Low serum brain-derived neurotrophic factor may predict poor response to cardiac rehabilitation in patients with cardiovascular disease.

BACKGROUND: It has been shown that serum brain-derived neurotrophic factor (BDNF) is associated with skeletal muscle energy metabolism and that BDNF is a predictor of mortality in heart failure patients. However, little is known about the relationship between BDNF and cardiac rehabilitation (CR). Therefore, this study retrospectively investigated the effects of baseline serum BDNF levels on the CR-induced exercise capacity improvement in patients with cardiovascular disease (CVD). METHODS: We assigned 99 CVD patients (mean age 71±12 years, male = 60) to Low, Middle, and High groups based on the tertiles of baseline BDNF levels. Cardiopulmonary exercise testing was done using supervised bicycle ergometer twice before and after 3 weeks of CR. Analysis of covariance (ANCOVA) followed by post-hoc analysis using Tukey's HSD test was conducted to assess the multivariate associations between baseline BDNF levels categorized by BDNF tertiles (as independent variable) and %increases in AT and peak VO2 after 3-week CR (as dependent variables) after adjustment for age and gender (as covariates), as a main statistical analysis of the present study. RESULTS: The higher the baseline BDNF levels, the better nutritional status evaluated by the CONUT score (p<0.0001). Baseline anaerobic threshold (AT) and peak oxygen uptake (peak VO2) were similar among the three groups. ANCOVA followed by post-hoc analysis revealed that age- and gender-adjusted %increases in peak VO2 after 3-week CR were positively associated with baseline BDNF levels (p = 0.0239) and Low BDNF group showed significantly lower %increase in peak VO2 than High BDNF group (p = 0.0197). Significant association was not found between baseline BDNF and %increase in AT (p = 0.1379). CONCLUSIONS: Low baseline BDNF levels were associated with malnutrition in CVD patients. A positive association between baseline BDNF levels and CR-induced increases in peak VO2 was found. It was suggested that CVD patients with low baseline BDNF levels may be poor responders to CR.

Angiotensin II receptor blocker and statin combination therapy associated with higher skeletal muscle index in patients with cardiovascular disease: A retrospective study.

WHAT IS KNOWN AND OBJECTIVE: Reduction in skeletal muscle mass is the most important component in diagnosing sarcopenia. Ageing and chronic heart failure due to cardiovascular diseases (CVDs) accelerate the reduction of skeletal muscles. However, there are no currently available drugs that are effective for sarcopenia. The purpose of this study was to explore the association between prescribed medications and skeletal muscle mass in patients with CVD. METHODS: This was a single-centre, retrospective, cross-sectional study. The subjects were 636 inpatients with CVD who took prescribed medicines for at least 4 weeks at the time of admission. Skeletal muscle volume was assessed using a bioelectrical impedance assay. RESULTS AND DISCUSSION: Single regression analysis showed that 10 and 3 medications were positively and negatively associated with skeletal muscle index (SMI), respectively. Stepwise multivariate regression analysis revealed that angiotensin II receptor blocker (ARB)/statin combination, dipeptidyl peptidase-4 inhibitor, and antihyperuricemic agents were positively associated with SMI while diuretics and antiarrhythmic agents were negatively associated with SMI. After adjustment using propensity score matching, the SMI was found to be significantly higher in ARB/statin combination users than in non-users. WHAT IS NEW AND CONCLUSION: Combination use of ARB/statin was associated with a higher SMI in patients with CVD. A future randomised, controlled trial is warranted to determine whether the ARB/statin combination will increase the SMI and prevent sarcopenia in patients with CVD.

Overexpression of angiotensin-converting enzyme 2 by renin-angiotensin system inhibitors. Truth or myth? A systematic review of animal studies.

