Association between paroxysmal or persistent atrial fibrillation and hyperuricemia in patients who underwent coronary computed tomography angiography: from the FU-CCTA-AF Registry.

BACKGROUND: Hyperuricemia (HU) and hypertension (HTN) contribute to atherosclerotic cardiovascular disease, and both are also involved in the onset and development of atrial fibrillation (AF). OBJECTIVE: In the present study, we investigated the association between risk factors for atherosclerosis [including HU, HTN, blood pressure and serum uric acid (UA) levels] and paroxysmal atrial fibrillation (Paro-AF) or persistent atrial fibrillation (Pers-AF) in patients who underwent coronary computed tomography angiography (CCTA). METHODS: We enrolled 263 patients from the Fukuoka University-CCTA-AF (FU-CCTA-AF Registry) who underwent CCTA prior to AF ablation therapy. AF was classified as either Paro-AF (≤ 7 days) or Pers-AF (> 7 days). HU was diagnosed by a serum UA level > 7.0 mg/dl, and coronary artery disease (CAD) was diagnosed when CCTA results showed ≥ 50% significant coronary artery stenosis. The number of significantly diseased coronary artery vessels (VD), the Gensini score and the coronary artery calcification score (CACS) were measured. Left atrial morphology was also evaluated. RESULTS: Diastolic blood pressure and HbA1c in the Pers-AF group were significantly higher than those in the Paro-AF group. The Pers-AF group showed a significantly higher prevalence of HU and higher UA levels than the Paro-AF group. In a multivariate logistic regression analysis, HU was an independent associated factor to Pers-AF (odds ratio: 2.023, 95% confidence interval: 1.055-3.881, p = 0.034), while HTN was not. CONCLUSION: In patients with AF, HU is associated with Pers-AF.

The Effectiveness of Mobile Cloud 12-Lead Electrocardiogram Transmission System in Patients with ST-Segment Elevation Myocardial Infarction.

Backgroundand Objectives: Delay of reperfusion therapy is related to high mortality in cases of ST-segment elevation myocardial infarction (STEMI). Guidelines emphasize that the first-medical-contact-to-balloon (FMCTB) time should be within 90 min. A mobile cloud-based 12-lead electrocardiogram (MC-ECG) transmission system might be useful in such cases, especially in rural areas. Materials and Methods: From April 2019 to June 2021, both an MC-ECG transmission system and the conventional method in which a physician checks the ECG in a hospital (Conventional) were used for transport by emergency medical services in Shin-Yukuhashi Hospital, Fukuoka, Japan. During this period, 8684 consecutive patients were transported to this hospital. Among them, we investigated 48 STEMI patients. The MC-ECG group (n = 23) and the Conventional group (n = 25) were enrolled. Results: There was no significant difference in FMCTB time between the MC-ECG and Conventional groups (MC-ECG: 72.0 (60.5-107) min vs. Conventional: 80.0 (63.0-92.0) min, p = 0.77). The length of hospital stay in the MC-ECG group was significantly shorter than that in the Conventional group (12.0 (10.0-15.0) days vs. 16.0 (12.0-19.0) days, p = 0.039). The logistic regression model showed that patients' non-use of MC-ECG was associated with a risk of more than 15-day length of hospital stay with an adjusted odd ratio of 0.08 (95% CI: 0.013-0.55, p = 0.0098). Conclusions: Using the MC-ECG, the length of hospital stay in patients with STEMI was significantly reduced.

Differences in lesion characteristics and patient background associated with the medium-term clinical outcomes of bare-metal and first-, second- and third-generation drug-eluting stents.

