Mitral Regurgitation Research Articles

Insulin-like growth factor binding protein 2 predicts course of concomitant right-ventricular dilation and tricuspid regurgitation after transcatheter edge-to-edge mitral valve repair

Abstract Aims Right ventricular (RV) dilation and secondary tricuspid regurgitation (TR) are highly prevalent comorbidities in patients with mitral regurgitation and are associated with a worse prognosis. TR improvement after successful transcatheter edge-to-edge mitral valve repair (M-TEER) is reported regularly, however specific factors contributing to the recovery of RV function and TR after M-TEER are poorly understood. Particularly the role of serum biomarkers in this context is unclear. We aimed to identify specific biomarkers associated with the course of concomitant RV dilation and TR after M-TEER. Methods and Results We prospectively included 242 patients undergoing M-TEER at our center and obtained pre-procedural blood samples for biomarker analysis. A commercial multiplex protein assay (Cardiovascular III, Olink, Uppsala, Sweden) was used to quantify expression levels of 92 defined biomarkers. We then analyzed differences in biomarker expression between patients with and without right ventricular reverse remodeling (RVRR) as defined by improvement of concomitant TR by at least one grade and/or downsizing of the basal RV diameter of at least 10%. 242 patients were included in this analysis, 94 had no/mild concomitant TR at baseline, 148 had moderate/severe TR. RV diameters correlated with TR severity and were significantly larger in patients with moderate/severe TR. At baseline, expression of numerous cardiometabolic biomarkers was significantly higher in patients with moderate/severe TR. These included NT-proBNP (1.9-fold, p < 0.001), matrix metalloproteinase 2 (1.4-fold, p < 0.001) as well as insulin-like growth factor binding proteins 1 (1.7-fold, p < 0.001), -2 (1.3-fold, p = 0.001) and -7 (1.4-fold, p < 0.001). Follow-up analysis was performed in patients with initial moderate/severe TR. The course of TR and RV dimensions three months after M-TEER could be assessed in 99 patients (56 with moderate TR, 43 with severe TR). RVRR had occurred in 50 patients (50.5%). Patients without RVRR had a higher prevalence of chronic pulmonary disease (24.5 vs. 2.2%, p < 0.001). No further differences in clinical characteristics were found. Specifically, RV diameter, systolic pulmonary artery pressure (sPAP) and right-ventricular systolic function did not differ substantially between both groups. Strikingly however, the expression of insulin-like growth factor binding protein 2 (IGFBP-2) was significantly higher in patients, who did not develop RVRR (fold change 1.3 compared to patients with RVRR, p = 0.022). After adjustment for covariates IGFBP-2 was independently associated with absence of RVRR (Odds Ratio 2.078, 95% Confidence interval 1.108 – 3.897, p = 0.023). Conclusions In patients undergoing M-TEER with concomitant moderate or severe TR, numerous cardiometabolic biomarkers including IGFBP-2 are upregulated. Higher levels of IGFBP-2 at baseline are independently associated with persistent TR and/or RV dilation after M-TEER.

Role of negative transthoracic echocardiography in excluding infective endocarditis

Abstract Background Recent guidelines suggest an extensive role of transesophageal echocardiography (TOE) in the diagnostic work-up for suspected infective endocarditis (IE). However, the negative predictive value of transthoracic echocardiography (TTE) remains poorly investigated. Purpose The purpose of our study was to evaluate the accuracy of TTE in ruling out IE in order to avoid unnecessary TOE, a more invasive and expensive diagnostic exam. Methods We reviewed data of 637 consecutive patients referred to our laboratory of echocardiography with a suspected diagnosis of IE who underwent TOE within 14 days of TTE (median 4.4 days; interquartile range 2.4-7.4). For each patient we obtained age, sex, blood culture results, complete blood count, blood chemistry, evidence of systemic embolism or pulmonary embolism, and presence of moderate/severe heart valve disease, congenital heart disease, valve prostheses and intracardiac devices. Patients with initial doubtful findings at TOE were referred for a follow-up TOE after one week and/or 18F fluorodeoxyglucose positron emission tomography computed tomography to achieve a definitive clinical diagnosis. Patients in whom a clear diagnosis of IE could not be achieved (n=7) were considered to have the disease. Results Of the 637 patients enrolled, 375 had negative TTE for IE (59%). TOE was positive and doubtful for IE in 44 (12%) and 29 (8%) of these patients, respectively. After further assessment, a final diagnosis of IE was achieved in 56 patients (15%). Variables associated with IE at univariable analysis included presence of valve prostheses (p<0.001), systemic or pulmonary embolism (p<0.001), lower platelet count (p=0.003), positive blood culture (p=0.005), aortic valve regurgitation (p=0.02), aortic valve stenosis (p=0.03) and mitral regurgitation (p=0.03). At multivariable logistic regression, independent predictors of IE (OR=odds ratio; CI=confidence interval) included evidence of systemic or pulmonary embolism (OR 17.75, 95% CI 6.66-47.3, p<0.001), bioprosthetic heart valves (OR 2.93, 95% CI 1.31-6.53 p=0.023) and lower platelet count (OR 0.995, 95% CI 0.991-0.998, p=0.003). Among the subgroup of patients (n=183, 49%) with no evidence of embolism, no bioprosthetic valve and platelet count >190,000/mL (median value), IE was diagnosed in 11 patients only (6%). Conclusions In our study, a negative TTE in the subgroup of patients with suspected IE showing platelet count >190,000/mL and absence of embolism and valvular bio-prosthesis, had a negative predictive value for IE of 94%, suggesting that, in this subset of patients, TOE can initially be delayed and performed only if clinical suspicion continues to remain high.

