Chromosome 10q24.32 Variants Associate With Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

BACKGROUND: Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown. METHODS AND RESULTS: The authors studied 4150 participants from 6 geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome-wide association study revealed 14 variants at one locus associated with global BAD at genome-wide significance (P<5×10-8) (top single-nucleotide polymorphism, rs7921574; ß=0.06 [P=1.54×10-8]). This locus mapped to an intron of CNNM2. A trans-ancestry genome-wide association study meta-analysis identified 2 more loci at NT5C2 (rs10748839; P=2.54×10-8) and AS3MT (rs10786721; P=4.97×10-8), associated with global BAD. In addition, 2 single-nucleotide polymorphisms colocalized with expression of CNNM2 (rs7897654; ß=0.12 [P=6.17×10-7]) and AL356608.1 (rs10786719; ß=-0.17 [P=6.60×10-6]) in brain tissue. For the posterior BAD, 2 variants at one locus mapped to an intron of TCF25 were identified (top single-nucleotide polymorphism, rs35994878; ß=0.11 [P=2.94×10-8]). For the anterior BAD, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10-8). CONCLUSIONS: The current study reveals 3 novel risk loci (CNNM2, NT5C2, and AS3MT) associated with BADs. These findings may help elucidate the mechanism by which BADs may influence cerebrovascular health.

Association of brain arterial diameters with demographic and anatomical factors in a multi-national pooled analysis of cohort studies.

BACKGROUND AND PURPOSE: Brain arterial diameters are markers of cerebrovascular disease. Demographic and anatomical factors may influence arterial diameters. We hypothesize that age, sex, height, total cranial volume (TCV), and persistent fetal posterior cerebral artery (fPCA) correlate with brain arterial diameters across populations. METHODS: Participants had a time-of-flight MRA from nine international cohorts. Arterial diameters of the cavernous internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery (BA) were measured using LAVA software. Regression models assessed the association between exposures and brain arterial diameters. RESULTS: We included 6,518 participants (mean age: 70 ± 9 years; 41% men). Unilateral fPCA was present in 13.2% and bilateral in 3.2%. Larger ICA, MCA, and BA diameters correlated with older age (Weighted average [WA] per 10 years: 0.18 mm, 0.11 mm, and 0.12 mm), male sex (WA: 0.24 mm, 0.13 mm, and 0.21 mm), and TCV (WA: for one TCV standard deviation: 0.24 mm, 0.29 mm, and 0.18 mm). Unilateral and bilateral fPCAs showed a positive correlation with ICA diameters (WA: 0.39 mm and 0.73 mm) and negative correlation with BA diameters (WA: -0.88 mm and -1.73 mm). Regression models including age, sex, TCV, and fPCA explained on average 15%, 13%, and 25% of the ICA, MCA, and BA diameter interindividual variation, respectively. Using height instead of TCV as a surrogate of head size decreased the R-squared by 3% on average. CONCLUSION: Brain arterial diameters correlated with age, sex, TCV, and fPCA. These factors should be considered when defining abnormal diameter cutoffs across populations.

Mediterranean-style diet and intracranial large artery stenosis in the Northern Manhattan Study.

OBJECTIVES: Given Mediterranean-style diet (MeDi) reduces risk of cardiovascular events, we hypothesized MeDi may also be protective against intracranial large artery stenosis (ICAS), a common cause of stroke worldwide. METHODS: This cross-sectional study included stroke-free participants of the Northern Manhattan Study, a diverse population-based study of stroke risk factors. We represented MeDi continuously (range 0-8) based on enrollment food frequency questionnaires, excluding alcohol consumption. We evaluated ICAS both dichotomously at clinically relevant stenosis severities and continuously as a score (possible range 0-44), summated from stenosis severity scores of major intracranial arteries from time-of-flight magnetic resonance angiography. We used logistic or zero-inflated Poisson regression, adjusting for key confounders. RESULTS: Among 912 included participants (mean age 64±8 years, 59% female, 65% Hispanic, mean MeDi score 4±1.5), 5% and 8% of participants had ≥50% or ≥70% ICAS, respectively (score median [interquartile range]: 0 [0-2]). Increased MeDi score was inversely associated with ICAS, but did not reach statistical significance (≥50% stenosis odds ratio (OR) [95% confidence interval (CI)]: 0.89 [0.79-1.06]; ≥70% stenosis OR [95% CI]: 0.91 [0.74-1.13]; stenosis score ß-estimate [95% CI]: -0.02 [-0.06-0.01]). CONCLUSION: In this stroke-free subsample, we did not find a significant association between MeDi and ICAS. We may have been limited by statistical power.

