Eicosapentaenoic Acid Level Predicts Long-Term Survival and Cardiovascular or Limb Event in Peripheral Arterial Disease.

Objectives: We examined the relationship between plasma eicosapentaenoic acid (EPA) level and long-term all-cause death (ACD) and cardiovascular or limb events in patients with peripheral arterial disease (PAD). Method: We performed a prospective cohort study on 637 PAD patients. The endpoints were ACD, major adverse cardiovascular events (MACEs), and lower extremity arterial events (LEAEs). Results: The incidences of ACD, MACEs, and LEAEs had correlation with EPA levels (p <0.05). Plasma EPA level had significant positive correlations with high-density lipoprotein cholesterol, triglyceride, and estimated glomerular filtration rate (eGFR), and negative correlation with C-reactive protein (CRP). In Cox stepwise multivariate analysis, lower EPA (hazard ratio [HR]: 0.996, 95% confidence interval [CI]: 0.993-1.000, p = 0.034), ankle brachial pressure index (ABI), body mass index, serum albumin, eGFR, age, CRP, D-dimer, critical limb ischemia, diabetes, cerebrovascular disease (CVD), and statin were related to ACD (p <0.05); lower EPA (HR: 0.997, 95% CI: 0.994-1.000, p = 0.038), ABI, serum albumin, eGFR, age, diabetes, coronary heart disease, CVD, and statin were related to MACEs (p <0.05); and lower EPA (HR: 0.988, 95% CI: 0.982-0.993, p <0.001), ABI, and low-density lipoprotein cholesterol were related to LEAEs (p <0.05). Conclusions: Low plasma EPA level was a significant risk factor for ACD, MACEs, and LEAEs in patients with PAD.

Fifteen-year clinical prognosis and cardiovascular or limb event associated with homocysteine levels in peripheral arterial disease.

BACKGROUND: There are limited reports on the relationship between plasma homocysteine (Hcy) levels and long-term all-cause death (ACD), cardiovascular events, or limb events in patients with peripheral arterial disease (PAD). We examined the relationship between plasma Hcy levels and 15-year these events in PAD patients. METHODS: We performed a prospective cohort study in 955 PAD patients. The patients were divided into four groups based on plasma Hcy levels with median (interquartile range). The endpoints were cumulative incidences of ACD, major adverse cardiovascular events (MACE), and MACE plus limb events (MACLE). RESULTS: The incidences of ACD, MACE, and MACLE were correlated with plasma Hcy levels (P < 0.05). In multiple regression analysis, plasma Hcy had positive correlations with C-reactive protein (CRP), men, and critical limb ischemia (CLI) and negative correlations with estimated glomerular filtration rate (eGFR) and high-density lipoprotein cholesterol (p < 0.05). In Cox multivariate analysis, higher Hcy (HR 1.614, 95 % CI 1.229-2.119, p = 0.001), age, CRP, brain natriuretic peptide (BNP), D-dimer, lower body mass index, ankle brachial pressure index (ABI), serum albumin, eGFR, CLI, coronary heart disease (CHD), cerebrovascular disease, and diabetes were related to ACD; higher Hcy (HR 1.242, 95 % CI 1.004-1.535, p = 0.045), age, BNP, lower ABI, serum albumin, diabetes, and CHD were related to MACE; and higher Hcy (HR 1.290, 95 % CI 1.057-1.574, p = 0.012), BNP, lower ABI, serum albumin, CHD, and diabetes were related to MACLE (P < 0.05). Statins improved ACD, MACE, and MACLE (p < 0.01). CONCLUSIONS: Plasma Hcy was a risk factor for 15-year ACD, MACE, and MACLE in patients with PAD.

Lipoprotein(a) is a Promising Residual Risk Factor for Long-Term Clinical Prognosis in Peripheral Arterial Disease.

Objectives: We investigated the relationship between plasma lipoprotein(a) [Lp(a)] level and long-term prognosis, cardiovascular events, or pure leg events (LE) in patients with peripheral arterial disease (PAD). Materials and Methods: We prospectively enrolled 1104 PAD patients. The endpoints were LE, cerebrovascular- or cardiovascular-related death (CVRD), all-cause death (ACD), and major adverse cardiovascular events (MACE). Results: The incidences of LE, CVRD, ACD, and MACE were correlated with Lp(a) level (P<0.05). Lp(a) was positively correlated with low-density lipoprotein cholesterol and C-reactive protein (CRP) and negatively correlated with estimated glomerular filtration rate (eGFR). In the Cox multivariate regression analysis, high Lp(a), CRP, age, low ankle-brachial pressure index (ABI), eGFR, albumin, critical limb ischemia (CLI), cerebrovascular disease (CVD), and diabetes were associated with LE; high Lp(a), age, CRP, low ABI, body mass index, eGFR, albumin, CLI, coronary heart disease (CHD), CVD, and diabetes were associated with CVRD; high Lp(a), CRP, age, low ABI, eGFR, albumin, CLI, and CVD were associated with ACD; and high Lp(a), CRP, age, low eGFR, albumin, CLI, CHD, and diabetes were associated with MACE (P<0.05). Statins improved all endpoints (P<0.01). Conclusion: Lp(a) was a significant residual risk factor for LE, CVRD, ACD, and MACE in PAD patients.