Angiotensin-converting enzyme 2 (ACE2) protects against organ damage in hypertension and cardiovascular diseases by counter regulating the renin-angiotensin system (RAS). ACE2 is also the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on the claim that RAS inhibitors (RASIs) cause ACE2 overexpression in some animal experiments, concerns have arisen that RASIs may aggravate SARS-CoV-2 infection and coronavirus disease-2019 severity in RASI-treated patients. To achieve a comprehensive review, a systematic search of MEDLINE/PubMed was conducted regarding the effects of RASIs on tissue ACE2 mRNA/protein expression in healthy animals and animal models of human diseases. We identified 88 eligible articles involving 168 experiments in the heart, kidneys, lungs, and other organs. Three of 38 experiments involving healthy animals showed ACE2 expression greater than twice that of the control (overexpression). Among 102 disease models (130 experiments), baseline ACE2 was overexpressed in 16 models (18 experiments) and less than half the control level (repression) in 28 models (40 experiments). In 72 experiments, RASIs did not change ACE2 levels from the baseline levels of disease models. RASIs caused ACE2 overexpression compared to control levels in seven experiments, some of which were unsupported by other experiments under similar conditions. In 36 experiments, RASIs reversed or prevented disease-induced ACE2 repression, yielding no or marginal changes. Therefore, ACE2 overexpression appears to be a rare rather than common consequence of RASI treatment in healthy animals and disease models. Future studies should clarify the pathophysiological significance of RASI-induced reversal or prevention of ACE2 repression in disease models.

Increased arterial velocity pulse index is an independent factor related to skeletal muscle mass reduction and tissue damage in patients with cardiovascular disease.

Reduced skeletal muscle mass is the most important component of sarcopenia. Aging and chronic diseases, including chronic heart failure, are the causes of reduced skeletal muscle mass. However, little is known about the mechanism of skeletal muscle mass reduction in patients with cardiovascular disease (CVD). The purpose of this study was to assess the associations among skeletal muscle mass reduction, endothelial function, and other markers of advanced vascular damage in CVD patients. This was a retrospective cross-sectional analysis that included 310 inpatients with CVD in our hospital. Flow-mediated vasodilation (FMD) was performed to assess early vascular damage, i.e., endothelial dysfunction. The arterial velocity pulse index (AVI) and arterial pressure volume index (API) were assessed to reveal signs of advanced vascular damage, such as arterial stiffening and increased peripheral resistance. The bioelectrical phase angle (PA), as a marker of tissue damage, and the skeletal muscle index (SMI) were measured. Correlation analyses were performed among these parameters. Sarcopenia was diagnosed in 25.5% of patients according to the Asian Working Group for Sarcopenia criteria. Greater progression of arterial stiffness, shown by a higher AVI, and more severe tissue damage, shown by a narrower PA, were found in individuals with sarcopenia. Stepwise multivariate regression analysis showed that sex, age, PA, hypertension, and AVI were factors independently correlated with SMI. In conclusion, advanced vascular damage, such as increased arterial stiffness and peripheral resistance, might play an important role in the reduction in skeletal muscle mass, possibly through damage to skeletal muscle tissue in CVD patients.

Low blood pressure and cardiovascular events in diabetic patients with coronary artery disease after revascularization: the CREDO-Kyoto registry cohort-1.

The current American, European, and Japanese guidelines for hypertension treatment have lowered blood pressure (BP) targets to <130/80 mmHg in patients with diabetes mellitus (DM) and patients with coronary artery disease (CAD). However, there is concern that low BP may increase cardiovascular events in diabetic CAD patients. Currently, coronary revascularization has become widespread in diabetic CAD patients. Thus, whether low BP is an independent risk factor for cardiovascular events in diabetic CAD patients after revascularization was investigated. We examined 2718 stable CAD patients with DM in the CREDO-Kyoto cohort-1 registry enrolling 9877 patients who underwent their first percutaneous coronary intervention or coronary bypass grafting. There were no cutoff points for systolic BP (SBP) below which the age- and sex-adjusted hazard ratios for cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke increased. The cutoff diastolic BP (DBP) for increasing cardiovascular death was 70 mmHg (P = 0.014), whereas there was no cutoff DBP for increasing nonfatal MI and nonfatal stroke. However, on stepwise Cox hazard proportional regression analysis, the independent factors increasing cardiovascular death were hypertension, low creatinine clearance, wide pulse pressure, prior MI, and nonuse of statins, but DBP < 70 mmHg was not a significant factor. In conclusion, in diabetic CAD patients after coronary revascularization, low SBP and DBP were not significant factors that increased cardiovascular events. Careful attention should be paid to vascular lesions and organ damage that have already progressed.