Deep resequencing of the 1q22 locus in non-lobar intracerebral hemorrhage.

Objective: Genome-wide association studies have identified 1q22 as a susceptibility locus for cerebral small vessel diseases (CSVDs), including non-lobar intracerebral hemorrhage (ICH) and lacunar stroke. In the present study we performed targeted high-depth sequencing of 1q22 in ICH cases and controls to further characterize this locus and prioritize potential causal mechanisms, which remain unknown. Methods: 95,000 base pairs spanning 1q22 , including SEMA4A, SLC25A44 and PMF1 / PMF1-BGLAP were sequenced in 1,055 spontaneous ICH cases (534 lobar and 521 non-lobar) and 1,078 controls. Firth regression and RIFT analysis were used to analyze common and rare variants, respectively. Chromatin interaction analyses were performed using Hi-C, ChIP-Seq and ChIA-PET databases. Multivariable Mendelian randomization (MVMR) assessed whether alterations in gene-specific expression relative to regionally co-expressed genes at 1q22 could be causally related to ICH risk. Results: Common and rare variant analyses prioritized variants in SEMA4A 5'-UTR and PMF1 intronic regions, overlapping with active promoter and enhancer regions based on ENCODE annotation. Hi-C data analysis determined that 1q22 is spatially organized in a single chromatin loop and that the genes therein belong to the same Topologically Associating Domain. ChIP-Seq and ChIA-PET data analysis highlighted the presence of long-range interactions between the SEMA4A -promoter and PMF1 -enhancer regions prioritized by association testing. MVMR analyses demonstrated that PMF1 overexpression could be causally related to non-lobar ICH risk. Interpretation: Altered promoter-enhancer interactions leading to PMF1 overexpression, potentially dysregulating polyamine catabolism, could explain demonstrated associations with non-lobar ICH risk at 1q22 , offering a potential new target for prevention of ICH and CSVD.

Chromosome 10q24.32 Variants Associate with Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

Background: Brain arterial diameters are novel imaging biomarkers of cerebrovascular disease, cognitive decline and dementia. Traditional vascular risk factors have been associated with brain arterial diameters but whether there may be genetic determinants of brain arterial diameters is unknown. Results: We studied 4150 participants from six geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). We measured brain arterial diameters for 13 segments and averaged them to obtain a global measure of brain arterial diameters as well as the posterior and anterior circulations. A genome-wide association study (GWAS) revealed 14 variants at one locus associated with global brain arterial diameter at genome-wide significance (P<5×10-8) (top SNP, rs7921574; ß =0.06, P=1.54×10-8). This locus mapped to an intron of CNNM2. A trans-ancestry GWAS meta-analysis identified two more loci at NT5C2 (rs10748839; P=2.54×10-8) and at AS3MT (rs10786721; P=4.97×10-8), associated with global brain arterial diameter. In addition, two SNPs co-localized with expression of CNNM2 (rs7897654, ß=0.12, P=6.17×10-7) and AL356608.1 (rs10786719, ß =-0.17, P=6.60×10-6) in brain tissue. For the posterior brain arterial diameter, two variants at one locus mapped to an intron of TCF25 were identified (top SNP, rs35994878; ß =0.11, P=2.94×10-8). For the anterior brain arterial diameter, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10-8). Conclusion: Our study reveals three novel risk loci (CNNM2, NT5C2 and AS3MT) associated with brain arterial diameters. Our finding may elucidate the mechanisms by which brain arterial diameters influence the risk of stroke and dementia.

Gut permeability and cognitive decline: A pilot investigation in the Northern Manhattan Study.

