Renoprotective effect of chronic treatment with sodium-glucose cotransporter 2 inhibitors and its associated factors in Japanese patients with chronic heart failure and diabetes.

Background: Recent clinical trials have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on renal function in heart failure patients. This study confirmed the renoprotective effect of treatment with SGLT2 inhibitors in Japanese patients with chronic heart failure and diabetes and further investigated what cardiac/hemodynamic and noncardiac factors are involved in its effect. Methods: Eligible 50 outpatients with chronic heart failure and type-2 diabetes mellitus chronically taking SGLT2 inhibitors were enrolled. Annual changing rates of estimated glomerular filtration rate (eGFR) were compered before and after treatment with SGLT2 inhibitors and the associations of the change in eGFR slope after SGLT2 inhibitor administration with changes in various clinical and echocardiographic parameters were evaluated. Results: The mean follow-up periods before and after SGLT2 inhibitor administration were 2.6 and 1.9 years, respectively. Changing rates of eGFR per year were significantly improved after treatment with SGLT2 inhibitors (-5.78 ± 7.67 to -0.43 ± 10.81 mL/min/1.73 m2/year, p = 0.006). The daily doses of loop diuretics were not altered after SGLT2 inhibitor administration. Neither decreased body weight nor increased hematocrit was associated with the change in eGFR slope before and after SGLT2 inhibitor administration. While, the decrease in inferior vena cava diameter and the increase in its respiratory collapsibility were significantly correlated with the improvement of eGFR decline slope after SGLT2 inhibitor administration. Conclusions: Our findings indicated that chronic treatment with SGLT2 inhibitors ameliorated annual decline in eGFR in Japanese patients with chronic heart failure, suggesting the possibility that the improvement of venous congestion was involved in its renoprotective effect.

Impact of Percutaneous Transluminal Renal Angioplasty on Autonomic Nervous System and Natriuresis in Hypertensive Patients With Renal Artery Stenosis.

Background We investigated the early postoperative effect of percutaneous transluminal renal angioplasty on ambulatory blood pressure (BP) and the circadian characteristics of natriuresis and autonomic nerve activity. Methods and Results A total of 64 patients with hypertension with hemodynamically significant renal artery stenosis (mean age, 60.0±21.0 years; 31.3% fibromuscular dysplasia) who underwent angioplasty were included, and circadian characteristics of natriuresis as well as heart rate variability indices, including 24-hour BP, low-frequency and high-frequency (HF) components, and the percentage of differences between adjacent normal R-R intervals >50 ms were evaluated using an oscillometric device, TM-2425, both at baseline and 3 days after angioplasty. In both the fibromuscular dysplasia and atherosclerotic stenosis groups, 24-hour systolic BP (fibromuscular dysplasia, -19±14; atherosclerotic renal artery stenosis, -11±9 mm Hg), percentage of differences between adjacent normal R-R intervals >50 ms, HF, brain natriuretic peptide, and nighttime urinary sodium excretion decreased (all P<0.01), and heart rate increased (both P<0.05) after angioplasty. In both groups, revascularization increased the night/day ratios of percentage of differences between adjacent normal R-R intervals >50 ms (both P<0.01) and HF, and decreased those of low frequency/HF (all P<0.05) and nighttime urinary sodium excretion (fibromuscular dysplasia, 1.17±0.15 to 0.78±0.09; atherosclerotic renal artery stenosis, 1.37±0.10 to 0.99±0.06, both P<0.01). Multiple logistic regression analysis indicated that a 1-SD increase in baseline low frequency/HF was associated with at least a 15% decrease in 24-hour systolic BP after angioplasty (odds ratio, 2.30 [95% CI, 1.03-5.67]; P<0.05). Conclusions Successful revascularization results in a significant BP decrease in the early postoperative period. Intrarenal perfusion might be a key modulator of the circadian patterns of autonomic nerve activity and natriuresis, and pretreatment heart rate variability evaluation seems to be important for treatment success.

