The left ventricular (LV) ejection fraction (EF) is the preferred parameter applied for the non-invasive evaluation of LV systolic function in clinical practice. It has a well-recognized and extensive role in the clinical management of numerous cardiac conditions. Many imaging modalities are currently available for the non-invasive assessment of LVEF. The aim of this review is to describe their relative advantages and disadvantages, proposing a hierarchical application of the different imaging tests available for LVEF evaluation based on the level of accuracy/reproducibility clinically required. The left ventricular (LV) ejection fraction (EF) is the preferred measure for the evaluation of LV systolic function. It reflects the amount of blood being pumped out of the LV during each cardiac cycle and is expressed as a percentage, where a value ≥50–55% is considered normal. The accurate measurement of LVEF and volumes is the cornerstone of routine cardiology practice, being crucial for diagnostic definition, prognostic classification, and clinical management. In heart failure (HF), LVEF is used to categorize patients with preserved (HFpEF), mid-range (HFmrEF), or reduced systolic function (HFrEF), as well as to stratify for arrhythmic risk . In valvAlthough LVEF can be measured during cardiac catheterization by contrast left ventriculography, there are several non-invasive imaging modalities that are routinely used in clinical practice. With every technique, LVEF assessment can be estimated either subjectively by visual evaluation or objectively by quantitative methods. Whenever possible, the preference is to employ quantitative measures to minimize variability and to favor greater precision and accuracy.Transthoracic echocardiography (TTE);Cardiovascular Magnetic Resonance (CMR);Cardiac computed tomography (CT); andNuclear cardiology imaging modalities: radionuclide multiple-gated acquisition (MUGA) ventriculography, or ECG-gated single photon emission computed tomography (SPECT).Non-invasive imaging modalities for LVEF assessment include:Of note, when measuring LVEF using different modalities in the same subject, the obtained values may differ due to differences in the methodology applied. Thus, the modalities available for non-invasive LVEF should not be considered interchangeable, and when serial LVEF measures are needed, the same imaging test  should be consistently used.The aim of this review is to describe the relative advantages and disadvantages of each non-invasive imaging modality available for LVEF evaluation  and to pBecause of its wide availability and high safety profile, TTE still represents the main technique used to evaluate LVEF in the clinical arena. LVEF measures can be obtained using various methods, based on the settings of image acquisition  or three-dimensional (3D)) and the geometric assumptions used for calculations . Currently, the biplane method of disks (modified Simpson’s rule) is the recommended two-dimensional method to assess LVEF . It requThese tracings are used by the applied software to divide the LV cavity into a predetermined number of disks . This method requires substantial geometric assumption because the entire LV cavity border is not traced. Moreover, the shape of the LV cavity cannot be approximated to any single solid figure, but is considered the sum of a cylinder , a truncated cone , and another cone (attributed to the cardiac apex) . AlthougContrast EchocardiographyAn intravenous (i.v.) contrast agent can be administered to improve endocardial border detection during TTE, thus improving the accuracy of LV volumes and EF measurements. Moreover, contrast-enhanced echocardiography was shown to substantially reduce inter- and intra-observer variability (mean percentage of inter-reader variability for LVEF can be reduced from 14.3% to 7.4%) . However3D TTE is considered the best technique to assess LVEF with ultrasound, as it does not require any geometric assumptions .Images must be acquired over several heartbeats using specific 3D imaging probes. Unlike 2D, 3D methods are less affected by the shape of LV cavity. When compared to other echocardiographic methods, LVEF evaluation using a 3D modality proved to be more accurate and far less variable ,11. HowePros. The negligible harm and lack of ionizing radiation works in favor of TTE, making it an ideal modality for the initial and follow-up evaluation of LV function; additional advantages include its ability to provide real-time heart images together with the technique’s wide availability, portability, and bedside feasibility.Cons. All TTE methods require an acoustic window that allows for the adequate visualization of the blood/endocardial border in all the required LV segments to guarantee accurate tracing and measurements. Obese patients, those with chronic obstructive pulmonary disease, and/or reduced intercostal space will often have poor image quality, which may significantly affect the accuracy of the measurements. Suboptimal image quality is also responsible for limited reproducibility and high inter- and intra-observer variability. Moreover, every echocardiographic technique is strictly dependent on operator experience [perience .In the last few decades, CMR has been established as a robust method for the quantification of LV function and volumes. The high spatial, temporal, and contrast resolution of CMR allows clear identification of the blood–myocardium interface, providing highly accurate measurements of LV function and volumes. Furthermore, CMR has shown superiority over 2D TTE in terms of inter-study reproducibility, required when imaging parameters are to be obtained in serial examinations . In a muThe acquisition of cine images with 25–30 phases allows to obtain an adequate temporal resolution to correctly identify the end-systolic and end-diastolic phases. The endocardial border is traced in every slice in both end-diastolic and end-systolic phases, the resulting areas are added together and then multiplied for slice thickness and slice gap providing end-diastolic and end-systolic volumes, stroke volumes, and EF. The tracing of the endocardial contours must exclude the anatomical structures such as the papillary muscles and the trabeculae to obtain the correct calculation of the volumes ,17. ManyPros. What contributed to make CMR the standard of care for the assessment of LV volumes and function is the possibility of obtaining a 3D reconstruction of the LV chamber, which frees CMR from the limit of geometric assumptions [umptions ,19, togeCons. Drawbacks of CMR are mainly represented by the low availability of dedicated scanners, as well as technicians and physicians with adequate expertise in performing and interpreting cardiac studies. Furthermore, the presence of some medical devices or metallic foreign bodies may contraindicate the execution of a CMR scan in some patients. In a small number of cases, claustrophobia prevents from performing a CMR study. Finally, breathing artifacts and heart rhythm disturbances can prevent the acquisition of good-quality images.CT has recently become more widely used as it allows for accurate, non-invasive evaluation of coronary anatomy and detection of atherosclerotic disease. Additionally, cardiac CT raw data acquired with retrospective gating can be used for the measurement of LV volumes, wall thickness, and the assessment of both global and regional function ,21. FullPros. When compared to CMR, CT showed accuracy in assessing LV volumes and function, with the advantage of combining the assessment of coronary anatomy in one single examination [mination .Cons. Systematic use of cardiac CT for LVEF evaluation may be limited by the need for radiation exposure (higher levels of exposure are caused by retrospective gating used to study LVEF), as well as the need for contrast administration, particularly in the case of poor renal function or contrast allergies. Moreover, a low temporal resolution may lead to under-sampling and therefore an underestimation of LV volumes and function [function .ECG-Gated Single Photon Emission Computed Tomography (SPECT)SPECT represents the procedure most commonly performed for the assessment of myocardial perfusion. It is based on the injection of a radiotracer , which is extracted from the blood by the perfused myocytes and retained for some period of time. Photons are then emitted from the myocardium and captured by a gamma camera, where the information is turned into digital data representing the magnitude of uptake and the location of the emission. The result is the creation of multiple tomograms (or slices) of the heart, with a digital display of the radiotracer distribution throughout the organ. Most commonly, a cardiac SPECT study includes two datasets of image acquisition, including one under resting conditions and another after physical exercise or pharmacologic stress. This test is still widely used for the identification of myocardial perfusion defects, as well as for the study of myocardial viability . Gated SRadionuclide Multiple-Gated Acquisition( MUGA) VentriculographyMUGA ventriculography has also been used for EF calculation. This technique is based on the labelling of the patient’s red blood cells with technetium-99 and the subsequent evaluation of cell counts in end-diastolic and end-systolic phases, offering the possibility to calculate LVEF. Being characterized by good reproducibility, this technique may be excellent for serial evaluation of EF; however, accurate LVEF measurements using MUGA may present some challenges, including the need for patient collaboration and particular care in performing adequate attenuation correction. Nowadays, it is not routinely performed in many nuclear medicine imaging laboratories .Pros. Advantages of nuclear cardiology in the assessment of LVEF are mainly the high availability of the techniques and the possibility, with gated-SPECT, to obtain data on cardiac function and perfusion in one single exam.Cons. The main disadvantage is the high dose of radiation exposure, which makes such techniques unsuitable in clinical conditions, requiring repeated measures of LVEF and volumes. Moreover, low temporal resolution may lead to an underestimation of LV volumes [ volumes .Although the assessment of LVEF remains one of the main tasks of all cardiac imaging modalities, it is clear that changes in LVEF only occur in the late stages of many cardiac diseases. Moreover, LVEF is a surrogate marker of myocardial contractility and is highly dependent on loading conditions at the moment of evaluation.Myocardial strain refers to the deformation of a myocardial segment from its initial length to its maximum length, following the different fiber orientations. It is expressed as a percentage. LV longitudinal strain represents the longitudinal shortening from the base to the apex. It is expressed by negative values. Radial strain is the radially directed myocardial deformation towards the center of the LV cavity and represents the LV thickening and thinning motion during the cardiac cycle; radial strain is expressed by positive values. Circumferential strain derives from LV myocardial fibers shortening along the circular perimeter observed on a short-axis view and is consequently represented by negative values .Speckle tracking echocardiography (STE) is considered an accurate and convenient method to assess myocardial strain, as it is easy to perform and largely available . SeveralThe clinical utility of myocardial strain imaging has been increasingly investigated over the past two decades in both ischemic and non-ischemic cardiomyopathies, and in many other cardiac conditions potentially affecting LV function. In every clinical scenario, however, the assessment of longitudinal and circumferential strains appears to be very useful in detecting sub-clinical dysfunction in patients with preserved EF; therefore, these strain calculations should be considered in daily clinical practice ,37,38,39Given the availability of many different imaging modalities for the non-invasive assessment of LV function and volumes, each with peculiar strengths and weaknesses, differences in terms of spatial and temporal resolution may lead to variable accuracy levels when using these techniques  40,41,4,441,42, High spatial and contrast resolution, excellent intra- and inter-observer reproducibility, and lack of radiation exposure make CMR the current gold standard for the evaluation of LV volumes and function ,38,43. OCT