Efficacy and Safety of Esaxerenone in Hypertensive Patients with Left Ventricular Hypertrophy (ESES-LVH) Study: A Multicenter, Open-Label, Prospective, Interventional Study.

INTRODUCTION: In contrast to the antihypertensive effect of esaxerenone, there is little evidence of its cardioprotective effect. We investigated the efficacy and safety of esaxerenone in patients with uncontrolled hypertension and left ventricular hypertrophy taking a renin-angiotensin system inhibitor (RASi) or calcium-channel blocker (CCB). METHODS: This was a multicenter, open-label, exploratory study with a 24-week treatment period. Esaxerenone was orally administered at an initial dose of 2.5 mg/day (maximum dose: 5 mg/day). The primary endpoints were the change in morning home systolic blood pressure (BP)/diastolic BP and change and percentage change in left ventricular mass index (LVMI) from baseline to end of treatment (EOT). Key secondary endpoints included change from baseline in bedtime home and office BP, achievement rate of target BP, and safety. RESULTS: In total, 60 patients were enrolled. Morning home systolic/diastolic BP was significantly decreased from baseline to EOT in the total population (- 11.5/ - 4.7 mmHg, p < 0.001) and in both the RASi and CCB subcohorts (all p < 0.01). Significant reductions in bedtime home and office BP were shown in the total population and both subcohorts. LVMI was also significantly decreased from baseline to EOT in the total population (- 9.9 g/m2, - 8.5%, both p < 0.001) and both subcohorts (all p < 0.05). The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 35.0% and 3.3%, respectively; most were mild or moderate. No new safety concerns were identified. CONCLUSION: Esaxerenone showed favorable antihypertensive and cardioprotective effects and safety in hypertensive patients with cardiac hypertrophy. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs071190043).

Incidence, clinical characteristics, and diagnostic approach in transthyretin amyloid cardiomyopathy: The Kumamoto Cardiac Amyloidosis Survey.

BACKGROUND: In recent years, transthyretin amyloid cardiomyopathy (ATTR-CM) has received increasing attention; however, the epidemiology of ATTR-CM in Japan is not yet understood. In the Kumamoto Cardiac Amyloid Survey, we evaluated the current incidence, clinical characteristics, diagnostic approaches, and treatment strategies for ATTR-CM and compared tafamidis-prescription hospitals with regional hospitals. METHODS: We conducted a retrospective multicenter observational cohort study. The registry included patients with ATTR-CM diagnosed in two tafamidis-prescription hospital institutes [Japanese Circulation Society (JCS)-certified facilities] and 15 regional cardiovascular facilities in Kumamoto between January 2018 and December 2020. RESULTS: In total, 174 patients were diagnosed with ATTR-CM. The incidence of ATTR-CM was estimated to be approximately 1 per 10,000 person-years in the elderly population (>65 years old) in Kumamoto. Compared with that in the JCS-certified facilities cohort (n=115), age at diagnosis was significantly older (84.5 ± 5.6 vs. 77.5 ± 6.3 years old; p<0.01) in the regional hospitals cohort (n=59). Histological (25% vs. 81%; p<0.01) and genetic diagnosis (7% vs. 82%) were also less frequently performed. Probable (as indicated by positive bone scintigraphy findings with confirmation of monoclonal protein absence) and possible (as indicated by positive bone scintigraphy findings without confirmation of monoclonal protein absence) ATTR-CM accounted for the majority of cases (75% vs. 19%; p<0.01) in the regional hospitals cohort compared to the JCS-certified facilities cohort. There were no cases of hereditary ATTR-CM among the patients who underwent TTR genetic testing (n=98). CONCLUSIONS: We confirmed the incidence of ATTR-CM in Kumamoto and the diagnostic approach used in patients with ATTR-CM. Further prospective studies with a larger sample are needed to validate our results and to further shed light on the epidemiology of ATTR-CM in Japan.

HFA-PEFF scores: prognostic value in heart failure with preserved left ventricular ejection fraction.

