vessel stenosis of the LAD (single-vessel group), significant stenoses of ≥ 2 vessels including the LAD (multivessel group), and no significant stenosis in any vessel (no stenosis group). Patients with left ventricular ejection fraction (LVEF) < 50%, atrial fibrillation, frequent arrhythmia, significant valvular disease (more than moderate degree), suboptimal echo images, or ≥ 1 unanalyzable segment in the speckle-tracking analysis were excluded from the study. Finally, 102 patients were included in this study. The study protocol conformed to the ethical principles outlined in the Declaration of Helsinki and was approved by the Shiga University of Medical Science Research Ethics Committee. Written informed consent was acquired from all patients.One hundred thirty-three patients with clinically suspected CAD but without visual wall motion abnormalities on echocardiography at rest between April 2011 and November 2016 were enrolled. In this study, patients with ST elevation or depression on the electrocardiogram were not enrolled because there was a possibility that direct coronary angiography was needed before echocardiography for this population. For all enrolled patients, quantitative coronary angiography (QCA) was performed within 48 h after echocardiography, and the % diameter stenosis was analyzed by one investigator who was blinded to the echocardiographic data. Greater than or equal to 50% diameter stenosis was defined as significant. ESL and PSS can be detected even in the normal myocardium and the incidence is different within the LV segments12.Two-dimensional echocardiography was performed using Vivid E9 with an M5S-D transducer  and saved in raw data format. The tissue harmonic mode was used, and the frame rate was set at 52–84 frames/s. LVEF was calculated by the biplane method of disks, and other conventional parameters were also measured according to the recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging, except that early diastolic mitral annular velocity (e′) was obtained only from the septal sideSpeckle-tracking analysis was performed offline using EchoPAC BT11 software . Apical long-axis, apical 4-chamber, and apical 2-chamber views were captured under breath-hold conditions. End-diastole was defined at the peak of the R wave on the electrocardiogram, and end-systole was defined at the time of aortic valve closure (AVC) determined from the LV outflow velocity. In each apical view, the endocardial border in the end-systolic frame was manually traced, and the wall thickness was set to a width equal to that of the myocardium. The borders were manually adjusted when necessary to optimize the boundary position and tracking. The whole-wall longitudinal strain was then analyzed automatically.ESL), and the time to PSS (TPSS) were measured from the strain–time curve in one cardiac cycle. TESL was defined as the time from end-diastole to peak ESL, and TPSS was defined as the time from end-systole  to the peak strain during the cardiac cycle. When the peak strain preceded the AVC, TPSS was represented as a negative value. Parameters associated with the amplitude of ESL and PSS were not used because in a preliminary study, we confirmed that the amplitude changes of ESL and PSS were small for patients with significant coronary stenosis but without visual wall motion abnormalities.The peak systolic strain, the time to ESL 11. The global longitudinal strain (GLS) was also calculated from the 3 apical views. All speckle-tracking analyses were performed by an investigator who was blinded to the QCA data.The peak systolic strain, TESL, and TPSS could improve the diagnostic accuracy was evaluated in the single-vessel group and the multivessel group. Furthermore, in patients with successful revascularization confirmed by follow-up QCA, follow-up echocardiography was performed, and the changes in echocardiographic parameters before versus after revascularization were assessed.In the 11 segments, we first analyzed the diagnostic accuracy of each parameter to differentiate the single-vessel group from the no stenosis group and selected the segment that showed the best diagnostic accuracy in detecting LAD stenosis. Then, in the selected segment, whether the integrated analysis of peak systolic strain, TESL, and TPSS in the apical anterior segment. To determine interobserver reliability, the analysis was repeated by a second observer who was blinded to the values obtained by the first observer. To determine the intraobserver reliability, the analysis was repeated > 2 weeks later by the same observer.Fifteen image clips were randomly selected from among the total clips to assess interobserver and intraobserver reliability for peak systolic strain, T2-test or Fisher’s exact test was performed to compare categorical data. The diagnostic accuracy of the single-parameter analysis and the integrated analysis in differentiating the single-vessel or multivessel group from the no stenosis group was evaluated by the area under the receiver operator characteristic (ROC) curve (AUC). The comparison between AUCs was conducted using the method of DeLong et al.13. Multivariable logistic regression analysis was performed to establish the independent determinants for the