Differing Efficacy of Dapagliflozin Versus Empagliflozin on the Risk of Incident Atrial Fibrillation in Patients With Type 2 Diabetes: A Real-World Observation Using a Nationwide, Population-Based Cohort.

BACKGROUND: Meta-analyses of large clinical trials investigating SGLT2 (sodium-glucose cotransporter-2) inhibitors have suggested their protective effects against atrial fibrillation in patients with type 2 diabetes. However, the results were predominantly driven from trials involving dapagliflozin. METHODS AND RESULTS: We used a nationwide, population-based cohort of patients with type 2 diabetes who initiated either dapagliflozin or empagliflozin between May 2016 and December 2018. An active-comparator, new-user design was used, and the 2 groups of patients were matched using propensity scores. The primary outcome was incident nonvalvular atrial fibrillation, which was analyzed using both the main intention-to-treat and sensitivity analysis that censored patients who skipped their medications for ≥30 days. Men ≥55 years of age and women ≥60 years of age with ≥1 traditional risk factor or those with established cardiovascular disease were categorized as high cardiovascular risk group. Patients not included in the high-risk group were categorized as low risk. After 1:1 propensity-score matching, a total of 137 928 patients (mean age, 55 years; 58% men) were included and followed up for 2.2±0.6 years. The risk of incident atrial fibrillation was significantly lower in the dapagliflozin group in both the main (hazard ratio [HR], 0.885 [95% CI, 0.789-0.992]) and sensitivity analyses (HR, 0.835 [95% CI, 0.719-0.970]). Notably, this was consistent in both the low and high cardiovascular risk groups. There was no effect modification by age, sex, body mass index, duration of diabetes, or renal function. CONCLUSIONS: This real-world, population-based study demonstrates that patients with type 2 diabetes using dapagliflozin may have a lower risk of developing nonvalvular atrial fibrillation than those using empagliflozin.

Age-dependent association of metabolic dyslipidemia with clinical expression of hypertrophic cardiomyopathy.

BACKGROUND: Previous studies have shown that the clinical expression of hypertrophic cardiomyopathy (HCM) can be determined by obesity and metabolic syndrome. The present study aimed to investigate the association between triglyceride and high-density lipoprotein cholesterol (HDLC) level, the two dyslipidemia-related components of metabolic syndrome, and the incidence of HCM. We also explored an age-dependent association between them. METHODS: Individuals without previous HCM diagnosis who underwent a designated national health examination in 2009 were recruited. Individuals who used lipid-lowering medications within 1-year of the baseline were excluded. The outcome of interest was a newly diagnosed HCM. RESULTS: Our cohort consisted of 8,652,709 individuals (mean 46 years, 55.6% men). During the median 9.3 years of follow-up, 5932 (0.07%) individuals were newly diagnosed with HCM. There was a gradual increase in the incidence of HCM towards higher triglyceride and lower HDL-C levels (log-rank p < 0.001). When stratified by age, the incidence of HCM was highest in individuals aged ≥65 years, followed by those aged 40-64 and 20-39 years (0.22% vs. 0.07% vs. 0.03%, log-rank p < 0.001). In individuals aged 20-39 years, a higher triglyceride level was associated with a higher incidence of HCM (i.e., ≥200 vs. <100 mg/dL: adjusted hazard ratio 2.28, 95% confidence interval 1.89-2.75), whereas there was no significant association in older groups (p-for-interaction<0.001). Similarly, a lower HDL-C level was associated with a higher incidence of HCM, particularly in individuals aged 20-39 years (p-for-interaction = 0.001). CONCLUSIONS: High triglyceride and low HDL-C levels are associated with a higher incidence of HCM, particularly in young individuals.

Sacubitril/valsartan and the risk of incident dementia in heart failure: a nationwide propensity-matched cohort study.

