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Background: Optimal medical treatment can lead to improvement in left ventricular ejection fraction (LVEF) in patients with heart failure with reduced EF (HFrEF). We investigated the characteristics, predictors, and outcomes of HFrEF according to the 1-year LVEF following angiotensin receptor-neprilysin inhibitors therapy (ARNI)., Methods and Results: Using the STRATS-HF-ARNI (Strain for Risk Assessment and Therapeutic Strategies in Patients With Heart Failure Treated With Angiotensin Receptor-Neprilysin Inhibitor) registry, we identified 1074 patients with HFrEF who took ARNI and underwent baseline and 1-year echocardiography. Patients were classified as HF with improved ejection fraction (HFimpEF) and persistent HFrEF (perHFrEF) (1-year LVEF >40% and ≤40%). The primary and secondary outcomes were all-cause and cardiac mortality from the 1-year follow-up. Among 1074 included patients, 498 (46.4%) had HFimpEF, and 576 (53.6%) had perHFrEF. Older age, male sex, and large LV end-diastolic volumes were positive predictors of perHFrEF, whereas atrial fibrillation and high systolic blood pressure were identified as inverse predictors. Patients with HFimpEF showed lower all-cause and cardiac mortality rates (both log-rank P <0.001). In the multivariable analysis, perHFrEF (hazard ratio, 2.402 [95% CI, 1.251-4.610]; P =0.008) was an independent predictor of poor outcomes. The risk of all-cause mortality decreased as the 1-year LVEF increased up to 40%; however, no additional risk reduction was observed beyond 40%. Compared with patients taking renin-angiotensin-aldosterone system inhibitors in the STRATS-AHF (Strain for Risk Assessment and Therapeutic Strategies in Patients With Acute Heart Failure) registry, those in the STRATS-HF-ARNI registry demonstrated better outcomes in both HFimpEF and perHFrEF., Conclusions: Patients with HFimpEF had better prognosis than those with perHFrEF, and ARNI treatment in HFrEF could be more beneficial than renin-angiotensin-aldosterone system inhibitors for both HFimpEF and perHFrEF., Registration: URL: https://www.who.int/clinical-trials-registry-platform; Unique identifier: KCT0008098.

