GEM-IL: A highly responsive fluorescent lactate indicator.

Lactate metabolism has been shown to have increasingly important implications in cellular functions as well as in the development and pathophysiology of disease. The various roles as a signaling molecule and metabolite have led to interest in establishing a new method to detect lactate changes in live cells. Here we report our development of a genetically encoded metabolic indicator specifically for probing lactate (GEM-IL) based on superfolder fluorescent proteins and mutagenesis. With improvements in its design, specificity, and sensitivity, GEM-IL allows new applications compared with the previous lactate indicators, Laconic and Green Lindoblum. We demonstrate the functionality of GEM-IL to detect differences in lactate changes in human oncogenic neural progenitor cells and mouse primary ventricular myocytes. The development and application of GEM-IL show promise for enhancing our understanding of lactate dynamics and roles.

Association Between Central Blood Pressure and Subclinical Cerebrovascular Disease in Older Adults.

Elevated blood pressure (BP) level is one of the most consistently identified risk factors for silent brain disease. BP values obtained at the proximal segment of the aorta (central BP) are more directly involved than brachial BP in the pathogenesis of cardiovascular disease. However, the association between central BP and silent cerebrovascular disease has not been clearly established. Participants in the CABL (Cardiovascular Abnormalities and Brain Lesions) study (n=993; mean age, 71.7±9.3 years; 37.9% men) underwent 2-dimensional echocardiography, arterial wave reflection analysis for determination of central BPs, and brain magnetic resonance imaging. Central BPs were calculated from the radial pulse waveform. Subclinical silent cerebrovascular disease was defined as silent brain infarction and white matter hyperintensity volume. Both brachial (P=0.014) and central pulse pressure (P=0.026) were independently associated with silent brain infarctions after adjustment for clinical variables, but not adjusting for each other. None of the brachial BP values was associated with upper quartile of white matter hyperintensity volume in multivariable analysis. Both central systolic BP (P<0.001) and central pulse pressure (P<0.001) were significantly associated with upper quartile of white matter hyperintensity volume in multivariable analysis, even after adjustment for brachial BP. In a predominantly older population-based cohort, both brachial and central pulse pressure were independently associated with silent brain infarction. However, higher central systolic BP and central pulse pressure, but not brachial BP, were significantly associated with white matter hyperintensity volume.

Cognitive Decline Over Time in Patients With Systolic Heart Failure: Insights From WARCEF.

OBJECTIVES: This study sought to characterize cognitive decline (CD) over time and its predictors in patients with systolic heart failure (HF). BACKGROUND: Despite the high prevalence of CD and its impact on mortality, predictors of CD in HF have not been established. METHODS: This study investigated CD in the WARCEF (Warfarin versus Aspirin in Reduced Ejection Fraction) trial, which performed yearly Mini-Mental State Examinations (MMSE) (higher scores indicate better cognitive function; e.g., normal score: 24 or higher). A longitudinal time-varying analysis was performed among pertinent covariates, including baseline MMSE and MMSE scores during follow-up, analyzed both as a continuous variable and a 2-point decrease. To account for a loss to follow-up, data at the baseline and at the 12-month visit were analyzed separately (sensitivity analysis). RESULTS: A total of 1,846 patients were included. In linear regression, MMSE decrease was independently associated with higher baseline MMSE score (p < 0.0001), older age (p < 0.0001), nonwhite race/ethnicity (p < 0.0001), and lower education (p < 0.0001). In logistic regression, CD was independently associated with higher baseline MMSE scores (odds ratio [OR]: 1.13; 95% confidence interval [CI]: 1.07 to 1.20]; p < 0.001), older age (OR: 1.37; 95% CI: 1.24 to 1.50; p < 0.001), nonwhite race/ethnicity (OR: 2.32; 95% CI: 1.72 to 3.13 for black; OR: 1.94; 95% CI: 1.40 to 2.69 for Hispanic vs. white; p < 0.001), lower education (p < 0.001), and New York Heart Association functional class II or higher (p = 0.03). Warfarin and other medications were not associated with CD. Similar trends were seen in the sensitivity analysis (n = 1,439). CONCLUSIONS: CD in HF is predicted by baseline cognitive status, demographic variables, and NYHA functional class. The possibility of intervening on some of its predictors suggests the need for the frequent assessment of cognitive function in patients with HF. (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction [WARCEF]; NCT00041938).

Changes in Left Ventricular Mass and Geometry in the Older Adults: Role of Body Mass and Central Obesity.

BACKGROUND: Left ventricular (LV) hypertrophy is an independent risk factor for cardiovascular outcomes. There are limited data about modifiable factors associated with progression of LV hypertrophy in older adults. Our objective is to describe the changes in LV mass and geometry over time in a predominantly older multiethnic cohort and to identify possible predictors of changes over time. METHODS: We analyzed data from participants in the Northern Manhattan Study who underwent serial echocardiographic studies, comparing the baseline and the most recent echocardiograms. We recorded changes in LV mass and geometry and correlated them with baseline characteristics using linear regression models. RESULTS: There were 826 participants (mean age, 64.2 ± 8.0 years) included in the analysis (time between measurements, 8.5 ± 2.7 years). Overall, LV mass index increased from 45.0 ± 12.7 to 50.3 ± 14.6 g/m2.7 (P < .001). There were 548 participants (66.3%) with LV mass increase; 258 individuals (31.2%) showed worsening LV geometry. Multivariable analysis showed that change in LV mass index was independently associated with baseline LV mass index (ß estimate, -17.000 [standard error, 1.508]; P < .001), hypertension (2.094 [0.816], P = .011), body mass index (0.503 [0.088], P < .001), and waist-to-hip ratio (1.031 [0.385], P = .008). Both waist-to-hip ratio and waist-to-height ratio remained significantly associated with LV mass increase even after adjusting for body mass index (P = .008 and P = .036, respectively). CONCLUSIONS: Regardless of race/ethnicity, LV mass progressed over time in older adults. We also observed that worsening geometry was frequent. Assessment of central obesity in the older population is important because indicators of central obesity add prognostic value over body mass index for the risk of LV mass increase.

