Chiharu Noda

Protective effect of urinary trypsin inhibitor on myocardial mitochondria during hemorrhagic shock and reperfusion.

ObjectiveTo examine the mitochondrial function in the myocardium after hemorrhagic shock and reperfusion and to evaluate the protective effect of urinary trypsin inhibitor (UTI) on mitochondria. DesignAnimal experiment. SettingUniversity research laboratory. SubjectsWistar rats receiving 50,000 units/kg/hr of UTI (n = 27; UTI group) and control rats (n = 26; control group). InterventionsRats were subjected to low-perfusion ischemia with the left ventricular systolic pressure maintained at 50 mm Hg for 60 mins by bleeding, followed by a 60-min reperfusion by transfusion of shed blood. UTI was infused continuously from 10 mins before bleeding. Cardiac function was measured before bleeding, after bleeding, and after transfusion; at each determination point, the myocardial contents of adenosine triphosphate (ATP), creatine phosphate (P-Cr), pyruvate (Pyr), and lactate (Lac) were measured enzymatically. The cytosolic phosphorylation potential (PP) as well as the redox potential of the oxidized form of nicotinamide adenine dinucleotide/reduced form of nicotinamide adenine dinucleotide couple in mitochondria (EhNAD+/NADH) and change of Gibbs free energy in ATP hydrolysis (&Dgr;GATP hydrolysis energy) were calculated. Measurements and Main ResultsCardiac function decreased during hemorrhagic shock but improved significantly in the UTI group after transfusion compared with the control group. Lac and the Lac/Pyr ratio were significantly lower in the UTI group than in the control group after transfusion. ATP and P-Cr were significantly higher in the UTI group than in the control group after transfusion. PP (×10 3 M−1), EhNAD+/NADH (x − 1 mV), and &Dgr;GATP hydrolysis (x − 1 kcal/mol) were 1.9 ± 0.4, 266 ± 4, and 9.7 ± 0.2, respectively, in the control group and 4.0 ± 0.9, 274 ± 5 and 13.0 ± 0.2, respectively, in the UTI group after transfusion (p < .001, p < .001, and p < .001, respectively). ConclusionsIn reperfusion after hemorrhagic shock, oxidative phosphorylation in myocardial mitochondria is impaired and energy production remains reduced, even after reperfusion. UTI contributed to the recovery of cardiac function after reperfusion, probably by reducing the severity of mitochondrial dysfunction during a state of shock and by maintaining energy production.

Quadriceps isometric strength as a predictor of exercise capacity in coronary artery disease patients

Background Quadriceps strength is related to exercise capacity in normal subjects and different patient populations, but the relationship between maximal quadriceps isometric strength (QIS) and different exercise capacity levels in coronary artery disease (CAD) patients has not been systematically evaluated yet. Method We studied 621 patients (60.6 ± 9.9 years, 538 males) with recent coronary artery bypass grafting or myocardial infarction, who underwent treadmill exercise testing, maximal QIS measurement (hand-held dynamometry), and coronary arteriography. Maximal QIS was expressed as absolute value (kg), %bodyweight, and %predicted maximum. Logistic regression was used to assess the relationship of maximal QIS, age, sex, number of diseased coronary vessels, peak systolic blood pressure, peak heart rate, brain natriuretic peptide, and left ventricular ejection fraction with 5, 7, and 10 estimated metabolic equivalents (eMETs) exercise capacity levels. Results Maximal QIS %bodyweight was the strongest predictor of exercise capacity in each eMETs category. Receiver-operating characteristics curves identified maximal QIS of 46, 51, and 59 % bodyweight as the best predictive cut offs for 5, 7 and 10 eMETs, respectively, with positive predictive values of 0.72, 0.66, and 0.67, respectively. Conclusions Maximal QIS is related with eMETs levels reached at exercise testing in CAD patients, and identified maximal QIS cut-off values for eMETs prediction may be used to set strength training goals according to patients’ needs with regard to habitual physical activity level. Hand-held dynamometry may meet the need of easiness of use and low cost required for strength evaluation in large-scale clinical trials.

