Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.

BACKGROUND AND OBJECTIVES: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT. METHODS: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT. RESULTS: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up. DISCUSSION: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.

Deep learning to detect left ventricular structural abnormalities in chest X-rays.

BACKGROUND AND AIMS: Early identification of cardiac structural abnormalities indicative of heart failure is crucial to improving patient outcomes. Chest X-rays (CXRs) are routinely conducted on a broad population of patients, presenting an opportunity to build scalable screening tools for structural abnormalities indicative of Stage B or worse heart failure with deep learning methods. In this study, a model was developed to identify severe left ventricular hypertrophy (SLVH) and dilated left ventricle (DLV) using CXRs. METHODS: A total of 71 589 unique CXRs from 24 689 different patients completed within 1 year of echocardiograms were identified. Labels for SLVH, DLV, and a composite label indicating the presence of either were extracted from echocardiograms. A deep learning model was developed and evaluated using area under the receiver operating characteristic curve (AUROC). Performance was additionally validated on 8003 CXRs from an external site and compared against visual assessment by 15 board-certified radiologists. RESULTS: The model yielded an AUROC of 0.79 (0.76-0.81) for SLVH, 0.80 (0.77-0.84) for DLV, and 0.80 (0.78-0.83) for the composite label, with similar performance on an external data set. The model outperformed all 15 individual radiologists for predicting the composite label and achieved a sensitivity of 71% vs. 66% against the consensus vote across all radiologists at a fixed specificity of 73%. CONCLUSIONS: Deep learning analysis of CXRs can accurately detect the presence of certain structural abnormalities and may be useful in early identification of patients with LV hypertrophy and dilation. As a resource to promote further innovation, 71 589 CXRs with adjoining echocardiographic labels have been made publicly available.

Diabetes mellitus in patients with heart failure and reduced ejection fraction: a post hoc analysis from the WARCEF trial.

Patients with heart failure with reduced ejection fraction (HFrEF) and diabetes mellitus (DM) have an increased risk of adverse events, including thromboembolism. In this analysis, we aimed to explore the association between DM and HFrEF using data from the "Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction" (WARCEF) trial. We analyzed factors associated with DM using multiple logistic regression models and evaluated the effect of DM on long-term prognosis, through adjusted Cox regressions. The primary outcome was the composite of all-cause death, ischemic stroke, or intracerebral hemorrhage; we explored individual components as the secondary outcomes and the interaction between treatment (warfarin or aspirin) and DM on the risk of the primary outcome, stratified by relevant characteristics. Of 2294 patients (mean age 60.8 (SD 11.3) years, 19.9% females) included in this analysis, 722 (31.5%) had DM. On logistic regression, cardiovascular comorbidities, symptoms and ethnicity were associated with DM at baseline, while age and body mass index showed a nonlinear association. Patients with DM had a higher risk of the primary composite outcome (Hazard Ratio [HR] and 95% Confidence Intervals [CI]: 1.48 [1.24-1.77]), as well as all-cause death (HR [95%CI]: 1.52 [1.25-1.84]). As in prior analyses, no statistically significant interaction was observed between DM and effect of Warfarin on the risk of the primary outcome, in any of the subgroups explored. In conclusion, we found that DM is common in HFrEF patients, and is associated with other cardiovascular comorbidities and risk factors, and with a worse prognosis.

Educational status affects prognosis of patients with heart failure with reduced ejection fraction: A post-hoc analysis from the WARCEF trial.

