Background: Determining the value of new imaging markers to predict aortic valve (AV) surgery in asymptomatic patients with severe aortic regurgitation (AR) in a prospective, observational, multicenter study. Methods: Consecutive patients with chronic severe AR were enrolled between 2015–2018. Baseline examination included echocardiography (ECHO) with 2- and 3-dimensional (2D and 3D) vena contracta area (VCA), and magnetic resonance imaging (MRI) with regurgitant volume (RV) and fraction (RF) analyzed in CoreLab. Results: The mean follow-up was 587 days (interquartile range (IQR) 296–901) in a total of 104 patients. Twenty patients underwent AV surgery. Baseline clinical and laboratory data did not differ between surgically and medically treated patients. Surgically treated patients had larger left ventricular (LV) dimension, end-diastolic volume , and the LV ejection fraction was similar. The surgical group showed higher prevalence of severe AR . Out of all imaging markers 3D VCA, MRI-derived RV and RF were identified as the strongest independent predictors of AV surgery . Conclusions: Parameters related to LV morphology and function showed moderate accuracy to identify patients in need of early AV surgery at the early stage of the disease. 3D ECHO-derived VCA and MRI-derived RV and RF showed high accuracy and excellent sensitivity to identify patients in need of early surgery. Chronic aortic regurgitation (AR) is the third most common valvular heart disease in Western countries, with a prevalence of 0.1% to 2.0%. Degenerative etiology on tricuspid or bicuspid aortic valves and annuloaortic ectasia are the most common causes of chronic AR. Rheumatic fever remains a frequent cause of chronic AR in developing countries ,4. In chA combination of several clinical and imaging characteristics makes the timing of aortic valve (AV) intervention challenging. Patients with severe AR are often middle-aged males with a long asymptomatic course ,2,5. FurSeveral promising imaging approaches to assess AR or its impact on LV structure and function have emerged recently ,18,19,20A prospective, observational and multicenter study was conducted in three tertiary cardiology centers. All imaging markers were evaluated centrally in a CoreLab , which holds the European Association of Cardiovascular Imaging (EACVI) Laboratory accreditation and individual certification for both ECHO and MRI.2); and (5) sinus rhythm. Patients with guideline indications for AV intervention, acute AR, aortic dissection, endocarditis, irregular heart rate, associated with more than mild valvular disease, complex congenital heart disease, intracardiac shunt, creatinine clearance <30 mL/min, pregnancy, or contra indication for MRI were excluded [The study population consisted of all consecutive patients  with chronic severe AR and no indication for AV intervention who were referred to participating heart valve centers for AR assessment between March 2015 and September 2018. To be eligible for the study patients had to fulfil the following inclusion criteria: (1) severe AR defined by using the integrative 2D ECHO approach ; (2) absAn initial assessment was performed by specialized heart valve cardiologist in all participating centers. It included a history, clinical examination, Electrocardiography (ECG), bicycle ergometry, blood sampling, and comprehensive 2D and 3D ECHO. A cardiac MRI was performed in the center where the CoreLab was based for all participants. Patients from this particular center underwent MRI on the day of enrollment while patients from other two centers underwent an MRI within 2 weeks after the enrollment. Analysis of all ECHO- and MRI-derived markers were centralized in the CoreLab. After enrollment, patients were followed in participating heart valve centers every 6 months till 30 September 2018. The decision-making on conservative versus surgical treatment was left at the discretion of a particular heart valve team. In patients undergoing AV surgery, a perioperative biopsy was performed at the level of basal interventricular septum to assess the extent of myocardial fibrosis as previously described in our pilot study . The folA comprehensive 2D and 3D transthoracic ECHO was performed using a Vivid 7 and Vivid 9  ultrasound system equipped with 4-dimensional active matrix 4-D volume phased array probe. Several 3D ECHO loops in each view were recorded using ECG-gated full-volume acquisition over four (LV function) to six (color Doppler) cardiac cycles during end-expiratory apnea. Images were optimized by adjusting the depth, sector size, gain, number of frames per second (FPS), the number of heart beats, and breath hold. All acquired images were digitally stored, anonymized, and analyzed using the commercially available software EchoPac BT 202, GE HealthCare. An average of at least 3 beats was taken for each measurement. Blood pressure and heart rate was recorded during each examination.LV internal diameters were derived from an LV internal cavity using M-mode whenever possible. The biplane Simpson method was used to assess 2D LV volumes and Ejection fraction (EF) . A semi-An examination was performed using a 1.5T scanner . The protocol consisted of pilots, T2 weighted dark blood, cine with 2-, 4-, 3-chambers, and short axis (SA) images covering the entire end-diastolic ventricular length, through-plane phase-contrast velocity mapping at the level of the aortic root, contrast late gadolinium enhancement (LGE), and modified Look–Locker Inversion recovery sequence (MOLLI) ,23. AnalLV volumes and LVEF were calculated using the steady state free precession cine imaging in short-axis stack  with correction for the valve position in long-axis planes. LV radial, circumferential and longitudinal strain were assessed in the short axis and apical views. Native T1 relaxation time and extracellular volume fraction (ECV) were evaluated using the MOLLI sequence as previously described . The T1 Aortic forward and regurgitation flow were obtained by using the through-plane phase-contrast velocity mapping during breath-hold over 10–20 ms with retrospective ECG gating D. ParameApart from conventional clinical and imaging parameters, the value of the following new imaging markers to predict AV surgery was tested: 2D GLS, 2D myocardial work, 3D GLS, 3D VCA, MRI-derived native T1 relaxation time and ECV, MRI-derived GLS and circumferential strain, and MRI-derived RV and RF.t-test, Pearson χ2 or Fisher exact tests were used as appropriate. Receiver-operating characteristic curve analysis was used to identify imaging markers to predict future AV surgery. The optimal cutoff value for sensitivity and specificity was calculated according to the Youden’s index and according to the clinical relevance. Several Cox proportional hazard models were used to identify independent predictors of aortic valve surgery (AVR). The selection of variables for the models was based on clinical relevance. Care was taken to avoid overfitting and to avoid combining mutually dependent variables in one analysis. Results were reported as hazard ratios (HRs) with the 95% of confidence interval (95% CI) of probability values. The Kaplan–Meier method and log-rank test was used for temporal analysis of differences in AV surgery between groups. For all tests, values of p < 0.05 were considered significant. Statistical analysis was performed using the SPSS version 20  and the GraphPad Prism version 6.0 .Data are expressed as mean ± SD for continuous variables and as counts or percentages for categorical variables. Unpaired Student n = 2) or severe spine deformity (n = 1). Feasibility of MRI-derived T1 mapping and LV strain was 96% and 95%, respectively. Blood pressure and heart rate was similar during ECHO and MRI examination. The majority of patients were middle-aged males (86%) with bicuspid AV (76%). The most prevalent risk factor for coronary artery disease was hypertension (47%) with corresponding medication. Per study inclusion criteria, all patients were asymptomatic, in sinus rhythm, with normal LV dimensions, and LVEF. A total of 56 (54%) individuals had moderate-to-severe AR while the remaining 48 (46%) showed severe AR. During median follow-up of 587 days (interquartile range (IQR) 296–901 days), no patient died. A total of 20 (19%) individuals underwent AV surgery  while the remaining patients were treated conservatively (conservative group). Median time to AV surgery was 236 days (IQR 125–460 days). Clinical characteristics, BNP, and creatinine values were similar between groups (n groups .p < 05) and tended to have larger end-systolic volume (LVESV) than patients treated conservatively (p < 0.01). In contrast, LVEF derived by using whatever method was similar. Imaging markers of subtle myocardial damage , did not show statistically significant differences between groups, although 2D GLS tended to be lower in the surgical versus the conservative group (p = 0.07). Average myocardial fibrosis on perioperative myocardial biopsy (n = 14) was 15 ± 20%. The degree of myocardial fibrosis correlated significantly with MRI-derived LV mass (r = 0.66), native T1 relaxation time (r = 0.56), ECV (r = 0.31), and 2D ECHO-derived GLS (0.46).At 2D ECHO, patients who underwent AV surgery had significantly larger LV dimensions, end-diastolic volume (LVEDV) . Accordingly, we observed significantly larger velocity of the diastolic flow reversal in the descending aorta, 2D ECHO RV and RF of AR, and 3D ECHO VCA in patients treated surgically versus conservatively  (p < 0.01).Using the integrative approach, the surgical group showed a significantly higher prevalence of severe AR than the conservative group  . In cont2, had the largest AUC. Higher cutoff values of LVESD (>45 mm) or LVESDi (>22 mm/m2), approaching the guideline recommendations, were highly specific (>90%) but lacked the sensitivity (<20%). The MRI-derived volumes and their indexed values were also rather specific than sensitive. Out of the ECHO-derived indices of AR severity, the largest AUC was observed for velocity of diastolic flow reversal in aorta descendens and 3D VCA. The optimal cutoff value of 3D VCA ≥30 mm2 had a sensitivity of 80% and a specificity of 63% to identify future AV surgery . Combining VCA with LVESD or LVESDi increased the specificity up to 97% depending on the cutoff , and LVEF (LVEF <50%) are currently used as indications for AV intervention [2), with acceptable sensitivity (80%), was lower than previously proposed [2 increased specificity (75%–93%) at the expense of unacceptably low sensitivity (15%–30%). MRI-derived volumes were rather specific but had lower sensitivity. It is of note, that a considerable proportion of patients (38%) showed increased LV volumes at MRI despite normal 2D ECHO dimensions. Nevertheless, the predictive accuracy of LV dimensions or volumes, derived by either technique, were moderate with an area under the curve <0.7 in all cases. Several new markers describing subtle myocardial damage or dysfunction have emerged recently [p < 0.01) and 2D GLS significantly lower  compared with 30 healthy controls. Yet, these parameters failed to identify patients with early disease progression. This suggests that at the early stage of AR disease, the parameters reflecting subtle myocardial damage may not be accurate enough to predict early disease progression. Chronic AR leads to LV volume and pressure overload with subsequent hypertrophy, dilatation, systolic dysfunction, and heart failure. LV dimensions (LVESD >50 mm or LVESDi >25 mm/mrvention . Severalrvention ,8. In thproposed ,6,8. Usisitivity %–30%. MRrecently ,18,19,20recently ,23,26. Erecently . Severalrecently ,15,17. Irecently ,15. Of irecently ,28. BothThe majority of recommended indices to assess AR are semiquantitative, lack the sensitivity or their accuracy is hampered by jet eccentricity ,9,10. AcThe present study assessed the clinical value of new imaging markers in asymptomatic patients with chronic severe AR at the early stage of the disease. Parameters related to LV morphology and function showed moderate accuracy to identify patients in need for early AV surgery. This suggests their limited accuracy at the early stage of AR disease while they may become useful later in the disease course with ongoing LV remodeling. In contrast, 3D ECHO-derived VCA and MRI-derived RV and RF showed the highest accuracy and excellent sensitivity to identify patients in need for early AV surgery. This suggests their clinical potential since the recommended integrative approach is rather specific than sensitive.


