Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.

BACKGROUND: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001). INTERPRETATION: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors. FUNDING: Eli Lilly and Company.

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.

BACKGROUND: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING: Eli Lilly and Company.

Design and baseline characteristics of participants in the Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial on the cardiovascular effects of dulaglutide.

The aim was to determine the effects of dulaglutide, a synthetic once-weekly, injectable human glucagon-like peptide 1 analogue that lowers blood glucose, body weight, appetite and blood pressure, on cardiovascular outcomes. People with type 2 diabetes, aged ≥50 years, with glycated haemoglobin (HbA1c) ≤9.5%, and either a previous cardiovascular event, evidence of cardiovascular disease or ≥2 cardiovascular risk factors were randomly allocated to a weekly subcutaneous injection of either dulaglutide (1.5 mg) or placebo and followed within the ongoing Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) trial every 3 to 6 months. The primary cardiovascular outcome is the first occurrence of the composite of cardiovascular death or non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes include each component of the primary composite cardiovascular outcome, a composite clinical microvascular outcome comprising retinal or renal disease, hospitalization for unstable angina, heart failure requiring hospitalization or an urgent heart failure visit, and all-cause mortality. Follow-up will continue until the accrual of 1200 confirmed primary outcomes. Recruitment of 9901 participants (mean age 66 years, 46% women) occurred in 370 sites located in 24 countries over a period of 2 years. The mean duration of diabetes was 10 years, mean baseline HbA1c was 7.3%, and 31% had prior cardiovascular disease. The REWIND trial's international scope, high proportion of women, high proportion of people without prior cardiovascular disease and inclusion of participants whose mean baseline HbA1c was 7.3% suggests that its cardiovascular and safety findings will be directly relevant to the typical middle-aged patient seen in general practice throughout the world.

Post-operative left atrial volume index is a predictor of the occurrence of permanent atrial fibrillation after mitral valve surgery in patients who undergo mitral valve surgery.

BACKGROUND: Atrial fibrillation (AF) can occur even after the correction of mitral valve (MV) pathology in patients who have pre-operative sinus rhythm and undergo MV surgery. However, the factors associated with the occurrence of AF after MV surgery are still unclear. The aim of this retrospective study was to investigate the factors determining the occurrence of permanent AF after MV surgery in patients with preoperative sinus rhythm who underwent MV surgery. METHODS: Four hundred and forty-two patients (mean age 46 ± 12, 190 men) who underwent MV surgery and sinus rhythm were investigated retrospectively. Transthoracic echocardiography was performed before and after MV surgery at the time of dismissal. RESULTS: Permanent post-operative AF occurred in 81 (18%) patients even after successful MV surgery and preoperative sinus rhythm. It was more common in rheumatic etiology, a presence of mitral stenosis, lower pre- and post-operative left ventricular ejection fraction, higher post-operative mean diastolic pressure gradient across mitral prosthesis, larger post-operative left atrial volume index (LAVI) and lesser degrees of reduction in LAVI after surgery. In multiple regression analysis, post-operative LAVI was found to be an independent predictor for occurrence of AF. Post-operative LAVI > 39 ml/m2 was the cut-off value for best prediction of new onset permanent AF (sensitivity: 79%, AUC: 0.762, SE: 0.051, p < 0.001). CONCLUSION: New-onset permanent post-operative AF is not uncommon, even after successful MV surgery despite pre-operative sinus rhythm. Larger post-operative LAVI was an independent predictor for the occurrence of AF.

Clinical Implications and Determinants of Left Atrial Mechanical Dysfunction in Patients With Stroke.

