Subjects with Type 1 diabetes mellitus (T1DM) have an increased incidence of heart failure (HF). Several pathophysiological mechanisms have been involved in its development. The aim of this study was to analyze the potential contribution of the advanced lipoprotein profile and plasma glycosylation (GlycA) to the presence of subclinical myocardial dysfunction in subjects with T1DM.Thousand & 1 study) with either diastolic and/or systolic subclinical myocardial dysfunction, and a control group without myocardial dysfunction, matched by age, sex and HbA1c. All underwent a transthoracic echocardiogram and an advanced lipoprotein profile obtained by using the NMR-based Liposcale® test. GlycA NMR signal was also analyzed. Systolic dysfunction was defined as left ventricular ejection fraction ≤ 45% and diastolic dysfunction was considered as E/e′≥12 or E/e′ 8–12 + volume of the left atrium > 34 ml/m2. To identify a metabolic profile associated with the presence of subclinical myocardial dysfunction, a multivariate supervised model of classification based on least squares regression (PLS-DA regression) was performed.We included subjects from a Danish cohort of T1DM subjects , and higher BMI (p = 0.013), serum NTproBNP concentration (p = 0.001), systolic blood pressure (p < 0.001), albuminuria (p < 0.001), and incidence of advanced retinopathy (p < 0.001). The supervised classification model identified a specific pattern associated with myocardial dysfunction, with a capacity to discriminate patients with myocardial dysfunction from controls. PLS-DA showed that triglyceride-rich lipoproteins (TGRLs), such as VLDL  and IDL (IDL cholesterol content), as well as the plasma concentration of GlycA, were associated with the presence of subclinical myocardial dysfunction.Proatherogenic TGRLs and the proinflammatory biomarker Glyc A are strongly associated to myocardial dysfunction in T1DM. These findings suggest a pivotal role of TGRLs and systemic inflammation in the development of subclinical myocardial dysfunction in T1DM.The online version contains supplementary material available at 10.1186/s12933-022-01652-z. Diabetes mellitus (DM) and heart failure (HF) are two multifaceted entities that involve high morbidity and mortality when both conditions coexist , 2. The In population-based studies, the risk of HF in patients with diabetes (particularly T2DM) is significantly increased following adjustment for well-established HF risk factors . The resSeveral pathophysiological mechanisms directly affecting the structure and function of the myocardium have been proposed to contribute to the development of diabetic cardiomyopathy. Among those described are hyperglycemia, hyperinsulinemia, inflammation and increased levels of circulating fatty acids (FAs) and triglycerides (TGs) –17. SystLipotoxicity and cardiac lipid accumulation are other factors that have been related to the etiopathogenesis of diabetic cardiomyopathy . In thisDiabetic dyslipidaemia may also contribute to the diabetic myocardial dysfunction. Particularly, the excess flux of mobilized FAs to the liver promotes overproduction of TG-rich lipoproteins (TGRLs) and their remnants. Elevations in circulating TGRLs are frequently associated with increased concentrations of remnant cholesterol and with reduced high-density lipoproteins (HDL) cholesterol, and all contribute to the development of ischemic heart disease . HoweverTo the best of our knowledge, no previous studies in T1DM patients have studied the relationship between metabolic advanced profile with subclinical HF, defined as presence of impaired cardiac diastolic and/or systolic function without previous clinical manifestation of HF. Thus, the present study aims to analyze the contribution of inflammation (GlycA) and an advanced lipoprotein profile to the presence of subclinical myocardial dysfunction in a well-defined cohort of T1DM patients.Thousand & 1 study cohort study. This study was carried out at the Steno Diabetes Center in Copenhagen (SDCC) with cardiology examinations conducted at the Department of Cardiology, Copenhagen University Hospital Herlev-Gentofte. It was conducted between April 1st, 2010, and April 1st, 2012, and was based on a large cohort of 1.093 patients with T1DM without known heart disease. Patients were included if they were 18 years of age or older, attending the outpatient clinic at the SDCC, diagnosed with T1DM, without known heart disease , and if willing to participate in the study. The study population has been described in detail elsewhere  concentrations of N-terminal fragment of pro-B-type natriuretic peptide (NTproBNP) , and mid-regional pro atrial natriuretic peptide (MRproANP) . Also, the percentage of subjects with E/e′ >8 on echocardiography was higher in subjects with myocardial dysfunction compared with those without myocardial dysfunction . Additionally, the use of statin and antihypertensive therapies was more frequent in subjects with myocardial dysfunction than in those without (p = 0.039 and p < 0.001 respectively). Finally, subjects with myocardial dysfunction were more likely to have advanced stages of retinopathy and albuminuria (p < 0.001 for both comparisons) than those without.Our study population comprised a total of 304 T1DM subjects  with a median  age of 62.1  years at inclusion, median diabetes duration of 33 years and a median HbA1c value of 8.0%. Clinical characteristics by group are shown in Table Results from the lipoprotein and glycoprotein profile are shown in Table We used a multivariant classification approach based on PLS-DA in order to identify a specific lipoprotein and glycoprotein profile associated with myocardial dysfunction in subjects with T1DM. Figure This supervised classification model succeeded in identifying a specific pattern associated with myocardial dysfunction, with a capacity to discriminate diabetic patients with myocardial dysfunction from the rest of the individuals without CVD, in a modest but significant way in relation to fortuitously obtaining the correct classification .In that sense, we used the PLS-DA classification approach to investigate which variables discriminated best between subjects with myocardial dysfunction and controls . LV1 showed that the variables with the most significant contribution to explain the presence of myocardial dysfunction in T1DM subjects beyond well-established risk factors included: NMR-determined GlycA area and H/W GlycA ratio as well as TGRLs, such as VLDL  and IDL (IDL cholesterol content). In the second latent variable , other clinical variables including diabetes duration and LDL related characteristics (LDL-Z) became discriminative, whereas VLDL related variables were no longer discriminant. Furthermore, we compared the predicted probability of the presence of myocardial dysfunction when NMR variables were added together with traditional risk factors by using logistic regressions. Supplementary Fig. 1 shows the predicted probability of myocardial dysfunction in a model (model 1) including only classical risk variables . We built a second model (model 2) including both classical variables and the NMR-assessed biomarkers. The inclusion of the NMR variables in this second model significantly increased the area under the ROC curve from 0.62 [0.56–0.68] to 0.67 [0.61–0.73], with a net reclassification analysis improvement considering NMR-assessed parameters of 21%.To our knowledge, this is the first study to date evaluating the association between a metabolic advanced profile with subclinical myocardial dysfunction assessed with echocardiography in subjects with T1DM. The analysis has been performed in a well characterized large cohort of T1DM patients without prior CVD. Our data showed that the inflammation biomarker GlycA as well as VLDL-related variables  and IDL-related variables (IDL cholesterol content) were associated with the presence of myocardial dysfunction in T1DM subjects.Although the underlying mechanisms explaining the myocardial dysfunction remain still obscure, accumulating evidence supports the role of chronic inflammation in its manifestation and progress to HF –33. In sA main finding of our study was that GlycA values allowed identification of T1DM subjects with and without subclinical myocardial dysfunction. Our data are in line with other study that support the concept that GlycA is associated with an increased risk of HF, particularly HFpEF, which is independent of traditional CVD risk factors and other inflammatory markers . To our Our data also showed that some characteristics of VLDL-related particles, together with GlycA, could help to better discriminate between T1DM subjects with and without subclinical myocardial dysfunction. Regarding T1DM, the advanced characteristics of VLDL has been positively and independently associated with arterial stiffness . LikewisAdditionally, the role of TGRLs in HF has been previously established. In two prospective studies of 113,554 individuals from the general population in Denmark, a higher risk of HF for stepwise higher non-fasting TGs  was found .Although evidence supporting a relationship between cholesterol remnants and non-ischemic causes of HF is limited, the induction of VLDL receptor (VLDLR) abundance and TGRL uptake by cardiomyocytes in an experimental postprandial setting  suggest According to previous studies, the circulating baseline levels of GlycA exhibit significant