Oral Administration of Glucosamine Improves Vascular Endothelial Function by Modulating Intracellular Redox State.

Glucosamine, used to treat osteoarthritis, has been shown to have anti-inflammatory and anti-atherosclerotic effects in experimental studies. A recent cohort study has demonstrated that the use of glucosamine was significantly associated with decreased total mortality. Vascular endothelial function is a potent surrogate marker of atherosclerosis and cardiovascular mortality where oxidative stress could participate. Therefore, we investigated whether glucosamine improves vascular endothelial function and intracellular redox state. We examined the effects of oral glucosamine administration (3000 mg/day) for 4 weeks on flow-mediated vasodilation (FMD) and intraerythrocyte glutathione parameters in 20 volunteers. Nineteen age-matched volunteers served as controls. Glucosamine administration significantly increased FMD (from 7.0 ± 2.3 to 8.7 ± 2.3%, P = 0.022). In the control group, FMD did not change. Glucosamine administration significantly increased intraerythrocyte total glutathione levels (from 212.9 ± 46.2 to 240.6 ± 49.4 µmol/L, P = 0.006), intraerythrocyte reduced form of glutathione (GSH) levels (from 124.7 ± 42.6 to 155.2 ± 47.7 µmol/L; P = 0.004) and intraerythrocyte GSH/oxidized form of glutathione (GSSG) ratios (from 3.18 ± 1.64 to 3.88 ± 1.61, P = 0.04). In the control group, any glutathione parameters did not change. Moreover, a stepwise multivariate analysis revealed percent change of GSH/GSSG is the only independent predictor for those of FMD (standardized ß = 0.58, P = 0.007) in the glucosamine group. Glucosamine administration improved FMD in association with amelioration of intraerythrocyte GSH/GSSG ratios. These results suggest that oral glucosamine administration might improve vascular endothelial function by modulating intracellular redox state.

New diagnostic index for sarcopenia in patients with cardiovascular diseases.

BACKGROUND: Sarcopenia is an aging and disease-related syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, with the risk of frailty and poor quality of life. Sarcopenia is diagnosed by a decrease in skeletal muscle index (SMI) and reduction of either handgrip strength or gait speed. However, measurement of SMI is difficult for general physicians because it requires special equipment for bioelectrical impedance assay or dual-energy X-ray absorptiometry. The purpose of this study was, therefore, to explore a novel, simple diagnostic method of sarcopenia evaluation in patients with cardiovascular diseases (CVD). METHODS: We retrospectively investigated 132 inpatients with CVD (age: 72±12 years, age range: 27-93 years, males: 61%) Binomial logistic regression and correlation analyses were used to assess the associations of sarcopenia with simple physical data and biomarkers, including muscle-related inflammation makers and nutritional markers. RESULTS: Sarcopenia was present in 29.5% of the study population. Serum concentrations of adiponectin and sialic acid were significantly higher in sarcopenic than non-sarcopenic CVD patients. Stepwise multivariate binomial logistic regression analysis revealed that adiponectin, sialic acid, sex, age, and body mass index were independent factors for sarcopenia detection. Sarcopenia index, obtained from the diagnostic regression formula for sarcopenia detection including the five independent factors, indicated a high accuracy in ROC curve analysis (sensitivity 94.9%, specificity 69.9%) and the cutoff value for sarcopenia detection was -1.6134. Sarcopenia index had a significant correlation with the conventional diagnostic parameters of sarcopenia. CONCLUSIONS: Our new sarcopenia index using simple parameters would be useful for diagnosing sarcopenia in CVD patients.

Laronidase replacement therapy and left ventricular function in mucopolysaccharidosis I.

