In this new model of heart failure/hypertrophy, the abnormal myocardial HEP metabolism is related to the decreased CK-Mt protein level, which in turn is related to the severity of the hypertrophy.

Current therapies for heart failure due to transmural left ventricular (LV) infarction are limited. We have developed a novel patch method for delivering autologous bone marrow stem cells to sites of myocardial infarction for the purpose of improving LV function and preventing LV aneurysm formation. The patch consisted of a fibrin matrix seeded with autologous porcine mesenchymal stem cells labeled with lacZ. We applied this patch to a swine model of postinfarction LV remodeling. Myocardial infarction was produced by using a 60-min occlusion of the left anterior descending coronary artery distal to the first diagonal branch followed by reperfusion. Results were compared between eight pigs with stem cell patch transplantation, six pigs with the patch but no stem cells (P), and six pigs with left anterior descending coronary artery ligation alone (L). Magnetic resonance imaging data collected 19 +/- 1 days after the myocardial infarction indicated a significant increase of LV systolic wall thickening fraction in the infarct zone of transplanted hearts compared with P or L hearts. Blue X-gal staining was observed in the infarcted area of transplanted hearts. PCR amplification of specimens from the X-gal-positive area revealed the Ad5 RSV-lacZ vector fragment DNA sequence. Light microscopy demonstrated that transplanted cells had differentiated into cells with myocyte-like characteristics and a robust increase of neovascularization as evidenced by von Willebrand factor-positive angioblasts and capillaries in transplanted hearts. Thus this patch-based autologous stem cell procedure may serve as a therapeutic modality for myocardial repair.

Although high-energy phosphate metabolism is abnormal in failing hearts [congestive heart failure (CHF)], it is unclear whether oxidative capacity is impaired. This study used the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) to determine whether reserve oxidative capacity exists during the high workload produced by catecholamine infusion in hypertrophied and failing hearts. Left ventricular hypertrophy (LVH) was produced by ascending aortic banding in 21 swine; 9 animals developed CHF. Basal myocardial phosphocreatine (PCr)/ATP measured with 31 P NMR spectroscopy was decreased in both LVH and CHF hearts (corresponding to an increase in free [ADP]), whereas ATP was decreased in hearts with CHF. Infusion of dobutamine and dopamine (each 20 g ⅐ kg Ϫ1 ⅐ min Ϫ1 iv) caused an approximate doubling of myocardial oxygen consumption (MV O2) in all groups and decreased PCr/ATP in the normal and LVH groups. During continuing catecholamine infusion, DNP (2-8 mg/kg iv) caused further increases of MV O2 in normal and LVH hearts with no change in PCr/ATP. In contrast, DNP caused no increase in MV O2 in the failing hearts; the associated decrease of PCr/ATP suggests that DNP decreased the mitochondrial proton gradient, thereby causing ADP to increase to maintain adequate ATP synthesis. heart failure; left ventricular hypertrophy; mitochondria; high-energy phosphates; nuclear magnetic resonance IN NORMAL MYOCARDIUM, it is unclear whether peak O 2 utilization is ultimately limited by maximal oxidative ATP synthetic capacity or by the maximal capacities of the myosin and other ATPases to utilize ATP. In failing myocardium, abnormalities of excitation-contraction coupling as well as downregulation of ␤-adrenergic receptors and the downstream adenylyl cyclase system (25) make it even more difficult to determine whether ATP synthetic capacity limits contractile performance. Hence, the hypothesis that primary "energy starvation" limits function in heart failure (14) remains to be rigorously tested in vivo despite evidence that left ventricular (LV) hypertrophy (LVH) and congestive heart failure (CHF) are associated with abnormalities of myocardial energy metabolism (2,21,22,38,39).Consequently, the present study was performed to determine whether administration of a classical mitochondrial uncoupling agent [2,4-dinitrophenol (DNP)] could further increase myocardial oxygen consumption (MV O 2 ) in hearts with compensated LVH or overt cardiac failure that were already functioning at a high work state produced by catecholamine stimulation. DNP accelerates intramitochondrial metabolism proximal to ATP synthase by decreasing the proton gradient across the inner mitochondrial membrane (17,30). In response to DNP, MV O 2 increases in concert with intermediary metabolism and electron transport activity to maintain the mitochondrial proton gradient that drives ATP synthesis (15,17,30). Although it is unlikely that DNP can define the maximal oxygen utilization capacity in the intact heart (8), it can be used to determine whether there ...

This study tested the hypothesis that the loss of myocardial high-energy phosphates (HEP), which occurs during high cardiac work states [J. Zhang, D. J. Duncker, Y. Xu, Y. Zhang, G. Path, H. Merkle, K. Hendrich, A. H. L. From, R. Bache, and K. Uğurbil. Am. J. Physiol. 268: ( Heart Circ. Physiol. 37): H1891–H1905, 1995], is not the result of insufficient intracellular O2 availability. To evaluate the state of myocardial oxygenation, the proximal histidine signal of deoxymyoglobin (Mb-δ) was determined with1H nuclear magnetic resonance spectroscopy (MRS), whereas HEP were examined with31P MRS. Normal dogs ( n = 11) were studied under basal conditions and during combined infusion of dobutamine and dopamine (20 μg ⋅ kg−1 ⋅ min−1iv each), which increased rate-pressure products to >50,000 mmHg ⋅ beats ⋅ min−1. Creatine phosphate (CP) was expressed as CP/ATP, and myocardial myoglobin desaturation was normalized to the Mb-δ resonance present during total coronary artery occlusion. This Mb-δ resonance appeared at 71 parts per million downfield from the water resonance. CP/ATP decreased from 2.22 ± 0.12 during the basal state to 1.83 ± 0.09 during the high work state ( P < 0.01), whereas ΔPi/CP increased from 0 to 0.21 ± 0.04 ( P < 0.01). Despite these HEP changes, Mb-δ remained undetectable. In contrast, when a coronary stenosis was applied to produce a similar decrease in CP/ATP, Mb-δ reached 0.38 ± 0.10 of the value present during total coronary occlusion. These data demonstrate that Mb-δ is readily detected in vivo during limitation of coronary blood flow sufficient to cause a decrease of myocardial CP/ATP. However, similar HEP changes that occur at high work states in the absence of coronary occlusion are not associated with a detectable Mb-δ resonance. The findings support the hypothesis that the myocardial HEP changes observed at high work states are not due to inadequate O2 availability to the mitochondria and emphasize the limitations of interpreting HEP alterations in the absence of knowing the level of myocyte oxygenation.