The European/International Fibromuscular Dysplasia Registry and Initiative (FEIRI)-clinical phenotypes and their predictors based on a cohort of 1000 patients.

AIMS: Since December 2015, the European/International Fibromuscular Dysplasia (FMD) Registry enrolled 1022 patients from 22 countries. We present their characteristics according to disease subtype, age and gender, as well as predictors of widespread disease, aneurysms and dissections. METHODS AND RESULTS: All patients diagnosed with FMD (string-of-beads or focal stenosis in at least one vascular bed) based on computed tomography angiography, magnetic resonance angiography, and/or catheter-based angiography were eligible. Patients were predominantly women (82%) and Caucasians (88%). Age at diagnosis was 46 ± 16 years (12% ≥65 years old), 86% were hypertensive, 72% had multifocal, and 57% multivessel FMD. Compared to patients with multifocal FMD, patients with focal FMD were younger, more often men, had less often multivessel FMD but more revascularizations. Compared to women with FMD, men were younger, had more often focal FMD and arterial dissections. Compared to younger patients with FMD, patients ≥65 years old had more often multifocal FMD, lower estimated glomerular filtration rate and more atherosclerotic lesions. Independent predictors of multivessel FMD were age at FMD diagnosis, stroke, multifocal subtype, presence of aneurysm or dissection, and family history of FMD. Predictors of aneurysms were multivessel and multifocal FMD. Predictors of dissections were age at FMD diagnosis, male gender, stroke, and multivessel FMD. CONCLUSIONS: The European/International FMD Registry allowed large-scale characterization of distinct profiles of patients with FMD and, more importantly, identification of a unique set of independent predictors of widespread disease, aneurysms and dissections, paving the way for targeted screening, management, and follow-up of FMD.

How should we define appropriate patients for percutaneous transluminal renal angioplasty treatment?

Renovascular hypertension (RVH) is one of the most common causes of secondary hypertension and can result in resistant hypertension. RVH is associated with an increased risk for progressive decline in renal function, cardiac destabilization syndromes including "flash" pulmonary edema, recurrent congestive heart failure, and cerebrocardiovascular disease. The most common cause of renal artery stenosis (RAS) is atherosclerotic lesions, followed by fibromuscular dysplasia. The endovascular technique of percutaneous transluminal renal angioplasty (PTRA) with or without stenting is one of the standard treatments for RAS. Randomized controlled trials comparing medical therapy with PTRA to medical therapy alone have failed to show a benefit of PTRA; however, the subjects of these randomized clinical trials were limited to atherosclerotic RAS patients, and patients with the most severe RAS, who would be more likely to benefit from PTRA, might not have been enrolled in these trials. This review compares international guidelines related to PTRA, reevaluates the effects of PTRA treatment on blood pressure and renal and cardiac function, discusses strategies for the management of RVH patients, and identifies factors that may predict which patients are most likely to benefit from PTRA.

Impact of Percutaneous Revascularization on Left Ventricular Mass and Its Relationship to Outcome in Hypertensive Patients With Renal Artery Stenosis.