The histologic difference between alcoholic cardiomyopathy (ACM) and idiopathic dilated cardiomyopathy (IDCM) is unclear. The present study aimed to identify the quantitative pathologic features of ACM compared with IDCM.Specimens from 6 regions  were sampled from each explanted heart. Specimens from 4 healthy donor hearts were obtained as normal control. Tissues were sectioned and Masson trichrome stained. Histomorphometry was performed to evaluate the amount of myocyte, fibrosis, fatty tissue, and interstitium by Image-Pro Plus 6.0 (Media Cybernetics).P < .05). The percentage of interstitium was 10.8 ± 4.8% in ACM vs 9.2 ± 6.2% in IDCM (P < .05). A significant difference of fibrosis, fatty tissue was not discovered. Moreover, the myocyte area was 65.37 ± 11.8% in ACM LV vs 70.03 ± 9.0% in IDCM LV (P < .001).A total of 408 specimens were obtained from 34 ACMs and 34 IDCMs; 8 specimens were obtained from 4 healthy donor hearts. Compared to healthy donor hearts, we observed an increase in fibrosis which replaces myocytes in myocardium of end-stage cardiomyopathy. The overall myocyte ratio in myocardium was 69.5 ± 8.7% in ACM vs 71.9 ± 7.4% in IDCM (We described histologic characteristics in ACM and IDCM. There might be a quantitative difference of myocyte, interstitium in myocardium between ACM and IDCM, especially in LV. No difference was found in the percentage of fibrosis between the 2 groups. The 5-year mortality of DCM is approximately 50% after diagnosis. In most cases, the cause of DCM was unclear, defined as “idiopathic” dilated cardiomyopathy (IDCM). Up to 40% cases were speculated to be associated with chronic alcohol consumption, which was termed as alcoholic cardiomyopathy (ACM).,5Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by progressive ventricular chamber enlargement and contractile dysfunction without increased left ventricle (LV) thickness. However, any specific clinical characteristics, immunologic biomarkers, or other criteria are not yet identified for distinguishing ACM from IDCM. We collected transmural samples from 178 patients with DCM when they underwent heart transplantation during the past decade at Fuwai Hospital, China. Among them, approximately 18% were diagnosed as ACM, providing an opportunity for quantitative investigation of the pathologic characteristics of ACM.In clinical practice, ACM is diagnosed by combining the dilated LV phenotype and a lengthy history of heavy alcohol abuse.The present study aimed to identify the histopathologic features of ACM compared to IDCM, which might be helpful to understand the development of ACM and differentiate it from IDCM.22.1In a retrospective analysis, 280 patients with end-stage cardiomyopathies who underwent heart transplantation at Fuwai Hospital from June 2004 to June 2015 were screened. Patients were excluded if they demonstrated evidence of uncontrolled hypertension, history of myocardial infarction or coronary artery disease with >50% stenosis of one or more epicardial coronary arteries or other identified causes. The diagnosis of ACM was patient with DCM with no identified cause and a long history of heavy alcohol abuse . IDCM was defined as left ventricular dilatation with impaired systolic function in the absence of known cardiac or systemic causes.Heart tissues from 4 healthy donors were chosen as normal controls. Their hearts were un-useful for transplantation due to blood-type incompatibility or other surgical reasons. These individuals died because of cerebrovascular or motor vehicle accident.The present study was approved by the Committee on Human Investigation at Fuwai Hospital  conforming to the principles of the Helsinki Declaration.2.2 Full-thickness samples from 6 regions including anterior LV, lateral LV, inferior LV, IVS, anterior right ventricle (anterior RV), and inferior RV were acquired at the junction of base-mid ventricle of heart. In normal control group, full-thickness samples were obtained from 2 regions including left free ventricle wall and right free ventricle wall. Specimens were fixed in 10% neutral buffered formalin, embedded in paraffin, cut into 3 μm sections, and stained with Masson trichrome.The tissues used in our study were obtained from explanted failing human hearts at the time of heart transplantation.2.3 The pixel intensity corresponding to myocyte, fibrosis, fatty tissue was acquired, respectively.,9 The interstitium space could be calculated by substracting the readily identifiable myocyte, fibrosis, fatty tissue from the total tissue.,11 The extent of myocyte, fibrosis, fatty tissue, and interstitium was presented as percentage of the whole examined section area.Whole slide images were acquired by a microscopic digital scanner  with 20× magnification. These scanned tiff image files are stored on the computer. We analyzed the pathologic images using Adobe Photoshop CS5 and Image-Pro Plus 6.0 .2.4T-test was used when compared to normal healthy donor hearts. For comparison of the histologic difference between ACM and IDCM, the general linear model (GLM) was used. Discontinuous variables were compared using the Chi-squared test. The SPSS software  was used, and a 2-tailed P < .05 was considered statistically significant.Continuous variables were presented as mean ± standard deviation, and categorical variables were expressed as numbers (%). 33.1P < .05) , valvular disease (n = 5), hypertensive cardiomyopathy (n = 25), congenital heart disease (n = 1), inflammatory disease (n = 19), left ventricular noncompaction disease (n = 3), arrhythmogenic right ventricular cardiomyopathy (n = 2), and end-stage hypertrophic cardiomyopathy (n = 6), 178 patients were with no identified causes. Among the 178 cases, 34 cases were confirmed as ACM based on their medical history . Another 34 patients with IDCM were selected for histomorphometrical comparison, matched by age and sex. A statistically significant difference was not observed in the clinical, laboratory examination, echocardiographic, and medical treatment data between the 2 group except for body mass index and total bilirubin level, which was moderately higher in patients with ACM compared to patients with IDCM  . The amount of fibrosis and fatty tissue was detected no quantitative difference . We found a significant difference in the percentage area of myocyte and interstitium between ACM and IDCM   of mitochondria, dehiscence of intercalated disks, and large vacuoles in cardiomyocytes.–16 In previous study, they reported milder changes in myocytic hypertrophy, fibrosis compared to IDCM using samples obtained by endomyocardial biopsy (EMB). Although EMB is considered to be safe in patients with cardiomyopathies, the size of the biopsy is about 2 to 5 mm3, leading great variability when comparing 2 biopsies from the same ventricle, and may not reveal the ventricle full-thickness changes.,19 In present study, we took advantage of transmural myocardial specimens avoiding the endocardial–epicardial distribution bias. The size of transmural sample in our study is approximately 0.6 to 0.8 cm3, making it more reliable when compared with EMB specimens in evaluation of histopathologic changes. We found there was a quantitative difference of myocyte, interstitium in myocardium between ACM and IDCM.Since the introduction of the term “alcoholic cardiomyopathy” in 1902, diagnosis for ACM is mainly based on a history of long-term heavy alcohol intake without abnormal loading conditions  or coronary artery disease and certain drugs , or other certain disease.P < .05). Our result was consistent with this finding. Moreover, they also reported that fibrosis differed among ACM and IDCM . This result was inconsistent with our data. In DCM, the percentage of fatty tissue was 0.07 ± 0.31%, the percentage of interstitium was 14.55 ± 3.93%. There was no statistical difference of interstitium between DCM and controls (EMB from hearts 7 days after transplantation). In our results, the percentage of fatty tissue was high. Our analysis was based on transmural specimens, the endocardial–epicardial distribution bias may contribute to this difference. In previous study, they reported the extent, distribution of ventricular pathologically characteristics varied between LV and RV. The histologic changes were maximally involved in LV, while right ventricle was usually spared. Also, in our study, we found histologic alternations in LV were more remarkable and valuable to that of RV in ACM and IDCM.In a previous study, extent of interstitial fibrosis was found higher in patients with DCM with end-stage HF than in tissue samples without heart disease (autopsy cases) (4.97 ± 0.83% vs1.12 ± 0.18%, 4.1Notably, there were several limitations in our study. First, population size in our study was modest, results of our study should be further validated in a larger cohort of patients. Second, in our study, patients with ACM were male, because of heavy drinking is common among men in China. Further study should be conducted to detect the effect of sex and race on the histologic characteristics. Finally, these samples were collected from patients with end-stage heart failure, so results could not reflect alcohol induced toxic effect on heart in early phase. But available transmural samples could only be collected from patients with heart failure when they receiving heart transplantation.In conclusion, we firstly described the histopathologic aspects in ACM based on transmural tissues. Our results provided insight into the histologic changes in ACM and IDCM.Data curation: Yu Nie.Formal analysis: Yu Nie.Funding acquisition: Yu Nie, Shengshou Hu.Investigation: Xuebiao Li.Methodology: Yu Nie, Shengshou Hu.Project administration: Yu Nie.Resources: Shengshou Hu.Supervision: Shengshou Hu.Validation: Hong Lian.Writing – original draft: Xuebiao Li.Writing – review & editing: Hong Lian, Shengshou Hu.


