Ambulatory Blood Pressure Is a Better Marker Than Clinic Blood Pressure in Predicting Cardiovascular Events in Patients With/Without Type 2 Diabetes

Background - The prognostic significance of ambulatory blood pressure (ABP) has not been established in patients with type 2 diabetes (T2DM). Methods - In order to clarify the impact of ABP on cardiovascular prognosis in patients with or without T2DM, we performed ABP monitoring (ABPM) in 1,268 subjects recruited from nine sites in Japan, who were being evaluated for hypertension. The mean age of the patients was 70.4 ± 9.9 years, and 301 of them had diabetes. The patients were followed up for 50 ± 23 months. We investigated the relation between incidence of cardiovascular diseases (CVDs) and different measures of ABP, including three categories of awake systolic blood pressure (SBP 150 mm Hg), sleep SBP (135 mm Hg), and dipping trends in nocturnal blood pressure (BP) (dippers, nondippers, and risers). Cox regression models were used in order to control for classic risk factors. Results - Higher awake and sleep SBPs predicted higher incidence of CVD in patients with and without diabetes. In multivariable analyses, elevated SBPs while awake and asleep predicted increased risk of CVD more accurately than clinic BP did, in both groups of patients. The relationships between ABP level and CVD were similar in both groups. In Kaplan–Meier analyses, the incidence of CVD in nondippers was similar to that in dippers, but risers experienced the highest risk of CVD in both groups (P < 0.01). The riser pattern was associated with a ∼150% increase in risk of CVD, in both groups. Conclusions - These findings suggest that ABPM is a better predictor of cardiovascular risk than clinic BP, and that this holds true for patients with or without T2DM

Changes in Home Versus Clinic Blood Pressure With Antihypertensive Treatments: A Meta-Analysis

Home blood pressure (HBP) monitoring is recommended for assessing the effects of antihypertensive treatment, but it is not clear how the treatment-induced changes in HBP compare with the changes in clinic blood pressure (CBP). We searched PubMed using the terms “home or self-measured blood pressure,” and selected articles in which the changes in CBP and HBP (using the upper arm oscillometric method) induced by antihypertensive drugs were presented. We performed a systematic review of 30 articles published before March 2008 that included a total of 6794 subjects. As there was significant heterogeneity in most of the outcomes, a random effects model was used for the meta-analyses. The mean changes (±SE) in CBP and HBP (systolic/diastolic) were −15.2±0.03/−10.3±0.03 mm Hg and −12.2±0.04/−8.0±0.04 mm Hg respectively, although there were wide varieties of differences in the reduction between HBP and CBP. The reductions in CBP were correlated with those of HBP (systolic BP; r=0.66, B=0.48, diastolic BP; r=0.71, B=0.52, P<0.001). In 7 studies that also included 24-hour BP monitoring, the reduction of HBP was greater than that of 24-hour BP in systolic (HBP; −12.6±0.06 mm Hg, 24-hour BP; −11.9±0.04 mm Hg, P<0.001). In 5 studies that included daytime and nighttime systolic BP separately, HBP decreased 15% more than daytime ambulatory BP and 30% more than nighttime ambulatory BP. In conclusion, HBP falls ≈20% less than CBP with antihypertensive treatments. Daytime systolic BP falls 15% less and nighttime systolic BP falls 30% less than home systolic BP

Age and the difference between awake ambulatory blood pressure and office blood pressure: a meta-analysis

Background: Ambulatory blood pressure (BP) (ABP) is a better predictor of adverse cardiovascular events than office BP (OBP). Owing to the extensive literature on the ‘white coat effect’, it is widely believed that ABP tends to be lower than OBP, with statements to this effect in Joint National Committee VII. However, recent evidence suggests that the difference varies systematically with age. Methods: We searched PubMed to identify population studies, published before April 2009, which assessed OBP and either ABP or home BP (HBP). On account of significant heterogeneity in the outcomes, random effect models were used for the meta-analyses. Results: OBP increased with age more steeply than awake ABP. OBP became higher than awake systolic/diastolic ABP at the age of 51.3/42.7 years in men (13 studies, N=3562) and 51.9/42.3 years in women (11 studies, N=2585). In the data in which OBP and HBP were measured (eight studies, N=4916), OBP was higher than HBP at all ages. In the data in which OBP, awake ABP, and HBP were all measured (two studies, N=895), awake ABP was higher than HBP at younger ages, becoming similar at the older age. Conclusion: OBP tends to be higher than awake ABP only after the age of 50 years for systolic and after the age of 45 years for diastolic BP, but is lower than ABP at younger ages; in contrast OBP tends to exceed HBP at all ages