BACKGROUND: We investigated the effects of percutaneous transluminal renal angioplasty on left ventricular (LV) mass, and the impact of LV mass reduction on outcomes. METHODS: A total of 144 hypertensive patients with renal artery stenosis (RAS) (mean age 69 years; 22.2% fibromuscular dysplasia (FMD)) who underwent angioplasty were included. Echocardiography was performed at baseline and after 1 year, and patients were thereafter followed up for a median of 5.6 years for primary composite outcomes. RESULTS: In both the FMD and atherosclerotic stenosis (ARAS) groups, LV mass decreased after angioplasty, but the decrease in LV mass index (-15.4 ± 18.3% vs. -0.8 ± 27.8%, P < 0.01) as well as the regression rate of LV hypertrophy was greater in FMD. Multiple logistic regression analysis indicated that FMD (odds ratio (OR) 2.94, P < 0.01), severe RAS (≥90%) (OR 2.94, P < 0.05), and higher LV mass index at baseline (OR 2.94 for 1 SD increase, P < 0.001) were independent predictors of LV mass index decrease of at least 20%. The primary composite outcomes occurred in 45 patients (31.3%). In FMD, lower LV mass index after 1 year (hazard ratio 2.81 for 1 SD increase, P < 0.05) or regression of LV mass (hazard ratio 0.75 for 5% decrease, P = 0.054) showed a tendency to be associated with better outcomes; however, these associations were not found in ARAS. CONCLUSIONS: Hypertensive patients with ARAS have less regression of LV mass in response to angioplasty than those with FMD, and LV mass regression is less useful as a surrogate marker of outcomes especially in ARAS.

Gene and environmental interactions according to the components of lifestyle modifications in hypertension guidelines.

Risk factors for hypertension consist of lifestyle and genetic factors. Family history and twin studies have yielded heritability estimates of BP in the range of 34-67%. The most recent paper of BP GWAS has explained about 20% of the population variation of BP. An overestimation of heritability may have occurred in twin studies due to violations of shared environment assumptions, poor phenotyping practices in control cohorts, failure to account for epistasis, gene-gene and gene-environment interactions, and other non-genetic sources of phenotype modulation that are suspected to lead to underestimations of heritability in GWAS. The recommendations of hypertension guidelines in major countries consist of the following elements: weight reduction, a healthy diet, dietary sodium reduction, increasing physical activity, quitting smoking, and moderate alcohol consumption. The hypertension guidelines are mostly the same for each country or region, beyond race and culture. In this review, we summarize gene-environmental interactions associated with hypertension by describing lifestyle modifications according to the hypertension guidelines. In the era of precision medicine, clinicians who are responsible for hypertension management should consider the gene-environment interactions along with the appropriate lifestyle components toward the prevention and treatment of hypertension. We briefly reviewed the interaction of genetic and environmental factors along the constituent elements of hypertension guidelines, but a sufficient amount of evidence has not yet accumulated, and the results of genetic factors often differed in each study.

Factors Associated with Outcomes of Percutaneous Transluminal Renal Angioplasty in Patients with Renal Artery Stenosis: A Retrospective Analysis of 50 Consecutive Cases.

BACKGROUND: The results of recent trials have brought some confusion to the treatment strategy for renal artery stenosis (RAS). To evaluate the applicability of percutaneous transluminal renal angioplasty (PTRA) for RAS, we extracted the factors that may affect the effectiveness of PTRA from cases experienced at a hypertension center. METHODS AND RESULTS: We retrospectively assessed the blood pressure (BP) lowering effects and renoprotective effects in 50 consecutive patients that had hemodynamically significant RAS and had undergone PTRA and stenting during 2001-2005. Subjects were diagnosed with atherosclerotic RAS (42), fibromuscular dysplasia (6), or Takayasu disease (2). After PTRA, BP significantly lowered from 152.3/80.3 mmHg to 132.6/73.2 mmHg (p < 0.05), but the estimated glomerular filtration rate (eGFR) did not change significantly. There were no factors associated with the BP lowering effects of PTRA. The baseline resistive index (RI) was negatively correlated with the change in eGFR (p < 0.05). After correction for age, sex, BMI, and the dose of contrast medium, the association of RI with change in eGFR remained significant. CONCLUSION: In cases with hemodynamically significant RAS, PTRA lowered BP but was not effective in improving renal function. Higher baseline RI may be a factor for predicting poor clinical course of renal function after PTRA.

Effects of Percutaneous Transluminal Renal Angioplasty on Office and Home Blood Pressure and Home Blood Pressure Variability in Hypertensive Patients With Renal Artery Stenosis.

