First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-962212, a direct, reversible, small molecule factor XIa inhibitor in non-Japanese and Japanese healthy subjects.

AIMS: The aims of the present study were to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of BMS-962212, a first-in-class factor XIa inhibitor, in Japanese and non-Japanese healthy subjects. METHODS: This was a randomized, placebo-controlled, double-blind, sequential, ascending-dose study of 2-h (part A) and 5-day (part B) intravenous (IV) infusions of BMS-962212. Part A used four doses (1.5, 4, 10 and 25 mg h-1 ) of BMS-962212 or placebo in a 6:2 ratio per dose. Part B used four doses (1, 3, 9 and 20 mg h-1 ) enrolling Japanese (n = 4 active, n = 1 placebo) and non-Japanese (n = 4 active, n = 1 placebo) subjects per dose. The PK, PD, safety and tolerability were assessed throughout the study. RESULTS: BMS-962212 was well tolerated; there were no signs of bleeding, and adverse events were mild. In parts A and B, BMS-962212 demonstrated dose proportionality. The mean half-life in parts A and B ranged from 2.04 to 4.94 h and 6.22 to 8.65 h, respectively. Exposure-dependent changes were observed in the PD parameters, activated partial thromboplastin time (aPTT) and factor XI clotting activity (FXI:C). The maximum mean aPTT and FXI:C change from baseline at 20 mg h-1 in part B was 92% and 90%, respectively. No difference was observed in weight-corrected steady-state concentrations, aPTT or FXI:C between Japanese and non-Japanese subjects (P > 0.05). CONCLUSION: BMS-962212 has tolerability, PK and PD properties suitable for investigational use as an acute antithrombotic agent in Japanese or non-Japanese subjects.

Association of anti-citrullinated protein or peptide antibodies with left ventricular structure and function in rheumatoid arthritis.

Objective: High levels of ACPAs in RA are associated with more severe arthritis and worse prognosis. However, the role of ACPAs in mediating the increased risk of heart failure in RA remains undefined. We examined whether specific ACPAs were associated with subclinical left ventricular (LV) phenotypes that presage heart failure. Methods: Sera from RA patients without clinical cardiovascular disease were assayed for specific ACPAs using a custom Bio-Plex bead assay, and their cross-sectional associations with cardiac magnetic resonance-derived LV measures were evaluated. High ACPA level was defined as ⩾ 75th percentile. Findings were assessed in a second independent RA cohort with an expanded panel of ACPAs and LV measures assessed by 3D-echocardiography. Results: In cohort 1 (n = 76), higher levels of anti-citrullinated fibrinogen 41-60 and anti-citrullinated vimentin antibodies were associated with a 10 and 6% higher adjusted mean LV mass index (LVMI), respectively, compared with lower antibody levels (P < 0.05). In contrast, higher levels of anti-citrullinated biglycan 247-266 were associated with a 13% lower adjusted mean LVMI compared with lower levels (P < 0.001). In cohort 2 (n = 74), the association between ACPAs targeting citrullinated fibrinogen and citrullinated vimentin peptides or protein and LVMI was confirmed: higher anti-citrullinated fibrinogen 556-575 and anti-citrullinated vimentin 58-77 antibody levels were associated with a higher adjusted mean LVMI (19 and 15%, respectively; P < 0.05), but no association with biglycan was found. Conclusion: Higher levels of antibodies targeting citrullinated fibrinogen and vimentin peptides or protein were associated with a higher mean LVMI in both RA cohorts, potentially implicating autoimmune targeting of citrullinated proteins in myocardial remodelling in RA.

Race-ethnic differences in subclinical left ventricular systolic dysfunction by global longitudinal strain: A community-based cohort study.