BACKGROUND: Sacubitril acts to inhibit neprilysin and as neprilysin is involved in amyloid-beta degradation in the central nervous system, and there is concern that sacubitril/valsartan may increase the risk of dementia. We aimed to compare the risk of incident dementia associated with sacubitril/valsartan and angiotensin II receptor blockers (ARBs). METHODS: Patients with heart failure with reduced ejection fraction treated with either sacubitril/valsartan or ARB, identified from the Korean National Health Insurance Service database, were matched in a 1:2 ratio using propensity scores (6789 on sacubitril/valsartan and 13,578 on ARBs) and followed up for incident dementia. RESULTS: During a mean follow-up of 2.5 years, 526 (2.6%) patients were newly diagnosed with dementia: Alzheimer dementia in 282, vascular dementia in 8, and other dementia in 236. There was no significant difference in the risk of overall dementia (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.70-1.01), Alzheimer dementia (HR 0.85, 95% CI 0.67-1.10), vascular dementia (HR 0.98, 95% CI 0.23-4.11), and all other dementias (HR 0.81, 95% CI 0.62-1.07) between sacubitril/valsartan users and ARB users. These results were consistent regardless of initial sacubitril/valsartan dose and subgroups including old age, previous mild cognitive impairment, previous stroke, and concomitant antiplatelet or anticoagulation. Sensitivity analysis with a 1-year lag period for dementia assessment confirmed the main analysis. Meanwhile, risk of incident stroke was lower in sacubitril/valsartan users compared to ARBs users. CONCLUSIONS: In a nationwide propensity-matched cohort of patients with heart failure, sacubitril/valsartan was not associated with an increased risk of incident dementia compared to ARBs. Sacubitril/valsartan and the risk of incident dementia in heart failure. ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor.

Machine learning reveals sex-specific associations between cardiovascular risk factors and incident atherosclerotic cardiovascular disease.

We aimed to investigate sex-specific associations between cardiovascular risk factors and atherosclerotic cardiovascular disease (ASCVD) risk using machine learning. We studied 258,279 individuals (132,505 [51.3%] men and 125,774 [48.7%] women) without documented ASCVD who underwent national health screening. A random forest model was developed using 16 variables to predict the 10-year ASCVD in each sex. The association between cardiovascular risk factors and 10-year ASCVD probabilities was examined using partial dependency plots. During the 10-year follow-up, 12,319 (4.8%) individuals developed ASCVD, with a higher incidence in men than in women (5.3% vs. 4.2%, P < 0.001). The performance of the random forest model was similar to that of the pooled cohort equations (area under the receiver operating characteristic curve, men: 0.733 vs. 0.727; women: 0.769 vs. 0.762). Age and body mass index were the two most important predictors in the random forest model for both sexes. In partial dependency plots, advanced age and increased waist circumference were more strongly associated with higher probabilities of ASCVD in women. In contrast, ASCVD probabilities increased more steeply with higher total cholesterol and low-density lipoprotein (LDL) cholesterol levels in men. These sex-specific associations were verified in the conventional Cox analyses. In conclusion, there were significant sex differences in the association between cardiovascular risk factors and ASCVD events. While higher total cholesterol or LDL cholesterol levels were more strongly associated with the risk of ASCVD in men, older age and increased waist circumference were more strongly associated with the risk of ASCVD in women.

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.

Atrial Functional Tricuspid Regurgitation: Importance of Atrial Fibrillation and Right Atrial Remodeling and Prognostic Significance.