This study included 126 hypertensive patients with renal artery stenosis (mean age, 63 years; 22.2% fibromuscular dysplasia [FMD]) and investigated the effects of percutaneous transluminal renal angioplasty on office and home blood pressure (BP), and BP variability estimates derived from home BP, both at baseline and up to 12 months after angioplasty. Home BP was measured for 7 consecutive days, and the threshold defining uncontrolled home BP was ≥135/85 mm Hg. In both the FMD and atherosclerotic stenosis (ARAS) groups, office and home BP decreased significantly after angioplasty (all P<0.01), but the decrease in morning home (-22±19 versus -10±20 mm Hg; P<0.01) but not in office (-32±24 versus -23±28 mm Hg; P=0.11) systolic BP at 12 months was significantly greater in FMD. In both groups, all morning BP variability indices except the coefficient of variation in ARAS decreased significantly after revascularization (all P<0.05 by repeated-measures ANOVA). The decrease in all morning systolic BP variability estimates was greater for FMD than for ARAS (all P<0.05 by 2-way repeated-measures ANOVA), with the exception of variability independent of the mean (P=0.11). The prevalence of uncontrolled home BP was 77.0% at baseline and 38.9% after revascularization. Duration of hypertension (odds ratio, 1.48), ARAS (odds ratio, 3.18), and the presence of proteinuria (odds ratio, 2.10) were independent predictors of uncontrolled home BP after revascularization (all P<0.05). In conclusion, renal angioplasty produced a greater decrease of morning home systolic BP in FMD; however, in both groups, it decreased BP variability irrespective of BP response. Measurement of home BP seems to be important for treatment success, especially in ARAS.

Effects of cigarette smoking on ambulatory blood pressure, heart rate, and heart rate variability in treated hypertensive patients.

We investigated the influence of cigarette smoking on the levels and circadian patterns of blood pressure (BP), heart rate (HR), and HR variability (HRV) in hypertensive patients. Sixteen hypertensive smokers (57 ± 2 years old) receiving antihypertensive treatments participated in this study. Ambulatory monitoring of BP, HR, and electrocardiograms was performed every 30 min for 24 hours on a smoking day and nonsmoking day in a randomized crossover manner. Average 24-hour BP and daytime BP were significantly higher in the smoking period than in the nonsmoking period. No significant differences were observed in nighttime BP between the two periods. Average 24-hour and daytime HR, but not nighttime HR, were also higher in the smoking period than in the nonsmoking period. The daytime high frequency (HF) component of HRV was attenuated more in the smoking period than in the nonsmoking period. No significant differences were observed in the low frequency (LF) components of HRV or LF/HF ratio between the two periods. These results demonstrated that cigarette smoking increased the daytime and average 24-hour BP and HR, and the increases observed in daytime BP and HR were associated with the attenuation of parasympathetic nerve activity.

Incidence and risk factors for restenosis, and its impact on blood pressure control after percutaneous transluminal renal angioplasty in hypertensive patients with renal artery stenosis.

OBJECTIVE: Percutaneous transluminal renal angioplasty (PTA) is one of the standard treatments for renal artery stenosis (RAS). We investigated the frequency and risk factors for restenosis, and its impact on blood pressure (BP) control. METHODS: A total of 175 hypertensive patients with RAS [mean age 60 years; 34% women; 30.3% fibromuscular dysplasia (FMD)] with 207 treated renal arteries were included and followed for more than 1 year without reangioplasty. Diagnosis of restenosis was based on duplex ultrasonographic findings, and data including BP and antihypertensive medication were collected consecutively. RESULTS: During follow-up (mean, 5.1 years), 56 patients (32.0%) developed restenosis. In multivariate Cox regression analysis, FMD was an independent predictor of restenosis (hazard ratio 2.65, P < 0.05). When divided into two groups based on FMD or atherosclerotic RAS (ARAS), the presence of previous cardiovascular disease (hazard ratio 2.84) as well as severe RAS (≥90%) (hazard ratio 3.95) in ARAS were independent predictors of restenosis (P < 0.05, respectively). At 1 year after PTA, 35 patients (20.0%) had developed restenosis. When divided into four groups on the basis of FMD or ARAS, and the absence/presence of restenosis at 1 year, the number of antihypertensive drugs was significantly lower in both FMD and ARAS patients without restenosis (P < 0.01, respectively); however, a significant difference in decrease in SBP (-31 ±â€Š19 vs. -12 ±â€Š25 mmHg, P < 0.05) as well as cure of hypertension (36.4 vs. 5.0%, P < 0.01) between the absence/presence of restenosis was found only in FMD patients. CONCLUSION: The frequency of restenosis after renal PTA is significant, and the presence of restenosis diminishes the benefit of its treatment, especially for FMD.