BACKGROUND: Race-ethnic differences exist in the epidemiology of heart failure, with blacks experiencing higher incidence and worse prognosis. Left ventricular (LV) systolic dysfunction (LVSD) detected by speckle-tracking global longitudinal strain (GLS) is a predictor of cardiovascular events including heart failure. It is not known whether race-ethnic differences in GLS-LVSD exist in subjects without overt LV dysfunction. METHODS: Participants from a triethnic community-based study underwent 2-dimensional echocardiography with assessment of LV ejection fraction (LVEF) and GLS by speckle-tracking. Participants with LVEF <50% were excluded. Left ventricular systolic dysfunction by GLS was defined as GLS >95% percentile in a healthy sample (-14.7%). RESULTS: Of the 678 study participants (mean age 71 ± 9 years, 61% women), 114 were blacks; 464, Hispanics; and 100, whites. Global longitudinal strain was significantly lower in blacks (-16.5% ± 3.5%) than in whites (-17.5% ± 3.0%) and Hispanics (-17.3% ± 2.9%) in both univariate (P = .015) and multivariate analyses (P = .011), whereas LVEF was not significantly different between the 3 groups (64.3% ± 4.6%, 63.4% ± 4.9%, 64.7% ± 4.9%, respectively, univariate P = .064, multivariate P = .291). Left ventricular systolic dysfunction by GLS was more frequent in blacks (27.2%) than in whites (19.0%) and Hispanics (14.9%, P = .008). In multivariate analysis adjusted for confounders and cardiovascular risk factors, blacks were significantly more likely to have GLS-LVSD (adjusted odds ratio 2.6, 95% CIs 1.4-4.7, P = .002) compared to the other groups. CONCLUSIONS: Among participants from a triethnic community cohort, black race was associated with greater degree of subclinical LVSD by GLS than other race-ethnic groups. This difference was independent of confounders and cardiovascular risk factors.

Subclinical left ventricular dysfunction and silent cerebrovascular disease: the Cardiovascular Abnormalities and Brain Lesions (CABL) study.

BACKGROUND: Silent brain infarcts (SBIs) and white matter hyperintensities are subclinical cerebrovascular lesions associated with incident stroke and cognitive decline. Left ventricular ejection fraction (LVEF) is a predictor of stroke in patients with heart failure, but its association with subclinical brain disease in the general population is unknown. Left ventricular global longitudinal strain (GLS) can detect subclinical cardiac dysfunction even when LVEF is normal. We investigated the relationship of LVEF and GLS with subclinical brain disease in a community-based cohort. METHODS AND RESULTS: LVEF and GLS were assessed by 2-dimensional and speckle-tracking echocardiography in 439 participants free of stroke and cardiac disease from the Cardiovascular Abnormalities and Brain Lesions (CABL) study. SBIs and white matter hyperintensities were assessed by brain MRI. Mean age of the study population was 69±10 years, 61% were women, LVEF was 63.8±6.4%, GLS was -17.1±3.0%. SBIs were detected in 53 participants (12%), white matter hyperintensity volume was 0.63±0.86%. GLS was significantly lower in participants with SBI versus those without (-15.7±3.5% versus -17.3±2.9%, P<0.01), whereas no difference in LVEF was observed (63.3±8.6% versus 63.8±6.0%, P=0.60). In multivariate analysis, lower GLS was associated with SBI (odds ratio/unit decrease=1.18; 95% confidence interval, 1.05-1.33; P<0.01), whereas LVEF was not (odds ratio/unit increase=1.00; 95% confidence interval, 0.96-1.05; P=0.98). Lower GLS was associated with greater white matter hyperintensity volume (adjusted ß=0.11, P<0.05), unlike LVEF (adjusted ß=-0.04, P=0.42). CONCLUSIONS: Lower GLS was independently associated with subclinical brain disease in a community-based cohort without overt cardiac disease. GLS can provide additional information on cerebrovascular risk burden beyond LVEF assessment.

Left ventricular longitudinal strain by speckle-tracking echocardiography is associated with treatment-requiring cardiac allograft rejection.

