The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy.

PURPOSE: This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. METHODS: Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FINDINGS: In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were -14.78 (12.35) mmHg, -21.47 (12.78) mmHg, and -8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were -13.30 (12.47) mmHg and -7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. IMPLICATIONS: The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).

Rate of Change in 10-Year Atherosclerotic Cardiovascular Disease Risk and Its Implications for Primary Prevention.

BACKGROUND: Contemporary cardiovascular primary prevention is based on the assessment of the 10-year risk of atherosclerotic cardiovascular disease (ASCVD). However, the clinical implications of temporal change in the 10-year ASCVD risk estimate (∆10-year ASCVD risk/year) are unknown. METHODS: A total of 211 077 participants without established ASCVD and with repetitive 10-year ASCVD risk assessment at an interval of 4 to 5 years were selected from the Korean National Health Insurance Service data. The primary end point was a composite of myocardial infarction, stroke, coronary revascularization, and all-cause death. RESULTS: ASCVD event rates were proportional to the ∆10-year ASCVD risk/year regardless of the baseline 10-year ASCVD risk. Adjusted hazard ratio for ASCVD events per 1% increase in ∆10-year ASCVD risk/year was 1.53 (95% CI, 1.44-1.63), 1.24 (95% CI, 1.15-1.32), 1.18 (95% CI, 1.13-1.23), and 1.05 (95% CI, 1.00-1.10) in those with a baseline 10-year ASCVD risk of <5%, 5% to 7.5%, 7.5% to 20%, and ≥20%, respectively. Appropriate control of risk factors, including low-density lipoprotein cholesterol, blood pressure, body mass index, exercise habits, and smoking status, was associated with lower ASCVD event rates, whereas failure to control these risk factors resulted in higher ASCVD event rates. CONCLUSIONS: The temporal change in 10-year ASCVD risk over a period of 4 to 5 years reflects success or failure in controlling major cardiovascular risk factors and indicates the risk of future ASCVD events. The ∆10-year ASCVD risk/year can be used as an indicator of primary prevention and guide the application of preventive measures.

Data-driven mortality risk prediction of severe degenerative mitral regurgitation patients undergoing mitral valve surgery.

AIMS: The outcomes of mitral valve replacement/repair (MVR) in severe degenerative mitral regurgitation (MR) patients depend on various risk factors. We aimed to develop a risk prediction model for post-MVR mortality in severe degenerative MR patients using machine learning. METHODS AND RESULTS: Consecutive severe degenerative MR patients undergoing MVR were analysed (n = 1521; 70% training/30% test sets). A random survival forest (RSF) model was constructed, with 3-year post-MVR all-cause mortality as the outcome. Partial dependency plots were used to define the thresholds of each risk factor. A simple scoring system (MVR-score) was developed to stratify post-MVR mortality risk. At 3 years following MVR, 90 patients (5.9%) died in the entire cohort (59 and 31 deaths in the training and test sets). The most important predictors of mortality in order of importance were age, haemoglobin, valve replacement, glomerular filtration rate, left atrial dimension, and left ventricular (LV) end-systolic diameter. The final RSF model with these six variables demonstrated high predictive performance in the test set (3-year C-index 0.880, 95% confidence interval 0.834-0.925), with mortality risk increased strongly with left atrial dimension >55 mm, and LV end-systolic diameter >45 mm. MVR-score demonstrated effective risk stratification and had significantly higher predictability compared to the modified Mitral Regurgitation International Database score (3-year C-index 0.803 vs. 0.750, P = 0.034). CONCLUSION: A data-driven machine learning model provided accurate post-MVR mortality prediction in severe degenerative MR patients. The outcome following MVR in severe degenerative MR patients is governed by both clinical and echocardiographic factors.

Cardioprotection Using Strain-Guided Management of Potentially Cardiotoxic Cancer Therapy: 3-Year Results of the SUCCOUR Trial.