BACKGROUND: Gut microbiota may impact cognitive function and decline, though data are limited. This pilot study examines the associations between gut dysbiosis products, plasma lipopolysaccharide (LPS) and soluble CD14 (sCD14), with cognitive decline and immune molecule activation among 40 participants in the longitudinal population-based Northern Manhattan Study. METHODS: We selected stroke- and dementia-free participants at baseline with high activation levels of core components of the immune signaling pathways underlying microbiota metabolite-cognitive associations (IL-1, IL-17, TNF). Participants were followed with up to three complete neuropsychological assessments, at least 5 years apart. RESULTS: Elevated sCD14 was associated with high levels of IL-1 pathway activation (p < 0.05), whereas in samples where only those molecules within the IL-17 and TNF pathways were increased, LPS and sCD14 levels were not elevated. LPS was associated with decline in global cognitive performance over 2-3 assessments (adjusted ß = -0.023 per SD per year, 95% CI:-0.036, -0.010). The association between sCD14 and cognitive decline was marginal (adjusted ß = -0.018 per SD per year, 95% CI:-0.040, 0.004). CONCLUSIONS: These preliminary data support the hypothesis that gut dysbiosis leads to systemic and neuro-inflammation, and subsequently cognitive decline. Further large targeted and untargeted gut microbiota-derived metabolomic studies are needed.

Lacunar stroke: mechanisms and therapeutic implications.

Lacunar stroke is a marker of cerebral small vessel disease and accounts for up to 25% of ischaemic stroke. In this narrative review, we provide an overview of potential lacunar stroke mechanisms and discuss therapeutic implications based on the underlying mechanism. For this paper, we reviewed the literature from important studies (randomised trials, exploratory comparative studies and case series) on lacunar stroke patients with a focus on more recent studies highlighting mechanisms and stroke prevention strategies in patients with lacunar stroke. These studies suggest that lacunar stroke is a heterogeneous disease with various mechanisms, including most commonly lipohyalinosis and less commonly atheromatous disease and cardioembolism, highlighting the importance of a careful review of brain and neurovascular imaging, a cardiac and systemic evaluation. A better understanding of pathomechanisms of neurological deterioration may lead to investigating the utility of novel treatment strategies and optimisation of short-term antithrombotic treatment strategies to reduce the risk of neurological deterioration and prevent long-term disability in patients with lacunar stroke.

Influenza-Like Illness is Associated with Increased Short-Term Risk of Cervical Artery Dissection.

INTRODUCTION: Non-traumatic Cervical Artery Dissection (CeAD) is a leading cause of ischemic stroke in the young. Influenza-like illnesses (ILI) trigger ischemic strokes. We hypothesized that influenza and ILI are associated with CeAD. METHODS: In a case-crossover study within the New York State (NYS) Department of Health Statewide Planning and Research Cooperative System (2006-2014), we used ICD-9 codes to exclude major trauma and to define CeAD, influenza, and the Centers for Disease Control defined ILI. We estimated the association of ILI and influenza with CeAD by comparing their prevalence in intervals immediately prior (0-30,0-90,0-180, and 0-365 days) to CeAD (case period) to their prevalence exactly one and two years earlier (control periods). Conditional logistic regression models generated odds ratios and 95% confidence intervals (OR, 95% CI). Models were adjusted for NYS estimates of influenza prevalence rates. RESULTS: Our sample included 3,610 cases of CeAD (mean age 52±16 years, 54.7% male, 6.2% Hispanic, 9.9% Black, 68.7% White). During case periods, 7.3% had one or more ILI. ILI was more likely within 90 days of CeAD compared to the same time interval one and two years before (0-15 days: adjusted OR 1.88, 95%CI 1.20-2.94; 0-30 days: adjusted OR 1.74, 95%CI 1.22-2.46; 0-90 days: adjusted OR 1.35, 95%CI 1.00-1.81). Influenza trended with CeAD (adjusted OR 1.86, 95%CI 0.37-9.24), but these results were not statistically significant, due to limited instances of confirmed influenza. CONCLUSIONS: ILI may increase risk of CeAD for 15 days, and possibly up to three months.

Preceding infection and risk of stroke: An old concept revived by the COVID-19 pandemic.

