Atsuhiko Matsunaga

Sympathetic Nervous Activity and Myocardial Damage Immediately After Subarachnoid Hemorrhage in a Unique Animal Model

Background and Purpose— Obvious cardiac dysfunction, including ECG abnormalities and left ventricular asynergy, is known to develop after subarachnoid hemorrhage (SAH). To clarify the close relationship between myocardial damage and sympathetic nervous activity immediately after SAH, a novel experimental animal model was used. Methods— SAH was provoked by perforation of the basilar artery with the use of a microcatheter inserted through the femoral artery in 18 beagle dogs. Hemodynamic changes were recorded, and plasma concentrations of noradrenaline, adrenaline, and 3-methoxy-4-hydroxy-phenylethylene glycol (MHPG) and serum levels of creatine kinase–MB (CK-MB) and troponin T were measured at 0, 5, 15, 30, 60, 120, and 180 minutes after SAH. Results— Noradrenaline (pg/mL), adrenaline (pg/mL), and MHPG (ng/mL) increased abruptly from 120±70, 130±70, and 1.3±0.5 before SAH to 1700±1200, 5600±3500, and 3.2±1.2 at 5 minutes after SAH, respectively. Aortic pressure, left ventricular wall motion, and cardiac output increased by 60%, 40%, and 30%, respectively (P <0.001) at 5 minutes and then decreased by 50%, 55%, and 40%, respectively (P <0.001) >60 minutes after SAH compared with baseline values. The peak value of CK-MB correlated positively with the peak values of noradrenaline and adrenaline (r =0.730 and r =0.611, respectively). The peak value of troponin T also correlated positively with the peak values of noradrenaline and adrenaline (r =0.828 and r =0.792, respectively). Conclusions— These results suggest that the elevated activity of the sympathetic nervous system observed in the acute phase of SAH induced myocardial damage and contributed to the development of cardiac dysfunction.

Habitual Physical Activity Measured by Accelerometer and Survival in Maintenance Hemodialysis Patients

BACKGROUND AND OBJECTIVES The association between mortality and physical activity based on self-report questionnaire in hemodialysis patients has been reported previously. However, because self-report is a subjective assessment, evaluating true physical activity is difficult. This study investigated the prognostic significance of habitual physical activity on 7-year survival in a cohort of clinically stable and adequately dialyzed patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 202 Japanese outpatients who were undergoing maintenance hemodialysis three times per week at the hemodialysis center of Sagami Junkanki Clinic (Japan) from October 2002 to February 2012 were followed for up to 7 years. Physical activity was evaluated using an accelerometer at study entry and is expressed as the amount of time a patient engaged in physical activity on nondialysis days. Cox proportional hazard regression was used to assess the contribution of habitual physical activity to all-cause mortality. RESULTS The median patient age was 64 (25th, 75th percentiles, 57, 72) years, 52.0% of the patients were women, and the median time on hemodialysis was 40.0 (25th, 75th percentiles, 16.8, 119.3) months at baseline. During a median follow-up of 45 months, 34 patients died. On multivariable analysis, the hazard ratio for all-cause mortality per 10 min/d increase in physical activity was 0.78 (95% confidence interval, 0.66-0.92; P=0.002). CONCLUSIONS Engaging in habitual physical activity among outpatients undergoing maintenance hemodialysis was associated with decreased mortality risk.

Elevated circulating levels of an incretin hormone, glucagon-like peptide-1, are associated with metabolic components in high-risk patients with cardiovascular disease

BackgroundGlucagon-like peptide-1 (GLP-1) is an incretin hormone that has a wide range of effects on glucose metabolism and cardiovascular function (e.g., improving insulin sensitivity, reduction in appetite, modulation of heart rate, blood pressure and myocardial contractility). Metabolic syndrome (MetS) is associated with an increased risk of developing atherosclerotic cardiovascular diseases. Novel glycemic control drugs, the dipeptidyl-peptidase-4 (DPP-4) inhibitors, work by inhibiting the inactivation of incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In spite of good effects of these drugs in diabetic patients, circulating levels of incretins and their role in MetS are largely unknown.MethodsTo examine relationships between incretin hormones and MetS risk factors, we measured circulating levels of incretins in obese high-risk patients for cardiovascular disease. Fasting serum GLP-1 and GIP levels were measured by ELISA. We performed a cross-sectional analysis of metabolic variables in the fasting state in two subject groups: with MetS (n = 60) and pre-MetS (n = 37).ResultsFasting levels of Serum GLP -1 in the peripheral circulation were significantly increased correlated with the accumulation of MetS risk factors components (r = 0. 470, P < 0.001). There was a significant interaction between circulating GLP-1 and GIP, serum high-density lipoprotein cholesterol, triglyceride, and serum uric acid concentrations but not waist circumference, fasting glucose, HbA1c, or presence of diabetes.ConclusionCirculating levels of GLP-1 in relation to the accumulation in MetS factors suggested that MetS patients with elevated levels of GLP-1 are high-risk patients for cardiovascular disease, independent with the presence of diabetes.