Serum Brain Natriuretic Peptide Concentration 60 Days After Surgery as a Predictor of Long-Term Prognosis in Patients Implanted With a Left Ventricular Assist Device.

Mechanical circulatory support by a left ventricular assist device (LVAD) is used to bridge patients with advanced heart failure to transplant or as a definitive treatment. We retrospectively sought predictors of long-term outcome in a cohort of 83 patients who had undergone LVAD treatment. We subjected perioperative clinical data of patients to statistical analysis to establish parameters associated with all-cause mortality, and the cutoff values, sensitivity, and specificity of those that had a statistically significant relation with survival. Mean follow-up was 717 days (standard deviation, 334 days; range, 17-1,592 days). Fourteen patients (16.8%) died, but nine (10.8%) were weaned from support. Serum brain natriuretic peptide (BNP) concentration measured 60 days after implantation was significantly associated with all-cause mortality. The optimal BNP cutoff value to predict death during LVAD support was 322 pg/ml, with a sensitivity of 71.4% and specificity of 79.8%. Two-year survival was 92.0% in those with 60 days serum BNP concentration <322 pg/ml compared with 70.5% in those in whom it was ≥322 pg/ml (p = 0.003). The relation between BNP and survival likely reflects recovery of native myocardial function and improvements in global health and should assist clinicians in the on-going management of long-term LVAD therapy.

Higher circulatory level of endothelin-1 in hypertensive subjects screened through a cross-sectional study of rural Bangladeshi women.

Endothelin-1 (ET-1) is a potential marker of the endothelial dysfunction, which has been shown to be elevated in hypertensive subjects. No previous study has investigated the circulatory level of ET-1 and hypertension in a South Asian country. The present study assessed the circulating levels of ET-1 in subjects with or without hypertension and further examined the association of ET-1 with clinical and metabolic parameters. A total of 2543 rural Bangladeshi women with a mean age of 44.5 years were studied using a cross-sectional survey. Multiple regressions were used to examine the association between the circulatory ET-1 levels and hypertension. The prevalence of hypertension was 29.3%. The ET-1 levels were significantly higher in the hypertensive (mean 3.08 pg ml(-1), s.e. (0.19)) than in the non-hypertensive subjects (mean 2.01 pg ml(-1), s.e. (0.03)) (P = 0.001). After adjusting for age, the ET-1 level had significant positive associations with the diastolic blood pressure (P = 0.002), systolic blood pressure (P = 0.001), mean arterial pressure (P = 0.002) and fasting blood glucose (P = 0.002). In a tertile analysis, we found that hypertension in the subjects was significantly increased as the levels of ET-1 increased (P for the trend = 0.001). In a stepwise multiple regression analysis, after adjusting for age and all other potential variables, we found that the mean arterial pressure and the fasting plasma levels have significant associations with the ET-1 level. The present study demonstrates that there is a higher concentration of ET-1 among the hypertensive subjects in an apparently healthy population of Bangladeshi rural women. The relationship between ET-1 and hypertension requires further investigation to define the clinical utility and predictive value of serum ET-1 levels for hypertension for a South Asian population.