Left ventricular dysfunction is a rare side effect of bevacizumab occurring in 2–4% of cases. We report the case of a 68-year-old woman who presented to the emergency department (ED) with sudden onset of shortness of breath, orthopnea, and paroxysmal nocturnal dyspnea. She was tachypneic and in respiratory distress. Physical examination revealed jugular venous distention, diffuse expiratory wheeze, and bipedal edema. She had been started on bevacizumab for the treatment of hereditary hemorrhagic telangiectasia 1 month prior to presentation. Laboratory tests revealed BNP of 1697 pg/ml with slightly elevated troponin 0.05 ng/ml. Chest X-ray showed interstitial edema with cardiomegaly, and transthoracic echocardiogram showed ejection fraction of 30% with global hypokinesia. Left heart catheterization revealed widely patent coronary arteries. Flash pulmonary edema secondary to acute left ventricular dysfunction in this case was attributed to recent treatment with bevacizumab after ruling out other possible etiologies. This case highlights the importance of early recognition of this rare but potentially reversible side effect of bevacizumab to prevent long-term sequelae. Bevacizumab is a humanized monoclonal IgG antibody against vascular endothelial growth factor (VEGF) . VEGF plA 68-year-old woman with past medical history of hypertension, chronic kidney disease stage 3, hyperlipidemia, and hereditary hemorrhagic telangiectasia (HHT) presented to the emergency department with sudden onset of shortness of breath. She also reported chest pain, orthopnea, and paroxysmal nocturnal dyspnea. Review of systems was otherwise unremarkable. Her HHT was previously managed by regular blood transfusions and epsilon-aminocaproic acid. Because of the need for frequent blood transfusion due to persistent epistaxis and gastrointestinal bleeding, she was started on bevacizumab infusion at 15 mg/kg/dose  by her haematologist a month prior to presentation. Initial vital signs on presentation revealed respiratory rate of 25/min, oxygen saturation of 65% on ambient air, blood pressure of 138/83 mmHg, and pulse rate of 92/min. Physical examination revealed respiratory distress with diffuse wheeze, jugular venous distention, and trace pedal edema. Laboratory tests revealed markedly elevated brain natriuretic peptide (BNP) of 1697 pg/ml  with initial troponin of 0.05 ng/ml . Chest X-ray revealed pulmonary vascular congestion and interstitial edema with mild cardiomegaly. She was immediately placed on noninvasive ventilation and started on intravenous furosemide with quick symptomatic improvement. Transthoracic echocardiogram (TTE) showed ejection fraction of 30% and global hypokinesia . Of notShe refused to wear LifeVest and was placed on guideline-directed medical therapy including beta-blocker, angiotensin-converting enzyme inhibitor (ACEi), and aldosterone antagonist along with an oral diuretic. The patient progressively improved and was discharged three days later and scheduled for follow-up with cardiology for outpatient right and left heart catheterization. Two weeks later, she developed another episode of flash pulmonary edema deemed to be due to medication noncompliance. On this occasion, she underwent left and right heart catheterization which revealed widely patent coronary vessels , elevateDrug-induced cardiotoxicity usually manifests as heart failure or left ventricular systolic dysfunction. It is commonly caused by chemotherapeutic medications such as anthracyclines and alkylating agents but is becoming increasingly reported among biologic drugs such as trastuzumab and bevacizumab .Bevacizumab is a recombinant humanized monoclonal IgG1 antibody containing human framework regions and murine complementarity-determining regions. By binding to vascular endothelial growth factor (VEGF), bevacizumab prevents interaction with its receptors (Flt-1 and KDR) on endothelial cell surfaces therefore inhibiting angiogenesis . BevacizCommon side effects include bowel perforations, haemorrhage, delayed wound healing, hypertension, and venous and arterial thromboembolism. Left ventricular dysfunction is a rarely reported side effect of bevacizumab with an incidence of 1.2%, and this occurs irrespective of the route of administration .In this case, the probability of causal relationship of acute left ventricular dysfunction and bevacizumab can be rated as certain based on the World Health Organization and the Uppsala Monitoring Centre (WHO-UMC) algorithm .As with other antineoplastic medications, the pathogenesis of left ventricular dysfunction is unknown. Several mechanisms have been proposed including the formation of free radicals in the myocardium and inflammatory cytokines with resultant cardiac depression and congestive heart failure . This siSerial measurement of left ventricular ejection fraction either by transthoracic echocardiogram or by radionuclide angiocardiography, as done in patients receiving doxorubicin, may be a useful modality in monitoring patients planned for bevacizumab therapy via any route while the search for more sensitive and reliable predictors of eventual left ventricular dysfunction continues.In conclusion, bevacizumab causes reversible dose-dependent left ventricular dysfunction irrespective of the route of administration. It is prudent for clinicians to consider serial transthoracic echocardiogram and monitoring of systolic function to facilitate early detection of this medication side effect and dose adjustment. This is particularly important in patients at high risk of side effects from this class of drugs such as those with low body mass index, advanced age, preexisting or bevacizumab-induced hypertension, and other concurrent chemotherapies . Further


Tachycardiomyopathy (TCM) is an underestimated cause of reversible left ventricle dysfunction. The aim of this study was to identify the predictors of recurrence and incidence of major cardiovascular events in TCM patients without underlying structural heart disease (pure TCM). The prospective, observational study enrolled all consecutive pure TCM patients. The diagnosis was suspected in patients admitted for heart failure (HF) with a reduced ejection fraction and concomitant persistent arrhythmia. Pure TCM was confirmed after the clinical and echocardiographic recovery during follow-up. From 107 pure TCM patients , 17 recurred, 51 were hospitalized for cardiovascular reasons, two suffered from thromboembolic events and one died. The diagnosis of obstructive sleep apnoea syndrome  5.44), brain natriuretic peptide on admission (HR 1.01 for each pg/mL) and the heart rate at discharge (HR 1.05 for each bpm) were all independent predictors of TCM recurrence. The left ventricular ejection fraction at discharge (HR 0.96 for each%) and the heart rate at discharge (HR 1.02 for each bpm) resulted as independent predictors of cardiovascular-related hospitalization. Pure TCM is more common than previously thought and associated with a good long-term survival but recurrences and hospitalizations are frequent. Reversing OSAS and controlling the heart rate could prevent TCM-related complications. Tachycardiomyopathy (TCM) is an important cause of dysfunction of the left ventricle . It is dThe first descriptions of TCM were collected by Phillips and Levine in 1949. In their milestone paper, they hypothesized that patients with long-lasting atrial fibrillation could develop heart failure without any other evidence of structural heart disease, and such heart failure could completely disappear after the restoration of the sinus rhythm .TCM is estimated to be under-recognized  and the The diagnosis of TCM is retrospective and based on the evidence of recovery after appropriate treatment. In fact, although, an arrhythmia is present with a concomitant left ventricular ejection fraction (LVEF) impairment, a cause-effect relationship is not always ascertainable . There iThe aim of this study was to identify the possible predictors of recurrence and long-term morbidity and mortality of pure TCM.This is a prospective, observational study taking into account all patients admitted for acute HF with reduced ejection fraction from January 2012 to the end June 2018 in the Cardiology and Arrhythmology Clinic of the University Hospital “Ospedali Riuniti” of Ancona, Italy, and presenting with evidence of atrial or ventricular arrhythmias on admission.The potential triggering arrhythmias considered were: Atrial fibrillation (AF), atrial flutter, supraventricular tachycardia, ventricular tachycardia and premature atrial and ventricular complexes. More specifically, this study considered significant > 20000 premature ventricular complexes per day, according to the current available literature .The selection process is detailed in The study was conducted according to institutional guidelines, national legal requirements, European standards and the revised Declaration of Helsinki. Being an observational study, a formal approval of the