BACKGROUND: Noninvasive detection of rejection is a major objective in the management of heart transplant recipients. METHODS AND RESULTS: To investigate the utility of 2-dimensional speckle-tracking echocardiography (2D-STE), we retrospectively evaluated 160 sets of endomyocardial biopsies and echocardiograms from 59 asymptomatic heart transplant recipients. Conventional International Society for Heart and Lung Transplantation grade 1B or higher rejection was considered as treatment-requiring rejection (group R), whereas International Society for Heart and Lung Transplantation grade 0 or 1A was classified as group Non-R. Left ventricular global longitudinal strain (GLS), global circumferential strain, and global radial strain were assessed by 2D-STE. Twenty-five specimens were classified into group R. GLS was significantly associated with treatment-requiring rejection, whereas neither global radial strain nor global circumferential strain were. Lower GLS remained significantly associated with an increased risk of treatment-requiring rejection (odds ratio, 1.15 [95% CI, 1.01-1.30]; P=0.03) even in multivariate analysis. GLS with the absolute value of less than 14.8% showed sensitivity and specificity of 64% and 63%, respectively, for detection of treatment-requiring rejection. CONCLUSION: The 2D-STE-derived left ventricular GLS was associated with treatment-requiring rejection. Two-dimensional STE might be useful as a noninvasive supplemental tool for monitoring heart transplant recipients for possible treatment-requiring rejection.

Relationship of multidirectional myocardial strain with radial thickening and ejection fraction and impact of left ventricular hypertrophy: a study in a community-based cohort.

BACKGROUND: Left ventricular (LV) systolic strain provides additional prognostic value to LV ejection fraction (LVEF) and wall motion analysis. However, the relationship between myocardial multidirectional strain and LVEF, and the effect of LV hypertrophy on this relationship, are not completely understood especially in unselected populations. METHODS: LV global longitudinal (εL ) and circumferential (εC ) systolic strain analysis was performed by two-dimensional speckle tracking echocardiography in 215 participants from a community-based study. LV radial wall thickening was measured as global radial strain (εR ), and LVEF was assessed by biplane Simpson's method. RESULTS: εR was significantly associated with εC (ß = -0.56, P < 0.01) and with εL (ß = -0.18, P < 0.01). The contribution of εL to εR was especially evident in subjects with lower εC and in presence of LV hypertrophy (ß = -0.30, P < 0.01). εL and εC were significantly associated with LVEF (ß = -0.36 and ß = -0.49, both P < 0.01) independent of LV mass and other confounders, and their interaction significantly improved the prediction of LVEF (R(2) -change = 0.14) but not of εR (R(2) -change = 0.002). CONCLUSIONS: εR is mainly related to εC with a smaller contribution of εL , which becomes especially evident in subjects with lower εC and in presence of LV hypertrophy. Therefore, radial thickening may not detect subclinical LV longitudinal function reduction in normal ventricles and when εC is preserved. While a reduction in εL has a limited impact on εR , it exerts a greater effect on global LVEF, therefore for a more accurate LVEF prediction both εL and εC need to be considered.

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.

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.

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.

Intra- and interobserver reproducibility of left ventricular mechanical dyssynchrony assessment by real time three-dimensional echocardiography.

BACKGROUND: Real time three-dimensional (3D) echocardiography allows the assessment of left ventricular (LV) mechanical dyssynchrony and may be useful in predicting response to cardiac resynchronization therapy. However, reproducibility of 3D dyssynchrony in past reports varied widely. We evaluated intra- and interobserver reproducibility of parameters of LV mechanical dyssynchrony by 3D echocardiography and explored the impact of image quality as a possible source of variability. METHODS: LV volumes and ejection fraction (LV EF) were measured by 3D echocardiography in 90 subjects. LV mechanical dyssynchrony was calculated as the standard deviation of the time-to-minimum segmental volume (Tmsv) over 16 (SDI16) and 12 (SDI12) segments and as the maximum time-difference in Tmsv over 16 (Dif16), 12 (Dif12), and 2 (DifS-L) segments. Opposing wall delay in peak myocardial systolic velocity (S-L delay) by tissue Doppler imaging (TDI) was also evaluated. RESULTS: Feasibility of 3D measurements was 88.9%. Intra- and interobserver intraclass correlation coefficients were excellent for LV volumes, LV EF, and S-L delay (all ≥ 0.90), very good for SDI16 (0.83 and 0.85), moderate to good for SDI12, Dif16, Dif12, and DifS-L (0.51-0.81). No systematic bias was present between readings for 3D dyssynchrony, but limits of agreement resulted fairly large for most parameters with the exception of SDI16, which showed reproducibility slightly lower than TDI. Suboptimal image quality was a significant source of variability in 3D-dyssynchrony assessment. CONCLUSIONS: The 3D assessment of LV volumes and dyssynchrony was feasible in our community-based cohort. SDI16 was the most reproducible among 3D-dyssynchrony parameters and the least affected by image quality.