Antihypertensive Effect of Long-Term Monotherapy with Esaxerenone in Patients with Essential Hypertension: Relationship Between Baseline Urinary Sodium Excretion and Its Antihypertensive Effect.

INTRODUCTION: The blood pressure (BP) control mechanism for mineralocorticoid receptor blockers is unclear, and analysis of their use as a single agent in the clinical setting is required to resolve this uncertainty. There is a paucity of data on esaxerenone monotherapy assessing its long-term antihypertensive effect and urinary biomarkers. METHODS: This post hoc exploratory substudy of a long-term phase 3 study evaluated the effect of esaxerenone monotherapy (2.5 or 5 mg/day) in treatment-naïve patients who continued the therapy during the 52-week study period (n = 25). In addition to blood biomarkers, urinary biomarkers were also assessed in 24-h urine collection samples. RESULTS: Esaxerenone monotherapy was associated with consistent reductions in systolic/diastolic BP in the substudy population (- 23.5/- 13.1 mmHg at week 52, p < 0.001 vs baseline). Plasma aldosterone concentrations and plasma renin activity significantly increased during esaxerenone monotherapy at all time points. On the basis of the observations that both urine volume and urinary sodium excretion also decreased up to the end of the study, and were significantly lower at 12 weeks, patients were further categorized into higher/lower urinary sodium excretion subgroups according to whether their baseline values were above or below the median. In the group with higher baseline urinary sodium excretion, esaxerenone exhibited a significantly greater decrease in systolic/diastolic BP compared to the lower baseline group. CONCLUSION: Esaxerenone exhibited sustained and stable antihypertensive activity even when administered as a single agent for 52 weeks in patients with essential hypertension. The additional urinary biomarker analysis suggests that the BP-lowering effects of esaxerenone may be partly exerted via mechanisms related to salt and water retention, and that the effect is particularly pronounced in patients with hypertension and higher baseline urinary sodium excretion, which may reflect a state of excessive salt intake. TRIAL REGISTRATION: NCT02722265.

Influence of Microalbuminuria on Long-Term Survival and Cardiovascular or Limb Events in Peripheral Arterial Disease.

Objective: This study aimed to examine the relationship between microalbuminuria and long-term life expectancy or limb events in patients with peripheral arterial disease (PAD). Materials and Methods: A prospective cohort study was performed in 714 patients with PAD. The primary outcomes were cardiovascular or cerebrovascular death (CCVD) and all-cause death (AD), and secondary outcomes were major adverse cardiovascular events (MACE) and cardiovascular and/or limb events (CVLE). Results: The 5, 10, and 15 year survival rates were 82.4%, 53.1%, and 33.0%, respectively. The prevalence of patients with increased microalbuminuria was 39.2%. Higher microalbuminuria, age, C-reactive protein (CRP), lower serum albumin, estimated glomerular filtration rate (eGFR), ankle-brachial pressure index (ABI), diabetes, cerebral infarction, and coronary heart disease (CHD) were associated with CCVD; higher microalbuminuria, age, CRP, D-dimer, lower serum albumin, eGFR, and critical limb ischemia were related to AD; higher microalbuminuria, age, CRP, lower serum albumin, ABI, diabetes, and CHD were related to MACE; higher microalbuminuria, age, lower ABI, cerebral infarction, and CHD were related to CVLE in Cox multivariate analyses (p<0.05). Statins reduced CCVD, AD, MACE, and CVLE (p<0.001). Conclusion: Higher microalbuminuria was a significant predictor for CCVD, AD, MACE, and CVLE in PAD patients.

Impact of brain natriuretic peptide for predicting long-term life expectancy and cardiovascular or limb events in peripheral arterial disease.