Impact of pump replacement on outcome in advanced heart failure patients with left ventricular assist system.

Pump thrombosis is one of the major adverse events associated with the use of a left ventricular assist system (LVAS) in patients with advanced heart failure. We investigated the clinical implication of pump replacement because of thrombus formation. This study included 87 patients who underwent implantation of a Nipro (Toyobo) pulsatile extracorporeal LVAS intended as a bridge to transplantation and were alive more than 3 months after implantation. The pump of this device is translucent, and daily evaluation for signs of thrombus formation was performed. Pump replacement was performed for significant thrombus formation that became visible. Data collection including demographics as well as hematologic values were performed 1 day before (baseline) and 3 months after implantation, and all patients were followed for 2 years or until death. At 3 months after LVAS implantation, 41 patients (47.1%) had undergone pump replacement because of pump thrombus. Baseline body surface area <1.63 m(2) was a significant predictor of pump replacement (hazard ratio [HR] 2.15, P = 0.04). At 3 months after implantation, there was a significantly higher incidence of stroke (P < 0.05) as well as a significantly greater decrease in body weight (F = 4.92, P = 0.03) in patients who underwent pump replacement as compared to those without. The 2-year mortality after implantation was 26.4%. Multivariate Cox regression analysis showed that pump replacement within 3 months after implantation was an independent predictor of mortality (HR 2.50, P = 0.03). In conclusion, pump replacement for thrombus formation may have a strong association with worse outcome. Our results reconfirm the clinical importance of device thrombus in the management of LVAS.

Serial changes in renal function as a prognostic indicator in advanced heart failure patients with left ventricular assist system.

BACKGROUND: Left ventricular assist system (LVAS) implantation is an established treatment for patients with advanced heart failure. We investigated the clinical implication of serial changes in renal function after LVAS implantation. METHODS: This study included 110 patients who underwent pulsatile LVAS implantation intended as a bridge to transplantation and were alive more than 2 weeks after implantation. Data collection of demographic and hematologic values was performed 1 day before (baseline) and 2 weeks after implantation. All patients were monitored for 2 years or until death. RESULTS: The 2-year postimplantation mortality rate was 31.8%. Multivariate Cox regression analysis showed the baseline estimated glomerular filtration rate (eGFR) was an independent predictor of death (hazard ratio, 0.90 for each 10 mL/min increase, p<0.05). The eGFR significantly increased at 2 weeks after LVAS implantation (70.5±37.8 to 121.0±78.8 mL/min, p<0.01). Kaplan-Meier curves with log-rank tests showed significantly poorer event-free survival rates in the group with an inframedian value of change in eGFR at 2 weeks after implantation (ΔeGFR; p=0.03) as well as in the group with the lowest tertile of eGFR at 2 weeks after implantation (2w-eGFR; p<0.01). Multivariate Cox regression analysis showed that ΔeGFR (hazard ratio, 0.89 for each 10 mL/min increase) and 2w-eGFR (hazard ratio, 0.92 for each 10 mL/min increase) were independent predictors of death (p<0.01, respectively). CONCLUSIONS: Impaired renal function, and in particular, a poor response of eGFR to LVAS implantation, may have a strong association with worse outcome.

Time-dependent alterations of VEGF and its signaling molecules in acute lung injury in a rat model of sepsis.