BACKGROUND: Global longitudinal strain (GLS) can predict cancer therapeutics-related cardiac dysfunction and guide initiation of cardioprotection (CPT). OBJECTIVES: In this study, the authors sought to determine whether echocardiography GLS-guided CPT provides less cardiac dysfunction in survivors of potentially cardiotoxic chemotherapy, compared with usual care at 3 years. METHODS: In this international multicenter prospective randomized controlled trial, patients were enrolled from 28 international sites. All patients treated with anthracyclines with another risk factor for heart failure were randomly allocated to GLS-guided (>12% relative reduction in GLS) or ejection fraction (EF)-guided (>10% absolute reduction of EF to <55%) CPT. The primary end point was the change in 3-dimensional (3D) EF (ΔEF) from baseline to 3 years. RESULTS: Among 331 patients enrolled, 255 (77%, age 54 ± 12 years, 95% women) completed 3-year follow-up (123 in the EF-guided group and 132 in the GLS-guided group). Most had breast cancer (n = 236; 93%), and anthracycline followed by trastuzumab was the most common chemotherapy regimen (84%). Although 67 (26%) had hypertension and 32 (13%) had diabetes mellitus, left ventricular function was normal at baseline (EF: 59% ± 6%, GLS: 20.7% ± 2.3%). CPT was administered in 18 patients (14.6%) in the EF-guided group and 41 (31%) in the GLS-guided group (P = 0.03). Most patients showed recovery in EF and GLS after chemotherapy; 3-year ΔEF was -0.03% ± 7.9% in the EF-guided group and -0.02% ± 6.5% in the GLS-guided (P = 0.99) group; respective 3-year EFs were 58% ± 6% and 59% ± 5% (P = 0.06). At 3 years, 17 patients (5%) had cancer therapeutics-related cardiac dysfunction (11 in the EF-guided group and 6 in the GLS guided group; P = 0.16); 1 patient in each group was admitted for heart failure. CONCLUSIONS: Among patients taking potentially cardiotoxic chemotherapy for cancer, the 3-year data showed improvement of LV dysfunction compared with 1 year, with no difference in ΔEF between GLS- and EF-guided CPT. (Strain Surveillance of Chemotherapy for Improving Cardiovascular Outcomes [SUCCOUR]; ACTRN12614000341628).

Long-term outcomes in distinct phenogroups of patients with primary mitral regurgitation undergoing valve surgery.

OBJECTIVES: Patients with mitral regurgitation (MR) may be heterogeneous with different risk profiles. We aimed to identify distinct phenogroups of patients with severe primary MR and investigate their long-term prognosis after mitral valve (MV) surgery. METHODS: The retrospective cohort of patients with severe primary MR undergoing MV surgery (derivation, n=1629; validation, n=692) was analysed. Latent class analysis was used to classify patients into subgroups using 15 variables. The primary outcome was all-cause mortality after MV surgery. RESULTS: During follow-up (median 6.0 years), 149 patients (9.1%) died in the derivation cohort. In the univariable Cox analysis, age, female, atrial fibrillation, left ventricular (LV) end-systolic dimension/volumes, LV ejection fraction, left atrial dimension and tricuspid regurgitation peak velocity were significant predictors of mortality following MV surgery. Five distinct phenogroups were identified, three younger groups (group 1-3) and two older groups (group 4-5): group 1, least comorbidities; group 2, men with LV enlargement; group 3, predominantly women with rheumatic MR; group 4, low-risk older patients; and group 5, high-risk older patients. Cumulative survival was the lowest in group 5, followed by groups 3 and 4 (5-year survival for groups 1-5: 98.5%, 96.0%, 91.7%, 95.6% and 83.4%; p<0.001). Phenogroups had similar predictive performance compared with the Mitral Regurgitation International Database score in patients with degenerative MR (3-year C-index, 0.763 vs 0.750, p=0.602). These findings were reproduced in the validation cohort. CONCLUSION: Five phenogroups of patients with severe primary MR with different risk profiles and outcomes were identified. This phenogrouping strategy may improve risk stratification when optimising the timing and type of interventions for severe MR.

Differential diagnosis of common etiologies of left ventricular hypertrophy using a hybrid CNN-LSTM model.

Differential diagnosis of left ventricular hypertrophy (LVH) is often obscure on echocardiography and requires numerous additional tests. We aimed to develop a deep learning algorithm to aid in the differentiation of common etiologies of LVH (i.e. hypertensive heart disease [HHD], hypertrophic cardiomyopathy [HCM], and light-chain cardiac amyloidosis [ALCA]) on echocardiographic images. Echocardiograms in 5 standard views (parasternal long-axis, parasternal short-axis, apical 4-chamber, apical 2-chamber, and apical 3-chamber) were obtained from 930 subjects: 112 with HHD, 191 with HCM, 81 with ALCA and 546 normal subjects. The study population was divided into training (n = 620), validation (n = 155), and test sets (n = 155). A convolutional neural network-long short-term memory (CNN-LSTM) algorithm was constructed to independently classify the 3 diagnoses on each view, and the final diagnosis was made by an aggregate network based on the simultaneously predicted probabilities of HCM, HCM, and ALCA. Diagnostic performance of the algorithm was evaluated by the area under the receiver operating characteristic curve (AUC), and accuracy was evaluated by the confusion matrix. The deep learning algorithm was trained and verified using the training and validation sets, respectively. In the test set, the average AUC across the five standard views was 0.962, 0.982 and 0.996 for HHD, HCM and CA, respectively. The overall diagnostic accuracy was significantly higher for the deep learning algorithm (92.3%) than for echocardiography specialists (80.0% and 80.6%). In the present study, we developed a deep learning algorithm for the differential diagnosis of 3 common LVH etiologies (HHD, HCM and ALCA) by applying a hybrid CNN-LSTM model and aggregate network to standard echocardiographic images. The high diagnostic performance of our deep learning algorithm suggests that the use of deep learning can improve the diagnostic process in patients with LVH.