BACKGROUND: Brain natriuretic peptide (BNP) is introduced as a predictor of the degree of ventricular dysfunction and is associated with mortality. There are limited reports on the relationship of BNP with long-term all-cause death (AD) and cardiovascular or limb events in peripheral artery disease (PAD). We examined the relationship between BNP level and these events in PAD patients. METHODS: We performed a prospective cohort study in 938 PAD patients. The patients were divided into four groups based on BNP levels with median (interquartile range): Q1: ≤20.4; Q2: 20.5-42.8; Q3: 42.9-103.4; and Q4: ≥103.5 pg/mL. The endpoints were AD, freedom from major adverse cardiovascular events (MACE), and MACE plus limb events (MALE). RESULTS: The median follow-up time was 65 months. There were 383 deaths (40.8%) during follow-up period. AD depended on BNP levels (P<0.01), with 5-year freedom from AD rates of Q1: 94%, Q2: 84%, Q3: 69%, and Q4: 55%. The Kaplan-Meier estimates of freedom from AD, MACE, and MALE had significant differences among Q1- Q4 groups (P<0.001). In multiple regression analysis, BNP had significant negative correlations with eGFR, serum albumin, and BMI and positive correlations with diabetes (P<0.05). In Cox multivariate analysis, higher BNP, age, CRP, D-dimer, lower BMI, ABI, serum albumin, and eGFR were related to AD; and higher BNP, age, lower ABI, serum albumin, CAD, and DM were related to MACE and MALE (P<0.05). Statins improved AD, MACE, and MALE (P<0.01). CONCLUSIONS: BNP was a promising biomarker for AD, MACE, and MALE in patients with PAD.

The Geriatric Nutritional Risk Index Predicts Long-Term Survival and Cardiovascular or Limb Events in Peripheral Arterial Disease.

AIM: The Geriatric Nutritional Risk Index (GNRI) was developed to assess the nutritional risk and is associated with mortality. However, there are limited reports on the relationship between the GNRI and overall survival (OS) in peripheral artery disease (PAD). Therefore, the purpose of this study was to examine the relationship between GNRI and OS and cardiovascular or limb events in patients with PAD. METHODS: A prospective cohort study was performed on 1,219 patients with PAD. The baseline GNRI was calculated from the serum albumin level and body mass index obtained at the first visit. The patients were divided into four groups according to the GNRI: G0 (＞98), G1 (92-98), G2 (82-91), and G3 (＜82). The endpoints were OS and freedom from major adverse cardiovascular events (MACE) and MACE plus limb events (MACLE). RESULTS: The median follow-up period was 73 months. There were 626 deaths (51.4%) during the follow-up. The rate of cardiovascular death was 51.3%. OS clearly depended on the GNRI (p＜0.01), with five-year OS rates of 80.8% for G0, 62.0% for G1, 40.0% for G2, and 23.3% for G3. In multivariate analyses, the GNRI, age, ankle-brachial pressure index (ABPI), critical limb ischemia, estimated glomerular filtration rate (eGFR), and C-reactive protein (CRP) were independent factors associated with OS, and GNRI, age, ABPI, coronary artery disease, diabetes mellitus, eGFR, and CRP were associated with MACE and MACLE (all p＜0.05). Statins were found to improve OS, MACE, and MACLE (p＜0.01). CONCLUSIONS: GNRI is an independent predictor for OS, MACE, and MACLE in patients with PAD.

Asymptomatic cerebral infarction is a predictor of long-term survival and vascular or limb events in peripheral arterial disease.

Aims: The purpose of this study was to examine long-term life expectancy including cerebrovascular events (CVE) and fate of the leg in patients with peripheral arterial disease (PAD) with or without cerebral infarction (CI) detected by computed tomography (CT). Methods and results: A prospective cohort study was performed in 932 patients with PAD. The endpoints were overall survival (OS), CVE, stroke-free survival (SFS), freedom from major adverse cardiovascular events (MACE), and freedom from major adverse cardiovascular and limb events (MACLE). The prevalence of CI on CT was 56.8%. There were 413 deaths (44.3%) during follow-up. The rate of cardiovascular deaths among those who died was 53.5%. The 3-, 5-, and 10-year OS rates were 82.0%, 76.9%, and 46.2%, respectively. In Cox multivariate analyses, age, ankle brachial pressure index (ABI), critical limb ischaemia (CLI), estimated glomerular filtration rate (eGFR), albumin level, and CI were independent factors associated with OS (P < 0.05); age, ABI, CLI, atrial fibrillation (AF), and CI were related to CVE (P < 0.05); age, ABI, CLI, diabetes, coronary heart disease (CHD), AF, eGFR, lower albumin, and CI were related to SFS (P < 0.05); age, ABI, CLI, diabetes, CHD, eGFR, lower albumin, and CI were associated with MACE (P < 0.05); and age, ABI, diabetes, CHD, eGFR, lower albumin and CI were related to MACLE (P < 0.05). Statins improved MACE and MACLE (P < 0.05), and AF increased MACLE (P < 0.05). Conclusions: CI on CT was an independent predictor for mortality, CVE, SFS, MACE, and MACLE. Statins improved MACE and MACLE, but AF increased CVE and MACLE in patients with PAD.

