Background: Evaluation of the right ventricle (RV) in patients with acute myocarditis (MY) remains challenging with both 2D transthoracic echocardiography (TTE) and cardiovascular magnetic resonance (CMR). We examined the incremental diagnostic value of CMR feature tracking (FT) to evaluate RV involvement in patients with myocarditis. Methods: We enrolled 54 patients with myocarditis and preserved left ventricle (LV) ejection fraction (EF). The CMR protocol included T2-weighted images for edema detection and late gadolinium enhancement (LGE) images. Global longitudinal strain (GLS) of the left ventricle (LV) and RV free wall strain (CMR-FWS) were obtained with CMR-FT. We identified 34 patients (62%) with inferior and lateral segment (IL-MY) involvement and 20 (38%) noIL-MY in case of any other myocardial segment involved. Here, 20 individuals who underwent CMR for suspected cardiac disease, which was not confirmed thereafter, were considered as the control population. Results: TTE and CMR showed normal RV function in all patients without visible RV involvement at the LGE or T2-weighted sequences. At CMR, LV-GLS values were significantly lower in patients with MY compared to the control group . Overall, CMR RV-FWS was no different between MY patients and controls  while a significant difference was found between RV FWS in IL-MY and noIL-MY . Conclusions: CMR-FT has the potential to unravel subclinical RV involvement in patients with acute myocarditis, specifically in those with inferior and lateral injuries that exhibit lower RV-FWS values. In this setting, RV deformation analysis at CMR may be effectively implemented for a comprehensive functional assessment. Acute Myocarditis (MY) is an inflammatory disease of the myocardium whose diagnosis may be challenging in a sizeable proportion of patients due to the frequent heterogeneity of symptoms, ECG, and echocardiographic findings . RecentlAll consecutive patients with myocarditis referred to our center between January 2014 and October 2021 who underwent CMR were retrospectively considered for the study. Inclusion criteria were: (1) new ECG abnormalities; (2) a raise in myocardial cytolysis markers (high sensibility troponin T > 14 ng/L); (3) the absence of coronary artery disease; and (4) normal LVEF assessed by 2D TTE. Exclusion criteria included: (1) the presence of acute ischemic heart disease; (2) previous myocarditis; (3) the inability to undergo CMR; and (4) poor cine image quality caused by respiratory motion and arrhythmias during CMR. Acute ischemic heart disease was diagnosed in the presence of severe coronary stenosis detected in the invasive coronary angiography, defined as the presence of a luminal reduction of ≥50% in at least one angiographic view of all epicardial vessels with a diameter exceeding ≥1.5 mm.A definite diagnosis of acute myocarditis was made according to the modified Lake-Louis criteria as the combined presence of a T1 , higher extracellular volume (ECV), and a T2 criteria, hyperintensity in T2-weighted short-tau inversion recovery (TwSTIR) or increased T2 mapping values . The absA comparative age and sex match of 20 asymptomatic patients were considered as the control group. All patients were free from known cardiovascular risk factors and underwent CMR for a different suspected cardiac condition, but finally, all cases presented normal CMR findings.All patients underwent 2D TTE, which was performed on the day of their hospital admission. Echocardiographic images were obtained with standard transducer positions in the parasternal long-axis, short-axis, and apical 4-, 2-, and 3-chamber views , according to standard technique . Examinations were analyzed offline on dedicated workstations  by two experienced but independent readers blinded to clinical data . Left ventricular (LV) dimensions, volumes, EF, and global longitudinal strain (GLS) were measured as described in the literature . Normal 2D TTE speckle LV tracking analyses were performed offline using commercially available software . In detail, 2D grayscale images of all apical views  with optimized focus on the LV and frame rate > 50 frames/second were considered for the analysis. The software semi-automatically detected the LV end-diastolic and LV end-systolic myocardial contours, which were thereafter manually corrected in case of discrepancy. The cardiac strain was displayed in a 17-segment model according to AHA guidelines. RV strain was evaluated in an apical 4-chamber view and acquired and analyzed with the same characteristics. Since it is known that the GLS of the septum is mainly affected by LV deformation, it was not considered in the analysis. Therefore, only the FWS values were considered for RV strain. ®, Bayer Healthcare, Berlin, Germany) and a 10–15 min waiting time. LGE images were acquired using a 2D breath-hold phase-sensitive segmented inversion-recovery Gradient echo (GRE)-based pulse sequences in the same orientations as the cine acquisitions. The inversion time was individually optimized to nullify normal myocardium. All patients underwent ECG-gated CMR performed using a 3 Tesla unit  with a 32-channel phased-array surface receiver coil within their hospital stay. Cine images were acquired using a breath-hold steady-state free precession (SSFP) pulse sequence in long-axis  and short-axis views . The presence of myocardial edema was evaluated in T2wSTIR. Short-axis image positions used for T2-weighted images were at the same image positions as the cine images in SSFP, ensuring complete LV coverage. Finally, the myocardial scar was evaluated in late gadolinium enhancement (LGE) images after 0.2 mmol/kg body weight gadobutrol  to calculate LV and RV volumes, LV mass, LVEF, and RVEF by delineating endocardial and epicardial borders in the stack of short-axis cine images. The presence of fibrosis by LGE was visually assessed and categorized in epicardial, mid wall, or diffuse/transmural patterns, and its extent was reported according to the AHA 17-segment model . For theCMR-FT analyses were performed using commercially available software . Long-axis SSFP cine images were used to derive global longitudinal strain (CMR-GLS). Endocardial and epicardial contours were manually traced from SSFP cine images in the end-diastolic phase. All contours were automatically propagated throughout the cardiac cycle and manually corrected in cases of errors. RV myocardial strain was measured blinded to clinical data under the supervision of an experienced CMR cardiologist . RV endocardial contours were drawn manually during the end-diastolic and end-systolic phases. Subsequently, the software traced the cardiac contours during all the cardiac cycles, resulting in the peak global longitudinal strain (CMR-GLS) of the entire right ventricle, the GLS of the RV free wall (CMR-FWS), and the GLS of the septum. Similarly to echocardiographic parameters, since it is known that the GLS of the septum is mainly affected by LV deformation, it was not considered in the analysis, so for the RV strain only the CMR-FWS values were considered. The reproducibility of 2D speckle tracking analysis and CMR-FT analysis was assessed on a random sample of 20 patients, analyzed by 2 different operators blinded to previous analysis . t-test in the case of a normal distribution or the Mann–Whitney test in the case of non-normal distribution. One-way analysis of variance (ANOVA) was used to determine statistically significant differences in the presence of three or more independent groups. A Bonferroni correction for post-hoc analysis was used. Continuous variables underwent the Shapiro–Wilks test for normality. Continuous variables were expressed as mean ± SD in the case of a normal distribution or as median [interquartile range] in the case of a non-normal distribution. Comparison of continuous variables between two groups was performed using the independent-sample Student’s The association between any categorical variable was analyzed using Fisher’s exact test or the chi-square test. Correlation analysis was performed using Spearman’s correlation test. Reproducibility analyses for the measurement of 2D speckle tracking analysis and CMR-FT parameters were performed using Pearson’s correlation and Bland–Altman statistics.p-value of <0.05 was considered statistically significant.Considering AHA segmentation, we identified 6 macro-areas: anterior wall , anteroseptal wall , anterolateral wall , inferior wall , inferolateral , and inferoseptal wall . The study population was divided into two groups according to myocardial wall involvement. In the IL-MY, group we considered all patients presenting inferior and lateral LV wall abnormalities, while the noIL-MY group was made up of all patients without any abnormalities detected in the inferior and lateral LV myocardial walls. All statistical analyses were performed using SPSS 25.0 . A p < 0.001) and predominantly male . There was a similar prevalence of cardiovascular risk factors between the two groups. Among patients with myocarditis . No evident LV and RV wall motion abnormalities were detected . 