Background: Aortic stenosis (AS) is characterized by calcification and fibrosis. The ability to quantify these processes simultaneously has been limited with previous imaging methods., Objectives: The purpose of this study was to evaluate the aortic valve fibrocalcific volume by computed tomography (CT) angiography in patients with AS, in particular, to assess its reproducibility, association with histology and disease severity, and ability to predict/track progression., Methods: In 136 patients with AS, fibrocalcific volume was calculated on CT angiograms at baseline and after 1 year. CT attenuation distributions were analyzed using Gaussian-mixture-modeling to derive thresholds for tissue types enabling the quantification of calcific, noncalcific, and fibrocalcific volumes. Scan-rescan reproducibility was assessed and validation provided against histology and in an external cohort., Results: Fibrocalcific volume measurements took 5.8 ± 1.0 min/scan, demonstrating good correlation with ex vivo valve weight (r = 0.51; P < 0.001) and excellent scan-rescan reproducibility (mean difference -1%, limits of agreement -4.5% to 2.8%). Baseline fibrocalcific volumes correlated with mean gradient on echocardiography in both male and female participants (rho = 0.64 and 0.69, respectively; both P < 0.001) and in the external validation cohort (n = 66, rho = 0.58; P < 0.001). The relationship was driven principally by calcific volume in men and fibrotic volume in women. After 1 year, fibrocalcific volume increased by 17% and correlated with progression in mean gradient (rho = 0.32; P = 0.003). Baseline fibrocalcific volume was the strongest predictor of subsequent mean gradient progression, with a particularly strong association in female patients (rho = 0.75; P < 0.001)., Conclusions: The aortic valve fibrocalcific volume provides an anatomic assessment of AS severity that can track disease progression precisely. It correlates with disease severity and hemodynamic progression in both male and female patients., Competing Interests: Funding Support and Author Disclosures The SALTIRE 2 trial was funded by the British Heart Foundation (FS/14/78/31020). This work was partially supported by a grant from the Korea Health Technology R and D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (grant number HI22C0154 to Dr Lee). Dr Joshi has received funding from the British Heart Foundation through a Clinical Research Training Fellowship and Research Excellence Award (FS/CRTF/20/24087 and RE/18/5/34216). Dr Williams is supported by the British Heart Foundation (FS/ICRF/20/26002); and has given talks for Canon Medical Systems, Siemens Healthineers and Novartis. Dr Newby is supported by the British Heart Foundation (CH/09/002, RG/20/10/34966, RE/18/5/34216, CH/F/21/90010); and is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). Dr Dweck is supported by the British Heart Foundation (FS/SCRF/21/32010); is the recipient of the Sir Jules Thorn Award for Biomedical Research 2015 (15/JTA); has received speaker fees from Pfizer, Radcliffe Cardiology, Bristol Myers Squibb, Edwards, and Novartis; has received consultancy fees from Novartis, Jupiter Bioventures, Beren, and Silence therapeutics; and is Director of the Imaging Corelab at the University of Edinburgh. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder with varying risks of clinical outcomes, including sudden cardiac death (SCD). We aimed to identify distinct phenotypes among patients with HCM in relation to SCD risk factors, interpret their clinical characteristics, and examine their outcomes., Methods and Results: This retrospective study analyzed 1231 consecutive patients with HCM from 2 tertiary hospitals. We performed latent class analysis to categorize patients into phenotypic groups. Three distinct phenotypic groups were identified using latent class analysis. Group 1 (n=554) consisted of young patients with HCM with minimal SCD risk factors and favorable cardiac remodeling. Group 2 (n=114) comprised young patients with HCM and a high prevalence of SCD risk factors, whereas Group 3 (n=563) included older patients (median age, 68 years). Over a median 6.5-year follow-up, 34 SCD-related events, 131 cardiovascular events, 133 all-cause mortality events, and 70 noncardiovascular mortality events were observed. Group 2 exhibited the highest rate of SCD-related events (5-year SCD rate: Group 1 versus 2 versus 3: 0.8% versus 8.2% versus 4.0%, respectively, P <0.001), and cardiovascular events were more frequent in Groups 2 and 3 compared with Group 1. All-cause and noncardiovascular mortality were the most frequent in Group 3. A simplified decision tree was developed for the straightforward assignment of phenotypic group membership, demonstrating fair concordance., Conclusions: This study identified 3 distinct clinical phenotypes in patients with HCM, each associated with different SCD risks and outcomes. Data-driven phenotyping of patients with HCM offers effective risk stratification and may optimize patient management.

Background: Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment., Methods and Results: In a double-blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F-sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24-month change in coronary calcium score, and 12-month changes in thoracic aorta calcium score, coronary and aortic 18F-sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [-64 to 148] Agatston units) and either denosumab (94 [0-212] Agatston units, P =0.24) or alendronic acid (34 [-62 to 134], P =0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22-512] Agatston units) and either denosumab (118 [11-340], P =0.75) or alendronic acid (116 [26-498] Agatston units, P =0.62). There were no differences in changes in coronary or aortic 18F-sodium fluoride activity between treatment groups., Conclusions: Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis., Registration: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Introduction: Various strategies aim to better assess risks and refine prevention for patients with type 2 diabetes mellitus (T2DM), who vary in cardiovascular disease (CVD) risk. However, the prognostic value of personality and its association with lifestyle factors remain elusive., Research Design and Methods: We identified 8794 patients with T2DM from the UK Biobank database between 2006 and 2010 and followed them up until the end of 2021. We assessed personality traits using the Big Five proxies derived from UK Biobank data: sociability, warmth, diligence, curiosity, and nervousness. Healthy lifestyle behaviors were determined from information about obesity, smoking status, and physical activity. The primary outcome was a composite of incident CVD, including myocardial infarction (MI), ischemic stroke (IS), atrial fibrillation (AF), and heart failure (HF)., Results: During a median follow-up of 13.6 years, a total of 2110 patients experienced CVDs. Among personality traits, diligence was significantly associated with a reduced risk of primary and secondary outcomes. The adjusted HRs with 95% CIs were: composite CVD, 0.93 (0.89-0.97); MI 0.90 (0.82-1.00); IS 0.83 (0.74-0.94); AF 0.92 (0.85-0.98); HF 0.84 (0.76-0.91). Healthy lifestyle behaviors significantly reduced the risk of composite CVDs in groups with high and low diligence. The findings of a structural equation model showed that diligence directly affected the risk of the primary outcome or indirectly by modifying lifestyle behaviors., Conclusion: This study revealed which personality traits can influence CVD risk during T2DM and how patients might benefit from adopting healthy lifestyle behaviors in relation to personality., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Right ventricular (RV) systolic dysfunction is an established prognostic factor in patients with severe tricuspid regurgitation (TR). However, accurate assessment of RV systolic function using conventional echocardiography remains challenging. We investigated the accuracy of strain measurement using speckle tracking echocardiography (STE) for evaluating RV systolic function in patients with severe TR., Methods: We included consecutive patients with severe TR who underwent echocardiography and cardiac magnetic resonance imaging (CMR) within 30 days between 2011 and 2023. Two-dimensional STE was used to measure RV free wall longitudinal strain (RVFWLS) and global longitudinal strain (RVGLS). These values were compared with the RV ejection fraction (RVEF) from CMR. RV systolic dysfunction was defined as a CMR-derived RVEF < 35%., Results: A total of 87 patients with severe TR were identified during the study period. Among echocardiographic RV strain measurements, RVFWLS was the best correlate of CMR-derived RVEF (r = -0.37, P < 0.001), followed by RVGLS (r = -0.27, P = 0.012). Receiver operating characteristic (ROC) curve analysis revealed that RVFWLS provided better discrimination of RV systolic dysfunction, yielding an area under the ROC curve (AUC) of 0.770 (95% confidence interval [CI], 0.696-0.800) than RV fractional area change (AUC, 0.615; 95% CI, 0.500-0.859)., Conclusions: In patients with severe TR, STE-derived RVFWLS showed the best correlation with RVEF on CMR and displayed superior discrimination of RV systolic dysfunction compared with the RV fractional area change. This study suggests the potential usefulness of STE in assessing RV systolic function in this population., (© 2024. The Author(s).)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