We investigated the lesion characteristics and patient background factors associated with the medium-term incidence of major adverse cardiac events (MACEs) for bare-metal stents (BMS) and 1st-, 2nd- and 3rd-generation drug-eluting stents (DES) using the PCI-Registry (FU-Registry). Between January 2003 and March 2016, 2967 cases/3508 lesions for which percutaneous coronary intervention was performed at Fukuoka University Hospital and related facilities were enrolled. Patients were divided into BMS and 1st-, 2nd- and 3rd-generation drug-eluting stent (DES) groups. The incidence of MACEs in the BMS group (26.2%) was significantly higher than those in the 1st, 2nd and 3rd DES groups (18.0%, 12.5%, and 11.0%, respectively). The incidence of MACEs in the BMS group was strongly associated with insulin use, hemodialysis, low high-density lipoprotein cholesterol, stent minimum lesion diameter, stent length, severe calcification and a small vessel diameter of less than 2.5 mm. Some of these factors showed no association with MACEs among the drug-elution groups, and only hemodialysis, arteriosclerosis obliterans and severe calcification showed a strong correlation in the 2nd DES group. In the 3rd DES group, none of the factors considered were associated with MACEs. In conclusion, in stent implantation, the number of factors associated with MACEs has gradually decreased as the stent generation increased.

Association between high-density lipoprotein cholesterol levels and major adverse cardiovascular events in patients who underwent coronary computed tomography angiography: FU-CCTA registry.

It is unclear whether higher levels of serum high-density lipoprotein cholesterol (HDL-C) prevent major adverse cardiovascular events (MACE). We prospectively evaluated 501 patients who had undergone coronary computed tomography angiography at Fukuoka University Hospital and either were clinically suspected of having coronary artery disease (CAD) or had at least one cardiovascular risk factor with a follow-up of up to 5 years. The primary endpoint was MACE (cardiovascular death, ischemic stroke, acute myocardial infarction and coronary revascularization). The patients were divided into tertiles according to the HDL-C level: 47 mg/dl ≥ HDL-C level [n = 167, lower HDL-C level (L-HDL)], 58 mg/dl ≥ HDL-C level ≥ 48 mg/dl [n = 167, middle HDL-C level (M-HDL)] and HDL-C level ≥ 59 mg/dl [n = 167, higher HDL-C level (H-HDL)] groups. There were significant differences in %CAD among the L-HDL, M-HDL and H-HDL groups. Unexpectedly, there was no difference in %MACE between M-HDL and H-HDL, although %MACE in M-HDL was significantly lower than that in L-HDL (p < 0.05). By a multivariate logistic regression analysis, MACE in H-HDL-C was independently associated with diabetes mellitus (DM) (p = 0.03). A Kaplan-Meier curve according to the HDL subgroup indicated that M-HDL, not H-HDL, enjoyed the greatest freedom from MACE among the 3 groups (log-rank test p = 0.047). Finally, the results of a Cox regression model indicated that L-HDL and H-HDL had significantly higher risk of MACE than M-HDL. In conclusions, patients with middle HDL-C levels, not higher HDL-C levels, showed the greatest freedom from MACE. Patients with higher HDL-C levels need to be strictly managed for DM to prevent MACE.

Association between lipid profile and endothelial dysfunction as assessed by the reactive hyperemia index.

INTRODUCTION: We investigated the associations between endothelial dysfunction (ED) as evaluated by the reactive hyperemia index (RHI) obtained using Endo-PAT2000® and atherosclerotic risk factors in patients who underwent coronary artery angiography (CAG). METHODS: The subjects consisted of 191 patients who were clinically suspected to have CAD and underwent CAG, and in whom we could perform Endo-PAT2000®. We divided the patients into ED (RHI<1.67, n = 71) and non-ED (RHI≥1.67, n = 120) groups. RESULTS: The ED group was significantly older and showed a higher ratio of low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol (HDL-C) (L/H) than the non-ED group. A multivariate logistic regression analysis was performed to examine the associations between the presence of ED and age, gender, and BMI in addition to L/H. Age [odds ratio (OR) = 1.03, p = .02] and L/H (OR = 1.64, p = .01) were identified as significant independent markers of the presence of ED. Next, we divided 122 patients with statin treatment into ED (n = 40) and non-ED (n = 82) groups. The ED group tended to have higher L/H and lower HDL-C than the non-ED group. HDL-C (OR = 0.95, p = .01) and age (OR = 1.05, p = .04) were identified as independent markers of the presence of ED. CONCLUSIONS: L/H was an independent marker of the presence of ED in patients without dyslipidemia. In addition, among patients with statin treatment, HDL-C was an independent marker of the presence of ED.