BACKGROUND: Little is known about the determinants and outcomes of significant atrial functional tricuspid regurgitation (AFTR). OBJECTIVES: The authors aimed to identify risk factors for significant TR in relation to atrial fibrillation-flutter (AF-AFL) and assess its prognostic implications. METHODS: The authors retrospectively studied patients with mild TR with follow-up echocardiography examinations. Significant TR was defined as greater than or equal to moderate TR. AFTR was defined as TR, attributed to right atrial (RA) remodeling or isolated tricuspid annular dilatation, without other primary or secondary etiology, except for AF-AFL. The Mantel-Byar test was used to compare clinical outcomes by progression of AFTR. RESULTS: Of 833 patients with mild TR, 291 (34.9%) had AF-AFL. During the median 4.6 years, significant TR developed in 35 patients, including 33 AFTRs. Significant AFTR occurred in patients with AF-AFL more predominantly than in those patients without AF-AFL (10.3% vs 0.6%; P < 0.001). In Cox analysis, AF-AFL was a strong risk factor for AFTR (adjusted HR: 8.33 [95% CI: 2.34-29.69]; P = 0.001). Among patients with AF-AFL, those who developed significant AFTR had larger baseline RA areas (23.8 vs 19.4 cm2; P < 0.001) and RA area-to-right ventricle end-systolic area ratio (3.0 vs 2.3; P < 0.001) than those who did not. These parameters were independent predictors of AFTR progression. The 10-year major adverse cardiovascular event was significantly higher after progression of AFTR than before or without progression (79.8% vs 8.6%; Mantel-Byar P < 0.001). CONCLUSIONS: In patients with mild TR, significant AFTR developed predominantly in patients with AF-AFL, conferring poor prognosis. RA enlargement, especially with increased RA area-to-right ventricle end-systolic area ratio, was a strong risk factor for progression of AFTR.

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.

Association of Longitudinal Trajectories of Insulin Resistance With Adverse Renal Outcomes.

OBJECTIVE: To analyze the relationship between time-serial changes in insulin resistance and renal outcomes. RESEARCH DESIGN AND METHODS: A prospective cohort of subjects from the general population without chronic kidney disease (CKD) underwent a biennial checkup for 12 years (n = 5,347). The 12-year duration was divided into a 6-year exposure period, where distinct HOMA for insulin resistance (HOMA-IR) trajectories were identified using latent variable mixture modeling, followed by a 6-year event accrual period, from which the renal outcome data were analyzed. The primary end point was adverse renal outcomes, defined as a composite of estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 in two or more consecutive checkups or albumin ≥1+ on urine strip. RESULTS: Two distinct groups of HOMA-IR trajectories were identified during the exposure period: stable (n = 4,770) and increasing (n = 577). During the event accrual period, 449 patients (8.4%) developed adverse renal outcomes, and the risk was higher in the increasing HOMA-IR trajectory group than in the stable group (hazard ratio 2.06, 95% CI 1.62-2.60, P < 0.001). The results were similar after adjustment for baseline clinical characteristics, comorbidities, anthropometric and laboratory findings, eGFR, and HOMA-IR. The clinical significance of increasing HOMA-IR trajectory was similar in three or four HOMA-IR trajectories. The increasing tendency of HOMA-IR was persistently associated with a higher incidence of adverse renal outcomes, irrespective of the prevalence of diabetes. CONCLUSIONS: An increasing tendency of insulin resistance was associated with a higher risk of adverse renal outcomes. Time-serial tracking of insulin resistance may help identify patients at high risk for CKD.

Sex-specific associations of brachial-ankle pulse wave velocity with adverse cardiac remodeling and long-term cardiovascular outcome.

BACKGROUND: It remains unclear whether the cardiovascular consequences of arterial stiffness differ by sex. This study aimed to investigate the sex-specific association of brachial-ankle pulse wave velocity (baPWV) with adverse cardiac remodeling and cardiovascular outcome. METHOD: We studied 11 767 patients (57.6% men) with cardiovascular risk factors, whose baPWV was measured. The primary endpoint was composite cardiovascular events. Restricted cubic spline (RCS) analyses were performed to delineate the association of baPWV with echocardiography parameters and risks of cardiovascular events. RESULTS: RCS curves showed that structural/functional echocardiography parameters gradually worsened with increasing baPWV more prominently in women than in men. The prevalence of left ventricular hypertrophy and diastolic dysfunction increases with baPWV increase more steeply in women (P-for-interaction by sex <0.001). During the median follow-up of 3.64 years (interquartile interval, 1.56-5.38 years), 350 cardiovascular events (3.0%) and 155 deaths (1.3%) occurred. Cumulative cardiovascular events and deaths were significantly higher in patients with elevated baPWV in both sexes (P < 0.001). Cox analyses showed that the increase in baPWV was associated with the higher risks of cardiovascular events and deaths more strongly in women [cardiovascular events: men, adjusted hazard ratio 1.10, 95% confidence interval (1.08-1.13), P < 0.001; women, adjusted hazard ratio 1.18, 95% confidence interval (1.13-1.24), P < 0.001 by 100 cm/s increase in baPWV; P-for-interaction by sex = 0.022]. CONCLUSION: The detrimental effects of baPWV on adverse cardiac remodeling and cardiovascular outcome were stronger in women than in men. The prognostic information provided by baPWV may be particularly crucial for women.