Body Mass Index, Muscle Mass, and All-Cause Mortality in Patients With Acute Heart Failure: The Obesity Paradox Revisited.

Background and Objectives: Lower body mass index (BMI) is considered a poor prognostic factor in patients with heart failure (HF). We aimed to investigate the clinical impact of BMI on the risk of mortality in patients with acute HF (AHF) across various phenotypes. Methods: We retrospectively identified 4,146 registry patients with AHF and BMI data. The study population was categorized according to the WHO Asia-Pacific BMI classification: BMI <18.5 kg/m2 (underweight; n=418), BMI 18.5-23 kg/m2 (ideal; n=1,620), BMI 23-25 kg/m2 (overweight; n=828), BMI 25-30 kg/m2 (obesity I; n=1,047), and BMI ≥30 kg/m2 (obesity II; n=233). The risk of all-cause mortality was compared between these 5 groups. Results: During a median follow-up of 32 months, 1,732 patients (41.8%) died. Compared to patients with obesity II, those with overweight, ideal BMI or underweight status had a higher risk of mortality (overweight: hazard ratio [HR], 1.606; 95% confidence interval [CI], 1.016-2.539; p=0.042) (ideal BMI: HR, 1.744; 95% CI, 1.112-2.734; p=0.015) (underweight: HR, 2.729; 95% CI, 1.686-4.417; p<0.001). Higher risk of mortality among patients with lower BMI was observed regardless of age, sex, hypertension, diabetes, ischemic heart disease, atrial fibrillation, and HF phenotype. Furthermore, low muscle index (total muscle mass/height2), calculated using serum cystatin C data in a subset of 579 patients, was associated with higher mortality risk. Conclusions: A lower BMI is associated with a higher risk of mortality in patients with AHF. This obesity paradox is observed in AHF regardless of comorbidities and HF phenotype.

Reverse Remodeling Assessed by Left Atrial and Ventricular Strain Reflects Treatment Response to Sacubitril/Valsartan.

BACKGROUND: The left ventricular global longitudinal strain (LVGLS) and left atrial reservoir strain (LARS) are considered as sensitive and reliable markers of cardiac remodeling and function. However, their temporal changes during optimal management of heart failure with reduced ejection fraction (HFrEF) are unknown. OBJECTIVES: This study investigated the time trajectories of the LARS and LVGLS in patients with HFrEF treated with angiotensin receptor-neprilysin inhibitors, and assessed whether the LARS and LVGLS could define left heart reverse remodeling (LHRR) and reflect the treatment response and prognosis. METHODS: Using a retrospective cohort of patients with HFrEF prescribed sacubitril/valsartan, we assessed the time trajectories of the LVGLS and LARS in 409 patients (1,258 echocardiograms), and investigated their association with the occurrence of cardiovascular death and hospitalization for heart failure (HHF), after the determination of LHRR, during a median follow-up of 27.1 (IQR: 18.3-36.3) months. RESULTS: Among patients with HFrEF prescribed sacubitril/valsartan, both the LVGLS and LARS improved over time. The improvements in the LVGLS and LARS were prominent within 6 months of sacubitril/valsartan treatment: the LVGLS improved from 10.2% (IQR: 7.9%-12.7%) to 13.9% (IQR: 10.5%-16.3%) (P < 0.001), and the LARS improved from 11.4% (IQR: 8.4%-15.6%) to 15.9% (IQR: 11.5%-21.4%) (P < 0.001). These improvements were larger among patients who did not experience the study outcome than in patients with events. Improvement in the LVGLS to ≥13% and LARS to ≥12.5% (ie, complete LHRR) was significantly associated with a lower risk of cardiovascular death and HHF, and this association was stronger than that of changes in other conventional echocardiographic parameters. CONCLUSIONS: In patients with HFrEF treated with sacubitril/valsartan, the LVGLS and LARS were improved, typically within 6 months of treatment. Complete LHRR, defined by improvement in the LVGLS and LARS, can be an indicator of treatment response and prognosis.

Augmented risk of dementia in hypertrophic cardiomyopathy: A propensity score matching analysis using the nationwide cohort.