AIMS: The influence of social determinants of health (SDOH) on the prognosis of Heart Failure and reduced Ejection Fraction (HFrEF) is increasingly reported. We aim to evaluate the contribution of educational status on outcomes in patients with HFrEF. METHODS: We used data from the WARCEF trial, which randomized HFrEF patients with sinus rhythm to receive Warfarin or Aspirin; educational status of patients enrolled was collected at baseline. We defined three levels of education: low, medium and high level, according to the highest qualification achieved or highest school grade attended. We analysed the impact of the educational status on the risk of the primary composite outcome of all-cause death, ischemic stroke (IS) and intracerebral haemorrhage (ICH); components of the primary outcome were also analysed as secondary outcomes. RESULTS: 2295 patients were included in this analysis; of these, 992 (43.2%) had a low educational level, 947 (41.3%) had a medium education level and the remaining 356 (15.5%) showed a high educational level. Compared to patients with high educational level, those with low educational status showed a high risk of the primary composite outcome (adjusted hazard ratio [aHR]: 1.31, 95% confidence intervals [CI] 1.02-1.69); a non-statistically significant association was observed in those with medium educational level (aHR: 1.20, 95%CI: .93-1.55). Similar results were observed for all-cause death, while no statistically significant differences were observed for IS or ICH. CONCLUSION: Compared to patients with high educational levels, those with low educational status had worse prognosis. SDOH should be considered in patients with HFrEF. CLINICAL TRIAL REGISTRATION: NCT00041938.

Aortic Arch Plaques and the Long-Term Risk of Stroke and Cardiovascular Events in the Statin Era.

BACKGROUND: Aortic arch plaques are associated with an increased risk of ischemic stroke in patients with cryptogenic stroke or prior embolic events. However, this relationship is unclear in the community. We investigated (1) the long-term risk of stroke and cardiovascular events associated with arch plaques and (2) whether statin therapy prescribed for any indication modified the association. METHODS: A total of 934 stroke-free participants (72±9 years; 37% men) from the CABL study (Cardiovascular Abnormalities and Brain Lesion) were evaluated. Arch plaques were assessed by suprasternal transthoracic echocardiography; plaques ≥4 mm in thickness were classified as large plaques. The primary outcome was ischemic stroke; the secondary outcome was combined cardiovascular events (ischemic stroke, myocardial infarction, and cardiovascular death). The plaque-related risk of outcomes was also analyzed according to the presence of statin treatment. No plaque was used as a reference. RESULTS: Aortic arch plaques were present in 645 participants (69.1%), with large plaques in 114 (12.2%). During a mean follow-up of 11.3±3.6 years, 236 (25.3%) cardiovascular events occurred (76 ischemic strokes, 27 myocardial infarctions, and 133 cardiovascular deaths). Large arch plaques were independently associated with combined events (adjusted hazard ratio, 2.19 [95% CI, 1.40-3.43]) but not stroke alone (adjusted hazard ratio, 1.09 [95% CI, 0.50-2.38]). The association between large plaques and cardiovascular events was significant in participants receiving statins (adjusted hazard ratio, 2.57 [95% CI, 1.52-4.37]) but not in others; however, participants on statin treatment also had a worse risk profile (higher body mass index, greater frequencies of hypertension, diabetes, and coronary artery disease). CONCLUSIONS: Aortic arch plaques may be a marker of cardiovascular risk rather than a direct embolic stroke source in older adults without prior stroke. The efficacy of broader cardiovascular risk factors control, beyond cholesterol levels alone, for primary prevention of cardiovascular events in individuals with aortic arch plaques may require further investigation.

Association between non-alcoholic fatty liver disease and subclinical left ventricular dysfunction in the general population.

Aims: Emerging evidence suggests an association between non-alcoholic fatty liver disease (NAFLD) and heart failure (HF). We investigated the relationship between NAFLD and left ventricular (LV) functional remodelling in a general population sample without overt cardiac and liver disease. Methods and results: We included 481 individuals without significant alcohol consumption who voluntarily underwent an extensive cardiovascular health check. The fatty liver index (FLI) was calculated for each participant, and NAFLD was defined as FLI ≥ 60. All participants underwent 2D transthoracic echocardiography; LV global longitudinal strain (LVGLS) was assessed with speckle-tracking analysis. Univariable and multivariable linear regression models were constructed to investigate the possible association between NAFLD and LVGLS. Seventy-one (14.8%) participants were diagnosed with NAFLD. Individuals with NAFLD exhibited larger LV size and LV mass index than those without NAFLD, although left atrial size and E/e' ratio did not differ between groups. Left ventricular global longitudinal strain was significantly reduced in participants with vs. without NAFLD (17.1% ± 2.4% vs. 19.5% ± 3.1%, respectively; P < 0.001). The NAFLD group had a significantly higher frequency of abnormal LVGLS (<16%) than the non-NAFLD group (31.0% vs. 10.7%, respectively; P < 0.001). Multivariable linear regression analysis demonstrated that higher FLI score was significantly associated with impaired LVGLS independent of age, sex, conventional cardiovascular risk factors, and echocardiographic parameters (standardized ß -0.11, P = 0.031). Conclusion: In the general population without overt cardiac and liver disease, the presence of NAFLD was significantly associated with subclinical LV dysfunction, which may partly explain the elevated risk of HF in individuals with NAFLD.