Markers of Myocardial Damage Predict Mortality in Patients With Aortic Stenosis.

BACKGROUND: Cardiovascular magnetic resonance (CMR) is increasingly used for risk stratification in aortic stenosis (AS). However, the relative prognostic power of CMR markers and their respective thresholds remains undefined. OBJECTIVES: Using machine learning, the study aimed to identify prognostically important CMR markers in AS and their thresholds of mortality. METHODS: Patients with severe AS undergoing AVR (n = 440, derivation; n = 359, validation cohort) were prospectively enrolled across 13 international sites (median 3.8 years' follow-up). CMR was performed shortly before surgical or transcatheter AVR. A random survival forest model was built using 29 variables (13 CMR) with post-AVR death as the outcome. RESULTS: There were 52 deaths in the derivation cohort and 51 deaths in the validation cohort. The 4 most predictive CMR markers were extracellular volume fraction, late gadolinium enhancement, indexed left ventricular end-diastolic volume (LVEDVi), and right ventricular ejection fraction. Across the whole cohort and in asymptomatic patients, risk-adjusted predicted mortality increased strongly once extracellular volume fraction exceeded 27%, while late gadolinium enhancement >2% showed persistent high risk. Increased mortality was also observed with both large (LVEDVi >80 mL/m2) and small (LVEDVi ≤55 mL/m2) ventricles, and with high (>80%) and low (≤50%) right ventricular ejection fraction. The predictability was improved when these 4 markers were added to clinical factors (3-year C-index: 0.778 vs 0.739). The prognostic thresholds and risk stratification by CMR variables were reproduced in the validation cohort. CONCLUSIONS: Machine learning identified myocardial fibrosis and biventricular remodeling markers as the top predictors of survival in AS and highlighted their nonlinear association with mortality. These markers may have potential in optimizing the decision of AVR.

Sex-specific impact of diabetes mellitus on left ventricular systolic function and prognosis in heart failure.

We aimed to investigate the sex differences in associations of diabetes mellitus (DM) with echocardiographic phenotypes and clinical outcomes of heart failure (HF). We studied 4,180 patients admitted for acute HF between 2009 and 2016 (median follow-up, 31.7 months) whose left ventricular global longitudinal strain (LV-GLS) data were available. Patients were compared by sex and DM. Structural equation model (SEM) analysis was performed to evaluate the moderating effects of two causal paths, via ischemic heart disease (IHD) and LV-GLS, linking DM with mortality. Compared to non-diabetic women, diabetic women had significantly lower LV-GLS (11.3% versus 10.1%, p < 0.001), but the difference was attenuated within men (9.7% versus 9.2%, p = 0.014) (p-for-interaction by sex = 0.018). In Cox analyses, DM was an independent predictor for higher mortality in both sexes (women: adjusted hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.15-1.59 versus men: HR 1.24, 95% CI 1.07-1.44, p-for-interaction by sex = 0.699). Restricted cubic spline curves showed that LV-GLS consistently declined, and mortality increased in women with worsening hyperglycemia, but these trends were not evident in men. In SEM analysis, the main driver from DM to mortality differed by sex; men had a stronger effect via IHD than LV-GLS, whereas LV-GLS was the only predominant path in women.

Associations of Brachial-Ankle Pulse Wave Velocity With Left Ventricular Geometry and Diastolic Function in Untreated Hypertensive Patients.