BACKGROUND: Dementia is a big medical and socioeconomic problem on aging society, and cardiac diseases have already shown a significant contribution to developing dementia. However, the risk of dementia related to hypertrophic cardiomyopathy (HCM), the most common inherited cardiomyopathy, has never been evaluated. METHODS: In a large-scale longitudinal cohort using National Health Insurance database, 4,645 subjects with HCM aged ≥50 years between 2010 and 2016 were collected and matched with 13,935 controls, based on propensity scores (1:3). We investigated the incidence and risk of dementia, Alzheimer's disease (AD), and vascular dementia (VaD) between groups. RESULTS: During follow-up (median 3.9 years after 1-year lag), incident dementia occurred in 739 subjects (4.0%): 78.2% for AD and 13.0% for VaD. The incidence of dementia, AD, and VaD were 23.0, 18.0, and 2.9/1,000 person-years, respectively, and was generally more prevalent in HCM. HCM group had a 50% increased risk of dementia, particularly AD, whereas there was no difference in the risk of VaD. The impact of HCM on AD (HR 1.52, 95% CI 1.26-1.84, p<0.001) was comparable with that of diabetes mellitus and smoking. Increased risk of AD in relation to HCM was consistent in various subgroups including younger healthier population. CONCLUSIONS: This is the first to demonstrate the increased risk of dementia, mainly AD rather than VaD, in subjects with HCM. Early surveillance and active prevention for cognitive impairment could help for a better quality of life in an era that HCM is considered a chronic manageable disease with low mortality.

Incremental Value of Myocardial Work over Global Longitudinal Strain in the Surveillance for Cancer-Treatment-Related Cardiac Dysfunction: A Case-Control Study.

The load dependence of global longitudinal strain (GLS) means that changes in systolic blood pressure (BP) between visits may confound the diagnosis of cancer-treatment-related cardiac dysfunction (CTRCD). We sought to determine whether the estimation of myocardial work, which incorporates SBP, could overcome this limitation. In this case-control study, 44 asymptomatic patients at risk of CTRCD underwent echocardiography at baseline and after oncologic treatment. CTRCD was defined on the basis of the change in the ejection fraction. Those with CTRCD were divided into subsets with and without a follow-up SBP increment >20 mmHg (CTRCD+BP+ and CTRCD+BP-), and matched with patients without CTRCD (CTRCD-BP+ and CTRCD-BP-). The work index (GWI), constructive work (GCW), wasted work (GWW), and work efficiency (GWE) were assessed in addition to the GLS. The largest increases in the GWI and GCW at follow-up were found in CTRCD-BP+ patients. The CTRCD+BP- patients demonstrated significantly larger decreases in GWI and GCW than their CTRCD+BP+ and CTRCD-BP- peers. ROC analysis for the discrimination of LV functional changes in response to increased afterload in the absence of cardiotoxicity revealed higher AUCs for GCW (AUC = 0.97) and GWI (AUC = 0.93) than GLS (AUC = 0.73), GWW (AUC = 0.51), or GWE (AUC = 0.63, all p-values < 0.001). GCW (OR: 1.021; 95% CI: 1.001-1.042; p < 0.04) was the only feature independently associated with CTRCD-BP+. Myocardial work is superior to GLS in the serial assessments in patients receiving cardiotoxic chemotherapy. The impairment of GLS in the presence of an increase in GWI and GCW indicates the impact of elevated afterload on LV performance in the absence of actual myocardial impairment.

Independent Prognostic Utility of 11C-Pittsburgh Compound B PET in Patients with Light-Chain Cardiac Amyloidosis.

11C-Pittsburgh compound B (PiB) PET/CT visualizes the amount of myocardial amyloid deposit and can be used to prognosticate patients with amyloid light-chain (AL) cardiac amyloidosis (CA). However, whether 11C-PiB PET/CT has any independent additional prognostic value beyond the commonly used biomarkers remains unknown. Methods: This prospective study was on a cohort of 58 consecutive patients with AL CA who underwent 11C-PiB PET/CT. The patients were stratified into 2 groups on the basis of a visual assessment of whether there was myocardial 11C-PiB uptake on PET/CT. The primary endpoint was 1-y overall mortality. The independent prognostic utility of 11C-PiB PET/CT was analyzed using net reclassification improvement and integrated discrimination improvement. Results: Among the 58 patients enrolled, 35 were positive for myocardial 11C-PiB uptake on PET/CT. Patients with myocardial 11C-PiB PET uptake had a worse 1-y overall survival rate than those without (81.8% vs. 45.5%, P = 0.003 by log-rank test). In the multivariate analysis, positivity for myocardial 11C-PiB uptake on PET/CT was an independent predictor of 1-y mortality (adjusted hazard ratio, 3.382; 95% CI, 1.011-11.316; P = 0.048). In analysis of 3 subgroups of patients-those with a troponin I level of at least 0.1 ng/mL, those with an N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of at least 1,800 pg/mL, and those with a difference of at least 180 mg/L between free light chains (the 3 commonly used biomarkers and their thresholds for staging in AL amyloidosis)-Kaplan-Meier curves showed for all 3 subgroups that patients positive for myocardial 11C-PiB uptake on PET/CT had a worse prognosis than those who were negative. Additionally, when the results of 11C-PiB PET/CT were added to these 3 biomarkers, the performance of 1-y mortality prediction significantly improved by net reclassification improvement (troponin I, 0.861; NT-proBNP, 0.914; difference between free light chains, 0.987) and by integrated discrimination improvement (0.200, 0.156, and 0.108, respectively). Conclusion:11C-PiB PET/CT is a strong independent predictor of 1-y overall mortality and provides incremental prognostic benefits beyond the 3 commonly used biomarkers of AL amyloidosis staging. Considering the recent development of numerous amyloid-targeting molecular imaging agents, further investigations are warranted on whether PET/CT should be included in risk stratification for patients with AL CA.