Left Atrial Strain and Incident Atrial Fibrillation in Older Adults.

Atrial fibrillation (AF) is frequent in older adults and associated with left atrial (LA) dysfunction. LA strain (LAε) and LA strain rate (LASR) may detect subclinical LA disease. We investigated whether reduced LAε and LASR predict new-onset AF in older adults without history of AF or stroke. LAε and LASR were assessed by speckle-tracking echocardiography in 824 participants from the community-based Cardiovascular Abnormalities and Brain Lesions study. Positive longitudinal LAε and LASR during ventricular systole, LASR during early ventricular diastole, and LASR during LA contraction were measured. Cause-specific hazards regression model evaluated the association of LAε and LASR with incident AF, adjusting for pertinent covariates. The mean age was 71.1 ± 9.2 years (313 men, 511 women). During a mean follow-up of 10.9 years, new-onset AF occurred in 105 participants (12.7%). Lower LAε and LASR at baseline were observed in patients with new-onset AF (all p <0.01). In multivariable analysis, positive longitudinal LAε (adjusted hazard ratio [HR] per SD decrease 2.05, confidence interval [CI] 1.24 to 3.36) and LASR during LA contraction (HR per SD increase 2.24, CI 1.37 to 3.65) remained associated with new-onset AF, independently of LA volumes and left ventricular function. Along with positive longitudinal LAε, reduced LASR during ventricular systole predicted AF in participants with LA volume below the median value (HR 2.54, CI 1.10 to 6.09), whereas reduced LASR during LA contraction predicted AF in participants with larger LA (HR 2.35, CI 1.31 to 4.23). In conclusion, reduced positive longitudinal LAε and LASR predict new-onset AF in older adults regardless of LA size and may improve AF risk stratification.

Subclinical Left Ventricular Dysfunction and Ventricular Arrhythmias in Older Adults With Normal Ejection Fraction.

Background Premature ventricular contractions (PVCs) and nonsustained ventricular tachycardia (NSVT) are known to be associated with reduced left ventricular (LV) ejection fraction and adverse outcomes in patients with structural heart disease. The relationship between subclinical LV dysfunction and ventricular arrhythmias in the general population is not established. Methods and Results Participants in the SAFARIS (Subclinical Atrial Fibrillation and Risk of Ischemic Stroke) study with normal left ventricular ejection fraction (n=503; mean age 77 years, 63% women) underwent 14-day electrocardiographic monitoring and 2-dimensional echocardiography. Frequent PVCs were defined as PVCs >500 per 24 hours and NSVT as ≥4 consecutive ventricular ectopic beats. Reduced LV global longitudinal strain (GLS) was used as an indicator of subclinical LV dysfunction. Seventy-six participants (15.1%) had PVCs >500/d, 117 (23.3%) had NSVT episodes. LV GLS was significantly reduced in both frequent PVCs and NSVT groups (P<0.01). In multivariable analyses, lower LV GLS was associated with frequent PVCs (adjusted odds ratio [aOR], 1.19 [95% CI, 1.09-1.30 per unit reduction]; P<0.001) and NSVT (aOR, 1.09 [95% CI, 1.01-1.17]; P=0.036) independently of established risk factors and other echocardiographic parameters. Abnormal LV GLS (>-15.8%) carried a 2-fold increase in risk of ventricular arrhythmias (aOR, 2.18, P=0.029 for PVCs; aOR, 2.09, P=0.026 for NSVT). Conclusions PVCs and NSVT episodes were frequent in this community-based elderly cohort with normal left ventricular ejection fraction and were independently associated with lower LV GLS. The association between LV dysfunction and ventricular arrhythmias is present at an early, subclinical stage, an observation that carries possible preventative implications.