Long-term survival and fate of the leg in de novo intermittent claudication.

Aims: The long-term life expectancy and fate of the leg, including progression rate to critical limb ischaemia (CLI), were analysed in de novo patients with intermittent claudication (IC). Methods and results: A prospective cohort study was performed in 1107 patients with de novo IC. The endpoints were overall survival (OS), freedom from major adverse cardiovascular events (MACE), freedom from major adverse cardiovascular and limb events (MACLE), and fate of the leg. The 5-, 10-, 15-, and 20-year rates were 73.3, 47.8, 28.1, and 14.9% for OS, and 63.0, 35.6, 18.5, and 5.7% for freedom from MACE, respectively. In Cox multivariable analysis, body mass index, diabetes, haemodialysis, and C-reactive protein (CRP) level were correlated with OS (P < 0.05). Ankle brachial pressure index, diabetes, coronary artery disease, haemodialysis, and CRP level were independently correlated with freedom from MACE and MACLE. Statins improved mortality, MACE, and MACLE (P < 0.05). Revascularization did not improve mortality and MACE, and femoropopliteal revascularization increased MACLE (P < 0.05). There was no deterioration of claudication in 881 patients (79.6%). Worsening claudication was noted in 211 patients (14.8% per 5 years), and 15 patients (1.1% per 5 years) worsened to CLI. Diabetes and haemodialysis were independent predictors of CLI. A history of cerebral infarction and femoropopliteal revascularization tended to increase CLI. Conclusions: Life expectancy in patients with IC was poor, but the rate of IC progression to CLI was low. Statins improved mortality and morbidity, revascularization did not improve mortality and MACE, and femoropopliteal revascularization reduced freedom from MACLE with a risk of CLI.

Comparative effects of long-acting and short-acting loop diuretics on cardiac sympathetic nerve activity in patients with chronic heart failure.

OBJECTIVE: Short-acting loop diuretics are known to enhance cardiac sympathetic nerve activity (CSNA) in patients with chronic heart failure (CHF). The effects of two loop diuretics-long-acting azosemide and short-acting furosemide-on CSNA were evaluated using (123)I-metaiodobenzylguanidine (MIBG) scintigraphy in patients with CHF. METHODS: The present study was a subanalysis of our previously published study, which had reported that serial (123)I-MIBG studies were the most useful prognostic indicator in patients with CHF. Patients with CHF (n=208, left ventricular ejection fraction <45%) but no history of cardiac events for at least 5 months prior to the study were identified according to their histories of acute decompensated heart failure requiring hospitalisation. Patients underwent (123)I-MIBG scintigraphy immediately before hospital discharge and at a 6-month follow-up. The delayed % denervation, delayed heart/mediastinum count (H/M) ratio and washout rate (WR) were determined using (123)I-MIBG scintigraphy. A total of 108 patients were selected, and propensity score matching was used to compare patients treated with either oral azosemide (n=54) or furosemide (n=54). RESULTS: After treatment, (123)I-MIBG scintigraphic parameters improved in both groups. However, the degree of change in % denervation was -13.8±10.5 in the azosemide group and -5.7±12.7 in the furosemide group (p<0.01), the change in H/M ratio was 0.20±0.16 in the azosemide group and 0.06±0.19 in the furosemide group (p<0.01), and the change in WR was -11.3±9.2% in the azosemide group and -3.0±12.7% in the furosemide group (p<0.01). Moreover, multivariate analysis showed an independent and significant positive relationship between furosemide and δ-WR from hospital discharge to 6 months after treatment in patients with CHF (p=0.001). CONCLUSIONS: These findings indicate that azosemide suppresses CSNA compared with furosemide in patients with CHF. TRIAL REGISTRATION NUMBER: UMIN000000626 (UMIN-CTR Clinical Trial).

Lipoprotein(a) is a risk factor for aortic and mitral valvular stenosis in peripheral arterial disease.