and nuclear cardiology imaging are mainly indicated for EF evaluation in cases where there is a need for the simultaneous assessment of coronary anatomy and myocardial perfusion, respectively. However, both techniques expose patients to a certain dose of radiation and this may preclude their use in cases where repetitive measures of EF are required, or in younger patients.All the described imaging modalities can provide measurements for LV volumes and EF. However, normal ranges may substantially differ among the different modalities and the same approach should be used when a repeating measurement is required over time . Table 3In addition, what should be interpreted as a “normal EF” may slightly change according to age and sex based on physiological variations, and this should be considered when applying each imaging modality, especially during long-term monitoring ,46.It would be ideal, but highly unlikely, that every cardiologist has the same access to all the different imaging modalities and that the cardiac volumes and function of every patient would be assessed in the same way everywhere. Alternatively, based on the premises, a scheme based on the technique’s availability is proposed below. In summary, in a routine EF evaluation, standard 2D echocardiography can be enough for a patient’s clinical management. However, in patients in whom the value of EF can drastically change clinical management, i.e., in pre-ICD-CRT implant, cardiotoxicity evaluation, post-heart transplant follow-up, and timing of surgery for valvular heart disease, volumetric- and geometrical-assumption-free techniques should be preferred, with CMR, 3D TTE, or contrast echocardiography chosen based on local availability and expertise. CT and nuclear cardiology should only be considered in conditions where coronary anatomy or myocardial perfusion imaging is also required . Moreove


The cardiothoracic ratio (CTR), expressing the relationship between the size of the heart and the transverse dimension of the chest measured on a chest PA radiograph, is a commonly used parameter in the assessment of cardiomegaly with a cut-off value of 0.5. A value of >0.5 should be interpreted as enlargement of the heart. The following review describes the current state of available knowledge in terms of contentious issues, limitations and useful aspects regarding the CTR. The review was carried out on the basis of an analysis of scientific articles available in the PubMed database, searched for using the following keywords: “CTR”, “cardiothoracic ratio”, “cardiopulmonary ratio”, “cardiopulmonary index”, and “heart-lung ratio”. According to the accumulated knowledge, the CTR can still be used as an important parameter that can be easily determined in establishing enlargement of the heart. However, an increased CTR does not directly relate to heart function. In the era following the development of diagnostic methods such as computed tomography, magnetic resonance imaging, and ultrasonography, CTR modifications based on these methods are used with varying clinical usefulness. It is important to consider the definition of the CTR and remember to base measurements on PA radiographs, as attempts to mark it in other projections face many limitations. A chest PA examination, apart from its usefulness in oncology, pulmonology, pediatrics, etc., is also used as a screening tool to assess the size of the heart′s silhouette. A commonly used parameter for the heart′s evaluation is the cardiothoracic ratio (CTR), first described in 1919 . Normal The assessment of the heart’s silhouette on a chest radiograph, in addition to the CTR mentioned above, may allow us to obtain additional, clinically useful information at a much lower dose of ionizing radiation (between 80 and 100 times) compared with computed tomography. Assessing the silhouette of the heart enables, among others suspicion of aortic dilatation, information about the presence of rings of implanted valves, calcifications in the projection of the valve fields, assessment of the position of pacemaker electrodes, etc. Additionally, it should be remembered that chest radiographs are not performed only to determine the CTR; it is determined along with other diagnostic purposes of the study.The cardiothoracic ratio should only be determined by a PA radiograph projection. Although in the literature we find appropriate values of the coefficient, for example, for the AP projection , we shouThe above-described variables and the inconvenience in determining the CTR via AP radiographs were reflected in numerous research studies that sought methods to determine this easy parameter. Chon et al.  proposedKabala and Wilde  proposedp < 0.0001) in exhalation than in inspiration. This indirectly proves a significant disproportion of changes in lung size and the cardiac silhouette during respiratory phases, and emphasizes the importance of the pre-evaluation of data prior to CTR determination. These data are also confirmed in populations of children. The textbook Pediatric Radiology [Another variable that significantly affects the CTR value is the respiratory phase; the silhouette of the heart is larger during exhalation and smaller if the radiograph of the same patient is taken during inspiration. The dimensions of the chest are also variable in both breathing phases, but the work of Tomita et al. , based oadiology  describeadiology .The CTR is determined (according to its definition) on the basis of a flat chest PA radiograph. Assessment of cardiomegaly on the basis of the CTR may not always be appropriate due to the inability to account for changes in the anterior-posterior heart size and changes in the long axis of the heart. Researchers from Japan  showed tThe CTR was found to be one of the prognostic factors in several groups of diseases. An example is the population of people undergoing hemodialysis. A large, prospective, cohort study on a group of almost 3500 people with a four-year follow-up showed that in people undergoing hemodialysis, a higher CTR is associated with a higher risk for both general and cardiovascular reasons .In an animal model, it was shown that chronic vitamin D deficiency is associated with myocardial remodeling, leading to fibrosis, myocardial hypertrophy, myocarditis, and heart systolic disorders. Based on these observations, a study was conducted on a group of chronic hemodialysis patients to assess the impact of vitamin D deficiency in conjunction with CTR determination on the prognosis in this group. The study found that the CTR was higher in patients with vitamin D deficiency, and may be an independent prognostic factor of vitamin D deficiency in this group of patients .It was also shown in the group of hemodialysis patients that a CTR > 55% is one of the most important independent factors influencing the two-year all-cause mortality rate . Hence, At the time of the development of the CTR, and for many years of its use, values > 0.5 were interpreted not only as enlargement of the heart but also as impaired heart function (left and/or right ventricle). Interesting conclusions were drawn by researchers from London, who related the CTR measured on radiographs of PA and AP to the measurement data obtained in echocardiography in patients treated in the emergency mode. The first conclusions were similar to those described several times above and concern a limited CTR value determined on AP radiographs; the researchers demonstrated that this a CTR was not correlated with left or right ventricular dysfunction. According to the researchers, the CTR determined on the PA radiograph has moderate sensitivity and specificity but low positive predictive value in the diagnosis of right or left ventricular systolic disorders. The researchers highlighted the problem of a lack of correlation between a “big heart” and its dysfunction. This is probably due to the development of diagnostics and the implementation of prior treatment; therefore, a large heart cannot be equated to a heart with the presence of dysfunction . It is ir = 0.82); however, on comparing both coefficients with the left ventricular ejection fraction, they concluded that an increased 2D CTR better correlated with a reduced ejection fraction (r = −0.52) than the classic CTR (r = −0.45). They proposed a value of a 0.23 2D CTR (or a ratio of 1/4) or less as the correct value, which should indirectly indicate a fraction of ≥55%.Researchers from Ireland tried to link the classical one-dimensional CTR and their two-dimensional CTR with the left ventricular ejection fraction . The 2D On the basis of computed tomography studies, it was shown that the size of the left ventricle can be more accurately predicted on the basis of a simple and highly reproducible measurement of the left ventricular surface on axial chest computed tomography scans than on the CTR . Images However, it was shown that a baseline CTR > 0.5 in patients with chronic heart failure is associated with higher mortality and higher hospitalization rates, and a routine PA radiograph along with CTR measurement was indicated as an important part of the management of such patients. The CTR in this case can be used as a value to stratify cardiovascular risk .Due to the above-described limitations of the use of the CTR in children, there are several studies investigating this problem in the literature.Canadian researchers from Toronto conducted a retrospective study of 127 children (mean age 11.2 ± 5.5 years) with the most common structural and myopathic congenital myocardial defects, in which they checked the correlation of the CTR with the volume of the heart cavities measured by magnetic resonance . It was p < 0.05). As a conclusion, it was proposed that in children with ICCAVB, measuring the CTR during their follow-up cab be a useful tool in assessing the load on the heart.In an interesting case report of an eight-year follow-up on a girl with isolated congenital complete atrioventricular block (ICCAVB) with long-term serum NT-proBNP measurement in conjunction with CTR measurement , the girThe CTR measurement was found to have a role during the fetal stage. Obstetricians from Thailand performed CTR measurements using ultrasound in fetuses from pregnancies at risk of Bart′s hemoglobin disease and demonstrated that such measurements have a great prognostic value . ResearcAnother example of the use of a modified form of CTR in fetal life is the prediction of lethal obstruction of the pulmonary veins in fetuses diagnosed by prenatal ultrasound of a single ventricle with the coexistence of total abnormal pulmonary vein connection (TAPVC). Researchers from Japan using the cardiothoracic area ratio (CTAR), calculated as the ratio of the heart area to the thoracic area on the ultrasound data, showed that a reduced prenatal CTAR is a good predictor of lethal obstruction of the pulmonary veins after birth . Such inhttp://calc.chuv.ch/CTR (accessed on 8 May 2021)). The values calculated in this way are characterized by 84.04% sensitivity, 78.79% specificity, and 81.87% of correctly classified cases.The CTR is also applicable in autopsy. A benefit of such studies is the negligible harmful effect of ionizing radiation on the study group. Researchers from Switzerland, based on post-mortem computed tomography studies, proposed the new CTR formula for the diagnosis of cardiomegaly . In deteThe researchers came to an interesting conclusion on the basis of earlier post-mortem CT research. They found large discrepancies in the CTR measurements on the CT pilot images and the measurements on the axial chest scans performed. Their conclusions indicated a very large upward overestimation of the CTR in the pilot CT scans; hence, these should not be trusted .As demonstrated in the review above, the CTR as a simple, cheap, and quick tool still remains an important parameter in patient assessment in many clinical situations. In many cases, it has been shown that an increased CTR may be a good, initial parameter of the heart size preceding a more accurate assessment of the size of the heart and its cavities in echocardiography, computed tomography  and magnetic resonance imaging . When aw