Prognostic value of lower bone mineral density in predicting adverse cardiovascular disease in Asian women.

OBJECTIVE: We investigated whether the evaluation of bone mineral density (BMD) provides independent and incremental prognostic value for predicting atherosclerotic cardiovascular disease (ASCVD) in women. METHODS: A total of 12 681 women aged 50-80 years (mean, 63.0±7.8 years) who underwent dual-energy X-ray absorptiometry were retrospectively analysed. We assessed the hazard ratio (HR) for ASCVD events (ASCVD death, non-fatal myocardial infarction and ischaemic stroke) according to the BMD or a clinical diagnosis of osteopenia or osteoporosis, with adjustment for clinical risk factors, including age, body mass index, hypertension, type 2 diabetes, hyperlipidaemia, current smoking and previous fracture. We also evaluated whether the addition of BMD or a clinical diagnosis of osteopenia or osteoporosis to clinical risk factors improved the prediction for ASCVD events. RESULTS: In total, 468 women (3.7%) experienced ASCVD events during follow-up (median, 9.2 years). Lower BMD at the lumbar spine, femur neck and total hip was independently associated with higher risk for ASCVD events (adjusted HR per 1-standard deviation decrease in BMD: 1.16, p<0.001; 1.29, p<0.001; 1.38, p<0.001; respectively). A clinical diagnosis of osteoporosis was also independently associated with higher risk for ASCVD events (adjusted HR: 1.79, p<0.001). The addition of BMD or a clinical diagnosis of osteopenia or osteoporosis to clinical risk factors demonstrated significant incremental value in discriminating ASCVD events (addition of total hip BMD, p for difference <0.001). CONCLUSION: The evaluation of BMD provides independent and incremental prognostic value for ASCVD in women and thus may improve risk stratification in women.

Reverse remodelling by sacubitril/valsartan predicts the prognosis in heart failure with reduced ejection fraction.

AIMS: Despite well-established benefits of sacubitril/valsartan for cardiac reverse remodelling and the prognosis of patients with heart failure with reduced ejection fraction (HFrEF), there are some patients with limited therapeutic response, even with optimal therapy. We assessed the treatment response to sacubitril/valsartan in patients with HFrEF, focusing on the association between reverse remodelling and the prognosis. METHODS AND RESULTS: Using a retrospective cohort of consecutive patients with HFrEF treated with sacubitril/valsartan, we compared the time trajectory of cardiac function in 415 patients (1258 echocardiograms), according to the occurrence of cardiovascular death and hospitalization for HF during a median follow-up of 19.1 (interquartile range, 10.9-27.6) months. A higher sacubitril/valsartan dose was associated with a better prognosis, whereas advanced age, diabetes, left ventricular (LV) hypertrophy, left atrial enlargement, and pulmonary hypertension were associated with a worse prognosis. Patients without an event (n = 337; 81.2%) showed LV reverse remodelling (LV ejection fraction ≥45% or LV end-systolic volume reduction by 15% from baseline), which was typically observed within 6 months of sacubitril/valsartan treatment. Reverse remodelling achievement was significantly associated with a better prognosis. However, patients without reverse remodelling had a worse prognosis, as poor as that in patients with HFrEF not treated with sacubitril/valsartan. CONCLUSIONS: In patients with HFrEF treated with sacubitril/valsartan, LV reverse remodelling reflects the treatment response and predicts the prognosis, whereas a lack of reverse remodelling indicates the lack of treatment benefits. Prediction and assessment of reverse remodelling may facilitate the selection of patients with greater benefits by sacubitril/valsartan.

