An exploratory study on the efficacy and safety of a BCAA preparation used in combination with cardiac rehabilitation for patients with chronic heart failure.

BACKGROUND: Sarcopenia is generally complicated with patients with chronic heart failure (CHF) and its presence negatively affects the course of heart failure, however effective nutritional intervention had not been elucidated yet. The primary objective of this study is to explore whether the addition of a branched-chain amino acid (BCAA) preparation for cardiac rehabilitation (CR) of patients with CHF further improves cardiopulmonary functions, skeletal muscle functions, and metabolism in comparison with conventional CR. METHODS: This is a randomized, parallel-group comparative study. The elderly patients that were participated in CR and complicated with left ventricular systolic or diastolic dysfunction are randomized into two groups, CR + BCAA and CR. 20 weeks later, the second randomization is performed, which divide subjects into two groups with and without BCAA intervention without CR. Primary outcome measure is the rate of change of the anaerobic threshold workload from baseline to post-intervention. Secondary outcome include parameters of exercise capacity, cardiac function and psychological status. DISCUSSION: In the current study the effect of a promising new intervention, BCAA, will be assessed to determine whether its addition to CR improve exercise capacity in patients with heart failure, who are generally complicated with sarcopenia. TRIAL REGISTRATION: This clinical trial was registered with the University Hospital Medical Information Network-Clinical Trials Registry (UMIN-CTR; JPRN-UMIN R000022440 ).

Effects of methylglyoxal on human cardiac fibroblast: roles of transient receptor potential ankyrin 1 (TRPA1) channels.

Cardiac fibroblasts contribute to the pathogenesis of cardiac remodeling. Methylglyoxal (MG) is an endogenous carbonyl compound produced under hyperglycemic conditions, which may play a role in the development of pathophysiological conditions including diabetic cardiomyopathy. However, the mechanism by which this occurs and the molecular targets of MG are unclear. We investigated the effects of MG on Ca(2+) signals, its underlying mechanism, and cell cycle progression/cell differentiation in human cardiac fibroblasts. The conventional and quantitative real-time RT-PCR, Western blot, immunocytochemical analysis, and intracellular Ca(2+) concentration [Ca(2+)]i measurement were applied. Cell cycle progression was assessed using the fluorescence activated cell sorting. MG induced Ca(2+) entry concentration dependently. Ruthenium red (RR), a general cation channel blocker, and HC030031, a selective transient receptor potential ankyrin 1 (TRPA1) antagonist, inhibited MG-induced Ca(2+) entry. Treatment with aminoguanidine, a MG scavenger, also inhibited it. Allyl isothiocyanate, a selective TRPA1 agonist, increased Ca(2+) entry. The use of small interfering RNA to knock down TRPA1 reduced the MG-induced Ca(2+) entry as well as TRPA1 mRNA expression. The quantitative real-time RT-PCR analysis showed the prominent existence of TRPA1 mRNA. Expression of TRPA1 protein was confirmed by Western blotting and immunocytochemical analyses. MG promoted cell cycle progression from G0/G1 to S/G2/M, which was suppressed by HC030031 or RR. MG also enhanced α-smooth muscle actin expression. The present results suggest that methylglyoxal activates TRPA1 and promotes cell cycle progression and differentiation in human cardiac fibroblasts. MG might participate the development of pathophysiological conditions including diabetic cardiomyopathy via activation of TRPA1.

Influence of atrial fibrillation on oxygen uptake and exercise tolerance in cardiovascular patients; close association with heart rate response.

To investigate the effect of atrial fibrillation (AF) on the oxygen uptake and exercise tolerance, we evaluated cardiopulmonary exercise test (CPET) data in AF patients and heart rate-matched controls with sinus rhythm (cSR) who received ambulatory cardiac rehabilitation. We compared CPET data between AF (N = 27) and cSR patients (N = 106) who had similar HRs at rest and the peak points. Oxygen uptake (VO2)/kg and relative O2 pulse (ml/bpm/kg) at rest and the anaerobic threshold (AT) level was not different between AF and cSR patients, but these parameters above the AT level were significantly lower in AF than in cSR patients. Concisely the parallel increase of relative O2 pulse during exercise was blunted above the respiratory compensation level (Rc) in the AF group. In addition, the HR change during exercise was inversely correlated with the increase of the O2 pulse above the AT level and this inverse correlation was more prominent in AF patients than in cSR patients. In conclusion, the value of VO2 was significantly lower above the AT level in AF patients. The trend of O2 pulse above the AT level was strongly associated with the detrimental response of HR increase and the response was markedly exaggerated in the AF patients.

