To evaluate systolic cardiac dysfunction in paediatric MFS patients with chest wall deformity using cardiac magnetic resonance (CMR) imaging and feature-tracking strain analysis.Forty paediatric MFS patients  and 20 age-matched healthy controls  were evaluated retrospectively. Biventricular function and volumes were determined using cine sequences. Feature-tracking CMR was used to assess global systolic longitudinal (GLS), circumferential (GCS) and radial strain (GRS). A dedicated balanced turbo field echo sequence was used to quantify chest wall deformity by measuring the Haller index (HI).2, p = 0.08), RV stroke volume  and RVEF  in MFS patients. A subgroup of MFS patients had an increased HI compared to controls . They demonstrated a reduced RVEF compared to MFS patients without chest wall deformity  and controls (p < 0.001). LV GLS was attenuated when HI ≥ 3.25 , but not GCS and GRS. LV GLS (p < 0.01) and GCS (p < 0.0001) were attenuated in MFS patients compared to controls, but not GRS (p = 0.31). RV GLS was attenuated in MFS patients compared to controls .LV volumes and ejection fraction (EF) were similar in MFS patients and controls. There was a trend for lower right ventricular (RV) volume (75 ± 17 vs. 81 ± 10 ml/mChest wall deformity in paediatric MFS patients is associated with reduced RV volume, ejection fraction and GLS. Feature-tracking CMR also indicates impairment of systolic LV function in paediatric MFS patients.• Paediatric Marfan patients demonstrate reduced RV volume and ejection fraction compared to healthy controls.• A concordant attenuation in RV global longitudinal strain was observed in Marfan patients, while the RV global circumferential strain was increased, indicating a possible compensatory mechanism.• Subgroup analyses demonstrated alterations in RV ejection fraction and RV/LV global strain parameters, indicating a possible association of severe chest wall deformity with biventricular dysfunction in paediatric Marfan patients.The online version contains supplementary material available at 10.1007/s00330-020-07616-9. Marfan syndrome (MFS) is a heritable systemic connective tissue disorder, with a prevalence of 2−3:10,000 . HoweverPrevious studies assessing the ventricular dimensions and function in MFS patients report discordant results. While Meijboom et al and Chatrath et al could identify dilatation of the left ventricle (LV) in some of their patients , 11, volTo the best of our knowledge, there are no studies reporting the effect of chest wall deformity on cardiac function in patients with MFS. The purpose of our study was to evaluate systolic cardiac dysfunction in paediatric MFS patients with chest wall deformity using CMR imaging and feature-tracking strain analysis.The local clinical institutional review board approved our retrospective study and waived the requirement for informed consent due to the anonymous analysis of all data. The medical image archive of our institution was reviewed for paediatric patients with the established diagnosis of MFS according to the revised Ghent nosology , who had3; reconstructed voxel size, 1.36 × 1.36 × 6 mm3; gap, 4 mm; 9–10 slices for full LV coverage; echo time, 1.67 ms; time to repetition, 3.34 ms; flip angle, 60°; sense factor, 2.0; 25 phases per RR interval.Studies were performed on a 1.5-T Achieva scanner with a 5-channel cardiac phased array receiver coil . ECG-triggered steady-state free-precession (SSFP) cine sequences were acquired in short axis and 2-, 3- and 4-chamber views. The following typical imaging parameters were used for cine series: acquired voxel size, 1.98 × 1.80 × 6 mm3; reconstructed voxel size, 1.41 × 1.41 × 10 mm3; gap, 5.10 mm; echo time, 1.53 ms; time to repetition, 3.06 ms; flip angle, 90°.In addition, images dedicated for the evaluation of chest wall deformities were acquired as ECG-triggered balanced turbo field echo (BTFE) on the transversal plane with the following imaging parameters: acquired voxel size, 1.68 × 1.67 × 10 mmCardiac volumes and myocardial mass were determined with CVi42 (Circle Cardiovascular Imaging Inc.). Endocardial contours were manually traced in end-diastole and end-systole on short-axis cine images to calculate end-systolic (ESV) and end-diastolic volumes (EDV) as well as stroke volume (SV) and ejection fraction (EF) , 23. EpiGlobal peak systolic strain was quantified using the software Segment  by contouring endo- and epicardial borders in end-diastole. Contours were then automatically propagated throughout all cardiac phases to calculate strain values  on a BTFE sequence. HI was calculated as the ratio of the maximum transverse diameter of the chest wall to the minimum sternovertebral diameter Fig.  27].Fig.Fig27].FTo further assess the influence of a chest wall deformity on cardiac function, we stratified MFS patients using a cut-off for HI of 3.25 or greater. This cut-off is considered to indicate a severe chest wall deformity and surgical correction is recommended .t test, if not the Welch test was used. Categorical variables were compared using the chi2 test or Fisher’s exact test as appropriate. Continuous variables are shown as mean ± SD and two-sided p values < 0.05 were considered significant.Statistical analyses were performed with IBM SPSS Statistics 25 . Homogeneity of variance was tested with the Levene test. When homogeneity of variance was given, the mean differences between groups were compared with the independent sample p = 0.03), while having similar weight , resulting in a significantly lower BMI . BSA did not show any differences (p = 0.44). MFS patients had a significantly higher HI .Demographics of MFS patients and controls are shown in Table p = 0.66). There were no significant differences in left ventricular volumes including LVEDV  and LV mass (p = 0.85). RVEF was significantly lower in MFS patients compared to controls . There was a trend for reduced RVEDV in MFS patients . RVESV was not different (p = 0.35). RVSV was significantly lower in MFS patients compared to controls . Using the cine series, valvular regurgitation was identified in 12 MFS patients (mild tricuspid (5), mild mitral (6) and mild aortic regurgitation (2)) and one MFS patient had mild tricuspid and aortic regurgitation. Ten controls also showed valvular regurgitation (mild tricuspid (8) and mild aortic regurgitation (2)). CMR characteristics of MFS patients with and without mild valvular regurgitation are given in Supplemental Table Cardiac function parameters are given in Table p < 0.01) and LV GCS  were attenuated in MFS patients compared to controls (Table p = 0.31) showed no significant differences between both groups (Table p < 0.05), while RV GCS was increased in MFS patients  , respectively. A significant difference was seen in the sternovertebral diameter , but not in the transverse diameter (p = 0.71). MFS patients with a HI ≥ 3.25 were younger (p = 0.04) and weighted less (p < 0.01). The height was not different (p = 0.11). BMI (p < 0.001) and BSA (p < 0.01) were both lower in the HI ≥ 3.25 group. LV volumes and mass showed no differences (Table p = 0.01), while there was a trend for increased RVESV  and reduced RVSV . LV GLS was attenuated when HI ≥ 3.25 , but LV GCS and LV GRS were not significantly different between both groups. RV GLS and GCS were similar in both groups . There were no differences in LV morphological and functional parameters. RVEF  and RVSV  were decreased in patients with HI ≥ 3.25. There was a trend for increased RVESV in MFS patients with chest wall deformity . LV GLS  and LV GCS  were attenuated in MFS patients with HI ≥ 3.25. LV GRS (p = 0.22) was not significantly different. RV GLS was attenuated , while RV GCS was increased  in patients with HI ≥ 3.25  RVEF and RVSV were reduced in MFS patients and especially in those with severe chest wall deformity. (2) LV volumes, mass and function were similar between MFS patients and healthy controls. However, LV GLS and LV GCS were attenuated in MFS patients, suggesting subtle LV function alterations, which were only detectable by feature-tracking CMR analysis. (3) RV GLS was attenuated, and RV GCS was increased in MFS patients.Early echocardiographic and CMR studies have demonstrated impairment of cardiac function in MFS patients without valvular diseases, which was interpreted as Marfan cardiomyopathy , 13, 14.Only a few studies have reported a possible impairment of RV function in MFS patients , 7. Alpe. Kiotsekoglou et al used echocardiography and demonstrated reduced LV longitudinal and radial strain in adult MFS patients compared to controls [. Angtuaco et al did not observe any significant differences in LV longitudinal, radial and circumferential strain in a small cohort of paediatric MFS patients (N = 16) compared to controls, but detected reduced regional strain rates, suggesting that the study might be underpowered [. To date, there is only one retrospective CMR study by Winther et al that used feature-tracking CMR to characterise adult MFS patients, demonstrating a reduced LV longitudinal strain pattern in some patients [In our cohort of MFS patients, LVEF was similar to healthy controls. However, strain analysis by feature-tracking CMR showed an attenuation of LV global longitudinal and circumferential strain in MFS patients. Furthermore, MFS patients with severe chest wall deformity had a lower LV contractility than those with HI < 3.25 as indicated by attenuated LV global longitudinal strain. Studies reporting on a comprehensive strain analysis in MFS patients are scarce. Scherptong et al investigated 50 adult MFS patients and 50 controls using echocardiography and concordant to our findings LV longitudinal strain was significantly decreased in MFS patients, while LV circumferential strain and EF did not differ . Kiotsekcontrols . Angtuacrpowered . To datepatients . Howeverpatients . The majpatients . Also, opatients , 37. OurIn our study, we observed a borderline significant RV GLS attenuation in MFS patients concordant with the reduced RVEF. On the contrary, RV GCS was increased in MFS patients compared to controls. Currently, there is a gap of knowledge regarding RV strain in MFS patients, but there are some CMR studies on RV strain in patients with PE , 38. In Our study has several limitations. First, we had a small sample size. However, the number of studies reporting paediatric CMR data in general and strain analysis by feature-tracking CMR in particular is very limited and we believe that our study would add to the scientific knowledge of the research community. Second, this study was conducted with a retrospective design. Our CMR protocol included a short-axis cine stack in contrast to the only other CMR study by Winther et al reporting on adult MFS patients . Third, This study investigated the effect of chest wall deformity in paediatric MFS patients on cardiac systolic function suggesting that increased Haller index may be associated with a decrease in RV volume, ejection fraction and longitudinal strain. Conversely, RV circumferential strain was increased in MFS patients, which may indicate a compensatory mechanism. Although MFS patients had normal LV volumes and ejection fraction, they demonstrated lower global LV longitudinal and circumferential strain compared to healthy controls. Our results are indicative of the existence of Marfan-related cardiomyopathy. Furthermore, follow-up studies are warranted to investigate the prognostic value of chest wall deformity and attenuated LV and RV strain in young MFS patients.ESM 1(DOCX 31 kb)