Aortic arch plaques and risk of recurrent stroke and death.

BACKGROUND: Aortic arch plaques are a risk factor for ischemic stroke. Although the stroke mechanism is conceivably thromboembolic, no randomized studies have evaluated the efficacy of antithrombotic therapies in preventing recurrent events. METHODS AND RESULTS: The relationship between arch plaques and recurrent events was studied in 516 patients with ischemic stroke who were double-blindly randomized to treatment with warfarin or aspirin as part of the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), based on the Warfarin-Aspirin Recurrent Stroke Study (WARSS). Plaque thickness and morphology were evaluated by transesophageal echocardiography. End points were recurrent ischemic stroke or death over a 2-year follow-up. Large plaques (> or =4 mm) were present in 19.6% of patients; large complex plaques (those with ulcerations or mobile components) were seen in 8.5%. During follow-up, large plaques were associated with a significantly increased risk of events (adjusted hazard ratio [HR], 2.12; 95% confidence interval [CI], 1.04 to 4.32), especially those with complex morphology (HR, 2.55; 95 CI, 1.10 to 5.89). The risk was highest among cryptogenic stroke patients, both for large plaques (HR, 6.42; 95% CI, 1.62 to 25.46) and large complex plaques (HR, 9.50; 95% CI, 1.92 to 47.10). Event rates were similar in the warfarin and aspirin groups in the overall study population (16.4% versus 15.8%; P=0.43). CONCLUSIONS: In patients with stroke, especially cryptogenic stroke, large aortic plaques remain associated with an increased risk of recurrent stroke and death at 2 years despite treatment with warfarin or aspirin. Complex plaque morphology confers a slight additional increase in risk.

Race/ethnic disparities in left ventricular diastolic function in a triethnic community cohort.

BACKGROUND: Racial-ethnic disparities exist in cardiovascular risk factors, morbidity, and mortality. Left ventricular diastolic dysfunction is a predictor of mortality and of cardiovascular outcome including incident heart failure. We sought to assess whether race-ethnic differences in diastolic function exist. Such differences may contribute to the observed disparities in cardiovascular outcomes. METHODS: Two-dimensional echocardiography was performed in 760 participants (539 Hispanic, 117 non-Hispanic black, 104 non-Hispanic white) from the Cardiac Abnormalities and Brain Lesions study. Left ventricular diastolic function was assessed by standard Doppler flow profile and tissue Doppler imaging. Early (E) and late (A) transmitral diastolic flow, and mitral annulus early diastolic velocities (E') were recorded; and E/A and E/E' ratios were calculated. RESULTS: Blacks and Hispanics had higher body mass index (P = .04, P < .01), higher prevalence of hypertension (both Ps

Novel wall motion score-based method for estimating global left ventricular ejection fraction: validation by real-time 3D echocardiography and global longitudinal strain.