ethics committee was not sought. All patients provided prior written informed consent for anonymous collection and publication of their clinical data. The present report complies with the STROBE initiative  14]..14].The primary endpoint was the recurrence of TCM, defined as a new episode of acute HF with reduced ejection fraction along with the evidence of atrial or ventricular arrhythmia, occurring after complete clinical (no HF symptoms) and echocardiographic (LVEF ≥ 50%) recovery of the original episode.The secondary endpoints were: Death from all causes, major adverse cardiovascular events , and cardiovascular hospitalizations. Cardiovascular hospitalizations were defined as any hospitalization longer than 12 h for one or more of the following reasons: Acute coronary syndrome, unstable angina, HF, atrial or ventricular arrhythmia, valvular heart disease, infective endocarditis, myocarditis, pericarditis, aortic disease, pulmonary embolism, stroke/transient ischemic attack, syncope, cardiovascular-related elective and urgent procedures and complications of such procedures.Two expert physicians were responsible for the prospective data collecting regarding the patients’ demographics, risk factors, medical history and treatment. Continuous 12-lead ECG monitoring  was used to assess the heart rate during hospitalization and underlying arrhythmias. The blood samples for brain natriuretic peptide (BNP) and troponin I were collected on admission and at discharge. Echocardiographic examinations were performed with a monoplane ultrasound probe 4 MHz (M4S) of Vivid 7 Pro . The digital loops were captured, recording at least three consecutive beats, and analysed off-line using a dedicated software  according to the most recent recommendations. A complete echocardiogram was performed on admission, at discharge, at a 3-month follow-up. Serial echocardiograms were then performed at least every 6 months until complete recovery of LVEF. The echocardiographic loops were obtained with the patient supine and in the left lateral decubitus at the end of a normal breath, minimizing the depth in order to optimize the frame rate (40–80 fps).s LVEF was calculated by the Simpson biplane method. All echo exams were reviewed by two authors (G.S. and F.G.), who were responsible for the off-line analysis and collected all measurements blinded to the recurrence or other clinical endpoints. The inter-operator coefficient of variations for LVEF was 3.2% and the intra-operator coefficient of variation was 2.4%.To allow for the comparability of drug regimens across the patients taking many different medications, a treatment intensity score (TIS) was calculated. As previously reported,  the recoAll continuous variables were checked for normality through the Kolmogorov-Smirnov test. The normally-distributed variables were described by the mean and standard deviation and compared by analysis of variance. The not-normally-distributed variables were described as the median and 1st–3rd IQR and compared by non-parametric tests. The categorical variables were described as the absolute and relative values, and compared by chi-square test or Fisher exact test, as appropriate.The Kaplan-Meier analysis was used in order to assess the time free from primary and secondary endpoints. The association between the individual variables and the risk of TCM recurrence and cardiovascular hospitalization was investigated by using univariate Cox proportional hazards models. The variables that showed an association with each endpoint with a significance level < 0.1 on univariate analyses were entered into the multivariable Cox proportional hazards model. The independent risk factors for each endpoint were then presented as hazard ratios (HRs) and 95% confidence intervals (CIs).The linearity assumption of the relationship between the independent continuous risk factors and the outcome of interest was represented using restricted cubic splines with three knots located to the 10th, 50th, and 90th percentiles according to the Harrell rule, and assessed by the Wald test for linearity.p < 0.05 (two-tailed) were considered as statistically significant.SPSS 22.0 for Windows  and R  were used for statistical analysis. The values of The population included 107 patients . The patients’ characteristics are summarized in During the follow-up, 17 patients experienced at least one recurrence  and 51 were hospitalized for cardiovascular reasons (47.7%). Among the major adverse cardiovascular events, two patients suffered from thromboembolic events (1.8%) and one died from cardiovascular causes (0.9%). No non-fatal myocardial infarctions were reported. The annual incidence of recurrence was 8.4% per year, 0.9% per year for thromboembolic events and 0.4% per year for cardiovascular mortality.The only death occurred in a 58-year old male, one year and three months after recovery of both NYHA class and LVEF. The patient had no evidence of progression to any kind of structural heart disease and died suddenly after an out-of-hospital cardiac arrest due to idiopathic ventricular fibrillation. One transient ischemic attack and one non-fatal stroke occurred in two different patients after 3 and 832 days, respectively. The treatment strategies at discharge are described in Out of the 17 patients experiencing recurrences, seven had multiple recurrences, with six patients experiencing two recurrences and one experiencing four. The arrhythmic disorder underlying TCM recurrences was AF in 15 cases (88%) and atrial flutter in two cases (12%).The majority of recurrences occurred between the fifth and the sixth year after the first diagnosis as seen in The multivariate Cox regression analysis showed that presence of obstructive sleep apnoea syndrome (OSAS), BNP on admission and the heart rate at discharge were all independent predictors of TCM recurrence .The univariate model included: The male gender, age, body mass index, hypertension, diabetes, dyslipidaemia, chronic kidney disease, chronic obstructive pulmonary disease, OSAS, hyperthyroidism, hypothyroidism, type of arrhythmia, NYHA class on admission and at discharge, heart rate on admission and at discharge, BNP on admission and at discharge, Troponin I on admission and at discharge, LVEF on admission and at discharge, iLAV, rate or rhythm control (dummy variable) and pharmacological treatment at discharge . The mean values for both the heart rate and LVEF throughout the index event, the follow-up and at the time of recurrence are shown in According to the spline curves, the heart rate at discharge and the risk or TCM recurrence had a linear association (p > 0.05).Comparing TIS for each drug class considered in From the 17 patients experiencing recurrences, 13 were under a rhythm-control strategy and four were under a rate-control strategy. Twelve patients underwent catheter ablation of AF and two underwent ablation of atrial flutter. The patients undergoing catheter ablation of atrial flutter experienced no further TCM recurrences, while five patients presented a second TCM recurrence after the procedure. Three patients with AF refused consent to catheter ablation and were therefore shifted to a rate-control strategy, with one patient experiencing no further recurrences, one experiencing a second recurrence and another patient experiencing three more recurrences over the follow-up.From the 51 patients hospitalized for cardiovascular reasons during the follow-up, 15 were hospitalized more than once.More than 40% of all cardiovascular-related hospitalizations occurred within the first year after the first diagnosis .EF at discharge and the heart rate at discharge resulted as independent predictors of cardiovascular-related hospitalization according to the multivariate Cox regression model .The univariate model included: The male gender, age, body mass index, hypertension, diabetes, dyslipidaemia, chronic kidney disease, chronic obstructive pulmonary disease, OSAS, hyperthyroidism, hypothyroidism, type of arrhythmia, NYHA class on admission and at discharge, heart rate on admission and at discharge, BNP on admission and at discharge, Troponin I on admission and at discharge, LVEF on admission and at discharge, iLAV, rate or rhythm control (dummy variable) and pharmacological treatment at discharge .Comparing TIS for each drug class considered in The main message of the present study is that, while TCM is associated with an overall good prognosis, TCM patients do recur over a long-time follow-up.This represents an outstanding difference between HF patients and pure TCM patients as the former is known to be a progressive, worsening condition commonly culminating in the patient’s exitus. Although under-recognized, this study shows that almost 10% of all hospitalizations for acute HF meet the diagnostic criteria for TCM. Therefore, early recognition of the possible triggering arrhythmia is of paramount importance as it can lead to treatment strategies which can favour patient recovery. A