Radiotherapy (RT) is one of the pillars of cancer therapy. High-dose radiation exposure on the thorax is mainly used in the context of adjuvant RT after breast surgery, in lung and esophageal cancer, and as a complement to systemic treatment in lymphoma. Due to the anatomical proximity, the heart inevitably receives some radiation that can result in acute and chronic cardiotoxicity, leading to heart failure, coronary artery disease, pericardial and valvular heart disease. Current evidence suggests there is no safe radiation dose to the heart, which poses a need for early recognition of RT-induced cardiac injury to initiate cardioprotective treatment and prevent further damage. Multimodality cardiac imaging provides a powerful tool to screen for structural and functional abnormalities secondary to RT. Left ventricular ejection fraction, preferably with three-dimensional echocardiography or cardiovascular magnetic resonance (CMR), and global longitudinal strain with speckle-tracking echocardiography are currently the key parameters to detect cardiotoxicity. However, several novel imaging parameters are tested in the ongoing clinical trials. CMR parametric imaging holds much promise as T1, T2 mapping and extracellular volume quantification allow us to monitor edema, inflammation and fibrosis, which are fundamental processes in RT-induced cardiotoxicity. Moreover, the association between serum biomarkers, genetic polymorphisms and the risk of developing cardiovascular disease after chest RT has been demonstrated, providing a platform for an integrative screening approach for cardiotoxicity. The present review summarizes contemporary evidence of RT-induced cardiac injury obtained from multimodality imaging—echocardiography, cardiovascular computed tomography, CMR and nuclear cardiology. Moreover, it identifies gaps in our current knowledge and highlights future perspectives to screen for RT-induced cardiotoxicity. Radiotherapy (RT) is one of the pillars of cancer therapy . It has Awareness that delayed effects on the heart may lower the therapeutic benefits from RT has an important impact on modern cardio-oncology clinical practice. To minimize the radiation to the surrounding tissues, treatment plans for patients with Hodgkin lymphoma have evolved from extended-field to involved-field and then to involved-site/involved-node RT . FurtherThe present review focuses on the current evidence of RT-induced cardiac injury obtained from multimodality imaging—echocardiography, cardiovascular computed tomography (CT), cardiovascular magnetic resonance (CMR), and nuclear cardiology. In addition, it identifies gaps in our knowledge and highlights future perspectives to diagnose and monitor RT-induced cardiotoxicity.Radiation damage is characterized by acute and chronic changes in the myocardium, pericardium, coronary vasculature, valvular apparatus and the conduction system. The pathophysiology shares several common pathways and mechanisms that ultimately lead to a progressive decline in left ventricular (LV) diastolic and systolic function and cause symptoms of heart failure .Central to the RT-induced myocardial injury is the vascular endothelial cell damage, occurring within minutes of ionizing radiation and leading to an acute inflammatory response . The acuAcute inflammatory changes involving the pericardium may cause acute pericardial effusion . EnsuingRadiation exposure affects as well the coronary vascular bed. The initiation of RT-induced injury is similar to that of the myocardium—the radiation damages the endothelial cells, which respond with inflammatory markers and adhesion molecules to recruit peripheral leukocytes . Once moThe hallmarks of RT-induced valvular heart disease are thickening, fibrosis and calcification of the valve apparatus . RT predEchocardiography is the first-line imaging modality to assess cardiotoxicity in cancer patients. Owing to its wide availability and accessibility, low-risk profile, and ability to assess systolic and diastolic function, valvular pathophysiology, and pericardial disease, it is ideal technique for screening and diagnosing RT-related cardiovascular toxicity .Traditionally, LV ejection fraction (LVEF) is the gold standard to assess global systolic function. More than 10 percentage points decrease in LVEF to a value below the lower limit of normal [54% for women and 52% for men according to the current European and American recommendations ] has beeP < 0.01). No decline in GLS was observed in patients with right-sided breast cancer. When comparing the segmental strain values, the strain of the anterior LV wall receiving the highest radiation dose was significantly reduced, while the strain of the inferior LV wall receiving the lowest radiation dose did not change. Similar findings were confirmed in breast cancer patients receiving RT without concomitant chemotherapy (P < 0.001)  is the most commonly used deformation parameter and a 15% relative reduction in GLS or absolute reduction below −18% suggest cardiotoxicity , 17. Sevotherapy –25. Tuohotherapy  observedotherapy , 24, the< 0.001) .Furthermore, the segmental strain analysis demonstrated that variability in dose distribution across the heart plays an important role in cardiotoxicity. Breast cancer patients had the greatest reductions in myocardial strain in the anterior wall followed by the anteroseptal and the anterolateral walls with a base-to-apex gradient and this was correlated with the segmental distribution of the received radiation dose . MoreoveA population-based study has shown that the predominant form of heart failure after contemporary RT for breast cancer is heart failure with preserved ejection fraction (LVEF ≥ 50%), implying impaired LV diastolic function . This haP < 0.001), tricuspid annular plane systolic excursion , peak systolic tricuspid annular velocity , and RV free wall strain . Signs of RV systolic dysfunction were 3 times more often in patients with concomitant LV dysfunction. These findings were confirmed in another cohort of 274 adult lymphoma survivors examined with echocardiography 13 ± 6 years after diagnosis (P < 0.001) and the majority of patients with RV dysfunction were asymptomatic, leading the authors to conclude that RV dysfunction is most likely of subclinical importance. Impaired global and free wall RV strain was observed in 128 patients with non-small lung cell carcinoma 6 months after receiving chemo- and RT (Right ventricular (RV) abnormalities may also occur in oncological patients, however, much less is known about RV than LV impairment . Christiiagnosis . After m- and RT . Both st- and RT .Echocardiography is also an excellent method to diagnose valvular heart disease. The echocardiographic characteristics of RT-induced valve disease include fibrosis and calcification of the aortic root, aortic valve annulus and leaflets, mitral valve annulus, and the base and mid-portions of the mitral valve leaflets , 20. TypCardiovascular CT provides detailed cross-sectional anatomical imaging of the chest with a powerful depiction of coronary, pericardial, myocardial, and vascular anatomy. It includes non-contrast CT, highly sensitive for calcified tissues, and CT angiography (CTA), where cardiac cavities and vessels are distinguished from the surrounding tissues by contrast medium opacification. The acquisition and reconstruction of images must be synchronized to the ECG to obtain robust motion-free images of moving structures like coronary arteries. The main disadvantages of CT are the ionizing radiation , the need for iodine-containing contrast media, and the susceptibility to arrhythmias and breath-hold motion artifacts –41.Cardiovascular CT can be used to assess cardiac chamber dimensions, mass, LV, and RV ejection fraction with good accuracy and reproducibility compared to CMR . The temP = 0.004)  score, a low radiation dose ECG-gated non-contrast CT scan is performed  44). A . A 44). = 0.004) . The rel= 0.004) . The int= 0.004) . HoweverWhile CAC scans are limited to identifying coronary calcium deposits, coronary CTA depicts complete coronary anatomy, including non-calcified plaques, but at the expense of slightly higher radiation dose and the use of contrast agents . CoronarCardiovascular CT is a valuable tool to identify pericardial complications of chest RT . Normal Cardiovascular CT has a vital role in evaluating aortic, valvular and myocardial calcifications. In patients requiring cardiac surgery, preoperative assessment of mediastinal fibrosis and aortic calcifications is essential to determine the suitability of a surgical approach and the site of aortic cross-clamping . SignifiCMR is a relatively new cardiac imaging technique that has witnessed major technical advancements, application to a broad range of cardiovascular diseases, as well as incorporation into consensus statements and clinical practice guidelines in the last 2 decades . CMR comT1- and T2-weighted anatomical images in the axial, coronal, and sagittal planes provide basic morphological data regarding cardiothoracic structures. In RT-induced cardiac disease pericardial thickening or pericardial effusion might be found. In addition, extracardiac findings of interest might be diagnosed .Cine balanced steady-state free precession images in multiple views allow essential functional and anatomical evaluation of cardiac chambers, including measurements of LV and RV volumes, ejection fraction and mass, as well as the assessment of segmental wall motion abnormalities, valve anatomy and pericardium  58)..58).T2-weighted short tau inversion recovery and bright blood T2-weighted sequences are most commonly used to evaluate myocardial edema .Late gadolinium enhancement (LGE) is considered the gold standard for non-invasive evaluation of myocardial fibrosis . About 1Novel CMR sequences for detection of myocardial inflammation, edema and fibrosis allow quantification of changes in T1 and T2 relaxation times and computation of extracellular volume (ECV)  60, 61), 6160, 6Several CMR techniques have been developed in the past to analyze myocardial deformation, e.g., myocardial tagging, displacement encoding with stimulated echoes, strain-encoded imaging. Their main shortcoming was the need for special scan sequences. Recently, feature-tracking CMR has been developed, which is based on tissue tracking algorithm applied to standard cine images during postprocessing, similar to speckle-tracking echocardiography  63). LV. LV63). P < 0.001) and LV mass  were found in lymphoma survivors. Global LV longitudinal, circumferential and radial strain with feature-tracking CMR were reduced compared to healthy controls. LGE was present in 11% of the survivors  and the native T1, indicative of diffuse myocardial fibrosis, was significantly increased compared to healthy controls .CMR has been increasingly utilized in cardio-oncology research trials . van derP = 0.005), resolving at 24 months. No wall motion abnormalities and no LGE were found. Similarly, Bergom et al. , indicating myocardial edema. Both native T1 and T2 returned to baseline values approximately 1 year after completion of therapy. In contrast, patients undergoing left-sided RT did not show increased T1 or T2 values