presence of significant LAD stenosis. The independence and incremental value of each measurement were assessed by comparing the model χ2 at each step. The comparison of parameters obtained before and after revascularization was performed by the paired t test or the Wilcoxon test according to the data normality. Interobserver and intraobserver reliability were determined using intraclass correlation coefficients and Bland–Altman analyses. A P value of < 0.05 was defined as statistically significant. The statistical analysis was carried out using IBM SPSS Statistics version 20.0.0 , JMP version 12.0.1, , and MedCalc version 19.8 .Data are presented as the mean values ± standard deviation or n (%). Normality of the data was assessed with the Shapiro–Wilk test. The comparison among the three groups was performed with the analysis of variance or the Kruskal–Wallis test according to the data normality. For post hoc paired comparisons in normally distributed data, Tukey’s honestly significant difference test or the Games-Howell test was used depending on Levene’s test for equality of variance, whereas Dunn’s test was used in nonnormally distributed data. Pearson’s χOf the patients included in this study, 59 patients had significant LAD stenosis , and 43 patients had no significant stenosis of any vessel (no stenosis group). In these patients, the strain–time curves could be obtained in all LV segments. There were no significant differences in clinical and echocardiographic data among the three groups except the GLS. The absolute value of the GLS was significantly lower in the multivessel group than in the no stenosis group. Although three patients in the no stenosis group had positive troponin values (> 0.05 ng/mL), two of them seemed to be false positives because their values were 0.06 ng/mL Table .Table 1PESL and TPSS. There was no significant difference among the AUCs for the peak systolic strain, TESL and TPSS. In contrast, the apical septal segment in the apical 4-chamber view did not show significant diagnostic accuracy except for TPSS  = 1.59 + 0.14εS + 0.03TESL + 0.02TPSS, where εS = the peak systolic strain. In the multivessel group, however, the addition of TESL and TPSS to the peak systolic strain did not generate a significant increase in the model power  over the peak systolic strain alone. However, the integrated analysis did not improve the diagnostic accuracy in diagnosing multivessel LAD stenosis Fig. .Figure 4PSS were significantly improved after revascularization. TESL tended to be improved after revascularization but it was not significant due to large variation . The duration between the first and follow-up echocardiography was 378 ± 229 days. Compared with those before revascularization, peak systolic strain and TESL, and TPSS are summarized in Tables ESL and TPSS in the Bland–Altman analyses were within ± 35 ms in the interobserver measurement and within ± 25 ms in the intraobserver measurement.The intraclass correlation coefficients and Bland–Altman analyses of peak systolic strain, TESL and TPSS were prolonged in the single-vessel group. (3) TESL and TPSS were determinants independent of the peak systolic strain in detecting the single-vessel LAD stenosis. (4) The integrated analysis of the three parameters significantly improved the diagnostic accuracy of single-vessel LAD stenosis over that of the peak systolic strain alone, but it could not improve the diagnostic accuracy of multivessel LAD stenosis.The main findings of this study are as follows: (1) The apical anterior segment in the 2-chamber view was the optimal segment for detecting single-vessel LAD stenosis by using nonstress speckle-tracking echocardiography. (2) In the apical anterior segment, the absolute value of the peak systolic strain decreased, and TIt is difficult to diagnose the presence of significant CAD in patients referred with suspected CAD using nonstress echocardiography because ischemia does not always occur in myocardium perfused by the culprit coronary artery. A stress test should be performed for such patients; however, it is often withheld in the acute phase of the ischemic episode as the patient may be in an unstable condition.3. ESL and PSS occur in myocardium with contractile dysfunction through an imbalance of tension between the damaged myocardium and the surrounding normal (or less damaged) myocardium15 and become larger with the severity of myocardial ischemia17. Each assessment of ESL or PSS allows the sensitive detection of significant CAD in the clinical setting9. Moreover, it has been reported that ESL and/or PSS allow assessing myocardial ischemic memory because they persist after transient ischemia in animal studies20. Therefore, we hypothesized that in some patients referred with suspected CAD, ESL and PSS might appear in the ischemic myocardium even at rest due to silent ischemia or ischemic memory. In the present study, the decrease in the peak systolic strain and the prolongation of TESL and TPSS were demonstrated in the single-vessel group despite the use of nonstress echocardiography, which seems to support our hypothesis.Myocardial strain analysis with tissue Doppler or speckle-tracking echocardiography can not only quantify regional