clinical suspicion of TCM should arise in all patients presenting with new and quickly worsening symptoms of HF, a low overall cardiovascular risk profile and the recent evidence of high-rate arrhythmia. In these cases, a prompt reduction of the heart rate (either through rate control drugs or restoration of sinus rhythm) should be performed as soon as possible, and possibly even while the diagnostic workup for the exclusion of structural heart disease is still in progress. A cardioversion attempt should be made (when feasible) in order to prevent further deterioration of the systolic function and catheter ablation should be taken into serious consideration [The rate of TCM recurrence is higher between the fifth and the sixth year after diagnosis. It can only be speculated that this could be due to the natural progressive reduction of the patients’ adherence to treatment over time.Our multivariate analysis found three major independent predictors of TCM recurrence. The most important was a concomitant diagnosis of OSAS, which increased the risk of recurrence 5-fold. It was hypothesized that this could be related to the fact that OSAS can alter the physiological parasympathetic modulation of the heart during sleep leading to sympathetic excitation and favouring ventricular and atrial ectopic beats ,17. MoreAnother striking result that warrants discussion is that the heart rate at discharge is associated with an increased risk of TCM recurrence. More precisely, for each increased beat per minute, the risk of recurrence increases by 5%. Moreover, this association proved to be linear, at least within the ranges of the heart rate seen in our population, and holds true independently of the rhythm at discharge, the treatment strategy and the class of medications used. To make an example, a patient with a lenient rate control strategy (110 bpm) has a 2.5-fold risk of TCM recurrence when compared to the same patient undergoing a strict rate control strategy (80 bpm). This is in contrast to the known evidence that both the heart rate targets are considered similarly effective in preventing adverse events in patients with AF . The reaAlthough recent reviews and small case series ,26,27 haRegarding major clinical events, there were a few and potentially unrelated to the combination between HF and tachyarrhythmia. Finally, in terms of cardiovascular related hospitalizations, almost half of this study’s population was re-hospitalized, even though by definition, none had structural heart disease. Most hospitalizations occurred during the first year after the event and were related to rhythm control procedures, such as elective cardioversions and catheter ablations. Moreover, 16 hospitalizations were due to the recurrence of TCM. The heart rate at discharge confirmed its predicting value along with the LVEF at discharge. Similar to the fact that heart rate reduction has been demonstrated to be beneficial in HF , our datThis paper shares all the limitations characterizing all prospective observational studies. In addition, this study’s population was relatively small, and the low sample size made subgroup analyses unfeasible. Nonetheless, current available literature relies on case series and, to our knowledge, this is the largest dataset on pure TCM taken into account so far.The cut-off used to define pure TCM (improvement of at least one NYHA class and > 5% EF) could seem rather small, but unfortunately, there is no consensus on any cut-off for TCM. Although surely arbitrary, the authors chose this cut-off because it was thought that, after ruling out all causes of structural heart disease, a patient undergoing a clinical and echographic improvement could be considered as having TCM, being the arrhythmia the only remaining and plausible cause of his/her condition. A higher cut-off, as the one proposed by Jeong and colleagues , could hFurthermore, HF treatment could be considered as a potential confounder in the association between the heart rate and EF improvement/worsening. However, the heart rate was a predictor of the recurrence independently of any kind of pharmacological treatment at discharge . As the In conclusion, TCM is an under-diagnosed entity, affecting nearly one out of ten patients admitted for HF. Pure TCM  is associated with a good long-term survival. Nonetheless, recurrences are frequent and can occur after many years. The treatment aimed at reversing OSAS and lowering the heart rate after the acute event could prevent these recurrences and their related hospitalizations.


Mechanical circulatory support (MCS) is often required to stabilize patients with acute fulminant myocarditis with cardiogenic shock. This review gives an overview of the successful use of left-sided Impella in the setting of fulminant myocarditis and cardiogenic shock as the sole means of MCS as well as in combination with right ventricular (RV) support devices including extracorporeal life support (ECLS) (ECMELLA) or an Impella RP (BI-PELLA). It further provides evidence from endomyocardial biopsies that in addition to giving adequate support, LV unloading by Impella exhibits disease-modifying effects important for myocardial recovery  achieved by this newly termed “prolonged Impella” (PROPELLA) concept in which LV-IMPELLA 5.0, implanted via an axillary approach, provides support in awake, mobilized patients for several weeks. Finally, this review addresses the question of how to define the appropriate time point for weaning strategies and for changing or discontinuing unloading in fulminant myocarditis.The online version of this article (10.1007/s12265-018-9820-2) contains supplementary material, which is available to authorized users. The diagnosis and treatment of myocarditis is still a clinical challenge due to the variability of its clinical presentation ranging from mild dyspnea or chest pain to cardiogenic shock and death . In patiIn this review, we provide an overview of the successful use of an Impella-based strategy for treatment of fulminant myocarditis and cardiogenic shock as a sole means of supporting the circulation, and in combination with ECLS (ECMO plus Impella: ECMELLA), or in combination with RV-Impella RP (BI-PELLA). Furthermore, we provide new evidence that this “unloading” strategy not only provides the required circulatory support but also provides additional disease-modifying effects important for myocardial recovery (bridge-to-recovery) in these patients. Specifically, we emphasize the importance of prolonged use of the LV-Impella for several weeks in this setting, a newly termed PROPELLA (prolonged Impella) concept. Finally, we also address the important questions of how to define the optimal time points and strategies for initiating weaning, escalating, or discontinuing support in fulminant myocarditis.Several case reports have demonstrated successful short-time use of LV-Impella in patients with fulminant myocarditis in which RV function was not significantly impaired and patients were not in need of biventricular support –10. In tIn cases of fulminant myocarditis with additional severe impairment of the RV, ECLS is the most frequently used form of MCS –6. NeverLV venting via cannulation of the left atrium, via transvenous balloon atrial septostomy , 13, viaA study comprising 135 patients who underwent ECLS and concomitant IABP implantation has shown that ECLS combined with IABP can be an effective therapy in some cases. In that study, prior IABP use was an independent predictor of reduced in-hospital mortality, stroke, or vascular injury . UnfortuP < 0.001) and a higher rate of successful bridging to either recovery or further therapy  compared to ECLS patients. This study comprised ischemic as well as non-ischemic-induced cardiogenic shock patients, including myocarditis patients. These promising results need further validation, ideally in randomized studies, in patients with refractory cardiogenic shock. Besides this trial, only a few case reports are available reporting the short-time use of the ECMELLA concept as bridge-to-recovery in fulminant myocarditis [Comparing Impella with the abovementioned methods of LV unloading, LV-Impella 2.5 or CP has the advantage to be inserted percutaneously avoiding the need of surgical interventions and provides a higher degree of hemodynamic support compared to IABP. Besides being less invasive than classical decompressive techniques, Impella is associated with lower requirements for blood products with fewer thromboembolic complications , 18. Thecarditis , 21, indAs an alternative to the ECMELLA concept to achieve biventricular support, Pappalardo et al.  recentlyAs discussed, a strategy that simultaneously provides both sufficient circulatory support and LV unloading can be particularly effective in patients with fulminant myocarditis and cardiogenic shock. However, hemodynamic stabilization alone does not guarantee recovery of myocardial function. Myocarditis is usually characterized by a systemic