BACKGROUND/AIMS: The Heart Failure Association (HFA)-PEFF score is recognized as a simple method to diagnose heart failure (HF) with preserved ejection fraction (HFpEF). This study aimed to evaluate the relationship between HFA-PEFF scores and cardiovascular outcomes in HFpEF patients. METHODS: A total of 502 consecutive HFpEF patients were prospectively observed for up to 1,500 days. Cardiovascular outcomes were compared between two groups of patients, defined by their HFA-PEFF scores: those who scored 2-4 (the intermediate-score group) and those who scored 5-6 group (the high-score group). Overall, 236 cardiovascular events were observed during the follow-up period (median, 1,159 days). RESULTS: Kaplan-Meier analysis showed that there were significant differences in composite cardiovascular events and HF-related events between the intermediate-score group and the high-score group (p = 0.003 and p < 0.001, respectively). Multivariate Cox proportional hazards analysis showed that the HFA-PEFF scores significantly predicted future HF-related events (hazard ratio, 1.66; 95% confidence interval [CI], 1.11 to 2.50; p = 0.014); receiver operating characteristic analysis confirmed this relationship (area under the curve, 0.633; 95% CI, 0.574 to 0.692; p < 0.001). The cutoff HFA-PEFF score for the identification of HF-related events was 4.5. Decision curve analysis revealed that combining the HFA-PEFF score with conventional prognostic factors improved the prediction of HF-related events. CONCLUSION: HFA-PEFF scores may be useful for predicting HF-related events in HFpEF patients.

Prognostic significance of liver stiffness assessed by fibrosis-4 index in patients with heart failure.

BACKGROUND: Heart failure (HF)-related congestive hepatopathy is a well-recognized problem in management of HF. The fibrosis-4 (FIB4) index calculated by [age × aspartate aminotransferase (IU/L)/platelet count (109 /L) × square root of alanine aminotransferase (IU/L)] is useful for evaluating liver stiffness. We aimed to investigate the impact of the FIB4 index on prognosis in patients with HF. METHODS AND RESULTS: Consecutive HF patients referred for hospitalization at Kumamoto University Hospital, Japan, were registered between 2006 and 2015. We observed cardiovascular outcomes in each type of HF [HF with reduced left ventricular ejection fraction (LVEF) (HFrEF), HF with mid-range LVEF (HFmrEF) and with preserved LVEF (HFpEF)] according to their FIB4 index; Group 1 (FIB4 index <1.3), Group 2 (FIB4 index: 1.3-2.67), and Group 3 (FIB4 index >2.67). This study enrolled 83 HFrEF patients, 117 HFmrEF patients, and 504 HFpEF patients. In HFpEF patients, the Kaplan-Meier curve revealed that Group 3 had a significantly higher rate of total cardiovascular events compared with the other two groups. By contrast, the occurrences of total cardiovascular events were not different among three groups in HFrEF and HFmrEF patients. Multivariate Cox proportional hazard analysis with significant factors in univariate analysis identified that the FIB4 index as an independent and significant predictor for future total cardiovascular events in HFpEF patients (hazard ratio: 1.09, 95% confidence interval: 1.03-1.15, P = 0.001). CONCLUSIONS: The FIB4 index was a significant predictor for total cardiovascular events in HFpEF.

Clinical significance of reactive oxidative metabolites in patients with heart failure with reduced left ventricular ejection fraction.

BACKGROUND: We investigated the clinical significance of the derivative of reactive oxygen metabolites (DROM), a new marker of reactive oxygen species (ROS), in patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF) (HFrEF). METHODS AND RESULTS: Serum DROM concentrations were measured in 201 consecutive patients with HFrEF (EF < 50%) in stable condition. DROM values were significantly higher in patients with HFrEF than in risk-matched patients without HF (P < 0.01). They also correlated significantly with high-sensitivity C-reactive protein and B-type natriuretic peptide. Kaplan-Meier analysis demonstrated significantly higher probabilities of HF-related events in the high-DROM group than in the low-DROM group (log-rank test, P < 0.01). Multivariable Cox hazard analysis revealed that DROM were independent and significant predictors of cardiovascular events. In a subgroup analysis, DROM levels were also measured at the aortic root and coronary sinus in 49 patients. The transcardiac gradient of DROM values was significantly higher in patients with HFrEF than in patients without HF (P = 0.04), indicating an association between DROM production in the coronary circulation and HFrEF development. Changes in DROM following optimal therapy were significantly associated with LVEF improvement (r = 0.34, P = 0.04). CONCLUSIONS: The higher levels of DROM and their association with cardiovascular events suggest the clinical benefit of DROM measurements in the risk stratification of patients with HFrEF.

