phosphocreatine and Cardiomegaly

Topics: Blood Circulation; Cardiac Volume; Cardiomegaly; Cyclic AMP; Electric Countershock; Glycolysis; Heart; Heart Failure; Heart Transplantation; Heart, Artificial; Humans; Kidney; Myocardial Contraction; Myocardium; Oxidative Phosphorylation; Pacemaker, Artificial; Phosphocreatine; Protein Biosynthesis; Sympathetic Nervous System; Transplantation, Homologous

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Calcium; Cardiomegaly; Coronary Disease; Digitalis Glycosides; Heart Failure; Hemodynamics; Humans; Myocardium; Myosins; Necrosis; Norepinephrine; Oxygen Consumption; Phosphocreatine; Propranolol

Topics: Acclimatization; Adenosine Triphosphate; Animals; Cardiomegaly; Chick Embryo; Cold Temperature; DNA; Humans; Hypoxia; Myocardium; Phosphocreatine; Rats; RNA; Stress, Physiological

Topics: Adenosine Triphosphate; Amino Acids; Calcium; Cardiomegaly; Endoplasmic Reticulum; Heart Failure; Humans; Mitochondria; Muscle Contraction; Myocardium; Oxygen Consumption; Phosphocreatine; Protein Biosynthesis; Stress, Physiological; Synaptic Transmission

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Biomechanical Phenomena; Calcium; Cardiomegaly; Catecholamines; Cats; Chemoreceptor Cells; Dogs; Guinea Pigs; Heart Failure; Heart Ventricles; Humans; Mitochondria, Muscle; Mixed Function Oxygenases; Muscle Contraction; Muscle Proteins; Norepinephrine; Oxidative Phosphorylation; Phosphocreatine; Sympathetic Nervous System; Tyrosine

Impaired oxidative phosphorylation is a crucial factor in the pathogenesis of Friedreich's ataxia (FA). L-carnitine and creatine are natural compounds that can enhance cellular energy transduction. We performed a placebo-controlled triple-phase crossover trial of L-carnitine (3 g/d) and creatine (6.75 g/d) in 16 patients with genetically confirmed FA. Primary outcome measures were mitochondrial ATP production measured as phosphocreatine recovery by 31Phosphorus magnetic resonance spectroscopy, neurological deficits assessed by the international co-operative ataxia rating scale and cardiac hypertrophy in echocardiography. After 4 months on L-carnitine phosphocreatine recovery was improved compared to baseline (p<0.03, t-test) but comparison to placebo and creatine effects did not reach significance (p=0.06, F-test). Ataxia rating scale and echocardiographic parameters remained unchanged. Creatine had no effect in FA patients. L-carnitine is a promising substance for the treatment of FA patients, and larger trials are warranted.

Topics: Adenosine Triphosphate; Adolescent; Adult; Cardiomegaly; Carnitine; Child; Creatine; Female; Friedreich Ataxia; Heart; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria; Phosphocreatine; Treatment Outcome

Cardiac hypertrophy is accompanied by significant alterations in energy metabolism. Whether these changes in energy metabolism precede and contribute to the development of heart failure in the hypertrophied heart is not clear.. Mice were subjected to cardiac hypertrophy secondary to pressure-overload as a result of an abdominal aortic constriction (AAC). The rates of energy substrate metabolism were assessed in isolated working hearts obtained 1, 2, and 3 weeks after AAC. Mice subjected to AAC demonstrated a progressive development of cardiac hypertrophy. In vivo assessment of cardiac function (via echocardiography) demonstrated diastolic dysfunction by 2 weeks (20% increase in E/E'), and systolic dysfunction by 3 weeks (16% decrease in % ejection fraction). Marked cardiac insulin-resistance by 2 weeks post-AAC was evidenced by a significant decrease in insulin-stimulated rates of glycolysis and glucose oxidation, and plasma membrane translocation of glucose transporter 4. Overall ATP production rates were decreased at 2 and 3 weeks post-AAC (by 37% and 47%, respectively) because of a reduction in mitochondrial oxidation of glucose, lactate, and fatty acids that was not accompanied by an increase in myocardial glycolysis rates. Reduced mitochondrial complex V activity was evident at 3 weeks post-AAC, concomitant with a reduction in the ratio of phosphocreatine to ATP.. The development of cardiac insulin-resistance and decreased mitochondrial oxidative metabolism are early metabolic changes in the development of cardiac hypertrophy, which create an energy deficit that may contribute to the progression from hypertrophy to heart failure.

Topics: Adenosine Triphosphate; Animals; Aorta, Abdominal; Arterial Pressure; Blood Glucose; Cardiomegaly; Disease Models, Animal; Disease Progression; Energy Metabolism; Fatty Acids; Glucose Transporter Type 4; Glycolysis; Heart Failure, Systolic; Insulin; Insulin Resistance; Lactic Acid; Ligation; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Mitochondrial Proton-Translocating ATPases; Myocardium; Oxidation-Reduction; Phosphocreatine; Stroke Volume; Time Factors; Ventricular Function, Left; Ventricular Pressure

This study was designed to test whether reduced levels of cardiac fructose-2,6-bisphosphate (F-2,6-P(2)) exacerbates cardiac damage in response to pressure overload. F-2,6-P(2) is a positive regulator of the glycolytic enzyme phosphofructokinase. Normal and Mb transgenic mice were subject to transverse aortic constriction (TAC) or sham surgery. Mb transgenic mice have reduced F-2,6-P(2) levels, due to cardiac expression of a transgene for a mutant, kinase deficient form of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) which controls the level of F-2,6-P(2). Thirteen weeks following TAC surgery, glycolysis was elevated in FVB, but not in Mb, hearts. Mb hearts were markedly more sensitive to TAC induced damage. Echocardiography revealed lower fractional shortening in Mb-TAC mice as well as larger left ventricular end diastolic and end systolic diameters. Cardiac hypertrophy and pulmonary congestion were more severe in Mb-TAC mice as indicated by the ratios of heart and lung weight to tibia length. Expression of α-MHC RNA was reduced more in Mb-TAC hearts than in FVB-TAC hearts. TAC produced a much greater increase in fibrosis of Mb hearts and this was accompanied by 5-fold more collagen 1 RNA expression in Mb-TAC versus FVB-TAC hearts. Mb-TAC hearts had the lowest phosphocreatine to ATP ratio and the most oxidative stress as indicated by higher cardiac content of 4-hydroxynonenal protein adducts. These results indicate that the heart's capacity to increase F-2,6-P(2) during pressure overload elevates glycolysis which is beneficial for reducing pressure overload induced cardiac hypertrophy, dysfunction and fibrosis.

Topics: Adenosine Triphosphate; Animals; Aorta; Cardiomegaly; Constriction, Pathologic; Fibrosis; Fructosediphosphates; Glycolysis; Male; Mice; Mice, Transgenic; Myocardium; Oxidative Stress; Phosphocreatine; Phosphofructokinase-2; Ventricular Remodeling

The metabolic phenotype of the failing heart includes a decrease in phosphocreatine and total creatine concentration [Cr], potentially contributing to contractile dysfunction. Surprisingly, in 32- week-old mice over-expressing the myocardial creatine transporter (CrT-OE), we previously demonstrated that elevated [Cr] correlates with left ventricular (LV) hypertrophy and failure. The aim of this study was to determine the temporal relationship between elevated [Cr] and the onset of cardiac dysfunction and to screen for potential molecular mechanisms. CrT-OE mice were compared with wild-type (WT) littermate controls longitudinally using cine-MRI to measure cardiac function and single-voxel (1)H-MRS to measure [Cr] in vivo at 6, 16, 32, and 52 weeks of age. CrT-OE mice had elevated [Cr] at 6 weeks (mean 1.9-fold), which remained constant throughout life. Despite this increased [Cr], LV dysfunction was not apparent until 16 weeks and became more pronounced with age. Additionally, LV tissue from 12 to 14 week old CrT-OE mice was compared to WT using 2D difference in-gel electrophoresis (DIGE). These analyses detected a majority of the heart's metabolic enzymes and identified seven proteins that were differentially expressed between groups. The most pronounced protein changes were related to energy metabolism: alpha- and beta-enolase were selectively decreased (p<0.05), while the remaining enzymes of glycolysis were unchanged. Consistent with a decrease in enolase content, its activity was significantly lower in CrT-OE hearts (in WT, 0.59+/-0.02 micromol ATP produced/microg protein/min; CrT-OE, 0.31+/-0.06; p<0.01). Additionally, anaerobic lactate production was decreased in CrT-OE mice (in WT, 102+/-3 micromol/g wet myocardium; CrT-OE, 78+/-13; p=0.02), consistent with decreased glycolytic capacity. Finally, we found that enolase may be regulated by increased expression of the beta-enolase repressor transcription factor, which was significantly increased in CrT-OE hearts. This study demonstrates that chronically increased myocardial [Cr] in the CrT-OE model leads to the development of progressive hypertrophy and heart failure, which may be mediated by a compromise in glycolytic capacity at the level of enolase.