BACKGROUND AND PURPOSE: The evaluation of sources of cardioembolism with transesophageal echocardiography (TEE) in patients with stroke is crucial but semi-invasive. We hypothesized that the size and mechanical function of the left atrium (LA) assessed by transthoracic echocardiography (TTE) could provide useful information on high risk of cardioembolism on TEE in patients with stroke. Furthermore, we sought to define the determinants of LA mechanical dysfunction in these patients. METHODS: A total of 248 patients with acute ischemic stroke (147 men; 64±13 years) who underwent 2-dimensional and speckle tracking TTE followed by TEE were analyzed. RESULTS: LA appendage emptying velocity, prevalence of LA or LA appendage thrombus, prevalence of aortic plaques, and incidence of embolic stroke showed significant differences among the 4 groups classified according to the median values of the LA volume index and global LA longitudinal strain (LALS). Patients at high risk of cardioembolism evidenced by TEE revealed significantly larger LA volume index and lower global LALS than those without. Global LALS (cutoff, 11.5%; area under the curve, 0.947; sensitivity, 100%; specificity, 91%; P<0.001) revealed a significantly better diagnostic power (P=0.04) for LA or LA appendage thrombus than LA volume index (cutoff, 36.2 mL/m(2); area under the curve, 0.823; sensitivity, 88%; specificity, 75%; P=0.002). Age, left ventricular systolic function, LA volume index, and pulse wave velocity were independent determinants for global LALS. CONCLUSIONS: LA mechanical dysfunction is closely associated with high risks of cardioembolism. Global LALS assessed by speckle tracking TTE well discriminates the presence of LA or LA appendage thrombus on TEE in patients with acute ischemic stroke.

Rationale and design of the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry: A comprehensive exploration of plaque progression and its impact on clinical outcomes from a multicenter serial coronary computed tomographic angiography study.

BACKGROUND: The natural history of coronary artery disease (CAD) in patients with low-to-intermediate risk is not well characterized. Although earlier invasive serial studies have documented the progression of atherosclerotic burden, most were focused on high-risk patients only. The PARADIGM registry is a large, prospective, multinational dynamic observational registry of patients undergoing serial coronary computed tomographic angiography (CCTA). The primary aim of PARADIGM is to characterize the natural history of CAD in relation to clinical and laboratory data. DESIGN: The PARADIGM registry (ClinicalTrials.govNCT02803411) comprises ≥2,000 consecutive patients across 9 cluster sites in 7 countries. PARADIGM sites were chosen on the basis of adequate CCTA volume, site CCTA proficiency, local demographic characteristics, and medical facilities to ensure a broad-based sample of patients. Patients referred for clinically indicated CCTA will be followed up and enrolled if they had a second CCTA scan. Patients will also be followed up beyond serial CCTA performance to identify adverse CAD events that include cardiac and noncardiac death, myocardial infarction, unstable angina, target vessel revascularization, and CAD-related hospitalization. SUMMARY: The results derived from the PARADIGM registry are anticipated to add incremental insight into the changes in CCTA findings in accordance with the progression or regression of CAD that confer prognostic value beyond demographic and clinical characteristics.

Fabry disease in patients with hypertrophic cardiomyopathy: a practical approach to diagnosis.

This study aimed to develop a new set of screening criteria that is easily applicable and highly sensitive for the detection of patients at high risk of Fabry disease (FD) among hypertrophic cardiomyopathy (HCM) patients. We prospectively studied 273 consecutive unrelated patients who were referred to HCM clinic for unknown left ventricular hypertrophy. Among the 273 patients, we selected 65 high-risk patients who fulfilled at least one of our newly proposed screening criteria. All 273 patients were assayed for plasma α-galactosidase A (α-GAL A) activity. The new screening criteria were: (1) atypical HCM, (2) history or presence of documented arrhythmia, (3) short PR interval defined as <120 ms on electrocardiogram, and (4) symptoms of autonomic dysfunction. From this screening study, three unrelated patients (4.6%; 2 females and 1 male) were newly diagnosed with FD using α-GAL A activity and mutation analysis of the GLA gene. Using the screening method based on the newly proposed criteria, the prevalence of FD in our HCM population was 4.6% if at least one criterion was met and 18.8% if ⩾3 criteria were met. Therefore, our proposed criteria are easily applicable and highly sensitive for classifying patients at high risk of FD from HCM patients.