positive associations with incident CVD event rates and associated mortality . RemarkaThe multivariant approach used in the present study by using the PLS-DA methodology helped in identifying concomitant lipoprotein characteristics (TGRLs) that, together with the proinflammatory GlycA, could mainly account for myocardial dysfunction in T1DM subjects on top of the commonly used traditional and well-established risk factors, including BMI, gender, HbA1c or diabetes duration. Inflammation showed the higher discriminant ability distinguishing myocardial dysfunction among T1DM patients, with the GlycA area being the highest contributor to the first multidimensional latent variable (LV1). Of note, diabetes duration helped to discriminate myocardial dysfunction from non-myocardial dysfunction T1DM patients only once the inflammatory signature was considered, as shown in the second latent variable (LV2) of the multivariable classification analysis. Furthermore, this second multidimensional latent variable showed a loss of association between isolated increased TG-rich parameters and myocardial dysfunction. Therefore, our data revealed an interaction between GlycA and TGRLs in T1DM subjects with myocardial dysfunction. This association was lost in those patients without myocardial dysfunction.Thousand & 1 study results, patients with myocardial dysfunction were likely to be older and have longer diabetes duration than subjects with normal function. Therefore, by selecting subjects who were similar for these criteria, at least one group may be unrepresentative of the population from which it came, and the abnormalities observed in the NMR profile may be different from a truly representative population. Furthermore, considering the condition of hypertension as a risk factor for myocardial dysfunction, is important to emphasize that the use of antihypertensive therapies was significantly more frequent in the group of subjects with myocardial dysfunction. Nevertheless, due to the fact that these drugs can be used both as an antihypertensive treatment as well as a nephroprotective intervention, we consider this as a limitation to assess the condition of hypertension associated with myocardial dysfunction. Additionally, the small number of subjects who presented systolic dysfunction within subjects with myocardial dysfunction  implies that the results obtained in the present study should be primordially referred to diastolic dysfunction. Finally, since this study is cross-sectional we cannot infer causality between the metabolic profile and presence of myocardial dysfunction. Possible strengths should also be mentioned, since the current population is selected from a large study of ambulatory T1DM patients without previous known heart disease. This cohort had the advantage of a relatively low HbA1c and may therefore be at a lower risk of HF than typical T1DM patients and that may potentially have strengthened our findings.Our study had some limitations that should be taken into account. We matched individuals with and without subclinical myocardial dysfunction by age, sex and glycemic control. This may have resulted in a biased comparison because, according to original The present study uncovered associations between subclinical myocardial dysfunction and advanced NMR metabolic characteristics in patients with T1DM that were hidden in conventional analyses. The GlycA area and the H/W GlycA ratio, as well as TGRLs (VLDL and IDL) related variables, were revealed as strong contributors of subclinical myocardial dysfunction. According to the aforementioned results, we propose a pivotal role of TGRLs characteristics and systemic inflammation reflected by the GlycA biomarker in subclinical myocardial dysfunction in T1DM patients.Estimation of the presence of subclinical myocardial dysfunction among T1DM patients and its relationship with lipoprotein and glycoprotein characteristics revealed in this study still deserves more attention in the future. Therefore, further studies will be required to clarify the potential clinical applications of these findings as well as to investigate their biological basis.Below is the link to the electronic supplementary material.Supplementary Material 1: Supplementary Fig. 1: Comparison of the distribution of the predicted probabilities showing the classification performance of the presence of MCD between two different models, being the x-axis the predicted probabilities for both classes and the y-axis the count of observations. A: Model 1 includes classical risk variables . B: Model 2 includes classical risk variables and the NMR-assessed biomarkers. The inclusion of NMR parameters significantly increased the AUROC from 0.62 [0.56–0.68] to 0.67 [0.61–0.73], with a NRI considering NMR-assessed parameters of 21%. MCD: myocardial dysfunction, BMI: body mass index, NMR: nuclear magnetic resonance, AUROC: area under the ROC curve, NRI: net reclassification improvement.


The incidence of late TLR was significantly lower in the statin than non-statin group , and within the statin group, it was significantly lower in the follow-up low-density lipoprotein cholesterol (LDL-C) < 100 than ≥ 100 mg/dL level subgroup . Furthermore, in positive remodeling lesions and non-small vessel size lesions, the incidence of late TLR was significantly lower in the statin than non-statin group . Lowering the LDL-C level using statins was more effective for preventing late TLR after everolimus-eluting stent implantation. Evaluating pre-interventional vessel remodeling patterns and vessel size might be helpful to stratify lesions at high risk of late TLR.Clinical evidence demonstrating the impact of statins for preventing late target lesion revascularization (TLR) after newer-generation drug-eluting stent implantation and differences in the effect of statins on late TLR according to pre-interventional vessel remodeling and vessel size is limited. We retrospectively evaluated 1193 de novo lesions in 720 patients who underwent everolimus-eluting stent implantation using intravascular ultrasound from January 2010 to December 2012. The primary endpoint was late TLR. Lesions were divided into the statin group (The online version contains supplementary material available at 10.1007/s00380-022-02104-0. Despite improvements in percutaneous coronary intervention (PCI) techniques and advancements in newer-generation drug-eluting stent (DES) technology and adjunctive medical therapy, late target lesion revascularization (TLR) beyond 1 year after DES implantation still exists, and the prevalence of late TLR is not negligible. It is now understood that some cases of late TLR arise from the pathogenic concept of neoatherosclerosis. Recent studies of histopathology and intracoronary imaging have shown that neoatherosclerotic changes within the stented segment are characterized by accumulation of lipid-laden foamy macrophages, and such changes have been identified as a primary cause of delayed failure such as late TLR . AlthougWe also tested the hypothesis that the characteristics of underlying plaques are associated with an increase in late TLR. A pathological study showed that coronary artery plaques that undergo positive remodeling have a significantly larger lipid core and a higher macrophage count than those that undergo vessel shrinkage . FurtherThis retrospective cohort study was performed to evaluate the incidence of TLR after EES implantation for de novo coronary artery lesions from January 2010 to December 2012 in two centers . Patients who underwent implantation of at least one EES were included in the study, regardless of whether they had received stents other than an EES. The study flow chart is shown in Fig. To evaluate the association between the follow-up LDL-C level and late TLR, both the statin group and non-statin group were subdivided into three groups according to the follow-up LDL-C level and in accordance with practice guidelines: the ≤ 70, 71–99, and ≥ 100 mg/dL subgroups. Furthermore, we evaluated the association between the follow-up LDL-C level and late TLR according to pre-interventional vessel remodeling and the vessel size based on IVUS data. Therefore, the lesions were divided into two groups according to pre-interventional vessel remodeling and the vessel size.The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice standard, and it was approved by the ethics committee at each institution. We obtained consent from all individual participants in the study using an opt-out procedure.Demographic, clinical, angiographic, procedural, and outcome data were obtained from the hospital records or databases at each institution. Follow-up information was obtained from hospital charts or by contacting the patients or their referring physicians.The follow-up coronary angiography plan was left to the discretion of each referring physician; routine follow-up angiography was not performed. The angiographic follow-up or coronary computed tomography angiography follow-up rate was 84.6%, and the median follow-up duration was 387 days .Clinical follow-up data were retrospectively evaluated at 4 years, and follow-up intervals were calculated from the day of the index PCI procedure. The median follow-up duration was 1460 days . Follow-up LDL-C data after the index procedure were retrospectively obtained from the electronic database. When several follow-up LDL-C data were available in a given