myocardial function but also detect subtle myocardial deformations, such as ESL or PSS, which are difficult to detect with conventional echocardiography10. Since the presence of myocardial ischemia at rest could not be indicated in each patient, it is unclear whether the ESL and PSS observed in this study reflect myocardial ischemia. However, compared with those before revascularization the peak systolic strain and TPSS were significantly improved, and TESL tended to be improved after revascularization. This recovery suggests that the decrease in peak systolic strain and the prolongation of TESL and TPSS were caused by ischemia.ESL and PSS can be observed in the normal myocardiumESL and TPSS in the apical anterior segment were significantly larger than the line of random chance, as shown in Table ESL or TPSS alone could not improve the diagnostic accuracy over that of the peak systolic strain in our cohort.In the detection of single-vessel LAD stenosis, although the AUCs of TESL and TPSS were independent determinants in the differentiation of the single-vessel group from the no stenosis group. Furthermore, the integrated analysis of the peak systolic strain, TESL, and TPSS improved the diagnostic accuracy in detecting single-vessel LAD stenosis. These results suggest that the integrated analysis of the three parameters is useful for better screening single-vessel LAD stenosis by using nonstress echocardiography.To date, it had not been fully ascertained whether ESL and PSS are determinants independent of the peak systolic strain in diagnosing CAD. In this study, we proved that TESL and TPSS tended to be prolonged, they were not determinants independent of the peak systolic strain, and the integrated analysis could not improve the diagnostic accuracy. As mentioned above, ESL and PSS occur through an imbalance of tension between the damaged and surrounding myocardium. In the multivessel group, LVEF was preserved, but the GLS was significantly smaller than that of the no stenosis group. Dysfunction in the myocardium perfused by RCA and/or LCX may affect the occurrence of ESL and PSS in the LAD territory.In multivessel LAD stenosis, although TESL and TPSS. Since it was set at 52– 84 frames/s in the present study, the time interval between frames was 11.9–19.2 ms. Although ESL and PSS shorter than this duration may not have been detectable, we think that the temporal resolution was enough to detect significant ESL and PSS.The frame rate strongly influences the assessment of TOur study has limitations that are described below. Although the integrated analysis of the three parameters improved the diagnostic accuracy, whether the regression function used in this study could be adapted to other similar cohorts was not assessed. The usefulness of the integrated analysis in detecting RCA and LCX stenosis must also be tested in further studies. In addition, the use of the regression function may be complicated in the clinical setting. A simpler parameter that reflects ESL and PSS should be devised.The apical anterior segment was selected as optimal for detecting LAD stenosis. We initially expected that the apical septal segment in the apical 4-chamber view would show similar diagnostic accuracy, but the diagnostic accuracy in the apical septal segment was lower than that in the apical anterior segment. Although the reason for this is unclear, some patients’ true apex may not have been able to be included due to the foreshortened 4-chamber view. Analysis in multiple segments should be done in future investigations.As mentioned above, the presence or absence of myocardial ischemia at rest was not confirmed for each patient. The integrated analysis demonstrated a high diagnostic accuracy in this study; however, false negatives can be present as long as nonstress echocardiography is performed. We therefore recommend that integrated analysis be used as a screening test for patients with suspected CAD but without visual wall motion abnormalities. In the apical anterior segment, a decrease in the peak systolic strain suggests LAD stenosis, including multivessel LAD stenosis, but if the peak systolic strain is normal, we should add an integrated analysis to increase the diagnostic accuracy in patients with single-vessel LAD stenosis.ESL, and TPSS significantly improved the diagnostic accuracy of single-vessel stenosis. In contrast, the incremental diagnostic value of TESL and TPSS could not be demonstrated in multivessel stenosis.ESL and PSS were determinants independent of the peak systolic strain in detecting single-vessel LAD stenosis by using nonstress speckle-tracking echocardiography, and compared with the peak systolic strain alone, the integrated analysis of the peak systolic strain, T


