BACKGROUND Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective non-interventional study of stroke prevention in patients with newly diagnosed non-valvular AF (NAVF) that is being conducted in 35 countries. Methods and Results: A total of 52,081 patients with a new diagnosis of NVAF were enrolled prospectively in GARFIELD-AF. Of these, 4859 (9.3%) were recruited in Japan (2010-2016). In cohort 1 (2010-2011), few patients were on non-vitamin K antagonist oral anticoagulants (NOAC) globally. From cohort 2 onwards (2011-2016), however, there was a rapid increase in NOAC use around the globe, especially in Japan. By the last year of enrolment (2015-2016), 67.9% of patients in Japan and 43.1% of patients globally were on NOAC±antiplatelet therapy (AP). In Japan and globally, 17.0% and 12.2% of patients, respectively, did not receive stroke prevention treatment. Few patients in Japan (5.7%) received AP only. Compared with the other countries, the unadjusted rates of all-cause mortality and major bleeding were low, while rates of stroke/systemic embolism were similar after 1 year of follow-up. CONCLUSIONS GARFIELD-AF continues to provide important information on the homogeneity and heterogeneity of baseline characteristics and treatment patterns in patients with newly diagnosed NVAF. This diversity reflects the differences in outcomes in Japan compared with the rest of the world.

Blood pressure (BP) control throughout the entire day is recommended for cardiovascular protection. Angiotensin-II receptor blockers (ARBs) are widely used in hypertensive patients because of beneficial class effects. It is uncertain, however, whether are there any differences in 24-h BP profiles among ARBs. We examined ambulatory blood pressure monitoring (ABPM) among 211 Japanese hypertensive patients (age, 69.4 +/- 9.6 years; female, 59.2%) under treatment with five different ARBs. Patients were divided into five groups according to ARBs prescribed. Patient backgrounds were almost identical in all the groups and there were no differences in office, 24-h and daytime BP; however, nighttime BP with olmesartan was significantly lower than with other ARBs. Office BPs with candesartan and telmisartan, but not other ARBs, correlated well with 24-h BP (p < 0.01). Also, there were higher correlations between daytime and nighttime BP with candesartan and telmisartan. In all patients, pulse pressure with office BP was significantly correlated with ambulatory arterial stiffness index (p = 0.001) and fluctuation of systolic BP on ABPM (p = 0.002). In conclusion, different ARB treatments produced meaningful differences in 24-h profiles.

Abstract Although blockade of the renin-angiotensin system by increasing the dose of angiotensin II receptor blockers (ARBs) is recommended to achieve clinical benefits in terms of blood pressure (BP) control and cardiovascular and renal outcomes, the effect of this increased dose on ambulatory BP monitoring has not been evaluated completely in Japanese patients with uncontrolled hypertension undergoing medium-dose ARB therapy. The primary objective of this study was to examine the effect of the relatively high dose of the ARB candesartan (12 mg/day) on 24-h systolic BP and the attainment of target BP levels in uncontrolled hypertension treated with a medium dose of ARBs. A total of 146 hypertensive patients (age: 69.9 ± 9.3 years; females: 65.8%) completed the study. After switching to candesartan at 12 mg/day, all these BP measurements decreased significantly (p<0.001). Attainment of the target office BP (p=0.0014) and 24-h BP levels (p=0.0296) also improved significantly. Subgroup analysis indicated that the reduction of 24-h systolic BP was larger in patients treated with diuretics than those without (p=0.0206). Multivariate analysis revealed a significant correlation between the combined ARB and diuretic therapy, and the change in 24-h systolic BP irrespective of preceding ARBs. In conclusion, the switching therapy to increased dose of candesartan caused significant reductions in office and ambulatory BP levels, and improved the attainment of target BP levels in patients with uncontrolled hypertension treated with a medium dose of ARBs. Combination with diuretics enhanced this effect.