The controlling nutritional status score predicts outcomes of cardiovascular events in patients with heart failure with preserved ejection fraction.

BACKGROUNDS: The relationship between cardiovascular outcomes and the Controlling Nutritional Status (CONUT) score in heart failure (HF) with preserved ejection fraction (HFpEF) patients is unknown. This study aimed to evaluate the relationship between the score and cardiovascular outcomes in HFpEF patients. METHODS AND RESULTS: A total of 506 consecutive HFpEF patients were prospectively observed for up to 1500 days or until the occurrence of cardiovascular events. The mean age was 71.6 ± 9.4 years. Cardiovascular outcomes were compared between the CONUT score 0-1 group with a normal nutritional state (normal group), the CONUT score 2-4 group with a light degree of undernutrition (light group), and the CONUT score 5-8 group with a moderate degree of undernutrition (moderate group). In this study, there were no patients who scored 9-12, which was defined as a severe state of undernutrition. Overall, 238 cardiovascular events were observed during the follow-up period (median: 1159 days). Kaplan-Meier analysis showed that the moderate group was at higher risk of composite cardiovascular events than the normal group (P < 0.001) and the light group (P = 0.031). The analysis also showed that the light group was at higher risk of composite cardiovascular events than the normal group (P = 0.038). Multivariable Cox proportional hazards analysis with the significant factors from the univariate analysis showed that the CONUT score (hazard ratio: 1.12, 95% confidence interval: 1.03-1.21, P = 0.005) significantly predicted future cardiovascular events. CONCLUSION: Nutritional screening using the CONUT score may be useful for predicting cardiovascular events in HFpEF patients.

Clinical significance of diastolic late mitral annular velocity in heart failure with preserved ejection fraction.

OBJECTIVES: Because diastolic late mitral annular velocity (a') obtained by transthoracic-echocardiography (TTE) represents left atrial (LA) function, we investigated the clinical significance of a' in heart failure (HF) with a preserved left ventricular (LV) ejection fraction (HFpEF). METHODS: We enrolled 448 consecutive HFpEF patients (sinus rhythm: 66.3%, atrial fibrillation [AF] rhythm: 33.7%) and performed TTE under stable conditions after optimal therapy. In patients with sinus rhythm, a' values were measured at septal mitral annuli. RESULTS: A' had weak but significant negative correlations with the natural-logarithm-B-type natriuretic peptide (Ln-BNP), LA diameter, LV mass index and tricuspid regurgitation pressure gradient. Receiver operating characteristic (ROC) curve analysis showed that the best cut-off value of a' and systolic mitral annular velocity (s') for the prediction of HF-related events were 7.45 cm/s and 6.5 cm/s with areas under the curve (AUC) of 0.841 and 0.682, respectively. The AUC of ROC analysis for the logistic regression model of a' plus s' was improved to 0.97. In Kaplan-Meier analysis, HFpEF patients with low-a' (<7.45 cm/s) had a significantly higher risk of total cardiovascular and HF-related events (both p < .01 by log-rank test) than those with high-a' (≥ 7.45 cm/s) and were prognostically equivalent to those with AF. Multivariate Cox proportional hazard analysis identified low-a' as an independent predictor of both total cardiovascular (hazard ratio [HR]: 0.823, 95% confidence interval [CI]: 0.714-0.949, p = .007) and HF-related events (HR: 0.551, 95% CI: 0.422-0.720, p < .001). CONCLUSION: A' value measurement is a non-invasive and useful method for risk stratification in HFpEF.

Prognostic significance of polyvascular disease in heart failure with preserved left ventricular ejection fraction.