Machine Learning Predicting Atrial Fibrillation as an Adverse Event in the Warfarin and Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) Trial.

BACKGROUND: Atrial fibrillation and heart failure commonly coexist due to shared pathophysiological mechanisms. Prompt identification of patients with heart failure at risk of developing atrial fibrillation would allow clinicians the opportunity to implement appropriate monitoring strategy and timely treatment, reducing the impact of atrial fibrillation on patients' health. METHODS: Four machine learning models combined with logistic regression and cluster analysis were applied post hoc to patient-level data from the Warfarin and Aspirin in Patients with Heart Failure and Sinus Rhythm (WARCEF) trial to identify factors that predict development of atrial fibrillation in patients with heart failure. RESULTS: Logistic regression showed that White divorced patients have a 1.75-fold higher risk of atrial fibrillation than White patients reporting other marital statuses. By contrast, similar analysis suggests that non-White patients who live alone have a 2.58-fold higher risk than those not living alone. Machine learning analysis also identified "marital status" and "live alone" as relevant predictors of atrial fibrillation. Apart from previously well-recognized factors, the machine learning algorithms and cluster analysis identified 2 distinct clusters, namely White and non-White ethnicities. This should serve as a reminder of the impact of social factors on health. CONCLUSION: The use of machine learning can prove useful in identifying novel cardiac risk factors. Our analysis has shown that "social factors," such as living alone, may disproportionately increase the risk of atrial fibrillation in the under-represented non-White patient group with heart failure, highlighting the need for more studies focusing on stratification of multiracial cohorts to better uncover the heterogeneity of atrial fibrillation.

Long term aortic arch plaque progression in older adults.

Background and aims: The presence of aortic arch plaques (AAP) is significantly associated with increased cardiovascular morbidity and mortality. Few studies have examined the incidence of AAP progression and factors which may contribute to it using transthoracic echocardiography (TTE). The objective of this study was to utilize sequential imaging of the aortic arch using TTE to examine the rate of AAP progression and its risk factors in a cohort of older adults. Methods: Participants enrolled in both the Cardiovascular Abnormalities and Brain Lesion study (years 2005-2010) and the Subclinical Atrial Fibrillation and Risk of Ischemic Stroke study (2014-2019) who underwent TTE with assessment of aortic arch plaques at both time points represent the study cohort. Results: 300 participants were included in the study. Mean age was 67.8 ± 7.5 years at baseline, and 76.7 ± 6.8 years at follow-up; 197 (65.7%) were women. At baseline, 87 (29%) had no significant AAP, 182 (60.7%) had evidence of small AAP (2.0-3.9 mm) and 31 (10.3%) had evidence of large (≥4 mm) AAP. At the time of follow-up assessment, 157 (52.3%) of participants exhibited progression of AAP with 70 (23.3%) having mild progression and 87 (29%) having severe progression. There were no significant demographic or clinical predictors of AAP progression except baseline plaque thickness itself which was significantly lower in the group with AAP progression. Conclusions: Our study demonstrates a high prevalence of AAP on TTE exam in a population-based cohort of older adults with a high incidence of AAP progression. TTE is a useful test for baseline and follow up imaging of AAP, even in subjects with no or little AAP at baseline.

Factors associated with the progression of aortic valve calcification in older adults.

BACKGROUND: Aortic valve calcification (AVC) is a common valvular abnormality that predisposes to stenosis; AVC progression and factors associated with it remain unclear. We investigated the association of clinical factors and serum biomarkers with AVC progression in a population-based cohort of older adults. METHODS: Participants enrolled in both the Cardiovascular Abnormalities and Brain Lesion study (CABL; years 2005-2010) and the Subclinical Atrial Fibrillation And Risk of Ischemic Stroke study (SAFARIS;2014-2019) represent the study cohort. AVC was defined as bright dense echoes >1 mm in size on ≥1 cusps; each cusp was graded on a scale of 0 (normal) to 3 (severe calcification) at baseline and follow up. Serum biomarkers were measured at the time of follow-up assessment. RESULTS: 373 participants (mean 68.1 ± 7.6 years of age, 146 M/ 227F) were included. 139 (37%) had AVC progression;93 (25%) had mild progression (1 grade), and 46 (12%) had moderate-severe progression (≥2 grades). The only significant clinical predictor of any progression was the use of anti-hypertensive medication which was associated with older age, higher BMI and more frequent hypertension, diabetes and hyperlipidemia. In multivariable analysis including biomarkers, transforming growth factor beta 1 (TGF-ß1) was significantly associated with both all and moderate-severe AVC progression. CONCLUSIONS: A significant number of elderly subjects with AVC show progression of their valve disease; individual vascular risk factors are not associated with AVC progression, although a combined effect may exist. Higher levels of TGF-ß1 are observed in individuals with AVC progression.