neither immediately after RT nor at 1-year follow-up. Both groups also had normal ECV values at 1-year follow-up.Tahir et al.  studied 2; defined as < 85% age-predicted values) and despite having similar resting cardiac function in terms of LVEF and GLS (with feature-tracking) compared to their counterparts with normal peak VO2, they demonstrated reduced cardiac reserve on exercise CMR. Their maximum cardiac index was less than in patients with normal peak VO2  and increased mainly due to the increase in the heart rate, while their maximum stroke volume index was markedly reduced .Foulkes et al.  studied 123I-metaiodobenzilguanidine (123I-mIBG) imaging represents the reference for non-invasive evaluation of cardiac adrenergic nervous function and has proven useful in the subclinical cardiac damage assessment as well as in the prognostication of patients with chronic heart failure  and positron emission tomography (PET), have been used to assess cardiac disease in cancer survivors , 73. ECG failure . However failure  and makeMyocardial perfusion imaging with SPECT can provide valuable information on inducible ischemia and myocardial viability . A 14–6082Ru or 13NH4, offers several advantages over SPECT, including increased spatial and temporal resolution and reliable quantification of absolute myocardial blood flow. PET with 18F- fluorodeoxyglucose allows assessment of myocardial inflammation and viability (18F-NaF can identify high-risk coronary atherosclerotic plaques by detecting active calcification processes (Myocardial perfusion imaging with PET, most commonly performed with radiotracers iability . PET witrocesses . HoweverDespite the progress in recent years, our knowledge about RT-induced cardiotoxicity is incomplete. The role of multimodality cardiac imaging to address some of the key questions is discussed in the following section.Large-population studies involving patients with breast cancer and Hodgkin lymphoma have shown a clear dose-effect relationship with adverse cardiac events with no apparent threshold , 85, 86.The RT-induced cardiovascular disease also depends on the type and localization of the thoracic tumor and the dose received by a specific cardiac substructure might be more important for the development of cardiac disease than the mean heart dose . In a coSeveral studies have tried to elucidate the best imaging parameters to predict cardiotoxicity in patients after chest RT. Armstrong et al.  have comWhile measuring LVEF and GLS currently represents a cornerstone in detecting and monitoring RT-induced cardiac toxicity , 17, futIn addition to imaging biomarkers, blood-based and genetic biomarkers could help identify patients at higher risk for cardiovascular complications. Classic cardiac biomarkers such as N-terminal pro b-type natriuretic peptide, troponin I and T have been linked to RT-induced cardiotoxicity , 91–93. Several ongoing clinical trials aim to close the gaps in our current knowledge about RT-induced cardiotoxicity. The CareBest is a single-center prospective clinical trial, which will enroll over 2,000 breast cancer patients undergoing chemotherapy and RT . The stuCardiovascular imaging has shown remarkable progress in the developing field of cardio-oncology, providing highly sensitive methods for diagnosing cardiotoxicity. LVEF, preferably with 3D echocardiography or CMR, and GLS with speckle-tracking echocardiography are currently the recommended parameters to detect RT-induced cardiotoxicity , 17. HowTP, BB, JD, KG, and TM involved in drafting and writing the manuscript. All coauthors provided final approval of the submitted manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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A systemic right ventricle (sRV) cannot support cardiac output in the long run, eventually decompensating and causing heart failure. The burden of d-TGA patients with previous atrial switch repair and cc-TGA patients with heart failure will only increase in the coming years due to the aging adult congenital heart disease population and improvements in the management of advanced heart failure. Clinical data still lags behind in developing evidence-based guidelines for risk stratification and management of sRV patients, and clinical trials for heart failure in these patients are underrepresented. Recent studies have provided foundational data for the commencement of robust clinical trials in d-TGA and cc-TGA patients. Further insights into the multifactorial nature of sRV failure can only be provided by the results of such studies. This review discusses the mechanisms of heart failure in sRV patients with biventricular circulation and how these mediators may be targeted clinically to alleviate sRV failure. Right ventricular (RV) dysfunction is a key prognostic determinant of patient status in various cardiac diseases, including pulmonary hypertension (PHTN), cor pulmonale, left-sided heart failure, valvular heart disease, and coronary artery disease. Congenital heart diseases (CHDs) such as tetralogy of Fallot, transposition of the great vessels (TGA), Ebstein’s anomaly, and Eisenmenger syndrome are important causes of RV dysfunction . About 1d-TGA features isolated ventriculoarterial discordance, resulting in venous return to the right heart being pumped back into the systemic circuit by the right ventricle and oxygenated blood returning to the left atrium (LA) being pumped back into the pulmonary circulation by the left ventricle (LV). d-TGA patients present with neonatal cyanosis and require emergent surgical correction. Left untreated, d-TGA carries a 90% mortality risk in the first year of life , 6. The In contrast, cc-TGA exhibits discordant atrioventricular and ventriculoarterial connections. The right atrium (RA) is connected to the subpulmonary LV through the mitral valve, while the LA empties blood into the sRV via the tricuspid valve. Therefore, as physiologic blood circulation is preserved, cc-TGA infants do not present with cyanosis and can be asymptomatic at birth. However, associated anomalies such as a ventricular septal defect, an Ebsteinoid malformation of the tricuspid valve, subpulmonic stenosis, accompany cc-TGA in 80% of cases and may necessitate surgery during infancy . In the Therefore, the pathophysiology of sRV failure is multifactorial, and the unclear prognosis of sRV patients hinders effective management. Furthermore, clinical trials evaluating traditional heart failure drugs, such as angiotensin-converting enzyme inhibitors (ACEis), angiotensin-receptor blocker (ARBs), and others, have yielded disappointing results. Recommendations for managing arrhythmias and conduction abnormalities in TGA patients are also unclear. Lastly, only a handful of single-center data have been published regarding the role of mechanical circulatory support (MCS) devices in advanced sRV failure patients. Therefore, in this review, we summarize the primary mechanisms of sRV failure and review the latest studies on the stratification and management of sRV patients.Myocardial fibrosis is a pathological process induced by many cardiac pathologies, including those characterized by a pressure overload, such as aortic stenosis and hypertension. Myocardial fibrosis has proven predictive value in determining the risk of heart failure progression and mortality , 13. DetsRV patients also experience a state of chronic pressure overload as the sRV pumps blood against the afterload of the systemic circulation, suggesting that myocardial fibrosis may be a prominent structural alteration in sRV patients. Indeed, compared with other CHDs, such as tetralogy of Fallot and cyanotic diseases, sRV patients feature the highest fibrotic indices . The preSerum levels of collagen turnover markers have been used as indicators of myocardial fibrosis. A hallmark of fibrosis is the transformation of cardiac fibroblasts into myofibroblasts expressing a-smooth muscle antigen (α-SMA) . α-SMA-eFrom a mechanistic standpoint, RV pressure overload induces collagen deposition by fibroblasts and myofibroblast proliferation and contraction  21). Th. Th21). Other data argue against a significant role of myocardial fibrosis in sRV failure. For example, Fratz et al. found no myocardial fibrosis or scarring, assessed by LGE and positron emission tomography (PET) scan, respectively, in 18 d-TGA patients over 20 years after the atrial switch operation, even in patients with reduced sRV ejection fraction and wall motion abnormalities . SimilarCheung et al. utilized T1 mapping on CMR to assess sRV and subpulmonary LV fibrosis in d-TGA patients after the atrial switch operation and found the LV to be significantly more fibrotic than the sRV, but neither correlated with the ejection fractions of the respective ventricles . AnotherMyocardial ischemia and perfusion defects are crucial players in heart failure with preserved (HFpEF) and reduced ejection fractions (HFrEF) . For insP = 0.02)  is a diagnostic marker for acute coronary syndrome (ACS). It has also been used as a biomarker for cardiac dysfunction in adult CHDs. Profound hsTnT elevations above the 99th percentile are detected in sRV patients and CHDs with PHTN . hsTnT l = 0.02) .2 demand and blood supply by the right coronary artery  instead of the mitral valve, chronically causing tricuspid dysfunction. The tricuspid valve is ill-equipped to serve as the SAVV due to morphological differences between it and the mitral valve, predisposing it to TR . TR is ap < 0.001)  . d-TGA p< 0.001) . Therefo< 0.001) .One of the unique features of cc-TGA distinguishing it from d-TGA is the intrinsically abnormal tricuspid valve in the former. Studies have found that 94% of patients with cc-TGA suffered from intrinsic tricuspid valve abnormalities, including Ebstein anomaly, dysplasia, straddling, stenosis, and overriding . Indeed,In summary, SAVV regurgitation in sRV has been incorporated into several prognostic prediction models to stratify cc-TGA and d-TGA patients. However, considering the multifactorial pathophysiology of sRV failure, it is difficult to delineate the exact contribution of TR in this context.Approximately 25% of adult CHD-related admissions are due to arrhythmias . BradyarCardiac dyssynchrony is defined as non-synchronous peak myocardial fiber shortening caused by a delay in the electrical and mechanical activation of the heart . Mechanide novo AV block of approximately 2%  pacing. However, pacing-induced dyssynchrony is a well-known phenomenon that worsens sRV dysfunction and contributes to sRV failure. Indeed, LV pacing is a risk factor for progressing sRV dysfunction in cc-TGA patients . For insEvidence-based guidelines on pharmacologic treatment of sRV failure have not been established . Drugs an = 18) treated with sacubitril/valsartan, an angiotensin receptor/neprilysin inhibitor (ARNI), reported significant improvements in 6-min walking distance, cardiac function assessed by echocardiography, and quality of life (The first sRV failure patient cohort ( of life . Larger  of life . A signi of life .Sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as empagliflozin and dapagliflozin, decrease cardiovascular mortality and hospitalizations related to heart failure