AIMS: Lipoprotein(a) (Lp(a)) levels have been associated with aortic valvular calcification and stenosis. The prevalence and risk factors, including Lp(a) level, for valvular heart disease (VHD) were investigated in patients with peripheral arterial disease (PAD). METHODS AND RESULTS: Echocardiography was performed in 861 patients with PAD to detect abnormal cardiac findings. Relationships between VHD and risk factors were analysed. The prevalence of VHD was 43.6%, and the prevalences of aortic valve regurgitation (AR), mitral valve regurgitation (MR), aortic valve stenosis (AS), mitral valve stenosis (MS), and tricuspid regurgitation (TR) were 26.8, 19.7, 5.9, 1.3, and 9.4%, respectively. In stepwise multiple regression analysis, severity of AR was related to age, albumin, and estimated glomerular filtration rate (eGFR); MR was related to eGFR and age; AS was related to eGFR, Lp(a), and age; MS was related to Lp(a) and female gender; and TR was related to age, body mass index, and total cholesterol (all P < 0.05). Lp(a) level was higher in patients with AS compared with those without AS [34.0 (16.7-50.0) vs. 20.0 (11.0-35.0) mg/dL, P = 0.002], in patients with MS compared with those without MS [37.0 (21.5-77.3) vs. 21.0 (11.0-35.0), P = 0.037], and in patients with AS and/or MS compared with those without AS and MS [34.0 (17.3-50.0) vs. 20.0 (11.0-35.0), P = 0.001]. Lp(a) levels were related to low-density lipoprotein cholesterol and high-sensitivity C-reactive protein levels (P = 0.004). CONCLUSIONS: The high prevalence of VHD is found, especially in AR and MR, and the Lp(a) level is associated with increased risks of AS and MS in patients with PAD.

15-Year Patency and Life Expectancy After Primary Stenting Guided by Intravascular Ultrasound for Iliac Artery Lesions in Peripheral Arterial Disease.

OBJECTIVES: The purpose of this study was to evaluate 15-year patency and life expectancy after endovascular treatment (EVT) with primary stenting guided by intravascular ultrasound (IVUS) for iliac artery lesions. BACKGROUND: Fifteen-year patency, factors causing restenosis, and survival after IVUS-guided EVT are unclear based on the TransAtlantic Inter-Society Consensus II (TASC-II) classification in peripheral arterial disease (PAD). METHODS: EVT was performed for 507 lesions in 455 patients with PAD. The 15-year endpoints were primary, primary-assisted, and secondary patency; overall survival; freedom from major adverse cardiovascular events (MACE); and freedom from major adverse cardiovascular and limb events (MACLE). RESULTS: The 5-, 10-, and 15-year primary and secondary patencies were 89%, 83%, and 75%, respectively, and 92%, 91%, and 91%, respectively. There were no significant differences among TASC-II categories. CONCLUSIONS: IVUS-guided stenting for the iliac artery had favorable 15-year patency in all TASC categories. Life expectancy after EVT was poor, but stenting is feasible for patients with PAD.

Effects of adding intravenous nicorandil to standard therapy on cardiac sympathetic nerve activity and myocyte dysfunction in patients with acute decompensated heart failure.

PURPOSE: Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, improves cardiac sympathetic nerve activity (CSNA) in ischemic heart disease or chronic heart failure. However, its effects on CSNA and myocyte dysfunction in acute heart failure (AHF) remain unclear. We investigated the effects of adding intravenous nicorandil to standard therapy on CSNA and myocyte dysfunction in AHF. METHODS: We selected 70 patients with mild to moderate nonischemic AHF who were treated with standard conventional therapy soon after admission. Thirty-five patients were assigned to additionally receive intravenous nicorandil (4-12 mg/h; group A), whereas the remaining patients continued their current drug regimen (group B). Delayed total defect score (TDS), delayed heart to mediastinum count (H/M) ratio, and washout rate (WR) were determined by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy within 3 days of admission and 4 weeks later. High sensitivity troponin T (hs-TnT) level was also measured at the same time points. RESULTS: After treatment, MIBG scintigraphic parameters significantly improved in both groups. However, the extent of the changes in these parameters in group A significantly exceeded the extent of the changes in group B [TDS -11.3 ± 4.3 in group A vs -4.0 ± 6.0 in group B (p < 0.01); H/M ratio 0.31 ± 0.16 vs 0.14 ± 0.16 (p < 0.01); WR -13.8 ± 7.8 % vs -6.1 ± 8.9 % (p < 0.01)]. The hs-TnT level decreased significantly from 0.052 ± 0.043 to 0.041 ± 0.033 ng/ml (p < 0.05) in group A, but showed no significant change in group B. Moreover, in both groups, no relationships between the extent of changes in MIBG parameters and hs-TnT level were observed. CONCLUSION: Adding intravenous nicorandil to standard therapy provides additional benefits for CSNA and myocyte dysfunction over conventional therapy alone in AHF patients. Furthermore, the mechanisms of improvement in CSNA and myocyte dysfunction after nicorandil treatment in AHF patients were distinct.