Anecdotal reports and clinical observations have recently emerged suggesting a relationship between COVID-19 disease and stroke, highlighting the possibility that infected individuals may be more susceptible to cerebrovascular events. In this review we draw on emerging studies of the current pandemic and data from earlier, viral epidemics, to describe possible mechanisms by which SARS-CoV-2 may influence the prevalence of stroke, with a focus on the thromboinflammatory pathways, which may be perturbed. Some of these potential mechanisms are not novel but are, in fact, long-standing hypotheses linking stroke with preceding infection that are yet to be confirmed. The current pandemic may present a renewed opportunity to better understand the relationship between infection and stroke and possible underlying mechanisms.

Are patients afraid to go home? Disposition preferences after transient ischaemic attack and minor stroke.

BACKGROUND: Recent evidence suggests clinical equipoise for managing transient ischaemic attack and minor stroke (TIAMS) either via discharge from the emergency department (ED) with rapid outpatient follow-up or inpatient admission. Understanding patient preferences may guide decision-making around disposition after TIAMS that can lead to higher patient satisfaction and adherence. Psychological distress, particularly a sense of vulnerability (eg, 'threat perception') is associated with adverse psychological outcomes following TIAMS and may influence patient disposition preference. We hypothesised patients with higher threat perceptions in the ED would prefer inpatient admission versus early discharge with rapid outpatient follow-up. METHODS: This was a planned secondary analysis of a prospective observational cohort study of ED patients with suspected TIAMS (defined as National Institutes of Health Stroke Scale (NIHSS) score of ≤5). Patients reported disposition preferences and completed a validated scale of threat perception while in the ED (score range: 1-4). RESULTS: 147 TIAMS patients were evaluated (mean age: 59.7±15.4, 45.6% female, 39.5% Hispanic, median NIHSS=1, IQR: 0, 3). A majority of patients (98, 66.7%) preferred inpatient admission compared with discharge from the ED. Overall threat scores were median 1.0 (IQR: 0.43, 1.68). Those preferring admission had similar threat scores compared with those who preferred early disposition (median: 1.00, IQR: 0.43, 1.57) versus 1.00, (IQR: 0.49, 1.68); p=0.40). In a model adjusted for demographic characteristics, threat perceptions remained unassociated with disposition preference. CONCLUSION: Overall, two-thirds of TIAMS patients preferred inpatient admission over discharge. Disposition preference was not associated with higher threat perception in the ED. Further research examining potential drivers of patient disposition preferences may inform patient discussions and optimise patient satisfaction.

The AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke randomized trial: Rationale and methods.

RATIONALE: Recent data suggest that a thrombogenic atrial substrate can cause stroke in the absence of atrial fibrillation. Such an atrial cardiopathy may explain some proportion of cryptogenic strokes. AIMS: The aim of the ARCADIA trial is to test the hypothesis that apixaban is superior to aspirin for the prevention of recurrent stroke in subjects with cryptogenic ischemic stroke and atrial cardiopathy. SAMPLE SIZE ESTIMATE: 1100 participants. METHODS AND DESIGN: Biomarker-driven, randomized, double-blind, active-control, phase 3 clinical trial conducted at 120 U.S. centers participating in NIH StrokeNet. POPULATION STUDIED: Patients ≥ 45 years of age with embolic stroke of undetermined source and evidence of atrial cardiopathy, defined as ≥ 1 of the following markers: P-wave terminal force >5000 µV × ms in ECG lead V1, serum NT-proBNP > 250 pg/mL, and left atrial diameter index ≥ 3 cm/m2 on echocardiogram. Exclusion criteria include any atrial fibrillation, a definite indication or contraindication to antiplatelet or anticoagulant therapy, or a clinically significant bleeding diathesis. Intervention: Apixaban 5 mg twice daily versus aspirin 81 mg once daily. Analysis: Survival analysis and the log-rank test will be used to compare treatment groups according to the intention-to-treat principle, including participants who require open-label anticoagulation for newly detected atrial fibrillation. STUDY OUTCOMES: The primary efficacy outcome is recurrent stroke of any type. The primary safety outcomes are symptomatic intracranial hemorrhage and major hemorrhage other than intracranial hemorrhage. DISCUSSION: ARCADIA is the first trial to test whether anticoagulant therapy reduces stroke recurrence in patients with atrial cardiopathy but no known atrial fibrillation.

Perfusion imaging and recurrent cerebrovascular events in intracranial atherosclerotic disease or carotid occlusion.