Topics: Animals; Aorta; Cardiomegaly; Creatine; Electrophoresis, Gel, Two-Dimensional; Female; Glycolysis; Heart Failure; Heart Ventricles; Magnetic Resonance Imaging; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Myocardium; Phosphocreatine; Phosphopyruvate Hydratase

Adenoviral gene transfer of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a to the hypertrophic heart in vivo has been consistently reported to lead to enhanced myocardial contractility. It is unknown if the faster skeletal muscle isoform, SERCA1, expressed in the whole heart in early failure, leads to similar improvements and whether metabolic requirements are maintained during an adrenergic challenge. In this study, Ad.cmv.SERCA1 was delivered in vivo to aortic banded and sham-operated Sprague-Dawley rat hearts. The total SERCA content increased 34%. At 48-72 h posttransfer, echocardiograms were acquired, hearts were excised and retrograded perfused, and hemodynamics were measured parallel to NMR measures of the phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) and energy substrate selection at basal and high workloads (isoproterenol). In the Langendorff mode, the rate-pressure product was enhanced 27% with SERCA1 in hypertrophic hearts and 10% in shams. The adrenergic response to isoproterenol was significantly potentiated in both groups with SERCA1. 31P NMR analysis of PCr/ATP revealed that the ratio remained low in the hypertrophic group with SERCA1 overexpression and was not further compromised with adrenergic challenge. 13C NMR analysis revealed fat and carbohydrate oxidation were unaffected at basal with SERCA1 expression; however, there was a shift from fats to carbohydrates at higher workloads with SERCA1 in both groups. Transport of NADH-reducing equivalents into the mitochondria via the alpha-ketoglutamate-malate transporter was not affected by either SERCA1 overexpression or adrenergic challenge in both groups. Echocardiograms revealed an important distinction between in vivo versus ex vivo data. In contrast to previous SERCA2a studies, the echocardiogram data revealed that SERCA1 expression compromised function (fractional shortening) in the hypertrophic group. Shams were unaffected. While our ex vivo findings support much of the earlier cardiomyocyte and transgenic data, the in vivo data challenge previous reports of improved cardiac function in heart failure models after SERCA intervention.

Topics: Adenosine Triphosphate; Adenoviridae; Adrenergic beta-Agonists; Animals; Calcium-Binding Proteins; Calsequestrin; Cardiomegaly; Carrier Proteins; Citric Acid Cycle; Disease Models, Animal; Energy Metabolism; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Hemodynamics; Isoproterenol; Magnetic Resonance Spectroscopy; Male; Mitochondria, Heart; Muscle, Skeletal; Myocardial Contraction; Myocardium; Oxidation-Reduction; Palmitic Acid; Phosphocreatine; Rats; Rats, Sprague-Dawley; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Time Factors; Ultrasonography

Primary systemic carnitine deficiency is an autosomal recessive disorder caused by a decreased renal reabsorption of carnitine because of mutations of the carnitine transporter OCTN2 gene, and hypertrophic cardiomyopathy is a common clinical feature of homozygotes. Although heterozygotes for OCTN2 mutations are generally healthy with normal cardiac performance, heterozygotes may be at risk for cardiomyopathy in the presence of additional risk factors, such as hypertension. To test this hypothesis, we investigated the effects of surgically induced pressure overload on the hearts of heterozygous mutants of a murine model of OCTN2 mutation, juvenile visceral steatosis mouse (jvs/+). Eleven-week-old jvs/+ mice and age-matched wild-type mice were used. At baseline, there were no differences in physical characteristics between wild-type and jvs/+ mice. However, plasma and myocardial total carnitine levels in jvs/+ mice were lower than in wild-type mice. Both wild-type and jvs/+ mice were subjected to ascending aortic constriction with or without 1% l-carnitine supplementation for 4 weeks. At 4 weeks after ascending aortic constriction, jvs/+ mice showed an exaggeration of cardiac hypertrophy and pulmonary congestion, further increased gene expression of atrial natriuretic peptide in the left ventricles, further deterioration of left ventricular fractional shortening, reduced myocardial phosphocreatine:adenosine triphosphate ratio, and increased mortality compared with wild-type mice; l-carnitine supplementation prevented these changes in jvs/+ mice subjected to ascending aortic constriction. In conclusion, cardiomyopathy and heart failure with energy depletion may be induced by pressure overload in heterozygotes for OCTN2 mutations and could be prevented by l-carnitine supplementation.

Topics: Adenosine Triphosphate; Animals; Aorta; Atrial Natriuretic Factor; Blood Pressure; Cardiomegaly; Cardiomyopathies; Carnitine; Constriction; Echocardiography; Genetic Predisposition to Disease; Heterozygote; Hypertension; Lung; Male; Mice; Mice, Mutant Strains; Mutation; Myocardium; Organ Size; Organic Cation Transport Proteins; Phosphocreatine; RNA, Messenger; Solute Carrier Family 22 Member 5

The role of the creatine kinase (CK)/phosphocreatine (PCr) energy buffer and transport system in heart remains unclear. Guanidinoacetate-N-methyltransferase-knockout (GAMT-/-) mice represent a new model of profoundly altered cardiac energetics, showing undetectable levels of PCr and creatine and accumulation of the precursor (phospho-)guanidinoacetate (P-GA). To characterize the role of a substantially impaired CK/PCr system in heart, we studied the cardiac phenotype of wild-type (WT) and GAMT-/- mice.. GAMT-/- mice did not show cardiac hypertrophy (myocyte cross-sectional areas, hypertrophy markers atrial natriuretic factor and beta-myosin heavy chain). Systolic and diastolic function, measured invasively (left ventricular conductance catheter) and noninvasively (MRI), were similar for WT and GAMT-/- mice. However, during inotropic stimulation with dobutamine, preload-recruitable stroke work failed to reach maximal levels of performance in GAMT-/- hearts (101+/-8 mm Hg in WT versus 59+/-7 mm Hg in GAMT-/-; P<0.05). (31)P-MR spectroscopy experiments showed that during inotropic stimulation, isolated WT hearts utilized PCr, whereas isolated GAMT-/- hearts utilized P-GA. During ischemia/reperfusion, GAMT-/- hearts showed markedly impaired recovery of systolic (24% versus 53% rate pressure product recovery; P<0.05) and diastolic function (eg, left ventricular end-diastolic pressure 23+/-9 in WT and 51+/-5 mm Hg in GAMT-/- during reperfusion; P<0.05) and incomplete resynthesis of P-GA.. GAMT-/- mice do not develop hypertrophy and show normal cardiac function at low workload, suggesting that a fully functional CK/PCr system is not essential under resting conditions. However, when acutely stressed by inotropic stimulation or ischemia/reperfusion, GAMT-/- mice exhibit a markedly abnormal phenotype, demonstrating that an intact, high-capacity CK/PCr system is required for situations of increased cardiac work or acute stress.

Topics: Animals; Cardiomegaly; Creatine Kinase; Disease Susceptibility; Energy Metabolism; Guanidinoacetate N-Methyltransferase; Heart Function Tests; Hemodynamics; Mice; Mice, Knockout; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Phosphocreatine; Stress, Physiological

Friedreich's ataxia is a neurodegenerative disease frequently associated with hypertrophic cardiomyopathy. We have determined mitochondrial ATP, phosphocreatine, and intracellular inorganic phosphate levels by 31P nuclear magnetic resonance spectroscopy in the heart of 11 Friedreich's ataxia patients and 11 healthy controls. For the first time, to our knowledge, we showed a significant correlation between the extent of myocardial energy deficiency and the degree of myocardial hypertrophy. When combining our results with previous works on Friedreich's ataxia, these novel findings suggest that energy metabolism is most likely the cause and hypertrophy the effect in Friedreich's ataxia.