In conclusion, in NSTE-ACS, E/(e’×s’) is a powerful predictor of clinical outcome, particularly if it is accompanied by worsening after 6-weeks.It has been shown that the E/(e’×s’) index, which associates a marker of diastolic function  and a parameter that explores LV systolic performance , is a good predictor of outcome in acute anterior myocardial infarction. There are no studies that have investigated the prognostic value of E/(e’×s’) in a non-ST-segment elevated acute coronary syndrome (NSTE-ACS) population. Echocardiography was performed in 307 consecutive hospitalized patients with NSTE-ACS and succesful percutaneous coronary intervention, before discharge and six weeks after. The primary endpoint consisted of cardiac death or readmission due to re-infarction or heart failure. During the follow-up period (25.4 ± 3 months), cardiac events occurred in 106 patients (34.5%). Receiver operating characteristic (ROC) analysis identified E/(e’×s’) at discharge as the best independent predictor of composite outcome. The optimal cut-off value was 1.63 . By multivariate Cox regression analysis, E/(e’×s’) was the only independent predictor of cardiac events. Kaplan–Meier analysis identified that patients with an initial E/(e’×s’) > 1.63 that worsened after six weeks presented the worst prognosis regarding composite outcome, readmission, and cardiac death (all  Patients admitted to hospital because of an acute coronary syndrome (ACS) constitute a heterogeneous population with a varying risk of future cardiac events ,2. Non-SMany parameters for the indirect assessment of LV filling pressures have been used to assess cardiac outcomes in patients with coronary artery disease. Recent studies have shown tissue Doppler imaging (TDI) to be a strong predictor of adverse outcomes in several cardiac diseases. A significant decrease of systolic mitral annulus velocity (s’) and/or early diastolic mitral annulus velocity (e’) has been observed in patients with ischemic heart disease, even if cut-off values for peak systolic and diastolic velocities which detect significant coronary artery stenosis are still unclear ,6. SeverThe idea of a complex marker that incorporates several tissue Doppler parameters was used by several study teams. Our group proposed a new TDI index, E/(e’×s’), that associates a marker of diastolic function (E/e’) and a parameter that explores LV systolic performance (s’). We demonstrated the utility of this index to assess the LV filling pressure in a heterogeneous population of cardiac patients, regardless of LVEF  and to iThe Cardiology Department of Timisoara Institute of Cardiovascular Diseases is an invasive hub for 15 non-invasive cardiology departments. In the period November 2017 to January 2019, 2758 patients were admitted to the department for percutaneous coronary intervention (PCI). These patients were all included in a clinical registry. We analyzed prospectively 439 consecutive patients with NSTE-ACS and successful PCI, in sinus rhythm, hospitalized in our clinic. Successful PCI was defined as residual stenosis ≤20%; non-culprit intervention was performed during the same hospitalization. Patients with inadequate echocardiographic images, previous myocardial infarction, open-chest surgery, cardiac pacemaker/defibrillator, significant valvular heart disease, renal failure (serum creatinine >1.3 mg/dL), and non-cardiac disease with a life expectancy <1 year were excluded from the study group. The remaining 307 patients formed our study population. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Ethics Committee of Institute of Cardiovascular Diseases Timisoara (protocol code 1658 and 28 March 2014). Informed consent was obtained from all participants.The following clinical variables were recorded and included in the prognostic model: age, sex, mean arterial pressures, heart rate, body mass index, peak high sensitivity cardiac troponin I level (hs-cTnI), and N-terminal pro-brain natriuretic peptide (NTproBNP) levels. Prescription of the main therapeutic classes was also recorded.For study purposes, five cardiovascular risk factors were considered as follows: hypertension , cardiovascular disease heredity, smoking , diabetes mellitus (fasting glycemia >126 mg/dL or in drug treatment), and hypercholesterolemia (>200 mg/dL or in drug treatment).Echocardiography was performed after PCI, at hospital discharge, using a Vivid 9 General Electric, Milwaukee, WI system, USA. Left atrial volume (LAV) and indexed LAV to the body surface area (LAVI) were determined according to current guidelines . LVEF waThe TDI program was set in pulsed-wave Doppler mode. In the apical four-chamber view, a 4–5 mm sample volume was positioned sequentially at the lateral and septal corner of the mitral annulus . Peak e’All measurements were performed by an experienced echocardiographer. The inter- and intra-observer variability for E/e’, s’ and E/(e’×s’) were examined. Measurements were performed in a group of 30 randomly selected subjects by one observer at two separate times and by two investigators who were unaware of the other’s measurements and of the study time point.Patients were followed for ≥24 months. The primary event consisted of cardiac death or hospital readmission for HF or re-infarction. Cardiac death was defined as either a death directly related to cardiac disease, mainly congestive HF, re-infarction, or sudden death. The follow-up information was obtained from electronic medical files or by telephone contact with the patients or their family members.t-test  or Mann–Whitney U test . Proportions were compared using χ2 test and Fischer’s exact test. Receiver operating characteristic (ROC) curves for predicting cardiac events were determined