Bioenergetic Abnormalities Associated with Severe Left Ventricular Hypertrophy

Abstract Transmurally localized 31P-nuclear magnetic resonance spectroscopy (NMR) was used to study the effect of severe pressure overload left ventricular hypertrophy (LVH) on myocardial high energy phosphate content. Studies were performed on 8 normal dogs and 12 dogs with severe left ventricular hypertrophy produced by banding the ascending aorta at 8 wk of age. Spatially localized 31P-NMR spectroscopy provided measurements of the transmural distribution of myocardial ATP, phosphocreatine (CP), and inorganic phosphate (Pi); spectra were calibrated from measurements of ATP content in myocardial biopsies using HPLC. Blood flow was measured with microspheres. In hypertrophied hearts during basal conditions, ATP was decreased by 42%, CP by 58%, and the CP/ATP ratio by 32% in comparison with normal. Increasing myocardial blood flow with adenosine did not correct these abnormalities, indicating that they were not the result of persistent hypoperfusion. Atrial pacing at 200 and 240 beats per min caused no change in high energy phosphate content in normal hearts but resulted in further CP depletion with Pi accumulation in the inner left ventricular layers of the hypertrophied hearts. These changes were correlated with redistribution of blood flow away from the subendocardium in LVH hearts. These findings demonstrate that high energy phosphate levels and the CP/ATP ratio are significantly decreased in severe LVH. These abnormalities are proportional to the degree of hypertrophy but are not the result of persistent abnormalities of myocardial perfusion. In contrast, depletion of CP and accumulation of Pi during tachycardia in LVH are closely related to the pacing-induced perfusion abnormalities and likely reflect subendocardial ischemia. (J. Clin. Invest. 1993. 92:993-100

Aging Kit Mutant Mice Develop Cardiomyopathy

Both bone marrow (BM) and myocardium contain progenitor cells expressing the c-Kit tyrosine kinase. The aims of this study were to determine the effects of c-Kit mutations on: i. myocardial c-Kit+ cells counts and ii. the stability of left ventricular (LV) contractile function and structure during aging. LV structure and contractile function were evaluated (echocardiography) in two groups of Kit mutant (W/Wv and W41/W42) and in wild type (WT) mice at 4 and 12 months of age and the effects of the mutations on LV mass, vascular density and the numbers of proliferating cells were also determined. In 4 month old Kit mutant and WT mice, LV ejection fractions (EF) and LV fractional shortening rates (FS) were comparable. At 12 months of age EF and FS were significantly decreased and LV mass was significantly increased only in W41/W42 mice. Myocardial vascular densities and c-Kit+ cell numbers were significantly reduced in both mutant groups when compared to WT hearts. Replacement of mutant BM with WT BM at 4 months of age did not prevent these abnormalities in either mutant group although they were somewhat attenuated in the W/Wv group. Notably BM transplantation did not prevent the development of cardiomyopathy in 12 month W41/W42 mice. The data suggest that decreased numbers and functional capacities of c-Kit+ cardiac resident progenitor cells may be the basis of the cardiomyopathy in W41/W42 mice and although defects in mutant BM progenitor cells may prove to be contributory, they are not causal

Serum Creatine Kinase MB Isoenzyme Activity in Long-term Hemodialysis Patients

• Serum creatine kinase MB isoenzyme (CK-MB) activity was determined in 46 male long-term hemodialysis patients without evidence of myocardial infarction. Thirteen (28.3%) showed mild elevations. The abnormality persisted in seven of eight patients on repeated measurement at three- to eight-month intervals. There was a significant correlation between serum CK-MB and CK-MN activity, and the activity of both enzymes rose after intramuscular injection The reason for the abnormality is not known. It is possible that skeletal muscle is the source of elevated enzyme activity. Caution should be exercised in the interpretation of serum CK-MB activity in the diagnosis of acute myocardial infarction in this patient population. (Arch Intern Med 141:164-166, 1981

Intra-Myocardial Injection of Both Growth Factors and Heart Derived Sca-1⁺/CD31⁻ Cells Attenuates Post-MI LV Remodeling More Than Does Cell Transplantation Alone: Neither Intervention Enhances Functionally Significant Cardiomyocyte Regeneration

<div><p>Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are two potent cell survival and regenerative factors in response to myocardial injury (MI). We hypothesized that simultaneous delivery of IGF+HGF combined with Sca-1⁺/CD31⁻ cells would improve the outcome of transplantation therapy in response to the altered hostile microenvironment post MI. One million adenovirus nuclear LacZ-labeled Sca-1⁺/CD31⁻ cells were injected into the peri-infarction area after left anterior descending coronary artery (LAD) ligation in mice. Recombinant mouse IGF-1+HGF was added to the cell suspension prior to the injection. The left ventricular (LV) function was assessed by echocardiography 4 weeks after the transplantation. The cell engraftment, differentiation and cardiomyocyte regeneration were evaluated by histological analysis. Sca-1⁺/CD31⁻ cells formed viable grafts and improved LV ejection fraction (EF) (Control, 54.5+/−2.4; MI, 17.6+/−3.1; Cell, 28.2+/−4.2, n = 9, P<0.01). IGF+HGF significantly enhanced the benefits of cell transplantation as evidenced by increased EF (38.8+/−2.2; n = 9, P<0.01) and attenuated adverse structural remodeling. Furthermore, IGF+HGF supplementation increased the cell engraftment rate, promoted the transplanted cell survival, enhanced angiogenesis, and minimally stimulated endogenous cardiomyocyte regeneration in vivo. The in vitro experiments showed that IGF+HGF treatment stimulated Sca-1⁺/CD31⁻ cell proliferation and inhibited serum free medium induced apoptosis. Supperarray profiling of Sca-1⁺/CD31⁻ cells revealed that Sca-1⁺/CD31⁻ cells highly expressed various trophic factor mRNAs and IGF+HGF treatment altered the mRNAs expression patterns of these cells. These data indicate that IGF-1+HGF could serve as an adjuvant to cell transplantation for myocardial repair by stimulating donor cell and endogenous cardiac stem cell survival, regeneration and promoting angiogenesis.</p></div

Effects of IGF+HGF supplementation increase the engraftment rates of transplanted Sca-1⁺/CD31⁻ cells.

<p>The <i>y</i>-axis indicates the number of X-gal and DAPI double stained cells in the whole heart relative to total cell numbers injected. Data were acquired at 1, 2, and 4 weeks after transplantation (n = 6, P<0.01 vs Sca-1⁺/CD31⁻ cells without HGF+IGF). X-gal, 5-bromo-4-chloro-3-indolyl-β-D-galactoside. DAPI, 4, 6-diamidino-2-phenylindole.</p