Cardiac amyloidosis is a rare disease caused by the accumulation of protein-based fibrils that deposit into the myocardium, causing disease. The accumulation of amyloid in the heart tissue causes the heart to become increasingly stiff, reducing compliance, with the eventual decline of the heart’s systolic function over time as the disease progresses. The restrictive physiology of the disease usually prompts investigation; however, if allowed to progress, the systolic function becomes affected in the later stages of the disease. We present a case of late-stage transthyretin-related amyloidosis (ATTR). There are several different types of amyloidosis, with each derived from different proteins, including amyloid light chain (AL) amyloidosis , AA amyloidosis (wild-type amyloidosis (wt-ATTR)), and hereditary transthyretin-related amyloidosis (mATTR), seen in older individuals . AlthougAL amyloidosis is caused by misfolded monoclonal immunoglobulin light chains (ALs) due to an abnormal proliferation of plasma cells in the bone marrow. Approximately, 2000 to 3000 cases of AL amyloidosis are diagnosed in the US each year .Cardiac transthyretin amyloidosis routinely presents as restrictive physiology in the advanced stage of the disease, which only then prompts further investigation . In thisOur patient is a 51-year-old African American male who was presented to the hospital with uncontrolled hypertension and elevated troponins. His troponins were flat and did not trend with the typical acute coronary rise and fall pattern.His past medical history included a remote past myocardial infarction (MI), hypertension, insulin-dependent diabetes , peripheral vascular disease status post left lower extremity digit amputation of the hallux and second metatarsal, and chronic kidney disease (CKD) stage III. His history revealed non-adherence to his medication regimen.He described occasional chest pains as a sharp sensation that predominantly occurred at rest. He appeared volume overloaded, including lower extremity edema and increased abdominal swelling. The patient also noted a history of myocardial infarction (MI) two years prior, where he presented similarly with elevated blood glucose and elevated blood pressure but lacked chest pain. On exam, the patient was 67.8 kg (body mass index (BMI) = 19.2), with blood sugar over 500 mg/dL, and blood pressure peaking at 261/152 mmHg. His creatinine was 1.73 mg/dL, indicative of baseline chronic kidney disease (CKD) stage III. An electrocardiogram (ECG) was performed, which demonstrated sinus rhythm with T-wave inversions in the lateral leads and anterior q waves, as well as left atrial enlargement. He was referred for an echocardiogram on account of elevated troponin and hypertensive emergency.The left ventricle demonstrated severe concentric hypertrophy, highly suspicious for infiltrative cardiomyopathy. Unfortunately, cardiology was not consulted during this admission, the on-call cardiologist who read the echocardiogram did not suggest the possibility of an infiltrative disease process, and the patient was treated for hypertensive heart disease. The left ventricular systolic function was mildly reduced, with an ejection fraction of 50-55%. The mitral inflow and tissue Doppler flow patterns were suggestive of stage two diastolic dysfunction. There was severe left atrial dilation and moderate right atrial dilation. There was mild mitral regurgitation and trace tricuspid regurgitation. The aortic valve demonstrated mild calcification, with nodular calcification on the non-coronary cusp. There was also mild aortic stenosis, as well as trace pulmonic valvular regurgitation present. He was treated medically and sent home.The patient’s clinical course was complicated four months after initial presentation by a foot abscess, and he was once again admitted to the hospital where he now had left foot wet gangrene due to uncontrolled diabetes mellitus and peripheral arterial disease. At this presentation, the patient was 70.31 kg (BMI = 19.2), with a blood pressure of 152/77 mmHg. High-risk femoral artery bypass for the better profusion of the left leg was planned and a Lexiscan stress test with nuclear myocardial perfusion imaging was ordered prior to surgery. The stress test revealed overall abnormal left ventricular systolic function with global hypokinesis of the left ventricle. The myocardial perfusion imaging was abnormal, with a small zone of mild intensity ischemia present in the basal to the mid-inferolateral wall.The patient then underwent left heart catheterization and selective coronary angiography, which revealed a moderate disease of the left anterior descending, second diagonal, and first obtuse marginal arteries, as well as a chronically occluded mid-right coronary artery. After this, he finally underwent a left femoropopliteal bypass using the reverse saphenous vein approach. He was discharged to rehab but could not maintain adequate blood pressure control. A month later , he again went to the emergency department for a hypertensive crisis. At presentation, his blood pressure was 213/104 mmHg, his weight was now 78.4 kg (BMI = 22.6), labs indicated microcytic anemia (hemoglobin = 8.7 mg/dL), and creatinine was 2.3 mg/dL. An ECG was performed, which demonstrated left axis deviation, sinus rhythm, poor R-wave progression, and T-wave inversions unchanged from previous EKGs. He reported left lower leg edema and swelling, as well as mild headache and weight loss. A cardiology consult was now attained for atypical chest pain and for the management of uncontrolled hypertension.The patient underwent another complete two-dimensional transthoracic echocardiogram. At the time of the echo, the patient was 81.2 kg (BMI = 23.0). The left ventricle demonstrated severe concentric hypertrophy. The mitral inflow and tissue Doppler flow patterns indicated stage one diastolic dysfunction. The transmitral spectral Doppler flow pattern was suggestive of impaired left ventricle (LV) relaxation. There was an abnormal longitudinal strain present with apical sparing. The left ventricular ejection fraction was normal (55-60%). The left atrium was severely dilated, and the right atrium was moderately dilated. The mitral valve leaflets appear thickened but opened well. There was trace mitral regurgitation and mild tricuspid regurgitation. There was mild aortic valve calcification and trace aortic regurgitation. There was also mild pulmonic valvular regurgitation. The inferior vena cava (IVC) was dilated with a dimension of 2.3 cm, resulting in elevated right-sided filling pressures. There was trace pericardial effusion present, with a large left pleural effusion. An atelectatic lung was noted with a jellyfish sign. Pharmacologic management was once again recommended and his anti-anginal and blood pressure medications were once again up-titrated; it was at this time during our post hoc review that the concept of amyloidosis should have been considered, unfortunately.Two months later , the patient was admitted to the hospital with diabetic ketoacidosis and altered mental status. He had failed to follow up in the cardiology clinic during any of the time periods between discharges and readmissions. He was subsequently intubated and placed on mechanical ventilation. Cardiology was once again consulted for “abnormal heart rhythm.” After clinical stabilization and extubation, cardiology assessed the patient. A review of the telemetry demonstrated intermittent atrioventricular nodal reentrant tachycardia, paroxysmal atrial fibrillation, and episodes of junctional rhythm. The EKG obtained at the bedside, as demonstrated in Figure The patient’s clinical course was further complicated by recurrent diabetic ketoacidosis, hypertensive crisis, and gastrointestinal bleeding. After undergoing colonoscopy and esophagogastroduodenoscopy, the patient was also found to have Los Angeles grade A esophagitis, gastritis, and duodenitis, along with a 10 mm rectal polyp. The patient then underwent left adrenalectomy to remove the previously found nodule suspicious for an active adrenal adenoma given resistant hypertension.Roughly three months later , as he was recovering in the long-term care unit, a complete two-dimensional transthoracic echocardiogram was ordered on account of ECG changes and persistent hypertension despite the left adrenalectomy. Left ventricular systolic function was found to be mild/moderately reduced, and the right ventricular systolic function was severely reduced. The left ventricular cavity was small, and the left ventricular wall exhibited severe concentric hypertrophy, as seen in Figure This is when the diagnosis of ATTR amyloidosis was first seriously entertained. This diagnosis had been overlooked in retrospect, as the patient was likely suffering from amyloidosis and not from uncontrolled hypertension due to an active adrenal adenoma. Even though multiple cardiologists had evaluated the patient throughout this time, the diagnosis of amyloidosis was protracted due to the confounding adrenal tumor and focusing on the comorbid conditions like long-standing hypertension, diabetes mellitus, and the patient’s non-adherence to medical therapy and physician appointments.He was then admitted to the hospital for further inpatient evaluation, where 99m Technetium-Pyrophosphate imaging was performed to evaluate for cardiac amyloidosis as seen in Figure To further evaluate for the differential diagnosis of cardiac amyloidosis, a serum free-light-chain assay was performed. The results demonstrated high elevations of both free Kappa and Lambda light chain levels, with Kappa at 167.48 mg/dL (H)  and Lambda at 129.39 mg/dL H . The free Kappa/Lambda ratio was found to be 1.29, which falls in the normal range . These findings are confounded by the patient’s now end-stage renal disease and ongoing hemodialysis. His pleural effusions were never interrogated. Genetic testing was then to be arranged post-discharge in the