Automatic Detection and Tracking of Anatomical Landmarks in Transesophageal Echocardiography for Quantification of Left Ventricular Function.

OBJECTIVE: Evaluation of left ventricular (LV) function in critical care patients is useful for guidance of therapy and early detection of LV dysfunction, but the tools currently available are too time-consuming. To resolve this issue, we previously proposed a method for the continuous and automatic quantification of global LV function in critical care patients based on the detection and tracking of anatomical landmarks on transesophageal heart ultrasound. In the present study, our aim was to improve the performance of mitral annulus detection in transesophageal echocardiography (TEE). METHODS: We investigated several state-of-the-art networks for both the detection and tracking of the mitral annulus in TEE. We integrated the networks into a pipeline for automatic assessment of LV function through estimation of the mitral annular plane systolic excursion (MAPSE), called autoMAPSE. TEE recordings from a total of 245 patients were collected from St. Olav's University Hospital and used to train and test the respective networks. We evaluated the agreement between autoMAPSE estimates and manual references annotated by expert echocardiographers in 30 Echolab patients and 50 critical care patients. Furthermore, we proposed a prototype of autoMAPSE for clinical integration and tested it in critical care patients in the intensive care unit. RESULTS: Compared with manual references, we achieved a mean difference of 0.8 (95% limits of agreement: -2.9 to 4.7) mm in Echolab patients, with a feasibility of 85.7%. In critical care patients, we reached a mean difference of 0.6 (95% limits of agreement: -2.3 to 3.5) mm and a feasibility of 88.1%. The clinical prototype of autoMAPSE achieved real-time performance. CONCLUSION: Automatic quantification of LV function had high feasibility in clinical settings. The agreement with manual references was comparable to inter-observer variability of clinical experts.

Automatic assessment of left ventricular function for hemodynamic monitoring using artificial intelligence and transesophageal echocardiography.

We have developed a method to automatically assess LV function by measuring mitral annular plane systolic excursion (MAPSE) using artificial intelligence and transesophageal echocardiography (autoMAPSE). Our aim was to evaluate autoMAPSE as an automatic tool for rapid and quantitative assessment of LV function in critical care patients. In this retrospective study, we studied 40 critical care patients immediately after cardiac surgery. First, we recorded a set of echocardiographic data, consisting of three consecutive beats of midesophageal two- and four-chamber views. We then altered the patient's hemodynamics by positioning them in anti-Trendelenburg and repeated the recordings. We measured MAPSE manually and used autoMAPSE in all available heartbeats and in four LV walls. To assess the agreement with manual measurements, we used a modified Bland-Altman analysis. To assess the precision of each method, we calculated the least significant change (LSC). Finally, to assess trending ability, we calculated the concordance rates using a four-quadrant plot. We found that autoMAPSE measured MAPSE in almost every set of two- and four-chamber views (feasibility 95%). It took less than a second to measure and average MAPSE over three heartbeats. AutoMAPSE had a low bias (0.4 mm) and acceptable limits of agreement (- 3.7 to 4.5 mm). AutoMAPSE was more precise than manual measurements if it averaged more heartbeats. AutoMAPSE had acceptable trending ability (concordance rate 81%) during hemodynamic alterations. In conclusion, autoMAPSE is feasible as an automatic tool for rapid and quantitative assessment of LV function, indicating its potential for hemodynamic monitoring.

Mechanical Wave Velocities in Left Ventricular Walls in Healthy Subjects and Patients With Aortic Stenosis.