Topics: Adenosine Triphosphate; Adolescent; Adult; Cardiomegaly; Energy Metabolism; Female; Friedreich Ataxia; Heart Septum; Humans; Magnetic Resonance Spectroscopy; Male; Phosphocreatine

It is well established that severe hypertrophy induces metabolic and structural changes in the heart which result in enhanced susceptibility to ischemic damage during cardioplegic arrest while much less is known about the effect of cardioplegic arrest on moderately hypertrophied hearts. The aim of this study was to elucidate the differences in myocardial high energy phosphate metabolism and in functional recovery after cardioplegic arrest and ischemia in mildly hypertrophied hearts, before any metabolic alterations could be shown under baseline conditions. Cardiac hypertrophy was induced in rats by constriction of the abdominal aorta resulting in 20% increase in heart weight/body weight ratio (hypertrophy group) while sham operated animals served as control. In both groups, isolated hearts were perfused under normoxic conditions for 40 min followed by infusion of St.Thomas' Hospital No. 1 cardioplegia and 90 min ischemia at 25 degrees C with infusions of cardioplegia every 30 min. The changes in ATP, phosphocreatine (PCr) and inorganic phosphate (Pi) were followed by 31P nuclear magnetic resonance (NMR) spectroscopy. Systolic and diastolic function was assessed with an intraventricular balloon before and after ischemia. Baseline concentrations of PCr, ATP and Pi as well as coronary flow and cardiac function were not different between the two groups. However, after cardioplegic arrest PCr concentration increased to 61.8+/-4.9 micromol/g dry wt in the control group and to 46.3+/-2.8 micromol/g in hypertrophied hearts. Subsequently PCr, pH and ATP decreased gradually, concomitant with an accumulation of Pi in both groups. PCr was transiently restored during each infusion of cardioplegic solution while Pi decreased. PCr decreased faster after cardioplegic infusions in hypertrophied hearts. The most significant difference was observed during reperfusion: PCr recovered to its pre-ischemic levels within 2 min following restoration of coronary flow in the control group while similar recovery was observed after 4 min in the hypertrophied hearts. A greater deterioration of diastolic function was observed in hypertrophied hearts. Moderate hypertrophy, despite absence of metabolic changes under baseline conditions could lead to enhanced functional deterioration after cardioplegic arrest and ischemia. Impaired energy metabolism resulting in accelerated high energy phosphate depletion during ischemia and delayed recovery of energy equilibrium after cardioplegic arrest

Topics: Adenosine Triphosphate; Animals; Cardiomegaly; Energy Metabolism; Heart; Heart Arrest, Induced; Hydrogen-Ion Concentration; Male; Myocardium; Phosphates; Phosphocreatine; Rats; Rats, Wistar

Stimulation of alpha-adrenoceptors on ventricular cardiomyocytes isolated from adult rat hearts leads to cellular alkalization, increases of creatine phosphate concentration, RNA mass, and protein synthesis. This study investigated whether the increase of creatine phosphate concentrations is causally linked to the hypertrophic response of cardiomyocytes under alpha-adrenoceptor stimulation. Cellular alkalization achieved with phenylephrine (10 microM), an alpha-adrenoceptor agonist, was abolished in the presence of the sodium-proton-exchange (NHE)-inhibitor HOE 694 (1 microM). HOE 694 inhibited also the alpha-adrenoceptor-mediated increase in cellular creatine phosphate and the increase in cellular RNA mass. The phenylephrine-induced stimulation of protein synthesis (determined by incorporation of 14C-phenylalanine) was reduced by one-third when HOE 694 was present. beta-Guanidinopropionic acid was added to cardiomyocytes to reduce cellular creatine phosphate concentrations. In these cultures, alpha-adrenoceptor stimulation activated NHE, but creatine phosphate concentrations were not increased. Protein synthesis was augmented to the same extent as in control cultures, but total RNA mass did not increase. From these results we conclude that alpha-adrenoceptor stimulation causes the increase in protein synthesis via activation of NHE, but independent of the concomitant increase in creatine phosphate contents. The effect of alpha-adrenoceptor stimulation on total RNA mass (translational capacity) is also caused by NHE activation, but depends on the changes in creatine phosphate contents as well.

Topics: Adrenergic alpha-Agonists; Animals; Cardiomegaly; Cell Division; Cells, Cultured; Guanidines; Heart Ventricles; Hydrogen-Ion Concentration; Male; Myocardium; Phenylephrine; Phosphocreatine; Propionates; Protein Biosynthesis; Rats; Rats, Wistar; Receptors, Adrenergic, alpha; RNA; Sodium-Hydrogen Exchangers; Sulfones

Using an isolated ferret heart preparation (Langendorff perfusion, perfusion pressure 90 mmHg), energy metabolism has been characterized in right and left ventricles from control and hypertrophied hearts. Hypertrophy was induced by pulmonary artery clipping for 30-45 days (right ventricle wall weight/body weight ratio increased by 70%). Myocardial contents of high energy phosphate compounds, glycogen and lactate, and the activities of some enzymes were biochemically measured in perfused hearts and also after ischemic arrest (30 min global ischemia). In hypertrophied right ventricles, PCr (-46%), Cr (-34%) levels, creatine kinase activity (-18%) were significantly decreased compared with control. ATP and Pi levels were not affected by hypertrophy. The adenylate energy charges were similar (0.85-0.86) in both types of heart. The activities of hexokinase (+26%), aldolase (+212%), pyruvate kinase (+14%) and glucose 6-phosphate dehydrogenase (+107%) were increased by hypertrophy. The LDH isozyme pattern was significantly changed such that LDH3 was decreased by 11%, and LDH4 and LDH5 were increased by a factor 1.4 and 2.9 respectively in hypertrophy. After 30 min of global ischemia, PCr level was decreased by 89 and 79% in control and hypertrophied ventricles respectively. ATP level was depressed by 41 in control and only by 21% in hypertrophied muscles. Altogether, the present data suggested that, in the adult ferret heart, the capacity for the ATP synthesis could be maintained during hypertrophy by the enhancement of the glycolytic pathway. The smaller decline of ATP after ischemia in hypertrophied tissue could be explained by a lower consumption of ATP in the hypertrophied compared to the control heart during the earliest period of ischemia.

Topics: Adenosine Triphosphate; Age Factors; Animals; Cardiomegaly; Creatine Kinase; Energy Metabolism; Ferrets; Glycolysis; Myocardium; Phosphates; Phosphocreatine

Studies on the benefit of methods for protection of the hypertrophied immature myocardium are rare and controversial.. We assessed the effects of (1) rapid cooling by topical hypothermia alone, (2) slow prearrest cooling by coronary perfusion hypothermia, and (3) cardioplegic cardiac arrest with St. Thomas' Hospital solution no. 2 for protection of isolated immature rat hearts (age, 28 days) during 8 hours of global ischemia at 10 degrees C. Myocardial hypertrophy was induced noninvasively by lifelong feeding of a low iron diet. Recovery of left ventricular function, metabolism, and myocardial fine structure were assessed.. In hypertrophied hearts, protection by topical hypothermia alone resulted in significantly improved postischemic recoveries of maximum left ventricular pressure and rate of pressure rise compared with the method of slow cooling or application of cardioplegia (40.6% +/- 5.0% and 38.1% +/- 5.9%, mean +/- standard error of the mean; p < 0.05). The same pattern of recovery was observed among nonhypertrophied control hearts. Regardless of the method of protection, hypertrophied hearts revealed a significantly larger interstitial space at the end of reperfusion than control hearts. In hypertrophied hearts, postischemic adenosine triphosphate concentrations were higher with topical hypothermia alone for protection than with the other methods.. Rapid cooling by topical hypothermia alone provides superior protection of hypertrophied immature rat hearts as compared with slow prearrest cooling. Application of St. Thomas' Hospital cardioplegic solution no. 2 does not improve protection and even hinders postischemic functional recovery.

Topics: Adenosine Triphosphate; Age Factors; Animals; Bicarbonates; Calcium Chloride; Cardiomegaly; Cardioplegic Solutions; Coronary Circulation; Crystalloid Solutions; Heart; Heart Arrest, Induced; Hypothermia, Induced; Isotonic Solutions; Magnesium; Male; Myocardial Reperfusion Injury; Myocardium; Phosphocreatine; Plasma Substitutes; Potassium Chloride; Rats; Rats, Wistar; Sodium Chloride; Time Factors

We studied peripheral skeletal muscle metabolism in monocrotaline-treated rats. Two distinct groups emerged: a percentage of the animals developed ventricular hypertrophy, with no signs of heart failure (compensated group), whilst others, besides ventricular hypertrophy, developed the syndrome of congestive heart failure (CFH group). Oxidative metabolism and redox cellular state were expressed in terms of creatine phosphate, purine (ATP, ADP and AMP) and pyridine (NAD and NADH) nucleotides tissue content. Skeletal muscles with different metabolism were studied: (a) Soleus (oxidative), (b) extensor digitorium longus (glycolytic) and tibialis anterior (oxidative and glycolytic). The results showed that in CFH animals a decreased high-energy phosphates content occurs in the soleus and extensor digitorum longus, but not in the tibialis anterior. In the soleus. ATP declined from 20.31 +/- 2.5 of control group to 9.55 +/- 0.61 mumol/g dry wt. while in the extensor digitorum longus ATP declined from 30.92 +/- 2.68 to 22.7 +/- 1.54 mumol/g dry wt. In both these muscles, a shift of NAD/NADH couple towards oxidation was also observed (from 26.58 +/- 3.34 to 6.95 +/- 0.97 and from 18.88 +/- 3.43 to 10.57 +/- 1.61, respectively). These alterations were more evident in the aerobic soleus muscle. On the contrary, no major changes occurred in skeletal muscle metabolism of compensated animals. The results show that: (1) a decrease in muscle high-energy phosphates occurs in CFH; (2) this is accompanied by a decrease of NAD/NADH couple suggesting an impairment in oxygen utilization or availability.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Cardiomegaly; Disease Models, Animal; Female; Heart Failure; Monocrotaline; Muscle, Skeletal; NAD; Organ Size; Oxidation-Reduction; Phosphocreatine; Rats; Rats, Sprague-Dawley