for different parameters, and area under the ROC curves (AUC) were compared. Patients who died of non-cardiac causes were censored at the time of death.Data were expressed as mean ± standard deviation (SD) for continuous variables and as proportions for categorical variables. Continuous variables were compared between groups using an unpaired p-value < 0.05 was considered significant. Intra-observer variability and inter-observer variability for E/e’, s’ and E/(e’×s’) were measured by Bland–Altman analysis, and intraclass correlation coefficients. We used STATA Statistics/Data analysis, MP 12.0  as statistical software.Uni- and multivariable Cox regression models were created to correlate clinical, biological, and echocardiographic findings to the primary endpoint. For multivariable Cox regressions, three models with an incremental number of confounders were constructed. Model 1 included either E/(e’×s’), s’, or E/e’ and the following confounders: age, gender, mean blood pressure, heart rate, body mass index, prior coronary artery disease, family history of cardiovascular disease, diabetes mellitus, current smoker, hypercholesterolemia, and hypertension. In Model 2, we also included variables obtained from the laboratory , coronary angiography , and ACS category. Model 3 additionally included all significant echocardiographic parameters . Harrell’s c-statistics was calculated from univariable Cox regression for all measures included in the multivariable Cox regression to compare the predictive potential of baseline predictors. The cardiac event-free survival rates were calculated using the Kaplan–Meier analysis, and the event rates were compared using the log-rank test. A In the period of November 2017 to January 2019, 307 consecutive patients hospitalized for NSTE-ACS who underwent successful PCI were included in this prospective study. All patients received standard management according to the institutional recommendation. The mean age of our study sample was 61 ± 12 years and 70.7% were males (217 patients). In this study, no patient was lost to follow-up. During the follow-up period (25.4 ± 3 months), cardiac events occurred in 106 patients (34.5%). The first cardiac event was represented by cardiac death in seven patients (2.28%) and readmission in 99 patients (32.2%). Of our patients, 72 (23.4%) were hospitalized for heart failure, and 17 (5.5%) had a non-fatal re-infarction. During the follow-up, cardiac death occurred in 22 patients (7.16%).p < 0.001).Patients’ baseline characteristics are presented in p < 0.001). The baseline s’ and E/e’ ratio were also significant for predicting composite outcomes . A statistical comparison of the ROC curves demonstrates significant differences between E/(e’×s’) and s’ (p = 0.009) and between E/(e’×s’) and E/e’ (p = 0.003). All the other analyzed echocardiographic parameters presented a lower AUC. The optimal cut-off value for E/(e’×s’) at discharge to predict the composite outcome was 1.63 (74% sensitivity and 67% specificity).p < 0.05) are shown in (p = 0.007).The echocardiographic variables that predicted cardiac events on univariate Cox regression analysis , the E/(e’×s’) ratio remained the only independently parameter associated with the composite outcomes and hospital readmission, respectively. Other echocardiographic measures were not associated with cardiac events and readmission for HF and/or re-infarction . HoweverModel 1 is adjusted for age, gender, mean blood pressure, heart rate, body mass index, prior coronary artery disease, family history of cardiovascular disease, diabetes mellitus, current smoker, hypercholesterolemia, and hypertension.Model 2 is adjusted for previous mentioned variables in Model 1 as well as laboratory data , coronary angiography , and acute coronary syndrome category.Model 3 is adjusted for all previous mentioned variables in Models 1 and 2, additionally left ventricular ejection fraction, systolic pulmonary artery pressure, left atrial volume, indexed left atrial volume, E velocity, E/A ratio, and e’ velocity.p = 0.027), and along with E/e’ provided the highest c-statistics among all baseline predictors (0.721 for E/(e’×s’) vs. 0.679 for E/e’, p = 0.009). Adding E/(e’×s’) to all the variables included in Model 1 resulted in a significant increase in the c-statistics than Model 1 alone (Model 1 with E/(e’×s’): 0.730 (0.69–0.77) vs. 0.689 (0.65–0.72), p = 0.034). Model 2 significantly improved when adding E/(e’×s’) ratio: 0.741 (0.70–0.78) with E/(e’×s’) vs. 0.722 (0.68–0.76) without E/(e’×s’), p = 0.041. Adding E/(e’×s’) to the variables included in Model 3 displayed a significant increase in the c-statistics when compared to Model 3 alone (0.761 (0.72–0.80) vs. 0.743 (0.70–0.77), p = 0.047). When E/(e’×s’) was already included in the models, we identified no significant changes in Harrell’s c-statistics by adding all the analyzed echocardiographic parameters.Harrell c-statistics revealed that the E/(e’×s’) index contributed with a higher c-statistics compared with s’ velocity . The subgroup of patients with an initial E/(e’×s’) ratio >1.63 and worsening after six weeks presented the worst prognosis regarding composite outcome  ratio in 140 patients (45.6%). Of these