patient, we used the measurement closest to 1 year after PCI. Follow-up serum lipid levels were optionally measured, and the median interval from the index procedure to the measurement of the LDL-C level was 352 days .Lesions were treated with standard interventional techniques, including mandated balloon dilatation before stent implantation, if required. The duration of dual antiplatelet therapy was left to the discretion of each referring physician. For statin therapy, we did not set indications for the use of statins, and the type of statin was left to the discretion of each referring physician.IVUS imaging procedures were performed before the coronary intervention and immediately after the guide wire crossed the lesion or pre-balloon dilatation if the IVUS catheter could not pass the lesion. All IVUS images were obtained after the intracoronary administration of nitrates using a 20-MHz, 2.9-Fr IVUS imaging catheter . The cross-sectional areas (CSA) of the external elastic membrane (EEM), lumen, and stent were measured at the minimum lumen site and reference segments. The proximal reference was defined as the site with the largest lumen proximal to a stenosis and the distal reference site was defined as the site with the largest lumen distal to a stenosis. The remodeling index (RI) was defined as lesion EEM CSA/average of the proximal and distal reference segment EEM CSA, and the patterns of pre-intervention vessel remodeling were classified into two categories: positive and negative remodeling, defined as a RI > 1.00 and RI ≤ 1.00, respectively . Vessel The primary outcome in this study was late TLR assessed during the 4-year follow-up interval after EES implantation. TLR was defined as repeat PCI or coronary artery bypass grafting due to restenosis of the target lesion in association with recurrent angina and/or evidence of myocardial ischemia. Early TLR was defined as TLR performed within 1 year after stent implantation, and late TLR was defined as TLR performed > 1 year after stent implantation. Retreatment for stent thrombosis was not considered part of TLR. Death, cardiovascular death, myocardial infarction, stroke, and target vessel revascularization were also assessed as endpoints.t test. The Wilcoxon rank-sum test was used for comparisons of non-normally distributed continuous variables. The cumulative incidence was estimated with the Kaplan–Meier method, and differences were assessed with the log-rank test. To evaluate the impact of statin therapy and the follow-up LDL-C level on late TLR, we used the landmark analysis at 1 year. We used a Cox proportional hazard model to identify the independent risk factors for early and late TLR separately. The variables included in the Cox multivariable regression analysis were age, sex, diabetes mellitus, hemodialysis, statin therapy, stent length of > 28 mm, lesion bending, ostial right coronary artery stenting, ostial left circumflex stenting, and a minimum stent area of < 5.0 mm2 with reference to previous reports [p value of < 0.05 was considered statistically significant. All data were analyzed using JMP version 16.0 software .Categorical variables are reported as number and percentage and were compared using the chi-square test or Fisher’s exact test. Continuous variables with a normal distribution are expressed as mean ± standard deviation. Variables with a non-normal distribution are expressed as median and interquartile range. Continuous variables with a normal distribution were compared using Student’s  reports , 14. We Among the study population of 720 patients with 1193 lesions, 39.4% patients were of advanced age (> 75 years), 40.2% had diabetes mellitus, and 1.8% were undergoing hemodialysis. The patients presented with either stable angina (1128 lesions) or acute coronary syndrome (65 lesions) (Table p = 0.001). The incidence of early TLR was not significantly different between the statin and non-statin groups , whereas the incidence of late TLR was significantly lower in the statin group than in the non-statin group    (Supplementary Table 1).During the 4-year follow-up period, the cumulative incidence of TLR in the overall lesions was 4.5% Fig. , that ofThere were no significant differences in the incidences of all-cause death, cardiac death, myocardial infarction, or stroke between the two groups Table .Table 3Ep < 0.001). In the statin group, the risk for late TLR was significantly lower in the follow-up LDL-C level < 100 mg/dL subgroup (≤ 70 + 71–99 mg/dL subgroups) than in the follow-up LDL-C level ≥ 100 mg/dL subgroup  . After adjusting for confounding factors included follow-up LDL-C level < 100 mg/dL by a Cox regression model, the follow-up LDL-C level < 100 mg/dL was associated with a significantly decreased incidence of late TLR in the statin group, whereas the follow-up LDL-C level < 100 mg/dL was not significantly associated in overall (Supplementary Table 2).No significant differences were found in the baseline lipid profile between the statin and non-statin groups, but the follow-up LDL-C level was significantly lower in the statin group than in the non-statin group , a total stent length of > 28 mm , and ostial left circumflex coronary artery stenting ; however, statin use was not significant . The risk factors for late TLR were lesion bending  and statin use .The results of the multivariable analysis of early TLR and late TLR are shown in Table The IVUS data are summarized in Table The positive remodeling group contained 439 (37%) lesions, and the negative remodeling group contained 754 (63%) lesions. In the positive remodeling group, the incidence of late TLR was significantly lower in the statin group than in the non-statin group. In negative remodeling group, however, the incidence of late TLR was not significantly different between the statin group and non-statin group  were non-small vessel size lesions and 462 (39%) were small vessel size lesions. Among the non-small vessel size lesions, the incidence of late TLR was significantly lower in the statin group than in the non-statin group. Among the small vessel size lesions, however, the incidence of late TLR was not significantly different between the statin and non-statin groups. Within the statin group, the incidence of late TLR in non-small vessel size lesions was significantly lower in the follow-up LDL-C < 100 than ≥ 100 mg/dL subgroup, whereas the incidence of late TLR in small vessel size lesions was not significantly different between the follow-up LDL-C < 100 and ≥ 100 mg/dL subgroups Fig. .Fig. 5InThe four main findings of this study can be summarized as follows. First, late TLR after EES implantation occurred without attenuation of the annual incidence up to 4 years, and statin therapy was associated with a significantly decreased incidence of late TLR. Second, a follow-up LDL-C level of ≥ 100 mg/dL was associated with a higher risk for late TLR than was a follow-up LDL-C level of < 100 mg/dL. Third, more severe positive remodeling in the culprit lesion was associated with a greater effect of statin therapy on late TLR. Finally, a larger vessel size in the culprit lesion was associated with a greater effect of statin therapy on late TLR.In the present study, late TLR continuously occurred without attenuation up to 4 years, and the incidence rate was similar to those reported in other previous registries evaluating second-generation DES implantation , 15. In It has been reported that LDL-C reduction therapy using statins can provide better clinical outcomes in ischemic heart disease patients , 21, andArterial remodeling is defined as geometric alteration of the arterial wall in response to the progression of atherosclerosis. Positive remodeling has been detected more frequently in unstable lesions, and unstable plaques generally have higher lipid content. A previous IVUS study showed a higher lipid content in coronary plaques with positive remodeling and a larger vessel size . AtherosAccording to a pathological study by Nakazawa et al. , the preOur study had several limitations. First, the present study was a retrospective study using data from a non-randomized, observational registry and selection bias in using statins might have affected the results. Second, there was a considerable difference in patients’ and lesions’ background characteristics among groups. Third, we used a less contemporary cohort of patients for our study, which may have affected both the LDL-C target level and rates of statin use compared with a more modern cohort. Fourth, because information about medical therapy was obtained only at hospital discharge, adherence to medications and crossover of medications were not evaluated in this study. Fifth, lesions without IVUS imaging and lesions that could not be evaluated by IVUS imaging because of calcification or ostium lesions were excluded from this analysis. These exclusions might have affected the results. Furthermore, exclusion of patients with no data after hospitalization may have resulted in selection bias.In this retrospective study, the lowering LDL-C level using statins was more effective for preventing late TLR after EES implantation. Evaluating pre-interventional vessel remodeling patterns and vessel size using imaging might be helpful to stratify lesions at high risk of late TLR.Supplementary file1 (DOCX 21 KB)Supplementary file2 (DOCX 21 KB)Below is the link to the electronic supplementary material.


