Coronary computed tomography angiography (CCTA) is widely used as a first-line noninvasive modality that frequently exhibits no or nonobstructive coronary artery disease (CAD) in clinical practice, along with abnormal left ventricular (LV) geometry on echocardiography. However, the combined prognostic value of these findings has not been well elucidated. Therefore, we aimed to evaluate the prognostic implications of abnormal LV geometry in individuals with no or nonobstructive CAD.2 in women and > 115 g/m2 in men, and/or relative wall thickness > 0.42. The primary outcome was all-cause mortality.A total of 5806 subjects with no CAD or nonobstructive CAD  on CCTA were included in the study. The major exclusion criteria were structural heart disease and a history of myocardial infarction or coronary revascularization. Abnormal LV geometry on echocardiography was defined as LV mass index > 95 g/mp < 0.001). After adjustment for confounding factors, abnormal LV geometry was an independent predictor of all-cause mortality . Moreover, abnormal LV geometry was significantly worse in survival when classified as those with no CAD  and nonobstructive CAD .A total of 5803 subjects without significant obstructive CAD . Of them, 4045 (69.7%) subjects had normal LV geometry and 1758 (30.3%) had abnormal LV geometry respectively. During a mean follow-up of 6.2 ± 1.48 years, 84 (1.44%) subjects died in the study population. Of these, 56 subjects were from the normal LV geometry group (1.24%) and 28 were from the abnormal LV geometry group (2.32%). Subjects with abnormal LV geometry had significantly worse survival rates (log-rank, Abnormal LV geometry portends a worse prognosis in subjects with no or nonobstructive CAD. These findings suggest that LV geometry assessment can help improve the stratification of individuals with these CCTA findings.The online version contains supplementary material available at 10.1186/s12872-021-02005-6. The emergence of coronary computed tomography angiography (CCTA) as a noninvasive imaging modality has made it possible to diagnose coronary artery disease (CAD) with excellent sensitivity (90–95%) and negative predictive value (93%–98%) . In addiIn previous studies, the prognostic importance of nonobstructive CAD has been substantiated already , 3. IndeLeft ventricular (LV) hypertrophy is a consequence of cardiac geometric adaptation in response to systemic hemodynamics and ventricular load . AbnormaThis was an observational retrospective multicenter cohort study. We reviewed 12,956 consecutive subjects who underwent CCTA and echocardiography between 2002 and 2011 at the Seoul National University Hospital, Seoul National University Bundang Hospital, and Seoul National University Hospital Gangnam Center. We excluded individuals with significant LV systolic dysfunction (defined as ejection fraction < 40%), hypertrophic or infiltrative cardiomyopathy, severe valvular heart disease, and those with a history of previous myocardial infarction, coronary revascularization, or cardiac surgery.A total of 5803 subjects were included in the final analysis, who had available echocardiographic data on the left ventricular mass index (LVMI) and relative wall thickness (RWT) and had no significant coronary artery stenosis  on CCTA , and was performed in accordance with the Declaration of Helsinki. Written informed consent was waived owing to the retrospective and observational nature of this study.Electrocardiographic-gated CCTA images were acquired using a 64-slice multidetector scanner . Before performing the scan, sublingual nitroglycerine (0.3 mg) was administered to provide transient coronary dilatation, and metoprolol (50 mg) was administered to subjects presenting with a heart rate of more than 60 beats per minute. The CCTA results were graded as none , nonobstructive , and obstructive  respectively based on the severity of narrowing in any of the major epicardial coronary arteries.3 − LVEDD3} + 0.6LV mass = 0.8 × 1.04 × {[LV end-diastolic dimension (LVEDD) + interventricular septal wall thickness + LV posterior wall thickness]LV mass index = LV mass/body surface areaAll patients underwent comprehensive two-dimensional echocardiography within 3 months of initial CCTA. Hypertrophic alteration of the LV structure was quantified based on LVMI and RWT by echocardiography . LVMI wa2 in women and > 115 g/m2 in men, and the cutoff for abnormal RWT was > 0.42, in both women and men [RWT was calculated as two times the posterior wall thickness divided by the LV diastolic diameter. Increased LVMI was defined as LVMI > 95 g/m and men . Normal Using electronic medical records, we obtained laboratory information, including serum hemoglobin, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, fasting blood glucose, creatinine, and estimated glomerular filtration rate (eGFR) accordingly for all the patients.The primary outcome was all-cause mortality. Mortality data were obtained and verified via a centralized database of death records from the Korean Ministry of Security and Public Administration.t-test and Mann–Whitney U test for continuous variables according to the data distribution and Chi-square test for categorical variables for the comparison between normal and abnormal LV geometry groups. Further, a comparison of mean values between multiple groups was performed using one-way analysis of variance, and Kruskal–Wallis tests were used for continuous variables according to the data distribution, and the chi-squared test was performed for categorical variables, followed by a post-hoc comparison. Event-free survival analysis was performed using the Kaplan–Meier method and compared using the log-rank test. To investigate the association between LV geometry and all-cause mortality, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using univariate and multivariate Cox proportional regression analyses. Multivariate analysis adjusting for statistically different baseline variables  was performed to provide independent effect estimates for abnormal LV geometry on the primary outcome.Descriptive data were reported as mean ± standard deviation for continuous variables and as numbers and percentages for categorical variables. Shapiro–Wilk Normality test was performed to determine the distribution of data. We performed the Student’s p value of < 0.05, was considered statistically significant. All statistical analyses were performed using SPSS version 23  and R programming version 3.2.4 .A two-tailed p < 0.001), and this was observed more frequently in men . There was no significant difference in the baseline laboratory results between the two groups, except for the decreased hemoglobin  and eGFR levels . With regard to echocardiographic parameters, the abnormal LV geometry group had increased LV wall thickness and chamber size, but also larger left atrial size , higher pulmonary artery systolic pressure , and a higher ratio of peak early transmitral inflow velocity to early diastolic velocity of the mitral annulus (E/e’)  than the normal LV geometry group. The baseline characteristics according to the four LV geometric patterns are shown in Additional file A total of 5803 subjects without significant obstructive CAD consisted of 3884 (66.9%) men with a mean age of 56.6 ± 8.87 years Table . Of themp = 0.040) (Table p < 0.001)  subjects died in the study population. Of these, 56 subjects were from the normal LV geometry group (1.24%) and 28 were from the abnormal LV geometry group (2.32%). After adjustment for confounding factors, abnormal LV geometry was independently associated with an increased risk of all-cause mortality  and those with nonobstructive CAD  had a higher risk of all-cause mortality (Table p = 0.024) and non-obstructive CAD   (Table We classified subjects into four groups according to the joint categories of LV geometry and CAD: 1) normal LV geometry with no CAD, 2) normal LV geometry with nonobstructive CAD, 3) abnormal LV geometry with no CAD, and 4) abnormal LV geometry with nonobstructive CAD. Compared to normal LV geometry without CAD, abnormal LV geometry without CAD  , followed by concentric hypertrophy , and concentric remodeling . After adjustment, the risk of all-cause mortality was significantly increased only in subjects with eccentric hypertrophy  .On repetition of the multivariate Cox proportional regression analysis after further adjusting for medications (beta-blockers and antidiabetic agents) that were significantly associated with all-cause mortality in the univariate analysis, it was found that abnormal LV geometry remained an independent predictor for the primary outcome  in this cohort with low risk for CAD confirmed by CCTA, echocardiography-determined abnormal LV geometry was associated with an increased risk of all-cause mortality; (2) the prognostic impact of abnormal LV geometry was consistent in both individuals with no CAD and nonobstructive CAD, and 3) eccentric hypertrophy carried the greatest risk of all-cause mortality among different types of abnormal LV geometry.The presence, extent, and severity of CAD confirmed by CCTA have been well recognized as a strong predictor of adverse outcomes, including death, myocardial infarction, and late revascularization , 16. In However, the prevalence of nonobstructive CAD is substantial, and its prognosis can vary among individual patients, making it challenging to apply preventive or therapeutic measures to patients with nonobstructive CAD in general. Specifically, in patients with stable angina, the prevalence of nonobstructive CAD was 67%, with 73% of patients referred to CCTA and 49% among those with invasive coronary angiography . Of noteIn the present study, we demonstrated that abnormal LV geometry determined by echocardiography, which is one of the most frequently used imaging tests in the field of cardiology, was associated with all-cause mortality in individuals with no or nonobstructive CAD confirmed by CCTA. Several lines of evidence support the concept that LV geometry is an imaging marker integrating long-term exposure to both hemodynamic abnormalities (pressure and/or volume overload) and non-hemodynamic factors. Specifically, LV geometry is considered to reflect the severity and chronicity of cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidemia, and obesity –27, suggGiven that abnormal LV geometry is a time-integrated indicator of several risk factors that are active in promoting the progression of coronary atherosclerosis and consequently leading to increased adverse clinical outcomes , it can The most compelling advantage of our study is that it is a well-constructed, large imaging database study containing both CCTA and echocardiographic images from all participants. Furthermore, our study has an advantage over prior research owing to the inclusion of many Asians in whom the association of LV geometry with prognosis has not been extensively investigated. Specifically, in the landmark Framingham Heart Study (FHS) by Levy et al. , particiHowever, several limitations should be considered when interpreting our findings. First, this was a retrospective observational study with inherent limitations, such as unmeasured confounders. Although we adjusted for a set of conventional cardiovascular disease risk factors, residual confounding cannot be completely excluded. Second, the exact clinical indications for CCTA scans were not documented, although most individuals underwent CCTA for the identification of CAD, owing to the presence of chest pain, dyspnea, and cardiovascular risk factors. However, since individuals with obstructive CAD confirmed by CCTA were excluded from our study, the difference in the clinical indications for CCTA scans might not substantially affect the results of this study. Third, since we focused on all-cause mortality as the primary outcome, data on specific causes of death were not available. In observational studies, all-cause mortality is generally considered a more robust and unbiased outcome than disease-specific mortality. However, data on the specific cause of death might have strengthened the association between LV geometry and cardiovascular prognosis in subjects with no or nonobstructive CAD. Fourth, there remains a possibility that certain conditions affecting both LV structure and mortality were not fully ruled out. To minimize this concern, we excluded individuals with cardiomyopathy and significant valvular heart disease from the analyses. Fifth, as Korean individuals were exclusively included in the present study, it is uncertain whether our findings can be generalized to other populations. Lastly, since there are no data on noninvasive stress testing, we could not entirely exclude the possibility of myocardial ischemia, which is clearly a confounding factor related to mortality.Abnormal LV geometry carried a worse prognosis than normal LV geometry in individuals with no or nonobstructive CAD confirmed by CCTA. These findings suggest that the use of echocardiography for LV geometry assessment has the potential to be a clinically useful and practical approach for risk stratification in this population.Additional file 1: Supplementary tables and figures.