Time trajectory of cardiac function and its relation with survival in patients with light-chain cardiac amyloidosis.

AIMS: We aimed to analyse the time-serial change of cardiac function in light-chain (AL) cardiac amyloidosis patients undergoing active chemotherapy and its relationship with patient outcome. METHODS AND RESULTS: Seventy-two patients with AL cardiac amyloidosis undergoing active chemotherapy who had two or more echocardiographic examinations were identified from a prospective observational cohort (n = 34) and a retrospective cohort (n = 38). Echocardiographic parameters were obtained immediately prior to 1-3, 3-6, 6-12, and 12-24 months after the first chemotherapy. Study endpoint was a composite of death or heart transplantation (HT). During a median of 32 months (interquartile range 8-51) follow-up, 33 patients (45.8%) died and 4 patients (5.6%) underwent HT. Echocardiograms immediately prior to the first chemotherapy did not show differences between the patients with adverse events vs. those without. Significant increase in mitral E/e' ratio and decline in left ventricular global longitudinal strain (LV-GLS) was observed, starting at 3-6 months after the first chemotherapy only in those who experienced adverse events on follow-up, which was also evident in those who responded to chemotherapy. Multivariate analysis demonstrated that B-natriuretic peptide >500 pg/mL and troponin I >0.15 ng/dL at initial diagnosis, hospitalization for heart failure, E/e' >15, and LV-GLS <10% during follow-up were independent predictors of outcome. CONCLUSIONS: In AL cardiac amyloidosis patients undergoing active chemotherapy, the deterioration of LV function may occur, starting even at 3-6 months after the first chemotherapy. Serial echocardiography may help identify those who experience a clinical event in the near future despite active chemotherapy.

Dipeptidyl peptidase-4 inhibition to prevent progression of calcific aortic stenosis.

OBJECTIVE: To evaluate whether the use of dipeptidyl peptidase-4 (DPP-4) inhibitors and their cardiac tissue distribution profile and anticalcification abilities are associated with risk of aortic stenosis (AS) progression. METHODS: Out of the five different classes of DPP-4 inhibitors, two had relatively favourable heart to plasma concentration ratios and anticalcification ability in murine and in vitro experiments and were thus categorised as 'favourable'. We reviewed the medical records of 212 patients (72±8 years, 111 men) with diabetes and mild-to-moderate AS who underwent echocardiographic follow-up and classified them into those who received favourable DPP-4 inhibitors (n=28, 13%), unfavourable DPP-4 inhibitors (n=69, 33%) and those who did not receive DPP-4 inhibitors (n=115, 54%). RESULTS: Maximal transaortic velocity (Vmax) increased from 2.9±0.3 to 3.5±0.7 m/s during follow-up (median, 3.7 years), and the changes were not different between DPP-4 users as a whole and non-users (p=0.143). However, the favourable group showed significantly lower Vmax increase than the unfavourable or non-user group (p=0.018). Severe AS progression was less frequent in the favourable group (7.1%) than in the unfavourable (29.0%; p=0.03) or the non-user (29.6%; p=0.01) group. In Cox regression analysis after adjusting for age, baseline renal function and AS severity, the favourable group showed a significantly lower risk of severe AS progression (HR 0.116, 95% CI 0.024 to 0.551, p=0.007). CONCLUSIONS: DPP-4 inhibitors with favourable pharmacokinetic and pharmacodynamic properties were associated with lower risk of AS progression. These results should be considered in the preparation of randomised clinical trials on the repositioning of DPP-4 inhibitors.

Left Atrial Strain as a Predictor of New-Onset Atrial Fibrillation in Patients With Heart Failure.