We assessed the effects of long-term laronidase replacement therapy (LRT) on the left ventricular (LV) function of a 52-year-old adult woman with mucopolysaccharidosis I (MPS I). The urinary uronic acid concentration significantly decreased by 78.7% (from 75 to 16 mg/g creatinine) after LRT; thereafter, estimated LV weight as assessed by two-dimensional (2D) echocardiography significantly decreased by 33.3% (from 189 to 126 g). Although systolic LV function of the ejection fraction as assessed by 2D echocardiogram did not change after LRT, the diastolic LV function parameters of the deceleration time (DcT) and the ratio of early (E) to late (A) ventricular filling velocities (E/A ratio) significantly improved. The DcT significantly decreased from 355 to 300 ms and the E/A ratio significantly decreased from 1.8 to 0.98. These diastolic parameters were normalized. In the contraction synchrony assessed by 2D speckle tracking imaging, the maximum time delay of contraction decreased from 148 to 14 ms. In addition, the LV weight significantly correlated with the E/A ratio (p < 0.001, r = 0.63), DcT (p < 0.05, r = 0.48), and contraction synchrony (p < 0.001, r = 0.61), respectively. This is the first study to report that LRT significantly improves diastolic LV function and contraction synchrony in a patient with MPS I.

New methodological approach to improve reproducibility of brachial artery flow-mediated dilatation.

BACKGROUND: Measurement of flow-mediated dilation (FMD) is well known as a noninvasive method for an assessment of vascular endothelial function. However, the reproducibility is a major issue of FMD measurement. The purpose of this study is to examine the reproducibility of the new FMD measurement with medial epicondyle method. METHODS: First, to evaluate the variability of the brachial artery diameter, 23 volunteers recruited from 32 healthy volunteers were examined for a brachial artery diameter at rest using with FMD equipment. Second, to evaluate the reproducibility of the FMD measurement, all volunteers underwent the FMD measurement, which was repeated at 2-week interval using the traditional method and the medial epicondyle method. The reproducibility in both methods was evaluated by 2 independent observers who measured on the same subject to assess the inter-observer reproducibility, and 1 observer who measured the same subject twice to assess the intra-observer reproducibility regarding the baseline value of arterial diameter and FMD. RESULTS: The variability of brachial artery diameter was 0.57 ± 0.27 mm in 23 healthy volunteers. In the study of inter- and intra-observer reproducibility, 2 parameters including intra-class correlation coefficient and Pearson's correlation coefficient by medial epicondyle method are superior to those by traditional method. CONCLUSIONS: These results suggest that medial epicondyle methodological approach to measure FMD is superior to traditional method.

Systolic blood pressure during recovery from exercise is related to flow-mediated dilatation in patients with coronary artery disease.

OBJECTIVE: To assess the relationship between exercise-induced parameters obtained from the routine exercise stress testing (EST) and flow-mediated vasodilatation (FMD) as an index of endothelial function. DESIGN: A retrospective study. SETTING: Kurume University Medical Center, Kurume, Japan. PATIENTS: All patients with stable coronary artery disease (CAD) who were admitted to Kurume University Medical Center. MAIN OUTCOME MEASURE: Results of EST and FMD. RESULTS: We studied 66 patients (35 male/31 female) with CAD. All patients underwent symptom-limited EST and measurement of FMD. Exercise parameters included exercise-induced heart rate and systolic blood pressure (SBP). FMD did not differ between male and female groups. In univariate analysis, determinants of FMD included age and the change in SBP at 1 min after exercise. In Cox hazard model analysis, the change in SBP at 1 min after exercise (p=0.011) was an independent determinant of FMD. FMD in patients with abnormal SBP response group was significantly lower than that in normal SBP response group (4.2±1.8 ns. 6.1±2.6%, p<0.05). CONCLUSIONS: These findings suggest that SBP during recovery from exercise is associated with endothelial function in patients with CAD.

Laronidase replacement therapy improves myocardial function in mucopolysaccharidosis I.