Preventing unnecessary echocardiograms in de novo patients referred to the cardiology outpatient clinic using electrocardiogram-based deep learning

Abstract Introduction The growing demand on European echocardiography labs, driven by the rise in structural heart disease (SHD), is further complicated by a shortage of skilled sonographers, necessitating resource optimisation strategies. Electrocardiogram (ECG)-based deep learning models may assist in streamlining the echocardiography workflow. Purpose This study sought to develop a deep learning model capable of identifying patients at very low risk of SHD in a population of de novo patients referred to the cardiology outpatient clinic. Methods We identified all adult patients who underwent a 12-lead ECG and echocardiogram at a Dutch academic teaching hospital between 2011 and August 2023. Echocardiogram outcomes were extracted from reports, including left ventricular systolic dysfunction (LVSD), left ventricular dilatation (LVD), aortic stenosis (AS), aortic regurgitation (AR), mitral regurgitation (MR), and tricuspid regurgitation (TR), from which a composite outcome label was derived. A cohort of patients newly referred to our cardiology outpatient clinic with a primary complaint of chest pain, dyspnea, palpitations, dizziness, a murmur, or an abnormal ECG was held out as a test set, while the remaining dataset was split patient-wise into training (90%) and validation (10%) sets. A convolutional neural network was trained using only the ECG tracing as input and the composite label as outcome. Results We included 92,210 ECG-echo pairs from 44,785 patients (19,717 female) with 25,543 (27.7%) abnormal ECG-echo pairs. Among 2724 newly referred patients in the test set, 210/1389 males (15.1%) and 201/1335 females (15.1%) were diagnosed with SHD. In the test set, the model for predicting composite outcome demonstrated an area-under-the-curve, negative predictive value, and specificity of 0.74 (95% confidence interval [CI] 0.71-0.79), 0.94 (95% CI 0.92-0.95), and 0.47 (95% CI 0.45-0.49), respectively. Conclusion This study demonstrates the feasibility of employing deep learning models based solely on electrocardiogram (ECG) data to identify patients at very low risk of structural heart disease (SHD). Further validation and prospective studies are warranted to confirm the generalizability and clinical utility of our findings in diverse patient populations and healthcare settings.

Atrial and ventricular mitral regurgitation in the general population

Abstract Background Functional mitral valve regurgitation (FMR) is the result of two concurrent pathomechanisms: (1) the dilatation of mitral valve annulus (atrial) or (2) remodelling of the left ventricle (ventricular) in the absence of relevant leaflet degeneration¹. Even though FMR has been reported to be the most common cause of relevant MR², there is no general accepted definition of the two subtypes, nor are there population-based data regarding their prevalence, distribution and risk profiles¹. Purpose We aimed to evaluate the prevalence of FMR and to provide an in-depth characterisation of the subtypes aFMR and vFMR in the general population. Methods The study included the first 10,000 participants of the population-based Hamburg City Health Study enrolled between 2016 and 2019. Of these, 8.543 echocardiographic samples were available for analysis. Mitral valve was assessed by two independent investigators. Isolated degenerative MRs as determined by valve mobility (prolapse or restrictive) were excluded. FMR was classified as ventricular when fulfilling one of the following criteria: history of myocardial infarction or coronary artery disease, left ventricular ejection fraction (LVEF) ≤ 40%, restrictive leaflet, tenting area ≥ 150 mm² or coaptation depth ≥ 10 mm. All FMR with LVEF > 55% were classified as atrial. Results After excluding the samples with an insufficient image quality or missing data and re-assessment by the second investigator, 216 of 282 participants with a relevant MR (i.e. moderate or severe) remained (2,6% of the total cohort, see figure 1). In the next step, 153 participants were classified as pure FMR (68.9%), the remaining were mainly functional with minor degenerative features. A total of 31 (14.4%) MRs were classified as vFMR, the remaining 185 participants had an aFMR. Female gender was significantly more common in the aFMR cohort. The remaining demographic variables (age, body mass index) as well as established cardiovascular risk factors (i.e., diabetes, smoking, hypertension) were comparable between the vFMR and aFMR cohort. However, vFMR patients had significantly higher levels of NT-proBNP or NHYA state and presented more frequently with an atrial fibrillation (see figure 2). LVEF and LV stroke volume, TAPSE, left atrial ejection fraction and E/A ratio as a parameter of diastolic dysfunction were lower in the vFMR cohort whereas tenting area and left atrial endsystolic volume was significantly increased. Conclusion In our population-based study, aFMR was found to be the predominant subtype of FMR. The established cardiovascular risk factors were comparable in the vFMR and aFMR cohort. Echocardiographic variables differed significantly and indicate more advanced heart failure and LV remodelling in the vFMR cohort. Further categorization of FMR, in particular regarding the prognostic impact and long-term outcomes, is strongly warranted to allow a clinically relevant definition of aFMR and vFMR.Figure 1:Overview of sample sizeFigure 2:Baseline characteristics

Incidence and factors associated with mitral valve reoperation in patients undergoing intervention for mitral regurgitation: a nationwide cohort study

Abstract Background When intervention is needed for the treatment of mitral regurgitation, the risk of reoperation is of concern for both patients and physicians. As such, contemporary and nationwide data on the incidence and factors associated with mitral reoperation can provide crucial information to support patient education and clinical follow-up after intervention. Purpose To examine the incidence of mitral reoperation in patients operated for mitral regurgitation. Second, to assess whether reoperation rates differed according to time since surgery and identify potential factors associated with reoperation. Methods Using Danish nationwide registries, patients undergoing first-time surgery for mitral regurgitation 1996–2021 were identified. Exclusion included first-time surgery due to endocarditis. According to index surgery, the population was categorized into 1) mitral repair; 2) mechanical prosthesis; 3) bioprosthesis. Patients were followed from date of discharge. Cumulative incidence of reoperation was examined using competing risk analysis during a maximum of 20-years follow-up. Crude incidence rates of reoperation were reported from 0-6 months and for overall study period. Multivariate Cox analysis was used to examine factors associated with reoperation. Results We identified 7,063 patients: 4,680 (66.3%) with repair (72% male, median age 66), 1,273 (18.0%) with mechanical prosthesis (52% male, median age 59), and 1,110 (15.7%) with bioprosthesis (57% male, median age 74). Median follow-up was 7.2 years, 10.7 years, and 4.5 years, respectively. At end of follow-up, cumulative incidences were 7.7% for repair, 6.8% for mechanical prostheses, and 7.5% for bioprostheses. Of these, reoperation was preceded by endocarditis in 8.0%, 21.5%, and 30.4% of the respective patient groups. The cumulative incidence function demonstrates that the highest proportion of reoperations occurred within first six months, Figure 1. From 0-6 months following surgery, incidence rates per 100 person-years were 9.1 for repair, 11.7 for mechanical prostheses, and 18.4 for bioprostheses, while this was 8.6, 9.4, and 17.0, respectively for the overall study period. Factors associated with increased rate of reoperation were heart failure (HR=1.80, 95% CI 1.40-2.32), chronic renal failure (HR=1.48, 95% CI 1.11-1.98) and chronic obstructive pulmonary disorder (COPD) (HR=1.34, 95% CI 1.01-1.77), Figure 2. Compared to mitral repair, mechanical prostheses were associated with lower rate of reoperation (HR=0.57, 95% CI 0.42-0.78), while there was no statistically significant difference between repair and bioprostheses (HR=1.10, 95% CI 0.81-1.50). Conclusion In patients operated for mitral regurgitation, cumulative incidences of reoperation with a maximum of 20-year follow-up were 7.7% for repair, 6.8% for mechanical prostheses, and 7.5% for bioprostheses. Comorbidities such as heart failure, renal failure and COPD were associated with increased risk of reoperation.Figure 1Figure 2