The prognostic significance of systemic atherothrombosis in heart failure (HF) with preserved ejection fraction (HFpEF) remains unclear. This study aimed to investigate the relation between the presence of polyvascular disease (PVD) and cardiovascular outcomes in HFpEF patients.A total of 510 consecutive HFpEF patients were prospectively observed for up to 1500 days or until occurrence of cardiovascular events. PVD was defined as ≥2 coexistence of coronary artery disease, peripheral arterial disease, and cerebrovascular disease.Overall, 124 cardiovascular events were observed during follow-up (median: 1430 days). Kaplan-Meier curve showed HFpEF with PVD (n = 84) experienced more cardiovascular events than did those without PVD patients (44.0% vs 20.4%, log-rank: P < .001). Multivariable Cox proportional hazards analysis with significant factors from univariate analysis showed the presence of PVD (hazard ratio [HR]: 2.875, 95% [CI]: 1.894-4.365, P < .001), previous HF hospitalization (HR: 1.578, 95% CI: 1.031-2.414, P = .036), hemoglobin (HR: 0.889, 95% CI: 0.805-0.983, P = .021), serum sodium (HR: 0.946, 95% CI 0.896-1.000, P = .048), ln-BNP (per 1.0, HR: 1.255, 95% CI: 1.055-1.494, P = .010), and E/e' (HR: 1.047, 95% CI: 1.020-1.075, P < .001) significantly predicted future cardiovascular events. Multivariable Cox hazard analysis with 4 established factors (age, BNP, diabetes mellitus, and previous HF hospitalization) from the I-PRESERVE (Irbesartan in HFpEF) study showed PVD was independently associated with cardiovascular events in HFpEF patients (HR: 2.562, 95% CI: 1.715-3.827, P < .001).The presence of PVD is significantly associated with cardiovascular events in HFpEF, suggesting the importance of screening PVD in HFpEF.

H2FPEF Score as a Prognostic Value in HFpEF Patients.

BACKGROUND: The H2FPEF score is recognized as a simple method to diagnose heart failure (HF) with preserved left ventricular ejection fraction (HFpEF). We investigated the value of the H2FPEF score in predicting subsequent cardiovascular events in HFpEF patients. METHODS: This study was a retrospective, single-center, observational study. We calculated the H2FPEF scores for 404 consecutive HFpEF patients. Subjects were subdivided into low- (0-3), intermediate- (4-6), and high-score (7-9) groups and followed for 50 months. The primary and secondary endpoints were composite cardiovascular/cerebrovascular events (cardiovascular death, nonfatal myocardial infarction, unstable angina pectoris, hospitalization for HF decompensation, and nonfatal stroke) occurrence and HF-related events (hospitalization for HF decompensation) occurrence at 50 months, respectively. RESULTS: Kaplan-Meier analyses demonstrated a significantly higher incidence of cardiovascular/cerebrovascular events among those with a higher H2FPEF score (log-rank test, P = 0.005). The HF-related event rate was higher in proportion to the H2FPEF score (log-rank test, P < 0.001). Multivariate Cox hazard analyses identified the H2FPEF score (per 1 point) as an independent predictor of cardiovascular and HF-related events (hazard ratio [HR], 1.179; 95% confidence interval [CI], 1.066-1.305; P = 0.001 and HR, 1.288; 95% CI, 1.134-1.463; P = 0.001, respectively). Receiver operating characteristic analysis showed that the H2FPEF significantly predicted cardiovascular events (area under the curve [AUC], 0.626; 95% CI, 0.557-0.693; P < 0.001) and HF-related events (AUC, 0.680; 95% CI, 0.600-0.759; P < 0.001). The cutoff H2FPEF score was 5.5 for the identification of cardiovascular and HF-related events. CONCLUSION: The H2FPEF score might be a potentially useful marker for the prediction of cardiovascular and HF-related events in HFpEF patients. CLINICAL TRAILS REGISTRATION: Trail Number UMIN000029600.

Clinical Significance of Brachial-Ankle Pulse Wave Velocity in Patients With Heart Failure With Reduced Left Ventricular Ejection Fraction.