with reduced LV ejection fraction . SGLT2 iArrhythmia prevention strategies in sRV patients are not well defined. Indeed, the burden of implantable cardioverter-defibrillator (ICD) placement in TGA patients is considerably greater than that of the current population; TGA is only second to tetralogy of Fallot for ICD implantation for adult CHDs. As per the European Society of Cardiology (ESC) 2020 guidelines on the management of adult CHDs, ICD implantation may be considered for secondary prevention of SCD in the setting of severe sRV dysfunction (ejection fraction < 35%) in the presence of additional risk factors, such as NYHA functional class II/III, severe SAVV regurgitation, and wide QRS duration ≥ 140 ms . AdjunctPacing is often required for d-TGA post-atrial switch repair patients with bradycardia and cc-TGA patients with heart block . HoweverThese findings indicate that early tricuspid valve replacement may prevent future sRV dysfunction and heart failure. An international multicenter study by Kharbanda et al. showed that CRT significantly reduced NYHA class and QRS duration in sRV patients on pre-existing univentricular pacing, but primary CRT had no significant benefit . TherefoPrecipitants of sRV failure may require invasive treatment. Treatment for patients with mild or moderate TR aims to reduce ventricular afterload and prevent arrhythmias . PatientThe major determinant of post-operative sRV function after SAVV replacement is preoperative sRV ejection fraction. At a follow-up of ∼8 years, 63% of cc-TGA patients with preoperative sRV EF ≥ 40% maintained sRV function, compared to only 10% with a preoperative sRV EF ≤ 40% . In agrePatients with decompensated sRV failure unresponsive to or unsuitable for CRT and refractory to medical therapy should be referred to a transplant center . HoweverVentricular assist devices (VADs) are increasingly used to manage advanced heart failure patients as either a bridge to transplant, bridge to candidacy, or destination therapy—indications are based on the INTERMACS profile . LVAD plThe guarded prognosis of sRV is due to the lack of evidence-based prognostic markers and treatment guidelines, particularly regarding pharmacologic management. We divided the mechanisms underpinning sRV dysfunction into myocardial fibrosis, ischemia/perfusion defects, arrhythmias and dyssynchrony, and TR. This classification encompasses the multifactorial nature of sRV dysfunction. Nevertheless, most data on the mediators of sRV dysfunction stem from studies on congenitally normal hearts. Mechanistic differences between sRV and LV failure need to be anticipated, exemplified by the poor efficacy of approved heart failure medications in relieving the radiologic and functional deterioration of sRV patients. Although the recent studies discussed above have significantly contributed to the scientific literature, the sRV patient population still seems to be an underrepresented community in clinical trials compared to heart failure in the systemic LV. Advancements in pediatric cardiology and surgery have ensured that 88% of children—including those with an sRV—reach adulthood, producing an aging sRV population with an annually increasing risk of cardiac complications, including heart failure , 134. AnBS, TA, AS, and DA-B: conceptualization. BS, TA, AS, SA, and AR: writing—original draft preparation. AS, SA, and DA-B: writing—review and editing. DA-B: supervision. All authors have read and agreed to the published version of the manuscript.


Abnormality in the cardiovascular system such as left ventricular dysfunction caused increased serum CRP and change in electrocardiography pattern. The present study aimed to understand the association between increased levels of highly sensitive CRP (hs-CRP) and non-arrhythmic ECG changes and electrocardiographic abnormalities in patients with the acute coronary syndrome.This study was done on 120 patients diagnosed with acute coronary syndrome and hospitalized at CCU. The patients were classified into two groups, one group with an increased level of hs-CRP and another with a normal hs-CRP level.The patients with an increased level of hs-CRP showed a significantly higher level of cardiac enzymes also ST-segment elevation myocardial infarction (STEMI) was seen in the group with an increased level of hs-CRP than those with normal serum hs-CRP level, but another diagnosis including unstable angina, non-STEMI, heart failure, and emergency hypertension was similarly observed in both groups. Two groups were assessed in terms of left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVeDD) the prevalence of valvular heart disease, and wall motion abnormality, also showed that groups with increased hs-CRP level, ST-segment elevation leads more significant differences than a normal group (P=0.001).Patients with an increased level of hs-CRP can be diagnosed as STEMI but not valuable to suppose as echocardiographic abnormalities such as left ventricular dysfunction or hypertrophy. C-reactive protein (CRP) is a kind of protein that normally circulates at a non-sensed low level in the serum, however, in some conditions including acute inflammatory processes, tissue injuries, or acute infections, it produces hepatic cells and rising in circulation can be markedly induced ,2. In thThis hypothesis has been strengthened by recent histological studies discovering activated circulating leucocytes, evidence of the systemic release of thromboxane, and other inflammatory mediators besides the elevated level of CRP in these abnormal cardiovascular conditions , 9. FurtThis cross-sectional study was performed on 120 patients finally diagnosed with acute coronary syndrome and eventually hospitalized at the cardiac care unit ward of Mostafa Khomeini Hospital in Ilam in 2011. The diagnosis of acute coronary syndrome is based on clinical manifestation, rising cardiac enzymes, and electrocardiographic ischemic changes, acute coronary syndrome is especially defined by laboratory blood factors such as troponin blood test in the setting of symptoms of angina or an angina equivalent and/or electrocardiographic changes consistent with a new q or evolutionary ST T-wave . Baseline characteristics of the participants including demographics, medical history, history of medications, and the level of cardiac enzymes were collected by interviewing on admission or reviewing hospital recorded charts. On admission, the level of hs-CRP was measured using a commercial kit in all participants. The patients were classified into two groups; increased level of hs-CRP (> 1 mg/dl) as the case group and normal hs-CRP level (≤ 1 mg/dl) as the control group. The patients in both groups were monitored during CCU hospitalization and any abnormal non-arrhythmic changes in ECGs were recorded in a study checklist. Also, the levels of lipid profiles were measured in all subjects.  Results were presented as mean ± standard deviation (SD) for quantitative variables and were summarized by frequency (percentage) for categorical variables. Continuous variables were compared using the t-test or Mann-Whitney U test whenever the data did not appear to have normal distribution or when the assumption of equal variances was violated across the study groups. Categorical variables were on the other hand compared using the chi-square test. For the statistical analysis, the statistical software SPSS Version 20.0 for windows  was used. P-values of 0.05 or less were considered statistically significant.Results were presented as mean ± standard deviation (SD) for quantitative variables and were summarized by frequency (percentage) for categorical variables. Continuous variables were compared using the t-test or Mann-Whitney U test whenever the data did not appear to have normal distribution or when the assumption of equal variances was violated across the study groups. Categorical variables were on the other hand compared using the chi-square test. For the statistical analysis, the statistical software SPSS Version 20.0 for windows  was used. P-values of 0.05 or less were considered statistically significant.Among the 120 patients that suffered from the acute coronary syndrome, 46 (38.3%) faced increased levels of hs-CRP. The inclusion criterion is ACS (acute coronary syndrome). There are almost very rare confounding factors that do not confuse the sample size, so we decided to not only enter this syndrome. Exclusion criteria include non-cardiac cases that increase or decrease CRP levels, as well as old ECG findings and patients with previous MI.Differences in echocardiographic parameters were seen in the group with increased hs-CRP and normal hs-CRP levels but left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVeDD), the prevalence of heart disease, aortic insufficiency, mitral regurgitation, tricuspid regurgitation as well as ventricular hypertrophy were compared. . RegardiOur study demonstrated a similar abnormal change in echocardiography parameters between the groups with and without serum hs-CRP elevation regarding left ventricular dysfunction, left ventricular hypertrophy, and wall motion abnormality, however, for non-arrhythmic ECG changes, ST-segment elevation indicating STEMI had more significant differences in those in the increased hs-CRP group. On the other hand, an increased level of hs-CRP could be one of the reasons STEMI effectively predicts the occurrence of STEMI, and thus the elevated level of hs-CRP may have a major role in the pathophysiological basis of STEMI. However, the elevation of this biomarker may not have a central role in the occurrence of other non-arrhythmic ECG changes. A similar finding was found in a study by Adler et al. revealed the level of CRP that significantly increased on the second and third day that following the first angina myocardial infarction and ST elevation shown in electrocardiography pattern , in contFor explaining pathophysiological fundaments of inducing STEMI following the elevation of hs-CRP, it has been revealed that acute coronary occlusion that caused myocardial infarction could be determined by complement-mediated inflammation factors and human CRP, indicating this in both human and animal studies, can be responsible for some of this complement activation .Some other mechanisms revealed for this event include increased phosphatidyl inositol 3-kinas activity, upregulated inducible nitric oxide synthase, keratin cell signal transduction pathway, nuclear factor k-B, and up-regulated angiotensin II type 1 receptor in vascular smooth muscle cells and direct production of nitric oxide by endothelial cells resulted in increased production of endothelial–1 also increase of von Willebrand factor which is known to be accompanied by endothelial dysfunction -27. In conclusion, increased levels of serum hs-CRP can effectively be related to the occurrence of STEMI in patients with acute coronary syndrome. The present study could not demonstrate the predictive role of this biomarker for abnormal echocardiographic changes including left ventricular hypertrophy or dysfunction as well as abnormal regional wall motion abnormality probably due to considering a narrow range of hs-CRP (less than 10) or employing a small sample size.