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.

Relationship Between Lower Extremity Muscle Strength and All-Cause Mortality in Japanese Patients Undergoing Dialysis

Background Skeletal muscle wasting is common and insidious in patients who are undergoing hemodialysis. However, the association between lower extremity muscle strength and all-cause mortality remains unclear in this population. Objective The purpose of this study was to investigate the prognostic significance of lower extremity muscle strength on 7-year survival in a cohort of patients who were clinically stable and undergoing hemodialysis. Design A prospective cohort study was conducted. Methods A total of 190 Japanese outpatients who were undergoing maintenance hemodialysis 3 times per week at a hemodialysis center were followed for up to 7 years. Lower extremity muscle strength was evaluated using a handheld dynamometer at the time of patient enrollment in the study. Muscle strength data were divided by dry weight and expressed as a percentage. A Cox proportional hazards regression model was used to assess the contribution of lower extremity muscle strength to all-cause mortality. Results The median age (25th and 75th percentiles) of this study population was 64 years (57 and 72 years), 53.2% of the patients were women, and the time on hemodialysis was 39.0 months (15.9 and 110.5 months) at baseline. During a median follow-up of 36.0 months, there were 30 deaths. With a multivariate Cox model, the hazard ratio in the group with a knee extensor strength of <40% was 2.73 (95% confidence interval=1.14–6.52) compared with that in the ≥40% group. Limitations This was a small-scale observational study, and the mechanisms underlying the higher mortality risk in patients with poor muscle strength undergoing hemodialysis than in other patients undergoing hemodialysis remain to be elucidated. Conclusions Decreased lower extremity muscle strength was strongly associated with increased mortality risk in patients undergoing hemodialysis.

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.

Physical Activity Is Necessary to Prevent Deterioration of the Walking Ability of Patients Undergoing Maintenance Hemodialysis

Maintenance of the walking ability is very important for smooth continuation of maintenance hemodialysis (HD). The aim of the present study was to clarify the physical activity level in daily living that HD patients should maintain to prevent deterioration of their walking ability. Outpatients undergoing maintenance HD, consisting of 65 males and 88 females with a mean age of 64 ± 11 years, were recruited for the present study. Their physical activity level was recorded over a week with an accelerometer. The physical activity level in daily living was defined as the sum of the lengths of time for which the patients were engaged in physical activity of light or greater intensity during the day, and expressed as the average duration per day. The walking ability was assessed by the normal walking speed and maximum walking speed. Data were analyzed using the receiver operating characteristic (ROC) curve, and the cut‐off point for the physical activity time was determined to predict deterioration of the walking ability. In the prediction of deterioration of the normal and maximum walking speeds, the areas under the ROC curve for the physical activity time were 0.78 (95% confidence interval, 0.69–0.87, P < 0.001) and 0.75 (95% confidence interval, 0.63–0.86, P < 0.001), respectively. Moreover, the ROC curve revealed that the cut‐off point for the physical activity time to prevent deterioration of the normal and maximum walking speeds was 50 min/day. Thus, HD patients should engage in physical activity for at least 50 min/day to prevent deterioration of their walking ability.

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.

Effects of resistance training on muscle strength, exercise capacity, and mobility in middle-aged and elderly patients with coronary artery disease: A meta-analysis

BACKGROUND Resistance training (RT) is a core component of cardiac rehabilitation. We investigated the effects of RT on exercise capacity, muscle strength, and mobility in middle-aged and elderly patients with coronary artery disease (CAD). METHODS We searched for randomized controlled trials of RT versus usual care, or combined RT and aerobic training (AT) versus AT alone, and identified 440 trials in total from inception to January 2014. Participants who had myocardial infarction, coronary revascularization, angina pectoris or CAD were included in the analysis. Those who had heart failure, heart transplants with either cardiac resynchronization therapy or implantable defibrillators were excluded. RESULTS Twenty-two trials totaling 1095 participants were analyzed. We performed random-effects meta-analysis. In middle-aged participants, RT increased lower extremity muscle strength [standardized mean difference (SMD): 0.65, 95% confidence interval (CI): 0.35 to 0.95], upper extremity muscle strength (SMD: 0.73, 95% CI: 0.48 to 0.99) and peak oxygen consumption (VO2) [weight mean difference (WMD): 0.92mL/kg/min, 95% CI: 0.12 to 1.72], but did not improve mobility compared with the control. In elderly participants, RT increased lower extremity muscle strength (SMD: 0.63, 95% CI: 0.05 to 1.21), upper extremity muscle strength (SMD: 1.18, 95% CI: 0.56 to 1.80), and peak VO2 (WMD: 0.70mL/kg/min, 95% CI: 0.03 to 1.37), and improved mobility (SMD: 0.61, 95% CI: 0.21 to 1.01) compared with the control. CONCLUSIONS Resistance training could increase exercise capacity and muscle strength in middle-aged and elderly patients, and mobility in elderly patients, with CAD.

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.