inflammatory immune system –27 whichThe impact of prolonged unloading on these myocardial processes and, ultimately, on myocardial recovery in fulminant myocarditis is so far unknown. In the context of chronic heart failure, it is well established that prolonged LV unloading achieved with durable LVADs can lead to reverse remodeling based on anti-fibrotic and anti-inflammatory mechanisms , 34, canWe report here, for the first time to our knowledge, the impact of a LV-Impella 5.0 implanted through an axillary approach for 39 days combined with standard heart failure therapy , which does not represent a causal therapy, and immunosuppressive therapy consisting of prednisolone  followed by 10 mg/day weaning all 2 weeks until reaching 10 mg/day maintenance dose), and azathioprine (100 mg/day) in a patient presenting with fulminant myocarditis and cardiogenic shock. With this approach, the patient did not require sedation and was able to be mobilized daily. No catecholamine treatment was needed despite an initial LV ejection fraction of < 10%. Anticoagulation was maintained with intravenous heparin . Improvements of cardiac function were observed within 5 days of MCS and inotropic support was not needed. Following temporary reduction of pump flow on day 21, LV performance was improved, indicating the ability of the native heart to provide circulatory support , and all other parameters of end organ dysfunction should be recovered to baseline.In principle, investigation of the LV and the RV function before PROPELLA or ECMELLA weaning is fundamental to anticipate univentricular or biventricular recovery and the need for possible subsequent LVAD placement. Before weaning, patients under Impella support must meet the criteria of being afebrile and euvolemic and compensated with resolution of pulmonary edema and adequate arterial PaOStage 1: baseline RV and LV function of the heart are measured by echocardiography on full LV-Impella support.Stage 2: after evaluation of baseline data, Impella RPMs (and therefore flow) is decreased in single steps  with the goal of achieving half of the original RPMs with maintenance of adequate hemodynamics. At every flow level, RV and LV function and hemodynamic responses (blood pressure and heart rate) are monitored over 5–10 min to allow estimation of ventricular function and volume status. If, at any period in the weaning protocol, RV or LV distension occurred or significant hypotension or increase in heart rate is observed, the weaning protocol is stopped and Impella support is returned to full flow.Stage 3: If stage 2 was successful, Impella support will continue to be reduced by one step for 24 h and then reevaluated like described under stage 2.Stage 4: If stable RV and LV function, hemodynamics and volume status are maintained for 48 h on P2 Impella support, inotrope stress test with dobutamine will be performed in which RV and LV functions and hemodynamics are observed for responses over 30 min. If both, RV and LV function are recovered, the patient will be considered for Impella removal. This procedure is not performed in patients who spontaneously increase their LV function during pump reduction flow, as is often detectable in myocarditis patients with recovery. Here, we decide to support unloading as long as possible to be able to invoke the proposed disease-modifying mechanism for complete recovery (PROPELLA concept). In our experience, a time frame of about 4 weeks is appropriate for this purpose, since the weaning stress test was positively completed. We also wanted to reduce potential side effects like embolism and infections under immunosuppression. Therefore, we found the explantation time point after 4 weeks in this case appropriate. However, the explantation time point can differ depending on the individual clinical scenario.In our department, we established a weaning protocol consisting of four stages:There is accumulating evidence showing that LV unloading via a transcutaneously placed axial flow pump is a viable treatment option for patients with fulminant myocarditis and cardiogenic shock. Such therapy is feasible as sole LV MCS when RV function is sufficient, but can be used in combination with ECLS (the ECMELLA concept) or in combination with a right-sided Impella RP (the Bi-PELLA concept). One of the advantages of the ECMELLA approach is the possibility to deescalate the ECLS flow rates and reduce loading effects on the LV. Improvement of RV function can permit removal of the more invasive ECLS approach, enabling the conversion of the ECMELLA to the PROPELLA concept, if longer LV hemodynamic support is still necessary.Besides circulatory support and LV decompression, of which the latter is required to reduce myocardial wall stress, decrease myocardial oxygen requirements, and enhance the chances of recovery, we report for the first time that prolonged unloading (the PROPELLA concept) leads to additional disease-modifying effects over time that can be important for enhancing myocardial recovery in patients with chronic fulminant myocarditis. These disease-altering effects include unloading-induced reductions of myocardial inflammation, modulation of cardiac remodeling, and restoration of more normal metabolic machinery. Such effects may be critical to the restoration of cardiac structure and function, suggesting that the therapeutic effects of Impella support go beyond its primary use as mechanic support for normalizing hemodynamics. Evidence illustrating the impact of LV unloading on cellular and molecular mechanisms influencing cardiac remodeling, fibrosis, inflammation, and calcium metabolism is so far mainly derived from studies of durable LVADs , 46. MecMovie 1A (movie 1): Full Impella 5.0 support at level P8: 5.2 L/min and severe reduced LV function. (MP4 871 kb)Temporary pump flow reduction maneuver under echocardiographic evaluation in a patient with fulminant myocarditis and a prolonged Impella 5.0 support (PROPELLA concept) at day 21. Movie 2B (movie 2): Temporary reduction of Impella 5.0 support at level P1: 1.2 L/min, showing an immediate increase in LV function indicating that reduced LV function during full circulatory support (movie 1) belongs to a beneficial LV unloading mechanism and can be used as a sign for recovery. A temporary pump flow reduction maneuver under echocardiographic evaluation is useful in clinical practice for assessing suitability for weaning of the PROPELLA-concept. (MP4 786 kb)Temporary pump flow reduction maneuver under echocardiographic evaluation in a patient with fulminant myocarditis and a prolonged Impella 5.0 support (PROPELLA concept) at day 21. Movie 3A (movie 3): Reduced ECMELLA support Temporary pump flow reduction maneuver under echocardiographic evaluation in a patient with cardiogenic shock based on a fulminant myocarditis and maximal mechanical circulatory support with ECLS and Impella (ECMELLA concept) at day 7. Movie 4B (movie 4): Temporary reduction of ECLS flow 1.8 L/min and Impella CP at level P1: 0.8 L/min, showing an immediate increase in LV function indicating that reduced LV function during higher circulatory support (movie 3) belongs to a beneficial unloading mechanism and can be used as a sign for recovery. A temporary pump flow reduction maneuver under echocardiographic evaluation is useful in clinical practice for assessing suitability for weaning of the ECMELLA-concept. (MP4 889 kb)Temporary pump flow reduction maneuver under echocardiographic evaluation in a patient with cardiogenic shock based on a fulminant myocarditis and maximal mechanical circulatory support with ECLS and Impella (ECMELLA concept) at day 7. Movie 5A (movie 5): Full Impella CP support at level P8: 3.4 L/min and severe reduced LV function. (MP4 1195 kb)Temporary pump flow reduction maneuver under echocardiographic evaluation in a patient with ischemic cardiomyopathy at day 7. Movie 6B (movie 6): Temporary reduction of Impella CP support at level P1: 1.2 L/min, showingno change in LV function, indicating that no LV function recovery can be expected at this time point. (MP4 1119 kb)Temporary pump flow reduction maneuver under echocardiographic evaluation in a patient with ischemic cardiomyopathy at day 7. Movie 7A (movie 7): Reduced ECMELLA support Temporary pump flow reduction maneuver under echocardiographic evaluation in a patient with cardiogenic shock based on an acute myocardial infarction under maximal mechanical circulatory support with ECLS and Impella (ECMELLA concept) at day 8. Movie 8B (movie 8): Temporary reduction of Impella CP at level P1: 0.8 L/min under reduced ECLS flow of 1.0 L/min, showing a close to comparable LV function, indicating that no LV function recovery can be expected at this time point. (MP4 347 kb)Temporary pump flow reduction maneuver under echocardiographic evaluation in a patient with cardiogenic shock based on an acute myocardial infarction under maximal mechanical circulatory support with ECLS and Impella (ECMELLA concept) at day 8.