Congenital heart disease is the most common group of congenital pathology. Over the past few decades, advances in surgical treatment have resulted in a rising population of adult patients with repaired complex congenital heart disease. Although the quality of life has greatly improved, a significant proportion of morbidities encountered in clinical practice is now seen in adults rather than in children. These patients often have significant haemodynamic pathophysiology necessitating repeat intervention. CT and MRI are excellent imaging modalities, which help elucidate potential complications that may need urgent management. Although imaging should be performed in specialised centres, occasionally patients may present acutely to emergency departments in hospitals with little experience in managing potentially complex patients. The purpose of this article is to provide an introductory overview to the radiologist who may not be familiar with complex congenital heart disease in adult patients. This educational review has three main sections: (1) a brief overview of the post-operative anatomy and surgical management of the most common complex conditions followed by (2) a discussion on CT/MRI protocols and (3) a review of the various complications and their CT/MRI findings. The population of adult patients with complex congenital heart disease is rising.These patients can present to hospitals with little relevant experience.CT and MRI are excellent diagnostic modalities in elucidating potential complications.There are numerous common complications radiologists should be familiar with.Congenital heart disease is the most common group of congenital pathology. Over the past few decades, advances in surgical treatment have improved long-term outcomes in adult patients with repaired complex congenital heart disease. The average age of patients with adult congenital heart disease (ACHD) is rapidly increasing with a 5–6% rate of annual growth. The estimated prevalence in the adult population is 1.4 million in the United States (US) . AlthougThe purpose of this article is to provide an introductory overview to radiologists who may not be familiar with complex ACHD. In the first section, the surgical management and post-operative anatomy of the most common complex ACHD conditions , D-Transposition of the Great Arteries (D-TGA), and single ventricle defects) will be reviewed. For the purposes of this article, complex ACHD refers to these three pathologies. CT and MRI protocols frequently implemented in repaired complex ACHD as well as associated common complications will be discussed. Complications organised by anatomical areas serve to provide a basis for systematically reviewing any CT or MRI study involving repaired complex ACHD. Given the myriad of conditions and complications present within the spectrum of repaired complex ACHD, extra-cardiothoracic complications are beyond the scope of this article.ACHD may present in two main ways, excluding incidental lesions picked up due to other reasons. Firstly, approximately 10% of ACHD patients may present with unrepaired disease that may have remained undiagnosed or has been previously diagnosed in childhood. The vast majority of these patients have simple ACHD conditions such as septal defects .The second set of ACHD patients who present acutely make up 90% of cases. These are ACHD patients who underwent surgery in childhood and normally have an extensive past surgical history, which is usually documented. The majority of these patients have complex ACHD, and the numbers are increasing as technological and surgical advances afford better survival rates. These patients have significantly altered haemodynamics and a neo-formed cardiovascular circulation due to the complex interventions performed . Their cTOF is the most common type of cyanotic congenital heart disease with an adult prevalence of 28,000 in the US . The claThe vast majority of patients will have been diagnosed and undergone surgical correction in the first year of life . The maiTGA has an estimated prevalence of 9000 adults in the US . There aAdults with D-TGA will have had corrective repair during infancy. Initially, atrial switch procedures, or physiologic repair, were the mainstay of treatment. This involved using a two-way baffle to redirect systemic venous return at the atrial level to the left ventricle (LV) and pulmonary venous blood to the RV. Two variants of this procedure exist—the Senning or Mustard technique . The overall aim of the procedure is to create an atrioventricular discordance in order to correct the circulation of the great arteries Fig.  13, 14], 1413, 1These procedures were superseded by arterial switch procedures, or anatomic repair, in the 1970s as long-term outcomes were better. The aorta and pulmonary trunks are separated. The distal aspects of both arteries are transposed and then anastomosed. Finally, the coronary arteries are translocated to the neo-aorta Fig. . This teSingle ventricle defects can be defined as any anomaly in which there is an abnormal mixture of systemic and pulmonary venous blood associated with atresia or significant hypoplasia of a cardiac chamber. This broad category of congenital heart disease includes hypoplastic left heart, double inlet/outlet ventricular defects, tricuspid atresia, and pulmonary atresia with an intact ventricular septum. Generally, there are several stages of operations performed sequentially during childhood with the objectives of providing continuous systemic outflow, unimpeded venous inflow, and adequate pulmonary blood flow .In hypoplastic left heart syndrome, which is the prototypical version of a univentricular heart, a three-staged surgical approach that culminates in a Fontan-type circulation has become common practice. The first stage is called the Norwood procedure Fig. , which iThe second surgery (stage 2) aims to create a superior cavopulmonary anastomosis. The goal of this anastomosis is to reduce the preload on the single ventricle by connecting the superior vena cava (SVC) to the pulmonary arteries. The bi-directional Glenn procedure involves dissection of the SVC near or at its junction with the right atrium, closing off the atrial end, and creating an end-to-side anastomosis between the SVC and the right pulmonary artery Fig. a. Of hisThe third surgery (stage 3) is the completion of the Fontan circulation, which allows venous blood returning from the body to flow directly into the lungs, effectively excluding the RV. The main aim is to connect the inferior vena cava (IVC) to the branch pulmonary arteries. These staged procedures may be performed for any of the single ventricle defects. There are three main variations of the Fontan surgery: atriopulmonary Fig. a, lateraCT is an excellent imaging modality for use in the acute setting due to its rapid acquisition times and high resolution. The latest generation of CT scanners yield a spatial resolution of less than 0.5 mm compared to 0.8–1.5 mm for MRI . A signiTo image small cardiac structures and to reduce motion artefact, breath holding has become common practice within cardiac imaging . On a siThe best location of a peripheral intravenous (IV) line is in the right antecubital fossa. Contrast injection protocols should be adapted according to patient weight. In adults, approximately 1.5 mL/kg injected at a rate of 3–5 mL/s is ideal. To further reduce artefact from undiluted contrast material, a saline bolus chasing protocol should be used. This protocol also increases the injection time, which improves the chances of obtaining adequate contrast enhanced images , 27.A dual- or single-phase injection protocol is suggested for pulmonary or systemic arterial angiography. Dual phase with single acquisition involves contrast administration at a constant rate followed by saline. In patients with repaired TOF or post-arterial switch for D-TGA, simultaneous pulmonary and aortic contrast opacification to visualise right and left heart structures requires a more complex approach such as a triphasic protocol. A triphasic, single acquisition protocol involves administering contrast during the first phase, a 50:50 contrast to saline mix in the second phase, and saline in the third phase all while keeping the injection rate constant. Alternatively, the contrast dosage can be halved so that the first half is administered at the arterial rate, the other half at a slower rate, and then followed by saline . A delayIn patients with a Fontan circuit, contrast injection protocols can be more complicated and can vary by institution. If a standard CT pulmonary angiogram protocol is performed in a patient who has a Fontan circuit, a pseudoembolism or pseudothrombus may be demonstrated due to the early acquisition time. The contrast will usually flow into the right main pulmonary artery from the SVC and very little in the left pulmonary artery if the cannula is in the right antecubital fossa. The unopacified blood travels through the IVC or right atrial connection before entering the pulmonary trunk. The poor enhancement of the left main pulmonary artery relative to the well opacified right main pulmonary artery causes a pseudothrombus appearance . AlthougA cannula in the arm and leg can be considered to rectify this problem although it is not necessary. A single contrast phase, delayed phase acquisition (80–100 s) protocol may sometimes be adequate enough to allow the systemic contrast enough time to return to the IVC and opacify the left main pulmonary artery with the use of more contrast than usual. For example, a total amount of 600–800 mg/kg iodine can be used in this case Fig. . HoweverOptimal scan acquisition timings can be obtained from bolus tracking or a test bolus. In bolus tracking, a region of interest (ROI) is first determined, which is usually the ascending aorta. After contrast injection, scan acquisition triggers once the predetermined Hounsfield unit (HU)  at the ROI has been reached. The bolus tracking technique is suggested only when the cardiac and great vessel anatomy is normal. For lower kV scanning, the HU trigger should be modified and increased accordingly to avoid early scan acquisition caused by the higher contrast opacification , 27, 28.ECG synchronisation is not necessary in all patients with repaired complex ACHD. However, ECG synchronisation is advised to reduce motion artefacts or to visualise small intracardiac abnormalities. In retrospective ECG gating, images are obtained continuously throughout the cardiac cycle. The best quality studies are acquired using this method since images can be reconstructed with little motion artefact throughout the cardiac cycle. The major disadvantage is a greater degree of radiation