Association between mortality and implantable cardioverter-defibrillators by aetiology of heart failure: a propensity-matched analysis of the WARCEF trial.

AIMS: There is debate on whether the beneficial effect of implantable cardioverter-defibrillators (ICDs) is attenuated in patients with non-ischaemic cardiomyopathy (NICM). We assess whether any ICD benefit differs between patients with NICM and those with ischaemic cardiomyopathy (ICM), using data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial. METHODS AND RESULTS: We performed a post hoc analysis using WARCEF (N = 2293; ICM, n = 991 vs. NICM, n = 1302), where participants received optimal medical treatment. We developed stratified propensity scores for having an ICD at baseline using 41 demographic and clinical variables and created 1:2 propensity-matched cohorts separately for ICM patients with ICD (N = 223 with ICD; N = 446 matched) and NICM patients (N = 195 with ICD; N = 390 matched). We constructed a Cox proportional hazards model to assess the effect of ICD status on mortality for patients with ICM and those with NICM and tested the interaction between ICD status and aetiology of heart failure. During mean follow-up of 3.5 ± 1.8 years, 527 patients died. The presence of ICD was associated with a lower risk of all-cause death among those with ICM (hazard ratio: 0.640; 95% confidence interval: 0.448 to 0.915; P = 0.015) but not among those with NICM (hazard ratio: 0.984; 95% confidence interval: 0.641 to 1.509; P = 0.941). There was weak evidence of interaction between ICD status and the aetiology of heart failure (P = 0.131). CONCLUSIONS: The presence of ICD is associated with a survival benefit in patients with ICM but not in those with NICM.

Night-time systolic blood pressure and subclinical cerebrovascular disease: the Cardiovascular Abnormalities and Brain Lesions (CABL) study.

AIMS: Although ambulatory blood pressure (BP) is a better predictor of cardiovascular outcomes than office BP, its association with subclinical cerebrovascular disease is not clarified. We investigated the associations of office and ambulatory BP values with subclinical cerebrovascular disease in a population based, predominantly elderly cohort without prior stroke. METHODS AND RESULTS: Eight hundred and twenty-eight participants underwent 24-h ambulatory BP monitoring (ABPM), 2D echocardiography and brain magnetic resonance imaging in the Cardiac Abnormalities and Brain Lesion (CABL) study. Daytime, night-time, and 24-h BPs, nocturnal dipping pattern, morning surge (MS), and 24-h variability were assessed. Subclinical cerebrovascular disease was defined as silent brain infarcts (SBIs) and white matter hyperintensity volume (WMHV). The association of BP measures with the presence of SBI and upper quartile of log-WMHV (log-WMHV4) was analysed. SBIs were detected in 111 patients (13.4%). Mean log-WMHV was -0.99 ± 0.94. In multivariable analysis, only night-time systolic BP (SBP) was significantly associated with SBI [odds ratio (OR) 1.15 per 10 mmHg, P = 0.042], independent of cardiovascular risk factors, and pertinent echocardiographic parameters. Although daytime, night-time, 24-h BPs, and non-dipping pattern were all significantly associated with log-WMHV4 (all P < 0.05), night-time SBP showed the strongest association (OR 1.21 per 10 mmHg, P = 0.003) and was the sole independent predictor when tested against the other BP parameters. Office BP measures, MS, and BP variability were not associated with subclinical cerebrovascular disease in adjusted analyses. CONCLUSION: Elevated night-time SBP is strongly associated with subclinical cerebrovascular disease. Night-time SBP by ABPM allows to identify individuals at higher risk of hypertensive brain injury.

Heart Failure Severity and Quality of Warfarin Anticoagulation Control (From the WARCEF Trial).

Previous studies in patients with atrial fibrillation showed that a history of heart failure (HF) could negatively impact anticoagulation quality, as measured by the average time in therapeutic range (TTR). Whether additional markers of HF severity are associated with TTR has not been investigated thoroughly. We aimed to examine the potential role of HF severity in the quality of warfarin control in patients with HF with reduced ejection fraction. Data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial were used to investigate the association between TTR and HF severity. Multivariable logistic regression models were used to examine the association of markers of HF severity, including New York Heart Association (NYHA) class, Minnesota Living with HF (MLWHF) score, and frequency of HF hospitalization, with TTR ≥70% (high TTR). We included 1,067 participants (high TTR, N = 413; low TTR, N = 654) in the analysis. In unadjusted analysis, patients with a high TTR were older and less likely to have had strokes or receive other antiplatelet agents. Those patients also had lower NYHA class, better MLWHF scores, greater 6-minute walk distance, and lower frequency of HF hospitalizations. Multivariable analysis showed that NYHA class III and/or IV (Odds ratio [OR] 0.68 [95% confidence intervals [CIs] 0.49 to 0.94]), each 10-point increase in MLWHF score (i.e., worse health-related quality of life) (OR 0.92 [0.86 to 0.99]), and higher number of HF hospitalization per year (OR0.45 [0.30 to 0.67]) were associated with decreased likelihood of having high TTR. In HF patients with systolic dysfunction, NYHA class III and/or IV, poor health-related quality of life, and a higher rate of HF hospitalization were independently associated with suboptimal quality of warfarin anticoagulation control. These results affirm the need to assess the new approaches, such as direct oral anticoagulants, to prevent thromboembolism in this patient population.