Changes in the function of angiotensin II type 1 receptor due to cholesterol depletion from cell membrane.

Blockers of G-protein coupled receptors (GPCRs), angiotensin II (Ang II) type 1 (AT1) receptor and ß1-adrenergic (Ad) receptor, have been shown to improve the prognosis of cardiovascular disease. Cholesterol molecules in the cell membrane are needed to stabilize GPCRs as well as the cell membrane itself. We determined whether the functions of AT1 and ß1-Ad receptors were changed by cholesterol depletion from cardiovascular cell membranes. Ang II-induced inositol phosphate production through AT1 receptor was suppressed by cholesterol depletion from cell membranes using rosuvastatin or methyl-ß-cyclodextrin (MßCD), whereas isoproterenol-induced cyclic AMP production through ß1-Ad receptor did not change after cholesterol depletion. In addition, the binding affinities of Ang II and AT1 receptor blocker after cholesterol depletion were significantly lower than those before depletion. Although AT1 receptor expression levels did not change after cholesterol depletion, the expression levels of AT1 receptor that could bind to Ang II significantly decreased after depletion. The changes in the structure of AT1 receptor due to depletion were confirmed by substituted-cysteine accessibility mapping. In conclusion, Ang II-induced activation of AT1 receptor is reduced without affecting the function of ß1-Ad receptor after cholesterol depletion from cardiovascular cell membranes.

Unique mode of binding between angiotensin II type 1 receptor and its blockers.

BACKGROUND: We hypothesized that the 5-oxo-1,2,4-oxadiazole moiety of azilsartan (AZL), which represents a small difference in the molecular structures of AZL and candesartan (CAN) [angiotensin II type 1 receptor (AT1R) blockers], may be responsible for the molecular effects of AZL. METHODS: We examined the binding affinities of AZL and CAN to AT1R, along with their ability to block receptor activity. A competition binding study, inositol phosphate (IP) production assay and extracellular signal-regulated kinase (ERK) assay were performed using wild-type (WT) and mutants AT1R-transfected cells. RESULTS: The binding affinities of CAN and AZL were reduced by > 5-fold for Y35F, W84F, R167K, K199Q and I288A compared with WT. In addition, AZL showed a > 5-fold reduction in its binding affinity to V108A. CAN and AZL exhibited > 20-fold and > 100-fold reductions in binding affinity to R167K, respectively. The loss of binding affinity of AZL to R167K was greater than that of CAN. CAN-7H exhibited a > 10-fold reduction in binding affinity to R167K compared with CAN. On the other hand, the binding affinity of AZL-7H to R167K was comparable to that of AZL. While 10-6M CAN and CAN-7H partly blocked Ang II-induced IP production in R167K, 10-6M AZL and AZL-7H did not. In addition, 10-6M CAN, but not 10-6M AZL, partly blocked Ang II-induced ERK activation in R167K. CONCLUSIONS: The interaction between 5-oxo-1,2,4-oxadiazole in AZL and Arg167 in the AT1R appears to be more important than the interaction between the tetrazole ring in CAN and Arg167.

The Phosphate Binder Ferric Citrate Alters the Gut Microbiome in Rats with Chronic Kidney Disease.

In chronic kidney disease (CKD), the gut microbiome is altered and bacterial-derived uremic toxins promote systemic inflammation and cardiovascular disease. Ferric citrate complex is a dietary phosphate binder prescribed for patients with end-stage kidney disease to treat hyperphosphatemia and secondary hyperparathyroidism. Iron is an essential nutrient in both microbes and mammals. This study was undertaken to test the hypothesis that the large iron load administered with ferric citrate in CKD may significantly change the gut microbiome. Male Sprague-Dawley rats underwent 5/6 nephrectomy to induce CKD. Normal control and CKD rats were randomized to regular chow or a 4% ferric citrate diet for 6 weeks. Fecal and cecal microbial DNA was analyzed via 16S ribosomal RNA gene sequencing on the Illumina MiSeq system. CKD rats had lower abundances of Firmicutes and Lactobacillus compared with normal rats and had lower overall gut microbial diversity. CKD rats treated with ferric citrate had improved hemoglobin and creatinine clearance and amelioration of hyperphosphatemia and hypertension. Ferric citrate treatment increased bacterial diversity in CKD rats almost to levels observed in control rats. The tryptophanase-possessing families Verrucomicrobia, Clostridiaceae, and Enterobacteriaceae were increased by ferric citrate treatment. The uremic toxins indoxyl sulfate and p-cresyl sulfate were not increased with ferric citrate treatment. Verrucomicrobia was largely represented by Akkermansia muciniphila, which has important roles in mucin degradation and gut barrier integrity. In summary, ferric citrate therapy in CKD rats was associated with significant changes in the gut microbiome and beneficial kidney and blood pressure parameters.