dose exposure compared to prospective ECG gating. Therefore, this method should be limited to patients with significant arrhythmias and patients with elevated heart rates, or when functional data are needed. In prospective ECG triggering, images are obtained at a fixed point or window during the cardiac cycle. This is usually during mid-systole or mid-diastole and is commonly known as the “step-and-shoot” technique. The radiation dose is less using this method compared to retrospective gating. The drawback is that the method is heavily reliant on a regular rhythm , 27. HowMRI is a good modality for assessing ventricular function and for quantifying blood flow . SpecifiAnatomic assessment of the heart is fundamentally based on the use of bright- or dark-blood pulse sequences. Dark-blood imaging consists of pulse sequences, which null the blood pool resulting in low signal intensity of fast flowing blood. In turn, this improves visualisation of surrounding cardiac structures. Conventional spin echo sequences, usually used in dark-blood imaging, have been superseded by newer techniques such as turbo spin echo and half-Fourier single-shot turbo spin echo sequences. The advantage of these newer rapid sequences in minimising cardiac motion artefact outweighs the fact that they offer lower signal-to-noise ratio when compared to conventional spin echo sequences. Dark-blood imaging should be performed prior to the administration of gadolinium contrast as gadolinium affects the nulling of the blood signal and results in unwanted artefact. Bright-blood imaging denotes the high signal intensity of fast flowing blood when using associated pulse sequences such as gradient-recalled echo (GRE) sequences or balanced steady-state free precession (SSFP) sequences. Bright-blood imaging is primarily applied to assess cardiac function, but is also frequently used for the assessment of anatomy. The advantages of using SSFP sequences when compared to GRE sequences are that they can be performed rapidly as well as allow higher-contrast and signal-to-noise ratios. Stacks of dark- and bright-blood images are acquired through the target of interest in the axial, sagittal, and coronal planes , 30. NewDynamic imaging consists mainly of cine two-dimensional SSFP imaging. Cine MRI produces a video sequence of the heart in a single predetermined plane. This allows for the evaluation of valvular and ventricular function as well as shunt detection. The standard planes taken vary greatly according to the clinical question, the ACHD type, as well as the type of repair that has taken place. Any combination of short-axis, long-axis, and specific chamber views can be taken according to preference and protocol, which may vary by institution. However, additional planes should be taken to assess for specific circumstances. For example, views through the RVOT or coronal views may be obtained depending on the specific heart defect. Additionally, Cine MRI can be employed to subjectively assess valve movements and to detect regurgitant or stenotic jets at the area of interest , 30.Blood flow quantification analysis is typically obtained using 2D cine phase-contrast (PC) MRI with velocity-encoded imaging. PC MRI imaging acquires both long- (in-plane imaging) and short-axis planes (through-plane imaging) of vessels and allows flow to be calculated as a product of area and pixel velocity in the through-plane acquisitions. Normally, through-plane imaging is used to calculate flow volumes, including regurgitant fractions and velocities at selected planes, while in-plane imaging is used to detect stenosis along the long axis of the jet in the affected vessel or chamber. Of note, velocity range (encoding) should be appropriately selected for the expected velocity in the vessel: for example, unobstructed venous flow would require encoding of 100 cm/s, while an unobstructed aortic flow would typically have velocity encoding of 150 cm/s. The general recommendation is to use the velocity that is approximately 25% higher than the expected value, and any aliasing artefact should be corrected with encoding adjustments . PC MRI Gadolinium contrast-enhanced MRI angiography can clarify aortopulmonary, venovenous collaterals, and arteriovenous malformations. This is especially useful when assessing for small collateral vessels that may be present in certain ACHD conditions such as arteriovenous malformations and SPCs in Fontan circulation patients (discussed in more detail later). The dose of contrast varies; however, 0.1 mmol/kg is adequate for the majority of applications and can be adapted as necessary. Contrast is injected intravenously through a cannula at a variable rate (0.5–4.0 mL/s). Conventional three-dimensional imaging can be performed with or without ECG triggering. ECG-triggered imaging is preferred to minimise artefact from cardiac motion , 30.For thrombus assessment in ACHD, the best approach is to use an early gadolinium phase (within the first minute after contrast injection) inversion recovery sequence with a long inversion time (500–600 ms) to distinguish between thrombus and tumour. Additional late enhancement imaging, according to circumstance, can be used to assess for fibrosis. Late gadolinium enhancement (10–15 min following administration) of myocardium with an inversion recovery sequence may occur in a subendocardial or transmural pattern, representing infarction or in non-ischaemic patterns, representing fibrosis. The TI is predetermined to ensure that imaging results in myocardium that appears black and areas of fibrosis appear bright , 35.Heart failure is the leading cause of morbidity in ACHD. An isolated rise in natriuretic peptides has been demonstrated in up to 53% of ACHD patients. The hospitalisation rate for symptomatic heart failure is approximately 1.2 per 1000 patient-years .In repaired complex ACHD, RV dysfunction is common. In patients who have had definitive TOF repair, pulmonary valve insufficiency leading to right heart failure is the most common long-term complication. The most significant issue with the atrial switch approach for D-TGA is creating a circuit with the RV and tricuspid valve opposing the systemic circulation. The RV is not morphologically designed to withstand long-standing high pressures; therefore, late RV failure and tricuspid regurgitation are expected in this patient group . In the Cross-sectional imaging findings of LV heart failure develop in a progressive manner. In stage 1, also known as the redistribution stage, cardiomegaly and an increased artery-to-bronchus ratio may be seen. Stage 2 is characterised by interstitial oedema from leaking fluid into the interlobular interstitium as a result of increased pressure in the capillary bed. Interstitial oedema manifests as peripheral septal (Kerley B) lines and interlobular septal thickening on cross-sectional imaging. In stage 3 alveolar oedema, perihilar groundglass opacity progressing to consolidation with bilateral pleural effusions is characteristic . IsolateStandard MRI protocols using SSFP sequences provide anatomic and volumetric information in the assessment of suspected congestive cardiac failure including the degree of volume overload. In addition to hypokinetic and dyssynchronous motion of the ventricle(s), other qualitative measures may be scrutinised such as interventricular septal motion. In patients with right heart failure, the interventricular septum may be shifted towards the LV in the context of RV dilatation Fig. . QuantitThe risk of infective endocarditis (IE) in patients with ACHD is substantially higher than in the general population. In ACHD, the incidence is around 1.1 per 1000 patient-years. IE accounts for up to 4% of admissions to a tertiary ACHD centre, with an associated mortality of approximately 4%. IE may occur in unrepaired, palliated, or corrected defects . Adults The pathogenesis in repaired complex ACHD is multifactorial. Mechanical disruption of the valvular or cardiac endothelium due to surgery and the resultant altered flow haemodynamics can trigger the beginning of a significant inflammatory cascade. This response results in the production of inflammatory cytokines, which facilitates bacterial adherence and triggers an immune response. Furthermore, endothelial inflammation activates integrin expression on endothelial cells. Integrins bind circulating fibronectin and promote adhesion of circulating staphylococci. Eventually, vegetation fragments of damaged endothelium can break off and embolise to the lungs and systemic circulation if a residual intracardiac shunt is present .On CT, endocarditic vegetations demonstrate hypoattenuating filling defects surrounded by contrast material. Cardiac CT angiography can also demonstrate the integrity of the valve and any complications such as pseudoaneurysm or fistula formation. If there is progression to septic emboli in the lungs, then the feeding vessel sign, subpleural nodule or wedge-shaped densities with or without cavitation may occur Fig. . The appSignificant dilatation of the aortic root is a known phenomenon in complex ACHD even after repair occurs . AlthougThe primary intrinsic cause associated with aortopathy in repaired complex ACHD is due to progressive aortic medial degeneration (defined as thinning and fragmentation of the elastic fibres of the aorta), seen in a milder extent than in connective tissue disorders such as Marfan’s. However, specific risk factors in addition to intrinsic medial degeneration are contributory causes. Patients who have had definitive TOF repair are at an increased risk of developing progressive aortic dilatation if there is associated pulmonary atresia and a right-sided aortic arch. Prior pulmonary artery banding and the presence of a VSD are known contributory factors in D-TGA post-arterial switch Fig. . FailurePulmonary arterial hypertension (PAH) is defined as a mean pulmonary arterial pressure of 25 mmHg or greater. It is estimated that the prevalence of PAH in ACHD is approximately 10%. Of the five main classifications of PAH, ACHD is classified as Type I  .The pathophysiology of PAH in complex repaired ACHD varies according to the type of condition present as well as the magnitude of any residual systemic to pulmonary shunts that exist. Moderately sized systemic-to-pulmonary residual VSD shunts (post-TOF repair or post-Rastelli repair for D-TGA) can lead to volume overload of the pulmonary circulation and eventual right heart failure as described previously. Muscular hypertrophy, intimal pulmonary artery thickening and the development of plexiform lesions are expected histological findings when PAH has become established . Even afDirect cross-sectional vascular findings of