BACKGROUND: Although pulse wave velocity (PWV) is recognized to be a risk predictor for various cardiovascular diseases, the association of brachial-ankle PWV (baPWV) with cardiovascular outcomes in heart failure (HF) with reduced ejection fraction (HFrEF) patients remains uncertain. METHODS: We measured ankle-brachial pressure index (ABI) and baPWV values at stable condition after optimal therapy for HF in 201 consecutive HFrEF patients admitted to Kumamoto University Hospital from 2007 to 2015 who were enrolled and followed until the occurrence of cardiovascular events. We defined peripheral artery disease (PAD) as ABI value ≤ 0.9. RESULTS: Kaplan-Meier analysis revealed that HFrEF patients with peripheral artery disease PAD had a significant higher risk of total cardiovascular and HF-related events than those without PAD (P = 0.03 and P = 0.01, respectively). Next, we divided HFrEF patients without PAD into 3 groups according to baPWV values. In the Kaplan-Meier analysis, total cardiovascular and HF-related events in the highest baPWV group (1,800 cm/second ≤ baPWV) had a significantly higher frequency than those in the mid-level baPWV group (1,400 cm/second ≤ baPWV < 1,800 cm/second) (P = 0.007 and P = 0.004, respectively). The hazard ratio between HFrEF patients in the mid-level baPWV group and those with other baPWV groups was compared after adjustment for other cofounders. The probabilities of HF-related events were significantly higher in the lowest and highest baPWV group. CONCLUSION: Identifying complications of PAD and measuring baPWV values in HFrEF patients were useful for predicting their prognosis.Trial Registration: UMIN000034358.

Serum Potassium and Cardiovascular Events in Heart Failure With Preserved Left Ventricular Ejection Fraction Patients.

BACKGROUND: Although serum potassium (sK) levels are closely associated with the prognosis of chronic heart failure patients, the clinical significance of sK levels in cardiovascular outcomes of heart failure with preserved ejection fraction (HFpEF) patients is not fully understood. METHODS: This study was a retrospective, single-center, observational study. We enrolled 506 consecutive HFpEF patients admitted to Kumamoto University Hospital and divided them into four groups according to the quartiles of the sK levels at discharge (Q1: sK < 4.1 mEq/l, Q2: 4.1 ≤ sK < 4.4 mEq/l, Q3: 4.4 ≤ sK < 4.7 mEq/l, and Q4: sK ≥ 4.7 mEq/l). RESULTS: No significant differences were observed in the use of all drugs (loop diuretics, mineralocorticoid receptor antagonists, renin-angiotensin-aldosterone system inhibitors, calcium channel blockers, ß-blockers, and statins) among the four groups. Hemoglobin, the estimated glomerular filtration rate, and pulse wave velocity levels were lower, and the serum sodium levels were higher in the Q4 group compared with those in the Q2 group. Kaplan-Meier analysis revealed significantly higher probabilities of both cardiovascular and HF-related events in the Q1, Q3, and Q4 groups than those in the Q2 group. Multivariate Cox proportional hazard analysis revealed that the Q1, Q3, and Q4 groups had significantly and independently higher probabilities of cardiovascular events compared with those in the Q2 group, indicating a J-shaped association between sK levels and cardiovascular events. CONCLUSIONS: sK levels at discharge could provide important prognostic information in regard to HFpEF. Further evaluation in a larger number of patients might be needed. Clinical Trials Registration: UMIN-CTR (http://www.umin.ac.jp/ctr/). Identifier: UMIN000029600. Public Access Information: Opt-out materials are available at the website: http://www.kumadai-junnai.com/home/wp-content/uploads/houkatsu.pdf.

Clinical significance of brachial-ankle pulse-wave velocity in patients with heart failure with preserved left ventricular ejection fraction.