To clarify the role of Na+i, pHi, and high-energy phosphate (HEP) levels in the initiation and maintenance of ischemia-induced ventricular fibrillation (VF), interleaved 23Na and 31P nuclear magnetic resonance spectra were collected on perfused rat hearts during low-flow ischemia (51 minutes, 1.2 mL/g wet wt). When untreated, 50% of the hearts from normal (sham) rats and 89% of the hypertrophied hearts from aorticbanded (band) rats (P < .01 versus sham) exhibited VF. Phosphocreatine content was significantly higher in sham than band hearts during control perfusion (53.3 +/- 1.6 versus 39.8 +/- 2.0 mumol/g dry wt). Before VF at 20 minutes of ischemia, Na+i accumulation was greater in hearts that eventually developed VF than in hearts that did not develop VF for both band and sham groups (144% versus 128% of control in sham; P < .005) and was the strongest metabolic predictor of VF; ATP depletion was also greater for VF hearts in the sham group. Infusion of the Na(+)-H+ exchange inhibitor 5-(N,N-hexamethylene)-amiloride prevented VF in sham and band hearts; reduced Na+i accumulation but similar HEP depletion were observed compared with VF hearts before the onset of VF. Rapid changes in Na+i, pHi, and HEP began with VF, resulting in intracellular Na+i overload (approximately 300% of control) and increased HEP depletion. A delayed postischemic functional recovery occurred in VF hearts, which correlated temporally with the recovery of Na+i. In conclusion, alterations in Na+i were associated with spontaneous VF transitions, consistent with involvement of excess Na+i accumulation in VF initiation and maintenance and with previously reported alterations in Ca2+i with VF.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Cardiomegaly; Energy Metabolism; In Vitro Techniques; Lactates; Magnetic Resonance Spectroscopy; Male; Myocardial Ischemia; Perfusion; Phosphocreatine; Phosphorus Isotopes; Rats; Rats, Sprague-Dawley; Sodium; Sodium Isotopes; Time Factors; Ventricular Fibrillation

The effect of calcium activation on energy production was investigated in isolated perfused hearts from rats treated with triiodothyronine (T3) during 15 days (0.2 mg/kg/day) and in hearts of rats allowed to recover after T3-treatment during 15 days. Changes in phosphorylated compound concentrations were followed in the isolated hearts perfused with a glucose-pyruvate medium by 31P-NMR spectroscopy, when the external calcium concentration was increased from 0.5-1, 1.5 and 2 mM. As expected, T3-treatment resulted in the hypertrophy of the heart (50% increase in HW/BW) that was nearly reversible 15 days after discontinuation of the treatment. When compared to controls, creatine, phosphocreatine (PCr) and glycogen contents were lower (58, 24 and 17% decrease respectively) in the hypertrophied hearts and higher (10, 14 and 18% respectively) after regression of hypertrophy. Intracellular pH, ATP, inorganic phosphate concentrations and the phosphorylation potential were not altered under T3-treatment and after regression of hypertrophy, while calculated free ADP concentration was lower in hypertrophied hearts (control: 40 +/- 2 microM, T3-treatment: 21 +/- 1 microM, regression: 37 +/- 1 microM). Increasing the calcium concentration induced a similar increase in left ventricular developed pressure in the three groups of hearts, with inorganic phosphate concentration increasing with cardiac work. The PCr concentration slightly decreased while the ATP concentration did not change. In spite of different initial PCr concentrations, the evolutions of PCr and Pi concentrations for each stepwise increase in external calcium were similar in the three groups. It is concluded that, in spite of the well-known decrease in efficiency induced by the drug, the mechanisms of PCr (ATP) production remain able to respond to an acute moderate increase in energy demand provoked by a physiological stimulus. This adaptation also persists after the treatment when the energy metabolism balance is apparently improved.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Calcium; Cardiomegaly; Creatine; Energy Metabolism; Female; Glycogen; Heart; Hyperthyroidism; Magnetic Resonance Spectroscopy; Myocardial Contraction; Myocardium; Organ Size; Phosphates; Phosphocreatine; Rats; Rats, Sprague-Dawley; Triiodothyronine; Ventricular Pressure

Alterations in energy metabolism, reduced fatty acid oxidation, and cardiac carnitine content have been implicated in the evolution from compensated to decompensated cardiac hypertrophy. We determined high-energy nucleotide levels in hypertrophied quiescent cardiomyocytes isolated from rat hearts 4 weeks after banding of abdominal aorta. In hypertrophied quiescent cardiomyocytes, a decrease in ATP content (p = 0.03), and ratios of ATP/total adenine nucleotides and of ATP/ADP were observed, together with an increase in ADP. In addition, palmitate, but not glucose oxidation, was markedly reduced in hypertrophied myocytes. In the presence of 25 microM propionyl-L-carnitine (PLC) or L-carnitine (LC), palmitate oxidation was significantly stimulated in hypertrophied myocytes. The ATP/ADP ratio was significantly increased only with PLC. This effect was not due to an enhanced PLC uptake, since total PLC uptake was 50% lower than that of LC. Changes in the energy generating system of quiescent myocytes occur early in pressure overload hypertrophy, and these alterations can be attenuated by PLC.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Cardiomegaly; Cardiotonic Agents; Carnitine; Cell Size; Disease Models, Animal; Energy Metabolism; Fatty Acids; Glucose; Heart; Heart Ventricles; In Vitro Techniques; Male; Myocardium; Oxidation-Reduction; Palmitates; Phosphocreatine; Rats; Rats, Inbred WKY

The purpose of the present study were to determine the contribution of Na+/H+ exchange to pressure overload-induced cardiac hypertrophy and to examine its potential interaction with cAMP-dependent signaling pathway. Isolated rat hearts were perfused as Langendorff preparations with aortic pressure of 60 mmHg. In pressure overload group, aortic pressure was increased to 120 mmHg. cAMP contents in the heart perfused at 2 min were examined by RIA. Rates of protein synthesis were examined by 14C-phenylalanine incorporation into myocardial protein during the second hour of perfusion. Expression of c-fos mRNA in the heart perfused at 1 hour was analyzed by Northern blotting. Elevation of aortic pressure from 60 mmHg to 120 mmHg in perfused rat hearts increased cAMP contents from 4.89 +/- 0.09 to 6.30 +/- 0.28 pmol/mg protein and accelerated rates of protein synthesis from 644 +/- 13 to 860 +/- 49 mmol Phe/g dry heart/hr. Expression of c-fos mRNA was induced by elevated aortic pressure. Amiloride, an inhibitor of Na+/H+ exchange, decreased rates of protein synthesis in a concentration-dependent manner (12.5, 25, 50, 100 microM) but did not change cAMP content (5.25 +/- 0.11 pmol/mg protein) or expression of c-fos mRNA. Furthermore, amiloride did not prevent the increases in cAMP (6.99 +/- 0.34 pmol/mg protein), protein synthesis rates (476 +/- 18 to 689 +/- 31 nmolPhe/g dry heart/hr) and expressions of c-fos mRNA that were induced by elevation of aortic pressure. These results indicate that amiloride, an inhibitor of Na+/H+ exchange system, while influencing rates of protein synthesis, does not play an important role in pressure overload-induced cardiac hypertrophy. The mechanism by which amiloride influences cardiac protein synthesis is independent of the cAMP-dependent mechanism by which pressure overload induces cardiac hypertrophy.

Topics: Adenine Nucleotides; Amiloride; Animals; Blood Pressure; Cardiomegaly; Cyclic AMP; Gene Expression; Genes, fos; Heart; In Vitro Techniques; Ion Transport; Male; Muscle Proteins; Myocardium; Perfusion; Phosphocreatine; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sodium

The relationship between intracellular energy parameters and myocardial O2 consumption (VO2) was studied in control and volume-overloaded hearts perfused with different lipid substrates and over a range of left ventricular work loads. In control hearts, a unique linear relationship between log of cytosolic [ATP]/[ADPf].[Pi] (where [ADPf] is concentration of free ADP) and myocardial VO2 was observed between low and high work loads for both fatty acids studied. In volume-overloaded hearts perfused in the presence of exogenous palmitate, the slope of the relationship between log [ATP]/[ADPf].[Pi] and myocardial VO2 was considerably depressed. It would seem that, under these conditions, much of the thermodynamic control of respiratory chain function has been lost. When myocardial VO2 was expressed as a function of cytosolic ADPf, the cytosolic ADPf was not regulatory. This may be related to a substrate limitation of the respiratory chain, as suggested by an excessive oxidation of pyridine nucleotides. When octanoate, instead of palmitate, was used, most of the above limitation of the respiration disappeared. With this substrate, the reduction of mitochondrial pyridine nucleotides in volume-overloaded hearts was similar to that in controls, and the linear relationship between log [ATP]/[ADPf].[Pi] and myocardial VO2 reappeared over the range of work loads studied. The above failure of cytosolic phosphate potential and ADPf to drive respiration when mitochondrial NADH is low fits well with the integrated model of kinetic regulation, as proposed by recent nuclear magnetic resonance studies. our results also indicate that, even at high respiratory rates, free-energy change of ATP synthesis of volume-overloaded hearts can be protected by use of an appropriate substrate. This, in turn, prevents contractile failure.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Caprylates; Cardiomegaly; Creatine; Energy Metabolism; Heart; In Vitro Techniques; Myocardium; NAD; Oxygen Consumption; Palmitic Acid; Palmitic Acids; Phosphates; Phosphocreatine; Rats; Rats, Wistar; Ventricular Function, Left