Molecular mechanisms of sepsis-associated acute lung injury (ALI) are poorly defined. Since vascular endothelial growth factor (VEGF) is a potent vascular permeability and mitogenic factor, it might contribute to the development of ALI in sepsis. Thus, using lipopolysaccharide (LPS)-induced (15 mg/kg, intraperitoneal) endotoxemic rat model, we studied the timeline (1, 3, 6, and 10 h) of pulmonary VEGF expression and its signaling machinery. Levels of pulmonary VEGF and its angiogenic-mediating receptor, Flk-1, were downregulated by LPS in a time-dependent manner; levels of plasma VEGF and its permeability-mediating receptor, Flt-1, in contrast, was upregulated with time. In addition, blockade of Flt-1 could improve the downregulated pulmonary VEGF level and attenuate the elevated plasma and pulmonary levels of TNF-α, followed by improvement of arterial oxygenation and wet-to-dry weight ratio of the lung. Expression of signaling, pro- and or apoptotic factors after LPS administration were as follows: phosphorylated Akt, a downstream molecule was downregulated time dependently; endothelial nitric oxide synthase levels were significantly reduced; pro-apoptotic markers caspase 3 and Bax were upregulated whereas levels of Bcl-2 were downregulated. The present findings show that VEGF may play a role through the expression of Flt-1 in LPS-induced ALI. Moreover, downregulation of VEGF signaling cascade may account for LPS-induced apoptosis and impaired physiological angiogenesis in lung tissues, which in turn may contribute to the development of ALI induced by LPS.

Time-dependent expression of endothelin-1 in lungs and the effects of TNF-α blocking peptide on acute lung injury in an endotoxemic rat model.

Endothelin (ET)-1 is a potent vasoconstrictor that has been implicated in the pathogenesis of a number of diseases, and some studies suggest that circulating ET-1 is elevated in sepsis. The present study investigated whether ET plays a role in sepsis-mediated acute lung injury and whether its expression could be down regulated by blockade of TNF-α in septic lung. Male Wistar rats at 8 weeks of age were administered with either saline or lipopolysaccharide (LPS) at different time points (1, 3, 6 and 10 h) and various tests were then performed. The features of acute lung injury were observed at 1 h after LPS administration, which gradually became severe with time. Systolic and diastolic pressures were reduced just about one hour after LPS administration, whereas pulmonary TNF-α levels were significantly increased at various time points after LPS administration. LPS induced a time-dependent expression of ET-1 and ET(A) receptor in the lungs compared to control, peaking and increasing by 3 fold at 6 h after induction of endotoxemia, whereas levels of ET(B) receptor, which has vasodilating effects, were remarkably down regulated time-dependently. We conclude that time-dependent increase of ET-1 and ET(A) receptor with the down regulation of ET(B) receptor may play a role in the pathogenesis of acute lung injury in endotoxemia. Finally, treatment of LPS-administered rats with TNF-α blocking peptide for three hours significantly suppressed levels of pulmonary ET-1. These data taken together, led us to conclude that differential alteration in ET expression and its receptors may be mediated by TNF-α and may, in part, account for the pathogenesis of acute lung injury in endotoxemia.

Interleukin-6 as an independent predictor of future cardiovascular events in high-risk Japanese patients: comparison with C-reactive protein.

Inflammation is associated with the development of atherosclerotic vascular lesions and some inflammatory parameters are used as cardiovascular (CV) risk markers. The present study was designed to assess the predictive power of interleukin (IL)-6 for future CV events. In 121 Japanese patients with multiple CV risk factors and/or disease, serum concentrations of IL-6 and high sensitive C-reactive protein (hs-CRP) were measured. During follow-up periods (mean, 2.9 years) after the baseline assessment, 50 patients newly experienced CV events such as stroke/transient ischemic attack (n=10), heart failure hospitalization (n=6), acute coronary syndrome (n=7), and revascularization for coronary artery disease (n=15) and peripheral arterial disease (n=12). The serum level of IL-6, but not hs-CRP, was significantly higher in patients who had CV events than in event-free subjects (3.9±2.6 and 3.0±2.2 pg/mL, P=0.04). When the patients were divided into three groups by tertiles of basal levels of IL-6 (<1.85, 1.85-3.77, and ≥3.77 pg/mL), cumulative event-free rates by the Kaplan-Meier method were decreased according to the increase in basal IL-6 levels (65%, 50%, and 19% in the lowest, middle, and highest tertiles of IL-6, respectively; log-rank test, P=0.002). By univariate Cox regression analysis, previous CV disease, creatinine clearance, and serum IL-6 levels were significantly associated with CV events during follow-up. Among these possible predictors, the highest tertile of IL-6 was only an independent determinant for the morbidity in the multivariate analysis (hazard ratio 2.80 vs. lowest tertile, P=0.006). These findings indicate that IL-6 is a powerful independent predictor of future CV events in high-risk Japanese patients, suggesting its predictive value is superior to that of hs-CRP.