Prognostic impact of left ventricular myocardial work in patients undergoing surgery for primary mitral regurgitation

Abstract Background Although left ventricular ejection fraction (LVEF) is widely used as a parameter for the assessment of LV systolic function, LVEF can overestimate LV systolic function in patients with severe mitral regurgitation (MR) due to its high load-dependency. Echocardiography-based, left ventricular myocardial work (LVMW) can assess LV function by incorporating LV afterload. Purpose This study aims to evaluate the prognostic value of LVMW indices in patients with primary MR undergoing mitral valve surgery. Methods Individuals who underwent mitral valve surgery for severe primary MR were included. All patients underwent transthoracic echocardiography before surgery. LVMW was derived from a vendor-specific package which integrates LV global longitudinal strain with sphygmomanometric blood pressure to construct pressure-strain loops during the cardiac cycle. (Figure 1) For the LVMW indices, previously-established normal values were used as thresholds. The primary endpoint was all-cause mortality after mitral valve surgery. Results A total of 309 patients (mean age 63 ± 12 years, 68% male) with severe, primary MR who underwent surgery, were included. The mean LV global work index (LVGWI) was 1977 ± 537 mmHg% and 132 (43%) patients had impaired LVGWI (≤ 1900 mmHg%). During a median follow-up of 5.0 years (interquartile range, 2.5-8.9), 27 (8.7%) patients died after mitral valve surgery. Patients with impaired LVGWI or LV GLS (≤ 20%) had lower survival rates compared to the group with preserved LVGWI (p <0.01) or LVGLS (p = 0.02), whereas there was no significant difference in the survival rate between patients with LVEF ≤ 60% and > 60%. (Figure 2) Furthermore, LVGWI ≤ 1900 mmHg% demonstrated incremental prognostic value over LVGLS (p = 0.049) for all-cause mortality. Conclusions In patients with severe, primary MR who underwent surgery, impaired pre-operative LVGWI was associated with a higher mortality risk. In addition, impaired LVGWI had incremental prognostic value over LVGLS. Based on these findings, LVMW is a promising parameter for predicting postoperative outcome and determining the optimal timing of valve surgery in patients with severe, primary MR.Fig1.Echo-derived Myocardial workFig2.Kaplan-Meier curves

Predictors for mitral regurgitation improvement in patients with pure severe aortic regurgitation undergoing transcatheter aortic valve replacement: when can kill two birds with one stone?

Abstract Objective Transcatheter aortic valve replacement (TAVR) has been recognized as a significant treatment for pure severe aortic regurgitation (PSAR). Part of patients with PSAR concurrently suffer from functional mitral regurgitation (FMR). Whether TAVR could improve FMR in patients with PSAR and the predictors have not yet been clarified. This study aims to explore predictors of FMR improvement in patients with PSAR undergoing TAVR and subsequently provide evidence for further clinical therapy. Method Patients with PSAR and FMR who underwent TAVR at Zhongshan Hospital Affiliated with Fudan University were enrolled from June 2021 to August 2023. Depending on whether FMR improved one month post-TAVR, they were divided into groups with or without FMR improvement. The baseline data, imaging results, and follow-up data of the patients were collected. Result This study included 75 patients, among whom 38 patients had improved FMR and 37 patients did not. Compared to patients without FMR improvement, more patients in the FMR-improved group were diagnosed with renal insufficiency (10.8% vs. 0%, p=0.018), left bundle branch block (8.1% vs. 0%, p= 0.037), and less right bundle branch block (0% vs. 10.5%, p=0.017). The transthoracic ultrasound examination showed that patients with FMR improvement were prone to have lower left ventricular ejection fraction (LVEF) and larger left ventricle end dimension diastole (LVEDd). A higher proportion of patients in the FMR-improved group were found to have had more moderate to severe FMR (28.9% vs. 2.7%, P=0.029). In both groups, the degree of aortic regurgitation was significantly improved during the 1-day and 1-month follow-ups post-TAVR (p<0.001). No significant differences were found in the incidence of postoperative adverse events between the two groups during the short-term follow-up. Conclusion FMR improvement is observed in approximately half of PSAR patients undergoing TAVR. A higher FMR degree, lower LVEF, and hypertension before TAVR are independent predictors of FMR improvement.Figure 1 AR and MR post TAVRTable 1 Logistic regression

Clinical profile of patients undergoing percutaneous stellate ganglion block for electrical storm and association with antiarrhythmic efficacy