TM device on the burden of VA and ICD (Implantable Cardioverter Defibrillator) therapies. Among 600 MitraClipTM implantations performed in our clinic between September 2009 and October 2018, we identified 86 patients with successful TEER and an active implantable cardiac device ) eligible for retrospective VA analyses. These patients presented with mainly functional MR (81.4%) and severely reduced left ventricular ejection fraction (mean LVEF 22.1% ± 10.3%). The observation period comprised 456 ± 313 days before and 424 ± 287 days after TEER. The burden of ventricular arrhythmias (sustained ventricular tachycardia (sVT) and ventricular fibrillation (VF)) was significantly reduced after TEER . Furthermore, the rate of ICD therapies (anti-tachycardia pacing (ATP) and ICD shock) decreased significantly after MitraClipTM implantation . However, reduction of VA burden did not result in improved two-year survival in this patient cohort with severely reduced LVEF. Mitral valve TEER using the MitraClip™ device was associated with a significant reduction of ventricular arrhythmias and ICD therapies.Transcatheter edge-to-edge repair (TEER) using the MitraClip™ device has been established as a suitable alternative to mitral valve surgery in patients with severe mitral regurgitation (MR) and high or prohibitive surgical risk. Only limited information regarding the impact of TEER on ventricular arrhythmias (VA) has been reported. The aim of the present study was to assess the impact of TEER using the MitraClip Chronic severe mitral regurgitation (MR) results in cardiac remodelling involving left ventricular (LV) and left atrial (LA) enlargement, deterioration of LV contractile function and increased myocardial fibrosis due to chronic volume overload ,2. SeverTranscatheter edge-to-edge mitral valve repair (TEER) is an established alternative to mitral valve surgery in patients with severe MR and high or prohibitive surgical risk ,9,10. PrTo date, only limited information regarding the effect of TEER on VA burden has been reported ,14,15. TTM device  for severe MR in our tertiary centre between September 2009 and October 2018. All patients suffered from symptomatic (New York Heart Association (NYHA) functional class ≥ II) severe MR despite GDMT. The decision to perform TEER and refrain from surgery was the result of an interdisciplinary evaluation of the heart team. Due to our centres heart transplantation programme the study cohort comprises 18 patients  enlisted for heart transplantation.The study cohort was recruited from 600 patients treated with the MitraClipTM implantation and an implanted electrical cardiac device  or CRT-D (Cardiac Resynchronization Therapy-Defibrillator)) were included in the study, irrespective of systolic LV-function prior TEER. Arrhythmic events and anti-arrhythmic therapies detected by the implanted electrical devices were analysed within a timeframe of two years before to two years after TEER.To retrospectively analyse the impact of TEER on VA and ICD therapies, only patients with successful MitraClipForty (46.5%) of the included 86 patients had already experienced a sustained ventricular tachycardia (sVT) or ventricular fibrillation (VF) prior to TEER in the analysed timeframe and in 37/80 (46.3%) patients an adequate ICD therapy, mainly anti-tachycardia pacing (ATP), had already occurred.TM device have been described in detail previously [Procedural characteristics of TEER using the MitraClipeviously ,16. All eviously . In someeviously . Of noteeviously . HoweverAll patients received baseline echocardiographic and haemodynamic evaluation . The echAnalyses of VA events and ICD therapies were performed on the basis of implanted device recordings. In addition, clinical follow-up reports and local databases comprising in-house or remote device Holter information were used. Assessment and classification of VA events were conducted by institutional electrophysiology experts. Ventricular tachycardia (VT) lasting for ≥30 or <30 s was classified as sustained (sVT) or non-sustained (nsVT), respectively. To fulfil nsVT criteria, at least ≥3 consecutive premature ventricular complexes (cycle length < 500 ms) were mandatory. Only appropriate ICD therapies (anti-tachycardia pacing and shocks due to VA) were included in the analyses.In order to achieve better comparability, VA episodes and ICD therapies were calculated as events per patient per month.t-test.Continuous variables were summarised as mean ± standard deviation or median and interquartile range and compared using paired or unpaired Student’s If normal distribution could not be demonstrated Wilcoxon rank sum test or the Mann–Whitney U test were used. Derangement from normal distribution was assessed using Shapiro-Wilk test. Categorical variables were described as percentages and compared using Chi-square or Fisher’s exact tests, respectively, depending on the expected frequency above or below 5. Paired categorical variables before and after TEER were compared using McNemar’s test. Survival data were summarised by Kaplan-Meier survival curves and unadjusted survival rates were compared using the log rank test. Multivariate Cox regression using stepwise forward selection was performed to analyse the influence of relevant variables on two-year mortality. Univariate regression was used to estimate procedural results.p-value < 0.05 was considered statistically significant. For statistical analysis SPSS Statistics 27 for Microsoft Windows and Stata 16 was used.A two-tailed Declaration of Helsinki. All patients were informed about the specific risks and alternatives of MitraClipTM therapy and gave informed written consent to the procedure. The study protocol was in accordance with the local ethics committee.Our retrospective study conforms with the principles outlined in the TM device between September 2009 and October 2018, 86 fulfilled the aforementioned inclusion criteria  were male. Predominant pathology of the mitral valve was functional MR . Mean LVEF of the included patients was severely reduced (LVEF 22.1% ± 10.3%) with 90.7% (78/86) presenting with LVEF ≤ 35%. All patients were severely symptomatic at the time of the procedure with 88.4% (76/86) presenting in NYHA functional class ≥ III.The advanced stage of disease is also displayed by advanced LV (left ventricular end diastolic diameter (LVEDD) 68.2 mm ± 11.0 mm) and LA dilatation (54.6 mm ± 9.7 mm) as well as pronounced elevation of NT-proBNP-levels .A detailed overview of patients’ baseline characteristics is shown in Baseline characteristics and procedural outcome data of the excluded 167 patients with missing cardiac device Holter information are summarised in TM device success rate was 97.7% (84/86). In one patient periprocedural partial clip detachment occurred during placement of a second MitraClipTM device, requiring a third MitraClipTM for stabilization and sufficient MR reduction. In another patient an arterio-venous fistula was observed, requiring surgical repair. More than one MitraClipTM was implanted in 31 (36.0%) patients. Only in the above mentioned patient with partial clip detachment were more than two devices necessary.Technical success rate among all patients subjected to TEER in the study period was 91% (546/600). Among the 86 patients with implanted electrical devices suitable for arrhythmic analyses, MitraClipThe observation period comprised 456 ± 313 days before and 424 ± 287 days after TEER.p = 0.08, data not shown).Overall, 61 patients (70.9%) had already experienced at least one VA episode  within the analysed study period prior to TEER. In 58.1% (50/86) at least one nsVT, in 41.9% (36/86) at least one sVT and in 12.8% (11/86) one VF episode had already occurred . No signAfter TEER, at least one VA occurred in 46 patients (53.5%). At least one nsVT, sVT or VF episode was recorded in 47.7% (41/86), 23.3% (20/86) or 3.5% (3/86) of patients, respectively.p = 0.019). While non-sustained VTs were not significantly decreased , the burden of sustained VTs was significantly reduced after TEER . Concerning VF episodes, a non-significant trend for less events could be detected  (p = 0.01).The burden of total VA episodes  was significantly reduced after TEER  . As a coOverall, 37 patients (46.3%) had already experienced at least one appropriate ICD therapy within the analysed study period prior TEER. In 41.3% (33/80) at least one appropriate anti-tachycardia pacing (ATP) and in 27.5% (22/80) at least one appropriate ICD shock had already occurred.After TEER at least one appropriate ICD therapy occurred in 21 patients (26.3%). At least one appropriate ATP or ICD shock was recorded in 21.3% (17/80) or 17.5% (14/80) of patients, respectively.p = 0.014). While there was only a non-significant trend towards reduction of appropriate ICD shocks , the burden of appropriate ATPs was significantly reduced after TEER  (The rate of appropriate ICD therapies (ATP and ICD shock) decreased significantly after TEER  .n = 14 patients) during follow-up (data not shown).Reduction of VA episodes and ICD therapies remained significant even when patients were excluded who received VT ablation, Amiodarone therapy or an upgrade to a CRT device (TM-implantation.In 44 patients (51.2%) a reduction of VA burden  was observed after TEER. No reduction could be detected in 24 patients (27.9%). The remaining 18 patients (20.9%) experienced no VA episode during the analysed study period, neither prior to nor post MitraClipp = 0.004), less frequently suffered from ischaemic cardiomyopathy  and revealed larger LV dimensions  prior TEER  echocardiographic and clinical data were available for all patients. Median MR grade was 1.5 . Seventy-six patients (88.4%) had an MR grade ≤ 2 and only two patients presented with recurrent severe MR (2.3%). Compared to pre-interventional MR grades, a significant reduction was achieved (p < 0.001) by TEER .In this cohort with severely depressed systolic LV function, improvements of MR grades were not associated with a significant change of LVEF  and MR grade (p = 0.561) did not correlate with change of VA burden.In a univariate regression analysis change of LVEF (p < 0.001) was observed. Median NYHA class was 2.0  with 51 patients (59.3%) presenting in NYHA functional class <3 after successful TEER  and after TEER at the time of the last available implanted electrical cardiac device control (“follow-up”). NYHA: New York Heart Association, TEER: Transcatheter Edge-to-Edge Mitral Valve Repair.p = 0.815, One-year mortality rate was 21.2% , two-year mortality rate was 38.6% . All-cause as well as cardiovascular mortality rates observed in patients with reduced VA burden  did not significantly differ compared to patients without VA burden reduction   1.33  0.66–2.66); multivariate: p = 0.84; HR 1.09 (95% CI 0.48–2.47)).Applying univariate as well as multivariate adjusted regression analysis  also revealed no significant mortality difference in patients with VA burden reduction compared to patients without VA burden reduction  Volume overload of the LV as a result of severe MR causes increased myocardial wall stress and progressive LV remodelling  Volume o, which aAn observational study has shown a significant MR reduction after TEER, resulting in a significant increase in cardiac output and a significant reduction in LV filling pressures and pulmonary hypertension in patients with end-stage HF . Thus, LAnalysis of pre-interventional clinical characteristics of patients showing a reduction of VA burden post TEER revealed higher NYHA functional class, non-ischaemic cardiomyopathy and larger left ventricular dimensions as significant parameters.p = 0.006) [In line with our findings, advanced NYHA functional class has been previously shown to be an independent predictor for the occurrence of ventricular arrhythmias , sudden = 0.006) . In line= 0.006)  and larg= 0.006) ,35.VA burden is related to worsening HF and is a predictor of sudden cardiac death in patients with systolic LV dysfunction . AlthougThe observed two-year mortality rate was in the range of the recently published expanded follow-up data of the Mitra-FR study (34.9%), the GIOTTO registry (34.6%) and the TRAMI registry (31.9%) ,42,43 anTM therapy in addition to GDMT suggest a more complex explanation of this observation [The failure to demonstrate the association of reduced VA burden with improved survival may be due to the limited number of patients studied. In addition, it is well known that in advanced HF with severely impaired LVEF and cardiac remodelling, HF per se and not arrhythmias may be the predominant cause of death. However, the contrasting results of the COAPT- and Mitra-FR studies regarding a mortality benefit of MitraClipervation . BaselinConsequently, one might conclude that in this severely ill patient cohort the progression