We assessed whether laronidase (recombinant human α-L-iduronidase) replacement therapy could improve left ventricular (LV) myocardial function in a 49-year-old woman with mucopolysaccharidosis I (MPS I) and valvular heart disease. After 6 months of laronidase treatment, the concentration of urinary uron acid decreased by 78.8%. Hepatosplenomegaly improved and LV weight decreased by 19.6%. LV ejection fraction assessed by two-dimensional echocardiogram did not change after laronidase treatment. However, in two-dimensional ultrasound speckle tracking imaging method, LV myocardial longitudinal strain (shortening ratio) increased from -13.2 to -17.4%. LV myocardial radial strain (thickening ratio) increased from 26.6 to 83.4%. LV myocardial torsion increased from +6 to +18°. These indexes of myocardial function were normalized after laronidase treatment. Thus, our findings were a first report that laronidase treatment had a beneficial effect on LV myocardial function in an adult patient with MPS I.

Systolic blood pressure response to exercise as a predictor of mortality in patients with chronic heart failure.

It is well known that peak oxygen consumption and heart rate (HR) recovery after exercise obtained from the cardiopulmonary exercise test are prognostic parameters in patients with chronic heart failure (CHF). However, it is unclear whether exercise-induced parameters obtained from the routine exercise stress test predict mortality in patients with CHF. We studied 136 patients (93 males/43 females) with CHF. All patients underwent symptom-limited exercise stress testing. Exercise parameters included exercise duration, exercise-induced HR and systolic blood pressure (SBP), and metabolic equivalents (METs). During the follow-up period (mean 6.2 years), 34 patients died. Survival rates at the 3rd and 5th years were 90% and 83%, respectively. Body mass index was significantly smaller in the nonsurvival group than in the survival group (P < 0.01). The incidence of patients with New York Heart Association III class was higher in the nonsurvival group than in the survival group (P < 0.05). In univariate analysis, predictors of mortality included peak HR and SBP, increases in HR and SBP during exercise, HR and SBP at the 1st minute after exercise, HR at the 3rd minute after exercise, and METs. The use of beta-adrenergic blocking agents was not associated with prognosis. In Cox hazard model analysis, the increase in SBP (P < 0.002), HR at the 3rd minute after exercise (P < 0.05), and METs (P < 0.05) were independent predictors of mortality. SBP response to exercise, HR recovery after exercise, and METs obtained from the routine exercise test predicted mortality in patients with CHF irrespective of the use of beta-adrenergic blocking agents.

Fluvastatin alters platelet aggregability in patients with hypercholesterolemia: possible improvement of intraplatelet redox imbalance via HMG-CoA reductase.

BACKGROUND: Hypercholesterolemia enhances platelet aggregability. Statins have beneficial effects on cardiovascular events. The purpose of this study is to investigate whether statins inhibit platelet aggregation and, if so, the mechanisms. METHODS AND RESULTS: Twelve patients with hypercholesterolemia were prospectively randomized in a crossover design to receive either fluvastatin (20 mg/d) or colestimide (3000 mg/d) for 12 weeks. The subjects were switched to the opposite arm for additional 12 weeks. Before and after first and second treatments, experiments were performed. Eleven age-matched volunteers with normal lipid profiles served as controls. ADP-induced platelet aggregation, platelet-derive nitric oxide (PDNO) release, intraplatelet levels of GSH and GSSG, and intraplatelet nitrotyrosine production during platelet aggregation were measured. Fluvastatin and colestimide equally lowered total and low density lipoprotein cholesterol levels in hypercholesterolemia. Platelet aggregation was greater in hypercholesterolemia than in normocholesterolemia before treatment and was altered by fluvastatin. PDNO release, intraplatelet glutathione level, and GSH/GSSG ratio were lower in hypercholesterolemia than in normocholesterolemia before treatment and were increased by fluvastatin. Intraplatelet nitrotyrosine formation was greater in hypercholesterolemia than in normocholesterolemia, and decreased by fluvastatin. Colestimide did not have such effects. In vitro application of fluvastatin dose-dependently inhibited platelet aggregation. Furthermore, in vitro application of fluvastatin dose-dependently inhibited platelet nitrotyrosine expressions and the inhibitory effects by fluvastatin were reversed by preincubation with geranylgeranylpyrophosphate. CONCLUSIONS: Fluvastatin altered platelet aggregability in hypercholesterolemic patients in a cholesterol-lowering independent manner, which was partly mediated by the improvement of intraplatelet redox imbalance.

Effect of physical training on insulin resistance in patients with chronic heart failure.