A spinal muscular atrophy modifier implicates the SMN protein in SNARE complex assembly at neuromuscular synapses.

Reduced survival motor neuron (SMN) protein triggers the motor neuron disease, spinal muscular atrophy (SMA). Restoring SMN prevents disease, but it is not known how neuromuscular function is preserved. We used model mice to map and identify an Hspa8G470R synaptic chaperone variant, which suppressed SMA. Expression of the variant in the severely affected mutant mice increased lifespan >10-fold, improved motor performance, and mitigated neuromuscular pathology. Mechanistically, Hspa8G470R altered SMN2 splicing and simultaneously stimulated formation of a tripartite chaperone complex, critical for synaptic homeostasis, by augmenting its interaction with other complex members. Concomitantly, synaptic vesicular SNARE complex formation, which relies on chaperone activity for sustained neuromuscular synaptic transmission, was found perturbed in SMA mice and patient-derived motor neurons and was restored in modified mutants. Identification of the Hspa8G470R SMA modifier implicates SMN in SNARE complex assembly and casts new light on how deficiency of the ubiquitous protein causes motor neuron disease.

Telemedicine is associated with reduced socioeconomic disparities in outpatient clinic no-show rates.

INTRODUCTION: The global pandemic caused by coronavirus (COVID-19) sped up the adoption of telemedicine. We aimed to assess whether factors associated with no-show differed between in-person and telemedicine visits. The focus is on understanding how social economic factors affect patient no-show for the two modalities of visits. METHODS: We utilized electronic health records data for outpatient internal medicine visits at a large urban academic medical center, from February 1, 2020 to December 31, 2020. A mixed-effect logistic regression was used. We performed stratified analysis for each modality of visit and a combined analysis with interaction terms between exposure variables and visit modality. RESULTS: A total of 111,725 visits for 72,603 patients were identified. Patient demographics (age, gender, race, income, partner), lead days, and primary insurance were significantly different between the two visit modalities. Our multivariable regression analyses showed that the impact of sociodemographic factors, such as Medicaid insurance (OR 1.23, p < 0.01 for in-person; OR 1.03, p = 0.57 for telemedicine; p < 0.01 for interaction), Medicare insurance (OR 1.11, p = 0.04 for in-person; OR 0.95, p = 0.32 for telemedicine; p = 0.03 for interaction) and Black race (OR 1.36, p < 0.01 for in-person; OR 1.20, p < 0.01 for telemedicine; p = 0.03 for interaction), on increased odds of no-show was less for telemedicine visits than for in-person visits. In addition, inclement weather and younger age had less impact on no-show for telemedicine visits. DISCUSSION: Our findings indicated that if adopted successfully, telemedicine had the potential to reduce no-show rate for vulnerable patient groups and reduce the disparity between patients from different socioeconomic backgrounds.

Association of Left Atrial Strain With Ischemic Stroke Risk in Older Adults.