BACKGROUND: Mechanical wave velocity (MWV) measurement is a promising method for evaluating myocardial stiffness, because these velocities are higher in patients with myocardial disease. OBJECTIVES: Using high frame rate echocardiography and a novel method for detection of myocardial mechanical waves, this study aimed to estimate the MWVs for different left ventricular walls and events in healthy subjects and patients with aortic stenosis (AS). Feasibility and reproducibility were evaluated. METHODS: This study included 63 healthy subjects and 13 patients with severe AS. All participants underwent echocardiographic examination including 2-dimensional high frame rate recordings using a clinical scanner. Cardiac magnetic resonance was performed in 42 subjects. The authors estimated the MWVs at atrial kick and aortic valve closure in different left ventricular walls using the clutter filter wave imaging method. RESULTS: Mechanical wave imaging in healthy subjects demonstrated the highest feasibility for the atrial kick wave reaching >93% for all 4 examined left ventricular walls. The MWVs were higher for the inferolateral and anterolateral walls (2.2 and 2.6 m/s) compared with inferoseptal and anteroseptal walls (1.3 and 1.6 m/s) (P < 0.05) among healthy subjects. The septal MWVs at aortic valve closure were significantly higher for patients with severe AS than for healthy subjects. CONCLUSIONS: MWV estimation during atrial kick is feasible and demonstrates higher velocities in the lateral walls, compared with septal walls. The authors propose indicators for quality assessment of the mechanical wave slope as an aid for achieving consistent measurements. The discrimination between healthy subjects and patients with AS was best for the aortic valve closure mechanical waves. (Ultrasonic Markers for Myocardial Fibrosis and Prognosis in Aortic Stenosis; NCT03422770).

Automatic measurements of left ventricular volumes and ejection fraction by artificial intelligence: clinical validation in real time and large databases.

AIMS: Echocardiography is a cornerstone in cardiac imaging, and left ventricular (LV) ejection fraction (EF) is a key parameter for patient management. Recent advances in artificial intelligence (AI) have enabled fully automatic measurements of LV volumes and EF both during scanning and in stored recordings. The aim of this study was to evaluate the impact of implementing AI measurements on acquisition and processing time and test-retest reproducibility compared with standard clinical workflow, as well as to study the agreement with reference in large internal and external databases. METHODS AND RESULTS: Fully automatic measurements of LV volumes and EF by a novel AI software were compared with manual measurements in the following clinical scenarios: (i) in real time use during scanning of 50 consecutive patients, (ii) in 40 subjects with repeated echocardiographic examinations and manual measurements by 4 readers, and (iii) in large internal and external research databases of 1881 and 849 subjects, respectively. Real-time AI measurements significantly reduced the total acquisition and processing time by 77% (median 5.3 min, P < 0.001) compared with standard clinical workflow. Test-retest reproducibility of AI measurements was superior in inter-observer scenarios and non-inferior in intra-observer scenarios. AI measurements showed good agreement with reference measurements both in real time and in large research databases. CONCLUSION: The software reduced the time taken to perform and volumetrically analyse routine echocardiograms without a decrease in accuracy compared with experts.

Automated estimation of mitral annular plane systolic excursion by artificial intelligence from 3D ultrasound recordings.

Perioperative monitoring of cardiac function is beneficial for early detection of cardiovascular complications. The standard of care for cardiac monitoring performed by trained cardiologists and anesthesiologists involves a manual and qualitative evaluation of ultrasound imaging, which is a time-demanding and resource-intensive process with intraobserver- and interobserver variability. In practice, such measures can only be performed a limited number of times during the intervention. To overcome these difficulties, this study presents a robust method for automatic and quantitative monitoring of cardiac function based on 3D transesophageal echocardiography (TEE) B-mode ultrasound recordings of the left ventricle (LV). Such an assessment obtains consistent measurements and can produce a near real-time evaluation of ultrasound imagery. Hence, the presented method is time-saving and results in increased accessibility. The mitral annular plane systolic excursion (MAPSE), characterizing global LV function, is estimated by landmark detection and cardiac view classification of two-dimensional images extracted along the long-axis of the ultrasound volume. MAPSE estimation directly from 3D TEE recordings is beneficial since it removes the need for manual acquisition of cardiac views, hence decreasing the need for interference by physicians. Two convolutional neural networks (CNNs) were trained and tested on acquired ultrasound data of 107 patients, and MAPSE estimates were compared to clinically obtained references in a blinded study including 31 patients. The proposed method for automatic MAPSE estimation had low bias and low variability in comparison to clinical reference measures. The method accomplished a mean difference for MAPSE estimates of (-0.16±1.06) mm. Thus, the results did not show significant systematic errors. The obtained bias and variance of the method were comparable to inter-observer variability of clinically obtained MAPSE measures on 2D TTE echocardiography. The novel pipeline proposed in this study has the potential to enhance cardiac monitoring in perioperative- and intensive care settings.

Reduced exercise capacity is associated with left ventricular systolic dysfunction in long-term survivors of allogeneic hematopoietic stem-cell transplantation.