AIMS: To evaluate the reliability of a regional wall motion score index (WMSI)-based method for assessment of left ventricular (LV) ejection fraction (EF). METHODS AND RESULTS: Two-dimensional (2D) echocardiography was used to assess a LV 16-segment-based regional wall motion. Each segment received a score based on contractility status: 4, normal kinesis; 3, mild; 2.5, moderate; and 1.5, severe hypo-kinesis; 0, akinesis; -1, dyskinesis; 3.5 and 4.5 were used for low-normal and high-normal kinesis; 5 for hyper-kinesis. Hence, WMSI-based EF was derived by summing the score assigned to each segment. Contextually, EF was evaluated by real-time three-dimensional (3D) echocardiography and by traditional Simpson's method (2D). Global longitudinal strain (GLS) by speckle-tracking method was derived as a volume-independent indicator of LV chamber contractility sensitive to regional wall motion abnormalities. In 40 subjects with 3D-EF ranging from 14 to 80%, including clinically healthy hypertensive and patients with Stage B-D congestive heart failure with global or segmental wall motion abnormalities, on average, WMSI-EF did not differ from EF measured by 3D or 2D (all P > 0.5). By intraclass correlation coefficients, reliability of WMSI-EF vs. 3D method was as good as the reliability of 2D method vs. 3D method. GLS correlated with WMSI-EF as strongly as with 3D-EF (both r(2) = 0.90). Moderate-severe mitral regurgitation was associated with increased difference between WMSI-EF and 3D-EF, independent to potential confounders. Intra-observer and inter-observer reproducibility of WMSI-EF was comparable to the reproducibility of EF estimated by 3D echocardiography. Feasibility (WMSI, 3D, 2D, and GLS all available) was 78%; however, feasibility of WMSI per se was approximately 92% in clinical series. CONCLUSION: Trained readers may rapidly estimate EF by a novel WMSI system, which was found to be accurate compared with 3D method and GLS.

Atherosclerotic disease of the proximal aorta and the risk of vascular events in a population-based cohort: the Aortic Plaques and Risk of Ischemic Stroke (APRIS) study.

BACKGROUND AND PURPOSE: Proximal aortic plaques are a risk factor for vascular embolic events. However, this association in the general population is unclear. We sought to assess whether proximal aortic plaques are associated with vascular events in a community-based cohort. METHODS: Stroke-free subjects from the Aortic Plaques and Risk of Ischemic Stroke (APRIS) study were evaluated. Aortic arch and proximal descending aortic plaques were assessed by transesophageal echocardiography (TEE). Vascular events (myocardial infarction, ischemic stroke, vascular death) were prospectively recorded, and their association with aortic plaques was assessed. RESULTS: 209 subjects were studied (age 67.0+/-8.6 years). Aortic arch plaques were present in 130 subjects (62.2%), large plaques (>or=4 mm) in 50 (23.9%). Descending aortic plaques were present in 126 subjects (60.9%), large plaques in 41 (19.8%). During a follow-up of 74.4+/-26.3 months, 29 events occurred (12 myocardial infarctions, 11 ischemic strokes, 6 vascular deaths). After adjustment for risk factors, large aortic arch plaques were not associated with combined vascular events (hazard ratio [HR] 1.03, 95% confidence intervals [CI] 0.35 to 3.02) or ischemic stroke (HR 0.59, 95% CI 0.10 to 3.39). Large descending aortic plaques were also not independently associated with vascular events (HR 1.99, 95% CI 0.52 to 7.69) or ischemic stroke (HR 1.43, 95% CI 0.27 to 7.48). CONCLUSIONS: In a population-based cohort, the incidental detection of plaques in the aortic arch or proximal descending aorta was not associated with future vascular events. Associated cofactors may affect the previously reported association between proximal aortic plaques and vascular events.

Changes in components of left ventricular mechanics under selective beta-1 blockade: insight from traditional and new technologies in echocardiography.