of the underlying cardiac disease as well as the multitude of comorbidities are the predominant limitations of life expectancy rather than malignant rhythm disorders.TM treatment in severe HF patients presenting with LVEF < 30% prior TEER [In conclusion, to avoid futility, future candidate selection for TEER should focus on patients with severe MR despite GDMT (including CRT) without too advanced adverse LV remodelling and dilatation, as recently published in the adjusted guideline recommendations based on the results of COAPT and Mitra-FR . Howeverior TEER . Thus, oTM device, and possibly arising effects on mortality rates in this severely diseased patient group, a randomised clinical trial is mandatory.The results of our study in conjunction with previously published data on this issue ,14,15 shTM was implanted. Meanwhile, 4th generation MitraClipTM and the Pascal and Pascal Ace devices  have been FDA-approved and CE-certified for TEER.The data were retrieved from a single centre in a retrospective approach. Although the completeness of the data is high and the follow-up period is comparatively long, the total number of studied patients is rather low. A potential selection bias due to a high proportion of patients enlisted for heart transplantation, thus providing more cardiac device Holter information in the context of frequent follow-up visits, is likely. In addition, the lack of an external core lab adjudicating the events may bias data interpretation. Changes in the dose of antiarrhythmic drugs, heart failure medication and in device programming as a result of a documented VA as well as the incidence of new ischaemic coronary events or revascularization procedures and potential metabolic disturbances were not addressed in this analysis. Furthermore, in this study 1st to 3rd generation MitraClipThe results of our study suggest that TEER results in a significant reduction of ventricular arrhythmias and ICD therapies in advanced HF patients. These effects were more prominent in patients presenting with non-ischaemic cardiomyopathy, higher baseline NYHA functional class and larger LV dimensions. While TEER did reduce VA burden, it did not result in improved two-year survival in this advanced HF cohort.


BackgroundAdjuvant radiotherapy plays an important role in the management of breast cancer, along with surgery and chemotherapy. However, postoperative radiotherapy poses an increased risk of radiation-induced heart diseases in patients with left-sided breast cancer due to damage of the coronary arteries, which can cause myocardial fibrosis and coronary artery disease; however, there is a lack of sufficient evidence for it. Hence, the present study aimed to assess the dosimetric parameters of the heart and left anterior descending (LAD) coronary artery in patients with left breast cancer treated with three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT).MethodologyThis study included 20 patients with left-sided breast cancer treated between January and July 2019. Patients were equally divided into two groups as follows: group I included those treated with 3DCRT and group II included those treated with IMRT. Radiotherapy was administered to the chest wall and regional lymph nodes. The dose administered for the planning target volume was 50 Gy in 25 daily fractions over five weeks with 6 MV photons. Dosimetric parameters of planning tumor volume  along with the heart  and LAD artery (mean and V25%) were evaluated. Dose-volume histograms were generated and compared. The LAD artery was contoured virtually retrospectively during the study to determine the dosimetric parameters; the dose to the LAD artery was not considered during planning.ResultsDosimetric parameters of the PTV were similar for 3DCRT and IMRT; D95 (38.53 vs. 41.61 Gy), D90 (43.67 vs. 44.77 Gy), Dmean (48.3 vs. 48.72 Gy), conformity index (1.10 vs. 1.06), and homogeneity index (0.50 and 0.28) did not show a significant difference. The Dmean for the LAD artery was significantly higher than that for the heart on 3DCRT  and IMRT . The V25 for the LAD artery was significantly higher than that for the heart on 3DCRT  and IMRT .ConclusionsRadiation doses to the LAD artery and heart must be evaluated prior to radiotherapy in patients with left breast cancer. Long-term follow-up is needed to evaluate cardiac complications and their association with dosimetric parameters. Radiotherapy plays a key role in the multimodal treatment of breast cancer in most cases. However, radiation doses to the heart and lungs cannot be estimated accurately in conventional radiotherapy techniques. This leads to unintentional long-term cardiac and pulmonary toxicities. Additionally, increased incorporation of computed tomography (CT) scans in radiotherapy planning and utilization of newer conformal radiotherapy techniques have resulted in increased doses to the heart and lungs.Women with left-sided breast cancer who undergo adjuvant radiotherapy have increased cardiac morbidity  and mortA landmark population-based study determined that patients with breast cancer who were treated with adjuvant radiotherapy had a 1.7-fold increased risk of cardiac death compared to those treated with surgery alone . AdditioDuring radiotherapy, the dose is not distributed homogeneously in the heart; the highest doses are likely to be delivered to the anterior part of the heart, including the left anterior descending (LAD) coronary artery. This is concerning because studies have suggested that arteries are sensitive to radiation, and the LAD artery is one of the typical sites of origin for ischemic heart disease . Dose reThis study aimed to assess the dosimetric parameters of the heart and LAD artery in patients with left breast cancer who were treated with three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT).This article was previously presented as a meeting abstract at the 41st Annual Conference of the Association of Radiation Oncologists of India (A9) on November 29, 2019.This was a single-center, retrospective, observational study. Institutional Review Board approval was not needed for this retrospective study according to our hospital’s policies. We included 20 patients with left-sided breast cancer who were treated from January to July 2019.Inclusion and exclusion criteriaPatients who had left-sided breast cancer, had undergone a modified radical mastectomy, and were aged ≥18 years were included in this study. Patients who had undergone previous breast surgery or radiotherapy, presented with other metastatic diseases, and had undergone breast-conserving surgery were excluded.Radiotherapy planningA simulation using contrast-enhanced CT with a slice thickness of 3 mm was performed with the patients’ hands above their heads. Patients were equally divided into two groups: groups I and II included those who were treated with 3DCRT and IMRT, respectively.DelineationThe delineation of clinical target volume and heart was performed as per the Radiation Therapy Oncology Group Breast Cancer Atlas . The LAD3DCRT PlanningTwo tangential beams were used for chest wall irradiation with gantry angles ranging from 225° to 315° on the lateral side and 45° to 135° on the medial side. A separate field was used from a 0° gantry angle for supraclavicular nodal irradiation. The isocenter was placed at the junction of the tangential fields and supraclavicular field, and a half-beam block technique with asymmetric jaws was used. Using the beam eye view, the beam angles were chosen to optimize the coverage of the pretreatment tumor volume with the maximum exclusion of the organs at risk. The fields extended a minimum of 1 cm anteriorly from the chest wall to provide coverage of the “flash” region. Enhanced dynamic wedges and field-in-field techniques were used when required for homogeneous dose distribution.IMRT PlanningA total of five to seven semi-opposing  beams were used in IMRT plans. Inverse planning was performed, and beam optimization was used to achieve the desired objectives and constraints. Tissue inhomogeneities were considered during the beam optimization process. The optimal planning objectives for both techniques were specified as the dose to the planning tumor volume (PTV) between 95% and 107% relative to the 100% prescription point.Dose PrescriptionRadiotherapy was administered to the chest wall and regional lymph node areas. The dose administered to the planning target volume was 50 Gy in 25 daily fractions over five weeks with 6 MV photons.Plan EvaluationDosimetric parameters of PTV  along with those of the heart  and LAD artery (mean and V25%) were evaluated. Dose-volume histograms were generated and compared. The LAD artery was contoured virtually retrospectively to determine dosimetric parameters, and the dose to the LAD artery was not considered during planning.Statistical analysisStatistical significance was set at p-values of <0.05. The chi-square test was used to determine the significance of study parameters on the categorical scale between the two groups. The Student’s t-test  was used to determine the significance of study parameters, such as the correlation between various dosimetric parameters on a continuous scale in each group.Dosimetric parameters of PTV were statistically and significantly better in IMRT than 3DCRT for V95% (p = 0.000) and V90% (p = 0.005). The other dosimetric parameters did not show any statistically significant differences Table .The Dmean for the LAD artery was significantly higher than that of the heart for both 3DCRT  and IMRT   for both the LAD artery (p = 0.02) and heart (p = 0.000); other LAD artery parameters  and heart parameters  were also significantly better in 3DCRT than IMRT. The maximum dose to the LAD artery was similar in 3DCRT and IMRT plans  and IMRT .Although there has been a considerable decrease in heart doses over the past few years -11, radiEvaluating the mean or Dmax doses to the LAD artery requires precise delineation of this structure. Although incorporating coronary angiography prior to radiotherapy planning may seem like the ideal option, it may not be feasible in most cases. Therefore, we began exploring the delineation guidelines for the LAD artery and came across those proposed by Lee et al. . These gThe International Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines have subsequently been developed to predict the risk of cardiac mortality due to radiotherapy . The QUAIn our study, the mean doses of the LAD artery were significantly higher than that of the heart using both conformal techniques. Based on the pathophysiology, the LAD artery is the most important site for ischemic heart disease . EvaluatIn a study by Poitevin-Chacón et al. , the meaIn our study, the mean dose to the heart was slightly lower (8.46 Gy in 3DCRT and 17.7 Gy in IMRT) than that to the LAD artery (23.66 Gy with 3DCRT and 31.53 Gy with IMRT). Tan et al.  and our A study by Jacob et al.  highlighFurthermore, Jacob et al.  emphasizAs per QUANTEC, no dose recommendation exists for coronary arteries . One DanWe would like to suggest that long-term cardiotoxicity should be evaluated dosimetrically by assessing mean doses to the substructures of the heart rather than to the entire heart. This study showed a wide difference in doses between the entire heart and the LAD artery. A few other studies have also studied the mean doses to the left ventricle. Assessment of left ventricular function is based on echocardiography and correlates with symptoms, complications, and prognosis in several cardiac conditions.In studies by Jacob et al.  and MehtStudy limitationsThis study had some limitations. First, the small sample size. This could be because the study analyzed data from a single center. Therefore, further studies with larger sample sizes are warranted. Second, this was a retrospective observational study. Therefore, causal relationships could not be established, and some unknown biases may have been introduced. Further prospective studies in this regard are warranted.There is a vast difference in the mean doses of the heart and LAD artery, and the mean doses of the heart as a long-term follow-up parameter for cardiac toxicity may be unreliable. In future studies, the mean doses to the cardiac substructures, especially to the LAD artery, should be evaluated, rather than those to the entire heart. Furthermore, long-term follow-up is needed to establish a dose-response relationship between radiation exposure and coronary artery stenosis.