Background: Although brachial-ankle pulse wave velocity (baPWV) is simple and convenient, its usefulness as an initial screening test for hypertensive patients is not well-known. This study aimed to investigate the association of baPWV with left ventricular (LV) geometry and diastolic function in treatment-naive hypertensive patients. Methods: A total of 202 untreated hypertensive patients (mean age, 62 years; males, 51.5%) without documented cardiovascular diseases were prospectively enrolled. Both baPWV and transthoracic echocardiography were performed on the same day before antihypertensive treatment. Results: In multiple linear regression analysis after adjustment for potential confounders, baPWV had significant correlations with structural measurements of LV including relative wall thickness (ß = 0.219, P = 0.021) and LV mass index (ß = 0.286, P = 0.002), and four diastolic parameters including septal e' velocity (ß = -0.199, P = 0.018), E/e' (ß = 0.373, P < 0.001), left atrial volume index (ß = 0.334, P < 0.001), and maximal velocity of tricuspid regurgitation (ß = 0.401, P < 0.001). The baPWV was significantly increased in patients with LV hypertrophy, abnormal LV remodeling, or diastolic dysfunction, compared to those without (P = 0.008, P = 0.035, and P < 0.001, respectively). In the receiver operating characteristic curve analysis, the discriminant ability of baPWV in predicting LV hypertrophy and diastolic dysfunction had an area under the curve of 0.646 (95% confidence interval 0.544-0.703, P = 0.004) and 0.734 (95% confidence interval 0.648-0.800, P < 0.001), respectively. Conclusion: baPWV was associated with parameters of LV remodeling and diastolic function in untreated hypertensive patients. The baPWV could be a useful screening tool for the early detection of adverse cardiac features among untreated hypertensive patients.

Differential risk of incident cancer in patients with heart failure: A nationwide population-based cohort study.

BACKGROUND: Heart failure (HF) and cancer are currently two leading causes of mortality, and sometimes coexist. However, the relationship between them is not completely elucidated. We aimed to investigate whether patients with HF are predisposed to cancer development using the large Korean National Health Insurance claims database. METHODS: This study included 128,441 HF patients without a history of cancer and 642,205 age- and sex-matched individuals with no history of cancer and HF between 1 January 2010 and 31 December 2015. RESULTS: During a median follow-up of 4.06 years, 11,808 patients from the HF group and 40,805 participants from the control were newly diagnosed with cancer (cumulative incidence, 9.2% vs. 6.4%, p < 0.0001). Patients with HF presented a higher risk for cancer development compared to controls in multivariable Cox analysis [hazard ratio (HR) 1.64, 95% confidence interval (CI) 1.61-1.68]. The increased risk was consistent for all site-specific cancers. To minimize potential surveillance bias, additional analysis was performed by eliminating participants who developed cancer within the initial 2 years of HF diagnosis (i.e. 2-year lag analysis). In the 2-year lag analysis, the higher risk of overall cancer remained significant in patients with HF (HR 1.09, 95% CI 1.05-1.13), although the association was weaker. Among the site-specific cancers, three types of cancer (lung, liver/biliary/pancreas, and hematologic malignancy) were consistently at higher risk in patients with HF. An exploratory analysis showed that patients with repeated HF hospitalization had a higher risk of cancer development compared to those without, in a pattern of stepwise increases across the three groups [controls vs. HF without re-hospitalization vs. HF with re-hospitalization ≥1; HR (95% CI), 1.00 (reference) vs. 1.55 (1.51-1.59) vs. 1.96 (1.89-2.03), respectively]. CONCLUSIONS: Cancer incidence is higher in patients with HF than the general population. Active surveillance of coexisting malignancy needs to be considered in these patients.

Impact of age on coronary artery plaque progression and clinical outcome: A PARADIGM substudy.