Left Atrial Volume as a Predictor of Left Ventricular Functional Recovery in Patients With Dilated Cardiomyopathy and Absence of Delayed Enhancement in Cardiac Magnetic Resonance.

BACKGROUND: Improvement of left ventricular (LV) systolic dysfunction can occur in patients with dilated cardiomyopathy (DCM), and it is more frequently observed if patients have no delayed enhancement (DE) in cardiac magnetic resonance imaging (CMR). However, even in the absence of DE, not all patients have functional recovery. We retrospectively investigated the predictors of LV functional recovery in patients with DCM who had no DE in CMR. METHODS: A total of 136 patients with DCM underwent CMR. Among them, 44 (29 male, age 55 ± 14 years) showed no DE and these patients composed the study population. The study patients were divided into 2 groups according to the occurrence of functional recovery defined as an increase in LV ejection fraction to a level of ≥50% and net increase in ejection fraction of 20% or more: group 1 (n = 14) with functional recovery and group 2 (n = 30) without functional recovery. RESULTS: In patients who showed functional recovery, left atrial volume index (LAVI [26 ± 8 mL/m(2) vs 45 ± 18 mL/m(2)]) and LV end-diastolic dimension (62 ± 6 mm vs 67 ± 7 mm) were significantly smaller when compared with those without functional recovery (P <.05 for all). In Cox multiple regression analysis, LAVI was the only significant parameter associated with LV functional recovery (hazard ratio 0.932, 95% confidence interval 0.877-0.991, P = .024). LAVI < 38 mL/m(2) had 100% specificity in predicting the improvement of LV systolic dysfunction. CONCLUSION: In DCM patients who had no DE in CMR, LAVI predicts LV functional recovery with high specificity.

Edoxaban vs. Warfarin in East Asian Patients With Atrial Fibrillation　- An ENGAGE AF-TIMI 48 Subanalysis.

BACKGROUND: In the multinational, double-blind, double-dummy ENGAGE AF-TIMI 48 phase 3 study, once-daily edoxaban was non-inferior to warfarin for prevention of stroke or systemic embolism event (SEE) in patients with non-valvular atrial fibrillation (AF). Here, we evaluated the efficacy and safety of edoxaban in patients from East Asia. METHODS AND RESULTS: Patients aged ≥21 years with documented AF and CHADS score ≥2 were randomized to receive once-daily edoxaban higher-dose (60 mg) or lower-dose (30 mg) regimen or warfarin dose-adjusted to an international normalized ratio of 2.0-3.0. Patients with a creatinine clearance of 30-50 ml/min, weighing ≤60 kg, or receiving strong p-glycoprotein inhibitors at randomization or during the study received a 50% dose reduction of edoxaban or matched placebo. This prespecified subanalysis included 1,943 patients from Japan, China, Taiwan, and South Korea. The annualized rate of stroke/SEE for higher-dose edoxaban was 1.34% vs. 2.62% for warfarin (hazard ratio [HR], 0.53; 95% confidence interval [CI]: 0.31-0.90, P=0.02) and 2.52% for lower-dose edoxaban (HR, 0.98; 95% CI: 0.63-1.54, P=0.93). Compared with warfarin (4.80%), major bleeding was significantly reduced for the higher-dose (2.86%; HR, 0.61; 95% CI: 0.41-0.89, P=0.011) and lower-dose regimens (1.59%; HR, 0.34; 95% CI: 0.21-0.54, P<0.001). CONCLUSIONS: Once-daily edoxaban provided similar efficacy to warfarin while reducing major bleeding risk in the East Asian population.

Clinical Feasibility of 3D Automated Coronary Atherosclerotic Plaque Quantification Algorithm on Coronary Computed Tomography Angiography: Comparison with Intravascular Ultrasound.