2D TTE findings are summarized in Speckle tracking analysis was feasible in all patients with myocarditis and in the control group. In 2D TTE, LV GLS values were significantly lower in patients with myocarditis compared to the control group . Considering LGE and edema distribution found in CMR, inferior segments were involved in 28 patients (51.8%), infero-lateral segments in 19 patients (35.1%), antero-lateral in 8 patients (14.8%), anterior segments in 11 patients (20.3%), infero-septal in 14 patients (25.9%), and antero-septal segments in 7 patients (12.9%). Overall, 34 patients (62.9%) had myocarditis involving both inferior and lateral segments (IL-MY), whereas 18 patients (33.3%) did not present such involvement (noIL-MY). The baseline characteristics of IL-MY and noIL-MY are summarized in p = 0.365) (The mean time from 2D TTE to CMR was 1.9 ± 1.2 days. CMR findings are summarized in = 0.365) .p = 0.068; s’TDI: 11.2 [9.7–13.1] cm/s vs. 9.9 [8.7–12.9] cm/s, p = 0.071) and also in IL-MY and noIL-MY TAPSE was within the normal range  as well as s’ TDI (10.9 [9.8–12.8] cm/s vs. 9.9 [9.2–12.7] cm/s p = 0.125). FAC values were found within the normal range in all patients: patients with myocarditis did not present any statistically significant difference with the control group , likewise, no statistically significant difference was found in IL-MY and noIL-MY patients . All patients presented normal RV function at 2D TTE. In particular, TAPSE and S’ TDI values were found within normal ranges in all patients with myocarditis as well as in control groups  as the RV-EF (67.7 mL/m2 [51.3–81.5 mL/m2]) and no abnormal wall motion was detected in cine images. Moreover, no signs of RV involvement in terms of edema on T2-weighted images or LGE were found. In CMR examination, the RV volumes were in the normal range (80.1 mL/mp = 0.201), while a statistically significant difference was found between RV-FWS in IL-MY and noIL-MY . (p = 0.003). . . Finally 0.003). .This study evaluates the diagnostic value of CMR-FT-derived myocardial strain parameters in detecting RV involvement in patients with myocarditis and preserved EF, specifically differentiating between inferolateral and non-inferolateral acute myocarditis.The main findings of the study are: (1) myocardial GLS in 2D TTE and CMR-FT is significantly reduced in all patients with myocarditis; (2) in patients with myocarditis and preserved ejection fraction, subtle RV involvement has been found in the presence of large myocardial involvement and acute inferolateral localizations; and (3) CMR-FT is able to detect subtle RV involvement on top of routine markers.Even if EMB is the gold standard in the diagnosis of myocarditis, it is an invasive procedure and has the inheritable drawback of sampling errors, so cardiovascular imaging is now considered crucial in the evaluation of patients with myocarditis. Previous studies identified 2D speckle-tracking TTE as a useful tool in the diagnostic work-up of myocarditis ,15 Our aHowever, due to its unique capacity for tissue characterization, CMR has recently become the preferred imaging modality to evaluate patients with suspected myocarditis. In this setting, CMR-FT is a novel tool that has been shown to have an important diagnostic role in patients with myocarditis by better evaluating LV myocardial deformation ,15. In tSo far, the role of RV involvement in myocarditis has been poorly investigated. Recently, Bernhard et al. evaluated the prognostic role of RV involvement in a large cohort of patients with acute myocarditis. They found that RV ejection fraction at CMR is an independent and incremental predictor for adverse cardiovascular events and strongly suggested including this parameter in future risk stratification. Actually, it is well known that patients with RV involvement present with worse clinical and hemodynamic conditions. Since EMB in the RV is challenging and usually gathered from the right side of the interventricular septum, which may be more reflective of the LV, the actual prevalence of RV myocarditis may be significantly underestimated. Yilmaz et al. performed EMB in 481 patients with clinically suspected myocarditis and impaired LV function, highlighting that biventricular involvement is present in nearly 70% of patients . LV dysfp = 0.003). All these features suggest the possible presence of subtle RV involvement in patients with IL-MY. A possible explanation for that may be linked to the presence of pericardial involvement, which was also more frequent in patients with IL-MY, so RV may be either involved due to direct contiguity with the inferolateral LV wall or as a consequence of adjacent pericardial inflammation. Finally, it is worth mentioning that this subgroup of patients tends to present a larger area of myocardial edema and necrosis detected in T2-weighted images and LGE compared to patients in noIL-MY groups.In our study, none of the patients with acute myocarditis showed RV involvement according to TTE. RV was found to have normal values in all cases, and no functional alterations were documented according to TAPSE, s’TDI, or FAC evaluation. Similarly, in CMR, RV volumes were in the normal range, and on top of that, T2-weighted images did not show the presence of edema, nor were signs of necrosis detected on LGE. Despite the results being in the normal range according to standard criteria ,9, in ouIn our study, the use of CMR-FT on the RV proved to be an effective tool to identify subtle RV involvement even in the absence of clear RV dysfunction or in the presence of necrosis/scar and edema. In this setting, the value of strain imaging might be of interest as it allows the identification of regional myocardial deformation that may evolve into ventricular dysfunction. Further studies are needed to explore the prognostic role of CMR-FT in detecting RV involvement in myocarditis in patients with preserved but also impaired LVEF.The present study presents some limitations. First of all, it is a retrospective study with relatively small sample size, and only patients with normal EF were considered. For this reason, no EMB as a reference standard was performed to diagnose myocarditis, which was defined by combining clinical and laboratory data and suggestive CMR findings, as previously reported. In this setting, the sensitivity and specificity of 2D TTE and CMR cannot be tested in this specific population. Even though our study population was young, without significant comorbidities, it must be kept in mind that alteration of myocardial strain parameters is non-specific and can be found in many cardiac diseases, so myocardial strain analysis must always be interpreted within the appropriate clinical context. The role of the 2D TTE RV strain was not assessed in most of the population with myocarditis due to poor acoustic window, which limited the accuracy of tracking. To note, patients with acute myocarditis in our population did not show any impairment of the RV function in both TTE and CMR standard parameters, so the role of CMR-FT in this subcategory of patients needs further evaluation. Finally, due to the retrospective nature of the study, no dedicated clinical and instrumental follow-up was planned at our institution, so the data were available only for 52% of patients. In all these cases, patients were clinically stable, and no RV dysfunction was assessed at TTE. However, due to the number of patients lost at follow-up, the implication of subtle RV impairment needs to be explored in a dedicated prospective study enrolling a larger population. Finally, no patients with RV involvement and preserved LV were admitted to our center during the study period, and not all patients with initially suspected myocarditis later confirmed to be free of the condition were routinely addressed to CMR, so the ability of CMR-FT to evaluate RV myocardial deformation in these specific populations cannot be assessed in the present study.In hemodynamically stable patients with normal LV EF with myocarditis, CMR-FT can discriminate between diseased and healthy patients. Strain parameters represent a standardized unit of measurement and can be determined using different imaging techniques (2D-TTE or CMR). Subtle involvement of the RV can be detected by CMR-FT in addition to the standard technique, and it is usually associated with inferolateral or inferior myocarditis.


We sought to compare native T1 mapping to conventional late gadolinium enhancement (LGE) and T2-STIR techniques in a cohort of consecutive patients undergoing cardiac MRI (CMR). CMR was performed in 323 patients, 206 males (64%), mean age 54 ± 8 years, and in 27 age- and sex- matched healthy controls. In T2-STIR images, myocardial hyperintensity suggesting edema was found in 41 patients (27%). LGE images were positive in 206 patients (64%). T1 mapping was abnormal in 171 (49%). In 206 patients (64%), a matching between LGE and native T1 was found. T1 was abnormal in 32 out of 41 (78%) with edema in T2-STIR images. Overall, LGE and/or T2-STIR were abnormal in 209 patients, whereas native T1 was abnormal in 154 (52%). Conventional techniques and T1 mapping were concordant in 208 patients (64%). In 39 patients, T1 mapping was positive despite negative conventional techniques (12%). T1 mapping was able in conditions with diffuse myocardial damage such as cardiac amyloidosis, scleroderma, and Fabry disease (additive role in 42%). In contrast, T1 mapping was less effective in cardiac disease with regional distribution of myocardial damage such as myocardial infarction, HCM, and myocarditis. In conclusion, conventional LGE/T2-STIR and T1 mapping are complementary techniques and should be used together in every CMR examination. Cardiovascular magnetic resonance (CMR) plays an increasingly crucial role in diagnosing cardiac diseases, serving as the gold standard imaging technique for assessing cardiac function and accurately measuring ventricular volumes and mass. What sets CMR apart is its unique ability to perform soft-tissue characterization . CMR empCertain features obtained by this technique, such as the presence, pattern of presentation, and extent of fibrosis, have been demonstrated to play a significant prognostic role in various cardiac conditions . HoweverThe T1 mapping technique may overcome these limitations by measuring the intrinsic myocardial T1 relaxation time on a pixel-wise basis . This meNon-contrast myocardial T1, often referred to as “native” T1, is a term used to distinguish it from post-contrast T1. The most important biological determinants of an increase in “native” T1 are edema , the increase in interstitial space for fibrosis , or for amyloidotic proteins deposition . In contT1 mapping techniques may be performed using two different families of pulse sequences: those based on inversion recovery (IR), including the standard Look-Locker sequence, the MOdified Look-Locker inversion recovery (MOLLI) sequence, and the shortened MOLLI (ShMOLLI) sequence; and those, less frequently used, based on a saturation recovery such as the saturation recovery single-shot acquisition (SASHA) and the saturation-pulse prepared heart-rate-independent inversion recovery (SAPPHIRE) . The MOLPost-processing methods play a