PURPOSE: Exercise intolerance is a common complication in survivors of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The aim of this study was to determine if cardiac function measured with echocardiography is associated with exercise capacity measured with cardio-pulmonary exercise tests in long-term survivors treated in their youth with allo-HSCT. METHODS: The study included 96 patients, of which 54.2% were female, aged 34.9 ± 11.6 years and 17.7 ± 9.3 years after allo-HSCT. Reduced exercise capacity was defined as <85% of predicted-peak oxygen uptake (VO2peak ). Linear regression was used in the prediction of VO2peak (ml/kg/min). Receiver operating characteristic evaluated the accuracy of predicting reduced exercise capacity. RESULTS: VO2peak was 36.2 ± 7.7 ml/kg/min and 43 (44.8%) had reduced exercise capacity. Left ventricular ejection fraction was 55.4 ± 5.9% and global longitudinal strain (GLS) was -17.6% ± 2.0%. Left and right ventricular functions were significantly lower in survivors with reduced exercise capacity. Increased body mass index, lower physical activity score, reduced pulmonary function (by forced expiratory volume in 1-s) and reduced left ventricular systolic function (by GLS) were significant independent predictors for reduced VO2peak . GLS was superior to other echocardiographical indices for identifying reduced exercise capacity (area under curve = 0.64, p = 0.014). CONCLUSIONS: Left ventricular systolic dysfunction measured by GLS is associated with reduced exercise capacity in long-term allo-HSCT survivors.

Relationship of Mechanical Dyssynchrony and LV Remodeling With Improvement of Mitral Regurgitation After CRT.

OBJECTIVES: The aim of this study was to explore the association between mechanical dyssynchrony of the left ventricle before cardiac resynchronization therapy (CRT) and improvement of mitral regurgitation (MR) after CRT. BACKGROUND: MR is very frequent among patients with dilated cardiomyopathy and conduction delay. METHODS: Echocardiograms (pre-CRT and 12 ± 3.8 months thereafter) of 314 patients with dilated cardiomyopathy and any degree of MR, who underwent CRT device implantation according to guidelines, were analyzed. Left ventricular (LV) mechanical dyssynchrony was assessed by apical rocking (ApRock) and septal flash (SF), while MR severity was graded from I to IV on the basis of vena contracta width, regurgitation jet size, and proximal isovelocity surface area. RESULTS: At baseline, 30% of patients presented with severe MR (grade III or IV). In 62% of patients, MR decreased after CRT, and these patients more frequently had left bundle branch block, had more severe MR, had more dilated left ventricles, had lower ejection fractions, and more often had ApRock and SF. Reverse remodeling was more frequent among patients with MR reduction (ΔLV end-systolic volume -35.5% ± 27.2% vs -4.1% ± 33.2%; P < 0.001). In a multivariable logistic stepwise regression, only ApRock (odds ratio [OR]: 3.8; 95% CI: 1.7-8.5; P = 0.001), SF (OR: 3.6; 95% CI: 1.6-7.9; P = 0.002), and baseline MR (OR: 1.4; 95% CI: 1.0-1.9; P = 0.046) remained significantly associated with MR reduction. CONCLUSIONS: ApRock, SF, and severity of MR at baseline are strongly associated with MR reduction after CRT, while LV reverse remodeling is its underlying mechanism. Therefore, in patients with heart failure with LV dyssynchrony on optimal medical treatment, CRT should be the primary treatment attempt for relevant MR.

Clinical and Echocardiographic Parameters Predicting 1- and 2-Year Mortality After Transcatheter Aortic Valve Implantation.