Abstract Background Percutaneous stellate ganglion block (PSGB) usage for patients with refractory ventricular arrhythmias (VAs) in form of electrical storm (ES) is in quickly expanding. The clinical profile of patients and the potential association with the antiarrhythmic efficacy of the procedure are mostly unexplored. Purpose To better characterize clinical profile and potential association with antiarrhythmic efficacy of patients undergoing PSGB for ES. Methods Patients undergoing PSGB for ES in our Center from 2/2021 to 2/2024 were enrolled; all the dynamic variables were evaluated in a per procedure analysis. Results 45 patients (93% male, 64 ± 10 years) received a total of 80 PSGB performed with the lateral, ultrasound (US) guided technique; most PSGB consisted of a single bolus anesthetic injection (lidocaine + ropivacaine), 26% in an additional continuous infusion, mostly with ropivacaine. All procedures except for 3 in a single patient who had previously received left cardiac sympathetic denervation, were performed on the left side. Most of the patients (60%) suffered ischemic cardiomyopathy (CMP), including 10 with an acute coronary syndrome; the rest had non-ischemic CMP; 60% had an ICD. The type of VAs was ventricular tachycardia (VTs) only in 86% of the procedures (cycle length 404 ± 143 msec), VT and VF in 10% and VF only in 3 (4%). Most PSGB (81%) were performed in the setting of impending or manifest cardiogenic shock (SCAI classification B or more), including 20% with sepsis. Cardiac US performed before (within 12 hours) each PSGB showed a severely depressed left ventricular (LV) function (mean LVEF 22 ± 10%, mean LV outflow tract velocity time integral 12 ± 4 cm), calculated at a mean heart rate of 81 ± 16 bpm. Mean LVEDV was 252 ± 104 ml, 79% had mitral regurgitation (MR) ≥2+/4+ (including 39% severe MR), 50% had ≥ moderate diastolic dysfunction, 29% had right ventricular dysfunction (mean fractional areal change 33± 7%). Most cases (75%) experienced a complete VAs suppression (sustained or treated) in the 12 hours after PSGB; only 3/80 cases required additional urgent antiarrhythmic strategies (intra-aortic ballon pump in one case, urgent pacing in another one, urgent revascularization in the last one). None of the assessed clinical or echocardiographic characteristics was significantly associated with VT cycle length or the response to PSGB. Only 1 (1%) major complication occurred (respiratory arrest), that was quickly and effectively treated with lipid emulsion. Conclusions PSGB in our Center was mostly performed in the setting of primary impending or manifest cardiogenic shock with severely impaired cardiac function, with an excellent safety profile. None of the assessed clinical or echocardiographic variables were associated with response to PSGB. Our data, despite preliminary and requiring confirmation, suggests always considering PSGB in the urgent/emergent setting independently from patients’ characteristics.

Perfusion metabolism mismatch predicts short-term complications in Takotsubo syndrome

Abstract Background Takotsubo syndrome (TTS) is a transient cardiac condition triggered by sudden emotional or physical stress characterized by LV dysfunction in the absence of obstructive epicardial coronary artery disease. 123I-BMIPP, an iodinated fatty acid analogue, can identify impaired myocardial metabolic activity. With the use of dual SPECT protocol, reduced uptake of 123I-BMIPP compared to perfusion which is called perfusion-metabolic mismatch is observed in apical regions in TTS. The mismatch may indicate jeopardized but viable myocardium, reflecting transient ischemic damage or metabolically stunned myocardium. However, the association between the perfusion metabolism mismatch in TTS and its complications remains underexplored. Purpose Our study aimed to analyze the degree of perfusion metabolism mismatch at the acute phase in TTS and investigate its association with short-term complications. Methods This retrospective study conducted between 2012 and 2024 at a single center included 82 patients diagnosed with TTS. Patients underwent dual SPECT imaging using 99mTc or 201 Tl and 123I-BMIPP within two weeks of admission. We applied quantitative analysis using QGS/QPS software from Cedars-Sinai. Total perfusion deficit ("TPD") was calculated based on sex-matched normal limits providing the extent of perfusion abnormality. Meanwhile, perfusion-metabolism mismatch scores ("worsen") were determined by comparing the total BMIPP counts to the total counts of perfusion. We then assessed the correlation of these imaging findings with biomarkers, regional wall motion abnormalities, and the occurrence of short-term complications. Short-term complications included heart failure, left ventricular outflow (LVOT) obstruction, mitral regurgitation, cardiac arrhythmia, cardiogenic shock, left ventricle (LV) rupture, and cardiac death during the hospitalization period. Results All study patients exhibited wall motion abnormalities seen in apical segments. The count of myocardial segments with regional wall motion abnormality was correlated with both TPD (r=0.34, p=0.002) and perfusion metabolic mismatch score (r=0.40, p<0.001). TPD had a moderate correlation coefficient with max CK-MB (r=0.44, p<0.001) and troponin T (r=0.40, p<0.001) levels. However, perfusion metabolic mismatch did not display correlations with max CK-MB (r=0.05, p=0.65), and Troponin T (r=0.12, p=0.28) levels. Among 82 patients, 37 patients experienced any short-term complications. Importantly, patients with short-term complications had elevated perfusion mismatch scores compared to those without short-term complications (14.0 [6.0-22.5] vs. 5.0 [3.0-10.0], p<0.001). However, no significant difference was observed in TPD between the two groups (9.0 [4.5-20.0] vs. 7.0 [3.0-12.0], p=0.130). Conclusions Our research highlights a significant association between perfusion-metabolism mismatch and an increased risk for short-term complications in patients with Takotsubo syndrome.

Adverse prognostic implications of increased left ventricular force in hypertrophic cardiomyopathy

Abstract Background The left ventricular (LV) force, also known as elastance, serves as a load-independent indicator of contractility and can be noninvasively assessed through echocardiography. In hypertrophic cardiomyopathy (HCM), the heightened presence of the active state of myosin heads results in an increased LV force. Purpose To assess the prognostic value of increased LV elastance at rest in patients with HCM. Methods We enrolled 1420 HCM patients (age 50±16 years, 907 males, 64%) with ejection fraction (EF) ≥50%, referred for rest transthoracic echocardiography (TTE) in 10 quality-controlled labs from 7 countries. TTE assessment included peak left ventricular outflow tract gradient (LVOTG), EF, and LV force (systolic blood pressure + LVOTG/LV end-systolic volume assessed with 2-D, mmHg/mL). All patients were followed up. All-cause death was the outcome measure. Results At a median follow-up of 83 months, 150 deaths occurred (Group 1). At study entry, Group 1 patients had the same ESC-Sudden cardiac death score compared to survivors (Group 2). In Group 1 compared to Group 2, TTE showed higher values of MR severity, E/e’ , left atrial volume index, estimated systolic pulmonary artery pressure, and force (see table). At multivariable Cox analysis, only age (HR =1.08, 95% CI=1.03-1.14, p=0.001) and force > median value of 5.3 mmHg/mL (HR = 2.14, 95% CI 1.53-2.99, p=0.020) were independent predictors of mortality. Ten-year survival was 95% in the pooled first (<3.8 mmHg/mL) and second (3.8-5.2 mmHg/mL) quartiles vs 80% in the pooled third (5.3-7.8 mmHg/mL) and fourth quartiles (>7.8 mmHg/mL), see figure. Conclusion HCM patients with higher values of resting LV elastance show a worse survival, highlighting the dark prognostic side of an excess of force in these patients. Table Legends E/e’, early mitral inflow to early mitral annulus motion ratio, EF, left ventricular ejection fraction, LAVI, left atrial volume index; LVOTG, left ventricular outflow tract peak gradient, MR, mitral regurgitation; MWT, maximal wall thickness, NYHA, New York Heart Association classification, RWT, relative wall thickness; SCD risk, risk score for sudden cardiac death in hypertrophic cardiomyopathy, SPAP, systolic pulmonary arterial pressure.Table.Clinical and TTE findingsFigure.Survival in the force quartiles