The aim was to examine differences between the postischaemic functional and biochemical recovery of adult and aged hypertrophied hearts.. Isolated hypertrophied hearts of adult and aged spontaneously hypertensive rats (SHRadult; SHRaged) and normal hearts of age matched Wistar-Kyoto rats (WKYadult; WKYaged) were perfused in an ejecting heart preparation. Haemodynamic function was monitored before and after 45 min of ischaemia. Coronary effluent samples and tissue biopsies were taken for biochemical analysis.. After ischaemia, in SHRadult and WKYadult the maximum positive first derivative of the left ventricular pressure (dP/dtmax) was restored to 105% and 97% respectively of the preischaemic values. Left ventricular developed pressure recovered to 80% (SHRadult) and 97% (WKYadult), while cardiac output reached 71% (SHRadult) and 99% (WKYadult) of preischaemic levels. In SHRaged and WKYaged the dP/dtmax recovered to 26% and 60% respectively (both p < 0.05 compared to the preischaemic values). The left ventricular developed pressure recovered to 36% in SHRaged and to 73% in WKYaged (both p < 0.05), while cardiac output was restored to 6% in SHRaged and 38% in WKYaged (both p < 0.05). Throughout reperfusion, left ventricular end diastolic pressure remained significantly elevated in SHRaged, and was associated with a prominent subendocardial underperfusion, suggesting an impaired diastolic functional recovery. Overall haemodynamic recovery was significantly better in the WKYaged than in the SHRaged. The preischaemic total adenine nucleotides content was comparable in all groups, but creatine phosphate levels were significantly lower in both aged groups than in adult groups. In all but the WKYadult, the total adenine nucleotides were depressed upon reperfusion, while creatine phosphate normalised, except in SHRaged. SHRaged lost more lactate dehydrogenase and tended to lose more xanthine and uric acid than other groups.. The aged hypertrophied heart shows a higher vulnerability to ischaemic damage than the adult hypertrophied heart. This phenomenon is associated with subendocardial underperfusion, increased membrane damage and inadequate recovery of creatine phosphate levels.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Aging; Animals; Cardiomegaly; Heart; Hypertension; Myocardial Ischemia; Myocardium; Perfusion; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Cardiac energy metabolism of pressure-overloaded rat hearts was examined under in vivo and in vitro conditions. Two, 4 and 6 weeks after constriction of the abdominal artery, the hemodynamic and metabolic profiles of hearts in vivo and of perfused hearts were determined. Significant increases in left ventricular weight/body weight (30 to 45% increase relative to the sham group), systolic and diastolic blood pressure (22 to 33% increase) and pressure-rate product (31 to 33% increase) were observed 2, 4 and 6 weeks after the operation, and a slight but significant decrease in heart rate was observed at 2 weeks after the operation. Tissue hydroxyproline content increased (17 to 93%) with time after pressure-overload. These findings are indicators of pressure-overloaded cardiac hypertrophy. The total high-energy phosphates of the in vivo rat myocardium under artificial respiration were lower than those of sham-operated rat myocardium 2 (23%) and 4 weeks (21%), but not 6 weeks after aortic constriction. The maximal oxygen consumption rates of mitochondria, when determined in the skinned cardiac fibers, also decreased 2 (47%) and 4 weeks (36%), but reversed 6 weeks after pressure-overload. However, the myocardial ATP, a utilizing form of high-energy phosphate, of pressure-overloaded rat myocardium remained normal at all times after cardiac hypertrophy. This suggests that alterations in hemodynamic variables of in vivo pressure-overloaded rats may not be attributable to a reduction in the myocardial energy production. In the perfused hearts isolated from pressure-overloaded rats, tissue ATP levels were similar to those of sham-operated rats, although the tissue creatine phosphate tended to be reduced in the pressure-overloaded animals at all stages of cardiac hypertrophy examined. Only a marginal decrease in the tissue high-energy phosphate (13%) was observed 4 weeks after the operation relative to that of sham-operated rats. In contrast, the developed tension of the perfused pressure-overloaded rat hearts was consistently lower (27 to 36%) than that of the sham-operated rat hearts. The results suggest that the high-energy phosphate levels of pressure-overloaded rat myocardium in vitro are unlikely to account for the observed decline in cardiac contractile function. The reduction of myocardial high-energy phosphates of pressure overloaded rats may be due to an adaptative change rather than a causal events.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiomegaly; Collagen; Energy Metabolism; Hemodynamics; Hydroxyproline; In Vitro Techniques; Male; Mitochondria, Heart; Myocardium; Oxygen Consumption; Phosphocreatine; Rats; Rats, Wistar

Recirculating, retrograde heart perfusion according to the Langendorff method was used in an attempt to further elucidate the cardiotoxicity of methyl-2-tetradecylglycidate (McNeil 3716, MTG) and the eccentric hypertrophy elicited by the compound. In subchronic experiments female rats were exposed to MTG 2 x 10 mg/kg and 2 x 25 mg/kg per day for 4 weeks. At various times hearts were perfused ex vivo for up to 2 hr with either 5 mmolar glucose or 0.5 mmolar palmitate as substrate. Substrate uptake (glucose or palmitate) and enzyme release (LDH-lactic dehydrogenase or CPK-creatine-phosphate kinase) were assessed during perfusion. Biochemical analysis (ATP, ADP, AMP, c-AMP, CP, creatine, pyruvate, lactate, glucose-6-phosphate, glycogen, phospholipids, triglycerides and non-esterified fatty acids) were done in hearts before (drug effect) and after perfusion (stress of perfusion). Besides changes in energy metabolism and high-energy phosphate production, as observed in previous experiments (Bachmann et al. 1984) massive changes were seen in energy reserves in heart tissue (ATP, CP, glycogen, phospholipids and triglycerides). As expected, MTG led to significant increases also in non-esterified fatty acids content in hearts.

Topics: Adenine Nucleotides; Animals; Cardiomegaly; Creatine Kinase; Energy Metabolism; Epoxy Compounds; Fatty Acids, Nonesterified; Female; Glucose; Glycogen; Hypoglycemic Agents; L-Lactate Dehydrogenase; Lipid Metabolism; Myocardium; Palmitic Acids; Perfusion; Phosphocreatine; Propionates; Rats; Triglycerides

1. Angiotensin converting enzyme (ACE)-inhibitors have been demonstrated to be effective in the treatment of cardiac hypertrophy when used in antihypertensive doses. The aim of our one year study with an ACE-inhibitor in rats was to separate local cardiac effects produced by a non-antihypertensive dose from those on systemic blood pressure when an antihypertensive dose was used. 2. Rats made hypertensive by aortic banding were subjected to chronic oral treatment for one year with an antihypertensive dose of the ACE inhibitor, ramipril 1 mg kg-1 daily, (RA 1 mg) or received a low dose of 10 micrograms kg-1 daily (RA 10 micrograms) which did not affect high blood pressure. 3. Chronic treatment with the ACE-inhibitor prevented left ventricular hypertrophy in the antihypertensive rats as did the low dose which had no effects on blood pressure. Similar effects were observed on myocardial fibrosis. Plasma ACE activity was inhibited in the RA 1 mg but not in the RA 10 micrograms group although conversion of angiotensin (Ang) I to Ang II in isolated aortic strips was suppressed in both treated groups. Plasma catecholamines were increased in the untreated control group, but treatment with either dose of ramipril normalized the values. The myocardial phosphocreatine to ATP ratio (an indicator of the energy state in the heart) was reduced in the vehicle control group whereas the hearts from treated animals showed a normal ratio comparable to hearts from sham-operated animals. 4. After one year, five animals were separated from each group, treatment withdrawn, and housed for additional six months. In the RA 1 mg group, blood pressure did not reach the value of the control vehicle group and surprisingly, left ventricular hypertrophy and myocardial fibrosis did not recur in animals during withdrawal of treatment.5. These data show that long term ACE inhibitor treatment with ramipril in antihypertensive and non-antihypertensive doses prevented cardiac hypertrophy and myocardial fibrosis. This protective effect was still present after 6 months treatment withdrawal.