High-sensitivity C-reactive Protein, Lipoprotein(a) and Homocysteine are Risk Factors for Coronary Artery Disease in Japanese Patients with Peripheral Arterial Disease.

AIM: The goal of the study was to investigate the relationships between coronary artery disease (CAD) and risk factors, including the serum levels of high-sensitivity C-reactive protein (hs-CRP), lipoprotein(a) (Lp(a)) and homocysteine, in Japanese patients with peripheral arterial disease (PAD). METHODS: Coronary angiography was performed in 451 patients with PAD, among whom the prevalence and clinical characteristics of CAD were analyzed. A multiple logistic analysis was used to evaluate the relationships between CAD and the risk factors. The relationships between the severity of coronary arterial lesions and the risk factors were evaluated using multiple regression analysis. RESULTS: The prevalence of CAD (≥70% luminal diameter narrowing or a history of CAD) and coronary artery stenosis (≥50%) was 55.9% and 74.1%, respectively, and the rate of CAD (≥70%) with single-, double- and triple-vessel disease was 25.9%, 13.5% and 10.6%, respectively. The prevalence of diabetes was higher among the patients with CAD than among those without. The serum levels of hs-CRP, Lp(a), and homocysteine were higher in the patients with CAD, whereas the estimated glomerular filtration rates and HDL-cholesterol levels were lower in these patients. According to the multiple logistic analysis, CAD was related to diabetes (hazard ratio [HR]: 2.253; 95% confidence interval [CI]: 1.137-4.464, p=0.020), hs-CRP (HR: 1.721; 95% CI: 1.030-2.875, p=0.038), Lp(a) (HR: 1.015; 95% CI: 1.001-1.029, p=0.041) and homocysteine (HR: 1.084; 95% CI: 1.012-1.162, p=0.021). Furthermore, diabetes and the D-dimer and LDL-cholesterol levels exhibited significant relationships with the number of stenotic coronary lesions in the stepwise multiple regression analysis (p＜0.05). CONCLUSIONS: Diabetes, hs-CRP, Lp(a), homocysteine and lipid abnormalities are critical risk factors for CAD in Japanese patients with PAD.

Effects of statin therapy on cardiac sympathetic nerve activity and left ventricular remodeling in patients with chronic heart failure: a propensity score-matched analysis.

Statin therapy reduces enhanced cardiac sympathetic nerve activity (CSNA) in patients with heart disease, and prevents left ventricular (LV) remodeling in chronic heart failure (CHF) patients. We sought to evaluate the effects of statin therapy on CSNA, as evaluated by I-metaiodobenzylguanidine (MIBG) scintigraphy, and LV remodeling in CHF patients. This study was sub-analysis of our previous report of the result that the serial I-MIBG studies were the most useful prognostic indicator in CHF patients. Patients with CHF (n = 208; left ventricular ejection fraction <45%) but no cardiac events for at least 5 months before the study, were identified according to their history of decompensated acute heart failure requiring hospitalization. The patients underwent I-MIBG scintigraphy and echocardiography immediately before hospital discharge and after 6 months. The delayed % denervation, delayed heart/mediastinum count (H/M) ratio, and washout rate (WR) were determined by I-MIBG scintigraphy. The LV end-diastolic volume (EDV) and end-systolic volume (ESV) were also determined by echocardiography. We selected 164 patients and used propensity score matching to compare patients who received oral statin (n = 82), and those who did not (n = 82).The changes in I-MIBG scintigraphic parameters improved, and in echocardiographic LVEDV and LVESV reduced in the statin group compared with those in the non-statin group. Moreover, there were significant correlations between changes in the I-MIBG scintigraphic findings and those in the LVEDV (% denervation, r = 0.534, P < 0.001; H/M ratio, r =  -0.516, P < 0.001; and WR, r = 0.558, P < 0.001); or the LVESV (% denervation, r = 0.479, P < 0.001; H/M ratio, r =  -0.450, P < 0.001; and WR, r = 0.520, P < 0.001) in the statin group. In contrast, there was no relationship between these parameters in the non-statin group.Statin therapy not only improved CSNA, but also reduced LV volume, in other wards, prevented LV remodeling in CHF patients.

Evaluation of cardiac sympathetic nerve activity and aldosterone suppression in patients with acute decompensated heart failure on treatment containing intravenous atrial natriuretic peptide.