MIRTH  is a transcatheter ventricular remodeling procedure. A transvenous tension element is placed within the walls of the beating left ventricle and shortened to narrow chamber dimensions. MIRTH uses 2 new techniques: controlled intramyocardial guidewire navigation and EDEN . MIRTH caused a sustained reduction in chamber dimensions in healthy swine. Midventricular implants approximated papillary muscles. MIRTH shortening improved myocardial contractility in cardiomyopathy in a dose-dependent manner up to a threshold beyond which additional shortening reduced performance. MIRTH may help treat dilated cardiomyopathy. Clinical investigation is warranted. Myocardial remodeling devices aim to treat heart failure and enhance ventricular mechanical efficiency by reducing chamber size and wall stress according to Laplace principles. Numerous surgical and transcatheter global and segmental remodeling strategiesWe engineered an approach to narrow the left ventricle circumferentially by implanting an intramyocardial tension element percutaneously within the ventricular walls using commercial off-the-shelf devices. This required new catheter techniques to navigate an extravascular guidewire within the heart muscle while remaining within the endocardial and epicardial boundaries in a procedure called MIRTH .We hypothesized that in a large-mammal model: 1) transvenous catheter tools can be directed purposefully within beating ventricular myocardium; 2) local electrograms indicating midmyocardial position can ensure the navigating guidewire remains between endocardial and epicardial boundaries; 3) basal- or midmyocardial-level MIRTH loops can narrow corresponding left ventricular regions in naive swine; 4) MIRTH navigation can be accomplished in naive and fibrotic myocardium; and 5) MIRTH traction exhibits a dose-response relationship on myocardial geometry and function.Animal experiments were approved by the institutional animal use and care committee and followed contemporary National Institutes of Health guidelines. Juvenile Yorkshire swine (40-53 kg) were pretreated with amiodarone and underwent general anesthesia, mechanical ventilation, percutaneous jugular venous and femoral arterial access, heparin anticoagulation, continuous invasive hemodynamic monitoring, and cefazolin prophylaxis.After technical development , MIRTH iA guidewire penetrates the myocardium from the proximal coronary sinus into the heart base, is directed to encircle the left ventricle along a “short-axis” trajectory between endocardial and epicardial walls, is retrieved and externalized, and then is exchanged for a tensioning element that is shortened to achieve the desired geometry and then locked in place.To conduct MIRTH, a transvenous catheter is first positioned in the coronary sinus to deliver a needle catheter  into the posterobasal left ventricular myocardium , Video 1We characterized unipolar intramyocardial electrogram patterns that reflected relative intramyocardial depth . ElectroProcedures were guided by biplane fluoroscopy  with projection angles selected by cone-beam computed tomography , EDEN electrograms (described later), and right-sided intracardiac echocardiography .Cardiac function was assessed using CMR at 0.55-T .,0 (x-intercept of linear ESPVR regression), end-diastolic pressure-volume relationship slope (of the linear end-diastolic pressure-volume relationship regression), load-independent measures of contractility , stroke work (area bounded by the pressure-volume loop), potential energy (LVESP [(ESV − V0)/2] − LVEDP [(EDV − V0)/4]), pressure-volume area , and ventricular mechanical efficiency (stroke work/PVA) were calculated for each condition. Implant integrity over time was assessed in vitro  during balloon caval occlusion.in vitro  and in vAfter euthanasia, histologic samples were collected at points of interest, fixed in 10% formalin, and stained with hematoxylin-eosin and Masson’s trichrome.P values <0.05 were deemed statistically significant, although there were no corrections for multiple comparisons in time series.CMR was analyzed using SuiteHeart v5.0.2 (NeoSoft) and computed tomography with 3mensio v10.2 . Data were analyzed using R v4.1.1 (R Core Team). Continuous variables are presented as median with 25th to 75th percentiles (quartile 1-quartile 3) and categoric variables as counts (percentages). Pre- and postimplant data were compared using Wilcoxon signed rank tests. The technique was developed in 18 nonsurvival procedures  and thenUnipolar EDEN electrogram morphology varied depending on the intramyocardial depth of the guidewire tip as depicted in Two early implants broke as revealed by computed tomography between days 60 and 90. The failure mechanism was abrasion of standard polyethylene suture, prompting a change to ultra-high molecular weight polyethylene suture. Nine of 12 survived to 90 days; the other 2 died of unrelated bacterial sepsis confirmed at necropsy.At 90 days, despite aggressive overshortening in growing animals, no MIRTH implant exhibited myocardial erosion. Minor (“protective”) fibrosis surrounded the implants, and the floor of the coronary sinus was fully endothelialized.In healthy animals, MIRTH implants were tailored to shorten the left ventricular perimeter by an arbitrarily selected one-third based on preprocedure CMR. An immediate reduction in diastolic and systolic chamber dimensions was evident at the level of the implant . SimilarP = 0.005) and 9 mL , respectively, in healthy animals, leading to a 6% increase in left ventricular ejection fraction (P = 0.045) (P = 0.041) in left ventricular end-diastolic pressure (LVEDP) that normalized during follow-up.Indexed left ventricular end-diastolic and -systolic volumes were immediately reduced by 13 mL  . MIRTH cBy design, MIRTH limited local myocardial strain; it induced an immediate reciprocal favorable increase in remote myocardial strain. This was observed consistently among naive  and card,o changed concordantly with Ees. After a peak, additional shortening degraded performance  after infarction . The mos(P = NS). By contrast, regional strain analysis revealed remote increases in the base and apex for midventricular implants and in the mid and apical ventricle for basal implants  MIRTH distributes the centripetal load uniformly within the myocardial wall, unlike anchor-based remodeling devices that focus load discretely at anchor locations; 2) MIRTH shortening achieves a predictable reduction in left ventricular chamber dimensions that is sustained for the months-long duration of testing without endomyocardial erosion; 3) MIRTH shortening favorably increases load-independent measures of myocardial contractility (Ees and PRSW) in a dose-dependent manner up to a maximum, beyond which additional shortening unfavorably reduces contractility and causes end-diastolic pressure to rise; 4) because it is a regional rather than a global myocardial remodeling device, MIRTH does not appear to have a deleterious effect on ventricular compliance; 5) MIRTH implants can be positioned at will ; and 6) at a midventricular level, MIRTH approximates papillary muscles, which may reduce leaflet traction contributing to functional mitral regurgitation.The MIRTH procedure introduces several novel techniques including: 1) controlled intramyocardial guidewire navigation; 2) EDEN unipolar electrogram guidance; 3) a transmural anchor guidewire into the left ventricular cavity inspired by Khelimskii et al,In MIRTH, we steer a commercially available angioplasty guidewire freely within the walls of the left ventricle. After the addition of a 30° to 40° CTO tip bend, and once delivered to the ventricular myocardium, a combination of forward and rotational movements grants the ability to “navigate” with multiple degrees of freedom. We show that wires can be steered at will to accomplish any desired intramyocardial position  irrespective of myofiber orientation.Identifying the guidewire tip position has proven difficult using conventional imaging modalities, which suffer from poor soft tissue definition, off-axis imaging planes, and poor intramyocardial device tracking. We developed the EDEN technique as a simple way to continuously ensure the operator of an appropriately deep intramyocardial position. Using the uninsulated guidewire tip as a unipolar electrode, we characterized local unipolar electrogram morphology that distinguishes the desirable position  from undesirable positions too close to the endocardial or epicardial surfaces. When subepicardial or subendocardial electrograms are encountered, the operator simply withdraws and redirects the guidewire until a deep myocardial signal is identified. This is analogous to a coronary guidewire operator withdrawing and redirecting a guidewire from an undesirable side branch.Finally, we were able to accomplish guidewire navigation and traversal even through fibrotic, chronically infarcted, and thinned (3 mm) myocardium using tactile feedback and imaging guidance even when the EDEN electrogram amplitude was attenuated or absent.An intracavitary anchor guidewire  permitted efficient equipment exchanges and delivery of a stent-retriever snare through a single access point. This new technique may have other applications beyond MIRTH when percutaneous access to the left ventricular myocardium is otherwise unavailable.Ventricular wall stress is a major determinant of myocardial oxygen consumption.,0 have a complex relationship that has been reviewed by Burkhoff et al0, similar to that observed in our cardiomyopathic animals. Importantly, we observed an inflection in LVEDP increase at optimum MIRTH shortening, which can serve as a useful and easily measured parameter to titrate shortening during implantation in patients.We show that in cardiomyopathic ventricles MIRTH exhibits a biphasic dose response in ventricular performance and myocardial energetics. Progressive MIRTH circumferential shortening improves Ees and PRSW (as load-independent measures of contractility) and ventricular mechanical efficiency up to a maximum, beyond which additional MIRTH shortening causes these measures to decline. In addition, PVA, which is directly proportional to myocardial oxygen demand,We observed no late myocardial erosion of MIRTH implants in a model that may increase erosion propensity; these rapidly growing juvenile swine increased myocardial mass by 175%.MIRTH addresses limitations of other ventricular remodeling approaches. It broadly redistributes the centripetal load to avoid avulsion and device fractures observed in endocardial anchor-based devices such as AccuCinch (Ancora Heart).,P values should be interpreted with caution. The sample size for animals undergoing pressure-volume loop analysis was small.We tested only commercial off-the-shelf clinical catheter tools rather than purpose-built devices that may be easier to use and may prove more durable. Our abbreviated fatigue testing does not meet contemporary standards for cardiovascular implants.We await survival tests of appropriate MIRTH shortening in animal models of cardiomyopathy. It is possible that ischemic cardiomyopathy, pacing-induced cardiomyopathy, or toxic cardiomyopathy models may not predict MIRTH performance in patients.MIRTH may have value in the treatment of dilated cardiomyopathy. MIRTH may also attenuate unfavorable remodeling after acute myocardial infarction. Purpose-built devices would be desirable for clinical investigation.Intramyocardial navigation is also a key step in the Septal Scoring Along Midline Endocardium technique of transcatheter ventriculomyotomy for left ventricular outflow obstructionPerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: Patients with dilated cardiomyopathy who fail to respond to optimal medical therapy and fail to respond to or are ineligible for cardiac resynchronization therapy have few options short of ventricular assist devices and heart transplantation. Mechanical heart failure therapies may fill this unmet clinical need and delay, reverse, or prevent the progression of left ventricular dilation.TRANSLATIONAL OUTLOOK: Controlled intramyocardial guidewire navigation is a new procedural technique that permits access to any location within the ventricular myocardium. Notoriously inaccessible locations in the basal interventricular septum (“summit”), base of the papillary muscles, or deep within the ventricular walls are now accessible percutaneously using commercially available devices for interventional electrophysiological and structural heart procedures.We describe MIRTH, a novel transcatheter myocardial remodeling device and strategy, in animals. Intramyocardial guidewire navigation and EDEN intracardiac electrogram guidance are completely new concepts that may inspire and enable new cardiovascular interventions. Clinical investigation is warranted.This work was supported by the Division of Intramural Research, National Heart Lung and Blood Institute, National Institutes of Health USA (grant Z01-HL006040 to Dr Lederman). Drs Bruce and Lederman are coinventors on patents, assigned to National Institutes of Health, on MIRTH-related devices. Dr Rogers is a consultant and physician proctor for Edwards Lifesciences and Medtronic; is a Medtronic advisory board member; and has an equity interest in Transmural Systems. Drs Babaliaros and Greenbaum receive institutional research support from Abbott Vascular, Ancora Heart, Edwards Lifesciences, Gore Medical, Jena Valve, Medtronic, Polares Medical, Transmural Systems, and 4C Medical; receive consulting fees from Abbott Vascular, Edwards Lifesciences, and Medtronic; and have equity interest in Transmural Systems. Drs Campbell-Washburn, Herzka, and Lederman are investigators on a U.S. Government Cooperative Research and Development Agreement with Siemens. Siemens participated in the modification of the MRI system from 1.5-T to 0.55-T and provided investigational intracardiac echocardiography devices. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.