outpatient setting to further assess for gene mutations associated with ATTR amyloidosis utilizing the Ambry Genetic next-generation sequencing assay. Unfortunately, the patient has yet to follow up with cardiology.This infiltrative deposition of abnormal protein within the heart causes progressive and potentially fatal restrictive cardiomyopathy . ProteinThis results in a phenotypic expression most common in younger females of African descent . This haMany of the early symptoms of cardiac amyloidosis are nonspecific such as weakness and fatigue, making the diagnosis often challenging and delayed. Progressive bi-ventricular wall thickening, diastolic dysfunction due to loss of cardiac compliance, and elevation in cardiac filling pressures lead to excess buildup of fluid in the body, manifesting as congestive heart failure. Associated symptoms of congestive heart failure include shortness of breath, angina, swelling of the lower extremities and abdomen, pleural effusions, and elevated jugular venous pressure ,6.Multisystem organ involvement can also occur. If the pericardium is involved, chronic or recurring pericardial effusions can be seen. If the coronary arteries or cardiac conduction system are involved, one may see typical angina and/or conduction abnormalities such as atrial fibrillation, complete heart block, and bundle branch blocks. The conduction disturbances can lead to clinical manifestations such as fatigue, palpitations, and syncope. Specifically, ATTR amyloid protein can infiltrate the autonomic and peripheral nervous systems. Therefore, symptoms such as paresthesia, weakness, orthostatic hypotension, diarrhea/constipation, gastroparesis, carpal tunnel syndrome, unexplained bruising, and weight loss have been known to occur. Other extra-cardiac manifestations due to infiltration and deposition would include hepatomegaly, macroglossia, and tendon rupture ,6.The diagnosis of cardiac amyloidosis can be based on a noninvasive approach or invasive heart biopsies. The noninvasive modalities that can suggest the diagnosis include echocardiography, cardiac magnetic resonance (CMR), EKG, and serum biomarker testing (B-type natriuretic peptide [BNP] and cardiac troponin). The finding of a wall thickness greater than 12 mm in the absence of other heart conditions, such as aortic valve disease or systemic hypertension, should warrant a strong suspicion of cardiac amyloidosis ,7.This is an interstitial myocardial infiltrative disease that typically manifests itself as a constellation of diagnostic features, such as concentric left ventricular hypertrophy, bi-atrial enlargement, and restrictive filling pattern on echocardiography, with characteristic findings of apical sparing on myocardial strain imaging . The ECGCardiac MRI is another diagnostic tool well-suited to evaluate for cardiac involvement of amyloidosis. CMR is more precise and reproducible in diagnosing cardiac amyloidosis than echocardiography; however, it is more expensive and less widely available. The benefit of CMR over echocardiography is the ability of CMR to identify amyloid deposits and myocardial edema with the use of ECV and native T1 times .Both amyloid light chain and transthyretin amyloidosis can be assessed using cardiac MRI, but we cannot characterize or differentiate one from the other strictly using cardiac MRI alone. The amyloid protein infiltration alters the myocardial kinetics creating difficulty in nulling the myocardium. This is usually the first recognizable feature of amyloidosis during the acquisition phase. The late gadolinium sequences are enhanced with T1 recovery-focused sequences; however, because of the diffuse nature of the infiltration, there is difficulty in finding the true nulling point of the myocardium and differentiating this from the blood pool . UtilizaAcquiring the cardiac extracellular volume (ECV) measurement is quite useful in helping differentiate amyloidosis from other infiltrative diseases: the formula is ECV = (1 - Hematocrit) × (Δ R 1 myocardium / Δ R 1blood); where ΔR1 is (1/T1 precontrast-1/T1 postcontrast) on a 1.5-tesla magnet . Out of Although typically, ATTR has a higher ECV in comparison to AL amyloidosis, it is worthwhile reiterating that there is considerable overlap of the ECV and elevation of native T1 times to differentiate between which type of amyloidosis is present . NeverthGenetic evaluation has opened the frontier to new treatment options as well. Until recently, only liver transplant, alone or combined with heart transplantation, was available to decrease disease progression and mortality .Treatment of cardiac amyloidosis is based on a two-step approach: management of cardiac complications due to amyloid infiltration and targeted treatment to suppress new amyloid formation and deposition by inhibiting the production and stabilizing the ATTR tetramer preventing destabilization ultimately into amyloid fibrils . The admIn ATTR, orthotopic liver and heart transplantation was the first to have been shown to prevent disease progression and was the established treatment for patients ,17. The Emerging therapies target transthyretin (TTR) deposition at various stages along the disease process. Patisiran is a small interfering RNA (siRNA) that blocks expression of both hATTR and wtATTR, has been approved for use in ATTR with polyneuropathy, and has also shown promise in ATTR-CM ,18. AnotTafamidis was the first drug to be approved for the treatment of TTR amyloid cardiomyopathy in 2019. Diflunasil, a non-steroidal anti-inflammatory drug, has also shown initial promise as a non-selective TTR tetramer stabilizer -22. A smOther therapeutic targets, such as the inhibition and disruption of oligomer aggregation and the degradation and reabsorption of amyloid fibrils, have so far yielded no reassuring long-term treatment data .Physicians being tricked into a diagnosis other than amyloidosis is not a new phenomenon, due to the rare extracardiac manifestations and cardiac manifestations alike. The authors would encourage a “step back and evaluate” approach, as it is very overwhelming to take care of patients with such a myriad of symptoms and try to put the pieces together, especially when reviewing prior documentation, to try to prevent what happened with our patient.This case illustrates the importance of early diagnosis of this rare, life-threatening disease, as well as the clinical course of late-stage ATTR-CM, from physicians that were not accustomed to seeing infiltrative diseases regularly. The diagnosis and treatment of ATTR-CM have advanced significantly in the last 10-20 years due to increased awareness and increased technological capabilities in genetic testing and advanced imaging as long as it is readily available. Unfortunately, most cases of cardiac amyloidosis are still diagnosed in later stages as in our patient’s case. Early intervention is the most important prognostic factor in disease progression. Unfortunately, our patient had been previously diagnosed with hypertensive heart disease and with a confounded diagnosis of hypertensive heart disease over amyloidosis in prior hospitalizations. It was only in the later echocardiograms that the question of amyloidosis was suspected. This reinforces the need to suspect alternative pathology despite the interpretation of prior physicians. This case exemplifies the classic progression of amyloidosis. The patient never followed up with his cardiology appointments and unfortunately was difficult to manage long-term. Continued work must be performed to earlier identify those at risk of developing ATTR-CM and to discover safe and effective medical treatment options. Awareness of classic symptoms is key to an early diagnosis and should direct the patient to further testing for ATTR-based therapies.


Nine modes captured 90% of the anatomical variation in the SSM. Functional simulation outputs correlated best with modes 2, 3 and 9 on average . We performed a global sensitivity analysis to identify the different modes responsible for different simulated electrical and mechanical measures of cardiac function. Modes 2 and 9 were the most important for determining simulated left ventricular mechanics and pressure-derived phenotypes. Mode 2 explained 28.56 ± 16.48% and 25.5 ± 20.85, and mode 9 explained 12.1 ± 8.74% and 13.54 ± 16.91% of the variances of mechanics and pressure-derived phenotypes, respectively. Electrophysiological biomarkers were explained by the interaction of 3 ± 1 modes. In the healthy adult human heart, shape modes that explain large portions of anatomical variance do not explain equivalent levels of electromechanical functional variation. As a result, in cardiac models, representing patient anatomy using a limited number of modes of anatomical variation can cause a loss in accuracy of simulated electromechanical function.Cardiac anatomy plays a crucial role in determining cardiac function. However, there is a poor understanding of how specific and localised anatomical changes affect different cardiac functional outputs. In this work, we test the hypothesis that in a statistical shape model (SSM), the modes that are most relevant for describing anatomy are also most important for determining the output of cardiac electromechanics simulations. We made patient-specific four-chamber heart meshes ( The heart adapts to physiological and pathological changes in loading. This can cause the heart to change size and shape. These changes can in turn have significant impact on cardiac function. However, it is not clear if large changes in function are caused by large changes in shape or can smaller changes also be important. Biophysical computational models of the heart provide a quantitative framework for mapping changes in anatomy to whole heart function. We created a publicly available healthy four-chamber heart virtual cohort from clinical images. Each patient’s heart anatomy in the virtual cohort was described by the contribution of different components of heart shape. The shape components are ranked by the amount of shape variance that they explain. Simulations of cardiac electrical activation and mechanical pump function in hearts with shapes described by different combinations of shape components were performed. This allowed us to show that some shape components that explain a large amount of electrical and mechanical function variance only explain a small amount of anatomical variance. This highlights the need to have high fidelity anatomical models in cardiac simulations and demonstrates that subtle changes in cardiac anatomy can have a large impact on cardiac function. Cardiac anatomy plays a crucial role in determining the function of the heart –3. HowevCardiac anatomy can be efficiently encoded through