Nocturnal nondipping of heart rate predicts cardiovascular events in hypertensive patients

Objective: It has not been established whether nocturnal nondipping of heart rate (HR) predicts future cardiovascular disease (CVD). We performed this study to test the hypothesis that nocturnal nondipping of HR predicts the risk of incident CVD independent of nocturnal blood pressure dipping pattern. Methods: Ambulatory blood pressure monitoring was performed in 457 uncomplicated patients, who were being treated or evaluated for hypertension. They were followed for an average of 72 ± 26 months. Nondipping HR was defined as a night/day HR ratio greater than 0.90. We chose two outcomes for this analysis: CVD events (defined as stroke, myocardial infarction, or sudden cardiac death) and all-cause mortality. Cox regression analyses (stepwise method) were used to estimate hazard ratios and their 95% confidence interval after adjusting for covariates. Results: In univariate analysis, increased sleep HR and nondipping of HR were associated with increased risk of CVD and all-cause mortality, but awake HR was not. In multivariable analyses, HR nondipping status significantly predicted an increased risk of CVD events (hazard ratio, 2.37; 95% confidence interval, 1.22–4.62; P = 0.01), but not for all-cause mortality. Increased 24-h HR was significantly associated with increased risk of all-cause mortality (hazard ratio, 1.67; 95% confidence interval, 1.11–2.51; P = 0.01). Conclusion: The risk of future CVD was shown to be 2.4 times higher in those whose HR does not exhibit the typical nocturnal decline. The relationship was independent of nondipping of SBP and was not dependent on diabetes status or blood pressure level

Night Time Blood Pressure Variability Is a Strong Predictor for Cardiovascular Events in Patients With Type 2 Diabetes

Background: We aimed this study to test the hypothesis that short-term blood pressure (BP) variability and abnormal patterns of diurnal BP variation, evaluated by ambulatory BP (ABP), predicts risk of incident cardiovascular disease (CVD) in patients with type 2 diabetes (T2DM). Methods: ABP monitoring (ABPM) was performed in 300 patients with uncomplicated T2DM without known CVD and without BP medications, who were followed for 54 ± 20 months. The relationships of different measures of BP variability, the presence of abnormal patterns of diurnal BP variation (nondipper, riser, or morning BP surge) and the standard deviations of awake and asleep ABP were determined. Cox proportional hazards models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) before and after controlling for various covariates. Results: The mean age was 67.8 ± 9.6 years, 48% were male, 253 (84%) had a diagnosis of hypertension, and the mean of the standard deviations of awake systolic BP/diastolic BP (SBP/DBP) were 18 ± 6/11 ± 4 mm Hg, and those of sleep SBP/DBP were 13 ± 5/9 ± 3 mm Hg. During follow-up, there were 29 cardiovascular events. In multivariable analyses, the standard deviations of sleep SBP (HR = 1.08; 95% CI, 1.01–1.16, P < 0.05) and sleep DBP (HR = 1.13; 1.04–1.23, P < 0.01) were independently associated with incident CVD. Neither the nondipper and riser patterns nor the morning BP surge were associated with incident CVD events independently of clinic and 24-h BP levels. Conclusions: Abnormal diurnal BP variation was not a predictor of CVD in patients with T2DM. Night time BP variability was an independent predictor of future incidence of CVD, suggesting that this measure could reflect pathophysiology of T2DM

Alterations in Diastolic Function in Masked Hypertension: Findings from the Masked Hypertension Study

BACKGROUND In a prior study of patients with diabetes, diastolic function was similarly impaired in masked hypertension (MHT) and sustained hypertension (SHT). We evaluated whether MHT is associated with impaired diastolic function compared with SHT and sustained normotension (NT) in the general population. METHODS From February 2005 to December 2010, 798 participants without a history of cardiovascular disease or treated hypertension, were enrolled in the Masked Hypertension Study. Participants underwent clinic blood pressure (CBP) and 24-hour ambulatory blood pressure (ABP) measurements. A 2-dimensional Doppler echocardiogram was performed to evaluate diastolic function,s cardiac structure, volume, and systolic function. The 9 CBPs obtained across 3 clinic visits and awake ABP measurements were averaged. Clinic hypertension was defined as systolic/diastolic blood pressure (SBP/DBP) ≥ 140/90 mmHg. Ambulatory hypertension was defined as awake SBP/DBP ≥ 135/85mm Hg. MHT was defined as having ambulatory but not clinic hypertension. White-coat hypertensives (n = 8) were excluded from the analysis. RESULTS Of the 790 participants, 116 (14.7%) participants had MHT, 37 (4.7%) participants had SHT, and 637 (80.6%) participants had NT. After age, sex, race/ethnicity, and body mass index adjustment, compared with NT, E’-velocities were significantly lower in MHT (P < 0.01) and SHT (P < 0.05), and E/E’ ratios were significantly higher MHT (P < 0.05) and SHT (P < 0.05). These associations were independent of left ventricular mass. Diastolic function parameters did not significantly differ between MHT and SHT. CONCLUSIONS Diastolic function was impaired in MHT compared with NT independent of changes in left ventricular mass