Clinical characteristics and outcomes of patients with takotsubo syndrome and dynamic left ventricular outflow tract obstruction

Abstract Background Left ventricular outflow tract obstruction (LVOTO) is recognized as a serious complication of Takotsubo syndrome (TTS). However, its impact on patient prognosis remains insufficiently investigated. Purpose This study aimed to assess clinical characteristics and short- and long-term outcomes of patients with TTS complicated by LVOTO. Methods Patients with TTS were enrolled from the Takotsubo Italian Network (TIN). The primary outcome was the composite of acute heart failure, cardiogenic shock, and mortality during hospitalization. Secondary outcomes included the single components of the primary outcome and the occurrence of death or TTS recurrence during follow-up. Results Overall, 881 patients were included in the study [median age 72.0 (63.0–78.0) years; 91.3% female], with LVOTO detected in 59 patients (6.7%). Low diastolic blood pressure, ST-segment elevation, and moderate-to-severe mitral regurgitation were independently associated with occurrence of LVOTO. Propensity score weighting regression analysis revealed a significant higher risk of the primary outcome (OR, 2.99; 95% CI, 2.22–4.02), acute heart failure (OR, 2.19; 95% CI, 1.59–3.02), cardiogenic shock (OR, 4.56; 95% CI, 3.07–6.78), and in-hospital mortality (OR, 2.42; 95% CI, 1.13–5.21) in patients with TTS complicated by LVOTO. No significant association between LVOTO and long-term mortality or TTS recurrence was observed during follow-up. Conclusions In this real-world evidence study, LVOTO was detected in about 7% of TTS patients and was associated with a significantly higher risk of adverse events during hospitalization, including mortality. Early detection of LVOTO can aid in prognostic assessment and guide therapeutic management in patients with TTS.

Left atrial reservoir strain as a prognostic indicator for cardiovascular events after mitral valvuloplasty

Abstract Background In patients after mitral valvuloplasty (MVP), assessing valve function and heart failure (HF) is crucial for prognostic predictions. Left ventricular diastolic function assessed by transthoracic echocardiography (TTE) plays an important role in the evaluation of HF in general practice. However, post-mitral valve surgery patients are excluded from the left ventricular diastolic function assessment guidelines proposed by the American Society of Echocardiography in 2016 due to their low correlation with left ventricular diastolic function indices. On the contrary, the left atrial reservoir strain (LARS) before MVP is considered as a prognostic factor, reflecting left atrial dysfunction caused by mitral regurgitation. Nevertheless, there are limited reports on the relationship between LARS and cardiovascular (CV) events after MVP. Purpose The study aims to investigate the utility of LARS in predicting CV events after MVP. Methods The study included 249 patients who underwent TTE between January 2011 and January 2023 after MVP at our hospital. Patient background data, including NYHA classification, medical history, medications, blood tests, and TTE data, were collected at the time of follow-up TTE. LARS, left ventricular global longitudinal strain (LV-GLS), and right ventricular free wall strain (RV-FWSL) analysis were performed using a vender-independent external strain analysis software for all patients in the cohort. The primary endpoints were cardiovascular death and HF rehospitalization. The predictor of cardiovascular events was assessed using the Cox proportional hazards model and Kaplan-Meier curve (KMC). Results The mean age was 61±14 years, and 159 patients (64%) were male. The median time from surgery to TTE was 4.8 (1.0-6.8) years, 32 patients (13%) had events within 8.5 (3.7-10.8) years after TTE. The event groups had higher age, NYHA classification, and NT-pro BNP compared to the non-event group. TTE parameters such as left ventricular mass index, left ventricular end-diastolic volume and end-systolic volume were larger, and LV-GLS and LARS were significantly lower in the event group. In multivariate Cox proportional hazards models showed that LARS was also a prognostic indicator even after adjustment for several variables (Table 1). The KMC showed that LARS was associated with events regardless of left atrial volume index (Log-rank p <0.001, chi-square:31.03) (Figure 1). Conclusion LARS was strongly associated with CV events after MVP. We consider LARS to be a useful prognostic indicator after MVP.

Clinical phenotypes in relation to outcomes in heart failure patients with cardiac resynchronization therapy and defibrillators (CRT-D): an unsupervised cluster analysis