Atrial cardiomyopathy (ACM) represents a constantly evolving concept, with increasing importance in contemporary research and clinical practice. A better understanding of the mechanisms involved in atrial remodeling and its clinical correlations especially with atrial fibrillation (AF) and other cardiometabolic comorbidities may induce a significant impact on the diagnosis, prognosis, and therapeutic approach of ACM-related comorbidities. Although initially described several decades ago, investigators have only recently highlighted that several renal, metabolic, and cardiovascular diseases are determining factors for atrial remodeling and subsequent ACM. Based on data from multiple recent studies, our research emphasizes the correlations between ACM and other coexisting pathologies including cardiovascular, respiratory, or metabolic diseases, with fibrosis being the most incriminated pathophysiological mechanism. In addition to the usual tests, the paraclinical assessment of ACM is increasingly based on the use of various cardiac biomarkers, while the cardiac magnetic resonance (CMR) has become an increasingly tempting diagnostic too for describing morphofunctional aspects of the heart chambers, with the gadolinium contrast enhanced CMR (LGE-CMR) emerging as a commonly used technique aiming to identify and quantify the precise extent of atrial fibrosis. Further research should be conducted in order to clarify our knowledge regarding atrial remodeling and, therefore, to develop new and improved therapeutic approaches in these patients. Atrial cardiomyopathy (ACM) and its clinical importance were first described in 1972 by Nagle et al. [The aim of this review is to depict some coordinates of ACM, from the molecular level to the therapeutic approach, for a better understanding of the mechanisms involved in atrial remodeling. Additionally, we reviewed some particular ACM clinical correlations, especially with atrial fibrillation (AF) and the common AF-related thromboembolic events, that may have an important impact concerning the diagnosis, prognosis, and therapeutic decision-making process in ACM.High-incidence pathologies like chronic heart failure (CHF), AF, hypertension, diabetes mellitus (DM), and some other conditions including aging and obesity, are well-established causes of atrial remodeling. Although the induced changes share many similarities, there is an important histopathological substrate variability between the different clinical disorders ,3. ConseClass I: primarily cardiomyocyte changes ;Class II: predominantly fibrotic changes (cigarette smokers and the elderly);Class III: combined cardiomyocyte-pathology/fibrosis ;Class IV: primarily non-collagen infiltration, with or without cardiomyocyte changes  .There is an intimate relationship between atrial activity and ventricular systolic and diastolic performance; the main role of the left atrium (LA) is to manage the left ventricular filling pressures and cardiovascular performance by acting as a reservoir for the venous return during ventricular systole and as an additional pump for ventricular filling via an active atrial contraction ,4,5.Atrial remodeling is defined as a persistent change in the LA structure or function, possibly due to the appearance of atrial tachyarrhythmias such as AF and atrial flutter or secondary to pressure or volume overload related to CHF and other fibrotic disorders . FurtherAtrial remodeling is based on three principal pathophysiological pillars: structural, electrical, and functional remodeling.Atrial structural remodeling is characterized by increased interstitial fibrosis and by maladaptive structural changes secondary to inflammation, pressure, or volume overload, leading to atrial enlargement ,8. One oAngiotensin II and transforming growth factor beta-1 are major stimulators of collagen production and key regulators of fibrosis. Angiotensin II and aldosterone are involved in inflammation and oxidative stress initiation. Recent studies have shown that inflammation and excess production of reactive species of oxygen seem to play a principal role in atrial remodeling ,13. EvenAtrial functional remodeling is encountered in many pathological systemic processes and can cause alterations in atrial functioning regardless of the LA size ,9. This 2+) and potassium fluxes from the myocytes [2+ based on Ca2+ overload can affect cardiomyocyte excitation-coupling [Electrical remodeling consists of a complex electrical substrate and ionic mechanism changes in the atria . Factorsmyocytes . The inacoupling  promotincoupling . The moscoupling . Anothercoupling . Autonomcoupling .Over the past decades, investigators have shown that many cardiovascular diseases such as high blood pressure , valvulaHigh blood pressure represents one of the main cardiovascular risk factors for ACM . PreviouConditions highly associated with AF  are often complicated by increased hemodynamic atrial load, leading to the overstretching of the atrial myofibriles. Available in vivo and in vitro data suggest that significant strain leads to hypertrophy, dedifferentiation, and ECM remodeling, as well as to electrical alterations, all these pathways being associated with an increased risk of AF and further atrial remodeling, thus closing a vicious pathophysiological circle .Normal function of the LA is necessary for optimal ventricular filling and adequate overall cardiac performance. Atrial dysfunction due to changes in the ventricular structure is a common finding in patients with CHF ,14.The LA volume is a sensitive indicator of LV filling pressure and reflects the degree of diastolic dysfunction, in the absence of severe valvular disease and/or AF. In order to reflect the LA volume’s capacity to reveal the chronicity of diastolic dysfunction, it has been proposed as the “glycosylated hemoglobin of diastolic dysfunction.” Also, because of divergent effects of preload and mural compliance on transmitral velocities, the mitral inflow patterns may appear normal  despite abnormal filling pressures. In such situations, the LA volume index (LAVI) provides the highest discriminative value in distinguishing between normal and pseudonormal transmitral filling patterns .2 was an independent predictor of the first CHF episode [Why are these aspects important in patients with CHF? Mainly because the diastolic dysfunction represents the first phase of the so-called heart failure (HF) with preserved ejection fraction (EF > 50%). In these patients, a LA volume of ≥32 mL/m episode .A study conducted on 198 HF patients and 40 healthy controls compared the LA properties between HF with preserved and reduced ventricular ejection fraction. Investigators revealed that LA conduit, reservoir, and contraction functions are affected in diseased patients compared to control groups. Furthermore, they found that HF with preserved ejection fraction is associated with more dilatation and systolic dysfunction, while HF with reduced ejection fraction has an increased stiffness and susceptibility to AF .AF is the most frequent arrhythmia worldwide, affecting 25% of the adult population during their life . AF occuThe pathways leading to thrombogenesis in AF are various, and there is evidence to suggest that all three elements of Virchow’s triad are present in AF: abnormal stasis of blood flow, endothelial dysfunction, and hypercoagulability .The electrical and structural substrate within the LA in patients with paroxysmal and persistent AF has been studied by Teh et al. The investigators have demonstrated slower conduction, a higher proportion of decreased voltage, a lower global LA voltage, and an increased prevalence of complex signals in AF patients compared to the control group. These changes were more extensive in persistent AF .Cardiac fibrosis consists of excessive deposition of collagen fibers in the ECM. High collagen accumulation has been revealed in LA tissue obtained from atriotomy in cadaveric patients with AF . Stiles It is incompletely understood why some patients present repetitive episodes of paroxysmal AF for years or even for their entire lifetime, while other patients having identical comorbidities evolve into persistent AF in a rather short period of time. The above-mentioned concept of the negative “auto-amplification” that characterizes AF does not provide a detailed explanation for these differences. On the other hand, the results of atrial electroanatomic mapping in patients with AF and similar clinical findings were very different. These conclusions suggest the importance of a structural atrial condition defined as fibrotic atrial myopathy. However, even the presence of the most affected substrate can be shown in patients with paroxysmal AF instead of the persistent form ,29.An important link between AF and ACM is the inflammatory state . The levAF is a well-known risk factor for thromboembolic events such as ischemic stroke. In addition, atrial remodeling leads to a hypercoagulable state involved in thrombogenesis ,15. Spec-atrial hypocontractility persists for up to two months following AF conversion to sinus rhythm;-atrial dilation and hypocontractility may aggravate despite catheter ablation of AF ;-atrial hypocontractility alone (without concomitant AF) is an independent risk factor for stroke .Specific echocardiographic assessment of atrial wall velocities in AF patients revealed that there is a significant impairment of atrial contractility. Several hypotheses were raised concerning the link between atrial contractile dysfunction and the increased stroke risk:Both OSA and LA enlargement are conditions that are commonly found in patients with cardiovascular diseases. Severe OSA may also increase LA size, independently of other risk factors. Several pathophysiological mechanisms induced by OSA have been suggested to explain why this condition may trigger or aggravate ACM. Increased sympathetic activity and systemic inflammation due to intermittent hypoxemia, increased intrathoracic pressure during the apneas are all causing supplementary atrial wall stress .The basic mechanism by which OSA syndrome affects the atrial myocardial tissue is not completely understood. Dimitri et al.  investigDeleterious effects of hyperglycemia in DM go beyond alterations in metabolic homeostasis, also modifying the vascular endothelium and inducing both direct and indirect myocardial injury. Increased inflammation and oxidative stress induce the formation of advanced glycation end products (AGEs), cellular apoptosis, mitochondrial dysfunction, and disorders of myocardial metabolism. An essential physiopathological step is the capacity of AGEs to infiltrate the myocardium leading to interstitial fibrosis and hypertrophy. All these events, reunited into the term DM cardiomyopathy, determine the substrate for anatomic and electrical atrial remodeling .Additional negative prognosis factors are represented by an increasing prevalence of obesity, lack of regular physical activity, and exposure to stress, nowadays type 2 DM becoming one of the most common cardiovascular risk factors.Over time, many studies have evaluated the influence of LA structural and functional remodeling in patients with type 2 diabetes by using various imaging methods. In patients with DM, echocardiography findings reveal that LA dysfunction can be a consequence of LA enlargement . A recenAlthough many studies have shown that obese individuals have LA enlargement, given that the atrial size is typically quantified by indexing it to height or body surface, the final figures are relatively similar to non-obese controls. However, given the increased prevalence of obesity-associated comorbidities which can also influence cardiovascular remodeling, the real, independent impact of obesity on ACM can be difficult to assess .Epicardial fat is metabolically active and releases inflammatory cytokines, adipokines, and free fatty acids that are involved in the progression of atrial