BACKGROUND: The association of age with coronary plaque dynamics is not well characterized by coronary computed tomography angiography (CCTA). METHODS: From a multinational registry of patients who underwent serial CCTA, 1153 subjects (61 ± 5 years old, 61.1% male) were analyzed. Annualized volume changes of total, fibrous, fibrofatty, necrotic core, and dense calcification plaque components of the whole heart were compared by age quartile groups. Clinical events, a composite of all-cause death, acute coronary syndrome, and any revascularization after 30 days of the initial CCTA, were also analyzed. Random forest analysis was used to define the relative importance of age on plaque progression. RESULTS: With a 3.3-years' median interval between the two CCTA, the median annual volume changes of total plaque in each age quartile group was 7.8, 10.5, 10.8, and 12.1 mm3/year and for dense calcification, 2.5, 4.6, 5.4, and 7.1 mm3/year, both of which demonstrated a tendency to increase by age (p-for-trend = 0.001 and < 0.001, respectively). However, this tendency was not observed in any other plaque components. The annual volume changes of total plaque and dense calcification were also significantly different in the propensity score-matched lowest age quartile group versus the other age groups as was the composite clinical event (log-rank p = 0.003). In random forest analysis, age had comparable importance in the total plaque volume progression as other traditional factors. CONCLUSIONS: The rate of whole-heart plaque progression and dense calcification increases depending on age. Age is a significant factor in plaque growth, the importance of which is comparable to other traditional risk factors. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT02803411.

Association of physical activity with all-cause and cardiovascular mortality in 7666 adults with hypertrophic cardiomyopathy (HCM): more physical activity is better.

OBJECTIVES: Recommendations on physical activity (PA) for adults with hypertrophic cardiomyopathy (HCM) are not well established. We investigated the association of PA intensity with mortality in the general adult HCM population. METHODS: A nationwide population-based cohort of individuals with HCM who underwent health check-ups including questionnaires on PA levels were identified from the years 2009 to 2016 in the National Health Insurance Service database. Subjects who reported no PA at baseline were excluded. To estimate each individual's PA level, the PA score (PAS) was calculated based on the self-reported questionnaires, and the study population was categorised into three groups according to tertiles of PAS. The associations of PAS with all-cause and cardiovascular mortality were analysed. RESULTS: A total of 7666 participants (mean age 59.5 years, 29.9% were women) were followed up for a mean 5.3±2.0 years. All-cause and cardiovascular mortality progressively decreased from the lowest to the highest tertiles of PA intensity: 9.1% (4.7%), 8.9% (3.8%) and 6.4% (2.7%), respectively (p-for-trend=0.0144 and 0.0023, respectively). Of note, compared with the middle PA group, the highest PA group did not have an increased risk of all-cause and cardiovascular mortality (HR 0.78, (95% CI 0.63 to 0.95) and HR 0.75 (95% CI 0.54 to 1.03), respectively). All subgroup and sensitivity analyses consistently showed that all-cause and cardiovascular mortality did not increase with higher PA levels. CONCLUSIONS: Moderate-to-vigorous-intensity PA, in a middle-aged population of patients with HCM, was associated with progressive reduction of all-cause and cardiovascular mortality. The impact of vigorous-intensity PA on a younger age group requires further investigation.

Unsupervised Cluster Analysis of Patients With Aortic Stenosis Reveals Distinct Population With Different Phenotypes and Outcomes.

BACKGROUND: There is a lack of studies investigating the heterogeneity of patients with aortic stenosis (AS). We explored whether cluster analysis identifies distinct subgroups with different prognostic significances in AS. METHODS: Newly diagnosed patients with moderate or severe AS were prospectively enrolled between 2013 and 2016 (n=398, mean 71 years, 55% male). Among demographics, laboratory, and echocardiography parameters (n=32), 11 variables were selected through dimension reduction and used for unsupervised clustering. Phenotypes and causes of mortality were compared between the clusters. RESULTS: Three clusters with markedly different features were identified. Cluster 1 (n=60) was predominantly associated with cardiac dysfunction, cluster 2 (n=86) consisted of elderly with comorbidities, especially end-stage renal disease, whereas cluster 3 (n=252) demonstrated neither cardiac dysfunction nor comorbidities. Although AS severity did not differ, there was a significant difference in adverse outcomes between the clusters during a median 2.4 years follow-up (mortality rate, 13.3% versus 19.8% versus 6.0% for cluster 1, 2, and 3, P<0.001). Particularly, compared with cluster 3, cluster 1 was associated with only cardiac mortality (adjusted hazard ratio, 7.37 [95% CI, 2.00-27.13]; P=0.003), whereas cluster 2 was associated with higher noncardiac mortality (adjusted hazard ratio, 3.35 [95% CI, 1.26-8.90]; P=0.015). Phenotypes and association of clusters with specific outcomes were reproduced in an independent validation cohort (n=262). CONCLUSIONS: Unsupervised cluster analysis of patients with AS revealed 3 distinct groups with different causes of death. This provides a new perspective in the categorization of patients with AS that takes into account comorbidities and extravalvular cardiac dysfunction.