Multivariate regression showed that GAS , GLS-3D , and GCS-3D  remained independent predictors of MACE . However, post hoc power analysis indicated adequate sample size (power of 80%) only for GAS and GCS-3D for the ROC curve analysis and for GAS, GCS-3D, and GRS-3D for the log-rank test. Conclusion: Patients with AMI might benefit from early risk stratification with the aid of 3D-STE measurements, particularly GAS and GCS-3D, but larger studies are necessary to determine the optimal cut-off values to predict MACE.Background: Three-dimensional speckle-tracking echocardiography (3D-STE) allows simultaneous assessment of multidirectional components of strain. However, there are few data on its usefulness to predict prognosis in patients with acute myocardial infarction (AMI). The objective of our pilot study was to evaluate the prognostic value of four different 3D-STE parameters , global circumferential strain (GCS-3D), global radial strain (GRS-3D), and global area strain (GAS)) in AMI, after successful revascularization by primary PCI. Methods: We enrolled 94 AMI patients  who underwent coronary angiography. All patients had been 3D-STE assessed and followed-up for 1 year for the occurrence of MACE. Results: A total of 25 MACE were recorded over follow-up. Cut-off values of −17% for GAS (HR = 3.1, 95% CI: 1.39–6.92,  The increased use of reperfusion strategies consisting of primary percutaneous coronary intervention (PCI) and antithrombotic therapy has improved survival in patients with acute myocardial infarction (AMI). However, major adverse cardiovascular events (MACE) are an important cause of morbidity and mortality in patients undergoing revascularization. Left ventricular ejection fraction (LVEF) has been the conventional parameter most used in the prediction of long-term post-AMI outcomes in these patients and has been incorporated into current guidelines ,2. HowevTwo-dimensional speckle-tracking echocardiography (2D-STE) imaging overcomes geometric assumptions that might limit the use of standard LVEF and provides a detailed analysis of myocardial deformation, leading therefore to a better understanding of cardiac mechanics ,6. Both Three-dimensional STE (3D-STE) is a recently developed echocardiographic technique allowing full 3D volume acquisitions of the LV, with simultaneous assessment of multidirectional components of strain and a single post-processing algorithm . First, Recently, there have been a few studies reporting the predictive value of 3D-STE in patients with AMI ,12,13,14The objective of our pilot study was to evaluate the role of four different 3D-STE parameters , global circumferential strain (GCS-3D), global radial strain (GRS-3D), and global area strain (GAS)) in the prediction of clinical outcomes after successful revascularization of AMI by primary PCI.2) were excluded. All remaining patients underwent coronary angiography and were successfully revascularized by primary PCI. PCI was performed in patients with multivessel coronary artery disease (CAD) in later sessions. Echocardiography using traditional and 3D strain parameters was performed within the first 48 h after coronary angiography.This study was conducted according to the guidelines of the Declaration of Helsinki and approved by Ethics Committee of “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca under number 250 on 13 July 2020. We prospectively enrolled 110 patients with AMI, which were admitted in our Cardiology Department from July to August 2019. The diagnosis and treatment of AMI were performed in compliance with the European Guidelines of ST- and non-ST-elevation myocardial infarction (STEMI and NSTEMI) [The echocardiography was performed on a Vivid E95 scanner  by using a real-time 3D phased-array transducer (4V-D) and analysed offline using EchoPac BT13 software (GE Vingmed Ultrasound). The LV end-diastolic volume (EDV) and end-systolic volume (ESV) were measured using a 2D matrix array probe (M5S) and LVEF was calculated using the modified Simpson’s biplane formula according to the current recommendations. Diastolic dysfunction parameters  were also measured. In this pilot study, the 4V-D probe was used to record a 3D full volume data set of the LV over four cardiac cycles at a frame rate of 25 to 30 frames/second. The acquired 3D datasets were transferred to a workstation for offline analysis. 3D-STE parameters were calculated using the 4D LV quantification function of the system (4D-autoLVQ). After the three apical long axis and short axis views alignment in order to minimize foreshortening, topographic markers were manually placed at the level of the mitral annulus and LV apex. The contour for the end-diastolic and end-systolic borders of the LV was automatically delineated and manual adjustment was performed where necessary; consequently, the automatic alignment of endocardial and epicardial contours was followed by manual adjustment, confirming the myocardial wall, where necessary, in order for all segments to be included in the strain analysis. The software automatically calculated mean peak systolic strain values before the end-systolic frame for GLS-3D, GCS-3D, GRS-3D, and GAS, and the LV mass. Tracked areas, bull’s eye diagrams, and tracking curves for each of the strain components were saved .As to evaluate the reproducibility of the 3D-STE measurements, we have randomly selected 20 patients for whom measurements were repeated by a second operator, who was blinded to the results of the first operator. We calculated the inter-observer correlation coefficients for GLS-3D, GCS-3D, GRS-3D, and GAS.The patients were evaluated at 1 year after first admission, by telephone or hospital record registration, in order to assess clinical symptoms. Clinical endpoints (MACE) were defined as heart failure (HF) requiring hospitalization, recurrent MI, repeat revascularization, and cardiac death. Hospitalization and death by non-cardiac cause were not considered events.t-tests or Mann–Whitney U test according to data distribution of continuous data and chi2 test for categorical data. As there are no currently established cut-off values for 3D strain parameters, as to determine the role in risk stratification for 1-year MACE of each parameter, we used the cut-off values derived from Receiver Operating Characteristic (ROC) curves. We performed the ROC analysis with a bootstrap Youden index confidence interval and we obtained the 95% CI for the Youden index and its optimal cut-point value to provide highest sensitivity and specificity in the prediction of MACE for each strain parameter. Survival at 1 year after AMI was determined by Kaplan–Meier analysis for each 3D-STE parameter using each cut-off value. Considering the number of subjects in our pilot study , a maximum of 2 variables were included in the multivariate analysis. Hazard ratios (HR) and confidence intervals (CI) of parameters related to remodelling were estimated by Cox regression analysis. A post hoc power analysis was conducted based on the AUC for each cut-off value obtained for the 3D-STE parameters. Power analysis for survival rates (log rank test) between formed groups according to the cut-off values for each strain parameter was also performed based on the survival rate in each group, using an alpha of 0.05 and power of 80%.Variables were expressed as the mean ± SD, median (IQR) or frequencies according to the type and distribution of the data. Normality was tested using the Kolmogorov–Smirnov test. We categorized the patients according to MACE presence or absence. Baseline parameters were compared using http://www.medcalc.org; 2020 (accessed on 12 March 2021)). A p value of <0.05 was considered significant.Statistical analysis was performed using MedCalc Statistical Software 19.6.1 , 3 patients were lost on follow-up, and 6 others were excluded due to death by non-cardiac cause.Therefore, 94 patients were included in the final analysis of this pilot study .n = 25, 27%) and without MACE  are summarized in p = 0.009) and multi-vessel CAD (p = 0.017) at admission. However, there was no difference regarding the infarct-related vessel between patients with or without MACE. Age and the presence of different cardiovascular risk factors were comparable between the two groups.At the 1-year follow-up there were 25 MACE reported: 11 cases of cardiac death, 6 cases of HF requiring hospitalization, 3 cases with recurrent MI, and 5 cases requiring repeated revascularization. Baseline characteristics of patients with MACE , but there was no difference considering diastolic dysfunction parameters and LV mass among groups. All 3D strain parameters  were significantly more impaired in MACE+ group, with the highest statistic significance for GCS-3D (p = 0.009) and GAS (p = 0.006), as shown in Considering echocardiographic parameters, patients in MACE+ group showed significantly increased LV volumes and reduced LVEF , GCS-3D > −12% , GAS > −17% , and GRS-3D ≤ 25% , as shown in Kaplan–Meier curves for event-free survival showed a significantly higher rate of MACE in patients with GLS-3D > −10% , GLS-3D , and GCS-3D  remained independent predictors of MACE, as seen in The post hoc power analysis for ROC curve analysis demonstrated that a total sample of 84 patients for GAS, 90 for GCS-3D, 120 for GLS-3D, and 228 for GRS-3D was required to achieve a power of 80%, showing an enough powered sample size only for GAS and GCS-3D. In the case of survival analysis, a total sample of 59 patients for GAS, 75 for GCS-3D, 112 for GLS-3D, and 75 for GRS-3D was required, showing insufficiently powered sample size for GLS-3D.Interobserver correlation coefficients for GLS-3D, GCS-3D, GRS-3D, and GAS were of 0.89, 0.92, 0.87, and 0.91, respectively. The observed variability was low, showing a good agreement between measurements in all 3D-STE parameters.Early estimation of the prognosis after AMI is important in daily clinical scenarios. As shown in other studies, although the entire spectrum of acute coronary syndromes (ACS) is a characteristic of the elderly population, over the past years there has been an increase in their incidence in young people . LV systWhile several studies demonstrated the utility of 3D strain in various clinical scenarios ,17,18, tWe emphasize the need for assessment of multiple strain components in order to determine the impact of 3D-STE on MACE in patients with AMI, where geometric assumptions are required, and ischemia might involve multiple myocardial layers. The goal of our study was to determine the prognostic value of 3D-STE parameters in the prediction of clinical outcomes of patients with AMI undergoing successful PCI and we demonstrated that GLS-3D, GCS-3D, GAS, and GRS-3D were significantly associated with a 3-fold increase in the risk of MACE. However, among all 3D strain parameters, GAS, GLS-3D, and GCS-3D were the only independently associated with increased risk of MACE. GAS reflects the shortening of both longitudinal and circumferential layers from end-diastole at end-systole . TherefoAs concerning the accuracy of 3-STE parameters, different studies reveal variability of the obtained values and their accuracy ,22,23,24Although previous research showed that all 3D-STE parameters are predictors of MACE ,14, GAS Other studies proposed GLS as a predictor of LV remodelling and long-term MACE ,24,25,26Even though the cut-off values for strain parameters were relatively low, there is a variability in the STE values reported in different studies. However, with the exception of Ivahashi et al. , which, As related to other echocardiographic parameters, we found no difference in diastolic dysfunction parameters in patients with MACE, and these results are similar to those of Ivahashi et al., who also found an association between MACE and 3D-STE, but not with E/e’ . This miRegarding clinical factors, although multivariate analysis did not demonstrate an independent association with MACE, we identified that the number of affected vessels and eGFR were the only clinical variables to be associated with MACE on the univariate regression. This associations have been documented by a previous study revealing that triple vessel disease is associated with a 4-fold increase in MACE, and eGFR is also a predictor of events . HoweverThe feasibility of 3D-STE is influenced by several factors. One of the major concerns of 3D-STE is the balance between temporal and spatial resolution, as higher frame rates may lead to some compromise in spatial resolution. Therefore, the accuracy of 3D-STE depends on optimal image quality, limiting the number of patients in whom 3D-STE is feasible in clinical practice. A stable image is important in order to obtain high temporal and spatial resolution and to avoid stitch artefacts. Thus, the acquisition is vulnerable to motion artefacts if the patient is unable to follow breath hold instructions. These limitations might occur in the setting of AMI, where temporal resolution and breath holding are more challenging ,33. ReprOur study has several limitations. It was a single-centre study and included a small population. While the post hoc power analysis indicated adequate sample size for the determination of the cut-off value to predict MACE in the case of GAS and GCS-3D and also for the survival analysis in the case of GRS-3D, more patients would be needed for a sufficiently powered sample size in the case of GLS-3D and GRS-3D. Follow-up duration was relatively short and all measurements were performed in the acute setting, with no follow-up data of echocardiographic measurements. At the same time, as it is well-known that the short- and long-term survival rates are different in STEMI and NSTEMI, the impact of 3D-STE on MACE according to the type of AMI might be the subject of a future, larger study. In addition, compared to 3D strain, the prognostic value of 2D-STE was already demonstrated by multiple studies, raising the question whether 3D-STE might bring additional benefits to 2D deformation parameters. Therefore, further studies should use longer follow-up periods with larger number of patients and should compare the accuracy of 3D-STE and 2D-STE in the prediction of MACE.Our study demonstrated that 3D strain parameters, particularly GAS and GCS-3D, are associated to an increased risk of 1-year MACE after AMI managed by primary PCI. Thus, with the aid of baseline echocardiographic examinations, patients might benefit from early risk stratification.