Clinic Blood Pressure Underestimates Ambulatory Blood Pressure in an Untreated Employer-Based US Population: Results From the Masked Hypertension Study

Background: Ambulatory blood pressure (ABP) is consistently superior to clinic blood pressure (CBP) as a predictor of cardiovascular morbidity and mortality risk. A common perception is that ABP is usually lower than CBP. The relationship of the CBP minus ABP difference to age has not been examined in the United States. Methods: Between 2005 and 2012, 888 healthy, employed, middle-aged (mean±SD age, 45±10.4 years) individuals (59% female, 7.4% black, 12% Hispanic) with screening BP <160/105 mm Hg and not taking antihypertensive medication completed 3 separate clinic BP assessments and a 24-hour ABP recording for the Masked Hypertension Study. The distributions of CBP, mean awake ABP (aABP), and the CBP−aABP difference in the full sample and by demographic characteristics were compared. Locally weighted scatterplot smoothing was used to model the relationship of the BP measures to age and body mass index. The prevalence of discrepancies in ABP- versus CBP-defined hypertension status—white-coat hypertension and masked hypertension—were also examined. Results: Average systolic/diastolic aABP (123.0/77.4±10.3/7.4 mm Hg) was significantly higher than the average of 9 CBP readings over 3 visits (116.0/75.4±11.6/7.7 mm Hg). aABP exceeded CBP by >10 mm Hg much more frequently than CBP exceeded aABP. The difference (aABP>CBP) was most pronounced in young adults and those with normal body mass index. The systolic difference progressively diminished, but did not disappear, at older ages and higher body mass indexes. The diastolic difference vanished around age 65 and reversed (CBP>aABP) for body mass index >32.5 kg/m2. Whereas 5.3% of participants were hypertensive by CBP, 19.2% were hypertensive by aABP; 15.7% of those with nonelevated CBP had masked hypertension. Conclusions: Contrary to a widely held belief, based primarily on cohort studies of patients with elevated CBP, ABP is not usually lower than CBP, at least not among healthy, employed individuals. Furthermore, a substantial proportion of otherwise healthy individuals with nonelevated CBP have masked hypertension. Demonstrated CBP−aABP gradients, if confirmed in representative samples (eg, NHANES [National Health and Nutrition Examination Survey]), could provide guidance for primary care physicians as to when, for a given CBP, 24-hour ABP would be useful to identify or rule out masked hypertension

PD-1 blockade therapy promotes infiltration of tumor-attacking exhausted T cell clonotypes

PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (T-ex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the T-ex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the T-ex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such T-ex clonotypes, mainly from TDLNs

Over-expression of lysophosphatidic acid receptor-2 in human invasive ductal carcinoma

INTRODUCTION: Lysophosphatidic acid (LPA) is a bioactive phospholipid with diverse effects on various cells. It interacts with at least three G-protein-coupled transmembrane receptors, namely LPA1, LPA2 and LPA3, whose expression in various tumours has not been fully characterized. In the present study we characterized the expression profile of LPA receptors in human breast cancer tissue and assessed the possible roles of each receptor. METHODS: The relative expression levels of each receptor's mRNA against β-actin mRNA was examined in surgically resected invasive ductal carcinomas and normal gland tissue using real-time RT-PCR. LPA2 expression was also examined immunohistochemically using a rat anti-LPA2 monoclonal antibody. RESULTS: In 25 cases normal and cancer tissue contained LPA1 mRNA at similar levels, whereas the expression level of LPA2 mRNA was significantly increased in cancer tissue as compared with its normal counterpart (3479.0 ± 426.6 versus 1287.3 ± 466.8; P < 0.05). LPA3 was weakly expressed in both cancer and normal gland tissue. In 48 (57%) out of 84 cases, enhanced expression of LPA2 protein was confirmed in carcinoma cells as compared with normal mammary epithelium by immunohistochemistry. Over-expression of LPA2 was detected in 17 (45%) out of 38 premenopausal women, as compared with 31 (67%) out of 46 postmenopausal women, and the difference was statistically significant (P < 0.05). CONCLUSION: These findings suggest that upregulation of LPA2 may play a role in carcinogenesis, particularly in postmenopausal breast cancer