High-frequency power within the QRS complex in ischemic cardiomyopathy patients with ventricular arrhythmias: Insights from a clinical study and computer simulation of cardiac fibrous tissue.

BACKGROUND: The distribution of frequency power (DFP) within the QRS complex (QRS) is unclear. This study aimed to investigate the DFP within the QRS in ischemic cardiomyopathy (ICM) with lethal ventricular arrhythmias (L-VA). A computer simulation was performed to explore the mechanism of abnormal frequency power. METHODS: The study included 31 ICM patients with and without L-VA (n = 10 and 21, respectively). We applied the continuous wavelet transform to measure the time-frequency power within the QRS. Integrated time-frequency power (ITFP) was measured within the frequency range of 5-300 Hz. The simulation model consisted of two-dimensional myocardial tissues intermingled with fibroblasts. We examined the relation between frequency power calculated from the simulated QRS and the fibroblast-to-myocyte ratio (r) of the model. RESULTS: The frequency powers significantly increased from 180 to 300 Hz and from 5 to 15 Hz, and also decreased from 45 to 80 Hz in patients with ICM and L-VA compared with the normal individuals. They increased from 110 Hz to 250 Hz in ICM alone. In the simulation, the high-frequency power increased when the ratio (r) were 2.0-2.5. Functional reentry was initiated if the ratio (r) increased to 2.0. CONCLUSIONS: Abnormal higher-frequency power (180-300 Hz) may provide arrhythmogenic signals in ICM with L-VA that may be associated with the fibrous tissue proliferation.

Relationship between chronotropic incompetence and ß-blockers based on changes in chronotropic response during cardiopulmonary exercise testing.

BACKGROUND: Chronotropic incompetence (CI), an attenuated heart rate (HR) response to exercise, is common in patients with cardiovascular disease. The aim of this study was to assess changes in the chronotropic response (CR) during cardiopulmonary exercise testing (CPET) in patients undergoing cardiac rehabilitation and investigate the effects of ß-blockers. METHODS: Patients undergoing cardiac rehabilitation performed CPET. Failure to achieve 80% of the age-predicted maximal HR (APMHR) defined CI. Values of the metabolic chronotropic relationship (MCR) were calculated from the ratio of the HR reserve to metabolic reserve at 4 stages, warm-up (MCR-Wu), anaerobic threshold (MCR-AT), respiratory compensation (MCR-Rc), and peak point (MCR-Pk), using the Wilkoff model. In patients who showed an increase in MCR at ≥ 3 of the 4 exercise stages, CR was considered to have improved. RESULTS: Patients with high BNP levels (≥ 80 pg/ml) had a lower MCR at all stages compared with those with low BNP levels (< 80 pg/ml). Of the 80 patients, 47 showed an increase in both peak VO2 and AT, and of these 31 (66.0%) were taking ß-blockers. Improvement in CR was observed in 30 of 47 patients with CI, and 70% of these were taking ß-blockers. In patients not taking ß-blockers, MCR-AT was lower than MCR-Rc, whereas in those taking ß-blockers MCR-AT was higher than MCR-Rc. CONCLUSIONS: An attenuated HR response may occur during the early stages of exercise. The HR response according to the presence or absence of ß-blockers is clearly identifiable by comparing MCR-AT and MCR-Rc using the Wilkoff model.

Roles of transient receptor potential canonical (TRPC) channels and reverse-mode Na+/Ca2+ exchanger on cell proliferation in human cardiac fibroblasts: effects of transforming growth factor ß1.

Expression of transient receptor potential canonical channels (TRPC) and the effects of transforming growth factor-ß1 (TGF-ß1) on Ca2+ signals and fibroblast proliferation were investigated in human cardiac fibroblasts. The conventional and quantitative real-time RT-PCR, western blot, immunocytochemical analysis, and intracellular Ca2+ concentration [Ca2+]i measurement were applied. Cell proliferation and cell cycle progression were assessed using MTT assays and fluorescence activated cell sorting. Human cardiac fibroblasts have the expression of TRPC1,3,4,6 mRNA and proteins. 1-oleoyl-2-acetyl-sn-glycerol (OAG) and thapsigargin induced extracellular Ca(2+)-mediated [Ca2+]i rise. siRNA for knock down of TRPC6 reduced OAG-induced Ca2+ entry. Hyperforin as well as angiotensin II (Ang II) induced Ca2+ entry. KB-R7943, a reverse-mode Na+/Ca2+ exchanger (NCX) inhibitor, and/or replacement of Na+ with NMDG+ inhibited thapsigargin-, OAG- and Ang II-induced Ca2+ entry. Treatment with TGF-ß1 increased thapsigargin-, OAG- and Ang II-induced Ca2+ entry with an enhancement of TRPC1,6 protein expression, suppressed by KB-R7943. TGF-ß1 and AngII promoted cell cycle progression from G0/G1 to S/G2/M and cell proliferation. A decrease of the extracellular Ca2+ and KB-R7943 suppressed it. Human cardiac fibroblasts contain several TRPC-mediated Ca2+ influx pathways, which activate the reverse-mode NCX. TGF-ß1 enhances the Ca2+ influx pathways requiring Ca2+ signals for its effect on fibroblast proliferation.