Background: Transcatheter aortic valve implantation (TAVI) has become a standard treatment option for patients with symptomatic aortic stenosis. Elderly high-risk patients treated with TAVI have a high residual mortality due to preexisting comorbidities. Knowledge of factors predicting futility after TAVI is sparse and clinical tools to aid the preoperative evaluation are lacking. The aim of this study was to evaluate if echocardiographic measures, including speckle-tracking analysis, in addition to clinical parameters, could aid in the prediction of mortality beyond 30 days after TAVI. Methods: This prospective observational cohort study included 227 patients treated with TAVI at the University Hospital of North Norway, Tromsø and Oslo University Hospital, Rikshospitalet from February 2010 to June 2013. All the patients underwent preoperative echocardiographic evaluation with retrospective speckle-tracking analysis. Primary endpoints were 1- and 2-year mortality beyond 30 days after TAVI. Results: All-cause 1- and 2-year mortality beyond 30 days after TAVI was 12.1 and 19.5%, respectively. Predictors of 1-year mortality beyond 30 days were body mass index [hazard ratio (HR): 0.88, 95% CI: 0.80-0.98, p = 0.018], previous myocardial infarction (HR: 2.69, 95% CI: 1.14-6.32, p = 0.023), and systolic pulmonary artery pressure ≥ 60 mm Hg (HR: 5.93, 95% CI: 1.67-21.1, p = 0.006). Moderate-to-severe mitral regurgitation (HR: 2.93, 95% CI: 1.53-5.63, p = 0.001), estimated glomerular filtration rate (HR: 0.98, 95% CI: 0.96-0.99, p = 0.002), and chronic obstructive pulmonary disease (HR: 1.9, 95% CI: 1.01-3.58, p = 0.046) were predictors of 2-year mortality. Conclusion: Both the clinical and echocardiographic parameters should be considered when evaluating high-risk patients for TAVI, as both are predictive of 1-and 2-year mortality. Our results support the importance of individual risk assessment using a multidisciplinary, multimodal, and individual approach.

Impaired right ventricular function in long-term survivors of allogeneic haematopoietic stem-cell transplantation.

AIMS: Survivors of allogeneic haematopoietic stem-cell transplantation (allo-HSCT) are at higher risk of cardiovascular disease. We aimed to describe right ventricular (RV) systolic function and risk factors for RV dysfunction in long-term survivors of allo-HSCT performed in their youth. METHODS AND RESULTS: This cohort included 103 survivors (53% female), aged (mean±SD) 17.6±9.5 years at allo-HSCT, with a follow-up time of 17.2±5.5 years. Anthracyclines were used as first-line therapy for 44.7% of the survivors. The RV was evaluated with echocardiography, and found survivors to have reduced RV function in comparison to a group of healthy control subjects: Tricuspid annular plane systolic excursion, (TAPSE, 20.8±3.7 mm vs 24.6±3.8 mm, p<0.001), RV peak systolic velocity (RV-s', 11.2±2.3 cm/s vs 12.3±2.3 cm/s, p=0.001), fractional area change (FAC, 41.0±5.2% vs 42.2±5.1%, p=0.047) and RV free-wall strain (RVFWS, -27.1±4.2% vs -28.5±3.3%, p=0.043). RV systolic dysfunction (RVSD) was diagnosed in 14 (13.6%), and was strongly associated with progressive left ventricular systolic dysfunction (LVSD). High dosages of anthracyclines were associated with greater reductions in RV and LV function. Multivariable linear regressions confirmed global longitudinal strain to be a significant independent predictor for reduced RV function. CONCLUSION: Impaired RV function was found in long-term survivors of allo-HSCT who were treated in their youth. This was associated with progressive left ventricle dysfunction, and pretransplant therapies with anthracyclines. The occurrence of RVSD was less frequent and was milder than coexisting LVSD in this cohort.

Risk scores for prediction of 30-day mortality after transcatheter aortic valve implantation: Results from a two-center study in Norway.

OBJECTIVES: Transcatheter aortic valve implantation (TAVI)-specific risk scores have been developed based on large registry studies. Our aim was to evaluate how both surgical and novel TAVI risk scores performed in predicting all cause 30-day mortality. In addition, we wanted to explore the validity of our own previously developed model in a separate and more recent cohort. METHODS: The derivation cohort included patients not eligible for open surgery treated with TAVI at the University Hospital of North Norway (UNN) and Oslo University Hospital (OUS) from February 2010 through June 2013. From this cohort, a logistic prediction model (UNN/OUS) for all cause 30-day mortality was developed. The validation cohort consisted of patients not included in the derivation cohort and treated with TAVI at UNN between June 2010 and April 2017. EuroSCORE, Logistic EuroSCORE, EurosSCORE 2, STS score, German AV score, OBSERVANT score, IRRMA score, and FRANCE-2 score were calculated for both cohorts. The discriminative accuracy of each score, including our model, was evaluated by receiver operating characteristic (ROC) analysis and compared using DeLong test where P< .05 was considered statistically significant. RESULTS: The derivation cohort consisted of 218 and the validation cohort of 241 patients. Our model showed statistically significant better accuracy than all other scores in the derivation cohort. In the validation cohort, the FRANCE-2 had a significantly higher predictive accuracy compared to all scores except the IRRMA and STS score. Our model showed similar results. CONCLUSION: Existing risk scores have shown limited accuracy in predicting early mortality after TAVI. Our results indicate that TAVI-specific risk scores might be useful when evaluating patients for TAVI.