OBJECTIVES: This study sought to identify whether left atrial strain can predict new-onset atrial fibrillation (NOAF) in patients with heart failure (HF) and sinus rhythm. BACKGROUND: Both HF and atrial fibrillation have common risk factors, and HF is a risk factor for the development of atrial fibrillation and vice versa. METHODS: Among 4,312 consecutive patients with acute HF from 3 tertiary hospitals, 2,461 patients with sinus rhythm and peak atrial longitudinal strain (PALS) were included in the study. Reduced PALS was defined as PALS ≤18%, and the primary endpoint was 5-year NOAF. RESULTS: During a 5-year follow-up, 397 (16.1%) patients developed NOAF. Patients with reduced PALS had higher NOAF than their counterparts (18.2% vs. 12.7%; p < 0.001). After adjustment for significant covariates, we identified 6 independent predictors of NOAF, including age >70 years (hazard ratio [HR]: 1.50; 95% confidence interval [CI]: 1.12 to 2.00), hypertension (HR: 1.45; 95% CI: 1.10 to 1.91), left atrial volume index ≥40 ml/m2 (HR: 2.03; 95% CI: 1.48 to 2.77), PALS <18% (HR: 1.60; 95% CI: 1.18 to 2.17), HF with preserved ejection fraction (HR: 1.47; 95% CI: 1.11 to 1.95), and no beta-blocker prescription at discharge (HR: 1.48; 95% CI: 1.14 to 1.92). A weighted score based on these variables was used to create a composite score, HAS-BAP (H = hypertension; A = age; S = PALS; B = no beta-blocker prescription at discharge; A = atrial volume index; P = HF with preserved ejection fraction [range 0 to 6] with a median of 3 [interquartile range: 2 to 4]). The probability of NOAF increased with HAS-BAP score. CONCLUSIONS: In patients with HF and sinus rhythm, 16.1% developed NOAF, and PALS could be used to predict the risk for NOAF. The HAS-BAP score allows determination of the risk of NOAF. (Strain for Risk Assessment and Therapeutic Strategies in Patients With Acute Heart Failure [STRATS-AHF] Registry; NCT03513653).

Myocardial Strain in Prediction of Outcomes After Surgery for Severe Mitral Regurgitation.

OBJECTIVES: We investigated whether global longitudinal strain (GLS) is a better predictor of clinical events after surgery for mitral regurgitation (MR) than conventional parameters. BACKGROUND: The optimal timing for surgery is guided by left ventricular (LV) dimension or left ventricular ejection fraction (LVEF), even though normal LVEF can mask depressed LV systolic function in severe mitral MR. METHODS: From 2006 to 2016, 506 patients (age 58.5 ± 13.7 years, 54.3% male) with severe primary MR who underwent mitral valve surgery were included. We measured GLS and global circumferential strain. Cardiac events included admission for worsening heart failure (HF), reoperation for failure of MV surgery, and cardiac death. RESULTS: During a median follow-up period of 3.5 years, 56 (11.1%) patients died, 41 (8.1%) were hospitalized for HF, and 10 (2.0%) underwent reoperation. In univariate analysis, LVEF, atrial fibrillation, left atrial dimension, age, previous ischemia, concomitant coronary artery bypass graft, and both GLS and global circumferential strain were predictive of cardiac events. On multivariate Cox models, age (hazard ratio [HR]: 1.429, 95% confidence interval [CI]: 1.116 to 1.831; p = 0.005), left atrial dimension (HR: 1.034, 95% CI: 1.006 to 1.063; p = 0.019) and GLS (HR: 1.229, 95% CI: 1.135 to 1.331; p < 0.001) were independent predictors of cardiac events. In subgroup analysis, LV GLS was a significant predictor of cardiac outcome, regardless of the presence of LV dysfunction, the presence of atrial fibrillation, and the type of surgery. Impaired GLS was associated with all-cause mortality (HR: 1.068, 95% CI: 1.003 to 1.136; p = 0.040). CONCLUSIONS: GLS appears to be a better predictor of cardiac events all-cause death than conventional parameters. Measuring preoperative GLS is helpful to predict post-operative outcome and determine optimal timing for surgery in patients with severe primary MR.

Single Versus Standard Multiview Assessment of Global Longitudinal Strain for the Diagnosis of Cardiotoxicity During Cancer Therapy.

OBJECTIVES: The goal of this study was to compare echocardiographic measurements of global longitudinal strain (GLS) (using 3 apical views) with single-view longitudinal strain (LS, 4- or 2-chamber [4CV_LS and 2CV_LS, respectively]) for detection of cancer-therapy related cardiotoxicity. BACKGROUND: GLS is useful for the detection of cardiotoxicity, but the need for repeated measurements poses a significant burden on busy echocardiography laboratories. A single-view LS measurement, possibly at point of care, could improve efficiency. METHODS: Seventeen international centers prospectively recruited 108 patients (mean age 54 ± 13 years) at high risk for cardiotoxicity as part of the ongoing SUCCOUR (Strain Surveillance for Improving Cardiovascular Outcomes During Chemotherapy) randomized controlled trial. Echocardiography performed at baseline and follow-up were analyzed in a core laboratory setting blinded to clinical information. Peak systolic GLS and LS were measured from raw data. Cardiotoxicity was defined by reduction in left ventricular ejection fraction >0.10 to <0.55 or a relative drop in GLS by ≥12%. RESULTS: Cardiotoxicity developed in 46 patients by either criteria. Baseline and follow-up 2-dimensional left ventricular ejection fraction were 61 ± 4% and 58 ± 5%, respectively (p < 0.001). The baseline GLS (-20.9 ± 2.4%) was not different from 4CV_LS (-20.7 ± 2.5%; p = 0.09) or 2CV_LS (-21.1 ± 3.1%; p = 0.25). The follow-up GLS (-19.5 ± 2.4%) was also similar to 4CV_LS (-19.5 ± 2.6%; p = 0.80) and 2CV_LS (-19.7 ± 3.1%; p = 0.19). There was good correlation between GLS and 4CV_LS at baseline (r = 0.86; p < 0.001) and follow-up (r = 0.89; p < 0.001) and with 2CV_LS at baseline (r = 0.87; p < 0.001) and follow-up (r = 0.88; p < 0.001). However, there was 15% to 22% disagreement between GLS and 4CV_LS or 2CV_LS for the detection of cardiotoxicity. The interobserver and intraobserver reproducibility was higher for GLS (intraclass correlation: 0.93 to 0.95; coefficient of variance: 2.9% to 3.7%) compared with either single-chamber-based LS measurement (intraclass correlation: 0.85 to 0.91; coefficient of variance: 4.1% to 4.8%). CONCLUSIONS: Although there was good correlation between GLS and single-view LS measurements, single-view LS measurement led to disagreement in the diagnosis of cardiotoxicity in up to 22% of patients. GLS measurements were more reproducible than single-view LS. GLS based on 3 apical views should remain the preferred technique for detection of cardiotoxicity. (Strain Surveillance for Improving Cardiovascular Outcomes During Chemotherapy [SUCCOUR]; ACTRN12614000341628).