crucial role in T1 mapping. To begin, the signal intensity of each voxel or group of voxels is measured in every image acquired at different inversion times . These sThe T1 mapping technique has some limitations: (1) the variability due to factors such as heart rate, motion artifacts, arrhythmias, and imaging parameters and, mostly, magnetic field inhomogeneity; (2) the lack of standardized reference values for myocardial T1 in the myocardium for which each CMR laboratory must create its own reference values; (3) in many cardiac conditions, different phenomena may coexist such as fibrosis, edema, inflammation, and even opposite phenomena (as fat and fibrosis) that may affect the myocardial T1 relaxation, leading to false-positive or false-negative findings; (4) the additional time required for T1 mapping sequences can lead to longer scan durations, while SCMR position documents suggest to only acquire three ventricular short-axis views for T1 mapping; 5) the differences in acquisition schemes have a direct effect on the range of normal and abnormal T1 with a given technique, which means that absolute T1 values can only be directly compared when they are obtained with the same acquisition scheme at the same field strength and using the same post-processing methods [ the diffThe aim of the present study was to compare the diagnostic role of conventional CMR techniques to native T1 mapping in a real-life cohort of non-selected consecutive patients undergoing CMR.A total of 340 consecutive patients who underwent CMR for clinically suspect of cardiac diseases from August 2019 to January 2020, and 27 healthy controls were included in this study. We excluded patients with congenital heart disease  and those with cardiac tumors. Finally, after CMR patients with sub-optimal images were excluded, those with contraindication for gadolinium-based agents and those that did not complete the CMR exam were excluded. The final population included 323 patients . The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of the Area Vasta Nord-Ovest (protocol code 0016706 of 26 September 2018). Informed consent was obtained from all subjects involved in the study.All CMR exams were performed on a 1.5 T scanner  using dedicated cardiac phased-array surface receiver coil, and vectorcardiogram triggering. According to the protocols recommended by the Society for Cardiovascular Magnetic Resonance, we acquired cine steady-state free precession (cine-SSFP) images, T1-FSE with and without Fat-saturation, T2-STIR, and LGE at 10 min after gadolinium injection in the short-axis (9–13 images covering the entire LV), 2-chamber, and 4-chamber planes. Short axis cine-SSFP images were acquired immediately after gadolinium injection for hyperemia assessment. The same protocol was repeated at CMR-II. According to the protocols recommended by the Society for Cardiovascular Magnetic Resonance , we acquWe obtained three parallel short-axis slices, including the base, mid cavity, and apex of the left ventricle, at the same cardiac phase (end diastole) .All CMR studies were analyzed offline using a workstation with dedicated cardiac software  and consensus was obtained among three experienced observers who were blinded to the clinical presentation results. To evaluate the LV global and regional function and calculate the LV mass, the endocardial and epicardial borders were manually drawn in the end-diastolic and end-systolic short-axis cine SSFP images. Papillary muscles and trabeculations were not included in the myocardium. LV end-diastolic volume (EDV), LV end-systolic volume, EF, and LV mass were determined.In T2-weighted images, edema was evaluated visually and confirmed if the ratio of signal intensity (SI) between the myocardium and the mean SI of the skeletal muscle was ≥2. The extent, diffuse, or focal, and the pattern of distribution of edema, ischemic-like , or non-ischemic  features were evaluated.LGE was qualitatively evaluated as for edema: the ischemic pattern  or non-ischemic pattern of distribution  was recorded. The presence of LGE was evaluated measured using a previously validated method. Criteria for CMR diagnosis of different cardiac conditions are shown in Absolute T1 values were directly compared with local sex- and age-referenced range obtained using the same acquisition scheme with the same MRI machine strength and pulse sequence parameters and the same post-processing method . To meast-test and ANOVA or by the Wilcoxon non-parametric test when appropriate. A p-value lower than 0.05 was considered statistically significant.Values are presented as the mean ± SD or as the median and interquartile range (IQR) for variables with normal and non-normal distributions, respectively. Values with non-normal distribution according to the Kolmogorov–Smirnov test were logarithmically transformed for parametric analysis. Qualitative data are expressed as percentages. Categorical variables were compared using the Chi-square test or Fisher’s exact test when appropriate. Continuous variables were compared by the Student’s independent The final population included 323 patients, 206 males (64%), mean age 54 ± 18 years. The baseline characteristics are shown in In T1 mapping, the average native T1 is 1040 ± 55 ms. A total of 65 (20%) patients show a global increase in native T1 (mean T1 1232 ± 85 ms), while it decreases in 11 (3%) patients (mean T1 885 ± 85 ms). A regional increase in native T1 is found in 160 (46%) patients, 52 of them with global increase in T1 values.Among the 41 patients with signs of myocardial edema at T2-STIR, 32 (78%) also have an increase in regional native T1; in 9 patients, edema is not associated with a consistent increase in T1. Overall, a matching between T2-STIR and native T1 is found in 185 (57%) patients.p = 0.81). Native T1 is normal in 2 out of 10 patients without gadolinium injection.T1 is normal in 74 (36%) patients with positive LGE and abnormal in 33 with negative LGE. Overall, a perfect matching between these two techniques is found in 206 (64%) patients . No significant differences are found for the pattern of LGE: native T1 is increased in 118 out of 186 patients (63%) with non-ischemic LGE vs. 14 out of 20 (65%) with ischemic pattern  have edema in T2-STIR imagesOverall, the CMR findings confirm the initial suspicion in 149 patients (50%), yielded an alternative diagnosis in 41 (14%), are non-specific  in 78 (26%), and completely negative in 28 (10%) .p < 0.0001). As evident in Conventional CMR techniques (LGE and/or T1-FSE and/or T2-STIR) are positive in 209 patients (71%), while native T1 is abnormal in 154 (52%) of patients (p < 0.0001). Similar results are found in the case of myocardial infarction, where a concordance appears in 79% of patients, whereas positive conventional techniques with negative mapping is apparent in 21% of patients .On the contrary, opposite results are found about amyloidosis and scleroderma where native T1 is abnormal in all the patients . ParticuAbnormal T1 mapping is the only CMR abnormality in 11% of DCM, in 3% of HCM, 16% of ARC, and in 18% of other conditions . On contp = 0.0006).In HCM, myocardial abnormalities are more frequently detected using conventional techniques than with T1 mapping .In contrast, T1 mapping is less effective in cardiac conditions with a regional\segmental distribution of myocardial damage such as myocardial infarction, myocarditis, and HCM. In these conditions, T1 is abnormal in 52 out of 88 patients (58%) but only demonstrated an additive role in one of them (1%). Conventional techniques have an additive role in 36 patients (41%).An explanation for the low effectiveness of T1 mapping in regional myocardial damage could refer to the limited coverage of LV myocardium. Indeed, T1 mapping is acquired in three short-axis slices, covering an average of 17 ± 4% of LV mass.In the present study, we evaluated the clinical impact of T1 mapping as an additive imaging tool in a cohort of non-selected patients undergoing CMR. The main results may be summarized as follows: (1) conventional CMR for tissue characterization  and T1 mapping are complementary techniques in most of the cardiac conditions: they provide concordant findings in 64% of patients; (2) native T1 mapping has an additive diagnostic role over conventional techniques in a range of 6–12% of cases; (3) in 24% of cases, conventional CMR techniques detect myocardial abnormalities despite normal native T1; (4) the role of T1 mapping is different in cardiac diseases: we find that T1 mapping is superior to conventional approaches in cardiac conditions such as amyloidosis, Fabry, and scleroderma, characterized by a diffuse myocardial involvement; (5) conventional techniques are superior to mapping for the evaluation of myocardial disease with segmental distribution such as myocardial infarction, hypertrophic cardiomyopathy, and myocarditis.T1 mapping is a quantitative CMR technique allowing voxel-wise quantification of myocardial native T1 . Native Increased native T1 may also be found in myocardial fibrosis because of augmented water content of interstitial space enlarged by the collagen matrix of scar .Myocardial T1 is also severely increased in amyloid deposition ,11, wherBy these premises, T1 mapping and conventional techniques, such as LGE and T2-STIR, are overlapping in many cardiac conditions, as confirmed by the results of the present study, where the concordance between these techniques is seen in 64% of patients. However, T1 mapping has some advantage over conventional techniques. Being a quantitative technique, T1 mapping may allow for the identification of myocardial disease characterized by a diffuse and homogeneous damage, as evident in early stages of DCM, amyloidosis, Fabry disease, and in scleroderma ,13,14,15In the matter of fact, T1 mapping demonstrates an additive diagnostic role in 12% of patients who present a negative LGE and T2-STIR but abnormal native T1.We find that the value of T1 mapping is particularly relevant in some conditions such as cardiac amyloidosis where it is positive in 17% more patients than LGE. In cardiac amyloidosis, LGE has a very specific pattern, characterized