Effect of Continuous Positive Airway Pressure on Arrhythmia in Atrial Fibrillation and Sleep Apnea: A Randomized Controlled Trial.

Rationale: Sleep apnea (SA) is highly prevalent in patients with atrial fibrillation (AF), and both conditions are associated with adverse cardiovascular outcomes.Objectives: To determine the effect of continuous positive airway pressure (CPAP) on AF burden.Methods: This open-label, parallel-group, randomized controlled trial included patients with paroxysmal AF and moderate to severe SA (apnea-hypopnea index ⩾15). A computerized system randomized eligible patients (1:1) to 5 months' treatment with CPAP plus usual care (CPAP, n = 55) or usual care alone (control, n = 54). The outcome assessment was blinded. The planned primary outcome was the difference between CPAP treatment and control groups in change of AF burden (percentage of time in AF) as measured by implantable loop recorder.Measurements and Main Results: A total of 579 patients with paroxysmal AF had respiratory polygraphy, of whom 244 (42%) had moderate to severe SA. Of these, 158 (65%) participated in the CPAP run-in period, of whom 39 (25%) patients did not tolerate the treatment. A total of 108 patients were available for the primary analysis. The mean time in AF decreased from 5.6% at baseline to 4.1% during the last 3 months of CPAP intervention and from 5.0% to 4.3% in the control group. The adjusted between-group difference at follow-up was -0.63 (95% confidence interval, -2.55 to 1.30) percentage points (P = 0.52). Seven serious adverse events (13%) occurred in the CPAP group, and two (4%) occurred in the control group.Conclusions: In patients with paroxysmal AF and SA, treatment with CPAP did not result in a statistically significant reduction in the burden of AF.Clinical trial registered with www.clinicaltrials.gov (NCT02727192).

Randomized Trial of Interleukin-6 Receptor Inhibition in Patients With Acute ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response. OBJECTIVES: This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI. METHODS: The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days. RESULTS: We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups. CONCLUSIONS: Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703).

3D Myocardial Mechanical Wave Measurements: Toward In Vivo 3D Myocardial Elasticity Mapping.

OBJECTIVES: This study aimed to investigate the potential of a novel 3-dimensional (3D) mechanical wave velocity mapping technique, based on the natural mechanical waves produced by the heart itself, to approach a noninvasive 3D stiffness mapping of the left ventricle. BACKGROUND: Myocardial fibrosis is recognized as a pathophysiological substrate of major cardiovascular disorders such as cardiomyopathies and valvular heart disease. As fibrosis leads to increased myocardial stiffness, ultrasound elastography measurements could provide important clinical information. METHODS: A 3D high frame rate imaging sequence was implemented on a high-end clinical ultrasound scanner to achieve 820 volumes/s when gating over 4 consecutive cardiac cycles. Five healthy volunteers and 10 patients with various degrees of aortic stenosis were included to evaluate feasibility and reproducibility. Mechanical waves were detected using the novel Clutter Filter Wave Imaging approach, shown to be highly sensitive to the weak tissue displacements caused by natural mechanical waves. RESULTS: 3D spatiotemporal maps of mechanical wave velocities were produced for all subjects. Only the specific mechanical wave at atrial contraction provided a full 3D coverage of the left ventricle (LV). The average atrial kick propagation velocity was 1.6 ± 0.2 m/s in healthy volunteers and 2.8 ± 0.8 m/s in patients (p = 0.0016). A high correlation was found between mechanical wave velocity and age (R2 = 0.88, healthy group), septal wall thickness (R2 = 0.73, entire group), and peak jet velocity across the aortic valve (R2 = 0.70). For 3 of the patients, the higher mechanical wave velocity coexisted with the presence of late gadolinium enhancement on cardiac magnetic resonance. CONCLUSIONS: In this study, 3D LV mechanical wave velocities were visualized and measured in healthy volunteers and patients with aortic stenosis. The proposed imaging sequence and measurement technique allowed, for the first time, the measurement of full spatiotemporal 3D elasticity maps of the LV using ultrasound. (Ultrasonic markers for myocardial fibrosis and prognosis in aortic stenosis; NCT03422770).