Managing HIV infection as a chronic condition includes encouraging adoption of healthy behaviors and promotion of physical activity (PA). However, people living with HIV (PLH) are often under social and programmatic vulnerability that may compromise behavior change. Understanding such barriers is crucial for successful incorporation of PA in their comprehensive care.In this study, we describe PA, energy intake from diet, and anthropometry of a cohort of PLH starting antiretroviral therapy (ART) at a Brazilian reference clinic, report how PA was addressed in routine care and investigate association between PA, energy intake and psychosocial constructs that may facilitate PA . Among 61 PLH  anthropometry was normal, but 47.5% reported PA below recommendations. Despite presenting high social support scores, family encouragement for PA was low, and self-efficacy classified as medium. Chart reviews yielded infrequent reports concerning PA. After adjusting for gender and age, we found a negative association between energy intake from diet and self-efficacy, but none between PA and energy intake or between PA and psychosocial constructs.We conclude that patients in our cohort were insufficiently active when starting ART, and that PA was poorly addressed by caretakers in routine HIV care. Nevertheless, social support and self-efficacy scores suggest potential for behavioral change. Caregivers should therefore start considering patients’ vulnerabilities and establishing strategies to help them overcome barriers to incorporate PA in their comprehensive care effectively. Combined antiretroviral therapy has remarkably reduced AIDS-related morbidity and mortality and enabled HIV infection to be managed as a chronic disease –3. HowevPromotion of healthy lifestyles have thus become a priority for PLH under antiretroviral therapy (ART) as part of more comprehensive care approaches that include health promotion and engagement in physical activity (PA) , 6. In fBrazil is known to have the largest number of PLH in Latin America and for playing a leading role in establishing public policies for HIV prevention and care within the national health system. Currently, ART is provided free of charge for over 700,000 PLH by the public health sector, following the “test-and-treat strategy”. Although recommendations for promotion of PA among PLH have been incorporated in national guidelines , 15, litOur study aimed to provide evidence to help specialized HIV care centers recognize patients’ vulnerabilities and particular needs to overcome barriers and engage in PA as soon as they are admitted to services and start ART. Using several assessment tools, we describe current PA patterns, energy intake from diet and physical assessment in a cohort of PLH who start ART in a university HIV outpatient clinic in São Paulo. We also evaluate psychosocial constructs that have been recognized as capable of facilitating engagement in PA  and explore how caregivers are addressing PA in routine patient care. Associations between current PA and other variables of interest  were also sought after.A cross-sectional study was conducted at the HIV outpatient reference clinic affiliated to the Division of Infectious Diseases, Hospital das Clinicas, School of Medicine, University of São Paulo, where 3,200 PLH are currently under multidisciplinary clinical follow-up.From June 2014 to May 2016 and from December 2017 to March 2018 we recruited PLH aged 18 to 59 years old who had started ART at the clinic for no longer than 4 months. The first recruitment period coincided with patient selection for a randomized pragmatic trial that investigated the impact of a multicomponent PA program to prevent body changes and metabolic disturbances associated with ART [We invited eligible subjects to take part in the study while waiting for a medical consultation at the clinic. After consenting, they were interviewed by a trained member of the research team in search of sociodemographic data and information about smoking and alcohol use. Additionally, the following data collection instruments were applied:a) International Physical Activity Questionnaire–IPAQ–long version : to asseb) Energy intake from diet: to quantify energy intake we used three 24h-food recalls, an instrument which is based on the patient’s description of his/her diet on the previous day, on a regular weekday and on a day during weekend or holiday . Data anc) Social Support Scale for PA : to assec) Self-efficacy scale for PA: to assess the confidence a patient has in performing PA or in changing his/her behavior regarding PA . The tood) Standardized physical evaluation: included assessment of heart rate , blood pressure (aneroid sphygmomanometer), body weight  and height (stadiometer). Duplicate measurements were performed of arm, calf, waist, abdomen, and hip circumferences (anthropometric tape). We calculated the average of the duplicate measurements, waist-hip ratios, and BMIs, and interpreted them based on WHO standards , 23.Finally, we reviewed patients’ charts in search of information concerning physical activity in medical histories or provider recommendations.rlm function . A statistical significance of 0.05 was adopted throughout the analysis.For descriptive statistics of study variables, we used absolute numbers and frequencies for categorical data, and central trend and dispersion measures for quantitative variables. Associations between current PA  and energy intake from diet and psychosocial constructs  that facilitate PA were sought after using the maximum likelihood estimation (MLE) for robust linear regression analysis after adjusting for patients’ gender and age, using the The study was approved by the Ethics Committee of the Faculty of Medicine, University of São Paulo . Subject participation was voluntary and followed informed consent. Patients’ anonymity and confidential data management were ensured throughout the study.The study cohort comprised 61 PLH, most of them males who reported themselves as non-white. Their mean age was 32.5 years old (SD = 8.4). Detailed socio-demographic data are described in Based on IPAQ scores calculated with combined light-intensity PA  and moderate-intensity or vigorous-intensity PA, 28/59 (47.5%) patients in our cohort reported low current PA, whereas 11 (18.6%) individuals were classified as highly active, according to the minimum WHO recommendation of 150–300 minutes/week of moderate-intensity aerobic PA or at least 75–150 minutes of vigorous-intensity PA or an equivalent combination of moderate- and vigorous-intensity PA throughout the week .The overall weekly energy expenditure was calculated transforming the metabolic equivalents (MET) assessed with IPAQ into kilocalories, using the Heymsfield formula  Despite Assessing patients’ energy intake from diet is important to evaluate energy balance. Based on information retrieved from the 24-hour food recall, we calculated a mean intake of about 2,200 kcal, with individual values ranging between 600 to 4,600 kcal, after excluding outliers , as shown in Social support scores were calculated separately according to the type of activity (light-intensity PA (LPA)—walking, moderate-intensity (MPA) and vigorous-intensity (VPA) and the involved supporters  Table 2Self-efficacy for PA was described separately according to the type of activity  and to the different contextual scenarios or domains . Based on the resulting scores , self-ef2) and waist-hip ratios of our patients fell within normal ranges. Table 3As for anthropometric measures, the median BMI  patients had PA addressed in their first consultation, and cumulatively it was registered in 27 (45%) charts along an 18-month clinical follow-up.After adjusting for patients’ gender and age regression models revealed no associations between current PA and energy intake (p = 0.928), current PA and social support (p = 0.254) or between current PA and self-efficacy for PA (p = 0.466). Table 4However, we found an inverse association between energy intake and self-efficacy for PA, i.e., the higher the confidence the patient had in engaging in PA, the lower his/her energy intake was. Table 5The increased survival of PLH under effective ART has brought about the need to reorganize HIV care to meet novel clinical demands. In this new scenario, a more comprehensive care approach is required to target health promotion and adoption of healthier lifestyles including PA. This task extends the scope of interventions from an exclusive medical perspective to incorporate a broader interdisciplinary view, involving other professionals, such as psychologists, dietitians, social workers, and physical education professionals.In our study, we addressed the need of incorporating PA in the comprehensive care provided to PLH and the challenges for its effectiveness from the perspective of patients followed up at a university HIV outpatient clinic in the city of São Paulo, Brazil. Our option to evaluate this relevant issue among PLH starting ART without body changes and metabolic abnormalities was due to the fact the PA has already been well recognized as useful to treat these long-term adverse effects of chronic HIV infection and ART –13, 26. Our cohort was predominantly composed of adult males, with a significant share of non-white patients, in accordance the current epidemiological features of the Brazilian HIV epidemic . As for When contrasting the median energy intake  with energy expenditure in our cohort, we concluded they would lead to a significant energetic imbalance. It is therefore crucial to describe how potential facilitators of behavioral change can be used to help patients adopt healthier habits and, more specifically, increase their engagement in PA. For this evaluation, we assessed the validated psychosocial constructs of Social Support and Self-efficacy for PA. In this regard, although a significant proportion of our cohort exhibited high scores of social support for PA, support of family members for walking or for engaging in moderate to vigorous physical activity was low. Moreover, no association was found between social support scores and currently performed PA after controlling for patients’ gender and age. An important aspect to consider in this scenario was described among adults on ART in Ohio, USA , among wSelf-efficacy for PA is understood as the level of belief/confidence the individual has in performing an activity, and as such can be applied to predict how likely behavior change towards PA is . In our In a different perspective we evaluated the association between patients’ self-efficacy for PA and their calorie intake, calculated from the 24-hour food recall, and found an inverse association between these variables, after adjusting for gender and age, i.e, the higher the confidence patients had of engaging in PA, the lower their calorie intake. We hypothesize that patients may have planned to eat less calories as they were expecting to adopt healthier habits that included performing PA. However, for unknown reasons this latter intent did not translate into practice.Health professionals engaged in HIV care should therefore intensify motivation strategies, reframing promotion of PA as an important component of comprehensive care. HIV caregivers are perceived as important actors of health promotion, who have frequent opportunities to integrate exercise into routine care of PLH , 36. NevLimitations of our study should however be considered. Although 38 (62.3%) subjects were included from 2014 to 2016 and the remaining 23 (37.7%) from 2017 to 2018, inclusion criteria were kept the same throughout the study. Moreover, participants’ socio-demographic profile , and reported smoking and alcohol use did not differ significantly between the two recruitment periods , renderiFurthermore, we should bear in mind that the psychosocial constructs of social support and self-efficacy for PA may not have been able to consider the multiple and complex barriers and challenges PLH face regarding behavior change. Both constructs emerged from the Socio-Cognitive Theory (SCT) framework , in whicUnderstanding care as the ultimate result of a fruitful interaction between patient and caregiver, in which the aims of interventions and the means how to use them are jointly defined using scientific and non-scientific knowledge and experiences of both patient and caregiver , we propOur results highlight a scenario in which Brazilian PLH starting antiretroviral report low engagement in PA and health professionals do not address PA in patient routine care as often as necessary. Despite exhibiting high-social support and medium self-efficacy for PA, these psychosocial constructs were not associated with current PA. Nevertheless, social support and self-efficacy scores still point out for the possibility of investing in behavioral change strategies aiming at increasing PA in this population. To maximize uptake of PA interventions and their impact healthcare professionals should therefore engage in dialogue with PLH to build customized care plans in which specific individual needs and vulnerabilities are taken into account along with current patterns of PA, calorie intake, health conditions, social support and self-efficacy for PA.S1 Table(DOCX)Click here for additional data file.


