Hiroaki Kusaka

Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice

BackgroundThere has been uncertainty regarding the benefit of glycemic control with antidiabetic agents in prevention of diabetic macrovascular disease. Further development of novel antidiabetic agents is essential for overcoming the burden of diabetic macrovascular disease. The renal sodium glucose co-transporter 2 (SGLT2) inhibitor is a novel antihyperglycemic agent for treatment of type 2 diabetes. This work was performed to determine whether empagliflozin, a novel SGLT2 inhibitor, can ameliorate cardiovascular injury and cognitive decline in db/db mouse, a model of obesity and type 2 diabetes.Methods(1) Short-term experiment: The first experiment was performed to examine the effect of 7 days of empagliflozin treatment on urinary glucose excretion and urinary electrolyte excretion in db/db mice. (2) Long-term experiment: The second experiment was undertaken to examine the effect of 10 weeks of empagliflozin treatment on cardiovascular injury, vascular dysfunction, cognitive decline, and renal injury in db/db mice.Results(1) Short-term experiment: Empagliflozin administration significantly increased urinary glucose excretion, urine volume, and urinary sodium excretion in db/db mice on day 1, but did not increase these parameters from day 2. However, blood glucose levels in db/db mice were continuously decreased by empagliflozin throughout 7 days of the treatment. (2) Long-term experiment: Empagliflozin treatment caused sustained decrease in blood glucose in db/db mice throughout 10 weeks of the treatment and significantly slowed the progression of type 2 diabetes. Empagliflozin significantly ameliorated cardiac interstitial fibrosis, pericoronary arterial fibrosis, coronary arterial thickening, cardiac macrophage infiltration, and the impairment of vascular dilating function in db/db mice, and these beneficial effects of empagliflozin were associated with attenuation of oxidative stress in cardiovascular tissue of db/db mice. Furthermore, empagliflozin significantly prevented the impairment of cognitive function in db/db mice, which was associated with the attenuation of cerebral oxidative stress and the increase in cerebral brain-derived neurotrophic factor. Empagliflozin ameliorated albuminuria, and glomerular injury in db/db mice.ConclusionsGlycemic control with empagliflozin significantly ameliorated cardiovascular injury and remodeling, vascular dysfunction, and cognitive decline in obese and type 2 diabetic mice. Thus, empagliflozin seems to be potentially a promising therapeutic agent for diabetic macrovascular disease and cognitive decline.

Endothelial function and cardiovascular events in chronic kidney disease

BACKGROUND As patients with chronic kidney disease (CKD) are at high risk of developing coronary artery disease (CAD), it is important to stratify their cardiovascular risk. We investigated whether peripheral endothelial dysfunction is associated with the presence of CAD in patients with CKD and is a predictor of cardiovascular events. METHODS We enrolled 383 CKD patients with at least one coronary risk factor. Peripheral endothelial function was assessed by reactive hyperemia peripheral arterial tonometry index (RHI). The presence of CAD was determined by coronary angiography. Cardiovascular events were assessed during follow-up. RESULTS Ln-RHI was significantly lower in risk factor-matched CKD patients (n=323) than risk factor-matched non-CKD patients (n=323) (0.527 ± 0.192 vs. 0.580 ± 0.218, p=0.001). In CKD patients (n=383), Ln-RHI was significantly lower in CAD (0.499 ± 0.183, n=262) than non-CAD (0.582 ± 0.206, n=121) (p<0.001) patients. Multivariate logistic regression analysis identified Ln-RHI as an independent factor associated with the presence of CAD (p=0.001). During a mean follow-up period of 30 months, 90 cardiovascular events were recorded in CKD patients. Multivariate Cox hazard analysis identified low-Ln-RHI as an independent predictor of cardiovascular events (hazard ratio=2.70, 95% confidence interval=1.62-4.51, p<0.001). The predictive value of combined Ln-RHI and Framingham risk score (FRS) was evaluated by net reclassification index (NRI) and C-statistics, which showed significant improvement (NRI=22%, p<0.001) (C-statistics: FRS=0.49, FRS+Ln-RHI=0.62, p=0.005). CONCLUSIONS Endothelial function was significantly impaired in CKD patients and correlated with the presence of CAD. Severe endothelial dysfunction was an independent and incremental predictor of cardiovascular events in CKD.

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.

Prognostic significance of peripheral microvascular endothelial dysfunction in heart failure with reduced left ventricular ejection fraction