fibrotic remodeling. As a result, local epicardial adiposity can promote the substrate for arrhythmias. There is also a strong relationship between the quantity of pericardial fat and AF prognosis. Lifestyle changes, weight loss, normal blood pressure, and optimal glycemic values were connected with a better rhythm control among obese patients with AF after catheter ablation .2) was related to adverse cardiovascular events and all-cause mortality [The prevalence of AF increases with age in line with a decline in the estimated glomerular filtration rate (eGFR). Various reports claim that 7–18% of patients with CKD had AF, while 10–33% of patients were incidentally found with CKD at the time of the newly diagnosed AF. The occurrence of AF may promote the progression of CKD and increase the risk of developing end-stage renal disease. Moreover, the coexistence of AF and CKD . A proposed algorithm is found in According to current literature data, the dosing of novel biomarkers, as well as imaging explorations aimed to quantify and identify fibrosis, can be effective for the diagnosis of atrial remodeling.Multiple studies have demonstrated that high blood levels of CRP and IL-6 are associated with an increased incidence of AF, both among patients undergoing cardiac surgery and the general population. Increased levels of the above-mentioned inflammatory biomarkers are also correlated with a significant risk of arrhythmia recurrence in patients who underwent electrical cardioversion or catheter ablation. Further supporting these findings, a recent study showed a decline in CRP levels after the conversion to sinus rhythm. Very interesting, the duration of AF does not influence the level of these markers ,13.IL-6 can also interfere with the pro-thrombotic state during AF, by endothelial activation and platelet aggregation ,10. IncrAn increased level of N-terminal pro-B-type natriuretic peptide (NT-proBNP) represents an established hallmark in patients with HF, however, this biomarker is markedly influenced by the presence of concomitant AF, making it difficult to distinguish between HF versus AF as the primary determinant of a raised NT-proBNP. To shed some light on this controversy, a very recent study compared the plasma levels of NT-proBNP in patients with HF in AF versus HF in sinus rhythm and found that baseline NT-proBNP serum concentrations of patients who had AF were higher than those of patients in sinus rhythm, regardless of whether the latter had a history of AF or not . MoreoveAtrial changes induced by AF, such as increased atrial size and fibrosis, stimulates the secretion of natriuretic peptides. Atrial natriuretic peptide (ANP) is a cardiac hormone with vasodilatory, antihypertrophic, diuretic, and natriuretic effects. Therefore, ANP is involved in maintaining the water-sodium balance and optimal blood pressure. A previous study revealed that mice with ANP deficiency developed hypertension and cardiac hypertrophy as a result of ischemic remodeling and pressure overload. More recently, ANP has been shown to have pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic properties, being consequently involved in the underlying mechanisms of cardiac remodeling ,43.Given the increased prevalence of AF and atrial remodeling among patients with HF, several studies aimed to evaluate the utility of HF biomarkers in detecting ACM. Denysiak et al. proved that soluble interleukin 1 receptor-like 1 (ST2) is a marker of advanced functional remodeling in patients with AF, and is associated with significantly longer ablation procedures independent of LA size , while oAnother promising biomarker of cardiac fibrosis is represented by syndecan-1, especially in patients with HF with preserved ejection fraction (EF). Given the predominance of diastolic dysfunction in these patients , an early assessment of the myocardial fibrotic injury is paramount in determining the chances for cardioversion or, if not the case, of maintaining an adequate heart rate .Numerous imaging explorations are used currently in clinical practice to identify LA remodeling . EchocarSome new techniques, like the evaluation of the LA volume by 3D-Echocardiography, represent more accurate methods than the classic determination of the LA size. Two-dimensional speckle-tracking echo is a more sensitive imaging method for the early assessment of functional remodeling, even before the appearance of visible anatomical changes in biopsies . Global Cardiac computed tomography is superior to 2D-Echocardiography in the assessment of atrial volumes, and it can be used in thrombus screening before undergoing AF ablation ,47.p < 0.001), even after adjusting it to LA volume. Moreover, combined evaluation of LA EAT and LA volume provided additive diagnostic value and superior performance in the detection of AF compared to the assessment of online LA volume (p < 0.001) [In the light of some latest research, the assessment of epicardial adipose tissue (EAT) depots in cardiovascular pathology is of particular interest. Various studies that successfully used CMR for the evaluation of EAT volume and thickness found interesting correlations between the presence of fatty tissue and the atrial remodeling, highlighting areas of low voltage, conduction impairment, and greater fractionation of electrograms in anatomical regions adjacent to significant epicardial fat depots . A study< 0.001) . Very in< 0.001) .Even if CMR is considered the gold standard for visceral adipose tissue assessment, the majority of clinical studies that assessed EAT to date were performed using computed tomography (CT), because of its adequate spatial resolution, excellent reproducibility, and ease to perform. Additionally, in several situations, EAT was quantified on a CT scan performed for other pathologies . The resA novel noninvasive method used for the assessment of atrial flow dynamics is the 4-dimensional (4D) flow CMR. This method is more accurate than the trans-esophageal echocardiography and provides a comprehensive detection and quantification of stasis in the LA and LA appendage (the most prone location for thrombus formation) .Electroanatomic mapping is the standard invasive method in ACM substrate characterization, through the geographic display of signal amplitude data and by rendering the atrial surfaces. It can be used to investigate atrial myopathy associated with sinus node disease, rheumatic mitral stenosis, atrial septal defects, CHF, OSA syndrome, and aging .Cardiac remodeling includes functional, electrical, and structural changes that are closely interconnected, and influence both the therapeutic approach and the prognosis. The practical management of ACM is based on stroke prevention, cardiac rhythm therapy, rate control, and ablation strategy .Amiodarone is the most effective and frequently used antiarrhythmic drug. However, recent recommendations emphasize catheter ablation rather than amiodarone for AF treatment . PreviouThe importance of metabolic effects on ACM is supported by the fact that weight loss and risk factor management induce better post-ablation results and a decreased rate of AF recurrence ,24. HoweFurthermore, other therapies have been shown to be useful in atrial remodeling. ANP promotes natriuresis, diuresis, vasodilation, and inhibits aldosterone and renin secretion. Given its effects, ANP is considered a promising drug for various cardiovascular diseases. It has been proven that ANP administration reduces maladaptive cardiac remodeling and has anti-inflammatory and proangiogenic effects. The inhibition of neprilysin results in an increased ANP secretion. Therefore, the inhibition of neprilysin and angiotensin receptors is a novel therapy in patients with HF . Thiazol2+- sensitizing agent levosimendan. This option is sustained by some evidence concerning dysregulation of the myofilament response to Ca2+ release or Ca2+ impaired sensitivity, which are significant contributors to contractile dysfunction in AF [2+ homeostasis and subsequent contractility efficiency rely upon phosphorylation processes, which, in AF, are pathologically altered. Some recent studies have shown that levosimendan increases cerebral blood flow, decreases NT-proBNP , and improves atrial pump function on echocardiography; however, it also increases the occurrence of AF in these patients, an undesired effect attenuated by concomitant treatment with ranolazine, an inhibitor of the late inward sodium current [Another potential therapeutic target in improving atrial contractility is the Caon in AF . Intrace current .Some very recent reports were focused on unravelling the pleiotropic, cardiovascular protective effects of sodium–glucose cotransporter-2 (SGLT2) inhibitors, a novel class of oral hypoglycemic medication that showed very promising results in the treatment of HF. A study conducted by Shao et al. revealed that empaglifozin, a SGLT2 inhibitor, can prevent atrial structural and electrical remodeling as well as ameliorate mitochondrial metabolism in diabetic rats, via the peroxisome proliferator-activated receptor-c coactivator 1α (PGC-1α)/nuclear respiratory factor-1 (NRF-1)/mitochondrial transcription factor A (Tfam) signaling pathway . MoreovePrevious studies have drawn an interesting new direction concerning the possible roles of oxidative stress and inflammation in the mechanisms of the electrical and structural substrates for atrial remodeling and subsequently, AF ,58. EvenIt was demonstrated that another SGLT2 inhibitor, canaglifozin, exhibited significant antioxidant properties in the atrial tissue. This effect was related to increased ketogenesis promoted by canaglifozin, thus enhancing the myocardial uptake of ketoacids , which competes with fatty acid oxidation. Cardioprotection is based exactly on this metabolic switch, the important metabolic efficiency of ketone body oxidation being well-established in the literature . Given tCardiac resynchronization therapy (CRT) has been shown to improve not only the LV ejection fraction but also LA function. A study including a total of 41 patients who received a de novo CRT implantation revealed that the P-wave duration measured in the surface 12-lead ECG significantly decreased following CRT therapy (at least 12 months since implantation and with adequate bi-ventricular pacing > 92% of the time). This is an important clue regarding the therapeutic potential use of CRT in patients with ACM because the prolongation of the P-wave duration represents a quantitative indirect marker for atrial electrical remodeling .CRT’s capacity to induce LV and LA reverse remodeling might be partly related to the improved LV filling and subsequent increase in LV contractility, cardiac output, and LV ejection fraction. In a similar manner, ameliorated diastolic function and optimal LA filling are also enhancing LV contractility. Furthermore, synchronous triggering of ventricular depolarization also decreases mitral regurgitation, thus contributing to LA reverse remodeling ,63,64.The results from a MADIT-CRT  study comprising 533 patients with CRT and defibrillator (CRT-D) showed that >40% of the patients presented complete left-sided reverse remodeling  and their increasing availability in patients with end-stage HF play an important role in the prognosis of patients with impaired atrial function. Commonly used either as a bridge therapy to heart transplantation or following precise, limited indications, LVADs can be an arrhythmogenic trigger, as was shown in many studies that highlighted the frequency of AF occurrence in both pre-LVAD or post-LVAD patients with advanced HF, with an estimated prevalence of 21–54% and a great impact upon patients’ outcome and mortality rates ,66. MoreUnder these circumstances, it was hypothesized that LVAD implantation may have a significant impact upon atrial remodeling through modifications in atrial filling pressures and myocardial strain. A recent study that evaluated