Abstract Background Patients with heart failure undergoing CRT are an heterogenous and complex population. Selecting patients before implantation is essential to obtain a favorable response to CRT-D. Data-driven cluster analysis may be an approach to identify different patients’ phenotypic categories. Purpose To identify different clusters of patients with CRT-D who share similar clinical phenotypes, and to evaluate the associations between clusters and clinical outcomes, using cluster analysis. Methods Three agglomerative hierarchical cluster analysis were performed in CRT-D patients seen between 2010 and 2019 in French hospitals. Associations between clusters and death at one year and death during whole follow-up (FU) were evaluated using Cox regression analyses. Results The study included 23,029 CRT-D patients with no prior history of VT/VF/cardiac arrest (mean age 67.7 ± 9.9 years; 78.8 % male), who were analyzed in relation to 3 ways, as follows: the first group was a 50% random sample of all patients (n = 11,514), the second group included patients dead at 1 year (n = 1,604) and the third group included those alive at 3 years FU (n = 14,228). A cluster analysis was performed on each group. Four clusters were identified in the first group: Cluster 1 identified young patients with dilated cardiomyopathy and low prevalence of coronary artery disease (CAD), cardiovascular (CV) risk factors and comorbidities (chronic kidney disease, lung and liver disease) (low-risk phenotype); Cluster 2 was composed of male patients with CAD but low burden of CV risk factors and comorbidities (CAD phenotype); Cluster 3 included CRT recipients with several CV risk factors but low prevalence of comorbidities (CV risk factors phenotype); Cluster 4 identified old patients with high prevalence of CAD, atrial fibrillation, CV risk factors and comorbidities (clinical complex phenotype). These phenotypes were maintained in the other two groups (dead at 1 year and alive at 3 years FU), with the highest consistency for low-risk and high-risk phenotypes(Cluster 1 and 4 respectively). Compared with Cluster 1, Clusters 2, 3 and 4 were independently associated with an increased risk of all-cause death at 1-year FU and during the whole FU (Cluster 2: HR 1.21, 95% CI 1.08 - 1.36; Cluster 3: HR 1.15, 95%CI 1.04 - 1.26; and Cluster 4: HR 1.79, 95%CI 1.65 - 1.96). There were high prevalences of CAD, atrial fibrillation, mitral regurgitation, and comorbidities (which are all predictors of CRT-nonresponse) not only in Cluster 4 at baseline, but also among patients who died at 1-year FU in all 4 clusters. Conclusion Cluster analysis identified four statistically driven groups of CRT recipients, with specific clinical phenotypes and associated with different risks for all-cause death. Identifying those patients at higher risk of adverse events might help in the selection of patients with heart failure undergoing CRT-D implantation, especially in relation to CRT-nonresponse.Risk of all-cause death in 4 clusters

The ventilatory efficiency parameters outperform peak oxygen consumption in monitoring the therapy effects on the right ventricular load in patients with hypertrophic cardiomyopathy

Abstract Aim We sought the cardiopulmonary exercise testing (CPET) parameter that is the most reflective of right ventricular (RV) load and its coupling with pulmonary artery (PA) in patients diagnosed with hypertrophic cardiomyopathy (HCM) undergoing medical therapy. Methods CPET on recumbent bike was performed in adult patients with symptomatic non-obstructive HCM with NYHA class I–III, during phase II, randomised, open-label multicentre study, before and after diverse medical treatment for 16 weeks. Endpoints were the changes in: 1) peak oxygen consumption (peak VO2); 2) minute ventilation (VE)/carbon-dioxide (CO2) production slope during the whole CPET; 3) VE/VCO2 slope before anaerobic threshold (AT); 4) VE/VCO2 slope after AT; 5) VE/VCO2 nadir; 6) VE/VCO2 at AT; and 7) VE/VCO2 intercept. Standard ehocardiography at rest was performed concomitantly with CPET to assess tricuspid annular plane systolic excursion (TAPSE), pulmonary artery systolic pressure (PASP), severity of mitral regurgitation (MR) and TAPSE/PASP ratio as a measure of RV-PA coupling. Results Of 115 screened patients, 61 (mean age 52 years [SD 14], 43% women) met the study inclusion criteria and underwent CPET. On regression analysis, among all CPET end-point variables, the best independent predictor of the change in PASP, TAPSE and MR severity after 16 weeks of medical treatment was VE/VCO2 below AT (B=-0.28, -0.01,-0.11; SE=0.10, 0.05, 0.01; CI=-0.48 to -0.08, -0.22 to -0.01; -0.02 to 0.01; p=0.007, 0.035, 0.004, respectively), whereas the best predictor of TAPSE/PASP ratio was intercept of the VE/VCO2 curve (B=0.014, CI=0.01to 0.03, p=0.005). Conclusion The changes in VE/VCO2 slope below anaerobic threshold, and intercept of the VE/VCO2 curve outperform peak VO2 in the monitoring of therapy effects on the right heart load and RV-PV coupling in patients with hypertrophic cardiomyopathy.

Prognosis in patients with residual pulmonary hypertension after transcatheter edge-to-edge repair for secondary mitral regurgitation

Abstract Background Pulmonary hypertension (PH) is an independent prognostic predictor in patients with heart failure (HF). Recently, transcatheter edge-to-edge repair (TEER) for secondary mitral regurgitation (MR) has been reported to reduce HF hospitalizations and mortality. Elevated pulmonary artery pressure (PAP) before TEER is associated with a poor prognosis; however, the impact of residual PH after TEER on clinical events has not been investigated. Purpose The purpose of this study is to clarify whether residual PH influences outcomes in patients with HF treated by TEER for secondary MR. Methods We included 63 patients who underwent TEER for severe secondary MR and post-procedural right heart catheterization in our institute from January 2016 to August 2023. Mean PAP after TEER was categorized as increased (>20mmHg) versus not increased (≤20mmHg), and we investigated the clinical outcomes between the two groups. The primary endpoint is a composite outcome of all-cause mortality and HF hospitalization. Results Among 63 patients, the average age was 78 years, and 60.3% were male. All patients had Secondary MR, and 52 patients (82.6%) had ventricular Secondary MR—right heart catheterization after TEER revealed a mean PAP of 21.6±7.7 mmHg, pulmonary vascular resistance (PVR) of 2.7±1.4 wood unit (WU), and pulmonary artery wedge pressure (PAWP) of 12.2±5.9 mmHg. Patients with residual PH had higher composite outcome rates of death from any cause or HF hospitalization compared to those without PH (56.1% vs. 19.5%; hazard ratio: 2.62; 95% confidence interval: 1.1 to 6.9; p=0.03). Multivariate Cox regression analysis showed that residual PH and higher PAWP after TEER were associated with higher mortality (hazard ratio: 1.14; 95% confidence interval: 1.03 to 1.28; p=0.01). Conclusion Our results suggest that patients with residual PH after TEER have a poor prognosis. Residual PH and high PAWP after TEER are associated with mortality.