by a diffuse subendocardial enhancement, an early darkening of signal of blood cavity, and a null defect of myocardium. The specificity of this pattern is near to 100% but it may be absent in the early stage of this disease . AmyloidScleroderma is usually associated with edema and microscopic fibrosis . Both ofT1 mapping is also instrumental for the diagnosis of the case of Fabry disease where conventional techniques are completely normal , with onAn advantage of T1 mapping is the absence of contrast injection that is required for LGE technique. The nephrogenic systemic sclerosis, a rare complication of gadolinium-based contrast agents, is associated with severe kidney disease. Contrast injection in patients can induce a severe reduction in glomerular filtration rate, which is potentially dangerous. The lack of LGE images make CMR less effective in ruling out cardiac disease and this is particularly relevant in subjects with ventricular arrhythmias (such as frequent PVC) with normal cardiac structure and function. In such conditions, the identification of myocardial fibrosis is very important because the prognosis depends on the presence of a structural myocardial disease ,16. T1 mIn contrast, T1 mapping results in a less effective ability to identify abnormalities in conditions such as myocarditis, small myocardial infarction, or in the case of non-ischemic fibrosis. Indeed, abnormal native T1 is found in 50% of patients with myocarditis, whereas LGE and/or T2-STIR are positive in all of these patients. Similarly, T1 native is abnormal in 71% of acute\chronic myocardial infarction patients, while LGE is positive in all of these patients and T2-STIR in all of the patients with acute myocardial infarction.A possible explanation of these findings may be found in some technical aspects of T1 mapping acquisition. T1 mapping images usually do not cover the entire left ventricle but the SCMR position paper  suggestsRecent modified Lake Louise criteria  includedHowever, results of our study demonstrate that T1 mapping with the three short-axis approach is not able to detect signal abnormalities associated with myocarditis, because, in most of the cases, the signs of myocardial damage are focal. Then, the effectiveness of the new Lake Louise criteria should be assessed by further larger population studies.The regional distribution of LGE and T2-STIR is also seen in HCM, where hypertrophy is usually asymmetric and LGE and edema are mostly located in hypertrophic segments . Then, iThe main results of the present study are that T1 mapping has an additive diagnostic role in only 12% of patients and is ineffective in 24% of them. To interpret these results, other limitations of T1 mapping should be considered. Indeed, the T1 mapping technique is far from being standardized, because it is well-known that differences in magnetic field shimming, pulse sequence and parameters, patient’s heart rate, and in the algorithm of the post-processing software could modify the result of this technique.Our results suggest that a complete CMR protocol cannot be exempt anymore from T1 mapping techniques. However, T1 mapping cannot substitute conventional approaches based on LGE and T2-STIR techniques. T1 mapping could be used as a substitute for LGE only in the presence of contraindication for contrast media.T1 mapping was acquired using only three short-axis slices and, as discussed above, this approach intrinsically limited the effectiveness of T1 mapping to identify focal and/or regional myocardial tissue abnormalities. However, this was indicated by the most recent SCMR consensus document .We did not include T2, T2*, and ECV mapping in the present study. T2 mapping was not available in our laboratory at the time we started the enrolment and in order to have a homogeneous population, we decided not to include T2 mapping data in the present study. T2* mapping was used in selected indications such as in cardiac hemochromatosis or in the suspicion of hemorrhagic infarction, and we followed these indications and did not acquire T2* in all the patients. Finally, ECV mapping required hematocrit obtained the day of CMR, and we had this in only a minority of patients (60 patients) and we preferred not to include these data.Finally, cardiac tumors and congenital heart disease, which are frequent indications for CMR, were not included in our population. However, we aimed to evaluate the effectiveness of T1 mapping in different cardiac diseases based on previous evidence. In contrast, the role of T1 mapping for the evaluation of cardiac tumors and congenital disease is still under evaluation.Conventional CMR techniques and T1 mapping are complementary. Globally, T1 mapping may give additive information in 12% of patients but cannot substitute conventional techniques, because it is less effective particularly in conditions presenting with regional or segmental distribution of myocardial damage. This limitation could be overcome by covering the entire myocardium with T1 mapping instead of a three short-axis approach. However, T1 mapping is more effective than conventional techniques in cardiac conditions with diffuse myocardial damage, such as in the early stages of scleroderma, Fabry disease, and cardiac amyloidosis. Results of this study suggest that both conventional and mapping techniques should be acquired in all the patients but with a substantial increase in exam duration.


Diffuse myocardial fibrosis and microvascular dysfunction are suggested to underlie cardiac dysfunction in patients with type 2 diabetes, but studies investigating their relative impact are lacking. We aimed to study imaging biomarkers of these and hypothesized that fibrosis and microvascular dysfunction would affect different phases of left ventricular (LV) diastole.In this cross-sectional study myocardial blood flow (MBF) at rest and adenosine-stress and perfusion reserve (MPR), as well as extracellular volume fraction (ECV), were determined with cardiovascular magnetic resonance (CMR) imaging in 205 patients with type 2 diabetes and 25 controls. Diastolic parameters included echocardiography-determined lateral e’ and average E/e’, and CMR-determined (rest and chronotropic-stress) LV early peak filling rate (ePFR), LV peak diastolic strain rate (PDSR), and left atrial (LA) volume changes.max /BSA , and circumferential (β = − 4.1%) and radial PDSR (β = 0.07%/sec). A 10% stress MBF increase was associated with lateral e′ (β = 1.4%) and average E/e’ (β = − 1.4%) and a 10% MPR increase to lateral e′ (β = 2.7%), and average E/e’ (β = − 2.8%). For all the above, p < 0.05. No associations were found with longitudinal PDSR or left atrial total emptying fraction.In multivariable analysis adjusted for possible confounders including each other (ECV for blood flow and vice versa), a 10% increase of ECV was independently associated with ePFR/EDV , LAIn patients with type 2 diabetes, imaging biomarkers of microvascular dysfunction and diffuse fibrosis impacts diastolic dysfunction independently of each other. Microvascular dysfunction primarily affects early left ventricular relaxation. Diffuse fibrosis primarily affects diastasis.Trial registrationhttps://www.clinicaltrials.gov. Unique identifier: NCT02684331. Date of registration: February 18, 2016.The online version contains supplementary material available at 10.1186/s12933-023-01804-9. Th. Th13]. outcomes . Additiooutcomes . Lastly,outcomes . In shorAnalysis of echo-Doppler and CMR variables diastolic variables were performed without blinding of the clinical patients information, but before knowledge of ECV or MBF/MPR was available.Continuous variables are presented as mean and standard deviation or median and interquartile range (IQR) as appropriate and were compared using an unpaired two-tailed Student t-test or Mann–Whitney U test. Categoric variables were presented as counts and percentages and compared using a chi-squared test or Fisher’s exact test as appropriate.2), hypertension, ischemic heart disease, albuminuria, retinopathy, autonomic neuropathy, and periphery neuropathy, in addition to ECV and MBF . Thus, in the large multivariable model, associations with ECV were adjusted for perfusion indices and vice versa. LV filling, ECV, and MBF are related to age and sex; therefore, we chose not to report a univariable model [Associations between ECV, MBF , and LV filling parameters were assessed in patients with type 2 diabetes in two general multivariable linear regression models, control subjects were excluded from these analyses. In a basic model, adjustments were made for age , sex, and RPP, all three with previous well-established effects on LV filling, ECV, and MBF , 27. Duele model , 18, 22.le model . AssumptAmong 296 patients, 205 had fully analyzable data on ECV, MBF, and MPR. Of these, 175 patients also had analyzable glycopyrrolate chronotropic stress scans. Patient selection is presented in the flow diagram in Fig. PEF, and lateral e´, as well as increased radial peak diastolic strain rates. However, LA maximum volume/BSA was actually decreased, and no differences were found in circumferential and longitudinal peak diastolic strain rates or for average E/e´. 