BACKGROUND: Although pulse-wave velocity (PWV) is a recognized risk predictor for cardiovascular diseases, its association with cardiovascular outcomes in heart failure with preserved left ventricular ejection fraction (HFpEF) is unclear. METHODS AND RESULTS: The 502 patients with HFpEF finally enrolled in this study (mean follow-up duration: 1017 days) were divided into those with or without peripheral artery disease (PAD). The latter were further grouped according to brachial-ankle PWV (baPWV) quintiles using an ankle-brachial pressure index device. Kaplan-Meier analysis revealed a significantly higher risk of all-cause mortality and total cardiovascular events (both P = 0.01) in HFpEF patients with than without PAD. Multivariate Cox hazard analysis, including predictors identified as significant by simple Cox hazard analysis, identified PAD as a significant and independent predictor of cardiovascular events (hazard ratio: 1.85; 95% confidence interval: 1.01-3.39; P = 0.04). In an analysis of HFpEF patients without PAD grouped according to baPWV quintiles, estimated glomerular filtration rate (r = 0.21, P < 0.01) and hemoglobin (r = 0.18, P = 0.01) levels correlated negatively with baPWV. In the Kaplan-Meier analysis, patients with a baPWV more than 1900 cm/s and those with the lowest baPWV (<1300 cm/s) had a significantly higher frequency of total cardiovascular events than patients with 1300 baPWV or less which is less than 1900, indicating a J-shaped association between baPWV and total cardiovascular events as well as similarities to HFpEF patients with PAD. By contrast, the lowest baPWV group had the highest risk of heart failure-related events, accompanied by the highest brain natriuretic peptide levels. CONCLUSION: Identifying complications of PAD and measuring baPWV values in HFpEF patients can improve risk stratification.

The clinical significance of plasma neopterin in heart failure with preserved left ventricular ejection fraction.

AIMS: Although inflammation plays an important role in the pathogenesis of heart failure (HF), the precise pathophysiological role of inflammation in HF with preserved left ventricular ejection fraction (HFpEF) still remains unclear. Hence, we examined the clinical significance of plasma neopterin, an inflammatory biomarker, in HFpEF patients. METHODS AND RESULTS: In the present study, we recruited consecutive HFpEF patients hospitalized in Kumamoto University Hospital, and further measured plasma neopterin by high-performance liquid chromatography and serum derivatives of reactive oxidative metabolites (DROM), a new biomarker of reactive oxygen species. Compared with risk factors (number of patients, age, sex, and equal incidence of diabetes mellitus, hypertension, and dyslipidemia) -matched non-HF patients (n = 68), plasma neopterin levels, but not serum high-sensitivity C-reactive protein levels, were significantly increased in patients with HFpEF (n = 68) (P < 0.001 and P = 0.15, respectively), accompanied by an elevation in serum DROM levels (P < 0.001). Plasma neopterin levels in New York Heart Association (NYHA) class III/IV HFpEF patients were significantly higher than in NYHA class II patients (P < 0.004). Furthermore, plasma ln-neopterin levels had significant and positive correlation with ln-DROM values (r = 0.57) and parameters of cardiac diastolic dysfunction [the ratio of early transmitral flow velocity to tissue Doppler early diastolic mitral annular velocity (r = 0.34), left atrial volume index (r = 0.17), and B-type natriuretic peptide (r = 0.38)]. Kaplan-Meier analysis showed that the high-neopterin group (>51.5 nM: median value of neopterin in HFpEF patients) had a higher probability of cardiovascular events than the low-neopterin group (log-rank test, P = 0.003). CONCLUSIONS: Plasma neopterin levels significantly increased in HFpEF and correlated with the severity of HF. Furthermore, high neopterin were significantly correlated with future cardiovascular events, indicating that measurement of plasma neopterin might provide clinical benefits for risk stratification of HFpEF patients. © 2015 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Prognostic significance of circulating leukocyte subtype counts in patients with coronary artery disease.