De novo malignancy risk in patients undergoing the first percutaneous coronary intervention: A nationwide population-based cohort study.

BACKGROUND: Although percutaneous coronary intervention (PCI) has been the mainstay of revascularization strategy for significant coronary artery disease, future cancer risk after PCI has never been explored. We aimed to investigate the risk of incident cancer in patients undergoing PCI for the first time. METHODS: We studied 125,613 patients who underwent the first PCI between 2010 and 2015 without a prior history of cancer. For comparison, we selected 628,065 age- and sex-matched controls without any history of cancer or PCI who completed the assigned national health examination during the same period. RESULTS: During a median 4.56 years (interquartile range, 3.06-6.13 years), 8528 patients from the PCI group and 40,166 controls were newly diagnosed with cancer (incidence rate, 15.1 vs. 13.9 per 1000 person-years, p < 0.0001). Patients undergoing PCI presented a higher risk for cancer development than the controls in multivariable Cox analysis (adjusted HR [aHR] 1.06, 95% CI 1.04-1.09, p < 0.0001). To minimize potential surveillance bias, we performed 1-year lag analysis by eliminating participants who developed cancer within 1 year from the PCI. In this analysis, the increased risk of overall cancer in the PCI group became insignificant (aHR 1.02, 95% CI 0.99-1.05, p = 0.2017). Regarding site-specific cancers, however, the risk of lung and hematologic malignancies remained higher and the risk of gastrointestinal, liver/biliary/pancreas, thyroid, and breast cancers remained lower in the PCI group. CONCLUSIONS: Differential future cancer risks were observed in patients undergoing PCI. The results suggest that specialized surveillance strategy might be warranted for this expanding population.

Pittsburgh B Compound Positron Emission Tomography in Patients With AL Cardiac Amyloidosis.

BACKGROUND: It remains unknown whether the noninvasive evaluation of the degree of amyloid deposition in the myocardium can predict the prognosis of patients with light chain (AL) cardiac amyloidosis. OBJECTIVES: The purpose of this study was to demonstrate that 11C-Pittsburgh B compound positron emission tomography (11C-PiB PET) is useful for prognostication of AL cardiac amyloidosis by noninvasively imaging the myocardial AL amyloid deposition. METHODS: This study consecutively enrolled 41 chemotherapy-naïve AL cardiac amyloidosis patients. The amyloid deposit was quantitatively assessed with amyloid P immunohistochemistry in endomyocardial biopsy specimens and was compared with the degree of myocardial 11C-PiB uptake on PET. The primary endpoint was a composite of all-cause death, heart transplantation, and acute decompensated heart failure. RESULTS: The degree of myocardial 11C-PiB PET uptake was significantly higher in the cardiac amyloidosis patients compared with normal subjects and correlated well with the degree of amyloid deposit on histology (R2 = 0.343, p < 0.001). During follow-up (median: 423 days, interquartile range: 93 to 1,222 days), 24 patients experienced the primary endpoint. When the cardiac amyloidosis patients were divided into tertiles by the degree of myocardial 11C-PiB PET uptake, patients with the highest PiB uptake experienced the worst clinical event-free survival (log-rank p = 0.014). The degree of myocardial PiB PET uptake was a significant predictor of clinical outcome on multivariate Cox regression analysis (adjusted hazard ratio: 1.185; 95% confidence interval: 1.054 to 1.332; p = 0.005). CONCLUSIONS: These proof-of-concept results show that noninvasive evaluation of myocardial amyloid load by 11C-PiB PET reflects the degree of amyloid deposit and is an independent predictor of clinical outcome in AL cardiac amyloidosis patients.