Statistical Shape Models (SSM) . These SThe first modes are most likely to be consistent between imaging modalities . If simuIn this study, we make four main contributions. First, we describe the creation and quality assurance tests of a virtual cohort of 20 hearts from asymptomatic patients, made publicly available online. Second, we study the relationship between cardiac electromechanical (EM) function and variation in shape modes, identifying the most relevant shape modes for EM simulations. Third, we perform a global sensitivity analysis (GSA) using Gaussian processes emulators (GPEs) to quantify the variance explained in EM function by each one of the anatomical modes. Fourth, we test the effect that several parameters of the EM simulations have on the simulations’ output through a local sensitivity analysis (LSA).Firstly, we describe the image acquisition protocol and the pipeline we built to generate four-chamber meshes from CT images. We then present the pipeline to build the SSM and the quality checks we performed on all the generated meshes. Secondly, we describe the functional simulations we ran and the statistical tests to relate generated anatomy to simulated function. Lastly, we present the sensitivity analyses, both global and local, to further understand the interaction between anatomy and simulated function.The imaging data were collected as part of a prospective study approved by the Health Research Authority (18/LO/1803). The study conformed with the Declaration of Helsinki (reference ID 15/LO/1803) and all participants provided written, informed consent.Healthy control static cardiac CT images were obtained from 20 asymptomatic patients at St. Thomas’ Hospital in London, United Kingdom. These patients went to the emergency room with acute chest pains. Since no cardiac conditions were detected in follow-up, these patients were taken as representative of “healthy” (or asymptomatic) hearts. CT images were acquired, 71.35% ± 3.57% through the R-R wave interval, during the diastolic phase. In- and out-plane resolution were 0.34 ± 0.03 mm and 0.49 ± 0.02 mm, respectively.The methods for mesh construction have been described previously . BrieflyWe then calculated the volume using the 3D Stokes theorem approach, described previously in . We quanWe built a SSM from the anatomical meshes using the method described in . In shorWe created two extra cohorts by modifying the weight of the modes explaining 90% of the variance in shape. We created these meshes with either ±2 or ±3 standard deviations (SD) of each mode added to the average mesh (extreme2 and extreme3 cohorts respectively). We also created two additional meshes with ± 1 SD for mode 2 (extreme1 cohort), since the simulations in the more extreme meshes failed to complete.We refer to the average mesh, extreme1, extreme2 and extreme3 cohorts as the synthetic cohort/meshes. As before, we added fibres and UVC to each mesh. Detailed information about the process can be found in We ran EM simulations using CARP , 28 as dWe simulated the effect of a Purkinje system by adding a fast endocardial conduction (FEC) layer , coverinTo simulate the active stress  × N points .We performed a GPE-based GSA as in . BrieflyWe performed the statistical analyses in R  and geneTo asses the influence of the main model parameters and on the simulation results, we carried out a local sensitivity analysis on the average mesh. We modified the values of parameters involved in the mesh construction as well as related to the different submodels used in the EM simulations.We quantified the role of the atria by using only a biventricular model, tunning the stiffness of the spring-like boundary conditions in the pericardium to achieve the same EF as with the presence of the atria (57.3%).αendo = 80° to αepi = −60° at the endocardium to epicardium, respectively, to either αendo = 75° to αepi = −55° or αendo = 85° to αepi = −65°. We will refer to these configurations as default, narrow or wide. We run simulations using the narrow configuration in both ventricles, only in the LV and only in the RV and using the wide configuration in both ventricles, only in the LV and only in the RV. In the ventricle not modified we used the default fibres.We modified fibre orientation from the default values of a , ,  be the original input-output, and the modified values respectively where x− = x0 − 10%x0 and x+ = x0 + 10%x0. Then we define the sensitivity coefficient SC asAs a measure of sensitivity for the continuous variables we used the slope of the segment containing the two new pair of parameter-output values normalised. Let . Similar effects are reflected in modes 3 and 7 as well. Mode 2 is the main mode accounting for difference in size. We notice that the difference in chamber volume is not followed by a similar change in LV wall thickness, creating a wall thinning when the chamber is more dilated. Low values in mode 5 achieve a more spherical heart .Several modes affect the shape of the LV. A more conic shape of the chamber is achieved decreasing mode 4, creating a less spherical apex. Mode 9 accounts for the thickening of the base, creating a bulge right below the aortic valve. With regards to the RV, increments on mode 3 create an increased basal diameter, pushing the lateral wall outwards. A similar effect is also observed with alterations in mode 7.Changes in the atria include mode 3, creating a more spherical RA, and pushing it closer to the RV. Mode 6 modifies the size of the LA, creating a smaller chamber with higher values of this mode. Changes in anatomy of the aorta and PA are driven by changes in mode 4 and mode 8 respectively. Mode 7 also modifies its shape, making it less spherical, but also reduces the size of the RA.http://www.archer.ac.uk/), the UK national high-performance computing service located at the University of Edinburgh. Before the cardiac cycle, an unloading step was needed to achieve an estimate of the stress-free reference configuration [EP simulations took 32.98 ± 16.87 seconds on a desktop machine using 20 cores. We ran mechanics simulations on ARCHER  to 0.38 ± 0.22 (mode 3).To study which modes are the most relevant for each one of the simulated EM outputs, we computed the correlation between each mode and each phenotype in the CT cohort . The mosWe considered the normalised range of simulation outputs from the synthetic cohort where each mode was adjusted independently . We obse−4 . The highest MSE occurred for the emulator of the dPdtmin, with a value of 0.001 mmHg2/s2. The square root of the dPdtmin MSE was 0.032 mmHg/s or 1.66% of the average value.We used GPEs to perform a GSA, using all the modes and training on each phenotype separately. The mean MSE, measured as the squared difference between the predicted and the observed phenotype, of all phenotypes is 10We present the GSA results as doughnut charts in To quantify the effect that has in our results fixing the parameters, we performed a local sensitivity analysis on the average mesh, shown in The model parameters with higher effect on LV outputs are peak isometric tension, aortic pressure and LV endocardial pressure with absolute coefficients of 0.32 ± 0.19, 0.29 ± 0.17 and 0.16 ± 0.15, respectively. In the case of the RV, RV endocardial pressure, peak isometric tension and LV endocardial pressure are the parameters with higher effect with absolute coefficients of 0.15 ± 0.14, 0.15 ± 0.06 and 0.12 ± 0.12, respectively. The initial endocardial pressures drive the changes in volume, being the volume-based phenotypes the group mainly affected by alterations in these parameters. The value of peak isometric tension is a key element in triggering the contraction and the force applied in it, affecting mainly the pressure-based phenotypes. Changes in conductivity do not have a noticeable effect except for a change in the CV in the FEC layer, affecting mainly dPdtmin in the LV with a value −0.6. We notice that even if the LV is more sensitive to changes in the input parameters than the RV , in both cases we consider the sensitivity to be low.In the case of the EP, the only two input parameters considered affecting its activation are the CV of the myocardium and the CV of the FEC layer. The higher sensitivity is found in the LV total activation time when modifying the CV of the myocardium, with a coefficient of −0.78.αendo = 85°, αepi = −65°), we observe the highest absolute changes in EF1 in the RV with a value of 10.51% being the mean absolute effect for all the outputs of 3.22% ± 3%. Analogously, with a narrower fibre span in both ventricles  the mean absolute effect is 2.16% ± 1.88% with the highest effect on AT1090 in the LV with a value of −8.29%. Four extra scenarios were analysed, when using the narrow or wide fibre configuration only in the LV or only on the RV. The biggest changes are observe when using the wide configuration in the RV (and the default in the LV), with absolute changes of 3.75 ± 3.16%.We considered three more scenarios modifying the mesh construction: modified fibre angle, including a fractal tree as model of Purkinje network instead of a FEC layer, and using only the ventricles but with pericardium boundary conditions. In this case, we show the increment of each output with respect to the baseline, normalised by the baseline value. In the case of the wide fibre span in both ventricles  as well, with a value of 38.8%. The minimum change is found in QRS duration with a change of 26.16%. Thirdly, when modelling only the ventricles, we find changes of 25.21% ± 18.18% across all phenotypes, with a maximum of 70.36% in dPdtmin in the RV.In this work we systematically studied the relationship and interplay between anatomical and functional variability in the heart. We created the first virtual cohort of healthy four chamber hearts tested using EM simulations. We showed that shape modes that explain large portions of anatomical variance do not explain equivalent levels of EM functional variation. We demonstrated that there are subtle anatomical changes (e.g. mode 9) that cause a large impact on function. Finally, we found that groups of simulated functional biomarkers  are dependent on distinct sets of shape modes.Our data consist of anonymised static CT imaging data obtained directly from healthy patients. We do not have access to clinical data such as QRS duration or EF, making a direct validation for each patient unfeasible. Moreover, since we fixed all the parameters for the EM simulations, we could not validate against clinical data . To validate the cohort, we compared average outcomes from the models and the simulations with published data from cohorts of healthy patients.n = 20) and by the fact that our cohort is drawn from a different population than UK