long-standing PAH include an enlarged pulmonary trunk, pruning of peripheral pulmonary vessels, and mural calcification. Secondary features that may suggest a degree of PAH includes findings in keeping with right heart strain: RV hypertrophy/dilatation and bowing of the interventricular septum, dilatation and reflux of contrast into the IVC and hepatic veins. Lung parenchymal signs include a mosaic lung attenuation pattern Fig.  52]. MR. MR52]. Patients with a significant impendence to flow due to resistance within the Fontan circuit may decompress through arterial or venous collaterals to the lower pressure pulmonary veins or left atrium. Venous collaterals may develop in several locations including the bronchial veins and the venae cavae as well as between the upper-limb veins and pulmonary venous system. Collaterals forming in these areas result in right-to-left shunts, which serve to naturally lower the pressure within the Fontan circuit in order to maintain ventricular preload. These patients are also at increased risk of developing pulmonary arteriovenous malformations. Lack of hepatic venous effluent and the slow non-pulsatile flow state of the Fontan circuit are both considered to be underlying mechanisms in their formation. Pulmonary arteriovenous malformations can occur even before Fontan circuit completion, when the superior cavopulmonary anastomosis is formed due to unilateral hepatic venous flow from caval offset. The primary consequence is decreased systemic oxygen saturation due to right-to-left shunting , 31, 37.Airway obstruction is often the result of the distorted anatomy in ACHD patients who have undergone complex surgical repair or due to the development of complications. Extrinsic compression caused by surrounding vascular structures such as dilated pulmonary arteries or due to cardiomegaly can occur. For example, in patients with repaired TOF, airway stenosis or obstruction may occur secondary to significantly dilated pulmonary arteries proximal to an area of branch pulmonary stenosis. If the left atrium is markedly dilated, splaying of the carina and compression of the main bronchi can be demonstrated . FurtherPlastic bronchitis is a relatively rare complication after Fontan correction with less than 1% developing this complication. Onset occurs from as early as one month to two decades after Fontan completion. It is characterised by formation of gelatinous plugs in the large airways that take the shape of bronchial casts due to chronically elevated lymphatic pressures. The acellular casts produce plugs of mucous in the tracheobronchial airway. Intrathoracic pressures increase as a result leading to interstitial pulmonary lymphoedema. Cross-sectional CT imaging often demonstrates indirect signs of plastic bronchitis such as groundglass change, consolidation and/or atelectasis Fig. . OccasioThere are several specific complications which may be seen in adults who have undergone surgical correction for TOF as children, including residual RVOT obstruction, pulmonary regurgitation, residual pulmonary artery stenosis, residual shunts (commonly VSD), and re-entrant atrial arrhythmia potentially resulting in thrombosis. A complication associated with transannular patch repair in TOF is aneurysmal dilatation of the RVOT. In patients who have had a RV to pulmonary artery conduit placed, additional complications such as conduit stenosis, calcification, and regurgitation should be actively considered before issuing a report Fig.  42].Fig.Fig42].F2D SSFP cine MRI, which is in plane with the RVOT, in addition to the standard planes, should be acquired to assess for RVOT obstruction, aneurysmal dilatation, or a pulmonary regurgitant jet and through the conduit (if present) to assess for stenosis Fig. . AdditioThe intra-atrial baffles created during the atrial switch procedure for D-TGA may become significantly narrowed or occluded as the patient grows. Baffle stenosis is more commonly seen in the superior vena cava limb, which is thought to be due to the constricted anatomy between the baffle and right atrial appendage. Small leaks in the constructed baffles, which most commonly present as a left to right abnormal flow, may also be present. Often, these are haemodynamically insignificant and can be compared to small shunts that occur in septal defects. CT can help detect stenotic areas and visualise leaks; however, it cannot quantify flow or severity. Stacks of coronal oblique and short-axis SSFP Cine or angiographic MRI images through the atria can allow for detection of baffle leaks and stenosis Fig. . FurtherIn patients who have had an arterial switch procedure, the most common complications are supravalvular and branch pulmonary artery stenosis (left more common than right) due to post-surgical manipulation of the pulmonary trunk to anastomose it to the former aortic root. There is also a considerable risk of coronary ostial stenosis and resultant ischaemia due to coronary artery translocation during surgery. Neo-aortic root dilatation may result in significant aortic regurgitation. Assessment of ventricular function using standard 2D SSFP cine sequences through the heart and both ventricular outflow tracts in addition to stack images in the short axis allows for adequate visualisation of potential complications and regurgitant/stenotic jets. Specifically, SSFP cine MRI oblique axial stacks through the main pulmonary arteries can be useful in detecting stenotic areas, and 3D SSFP sequences or a dedicated CT coronary angiogram can assess for coronary ostial stenosis Fig.  38, 58], 5838, 5Specific complications related to the Fontan circuit, whether it involves the extra-cardiac conduit or a lateral tunnel baffle used in the modified Fontan procedure, are due to the breakdown and growth-related senescence of these pathways. Thrombosis, leak, and stenosis are known complications Fig.  37]. Th. Th37]. For thrombus detection for all three types of repaired complex ACHD, CT angiography will show filling defects within the cardiac chambers and pulmonary vasculature, which do not enhance Fig.  60]. MR. MR60]. Basic knowledge and understanding of the most common appearances of the heart after repair in complex ACHD is a crucial first step in analysing images presented to the radiologist unfamiliar with repaired complex ACHD. Furthermore, knowledge of basic protocols used in CT and MRI allows for optimal and targeted assessment of relevant complications. By implementing a systematic checklist using key anatomical areas to identify the most common complications in repaired complex ACHD, the most relevant findings can then be reported in a meaningful manner that helps answer the referring clinician’s question. Table


Left ventricular ejection fraction (LVEF) is universally accepted as a cardiac systolic function index and it provides intuitive interpretation of cardiac performance. Over the last two decades, it has erroneously become the leading feature used by clinicians to characterize the left ventricular function in heart failure (HF). Notably, LVEF sets the basis for structural and functional HF phenotype classification in current guidelines. However, its diagnostic and prognostic role in patients with preserved or mildly reduced contractile function is less clear. This is related to several concerns due to intrinsic technical, methodological and hemodynamic limitations entailed in LVEF measurement that do not describe the chamber’s real contractile performance as expressed by pressure volume loop relationship. In patients with HF and preserved ejection fraction (HFpEF), it does not reflect the effective systolic function because it is prone to preload and afterload variability and it does not account for both longitudinal and torsional contraction. Moreover, a repetitive measurement could be assessed over time to better identify HF progression related to natural evolution of disease and to the treatment response. Current gaps may partially explain the causes of negative or neutral effects of traditional medical agents observed in HFpEF. Nevertheless, recent pooled analysis has evidenced the positive effects of new therapies across the LVEF range, suggesting a potential role irrespective of functional status. Additionally, a more detailed analysis of randomized trials suggests that patients with higher LVEF show a risk reduction strictly related to overall cardiovascular (CV) events; on the other hand, patients experiencing lower LVEF values have a decrease in HF-related events. The current paper reports the main limitations and shortcomings in LVEF assessment, with specific focus on patients affected by HFpEF, and it suggests alternative measurements better reflecting the real hemodynamic status. Future investigations may elucidate whether the development of non-invasive stroke volume and longitudinal function measurements could be extensively applied in clinical trials for better phenotyping and screening of HFpEF patients.  Since the beginning of the last century, heart failure (HF) has been recognized as ‘a condition in which the heart fails to deliver its contents adequately’ . In 19622 and LVEF <45% on echocardiography with sign and symptoms typical for heart failure (HF)  level ≥ 100 pg/mL, or an N-terminal pro-BNP [NT-proBNP] level ≥ 360 pg/mL . DespiteSubsequently, a multicenter, randomized, double-blind, parallel group, active-controlled study was designed to evaluate the efficacy and safety of LCZ696  angiotensin renin neprilysin inhibitors (ARNI) compared to Valsartan in HFpEF (PARAGON-HF) . The stuNotably, the high cut-off of NT-proBNP at enrollment was based on evidence that in the I-PRESERVE trial the plasma high concentration of the peptide was linked to the worse outcome. On the other hand, the study sample size was calculated through simulations for the proportional rates model, and the candesartan group of the CHARM-Preserved study, involving patients with EF ≥ 45%, provided the rates for statistical assumption. That decision seemed to contradict the adopted rigorous patient selection criteria, since in the CHARM-Preserved trial the LVEF value was adopted as an entry criterion at the time of enrollment without evaluating previous measurement. Therefore, the medical therapy did not include beta blockers and minaral corticoid receptor antagonists (MRA); conversely, digitalis was prescribed as a first line therapy. p = 0.06) [The study randomized 4822 patients  to receive sacubitril valsartan or valsartan, and narrowly missed the combined primary endpoint to decrease HF hospitalization and CV death  . The study’s subgroups analysis for the composite primary endpoint amazingly addressed female gender (RR 0.73: CI 0.58–0.90) and patients with