Sodium – glucose co-transporter 2 (SGLT2) inhibitors reduce blood glucose by inhibiting reabsorption of glucose from the proximal renal tubules. Initial studies showed that apart from reducing blood glucose they also reduce the combined endpoint of myocardial infarction, stroke, and cardiovascular death, hospitalization from heart failure, and occurrence of renal failure in patients with known cardiovascular disease or at high risk of developing cardiovascular disease. Recent studies have shown that these drugs also could be used in patients to treat heart failure or to slow the progression of renal failure, irrespective of whether the patients have diabetes or not. In this review, we discuss the clinical trial evidence for the use of SGLT2 inhibitors for the treatment of patients with heart failure with reduced ejection fraction and for the prevention of heart failure in patients with diabetes who are at high risk of cardiovascular events. We also discuss the plausible mechanisms of action for the cardiovascular beneficial effects of SGLT2 inhibitors. EMPA-REG OUTCOME TRIAL, DECLARE-TIMI 58, CANVAS, VERTIS-CV studies have shown that SGLT2 inhibitors namely empagliflozin, dapagliflozin, canagliflozin and ertugliflozin reduce the chances of hospitalisation in patients who have cardiovascular disease or at high risk of cardiovascular disease. The DAPA-HF study and the EMPEROR-REDUCED TRIAL have further shown that Dapagliflozin and Empagliflozin could be used to treat patients with heart failure, with or without diabetes. SGLT2 inhibitors provide us with a new armamentarium for treatment of patients with a triad of diabetes, heart or renal disease. Their mechanism of action in prevention or treatment of patients with heart failure however still remains speculative. Heart failure (HF) is a clinical syndrome consisting of typical symptoms that may be accompanied by signs caused by a structural and/or functional cardiac abnormality that results in elevated intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. When this is accompanied by a reduced ejection fraction (EF) ≤ 40%, it is called heart failure with reduced ejection fraction (HFrEF).Heart failure is one of the major causes of mortality in patients with type 2 diabetes mellitus (T2DM) , 2 and iConcomitant T2DM confers a worse prognosis in HF as the risk of cardiovascular (CV) and all-cause mortality are significantly increased, independent of other risk factors , 7.Although a modest cardiovascular benefit may be observed after a prolonged follow-up period , there wMost of the dipeptidyl peptidase-4 inhibitors demonstrated cardiovascular safety in patients with T2DM. Interestingly and somewhat surprisingly, sodium–glucose co-transporter (SGLT2) inhibitors and glucagon-like peptide-1 receptor (GLP1) agonists were found to have cardiovascular benefits additionally.Empagliflozin was the first SGLT2 inhibitor to show that it may prevent the development of heart failure in diabetic patients at risk of heart failure. In the EMPA-REG OUTCOME TRIAL , patientThe DECLARE-TIMI 58 trial  randomizSimilarly, canagliflozin in the CANVAS trial  showed aIn the CREDENCE study , patientMost patients in these trials did not have heart failure at baseline, so the benefit of treatment with an SGLT2 inhibitor largely reflected the prevention of incident heart failure. The reduction in the risk of hospitalization for heart failure was observed early after randomization which raised the possibility of mechanisms of action that differed from those usually postulated to explain the cardiovascular benefits of glucose-lowering therapies –20. BesiIn these large scale randomized, placebo-controlled trials, the risk of hospitalization for heart failure was 30–35% lower among patients who received SGLT2 inhibitors than among those who received placebo , and thiThe 2019 European Society of Cardiology guidelines on diabetes, prediabetes, and cardiovascular diseases , the 201If SGLT2 inhibitors can prevent the development of heart failure in T2DM, can they be used for the treatment of heart failure in patients with T2DM? Moreover, will they also be useful for the treatment of patients without T2DM?DAPA-HF study was the first to directly address these questions . In thisApart from the DAPA-HF trial, EMPEROR-REDUCED TRIAL is the only trial to date that included patients with symptomatic HFrEF, elevated natriuretic peptides, with or without T2DM. The trial was enriched for patients with more severe left ventricular function. The primary endpoint was CV death or heart failure hospitalization. Total (first and recurrent) heart failure hospitalization was a key secondary endpoint. There was a significant 25% reduction in the combined risk of cardiovascular death or first hospitalization for heart failure, and a significant 30% decrease in the total (first and recurrent) hospitalizations for heart failure. There was also significant improvement with empagliflozin in the exploratory endpoints such as urgent care visits for intravenous heart failure therapy and the Kansas City Cardiomyopathy score. Table The mechanisms of action of SGLT2 inhibitors in heart failure are still speculative although the drugs are shown to have several metabolic, hemodynamic, and organ-specific effects Fig. . In addiA rise in hematocrit was also seen with SGLT2 inhibitor therapy. The hemodynamic effects are mediated by several mechanisms including osmotic diuresis, and plasma and interstitial fluid volume reduction, leading to a reduction in ventricular preload and afterload , 35, 36.Another proposed mechanism for the beneficial effects of SGLT2 inhibitors is inhibition of the sodium-hydrogen exchanger (NHE1) activity which is up-regulated both in T2DM and heart failure . By inhiSGLT2 inhibitors may also exert direct effects on myocardial metabolism , 41, andA benefit on ventricular remodeling was also demonstrated in patients with T2DM and coronary artery disease in the EMPA-HEART CardioLink-6 study, which showed a reduction in left ventricular (LV) mass index and improvement in diastolic function without changes in LV systolic function after 6 months of treatment with empagliflozin . FurtherIt is known that neurohormonal activation causes increased oxidative and other forms of cellular stress, which leads to dysfunction and loss of cardiomyocytes. Another postulated mechanism is that by inhibiting the energy surplus sensors SGLT2 inhibitors mimic cellular starvation and induce nutrient deprivation signals such as sirtuin 1 (SIRT1) which in turn inhibit activation of proinflammatory pathways, reduce cellular stress and promote autophagy . This heSGLT2 inhibitors exemplify serendipity. Initially developed as glucose-lowering agents, they are found to have a more robust effect on heart failure and slowing of progression of renal dysfunction. Renal dysfunction often accompanies heart failure with reduced ejection fraction and these agents may be of particular value in such a clinical scenario. Trials are underway to answer whether SGLT2 inhibitors are also useful in patients with heart failure and preserved ejection fraction. One of them, the Emperor Preserved trial has already been published and the result shows that empagliflozin significantly reduces the combined primary endpoint of heart failure hospitalization and CV mortality in patients with heart failure and preserved ejection fraction regardless of whether T2DM was present or not .Currently, SGLT2 inhibitors  are recommended to reduce the risk of HF hospitalization in T2DM patients with either established cardiovascular disease or at high cardiovascular risk Moreover, the recently published European Cardiology Society (ESC) 2021 guidelines have given a Class I recommendation for dapagliflozin and empagliflozin for the treatment of HFrEF, with or without T2DM . Further


Right ventricular (RV) late gadolinium enhancement (LGE) occurs due to surgical scarring and RV remodeling, and has been shown to be associated with clinical outcomes in Tetralogy of Fallot (TOF). However, it is not known if cardiovascular magnetic resonance (CMR) LGE extent progresses over time, and therefore, it is not known if serial reassessment of LGE is necessary. We determined the rate of progression in the extent of RV LGE on serial CMR examinations in repaired TOF.Retrospective review of 127 patients after TOF repair  13.3,27.0) who had at least two CMRs ) was performed. 84/127 patients had no interventions between serial CMRs (Group 1) while 43/127 patients had transcatheter or surgical intervention between CMRs (Group 2). The extent of RV LGE was assessed using 2 methods: a semiquantitative RV LGE score and a quantitative RV LGE extent expressed as % of RV mass. Mixed effects linear regression modeling to estimate changes in LGE over time.p < 0.001) in Group 1, and − 1.9  in Group 2], and RV LGE score .RV LGE was present in all patients on the first CMR. % RV LGE extent and LGE score did not increase over time in either patient group. The mean 5 year rates of change were small and negative for both % RV LGE extent [− 2.3 (95% CI − 2.9, − 1.8, In this serial CMR evaluation of children and adults with repaired TOF, no significant progression in the extent of RV LGE was seen on intermediate term follow-up. Given recent concerns regarding the safety of gadolinium-based contrast agents, frequent assessment of LGE may not be necessary in follow-up. Despite advances in the surgical, transcatheter, and medical management of Tetralogy of Fallot (TOF), late morbidity and mortality remain unacceptably high, related to chronic pulmonary regurgitation, ventricular dysfunction, and ventricular or atrial arrhythmias –5. RightA retrospective review of all patients with repaired TOF who had undergone 2 or more CMR examinations with LGE imaging between January 2005 and November 2019 was performed. Patients with pulmonary atresia and major aortopulmonary collateral arteries and those with significant imaging artifacts were excluded. Demographic and clinical data were abstracted from electronic medical records. The hospital’s Committee on Clinical Investigation waived the requirement for informed consent.All CMR examinations were performed using a whole-body 1.5 T CMR scanner  using standard imaging techniques recommended by the Society for Cardiovascular Magnetic Resonance . VentricSemiquantitative RV LGE score: The score is a modification of a previously described technique [echnique . The RV echnique . BrieflyQuantitative RV LGE Extent (%): RV endocardial and epicardial contours were drawn manually on the stack of short-axis LGE images, avoiding epicardial fat. Areas of LGE were identified visually and then a semi-automated thresholding technique was applied until the visually identified areas of LGE were marked as areas of positive LGE  was used to evaluate the rate of change in RV LGE over time. For this study, assuming a standard deviation of 2.0 for the change in RV LGE score between 2 CMRs and a 2-sided 0.05-level test, with 40 subjects in each of 2 independent groups, there is 80% power to detect a mean group difference of 1.0 between the mean RV LGE change scores. Intra-rater and inter-rater reliability were assessed using the intra-class correlation coefficient (ICC). A p-value of less than 0.05 was considered significant. Analyses were performed using SAS  and R .Patient characteristics are summarized in Table p < 0.001 for both). Intra-observer reliability in measuring % RV LGE extent was good (ICC 0.83) in a subset of 40 CMR examinations that were reanalyzed at a later date by the same blinded observer (KS). Inter-observer reliability was modest (ICC 0.6), assessed in a subset of 20 CMR examinations by a blinded second observer (AP).RV LGE was present in all patients on the first CMR examination in both groups. The location of LGE was a basal superior segment in 127 subjects (100%), at the mid superior segment in 82 (65%), and at the mid anterior segment in 16 subjects 13%)  with a corresponding increase in RV mass may lead to a serial decline in RV LGE score or % RV LGE extent. However, we found no significant association between the rate of change in either parameter of RV LGE, and the rate of change in RVEDVI.In this serial CMR study of children and adults with repaired TOF, although RV LGE was present in all subjects on the initial CMR, the extent of RV LGE analyzed using 2 measures (LGE score and % LGE extent) did not significantly increase during follow-up, rather showing a slight decline over serial examinations.The patterns of RV LGE in our cohort were similar to those previously reported, with the most common site for LGE being the RV outflow tract.  