LCZ696 (Sacubitril/Valsartan), an Angiotensin-Receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy, Fibrosis, and Vasculopathy in a Rat Model of Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with cardiac hypertrophy, fibrosis, and increased risk of cardiovascular mortality. LCZ696 (sacubitril/valsartan) is a promising agent that has shown significant potential in treatment of heart failure. We hypothesized that LCZ696 is more effective than valsartan alone in the treatment of cardiovascular abnormalities associated with experimental CKD. METHODS AND RESULTS: Male Sprague-Dawley rats underwent 5/6 nephrectomy and were subsequently randomized to no treatment (CKD), 30 mg/kg valsartan (VAL), or 60 mg/kg LCZ696 (LCZ). After 8 weeks, cardiovascular parameters, including markers of inflammation, oxidative stress, mitochondrial abundance/function, hypertrophy, and fibrosis, were measured. Treatment with LCZ resulted in significant improvements in the heart-body weight ratio and serum concentrations of N-terminal pro-B-type natriuretic peptide and fibroblast growth factor 23 along with improvement of kidney function. In addition, LCZ ameliorated aortic fibrosis and cardiac hypertrophy and fibrosis, reduced markers of cardiac oxidative stress and inflammation, and improved indicators of mitochondrial mass/function. Although VAL also improved some of these indices, treatment with LCZ was more effective than VAL alone. CONCLUSIONS: CKD-associated cardiovascular abnormalities, including myocardial hypertrophy, fibrosis, inflammation, oxidative stress, and mitochondrial depletion/dysfunction, were more effectively attenuated by LCZ treatment than by VAL alone.

Evaluation of the antithrombotic abilities of non-vitamin K antagonist oral anticoagulants using the Total Thrombus-formation Analysis System®.

The Total Thrombus-formation Analysis System (T-TAS®) is a novel automated microchip flow-chamber system for the quantitative evaluation of thrombus formation under blood flow conditions. T-TAS® uses two types of microchip to evaluate thrombus formation: the AR-chip quantifies white thrombus formation and the PL-chip quantifies platelet thrombus formation. We assessed the antithrombotic abilities of various non-vitamin K antagonist oral anticoagulants (NOACs) using T-TAS®. One hundred and three consecutive patients who were hospitalized with cardiovascular diseases were enrolled. We divided the patients into 2 groups; a control group that did not receive an anticoagulant (non-AC group) and an anticoagulant group (AC group). The AC group was further divided into warfarin, dabigatran, rivaroxaban and apixaban groups. We performed common coagulation tests and evaluated the area under the flow pressure curve (AR-AUC and PL-AUC) to quantify antithrombotic ability using T-TAS® at the trough. There were no significant differences in patient characteristics between the non-AC and AC groups. Only 55.1 % of patients in the AC group achieved the target blood pressure (BP) of less than 130/80 mmHg. Compared with the non-AC group, AR-AUC was significantly decreased in the AC, warfarin, dabigatran and apixaban groups. Only the rivaroxaban group did not show a significant decrease in AR-AUC. NOACs showed a significant decrease in PL-AUC compared with the non-AC group. In conclusion, T-TAS® was a useful tool for evaluating anticoagulation activity. NOACs was significantly effective as an antiplatelet agent. BP control should be a higher priority than the selection of an anticoagulant drug, especially NOACs.

Significance of the percentage of cholesterol efflux capacity and total cholesterol efflux capacity in patients with or without coronary artery disease.