LVEF ≤ 57% (RR 0.78: CI 0.64–0.95). The benefit size in both subgroups was comparable to that achieved by the HFrEF population investigated in the PARADIGM HF study (RR 0.79: CI 0.71–0.89) , highligOne question that remained unanswered was what would be the response of HF patients presenting LVEF higher than 57% when HFrEF effective therapies were adopted. In the case of the absence of systolic dysfunction, the literature addresses the issue that beta-blocker treatment does not provide significant benefit ,24.A striking benefit was displayed by the sodium-glucose cotransporter inhibitors (SGLT2i) in HFrEF diabetic and non-diabetic patients with high CV risk . There w2 or ≥60 mL/min/1.73 m2, and LVEF cut-off subgroups for the efficacy end points <50%, between 50–60%, and >60% [The trial design aimed to demonstrate the superiority of empagliflozin 10 mg versus placebo in patients with symptomatic, chronic HFpEF, addressed by the LVEF > 40%, and under stable treatment of HF symptoms. In the protocol, the patient randomization had to be stratified by the following factors: status of diabetes at screening, eGFR (CKD-EPI) at screening <60 mL/min/1.73 mand >60% .The decision to make the change was probably driven by the publication of the combined data from PARADIGM-HF  and PARAGON-HF  in a prespecified pooled analysis at the end of 2020 . In the 2. The main study end point based on CV disease and HF hospitalization was successfully achieved , and this was the first time a drug therapy reached the goal in an HFpEF study [The EMPEROR Preserved study was performed on 5988 patients, aged 72 years, women were 45%, the median LVEF was 54%, nearly half of the patients had diabetes and half had eGFR reduction below 60 mL/min/1.73 mEF study .According to the prespecified baseline LVEF subgroups, the best therapy benefit was achieved in the cluster with LVEF < 50% , while the benefit was attenuated in patients with LVEF 50 to <60%  and was not evident in the subgroup with LVEF ≥ 60% . In a further pooled analysis performed on both the EMPEROR-Reduced and EMPEROR-Preserved trials, patients were grouped based on LVEF: <25% (n = 999), 25–34% (n = 2230), 35–44% (n = 1272), 45–54% (n = 2260), 55–64% (n = 2092), and ≥65% (n = 865). The analysis showed that the magnitude of the effect of empagliflozin on HF outcomes was similar in patients with ejection fractions <25% to <65%, but it was attenuated in patients with upper values .A potential limit of EMPEROR-Preserved was due to the relative minority of female gender, and the low NYHA class in the investigated population. Additionally, the lack of benefits of empagliflozin for overall mortality was observable . These items reinforced the post hoc PARAGON-HF study message that in elderly subjects with HF symptoms, CV death is more frequent among those in the lower LVEF range, whereas other conditions increasingly affect the survival of subjects with higher LVEF values . 2, requiring diuretic treatment or recent hospitalization or urgent visit requiring IV therapy or evidence of structural abnormalities at echocardiography [Finally, the DELIVER trial evaluated 6263 patients with LVEF > 45%, NT-proBNP levels > 225 pg/mL, or 375 pg/mL in patients with atrial fibrillation, with GFR > 25 mL/min/miography . Demograiography . During Subgroup analysis revealed that the benefit was consistent beyond the presence of diabetes and impaired renal function . TherefoDifferently from previous trials, the DELIVER study design included data showing that risk reduction was maintained across all LVEF range; however, authors did not report if the benefit was related to reduction of total CV events, HF events, or both, in subjects with LVEF > 60%. Altogether, the findings on SGLT2i raise some burning questions: Despite identical results on major events for both empaglifozin and dapaglifozin, what is the LVEF threshold providing patient benefit? In the upper LVEF values, was risk reduction related to a decrease in HF hospitalization or total mortality? And, are the positive drug effects consistent across all LVEF cut-offs irrespective of renal function? Although LVEF is the main feature for HF categorization, it has relevant mechanistic, methodological and intrinsic limitations.LVEF is the most common practical measurement to assess cardiac pump function, and for this reason it is recognized as the hallmark for systolic function classification. Notably, LVEF offers some advantages related to its ease of use, its wide application in clinical practice and study research, the short scan time, and its feasibility . TherefoMoreover, LVEF provides the basis for structural and functional phenotype classification, and it is particularly useful in patients with reduced systolic function ,37. HoweSince LVEF is a load-dependent measure, it is prone to changes in preload and afterload. Of note, the elevation or reduction in both systemic blood pressure or vascular stiffness can result in relevant LVEF changes . ConversBeyond these methodological observations, systolic function was initially calculated measuring stroke volume divided by end diastolic volume. This approach takes into consideration both a parameter of ejected flow and LV remodelling. Since LVEF calculated with the traditional method is simply the ratio between LV end diastolic volume (EDV) and LV end systolic volume (ESV), it significantly decreases when EDV is in the normal range or in LV concentric hypertrophy. Conversely, in LV eccentric remodelling, in which EDV enlargement acts as compensatory mechanism, LVEF is maintained into the normal range in the presence of identical ESV dilatation. Thus, impaired LVEF does not necessarily imply a reduced stroke volume, although LVEF impairment is often associated with an increase in LV filling pressure ,44.These assumptions prove that LVEF is not necessarily related to the cardiac output, and it has been erroneously considered as an indicator for LV remodelling. Indeed, an enlargement of diastolic dimension works as a compensatory factor in order to maintain an adequate stroke volume even during the occurrence of increased systolic volume ,46. NotaDespite LVEF being considered a measurement of systolic function, it really measures only radial contraction without measuring both longitudinal and circumferential contractility, representing two important features of the whole systolic performance. Accordingly, several studies including patients with preserved LVEF have shown significant longitudinal global function impairment, despite preserved ejection fraction ,49. The The most common modality of LVEF measurement is provided by echocardiography, adopting the biplane Simpson calculation. It is recognized as the most reliable method with a good relationship to the angiography measurement ,51. ThisSince HF is a transitional syndrome, LVEF may change across a patient’s history according to disease destabilization and hemodynamic fluctuations.ESC guidelines, and more recently ACC recommendations, have confirmed a new HF categorization theoretically capable of identifying patients with mildly reduced ejection fraction in which the cut-off ranges from 40 to 49% ,55. IndeThe retrospective analysis of the DIG trial demonstrated that HFmEF resembled patients with HFrEF in terms of mean age, sex and ischemic aetiology . In the Recent interventional trials and metanalysis have demonstrated a trend towards outcome improvement, and current findings are mainly related to total cardiovascular event reduction.HF is a syndrome with continuous disease progression and evolution related to functional and structural cardiac and extra-cardiac changes. Current knowledge leads to a wide phenotype spectrum with frequent overlapping . A novelHFpEF syndrome, characterized by an interplay of genetic predisposition, lifestyle factors and high burden of associated comorbidities, is proof that other parameters  matter more than LVEF .SGLT2i treatment has been demonstrated to improve CV outcomes in patients with HF over a wide range of LVEF, regardless of diabetic status, and has a strong reno-protective effect .Results from the DELIVER  and EMPERegarding the effects of therapy combinations across the LVEF spectrum, by using pooled data from PARADIGM-HF  and PARAData derived from DELIVER  and EMPEThe SGLT2i are reno-protective and vascular-protective, and kidney effects seem to predominate over all the other mechanisms of action.The benefit of SGLT2i goes beyond glycemic control, since inhibition of renal glucose reabsorption affects blood pressure and improves the hemodynamic profile and the tubule glomerular function . SGLT2i The improvement in renal function may justify the reduction in adverse outcomes in patients with or without HF, supporting the results of clinical trials. In fact, the efficacy of SGLT2i was mainly linked to the reduction in renal damage, as highlighted by the significant reduction in global mortality in the studies on diabetic and non-diabetic populations with advanced chronic kidney disease (CKD) . A renalUnlike traditional loop diuretics such as furosemide leading to a neurohormonal activation, natriuresis derived from Empagliflozin is not associated with neurohormonal activation or potassium loss or renal impaired function, and is usually associated with an improvement in uric acid levels. This favorable diuretic profile provides an important advantage in the management of patients with HFrEF and HFpEF and could partly explain the better long-term HF outcomes .The benefits of SGLT2i may also be due to favorable fatty acid, glucose uptake and metabolic effects on LV. The direct effects of SGLT2i on the endothelial and vascular function may contribute to hemodynamic effects . There aLVEF remains a universal parameter employed for macroscopic HF categorization but it contains several methodological and hemodynamic weaknesses. Recent trials have demonstrated that the benefit of treatment is consistent regardless of the LVEF value.The dynamic nature and ambiguity of HF requires repetitive assessment, looking at disease temporal changes depending on the natural history of diseases and the response to therapy. Additionally, traditional and new drugs may have different positive effects on HFpEF patients; in those with borderline LVEF, the risk reduction is related to an effective decrease in HF events, whereas in patients with higher LVEF values, the main benefit is due to a decrease in CV events. Because of these findings, future research may shift to different and more reliable cardiac functional parameters. Therefore, cardiac dysfunction should be assessed within a larger context, looking at the underlying causes of HF, its temporal trend and cardio-renal axis status.