Importance: The risk of ischemic stroke is higher among patients with left atrial (LA) enlargement. Left atrial strain (LAε) and LA strain rate (LASR) may indicate LA dysfunction when LA volumes are still normal. The association of LAε with incident ischemic stroke in the general population is not well established. Objective: To investigate whether LAε and LASR are associated with new-onset ischemic stroke among older adults. Design: The Cardiovascular Abnormalities and Brain Lesions study was conducted from September 29, 2005, to July 6, 2010, to investigate cardiovascular factors associated with subclinical cerebrovascular disease. A total of 806 participants in the Northern Manhattan Study who were aged 55 years or older without history of prior stroke or atrial fibrillation (AF) were included, and annual follow-up telephone interviews were completed May 22, 2022. Statistical analysis was performed from June through November 2022. Exposures: Left atrial strain and LASR were assessed by speckle-tracking echocardiography. Global peak positive longitudinal LAε and positive longitudinal LASR during ventricular systole, global peak negative longitudinal LASR during early ventricular diastole, and global peak negative longitudinal LASR during LA contraction were measured. Brain magnetic resonance imaging was used to detect silent brain infarcts and white matter hyperintensities at baseline. Main Outcomes and Measures: Risk analysis with cause-specific Cox proportional hazards regression modeling was used to assess the association of positive longitudinal LAε and positive longitudinal LASR with incident ischemic stroke, adjusting for other stroke risk factors, including incident AF. Results: The study included 806 participants (501 women [62.2%]) with a mean (SD) age of 71.0 (9.2) years; 119 participants (14.8%) were Black, 567 (70.3%) were Hispanic, and 105 (13.0%) were White. During a mean (SD) follow-up of 10.9 (3.7) years, new-onset ischemic stroke occurred in 53 participants (6.6%); incident AF was observed in 103 participants (12.8%). Compared with individuals who did not develop ischemic stroke, participants with ischemic stroke had lower positive longitudinal LAε and negative longitudinal LASR at baseline. In multivariable analysis, the lowest (ie, closest to zero) vs all other quintiles of positive longitudinal LAε (adjusted hazard ratio [HR], 3.12; 95% CI, 1.56-6.24) and negative longitudinal LASR during LA contraction (HR, 2.89; 95% CI, 1.44-5.80) were associated with incident ischemic stroke, independent of left ventricular global longitudinal strain and incident AF. Among participants with a normal LA size, the lowest vs all other quintiles of positive longitudinal LAε (HR, 4.64; 95% CI, 1.55-13.89) and negative longitudinal LASR during LA contraction (HR, 11.02; 95% CI 3.51-34.62) remained independently associated with incident ischemic stroke. Conclusions and Relevance: This cohort study suggests that reduced positive longitudinal LAε and negative longitudinal LASR are independently associated with ischemic stroke in older adults. Assessment of LAε and LASR by speckle-tracking echocardiography may improve stroke risk stratification in elderly individuals.

Identification of a tomato UDP-arabinosyltransferase for airborne volatile reception.

Volatiles from herbivore-infested plants function as a chemical warning of future herbivory for neighboring plants. (Z)-3-Hexenol emitted from tomato plants infested by common cutworms is taken up by uninfested plants and converted to (Z)-3-hexenyl ß-vicianoside (HexVic). Here we show that a wild tomato species (Solanum pennellii) shows limited HexVic accumulation compared to a domesticated tomato species (Solanum lycopersicum) after (Z)-3-hexenol exposure. Common cutworms grow better on an introgression line containing an S. pennellii chromosome 11 segment that impairs HexVic accumulation, suggesting that (Z)-3-hexenol diglycosylation is involved in the defense of tomato against herbivory. We finally reveal that HexVic accumulation is genetically associated with a uridine diphosphate-glycosyltransferase (UGT) gene cluster that harbors UGT91R1 on chromosome 11. Biochemical and transgenic analyses of UGT91R1 show that it preferentially catalyzes (Z)-3-hexenyl ß-D-glucopyranoside arabinosylation to produce HexVic in planta.

Epicardial fat accumulation and left heart remodelling in patients with chronic coronary syndrome.