We hypothesized that cholesterol efflux capacity is more useful than the lipid profile as a marker of the presence and the severity of coronary artery disease (CAD). Therefore, we investigated the associations between the presence and the severity of CAD and both the percentage of cholesterol efflux capacity and total cholesterol efflux capacity and the lipid profile including the high-density lipoprotein cholesterol (HDL-C) level in patients who underwent coronary computed tomography angiography (CTA). The subjects consisted of 204 patients who were clinically suspected to have CAD and underwent CTA. We isolated HDL from plasma by ultracentrifugation and measured the percentage of cholesterol efflux capacity using 3H-cholesterol-labeled J774 macrophage cells and calculated total cholesterol efflux capacity as follows: the percentage of cholesterol efflux capacity/100× HDL-C levels. While the percentage of cholesterol efflux capacity was not associated with the presence or the severity of CAD, total cholesterol efflux capacity and HDL-C in patients with CAD were significantly lower than those in patients without CAD. In addition, total cholesterol efflux capacity and HDL-C, but not the percentage of cholesterol efflux capacity, significantly decreased as the number of coronary arteries with significant stenosis increased. Total cholesterol efflux capacity was positively correlated with HDL-C, whereas the percentage of cholesterol efflux capacity showed only weak association. In a logistic regression analysis, the presence of CAD was independently associated with total cholesterol efflux capacity, in addition to age and gender. Finally, a receiver-operating characteristic curve analysis indicated that the areas under the curves for total cholesterol efflux capacity and HDL-C were similar. In conclusion, the percentage of cholesterol efflux capacity using the fixed amount of isolated HDL was not associated with CAD. On the other hand, the calculated total cholesterol efflux capacity that was dependent of HDL-C levels had a significant correlation with the presence of CAD.

[Uremic toxins and gut micro biome].

In the past, little attention had been paid to the intestine and its microbial flora as a potential source of systemic inflammation in chronic kidney disease(CKD). Systemic inflammation plays a central role in progression of CKD and its cardiovascular and various other complications. The gastrointestinal tract houses a large community of microbes that have a symbiotic relationship with the host. The normal microbial flora protects the host against pathogenic microorganisms. It also contributes to the energy metabolism, micronutrient homeostasis and nitrogen bal- ance. Recent studies have revealed significant changes in the composition and function of the microbial flora in CKD patients and animals. These changes are driven by altered intestinal bio- chemical environment caused by: I-heavy influx of urea and uric acid from body fluids into the gastrointestinal tract, II- restrictions of potassium-rich food including fruits and vegetables which as the main source of indigestible complex carbohydrates are the essential nutrients for the guts' symbiotic microbial com- munity, and III- various medications such as phosphate binders, antibiotics etc. Together the changes in intestinal milieu and the resultant microbial dysbiosis play a major role in systemic inflammation and uremic toxicity by several mechanisms : I-generation of several microbial derived uremic toxins such as indoxyl sulfate, p-cresol sulfate and trimethylamine-N-oxide etc. II-reduction of microbial derived micronutrients such a short chain fatty acids (SCFA) which are the main source of nutrients for colonocytes. This is caused by diminished substrates (indigestible complex carbohydrates) which leads to depletion of SCFA-making bacteria. In addition, III-Disruption of the intestinal epithelial barrier by ammonia and ammonium hydroxide generated from hydrolysis of urea by urease-possessing microbial species which are common complications of CKD, and bowel ischemia caused by excessive use of diuretics (in CKD patients) and aggressive ultrafiltration by hemodialysis (in ESRD patients) can impair gastrointestinal epithelial barrier. The resulting breakdown of the gut epithelial barrier (tight junction complex) leads to influx of endotoxin, microbial fragments, and other noxious luminal products in the sub-epithelial tissue and systemic circulation leading to local and systemic inflammation and oxidative stress which are the major cause of morbidity and mortality in CKD population. This review is intended to provide an overview of the effects of CKD on the gut microbiome and intestinal epithelial barrier structure and the potential interventions aimed at mitigating these abnormalities.

A relative difference in systolic blood pressure between arms by synchronal measurement and conventional cardiovascular risk factors are associated with the severity of coronary atherosclerosis.