BACKGROUND AND AIMS: This study investigated the association of leukocyte subtype counts with vascular endothelial dysfunction and future cardiovascular events in patients with coronary artery disease (CAD). METHODS: The study included 389 consecutive CAD patients (259 male, 130 female; mean age, 70.1 ± 9.9 years). The patients underwent coronary angiography, and measurement of blood parameters, including leukocyte subtype counts. RESULTS: There were 84 cardiovascular events during a mean follow-up of 586 ± 378 days. Kaplan-Meier analysis showed a higher probability of cardiovascular events in the high-monocyte group (≥360/mm3) compared with the low-monocyte group (<360/mm3) (log-rank test, p = 0.047). Multivariate Cox hazard analysis identified a high monocyte count as an independent predictor of cardiovascular events (hazard ratio: 1.63, 95% confidence interval:1.05-2.51, p = 0.028). Peripheral endothelial function in 355 of the CAD patients was assessed by reactive hyperemia peripheral arterial tonometry index (RHI) to examine the association of ln-RHI with leukocyte subtype counts. Total leukocyte, monocyte and neutrophil counts were significantly higher in CAD patients with low ln-RHI (<0.57: the mean ln-RHI value) compared with those with high ln-RHI (≥0.57). Univariate analyses revealed that ln-RHI in CAD patients was positively correlated with ln-total leukocyte (r = -0.187, p < 0.001), ln-monocyte (r = 0.316, p < 0.001), and neutrophil (r = -0.175, p = 0.001) counts. Multiple regression analysis showed that the monocyte count was a significant and independent factor associated with ln-RHI (adjusted R2 = 0.126, p < 0.001). CONCLUSIONS: A high monocyte count was an independent and incremental predictor of cardiovascular events in CAD patients. The monocyte count was also significantly correlated with peripheral endothelial dysfunction in CAD patients.

Clinical significance of pulse pressure in patients with heart failure with preserved left ventricular ejection fraction.

AIMS: Although pulse pressure (PP) is a recognized risk factor for various cardiovascular diseases, its association with cardiovascular outcomes in patients with heart failure with preserved ejection fraction (HFpEF) is uncertain. METHODS AND RESULTS: We enrolled 512 of 951 consecutive HFpEF patients admitted to the Kumamoto University Hospital between 2007 and 2013 and divided them into five groups according to PP quintiles. Blood pressure and pulse wave velocity (PWV) were measured by an ankle-brachial index device. The PP values in HFpEF were significantly and positively correlated with PWV and LV stroke volume index, and were negatively correlated with estimated glomerular filtration rate and haemoglobin levels. Furthermore, plasma B-type natriuretic peptide levels in HFpEF patients with the lowest (<45 mmHg) and highest PP (≥75 mmHg) were significantly higher than those with other PP (45-74 mmHg). The percentage of total cardiovascular and heart failure (HF)-related events by PP category resulted in U- and J-shaped curves. The higher frequency of coronary-related events was nearly linear. In the Kaplan-Meier analysis, HFpEF patients with the lowest and highest PP quintiles had a significantly higher risk of cardiovascular and HF-related events than those with other PPs (45-74 mmHg) (log-rank test, both P < 0.01). Conversely, the frequency of coronary-related events in the highest PP group, but not in the lowest PP group, was significantly higher than in other PP groups. CONCLUSION: Pulse pressure lower than 45 mmHg and higher than 75 mmHg was closely associated with HFpEF prognosis, indicating the clinical significance of PP for risk stratification of HFpEF.

High serum levels of thrombospondin-2 correlate with poor prognosis of patients with heart failure with preserved ejection fraction.

Thrombospondin-2 (TSP-2) is highly expressed in hypertensive heart. Interstitial fibrosis is frequently observed in hypertensive heart, and it is a characteristic feature of heart failure with preserved ejection fraction (HFpEF). We tested here the hypothesis that high TSP-2 serum levels reflect disease severity and can predict poor prognosis of patients with HFpEF. Serum TSP-2 levels were measured by ELISA in 150 patients with HFpEF. HFpEF was defined as left ventricular ejection fraction ≥ 50%, B-type natriuretic peptide (BNP) ≥ 100 pg/ml or E/e' ≥ 15. The endpoints were mortality rate, HF-related hospitalization, stroke and non-fatal myocardial infarction. The median serum TSP-2 level was 19.2 (14.4-26.0) ng/ml. Serum TSP-2 levels were associated with the New York Heart Association (NYHA) functional class. Circulating levels of BNP and high-sensitivity troponin T were positively correlated with serum TSP-2 levels. Kaplan-Meier survival curve showed high risk of adverse cardiovascular events in the high TSP-2 group (>median value), and that the combination of high TSP-2 and high BNP (≥ 100 pg/ml) was associated with the worst event-free survival rate. Multivariate Cox proportional hazard analysis identified TSP-2 as independent predictor of risk of death and cardiovascular events. Circulating TSP-2 correlates with disease severity in patients with HFpEF. TSP-2 is a potentially useful predictor of future adverse cardiovascular events in patients with HFpEF.