OBJECTIVE: To evaluate the diagnostic performance of automated coronary atherosclerotic plaque quantification (QCT) by different users (expert/non-expert/automatic). METHODS: One hundred fifty coronary artery segments from 142 patients who underwent coronary computed tomography angiography (CCTA) and intravascular ultrasound (IVUS) were analyzed. Minimal lumen area (MLA), maximal lumen area stenosis percentage (%AS), mean plaque burden percentage (%PB), and plaque volume were measured semi-automatically by expert, non-expert, and fully automatic QCT analyses, and then compared to IVUS. RESULTS: Between IVUS and expert QCT analysis, the correlation coefficients (r) for the MLA, %AS, %PB, and plaque volume were excellent: 0.89 (p < 0.001), 0.84 (p < 0.001), 0.91 (p < 0.001), and 0.94 (p < 0.001), respectively. There were no significant differences in the mean parameters (all p values >0.05) except %AS (p = 0.01). The automatic QCT analysis showed comparable performance to non-expert QCT analysis, showing correlation coefficients (r) of the MLA (0.80 vs. 0.82), %AS (0.82 vs. 0.80), %PB (0.84 vs. 0.73), and plaque volume (0.84 vs. 0.79) when they were compared to IVUS, respectively. CONCLUSION: Fully automatic QCT analysis showed clinical utility compared with IVUS, as well as a compelling performance when compared with semiautomatic analyses. KEY POINTS: • Coronary CTA enables the assessment of coronary atherosclerotic plaque. • High-risk plaque characteristics and overall plaque burden can predict future cardiac events. • Coronary atherosclerotic plaque quantification is currently unfeasible in practice. • Quantitative computed tomography coronary plaque analysis software (QCT) enables feasible plaque quantification. • Fully automatic QCT analysis shows excellent performance.

Automated quantification of left atrial size using three-beat averaging real-time three dimensional Echocardiography in patients with atrial fibrillation.

BACKGROUND: Left atrial (LA) sizing in patients with atrial fibrillation (AF) is crucial for follow-up and outcome. Recently, the automated quantification of LA using the novel three-beat averaging real-time three dimensional echocardiography (3BA-RT3DE) is introduced. The aim of this study was to assess the feasibility and accuracy of 3BA-RT3DE in patients with atrial fibrillation (AF). METHODS: Thirty-one patients with AF (62.8 ± 11.7 years, 67.7 % male) were prospectively recruited to have two dimensional echocardiography (2DE) and 3BA-RT3DE (SC 2000, ACUSON, USA). The maximal left atrial (LA) volume was measured by the conventional prolate-ellipse (PE) and area-length (AL) method using three-beat averaging 2D transthoracic echocardiography and automated software analysis (eSie volume analysis, Siemens Medical Solution, Mountain view, USA); measurements were compared with those obtained by computed tomography (CT). RESULTS: Maximal LA volume by 3BA-RT3DE was feasible for all patients. LA volume was 68.4 ± 28.2 by PE-2DE, 89.2 ± 33.1 by AL-2DE, 100.6 ± 31.8 by 3BA-RT3DE, and 131.2 ± 42.2 mL by CT. LA volume from PE-2DE (R(2) = 0.48, p < 0.001, ICC = 0.64, p < 0.001), AL-2DE (R(2) = 0.47, p < 0.001, ICC = 0.67, p < 0.001), and 3BA-RT3DE (R(2) = 0.50, p = 0.001, ICC = 0.65, p < 0.001) showed significant correlations with CT. However, 3BA-RT3DE demonstrated a small degree of underestimation (30.5 mL) of LA volume compared to 2DE-based measurements. Good-quality images from 3BA-RT3DE (n = 16) showed a significantly tighter correlation with images from CT scanning (R(2) = 0.60, p = 0.0004, ICC = 0.76, p < 0.001) compared to those of fair quality. CONCLUSION: Automated quantification of LA volume using 3BA-RT3DE is feasible and accurate in patients with AF. An image of good quality is essential for maximizing the value of this method in clinical practice.