Quadriceps Strength as a Predictor of Mortality in Coronary Artery Disease

BACKGROUND The purpose of this study was to investigate the prognostic value of quadriceps isometric strength (QIS) in coronary artery disease (CAD). METHODS The study population consisted of 1314 patients aged >30 years (64.7 ± 10.6 years, 1051 male) with CAD who were hospitalized for acute coronary syndrome or coronary artery bypass grafting. Maximal QIS was evaluated as a marker of leg strength and expressed relative to body weight (% body weight). The primary and secondary endpoints were all-cause death and cardiovascular (CV) death, respectively. RESULTS During a mean follow-up of 5.0 ± 3.5 years, corresponding to 6537 person-years, there were 118 all-cause deaths and 63 CV deaths. A higher QIS remained associated with decreased all-cause mortality and CV mortality risks (hazard ratio for increasing 10% body weight of QIS 0.77, 95% confidence interval 0.67-0.89, P < .001 for all-cause death; hazard ratio 0.66, 95% confidence interval 0.54-0.82, P < .001 for CV death) after adjustment for other prognostic factors. The inclusion of QIS significantly increased both continuous net reclassification improvement (cNRI) and integrated discrimination improvement (IDI) for all-cause death (cNRI: 0.25, P = .009; IDI: 0.007, P = .030) and CV death (cNRI: 0.34, P = .008; IDI: 0.013, P = .008). CONCLUSIONS A high level of quadriceps strength was strongly associated with a lower risk of both all-cause and CV mortality in patients with CAD. Evaluation of QIS offered incremental prognostic information beyond pre-existing risk factors.

Complementary Role of Arm Circumference to Body Mass Index in Risk Stratification in Heart Failure.

OBJECTIVES This study was performed to investigate the complementary role of arm circumference to body mass index (BMI) in risk stratification of patients with heart failure (HF). BACKGROUND High BMI is associated with improved survival in patients with HF. However, it does not discriminate between fat and lean muscle as a predominant factor. METHODS BMI, waist circumference (WC), and mid-upper arm circumference (MUAC) were evaluated in 570 consecutive Japanese patients with HF (mean age 67.4 ± 14.0 years). Patients were stratified into low and high groups according to BMI, WC, and MUAC and combined into low- or high-BMI and low- or high-WC groups or low- or high-BMI and low- or high-MUAC groups. The endpoint was all-cause mortality. RESULTS Seventy deaths occurred over a median follow-up period of 1.5 years (interquartile range: 0.7 to 2.8 years). After adjusting for several pre-existing prognostic factors, including Seattle Heart Failure Score and exercise capacity, BMI (hazard ratio [HR]: 0.68; p = 0.016), WC (HR: 0.76; p = 0.044), and MUAC (HR: 0.52; p < 0.001) were all inversely associated with prognosis. Compared with the high-BMI/high-WC group, both the low-BMI/high-WC and low-BMI/low-WC groups showed comparably poorer prognosis. However, the low-BMI/low-MUAC group but not the low-BMI/high-MUAC group showed poorer prognosis than the high-BMI/high-MUAC group. Adding MUAC to BMI (0.70 vs. 0.63, p = 0.012) but not WC to BMI (0.64 vs. 0.63, p = 0.763) significantly increased the area under the curve on receiver-operating characteristic curve analysis. CONCLUSIONS MUAC, but not WC, plays a complementary role to BMI in predicting prognosis in patients with HF.

Beneficial Effects of L‐ and N‐type Calcium Channel Blocker on Glucose and Lipid Metabolism and Renal Function in Patients with Hypertension and Type II Diabetes Mellitus

It has been proved that cilnidipine has N-type calcium channels inhibitory activity as well as L-type calcium channels and inhibits excessive release of norepinephrine from the sympathetic nerve ending. This study was undertaken to compare the efficacy of amlodipine (an inhibitor of L-type calcium channels) and cilnidipine (an inhibitor of both L-type and N-type calcium channels) in patients with hypertension and type II diabetes mellitus. Seventy-seven hypertensive patients were divided into two groups according to presence/absence of type II diabetes mellitus. In these two groups of patients, the effects of amlodipine and cilnidipine on glucose and lipid metabolism and renal function were compared. As for glucose and lipid metabolism, homeostasis model assessment insulin resistance (HOMA-R) level in the non-diabetic group and triglyceride in the diabetes group were significantly lower with cilnidipine than with amlodipine. As regards renal function in the diabetic group, estimated glomerular filtration rate (eGFR) was significantly higher and urinary albumin/creatinine ratio was significantly lower with cilnidipine than with amlodipine. Cilnidipine which inhibits N-type calcium channels is more useful for patients with hypertension and diabetes mellitus from its effects on glucose and lipid metabolism and renal function.