Topics: Adenosine Triphosphate; Angiotensins; Animals; Aorta, Thoracic; Blood Pressure; Cardiomegaly; Catecholamines; Cyclic GMP; Endomyocardial Fibrosis; Hypertension; Male; Myocardium; Peptidyl-Dipeptidase A; Phosphocreatine; Radioimmunoassay; Ramipril; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley

Evidence has been put forth that a number of human and experimental cardiomyopathies are associated with a lower myocardial carnitine content. This study was performed to test the hypothesis that the correction of carnitine derivative, propionyl-L-carnitine (PLC), may improve cardiac function. Repeated administration of PLC was compared to saline with respect to cardiac function in rats with pressure-overload cardiac hypertrophy and low myocardial carnitine levels. Cardiac hypertrophy was induced by abdominal aorta constriction in rats. Separate groups of rats were used for (a) determination of myocardial carnitine content, (b) evaluation of in vivo hemodynamics, and (c) evaluation of performance and metabolic state of Langendorff perfused hearts. Results showed the following: (i) The myocardial carnitine content was inversely correlated to cardiac hypertrophy (r = 0.68, p less than 0.05) and PLC treatment (50 mg/kg i.a. for 4 days) restored it to normal values (ii) The PLC effect on cardiac function was significantly and directly related to cardiac hypertrophy [correlations between heart weight and percent changes in cardiovascular parameters: cardiac output (CO), p less than 0.001; cardiac work (CW), p less than 0.01, stroke volume (SV) and stroke work (SW), p less than 0.02]. In animals with heart weight greater than 1,400 mg, the effect of PLC on CO, CW, SV, SW, and total peripheral resistance (TPR) was significantly different from that of saline (CO, CW, SV, and SW, p less than 0.005 each; TPR, p less than 0.05). The effect was observed 24 h after the first PLC administration and significantly diminished following a 4 day suspension of the treatment. (iii) Perfused hearts from PLC-treated rats displayed a significantly lower left ventricular end-diastolic pressure (p less than 0.01) and greater relaxation rate (p less than 0.05) than those from control rats. Moreover, in PLC-treated hearts, the content of creatine phosphate, ATP, and total adenine nucleotides (ATP+ADP+AMP; TAN) was significantly increased (CP, p less than 0.05; ATP and TAN, p less than 0.01 vs. control). These data show that PLC exerts a stimulatory activity on hearts with hypertrophy and low carnitine content, implying that carnitine deficiency may contribute to the depression of cardiac function in this model.

Topics: Adenine Nucleotides; Analysis of Variance; Animals; Blood Pressure; Cardiac Output; Cardiomegaly; Carnitine; Heart Rate; Hemodynamics; Male; Myocardial Contraction; Myocardium; Phosphocreatine; Rats; Rats, Inbred WKY; Ventricular Function, Left

Prolonged noradrenaline administration to rats in steadily increasing dosages for a period of one to four weeks (cumulative doses 25-35 mg/kg) resulted in the development of focal necrotic areas with abundant collagen fibers and marked hypertrophy of cardiomyocytes. Cellular diameter was higher by 37-44% and extracellular space area by 70-100%. A combination of overcontracted and overdistended sarcomeres in some cardiomyocytes and a twofold rise in serum creatine kinase presumably reflected cellular calcium overload. Myocardial high energy phosphate content was depleted to 50-62% of the control level. The extent of this depletion positively correlated with a decrease in heart rate and cardiac output of the isolated heart. The latter may be attributed to limited left ventricular filling caused by elevated LV diastolic pressure and stiffness. Minimal metabolic and functional changes were observed after lowest noradrenaline dose (5 mg/kg for nine days) that was followed by only moderate depletion of myocardial phosphocreatine content and moderate rise in LV diastolic stiffness. Results suggest that energy-deficient increase in myofibrillar stiffness may form the basis for decreased myocardial distensibility and cardiac pump failure.

Topics: Animals; Cardiomegaly; Creatine Kinase; Dose-Response Relationship, Drug; Energy Metabolism; Female; Heart; Male; Myocardium; Necrosis; Norepinephrine; Phosphocreatine; Rats

We report studies on the isolated hearts of rats treated with triiodothyronine (0.2 mg/kg daily) for 14 days, on spontaneously hypertensive rats (12 and 21 weeks old, Lyon strain) and on their respective controls. A 30% increase in cardiac weight was developed with triiodothyronine and a 40% increase in heart weight in the presence of spontaneous hypertension. The hearts were perfused in the presence of 2 mM pyruvate and the intracellular content of phosphocreatine, inorganic phosphate and ATP measured by nuclear magnetic resonance spectroscopy with 31P. The left ventricular developed pressure was measured with an intraventricular balloon. Changes in contractile strength were induced by stepwise modifications of the extracellular concentration of calcium from 0.5 mM to 1.0, 1.5 and 2.0 mM. In all experimental groups, each increase in the extracellular calcium induced an increase in the developed pressure, together with a decrease in phosphocreatine and an increase in inorganic phosphate; the ATP level remained unchanged. These metabolic changes increased progressively with the increase in developed pressure. In the hearts of animals treated with triiodothyronine and of the 21 weeks old hypertensive rats, the extent of changes in phosphocreatine and inorganic phosphate was the same as in the controls; but, in the hearts of 12 weeks old hypertensive rats, the changes were significantly greater than in their controls. These observations suggest that, during the development of cardiac hypertrophy from spontaneous hypertension, there is a transitory deficiency in the capacity for aerobic ATP production relative to the rate of hydrolysis of ATP induced by an inotropic effect.

Topics: Adenosine Triphosphate; Animals; Calcium; Cardiomegaly; Energy Metabolism; Female; Hypertension; In Vitro Techniques; Magnetic Resonance Spectroscopy; Myocardium; Phosphates; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Sprague-Dawley; Triiodothyronine; Ventricular Function, Left

To determine whether cardiac hypertrophy secondary to chronic renovascular hypertension is associated with altered in vivo myocardial metabolism, phosphorus-31 nuclear magnetic resonance saturation transfer techniques were used to study creatine kinase (CK) kinetics in six chronically hypertensive dogs with moderate cardiac hypertrophy and eight control dogs. The forward rate constant of CK and the flux of phosphocreatine to adenosine triphosphate were determined in both groups of dogs before and during norepinephrine administration (1 microgram/kg per min), used to increase heart rate x systolic blood pressure (rate-pressure product), cardiac output and oxygen consumption. Baseline and norepinephrine-induced changes in rate-pressure product, cardiac output and oxygen consumption were similar in both groups of dogs, as were baseline forward rate constant and flux of phosphocreatine to adenosine triphosphate. However, the norepinephrine-induced changes in forward rate constant and flux were significantly less in hypertensive than in control dogs (p less than 0.05) even though changes in hemodynamic and functional variables were similar in both groups. These data demonstrate that moderate myocardial hypertrophy is associated with altered CK kinetics, which do not appear to affect the heart's ability for global mechanical recruitment at this stage in the hypertensive process. It is possible that the changes in myocardial enzyme kinetics may contribute to diastolic dysfunction previously reported in this model and may be a precursor for ultimate development of heart failure if hypertension is maintained for prolonged periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Cardiomegaly; Chronic Disease; Creatine Kinase; Disease Models, Animal; Dogs; Echocardiography; Epinephrine; Heart; Hypertension, Renovascular; Kinetics; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine; Phosphorus Radioisotopes

The aim of the present study was to define the protective effects of verapamil and nifedipine on mechanical performance and energy and substrate metabolism of the postischemically reperfused myocardium in a chronic pressure overload cardiac hypertrophy model. The isolated beating rat heart preparation was used and left ventricular pressures and high-energy phosphates were continuously monitored during 30 min of global ischemia and reperfusion, respectively. Recovery of mechanical performance and high-energy phosphate and sugar monophosphate metabolism was significantly impaired in untreated hypertrophied hearts compared with normal control hearts and hypertrophied hearts treated with calcium antagonists. In hypertrophied hearts with chronic verapamil treatment, recovery was significantly improved compared to acute verapamil treatment, nifedipine treatment, and normal control hearts. Thus, verapamil and nifedipine exerted a protective effect on the postischemic recovery of the hypertrophied myocardium that was most prominent following long-term pretreatment with verapamil. Prolonged maintenance of adequate plasma levels and tissue distribution of calcium antagonists before an ischemic event may improve the postischemic prognosis in the presence of pressure-induced myocardial hypertrophy.