Left atrial volume index as a predictor for persistent left ventricular dysfunction after aortic valve surgery in patients with chronic aortic regurgitation: the role of early postoperative echocardiography.

BACKGROUND: This study aimed to explore whether echocardiographic measurements during the early postoperative period can predict persistent left ventricular systolic dysfunction (LVSD) after aortic valve surgery in patients with chronic aortic regurgitation (AR). METHODS: We prospectively recruited 54 patients (59 ± 12 years) with isolated chronic severe AR who subsequently underwent aortic valve surgery. Standard transthoracic echocardiography was performed before the operation, during the early postoperative period (≤2 weeks), and then 1 year after the surgery. RESULTS: Twelve patients with preoperative LVSD demonstrated LVSD at early after the surgery. Of the 42 patients without LVSD at preoperative echocardiography, 15 patients (36%) developed early postoperative LVSD after surgical correction. All 27 patients without LVSD at early postoperative echocardiography maintained LV function at 1 year after surgery. In the other 27 patients with postoperative LVSD, 17 patients recovered from LVSD and 10 patients did not at 1 year after surgery. Multiple logistic analysis demonstrated that postoperative left atrial volume index (LAVI) was the only independent predictor for persistent LVSD at 1 year after surgery in patients with postoperative LVSD (OR 1.180, 95% CI, 1.003-1.390, P = 0.046). The optimal LAVI cutoff value (>34.9 mL/m(2) ) had a sensitivity of 80% and a specificity of 88% for the prediction of persistent LVSD. CONCLUSION: Prevalence of early postoperative LVSD was relatively high, even in the patients without LVSD at preoperative echocardiography. Postoperative LAVI could be useful to predict persistent LVSD after aortic valve surgery in patients with early postoperative LVSD.

The additive value of multiple biomarkers in prediction of premature coronary artery disease.

OBJECTIVE: The aim of this study was to determine the value of additional multiple biomarkers in the prediction of premature coronary artery disease (CAD). METHODS AND RESULTS: Data from 503 CAD patients and 503 healthy control patients with matching age and sex were collected. The patient group consisted of male (25 to 55 years) and female (30 to 60 years) patients with documented angiographic multi-vessel CAD. Baseline characteristics of conventional risk factors and biomarkers were collected. We compared the conventional risk factors model with the model with six additional biomarkers (hs-CRP, IL-6, RAGE, Lp-LPA2, adiponectin, and RANTES), which have shown significant association with premature CAD. We also evaluated the effects of adding each of the six biomarkers to the conventional laboratory data. The additional biomarkers model resulted in improvements in the C-statistic (0.953 vs. 0.937, P=0.0003) in comparison with the conventional risk factors model. Among the 6 biomarkers added to the patient group, hs-CRP and IL-6 had a significant discriminative power to predict the risk of premature CAD (hs-CRP; P = 0.0005, IL-6; P= 0.003). CONCLUSIONS: Although conventional risk factors were more strongly associated with premature CAD than were biomarkers, adding the 6 biomarkers (hs-CRP, IL-6, RAGE, Lp-LPA2, adiponectin, and RANTES) improved the prediction of premature CAD moderately. We found that hs-CRP and IL-6 had shown a significant contribution in the prediction of premature CAD.

Differential association between metabolic syndrome and coronary artery disease evaluated with cardiac computed tomography according to the presence of diabetes in a symptomatic Korean population.