Trends of the prevalence and incidence of hypertrophic cardiomyopathy in Korea: A nationwide population-based cohort study.

Temporal trends of the prevalence and incidence of hypertrophic cardiomyopathy (HCM) have not been well established in Asian populations. Using the Korean National Health Insurance Services database, we identified patients with a confirmed diagnosis of HCM between 2010 and 2016. The annual prevalence and incidence of HCM, and their clinical characteristics were investigated. The prevalence of HCM has increased from 0.016% (n = 6313) in 2010 to 0.031% (n = 13,035) in 2016. During a 7-year period, 13,229 patients were newly diagnosed with HCM. The incidence rate increased from 4.15 (per 100,000 person-years) in 2010 to 5.6 in 2016. The prevalence and incidence of HCM increased with age and peaked during the 70s, with male predominance in all age groups. Chest pain is the most frequent clinical presentation followed by shortness of breath and syncope. Hypertension and dyslipidemia were the two most common comorbidities. Heart failure and atrial fibrillation was diagnosed in about 1/3 and 1/4 of patients with HCM, respectively. The prevalence and incidence of HCM gradually increased from 2010 to 2016, possibly due to heightened recognition of the disease. Given the progressively high incidence of HCM with age and high prevalence of coexisting modifiable risk factors, continued efforts are required to increase awareness regarding HCM-related symptoms and potential complications.

Nonalcoholic fatty liver disease is an early predictor of metabolic diseases in a metabolically healthy population.

AIMS: The relationship between nonalcoholic fatty liver disease and incident metabolic syndrome in metabolically healthy subjects is unknown. We aimed to investigate whether nonalcoholic fatty liver disease is a predictor of future metabolic syndrome in metabolically healthy subjects. MATERIALS AND METHODS: Subjects who underwent health evaluation at least twice between 2009 and 2015 from the National Health Insurance Service-National Sample Cohort in South Korea were included. Patients without obesity who had no metabolic syndrome components were finally analyzed (n = 28,880). The definition of nonalcoholic fatty liver disease was based on both the hepatic steatosis and fatty liver indices. The incidence of metabolic syndrome, prediabetes/type 2 diabetes, hypertension, and dyslipidemia was compared between the subjects with and without nonalcoholic fatty liver disease. RESULTS: The presence of nonalcoholic fatty liver disease was associated with a higher risk of incident metabolic syndrome, prediabetes/type 2 diabetes, hypertension, and dyslipidemia in the entire cohort (metabolic syndrome: adjusted hazard ratio, 2.10; 95% confidence interval, 1.18-3.71; prediabetes/type 2 diabetes: adjusted hazard ratio, 1.42; 95% confidence interval, 1.06-1.90; hypertension: adjusted hazard ratio, 2.36; 95% confidence interval, 1.35-4.12; dyslipidemia: adjusted hazard ratio, 1.49; 95% confidence interval, 1.07-2.06). A similar finding was observed in the age-, sex-, smoking status-, and body mass index-based 1:5 propensity score-matched cohort of 1,092 subjects (metabolic syndrome: adjusted hazard ratio, 3.56; 95% confidence interval, 1.79-7.07; prediabetes/type 2 diabetes: adjusted hazard ratio, 1.97; 95% confidence interval, 1.04-3.73; hypertension: adjusted hazard ratio, 2.57; 95% confidence interval, 1.35-4.88; dyslipidemia: adjusted hazard ratio, 1.61; 95% confidence interval, 1.12-2.32). CONCLUSIONS: Nonalcoholic fatty liver disease is an early predictor of metabolic dysfunction even in metabolically healthy populations.