The mechanism through which sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent the incidence of heart failure and/or affect cardiac structure and function remains unclear.The EMPA-HEART trial is aimed at verifying whether empagliflozin improves myocardial contractility  and/or cardiopulmonary fitness  in subjects with type 2 diabetes (T2D) without heart disease. Patients with T2D, normal LV systolic function (2D-Echo EF > 50%), and no heart disease were randomized to either empagliflozin 10 mg or sitagliptin 100 mg for 6 months and underwent repeated cardiopulmonary exercise tests with echocardiography and determination of plasma biomarkers.vs sitagliptin: + 0.44; [− 0.10/+ 0.98]%, p = 0.11) and 6 months of therapy , or in VO2peak . With empagliflozin, the subgroup with baseline LV-GLS below the median experienced a greater increase (time*drug p < 0.05) in LV-GLS at 1 month  and 6 months , while sitagliptin induced a modest improvement in LV-GLS only at 6 months .Forty-four patients completed the study, 22 per arm. Despite comparable glycaemic control, modest reductions in body weight  and plasma uric acid , as well as an increase in haemoglobin  were evident with empagliflozin. No difference was detectable in either LV-GLS at 1 month  it produces a rapid and sustained amelioration of LV contractility.Trial registration EUDRACT Code 2016-002225-10The online version contains supplementary material available at 10.1186/s12933-022-01618-1. In subjects with type 2 diabetes mellitus (T2D) and at high cardiovascular risk, hospitalization for heart failure (HF) were reduced by 30–40% already after 6 months of treatment with empagliflozin independently from the presence of established HF at baseline . NonetheThe difficulty in accruing clinical evidence in support for these hypotheses is possibly due to the inadequacy of the experimental design and/or of the methods employed to measure cardiopulmonary function with the necessary precision. Imaging cardiopulmonary exercise test (iCPET), being a powerful multiparametric technique capable of providing simultaneous measures of metabolic, pulmonary, cardiac, muscular, and vascular variables both at rest and during graded exercise , qualifiBy using iCPET, this study aimed at verifying whether the treatment with empagliflozin is associated with an improvement in cardiac systo-diastolic functions and/or in cardiopulmonary fitness in asymptomatic T2D patients without overt heart disease and normal LV ejection fraction (LVEF > 50%). To account for the potential positive effects of improved glycemic control, we used sitagliptin as an active control, an equally effective glucose-lowering agent that has been shown to be neutral on the prevention of HF-related events . As pre-1c 7.0–8.5%) were randomized to either Sitagliptin 100 mg or Empagliflozin 10 mg. Exclusion criteria were: (a) impaired kidney function (CK-EPI eGFR < 50 mL/min/1.76m2), (b) any heart disease defined as presence of clinically relevant cardiovascular symptom, cardiac or vascular disease or valvular defects, history of coronary artery disease or evidence of stress-induced ischemia, reduced (≤ 50%) 2D LV ejection fraction (LVEF), cardiac autonomic neuropathy, (c) any pulmonary, muscular, or orthopedic diseases potentially limiting exercise capacity. As pre-specified exploratory analysis, we evaluated whether the effect of the treatments on myocardial contractility differs in the subgroup of patients with more pronounced abnormalities at baseline (LV-GLS below the median) and whether there are treatment-related differences in the following plasma biomarkers: (a) inflammation: tumor necrosis factor-alpha (TNFα) and high-sensitive c-reactive protein (hsCRP); (b) oxidative stress: myeloperoxidase (MPO); (c) LV parietal stress: natriuretic peptides (BNP and NT-proBNP), pro-adrenomedullin (proADM); (d) cardiomyocyte damage: high-sensitive troponin T (hsTnT); and (e) extracellular matrix remodeling/fibrosis: procollagen (NT-PRO3). The rationale, study design, and the methods of the study have been previously described in detail  and by ANOVA for repeated measure on the whole data set; considering the time*drug interaction effect. All tests were conducted at a two-sided  α level of 0.05.Analyses were performed using JMP Pro software version 13.2.1 . Values are presented as mean ± SD, or as median and interquartile range (IQR), for variables with normal and non-normal distribution, respectively. Comparisons between treatment groups were performed by the Student t-test for unpaired data for continuous variables and by the chi-square test for categorical variables. Variations from baseline to follow-up in the parameters in each of the two groups were presented as mean and [95% CI], the effect of the therapy at each follow-up assessment  was assessed by According to inclusion and exclusion criteria, 106 consecutive patients were screened for the study from December 2017 to July 2020; after baseline evaluation, 37 were subsequently excluded because of definitive exclusion criteria and 13 did not participate for personal reasons. The recruitment was interrupted earlier due to lock-down imposed by COVID-19 pandemic. Fifty-six T2D subjects meeting the definitive inclusion/exclusion criteria were randomized to intervention, of which 27 were allocated to treatment with Empagliflozin 10 mg/die, and 29 to Sitagliptin 100 mg/die. During the follow-up, 3 patients abandoned the study for personal reasons and 1 patient in the Empagliflozin arm because of side effects . At follow-up, 8 further patients were excluded because of suboptimal echocardiography images and/or incomplete or unreliable follow-up CPET data. The analysis was performed on 44 subjects, 22 in the Empagliflozin arm and 22 in the Sitagliptin arm. Patient disposition with the Consort 2010 flow diagram is shown in Additional File Baseline characteristics of the study population are reported in Table 1c while an increase in plasma hemoglobin and hematocrit and a reduction in plasma uric acid were observed with empagliflozin. The remaining hematologic parameters  did not differ from baseline to follow-up in either group . From baseline to 1- and 6-months follow-up, no change in resting LV-GLS was seen in any of the treatment groups  in LV-GLS was comparable in the two treatment arms both at baseline  and at 6 months follow-up (+ 1.4 [+ 0.6/+ 2.1] vs + 2.0 [+ 1.2/+ 2.7]%). Likewise, cardiac chamber dimensions and/or geometry were not affected by either treatment, as well as Doppler and tissue-Doppler derived systo-diastolic indices  and SVR , as was comparable the achieved peak workload (118 ± 25 vs 119 ± 22 W). From baseline to 6 months follow-up, no change in VO2peak was seen in any of the treatment groups  were within the normal range and no change was observed at 6 months follow-up in either treatment arm or between the treatments. Specifically: hsCRP (mg/dL) from 0.114 [0.026–0.216] to 0.095 [0.048–0.153] with empagliflozin, from 0.177 [0.090–0.762] to 0.156 [0.081–0.405] with sitagliptin. BNP (pg/mL) from 25 [10–47] to 16 [10–46] with empagliflozin, from 12 [10–25] to 11 [10–20] with sitagliptin. TnHS (ng/mL) from 9.9 [6.7–16.4] to 10.0 [7.6–13.9] with empagliflozin, from 7.8 [5.8–27.0] to 8.2 [6.6–15.2] with sitaglitpin. ProADM (nmol/L) from 0.080 ± 0.065 to 0.150 ± 0.120 with empagliflozin, from 0.154 ± 0.198 to 0.119 ± 0.130 with sitagliptin. NT-PRO3 (ng/mL) from 5.6 [4.4–6.7] to 5.6 [4.0–7.7] with empagliflozin, from 6.7 [5.1–8.9] to 6.2 [4.7–7.6] with sitagliptin. TNFα (pg/mL) from 0.74 [0.46–0.96] to 0.79 [0.69–0.96] with empagliflozin, from 0.67 [0.59–0.88] to 0.80 [0.66–0.93] with sitagliptin. All p values > 0.05.t-test were + 0.92 [− 0.04/+ 1.89]% (p = 0.05 for 2-side and p = 0.03 for one-side superiority of empagliflozin) at 1 month and was maintained at 6 months . The ANOVA for repeated measures detected a significant effect for the interaction term time*drug (p = 0.04) as well as for the drug (p = 0.02) and for time (p < 0.0001) alone.As prespecified hypothesis-driven analysis, we divided each arm in two subgroups of 11 subjects according to the ranking of baseline resting LV-GLS values . The subgroups with higher LV-GLS showed no change during the study neither on empagliflozin nor sitagliptin. On the contrary, the subjects with lower baseline LV-GLS experienced an improvement in LV contractility absolute values already at 1 month after therapy with empagliflozin (+ 1.22 [+ 0.31/+ 2.13]%) followed by a further improvement at 6 months (+ 2.05 [+ 1.14/+ 2.96]%). The subjects with lower LV-GLS on sitagliptin showed no change at 1 month (+ 0.30 [− 0.13/+ 0.73]%) and a mild improvement at 6 months (+ 0.92 [+ 0.21/+ 0.62]%)  in 40 subject with T2D, normal LVEF, and no clinical diagnosis of HF [It is known from the literature that SGLT2i are associated with a relatively heterogeneous amelioration of LV-GLS  despite no increase in 2D-LVEF in subjects with T2D and HF with a gradient that is proportional to the degree of baseline dysfunction , 25. A 1is of HF ; unfortuis of HF . Consideis of HF , our fin2peak is associated with adverse cardiovascular outcomes [2peak was increased by 24% after 6 months of therapy with empagliflozin vs “usual therapy” in T2D patients with established cardiovascular disease or at high risk [2peak—i.e., cardiac output, peripheral extraction, ventilation—were unaffected by either treatment, further sustaining the observations of a neutral effect of either drug on cardiopulmonary capacity in this population. The amelioration of glycaemic control is known to improve VO2peak in T2D with established cardiac disease [2peak, which on the other hand confirms that volume regulation is unlikely to be the mechanism through which SGLT2i are effective in primary prevention . We have recently shown that both effort tolerance (VOpeak2) and peripheral oxygen extraction are correlated with LV contractility indices (S′ and GLS) in subjects with uncomplicated T2D [2peak values showed a trend to be lower in those with LV-GLS below the median . Nonetheless, our result of unchanged peak workload and peripheral oxygen extraction confirms the lack of clinically relevant effects of SGLT2i on skeletal muscle oxygen/work coupling in T2D subjects.Since in T2D the condition of reduced VOoutcomes , one mayigh risk , and by igh risk  and withigh risk  after 1 igh risk  or versuigh risk . In our  disease , 35 and  disease  and this disease . No patiated T2D  suggestiNo significant change in natriuretic peptides was evident from our data, which were in the normal reference values at baseline. This confirms that volume regulation is not relevant in this study population, aligning with the available literature that failed at demonstrating a consistent reduction in natriuretic peptides with SGLT2i, with a trend towards a greater efficacy in patients with HFrEF  and highIn T2D subjects free from heart disease empagliflozin has a neutral impact on aerobic fitness and LV systo-diastolic functions, both at rest and during exercise. Nevertheless, it can exert an early and sustained amelioration of myocardial contractility in those with subclinical dysfunction as defined by a mildly reduced resting LV-GLS (< 16.5%) despite normal LVEF. These data support the hypothesis that SGLT2i can directly affect myocardial contractility in selected patients with subclinical LV systolic dysfunction, possibly justifying their benefit in HF primary prevention.2peak) and the pre-defined exploratory analysis only to subgroup analysis according to baseline LV-GLS and to mechanism-oriented biomarkers. The a posteriori power calculation on LV-GLS measured on 44 (22 per arm) subjects, with paired comparison within each group, showed statistical power between 99 and 84% for differences ranging from 2.5 to 1.7% and the smallest difference in LV-GLS—keeping power at 95%—is 2.0%. Therefore, we acknowledge that changes smaller than 2% might be missed because of the reduced sample size. This value still is close to 1.5%, our definition of minimal clinically meaningful change. Although LV-GLS is considered an accurate method to evaluate LV contractility, there is evidence that it might be affected by the technology used, age, sex, BMI, and to some extent also by LV loading conditions [The recruitment was interrupted early due to the lock-down imposed by the COVID-19 pandemics, therefore the power of our study is lower than planned; therefore, we might have missed absolute changes in LV-GLS below 2.5% or 1.7%, which were considered relevant from a clinical and pathophysiologic point of view, respectively . The datnditions . In our Additional file 1: Figure S1. EMPA-HEART trial.Additional file 2: Table S1. Cardiopulmonary exercise test, 2D Echocardiograpy, Doppler, Tissue Doppler, and Speckle tracking parameters. P-value is the result of a two-point ANOVA for repeated measures.