several echocardiographic atrial parameters before and after LVAD implantation pointed out that LA size and volume index were significantly decreased after LVAD implantation, and a significant proportion of patients with previous paroxysmal AF presented no further documented AF episodes. Nevertheless, the occurrence of a post-implantation, new-onset AF was associated with poor outcome and increased mortality in patients receiving LVAD. Basically, these latest insights suggest that LVAD induces reverse atrial electrical and structural remodeling, but arrhythmic events may still severely influence the clinical outcome of patients with LVAD .p < 0.001) and six months  were significantly smaller compared with just after ablation in the patients without AF recurrence. Additionally, the authors found a significant decrease of the natriuretic peptide concentrations between baseline levels and those at three and six months , thus furtherly confirming the potential benefits of catheter ablation not just for AF management, but also for the outcome of patients with ACM and HF [Even if the topic is too vast to be exhaustively covered by this review, we need to mention the anti-remodeling role of catheter ablation for isolated AF which was confirmed in multiple studies during the last two decades ,69,70. TM and HF .In recent years, novel computational models and applications for atrial remodeling entered the spotlight, thus offering a framework for a better approach to AF ablation, pharmacotherapy, and the subsequent long-term prognosis of these patients .Basically, these complex, multi-scale atrial models are mathematical models that are bridging the molecular, cell-scale mechanisms with the tissue alteration and finally, with the whole atria scale dysfunction, integrating this pathophysiological continuum into a graphical representation of atrial electrophysiology .The cell scale provides information concerning the kinetics of different ionic channels and the coupling of some regulatory proteins in order to produce the transmembrane potential of the atrial myocytes, while the tissue scale highlights the intercellular coupling and fiber orientation that exerts a great influence upon electrical propagation. Finally, the whole atria scale of these computational models provides insights into the segmentary distribution of normal tissue or fibrotic areas, also generating a 3D reconstruction of the atrial geometry that simulates atrial activation .+ channel blockade with repolarization modulating drugs to generate ideal compound profiles that could reverse atrial remodeling or at least inhibit its underlying electro-structural mechanisms [The clinical utility of computational relies on their capacity to allow the study of some drugs’ effects on a wide range of cellular phenotypes, thus providing an improved prognosis tool concerning the impact of certain substances on the ionic currents. For example, recent research emphasizes the development of multi-target therapies that aim to combine the efficacy of Nachanisms .Another important aspect with direct clinical impact refers to the pharmacokinetic (PK) and pharmacodynamic (PD) modeling of some antiarrhythmic substances such as drug conversion from amiodarone to its derivative dronedarone. Both substances exhibit a similar main structure (removed iodine and added methanesulfonyl group) and overall electropharmacologic profile but with different effects on individual ion channels. Moreover, concerning PK models, amiodarone has increased affinity to accumulate in different tissues due to a longer half-life, thus raising the risk for non-cardiac side-effects. In this context, PK and PD modeling should be routinely considered for drug development, providing a better understanding of several dynamic drug–ion channel interactions involved in ACM and their subsequent positive or negative (non)cardiac outcomes .ACM represents a complex entity that is correlated with numerous commonly met conditions from clinical practice, including systemic hypertension, congestive HF, AF, type 2 diabetes, sleep apnea syndrome, and obesity. Fibrosis is the most important pathophysiological mechanism of atrial remodeling, its accurate assessment representing the foundation for an adequate therapeutic approach and an improved long-term prognosis.Besides the classic inflammatory biomarkers or natriuretic peptides, laboratory diagnosis of ACM is focused on modern biomarkers that could indicate the magnitude of the fibrogenic process and also assess the risk of future cardiovascular events. CMR has become a promising and increasingly used technique for describing heart chamber structure and function, LGE-CMR being commonly used to assess the extent of atrial fibrosis and offering an accurate characterization of scar tissue formation after the ablation procedure and thus ascertaining the need for an eventual reintervention.The ultimate goal will be to translate recent molecular and clinical findings into an algorithm-based therapy for patients diagnosed with conditions suggestive of ACM. In addition to classical pharmacological drugs used in HF or AF, invasive devices  or the use of computational models may be a viable option for both the acute and long-term therapeutic optimization of patients with HF and ACM.


Ventricular septal defect (VSD) and bicuspid aortic valve (BAV) are the two most common congenital heart defects. BAV may occur sporadically or in association with other cardiac malformations. VSDs have decreased incidence in the adult population due to spontaneous closure. Mitral valve prolapse (MVP) and patent foramen ovale (PFO) can be associated with these conditions but the simultaneous association of these defects has never been reported in the literature. We report the case of a 35-year-old male patient with persistent VSD, BAV, and PFO associated with new-onset heart failure and MVP. We aim to study the association between the coexistence of structural heart malformations and the increased risk of heart failure. Bicuspid aortic valves (BAV) have an incidence of 1%-2% in the general population . The co-A 35-year-old male with a history of BAV and a perimembranous VSD without hemodynamic consequences presented for follow-up echocardiography. The family history is negative for similar structural heart diseases but is positive for ischemic heart diseases in both parents. The last transesophageal echocardiography performed two years prior to presentation showed normal LV systolic and diastolic function and wall motion, a BAV with mild aortic regurgitation but no stenosis. A small perimembranous VSD of 0.7 cm was noted with a minimal shunt. The RV was normal with normal pulmonary artery systolic pressure. A foramen ovale was noted but the agitated saline test showed very minimal passage of bubbles to the left-sided cavities. There was no visible thrombus and the rest of the valves were normal. The patient was stable since the examination was performed but lost to follow up. Two years later, the patient started progressively complaining of new symptoms including dyspnea that started on exertion and progressed to less than ordinary physical activity and was partially relieved by rest condition attributable to New York Heart Association (NYHA) class three. There was no jugular venous distention but the presence of bilateral basal lung crackles and mild pitting edema of the lower limbs were seen on physical exam. The onset of the edema was associated with the appearance of symptoms. The new transthoracic echocardiography showed evidence of new-onset moderately dilated left ventricle (LV) with moderate systolic dysfunction (ejection fraction (EF) = 40%) Figures -2 Video-3. ThereThe aortic valve was bicuspid as confirmed by the previous examination but there was no progression of the regurgitant jet, only mild regurgitation with a pressure half time of 795 milliseconds and there was no valvular stenosis with a Vmax of 1.59 m/s and a normal mean gradient Figures -5 Video. There wThe RV systolic pressure was only mildly elevated without significant RV dilatation and the inferior vena cava was non-dilated with normal respiratory variations Figure . The gloThe patient was started on betablockers with bisoprolol 5 mg once daily and sacubitril/valsartan combination to treat his heart failure with EF<40% and was scheduled to perform a cardiac MRI to assess for underlying cardiomyopathy but the patient declined did not follow up. Closure of the VSD was not recommended for the moment since the LV-RV gradient is not very significant and the RV is not dilated with borderline systolic pulmonary artery pressure. The aortic valve was scheduled for observation to follow up on the regurgitation and the ascending aorta diameter. Congenital and structural heart defects are not uncommon in the general population and affect 1% of the total births per year . DiffereA study evaluating the genetic inheritance of structural heart defects on a population of mice revealed that genes on chromosome X code for the filamin proteins which are responsible for cardiac and vascular development . MutatioBAV is the most common adult congenital heart defect. It is often associated with both dilation and aneurysm of the ascending aorta . BAVs arThe echocardiography performed on our patient one year prior to presentation showed the presence of these structural defects without the presence of heart failure. The patient was advised for repair of the VSD, however, he was lost to follow-up. It is important to stress the frequent echocardiography follow-up from a young age in order to prevent irreversible detrimental effects . Our patient presented two years later with new-onset debilitating heart failure symptoms. The rapid onset of heart failure, which was associated with impaired global longitudinal strain on echocardiography, made us think of an associated cardiomyopathy such as sarcoidosis or amyloidosis. On echocardiography, there was evidence of left-to-right shunting, however, it was not associated with increased right-sided pressures. In order to rule out ischemic causes of his new-onset heart failure due to a family history of premature coronary artery disease, coronary angiography was performed and showed no evidence of ischemic heart disease.Following the abrupt deterioration of the patient’s condition, we postulate that all four mentioned structural adult heart defects work synergistically to hasten the onset of severe heart failure. Furthermore, we also hypothesize that the co-occurrence of these etiologies has unveiled and accelerated the onset of the underlying masked cardiomyopathy that was not evident on the old echocardiography.Heart failure  in our patient could be related to a different underlying condition, not necessarily from his structural heart defects. This is due to the fact that the right-sided pressures are not very elevated, meaning that the hemodynamic consequences of the VSD and the left-to-right shunt are not causing significant RV dilatation or strain. In addition, BAV has a relatively normal function in our patient without significant stenosis and regurgitation making it a less likely trigger to the new-onset heart failure. Accordingly, the patient was advised to do a cardiac MRI in order to look for an alternative etiology for his heart failure. The association of structural heart defects has been described in the literature and most of these defects are diagnosed incidentally during adulthood. However, the occurrence of four structural defects in the same patient  is not described in the literature. Heart failure is associated with congenital heart defects and the combination of these defects could worsen or accelerate the onset of heart failure symptoms at a young age. In case of association of defects, and in case of hemodynamic significance, it might be better to treat the defects instead of just observing in order to prevent complications including heart failure.