PURPOSE: Aldosterone prevents the uptake of norepinephrine in the myocardium. Atrial natriuretic peptide (ANP), a circulating hormone of cardiac origin, inhibits aldosterone synthase gene expression in cultured cardiocytes. We evaluated the effects of intravenous ANP on cardiac sympathetic nerve activity (CSNA) and aldosterone suppression in patients with acute decompensated heart failure (ADHF). METHODS: We studied 182 patients with moderate nonischemic ADHF requiring hospitalization and treated with standard therapy containing intravenous ANP and 10 age-matched normal control subjects. ANP was continuously infused for >96 h. In all subjects, delayed total defect score (TDS), heart to mediastinum ratio, and washout rate were determined by 123I-metaiodobenzylguanidine (MIBG) scintigraphy. Left ventricular (LV) end-diastolic volume, end-systolic volume, and ejection fraction were determined by echocardiography. All patients with acute heart failure (AHF) were examined once within 3 days and then 4 weeks after admission, while the control subjects were examined only once (when their hemodynamics were normal). Moreover, for 62 AHF patients, plasma aldosterone concentrations were measured at admission and 1 h before stopping ANP infusion. RESULTS: 123I-MIBG scintigraphic and echocardiographic parameters in normal subjects were more favorable than those in patients with AHF (all p < 0.001). After treatment, all these parameters improved significantly in AHF patients (all p < 0.001). We also found significant correlation between percent changes of TDS and aldosterone concentrations (r = 0.539, p < 0.001) in 62 AHF patients. CONCLUSION: The CSNA and LV performance were all improved in AHF patients. Furthermore, norepinephrine uptake of myocardium may be ameliorated by suppressing aldosterone production after standard treatment containing intravenous ANP.

Effects of oral nicorandil therapy on sympathetic nerve activity and cardiac events in patients with chronic heart failure: subanalysis of our previous report using propensity score matching.

PURPOSE: Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, improves cardiac sympathetic nerve activity (CSNA) in patients with ischaemic heart disease. However, the long-term effects on both CSNA, as evaluated by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy, and prognosis have not been determined in patients with chronic heart failure (CHF). METHODS: This study was a subanalysis of our previous results that serial (123)I-MIBG scintigraphic studies are the most useful prognostic indicator in CHF patients. The study group comprised 208 patients with CHF (left ventricular ejection fraction <45 %) but no cardiac events for at least 5 months identified on the basis of a history of decompensated acute heart failure requiring hospitalization. These patients underwent (123)I-MIBG scintigraphy and echocardiography just before leaving the hospital and again 6 months later. We selected 170 patients and used propensity propensity score matching to compare patients who received oral nicorandil (85 patients) and those who did not (85 patients). The patients were followed up for a median of 5.03 years, with the primary and secondary study end-points defined as the occurrence of a fatal cardiac event and a major adverse cardiac event (MACE), respectively. RESULTS: After treatment, the extent of changes in (123)I-MIBG scintigraphic and echocardiographic parameters in the nicorandil group were more favourable than in those not receiving nicorandil. Of the 170 patients, a fatal cardiac event occurred in 42, and a MACE in 68 during the study. Multivariate Cox regression analyses revealed that no nicorandil treatment was a significant predictor of both cardiac death and MACE in our patients with CHF. On Kaplan-Meier analysis, the rates of freedom from cardiac death or from MACE in the nicorandil group were significantly higher than in those not receiving nicorandil (all p<0.05). CONCLUSION: Long-term nicorandil treatment improves CSNA and left ventricular parameters in patients with CHF. Furthermore, this agent is potentially effective for reducing the incidence of cardiac events in patients with CHF.

Differences in brain natriuretic peptide and other factors between Japanese peripheral arterial disease patients with critical limb ischemia and intermittent claudication.

AIM: The goal of this study was to analyze differences in risk factors, including the level of brain natriuretic peptide (BNP) and the distribution of lesions, between cases of critical limb ischemia (CLI) and intermittent claudication (IC) among patients with peripheral arterial disease. METHODS: Risk factors and clinical characteristics were prospectively investigated in 817 consecutive patients, including 185 patients with CLI and 632 patients with IC. RESULTS: The patients in the CLI group were older than those in the IC group (p＜0.001). The prevalence of diabetes and cerebral infarction and the proportion of women were higher in the CLI group (p＜0.05). The plasma BNP levels in the CLI group were higher than those observed in the IC group (333±538 vs. 136±354 pg/mL, p＜0.001). In contrast, the levels of homocysteine and fibrinogen were higher and the levels of albumin and the estimated glomerular filtration rate were lower in the CLI group (p＜0.05). According to a multiple logistic analysis, the BNP level, diabetes, female gender, the albumin level, body mass index (BMI) and ankle-brachial pressure index (ABI) were associated with CLI (p＜0.05). Aortoiliac artery lesions were less common, whereas femoropopliteal and below-the-knee (BK) lesions were more common, in the CLI group (p＜0.05). The number of affected BK arteries was also higher in the CLI group (p＜0.001). Correlations were found between the presence of aortoiliac lesions and smoking and a low HDL cholesterol level, while femoropopliteal lesions were found to correlate with age, BMI and hypertension and BK lesions were found to correlate with diabetes, age, female gender and BMI (p＜0.05). The plasma BNP level correlated with the number of affected BK arteries (p＜0.05). CONCLUSIONS: A high BNP level, diabetes, female gender, a low albumin level, ABI and BMI are risk factors for CLI. In this study, differences in the levels of anatomical lesions and correlated risk factors were found between the CLI and IC groups.