BACKGROUND Endothelial dysfunction plays a crucial role in heart failure (HF), but the association between peripheral microvascular endothelial function assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and prognosis remains unknown in HF with reduced left ventricular (LV) ejection fraction (HFREF). We prospectively investigated the association between peripheral microvascular endothelial function and HF-related near-future cardiovascular outcomes in HFREF patients. METHODSANDRESULTS The 362 HFREF patients (LVEF <50%) were followed for HF-related events (composite of cardiovascular death and HF hospitalization) up to 3 years. A natural logarithmic-scaled RH-PAT index (Ln-RHI) was obtained for each patient. A total of 82 HF-related events were recorded. The lower-RHI group (Ln-RHI ≤0.49, median) experienced a higher rate of HF-related events compared with the higher-RHI group by Kaplan-Meier analysis (30.9% vs. 14.4%, log-rank test: P<0.001). Multivariable Cox hazard analysis identified Ln-RHI as an independent predictor for HF-related events (per 0.1, hazard ratio: 0.84, 95% confidence interval: 0.75-0.95, P=0.005). Adding Ln-RHI to the Meta-analysis Global Group in Chronic HF risk score (MAGGICs) and Seattle Heart Failure Model (SHFM), powerful prognostic predictors of HF, significantly improved the net reclassification index (MAGGICs: 20.11%, P=0.02, SHFM: 24.88%, P<0.001), and increased the C-statistics for prediction of HF-related events (MAGGICs+Ln-RHI: from 0.612 to 0.670, SHFM+Ln-RHI: from 0.662 to 0.695). CONCLUSIONS Peripheral microvascular endothelial dysfunction assessed by RH-PAT was associated with future HF-related events in HFREF.

LCZ696, Angiotensin II Receptor-Neprilysin Inhibitor, Ameliorates High-Salt-Induced Hypertension and Cardiovascular Injury More Than Valsartan Alone

BACKGROUND LCZ696, an angiotensin receptor-neprilysin inhibitor, has recently been demonstrated to exert more beneficial effects on hypertensive or heart failure patients than conventional renin-angiotensin system blockers. However, the mechanism underlying the benefit of LCZ696 remains to be understood. The present study was undertaken to examine the effect of LCZ696 compared with valsartan on hypertension and cardiovascular injury. METHODS (i) Using telemetry, we compared the hypotensive effect of LCZ696 and valsartan in spontaneously hypertensive rats (SHR) that were fed a high-salt diet followed by a low-salt diet. (ii) We also examined the comparative effect of LCZ696 and valsartan on salt loaded SHRcp, a model of metabolic syndrome. RESULTS (i) LCZ696 exerted a greater blood pressure (BP) lowering effect than valsartan in SHR regardless of high-salt or low-salt intake. Additive BP reduction by LCZ696 was associated with a significant increase in urinary sodium excretion and sympathetic activity suppression. (ii) LCZ696 significantly ameliorated cardiac hypertrophy and inflammation, coronary arterial remodeling, and vascular endothelial dysfunction in high-salt loaded SHRcp compared with valsartan. CONCLUSIONS LCZ696 caused greater BP reduction than valsartan in SHR regardless of the degree of salt intake, which was associated with a significant enhancement in urinary sodium excretion and sympathetic activity suppression. Furthermore, an additive BP lowering effect of LCZ696 led to greater cardiovascular protection in hypertensive rats.

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.

ASK1 is involved in cognitive impairment caused by long-term high-fat diet feeding in mice

Although high-fat diet intake is known to cause obesity and diabetes, the effect of high-fat diet itself on cognitive function remains to be clarified. We have previously shown that apoptosis signal-regulating kinase 1 (ASK1) is responsible for cognitive impairment caused by chronic cerebral hypoperfusion. The present work, by using ASK1 deficient mice, was undertaken to explore the influence of chronic high-fat diet intake on cognitive function and the role of ASK1. Cognitive function in wild-type mice fed high-fat diet from 2 to 24 months of age was significantly impaired compared to those fed control diet, which was associated with the significant white matter lesions, reduction of hippocampal capillary density, and decrement of hippocampal neuronal cell. However, ASK1 deficiency abolished the development of cognitive impairment and cerebral injury caused by high-fat diet. Our results provided the evidence that high-fat diet itself causes cognitive impairment and ASK1 participates in such cognitive impairment.

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.

Low-Normal Serum Sodium and Heart Failure-Related Events in Patients With Heart Failure With Preserved Left Ventricular Ejection Fraction.

BACKGROUND Hyponatremia has been shown to be a prognostic factor in heart failure (HF) with preserved ejection fraction (HFpEF). Serum sodium (sNa) cut-off, however, is not defined in HFpEF. Therefore, we investigated the relationship between sNa and HF-related events (cardiovascular death and hospitalization for HF decompensation) in HFpEF patients. METHODSANDRESULTS We assessed cardiac function using echocardiography and measured sNa in HFpEF patients with New York Heart Association class II (n=321) or III (n=84) in a compensated condition after implementing medical therapy for HF. During a mean follow-up of 27 months, 73 patients developed HF-related events. On multivariate Cox hazard analysis including established predictors in HF, sNa level as a continuous variable was identified as an independent predictor for HF-related events in HFpEF (per 1.0 mmol/L: HR, 0.93; 95% CI: 0.87-0.98; P<0.01). Kaplan-Meier analysis demonstrated significantly higher probability of HF-related events in the lower sNa group (sNa <140 mmol/L) than in the higher sNa group (sNa ≥140 mmol/L; P<0.001, log-rank test). Further, the low-normal sNa group (135 mmol/L<sNa<140 mmol/L) was significantly associated with HF-related events compared with the higher sNa group (P<0.001, log-rank test). CONCLUSIONS sNa as a continuous variable was independently correlated with future HF-related events in HFpEF. Low-normal sNa could provide important prognostic information for practical risk stratification in HFpEF.