It is not known the relationships between a difference in systolic blood pressure (SBP) or diastolic BP (DBP) between arms by synchronal measurement and the presence of coronary artery disease (CAD), and between a difference in BP between arms and the severity of coronary atherosclerosis. We enrolled 425 consecutive patients (M/F = 286/139, 67 ± 13 year) who were admitted to our University Hospital and in whom we could measure the absolute (|rt. BP - lt. BP|) and relative (rt. BP - lt. BP) differences in SBP and DBP using a nico PS-501(®) (Parama-Tech). We divided all patients into those who did and did not have CAD. The relative differences in SBP between arms in patients with CAD were significantly lower than those in patients without CAD. However, the relative difference in SBP between arms was not a predictor of the presence of CAD. We also divided 267 patients who underwent coronary angiography into tertiles according to the Gensini score (low, middle, and high score groups). Interestingly, the middle + high score groups showed significantly lower relative differences in SBP between arms than the low score group. The mean Korotkoff sound graph in the middle + high Gensini score group was significantly higher than that in the low Gensini score group. Among conventional cardiovascular risk factors and nico parameters, the relative difference in SBP between arms in addition to the risk factors (age, gender, body mass index, hypertension, dyslipidemia, and diabetes mellitus) was associated with the score by a logistic regression analysis. In conclusion, the relative difference in SBP between arms as well as conventional risk factors may be associated with the severity of coronary arteriosclerosis.

Association between smoking habits and severity of coronary stenosis as assessed by coronary computed tomography angiography.

Smoking promotes arteriosclerosis and is one of the most important coronary risk factors. However, few studies have investigated the association between smoking habits and the severity of coronary stenosis as assessed by coronary computed tomography angiography (CTA). We enrolled 416 patients [165/251 = smoker (past and current)/non-smoker)]. They had all undergone CTA and either were clinically suspected of having coronary artery disease (CAD) or had at least one cardiovascular risk factor. We divided the patients into smoking and non-smoking groups, and evaluated the presence of CAD, the number of significantly stenosed coronary vessels (VD), and the Gensini score as assessed by CTA in the two groups. The incidence of CAD, VD, the Gensini score, and coronary calcification score in the smoking group were all significantly greater than those in the non-smoking group (CAD, p = 0.009; VD, p = 0.003; Gensini score, p = 0.007; coronary calcification score, p = 0.01). Pack-year was significantly associated with VD and the Gensini score, and was strongly associated with multi-vessel disease (2- and 3-VD) (p < 0.05), whereas the duration of cessation in past smokers was not associated with VD or the Gensini score. Pack-year, but not the duration of cessation, may be the most important factor that was associated with the severity of coronary stenosis in terms of VD and the Gensini score.

Association between the severity of coronary artery stenosis and the combination of the difference in blood pressure between arms and brachial-ankle pulse wave velocity.

BACKGROUND: A difference in systolic blood pressure (SBP) ≥10 mmHg between the arms is associated with an increased risk of coronary artery disease (CAD) and mortality in high-risk patients. METHODS AND RESULTS: Four hundred and fourteen patients were divided into three groups according to the percent most severe luminal narrowing of a coronary artery as diagnosed by coronary computed tomography angiography: no or mild coronary stenosis (0-49%), moderate stenosis (50-69%) and severe stenosis (≥70%) groups. The relative difference in SBP between arms in the severe group was significantly lower than those in the no or mild and moderate groups. The brachial-ankle pulse wave velocity (baPWV) significantly increased as the severity of coronary stenosis increased. We confirmed that severe coronary stenosis was independently associated with both the relative difference in SBP between arms and baPWV, in addition to age, gender, hypertension, dyslipidemia, diabetes mellitus and ankle-brachial index by a logistic regression analysis. The group with a relative difference in SBP between arms of <1 mmHg and baPWV ≥ 1613 cm/s showed a higher percentage of patients with severe coronary stenosis than groups that met neither or only one of these criteria. CONCLUSION: The combination of the relative difference in SBP between arms and baPWV may be a more effective approach for the non-invasive assessment of the severity of CAD.