Topics: Adenosine Triphosphate; Animals; Calcium Channel Blockers; Cardiomegaly; Energy Metabolism; Hypertension; Myocardial Reperfusion Injury; Myocardium; Nifedipine; Phosphocreatine; Rats; Rats, Inbred Strains; Verapamil

The effects of regression of left ventricular hypertrophy following atenolol and bunazosin therapy on ischemic cardiac function and myocardial metabolism in spontaneously hypertensive rats (SHR) were studied. Atenolol (50 mg/kg/day) and bunazosin (5 mg/kg/day) were administered to SHR from 19 to 26 weeks of age, whereas tap water was given to control SHR and normotensive Wistar-Kyoto rats (WKY). Both atenolol and bunazosin significantly decreased arterial blood pressure and significantly decelerated the increase in left ventricular weight in SHR. At the end of the long-term treatment, hearts were removed and perfused by the working heart technique for 15 min, and then global ischemia was induced for either 10 or 30 min. The ischemic heart was reperfused for 30 min. The pressure-rate product and the extent of recovery of the coronary flow after reperfusion following 30 min of ischemia in the bunazosin-treated SHR were significantly higher than those in the control SHR and the atenolol-treated SHR. The levels of adenosine triphosphate (ATP), creatine phosphate (CrP), and energy charge potential in the SHR heart reperfused after 30 min of ischemia were significantly lower than those in the reperfused WKY. Both atenolol and bunazosin improved the restoration of ATP and CrP in SHR after reperfusion following 30 min of ischemia. In conclusion, antihypertensive therapy with either atenolol or bunazosin was effective in preventing cardiac hypertrophy and ischemic damage caused by different mechanisms. Factors resulting from stimulation of the cardiac alpha 1 adrenoceptor may play an important role in the development of hypertensive cardiac hypertrophy, just as factors resulting from stimulation of the beta 1-adrenoceptor do.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Atenolol; Blood Pressure; Cardiomegaly; Coronary Circulation; Coronary Disease; Lactates; Lactic Acid; Male; Myocardium; Phosphocreatine; Quinazolines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Remission Induction

The goals of this study were to determine whether abnormalities in phosphorus metabolism could be noninvasively detected using phosphorus-31 nuclear magnetic resonance spectroscopy in patients with dilated cardiomyopathy and left ventricular hypertrophy, and whether these patient groups could be distinguished from each other based on parameters obtained using this technique. Seventeen patients and 14 control subjects were studied using nuclear magnetic resonance spectroscopy. Spectra were obtained from the human heart at rest using 3-dimensional spectroscopic imaging as a localization technique. Data were acquired over an average volume of 48 cc in 26.3 minutes using a 2 tesla imaging and spectroscopy unit. The ratio of phosphocreatine to adenosine triphosphate was 0.89 +/- 0.88 (mean +/- standard error) in normal subjects and did not differ significantly in patients with dilated cardiomyopathy or left ventricular hypertrophy. A prominent peak in the phosphodiester region was seen much more frequently in patients with dilated cardiomyopathy, resulting in significantly higher ratios of phosphodiester to phosphocreatine (1.28 +/- 0.35) and phosphodiester to adenosine triphosphate (0.79 +/- 0.18) in this group compared to normal subjects (0.33 +/- 0.08 and 0.29 +/- 0.08, respectively). However, the various patient groups could not be reliably distinguished from each other based on spectral patterns. These studies demonstrate the feasibility of performing phosphorus-31 nuclear magnetic resonance spectroscopic imaging in patients with myocardial disease. The initial results indicate that, under resting conditions, the ratio of phosphocreatine to adenosine triphosphate is not consistently altered in patients with severe global cardiomyopathies or hypertrophy. Phosphodiesters are elevated in some patients with dilated cardiomyopathy, a finding that may signify abnormal phospholipid metabolism in this condition.

Topics: Adenosine Triphosphate; Adolescent; Adult; Cardiomegaly; Cardiomyopathy, Dilated; Echocardiography; Heart Diseases; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Middle Aged; Myocardium; Phosphocreatine; Phosphorus

Tolerance of the canine heart to prolonged ischemic arrest was studied in 10 hearts from normal control dogs and 15 hearts from dogs with left ventricular hypertrophy (LVH); experiments were performed 1 year after banding the aorta in 8-week-old puppies. At 1 year, hemodynamic studies revealed decreased left ventricular (LV) fiber shortening and elevated end-diastolic pressure (EDP) in five dogs (group with LVH failure); 10 dogs exhibited normal shortening and normal EDP (group with LVH compensation). The left ventricle-to-body weight ratio (g/kg) was 4.4 +/- 0.8 in the control group of dogs, 7.7 +/- 1.0 in the group with LVH compensation, and 10 +/- 2.5 in the group with LVH failure. The tolerance to 60 minutes of global ischemia (37 degrees C) followed by 90 minutes of reperfusion was studied in an isolated blood-perfused heart apparatus (isovolumic left ventricle, coronary perfusion pressure of 100 mm Hg). In the baseline (preischemic) state, coronary blood flow, myocardial oxygen consumption, lactate extraction, and myocardial high-energy phosphate content were essentially equal in the three groups; with LV volume adjusted to produce a systolic pressure of 100 mm Hg, there were no significant differences in LVEDP among the three groups. During ischemia, the diastolic (asystolic) pressure increased from 11 +/- 3 to 28 +/- 16 mm Hg (p less than 0.05) in the group with LVH failure; however, it did not increase in the control or the LVH compensation groups. Myocardial ATP levels declined equally in all three groups. During early reperfusion, lactate washout was lowest in the group with LVH failure. By 90 minutes of reperfusion, there were no significant differences in coronary blood flow, myocardial oxygen consumption, lactate extraction, or high-energy phosphate levels. High diastolic pressure persisted at 90 minutes of reperfusion in the LVH failure group (EDP was 34 +/- 19 mm Hg); however, there was no significant change in EDP during reperfusion in the control or with LVH compensation groups. After 90 minutes of reperfusion, developed pressures in the control (54 +/- 9 mm Hg), the LVH compensation (49 +/- 18 mm Hg), and the LVH failure (67 +/- 17 mm Hg) groups were not significantly different. These data indicate that hearts with compensated LVH do not exhibit an impaired tolerance to ischemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adenosine Triphosphate; Animals; Cardiomegaly; Coronary Circulation; Dogs; Heart Arrest, Induced; Heart Ventricles; Hemodynamics; Lactates; Lactic Acid; Myocardial Reperfusion Injury; Myocardium; Oxygen Consumption; Phosphocreatine

The effects of long-term treatment with diltiazem on the heart in normotensive (WKY) and spontaneously hypertensive rats (SHR) were studied. Diltiazem was added to the drinking fluid (900 mg/liter) and given ad libitum from 19 to 26 weeks of age, whereas tap water was given to the control animals. Although diltiazem did not decrease blood pressure in SHR, it decelerated the increase in their left ventricular weight (p less than 0.01). Hearts were removed and perfused by the working heart technique for 15 min, and then global ischemia was induced for either 10 or 30 min. The ischemic heart was reperfused for 30 min. The extent of recovery of coronary flow after reperfusion, following 30 min of ischemia in the diltiazem-treated SHR, was higher than that in the control SHR (p less than 0.01). The levels of adenosine triphosphate (ATP), creatine phosphate (CrP), and energy charge potential in the SHR heart reperfused after 30 min of ischemia were lower than those in the reperfused WKY heart (p less than 0.01, respectively). Diltiazem improved the restoration of ATP and CrP and prevented the decrease in energy charge potential in SHR after reperfusion following 30 min of ischemia (p less than 0.01, respectively). In conclusion, long-term treatment of SHR with diltiazem may protect the myocardium when myocardial ischemia occurs.

Topics: Adenine Nucleotides; Animals; Blood Pressure; Cardiomegaly; Coronary Circulation; Coronary Disease; Diltiazem; Energy Metabolism; Heart; Hypertension; In Vitro Techniques; Male; Myocardium; Perfusion; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Ultrastructural changes in normal and hypertrophied dog hearts under conditions of total ischemia were studied by electron microscope method. In the control group sings of irreversible damage appeared in 90 min, in the presence of phosphocreatine, 10 mM, these changes became apparent in 120 min. In the hypertrophied hearts signs of the irreversible damages became evident in 60 and 90 min in the absence and presence of phosphocreatine, respectively. Ability of phosphocreatine to protect both normal and hypertrophied myocardium allows to use it safely.

Topics: Animals; Cardiomegaly; Cardioplegic Solutions; Coronary Disease; Dogs; Heart; Heart Arrest, Induced; Microscopy, Electron; Myocardium; Phosphocreatine; Time Factors

The purpose of this study was to compare the degree of ischemic and hypoxic injury in normal versus hypertrophied rat hearts to investigate basic mechanisms responsible for irreversible myocardial ischemic injury. Hearts from rats with bands placed on the aortic arch at 23 days of age (BAND) and sham-operated rats (SHAM, 8 weeks postoperative) were isolated, perfused with Krebs buffer, and had a left ventricular balloon to measure developed pressure. Hearts were made globally ischemic until they developed peak ischemic contracture and were reperfused for 30 minutes. Additional hearts were perfused for 15 minutes with glucose-free hypoxic buffer followed by 20 minutes of oxygenated perfusion. There was an 87% increase in heart weight of BAND compared with SHAM (p less than 0.01). During ischemia, lactate levels increased faster in BAND compared with SHAM, ischemic contracture occurred earlier in BAND than in SHAM despite no difference in ATP levels, and postischemic recovery of left ventricular pressure was less in BAND (26.8 +/- 5.6% of control left ventricular pressure, mean +/- SEM) compared with SHAM (40 +/- 4.6%, p less than 0.05). During hypoxic perfusion, lactate release was greater in BAND than in SHAM (48.8 +/- 1.2 versus 26.6 +/- 0.97 mumols/g, p less than 0.01), and with reoxygenation, lactate dehydrogenase release was less in BAND than in SHAM (13.2 +/- 0.7 versus 19.5 +/- 0.2 IU/g, p less than 0.01). After hypoxia and reoxygenation, left ventricular pressure recovery was greater in BAND than in SHAM (93 +/- 8.4% versus 66 +/- 5.3%, p less than 0.01). Thus, this study suggests that hypertrophied hearts have a greater potential for glycolytic metabolism, resulting in an increased rate of by-product accumulation during ischemia, which may be responsible for the increased susceptibility of hypertrophied hearts to ischemic injury.