AIMS: Myocardial inotropism is considered to be reduced under beta-1 adrenoreceptor blockage (beta1-block). However, relationships between components of left ventricular (LV) systolic mechanics under beta1-block accounting for physiological correlates are only partially explored. METHODS AND RESULTS: Hypertensive outpatient without previous cardiovascular events and with normal LV ejection fraction (EF) at rest underwent echocardiographic evaluations of LV size and systolic function by standard, tissue-Doppler, and speckle-tracking methods before and after 2 weeks of treatment with bisoprolol to obtain change in LV systolic mechanics at a stable heart rate reduction (-20 +/- 10% from baseline) without significant change in LV mass. In the study sample (n = 26, 62% women, mean age 52 +/- 10 years), under bisoprolol, afterload [i.e. circumferential (CESS) and meridional (MESS) end-systolic stress], LV mass, left atrial volume, and EF did not change significantly; LV chamber contractility [i.e. CESS/LV end-systolic volume index (CESS/ESVi) as well as MESS/ESVi] and relative wall thickness (RWT) decreased; stroke volume increased (all P < 0.05). Circumferential LV contractility (i.e. stress-corrected midwall shortening) increased, whereas regional longitudinal strain and strain rate, and global longitudinal strain decreased (all P < 0.05). Peak velocities of the systolic displacement of the lateral and medial mitral anulus did not change under bisoprolol. Parameters of longitudinal LV systolic function did not correlate with preload, afterload, RWT, or with stoke volume. CONCLUSION: In hypertensive subjects with preserved LV EF, parameters of longitudinal LV systolic mechanics may not reflect the LV myocardial contractility status in steady-state conditions under short-term treatment with beta1-block.

Myocardial Microvascular Dysfunction in Rheumatoid ArthritisQuantitation by 13N-Ammonia Positron Emission Tomography/Computed Tomography.

BACKGROUND: The goal of this study was to assess the prevalence of myocardial microvascular dysfunction in rheumatoid arthritis (RA) patients without clinical cardiovascular disease and its association with RA characteristics and measures of cardiac structure and function. METHODS: Participants with RA underwent rest and vasodilator stress N-13 ammonia positron emission tomography and echocardiography. Global myocardial blood flow was quantified at rest and during peak hyperemia. Myocardial flow reserve (MFR) was calculated as peak stress myocardial blood flow/rest myocardial blood flow. A small number of asymptomatic and symptomatic non-RA controls were also evaluated. RESULTS: In RA patients, mean±SD MFR was 2.9±0.8, with 29% having reduced MFR (<2.5). Male sex and higher interleukin-6 were significantly associated with lower MFR, while the use of tumor necrosis factor inhibitors was associated with higher MFR. Lower MFR was associated with higher left ventricle mass index and higher left ventricle volumes but not with ejection fraction or diastolic dysfunction. RA and symptomatic controls had comparable MFR (mean±SD: 2.9±0.8 versus 2.55±0.6; P=0.48). In contrast, MFR was higher in the asymptomatic controls (mean±SD: 3.25±0.7) although not statistically different. CONCLUSIONS: Reduced MFR was observed in a third of RA patients without clinical cardiovascular disease and was associated with a measure of inflammation and with higher left ventricle mass and volumes. MFR in RA patients was similar to controls referred for clinical scans (symptomatic controls). Whether reduced MFR contributes to the increased risk for heart failure in RA remains unknown.

Myocardial Inflammation, Measured Using 18-Fluorodeoxyglucose Positron Emission Tomography With Computed Tomography, Is Associated With Disease Activity in Rheumatoid Arthritis.

OBJECTIVE: To determine the prevalence and correlates of subclinical myocardial inflammation in patients with rheumatoid arthritis (RA). METHODS: RA patients (n = 119) without known cardiovascular disease underwent cardiac 18-fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET-CT). Myocardial FDG uptake was assessed visually and measured quantitatively as the standardized uptake value (SUV). Multivariable linear regression was used to assess the associations of patient characteristics with myocardial SUVs. A subset of RA patients who had to escalate their disease-modifying antirheumatic drug (DMARD) therapy (n = 8) underwent a second FDG PET-CT scan after 6 months, to assess treatment-associated changes in myocardial FDG uptake. RESULTS: Visually assessed FDG uptake was observed in 46 (39%) of the 119 RA patients, and 21 patients (18%) had abnormal quantitatively assessed myocardial FDG uptake (i.e., mean of the mean SUV [SUVmean ] ≥3.10 units; defined as 2 SD above the value in a reference group of 27 non-RA subjects). The SUVmean was 31% higher in patients with a Clinical Disease Activity Index (CDAI) score of ≥10 (moderate-to-high disease activity) as compared with those with lower CDAI scores (low disease activity or remission) (P = 0.005), after adjustment for potential confounders. The adjusted SUVmean was 26% lower among those treated with a non-tumor necrosis factor-targeted biologic agent compared with those treated with conventional (nonbiologic) DMARDs (P = 0.029). In the longitudinal substudy, the myocardial SUVmean decreased from 4.50 units to 2.30 units over 6 months, which paralleled the decrease in the mean CDAI from a score of 23 to a score of 12. CONCLUSION: Subclinical myocardial inflammation is frequent in patients with RA, is associated with RA disease activity, and may decrease with RA therapy. Future longitudinal studies will be required to assess whether reduction in myocardial inflammation will reduce heart failure risk in RA.