Biobank. For instance, the UK Biobank population is known to be more health conscious, leaner and non-smokers than the general population [We observed an offset of the volume values in our CT cohort, where volumes were smaller (128 ± 24 mL vs 143 ± 34 mL) than those reported from the UK Biobank . This dipulation .Regarding simulated function, we only personalised the anatomical models. We did not have sufficient data to constrain the mechanics models for these patients. However, we selected material properties and boundary conditions from the literature  and demoWe found that 9 modes were required to explain 90% of the CT anatomical variance. This is considerably less compared to other whole-heart SSMs, such as the study by Ordas et al.  where ovWe discarded case #20 from the SSM due to the distinct atrial anatomy in that patient. The left PVs branched farther from the atrial body compared to the rest of the cases, creating a more elongated LA. This variability has been observed previously in anatomical studies where, in approximately 23% of the cases, the left atrium had four orifices but with a “short vestibule or funnel-like common vein” . In prevIn previous works on SSM, some cases have been also discarded. In , prior tThe cardiac simulations performed were deterministic with common material properties and boundary conditions between cases, therefore any change in the model outputs can only be attributed to changes in the input anatomy.We focused on phenotypes that were dependent on anatomy and their range was greater than 20% of a baseline mean value. We found that the LV EF, the duration of the isovolumic phases and the LV ESP did not exhibit high variation, fell below this threshold.The small variation in LV EF is consistent with previous studies  where thThe IRT timing phenortype also show relatively small clinical variability . NonetheVolume-based phenotypes in both ventricles demonstrate the highest variability. This can potentially be attributed to the variation in the EDV, which comes directly from the reconstruction of the CT images. This high variability in the EDV is likely to lead to higher variability in ESV and SV. Volumetric variability in the model derived form CT images appears to lead to higher variation in simulated volume based indexes of cardiac function.Finally, the high variability observed in the EP-based phenotypes depends on the area the electrical wave has to cover. The cases in the CT cohort present a high variability in EDV, possibly causing a high variability in ventricular surface area. All this variability can contribute to high variability in the EP-based phenotypes even with the same input conduction velocities.We found that latter modes can be more important than first modes for explaining simulated function. This is in contrast with earlier LV only studies, which found that the first modes were often the most important for determining strain fields . HoweverDifferent authors have proved in the past that latter modes can potentially lead to a better classification of patient outcomes. Lamata et al.  found thSimulations predicted that sets of phenotypes were explained by common sets of shape modes. Mode 2 and 3 were the principal determinants of LV myocardial mass, while modes 2, 3, 4 and 9 are the main drivers of changes in LV EDV. Increased wall thickness  is associated with increased contraction . SimilarWe found that the EP-based phenotypes were mainly affected by changes in modes 5, 7 and 8 . When anIn terms of the pressure-derived phenotypes, dPdtmax is mainly altered by modifications in mode 9, which explains less than 3% of the anatomical variability. This mode determines changes in shape in the atria and in the basal part of the LV septum, creating a bulge right below the aortic outflow tract see . This isWe performed a local sensitivity analysis modifying ±10% the key parameters of the simulations. In general, we observed a normalised sensitivity of less than 1, the maximum value is of 0.8, or a change in 8% for a change of 10% in the input. This compares with the variability in output with differences in anatomy  where thWe included the passive effect of the atria on the ventricle in the reference model. The specific passive properties of the atria did not have a big impact on ventricular function. First, we investigated the impact of a change in end-diastolic pressure, which would normally be informed by atrial contraction. We observed that for a change of 10% in the LV and RV pressure, the outputs change by a 1.6 ± 1.5% and 1.5 ± 1.4%, respectively. Second, we altered atrial passive stiffness to estimate the impact of changes in passive material properties that may be introduced by the presence of an atrial fibre model. In this case, the absolute changes observed for a 10% change in the stiffness are of 0.78% ± 1.22% and 0.03 ± 0.03% in the LV and the RV, respectively. In both cases, the phenotypes showed a low sensitivity to changes in these parameters, consistent with the absence of the atrial features not overly impacting our results.αendo = 85° and αepi = −65°) in both ventricles. The magnitude of these results suggests that, although the fibre direction is an essential factor in the EM simulations, small changes in their direction do not have a large impact the results.We also quantified the influence of the choice of the fibre direction with 6 different scenarios. The biggest changes are in the case of the wide configuration  on most of the phenotypes. This compares to a range of no multifactorial effects at all  to a maximum of 27.8% in the case of the AT1090. This means that the interaction between different modes is small compared with the the individual influence of the modes. In terms of clinical relevance, imaging protocols could then focus on detecting changes in individual shape modes that are found to be important for predicting function.To interpret and visualise each one of the modes, we measured the displacements from the meshes of the extreme3 cohort to the average mesh. The biggest deformations are present in mode 3, with maximum values of approximately 15 mm and mean displacements of 5.8 and 8.8 mm for the LV and the RV, respectively. In mode 9 for instance more subtle changes are present, where the biggest deformations are approximately 6 mm and mean deformations are 1.93 and 1.6 mm for the LV and RV, respectively. These findings suggest that the impact of modes on simulated function might be more dependent on the location than on the magnitude of the changes.The extreme3 meshes, used to interpret the modes, describe the range covered by over 99% of the expected observations, so we can safely compare with the resolution of the most common imaging protocols. Typical MRI resolution of approximately 1 − 2  mm in-plWe ran cardiac simulations using models built under certain assumptions and simplifications such as the FEC layer as a Purkinje system model or the ventricles as transversely isotropic materials. We solved the nonlinear equations numerically, which have both accuracy and stability limitations. Our results need to be interpreted considering these factors.The shape in our models is based on a semi-automatic segmentation. Except for the LV, we built the wall of the other chambers following the shape of the blood pools but fixing the wall thickness see . There mWe modelled organ-scale mechanics using large deformation mechanics solved using the finite element method. Each time step of the simulation requires the solution of a set of nonlinear equations coupled to an ODE boundary condition model. These equations have no guaranteed solution in complex geometries and failure of cardiac mechanics models to reach a converged solution is a known problem . In our A limitation of the SSM is that we do not include all anatomical variation in the LA. Firstly, we restricted the anatomical variability in the topology of the PVs, despite its significant effects on atrial function as , 87. SecIn this study we only focused on the impact of anatomy on simulations, despite the importance of fine-tuning and personalisation of parameters for personalised simulations . For insThe atria were modelled as a passive neo-hookean material. Although it is a significant simplification, simulations of atrial mechanics are not as widespread as ventricular mechanics. A more thorough investigation on atrial modelling and simulation for four-chamber cardiac meshes is out of the scope of this paper. Nevertheless, we added them to obtain more physiological boundary conditions on the pulmonary veins and venae cavae..vtk format available on 10.5281/zenodo.4590294 and 10.5281/zenodo.4593739. We have added 1000 more meshes modifying the PCA weights randomly withing 2 SD range, available in 10.5281/zenodo.4506930. The same anatomical structures are present in all the meshes described, but fibres and UVC were not included in the extra 1000 batch.We have made all the meshes from the CT and synthetic cohort available for the community in VTK file for each mesh was included (in ASCII) as an UNSTRUCTURED GRID. In all the cases the following fields were included: POINTS, with the coordinates of the points in mm; CELL_TYPES, having all of the points the value 10 since they are tetrahedra; CELLS, with the indices of the vertices of every element; and CELL_DATA corresponding to the meshing tags.A VECTORS fields, with the fibres and sheet directions (one fibre and sheet direction per element) and a POINT_DATA field with four LOOKUP_TABLE subfield corresponding to the UVC in the order ρ, ϕ, Z and V. Since the UVC were defined only in the ventricles, a value of −10 was established for all the coordinates in the elements not belonging to the ventricular myocardium.In the case of the CT and synthetic cohorts some extra fields were added: two For every cohort, a file with the value of the weights as well as the functional phenotypes has been included for each heart.Our results showed that using only the main modes of shape we may not capture sufficient anatomical variability to perform accurate functional cardiac simulations. Conversely, these simulations can map smaller shape modes, that may be found irrelevant in standard shape analysis, to meaningful changes in cardiac function. Moreover, the mechanical, electrical, and pressure-derived phenotypes are dependent on different subsets of anatomical modes. These results suggest that tailored imaging protocols should be used for creating models of specific cardiac function.S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file.S3 Text(PDF)Click here for additional data file.S4 Text(PDF)Click here for additional data file.S5 Text(PDF)Click here for additional data file.S6 Text(PDF)Click here for additional data file.