Objectives: Although blockade of renin-angiotensin system by increased dose of angiotensin II receptor blockers (ARBs) is recommended from the perspectives of clinical benefits on cardiovascular and renal outcomes, effect of high-dose ARBs on ambulatory blood pressure monitoring (ABPM) was not fully evaluated in Japanese patients with hypertension. The aim of present study was to examine the effect of switching therapy from medium-dose of ARBs to high-dose candesartan 12 mg on ABPM and office BP. Methods: 164 hypertensive patients (age, 69.9 ± 9.3 years; female, 65.8%) were enrolled. At baseline and 3- to 6-month-period after the switching, we examined ABPM, office BP and drug-related adverse effects. Results: Baseline values of 24-hour, day-time, night-time BPs obtained from ABPM and office BP were 139 ± 14/79 ± 9, 144 ± 15/82 ± 9, 129 ± 17/73 ± 10, 148 ± 17/82 ± 11 mmHg, respectively. After the switching therapy, 24-hour BP (135 ± 15/76 ± 9, p < 0.001), day-time BP (139 ± 15/80 ± 10, p < 0.001), night-time BP (125 ± 17/70 ± 10, p < 0.001) and office BP (134 ± 16/75 ± 10, p < 0.0001) decreased significantly. The attaining target level of office BP and that of ABPM also significantly improved (p < 0.05, respectively). Multivariate analysis indicated that there were significant correlations observed between baseline 24-hour systolic BP (ß = −0.29, p < 0.0001), past history of cardiovascular diseases (ß = 4.7, p < 0.05), diuretics use (ß = −5.4, p < 0.05) and the change in 24-hour systolic BP during the follow-up period. The estimated glomerular filtration rate was slightly but significantly decreased, however none of the patients exhibited clinically progressive renal dysfunction. Conclusions: Switching therapy from medium-dose ARBs to high-dose candesartan effectively decreased out of office BPs throughout 24-hour-period as well as office BP.

Concerns about metabolic complications often disturb prolonged use of diuretics in Japan. We investigated 3-year safety and efficacy in Japanese patients with hypertension who were uncontrolled with angiotensin receptor blocker or angiotensin-converting enzyme inhibitor regimens and then switched to losartan (50 mg)/hydrochlorothiazide (12.5 mg; HCTZ) combinations. Blood pressure decreased favorably and maintained a steady state for 3 years (157 ± 16/88 ± 11 mm Hg to 132 ± 13/75 ± 9 mm Hg, P < .0001). Metabolic parameters maintained a limited range of changes after 3 years, and adverse events were markedly decreased after 1-year treatment. The losartan/HCTZ combination minimized diuretic-related adverse effects and thus may be useful for the treatment of Japanese patients with hypertension.

Background: Angiotensin-II receptor blockers (ARBs) are widely used for hypertensive patients because of beneficial class effects. It is uncertain, however, whether are there any differences in clinical effects among each ARB or not. Methods: We enrolled uncontrolled hypertensive patients treated by any ARB alone or combined for clinical trials. Data of basic characteristics, blood test and ambulatory blood pressure monitoring (ABPM) were collected. We analyzed the data by each ARB. Results: We enrolled 211 patients treated with candesartan (74), valsartan (62), telmisartan (30), losartan (28) and olmesartan (17). Average office blood pressure (BP) was 150.7 ± 15.3 /83.0 ± 11.2 mmHg, and average 24-hour BP was 139.5 ± 13.9/78.2 ± 9.0 mmHg. There were no differences in office BP, 24-hour BP and day time BP among ARBs. But night time BP was significantly low in patients with olmesartan (p < 0.01), and the difference of BP between day time and night time was also large in patients with olmesartan. Although there were no differences in office and ambulatory BPs, ambulatory arterial stiffness index (AASI), a marker of arterial stiffness, was significantly high in patients with candesartan (candesartan 0.57 ± 0.12 vs. others 0.52 ± 0.10, p = 0.002). This difference was significant after adjustment of background. Conclusion: Although office BP distributes similar ranges, there may be some differences in 24-hour profile of ambulatory BP within each ARB, and the differences could be related future organ damages.

