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Histoenzymological changes, indicating inhibition of the main metabolic processes, were found in the conduction cardiomyocytes of the left ventricle and ventricular septum in experimental stenosis of the aorta. The histoenzymological changes in the conduction system of both ventricles and ventricular septum were similar in experimental stenosis of the pulmonary artery and indicated primarily activation of glycolysis. The histoenzymological profile of conduction cardiomyocytes differed little in cases when the increase of the pressure load was complicated or not complicated by the development of heart failure, particularly in pulmonary artery stenosis. The histoenzymological changes in the conduction system in response to increased afterload differed significantly from those in the contractile myocardium and correlated with the level of cellular functional activity and sensitivity to the regulatory and alterative exposure. These data attest to minor role of metabolic shifts in conduction cell injuries with increasing afterload, primarily, of the right ventricle.

Background: Prominent features of myocardial remodeling in heart failure with preserved ejection fraction (HFPEF) are high cardiomyocyte resting tension (F(passive)) and cardiomyocyte hypertrophy. In experimental models, both reacted favorably to raised protein kinase G (PKG) activity. The present study assessed myocardial PKG activity, its downstream effects on cardiomyocyte F(passive) and cardiomyocyte diameter, and its upstream control by cyclic guanosine monophosphate (cGMP), nitrosative/oxidative stress, and brain natriuretic peptide (BNP). To discern altered control of myocardial remodeling by PKG, HFPEF was compared with aortic stenosis and HF with reduced EF (HFREF)., Methods and Results: Patients with HFPEF (n=36), AS (n=67), and HFREF (n=43) were free of coronary artery disease. More HFPEF patients were obese (P<0.05) or had diabetes mellitus (P<0.05). Left ventricular myocardial biopsies were procured transvascularly in HFPEF and HFREF and perioperatively in aortic stenosis. F(passive) was measured in cardiomyocytes before and after PKG administration. Myocardial homogenates were used for assessment of PKG activity, cGMP concentration, proBNP-108 expression, and nitrotyrosine expression, a measure of nitrosative/oxidative stress. Additional quantitative immunohistochemical analysis was performed for PKG activity and nitrotyrosine expression. Lower PKG activity in HFPEF than in aortic stenosis (P<0.01) or HFREF (P<0.001) was associated with higher cardiomyocyte F(passive) (P<0.001) and related to lower cGMP concentration (P<0.001) and higher nitrosative/oxidative stress (P<0.05). Higher F(passive) in HFPEF was corrected by in vitro PKG administration., Conclusions: Low myocardial PKG activity in HFPEF was associated with raised cardiomyocyte F(passive) and was related to increased myocardial nitrosative/oxidative stress. The latter was probably induced by the high prevalence in HFPEF of metabolic comorbidities. Correction of myocardial PKG activity could be a target for specific HFPEF treatment.

Contractile cardiomyocyte metabolism was studied by histochemical methods in experimental stenosis of the aorta complicated and not by heart failure. Acceleration of the citric acid cycle, more intense oxidation of free fatty acids and their metabolites, glycolysis intensification, and higher activity of shuttle mechanisms were found in the contractile cardiomyocytes in stenosis of the aorta not complicated by heart failure. The presence of these metabolic shifts in the myocardium of all studied compartments suggests their association with not only more intense heart work, but also with the effects of total systems neurohumoral factors. Comparative study of myocardial metabolism in two variants of experimental stenosis of the aorta has revealed changes prognostically unfavorable for the development of heart failure. These changes include exhaustion of glycogen reserve, glycolysis inhibition, and metabolism shift towards biosynthetic processes. These data indicate an important role of glycolysis in support of myocardial contractile function during the acute phase of pressure overloading of the heart.

Background: The regulation of the cardiac neutral endopeptidase (EC 24.10, NEP) that degrades bradykinin and natriuretic peptides has been investigated in human cardiac hypertrophy and heart failure. Methods and Results- NEP mRNA was quantitated by real-time polymerase chain reaction (PCR) in left ventricular biopsies from patients with aortic valve stenosis (AS, n=19) and heart failure due to dilated cardiomyopathy (DCM, n=14), and control subjects with normal systolic function (CON, n=14). Left ventricular NEP mRNA content was increased 3-fold in AS (P<0.005) and 4.1-fold in DCM (P<0.002). The increase in NEP mRNA was related to the increase in end diastolic pressure in AS and DCM. In a second series, myocardial NEP enzymatic activity was determined. It increased 3.6-fold in AS (P<0.02) and 4-fold in DCM (P<0.002). NEP was localized in the myocardium by immunofluorescence microscopy and in situ PCR to myocytes and nonmyocyte areas and cells., Conclusions: Elevated cardiac NEP activity in pressure loaded and failing human hearts may increase the local degradation of bradykinin and natriuretic peptides.

Total creatine kinase (CK) and the myocardial isoenzyme CK MB activity were prospectively determined in 282 children hospitalized for cardiac catheterization and evaluation for suspected congenital cardiac abnormalities and compared with a hospitalized control group of children without such abnormalities. The percent CK MB and CK MB activity were abnormally elevated in symptomatic children with a large left to right shunt due either to a large ventricular septal defect (n = 22; p less than 0.001) or to complete atrioventricular canal (n = 10; p less than 0.001). Serum CK MB activity and percent CK MB were significantly related to the size of the shunt and the age of presentation with clinical symptoms of congestive heart failure in infants with a ventricular septal defect. CK MB activity was abnormally elevated in infants with symptomatic coarctation of the aorta, either with or without a ventricular septal defect (n = 15; p less than 0.001), and in infants with symptomatic aortic stenosis (n = 4; p less than 0.02). In contrast, CK MB activity was normal in asymptomatic children with coarctation of the aorta (n = 14) or aortic stenosis (n = 8) despite comparable systolic pressure gradients. CK MB activity and percent CK MB were abnormally elevated in those children with the cyanotic congenital cardiac abnormalities of either transposition of the great arteries (n = 32; p less than 0.001) or right ventricular outflow tract obstruction (n = 31; p less than 0.001). These results suggest that children with congenital cardiac abnormalities may have significant myocardial cell injury and release of CK MB that may be detected by the determination of serum CK MB activity. Cell injury may be secondary to arterial desaturation or acute pressure-volume overload, or both, as manifested by clinical symptoms of heart failure and measured hemodynamic variables.