BACKGROUND: Metabolic syndrome (MetS) is associated with increased risks of diabetes and coronary artery disease (CAD). Despite the controversial inclusion of established diabetes in MetS, the association between MetS and CAD according to diabetes status has not been elucidated in the Asian population. METHODS: We evaluated the association between MetS and CAD using the parameters including any plaque, obstructive plaque, and coronary artery calcium score (CACS) >100 according to diabetes status in 2,869 symptomatic Korean subjects who underwent cardiac computed tomographic angiography. RESULTS: The prevalence of MetS was significantly higher in the diabetic subjects than in the non-diabetic subjects (69% vs. 34%, P <0.001). The incidence of any plaque (64% vs. 43%, P <0.001), obstructive plaque (26% vs. 13%, P = 0.006), and CACS >100 (23% vs. 12%, P = 0.012) was significantly higher in diabetic subjects than in non-diabetic subjects. Among the MetS components, decreased high-density lipoprotein level was significantly associated with any plaque (odds ratio [OR] 1.35), obstructive plaque (OR 1.55), and CACS >100 (OR 1.57) in the non-diabetic subjects (P <0.01, respectively). However, none of the MetS components were associated with all the parameters in the diabetic subjects. Multivariate regression analysis revealed that MetS and the number of MetS components (MetSN) were independently associated with any plaque (MetS: OR 1.55, P <0.001; MetSN: OR 1.22, P <0.001), obstructive plaque (MetS: OR 1.52, P = 0.003; MetSN: OR 1.25, P <0.001), and CACS >100 (MetS: OR 1.46, P = 0.015; MetSN: OR 1.21, P = 0.004) only in the non-diabetic subjects, respectively. CONCLUSIONS: MetS was independently associated with the presence and severity of CAD only in the non-diabetic subjects among the symptomatic Korean population.

Predictors of prognosis in patients with mild to moderate paravalvular leakage after mitral valve replacement.

BACKGROUND: The aim of this study was to evaluate predictors of clinical events in patients with mild to moderate paravalvular leakage (PVL) after mitral valve replacement (MVR). METHODS AND RESULTS: We retrospectively reviewed all the medical records and echocardiography of 60 patients with PVL after MVR. After excluding 18 patients who required immediate surgical repair for severe symptoms or regurgitation and four patients with severe anemia who required transfusion, two patients with concomitant infective endocarditis, two patients with severe stenosis or regurgitation of other valves, and one patient with severe left ventricular systolic dysfunction, the remaining 33 patients who were not indicated for reoperation or immediate blood transfusion comprised the study population. During a median follow-up period of 19 months, there were 18 events, including two cardiac deaths, one noncardiac death, 13 repeat surgeries, and two admissions for heart failure. Cox regression analysis revealed that the presence of hemolytic anemia at the diagnosis of PVL was the only independent predictor of event-free survival (p=0.035). The estimated three-year event-free survival rates were 78 ± 12% in patients without hemolytic anemia and 16 ± 10% in those with hemolytic anemia (p=0.004). CONCLUSION: Presence of hemolytic anemia was associated with poor short-term clinical outcome in mild to moderate PVL after MVR, even in the cases when the degree of anemia was not severe at the time of diagnosis. Therefore, in PVL patients after MVR with hemolytic anemia, more early aggressive therapeutic approaches should be considered, regardless of the severity of anemia.

Extent of late gadolinium enhancement on cardiovascular magnetic resonance imaging and its relation to left ventricular longitudinal functional reserve during exercise in patients with hypertrophic cardiomyopathy.

