Takanori Tokitsu

Growth differentiation factor-15 is a useful prognostic marker in patients with heart failure with preserved ejection fraction.

BACKGROUND Circulating growth differentiation factor 15 (GDF-15) levels correlate with heart mass and fibrosis; however, little is known about its value in predicting the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). METHODS We measured serum GDF-15 levels in 149 consecutive patients with left ventricular diastolic dysfunction (LVDD) and normal LV ejection fraction (>50%) and followed them for cardiovascular events. LVDD was defined according to the European Society of Cardiology guidelines. RESULTS The New York Heart Association functional class and circulating B-type natriuretic peptide (BNP) levels were significantly higher in the high-GDF-15 group (n = 75; greater than or equal to the median value [3694 pg/mL]) than in the low-GDF-15 group (n = 74). Patients were divided into HFpEF and LVDD groups according to the presence or absence of HF. Serum GDF-15 levels were significantly higher in the HFpEF group (n = 73) than in the LVDD group (n = 76) (median, 4215 [interquartile range, 3382-5287] vs 3091 [interquartile range, 2487-4217 pg/mL]; P < 0.0001). Kaplan-Meier curve analysis showed a significantly higher probability of cardiovascular events in the high-GDF-15 group than in the low-GDF-15 group for data of all patients (log-rank test P = 0.006) and data of patients in the HFpEF group only (P = 0.014). Multivariate Cox hazard analysis identified age (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.87-0.98; P = 0.008), atrial fibrillation (HR, 7.95; 95% CI, 1.98-31.85, P = 0.003), lnBNP (HR, 3.37; 95% CI, 1.73-6.55; P < 0.0001), and GDF-15 (ln[GDF-15]) (HR, 4.74; 95% CI, 1.26-17.88, P = 0.022) as independent predictors of primary end points. CONCLUSIONS GDF-15 is a potentially useful prognostic biomarker in patients with HFpEF.

Reactive Oxygen Metabolites are Closely Associated With the Diagnosis and Prognosis of Coronary Artery Disease

Background Reactive oxygen species (ROS) are associated with development of coronary artery disease (CAD). However, theres no useful biomarker of ROS in CAD. Methods and Results We recruited 395 consecutive CAD patients who were performed coronary angiography (262 male and 133 female, age 70.2±10), and we measured serum derivatives of reactive oxidative metabolites (DROM) were measured. Two hundred twenty‐seven non‐CAD patients were also enrolled. We performed follow‐up study in these 395 CAD patients and case‐control study after risk factor and 1:1 pair matching (both, n=163). As subgroup analysis, DROM were also measured at the aortic root and the coronary sinus in 59 CAD patients. DROM were significantly higher in CAD patients (n=163, median [inter‐quartile range, IQR]=338 [302 to 386]) than in risk factor‐matched non‐CAD patients (n=163, 311 [282 to 352.5], effect size=0.33, P<0.001). During a mean follow‐up period of 20 months of 395 CAD patients, 83 cardiovascular events were recorded. Kaplan‐Meier analysis showed a higher probability of cardiovascular events in the high‐DROM group (>346 U.CARR) than in the low‐DROM group (≤346 U.CARR) (P=0.001 [log‐rank test]). Multivariate Cox hazard analysis identified ln‐DROM as an independent predictor for cardiovascular events (hazard ratio: 10.8, 95% confidence interval: 2.76 to 42.4, P=0.001). The transcardiac gradient of DROM was significantly higher in CAD patients than in non‐CAD patients (−2.0 [−9.0 to 9.0] versus 8 [−8.0 to 28.3], effect size=0.21, P=0.04), indicating that DROM production in coronary circulation is associated with development of CAD. Conclusion DROM are increased in CAD patients and associated with future cardiovascular events. DROM might provide clinical benefits for risk stratification of CAD. Clinical Trial Registration URL: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN000012990.

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

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.

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

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.

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 ± 268.1 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.

The pivotal role of a novel biomarker of reactive oxygen species in chronic kidney disease

Abstract 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 m2 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 ± 14 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.

Clinical significance of pulse pressure in patients with coronary artery disease

Clinical Significance of Pulse Pressure in Patients with Coronary ArteryDiseaseTakanori Tokitsu, Eiichiro Yamamoto, Yoshihiro Hirata, Koichiro Fu-jisue, Daisuke Sueta, Koichi Sugamura, Kenji Sakamoto, Koichi Kaikita, SeijiHokimoto, Seigo Sugiyama, Hisao OgawaPII: S0167-5273(15)00824-4DOI: doi: 10.1016/j.ijcard.2015.04.101Reference: IJCA 20306To appear in:

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, β-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.