99.5% (204 of the 205) of the patients with type 2 diabetes and all the control subjects were Caucasian.Table max/BSA both at rest and stress, as well as a decrease in circumferential and radial peak diastolic strain rates. However, ECV was not associated with Lateral e*, E/e*, or longitudinal peak diastolic strain rates (data not shown in the table). In the large multivariable regression model, ECV was still independent of MPR and other potential confounders associated with all the same LV diastolic parameters as in the basic model.The basic and the large multivariable regression model in patients with type 2 diabetes are shown in Table PEF during stress, circumferential, and radial peak diastolic strain rates were found for MBF at rest. All of the associations persisted after multivariable adjusting in the large model which included adjusting for ECV. MBF at rest did not associate with LA maximum volume, lateral e*, E/e*, or longitudinal peak diastolic strain rates (data not shown).MBF at rest was in the basic model Table  associatPEF, nor did stress MBF associate with longitudinal or radial peak diastolic strain rates (data not shown).MBF at stress associated in the basic model with LA maximum volume indexed to BSA at stress but not at rest, to circumferential peak diastolic strain rates, lateral e*, and Average E/e*. However, after multivariable adjusting in the large model, only the association with lateral e* and average E/e* was significant. MBF at stress did not associate with ePFR/EDV, LAEF or LAPEF, or any of the peak diastolic strain rate parameters (data not shown).MPR was associated with lateral e* and average E/e* in both the basic model and the large multivariable-adjusted model. The association with LA maximum size was not consistent. MRP did not associate with ePFR/EDV, LAEF, LAFigure In this work, we investigated the relationship between the myocardial extracellular volume, the myocardial blood flow at rest and during adenosine stress, and the myocardial perfusion reserve and left ventricular diastolic function. The myocardial extracellular volume  is an iIt is widely demonstrated that diabetes causes interstitial fibrosis and microvascular rarefaction and microvascular dysfunction –31. A geIn a CMR study of 135 Chinese patients with type 2 diabetes, an objective similar to ours was studied. The control subjects had similar ECV as ours, but despite the patients being younger with lower BMI and shorter duration of diabetes, the mean ECV in the patients with type 2 diabetes in this cohort was considerably higher (32.6 ± 4.6%) than in our study. In addition to quantifying ECV, they assessed MBF at rest and LV peak diastolic strain rate . In univLongitudinal peak diastolic strain rate is a measure of the same diastolic phase as e´. We did, however, not find an association between stress MBF or MPR and longitudinal peak diastolic stress as was found with lateral e′ and E/e′. In our study, lateral e′ and E/e′ were measured with echo-Doppler whereas longitudinal peak diastolic strain rate was measured with CMR. CMR has a lower temporal resolution than echocardiography. This could be part of the explanation. Thus, if longitudinal peak diastolic strain rate by echo-Doppler would be associated with microvascular function in our subjects cannot be concluded from our study.Other studies have also shown myocardial microvascular function to be related to cardiomyocyte relaxation. A case–control study of 66 patients using echocardiography showed that both the MPR and e’ were reduced in patients with type 2 diabetes when compared to controls, but no evaluation of ECV or other biomarkers of myocardial fibrosis was performed, and therefore, the relative impact of fibrosis could not be determined . In anotAs also previously presented , patientWe found ECV to be related primarily to measures of LV compliance, and of note, this included a positive association between increasing ECV and increasing maximal LA volume. This is despite the fact that LA maximum volume is lower in patients with type 2 diabetes compared to control subjects shown in our cohort as well as in other studies for example the UK biobank CMR study . This fi2 and patients with persistent or permanent atrial fibrillation, and our results must be interpreted accordingly. Especially concerning the assessment of glycopyrrolate stress, not all available scans were analyzable because we had to exclude patients due to contraindications, intolerance, or poor image quality. A sensitivity analysis indicates that the patients with available glycopyrrolate scans were somewhat healthier than patients without this test , whereas dobutamine increases myocardial contractility and (indirectly) stresses myocardial oxygen requirements. The usage of adenosine stress in the assessment of the microvascular function has been validated against invasive assessment  and is iIn patients with type 2 diabetes, increased myocardial ECV, a biomarker of interstitial fibrosis, and microvascular dysfunction are associated independently of each other with different aspects of left ventricular diastolic dysfunction. The ECV is predominantly associated with parameters that relate to left ventricular compliance, and MBF at stress and MPR are predominantly associated with the imaging parameters of cardiomyocyte relaxation. These different underlying pathophysiologic features should be considered when imaging these patients both in the clinic and in clinical trials..In animal studies interstitial fibrosis are related to LV diastolic function.In patients with type 2 diabetes, a sporadic variety of parameters of LV diastolic function have been associated with myocardial perfusion parametersECV and MBF/MPR can be quantified by CMR during the same examination with modern CMR techniqueBoth ECV and MBF/MPR were independently from each other associated with LV diastolic functionECV; a imaging biomarker of diffuse fibrosis, was associated with poor LV compliance – increasingly so this amplified during diastolic stressStress MBF and MPR; measures of the myocardial microvascular function, were associated with myocardial relaxation and restoring forcesAdditional file 1: Table S1. Clinical characteristics of patients that were excluded vs. included in the analysis of all rest parameters both CMR and Echo-Doppler.Additional file 2: Table S2. Clinical characteristics of patients that were excluded vs. included in the analysis of the glycopyrrolate stress parameters.


The use of endocardial pacing in patients with univentricular hearts and intracardiac shunts is limited, primarily due to the increased risk of thromboembolism. However, when accompanied by proper long‐term anticoagulation therapy, it may be safer than epicardial interventions in selected patients at high risk for surgery.We report transvenous endocardial pacing through the atrial septal defect in a patient with tricuspid atresia, transposition of the great arteries, severe pulmonary hypertension, and complete heart block. This study is among the first reported cases using this pacing method in a patient with a univentricular heart and intracardiac shunt. Dual‐Chamber Endocardial Pacing for a Univentricular Heart with Tricuspid Atresia. His electrocardiogram revealed a complete heart block with a right bundle branch block (Figure A 42‐year‐old man from Iraq with frequent episodes of syncope since 1 month ago was admitted to the Tehran heart center hospital. He had a history of tricuspid atresia type IIc without reparative surgery. On his admission, the patient had fatigue. On physical examination, he had nail clubbing and cyanosis with an OThe risk of the surgery for the epicardial lead placement was high due to pulmonary hypertension; on the other hand, the transvenous pacing would increase the risk of systemic thromboembolism. We discussed the risk associated with each procedure with the patient and recommended the endocardial route, which he accepted. Thus, endocardial pacemaker implantation was scheduled for the patient. After prep and drape, local anesthesia and light sedation were conducted. The left subclavian vein access was gained, and a dual‐chamber rate‐modulated permanent pacemaker was implanted using a peel‐away introducer. Atrial lead was inserted in the right atrial auricle. Ventricular lead was advanced through the atrial septal defect and mitral valve and was placed in the common ventricle. The final position of the leads is indicated in Figure 3Epicardial pacing has been a regular option for patients with complex congenital heart disease. Epicardial leads may be placed during cardiac surgery for underlying congenital heart disease with a plan to replace them in the future with transvenous leads.Endocardial ventricular pacing is technically possible in patients with univentricular hearts without previous reconstructive surgery, but the higher risk for thromboembolism limits this procedure.Our report explains a technique including the insertion of an endocardial ventricular lead through the intra‐atrial septum. This method is similar to the one employed in patients with normal cardiac anatomy who undergo transseptal puncture. In a similar study, Scott et al. reported endocardial ventricular pacing in a univentricular patient with tricuspid atresia and intracardiac shunt using the same method we used. The patient had no thromboembolic events or complications related to the procedure at the 1‐year follow‐up.Therefore, transvenous endocardial pacing may be the better option for high‐risk patients for surgery. This case was a candidate for a Fontan procedure with epicardial lead placement, but this was a high‐risk procedure considering his chronic high pulmonary artery pressure. As a result, we deemed that transvenous lead placement with a tight anticoagulant regimen has a lower risk.Only a few studies have compared the outcomes of dual‐chamber pacing versus single‐chamber ventricular pacing in patients with single ventricle physiology. Nevertheless, dual‐chamber pacemakers are generally considered in these patients because of AV synchrony, which enhances cardiac output and the capacity to interfere if atrial arrhythmia or sick sinus syndrome occurs.The bilateral perirenal fluid accumulation was a rare finding in the present case. It has been reported in cases with intracardiac shunt and pulmonary hypertension.In conclusion, endocardial pacing, in the presence of intracardiac shunts, has the risk of systemic thromboembolism. Nevertheless, when accompanied by proper anticoagulation therapy and tight control of INR at 2–3, it may be a safer alternative for epicardial interventions in patients at high risk for surgery.Ahmad Yamini‐Sharif: Conceptualization; supervision; writing – review and editing. Ramin Yaghoobian: Writing – original draft; writing – review and editing. Homa Ghaderian: Supervision; writing – review and editing. Najme‐Sadat Moosavi: Writing – review and editing.The authors declare that they have no conflicts of interest.Ethical approval for this case report was not required.Written informed consent was obtained from the patient for the publication of this report.