Assessing Impact of High-Dose Pitavastatin on Carotid Artery Elasticity with Speckle-Tracking Strain Imaging.

AIM: Speckle-tracking imaging has been introduced for the precise assessment of vessel mechanics. However, there are no data on the role of this imaging tool in assessing the changes in vasculature with statin therapy, which is known to enhance vascular elasticity. METHODS: This study was a prospective study including 48 statin-naïve patients (age, 58.2±8.4 years; 29.2% male) with hypercholesterolemia. Circumferential carotid artery strain (CAS) and stiffness index (ß2) were measured using speckle-tracking imaging before and after 3 months of high-dose pitavastatin treatment (4 mg daily). For the comparison, we measured conventional carotid elasticity parameters and intima-media thickness using B-mode ultrasound at the same time points. RESULTS: Compared with baseline, there was significant improvement in circumferential CAS (2.98%±1.18% to 3.40%±1.43%, p=0.008) and ß2 (0.19±0.07 to 0.17±0.08, p=0.047) after statin therapy. Contrariwise, there were no significant changes in all conventional carotid elasticity metrics and intima-media thickness. When stratifying patients into two subgroups by 10 year atherosclerotic cardiovascular disease (ASCVD) risk, speckle-tracking-derived circumferential CAS and ß2 improved significantly only in patients with ASCVD risk ≥ 7.5%. CONCLUSIONS: Short-term treatment with high-dose pitavastatin improved carotid artery elasticity measured by speckle-tracking method, but not conventional parameters by B-mode ultrasound. Speckle-tracking-based measurements may allow the early noninvasive assessment of statin effects on vascular function in hypercholesterolemic patients.

Clinical Characteristics of Korean Patients with Bicuspid Aortic Valve Who Underwent Aortic Valve Surgery.

BACKGROUND AND OBJECTIVES: Clinical data for Korean patients with bicuspid aortic valve (BAV) that underwent aortic valve (AV) surgery are currently limited. METHODS: Data for 1,160 consecutive adult BAV patients who underwent AV surgery from 2000 to 2014 in 4 tertiary referral centers were retrospectively analyzed. A standard case report form was used for clinical and echocardiographic parameters. RESULTS: Mean age at the time of AV surgery was 59±13 years. The most common cause of AV surgery was aortic stenosis (AS, 892 [77%]), followed by aortic regurgitation (AR, 199 [17%]), and infective endocarditis (69 [6%]). AS showed a skewed peak in the aged population and was the predominant cause of AV surgery (87%) in patients ≥50 years of age, whereas AR (46%) and active infective endocarditis (19%) were more common in younger patients (p<0.001). Echocardiographic determination of the BAV phenotype revealed that fusion of the right coronary cusp (RCC) and left coronary cusp (LCC) was most common (622 [53%]), followed by fusion of RCC and non-coronary cusp (NCC) (313 [27%]), and fusion of LCC and NCC (42 [4%]); the BAV phenotype could not be determined in the remaining 183 patients (16%). Fusion of RCC and LCC was more commonly observed in patients with AR than in those with AS (74% vs. 49%; p<0.001). CONCLUSION: BAV patients were characterized by distinct surgical indications according to their age. Possible associations between BAV phenotypes and surgical indications with potential impacts of ethnicity need to be tested in further studies.