Objective: Evidence is now available about the association between chronic kidney disease (CKD) and stroke. However, less is known about the underlying mechanisms, and there is currently no reliable marker for identifying stroke-prone high-risk patients among CKD patients.Methods: A total of 514 hypertensive patients aged >50 years (mean, 72.3 years; 37% men) underwent 24-h BP monitoring and measurement of circulatory high-sensitivity C-reactive protein (hs-CRP) and norepinephrine at baseline. CKD was defined as eGFR <60 ml/min/1.73 m(2) using the Cockcroft-Gault equation.Results and conclusion: During an average of 41 months (1751 person-years), there were 43 stroke events. Compared with hypertensive patients without CKD, those with CKD (n = 225) had higher levels of sleep systolic BP (SBP) (125 mmHg vs. 129 mmHg), circulatory hs-CRP (0.12 mg/L vs. 0.20 mg/L) and norepinephrine (332.2 pg/ml vs. 372.8 pg/ml; all P < 0.05). On multivariable analysis, the hazard ratio (HR) (95% CI) for stroke in CKD vs. non-CKD was 2.7 (1.2-6.9) (P < 0.05). CKD, as well as the baseline presence of silent cerebral infarction, sleep SBP increase, and high hs-CRP level (highest quartile: >= 0.42 mg/L) were independently and additively associated with stroke events; above all, there was a synergistic effect of CKD and high norepinephrine level (highest quartile: >= 538 pg/ml) on stroke risk (all P < 0.05). Among hypertensive patients with CKD, those within the highest quartiles of norepinephrine had a greater stroke risk compared to those who were in the lower quartiles of norepinephrine (HR (95% CI): 2.2 (1.0-4.5); P = 0.045).In conclusion, CKD is an independent predictor of stroke in Japanese hypertensive patients; in particular, hypertensive patients with CKD and a high norepinephrine level have a synergistically augmented stroke risk. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

The long-term antihypertensive efficacy and safety of losartan/hydrochlorothiazide (HCTZ) combinations have not been appropriately evaluated in Japan. In this study, treated hypertensive patients taking angiotensin-receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) regimens not at blood pressure (BP) goals proposed by the Japanese Society of Hypertension (JSH) were switched to losartan/HCTZ combinations and followed for 1 year. Data analysis included 244 patients aged 64.5±10.7 years, 56% male, 27% with diabetes mellitus and 36% with dyslipidemia. Pre-switching BP 157±16/88±10 mm Hg promptly decreased and maintained a steady state, reaching 132±15/77±9 mm Hg (P<0.001) 1 year later. After 1 year of treatment, 50% of patients cleared the goals of the JSH guideline for systolic BP and 79% for diastolic BP. Patients with maximal doses of ARBs tended to show larger decreases in BP (159±11/90±10 to 128±10/75±8 mm Hg, P<0.001, n=32). Clinical and laboratory adverse events were reported for 29 patients (11%), but serious abnormalities were not observed. In particular, plasma levels of uric acid (UA) were well-maintained for 1 year, and significant decreases in UA were observed in patients with higher levels of UA (⩾7.0 mg dl−1). Losartan/HCTZ combinations showed strong and steady hypotensive abilities and acceptable safety and tolerability in patients currently not at BP goals with regimens including ARBs or ACEIs in Japan.

Background-Matrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing LV failure.Methods and Results-LV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 months (n = 10), (2) SHHF at 13 months (n = 12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg . kg(-1) . d(-1) PO; n = 14), (4) normotensive Wistar-Furth rats (WF) at 9 months (n = 12), and (5) WF at 13 months (n = 12). Plasma concentrations of the MMP inhibitor (116+/-11 mu mol/L) reduced in vitro LV myocardial MMP-2 activity by approximate to 100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months was reduced in the SHHF group compared with WF (3578+/-477 versus 5983+/-109 mm Hg/s, P less than or equal to0.05). LV volume measured at an equivalent ex vivo pressure (10 mm Hg) was increased in SHHF at 9 months compared with WF (443+/-12 versus 563+/-33 mL, P less than or equal to0.05) and increased further by 13 months (899+/-64 mL, P less than or equal to0.05). LV myocardial MMP-2 activity was increased by approximate to2-fold in SHHF at 9 and 13 months. With MMP inhibition, LV peak +dP/dt was similar to WF values and LV volume was reduced compared with untreated SHHF values (678+/-28 mL, P less than or equal to0.05).Conclusions-MMP activity contributes to LV dilation and progression to LV dysfunction in a rodent HF model, and direct MMP inhibition can attenuate this process.