Acute coronary syndrome (ACS) causes pathophysiological changes in exercise capacity, N-terminal part of pro-brain natriuretic peptide (NT-proBNP), and adiponectin that impact the course of coronary artery disease and clinical outcomes after cardiac rehabilitation (CR). However, the serial changes and the relationship between the changes in these parameters for a prolonged term remain uninvestigated.  Eighty-one patients with ACS underwent a three- or four-week CR program after acute care and were followed up for 12 months. Exercise capacity on a cycle ergometer and blood levels of NT-proBNP and adiponectin were determined before and after CR as well as at the 12-month follow-up. µg/ml before CR) increased after CR (16.0 µg/ml) and at 12 months (17.2 µg/ml). There was no significant correlation among the changes in these parameters at each observation time point.  Exercise capacity increased from 100 watts (in median) before CR to 138 watts after CR and 150 watts at 12 months. The NT-proBNP level (526 pg/ml before CR) remained almost unchanged after CR (557 pg/ml) and then decreased at 12 months (173 pg/ml). The adiponectin level (14.5  During the observation period from before CR to the 12-month follow-up, exercise capacity, NT-proBNP, and adiponectin underwent significant changes; however, these changes were independent from each other and not correlated linearly, and they provide complementary information in clinical practice. Thus, all these parameters should be included and determined at different time points for a prolonged period of time. Acute coronary syndrome (ACS), composed of unstable angina pectoris and myocardial infarction with or without ST segment elevation, is a common, critical event that threatens public health and jeopardizes work ability and quality of life . CardiacAlthough there are a number of well-established parameters available for evaluating the effect of CR , most stDuring the myocardial remodeling process, the N-terminal part of pro-brain natriuretic peptide (NT-proBNP) undergoes changes that are associated with the severity of myocardial injury as well as left ventricular (LV) dysfunction ; therefoIt is known that a variety of factors, especially metabolic factors, can impact the long-term outcome of ACS, and the adipocytokine adiponectin is regarded as an important cardiovascular protective agent . EpidemiThere are different studies dealing with changes in exercise capacity, NT-proBNP, and adiponectin levels in patients with ACS; however, the relationship among these parameters during a prolonged follow-up was not reported. Because these parameters are different in terms of their regulation and dynamic changes in patients with ACS and provide information from different clinical aspects, investigating the serial changes in these parameters, especially their relationship for a prolonged period, is of clinical significance. The present study sought to investigate the changes in exercise capacity, NT-proBNP, and adiponectin levels in patients with ACS before and after CR as well as at the 12-month follow-up while paying special attention to the relationship among these parameters.T and serum creatine kinase-MB), including ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, or unstable angina; (3) accomplishment of acute treatment; and (4) consent to CR and subsequent follow-up at 12 months. Patients with the following conditions were excluded from the study: (1) decompensated cardiac conditions such as dyspnea at rest and pronounced congestion such as obvious edema in the lower limbs; (2) unfinished acute care, hypertrophic cardiomyopathy, valvular disease requiring surgery, pericarditis, and severe renal dysfunction ; and (3) patients suffering from any noncardiac disease that would impede participation over the full length of the study period.All patients were enrolled through the Department of Cardiology of University of Ulm and underwent percutaneous coronary intervention in acute care before CR. Patients treated with CABG from the Department of Cardiac Surgery were not included in the study. ACS was diagnosed according to the standards of the European Society of Cardiology . The criA total of 163 patients were initially enrolled in the study finally, after exclusion of drop-out cases.The data from 81 patients were taken for the present study . The basThis study was approved by the Ethics Committee of the Medical Faculty of the University of Ulm, and all the subjects gave their informed consent prior to the study.Upon the onset of ACS, all patients were acutely treated in the Department of Cardiology of University Hospital Ulm (Germany). After acute care, the patients were introduced to phase II CR according to the standards of the German Society of Prevention and Rehabilitation. After CR, the subjects were followed up for 12 months, and during the follow-up period, the patients were advised to join the phase III CR program. The measures performed in the phase III CR program were recommended by the American College of Sports Medicine and American Heart Association , and allA phase II CR program was performed according to the standards of the German Society of Prevention and Rehabilitation . The majE′ by tissue Doppler . Therefore, the major parameter, i.e., EF was taken to analyze LV dysfunction. LV function was assessed by standard routine echocardiography. LV dysfunction was classified when the ejection fraction was <50% [Clinical examination was performed according to the standards of the German Society of Cardiology. The LV function was assessed through routine clinical echocardiographic examination. Generally, all patients showed diastolic dysfunction with a disturbed E/A ratio by pulsed-wave Doppler and/or E/was <50% . Baselinwas <50% . The EQ-The exercise capacity was determined by symptom-limited exercise testing on a cycle ergometer. The standard protocol for ergometry was adopted from the guidelines of the German Society of Cardiology, beginning at 25 watts with 25 watt increments every 2 minutes until subjective exhaustion or criteria for termination of a stress test with continuous monitoring by a 12-lead ECG . Blood pFor determination of NT-proBNP and adiponectin levels, fasting venous blood samples were drawn into tubes containing ethylenediamine tetraacetic acid under identical conditions. No exercise training or testing was performed within 24 hours prior to blood sampling. The blood plasma was collected and stored at −70°C. NT-proBNP was determined using an ELISA kit , and the total adiponectin concentration was determined by using an ELISA kit .with a general linear model. Comparisons between groups were performed by the Mann–Whitney U test. Spearman's or Pearson's correlation method was used for correlation analysis. Statistical analysis was performed using SPSS software 25 . All tests were two-sided, and a difference was assumed to be statistically significant at P < 0.05.All data  were expressed as the median (interquartile range) for skewed continuous variables. NT-proBNP, adiponectin, and workload were logarithmically transformed to normalize their distribution for univariate analysis. The changes in a parameter with a series of measurements were examined by univariate analysis The basic data of the subjects, including anthropometry, cardiovascular risk factors, treatment, LV function, and quality of life (scores) are shown in P < 0.01) and at the 12-month follow-up (P < 0.01). This increase was found in both subjects with normal LV function and those with LV dysfunction  (P < 0.01). Furthermore, the decrease in NT-proBNP levels was greater in patients with LV dysfunction than in those with preserved LV function (P < 0.001).Compared to that before CR, the NT-proBNP level did not change after CR but significantly decreased at 12 months ( < 0.01) . In pati < 0.01) . NT-proBP < 0.05) and showed a further augmentation at the 12-month follow-up (P < 0.01). There was a tendency for adiponectin levels to be higher in the group with LV dysfunction than in the group with normal LV function, but the difference was not statistically significant (P < 0.05), whereas they did not change significantly in the group with LV dysfunction. Both groups showed an increase at 12 months (P < 0.05).The adiponectin level data are shown in nificant . The chaNo statistically significant correlation was found between changes in NT-proBNP, adiponectin, and exercise capacity from baseline to the 12-month follow-up . In addiWe performed further analysis based on changes in each parameter. According to changes in exercise capacity (increased or nonincreased), there was no significant difference in NT-proBNP after CR or at the 12-month follow-up , and a sACS is a critical event that significantly threatens public health, and phase II cardiac rehabilitation is of clinical importance for the outcome of patients with ACS. Exercise capacity, NT-proBNP, and adiponectin are proven meaningful parameters that are commonly used for evaluating the effects of secondary prevention. However, to date, most of the studies dealt with only one of these parameters or only at a single time point, and few studies have investigated serial changes in all these parameters. Therefore, we investigated the characteristic changes in these parameters over a prolonged follow-up period and specifically analyzed their relationship.Improving exercise capacity is of clinical relevance since physical performance serves as one of the most important predictors for the outcome of patients suffering from ACS . It is cThe level of NT-proBNP is well recognized as a marker for the severity of myocardial injury and subsequent LV dysfunction  and is eNT-proBNP levels at 12 months decreased significantly in patients with or without LV dysfunction in comparison with those before or after CR. This seemed to be accompanied by functional and clinical improvement. A previous study showed that the dynamic changes in NT-proBNP in patients with ACS decreased gradually for at least six months . FactorsA number of studies have shown that adiponectin levels are associated with the development and progression of coronary artery disease , and genAlthough previous studies have shown that CR improved exercise capacity and affected NT-proBNP and adiponectin levels , 35, no From acute care of an ACS through phase II CR to the 12-month follow-up, exercise capacity and blood levels of NT-proBNP and adiponectin undergo significant changes, but these changes are not parallel or not correlated with each other. Therefore, they provide complementary information from different aspects and should be taken together to evaluate the outcomes of ACS and CR.