VEGF signaling is disrupted in the hearts of mice lacking estrogen receptor alpha.

Estrogen has widely been credited for cardioprotection in women. However, the exact mechanisms that underlie these beneficial estrogenic effects are not completely understood. Here, we sought to: 1) elucidate estrogen's influence on levels of vascular endothelial growth factor (VEGF), a key regulator of cardiovascular processes, and components of its basic signaling machinery (VEGF receptors, Akt, and eNOS) in the heart, and 2) delineate the specific estrogen receptor signaling pathway that mediates its beneficial effects using mice lacking either estrogen receptor alpha or estrogen receptor beta. We analyzed pattern of VEGF signaling and the associated coronary capillary density in the hearts of wild-type (WT), estrogen receptor alpha knockout (ERalpha-KO), and estrogen receptor beta knockout (ERbeta-KO) female mice. Deletion of estrogen receptor alpha causes a marked decrease in coronary capillary density compared to wild-type (WT) mice, while that of estrogen receptor beta had a minimal effect. Consistent with reduced coronary capillary density, cardiac expression levels of VEGF and its signaling molecules (two receptors, phosphorylated Akt, and eNOS) in ERalpha-KO mice were reduced to half of WT, in contrast to ERbeta-KO mice that only showed a slight decrease. Moreover, activity of eNOS was greatly lowered in ERalpha-KO mice. These data suggest that estrogen acts largely via estrogen receptor alpha to regulate VEGF transcription and possibly components of its basic signaling and ultimately, the development of coronary microvasculature in the heart. This molecular and histological data, in part, sheds some insights into potential mechanisms that may likely underlie estrogen's cardioprotective effects.

Chronic kidney disease as an independent risk factor for new-onset atrial fibrillation in hypertensive patients.

OBJECTIVE: Chronic kidney disease (CKD) has recently been recognized to be a powerful predictor of cardiovascular morbidity and mortality. Atrial fibrillation (AF), which is a common arrhythmia in hypertensives, is associated with increased risks of cardiovascular events and death. However, the association between CKD and the onset of AF has not been fully elucidated. The present study assessed the hypothesis that CKD may influence the onset of AF in hypertensives. METHODS: A total of 1118 hypertensive patients (mean age, 63 years) without previous paroxysmal AF, heart failure, myocardial infarction, or valvular disease were enrolled. CKD was defined as decreased glomerular filtration rate (<60 ml/min per 1.73 m) and/or the presence of proteinuria (>or=1+). RESULTS: During follow-up periods (mean, 4.5 years), 57 cases of new-onset AF were found (1.1% per year). Kaplan-Meier curves revealed that the cumulative AF event-free rate was decreased in the CKD group (log-rank test P < 0.001). By univariate Cox regression analysis, age, smoking, left atrial dimension, left ventricular mass index, and the presence of CKD were significantly associated with the occurrence of AF. Among these possible predictors, CKD (hazard ratio 2.18, P = 0.009) was an independent determinant for the onset of AF in multivariate analysis. Advanced stages of CKD (stages 4 and 5) were strongly related to the increased occurrence of AF. CONCLUSION: The present study demonstrated that the complication of CKD, especially progressed renal dysfunction, was a powerful predictor of new-onset AF in hypertensive patients, independently of left ventricular hypertrophy and left atrial dilatation.