Strain-Guided Management of Potentially Cardiotoxic Cancer Therapy.

BACKGROUND: In patients at risk of cancer therapy-related cardiac dysfunction (CTRCD), initiation of cardioprotective therapy (CPT) is constrained by the low sensitivity of ejection fraction (EF) for minor changes in left ventricular (LV) function. Global longitudinal strain (GLS) is a robust and sensitive marker of LV dysfunction, but existing observational data have been insufficient to support a routine GLS-guided strategy for CPT. OBJECTIVES: This study sought to identify whether GLS-guided CPT prevents reduction in LVEF and development of CTRCD in high-risk patients undergoing potentially cardiotoxic chemotherapy, compared with usual care. METHODS: In this international, multicenter, prospective, randomized controlled trial, 331 anthracycline-treated patients with another heart failure risk factor were randomly allocated to CPT initiation guided by either ≥12% relative reduction in GLS (n = 166) or >10% absolute reduction of LVEF (n = 165). Patients were followed for EF and development of CTRCD (symptomatic EF reduction of >5% or >10% asymptomatic to <55%) over 1 year. RESULTS: Of 331 randomized patients, 2 died, and 22 withdrew consent or were lost to follow-up. Among 307 patients (age: 54 ± 12 years; 94% women; baseline LVEF: 59 ± 6%; GLS: -20.6 ± 2.4%) with a median (interquartile range) follow-up of 1.02 years (0.98 to 1.07 years), most (n = 278) had breast cancer. Heart failure risk factors were prevalent: 29% had hypertension, and 13% had diabetes mellitus. At the 1-year follow-up, although the primary outcome of change in LVEF was not significantly different between the 2 arms, there was significantly greater use of CPT, and fewer patients met CTRCD criteria in the GLS-guided than the EF-guided arm (5.8% vs. 13.7%; p = 0.02), and the 1-year EF was 57 ± 6% versus 55 ± 7% (p = 0.05). Patients who received CPT in the EF-guided arm had a larger reduction in LVEF at follow-up than in the GLS-guided arm (9.1 ± 10.9% vs. 2.9 ± 7.4%; p = 0.03). CONCLUSIONS: Although the change in LVEF was not different between the 2 arms as a whole, when patients who received CPT were compared, those in the GLS-guided arm had a significantly lower reduction in LVEF at 1 year follow-up. Furthermore, GLS-guided CPT significantly reduced a meaningful fall of LVEF to the abnormal range. The results support the use of GLS in surveillance for CTRCD. (Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes [SUCCOUR]; ACTRN12614000341628).

YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis.

BACKGROUND: Identification of novel biomarkers could provide prognostic information and improve risk stratification in patients with aortic stenosis (AS). YKL-40 (chitinase-3-like protein 1), a protein involved in atherogenesis, is upregulated in human calcific aortic valves. We hypothesized that circulating YKL-40 would be elevated and associated with the degree of AS severity and outcome in patients with symptomatic AS. METHODS: Plasma YKL-40 was analyzed in 2 AS populations, one severe AS (n=572) with outcome measures and one with mixed severity (n=67). YKL-40 expression in calcified valves and in an experimental pressure overload model was assessed. RESULTS: We found (1) patients with AS had upregulated circulating YKL-40 compared with healthy controls (median 109 versus 34 ng/mL, P<0.001), but levels were not related to the degree of AS severity. (2) High YKL-40 levels (quartile 4) were associated with long-term (median follow-up 4.7 years) all-cause mortality (adjusted hazard ratio, 1.93 [95% CI, 1.37-2.73], P<0.001). (3) YKL-40 protein expression in human calcific valves co-localized with its putative receptor IL-13rα2 in close proximity to valve interstitial cells. (4) Myocardial YKL-40 increased in experimental pressure overload (6-fold in decompensated versus sham mice). CONCLUSIONS: YKL-40 levels were elevated in AS and associated with mortality but not with other metrics of disease severity including the degree of AS severity. Despite scientific rationale for its role in AS, the clinical utility of circulating YKL-40 as a biomarker is limited. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794832.