Influence of nifedipine coat-core and amlodipine on systemic arterial stiffness modulated by sympathetic and parasympathetic activity in hypertensive patients.

The aim of this study was to compare the effects of nifedipine coat-core (once daily formulation) and amlodipine on systemic arterial stiffness in patients with hypertension. Study drugs were assigned by the randomized open-label crossover method. After the blood pressure was maintained below 130/85 mm Hg for 8 months by treatment with either drug in 48 hypertensive patients (aged 63.2±6.9 years; 64.5% men), they were switched to the other drug for another 8 months. The blood pressure, heart rate, plasma catecholamine level and brachial-ankle pulse wave velocity were measured before and after a bicycle ergometer testing. Heart rate recovery was calculated from the change of the heart rate after treadmill exercise testing. The high-frequency and low-frequency components of the heart rate variability spectrum were analyzed from 24-h Holter electrocardiograms. The change of blood pressure after exercise testing showed no significant difference between the two medications. However, the increases of heart rate, noradrenalin and branchial-ankle pulse wave velocity after exercise were significantly smaller with nifedipine treatment than with amlodipine (P=0.0472, P=0.006 and P=0.0472, respectively). Heart rate recovery was significantly faster with nifedipine treatment (P=0.0280). The nighttime high-frequency component of heart rate variability was significantly larger after nifedipine treatment than after amlodipine (P=0.0259), while the nighttime low/high-frequency ratio was significantly smaller with nifedipine (P=0.0429). Nifedipine reduced functional arterial stiffness and improved heart rate recovery by altering the autonomic activity balance in hypertensive patients.

Gait speed has comparable prognostic capability to six-minute walk distance in older patients with cardiovascular disease

Background Although gait speed and six-minute walk distance are used to assess functional capacity in older patients with cardiovascular disease, their prognostic capabilities have not been directly compared. Methods The study population was identified from the Kitasato University Cardiac Rehabilitation Database and consisted of 1474 patients ≥60 years old with a mean age of 72.2 ± 7.1 years that underwent evaluation of both usual gait speed and six-minute walk distance in routine geriatric assessment between 1 June 2008–30 September 2015. Both gait speed and six-minute walk distance were determined on the same day at hospital discharge. Results Mean gait speed and six-minute walk distance in the whole population were 1.04 m/s and 381 m, respectively, and were strongly positively correlated (r = 0.80, p < 0.001). A total of 180 deaths occurred during a follow-up of 2.3 ± 1.9 years. After adjusting for confounding factors, both gait speed (adjusted hazard ratio per 0.1 m/s increase: 0.87, 95% confidence interval: 0.81–0.93, p < 0.001) and six-minute walk distance (adjusted hazard ratio per 10-metre increase: 0.96, 95% confidence interval: 0.94–0.97, p < 0.001) were independent predictors of all-cause mortality. There was no significant difference in prognostic capability between gait speed and six-minute walk distance (c-index: 0.64 (95% confidence interval: 0.60–0.69) and 0.66 (95% confidence interval: 0.61–0.70), respectively, p = 0.357). Conclusions Gait speed and six-minute walk distance showed similar prognostic predictive ability for all-cause mortality in older cardiovascular disease patients, indicating the potential utility of gait speed as a simple risk stratification tool in older cardiovascular disease patients.