Background: Anthracycline-based chemotherapy (ANT) remains among the most effective therapies for breast cancer. Cardiotoxicity from ANT represents a severe adverse event and may predominantly manifest as heart failure. While it is well-recognised that left ventricular systolic heart failure assessment is key in ANT-treated patients, less is known about the relevance of LV diastolic functional impairment and its characterisation. Methods: Studies reporting on echocardiographic diastolic function parameters before and after ANT in breast cancer patients without cardiac disease were included. We evaluated pulsed wave ) and tissue Doppler  and E/e′ ratio) echocardiographic parameters. Results: A total of 892 patients from 13 studies were included. E/A ratio was significantly reduced at the end of ANT while EDT was not influenced by ANT. Additionally, e’ and E/e’ ratio showed no significant change after ANT. A modest reduction in LV ejection fraction and global longitudinal strain was observed at the end of ANT therapy. Conclusions: ANT had a modest early impact on E/A ratio, without changing EDT, e’, or E/e’ in patients with breast cancer without cardiac disease. Randomised studies on larger populations, using new parameters are required to define the role of diastolic dysfunction in the early diagnosis of ANT-induced cardiotoxicity. Breast cancer accounts for 30% of all new cancer diagnoses in women across all ages . The theThe most severe adverse event of anthracycline-based chemotherapy (ANT) is cardiotoxicity. The main mechanisms of ANT related cardiotoxicity are the production of free radicals and reactive oxygen species  and the The poor prognosis and the lack of specific treatment options for anthracycline-induced cardiotoxicity impose extensive efforts for the early detection of cardiac dysfunction during ANT, in order to avoid progression to heart failure . After iLeft ventricular (LV) diastolic dysfunction represents the inability of LV to fill to a normal end-diastolic volume and to provide an adequate stroke volume ,23. LV dMost of the studies on patients with breast cancer treated with ANT describe a reduction in LV systolic function using LVEF or GLS, while diastolic dysfunction has been reported as a secondary endpoint, using separate echocardiographic parameters of diastolic dysfunction in non-randomised studies on a small number of subjects ,27,28,29Consequently, available data regarding the impact of ANT on diastolic function is scarce and conflicting. This analysis aims to determine if an alteration in E/A, DTE, e’ or E/e’, as the most frequent reported echocardiographic parameters of diastolic dysfunction, could be used to early detect and to predict ANT related cardiotoxicity in patients with breast cancer without cardiac disease. This meta-analysis was performed in accordance with the PRISMA  guidelines and followed the Cochrane Handbook for Systematic Reviews of Interventions recommendations ,36. The A systematic search was conducted through Pubmed, Cochrane, Embase, and Web of Science databases using MeSH  terms and free text to identify relevant studies published in English until 31st of October 2020, according to the inclusion and exclusion criteria.Prospective or retrospective, randomised or non-randomised studies reporting on diastolic function parameter assessed through echocardiography in patients with breast cancer before and after ANT.Follow-up time more than 6 weeksSample size > 20 patientsOnly those studies that complied with all the inclusion criteria listed below were included:Abstracts, reviews, animal and in vitro studies, meta-analyses, and case-reports.Studies on patients with other cancer types except breast cancer  treated with ANT.Studies including patients with established cardiovascular disease.Studies that did not report the selected outcomes.Subgroup population studies: elderly population, pediatric population.All the studies that fulfilled one or more of the criteria listed below were excluded from the meta-analysis:After removing duplicates, RM and LL independently reviewed the abstracts. Any discrepancies in results between the two investigators were resolved by discussion with MT. When the inclusion criteria appeared to be met, the entire text was reviewed. At the end of the review process, the full texts of the studies considered eligible were reviewed by all investigators.Two authors (RM and LL) independently performed the data extraction using a standard data extraction form that contained the following fields: publication details (name of the first author and year of publication); study design; characteristics of the study population ; cumulative dose of anthracyclines; follow-up timing; diastolic function parameters; and the main findings of each study.The trial quality was assessed using the Newcastle Ottawa Scale , consideThe parameters of diastolic function were evaluated through echocardiography at two different timepoints: at baseline (before ANT start) and follow-up (after the last cycle of ANT). When a follow-up visit after the last cycle ANT was not reported, we used data reported at the six-month follow-up evaluation.(1)E/A ratio calculated as the ratio between mitral early E-wave filling velocity (E) and mitral atrial A-wave filling velocity (A) using pulsed Doppler interrogation at the level of the mitral valve;(2)mitral E-wave deceleration time (EDT) calculated as the time between the peak E-wave velocity to zero-velocity baseline;(3)mean velocities of the mitral ring in the early diastole (e’) assessed as the mean between the tissue Doppler mitral annular lateral and median velocities;(4)E/e’ ratio calculated as ratio between E and e’.The primary study endpoints consisted of changes of the following diastolic function parameters:As secondary endpoints we analysed changes in LVEF and GLS between the two assessment timepoints. Additionally, we analysed the influence of high doses ANT and the impact of cardioprotective therapy on the LV diastolic function.I2 statistical test. We considered the presence of significant heterogeneity at a 10% level of significance. A value of I2 of 0–40% denotes that heterogeneity might not be important, 30–60% may represent moderate heterogeneity, 50–90% may represent substantial heterogeneity, and 75–100% may represent considerable heterogeneity [The meta-analysis included patients with breast cancer without cardiac disease treated with ANT. The parameters of diastolic function were assessed at two different timepoints: baseline and follow-up. The mean values and standard deviations of the E/A, EDT, e’, and E/e’ at baseline were compared with the mean values at follow-up in the same population study. The data are expressed as difference in means (DM) and 95% confidence intervals (CI) and for each parameter. A positive value of DM represents a reduction of the mean value of E/A, EDT, e’, and E/e’ at the follow-up, while a negative value of DM represents an increase in the mean value of E/A, EDT, e’, and E/e’ at follow-up. We used random-effects models for all analyses. Heterogeneity between studies was tested using Q statistics, and inconsistencies were determined using the ogeneity . The preogeneity . The funogeneity . All anaThe meta-analysis included 13 studies with a total of 892 patients with breast cancer that received ANT ,39,40,41p < 0.001  at follow-up  when studied on 717 patients from nine studies   . Heterognificant .p < 0.001). The data was obtained from eleven studies with 621 patients . Data was analysed from five studies with 293 patients and showed low heterogeneity . The DTE and E/e’ were similar between the two timepoints.220 patients receiving ANT dose over 400 mg/m studies ,32,40 sh2 had a significant change in E/A and e’ at follow-up. This meta-analysis studied the influence of ANT on the LV diastolic function in 892 patients with breast cancer from 13 studies. The main findings of the study were (a) The E/A ratio showed a modest decrease at the follow-up timepoint; (b) EDT was not influenced by ANT; (c) Neither the early diastolic e’ velocity of the mitral ring, nor the E/e’ ratio was significantly alterated at follow-up; (d) LVEF and GLS showed a significant reduction at the end of the therapy; (e) Patients receiving ANT doses over 400 mg/mThe current data could neither support the use of these parameters for the early diagnosis of ANT cardiotoxicity, nor their use as predictors of ANT cardiotoxicity. The results demonstrate a modest reduction in E/A ratio after ANT, with no influence on EDT, e’ or E/e’ at the end of ANT. Whether ANT induces an alteration of LV diastolic function is incompletely studied. Echocardiographic diastolic function parameters depend on cardiac preload, cardiac rhythm, age, and differences in measurement technique. In cancer patients preload could be easily influenced by dehidration because of gastrointestinal adverse events during chemotherapy. This may explain the observed changes in E/A after therapy . The loaThe assessment of the diastolic function after ANT has been performed on a small number of patients with short follow-up time. Recently, persistent worsening of diastolic function in 361 patients with breast cancer detected through early reductions in E/A and e’ and increase in E/e’ over a median follow-up time of 2.1 years was reported . HoweverThe demonstrated reduction in LVEF, although statistically significant, was actually modest when evaluating the difference in means at the end of ANT. The current European Society of Cardiology position paper on cancer treatments and cardiovascular toxicity define LVEF and GLS as parameters to diagnose cardiotoxicity, while parameters of diastolic function do not belong to the standard . The useHigh-dose ANT caused an alteration of both E/A and e’, explained by the impairment of LV relaxation . When analysing the control groups of the cardioprotection studies, the results vary from significant changes in tissue Doppler e’ and E/e’ parameter, to no changes in the echocardiographic parameters of diastolic function ,30,31. AThe occurrence of diastolic dysfunction after ANT in patients with breast cancer without cardiac disease remains an open question for the clinical practice. Avilable data show conflicting results due to the lack of standardisation of the echocardiographic parameters of diastolic function, together with the lack of prognostic significance of the changes of these parameter. Consequently, a robust conclusion regarding the diastolic function after ANT is at this timepoint impossible. When assessing the diastolic function in patients with cancer, new echocardiographic parameter should be taken into consideration. Our data included two studies that reported on early diastolic strain rate as a parameter of diastolic function, yet with contradictory results ,40. Cardio-oncology units are essential for the assessment of cardiovascular function, including the standardised evaluation of diastolic function in cancer patients ,58,59. TThis analysis has some limitations that should be addressed. Firstly, most of the studies included in the analysis are not-randomised prospective cohorts, with increases in the risk of bias. Secondly, the analysis could not make a statement regarding the grade of diastolic dysfunction in the entire group of patients, because this requires an integrative assessment of more echocardiographic diastolic function parameters. Thirdly, a correlation with a pathological change in the described parameter with the appearance of ANT related adverse events could not be established. Fourthly, the lack of standardisation for the reporting of echocardiographic parameters to define the diastolic dysfunction could alter the general results.The assessment of LV diastolic function after ANT in patients with breast cancer without cardiovascular disease using echocardiography showed a modest early change in E/A ratio, without changes in EDT, e’, or E/e’. Other parameters should be considered to determine the diagnostic and prognostic role of LV diastolic function in ANT-related cardiotoxicity.