Background Large vessel disease stroke subtype carries the highest risk of early recurrent stroke. In this study we aim to look at the association between impaired perfusion and early stroke recurrence in patients with intracranial atherosclerotic disease or total cervical carotid occlusion. Methods This is a retrospective study from a comprehensive stroke center where we included consecutive patients 18 years or older with intracranial atherosclerotic disease or total cervical carotid occlusion admitted with a diagnosis of ischemic stroke within 24 h from symptom onset with National Institute Health Stroke Scale < 15, between 1 December 2016 and 30 June 2017. Patients with (1) evidence of ≥ 50% stenosis of a large intracranial artery or total carotid artery occlusion, (2) symptoms referable to the territory of the affected artery, and (3) perfusion imaging data using the RAPID processing software were included. The primary predictor was unfavorable perfusion imaging defined as Tmax > 6 s mismatch volume (penumbra volume-infarct volume) of 15 ml or more. The outcome was recurrent cerebrovascular events at 90 days defined as worsening or new neurological symptoms in the absence of a nonvascular cause attributable to the decline, or new infarct or infarct extension in the territory of the affected artery. We used Cox proportional hazards models to determine the association between impaired perfusion and recurrent cerebrovascular events. Results Sixty-two patients met our inclusion criteria; mean age 66.4 ± 13.1 years, 64.5% male (40/62) and 50.0% (31/62) with intracranial atherosclerotic disease. When compared to patients with favorable perfusion pattern, patients with unfavorable perfusion pattern were more likely to have recurrent cerebrovascular events (55.6% (10/18) versus 9.1% (4/44), p < 0.001). This association persisted after adjusting for potential confounders (adjusted hazard ratio 10.44, 95% confidence interval 2.30-47.42, p = 0.002). Conclusion Perfusion mismatch predicts recurrent cerebrovascular events in patients with ischemic stroke due to intracranial atherosclerotic disease or total cervical carotid occlusion. Studies are needed to determine the utility of revascularization strategies in this patient population.

C-reactive protein is associated with disability independently of vascular events: the Northern Manhattan Study.

Background: High-sensitivity C-reactive protein (CRP) has been associated with cardiovascular events and mortality, but the association of CRP with functional status is not well defined. We hypothesised that serum levels of high-sensitivity CRP are associated with long-term trajectories of functional status independently of vascular risk factors and stroke and myocardial infarction (MI) occurring during follow-up. Design: Prospective, population-based. Setting: Northern Manhattan Study. Participants: Stroke-free participants aged ≥40 years. Measurements: Annual assessments of disability with the Barthel index (BI) for a median of 13 years. BI was analysed as a continuous variable (range 0­100). Baseline demographics, risk factors and laboratory studies were collected, including CRP (n = 2,240). Separate generalised estimating equation models estimated standardised associations between CRP and (i) baseline functional status and (ii) change in function over time, adjusting for demographics, vascular risk factors, social variables, cognition, and depression measured at baseline, and stroke and MI occurring during follow-up. Results: Mean age was 69 (SD 10) years, 36% were male, 55% Hispanic, 75% hypertensive and 21% diabetic; 337 MIs and 369 first strokes occurred during follow-up. Mean CRP level was 5.24 mg/l (SD 8.86). logCRP was associated with baseline BI (−0.34 BI points per unit logCRP, 95% confidence interval −0.62, −0.06) but not with change over time. Conclusions: In this large population-based study, higher serum CRP levels were associated with higher baseline disability, even when adjusting for baseline covariates and stroke and MI occurring during follow-up. Systemic inflammation may contribute to disability independently of clinical vascular events.

Physical inactivity is a strong risk factor for stroke in the oldest old: Findings from a multi-ethnic population (the Northern Manhattan Study).