Associations between parameters of flow-mediated vasodilatation obtained by continuous measurement approaches and the presence of coronary artery disease and the severity of coronary atherosclerosis.

We investigated the associations between the parameters of flow-mediated vasodilatation (FMD) obtained by continuous measurement approaches and the presence of coronary artery disease (CAD) and the severity of coronary atherosclerosis. The subjects consisted of 282 consecutive patients who underwent coronary angiography (CAG) and in whom we could measure FMD. Using continuous measurement approaches, we measured FMD as the magnitude of the percentage change from brachial artery diameter from baseline to peak (bFMD), the maximum FMD rate calculated as the maximal slope of dilation (FMD-MDR), and the integrated FMD response calculated as the area under the dilation curve during the 60- and 120 s dilation periods (FMD-AUC60 and FMD-AUC120). We divided the patients into two groups, the CAD group and the non-CAD group, and defined the severity of coronary atherosclerosis according to the Gensini score. The CAD group showed significantly lower %FMD, FMD-MDR, FMD-AUC60, and FMD-AUC120. Gender, smoking, dyslipidemia (DL), and diabetes mellitus (DM), in addition to FMD-AUC120, were identified as significant independent variables that predicted the presence of CAD by a multivariate logistic regression. In addition, a multiple regression analysis indicated that gender, DL, and hypertension, in addition to FMD-AUC120, were predictors of the Gensini score. Finally, we defined the cutoff value of FMD-AUC120 for the prediction of CAD in all patients as 11.1 (sensitivity 0.582, specificity 0.652) by a receiver-operating characteristic (ROC) curve analysis. In conclusion, FMD-AUC120 as assessed by continuous measurement approaches may be a superior marker for evaluating the presence of CAD and the severity of coronary atherosclerosis.

Is pentraxin 3 a biomarker, a player, or both in the context of coronary atherosclerosis and metabolic factors?

The objective of this study is to determine whether pentraxin-3 (PTX-3) is clinically a biomarker of inflammation, a player in anti-inflammation, or both with regard to coronary atherosclerosis, we compared levels of PTX-3 with levels of adiponectin in addition to high-sensitivity C-reactive protein (hs-CRP). We enrolled 693 patients (51 % male; mean age 64 ± 12 years) at Fukuoka University Hospital. They were clinically suspected to have coronary artery disease (CAD) or had at least one cardiac risk factor and had undergone coronary computed tomography angiography (CTA). We evaluated the levels of PTX-3, hs-CRP, and adiponectin, the presence of CAD or metabolic factors, subcutaneous fat area, visceral fat area (VFA) and lipid profiles. The presence of CAD was independently associated with aging (p = 0.010) and the prevalence of hypertension (p < 0.0001), but not the levels of PTX-3, hs-CRP and adiponectin by a multivariate analysis. Although the number of significantly stenosed coronary vessels (VD) was not associated with PTX-3 or adiponectin, hs-CRP tended to increase as the number of VD increased. In addition, PTX-3 decreased as the number of metabolic factors increased, whereas hs-CRP increased as the number of metabolic factors increased. Interestingly, PTX-3 did not correlate with hs-CRP, but was positively correlated with adiponectin. In a multiple regression analysis, adiponectin (p = 0.003) and VFA (p = 0.008) were significant predictors of PTX-3 levels. In conclusion, PTX-3 and adiponectin showed similar associations with metabolic factors, whereas PTX-3 and hs-CRP showed opposite trends. Adiponectin and VFA were significant predictors of PTX-3 levels. PTX-3 might have an atheroprotective role as well as serving as a simple biomarker, like adiponectin.

Comparison of aldosterone synthesis in adrenal cells, effect of various AT1 receptor blockers with or without atrial natriuretic peptide.