Severe tricuspid valve regurgitation has been for a long time a neglected valve disease, which has only recently attracted an increasing interest due to the notable negative impact on the prognosis of patients with cardiovascular disease. It is estimated that around 90% of tricuspid regurgitation is diagnosed as “functional” and mostly secondary to a primary left-sided heart disease and, therefore, has been usually interpreted as a benign condition that did not require a surgical management. Nevertheless, the persistence of severe tricuspid regurgitation after left-sided surgical correction of a valve disease, particularly mitral valve surgery, has been associated to adverse outcomes, worsening of the quality of life, and a significant increase in mortality rate. Similar results have been found when the impact of isolated severe tricuspid regurgitation has been studied. Current knowledge is shifting the “functional” categorization toward a more complex and detailed pathophysiological classification, identifying various phenotypes with completely different etiology, natural history and, potentially, an invasive management. The aim of this review is to offer a comprehensive guide for clinicians and surgeons with a systematic description of “functional” tricuspid regurgitation subtypes, an analysis centered on the effectiveness of existing surgical techniques and a focus on the emergent percutaneous procedures. This latter may be an attractive alternative to a standard surgical approach in patients with high-operative risk or isolated tricuspid regurgitation. Right ventricle (RV) overload and tricuspid annular (TA) dilatation have been identified from the outset as the main causes in the pathogenesis of tricuspid regurgitation (TR) following left heart valvular disease (LHVD). The absence of primary abnormalities of the valvular apparatus has led TR, from the earliest studies, to be approached as of a “functional” nature mediated by pressure and volume overload that affect the geometry of RV, right atrium (RA), and TA , 2. In aIndeed, in the setting of LHVD, both the severe mitral regurgitation and aortic stenosis have a high percentage, up to 50 and to 25%, respectively, and the concomitant presence of at least moderate TR, with worsening or late onset of the TR when the solely left heart valvular disease was surgically corrected –11.In the light of these findings, the guidelines, supported by the absence of an increased operative risk, recommend tricuspid valve (TV) surgery during the surgical management of left-sided disease, with an improvement in RV function and functional status, if the disease is not very advanced .In contrast, knowledge about the natural history and the timing of intervention in isolated TR remain poor because its clinical onset usually occurs in an advanced stage of the disease, which may increase periprocedural morbidity and mortality . MoreoveIn the pathogenesis of FTR, valvular coaptation results impaired due to mainly two mechanisms: TA dilatation with distortion of its morphology and restricted motion of leaflets caused by increased tethering.Due to the peculiar anatomy of TV, when the functional dilatation of TA occurs, typically, the septal portion is spared, involving the anterior and the posterior leaflet attachment. Thus, the normal “saddle-shaped” structure is altered toward more circular and planar geometry .The magnitude of annular dilatation correlates with greater degrees of TR and, in particular, the threshold beyond which coaptation results significantly inadequate is notably lower than for mitral regurgitation, with 40 rather than 75%, respectively , 14.Therefore, the loss of coaptation is importantly influenced by the dilatation and distortion of TA, often coexisting with leaflets pulled down the annular plane due to increased tethering. In this latter case, anterior and posterior papillary muscles (PMs) are displaced due to RV cavity change in size and shape .in-vitro study that simulated annular dilatation and PMs displacement showed that when considered alone, both the conditions may lead to significant FTR  with or without pulmonary hypertension (PH).Right atrium enlargement and dysfunction.In the majority of FTR cases, the primary triggering condition is LHVD, mainly chronic mitral regurgitation followed by aortic valve stenosis and mitral valve stenosis , 17.The different causes of FTR determine significant anatomic differences in RV, TV, and TA anatomy.Interestingly, FTR secondary to PH, mainly associated to LHVD or in the setting of primary PH due to pulmonary disease such as chronic pulmonary embolism among others, showed only mild annular dilatation, but excessive valve tenting height with a conical deformation of RV .The progressive RV dilatation, promoted by the relative lack in muscular tissue of RV, due to the increased afterload, is triggered by PH. Different studies have demonstrated the role of PH as a determinant of FTR severity; in a vicious circle, the chronic pressure and volume overload increase leaflets tethering, ultimately worsening TR .Besides the absolute value of pulmonary artery systolic pressure in defining the severity of the PH, the onset of significant FTR is strongly associated with right heart remodeling . Indeed,On the other side of the spectrum lesions, FTR with a larger basal deformation of the RV and a lower annular/leaflet coverage ratio due to greater annular dilatation, typically occurs due to RA enlargement and dysfunction .Atrial FTR (AFTR) was for long time called idiopathic FTR, so categorized due to the absence of any obvious cause; recently, its accurate study has allowed to revise the pathophysiological classification, awarding to the RA a primary role as its main determinant , 21–23.Indeed, current literature has emphasized the underappreciated issue associated to the atrial failure and its prognostic implication in worsening natural history of heart failure among others .Atrial FTR reflects the TV leaflets malcoaptation because of the imbalance between TA and leaflets area, caused by RA enlargement and dysfunction.The advanced age and the presence of persistent/permanent atrial fibrillation (AF) are typically associated to the AFTR, reflecting as common denominator of the atrial contractile dysfunction , 23. In In the study of Utsunomyia et al. , who comInterestingly, they stratified AFTR according to severity of regurgitation in severe and massive/torrential TR, showing in this latter more complex lesions with excessive TA dilation associated to different degrees of leaflets tethering .What emerges by the afore discussed categorization is a strong association between RV, RA, and valvular changes and in the light of this complex interaction, FTR may be interpreted as a complex syndrome with multifaceted spectrum of pathogenesis, natural history, and outcome.Therefore, the qualitative evaluation of FTR based on pathophysiological categorization should be integrated with quantitative measurements and parameters exploited by imaging to improve the decision-making process and offer individualized management for our patients.The first-line imaging recommended in the assessment of TR is the transthoracic echocardiography, which is useful to provide information regarding to the main determinants of the disease and to estimate its severity.In the setting of FTR, the assessment of TV anatomy, in order to exclude any structural abnormalities, anticipates the measurement of TA diameter, RV size and function, RA size, and the estimation of pulmonary artery pressures (PAPs) .2 indexed for the body surface area has been established and still used as threshold in surgical decision-making to approach TV in concomitant procedures. Nevertheless, the two-dimensional (2D) echocardiographic measurements fail to consider the 3D nonplanar structure of TA and in addition the interindividual variability. In comparison, 3D echocardiography, obtained by the transthoracic window rather than the transesophageal one because of the better visualization, is significantly less influenced by TA shape and orientation  and also its relative size as compared to the left ventricle (LV) . Qualitative estimation of RV systolic motion from this view also provides a first impression of RV systolic motion. Longitudinal shortening of the basal segments is the main contributor to global RV function; therefore, the assessment of global function can also be provided by measuring the tricuspid annular plane systolic excursion (TAPSE) from M-mode scans through the TA in the four-chamber view . Determination of peak systolic annular velocity (S wave from tissue Doppler imaging of the tricuspid annulus) also provides a global index of RV systolic function . However, both the TAPSE and annular S wave values are influenced by loading conditions. Volumetric methods to assess RV ejection fraction are cumbersome by using 2D echocardiography due to the particular geometry of the RV and, therefore, 3D echocardiography, despite limited by visual quality and spatial resolution, is preferred. In the absence of 3D echocardiography, RV fractional area change obtained from the planimetry of the endocardial border of the RV performed in the four-chamber view and its relative change in systole and diastole is typically used to assess RV systolic function. Finally, myocardial deformation imaging determining global longitudinal strain of the RV is another essential tool in the evaluation of RV systolic function that can be successfully obtained with echocardiography. Typically, the free wall RV global strain is obtained from the four-chamber view with normal values above 20% or even higher in the presence of volume overload such as the case of patients with TR. This parameter has shown added prognostic value in several clinical settings such as cardiogenic shock and PH , 31.The extent of leaflet tethering , the mode of leaflet coaptation, and the RA size offer supplementary information regarding the natural history of the FTR, allowing to stage the severity of the disease according to the complexity of lesions .2, respectively, for the vena contracta and for the effective regurgitant orifice area, as threshold to quantify severe TR.Besides the qualitative description improved by the use of 3D echocardiography , the sevSeveral issues affect the staging role assigned to these quantitative values; in particular: the anatomical difference existing between TV and its left counterpart, associated to the higher respiratory function and loading variability. The 3D echocardiography allows to partly overcome the anatomical disagreement, even though failing to solve the limitations related to the assessment of a single frame developed on a tomographic plane in the setting of a variable dynamic disease , 32.Patients with TR are a heterogeneous population at different stages of right heart remodeling. CMR is the gold standard imaging technique for the quantitative and qualitative assessment of the heart, particularly the RV morphology and function and, indeed, it has diagnostic value and it can provide valuable information to improve the decision-making process on the management of TR  33)..33).Cardiac magnetic resonance allows a comprehensive assessment of FTR, starting from the qualitative visualization of valve regurgitation with flow turbulence and acceleration visualized in the cine images as an area of local signal drop. The qualitative grading has shown a moderate correlation with the quantitative assessment, although influenced by different limitations such as the difficult arising from the correct visualization in presence of pacemaker leads and the bias associated to various technical factors.The more accurate quantitative measurement, although limited by existing validated cutoff and, therefore, the still poor experience, allows to calculate the regurgitant volume (RVol) through TV with both the indirect and direct methods. In the first case, RVol is derived from the right ventricular volumetric stroke volume, demonstrating to be a good prognostic predictor in patients underwent to the surgical management of isolated TR.In contrast, the direct calculation of RVol depends by the flow assessment through the valve, but it is still challenging due to intrinsic factor associated to the atrioventricular annuli .2 measured by CMR, beyond which combined TV annuloplasty should be considered.Moreover, the determination of the RV morphology and RV cavity size assessed by CMR cine-sequence images has been proved to have prognostic value in different clinical settings , 36. RecBesides heart cavities assessment, CMR can also accurately evaluate the pulmonary vasculature and it has been proposed as an alternative to invasive right heart catheterization and echocardiography in assessing pulmonary circulation hemodynamics and to estimate pulmonary vascular resistance . The CMRAdditionally, myocardial strain has received growing interest as an alternative measure of myocardial performance since it has proven to better recognize and characterize subclinical biventricular systolic dysfunction as compared with conventional imaging modalities based on EF , 41. In Better