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.

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., Competing Interests: Declaration of Competing Interest There is no conflict of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2023. The Author(s).)

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 cm 2 ; 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., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Research Foundation of Korea of the Ministry of Science and ICT (NRF-2020R1C1C1010890). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: The authors declare that there is no conflict of interest to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2022 by the American Diabetes Association.)

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., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: Competing interests: H-KK reports research grants from Actelion, Handok Pharmaceuticals, Dae-Woong Pharmaceuticals, Yuhan, Hanmi, ChongKunDang Pharmaceuticals, and Norvatis., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

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/m 2 ) and small (LVEDVi ≤55 mL/m 2 ) 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., Competing Interests: Funding Support and Author Disclosures The work was supported by a National Research Foundation of Korea grant funded by the Korea government (Ministry of Science and ICT; No. 2019R1A2C2084099) and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI18C2383). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

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.

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 (β = 0.219, P = 0.021) and LV mass index (β = 0.286, P = 0.002), and four diastolic parameters including septal e' velocity (β = -0.199, P = 0.018), E/e' (β = 0.373, P < 0.001), left atrial volume index (β = 0.334, P < 0.001), and maximal velocity of tricuspid regurgitation (β = 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kwak, Kim, In, Lim, Seo, Kim, Zo and Kim.)

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 mm 3 /year and for dense calcification, 2.5, 4.6, 5.4, and 7.1 mm 3 /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., Competing Interests: Declaration of competing interest Dr. Min receives funding from the Dalio Foundation, National Institutes of Health, and GE Healthcare and serves on the scientific advisory board of Arineta and GE Healthcare, and has an equity interest in Clearly. Dr. Samady serves on the scientific advisory board of Philips, has equity interest in Covanos Inc., and has a research grant from Medtronic. The remaining authors have no relevant disclosures., (Copyright © 2020 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2020. Published by Elsevier Ltd.)

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., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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.

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., Competing Interests: Prof. Hyung-Kwan Kim (HK-K) reports research grants from Actelion, GSK, Handok Pharm, Dae-Woong Pharm, Yuhan, Hanmi, ChongKunDang Pharm and Norvatis. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors have nothing to disclose.