It is well recognized that organized management of heart failure patients, including care by heart failure specialists, improves outcomes of these patients. In response to this, the Heart Failure Association of the European Society of Cardiology proposed a basic framework of a heart failure curriculum, which became a blueprint for training programs across Europe. The present curriculum for heart failure was well coordinated with the version issued by the German Society for Cardiology in order to achieve good comparability. Training in this Austrian curriculum takes two years, during which the predominant activity focuses on the care of patients with heart failure. The first year includes general (basic) training, while in the second year special modules  must be chosen that impart in-depth knowledge, experience and/or skills. Of the five offered modules two must be completed for 6 months each. At least one specialist in internal medicine and cardiology with the additional qualification of heart failure must act as a supervisor at the training center. A certified Heart Failure Unit or a comparable structure should be available at the training center and integrated into the clinical routine of the cardiology department. Applications for recognition of curricular achievements in order to obtain the additional qualification “heart failure specialist” shall be evaluated by a dedicated committee of the nucleus of the Heart Failure Working Group of the Austrian Cardiological Society. The candidate will receive recognition of the additional qualification in heart failure, issued by the Austrian Cardiological Society. As a result of the enormous advances made in theoretical knowledge and methodologies, cardiology has become increasingly specialized in various areas. The board of the Austrian Cardiological Society (ÖKG) is aware of this development and has commissioned the Working Groups for Heart Failure, Interventional Cardiology, Cardiac Imaging and Rhythmology to draw up curricula for obtaining additional qualifications within cardiology. These curricula are intended to facilitate a further deepening of cardiological knowledge and technical skills within the discipline. On the one hand, they build on the contents of the training in internal medicine and cardiology, while on the other hand they go beyond the theoretical knowledge and technical skills required by the training regulations for cardiology. For these curricula the term additional qualification was chosen in order to distinguish the additional qualification under the umbrella of the scientific societies from the requirement for specializations that are laid down in the Physicians Act (ÄrzteG § 49). Specializations are regulated in the Framework Specialization Ordinance 2015 and in the Specialization Ordinance 2017 of the Austrian Medical Association. An internationally comparable format is explicitly required for a curriculum. The present curriculum for heart failure was therefore coordinated with the version issued by the Heart Failure Association (HFA) of the European Cardiological Society (ECS) .Acute and chronic heart failure are disease patterns that are playing an increasingly important role in cardiology and medicine as a whole. The clinical syndrome “heart failure” has become the most frequent cause for hospital admission in Austria . At the This curriculum is therefore intended to define a framework within which interested colleagues can acquire in-depth knowledge, practical experience and skills in the field of heart failure and obtain certification as such. In future, every cardiologist should have sufficient knowledge of the diagnosis and treatment of heart failure. Patients with advanced heart failure or rare cardiomyopathies in particular, benefit from treatment by colleagues who have been trained in depth and in a structured manner within the framework of a curriculum. In the interest of future Europewide compatibility, the basic structure of this curriculum is based on a proposal made by the Heart Failure Association of the European Society of Cardiology  and the The aim of specialization within the curriculum of heart failure is to train physicians in the etiology, pathophysiology, diagnostics and treatment of acute and chronic heart failure in all stages, namely beyond the standard of general cardiologists. In this process, comprehensive knowledge is acquired in diagnostics, drug-conservative and interventional, electrophysiological, “device” treatment and intensive care of heart failure. The curriculum is certified by the ÖKG Heart Failure Working Group on the basis of defined knowledge, practical experience and skills, thus ensuring the quality of this specialization. This concerns both the candidates to be trained and the training centers.Training in the curriculum “heart failure” takes 24 months (2 years), during which the predominant activity focuses on the care of patients with heart failure. According to the proposal made by the Heart Failure Association of the ESC, the first year should include general (basic) training, while in the second year special modules must be chosen that impart in-depth knowledge, experience and/or skills Fig. . Of the Advanced chronic and acute heart failure with specialized treatment optionsDevice treatment for heart failureInterventional heart failure treatmentOutpatient care or rehabilitationSpecific diagnostics for heart failureCurriculum modules:The possibility to choose special modules takes into account the fact that there is no uniform heart failure specialist, as patients are treated at different stages of the disease or in different situations (e. g. outpatient versus inpatient). Some treatment modalities  also require expertise that not every heart failure specialist can or must master. At the same time, basic training and proof of having attended pertinent training courses ensure that all heart failure specialists have a comparably high level of knowledge and basic skills. The modules should be completed semester by semester and within 5 years.The main aim of the first year of the curriculum is to gain in-depth clinical experience in the diagnosis and treatment of heart failure patients. The candidate should document at least 80 cases using a logbook . In addition to documentation of the  diagnostic procedure and the systematic recording of comorbidities, the indication for multimodal treatment of heart failure should be mastered . Each person completing the first year of the curriculum should also have acquired the knowledge and skills to care for patients with acute heart failure and have documented this in at least 20 cases using the logbook. A total of at least 100 patients with acute or chronic heart failure should be diagnosed.For specialization in the field of heart failure, the candidate must have completed at least two of the following modules , as well as ventricular assist devices will be introduced. The selection of patients for heart and heart/lung transplantation and the care of patients before and possibly after heart transplantation will also be taught and learnt.The device treatment module includes implantation and aftercare of implantable cardiac aggregates, e.g. cardiovascular implantable electronic devices (CIEDS), such as antibradycardia pacemakers, implantable cardioverter defibrillators (ICD), cardiac resynchronization therapies defibrillator (CRT-D), and cardiac resynchronization therapies pacemaker (CRT-P) systems.In this module, the candidate is assigned to the department’s cardiac catheterization laboratory and deals with interventional examinations and therapies in heart failure patients.In this module, the candidate is either (I) trained in the outpatient care of heart failure patients or (II) taught in the rehabilitation of heart failure patients .In this module the candidate will receive in-depth training in specific diagnostics related to cardiac imaging  and genetic analysis in heart failure patients.Basic training in internal medicine and cardiology of at least 3 years is required before commencing the curriculum. Moreover, basic echocardiographic knowledge and at least 6 months of intensive care experience are required. Credit may be given for equivalent knowledge, experience and skills in cardiology for a maximum period of 12 months. If all prerequisites are fulfilled, the candidate can be recognized as holding a specialisation in heart failure at the earliest 12 months after completion of training as a specialist in cardiology.At least one specialist in internal medicine and cardiology with the additional qualification of heart failure must act as a supervisor at the training center. The supervisor should have 5 years of experience in the care of heart failure patients (see below). Following the position paper heart failure unit (HFU) of the German Society of Cardiology   can be completed at an HFU specialty clinic or a supraregional HFU center.Depending on the modules completed, the special training (2nd year) can be completed at a department with a special HFU clinic, a supraregional HFU center, a special HFU outpatient clinic or a rehabilitation center for cardiovascular diseases with a focus on heart failure. During this period, the candidate is predominantly assigned to the care structures corresponding to the module. To achieve specialization, the candidate must have completed at least two different modules for a total training period of 12 months, namely 6 months for each module  can be completed at a heart failure outpatient clinic of a department with a specialized HFU clinic or a supraregional HFU center or in a specialized HFU outpatient clinic. The rehabilitation module can be completed in an outpatient or inpatient rehabilitation center for cardiovascular diseases with a focus on heart failure.The module specific diagnostics for heart failure should be completed at a department with an HFU specialty clinic or a supraregional HFU center.Regular conferences with case reviews of heart failure patients should be offered at the center. Instruments for quality assurance  should also be implemented. The candidate should regularly attend these meetings and have presented at least three cases. The requirements for an HFU in the heart failure network were drawn up on the basis of the corresponding consensus paper issued by the DGK/DGTHG . The folStaff: cardiology specialist, certified specialist assistant staff . Cooperation: effective cooperation with an HFU specialty clinic or HFU in the supraregional center. Diagnostics: electrocardiogram (ECG), long-term ECG, stress ECG, possibility for echocardiography and PM, ICD and CRT aftercare, possibility for testing for troponin and natriuretic peptide. Appointments to be given: acute <48 h, post-stationary <7 days.Staff at intensive care unit (ICU) or intermediate care unit (IMCU): specialist in cardiology and intensive care medicine or specialist in heart surgery and intensive care medicine, or interdisciplinary management, doctor 24/7 on site, specialist 24/7 on call, key care/patient = 1/4. Cooperation: proven cooperation with HFU in supraregional center. Structure: at least four hospital beds (IMCU or ICU), availability 24/7. Diagnostics: long-term blood pressure monitor, echocardiography , X ray, CT, hemodynamics. Treatment: ventilation (invasive and/or non-invasive), hemodialysis, cardiac catheterization laboratory with 24/7 percutaneous coronary intervention (PCI) availability, ICD/CRT implantation.Staff: heart team (cardiologist and heart surgeon) 24/7, ventricular assist device (VAD)/heart transplantation (HTx) coordinator 24/7, if necessary. Structure: at least four hospital beds (IMCU or heart failure ICU) in an area separate from the general intensive care unit, cooperation with heart transplantation or VAD center, if necessary. Diagnostics: sleep apnea screening, lung function test, spiroergometry, cardiac MRI, myocardial biopsy. Treatment: percutaneous cardiac support systems , extracorporeal life support systems (ECLS), transfemoral aortic valve implantation (TAVI), endovascular mitral valve reconstruction, ablation of complex ventricular tachycardia.A physician specialized in internal medicine and cardiology with a concentration on heart failure must act as supervisor at the training institution. The supervisor should have 5 years of experience in the care of heart failure patients.This head of the specialization program ensures that the candidates receive the necessary supervision when learning the diagnostic and therapeutic procedures dictated by the curriculum. The specialist also ensures that the candidates attend the formal learning units and courses and are involved in the department’s training and research activities.The following requirements apply for the training supervisor:Qualification report written by the supervisor of the specialization program. The report contains details on the activities, competence and achieved independence of the candidate. In addition to information on theoretical knowledge and experience, it also contains a description of progress made in practical activities and theoretical knowledge about heart failure.Documentation of the patient cases or the examinations/procedures conducted in a logbook (in hard copy or electronic form). The correctness of the logbook is confirmed in writing by the supervisor of the specialization center.Documentation of on-going specialist training in the subdiscipline in the form of confirmation of attendance at accredited congresses, workshops, symposia and training/simulation courses held by the specialist societies or their members . For attendance at a meeting of the major cardiological societies  the candidate will be credited a maximum of 2 days. At least five heart failure-specific training days must be documented per training year.Evaluation of the candidate with a view to their completion of the curriculum shall consist of the following components:Applications for recognition of curricular achievements in order to obtain the additional qualification “heart failure specialist” shall be evaluated by a dedicated committee of the nucleus of the Heart Failure Working Group of the Austrian Cardiological Society . For this purpose, the documents listed in Section 8 “Evaluation and quality control” are to be submitted. The candidate will receive recognition of the additional qualification in heart failure, issued by the ÖKG. Recognition is valid for 5 years, after which recertification must be applied for (proof of at least one heart failure-specific advanced training per year). Certification as a training institution and certification as a supervisor are granted by the abovementioned committee. The function of supervisor is in principle linked to certification of the training institution. Certification as a training center for the additional qualification is valid for 5 years, after which recertification must be applied for.Specialists in internal medicine and cardiology who have been clinically active in the field of heart failure for at least 2 of the last 5 years (including at least two of the required modules) and/or who can demonstrate special scientific expertise in heart failure can acquire the additional qualification “heart failure specialist” on application, without formally completing the curriculum. The applicant’s predominant activity in the area of heart failure as well as the required minimum numbers of the required examinations must be confirmed by the head of the particular institution. The transitional regulation is valid from 1 June 2019 until 30 May 2021.