Ultrasound-assisted local thrombolysis (USAT) is an effective and safe treatment modality for intermediate–high-risk patients with acute pulmonary embolism (PE) . USAT is2) was admitted to the hospital with progressive dyspnoea (NYHA IV), tachypnoea (35 breaths/min), and tachycardia (119 beats/min). A previous echocardiographic examination a week ago revealed normal biventricular function and normal pulmonary pressure .An 83-year-old man , elevated high-sensitive troponin T level of 0.08 ng/mL  and elevated NT-proBNP of 2105 pg/mL . A chest X-ray did not show significant findings. However, transthoracic echocardiography revealed a massive dilatation of the right ventricle , but tachycardia did not improve. In view of the elevated sPESI score (2 points), the right-ventricular strain, the elevated troponin and NT-proBNP, and the deterioration under anticoagulation, we decided to use USAT with EKOS . Two EKOS catheters were inserted into the pulmonary artery (PA). The invasive PA pressure was 76/48 (57) mmHg. Due to the delivery bottlenecks of rt-PA, we used urokinase . For a period of 10 h, 30,000 units per hour were given for each catheter. During therapy, the PA pressure dropped to 34/23 (28) mmHg, and NT-proBNP to 1831 pg/mL next day . The echocardiography revealed RV/LV ratio of 0.7 and estimated PAPs of 45 mmHg  therapy was initiated. Arterial blood gas analysis under PEEP of 6 mmHg and FiOThe patient could be transferred to the general ward with the recommendation, to continue the oral therapy with 10 mg of apixaban twice daily over 7 days followed by 5 mg twice daily and for a total of 6 months.Pulmonary embolism is the third leading cause of cardiovascular mortality. The technological landscape for the management of acute intermediate- and high-risk PE is rapidly evolving. Patients with large PE and RV strains, even if normotensive, are at high risk of in-hospital and latent mortality . ThromboThe effectiveness and safety of systemic fibrinolysis in intermediate PE patients who are still normotensive were investigated by the PEITHO Trial . The stuAlternatively to systemic fibrinolysis, a catheter-directed local thrombolytic therapy and thrombectomy can be considered . USAT wip = 0.41) [Regarding PE, UK has been used in different settings. In the Pilot Trial, effectiveness and safety of a low-dose UK regimen were compared with alteplase in patients with an intermediate–high-risk PE. UK was administered with a dose of 10,000 U/kg once a day for 7 days. The rt-PA group was given 50 mg of alteplase via an intravenous injection within 2 h of admission. The efficacy rates were not significantly different. Also, adverse bleeding reactions were higher in the rt-PA group (20.8%) than in the UK group (8.3%), but did not reach significance ( = 0.41) .n = 5; total 2.04 ± 0.56 million units delivered over a mean period of 25.3 ± 7.35 h) or rt-PA . In the CDT group, three major bleeding complications were observed: two groin hematomas and one retroperitoneal hematoma. No bleeding complications were documented in the EKOS group [Lin et al. compared 11 patients with massive PE who underwent EKOS with rt-PA (mean dose of 0.86 ± 0.16 mg/h over 17.4 ± 5.23 h) and 15 patients who underwent a catheter-directed-therapy (CDT) with either UK (p < 0.001). Five patients died, and nine had major bleeding [Cuculi et al. presented the results of a pharmacomechanical approach with prolonged infusion of urokinase after manual aspiration of thrombus using guide catheters on 63 patients. Local thrombolysis was initiated with bolus injection of urokinase of 125,000 U in each microcatheter. The catheters were left in place for at least 24 h with continuous infusion of urokinase . The PA pressure dropped significantly from 33 ± 8 to 21 ± 7 mmHg (bleeding .In the present case, we combined the use of UK with the EKOS system for the treatment of an intermediate–high risk, elder patient with acute PE. With our protocol, we could significantly improve the hemodynamic and respiratory situation. We thought to communicate this case because of the actual lack of or short-comings in the supply of rt-PA thrombolytic agent, requiring alternative approaches. Since the exact dose of UK with EKOS is not known, we have revised the published articles regarding CDT in submissive PE and UK as a treatment of PE. Lin et.al. found that CDT with 60,000 U/h UK over 25 h has a complete thrombus resolution rate of 50% and a partial thrombolysis of 14% . We assu


Thyroid hormones, mainly triiodothyronine, have genomic and non-genomic effects on cardiomyocytes related to the contractile function of the heart. Thyrotoxicosis, which is the set of signs and symptoms derived from the excess of circulating thyroid hormones, leads to increased cardiac output and decreased systemic vascular resistance, increasing the volume of circulating blood and causing systolic hypertension. In addition, the shortening of the refractory period of cardiomyocytes produces sinus tachycardia and atrial fibrillation. This leads to heart failure. Approximately 1% of patients with thyrotoxicosis develop thyrotoxic cardiomyopathy, a rare but potentially fatal form of dilated cardiomyopathy. Thyrotoxic cardiomyopathy represents a diagnosis of exclusion, and prompt identification is crucial as it is a reversible cause of heart failure, and heart function can be recovered after achieving a euthyroid state using antithyroid drugs. Radioactive iodine therapy and surgery are not the best initial therapeutic approach. Moreover, it is important to manage cardiovascular symptoms, for which beta blockers are the first-line therapeutic option. A narrative review was performed, commencing with a search for articles in PubMed, MEDLINE and the Scientific Electronic Library Online databases using the Medical Subject Heading terms “cardiomyopathies” and “thyrotoxicosis”. Data published in Spanish and English during the period 2005–2022 was collated. The research was limited to articles related to humans.Systematic reviews, clinical trials, prospective cohort studies, cross-sectional and retrospective studies, narrative reviews, case reports and case series related to the objective of this manuscript were included. We did not include letters to the editor or conference proceedings. Only studies in Spanish and English were included. A total of 91 citations were identified, of which 33 were removed based on eligibility criteria. Fifty-eight articles met the inclusion criteria and were used for the development of this narrative review.12The quality of this review was evaluated using the Scale for the Assessment of Narrative Review Articles, which includes the following items: explanation of the importance of the review, statement of objectives, description of the literature search, references, scientific reasoning and appropriate presentation of information. Twelve points were obtained corresponding to all the required items.15 Thyroid hormones enter and leave cells through different transporters, such as monocarboxylate transporters 8 (MCT8) and 10 (MCT10), which are present in the heart and mainly allow transportation of T3.16The myocardium does not have the enzymes to carry out deiodination, so it depends mainly on T3.17Thyroxine (T4) represents 85% of the hormonal production of the thyroid gland, and is converted into its active form, triiodothyronine (T3), by 5’-monodeiodinases. This occurs mainly in the liver, kidneys and skeletal muscles.3 The T3–THR complexes translocate to the nucleus to activate or repress the expression of genes , thus functioning as nuclear transcription factors regulated by thyroid hormones .7The classic effects of thyroid hormone on the transcription of specific genes in cardiomyocytes are mediated by the binding of T3 to thyroid hormone receptors (THR).2+) ATPase 2 (SERCA2a), voltage-gated potassium channels (Kv1.5 and Kv4.2), Na+/K+ ATPase and β1-adrenergic receptor adenine nucleotide translocase.18 Conversely, they negatively regulate the expression of myosin β heavy chains, phospholamban (SERCA2a inhibitor), Na+/Ca2+ exchangers (NCX1), adenylate cyclase types V and VI, and THR α1.18 The contraction and relaxation of cardiac muscle are regulated by the concentration of intracellular Ca2+, which is determined by the release of sarcoplasmic calcium through ryanodine receptors and its reuptake by SERCA2a.20The binding of T3 to TRH positively regulates the expression of several cardiac genes related to the contractile function of the heart, such as α-myosin heavy chains, sarco/endoplasmic reticulum free calcium  are also capable of inducing severe cardiomyopathy  in a concentration-dependent manner, decreasing cardiomyocyte viability by stimulating β-adrenergic receptors, which also increases systolic blood pressure, alters left ventricular contractility, and leads to left ventricular remodelling (including hypertrophy and dilation) and dysfunction.33While systemic mean arterial pressure decreases, pulmonary arterial pressure increases. This could be due to an increase in pulmonary blood flow that is not accompanied by a proportional decrease in pulmonary vascular resistance. Pulmonary arterial hypertension can result in an increased load on the right ventricle, leading to its dilation and increased right atrial pressure and central venous pressure. One consequence of this is right-sided heart failure.35The preload (measured as left ventricle end-diastolic volume) and cardiac performance (measured as cardiac output) are related according to the Frank-Starling Law (left ventricular performance curves). Normally, cardiac performance increases as preload increases, but when the left ventricle contractility decreases (as in dilated cardiomyopathy), the cardiac performance for a given preload is minor.33 Timely diagnosis of this group of patients is important, as it constitutes a reversible cause of heart failure within 6 months of reaching a euthyroid state.33 The signs and symptoms of heart failure are related to a structural and/or functional alteration of the heart related to hyperthyroidism. Initially, a so-called ‘high-output’ heart failure occurs because cardiac output can increase by 50–300% as a result of the combination of increased resting heart rate, contractility, ejection fraction, systolic volume and decreased systemic vascular resistance. In advanced stages, as a consequence of poor control of thyroid function, dilated cardiomyopathy may occur with systolic dysfunction of the left ventricle and low cardiac output.33TCM is a diagnosis of exclusion.33 On examination, patients with overt hyperthyroidism may present with hyperactivity, rapid speech, stare, lid lag, warm and moist skin, thin and fine hair, tachycardia, irregular pulse, systolic hypertension, hyperdynamic precordium, finger tremor, muscle weakness, hyperreflexia and exophthalmos. Thyroid palpation may or may not show enlargement or pain of the gland.36 Clinical manifestations related to high-output heart failure include general findings such as dyspnoea, tachypnoea, abdominal bloating, peripheral oedema, fatigue and signs of pleural effusion. Specific manifestations associated with thyrotoxicosis were described above.37The hyperthyroid patient usually presents with irritability, insomnia, anxiety, sweating, increased intestinal peristalsis, decreased libido, palpitations and exercise intolerance.33Three progressive stages have been described in heart failure due to thyrotoxicosis: the first, ‘hyperkinetic’, is characterized by preserved left ventricular systolic function that does not increase during physical exertion; the second, ‘normokinetic’, is where there is compensatory reversible myocardial hypertrophy to maintain a preserved cardiac output; and the third, ‘hypokinetic’, is a decompensated stage in which there is hypertrophy and reversible or irreversible dilation of the cardiac chambers, which