Sex differences in circulating proteins in heart failure with preserved ejection fraction.

BACKGROUND: Many patients with heart failure with preserved ejection fraction (HFpEF) are women. Exploring mechanisms underlying the sex differences may improve our understanding of the pathophysiology of HFpEF. Studies focusing on sex differences in circulating proteins in HFpEF patients are scarce. METHODS: A total of 415 proteins were analyzed in 392 HFpEF patients included in The Metabolic Road to Diastolic Heart Failure: Diastolic Heart Failure study (MEDIA-DHF). Sex differences in these proteins were assessed using adjusted logistic regression analyses. The associations between candidate proteins and cardiovascular (CV) death or CV hospitalization (with sex interaction) were assessed using Cox regression models. RESULTS: We found 9 proteins to be differentially expressed between female and male patients. Women expressed more LPL and PLIN1, which are markers of lipid metabolism; more LHB, IGFBP3, and IL1RL2 as markers of transcriptional regulation; and more Ep-CAM as marker of hemostasis. Women expressed less MMP-3, which is a marker associated with extracellular matrix organization; less NRP1, which is associated with developmental processes; and less ACE2, which is related to metabolism. Sex was not associated with the study outcomes (adj. HR 1.48, 95% CI 0.83-2.63), p = 0.18. CONCLUSION: In chronic HFpEF, assessing sex differences in a wide range of circulating proteins led to the identification of 9 proteins that were differentially expressed between female and male patients. These findings may help further investigations into potential pathophysiological processes contributing to HFpEF.

The association of mechanical dyssynchrony and resynchronization therapy with survival in heart failure with a wide QRS complex: a two-world study.

Setting up a randomized trial to assess the association of mechanical dyssynchrony (MD) and the success of cardiac resynchronization therapy (CRT) in heart failure with a wide QRS complex is ethically challenging. We therefore investigated this association in a retrospective cohort study observing different treatment strategies which were chosen based on the availability of health care resources. The survival of 500 patients from six Western European centers treated with CRT was compared to their 137 Eastern European counterparts not treated with CRT, with regard to the presence of MD. MD was visually assessed and was defined as the presence of apical rocking and/or septal flash. Patients were followed for a mean of 26 ± 8 months for the occurrence of death of any cause. As compared with medical therapy alone, CRT was associated with a more favorable survival (hazard ratio (HR), 0.53; 95% confidence interval (CI) 0.35-0.79; P = 0.002). Patients with MD treated by CRT had better survival than patients belonging to all other groups-they showed 72%, 66% and 56% reduction in all-cause mortality, respectively, compared to patients with MD not treated by CRT (HR 0.28; 95% CI 0.17-0.44), patients without MD treated by CRT (HR 0.34; 95% CI 0.22-0.52) and patients without MD not treated by CRT (HR 0.44; 95% CI 0.25-0.76). Patients with wide QRS complex who are treated with CRT have a significantly better survival when MD is present.

Enhanced clinical phenotyping by mechanistic bioprofiling in heart failure with preserved ejection fraction: insights from the MEDIA-DHF study (The Metabolic Road to Diastolic Heart Failure).

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome for which clear evidence of effective therapies is lacking. Understanding which factors determine this heterogeneity may be helped by better phenotyping. An unsupervised statistical approach applied to a large set of biomarkers may identify distinct HFpEF phenotypes.Methods: Relevant proteomic biomarkers were analyzed in 392 HFpEF patients included in Metabolic Road to Diastolic HF (MEDIA-DHF). We performed an unsupervised cluster analysis to define distinct phenotypes. Cluster characteristics were explored with logistic regression. The association between clusters and 1-year cardiovascular (CV) death and/or CV hospitalization was studied using Cox regression.Results: Based on 415 biomarkers, we identified 2 distinct clusters. Clinical variables associated with cluster 2 were diabetes, impaired renal function, loop diuretics and/or betablockers. In addition, 17 biomarkers were higher expressed in cluster 2 vs. 1. Patients in cluster 2 vs. those in 1 experienced higher rates of CV death/CV hospitalization (adj. HR 1.93, 95% CI 1.12-3.32, p = 0.017). Complex-network analyses linked these biomarkers to immune system activation, signal transduction cascades, cell interactions and metabolism.Conclusion: Unsupervised machine-learning algorithms applied to a wide range of biomarkers identified 2 HFpEF clusters with different CV phenotypes and outcomes. The identified pathways may provide a basis for future research.Clinical significanceMore insight is obtained in the mechanisms related to poor outcome in HFpEF patients since it was demonstrated that biomarkers associated with the high-risk cluster were related to the immune system, signal transduction cascades, cell interactions and metabolismBiomarkers (and pathways) identified in this study may help select high-risk HFpEF patients which could be helpful for the inclusion/exclusion of patients in future trials.Our findings may be the basis of investigating therapies specifically targeting these pathways and the potential use of corresponding markers potentially identifying patients with distinct mechanistic bioprofiles most likely to respond to the selected mechanistically targeted therapies.

