In dogs with HF, long-term CCM therapy improves LV systolic function. The improvements are additive to those seen with beta-blockers. These findings are further strengthened by the concomitant benefits of CCM therapy on LV global, cellular, and biochemical remodeling.

The structure and hydrogen bonding of water in the vicinity of phospholipid analogue random copolymers [poly(2-methacryloyloxyethyl phosphorylcholine-r-n-butyl methacrylate), Poly(MPC-r-BMA)] with various molecular weights were analyzed in their aqueous solutions and thin films with contours of O−H stretching of Raman and attenuated total reflection infrared (ATR-IR) spectra, respectively. The relative intensity of the collective band (C value) corresponding to a long-range coupling of O−H stretchings of the Raman spectra for the aqueous solution of Poly(MPC-r-BMA) was very close to that for pure water, which is in contrast with the smaller C value in the aqueous solution of ordinary polyelectrolytes. The number of hydrogen bonds collapsed by the presence of one monomer residue (N corr value) of Poly(MPC-r-BMA) (M w 1.3 × 104, 3.0 × 104, and 9.3 × 104) was much smaller than those for ordinary polyelectrolytes and close to those for neutral polymers such as poly(ethylene glycol) and poly(N-vinylpyrrolidone). Furthermore, water-insoluble Poly(MPC-r-BMA) with a large molecular weight (4.2 × 105) could be cast as a thin film (thickness, ca. 10 μm) on a ZnSe crystal for the ATR-IR spectroscopy. At an early stage of sorption of water into the Poly(MPC-r-BMA) film, the O−H stretching band of the IR spectra for the water incorporated in the film was similar to that for free water, which is in contrast with the drastic change in the O−H stretching band of water incorporated in polymer films such as poly(2-hydroxyethyl methacrylate), poly(methyl methacrylate), and poly(n-butyl methacrylate). These results suggest that the phospholipid analogue monomer residues with a zwitterionic structure do not significantly disturb the hydrogen bonding between water molecules in either the aqueous solution or the thin film systems.

Recent human and animal studies have demonstrated that in severe end-stage heart failure (HF), the cardiac muscle switches to a more fetal metabolic phenotype, characterized by downregulation of free fatty acid (FFA) oxidation and an enhancement of glucose oxidation. The goal of this study was to examine myocardial substrate metabolism in a model of moderate coronary microembolization-induced HF. We hypothesized that during well-compensated HF, FFA oxidation would predominate as opposed to a more fetal metabolic phenotype of greater glucose oxidation. Cardiac substrate uptake and oxidation were measured in normal dogs (n = 8) and in dogs with microembolization-induced HF (n = 18, ejection fraction = 28%) by infusing three isotopic tracers ([9,10-(3)H]oleate, [U-(14)C]glucose, and [1-(13)C]lactate) in anesthetized open-chest animals. There were no differences in myocardial substrate metabolism between the two groups. The total activity of pyruvate dehydrogenase, the key enzyme regulating myocardial pyruvate oxidation (and hence glucose and lactate oxidation) was not affected by HF. We did not observe any difference in the activity of carnitine palmitoyl transferase I (CPT-I) and its sensitivity to inhibition by malonyl-CoA between groups; however, malonyl-CoA content was decreased by 22% with HF, suggesting less in vivo inhibition of CPT-I activity. The differences in malonyl-CoA content cannot be explained by changes in the Michaelis-Menten constant and maximal velocity for malonyl-CoA decarboxylase because neither were affected by HF. These results support the concept that there is no decrease in fatty acid oxidation during compensated HF and that the downregulation of fatty acid oxidation enzymes and the switch to carbohydrate oxidation observed in end-stage HF is only a late-stage phenomenon.

Poly(N,N-dimethylaminopropyl methacrylamide) (poly(DMAPMA)) was incubated with 1,3-propanesultone and 1,4-butanesultone to afford polymers with various contents of N,N-dimethyl-N-(3-sulfopropyl)-3‘-methacrylamidopropanaminium inner salt residues and N,N-dimethyl-N-(4-sulfobutyl)-3‘-methacrylamidopropanaminium inner salt residues, respectively. The structure and hydrogen bonding of water in an aqueous solution of the sulfobetaine polymers were analyzed using the contours of the O−H stretching in the polarized Raman spectra. With an increase in the content of the sulfobetaine residue, the relative intensity of the collective band (C value) corresponding to a long-range coupling of the O−H stretching in the aqueous polymer solutions became larger and approached the C value of pure water. The number of hydrogen bonds disrupted because of the presence of one monomer residue (N value) for the polymers with a large sulfobetaine content was a small positive value and comparable to those for neutral polymers such as poly(ethylene glycol) and poly(N-vinylpyrrolidone). This is in significant contrast with the largely positive N values for the precursor polymer (poly(DMAPMA)), and ordinary polyelectrolytes such as sodium polyethylenesulfonate, poly-l-lysine hydrobromide, sodium polyacrylate, and poly(acrylic acid). The N value for a small molecular weight zwitterionic compound, 3-aminopropanesulfonic acid, was also slightly positive, which is consistent with the tendency observed for the sulfobetaine polymers. The present results clearly indicate that the zwitterionic polymers do not significantly disturb the hydrogen-bonded network structure of water, probably because of the counteraction of the electrostriction effect by the proximity between the anionic and cationic groups.

Objective-We used isolated cardiomyocytes to investigate a possible role of mitochondrial permeability transition pore in mitochondrial abnormalities associated with heart failure.Methods-Cardiomyocytes were isolated from LV myocardium of normal control dogs and dogs with heart failure produced by intracoronary microembolizations. Mitochondrial permeability transition was measured in isolated cardiomyocytes with intact sarcolemma with and without 0.2 μM Cyclosporin A using calcein AM and the fluorometer. State-3 mitochondrial respiration was also measured with the Clark electrode. Mitochondrial membrane potential was measured with JC-1 probe using the fluorometer. Propidium iodide was used to ensure sarcolemma integrity.Results-200 minutes after loading with calcein AM, mitochondria of failing cardiomyocytes showed only 50% of maximal level of calcein fluorescence while it remained unchanged in normal cells. The mitochondrial membrane potential in failing cardiomyocytes was significantly decreased by 38% compared to normal cardiomyocytes. Cyclosporine A significantly slowed the exit of calcein from mitochondria of failing cardiomyocytes and increased mitochondrial membrane potential by 29%. State-3 respiration was not affected with Cyclosporine A in normal cardiomyocytes while it was significantly increased in failing cardiomyocytes by 20%.Conclusions-Exit of calcein (m.w. 1.0 kDa) from mitochondria of viable failing cardiomyocytes with intact sarcolemma suggests an existence of a reversible transitory permeability transition opening in high conductance mode. Attenuation of calcein exit, ΔΨ m and improvement of state-3 respiration achieved with CsA (0.2 μM) show that permeability transition opening could be a cause of mitochondrial dysfunction described in the failing heart.