translates into a decrease in the systolic function of the left ventricle and low cardiac output.39 If an autoimmune process is suspected, the evaluation will continue with the measurement of serum levels of TSH-receptor antibodies,40 antithyroid peroxidase antibodies and thyroid-stimulating immunoglobulin.33The measurement of thyroid-stimulating hormone (TSH) is the initial diagnostic test of choice. Thyroid hormones exert negative feedback on the pituitary gland so that their elevation will lead to a decrease in TSH levels. This decreased TSH is usually followed by the measurement of free T4 and total T3 levels.23Previous reports described a correlation between the levels of brain natriuretic peptide (BNP) and the levels of thyroid hormones, noting that the level of BNP was four times higher in hyperthyroidism than in a euthyroid state. This is due to the fact that thyroid hormones stimulate BNP secretion by stretching the atrial myocardial tissue, and through the direct action of free T3 hormone on the increase in BNP secretion from myocardial cells due to increased gene expression.33 Other less frequent types include extrasystoles (5–7%), atrioventricular block (2.7–5%), atrial flutter (1.2–2.3%) and paroxysmal supraventricular tachycardia (0.2–3.3%).26 In some cases, patients with hyperthyroidism undergoing treatment report chest pain associated with electrocardiographic changes, such as alterations in the ST segment and the T wave, simulating myocardial ischaemia, and advanced stages of TCM with signs of volume overload can be observed.33 The findings described in the electrocardiogram are not specific; however, they are useful to raise suspicion of TCM, and are usually reversible after reaching a euthyroid state.17The most frequently reported arrhythmia is sinus tachycardia (42–73%), followed by atrial fibrillation (9–23%).41In severe thyrotoxicosis, biventricular dilatation and expansion of the pulmonary artery can be seen accompanied by right ventricular hypertrophy, simulating mitral valve disease, although without left atrial dilatation in oblique projection. Signs of pulmonary oedema can also be seen.2, dilation of the inferior vena cava, enlargement or dysfunction of the right ventricle, estimated pulmonary artery pressure elevation, or left ventricle enlargement.42 Left ventricular hypertrophy with thickening of the posterior wall and the interventricular septum can be found.43 Therefore, signs of diastolic dysfunction are common, such as increased end-diastolic volume and left ventricular hypertrophy, prolonged isovolumic relaxation time (greater than 90 ms) and E-wave deceleration time (greater than 210 ms).26Echocardiographic findings that may raise suspicion of high-output heart failure are estimated cardiac index greater or equal to 4 L/min/ m3 These are caused by dysfunction of the papillary muscles. Mitral valve prolapse is a common finding, more frequently in Graves’ disease, secondary to endocardial myxomatous degeneration and glycosaminoglycan deposition, or loss of muscle tone with papillary muscle overdistention.17 Valvular insufficiency, in addition to the effects of thyroid hormone on pulmonary circulation, causes right ventricular failure more frequently than left ventricular failure in thyrotoxicosis.26 In a small percentage, dilation of all four chambers and reduced systolic function can be seen.45Mitral and tricuspid regurgitation can also be identified in addition to indirect signs of pulmonary hypertension.17Stress echocardiography is useful to evaluate myocardial functional reserve, which is reduced in thyrotoxicosis. This is due to tachycardia at rest and low systemic vascular resistance, which limits adaptation to exercise.3Using thallium 201 chloride, a diffuse or focal decrease in the metabolic activity of the myocardium can be evidenced.46Cardiac magnetic resonance has a special application, primarily intended for one of the cardiac manifestations of thyrotoxicosis , capturing evidence of the three basic phenomena underlying myocardial inflammation . One study found a good correlation with endomyocardial biopsy patterns.17 With this reasoning, we propose the algorithm in Figure 4.Currently, the basic diagnostic strategy consists of determining TSH levels and excluding other causes of structural and functional cardiac alterations, using the tools described above.47 The achievement of permanent euthyroid status is of great importance as it is associated with a better prognosis and improves cardiovascular parameters, such as heart rate, number of extrasystoles and cardiac output.7The goal of the treatment in patients with TCM is to restore euthyroidism and to manage cardiovascular manifestations using oral antithyroid drugs.26 as surgical treatment is associated with high perioperative and intraoperative risk and radioactive iodine therapy is associated with worse prognosis. The latter is due to the development of radioactive thyroiditis leading to ‘leakage’ of preformed T4 and T3, which results in recurrence of atrial fibrillation, vasospasm and cardiovascular events .9 Currently available drugs are methimazole and propylthiouracil, which have been used since 1940.9 Both drugs work by inhibiting thyroid hormone synthesis. Propylthiouracil also inhibits the peripheral hepatic conversion of T4 to T3. T3 levels have been reported to decrease 4–8 hours after administration of 200 mg of propylthiouracil, which may be useful for patients with severe thyrotoxicity such as TCM.3Treating TCM using surgery or radioactive iodine instead of antithyroid drugs is not easy,39 The American Thyroid Association recommends using initial doses of methimazole based on free T4 levels, as shown in Table 1.39 Treatment should be administered for 6 months to 2 years, although the general recommendation is 18 months of continuous treatment.39 It is important to consider the side effects of antithyroid drugs, such as rash in up to 5% of patients and agranulocytosis in 0.5%. Other less frequent side effects include cholestatic jaundice, hepatocellular toxicity, angioneurotic oedema and arthralgias.17 The overall remission rate with treatment is in the range of 50% and can be as high as 80% in subgroups with mild disease.48 There is some evidence that continuation of treatment with antithyroid drugs beyond what is usually recommended may be associated with higher remission rates.49 Radioactive iodine therapy is usually recommended for older adults. However, long-term administration of an antithyroid drug is safe and some patients may prefer it rather than a destructive therapy. This is one of the current recommendations of the European Thyroid Association.49In Graves’ disease, a regimen starting with high doses of antithyroid medications (30–60 mg/day of methimazole or 300–600 mg/day of propylthiouracil) is usually prescribed and may be titrated at intervals of 4–8 weeks according to clinical response and serum thyroid hormone levels, evaluating therapeutic efficacy and guiding the dose to achieve euthyroidism.50 Beta blockers are safe and effective drugs for relieving symptoms, being the first choice for reducing heart rate in patients with hyperthyroidism.39The management of congestive heart failure with impaired systolic function usually includes fluid and sodium restriction, and administration of diuretics, vasodilators, renin–angiotensin system antagonists and beta blockers.51Treatment with propranolol , atenolol , metoprolol , or other beta blockers is recommended until thyroid hormone levels have normalized. The goal is to decrease heart rate rapidly, relieve left ventricular dysfunction related to the ventricular rate in hyperthyroidism, prevent palpitations, lower systolic blood pressure and reduce muscle weakness and exercise intolerance.52 Cardioselective beta blockers are better tolerated, but not completely safe. The risk of bronchospasm can be decreased by using the lowest possible dose and a beta-blocker with higher β1 selectivity.53 The use of beta blockers in asthma and TCM could be based on an individual risk assessment.54Beta blockers should be considered in all patients with TCM and other patients with thyrotoxicity with resting heart rates greater than or equal to 90 beats per minute or with coexisting cardiovascular disease. In patients with asthma, beta blockers should be avoided because of concerns regarding bronchoconstriction.56 In general, digoxin is not recommended to treat atrial fibrillation in hyperthyroidism because it increases renal clearance and sympathetic tone and decreases vagal tone. In addition, it requires a large volume of distribution, needing a higher dose of digoxin than usual, which can result in digoxin toxicity.55The mainstay of atrial fibrillation management in patients with hyperthyroidism is beta blockers and an antithyroid agent (propylthiouracil or methimazole).51 Digitalis and diuretics may be administered to patients with severe heart failure and pulmonary oedema. Both drugs are also safe and effective when given together with beta blockers.55For patients in whom the use of beta blockers is contraindicated, the careful use of calcium channel blockers like verapamil  and diltiazem  could be recommended for heart rate control, as they enhance the reduction of blood pressure through their effects on smooth muscle cells of the arterioles. Consideration needs to be given to cardiovascular shock and hypotension in the use of these drugs.56Calcium channel blockers should be avoided in reduced ejection fraction or haemodynamic instability due to their strong negative inotropic effect. Amiodarone can be used in these acute settings because it allows the patient to return to a sinus rhythm when combined with antithyroid medications and reduces the possibility of worsening thyrotoxicosis. The recommended loading dose is 800 mg daily for 1 week, followed by 600 mg daily for 1 week, then 400 mg daily for 4–6 weeks; the maintenance dose is 200 mg daily.57 In those patients with persistent atrial fibrillation despite achieving a euthyroid state, rhythm control may be an option. However, as in the general population with atrial fibrillation, rate control is generally initially preferred. Therapeutic options include class IA, IC and III antiarrhythmics.56Nearly two-thirds of patients return to normal sinus rhythm 8–10 weeks after achieving a euthyroid state.56The use of amiodarone may be indicated acutely, as mentioned above, during a thyroid storm to restore sinus rhythm or as chronic treatment in patients with atrial fibrillation refractory to rate control.58 However, the optimal use of anticoagulants represents a therapeutic dilemma due to the increased risk of bleeding. Thyroid disorders affect haemostatic balance, thus affecting the efficacy of anticoagulants in patients with atrial fibrillation.58 The risk of systemic or cerebral embolization must be weighed against the risk of bleeding and other complications of this therapy.58 The treatment regimen is summarized in Figure 5.The use of anticoagulation in patients with hyperthyroidism and atrial fibrillation has been controversial, although hyperthyroidism has been shown to increase the risk of thrombotic events in patients with atrial fibrillation regardless of CHADS2-VASc score.TCM is a rare but potentially lethal complication of thyrotoxicosis, which is reversible if euthyroid status is achieved. As it is a diagnosis of exclusion, additional tests are of great importance in the diagnostic approach. Antithyroid drugs are the first-line treatment.All authors recognize that, despite describing the methodology used for the development of this narrative review, a research question is not answered; therefore, the scientific evidence is less than a systematic review. Additionally, a minor limitation is the absence of clinical practice guidelines relating to the diagnosis and management of TCM.