Cardiac rehabilitation increases exercise capacity with a reduction of oxidative stress.

BACKGROUND AND OBJECTIVES: Reactive oxygen species (ROS) mediate various signaling pathways that underlie vascular inflammation in atherogenesis and cardiovascular diseases. Cardiac rehabilitation (CR) has a variety of multiple beneficial effects, including anti-inflammatory effects. The purpose of the present study was to investigate the effects of CR on ROS in patients with cardiovascular diseases. SUBJECTS AND METHODS: The serum level of derivatives of reactive oxidative metabolites, an index of oxidative stress, was measured in 100 patients with cardiovascular diseases before, and, subsequently, 3 and 6 months after, CR. A biological antioxidant potential (BAP) test was applied to assess the antioxidant power of the serum. RESULTS: The resting reactive oxidative metabolite levels decreased 3-6 months after CR {pre: 351±97 Carratelli unit (CARR U), 3 months: 329±77 CARR U, 6 months: 325±63 CARR U, all p<0.01} with the increase of the percentage of the predicted values of V̇O2 peak and the percentage of the predicted values of V̇O2 at the anaerobic threshold (V̇O2 AT) and the decrease of the B-type natriuretic peptide (BNP). The BAP test and antioxidative/oxidative stress ratio increased 6 months after CR. The % changes of the antioxidative/oxidative stress ratio was positively correlated with the % changes of V̇O2 AT, and negatively correlated with the % changes of the BNP. CONCLUSION: These results suggest that intensive supervised CR significantly improved exercise capacity, which may be attributable to an adaptive response involving more efficient oxidative metabolites or the increased capacity of endogenous anti-oxidative systems in patients with cardiovascular diseases.

Time frequency power profile of QRS complex obtained with wavelet transform in spontaneously hypertensive rats.

We evaluated whether frequency analysis could detect the development of interstitial fibrosis in rats. SHR/Izm and age-matched WKY/Izm were used. Limb lead II electrocardiograms were recorded. Continuous wavelet transform (CWT) was applied for the time-frequency analysis. The integrated time-frequency power (ITFP) between QRS complexes was measured and compared between groups. The ITFP at low-frequency bands (≤125Hz) was significantly higher in SHR/Izm. The percent change of ITFP showed the different patterns between groups. Prominent interstitial fibrosis with an increase in TIMP-1 mRNA expression was also observed in SHR/Izm. These results were partly reproduced in a computer simulation.

High-frequency powers hidden within QRS complex as an additional predictor of lethal ventricular arrhythmias to ventricular late potential in post-myocardial infarction patients.

BACKGROUND: Ventricular late potentials (VLPs) have been known to be a predictor of lethal ventricular arrhythmias (L-VAs); however, detection of other arrhythmogenic signals within the QRS complex remains obscure. OBJECTIVE: The aim of this study was to evaluate whether abnormal intra-QRS high-frequency powers (IQHFP) within the QRS complex become a new predictor of L-VAs in addition to VLPs. METHODS: Both 12-lead electrocardiograms (ECG) and VLPs were recorded from 142 subjects, including 37 patients without heart diseases, 97 patients post-myocardial infarction (MI), and 45 post-MI patients with L-VAs. Time-frequency analysis of ECG (leads V(1) or II) using wavelet transform with the Morlet function was performed. After the time-frequency powers were calculated, the ratios of the peak of signal power during the QRS complex in high-frequency bands against the peak power at 80 Hz (b/a ratio; P100, P150, P200, P250, or P300Hz/P80Hz) were measured. Abnormal IQHFP was defined when the b/a ratio exceeded the optimal cut-off values estimated by receiver-operator characteristic curves. RESULTS: The combination of abnormal IQHFP appearing at 200, 250, and 300 Hz with positive VLPs increased the sensitivity for prediction of L-VAs from 53.3% by VLPs to 89.5%, and the negative predictive value from 74.7% by VLPs to 87.7%. CONCLUSION: The combined use of VLPs and IQHFP hidden within the QRS complex improved the prediction of L-VAs in post-MI patients.