Several In the present analysis, we evaluated 2 groups of patients—those free of intervention between serial CMRs and those who had surgical or transcatheter intervention between serial CMRs. We analyzed these groups separately, since surgical manipulation of the outflow tract, as well as artifact caused by implanted valves could potentially confound the serial assessment of LGE extent. The findings of a similar lack of progression in RV LGE in both groups suggests that RV LGE in TOF patient possibly represents fixed post-surgical scarring that is not significantly modulated by long term volume loading due to pulmonary regurgitation, or by intervening procedures, at least in the intermediate term (median follow-up duration was 4 years).There are inherent difficulties in quantifying RV LGE due to the thin free wall. We used a previously described method for calculation a semiquantitative RV LGE score, in addition to a new method to quantify RV LGE extent . In usinOur results have important clinical implications. Since we did not observe a significant increase in RV LGE over a median follow-up duration of 4 years, this suggest that RV LGE does not progress rapidly. Therefore, frequent serial assessment of LGE may not be necessary, thereby avoiding the frequent administration of gadolinium-based contrast agents in these patients, in light of several reports of long-term retention of gadolinium in patients who receive multiple doses of contrast , 18. It Several limitations of the current work are worth considering. First, there are known limitations related to its retrospective single-center design. However, these are likely offset by the use of serial longitudinal data using a consistent imaging protocol and analysis by a single observer. Second, while we used serial CMRs, the median duration of follow-up was 4 years and therefore we are not able to exclude progression in RV LGE over longer periods of time. Studies with larger numbers of patients with a longer duration of follow-up may help answer this question more definitively. Third, due to its retrospective design, we did not have high resolution 3-D LGE imaging or imaging for diffuse fibrosis available for serial assessment, as these techniques have only become available more recently. It is possible that follow-up studies using these more sensitive techniques may detect progression in RV fibrosis. Finally, we did not have sufficient numbers of subjects with LV LGE to analyze longitudinal changes in LV LGE over time.In children and adults with repaired TOF, the RV LGE extent does not increase significantly based upon serial CMRs during a median follow-up of 4 years. Given recent concerns regarding long-term gadolinium retention, our data do not support the routine frequent serial assessment of LGE in TOF patients.


Diabetes mellitus can independently contribute to cardiovascular disease and represents a severe risk factor for premature development of cardiovascular disease. A three-fold higher mortality than the general population has been observed in type 1 diabetes mellitus whereas a two- to four-fold increased probability to develop cardiovascular disease has been observed in type 2 diabetes mellitus. Cardiovascular magnetic resonance, a non-radiative modality, is superior to all other modalities in detecting myocardial infarction. The main cardiovascular magnetic resonance sequences used include a) balanced steady-state free precession (bSSFP) for function evaluation; b) T2-W for oedema detection; c) T1 W for ischemia detection during adenosine stress; and d) late gadolinium enhanced T1-W images (LGE), evaluated 15 min after injection of paramagnetic contrast agent gadolinium, which permit the diagnosis of replacement fibrosis, which appears white in the middle of suppressed, nulled myocardium. Although LGE is the technique of choice for diagnosis of replacement fibrosis, it cannot assess diffuse myocardial fibrosis. The application of T1 mapping (native or pre contrast and post contrast) allows identification of diffuse myocardial fibrosis, which is not detectable my other means. Native T1 and Contrast-enhanced T1 mapping are involved in the extracellular volume fraction (ECV) calculation. Recently, 1H-cardiovascular magnetic resonance spectroscopy has been applied to calculate the amount of myocardial triglycerides, but at the moment it is not part of the routine assessment of diabetes mellitus. The multifaceted nature of cardiovascular magnetic resonance has the great potential of concurrent evaluation of function and myocardial ischemia/fibrosis in the same examination and represents an indispensable tool for accurate diagnosis of cardiovascular disease in diabetes mellitus. The clinical implications of diabetes mellitus (DM) on the cardiovascular system are profound with serious consequences that are reflected in patients’ survival worldwide. Insulin resistance can directly contribute to cardiovascular disease (CVD) . FurtherPatients with DM have increased CVD morbidity/mortality as a result of various pathophysiologic changes, including epicardial coronary artery disease (CAD) leading to myocardial infarction (MI), microvascular CAD, endothelial dysfunction, cardiac remodeling due to diffuse myocardial fibrosis, fatty myocardial infiltration and diastolic dysfunction leading to heart failure (HF). Finally, peripheral vascular disease, involving carotid arteries and brain vasculature, may cause claudication and stroke, respectively .Three-fold higher mortality has been identified in patients with type 1 diabetes mellitus (T1DM) compared to controls, due to premature atherosclerosis in both men and women . In thisCAD and myocardial infarction (MI) are two to four times more common in patients with T2DM . TherefoVarious noninvasive imaging modalities have been applied to diagnose early cardiovascular involvement in DM. Among them, echocardiography is the cornerstone modality applied in clinical practice, because it can be used for bedside evaluation, has low cost, is radiation free, and is widely available. However, echocardiography has some serious limitations, including dependency of operator and acoustic window, low reproducibility, and lack to provide information about tissue characteristics. Additionally, it is unable to differentiate between epicardial and microvascular CAD and cannot detect small MIs that do not cause significant wall motion abnormalities . FurtherSPECT imaging is the most commonly used modality to assess myocardial ischemia in DM. However, in DM patients, SPECT has some serious limitations. Its spatial resolution of ≈7 mm × 9 mm does not allow detection of subendocardial ischemia. SPECT relies on regional differences in myocardial blood flow and, therefore, is less accurate in patients with triple vessel disease and balanced ischemia, diffuse microvascular dysfunction and non-transmural MI . FurtherComputed coronary angiography (CTA) can play a role in assessing DM patients, and there is a great debate regarding its use in asymptomatic patients and the value of calcium screening as a gatekeeper for further ischemia testing . HoweverCardiovascular Magnetic Resonance is a non-radiative modality, with high spatial resolution (0.3-1mm) capable to provide details regarding both function and tissue characteristics in the same study . CMR is Cardiovascular sequelae constitute a substantial burden on the treatment of DM at both the patient and population levels . CMR canBalanced steady-state free precession (bSSFP). bSSFP is increasingly important to assess myocardial function. It is also the ideal approach to evaluate cardiac anatomy/mass/wall motion/biventricular/atrial function and cardiac remodeling . These images are produced due to increased water amount taken place during oedema  images. However, these images may present various limitations , includiTo overcome the STIR limitations, T2 mapping has been developed, based on the transverse relaxation time of each voxel. At 1.5 T, the normal myocardium T2 value was measured at 52 ± 3 ms by Giri et al. in 14 healthy volunteers and at 55 ± 5 ms in 73 healthy volunteers by Wassmuth et al. and were related to body surface area (BSA) or heart rhythm and had excellent reproducibility , 40.T1-weighted images (T1-W). The T1 relaxation time, an index of how quickly the spins return to equilibrium after a radiofrequency (RF) pulse, is a main parameter of tissue contrast . Although LGE is well validated as the technique of choice for the detection of replacement fibrosis, it has serious limitations in the assessment of diffuse myocardial fibrosis, because it is based on the signal intensity differences between fibrotic and normal myocardium to provide image contrast. To overcome this problem, a CMR imaging technique called T1 mapping has been created. T1 mapping identifies early myocardial fibrosis, which is undetectable using the current blood biomarkers  calculation together with native T1 mapping. The estimation of the ECV is an index of inter-and extra-cellular area and measurement of myocardial/blood T1 before/after gadolinium together with hematocrit is needed, with hematocrit representing the cellular fraction of blood.Normal ECV values equal to 25.3 ± 3.5% were found in healthy subjects, examined at 1.5T scanners . With thCompared to native T1 relaxation times, contrast-enhanced T1 values are depended on various parameters, such as contrast dose, time between contrast injection, and T1 imaging and renal function and therefore are more variable. ECV, on the other hand, is a physiologic index derived from the ratio of T1 values. Therefore, ECV is a more reproducible index in different magnetic fields, acquisition techniques, and vendors than both native/post-contrast T1 . FurtherUsing this approach, it was proven that elevated ECV is an independent factor of mortality in DM representing a novel non-invasive biomarker to evaluate the severity of diabetic heart disease . AdditioCMR found a correlation between myocardial lipid accumulation and LV diastolic dysfunction, independently of age, blood pressure, and obesity in T2DM  and imprCMR has been also used to evaluate the effect of treatment. A randomized study to pioglitazone, metformin or placebo for 24 weeks in 78 T2DM men without CVD showed no effect of treatment on myocardial lipids and energetic, measured by 1H and 31P CMR spectroscopy, respectively . SimilarIn a study using cardiac phosphocreatine-to-ATP ratio, it was found that this index was lower in T2DM patients compared with controls . Further1H-MRS, have provided valuable insight into the relationships between epicardial adiposity, myocardial fat content, and obesity-related cardiac disease. Whether increased epicardial adiposity in healthy subjects can lead to myocardial fat loading and subclinical impairment of myocardial function is an issue of great interest, with important clinical implications for obesity-related cardiac disease. However, further studies are needed to understand whether quantification of epicardial adiposity and myocardial fat content in normal hearts have any diagnostic, prognostic or therapeutic impact to reverse established myocardial disease in humans , LGE-CMR showed a sensitivity of 95% and a specificity of 98% for the diagnosis of CA. The combination of a characteristic LGE pattern indicating CA with unremarkable monoclonal protein studies resulted in the diagnosis of ATTR-CA (confirmed by EMB) with a specificity of 98% [95% confidence interval (CI) 92–100%] and a positive predictive value (PPV) of 99% (95% CI 92–100%), respectively, while the EMB risk of complications was 3.13%, but without any detrimental or persistent complications .Finally, a study assessing the diagnostic performance of CMR, compared with endomyocardial biopsy (ENB) in patients with suspected acute myocarditis (AMC) and chronic myocarditis (CMC) showed that the best diagnostic performance was observed in patients with suspected AMC . In contrast in suspected CMC, CMR was found to be unsatisfactory  .The 2019 ESC Guidelines on diabetes, pre-diabetes and cardiovascular diseases developed in collaboration with the EASD  support Resting ECG is recommended in patients with DM with hypertension or suspected CVDCarotid or femoral ultrasound should be considered for plaque detection as CV risk modifierScreening for CAD with coronary CT angiography and functional imaging may be considered,Coronary artery calcium (CAC) scoring may be considered as risk modifier,Ancle-branchial index (ABI) may be considered as risk modifier,Carotid ultrasound intima-media thickness for CV risk is not recommended.It is really impressive that this recent document does not recommend echocardiography, the cornerstone cardiovascular imaging modality, as a screening tool to detect early myocardial changes in DM. However, adolescents with T1D exhibit early changes in blood pressure, peripheral vascular function, and left ventricular myocardial deformation indices with a shift from longitudinal to circumferential shortening . AdditioIt is out of the scope of this article to analyze the role of all recommended imaging modalities in the evaluation of cardiac involvement in DM. However, a glimpse to the literature showed that ECG has low partial sensitivity and specificity for predicting coronary artery stenosis with accuracy ranged 58.5% to 62.0% based on coronary artery analysis . FurtherStress CMR perfusion, viability assessment, because it can detect lesions missed by both echocardiography or SPECT;Evaluation of heart failure and arrhythmia in DM patients, because it can reveal the pathophysiologic background behind these entities and guide further treatment;Assessment of ischemia/fibrosis burden in DM patients with known CAD in order to make to final decision regarding re-vascularization or heart transplantation;Inconclusive echocardiographic evaluation, due to technical reasons, such as obesity or obstructive lung diseases;Doubtful echocardiographic results that need further evaluation, such as differential diagnosis between diabetic cardiomyopathy and heart failure, due to coronary artery disease.The multifaceted nature of CMR allows the assessment of ventricular function/remodeling, myocardial oedema, ischemia during stress, and symptomatic or asymptomatic myocardial replacement/diffuse fibrosis. With increasing availability and easier acquisition/processing, CMR will rapidly become more widely available to the clinicians for early detection of CVD in DM, specifically in subclinical diabetic heart disease.SM, FB, and GM-M contributed to conception and design of the study. SM wrote the first draft of the manuscript. FB, GM-M, AG, OK, VV, GK, EC, and GC wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.The authors are responsible for the choice and presentation of views contained in this article and for opinions expressed therein, which are not necessarily those of UNESCO and do not commit the Organization.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.The reviewer AM-F declared a shared affiliation with some of the authors, SM, FB, EC, and GC, to the handling editor at time of review.


NYHA class improved significantly at 5 years compared to baseline. Six-min walk test distance increased at 2 years compared to the 6-month visit. Hybrid LV reconstruction using the anchoring system provides significant and durable LV volume reduction during 5-year follow-up in preselected patients with ischemic heart failure.The evidence supporting surgical aneurysmectomy in ischemic heart failure is inconsistent. The aim of the study was to describe long-term effect of minimally invasive hybrid transcatheter and minithoracotomy left ventricular (LV) reconstruction in patients with ischemic cardiomyopathy. Twenty-three subjects with transmural anterior wall scarring, LV ejection fraction 15–45%, and New York Heart Association class ≥ II were intervened using Revivent TC anchoring system. LV end-systolic volume index was reduced from 73.2 ± 27 ml at baseline to 51.5 ± 22 ml after 6 months (The online version contains supplementary material available at 10.1007/s12265-021-10133-9. Heart failure (HF) represents a substantial healthcare issue in developed countries , 2, and Exclusion of the scarred, akinetic, or dyskinetic tissue from the left ventricle (LV) might be beneficial in patients that have experienced extensive transmural myocardial infarction in the region of the left anterior descending artery. Remodeling procedure leads to volume reduction and geometry restoration of the dilated LV that secondarily results in decreased wall tension and lower myocardium energy demand , 7.short-term results [LV reconstruction in ischemic cardiomyopathy has generally been performed in the setting of standard open-heart surgery, where aneurysm resection is usually accompanied by other interventions, mostly coronary artery revascularization –12. Hybr results –15. It i results , 17 even results .Eligible subjects with ischemic LV dysfunction due to prior myocardial infarction leading to transmural scarring with akinesis or dyskinesis in the anteroseptal, apical, or apicolateral region were enrolled at our center between September 2013 and March 2019. The main inclusion criteria were age 18–80 years, LV EF 15–45%, New York Heart Association (NYHA) class II–IV, stable HF medication for > 90 days, and willingness and ability to comply with the study procedures. Localization, size, and transmural extent of the scar were objectified by cardiac magnetic resonance imaging or dynamic computed tomography prior to enrollment. The main exclusion criteria were intracardiac thrombus, myocardial infarction within 90 days before the procedure, systolic pulmonary arterial pressure > 60 mmHg assessed by echocardiography, previous left-sided thoracotomy, and contraindication to open-heart surgery (in case of a complication).The study was designed as prospective and single arm, evaluating 5-year follow-up data. The primary efficacy endpoint was the reduction of LVESVI. Secondary efficacy endpoints were changes in NYHA class, 6-min walk test (6-MWT), Minnesota Living with Heart Failure Questionnaire (MLHFQ), and a level of N-terminal prohormone of brain natriuretic peptide (NT-proBNP). Transthoracic echocardiography, NYHA class, 6-MWT, MLHFQ, and NT-proBNP were obtained at baseline and at 6-month, 2-year, and 5-year follow-up visits. NYHA class and 6-MWT were assessed by different physicians (trained persons), who were blinded to results from preceding follow-up visits. Echo data were evaluated by experienced cardiologist, who was blinded to echo results from other follow-up visits and to timing of echo control. LV volumes and EF were assessed offline on two-dimensional echocardiography images with Q-Station software, version 3.8.5 , using Simpson’s biplane method . The stuLV reconstruction was performed under general anesthesia as a stand-alone hybrid transcatheter and minimally invasive surgical remodeling procedure on the beating heart utilizing the Revivent TC system . As described in detail previously , 14, thet-test or an unpaired two-tailed t-test with Welch’s correction  were used to evaluate the association between baseline LVESVI and changes in clinical variables. Data are presented as mean ± standard deviation. Statistical analyses were performed using GraphPad Prism, version 8.2.1 ; p-values < 0.05 were considered statistically significant.To evaluate changes in variables over time, a repeated-measures one-way ANOVA using Tukey’s multiple comparisons test was used for analysis of complete data and a mixed-effects model using REML  method with fixed effect type III was applied for the analysis with missing data. An unpaired two-tailed 2, and mean NYHA class 2.3 ± 0.5. Mean follow-up time was 5.1 years . Twenty patients completed a 6-month visit, 18 patients a 2-year visit, and 11 patients a 5-year visit. Table Twenty-three patients  were recruited. Mean LV EF was 32 ± 7%, mean LVESVI 75 ± 25 ml/mOn average, 2.9 anchor pairs were used for reconstruction, of which 1.3 anchor pairs were implanted as LV-LV. The mean total operating time was 204 ± 50 min, and the mean time for implanting the anchoring system was 77 ± 34 min.p < 0.001), 1.18 ± 0.8 after 2 years (p = 0.08), and 1.65 ± 1.0 after 5 years (p = 0.003). Four patients died before their 5-year follow-up visit: the first patient died 2 weeks after the procedure due to combined shock with multiple organ failure and acute abdomen, the second 4 months after intervention as a consequence of periprocedural ischemic stroke, the third 8 months after the procedure due to lung carcinoma, and the fourth 4 years after the procedure as a result of alcohol abuse. This resulted in all-cause mortality rates 4% at 30 days, 13% at 2 years, and 24% at 5 years.The anchoring system was successfully implanted in 22 patients (96%). In one patient, conversion to sternotomy was indicated due to acute mitral regurgitation caused by chordae impairment. Two patients were subjected to conventional re-operation after 3 days and 6 weeks after LV reconstruction, respectively, due to deteriorating tricuspid valve insufficiency. Even at the rest of patients, we observed some tricuspid valve insufficiency progression compared to