In recent years, new interventional therapies for tricuspid regurgitation (TR) demonstrated their effectiveness in reducing TR severity and improving symptoms. Currently, tricuspid transcatheter edge-to-edge repair (T-TEER) and percutaneous annuloplasty are the most widely used techniques in Europe. In this retrospective study, we compared procedural characteristics and learning curves of both TR devices in a real-world cohort.Eligible patients with severe to torrential TR underwent either percutaneous annuloplasty or T-TEER as recommended by the local heart team. Patients with combined mitral and tricuspid interventions were excluded from the analysis. The study focused on procedural characteristics, TR reduction and learning curves.n = 64) or T-TEER (n = 58) with a technical and device success rate of 98% and 97%, respectively. Reasons for technical failure included right coronary artery (RCA) dissection prior to percutaneous annuloplasty, and two single leaflet device attachments (SLDA) during T-TEER implantation. The mean improvement of TR severity was 2.4 ± 0.8 degrees after T-TEER and 2.5 ± 0.8 after percutaneous annuloplasty. T-TEER procedures were shorter in terms of both procedure time and radiation exposure, while percutaneous annuloplasty, although taking longer, showed a significant reduction in procedure time over the course of the analysed period.A total of 122 patients underwent either percutaneous annuloplasty (In summary, both interventional therapies reduce TR severity by approximately two degrees when used in the appropriate anatomy. The learning curve for annuloplasty group showed a significant decrease of procedure times. Significant tricuspid regurgitation (TR) is a prevalent valvular heart disease that is observed in 4% of patients over 75 years of age . TR is mThe T-TEER approach primarily diminishes TR by clipping the leaflets, while tricuspid annuloplasty reduces the annular circumference. Consequently, both devices are implanted in varying TR morphologies , 7. T-TEA significant number of patients present with anatomies amenable by either T-TEER or annuloplasty. Therefore, other considerations such as procedure time and potential complications can play a role in the decision-making process for the appropriate device. In addition, as interventional TR repair is still a novel therapy, starting centers might be interested in expected learning curves for both approaches. Thus, the aim of present study was to provide a comparison of procedural characteristics and learning curves of the most widely used TR devices, i.e., percutaneous annuloplasty and T-TEER, in a real-world cohort.The retrospective multi-centre study compared percutaneous annuloplasty and T-TEER of the tricuspid valve in a real-world cohort. Patients with an age ≥18 years, high surgical risk and symptomatic severe to torrential TR of different pathologies and despite optimal medical therapy underwent either Cardioband® implantation  or T-TEER  from 2019 to 2022. Patients with combined procedures of the tricuspid and mitral valve were excluded from the analysis. In case of two sequential TR procedures, only the first intervention was evaluated. The study was approved by the institutional ethics committee of the Charité – Universitätsmedizin Berlin, Germany (EA1/005/23).Interventional therapy of TR was recommended by local heart team consisting of interventional cardiologists, cardiovascular surgeons, anesthetists, heart failure specialists, and imaging experts. The appropriate device was selected based on individual tricuspid anatomy and function according to current recommendations , 7. PatiOutcome parameters were the following procedural characteristics: technical and device success and complications based on the Mitral Valve Academic Research Consortium (MVARC) criteria  as well U-test, respectively. Continuous variables were presented as median with 25th and 75th percentile or mean with standard deviation depending on their skewness and uniform per variable for a better inter- and intragroup comparison. Continuous variables were assessed by t-test  and Wilcoxon-test or Mann-Whitney U-test . The impact of TR reduction on right ventricular function and learning curves were evaluated by linear regression analysis. TR improvement (difference between TR grade after intervention and at baseline) was assumed to be a continuous variable. A p-value of <0.05 was considered statistically significant.SPSS Statistics version 28 for Windows  was used for data analysis. Categorical and ordinal variables were listed in percentages and were analysed by chi-squared test or Mann-Whitney p = 0.003). There was no significant difference in leading TR pathology between annuloplasty or T-TEER group . Reasons for device failure were two single leaflet device attachments (SLDA) after T-TEER. Two additional SLDA occurred during the intra-hospital stay. One patient with planned Cardioband® implantation developed cardiac arrest due to iatrogenic coronary dissection after engagement of the right coronary artery, necessitating cardiopulmonary resuscitation. Therefore, the Cardioband® implantation was aborted. We did not include this case in the further analysis of procedural characteristic and durable repair. None of the patients died during the procedure. One patient of the annuloplasty group suffered from a major vascular access complication, a dissection of the left iliac artery due to pronounced kinking, treated by stent implantation. The implantation of the Cardioband® was performed during a second procedure without further complications.Technical and device success was achieved in 97% of patients in the T-TEER group and 98% of patients in the annuloplasty group .TR was reduced at least one grade in 100% of patients, with 91% of T-TEER patients and 80% of annuloplasty patients achieving a TR grade ≤2 post-intervention. The mean reduction was 2.4 ± 0.8 grades after T-TEER and 2.5 ± 0.8 grades after annuloplasty . MoreoveF-value 7.7, p = 0.008, regression coefficient 46.1, p < 0.001).In both groups, we observed a significant decrease of right ventricular function as assessed by right ventricular fractional area change (RVFAC) and a significant reduction of right atrial area, while tricuspid annular plane systolic excursion (TAPSE) was only reduced after annuloplasty . MoreoveThe procedure time of annuloplasty showed a significant reduction throughout the study period. There was neither a relevant effect of a learning curve on TR reduction in both groups nor on procedure time in the T-TEER group.The present study compares procedural characteristics and learning curves of percutaneous annuloplasty and T-TEER in a real-world setting. Both interventional therapies reduced TR severity by approximately two degrees. Technical and device success was achieved in 97% of patients in the T-TEER and 98% of patients in the annuloplasty group. Complications during percutaneous annuloplasty comprised intermittent bradycardia and injuries of the right coronary artery. SLDA occurred in 7% of patients after edge-to-edge repair. Overall, however, the number of clinically relevant complications was low.n = 10) could not be treated with the preferred device—either due to RCA proximity (for annuloplasty) or due to gap size (for T-TEER). This resulted in patients with large gaps (often associated with larger tenting height) being treated by annuloplasty especially in the early phase of the study period. Similarly, patients with suitable valve anatomy for annuloplasty had to undergo T-TEER when RCA proximity made annuloplasty not feasible. With the availability of larger edge-to-edge devices, e.g., TriClip G4 and PASCAL Ace, we observed a reduction of tenting height in the annuloplasty group and an increase of baseline gap size in T-TEER patients. In both groups, patients had right ventricular leads. Lurz et al. already reported comparable efficacy of T-TEER in patients with and without right ventricular leads  and up to discharge (n = 2) between the posterior and septal (n = 2) as well as the anterior and septal leaflets (n = 2). All T-TEER patients with SLDA presented a massive TR with degenerative and short leaflets as well as a larger tricuspid annulus diameter at baseline (45 [44–49] mm) compared to those without SLDA (40 [38–44] mm). However, the tenting height and coaptation gaps were comparable between the two groups, measuring approximately 4 ± 3 mm (n = 4) and ranging from 2 to 5 mm (n = 3) in the SLDA group, respectively. All patients underwent a re-intervention (T-TEER) resulting in a moderate (n = 1), severe (n = 2) or massive TR (n = 1) at discharge. Based on these findings, we propose that the combination of shortened and degenerative leaflets, along with excessive annular dilation, may represent potential risk factors for the development of SLDAs in T-TEER. SLDA is a well-known complication in tricuspid and mitral edge-to-edge repair (In the T-TEER cohort, four SLDA occurred during the procedure (e repair –22. Knowe repair , 22, 23.e repair , 25.We observed a significant learning curve only in the annuloplasty group in terms of procedural duration. Specifically, the first studies of Cardioband® implantation showed a mean procedure time of 4.2 h , which wIn summary, the following aspects might be considered when selecting patients for TR procedure beyond anatomical characteristics: The longer procedure time of percutaneous annuloplasty results in longer duration of general anesthesia and mechanical ventilation, which might increase complications such as pneumonia due to microaspiration and prolonged ventilation as well as delirium in older patients. The implantation requires the use of contrast, which should be taken into account in patients with renal failure including patients with cardiorenal syndrome. However, more severe TRs were treated successfully with annuloplasty compared to T-TEER. T-TEER might be challenging in patients with a big coaptation gap leading to an increased risk of SLDA. Nevertheless, percutaneous annuloplasty and T-TEER resulted in a comparable TR reduction in our study cohort. Long-term data for both devices revealed a durable TR improvement, which was associated with symptoms relief and reduction of mortality and heart failure hospitalizations , 26–28. The present study utilized a retrospective design, and patients were not randomized to specific treatment options. Device selection was based on the TR anatomy. As a result, baseline characteristics showed differences in three aspects: presence of CIEDs, bilirubin levels, and peripheral artery disease. These differences reflect real-world data. Therefore, the present study serves as a hypothesis-generating investigation for further randomized-controlled trials.To conclude, both T-TEER and percutaneous annuloplasty reduce TR severity by approximately two degrees when used in the appropriate anatomy without clinically significant complications. The learning curve of the annuloplasty group presented a significant decrease of procedure time, which might be a relevant aspect for starting centres.