BACKGROUND: The aim of this study was to investigate whether the extent of late gadolinium enhancement (LGE) on cardiovascular magnetic resonance imaging reflecting myocardial fibrosis correlates with left ventricular (LV) longitudinal function during exercise in hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: Mitral annular velocities (E' and S') were measured on echocardiography at rest and during graded bicycle exercise (25 W, 3-min increments) in 46 HCM patients (mean age, 53 years; 32 men). LV longitudinal diastolic and systolic functional reserve indices were calculated as ΔE'×E'base and ΔS'×S'base, where ΔE' and ΔS' are the changes in E' and S' from baseline to 50 W of exercise, respectively. The patients were divided into 2 groups according to the extent of LGE (as "percentage of LV mass containing LGE": %LV with LGE; range, 0-37%; median, 6%): group 1 (n=23), %LV with LGE <6%, and group 2, %LV with LGE ≥6%. Baseline echocardiographic parameters were similar between the 2 groups, but changes in E' and S' during exercise were smaller in group 2 (ΔE': 2.8±1.8 cm/s vs.1.5±1.0 cm/s, P=0.007; ΔS': 2.2±1.2 cm/s vs. 0.9±0.8 cm/s, P<0.0001). LV functional reserve indices were also significantly lower in group 2 (ΔE'×E'(base): 12.8±7.7 vs. 5.5±3.4, P=0.001; ΔS'×S'(base): 12.6±7.4 vs. 4.7±4.5, P<0.0001). CONCLUSIONS: LV longitudinal function during exercise is influenced by the extent of LGE in HCM. Myocardial fibrosis may represent a pathologic substrate that determines LV functional reserve in patients with HCM.

Impact of serum calcium and phosphate on coronary atherosclerosis detected by cardiac computed tomography.

AIMS: High calcium (Ca), phosphate (P), and Ca-P product (CPP) are associated with cardiovascular disease in patients with chronic kidney disease. Whether this relationship persists in individuals with normal kidney function is not yet elucidated. We explored the relationship of serum Ca, P, and CPP to coronary atherosclerosis assessed by cardiac computed tomography angiography (cCTA) in participants with normal kidney function. METHODS AND RESULTS: This study included 7553 participants (52 ± 10 years, male 57%) with near-normal kidney function (estimated glomerular filtration rate > 60 mL/min/1.73 m2) who underwent cCTA. The relationship of Ca, P, and CPP to coronary atherosclerosis [coronary artery Ca score (CACS) >100 and the presence of coronary artery disease (CAD)] was evaluated. Higher Ca, P, and CPP were significantly associated with CACS > 100 continuously [adjusted odds ratio (OR) per mg/dL: Ca 1.21, P = 0.026; P 1.29, P < 0.001; CPP 1.03, P < 0.001]. However, they correlate only weakly with the presence of CAD (OR: Ca 1.17, P = 0.001; P 1.05, P = 0.173; CPP 1.01, P = 0.034). This discrepancy was because calcified or mixed plaque and non-calcified plaque (NCP) were included in CAD. A significant relationship was demonstrated between calcified or mixed plaque and Ca, P, and CPP (OR: Ca 1.20, P = 0.001; P 1.13, P = 0.003; CPP 1.02, P = 0.001), but not NCP. CONCLUSION: Elevated serum levels of Ca, P, and CPP are significantly associated with the presence of calcified coronary atherosclerotic plaque. It is unclear if there is a causal relationship. This relationship is thought to contribute to vascular calcification, but is less closely associated with NCP.

Atherosclerosis Imaging Quantitative Computed Tomography (AI-QCT) to guide referral to invasive coronary angiography in the randomized controlled CONSERVE trial.

AIMS: We compared diagnostic performance, costs, and association with major adverse cardiovascular events (MACE) of clinical coronary computed tomography angiography (CCTA) interpretation versus semiautomated approach that use artificial intelligence and machine learning for atherosclerosis imaging-quantitative computed tomography (AI-QCT) for patients being referred for nonemergent invasive coronary angiography (ICA). METHODS: CCTA data from individuals enrolled into the randomized controlled Computed Tomographic Angiography for Selective Cardiac Catheterization trial for an American College of Cardiology (ACC)/American Heart Association (AHA) guideline indication for ICA were analyzed. Site interpretation of CCTAs were compared to those analyzed by a cloud-based software (Cleerly, Inc.) that performs AI-QCT for stenosis determination, coronary vascular measurements and quantification and characterization of atherosclerotic plaque. CCTA interpretation and AI-QCT guided findings were related to MACE at 1-year follow-up. RESULTS: Seven hundred forty-seven stable patients (60 ± 12.2 years, 49% women) were included. Using AI-QCT, 9% of patients had no CAD compared with 34% for clinical CCTA interpretation. Application of AI-QCT to identify obstructive coronary stenosis at the ≥50% and ≥70% threshold would have reduced ICA by 87% and 95%, respectively. Clinical outcomes for patients without AI-QCT-identified obstructive stenosis was excellent; for 78% of patients with maximum stenosis < 50%, no cardiovascular death or acute myocardial infarction occurred. When applying an AI-QCT referral management approach to avoid ICA in patients with <50% or <70% stenosis, overall costs were reduced by 26% and 34%, respectively. CONCLUSIONS: In stable patients referred for ACC/AHA guideline-indicated nonemergent ICA, application of artificial intelligence and machine learning for AI-QCT can significantly reduce ICA rates and costs with no change in 1-year MACE.