baseline grade 0.64 ± 0.6 : 1.68 ± 0.8 after 6 months (p < 0.001), 49.9 ± 20 ml after 2 years (p < 0.001), and 56.1 ± 16 ml after 5 years (p = 0.047). LVESVI reduction persisted throughout the 5-year follow-up period in individual subjects  — Fig. p = 0.02) and trend to the improvement at 2 years compared to baseline — Fig. NYHA class decreased significantly after 5 years compared to baseline . LV reverse remodeling effect was accompanied by improvement in NYHA class and 6-MWT in certain parts of the follow-up; however, significant changes in MLHFQ or NT-proBNP were not detected. An additional sub-analysis testing the role of baseline LVESVI on clinical outcome showed a trend towards improvement in all variables, but it did not reach statistical significance.n = 74) [32%. The largest randomized clinical trial (STICH), which compared CABG versus CABG plus surgical LV aneurysmectomy, failed to prove any benefit of LV reconstruction [13%). Post hoc subgroup analyses implied that patients with smaller baseline LV (LVESVI < 60 ml/m2) and better LV EF (≥ 33%) or patients that achieved postoperative LVESVI (< 60–70 ml/m2) may benefit from aneurysmectomy [with adequate LV volume reduction have been reported [n = 79 and 87, respectively), significant improvement in symptoms or functional capacity after surgical LV reconstruction performed as a concomitant procedure, combined mostly with CABG. Relative LVESVI reduction was 41% and 31%, respectively [n = 89) [n = 35) were subjected to a hybrid minimally invasive procedure without sternotomy and concomitant CABG. The study showed statistically significant LV volume reductions, increased EF, and clinical and functional improvement. Low preoperative LVESVI seemed predictive of positive response to remodeling therapy. Adequate volume reduction and early clinical improvement with the Revivent TC system was reported also by Wang et al. from a single-center series of 26 patients [Regarding surgical LV reconstruction, preliminary data from registries and one small prospective randomized study demonstrated favorable outcomes in surgical LV aneurysmectomy, generally with concomitant coronary artery bypass grafting (CABG), on ventricular volume reduction, functional status, ischemic mitral regurgitation, and HF hospitalization burden –11. Aguitruction . Howeversmectomy , 17. Folreported , 20. Witectively , 22. Lik[n = 89) , of whicpatients .In the present study, the short-term changes of LVESVI were very similar compared to 1-year data in Klein et al.’s trial. However, the main finding of the present study with potential clinical implication is that the significant volume reduction induced by index procedure persisted throughout the 5-year follow-up. Statistical non-significance of the majority of clinical parameters may be explained partially by the small sample size but may also be due to the less symptomatic cohort enrolled in our study compared to Klein et al. . Two- and 5-year all-cause mortality of the patients who underwent LV reconstruction in the STICH trial was approximately 50% higher than in our study. Nevertheless, this comparison is arguable for many reasons — different sample sizes, enrollment period difference more than a decade, or concomitant CABG in STICH trial.The present study has several limitations. First limitation is a non-randomized uncontrolled design of the trial. Lack of control group makes the interpretation of changes in NYHA class, MLHFQ, or exercise capacity after 2 or 5 years problematic. It is highly disputable whether the observed improvement in 6-MWT at 2 years and NYHA class at 5 years is in relation with the index intervention. Propensity matching with the patients receiving optimal medical therapy could be helpful. There might also be some influence of selection bias on observed variables due to mortality of patients during follow-up, in terms that only patients with more favorable outcome were finally included in the analysis. Similarly, interpretation of pre- and postoperative hospitalization rate is highly disputable in absence of control group, since HF with reduced EF is characterized by progressive character. Second limitation represents the small sample size that limits especially the statistical analysis of secondary endpoint variables at 5 years and proper subgroup analysis. Nonetheless, despite the fact that the interpretation of secondary endpoints, unscheduled hospitalizations, and subgroup analysis is disputable, to date, this is the largest presented cohort of patients intervened using the Revivent TC system with > 1-year follow-up and the effect on LV remodeling was clearly proven even with this sample size. Third limitation represents the echocardiographic evaluation of LV volumes. Echo data analysis may be impaired by artifacts after anchor implantation. Volume calculation was not done by multiple readers. Fourth limitation is that the background medical therapy of HF did not remain unchanged during the follow-up  that may also have an influence on patient outcome.Hybrid transcatheter and minithoracotomy LV reconstruction using the Revivent TC anchoring system appears to be a feasible treatment method achieving substantial and durable left ventricular volume reduction. It offers the advantage of minimally invasive procedure without need of sternotomy and cardiopulmonary bypass. Long-term effect on clinical parameters and mortality needs to be confirmed in a larger randomized controlled clinical trial.ESM 1Video 1a-d. Title: Representative example of two-dimensional echocardiography of one subject. Legend: Left ventricle is displayed from apical four-chamber view preoperatively (a), at 6 months (b), 2 years (c) and 5 years (d) after reconstruction. On postoperative images, the shadow of the anchor is visible on the apical part of interventricular septum (MP4 10856 kb)ESM 2(MP4 5782 kb)ESM 3(MP4 7853 kb)ESM 4(MP4 6952 kb)ESM 5(JPG 28 kb)ESM 6(DOCX 12 kb)


There is a high prevalence of asymptomatic (American Heart Association Stage B) heart failure (SBHF) in people with type 2 diabetes (T2D). We aimed to identify associations between clinical characteristics and markers of SBHF in adults with T2D, which may allow therapeutic interventions prior to symptom onset.n = 247, age 52 ± 12 years, glycated haemoglobin A1c (HbA1c) 7.4 ± 1.1% (57 ± 12 mmol/mol), duration of diabetes 61  months] underwent echocardiography and adenosine stress perfusion cardiovascular magnetic resonance imaging. Multivariable linear regression analyses were performed to identify independent associations between clinical characteristics and markers of SBHF.Adults with T2D from a multi-ethnic population with no prevalent cardiovascular disease [In a series of multivariable linear regression models containing age, sex, ethnicity, smoking history, number of glucose-lowering agents, systolic blood pressure (BP) duration of diabetes, body mass index (BMI), HbA1c, serum creatinine, and low-density lipoprotein (LDL)-cholesterol, independent associations with: left ventricular mass:volume were age (β = 0.024), number of glucose-lowering agents (β = 0.022) and systolic BP (β = 0.027); global longitudinal strain were never smoking (β = −1.196), systolic BP (β = 0.328), and BMI (β = −0.348); myocardial perfusion reserve were age (β = −0.364) and male sex (β = 0.458); and aortic distensibility were age (β = −0.629) and systolic BP (β = −0.348). HbA1c was not independently associated with any marker of SBHF.In asymptomatic adults with T2D, age, systolic BP, BMI, and smoking history, but not glycaemic control, are the major determinants of SBHF. Given BP and BMI are modifiable, these may be important targets to reduce the development of symptomatic heart failure. Isolated abnormalities of LV diastolic dysfunction and reduced global longitudinal strain (GLS) are associated with incident heart failure in T2D. Their identification may permit earlier recognition and treatment of patients most at risk of heart failure. This is especially significant given the vast majority of people with T2D develop heart failure with preserved ejection (HFpEF), a condition that has no proven effective treatments. We have recently demonstrated that subclinical concentric LV remodelling, arterial stiffening, abnormalities in diastolic and systolic function, and reduced myocardial perfusion are present in T2D,6 and these features are increasingly recognised as pathognomic features of SBHF and precursors to the onset of clinical heart failure.5 The clinical factors contributing to early cardiovascular dysfunction in people with T2D, however, are poorly understood. Previous imaging studies have been hindered by variations in methods of assessing cardiac structure and function, as well as small sample sizes (seldom greater than 100 subjects) and incomplete datasets with significant risk of overfitting the regression models.In asymptomatic individuals with type 2 diabetes (T2D) there is a high prevalence of left ventricular (LV) systolic and diastolic dysfunction and cardiac remodelling.Cardiovascular magnetic resonance (CMR) is the gold standard imaging modality for assessment of cardiac volumes and mass, and with the addition of stress perfusion imaging has the ability to provide accurate quantification of myocardial blood flow (MBF). By combining CMR with echocardiography, comprehensive cardiovascular phenotyping of asymptomatic adults with T2D is possible.The aim of this study was to identify independent associations between clinical characteristics and key cardiovascular perturbations typical of SBHF in a multi-ethnic cohort of asymptomatic adults with T2D .710 Adults with T2D were enrolled prospectively into these studies from primary and specialist care services in Leicestershire, UK, with support from the National Institute for Health Research (NIHR) East Midlands Clinical Research Network. Participants included in the current analyses were aged 18–75 years, with no prior history, clinical signs or symptoms of cardiovascular disease and no contraindications to CMR imaging. Exclusion criteria were: type 1 diabetes, stage 4 or 5 chronic kidney disease (estimated glomerular filtration rate <30 ml/min/1.73 m2), known macrovascular disease , presence of arrhythmia, history of heart failure, moderate or severe valvular heart disease, and cardiovascular symptoms . Ethical approval for each study was granted by the National Research Ethics Service, conducted according to the Declaration of Helsinki, and all participants provided written informed consent prior to any testing.This was a pooled analysis of individual baseline patient data from participants recruited to one of four studies evaluating the impact of T2D on cardiovascular structure and function .7–10 AduDemographics, medical history, and anthropometric measures were collected at the assessment visits. Glucose-lowering therapies taken by participants were categorised as: 0 = none, 1 = one oral agent; 2 = two oral agents; 3 = three or more oral agents, and 4 = insulin-treated. Smoking history was categorised as: never, ex-smoker, or current smoker. A fasting blood sample was collected for biochemical profile for diabetes control, lipids, liver, and kidney function.n = 175), by two accredited operators using an iE33 system with S5-1 transducer . Images were acquired and