Impact of surgical technique on postoperative ventricular arrhythmias in arrhythmic mitral valve prolapse

Abstract Background Mitral valve prolapse (MVP) is associated with progressive mitral regurgitation (MR) requiring surgical correction. A subset of patients with MVP may also constitute an "arrhythmic" phenotype suffering from malignant ventricular arrhythmias (VAs). Purpose To assess the impact of surgical technique for correction of degenerative MR including repair using artificial chords, repair with resection and mitral valve replacement (MVR) on longitudinal risk of VAs in patients with arrhythmic MVP. Methods Patients who had undergone mitral valve surgery for MVP with moderate to severe degenerative MR between 2010-2022 at a university hospital in Sweden were retrospectively included. Patients with ischemic heart disease, primary cardiomyopathy, channelopathy, or endocarditis were excluded. To examine changes in VAs (defined as sustained- or non-sustained ventricular tachycardias) as assessed by continuous Holter monitoring before and after surgery, generalized estimating equation (GEE) models were performed to account for the correlations between repeated monitoring in each patient and for differences in the time of measurement. Results Of 599 patients undergoing mitral valve surgery, 423 (71%) underwent repair using artificial chords, 62 (10%) repair with resection and 114 (19%) MVR. For those presenting with symptoms such as palpitations, presyncope, and/or syncope, Holter monitoring was conducted before (n=171; 29%) and/or after mitral valve surgery (n=184; 31%) (Figure 1). The distribution of VAs before and after surgery, stratified by surgical technique, is illustrated in Figure 2. In GEE models, repair using artificial chords was associated with increased postoperative VAs compared with the other surgical techniques (OR 2.14; 95% CI 1.19-3.83; p=0.01), repair with resection with reduced postoperative VAs compared with the other surgical techniques (OR 0.15; 95% CI 0.04-0.61; p=0.01), and no change in postoperative VAs was observed for MVR compared with the other surgical techniques (OR 0.724; 95% CI 0.39-1.35; p=0.31). The results remained similar after adjustment for age, sex, myxomatous disease/fibroelastic deficiency or bileaflet prolapse. Conclusion In patients with symptoms of palpitations, presyncope and/or syncope before or after mitral valve surgery, repair using artificial chords was associated with an increased risk of postoperative VAs. Prospective studies including continuous monitoring before and after surgery are needed to confirm these findings.

Impact of mitral transcatheter edge-to-edge repair in patients with advanced heart failure evaluated for heart transplantation

Abstract Background Heart transplantation is sometimes the only therapeutic option in patients with advanced heart failure (HF), impaired ventricular function and significant functional or secondary mitral regurgitation (MR). The shortage of organs and the limitations of the recipient make it necessary to consider other therapeutic alternatives in these patients, such as mitral transcatheter edge-to-edge repair (M-TEER). The MitraBridge registry has recently been published in which they analyze the potential effect of M-TEER in patients with advanced HF and moderate-severe MI who are candidates for heart transplantation (mean age 59 years, left ventricular ejection fraction (LVEF) 27%); after a mean follow-up of 24 months, complete in 82.4%, they report an overall survival of 78.5%, a combined event-free survival of 47%, with a 6.5 % need for urgent transplantation and an HF hospitalization rate after M-TEER of 44/100 patient-years. The aim of our study is to assess the impact of M-TEER on mortality and the combined events of death, HF rehospitalization and the need for urgent transplantation or a ventricular assistance device in patients with moderate-severe functional MI and advanced HF who have also been evaluated for cardiac transplantation in our hospital. Methods This is a retrospective analysis of a prospective registry. Of the patients treated by M-TEER for severe MI, we selected those with advanced HF (defined as LVEF≤35%, and/or advanced functional class (NYHA III-IV)) who had also been evaluated as possible candidates for inclusion in the heart transplant list. Results From November 2011 to December 2023, 191 patients were treated by M-TEER, of whom 38 patients met the established criteria (median age 59 years [48-65], 31 (81%) males, mean LVEF was 26 ± 6%). All patients had at least one previous hospitalization for HF and optimal medical treatment according to guidelines; the rest of the baseline clinical characteristics are listed in Table 1. During the follow-up after M-TEER, with a median of 34 months [7-70], the probability of overall survival at 2 years was 75.6%. The combined endpoint of death, need for urgent transplantation or a ventricular assist device, and rehospitalization for heart failure occurred in 26 patients with a 2-year event-free survival probability of 48% (Figure 1). Five patients (13%) were transplanted, one (2.6%) urgently. Prior to M-TEER therapy, the rate of HF hospitalization was 108 hospitalizations/100 patient-years, which was significantly reduced after the procedure to 33 hospitalizations/100 patient-years (rate ratio 0.31 [95% CI 0.21-0.45, p<0.0005]). Conclusions In patients with advanced HF and severe functional MR who are candidates for cardiac transplantation, M-TEER is an effective therapeutic alternative, achieving a survival rate of more than three-quarters of the patients at 2 years of follow-up, a significant reduction in HF hospitalizations, and a low rate of need for cardiac transplantation.

Diagnostic value of aortic valve displacement by tissue tracking for identification of aortic valve stenosis severity

