Smoking behavior change and risk of cardiovascular disease incidence and mortality in patients with type 2 diabetes mellitus.

BACKGROUND: We aimed to examine the association between smoking behavior change and risk of cardiovascular disease (CVD) incidence and mortality in patients with type 2 diabetes mellitus (T2DM). METHODS: This study used nationwide data from the Korean National Health Insurance System and included 349,137 T2DM patients who smoked. Smoking behavior changes were defined with five groups: quitters, reducers I (≥ 50% reduction), reducers II (20-50% reduction), sustainers (± 20%), and increasers (≥ 20% increase) from the number of cigarettes/day at the baseline. RESULTS: During a median follow-up of 5.1 years, 6,514 cases of myocardial infarction (MI) (1.9%), 7,837 cases of ischemic stroke (IS) (2.2%), and 14,932 deaths (4.3%) were identified. Quitters had a significantly decreased risk of MI (adjusted hazard ratio [aHR] 0.80, 95% CI 0.75-0.86) and IS (aHR 0.80, 95% CI 0.75-0.85) compared to sustainers, whereas reducers did not have a significant association with the risk of MI (aHR 1.03, 95% CI 0.94-1.13) and IS (aHR 1.00, 95% CI 0.92-1.08) in reducer I. Quitters also had a lower all-cause and CVD mortality than sustainers. CONCLUSIONS: Smoking cessation was associated with decreased CVD incidence, and all-cause and CVD mortality among T2DM patients. However, smoking reduction was not associated with decreased risks for these.

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.

Left atrial reservoir strain as a novel predictor of new-onset atrial fibrillation in light-chain-type cardiac amyloidosis.

AIMS: To investigate whether left arterial reservoir strain (LASr) could predict new-onset atrial fibrillation (NOAF) in patients with light-chain-type cardiac amyloidosis (ALCA). METHODS AND RESULTS: This study enrolled 427 patients with CA from two tertiary centres between 2005 and 2019. LASr was measured using a vendor-independent analysis programme. The primary outcome was NOAF. A total of 287 patients with ALCA were included [median age 63.0 (56.0-70.0) years, 53.3% male]. The median LASr was 13.9% (10.5-20.8%). During the median follow-up of 0.85 years, AF occurred in 34 patients (11.8%). In the receiver operating characteristics curve analysis, the optimal cut-off of LASr for predicting NOAF was 14.4%. Patients with LASr ≤14.4% had a higher risk of NOAF than those with LASr >14.4% (18.1% vs. 5.1%, P < 0.010). In the multivariate analysis adjusting for confounding factors, including left arterial volume index and left ventricular global longitudinal strain (LV-GLS), higher LASr (%) was independently associated with lower risk for NOAF [adjusted hazard ratio (aHR): 0.936, 95% confidence interval (95% CI): 0.879-0.997, P = 0.039]. Furthermore, LASr ≤14.4% was an independent predictor for NOAF (aHR: 3.370, 95% CI: 1.337-8.492, P = 0.010). This remained true after accounting for all-cause death as a competing risk. Compared with Model 1 (LV-GLS) and Model 2 (LV-GLS plus LAVI), Model 3, including LASr showed a better reclassification ability for predicting NOAF (net reclassification index = 0.735, P < 0.001 compared with Model 1; net reclassification index = 0.514, P = 0.003 compared with Model 2). CONCLUSION: LASr was an independent predictor of NOAF in patients with ALCA.

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.

Changes in Alcohol Consumption and Risk of Heart Failure: A Nationwide Population-Based Study in Korea.