A structural event during the evolution of a myocardial infarction (MI) is left ventricular (LV) remodeling. The mechanisms that contribute to early changes in LV myocardial remodeling in the post-MI period remain poorly understood. Matrix metalloproteinases (MMPs) contribute to tissue remodeling in several disease states. Whether and to what degree MMP activation occurs within the myocardial interstitium after acute MI remains to be determined. Adult pigs (n = 15) were instrumented to measure regional myocardial function and interstitial MMP levels within regions served by the circumflex and left anterior descending arteries. Regional function was measured by sonomicrometry, and interstitial MMP levels were determined by selective microdialysis and zymography as well as by MMP interstitial fluorogenic activity. Measurements were performed at baseline and sequentially for up to 3 h after ligation of the obtuse marginals of the circumflex artery. Regional fractional shortening fell by over 50% in the MI region but remained unchanged in the remote region after coronary occlusion. Release of soluble MMPs, as revealed by zymographic activity of myocardial interstitial samples, increased by 2 h post-MI. The increased zymographic activity after MI was consistent with MMP-9. Myocardial interstitial MMP fluorogenic activity became detectable within the ischemic region as early as 10 min after coronary occlusion and significantly increased after 1 h post-MI. MMP fluorogenic activity remained unchanged from baseline values in the remote region. The present study demonstrated that myocardial MMP activation can occur within the MI region in the absence of reperfusion. These unique results suggest that MMP release and activation occurs within the ischemic myocardial interstitium in the early post-MI period.

Changes in myocardial matrix metalloproteinase (MMP) activity and expression have been associated with left ventricular (LV) remodeling. A recent study demonstrated that LV myocytes synthesize and release MMPs, which suggests that LV myocytes may participate in myocardial remodeling. However, extracellular stimuli that may potentially influence LV myocyte MMP production remains to be defined. In the present study MMP activity and expression were measured in porcine LV myocyte preparations (10 5 total cells; n = 6) following incubation (6 h) with endothelin-1 (ET-1;50 pM), angiotensin II (ANG II; 1 μM), or the β-receptor agonist isoproterenol (Iso; 10 nM). LV myocyte-conditioned media were then subjected to gelatin zymography and an MMP-2 antibody capture assay. MMP zymographic gelatinase activity and MMP-2 content were increased by over 40% in LV myocyte-conditioned media after incubation with ET-1 or ANG II ( P < 0.05). Exposure to the phorbol ester phorbol 12-myristate 13-acetate (PMA; 50 ng/ml) resulted in a 30% increase in zymographic gelatinase activity and a 63% increase in MMP-2 content ( P < 0.05), suggesting that protein kinase C activation may be an intracellular mechanism for MMP induction. With the use of a confocal microscopy, membrane type-1 MMP (MT1-MMP) was localized to porcine LV myocytes, and immunoblotting for MT1-MMP using LV myocyte extracts revealed that after exposure to Iso, ET-1, ANG II, or PMA ( P < 0.05), MT1-MMP abundance increased over 50%. Thus stimulation of specific neurohormonal systems that are relevant to LV remodeling influences LV myocyte MMP synthesis and release.

BACKGROUND:Matrix metalloproteinases (MMPs) contribute to matrix remodeling in disease states such as tumor metastases. Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to increase MMP expression, and membrane-type MMP or MT1-MMP has been implicated to activate MMPs. The present study examined whether and to what degree EMMPRIN and MT1-MMP were expressed in human left ventricular (LV) myocardium as well as the association with MMP activity and expression in dilated cardiomyopathy (DCM).METHODS AND RESULTS:LV myocardial zymographic MMP activity increased by >2-fold with both nonischemic DCM (n=21) and ischemic DCM (n=16) compared with normal (n=13). LV myocardial abundance of MMP-9 was increased with both forms of DCM. MMP-2 and MMP-3 were increased with nonischemic DCM. MMP-1 levels were decreased with both forms of DCM. EMMPRIN increased by >250% and MT1-MMP increased by >1000% with both forms of DCM.CONCLUSIONS:Increased LV myocardial MMP activity and selective upregulation of MMPs with nonischemic and ischemic forms of DCM occurred. Moreover, a local MMP induction/activation system was identified in isolated normal human LV myocytes that was upregulated with DCM. The control of MMP activation and expression in the failing human LV myocardium represents a new and potentially significant therapeutic target for this disease process.