Aims: Patients with chronic coronary syndrome (CCS) suffer from subsequent cardiovascular events, even after complete revascularization; thus, elucidation of the underlying pathophysiological mechanisms is required. Epicardial adipose tissue (EAT) is increasingly recognized as a metabolically active organ with a key role in the pathogenesis of metabolic-related cardiac diseases. The present study investigated the association between EAT burden and left heart remodelling in patients with CCS. Methods and results: We studied 267 CCS patients (210 men; 71 ± 9 years) with complete revascularization and normal left ventricular (LV) ejection fraction who underwent follow-up echocardiography. All patients underwent the measurement of EAT thickness and speckle-tracking analysis to evaluate LV global longitudinal strain (LVGLS) and left atrial (LA) phasic strain. The mean EAT thickness was 5.0 ± 1.8 mm. Age, sex, body mass index, and diabetes mellitus were independently associated with EAT thickness (all P < 0.05). Multivariable linear regression analysis demonstrated that EAT thickness was significantly associated with LV mass index, early diastolic mitral annular velocity, and LA conduit strain independent of age, sex, and cardiovascular risk factors (all P < 0.05). On the other hand, there was no relationship between EAT thickness and LV systolic parameters including LV ejection fraction and LVGLS. Conclusion: CCS patients with increased EAT thickness had unfavourable left heart remodelling. The assessment of EAT thickness by echocardiography may have clinical utility as a simple surrogate to aid in risk stratification for impaired left heart function in CCS patients.

Prevalence, Determinants, and Prognostic Value of Left Atrial Dysfunction in Patients With Chronic Coronary Syndrome and Normal Left Ventricular Ejection Fraction.

Patients with chronic coronary syndrome (CCS), even when they have complete revascularization and normal left ventricular (LV) systolic function, experience subsequent cardiovascular disease (CVD), highlighting the importance of surrogate markers to prevent adverse consequences. Speckle-tracking echocardiography-derived left atrial (LA) reservoir strain has emerged as a sensitive marker for CVD in various clinical settings. The present study investigated the prevalence, determinants, and prognostic value of LA dysfunction in CCS. We included 278 consecutive patients with CCS with completed percutaneous coronary intervention and preserved LV ejection fraction who underwent follow-up echocardiography. Speckle-tracking analysis was performed to assess LA reservoir strain, and LA dysfunction was defined as LA reservoir strain ≤24%. The primary outcome comprised new-onset atrial fibrillation, heart failure hospitalization, acute coronary syndrome, stroke, or all-cause death. At baseline, 28 patients (10.1%) had LA dysfunction. Multivariable analysis identified age, hypertension, LV ejection fraction, and multivessel disease as independent determinants of LA reservoir strain (all p <0.05). During a median follow-up of 4.8 years, the primary outcome occurred in 60 patients (21.6%). LA dysfunction carried a significant risk for primary outcome independent of traditional risk factors, LV parameters, and LA size (adjusted hazard ratio 3.10, p = 0.003); the risk increase remained significant even after excluding atrial fibrillation from the primary outcome (adjusted hazard ratio 2.27, p = 0.043). In conclusion, approximately 10% of patients with CCS with normal LV ejection fraction had LA dysfunction associated with adverse cardiovascular outcomes. Further studies are needed to explore whether therapeutic interventions affecting LA remodeling may help prevent CVD events.

Subclinical left ventricular systolic dysfunction and incident stroke in the elderly: long-term findings from Cardiovascular Abnormalities and Brain Lesions.

AIMS: Heart disease is associated with an increased risk for ischaemic stroke. However, the predictive value of reduced left ventricular ejection fraction (LVEF) for stroke is controversial and only observed in patients with severe reduction. LV global longitudinal strain (LV GLS) can detect subclinical LV systolic impairment when LVEF is normal. We investigated the prognostic role of LV GLS for incident stroke in a predominantly elderly cohort. METHODS AND RESULTS: Two-dimensional echocardiography with speckle tracking was performed in the Cardiac Abnormalities and Brain Lesions (CABL) study. Among 708 stroke-free participants (mean age 71.4 ± 9.4 years, 60.9% women), abnormal LV GLS (>-14.7%: 95% percentile of the subgroup without risk factors) was detected in 133 (18.8%). During a mean follow-up of 10.8 ± 3.9 years, 47 participants (6.6%) experienced an ischaemic stroke (26 cardioembolic or cryptogenic, 21 other subtypes). The cumulative incidence of ischaemic stroke was significantly higher in participants with abnormal LV GLS than with normal LV GLS (P < 0.001). In multivariate stepwise logistic regression analysis, abnormal LV GLS was associated with ischaemic stroke independently of cardiovascular risk factors including LVEF, LV mass, left atrial volume, subclinical cerebrovascular disease at baseline, and incident atrial fibrillation [hazard ratio (HR): 2.69, 95% confidence interval (CI): 1.47-4.92; P = 0.001]. Abnormal LV GLS independently predicted cardioembolic or cryptogenic stroke (adjusted HR: 3.57, 95% CI: 1.51-8.43; P = 0.004) but not other subtypes. CONCLUSION: LV GLS was a strong independent predictor of ischaemic stroke in a predominantly elderly stroke-free cohort. Our findings provide insights into the brain-heart interaction and may help improve stroke primary prevention strategies.