Background: The association between alcohol intake and newly developed heart failure remains unclear. We aimed to measure the change in alcohol intake between two timepoints to evaluate the association of alcohol consumption with incident heart failure using a population-based study in Korea. Methods: Using the Korean National Health Insurance database, participants who underwent two subsequent national health examinations in 2009 and 2011 were included. Participants were classified into four groups according to total alcohol intake (none: 0 g alcohol/day; light: <15 g alcohol/day; moderate: 15−30 g alcohol/day; and heavy: ≥30 g alcohol/day), and changes in alcohol consumption between the two health exams were grouped into the following five categories: abstainers, sustainers (those who maintained their first examination drinking level), increasers, reducers, and quitters. After adjustment for age, sex, smoking status, regular exercise, socioeconomic information, and comorbidities, the Charlson Comorbidity Index, systolic blood pressure, and laboratory results, a Cox proportional hazards model was used to find the risk of newly diagnosed heart failure (according to ICD-10 code I50 from claims for the first hospitalization) as the primary endpoint. A subgroup analysis among those with a third examination was conducted to reflect further changes in alcohol consumption. Results: Among 3,842,850 subjects, 106,611 (3.0%) were diagnosed with heart failure during the mean follow-up period of 6.3 years. Increasers to a light level of drinking had a lower HF risk compared with abstainers (aHR = 0.91, 95% CI: 0.89−0.94). Those who increased their alcohol intake to a heavy level had a higher HF risk (from light to heavy (aHR = 1.19, 95% CI: 1.12−1.26) and from a moderate to heavy level (aHR = 1.13, 95% CI: 1.07−1.19). Reducing alcohol from a heavy to moderate level was associated with lower HF risk (aHR = 0.90, 95% CI: 0.86−0.95). Conclusion: This study found that light and moderate sustainers had lower incident heart failure risk compared with abstainers. Increased alcohol consumption from light to moderate to heavy was associated with a higher incident heart failure risk.

Reliability and feasibility of visual grading systems and quantitative indexes on [99mTc]Tc-DPD imaging for cardiac amyloidosis.

We aimed to evaluate the reliability and feasibility of visual grading systems and various quantitative indexes of [99mTc]Tc-DPD imaging for cardiac amyloidosis (CA). Patients who underwent [99mTc]Tc-DPD imaging with suspicion of CA were enrolled. On the planar image, myocardial uptake was visually graded using Perugini's and Dorbala's methods (PS and DS). As [99mTc]Tc-DPD indexes, heart-to-whole body ratio (H/WB) and heart-to-contralateral lung ratio (H/CL) were measured on planar image. SUVmax, SUVmean, total myocardial uptake (TMU), and C-index were measured on SPECT/CT. Inter-observer agreement of the indexes and their association with visual grading and clinical factors were evaluated. A total of 152 [99mTc]Tc-DPD images, of which 18 were positive, were analyzed. Inter-observer agreement was high for both DS (κ = 0.95) and PS (κ = 0.96). However, DS showed a higher correlation with quantitative indexes than PS. Inter-observer agreement was also high for SPECT/CT indexes, particularly SUVmax. SUVmax was significantly different between different DS groups (P = 0.014-0.036), and showed excellent correlations with H/WB and H/CL (r = 0.898 and 0.910). SUVmax also showed significant differences between normal, AL, and ATTR pathology (P = 0.022-0.037), and a significant correlation with extracellular volume on cardiac MRI (r = 0.772, P < 0.001). DS is a visual grading system for CA that is more significantly matched with quantitative indexes than PS. SUVmax is a reliable quantitative index on SPECT/CT, with a high inter-observer agreement, correlations with the visual grade, and potential association with cardiac MRI findings.

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.

Sox17 Deficiency Promotes Pulmonary Arterial Hypertension via HGF/c-Met Signaling.

BACKGROUND: In large-scale genomic studies, Sox17, an endothelial-specific transcription factor, has been suggested as a putative causal gene of pulmonary arterial hypertension (PAH); however, its role and molecular mechanisms remain to be elucidated. We investigated the functional impacts and acting mechanisms of impaired Sox17 (SRY-related HMG-box17) pathway in PAH and explored its potential as a therapeutic target. METHODS: In adult mice, Sox17 deletion in pulmonary endothelial cells (ECs) induced PAH under hypoxia with high penetrance and severity, but not under normoxia. RESULTS: Key features of PAH, such as hypermuscularization, EC hyperplasia, and inflammation in lung arterioles, right ventricular hypertrophy, and elevated pulmonary arterial pressure, persisted even after long rest in normoxia. Mechanistically, transcriptomic profiling predicted that the combination of Sox17 deficiency and hypoxia activated c-Met signaling in lung ECs. HGF (hepatocyte grow factor), a ligand of c-Met, was upregulated in Sox17-deficient lung ECs. Pharmacologic inhibition of HGF/c-Met signaling attenuated and reversed the features of PAH in both preventive and therapeutic settings. Similar to findings in animal models, Sox17 levels in lung ECs were repressed in 26.7% of PAH patients (4 of 15), while those were robust in all 14 non-PAH controls. HGF levels in pulmonary arterioles were increased in 86.7% of patients with PAH (13 of 15), but none of the controls showed that pattern. CONCLUSIONS: The downregulation of Sox17 levels in pulmonary arterioles increases the susceptibility to PAH, particularly when exposed to hypoxia. Our findings suggest the reactive upregulation of HGF/c-Met signaling as a novel druggable target for PAH treatment.

Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia.

Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPARγ pathway in Cd36+ valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.

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.

Effectiveness and safety of non-vitamin K direct oral anticoagulants in atrial fibrillation patients with bioprosthetic valve.

BACKGROUND: Non-vitamin K direct oral anticoagulant (DOAC) is effective for prevention of embolic events in nonvalvular atrial fibrillation (AF) patients. However, the effectiveness and safety of DOAC in AF patients who have bioprosthetic heart valve (BPHV) is largely unknown. METHODS: We retrospectively identified patients with AF and BPHV, using the diagnostic code and medical device and surgery information from the Korean National Health Insurance Service database, between 2013 and 2018. A 1:2 propensity score-matched cohort (n = 724 taking warfarin; n = 362 taking DOAC) was constructed and analyzed for the primary clinical outcome, a composite of ischemic stroke and systemic embolism. Important secondary outcomes included major bleeding, all-cause death, and the net clinical outcome, defined as a composite of all embolic events, major bleeding, and death. RESULTS: The mean age was 78.9±6.8 years old, and 45% (n = 489) were male. The mean CHA2DS2-VASc score was 4.7±1.4. DOAC was non-inferior to warfarin for preventing ischemic stroke and systemic embolism (hazard ratio [HR] 1.14, 95% confidence interval [CI] 0.56-2.34), major bleeding (HR 0.80, 95% CI 0.32-2.03) and all-cause death (HR 1.09, 95% CI 0.73-1.63). As for the net clinical outcome, DOAC was also similar to warfarin (HR 1.06, 95% CI 0.76-1.47). These outcomes were not different in various subgroups analyzed. CONCLUSION: In this nationwide Korean AF population with a BPHV, DOAC was at least as effective and safe as warfarin for the prevention of systemic embolic events. These results suggest that DOAC may be an excellent alternative to warfarin in AF patients with BPHV.

Network Analysis of Cardiac Remodeling by Primary Mitral Regurgitation Emphasizes the Role of Diastolic Function.

BACKGROUND: Topological data analysis (TDA) can generate patient-patient similarity networks by analyzing large, complex data and derive new insights that may not be possible with standard statistics. OBJECTIVES: The purpose of this paper was to discover novel phenotypes of chronic primary mitral regurgitation (MR) patients and to analyze their clinical implications using network analysis of echocardiographic data. METHODS: Patients with chronic moderate to severe primary MR were prospectively enrolled from 11 Asian tertiary hospitals (n = 850; mean age 56.9 ± 14.2 years, 57.9% men). We performed TDA to generate network models using 14 demographic and echocardiographic variables. The patients were grouped by phenotypes in the network, and the prognosis was compared by groups. RESULTS: The network model by TDA revealed 3 distinct phenogroups. Group A was the youngest with fewer comorbidities but increased left ventricular (LV) end-systolic volume, representing compensatory LV dilation commonly seen in chronic primary MR. Group B was the oldest with high blood pressure and a predominant diastolic dysfunction but relatively preserved LV size, an unnoticed phenotype in chronic primary MR. Group C showed advanced LV remodeling with impaired systolic, diastolic function, and LV dilation, indicating advanced chronic primary MR. During follow-up (median 3.5 years), 60 patients received surgery for symptomatic MR or died of cardiovascular causes. Kaplan-Meier curves demonstrated that although group C had the worst clinical outcome (P < 0.001), group B, characterized by diastolic dysfunction, had an event-free survival comparable to group A despite preserved LV chamber size. The grouping information by the network model was an independent predictor for the composite of MR surgery or cardiovascular death (adjusted HR: 1.918; 95% CI: 1.257-2.927; P = 0.003). CONCLUSIONS: The patient-patient similarity network by TDA visualized diverse remodeling patterns in chronic primary MR and revealed distinct phenotypes not emphasized currently. Importantly, diastolic dysfunction deserves equal attention when understanding the clinical presentation of chronic primary MR.

Age-dependent associations of body mass index with myocardial infarction, heart failure, and mortality in over 9 million Koreans.