patients, 63 (20.5%) presented the initial value of E/(e’×s’) greater than 1.63. However, as shown in  outcome a, hospit outcome b, and ca outcome c, respecIn 30 patients with ischemic heart disease, Bland–Altman analysis demonstrated the intra- and inter-observer agreements were good for E/(e’×s’), E/e’, and s’ measurements. The intraclass correlation coefficient for inter-observer and intra-observer variability was 0.90 and 0.89 for E/(e’×s’); 0.92 and 0.90 for E/e’; and 0.93 and 0.92 for s’, respectively.To the best of our knowledge, this is the first study investigating the value of E/(e’×s’) ratio to predict cardiac events  in patients with NSTE-ACS who underwent successful PCI. E/(e’×s’) provided superior prognostic information when added to all other analyzed predictors in the current population. Patients with an initial E/(e’×s’) > 1.63 and worsening after six weeks presented the worst prognosis regarding composite outcome, hospital readmission, and cardiac death.The clinical importance of predicting prognosis in patients with NSTE-ACS has been increasing. In patients with NSTE-ACS, the rapid recognition of high-risk patients who may benefit from an intensified treatment strategy, risk stratification improves effectiveness of care to those in highest need ,4,12. InPulsed TDI is widely used and validated in the literature to analyze cardiac function, and it is characterized by easy accessibility and strong reproducibility. TDI has proven incremental prognostic value with respect to routine clinical, laboratory, and imaging information. This new technique does not require tracing of endocardial contours, unlike LV volumes and LVEF. Wang et al. demonstrated in a heterogeneous population of cardiac patients a better prognostic value for both e’ and E/e’ than for wall motion score index and LVEF . An incrA significant decrease of e’ and s’ velocities has been observed in patients with myocardial ischemia, even if cut-off values for maximum systolic and diastolic velocities that detect significant coronary lesion are still unclear ,6,10. InLV diastolic dysfunction is usually the result of altered LV relaxation with or without reduced restoring forces (and early diastolic suction), and increased LV chamber stiffness, which increases LV filling pressures. Conceptually, it is very difficult to separate relaxation from contraction, and it can be considered together as part of a continuous cycle. The energy generated during systole is stored in myocardial collagen fibers, and following relaxation, the ventricle uncoils, creating LV suction. There seems to be a relation of proportionality between decline in contractile function and reduction in recoil, with parallel changes in the extracellular matrix ,27.Our group proposed several years ago a new TDI index, E/(e’×s’) that associates a marker of diastolic function (E/e’) and a parameter that explores LV systolic performance (s’). Recent studies have shown E/(e’×s’) to be a strong predictor of adverse outcomes in several cardiac diseases. We demonstrated the utility of this index to assess the LV filling pressure in a heterogeneous population of cardiac patients, regardless of LVEF  and to iIn patients with acute myocardial infarction and severe LV systolic dysfunction, current guidelines recommend to repeat echocardiography 6–12 weeks after initial hospitalization and to measure for systolic function evaluation only LVEF, but not s’ wave ,18. We rClinical studies have clearly demonstrated that NT-proBNP and troponin levels are increased after episodes of ischemia ,28,30. EOur results should be considered in the context of several limitations. The most important limitation of this study is its small sample size. Therefore, larger studies are needed to validate our results. The use of standard echocardiographic assessment instead of more sophisticated methods  could be considered both a limitation and a strength of the study. The limitation is that strain imaging has proved to be more sensitive for detecting subclinical abnormalities of both systolic and diastolic function. The strength of our parameter is its ease of use, thanks to its availability in most of the modern echo machines, making it readily applicable for the bedside assessment of patients. We limited the analysis at two sites , and we did not examine anterior and posterior velocities that might have provided additional information. We are conscious that the E/(e’×s’) ratio is a global index of cardiac function that unmasks a precocious systolic and diastolic myocardial suffering, and it cannot provide regional information about perfusion. The study center functioned as a tertiary invasive center, and therefore, the study population may not reflect a general population of patients with NSTE-ACS.In summary, our findings indicate that in patients with NSTE-ACS who underwent successful PCI, E/(E’×S’) is an important independent prognostic index of cardiac events . E/(e’×s’) provided superior prognostic information when added to other clinical, laboratory, and echocardiographic predictors. Patients with an initial E/(e’×s’) > 1.63 that worsened after six weeks presented the worst prognosis regarding composite outcome, hospital readmission, and cardiac death.