Despite the significant contribution of circumferential shortening to the global ventricular function, data are scarce concerning its prognostic value on long-term mortality. Accordingly, our study aimed to assess both left (LV) and right ventricular (RV) global longitudinal (GLS) and global circumferential strain (GCS) using three-dimensional echocardiography (3DE) to determine their prognostic importance.Three hundred fifty-seven patients with a wide variety of left-sided cardiac diseases were retrospectively identified  who underwent clinically indicated 3DE. LV and RV GLS, and GCS were quantified. To determine the prognostic power of the different patterns of biventricular mechanics, we divided the patient population into four groups. Group 1 consisted of patients with both LV GLS and RV GCS above the respective median values; Group 2 was defined as patients with LV GLS below the median while RV GCS above the median, whereas in Group 3, patients had LV GLS values above the median, while RV GCS was below median. Group 4 was defined as patients with both LV GLS and RV GCS below the median. Patients were followed up for a median of 41 months. The primary endpoint was all-cause mortality.p < 0.001) and RV GCS  were associated with increased risk of death by univariable Cox regression. Patients with both LV GLS and RV GCS below the median (Group 4) had a more than 5-fold increased risk of death compared with those in Group 1  and more than 3.5-fold compared with those in Group 2 . Interestingly, there was no significant difference in mortality between Group 3 (with LV GLS above the median) and Group 4, but being categorized into Group 3 versus Group 1 still held a more than 3-fold risk .Fifty-five patients (15%) met the primary endpoint. Impaired values of both LV GCS (HR, 1.056 , The impaired values of both LV and RV GCS are associated with long-term all-cause mortality, emphasizing the importance of assessing biventricular circumferential mechanics. Reduced RV GCS is associated with significantly increased risk of mortality even if LV GLS is preserved. Longitudinal strain (LS) of the left (LV) and right ventricles (RV) is a well-established biomarker of ventricular dysfunction, having a robust predictive power to future adverse outcomes in numerous cardiac diseases , 2. In cBesides longitudinal shortening, also circumferential deformation contributes significantly to the ventricular pump function , 5. ThusThe advantages of three-dimensional echocardiography (3DE) over conventional echocardiography opens the door for a more thorough understanding and quantification of the ventricular structure and function, including the measurement of the circumferential strain of both the LV and the RV.Although the detailed assessment of RV function is commonly neglected in left-sided heart diseases, it has been proved that patients who develop RV dysfunction are more symptomatic and carry a higher risk for long-term adverse outcomes than those who do not . ImportaAccordingly, we aimed to assess LV and RV GLS and GCS using 3DE to determine their prognostic relevance.https://rvenet.github.io/dataset/], which comprises of individuals underwent clinically indicated 2D and 3D transthoracic echocardiography at our Center between November 2013 and March 2021. Exclusion criteria were 1) suspicion or presence of any primary right-sided cardiac disease at the first report or during the review process of the previously acquired datasets and 2) suboptimal LV and RV 3D dataset image quality for the respective 3D analysis. Demographic and clinical data  were retrieved from the electronic clinical records. Obtaining written informed consent was waived due to the retrospective nature of the analysis. Our study protocol follows the Declaration of Helsinki and it was approved by the Semmelweis University Regional and Institutional Committee of Science and Research Ethics .Clinically and hemodynamically stable patients with an established diagnosis of left-sided cardiac disease were identified from the previously published RVENet dataset /cardiac resynchronization therapy [CRT]). Fourteen patients were investigated for candidacy for a long-term LV assist device (LVAD) implantation. Ninety-one subjects (26%) were heart transplant recipients (HTX) with a median of 157 days after the operation . Sixty-seven subjects (19%) were patients with severe primary mitral valve regurgitation (MVR) enrolled in a previous prospective study . SeventyPatients who died were older, had a higher prevalence of coronary artery disease and atrial fibrillation, and more frequently underwent ICD implantation in their medical history. Importantly, these patients had higher serum creatinine values than those who survived .2D echocardiographic parameters are summarized in 3DE parameters are summarized in p < 0.001]), nevertheless, RV GCS had the highest discriminative power among all the investigated 2D and 3D echocardiographic parameters . In Group 1, patients had both LV GLS and RV GCS above the median, while in Group 4, both LV GLS and RV GCS were below the median. Group 2 patients had LV GLS values below the median while RV GCS above the median. Group 3 had patients with LV GLS above the median and RV GCS below the median.Out of the 125 patients in Group 1, 37 (30%) were HTX recipients, 19 (15%) were evaluated before atrial fibrillation ablation, 18 (14%) had aortic stenosis, and 51 (41%) had mitral valve disease. Group 2 consisted of 53 patients, of whom 16 (30%) had HFrEF, 11 (21%) were HTX recipients, 6 (11%) were evaluated before atrial fibrillation ablation, and 20 (38%) had aortic stenosis. Group 3 had 54 patients in total, one (2%) with HFrEF, 30 (56%) HTX recipients, 8 (15%) with aortic stenosis, and 15 (28%) with mitral valve disease. Group 4 was composed of 125 patients and had 78 (62%) HFrEF patients, 13 (10%) HTX recipients, 33 (26%) patients with aortic stenosis, and 1 (1%) with mitral valve disease.via Kaplan-Meier curves  Impaired values of both LV and RV GCS were associated with all-cause mortality in univariable Cox models. (2) Among the evaluated multivariable models, the one with LV GLS and RV GCS fitted our data the best. Interestingly, however, only RV GCS was found to be an independent predictor of mortality, whereas LV GLS and creatinine levels were not. (3) Based on the median values of LV GLS and RV GCS, we created four groups that differed significantly in terms of all-cause mortality. Importantly, reduced RV GCS was associated with worse outcomes even if LV GLS was maintained .Recent advances in echocardiographic hardware and software environment enabled the automated and accurate quantification of myocardial mechanics. First and foremost, GLS by 2D speckle tracking echocardiography has emerged as a mainstay parameter of LV systolic function. Due to the representation of subendocardial longitudinally-oriented myofibers, LV GLS is more sensitive to subtle functional impairment in various clinical scenarios than conventional echocardiographic parameters . A meta-analysis comprising 16 published articles provided strong evidence about the prognostic value of LV GLS, which appeared to be superior to LV EF for predicting major adverse cardiac events in patients with different underlying cardiac abnormalities. GLS is now a well-validated and reproducible metric for the quantification of LV longitudinal deformation, and its integration into routine clinical practice is about to be completed in the upcoming years . Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.MTol, AFá, and AKov performed measurements, interpreted results, and drafted the manuscript. MTok, ZL, KS, and AFe performed measurements. MTok, BL, AA, ZL, KS, AFe, WS, BV, AKos, ÁS, BS, and BM reviewed and approved the manuscript. BL, AA, WS, BV, AKos, BS, and AKov enrolled, followed-up, and investigated patients. AKov and BM secured grant support. AFá, MTok, and ÁS performed statistical analysis. AFá prepared figures. All authors contributed to the article and approved the submitted version.