AIMS: While obesity is a well-known cardiovascular risk factor, little is known whether age has a modifying effect. The aim of this study is to determine the age-dependent associations of body mass index (BMI) with cardiovascular outcomes. METHODS AND RESULTS: A population-based cohort of 9 278 433 Koreans without prior cardiovascular disease were followed up for the incidence of myocardial infarction (MI), heart failure (HF), and all-cause death. The effect of BMI with optimal normal weight (18.5-22.9 kg/m2) as reference was analysed according to age groups [young (20-39 years), middle-aged (40-64 years), and elderly (≥65 years)] and age decades. During 8.2 years, MI, HF, and all-cause death occurred in 65 607 (0.71%), 131 903 (1.42%), and 306 065 (3.30%), respectively. Associations between BMI and all outcomes were significantly modified by age (P-for-interaction < 0.001). There was a proportional increase in incident MI according to BMI in young subjects; this relationship became U-shaped in middle-aged subjects and inversely proportional/plateauing in elderly subjects. A U-shaped relationship between BMI and incident HF was observed, but the impact of obesity was stronger in young subjects while the impact of underweight was stronger in middle-aged and elderly subjects. Meanwhile, lower BMI was associated with higher all-cause mortality in all ages, although this association was attenuated at the young age, and pre-obesity was associated with the greatest survival benefit. These associations were independent of sex, smoking, physical activity, and comorbidities. CONCLUSION: The impact of BMI on cardiovascular risk differs according to age. Weight loss may be recommended for younger overweight subjects, while being mildly overweight may be beneficial at old age.

Association of Change in Alcohol Consumption With Risk of Ischemic Stroke.

BACKGROUND: The effect of serial change in alcohol consumption on stroke risk has been limitedly evaluated. We investigated the association of change in alcohol consumption with risk of stroke. METHODS: This study is a population-based retrospective cohort study from National Health Insurance Service database of all Koreans. Four lakh five hundred thirteen thousand seven hundred forty-six participants aged ≥40 years who underwent 2 subsequent national health examinations in both 2009 and 2011. Alcohol consumption was assessed by average alcohol intake (g/day) based on self-questionnaires and categorized into non-, mild, moderate, and heavy drinking. Change in alcohol consumption was defined by shift of category from baseline. Cox proportional hazards model was used with adjustment for age, sex, smoking status, regular exercise, socioeconomic information, and comorbidities, Charlson Comorbidity Index, systolic blood pressure, and laboratory results. Subgroup analysis among those with the third examination was conducted to reflect further change in alcohol consumption. RESULTS: During 28 424 497 person-years of follow-up, 74 923 ischemic stroke events were identified. Sustained mild drinking was associated with a decreased risk of ischemic stroke (adjusted hazard ratio, 0.88 [95% CI, 0.86-0.90]) compared with sustained nondrinking, whereas sustained heavy drinking was associated with an increased risk of ischemic stroke (adjusted hazard ratio, 1.06 [95% CI, 1.02-1.10]). Increasing alcohol consumption was associated with an increased risk of ischemic stroke (adjusted hazard ratio, 1.11 [95% CI, 1.06-1.17] from mild to moderate; adjusted hazard ratio, 1.28 [95% CI, 1.19-1.38] from mild to heavy) compared with sustained mild drinkers. Reduction of alcohol consumption from heavy to mild level was associated with 17% decreased risk of ischemic stroke through 3× of examinations. CONCLUSIONS: Light-to-moderate alcohol consumption is associated with a decreased risk of ischemic stroke, although it might be not causal and could be impacted by sick people abstaining from drinking. Reduction of alcohol consumption from heavy drinking is associated with a decreased risk of ischemic stroke.

Prediction of incident atherosclerotic cardiovascular disease with polygenic risk of metabolic disease: Analysis of 3 prospective cohort studies in Korea.

BACKGROUND AND AIMS: Studies have demonstrated that the risk of atherosclerotic cardiovascular disease (ASCVD) can be assessed by polygenic risk score (PRS) using common genetic variants. Because metabolic syndrome is a well-known, robust risk factor of ASCVD, we established PRS of metabolic disease and analyzed whether this PRS could predict incident ASCVD. METHODS: We constructed PRSs for eight quantifiable metabolic phenotypes-systolic/diastolic blood pressure, body mass index (BMI), four blood lipid components, and fasting blood glucose-by genome-wide association studies of two prospective Korean cohorts (n = 37,285). We conducted a grid search of combinations of metabolic PRSs to identify the most optimal weighted score for incident ASCVD (PRSMetS-ASCVD). The utility of PRSMetS-ASCVD was validated in an independent prospective cohort (n = 4333). RESULTS: The individuals in the highest PRS quintile demonstrated a 1.4-2.0-fold increased risk of incident hypertension, obesity, hyperlipidemia, and diabetes. Using the PRSMetS-ASCVD, we identified 6.7% of the population as a high risk group demonstrating a 3.3-fold (95% confidence interval 1.7-6.1, p < 0.001) higher risk for incident ASCVD. The model combining the PRSMetS-ASCVD demonstrated a better performance for predicting ASCVD than that consisting of only conventional risk factors, such as age, sex, BMI, smoking, hypertension, diabetes and hyperlipidemia. The population with high PRSMetS-ASCVD minimally overlapped with that of high Framingham risk score, thus suggesting the additive independent benefits beyond the Framingham risk score, especially in younger individuals. CONCLUSIONS: The polygenic risk of metabolic disease independently predicts those at an increased risk of ASCVD, identifying those at a genetically high risk of incident ASCVD.