BACKGROUND: The effect of physical training on insulin resistance (IR) in chronic heart failure (CHF) remains unclear. METHODS AND RESULTS: Fourteen patients with CHF performed physical training using a bicycle ergometer; 9 patients (64%) were hyperinsulinemic and insulin resistant (HOMA IR > 1.97). Exercise tolerance increased (5.1 +/- 1.7 to 6.9 +/- 2.7 METs, p < 0.05) and heart rate at rest decreased (82 +/- 15 to 72 +/- 6, p < 0.05) in the IR group after physical training. Physical training also decreased the insulin level (15.1 +/- 5.6 to 9.8 +/- 2.6 microU/ml, p < 0.05) and HOMA IR (3.7 +/- 1.4 to 2.3 +/- 0.6, p < 0.05) in the IR group, but not in the 5 patients (36%) without IR or in 6 control patients. CONCLUSION: Physical training can improve hyperinsulinemia and IR in patients with CHF.

HMG-CoA reductase inhibitor protects against in vivo arterial thrombosis by augmenting platelet-derived nitric oxide release in rats.

Acute coronary syndromes are caused by platelet-mediated thrombosis following rupture of a plaque. HMG-CoA reductase inhibitors (statins) reduce the incidence of events early after acute coronary syndromes, which are independent of its cholesterol-lowering effect. Accordingly, we investigated whether statins inhibit platelet-mediated arterial thrombus formation in vivo and, if so, the underlying mechanisms. Rats were divided into 4 groups. Group 1 was treated with the vehicle, whereas groups 2, 3, and 4 were treated with cerivastatin for 7 days (1, 2, and 5 mg/kg i.p., respectively). Cerivatatin did not change serum cholesterol levels. Carotid arterial thrombosis was created by perivascular FeCl3 delivery. Cerivastatin significantly prolonged the time to thrombotic occlusion of carotid artery. Cerivastatin significantly dose-dependently inhibited both ex vivo platelet P-selectin expression, a marker of platelet activation, and platelet aggregation. Cerivastatin significantly augmented platelet-derived nitric oxide (NO) release, and up-regulated platelet and endothelial nitric oxide synthase (NOS) mRNA expressions. N-nitro-L-arginine methylester abolished the effects of cerivastatin. This study demonstrates that in vivo administration of statin protects against platelet-mediated arterial thrombosis, possibly by augmenting platelet- and endothelium-derived NO releases via up-regulation of platelet and endothelial NOS.

Inhibition of platelet adherence to mononuclear cells by alpha-tocopherol: role of P-selectin.

BACKGROUND: Platelet-leukocyte interaction is an early important event for thrombogenesis, and this process is mainly mediated by P-selectin on platelets. Although alpha-tocopherol has been shown to inhibit thrombotic disorders, the effect of alpha-tocopherol on platelet P-selectin expression and platelet-leukocyte interaction is little known. METHODS AND RESULTS: We examined whether alpha-tocopherol inhibited human platelet P-selectin expression and platelet-leukocyte interaction. Alpha-tocopherol (50 to 500 microg/mL) inhibited thrombin-induced or phorbol 12-myristate 13-acetate (PMA)-induced P-selectin expression on platelets. alpha-Tocopherol suppressed platelet-mononuclear cell (MNC) interaction, platelet aggregation, and platelet protein kinase C (PKC) activity stimulated with either PMA (100 nmol/L) or thrombin. Inhibitory actions of alpha-tocopherol against the platelet functions were mimicked by staurosporine, a selective PKC inhibitor. After oral supplementation of alpha-tocopherol (300 mg/d for 3 weeks) in healthy subjects, thrombin-mediated or PMA-mediated P-selectin expression, platelet-MNC interaction, and platelet aggregation ex vivo were suppressed. CONCLUSIONS: alpha-Tocopherol inhibited P-selectin expression on human platelets and thereby attenuated platelet-MNC interactions, which were mediated at least in part by the inhibition of intraplatelet PKC activity. These actions of alpha-tocopherol on platelet functions provide new insights into the antithromboatherogenic properties of alpha-tocopherol.