Background: Cardiac Magnetic Resonance (CMR) has a key role in subjects presenting with acute myocarditis, independent from left ventricular ejection fraction; it is widely used as a non-invasive imaging test for both diagnostic and prognostic purposes. However, poor data is available about the CMR-derived prognostic parameters of acute myocarditis with preserved ejection fraction (AMpEF). The aim of this study was to investigate the role of CMR in predicting outcomes in patients followed up for AMpEF, using a composite endpoint of all-cause mortality and hospitalization for heart failure (HF). Methods: We retrospectively enrolled 61 patients with diagnosed AMpEF. All patients underwent biohumoral, echocardiographic and CMR evaluation in the acute phase. Myocarditis was confirmed by Lake–Louis criteria assessed on CMR images. Mean follow-up was 4.8 ± 0.6 years during which a composite endpoint of all-cause mortality and hospitalization for HF was investigated. Results: The population was fairly homogeneous regarding baseline clinical features. In particular, no significant differences in age and main cardiovascular risk factors were found between patients with and without events at follow-up. Seven patients met the endpoint. They had significantly higher levels of circulating neutrophils in the acute phase  and a higher amount of left ventricular mass with delayed enhancement  vs. 12 (8–16) g, p = 0.028). At Cox univariate analysis, DE-LVM was the only significant predictor of endpoint, regardless of the site of inflammation. Conclusions: DE-LVM can predict the composite endpoint of all-cause mortality and hospitalization for HF in a population of patients with AMpEF, representing a new added tool for prognostic stratification. According to the World Health Organization and the International Society and Federation of Cardiology, myocarditis is an inflammatory disease of the heart muscle, whose diagnosis is based on histological, immunological and immunohistochemical criteria .Despite its clear anatomopathological findings, myocarditis is often underdiagnosed, especially in the context of a preserved left ventricular ejection fraction. Myocarditis is clinically evident in 8–10 persons out of 100,000 subjects, but its prevalence on autopsy reaches 44 persons out of every 100,000 . This suThe classification of myocarditis is controversial and still an object of debate. It can present with a wide clinical spectrum, from asymptomatic cases to cardiogenic shock, with variable symptoms according to the extension and the etiology . EtiologAccording to echocardiographic parameters, a classification based on left ventricular ejection fraction is often used because of its simple determination, with consequent impact on the therapeutic strategy. Acute myocarditis with preserved ejection fraction (AMpEF) is still a nebulous clinical entity with scarce and often conflicting evidence in the literature, without evidence-based therapeutic tools. Recently, Georgiopoulos et al. also showed that the presence of late gadolinium enhancement carries independent prognostic value, irrespective of LVEF . Other dIn particular, to our knowledge, no study has evaluated the amount of left ventricular mass with delayed enhancement (DE-LVM) as a tool for outcome stratification specifically in AMpEF patients . The ideWe retrospectively analyzed data of patients referred to our Cardiological Department for acute myocarditis from January 2011 to December 2018. In the acute phase, the diagnosis of myocarditis was suspected on the basis of the combination of personal history, symptoms, physical examination, transthoracic echocardiography and bio-humoral assays, and then confirmed by Lake–Louis criteria on CMR images. Ejection fraction was assessed both by transthoracic echocardiography and CMR in each subject, but only patients with preserved LVEF (≥50%) at CMR were included. Exclusion criteria were: LVEF at CMR < 50%, patients aged less than 18 years old, patients who underwent previous heart transplantation/left ventricular assist device implantation, patients with transvenous pacemaker/defibrillator, or acute HF at presentation.We considered a composite endpoint of all-cause mortality and hospitalization for HF. The study population was then divided into two groups according to occurrence of composite endpoint at follow-up. Informed consent regarding the anonymous use of personal data was obtained from each patient. The study was conducted in accordance with the Declaration of Helsinki .Blood samples were drawn after an overnight fasting period the day CMR was performed. Samples were stored at −80 °C. All patients underwent a thorough biohumoral investigation consisting of complete blood count, serum creatinine, C-reactive protein, hepatic function and high-sensitivity troponin. All the assays were run according to manufacturer instructions. Information about each biomarker was available for all patients.Echocardiographic examination was performed at admission, according to the American Society of Echocardiography/European Association of Cardiovascular Imaging recommendations for chamber quantification , using tLVEF, left ventricular and left atrial volume were assessed using the biplane modified Simpson method from the apical 4- and 2-chamber views. Dimensions of left ventricle and left atrium were indexed to body surface area. From the 4-chamber view, tricuspid annulus plane systolic excursion (TAPSE) was measured by M-mode . Systoli2-weighted imaging, and LGE at 10 min after gadolinium injection in the short-axis (9 to 13 images covering the entire LV), 2-chamber and 4-chamber planes [CMR was performed within three days from hospital admission, using a 1.5 T whole-body scanner . An eight-channel cardiac phased-array receiver surface coil was used for signal reception. In each patient, a set of contiguous short-axis views was acquired from the tricuspid plane to the apex with a minimum of 30 cineframes for each slice with the following parameters: slice thickness 8 mm, no gap, eight views per segment, NEX 1, field of view 40 cm, phase field of view 1, matrix 224 × 224, reconstruction matrix 256 × 256, flip angle 458, TR/TE 3.5/1.5 and bandwidth 125 kHz. According to the protocols recommended by the Society for Cardiovascular Magnetic Resonance, we acquired cine steady-state free precession (cine-SSFP) images, Tr planes . In order planes . On T2-wSemi-automated quantification was performed as follows: epicardial and endocardial left ventricular (LV) contours were carefully placed manually on all LGE images. The remote non-LGE reference region of each LGE slice was placed adjacent to the region of LGE so that the reference region was at approximately equal distance from the anterior receiver coils. We believe this method minimizes any modifying effect from LGE location on the robustness of the LGE quantification. LGE mass was then quantified by semi-automatic methods using a signal intensity threshold of > 2-SD above a reference region of remote myocardium  in the same slice, and using regions defined as above 50% of maximal signal intensity of the enhanced area for the full width at half maximum approach. Artifacts were manually erased. In all methods, LGE mass (in grams) was then expressed as a percentage of total LV mass determined by balanced steady-state free precession cine images .After inpatient baseline evaluation, patients were followed up at our outpatient clinic. Independent interviewers obtained data from the patients, relatives or general practitioners. Independent physicians performed follow-up resting echocardiography. The follow-up period lasted until May 2020. Information about the time and cause of death was retrieved from death certificates and post mortem reports.Statistical analysis was performed using IBM SPSS 25.0 program . The type of distribution of variables was assessed using the Kolmogorov–Smirnov test. Continuous variables with normal distribution are presented as mean ± standard deviation, whereas continuous variables with non-normal distribution as median and interquartile range. Non-continuous variables are presented as frequency and percentage.t-test for independent samples for what concerns normally-distributed continuous variables; to assess differences in non-normally-distributed continuous variables, a non-parametric Mann–Whitney test was performed; non-continuous variables were assessed using a Chi-square test or Fischer test as appropriate. In each of the above-mentioned cases, two tailed p values < 0.05 were considered significant. Survival was assessed with Kaplan–Meier analysis, after dividing our population into patients with left ventricular mass with delayed enhancement (DE-LVM) above and below median value. A Kaplan–Meier curve is presented at 66-month outcome. Differences in survival between groups were tested with a log-rank test (Mantel–Cox).Differences among the two groups (patients who met the primary endpoint and those who did not) were assessed using aStudent’s Univariate Cox analysis was performed in order to identify predictors of the composite endpoint.p = 0.506). Both groups were homogeneous as regards age, sex, body mass index and rates of cardiovascular risk factors (p > 0.05). All patients were in New York Heart Association (NYHA) Class I, as HF at admission represented an exclusion criterion.A thorough descriptive analysis of baseline clinical, biohumoral and instrumental features is presented in p = 0.775). This cohort of patients with events at follow-up also showed a higher relative neutrophilia , although the total count of white blood cells was homogeneous between groups. Similarly, no differences in serum creatinine levels or in troponin has emerged.A moderate increase in median C-reactive protein levels was observed  without significant difference between groups ((p = 0.459). Only two patients showed a mild left ventricular dilation, while the mean LV end-diastolic diameter was 50 ± 4 mm; eight patients showed an increase of right ventricular