Effects of mineralocorticoid receptor antagonist spironolactone on cardiac sympathetic nerve activity and prognosis in patients with chronic heart failure.

BACKGROUND: Aldosterone prevents norepinephrine uptake and promotes structural remodeling of the heart. Spironolactone is well known to have an anti-aldosteronergic effect, and this agent could improve cardiac sympathetic nerve activity (CSNA) in patients with chronic heart failure (CHF). On the other hand, we previously reported that the delta washout rate (WR) determined from serial (123)I-MIBG scintigraphic studies is the best currently available prognostic value in patients with CHF. METHODS: In total 208 patients with CHF (left ventricular ejection fraction [LVEF] <45%), but no cardiac events for at least 5 months, were identified on the basis of a history of decompensated acute heart failure requiring hospitalization. These patients underwent (123)I-MIBG scintigraphy and echocardiography just before leaving the hospital and after 6 months of treatment. The patients were retrospectively divided into a spironolactone (n=82) and a non-spironolactone (n=126) group. RESULTS: The extents of changes in (123)I-MIBG scintigraphic and echocardiographic parameters in the spironolactone group were significantly better than those in the non-spironolactone group. Of the 208 patients, 56 experienced fatal cardiac events during the study. The mean follow-up period was 4.45+/-1.82 years. On Kaplan-Meier analysis, the rate freedom from cardiac death was 81.7% (67/82) in the spironolactone group and 67.5% (85/126) in the non-spironolactone group (P<0.05). Moreover, stepwise multivariate analyses showed spironolactone therapy to have the most independent and significant negative relationship with delta-WR, during the period from hospital discharge until 6 months after starting treatment, in patients with CHF (P<0.001). CONCLUSIONS: Spironolactone treatment improves CSNA and prevents LV remodeling in patients with CHF. Furthermore, this agent is potentially effective for reducing the incidence of fatal cardiac events in CHF patients.

Prevalence and risk factors for cerebral infarction and carotid artery stenosis in peripheral arterial disease.

OBJECTIVE: The purpose of the study was to examine the prevalence and risk factors for cerebral infarction (CI) and carotid artery stenosis (CAS) in patients with peripheral arterial disease (PAD) compared with normal controls. METHOD: A cross-sectional analysis was performed in 857 subjects (PAD: 543, controls: 314). CI and lacunar infarction (LI) were evaluated using brain computed tomography. Intima-media thickening (IMT) and CAS were measured with ultrasound. RESULTS: The prevalences of CI and LI were higher in patients with PAD than in controls (15.0% vs. 9.8%, 41.0% vs. 13.4%, respectively, p < 0.05). In multiple logistic analysis, CI was associated with diabetes mellitus, low HDL cholesterol and CAS ≥ 70% (p < 0.05). LI was associated with age, PAD, diabetes mellitus, and estimated glomerular filtration rate (p < 0.05). The prevalences of CAS ≥ 70% and CAS ≥ 50% were higher in patients with PAD than in controls (5.2% vs. 0.6%, 17.6% vs. 3.8%, respectively, p < 0.01). Mean and max IMT differed significantly between the two groups (PAD vs. controls: 1.01 ± 0.45 vs. 0.90 ± 0.28, 2.67 ± 2.00 vs. 1.73 ± 1.05 mm, respectively, p < 0.001). CAS ≥ 70% correlated with high LDL cholesterol, and CAS ≥ 50% with age and PAD. IMT was positively correlated with PAD, high LDL cholesterol, age, and hypertension (p < 0.05). CONCLUSIONS: Prevalences of CI and CAS were markedly higher in patients with PAD than in controls, indicating that PAD is a meaningful risk factor for CI, LI, and CAS. This suggests that screening for CI and CAS is important for managements in PAD, as with screening for PAD in patients with stroke.