The Pivotal Role of a Novel Biomarker of Reactive Oxygen Species in Chronic Kidney Disease.

Risk stratification of chronic kidney disease (CKD) is clinically important because such patients are at high risk of cardiovascular events. Although reactive oxygen species (ROS) are reported to be closely associated with the pathophysiology of CKD, there are few useful ROS biomarkers known for CKD patients. Hence, our objectives in this study were to investigate whether serum derivatives of reactive oxygen metabolites (DROM), a novel biomarker of ROS, is involved in the pathophysiology of CKD (case-control study), and is a significant predictor of future cardiovascular events in CKD patients (follow-up study).Patients with suspected coronary artery disease (CAD) were enrolled and underwent coronary angiography. Patients with CKD (estimated glomerular filtration ratio <60  mL/min/1.73 m(2)  and/or proteinuria, n = 324) were compared with those without CKD (non-CKD). Serum DROM was measured at stable conditions. A case-control study of the 324 CKD patients and 263 non-CKD patients was conducted after matching risk factors, and a follow-up study of the 324 CKD patients was performed. CKD patients were divided into low- and high-DROM groups using their median value (348 unit; called the Carratelli unit [U.CARR]), and followed until the occurrence of cardiovascular events.DROM levels were significantly higher in risk factors-matched CKD patients than in risk factors-matched non-CKD patients (347.0 [301.8-391.8] U.CARR vs. 338.5 [299.8-384.3] U.CARR, P = 0.03). During mean 23 ±â€Š14 months follow-up of 324 CKD patients, 83 cardiovascular events were recorded. Kaplan-Meier analysis demonstrated a higher probability of cardiovascular events in CKD patients with high DROM than in those with low DROM (P < 0.001, log-rank test). Multivariate Cox hazard analysis including significant predictors in simple Cox hazard analysis demonstrated that high DROM was a significant and independent predictor of cardiovascular events in CKD patients (hazard ratio: 1.76, 95% confidence interval: 1.10-2.82, P = 0.02).In conclusion, serum DROM values were significant and independent predictors of cardiovascular events in CKD patients, indicating that the measurements of DROM might provide clinical benefits for risk stratification of CKD patients.

Relationship between inter-arm blood pressure differences and future cardiovascular events in coronary artery disease.

OBJECTIVE: Recent studies have shown that inter-arm blood pressure differences (IAD) may be a risk factor for cardiovascular events; however, none have addressed them in patients with coronary artery disease (CAD). METHODS: We measured blood pressure bilaterally with the ankle brachial index (ABI) in 657 patients with suspected CAD and assessed the presence of CAD by coronary angiography, and the severity of coronary atherosclerosis with the Gensini score. RESULTS: Mean IADs were significantly greater in risk factor matched patients with CAD than in those without it (P = 0.01), whereas Gensini scores were significantly greater in those with high IAD (≥10  mmHg) than in those with low-IAD (P = 0.01) according to cross-sectional analysis. Patients with high IAD had a significantly greater probability of cardiovascular events than those in whom it was low (log-rank test, P < 0.01, mean follow-up range; 827.3 ±â€Š268.1 days). The presence of hypertension, ABI, usage of calcium channel blocker and high IAD were independent predictors of cardiovascular events according to longitudinal analysis (IAD; hazard ratio: 2.90, 95% confidence interval: 1.41-5.94, P < 0.01) in these patients. Patients with high IAD and peripheral artery disease had the highest Gensini scores according to cross-sectional analysis (P < 0.01) and highest probability of cardiovascular events according to longitudinal analysis (log-rank test, P < 0.001). CONCLUSION: IADs were increased in CAD patients and correlated with its severity. Greater than 10  mmHg of IAD was independently associated with future cardiovascular events. Assessing IAD by ABI measurement may facilitate risk stratification in CAD patients.