Background The fastest growing segment of the population is those age ≥80 who have the highest stroke incidence. Risk factor management is complicated by polypharmacy-related adverse events. Aims To characterize the impact of physical inactivity for stroke by age in a multi-ethnic prospective cohort study (NOMAS, n = 3298). Methods Leisure time physical activity was assessed by a validated questionnaire and our primary exposure was physical inactivity (PI). Participants were followed annually for incident stroke. We fit Cox-proportional hazard models to calculate hazard ratios and 95% confidence intervals (HR 95% CI) for the association of PI and other risk factors with risk of stroke including two-way interaction terms between the primary exposures and age (<80 vs. ≥80). Results The mean age was 69 ± 10.3 years and 562 (17%) were ≥80 at enrolment. PI was common in the cohort (40.8%). Over a median of 14 years, we found 391 strokes. We found a significant interaction of age ≥80 on the risk of stroke with PI ( p = 0.03). In stratified models, PI versus any activity (adjusted HR 1.60, 95%CI 1.05-2.42) was associated with an increased risk of stroke among those ≥80. Conclusion Physical inactivity is a treatable risk factor for stroke among those older than age 80. Improving activity may reduce the risk of stroke in this segment of the population.

Association of chronic kidney disease with impaired left atrial reservoir function: A community-based cohort study.

Background Chronic kidney disease (CKD) is an independent risk factor for atrial fibrillation, although the pathophysiological mechanisms remain unclear. This study investigated the relationship between CKD and left atrial (LA) volume and function in a sample of the general population without overt cardiac disease. Design and methods We examined 358 participants from the Cardiovascular Abnormalities and Brain Lesions study. The LA minimum volume index (LAVImin), LA maximum volume index (LAVImax), and LA emptying fraction (LAEF) were assessed by real-time three-dimensional echocardiography. Based on their estimated glomerular filtration rate (eGFR), the participants were divided into a CKD group (eGFR <60 ml/min/1.73 m2) and a non-CKD group (eGFR ≥60 ml/min/1.73 m2). Results Of the 358 participants, 69 (19%) were classified as having CKD and 289 (81%) as non-CKD. Participants with CKD were older, had a greater prevalence of hypertension and use of antihypertensive drugs, a larger left ventricular (LV) mass index, and a higher prevalence of diastolic dysfunction than those without CKD (all p < 0.05). There was no significant difference in LAVImax between the CKD and non-CKD groups (23.4 ± 7.1 vs. 22.8 ± 5.8 ml/m2, p = 0.47), whereas significant differences were observed for LAVImin (13.6 ± 5.5 vs. 12.0 ± 4.6 ml/m2, p = 0.01) and LAEF (42.7 ± 11.4 vs. 47.8 ± 11.5%, p = 0.001). Multivariate regression analysis revealed that the eGFR was significantly associated with LAEF independent of age, LV mass index, and diastolic dysfunction (all p < 0.05). Conclusions Participants with CKD in an unselected community-based cohort had significantly impaired LA reservoir function. Assessment of LA function may add important information in the prognostic assessment of patients with CKD even in the absence of overt cardiac disease.

Arterial wave reflection and subclinical left ventricular systolic dysfunction.

OBJECTIVES: Increased arterial wave reflection is a predictor of cardiovascular events and has been hypothesized to be a cofactor in the pathophysiology of heart failure. Whether increased wave reflection is inversely associated with left-ventricular (LV) systolic function in individuals without heart failure is not clear. METHODS: Arterial wave reflection and LV systolic function were assessed in 301 participants from the Cardiovascular Abnormalities and Brain Lesions (CABL) study using two-dimensional echocardiography and applanation tonometry of the radial artery to derive central arterial waveform by a validated transfer function. Aortic augmentation index (AIx) and wasted energy index (WEi) were used as indices of wave reflection. LV systolic function was measured by LV ejection fraction (LVEF) and tissue Doppler imaging (TDI). Mitral annulus peak systolic velocity (Sm), peak longitudinal strain and strain rate were measured. Participants with history of coronary artery disease, atrial fibrillation, LVEF less than 50% or wall motion abnormalities were excluded. RESULTS: Mean age of the study population was 68.3 ± 10.2 years (64.1% women, 65% hypertensive). LV systolic function by TDI was lower with increasing wave reflection, whereas LVEF was not. In multivariate analysis, TDI parameters of LV longitudinal systolic function were significantly and inversely correlated to AIx and WEi (P values from 0.05 to 0.002). CONCLUSIONS: In a community cohort without heart failure and with normal LVEF, an increased arterial wave reflection was associated with subclinical reduction in LV systolic function assessed by novel TDI techniques. Further studies are needed to investigate the prognostic implications of this relationship.