Aortic valve sclerosis and subclinical LV dysfunction in the general population with normal LV geometry.

AIMS: Aortic valve sclerosis (AVS) without hemodynamically significant obstruction is related to cardiovascular morbidity and mortality independent of left ventricular (LV) hypertrophy, although the underlying mechanisms remain unknown. This study investigated the prevalence of AVS and its association with subclinical LV systolic and diastolic dysfunction in individuals with normal LV geometry free of cardiovascular disease. METHODS: We examined 962 participants with normal LV geometry and free from significant AV stenosis who underwent standard and speckle-tracking echocardiography. AVS was categorized into 4 groups as follows: no AVS, AV thickening, calcification on one leaflet and calcification on ≥2 leaflets. RESULTS: Among the 962 participants, 767 (79.7%) individuals were classified as no AVS, 74 (7.7%) as AV thickening, 87 (9.0%) as calcification on one leaflet, and 34 (3.5%) as calcification on ≥2 leaflets. The prevalence of subclinical LV diastolic dysfunction (E/e' ratio ≥13) and systolic dysfunction (LV global longitudinal strain (GLS) > -17.0% for men and > -18.0% for women) were greater in AVS groups than those in no AVS group. Subclinical LV diastolic impairment was evident from AV thickening and systolic dysfunction was observed at AV calcification. Multivariable logistic regression analysis demonstrated that AV thickening as well as calcification were independently associated with subclinical LV diastolic impairment (all p < 0.05), while only AV calcification on ≥2 leaflets conferred significant increased risk of impaired LVGLS. CONCLUSIONS: AVS was observed in approximately 20% individuals without cardiac disease and was associated with subclinical LV diastolic and systolic function even in the absence of LV morphological change.

We investigated the prevalence of aortic valve sclerosis (AVS) and its association with subclinical left ventricular (LV) systolic and diastolic dysfunction in 962individuals with normal LV geometry free of cardiac disease. In this study population, AVS characterized by thickening or calcification was present in 20% of individuals. Subclinical LV diastolic dysfunction appeared from AV thickening and systolic dysfunction by LV global longitudinal strain was observed at calcification on ≥2 leaflets; these associations were independent of age, sex and cardiovascular risk factors.

Association of arterial properties with left ventricular morphology and function in the community.

OBJECTIVES: Arterial structural and functional remodeling is recognized as a key determinant of incident heart failure, although the contribution of arterial properties on left ventricular (LV) remodeling is not fully studied. Aortic dilatation is an early manifestation of arterial remodeling and estimated pulse wave velocity (ePWV) is emerging as a simple measure of arterial stiffness. This study aimed to characterize the association of aortic size and ePWV with LV morphology and function. METHODS: The study cohort consisted of 539 participants without overt cardiac disease who underwent extensive cardiovascular examination. Aortic root diameter was measured by two-dimensional echocardiography and ePWV was calculated from a regression equation using age and mean blood pressure. LV global longitudinal strain (LVGLS) was obtained by speckle-tracking echocardiography. RESULTS: Aortic root diameter and ePWV were correlated with LV mass index and LVGLS, while only ePWV was related to E / e' ratio. In multivariable analysis, aortic root diameter and ePWV were significantly related to LV mass index and LVGLS (all P  < 0.05), and the association of aortic root size and ePWV with LVGLS was independent of LV mass index and E / e' ratio. Individuals with both aortic root enlargement and increased ePWV had significantly larger LV mass index and reduced LVGLS compared with those either or those with normal aortic size and ePWV (both P  < 0.05). CONCLUSION: Aortic root size and ePWV were independently associated with unfavorable LV remodeling in individuals free of cardiac disease, which might provide useful information into the pathogenesis-linking arterial remodeling and heart failure.