Low ankle brachial index is associated with the magnitude of impaired walking endurance in patients with heart failure

BACKGROUND Measurement of the ankle brachial index (ABI) is a simple, noninvasive means of diagnosing peripheral arterial disease, and has been shown to be associated with mortality rate. Here, we examined the association between ABI and physical function in patients with heart failure (HF). METHODS The study population consisted of 524 admitted patients (67.2±13.9years, 343 males) with HF. Blood pressure and the ABI were determined by oscillometry. Prior to hospital discharge, ABI, 6-minute walking distance, walking velocity, handgrip strength, quadriceps isometric strength, and standing balance were determined. The 524 patients were divided according to ABI as follows: ABI≤0.90 (low ABI), ABI 0.91 to 0.99 (borderline ABI), and ABI 1.00 to 1.40 (normal ABI). RESULTS Lower ABI values were associated with shorter 6-minute walking distance (p trend=0.001), slower walking velocity (p trend=0.023), and poorer standing balance (p trend=0.048). There were no significant associations between ABI and handgrip strength or quadriceps isometric strength. After adjusting for potential confounders, patients with ABI≤0.90 had shorter 6-minute walking distance compared to those with ABI 1.00 to 1.40 (adjusted mean value: 344m vs. 395m, respectively, p<0.001). There were no significant differences in any of the other physical function parameters examined. CONCLUSIONS In patients with HF, low ABI is associated with the magnitude of impairment in walking endurance.

Low Stroke Rate of Carotid Stenosis Under the Guideline-Oriented Medical Treatment Compared With Surgical Treatment

Medical treatment for asymptomatic carotid artery stenosis (ACAS) has advanced recently. The outcomes of medical treatment and surgical treatment were evaluated to clarify the optimal treatment for ACAS.Patients with ACAS of ≥ 50% luminal narrowing underwent serial follow-up carotid artery ultrasonography for one year or more at the Center for Cardiovascular Disease Prevention between November 2006 and October 2013. The incidence of cardiovascular events (stroke, myocardial infarction, cardiovascular death) was examined in 64 patients (medical treatment group), and in 47 patients (surgical group) who underwent surgical treatment (carotid endarterectomy or carotid artery stenting) during this same period at the Department of Neurosurgery.Annual cardiovascular event rate was 0.91% (2/219 person-year) in the group of guideline-oriented medical treatment with an annual check-up for disease management and 5.6% (6/107 person-year) in the surgical group (log-rank P = 0.027; HR in the medical treatment group, 0.19 [medical treatment/surgical]; 95% confidence interval [CI], 0.028 to 0.87). Annual stroke event rate was 0.46% (1/219 person-year) in the medical treatment group and 4.7% (5/107 personyear) in the surgical group (log-rank P = 0.016; HR in the medical treatment group, 0.11 [medical treatment/surgical]; 95% CI, 0.0057 to 0.70). Multivariate logistic analysis showed that the surgical group was an independent variable associated with cardiovascular events (P = 0.049).Annual cardiovascular and stroke event rates were low in patients receiving medical treatment for ACAS and better than surgical treatment. The present study shows that medical treatment is an important option for ACAS.

Incremental Value of Objective Frailty Assessment to Predict Mortality in Elderly Patients Hospitalized for Heart Failure

BACKGROUND The impact of frailty on long-term prognosis in patients with heart failure (HF) remains unclear, and there is no simple and objective assessment for it. This study was performed to examine the association between frailty score and clinical outcome in elderly patients hospitalized for HF. METHODS AND RESULTS A retrospective cohort study was performed with 603 elderly patients with HF (mean age 75 ± 6 years, 378 [62.7%] men). Frailty was measured by a composite of 4 markers combined into a frailty score (possible range 0-12): gait speed, handgrip strength, serum albumin, and activities of daily living status. The patient population was divided into 2 groups with frailty score <5 (non-frail) or ≥5 (frail). The end point was all-cause mortality. Over a mean follow-up period of 1.7 ± 0.5 years, 89 patients died. After adjustment for several preexisting factors associated with prognosis, the frailty score (hazard ratio [HR] 1.11; P = .014) and frailty (HR 1.75; P = .036) were independently associated with all-cause mortality. The inclusion of frailty score significantly increased both continuous net reclassification improvement (0.341; P = .002) and integrated discrimination improvement (0.016; P = .039) for all-cause mortality. CONCLUSIONS A simple and objective frailty score was associated with health outcome in elderly patients hospitalized for HF.