reported as per American Society of Echocardiography guidelines. Early diastolic transmitral flow velocities (E) and early diastolic mitral annular velocities (e′) to estimate LV filling pressures were assessed by Doppler echocardiography per current recommendations.Transthoracic echocardiography was performed in a subset of participants  at either 1.5T (Siemens Aera) or 3T (Siemens Skyra). In brief, after localisers, steady-state free precession cine images were acquired in four-, three- and two-chamber views. Perfusion images were then acquired after vasodilatory stress with adenosine . At peak stress, a gadolinium-based contrast agent was injected followed by a 20 ml bolus of normal saline, at a rate of 5 ml/s, and perfusion images were acquired at three short-axis slices . Rest imaging was performed approximately 10 min after stress. In between rest and stress imaging, a stack of short-axis slices was obtained using cine images to obtain coverage of the entire LV. For measurement of aortic distensibility, steady-state free precession aortic cine images were acquired in a plane perpendicular to the thoracic aorta at the level of the pulmonary artery bifurcation. Simultaneous brachial blood pressure (BP) was measured using an automatic oscillometric device. Late gadolinium enhancement (LGE) images were acquired approximately 10 min after the rest perfusion contrast dose for assessment of focal myocardial fibrosis. with signal intensity versus time curves converted to concentration curves using a linear signal response to contrast agent with Fermi-constrained deconvolution or using a dual sequence gradient echo method with inline automated reconstruction and post-processing for MBF quantification (at 3T) at base, mid and apical slice positions.14 Stress and rest MBF at basal, mid and apical slices were averaged to derive global stress and rest MBF, and determine myocardial perfusion reserve . Aortic distensibility was analysed by two experienced operators (KP and GS) using Java Image Manipulation version 6  as previously described. LGE images were assessed for focal fibrosis (GSG and GPM), categorised as present or absent, and individuals with a subendocardial pattern of late enhancement indicative of previous myocardial infarction were excluded from further analyses.Each CMR image set was assigned a unique study identifier using an independent online computerized random number generator. CMR images were analysed offline blinded to all patient details. Cardiac chamber volumes, function and strain were assessed by a single experienced observer (G.S.G) using cmr42 version 11 . Myocardial strain measurement was performed using cmr42 Tissue Tracking from balanced steady-state free-precession long axis cine images . Perfusion images were assessed qualitatively for focal and subendocardial perfusion defects, and individuals with reversible perfusion defects indicative of ischaemia due to epicardial coronary artery disease were excluded from further analyses. Quantitative myocardial perfusion analysis was performed using a saturation recovery gradient echo pulse sequence (at 1.5T),Normality was assessed using histograms. Continuous data are expressed as mean [± standard deviation (SD)], if normally distributed or median (interquartile range) if not.Correlations between clinical characteristics , and CMR and echocardiographic measures of cardiovascular structure and function  were assessed using Spearman’s rank correlation coefficient. was performed. The clinical variables included in each model were age, sex, ethnicity, smoking history, systolic BP, duration of diabetes, glucose-lowering therapies, BMI, HbA1c, serum creatinine and LDL cholesterol. Continuous predictor variables were standardised prior to inclusion in the regression models to permit more direct comparisons of the magnitude of their effects on the dependent variable. Categorical variables were set to have the largest group defined as the reference. Regression coefficients (β) are presented as point estimate and 95% confidence intervals (CIs). To minimise the risk of overfitting our regression models, multiple imputation was used to impute missing CMR and echocardiography data, which has been shown to be a valid general method for handling missing data.Generalised linear modelling was performed to identify independent associations between clinical characteristics with measures of cardiovascular structure and function; specifically LV mass:volume, GLS, MPR, aortic distensibility, E/A ratio and average E/e′. A separate model, with each CMR and echocardiographic measure as the dependent variable, tested individually against a combination of key clinical characteristics presumed to be associated with diabetic cardiomyopathy,p value < 0.05 was considered statistically significant.Statistical analysis was performed using SPSS version 25.0 . A The study profile is displayed in 2, mean HbA1c was 7.4 ± 1.1% (57 ± 12 mmol/mol), median duration of diabetes was 61  months, 45% were women and 37% were from a black or minority ethnic group. A total of 18 (7%) subjects had diet-controlled T2D, 128 (52%) were taking a single oral glucose-lowering agent, 64 (26%) were taking two or agents, 17 (7%) were taking three or more oral agents, and 20 (8%) were insulin-treated.The baseline demographic characteristics of subjects with T2D are shown in CMR and echocardiography data are displayed in Correlations of key CMR and echocardiographic measures of cardiovascular structure and function with patient clinical characteristics are displayed in Age (rho = 0.259), duration of T2D (rho = 0.192), number of glucose-lowering agents (rho = 0.136) systolic (rho = 0.252) and diastolic BP (rho = 0.192), and serum creatinine (rho = 0.146) correlated significantly with LV mass:volume. Body mass index (rho = −0.125), diastolic BP (rho = 0.194) and serum creatinine (rho = 0.129) correlated significantly with LV GLS.No significant correlations were observed between clinical characteristics and E/A ratio. Age (rho = 0.531), duration of T2D (rho = 0.389), body weight (rho = −0.196) and BMI (rho = −0.141), systolic BP (rho = 0.307), serum creatinine (rho = 0.283) and HbA1c (rho = −0.161) all correlated with echocardiographic estimates of LV filling pressure (E/e′).Age (rho = −0.302), duration of T2D (rho = −0.195) and systolic BP (rho = −0.195) were the only significant correlations with aortic distensibility, each of which had an inverse association.Age (rho = −0.657), duration of T2D (rho = −0.332), body weight (rho = 0.258) and BMI (rho = 0.284), serum creatinine (rho = −0.217) and LDL cholesterol (rho = 0.190) were significantly correlated with stress MBF. Similarly, age (rho = −0.588), duration of T2D (rho = −0.322) and BMI (rho = 0.286), correlated significantly with rest MBF. Only age (rho = −0.227) and serum creatinine (rho = 0.168) were significantly associated with MPR.Multivariable associations of key clinical parameters with CMR and echocardiographic measures of cardiovascular structure and function are presented in p = 0.041), systolic BP  and number of glucose-lowering drugs  were independently associated with LV mass:volume ratio.Age , sex , systolic BP  and serum creatinine  were all independently associated with average E/e′.Age , systolic BP  and BMI  were independently associated with GLS.Smoking history  and sex  were the only independent associations with MPR.Age  and systolic BP .The variables associated independently with aortic distensibility were age  and only utilised echocardiography, with significant risk of overfitting regression analyses. We did find a modest association between the number glucose-lowering therapies and LV mass:volume, which could indicate a weak link between severity of dysglycaemia and concentric LV remodelling. However, the number of diabetes drugs was not associated with any other measure of cardiovascular function. Overall these findings suggest that glycaemic control is not itself a central mechanism driving heart failure in T2D.Contrary to some reports, neither HbA1c nor duration of diabetes were associated with any measure of cardiovascular function in our multivariable analyses, although there was a modest correlation between HbA1c and GLS. The lack of association between glycaemic control and measures of diastolic and systolic dysfunction is perhaps not surprising given the lack of evidence to suggest that improved glycaemic control lowers incident heart failure in people with T2D.22 and these relationships are confirmed in our own cohort. Hypertension has been shown to cause reductions in GLS , is associated with a higher prevalence of diastolic dysfunction in asymptomatic individuals and is a recognised risk factor for HFpEF.25 Co-existence of T2D and hypertension confers a greater risk of cardiovascular disease compared with either diabetes or hypertension in isolation. Intensive BP reduction, however, does not appear to lower the risk of incident heart failure . As with T2D duration, perhaps earlier, aggressive BP reduction in younger adults with T2D at highest risk may be required to halt progression of subclinical cardiac dysfunction and prevent heart failure development. Similarly, a history of never having smoked was strongly associated better GLS, potentially supporting a role for smoking cessation to prevent or reduce systolic dysfunction in people with T2D, amongst other cardiovascular benefits.Increasing systolic BP was associated independently with more concentric LV remodelling, worse GLS and E/e′, and lower aortic distensibility. The associations between T2D, BP, arterial stiffening and LV hypertrophy are well described, Weight loss with a 12-week low-energy diet has been suggested recently to reduce supra-normal LV ejection fraction in people with T2D, which may represent normalisation of hyperdynamic LV function, although further studies are needed to confirm the effects of weight loss on GLS.The other marker of metabolic disease examined in this study – BMI – was associated with “higher” GLS (described by an inverse regression coefficient). This suggests that increasing BMI leads to hyperdynamic LV function. It is recognised that obesity is associated with increased sympathetic activity, which may result in hyperdynamic LV function.n = 25 and n = 23) preventing multivariable analyses.30 The metabolic determinants of microvascular dysfunction and the relationship between MPR and cardiac systolic and diastolic dysfunction in T2D, therefore, warrant further investigation. Indeed, we have recently shown that MPR is associated with aerobic exercise capacity in asymptomatic adults with T2D, independent of age, sex, ethnicity, smoking status, glycaemia and diastolic function. This suggests a central role for microvascular dysfunction in SBHF in people with T2D.Lastly, we found in our T2D patients that only increasing age and female sex were associated with lower MPR. Although microvascular dysfunction is thought to be a key determinant of diabetic cardiomyopathy, none of our modifiable clinical risk factors were significantly associated with MPR in multivariable analysis. Two previous studies have reported correlations between fasting glucose and HbA1c, but both were limited by small sample sizes  improve subclinical cardiovascular dysfunction is not known.