Prognostic value of change in red cell distribution width 1 month after discharge in acute decompensated heart failure patients.

BACKGROUND: Red cell distribution width (RDW) is a novel prognostic marker independently associated with adverse outcomes in acute decompensated heart failure (ADHF) patients. The aim of the present study was to assess whether the change in RDW after discharge had prognostic value in patients with ADHF. METHODS AND RESULTS: RDW was measured in 261 patients admitted with ADHF, at admission and at discharge and 1 month after discharge. Cardiovascular (CV) events were defined as CV mortality and heart failure rehospitalization. Kaplan-Meier analysis showed that patients with positive RDW change between admission and 1 month after discharge (RDWΔ(1Mdis-adm); n=136) had a significantly higher number of CV events compared with patients with no positive RDWΔ(1Mdis-adm) (n=125; 60.3% vs. 47.2%, log-rank: P=0.007). On Cox hazards analysis, a positive RDWΔ(1Mdis-adm) was an independent predictor of CV events after adjusting for other CV risk factors (hazard ratio, 1.740; 95% confidence interval: 1.149-2.633, P=0.009). CONCLUSIONS: A novel relationship was noted between positive RDWΔ(1Mdis-adm) and CV events in ADHF patients. Measurement of RDW at 1 month after ADHF assists in the prediction of adverse CV outcomes. Therefore, repeated measurement of RDW is a simple and inexpensive method that may facilitate assessment of CV risk stratification in patients with ADHF.

Abnormal left ventricular vortex flow patterns in association with left ventricular apical thrombus formation in patients with anterior myocardial infarction: a quantitative analysis by contrast echocardiography.

BACKGROUND: The current study was designed to investigate the correlation between the left ventricular (LV) vortex flow pattern and LV apical thrombus formation in patients with acute anterior wall myocardial infarction (MI). METHODS AND RESULTS: Fifty-seven patients with acute anterior wall MI were enrolled in this study. Eighteen patients with apical thrombus (thrombus group) and 39 patients without apical thrombus (non-thrombus group) underwent 2-dimensional contrast echocardiography (CE). Morphology and pulsatility parameters of the LV vortex were measured using Omega flow(®) and compared between the 2 groups. In the thrombus group, the vortex was located more centrally and did not extend to the apex. In the thrombus group, quantitative vortex parameters of vortex depth (0.409±0.101 vs. 0.505±0.092, respectively; P=0.002) and relative strength (1.574±0.310 vs. 1.808±0.376, respectively, P=0.034) were significantly lower than the non-thrombus group. Following multivariate analysis, the vortex depth below 0.45 remained a significant independent parameter for formation of the LV apical thrombus (odds ratio 9.714, 95% confidence interval 1.674-56.381, P=0.011). CONCLUSIONS: These findings suggest that the location and pulsatility power of the LV vortex are strongly associated with the LV thrombus formation in patients with anterior MI. Therefore, LV vortex flow analysis using CE can be clinically useful for characterizing and quantifying the risk of LV apical thrombus in patients with anterior MI.