identification of high-risk patients that benefit from a closer follow-up together with the implementation of a global RV imaging evaluation that includes the assessment of estimated PVR and the early detection of RV dysfunction by using FT may potentially play a role in determining optimal timing of intervention of patients with FTR.A recent growing surgical interest in the management of FTR has reversed course, polarized in the past by the wrong concept of disease regression after properly solving LHVD .The consequence of the less attention received rather than for mitral valve regurgitation has been easily translated in a still lacking surgical experience in offering a targeted approach.Although, in absence of a clear evidence demonstrating superiority of one surgical approach over others, TV repair, mainly annuloplasty, represents the preferred options in the management of FTR. A growing interest emerged at the end of 90' in various minimally invasive and video-assisted surgical approaches –50. TV rA great challenge, in the surgical decision-making, is represented by the management of electrical conduction abnormalities in concomitance with TR, which can facilitate the need for pacemaker implantation in the postoperative period. An accurate evaluation of the possibility to implant epicardial leads is necessary in order to reduce the risk of TR recurrence mainly due to prosthesis leaflets damage following the traditional leads implantation.In this paragraph, we review the most commonly TV repair techniques to offer a focus insight into the future perspectives of surgery in the management of FTR in the era of transcatheter approach. The cornerstone of the TV repair techniques has found its foundation in counteracting the dilatation of TA, with annuloplasty being the most widely used approach.First, the way of the annular plication was undertaken following the concept of the suture bicuspidization. The posterior annular portion of TV, being the less unsupported segment of TV ring, dilates achieving up to 80% from its normal dimension in the setting of FTR. This anatomic finding was at the basis of suture bicuspidization technique . The tecAlthough highly reproducible, the tension created by the suture lines and the high technical failure associated to severe TA dilatation have limited the use of the suture annuloplasty toward alternative strategies such as the implantation of prosthetic ring or band .De Vega proposed, after understanding the way TA was dilated, a double continuous running suture with the aim to plicate the anterior and the posterior portions of the annulus avoiding the septal due to the lack of distension and to avoid the conduction tissue. Even though this semicircular suture annuloplasty was initially designed for rheumatic TV disease, it reached a great success in the management of FTR, mainly because it was safe, effective, at least in the short term, easily reproducible, and cheap , 55. NevThe technical aspects of the various De Vega annuloplasty modifications followed the rationale to achieve better coaptation, reduced annular dimensions, and a better distribution of forces along the suture in order to prevent tear in the endocardium –60. The Alain Carpentier, emphasizing the criticisms associated to the principles of the suture annuloplasty, proposed the use of suitably sized and shaped prosthetic rings. In the former, the asymmetric placement of the sutures results in localized plication and in variable degrees of functional stenosis. On the contrary, the rationale for the implantation of a prosthetic rigid ring was based on the respect of anatomic and physiologic TA geometry, allowing to avoid recurrent dilatation with a nondeformable frame .The Duran-Medtronic totally flexible tricuspid and the Carpentier-Edwards semi-rigid rings were later followed by the flexible Cosgrove-Edwards and Duran-Medtronic bands.The flexible band was specifically designed on the basis of the improved knowledge regarding dynamic saddle-shaped structure of TA and about its pathological dilatation that involves particularly anterior and posterior segments .McCarthy et al.  comparedThe superiority of the prosthetic annuloplasty ring, in ensuring a higher durability of FTR correction, a better long-term survival, and event free-survival, was largely demonstrated –68.Nevertheless, the main finding of the retrospective study published by McCarthy et al.  was the Over the years, a variety of prosthesis for annuloplasty has been presented, notably ensuring improvement in remodeling TV annulus, respecting the 3D anatomical dynamic characteristics. The development of the 3D-shaped prosthetic rings has allowed to resemble more accurately the healthy human TA, reducing the recurrence of the TR in the long-term follow-up, with an incidence reported in a recent study, which compared the use of the Medtronic 3D Contour and the Edwards MC3 prosthetic rings, of almost 15% of TR > 2+, mainly of moderate nature , 71. NewThe late onset of TR after left-sided surgery, regardless by the presence of preoperative TR, highlights the dynamic nature of TR, which, in contrast with what Nina Braunwald believed, does not regress spontaneously . DreyfusThe echocardiographic equivalent of the intraoperative threshold has been identified in 40 mm. Tricuspid annuloplasty was performed, in addition to left-sided surgery, in patients with TA dilatation more than 40 mm, independently by the grade of TR, in a cohort of 43 patients in the study published by Van de Veire et al. .The authors analyzed retrospectively two cohorts temporally distinct, with the introduction of the “prophylactic annuloplasty” in the management of FTR in the more recent group of patients. A significant decrease of TR, transtricuspid gradient and a reduction of the RV volumes leading to reverse remodeling were observed . These fBenedetto et al.  observedInterestingly, the subgroup analysis demonstrated an advantage of TV annuloplasty toward TR caused by rheumatic or ischemic injury, failing to show significant benefits in degenerative etiology. The authors explained the ineffectiveness of the additional treatment identifying some predisposing risk factors such as worse functional class and the presence of AF, responsible of long-standing RV pressure overload.In addition, the high variability correlated to the broad range of degenerative disease raised various questions about the predictivity of TA diameter as a valid cutoff for decision-making .Although tricuspid annuloplasty represents a coherent surgical approach in counteracting TA dilatation in the early stage of disease when LVHD correction is performed, a single threshold in the setting of a multifaceted syndrome is a limitation in achieving excellent results. Studies, tailored on the different etiology and pathophysiology, designed in order to identify targeted parameters, are mandatory.2.The wrong assumption that TA dilation is always the primary cause of leaflet malcoaptation and that TV annuloplasty is able to correct FTR counteracting also leaflet tethering, is generally incorrect; in fact, there is a high early residual rate of TR when tethering is excessive . Indeed,Therefore, the geometry of the TV can vary according to the major determinants of its severity, TA dilatation, leaflet tethering , and the grade of PH, designing a complex variety of lesions .In such cases, additional surgical strategies in order to improve results of TV repair are necessary, allowing to reduce early technical failure and TR recurrence.Surgery at subvalvular level with PMs approximation has demonstrated to be effective in reducing TR independently by the use of tricuspid annuloplasty and it is able to promote changes in the RV geometry leading to reverse remodeling. The technical aspects of this surgical strategy are based on the approximation of the anterior PM, attached to the RV free wall and more prone to displacement, toward the interventricular septum .Excellent outcomes have been achieved by using PMs “septalization” in the management of the massive FTR caused by distorted geometry of the TV and adverse remodeling of the RV –83.In the setting of severe tethering, the restricted mobility leads to the failure of the leaflets in covering the whole orifice; leaflet augmentation using an autologous pericardial patch found its rationale in this concept. Dreyfus et al.  promotedThe great technological improvements and the experience achieved in the field of the transcatheter repair or replacement of the aortic and mitral valves have accelerated the use of the transcatheter tricuspid valve interventions (TTVIs) in high-risk surgical patients. The possibility to recur to a less invasive surgical option of treatment, in particular in selected patients such as who underwent to previous TV surgery, allows to reduce the high incidence of postoperative mortality and morbidity associated to the reintervention. Nevertheless, the lack of a complete understanding of the role and timing of the TV surgery represented a limitation in allowing a standardized management .A broad armamentarium including multiple devices aimed to repair and replacement has been developed in the field of tricuspid disease.Transcatheter TV replacement includes the orthotopic implantation of a prosthetic valve in the tricuspid location or the heterotopic implantation of prosthetic valves in the vena cava. These approaches are particularly limited to the patients with degeneration of previous TV correction (repair or replacement) and particularly for those with very advances stages of TR where repair is not going to provide a durable solution , 89.The coaptation and annuloplasty devices represent other available options of the transcatheter TV repair.The MitraClip system  has found in the TriClip system , the corresponding leaflets coaptation device. In particular, the edge-to-edge repair of the TV with the TriClip system  or the Pascal system  is the most largely performed coaptation technique , with reOn a scaled-down, the early feasibility of other TTVR system, conceptualized in order to improve the leaflet coaptation, has been achieved in smaller sample size with the Forma system . The regurgitant orifice area results reduced with a balloon spacer anchored to the RV apex , 94. BesOn the other hand, the suture annuloplasty devices, Trialign  and Tricinch , provide to counteract TA dilatation, reducing the orifice dimension with a system of anchors placed on the anterior and posterior segments , 96.The release of annuloplasty ring devices was performed by using the Cardioband system  and the Millipede IRIS system . At early follow-up, the impact on TR and clinical status was promising in high-risk surgical patients deemed inoperable, including those who underwent prior surgical repair showing residual or recurrent TR.The analysis of data collected on patients undergoing any type of TTVI (>70% transcatheter edege-to-edge repair) in multiple centers in Europe and North America was performed by Taramasso et al. , showingNevertheless, similar outcomes to those managed medically have been showed in patient with unsuccessful TTVI. Interestingly, a coaptation depth > 1 cm has been identified as predictive of technical failure, suggestive of excessive valve tethering and RV remodeling, expression of the late phase of disease . The devPercutaneous or transthoracic insertion of a bioprosthesis to replace the nonrepairable TV has been attempted in several patients successfully. Sizes up to 54 F required are indeed a limitation to solve in coming years .These findings emphasize the necessity to improve knowledge regarding FTR pathophysiology, in order to better understand the role of TTVI in the natural history of the disease.The concept of TV as a passive bystander to the LHVD should be abandoned. FTR is a multifaceted disease, including a broad spectrum of lesions. The technological advances in cardiac imaging with the use of 3D echocardiography and CMR have restored notoriety to the study and management of the FTR and may ensure to accurately categorize FTR phenotypes and establish quantitative parameters useful to guide clinicians and surgeons.Annuloplasty has demonstrated to be limited to address FTR in its early stage with the necessity to integrate the repair technique by using a more targeted approach, which ensures an improved valvular coaptation counteracting excessive leaflet tethering. Nevertheless, the use of annuloplasty with prosthetic ring may successfully treat TA dilatation in the setting of mild-to-moderate FTR when left-sided surgery is performed.Therefore, the role of surgery in the transcatheter era, with TTVI representing a valid option for high-surgical risk patients, depends mostly by the correct understanding of the natural history of disease, with a growing armamentarium of techniques in the surgeon's hands.MV and EG: conceptualization. MV, MS, BD-X, and JL: writing—original draft preparation. EG, FM, SR, EW, and MD'A: review and editing. All authors contributed to the article and approved the submitted version.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. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.