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., Competing Interests: This study was supported by an unrestricted grant from the Yuhan Pharmaceuticals, South Korea. This study was not related to employment, consultancy, patents, products in development, marketed products of the funders. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: The association of lifetime exposure to endogenous sex hormone with incident atrial fibrillation (AF) and subsequent ischemic stroke has never been studied., Methods: This study involved 4 638 299 natural postmenopausal waomen aged ≥40 years without prior history of AF and with national breast cancer check-up between January 1, 2009 and December 31, 2014. The primary end point was incident AF, and the secondary end point was subsequent ischemic stroke once AF has developed. Cox proportional hazard regression analysis was used to estimate the risk of end points., Results: During the mean follow-up of 6.3 years, shorter total reproductive years (<30 years) were associated with 7% increased risk of AF after adjusting for confounding variables (adjusted hazard ratio [aHR], 1.07 [95% CI, 1.05-1.09]). Risk of AF declined progressively with every 5-yearly increment in total reproductive years ( P -for-trend <0.001). However, the prolonged (≥2 years) use of hormone replacement therapy after menopause was paradoxically associated with a 3% increase in AF risk (aHR, 1.03 [95% CI, 1.01-1.05]). For the secondary end point analysis, the risk of ischemic stroke after AF development significantly decreased with each 5-yearly increment in total reproductive years (with <30 years as reference; aHR, 0.93 [95% CI, 0.88-0.99] for 30-34 years; aHR, 0.84 [95% CI, 0.79-0.89] for 35-39 years; and aHR, 0.88 [95% CI, 0.80-0.97] for ≥40 years, P -for-trend <0.001)., Conclusions: In women with natural menopause, shorter lifetime exposure to endogenous sex hormone, that is, shorter total reproductive years, was significantly associated with a higher risk of AF and subsequent ischemic stroke. Paradoxically, prolonged exogenous hormone replacement therapy increased the risk of incident AF.

Choosing antithrombotic regimens for patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI) with stent placement is challenging. Until recently, the guidelines recommended warfarin-based triple therapy, which causes frequent major bleeding events in up to 12% of patients during the first year of treatment. The WOEST trial, however, revealed that dual therapy, by without aspirin, resulted in significantly lower bleeding risks with similar thromboembolic events to triple therapy. Subsequently, efforts to seek the optimal dual therapy regimens, especially with the combination of a non-vitamin K antagonist oral anticoagulant (NOAC), were initiated. This review highlights the evidence for dual therapy using an NOAC for patients with AF who underwent PCI, with an emphasis on reduced bleeding risk., Competing Interests: Conflict of Interest: The authors have no conflicts of interest to declare., (Copyright © 2019 The Korean Society of Lipid and Atherosclerosis.)

Background: The prognostic efficacy of quantitative platelet activity in atrial fibrillation (AF) remains unclear., Objective: The purpose of this study was to evaluate the platelet count (PLT) as a prognostic indicator in patients with nonvalvular AF., Methods: Data on 10,978 patients with nonvalvular AF were retrieved from a prospective registry of a single medical center in Korea. Cumulative risk for stroke and bleeding events were compared between patients with normal PLT (n = 8322), mild thrombocytopenia (n = 1791), and moderate to severe thrombocytopenia (n = 865) after propensity score matching. Prediction models for stroke were derived by conventional risk factors (model 1) and by combining PLT with model 1 (model 2), and model performance was assessed by area under the receiver operator characteristics curve (AUC)., Results: During the follow-up period, 7.3%, 7.0%, and 4.5% had stroke and 7.6%, 10.8%, and 17.2% had bleeding events in the normal PLT, mild, and moderate to severe thrombocytopenia groups, respectively. Compared to the normal PLT group, the moderate to severe thrombocytopenia group showed a lower risk of stroke (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.40-0.80; P = .002). A reverse relationship was found between PLT and bleeding risk (moderate to severe thrombocytopenia: HR 2.19; 95% CI 1.77-2.70; P <.001; mild thrombocytopenia: HR 1.43; 95% CI 1.18-1.73; P <.001). Compared to model 1, model 2 showed significant improvement in risk prediction (AUC 0.628 vs 0.644; P <.001)., Conclusion: A lower PLT was associated with a lower risk of stroke and a higher risk of bleeding events. PLT combined with conventional risk factors showed significant improvement in prediction for stroke., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

High-grade serous ovarian carcinoma presents significant clinical and therapeutic challenges. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, recent studies suggest that there may be additional sites of origin outside the ovary, namely the secretory cells of the fallopian tube. Our study demonstrates that high-grade serous tumors can originate in fallopian tubal secretory epithelial cells and also establishes serous tubal intraepithelial carcinoma as the precursor lesion to high-grade serous ovarian and peritoneal carcinomas in animal models targeting the Brca, Tp53, and Pten genes. These findings offer an avenue to address clinically important questions that are critical for cancer prevention and early detection in women carrying BRCA1 and BRCA2 mutations., (Copyright © 2013 Elsevier Inc. All rights reserved.)