Cumulative exposure amount of PM2.5 in the ambient air is associated with coronary atherosclerosis - Serial coronary CT angiography study.

BACKGROUND: We investigated the change of coronary atherosclerosis with long-term exposure to fine particulate matter of aerodynamic diameter <2.5 â€‹µm (PM2.5) using coronary computed tomography angiography (CCTA). METHODS: Subjects undergoing serial CCTAs between January 2007 and December 2017 (n â€‹= â€‹3,127) were analyzed. Each individual's cumulative amount of PM2.5 exposure between the two CCTAs was evaluated by Kriging interpolation and zonal analysis, considering the time interval between the two CCTAs. The main outcome was progression of coronary artery calcium (CAC) with additional semiquantitative analysis on the changes in the severity and composition of atherosclerotic plaques. RESULTS: The CAC scores increased by 30.8 Agatston units per-year under a median PM2.5 concentration 24.9 â€‹µg/m3 and tended to increase with the cumulative amount of PM2.5 exposure (r â€‹= â€‹0.321, p â€‹<0.001). The CAC progressed in 1,361 (43.5%) subjects during a median 53 months follow-up. The cumulative amount of PM2.5 exposure was independently associated with CAC progression (adjusted OR 1.09, p â€‹<0.001). By random forest analysis, the relative impact of cumulative amount of PM2.5 exposure on CAC progression was higher than that of traditional cardiovascular risk factors and the average concentration of PM2.5. The extent of coronary atherosclerosis and newly developed calcified plaque on follow-up were also significantly associated with the cumulative amount of PM2.5 exposure. CONCLUSIONS: Cumulative exposure to air pollution is associated with the progression of diffuse coronary calcification, the importance of which may be more significant than other traditional cardiovascular risk factors. Further investigations into the causality between PM2.5 and coronary atherosclerosis are warranted to improve global cardiovascular health.

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.

Smoking cessation, but not reduction, reduces cardiovascular disease incidence.

AIMS: The aim of this study was to assess the association of smoking cessation and reduction with risk of cardiovascular disease (CVD). METHODS AND RESULTS: A total of 897 975 current smokers aged ≥40 years who had undergone two consecutive national health examinations (in 2009 and 2011) were included. Participants were classified as quitters (20.6%), reducers I (≥50% reduction, 7.3%), reducers II (20-50% reduction, 11.6%), sustainers (45.7%), and increasers (≥20% increase, 14.5%). During 5 575 556 person-years (PY) of follow-up, 17 748 stroke (3.2/1000 PY) and 11 271 myocardial infarction (MI) (2.0/1000 PY) events were identified. Quitters had significantly decreased risk of stroke [adjusted hazard ratio (aHR) 0.77 95% confidence interval (CI) 0.74-0.81; absolute risk reduction (ARR) -0.37, 95% CI -0.43 to -0.31] and MI (aHR 0.74, 95% CI 0.70-0.78; ARR -0.27, 95% CI -0.31 to -0.22) compared to sustainers after adjustment for demographic factors, comorbidities, and smoking status. The risk of stroke and MI incidence in reducers I (aHR 1.02, 95% CI 0.97-1.08 and aHR 0.99, 95% CI 0.92-1.06, respectively) and reducers II (aHR 1.00, 95% CI 0.95-1.05 and aHR 0.97, 95% CI 0.92-1.04, respectively) was not significantly different from the risk in sustainers. Further analysis with a subgroup who underwent a third examination (in 2013) showed that those who quit at the second examination but had starting smoking again by the third examination had 42-69% increased risk of CVD compared to sustained quitters. CONCLUSIONS: Smoking cessation, but not reduction, was associated with reduced CVD risk. Our study emphasizes the importance of sustained quitting in terms of CVD risk reduction.