Association of body size metrics with left atrial phasic volumes and reservoir function in the elderly.

Aims: General obesity, defined by increased body mass index (BMI), is associated with left atrial (LA) enlargement, a marker of cardiovascular risk in the general population. The association between abdominal adiposity, defined by increased waist circumference (WC) or waist-to-hip ratio (WHR), and LA phasic volumes and reservoir function is not well known. The aim of this study was to evaluate the association between different body size metrics and LA phasic volumes and reservoir function in the elderly. Methods and results: Participants from the CABL (Cardiovascular Abnormalities and Brain Lesions) study underwent measurement of BMI, WC, and WHR. The LA maximum (LAVmax) and minimum (LAVmin) volumes, and LA reservoir function, measured as total emptying volume index (LAEVI), total emptying fraction (LAEF), and expansion index (LAEI), were assessed by real-time 3D echocardiography. The study population included 629 participants (mean age 71 ± 9 years, 61% women). Mean BMI was 27.9 ± 4.6 kg/m2, WC was 95.0 ± 11.7 cm, WHR was 0.91 ± 0.08. After adjusting for multiple potential confounders (demographics, cardiovascular risk factors, left ventricular mass index, and diastolic function), higher WC was significantly associated with higher LA phasic volumes (LAVmax, ß = 0.10, P = 0.007 and LAVmin, ß = 0.12, P = 0.002) and reduced reservoir function (LAEVI, ß = -0.15, P = 0.001 and LAEI, ß = -0.09, P = 0.027). WHR was significantly associated only with reduced reservoir function (LAEVI, ß = -0.11, P = 0.012), whereas BMI was not associated with either LA phasic volumes or reservoir function. Conclusion: In the elderly, WC may have more impact on LA phasic volumes and reservoir function, and therefore risk for cardiovascular events, than WHR and BMI.

Relationship between body mass and ambulatory blood pressure: comparison with office blood pressure measurement and effect of treatment.

Epidemiologic studies assessing the relationship between blood pressure (BP), body mass, and cardiovascular events have primarily been based on office BP measurements, and few data are available in the elderly. The aim of the present study was to evaluate the relationship between body mass index (BMI) and BP values obtained by ambulatory blood pressure monitoring (ABPM) as compared to office BP measurements, and the effect of anti-hypertensive treatment on the relationship. The study population consisted of 813 subjects participating in the cardiovascular abnormalities and brain lesions (CABL) study who underwent 24-h ABPM. Office BP (mean of two measurements) was found to be associated with increasing BMI, for both SBP (p ≤ 0.05) and DBP (p ≤ 0.001). In contrast, there was no association seen of increasing BMI with ABPM parameters in the overall cohort, even after adjusting for age and gender. However, among subjects not on anti-hypertensive treatment, office SBP and DBP measurements were significantly correlated with increasing BMI (p ≤ 0.01) as were daytime SBP and 24-h SBP, although with a smaller spread across BMI subgroups compared with office readings. In treated hypertensives, there was only a trend toward increasing office DBP and increasing DBP variability with higher BMI. Our results suggest that body mass may have a less significant influence on BP values in the elderly when ABPM rather than office measurements are considered, particularly in patients receiving anti-hypertensive treatment.