Abstract Background The assessment of aortic stenosis (AS) severity on transthoracic echocardiography (TTE) may be challenging, especially in normal flow, low gradient (NF LG) group with preserved ejection fraction (EF), where reclassification of AS severity after initial TTE was observed in 52% pts (1). Calcifications and fibrosis of valve leaflets result in increased stiffness and impaired mobility, which can be quantified by tissue tracking (TT). TT is an echocardiographic modality that displays longitudinal displacement of selected area by integrating tissue velocity over time. Purpose Assessment of the diagnostic value of aortic valve displacement (AVD) by TT as a test that may increase accuracy of AS severity diagnosis in TTE. Methods 205 pts (aged 71±10 yrs, men 43%) without more than mild aortic regurgitation, mitral or tricuspid valve disease, EF ≤55%, indexed stroke volume (SVI) ≤35 ml/m2, cardiac rhythm disturbances and poor acoustic window were selected out of 842 pts screened for AS in our institution between 2020 and 2023. Based on aortic valve area (AVA) value, moderate (n=51, AVA >1.0 cm2) or severe (n=154, AVA ≤1.0 cm2) AS was diagnosed. In severe AS group, 45 pts were classified as NF LG AS (mean gradient <40 mmHg). Additionally 30 pts (aged 68±10 yrs, men 46%) without abnormalities on TTE entered control group. During TTE in five- and three-chamber views, TT was applied and region of interest was adjusted to cover whole aortic valve (AV) during cardiac cycle. Single loop was analysed with Q-analysis software. The measurement in millimetres (mm) of positive wave representing displacement of AV was performed in both views by two independent echocardiographers (Figure 1). AVD was calculated by summing up results from both views. Receiver-operating characteristic curves for AVD in the whole study group and NF LG AS to diagnose severe AS were plotted. Results AVD was already significantly decreased in moderate AS compared with age- and sex-matched healthy controls, being 22.8±2.8 mm and 24.3±2.1 mm respectively (P=0.01). In pts with severe AS, AVD was further significantly reduced compared to moderate AS pts, being 19.3±3.2 mm (P<0.0001). In the whole study group, AVD with a cut-off point <19.6 mm provided 55.8% sensitivity but 96.1 % specificity to diagnose severe AS (Figure 2B). In pts with NF LG AS, AVD with a cut-off point <20.6 mm provided 71.4% sensitivity and a specificity of 79.6% (Figure 2A). Intraclass correlation coefficient of 0.87; 95% CI (0.84–0.89) indicated good interobserver reproducibility of AVD measurement. Conclusions Aortic valve displacement by tissue tracking in TTE is a valuable, new echocardiographic tool for identification of AS severity and may improve diagnostic accuracy of AS severity in NF LG AS.Figure 1Figure 2

Systemic manifestations of connective tissue abnormalities in patients with Mitral Valve Prolapse assessed by Cardiac Magnetic Resonance

Abstract Background Mitral valve prolapse (MVP) reflects a connective tissue abnormality of the mitral leaflets leading to myxomatous degeneration. Early echocardiography and semeiotic assessment investigations suggested that connective tissue abnormalities might be extended to heart chambers, great vessels, and the skeletal system. Cardiac Magnetic Resonance (CMR) has unique potentials in evaluating MVP, cardiac chambers, aortic dimensions, and Haller Index, an expression of the deformity of the thoracic cage, at one time. Purpose We aimed to investigate the potential phenotypic systemic expressions of connective tissue disease in patients with MVP by CMR assessment. Methods This case-control study included consecutive patients with MVP and a control group of healthy volunteers undergoing CMR at our Institution from September 2020 to November 2023. Patients with more than mild mitral or aortic regurgitation, bicuspid aortic valve, or known systemic connective diseases were excluded. The MVP, cardiac chambers, aortic dimensions, and Haller Index were assessed according to standard practice. Results 103 patients with MVP and 57 healthy volunteers (51± 17 vs. 47±18 years, p=0.2, and 5% females vs. 54.4% females, p=0.8, respectively) were enrolled. Patients with MVP showed greater left ventricular end-diastolic (91±25 vs. 78±17 ml/m2; p=0.005) and end-systolic volumes (36±12 vs. 27±6; ml/m2; p<0.001), aortic annulus (13±2 vs. 12±2 mm/m2; p<0.001), sino-tubular junction (15±3 vs. 14±3 mm/m2; p=0.03), aortic root (19±3 vs. 17±3 mm/m2; p<0.001), and descending aorta (13±2 vs. 12±2 mm/m2; p=0.03), and higher Haller Index (2.8±0.6 vs. 2.6±0.4; p=0.02) than healthy controls. No differences were found in ascending aorta (18±3 vs. 17±3 mm/m2; p=0.3), pulmonary trunk (13±2 vs. 13±2 mm/m2; p=0.5), left atrial volume (38±18 vs. 30±15 ml/m2; p=0.20), right ventricular end-diastolic-volume (86±20 vs. 81±20 ml/m2; p=0.3) were found. At ANCOVA, sex and MVP affected the Haller Index values (p = 0.005 and 0.04). The association between MVP and Haller Index persisted after controlling for sex, age, and body surface area. In multivariate regression analysis, MVP and sex had an independent impact on ventricular and aortic dimensions, with MVP and male patients showing greater values. In particular, MVP was associated with an increase in the aortic annulus (Coefficient=1.2; p< 0.001), aortic root (Coefficient=1.5, p=0.001), descending aorta (Coefficient=0.7, p = 0.026), left ventricular end-diastolic-volume (Coefficient=11.1, p=0.01) and mass (Coefficient=5.7, p=0.02) after controlling for sex, age, and body surface area. Conclusions This pivotal study assessing systemic connective tissue disorders by CMR suggests abnormalities in the aorta and the skeletal system of patients with MVP, paving the way to larger investigations exploring the clinical impact of these findings.CMR findings in the study populationBox plots showing variables distribution

Good agreement between cardiac magnetic imaging protocols using free-breathing and breath-holding techniques for flow quantification in valvular heart disease

Abstract Background Cardiac magnetic resonance (CMR) evaluation of valvular heart disease is an important diagnostic tool when echocardiography is inconclusive. Flow quantification is usually performed during breath hold, which can be challenging in valvular heart disease patients often suffering from dyspnea and heart failure. Purpose The purpose of the present study is to evaluate a free-breathing protocol of flow measurement in the aortic, pulmonary and tricuspid valves in healthy subjects (HS) and patients with tricuspid regurgitation (TR). Methods Phase contrast flow volume measurements were performed in 20 HS and 25 patients with TR using standard breath-holding (BH) and a free-breathing (FB) technique. Two venc-adjusted volume acquisition were acquired in the aortic, pulmonary and tricuspid valve during BH and one during FB. Mean, standard deviation (SD) and limits of agreement (LoA) for aortic forward flow volume (AoFF), pulmonary forward flow volume (PuFF) and tricuspid inflow volume (TrIF) were evaluated. Results Figure 1 presents flow volume (ml) of AoFF, PuFF and TrIF during BH (mean of 2 measurements) and FB. Conclusions The present study demonstrated good agreements between phase contrast flow measurements using FB and BH techniques. These parameters are used in the evaluation of aortic, mitral, pulmonary and tricuspid regurgitations using CMR imaging. Thus, free-breathing CMR acquisition can be an important complement in the assessment of valvular heart disease and may be applied in patients with difficulty to hold their breath.