Acute pulmonary embolism (APE) is one of the leading causes of death in cardiovascular disease. The 30-day mortality can still be 1.7–15% in non-high-risk APE patients. Some non-high-risk patients can progress into the high-risk group and even die, which is referred to as an adverse outcome. Promoting the diagnosis and predictive ability of adverse short-term prognosis was still a problem that needed to be solved. Computed tomography pulmonary angiography (CTPA) may be a way to promote the predictive ability. Our aim to develop predictive tools based on parameters obtained by computed tomographic pulmonary angiography (CTPA) in the form of a decision tree for use in non-high-risk acute pulmonary embolism (APE) patients.Adverse outcome was defined within 30 days after admission to the hospital. A decision tree was built to predict adverse outcomes based on discriminating factors screened from cardiac volume and clot characteristics from recursive partitioning analysis and compared with simplified pulmonary embolism severity index (sPESI), Bova scores and risk stratification. The area under the receiver operating characteristic curve (ROC-AUC) was used to confirm the predictive ability.A total of 38 patients with and 303 patients without adverse outcomes were enrolled. Right ventricular/left ventricular (RV/LV) volume ratio, central pulmonary artery (CPA) embolism and right atria/left atria (RA/LA) volume ratio were used as splits in the decision tree to predict adverse outcomes in all patients. The ROC-AUC was 0.858. In CPA embolism patients, a recursive partitioning analysis was performed with cardiac volume and novel clot burden, but only the obstructing area (OA) ratio was included as a discriminating factor to build a second decision tree. The ROC-AUC for the second decision tree was 0.810. The decision trees were superior to those of sPESI, Bova scores and risk stratification, and there were no significant differences between the two decision trees.A decision tree built by CTPA parameters can predict adverse outcomes in non-high-risk APE patients. Acute pulmonary embolism (APE) is one of the leading causes of death in cardiovascular disease , 2. DiffCurrently, risk stratification , simplifBased on the needs of promoting the predictive ability and the usefulness of CTPA in APE, we measured cardiac volumes and evaluated novel clot burden methods, which referred to coronary computed tomographic clot burden , 13. WitThis was a retrospective study from two research centers  in Shenyang, China. Between May 2014 to Dec 2018, 424 patients were collected from initially selected patients who were diagnosed with APE by CTPA, who were ≥ 18 years of age and non-high-risk APE patients  [Demographic and baseline characteristics, heart rate, systolic pressure and past disease history were measured and defined from medical records upon admission to the hospital. Short-term prognosis was defined as adverse outcomes within 30 days after admission to the hospital. A positive adverse outcome (+) was defined as the occurrence of at least one of the following conditions: death; cardiopulmonary resuscitation; endotracheal intubation; vasopressor requirement for systemic hypotension (more than 5 μg per kilogram); or reperfusion treatment to save the patient’s life , 9. ThesAll enrolled patients were divided into an intermediate–high-risk group, an intermediate-low-risk group and a low-risk group by right ventricular dysfunction (RVD), cTnI, and NT-proBNP ; RVD wasThe Bova  and sPESCTPA was performed with an Aquilion KV-120 system  with a 64-detector row scanner. The parameters were set to 380 mA, 120 kV, and a 1-mm section thickness for reconstruction from the thoracic inlet to the upper abdomen. An iodinated nonionic solution (100 mL) was injected by an automatic dual-tube high-pressure injector  into the antecubital vein at 4 mL/s.All parameters were measured using Mimics Medical software  and were recorded in the digital imaging and communications in medicine format. The central pulmonary artery (CPA) was reconstructed, including embolism from the main pulmonary artery (MPA) trunk inlet to outlets of the right and left pulmonary arteries (RPA and LPA). The centerline was established, and redundant lines were deleted manually based on the reconstructed CPA. Six center points were identified at six respective planes, including the MPA trunk inlet plane, the MPA trunk outlet plane, the LPA inlet plane, the LPA outlet plane, the RPA inlet plane and the RPA outlet plane on the reconstructed centerline. The segmenting CPA and selecting plane method refers to Schievano, S. et al.  and BarkClot locations were classified as follows: Saddle CPA embolism: embolism at the bifurcation location of the CPA ; CPA embIn CPA embolism patients, clots were segmented from the reconstructed CPA. Clot burden was then evaluated by five methods: (1) the widest clot diameters orthogonal to the long axis of the RPA and LPA were measured, and the total of the widest diameters in the RPA and LPA was recorded as the clot maximal diameter ; (2) theThe cardiac chambers were segmented and reconstructed semi-automatically. The interatrial septum, interventricular septum and heart chamber walls were excluded, and the cardiac valves were used to segment different heart chambers and vessels. The cardiac capacity was measured according to the previous methods , 9. The 2 test to compare differences. A tree-based methodology was built to model predictive prognosis factors and to identify effect modifications with recursive partitioning analysis between different variables to determine which variables were identified less easily by other regression models [p value less than 0.05 was considered to indicate a significant difference. The statistical analysis was performed with R software version 3.3.2 (http://www.R-project.org) and Medical statistical software .Quantitative variables are expressed as the mean ± standard deviation (SD) and were analyzed by Student’s t-test to compare differences. Categorical variables are expressed as (+)/(−) and were analyzed by χn models . Recursin models , 21. Aftn models . After pn models , 24. A tp < 0.001). LA and LV volumes in the adverse outcome (+) group were lower than those in the adverse outcome (−) group, with significance (p < 0.001) , and 303 patients were defined as adverse outcome (−). The RV volume, RA/LA volume ratio, RV/LV volume ratio, and the ratio of CPA embolism (+) to saddle CPA embolism (+) in the adverse outcome (+) group were higher than those in the adverse outcome (−) group, with significance . The LA and LV volumes in the adverse outcome (+) group were lower than those in the adverse outcome (−) group, with significance   group were higher than those in the adverse outcome (−) group, with significance (y) Table .Table 5n = 287) or ≥ 1.11 (n = 54), with adverse outcome ratios of 3.1 and 53.7%, respectively; (b) Split: patients were divided based on RV/LV volume ratio ≥ 1.11 patients with CPA embolism (+)/(−) (n = 42/12), with adverse outcome ratios of 61.9 and 25%, respectively; (c) Split: patients were divided based on RV/LV volume ratio ≥ 1.11 patients and CPA embolism (+) patients with RA/LA volume ratios < 1.28 (n = 23) or ≥ 1.28 (n = 19), with adverse outcome ratios of 39.1 and 89.5%, respectively  Split: all 341 enrolled patients were divided based on RV/LV volume ratio < 1.11  or ≥ 0.31 (n = 27), with adverse outcome ratios of 9.3 and 77.6%, . We also compared the predictive ability between the decision tree and the risk stratification, Bova scores and sPESI scores  patients and screening for adverse outcome (−) patients were superior than risk stratification and Bova scores. Discriminating using the decision trees built in our study would be easier, faster and more accurate than traditional methods. If only the cardiac volume index is available, or the CPA embolism is negative, the decision tree built by the integration of RV/LV volume ratio, CPA embolism and RA/LA volume ratio would be helpful in the discrimination. However, when the OA is available as the clot characteristics, while the patient is CPA embolism (+), the decision tree built with CPA embolism and OA would be easier than the cardiac volume index. Having PE diagnosis and prediction of PE severity in a single test is a potential advantage of using the decision trees built in our study.The retrospective research design of our study limits the strength of our results. Additionally, our sample size was only 341. Different cardiac cycles could influence measurement cardiac volume. However, most studies describe measuring cardiac volume parameters with non-electrocardiographically gated computed tomographic angiography, including ours. The two decision trees in our study and the OA ratio, as a novel method for evaluating clot burden, still require further validation.Following the decision tree built using the RV/LV volume ratio, the RA/LA volume ratio and identifying a CPA embolism would facilitate the prediction of adverse outcomes in non-high-risk APE patients. In the CPA subgroup of patients, measuring the OA ratio is another way to predict adverse outcomes as a supplemental method.