end-diastolic diameter (population mean 32 ± 3 mm). Both indices were comparable in patients with and without events, as well as in the estimation of systolic pulmonary artery pressure. A total of 23 patients showed LV wall motion abnormalities, but the wall motion score index did not show statistically significant differences between the groups. No patient in the event group presented anterior wall hypokinesia.Mean LVEF at admission was 57 ± 3%, with similar values between the two groups 2), and only one had an event at follow-up. Among them, only one patient had a slight reduction in LVEF at admission echocardiography that was not confirmed once CMR was performed. That patient did not meet the endpoint at follow-up. Only five males presented a slight decrease of LVEF at CMR (LVEF 50–55%), while mean CMR LVEF was 62 ± 5% with no difference between groups (p = 0.666). Interestingly, 15 patients showed a mild decrease in right ventricular EF, and four of them had events at follow-up. All patients presented normal RV dimensions.CMR confirmed a mild LV dilation in only three patients, all males (indexed LV end-diastolic volume ≥ 105 mL/mp > 0.05). Myocardial edema was found in 30 patients (49%) and LGE in 57 (93%). Despite similar distribution, the total amount of DE-LVM was statistically higher in patients with events at follow-up (18 (14–29.5) vs. 12 (8–16) g, p = 0.028; see p = 0.047).Regional LV wall motion abnormalities were comparable between those with and without events, as were regional distribution of edema and LGE . Furthermore, after splitting the population according to DE-LVM median value  helps in addressing clinical goals and investments towards a better comprehension of disease, especially as regards mid-to-long term management of myocarditis both with reduced and with preserved ejection fraction. The main result of the present study is that the amount—and not merely the presence or absence—of DE-LVM can predict the composite endpoint of all-cause mortality and hospitalization for HF in subjects presenting with AMpEF.Although preserved systolic function is a good predictor of survival in many cases of heart disease, the presence of myocardial scar is generally associated with increased risk for adverse cardiovascular events , even in patients with preserved systolic function . WhetherThere are contrasting data in the literature about the importance of CMR findings in patients with AMpEF. In 2014, Schumm et al.  evaluateMore recently, Aquaro et al.  in the Ip = 0.022). This was further confirmed when evaluating the percentage of DE-LVM to the LVM (p = 0.018). It might mean that also for relatively small fibrotic involvement that does not impair LVEF, even small differences in the percentage of left ventricular myocardium with LGE may affect outcome. In our population of AMpEF, no specific localization could predict the composite endpoint in our cohort. This finding is actually in discordance with results from the ITAMY study, but the small number of patients enrolled may explain this bias. Data from larger populations are awaited in order to clarify these different results.Despite the small sample size and being a single-center analysis, with our study we added a new datum in the comprehension of AMpEF: not only the presence of LGE, but also its amount is predictive of a worse outcome (Both groups of our study (patients with and without events at follow-up) were homogenous regarding clinical features, but AMpEF patients with events had higher levels of circulating neutrophils at admission. This may reflect a higher degree of inflammation, even if C-reactive protein levels were not significantly different between groups and routine assay of interleukins was not performed. In the ITAMY study , patientThese findings might have several consequences, although derived from a single-center, retrospective analysis. First of all, CMR should be performed in all patients with AMpEF for different purposes: making diagnosis, confirming preliminary echocardiographic data of preserved LVEF and quantifying the extent of myocardial fibrosis. Our results may also reflect the need for a closer follow-up in order to re-assess myocardial function and arrhythmic burden. Moreover, a higher degree of fibrosis would require an early therapeutic approach that is still not available for this population. Randomized clinical trials, investigating the antagonism of both neurohormonal activity and directly fibrosis, are strongly required. As in HF, fibrosis is emerging not only as merely the consequence of myocardial insult, but also as a primary therapeutic target, and AMpEF should be no exception, especially if a large fibrotic process is detected.This study has some limitations. First of all, this is a retrospective, single-center analysis on a small population of patients with AMpEF. We did not perform endomyocardial biopsy and the diagnosis was made by the summation of clinical and CMR findings; nonetheless, in clinical practice endomyocardial biopsy is rarely performed in patients with AMpEF because of disproportional risk-to-benefit ratio . FurtherAMpEF is a subpopulation of patients currently having no evidence-based management. In our study, DE-LVM and the percentage of DE-LVM to LVM were the only predictors at long-term follow-up of the composite endpoint of all-cause mortality and hospitalization for HF in subjects presenting with AMpEF at baseline, according to a univariate analysis. These data confirm that not only the presence of LGE, but also the amount of DE-LVM, may have important prognostic roles also in AMpEF, as already demonstrated in other cardiomyopathies.


Cardiotoxicity has become the most common cause of non-cancer death among breast cancer patients. Pyrotinib, a tyrosine kinase inhibitor targeting HER2, has been successfully used to treat breast cancer patients but has also resulted in less well-understood cardiotoxicity. This prospective, controlled, open-label, observational trial was designed to characterize pyrotinib’s cardiac impacts in the neoadjuvant setting for patients with HER2-positive early or locally advanced breast cancer.The EARLY-MYO-BC study will prospectively enroll HER2-positive breast cancer patients who are scheduled to receive four cycles of neoadjuvant therapy with pyrotinib or pertuzumab added to trastuzumab before radical breast cancer surgery. Patients will undergo comprehensive cardiac assessment before and after neoadjuvant therapy, including laboratory measures, electrocardiography, transthoracic echocardiography, cardiopulmonary exercise testing (CPET), and cardiac magnetic resonance (CMR). To test the non-inferiority of pyrotinib plus trastuzumab therapy to pertuzumab plus trastuzumab therapy in terms of cardiac safety, the primary endpoint will be assessed by the relative change in global longitudinal strain from baseline to completion of neoadjuvant therapy by echocardiography. The secondary endpoints include myocardial diffuse fibrosis (by T1-derived extracellular volume), myocardial edema (by T2 mapping), cardiac volumetric assessment by CMR, diastolic function  by echocardiography, and exercise capacity by CPET.This study will comprehensively assess the impacts of pyrotinib on myocardial structural, function, and tissue characteristics, and, furthermore, will determine whether pyrotinib plus trastuzumab is a reasonable dual HER2 blockade regimen with regard to cardiac safety. Results may provide information in selecting an appropriate anti-HER2 treatment for HER2-positive breast cancer.https://clinicaltrials.gov/, identifier NCT04510532 Breast cancer is the most commonly diagnosed tumor and is also the most malignant female tumor . AdvanceHER2-directed drugs have become a cornerstone for the treatment of HER2-positive breast cancer, and they have shown less cardiotoxicity than traditional anthracyclines . HoweverPyrotinib is a small-molecule tyrosine kinase inhibitor (TKI) that simultaneously inhibits HER2 homodimerization and heterodimerization. After demonstrating significant anticancer activity in the PHOEBE trial and other clinical trials, the National Medical Products Administration of China approved pyrotinib in 2020 for the treatment of HER2-positive advanced or metastatic breast cancer . As a prCardiac imaging, including echocardiography and cardiac magnetic resonance (CMR), is critical for cardiac assessment in breast cancer patients. Of the cardiac functional parameters, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) derived from echocardiography are the most widely used to define CTRCD. Up to 39.1% of breast cancer patients exposed to trastuzumab and anthracycline presented with CTRCD during treatment or follow-up . FurtherHere, we registered the EARLY-MYO-BC study in order to describe pyrotinib’s cardiac impacts and to further determine whether novel dual HER2 blockade using pyrotinib plus trastuzumab is non-inferior to the NCCN-recommended regimen (pertuzumab plus trastuzumab) with regard to cardiac safety during the course of neoadjuvant treatment.ClinicalTrials.gov identifier NCT04510532) that will enroll patients with early or locally advanced HER2-positive breast cancer from the Department of Breast Surgery at the Renji Hospital for cardiac assessment from the initiation of neoadjuvant pyrotinib or pertuzumab therapy. The registry has been approved by the local Ethics Committee of Renji Hospital. All patients will provide fully informed written consent. The study protocol conforms with the principles of the 2013 Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guideline.The EARLY-MYO-BC  is a prospective, open-label, observational study  female patients between 18 and 70 years of age; (2) newly diagnosed and histologically confirmed early or locally advanced HER2-positive invasive breast cancer (Stage IIA-IIIC); (3) no signs of cardiac discomfort; (4) normal range of baseline cardiac biomarkers , electrocardiography (ECG), and baseline LVEF ≥ 50% from echocardiography; (5) able to complete