Bifunctional angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) that can block the activation of not only AT1 receptor, but also neprilysin, which metabolizes vasoactive peptides including atrial natriuretic peptide (ANP), are currently being developed. However, the usefulness of the inactivation of ANP in addition to the AT1 receptor with regard to aldosterone (Ald) synthesis is not yet clear. We evaluated the inhibitory effects of various ARBs combined with or without ANP on Ang II-induced adrenal Ald synthesis using a human adrenocortical cell line (NCI-H295R). Ang II increased Ald synthesis in a dose- and time-dependent manner. Ald synthesis induced by Ang II was completely blocked by azilsartan, but not PD123319 (AT2 receptor antagonist). CGP42112 AT2 receptor agonist did not affect Ald synthesis. While most ARBs block Ang II-induced Ald synthesis to different extents, azilsartan and olmesartan have similar blocking effects on Ald synthesis. The different effects of ARBs were particularly observed at 10(-7) and 10(-8 )M. ANP attenuated Ang II-induced Ald synthesis, and ANP-mediated attenuation of Ang II-induced Ald synthesis were blocked by inhibitors of G-protein signaling subtype 4 and protein kinase G. ANP (10(-8) and 10(-7 )M) without ARBs inhibited Ald synthesis, and the combination of ANP (10(-7 )M) and ARB (10(-8 )M) had an additive effect with respect to the inhibition of Ald synthesis. In conclusions, ARBs had differential effects on Ang II-induced Ald synthesis, and ANP may help to block Ald synthesis when the dose of ARB is not sufficient to block its secretion.

Addition of a Nitric Oxide Donor to an Angiotensin II Type 1 Receptor Blocker May Cancel Its Blood Pressure-Lowering Effects.

While physiological levels of nitric oxide (NO) protect the endothelium and have vasodilatory effects, excessive NO has adverse effects on the cardiovascular system. Recently, new NO-releasing pharmacodynamic hybrids of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) have been developed.We analyzed whether olmesartan with NO-donor side chains (Olm-NO) was superior to olmesartan (Olm) for the control of blood pressure (BP). Although there was no significant difference in binding affinity to AT1 wild-type (WT) receptor between Olm and Olm-NO in a cell-based binding assay, the suppressive effect of Olm-NO on Ang II-induced inositol phosphate (IP) production was significantly weaker than that of Olm in AT1 WT receptor-expressing cells. While Olm had a strong inverse agonistic effect on IP production, Olm-NO did not. Next, we divided 18 C57BL mice into 3 groups: Ang II (infusion using an osmotic mini-pump) as a control group, Ang II (n = 6) + Olm, and Ang II (n = 6) + Olm-NO groups (n = 6). Olm-NO did not block Ang II-induced high BP after 10 days, whereas Olm significantly decreased BP. In addition, Olm, but not Olm-NO, significantly reduced the ratio of heart weight to body weight (HW/BW) with downregulation of the mRNA levels of atrial natriuretic peptide.An ARB with a NO-donor may cancel BP-lowering effects probably due to excessive NO and a weak blocking effect by Olm-NO toward AT1 receptor activation.

Impact of cigarette smoking cessation on high-density lipoprotein functionality.

BACKGROUND: Smoking cessation reduces the risk of cardiovascular disease (CVD) and improves clinical outcomes in public health. We studied the effect of smoking cessation on high-density lipoprotein (HDL) functionality. METHODS AND RESULTS: We randomly treated 32 smokers with varenicline or a transdermal nicotine patch as part of a 12-week smoking cessation program (The VN-SEESAW Study). The plasma lipid profiles, plasma and HDL malondialdehyde (MDA) levels, HDL subfractions as analyzed by capillary isotachophoresis, cholesterol efflux capacity, and antiinflammatory activity of HDL were measured before and after the anti-smoking intervention. After smoking cessation, HDL-C, apoA-I levels and HDL subfractions were not significantly different from the respective baseline values. However, cholesterol efflux capacity and the HDL inflammatory index (HII) were significantly improved after smoking cessation. The changes in both parameters (%∆ cholesterol efflux capacity and ∆HII) were also significantly improved in the successful smoking cessation group compared with the unsuccessful group. The changes in cholesterol efflux capacity and HII also correlated with those in end-expiratory CO concentration and MDA in HDL, respectively. CONCLUSIONS: Our findings indicate that smoking cessation leads to improved HDL functionality, increased cholesterol efflux capacity and decreased HII, without changing HDL-C or apoA-I levels or HDL subfractions. This may be one of the mechanisms by which smoking cessation improves the risk of CVD.