Elevated levels of the secreted wingless agonist R-spondin 3 in preeclamptic pregnancies.

OBJECTIVE: Preeclampsia is a syndrome characterized by hypertension and poor placental development. The developmental wingless (Wnt) pathway plays an important role in placental development and we hypothesized that Wnt signaling would be dysregulated in preeclampsia. METHODS: To elucidate aberrations in the Wnt signaling pathway we conducted a pathway analysis on placental mRNA in late-onset preeclampsia and normal pregnancy from the STORK study [n = 10 in each group, RNA sequencing (RNAseq)] to identify differentially expressed genes. In addition, we compared circulating levels of secreted Wnt agonists and antagonists at term pregnancy and 6 months postpartum from an acute preeclampsia study (preeclampsia n = 34, normal pregnancy n = 61). RESULTS: We found circulating and placental mRNA levels of the secreted Wnt agonist R-spondin 3 (RSPO3) at term elevated in preeclampsia. Increased plasma RSPO3 was associated with high mean arterial pressure. Further, pathway analysis of placental tissue revealed elevated mRNA levels of upstream ligands WNT6 and WNT10A and frizzled receptors 2 and 4 in preeclampsia and downstream activation of the noncanonical Ca/NFAT pathway. Finally, plasma dickkopf 3 was decreased in preeclampsia 6 months postpartum. CONCLUSION: We identify a potential role for RSPO3 and activation of noncanonical Wnt signaling in preeclampsia.

Left Ventricular Systolic Function in Long-Term Survivors of Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a potentially curative therapy for malignant and nonmalignant diseases, is being increasingly used in younger patients. Although allo-HSCT survivors have an established increased risk of cardiovascular disease, there is limited knowledge of the long-term effects on cardiac function in survivors. OBJECTIVES: The purpose of this study was to describe left ventricular (LV) systolic function in long-term allo-HSCT survivors treated in childhood, adolescence, or early adulthood. METHODS: Our cross-sectional cohort study included 104 patients (56% women), age 18 ± 10 years at time allo-HSCT with 17 ± 6 years of follow-up. Echocardiography included 2-dimensional (2D) and 3-dimensional (3D) analyses and speckle tracking imaging. In total, 55 healthy control subjects with a similar age, sex, and body mass index were used for comparison. Left ventricular systolic dysfunction (LVSD) was defined as reduced 2D left ventricular ejection fraction (LVEF) of <52% in men and <54% in women, and/or a reduced global longitudinal strain (GLS) of ≥-17%. Multivariable linear regression was used to determine independent predictors of 2D-LVEF and GLS. RESULTS: Allo-HSCT survivors had significantly reduced LV systolic function compared with control subjects: 2D-LVEF (55.2 ± 5.8% vs. 59.0 ± 2.9%; p < 0.001), 3D LVEF (54.0 ± 5.1% vs. 57.6 ± 2.7%; p < 0.001), and GLS (-17.5 ± 2.2% vs. -19.8 ± 1.4%; p < 0.001). LVSD was found in 44.2%, of whom 28.3% were symptomatic. Clinical factors independently associated with 2D-LVEF and/or GLS included age, anthracyclines, graft versus host disease (GVHD), heart rate, and hypertension. In the 45% of survivors pre-treated with anthracyclines, the effect of anthracyclines on 2D-LVEF and GLS was dose-dependent. CONCLUSIONS: LVSD is common in long-term survivors of allo-HSCT treated in their youth. Pre-HSCT therapies with anthracyclines, age, heart rate, hypertension, and graft versus host disease are associated with measures of LV function.