face-to-face follow-up visits during neoadjuvant therapy; (6) provide signed written informed consent.2); (9) severe liver diseases; (10) prior history of immunodeficiency or organ transplantation; (11) pregnant or lactating; (12) unable to take or absorb tablets; (13) contraindications to CMR; (14) any other medical condition assessed by the investigator as inappropriate to participate.The exclusion criteria are as follows: (1) metastatic breast cancer confirmed histologically or by imaging tests; (2) prior history of medical anticancer treatments; (3) documented coronary heart disease or cardiomyopathy; (4) angina pectoris requiring medication; (5) clinically significant valvular disease; (6) unstable arrhythmias; (7) uncontrolled blood pressure; (8) severe chronic or acute renal failure , paclitaxel , and trastuzumab  will be administered intravenously to patients in the ambulatory chemotherapy ward. Patients will take 400 mg pyrotinib orally once per day.Pyrotinib group treatment regimen: Cisplatin  will be recruited as negative controls.Demographic features including age and body mass index (BMI) will be prospectively collected at baseline, as well as blood pressure, heart rate, risk factors for cardiovascular events , tumor location, tumor stage, and history of cancer and other diseases. Baseline cardiac risk assessment will be performed using the statement-recommended algorithm .Laboratory measurements will include: (1) cardiac markers ; (2) complete blood counts ; (3) hepatic function markers ; (4) renal function markers (creatinine and blood urea nitrogen); (5) lipid profile ; (6) fasting glucose; (7) inflammatory markers .ECG, echocardiography, cardiopulmonary exercise testing (CPET), and CMR data will be recorded in the study database.A resting 12-lead ECG will be used following the current guideline-recommended standard protocols to record the cardiac electrophysiology of breast cancer patients .Echocardiography will be performed to obtain left ventricular (LV) morphology and function  following the standard recommendation . Two levDiastolic function will be assessed by the ratio between early (E) and atrial (A) peak diastolic velocities of LV inflow (E/A), the ratio between E and peak early (E’) tissue Doppler of the mitral annulus (E/E’), and the LA dimension. Within 24 h of the ECG and echocardiographic examination, a CMR scan and CPET will be scheduled.CPET will be conducted to evaluate the cardiac-pulmonary function of breast cancer patients by continuously measuring breath-by-breath expired gases before, during, and after exercise. Testing will start with 3-min unloaded cycling and gradually achieve peak exercise using the 10 Watt/minute incremental ramp protocol. Patients are encouraged to maintain exercise until exhaustion. The test will be considered valid with a perceived exertion rating >18 on the Borg scale or a respiratory exchange ratio > 1.1 –22. A 12CMR will be performed using a Prisma 3.0-Tesla magnetic resonance (MR) scanner . The imaging protocol is consistent with the statement from the Society for Cardiovascular Magnetic Resonance . The ful3. The LV endocardial and epicardial borders are end-diastole and end-systole contoured to accomplish cardiac volumetric and strain analysis. All volumetric indices and mass will be indexed to body surface area. Trabeculations and papillary muscles will be included in LV mass calculations and excluded from LV volumes. Myocardial strain will also be assessed. GCS and GRS will be obtained in the short-axis view at the apical, midventricular, and basal levels, and GLS will be obtained in the long-axis view .Cine imaging: Standard cine images will be acquired with end-expiratory breath hold using retrospectively gated, balanced, steady-state, free precession sequences in three long-axis planes and sequential short-axis slices from the atrioventricular ring to the LV apex. The typical cine sequence parameters are as follows: field of view (FOV), 360 × 360 mm; repetition time (TR), 3.39 ms; echo time (TE), 1.49 ms; flip angle (FA), 58°; voxel size, 1.4 × 1.4 × 8.0 mm3, bandwidth, 1175 Hz/Px.T2 mapping: T2 mapping will be performed with a T2-prepared, single-shot, multi-echo, steady-state free precession (SSFP) technique, and three T2P-SSFP images will be obtained in the short axis at the basal, mid, and apical levels. Typical sequence parameters are as follows: FOV, 360 × 360 mm; TR, 3.15 ms; TE, 1.38 ms; FA, 12°; matrix, 224 × 160; voxel size, 1.6 × 1.6 × 8.0 mm3; 160 phase-encoding steps; sensitivity encoding factor = 2. Regions of interest will be placed on the entire myocardium to obtain T1 values, but will exclude the blood pool, papillary muscles, chordae, and trabeculations. To detect interstitial matrix changes ECV is calculated based on the combination of pre- and post-contrast T1 values with the formula: ECV = (ΔR1myocardium/ΔR1blood) • (1 - hematocrit) where R1 = 1/T1 time .LGE: A LGE scan will be performed 10 min after intravenous administration of gadolinium contrast and will employ a phase-sensitive reconstruction (PSIR) covering the entire left ventricle from basal to apex in short-axis views. Typical parameters are as follows: TR, 3.87 ms; TE, 1.52 ms; FA, 20°; voxel size, 0.8 × 0.8 × 8.0 mmTo determine whether pyrotinib is non-inferior to pertuzumab with regard to cardiac safety when combined with trastuzumab during the course of neoadjuvant therapy, our primary endpoint is designed to compare the relative change in GLS between the two groups by echocardiography. The secondary endpoints are assessed by CMR and CPET including the relative changes in (1) myocardial diffuse fibrosis (by T1-derived ECV), (2) myocardial edema (by T2 mapping), (3) myocardial volumetric and diastolic function  and (4) exercise capacity between the two groups.One-fourth of the patients will be randomly chosen for imaging measurement reproducibility assessment 1 month after the first measurement. The interobserver and intraobserver imaging measurement reproducibility will be assessed by intraclass correlation analyses.The sample size calculation is based on our preliminary research. The mean relative changes in GLS before and after treatment of 10 patients receiving pyrotinib and 10 patients receiving pertuzumab were 6.15 and 5.00 with standard deviations (SDs) of 8.10 and 7.73, respectively. Assuming a non-inferiority margin of 3.8, a sample ratio (n pyrotinib/n pertuzumab) of 1, a type I error (one-sided) of 5%, a power of 80%, and a missing rate of 10%, a final sample size of at least 61 subjects in each group will be required to detect the non-inferiority of pyrotinib to pertuzumab with regard to cardiac safety.t-test or Mann–Whitney U test for continuous variables that are normally or non-normally distributed, respectively, or using chi-square test or Fisher exact test for categorical data. Logistic regression will be employed to identify the predictive value of baseline clinical features , biomarkers , and imaging indicators in CTRCD development. The interobserver reliability will be evaluated by intraclass correlation coefficient (ICC) for continuous variable and Kappa value for categorical variable. Except for the non-inferiority test of the primary endpoint, all reported P-values are two-sided; those under 0.05 are considered to be statistically significant. Analyses are performed using SPSS 26.0 and R software (version 3.4.1).Data will be tested for normal distribution by the Kolmogorov–Smirnov test. Normally distributed data are expressed as mean ± SD. Non-normally distributed data are expressed by median and interquartile range (IQR). Categorical data are expressed as frequencies and percentages. Non-inferiority will be assessed on the primary endpoint to compare the differences between the two groups in terms of relative changes in GLS from baseline to completion of neoadjuvant therapy. Baseline characteristics and secondary endpoints will be analyzed using Student’s To the best of our knowledge, the EARLY-MYO-BC registry is the first to explore pyrotinib’s cardiac impacts in the neoadjuvant setting for patients with early or locally advanced HER2-positive breast cancer.de novo cardiac problems. Furthermore, cardiotoxicity can complicate and even cause interruption or discontinuation of cancer therapy, which significantly reduces breast cancer patients’ survival benefit , has been recommended as part of the preferred neoadjuvant therapy by the NCCN . NotablyPyrotinib is an oral small-molecule TKI of multiple HER family members, enabling concomitant blockade of HER2 homodimerization and heterodimerization. In patients with HER2-positive relapsed or metastatic breast cancer, pyrotinib was shown to prolong the median progression-free survival more significantly than lapatinib (12.5 months vs 6.8 months) . As a noTo date, assessment of cancer therapy-related cardiotoxicity has relied largely on serum biomarker measures  and cardiac imaging tests  , 38, 39.In conclusion, this study aims to comprehensively assess pyrotinib’s cardiac impacts and, further, to determine whether pyrotinib plus trastuzumab is non-inferior to pertuzumab plus trastuzumab with regard to cardiac safety. The myocardial structure, function, and tissue characteristics will be explored, and the findings will provide valuable information for oncologists with respect to selecting appropriate treatment options for patients with breast cancer.The studies involving human participants were reviewed and approved by the local Ethics Committee of Renji Hospital. The patients/participants provided their written informed consent to participate in this study.YC and YW: design, patient recruitment, data acquisition and analysis, manuscript drafting and revision, and approval of the final version of the manuscript. QML, QFL, ZT, and QW: data acquisition. MJ, WY, JL, and JP: study concept and design, study supervision, drafting, revision, and approval of the final version of the manuscript. All authors contributed to the article and approved the submitted version.