Topics: Adenosine Triphosphate; Animals; Aorta; Cardiomegaly; Constriction; Coronary Disease; Glycogen; Heart Ventricles; Hypoxia; Lactates; Lactic Acid; Male; Microscopy, Electron; Myocardial Contraction; Myocardium; Phosphocreatine; Pressure; Rats; Rats, Inbred Strains

The aim of this study was to test for metabolic differences in the response of hypertrophic and normal hearts to hypothermic cardioplegia. Hypertrophic dog hearts and normal control hearts were subjected to 6 hours of hypothermic cardioplegia with the St. Thomas' Hospital solution. Levels before arrest of subepicardial and subendocardial adenosine triphosphate, creatine phosphate, and lactate in eight hypertrophic hearts were the same as those levels in 12 normal hearts. In hypertrophic hearts, but not in normal hearts, the induction of arrest was slow and was associated with an 11% increase in adenosine triphosphate levels, a 59% decrease in creatine phosphate levels, and a 12-fold increase in lactate levels. Seven hypertrophic hearts and eight normal hearts were studied during 6 hours of arrest and showed no further differences in metabolic response. Reducing the myocardial temperature from 20 degrees C to 12 degrees C slowed the rate of depletion of adenosine triphosphate and the rate of accumulation of lactate in both groups. We conclude that in the nonfailing, severely hypertrophic heart, levels before arrest of high-energy phosphates and lactate are normal, but that marked biochemical changes may occur if the induction of arrest is prolonged because of underdosing with cardioplegic solution. Cooling from 20 degrees C to 12 degrees C improves myocardial preservation in both hypertrophic and normal hearts.

Topics: Adenosine Triphosphate; Animals; Body Temperature; Cardiomegaly; Dogs; Heart Arrest, Induced; Lactates; Myocardium; Organ Size; Phosphocreatine; Reference Values

Serial changes in left ventricular (LV) size and function during the adaptation to chronic pressure overload and the transition to pump failure were studied in 16 conscious dogs (aortic bands placed at 8 weeks of age). Echocardiographic data at baseline and at 3, 6, 9, and 12 months after banding revealed a progressive increase in LV mass in all dogs. In six dogs with LV pump failure, there was a progressive decline in circumferential fiber shortening (29 +/- 4% at 12 months); this was significantly less than that seen in five littermate controls (38 +/- 3%, p less than 0.05). The average LV to body weight ratio in this group was 9.8 +/- 2.7 g/kg. In 10 dogs without pump failure (compensated LVH group), shortening exceeded that seen in the controls (43 +/- 4%, p less than 0.05); the LV to body weight ratio was 7.7 +/- 1.0 g/kg. At 12 months (cardiac catheterization), the LV end-diastolic pressure was higher in the failure (25 +/- 15 mm Hg) than in the compensated group (8 +/- 5 mm Hg, p less than 0.05); mean systolic stress was also higher in the failure group (313 +/- 67 g/cm2) than in the compensated group (202 +/- 53 g/cm2, p less than 0.05). The transmural distribution of myocardial blood flow was measured (at 12 months) with the radioactive microsphere technique; flow data were then related to an index of demand (a stress-time index). There was preferential blood flow to the subendocardial layers in the control (endo/epi = 1.28) and compensated hearts (endo/epi = 1.10), but in the failure group there was a relative decrease in subendocardial flow (endo/epi = 0.92). However, the absolute values for subendocardial flow in the normal, compensated, and failure groups were 77 +/- 54, 125 +/- 48, and 113 +/- 64 ml/min/100 g; the stress-time indexes in the subendocardial shell were 38 +/- 11, 74 +/- 19, and 93 +/- 34 g sec.10(2)/cm2/min. Despite what appears to be a marginal balance between blood flow and the stress time index in the failure group, the myocardial high energy phosphates were not depleted and the inoptropic state was not depressed. In this model of LV hypertrophy, the observed differences in fiber shortening can be explained on the basis of the inverse afterload-shortening relation; pump failure was due to an inadequate LV hypertrophy with afterload excess.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adenosine Triphosphate; Animals; Cardiac Catheterization; Cardiomegaly; Coronary Circulation; Dogs; Echocardiography; Heart Failure; Myocardial Contraction; Myocardium; Phosphocreatine; Stroke Volume

The ability to resist transient ischemia was studied in isolated hearts of 18 months old spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Both types of hearts showed optimal performance during the preischemic period when perfused at a diastolic perfusion pressure of 8.0 (WKY) and 13.3 (SHR) kPa. Hemodynamic recovery of WKY hearts during reperfusion at 8.0 kPa, following 45 min global ischemia, was satisfactory. coronary perfusion completely normalized, contractility (dPlv/dtmax) was slightly depressed and cardiac output returned, on the average, to 40% of the preischemic values. In contrast, hemodynamic function of SHR hearts reperfused at 13.3 kPa was greatly depressed, as evidenced by almost complete abolition of cardiac output, severe reduction of dPlv/dtmax and persistent underperfusion of the endocardial layers. In addition, the postischemic release of lactate dehydrogenase was retarded and enhanced. The release patterns of degradation products of adenine nucleotides showed a shift to the endstage products xanthine and uric acid. The enhanced vulnerability of the hypertrophied heart to ischemia was even more expressed when the SHR hearts were reperfused at 8.0 kPa. Postischemic function was characterized by electrical instability, loss of contractility and cardiac output, and noreflow in the endocardial layers. Persistent accumulation of lactate and degradation products of adenine nucleotides in the postischemic hearts are in line with the lack of reperfusion. The present results indicate that a detailed mechanistic explanation for the reduced ability to withstand ischemia of SHR cannot be based on differences in ATP content or an altered anaerobic glycolitic activity prior and during ischemia. It is suggested that a defect on the circulatory level, probably caused by enhanced reactivity of the coronary vessels towards ischemia-elicited factors, is responsible for the higher vulnerability of hypertrophied heart to an ischemia insult.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiac Output; Cardiomegaly; Coronary Circulation; Coronary Disease; Glycogen; L-Lactate Dehydrogenase; Myocardial Contraction; Myocardial Reperfusion; Phosphates; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The influence of pressure-controlled postischemic reperfusion (Rp) on functional and metabolic parameters in hearts of sham-operated rats and hypertrophied hearts of rats with aortic constriction were studied. Hypertrophied hearts are considered to be more susceptible to ischemia. The hearts were perfused in the Langendorff-technique for thirty minutes at 35 degrees C with Krebs-Henseleit bicarbonate buffer at a perfusion pressure (PP) of 75 mmHg and for five minutes at 15 degrees C with St. Thomas' Hospital cardioplegic solution at a PP of 60 mmHg. After a period of global ischemia of forty minutes' duration at 15 degrees C, reperfusion was started either abruptly (aRp: PP 75 mmHg immediately) or gently (gRp: PP 75 mmHg within thirty minutes); it lasted for forty-five minutes. Intraventricular peak systolic pressure (ISP) was monitored and energy-rich compounds (ATP, ADP, AMP, CrP, free Cr) were analyzed. In normal hearts, metabolic recovery was not affected by the mode of reperfusion, but functional recovery (ISP) averaged 88% of the preischemic control value after gRp as compared with 73% after aRp. In hypertrophied hearts, gentle reperfusion ameliorated both metabolic and functional recovery. At forty-five minute recovery, CrP averaged 5.1 mumol/g ww after aRp and 6.6 mumol/g ww after gRp (p less than 0.01), and ISP amounted to 73% of the preischemic control after aRp and to 85% after gRp.

Topics: Adenine Nucleotides; Animals; Cardiomegaly; Male; Myocardial Reperfusion; Phosphocreatine; Rats; Rats, Inbred Strains

While calcium entry blockers have a beneficial influence on the postischemic recovery of the nonhypertrophied heart, their influence on the hypertrophied heart has not been determined. The aim of this study was to assess postischemic recovery of myocardial performance and energy metabolites in rat hearts with left ventricular hypertrophy pretreated either chronically or acutely with verapamil. Left ventricular hypertrophy was induced by suprarenal constriction of the abdominal aorta. Hemodynamics and phosphorus 31 magnetic resonance spectra were monitored simultaneously in the isolated hearts during control perfusion, after 30 minutes of global ischemia, and after 30 minutes of reperfusion. All hypertrophied hearts had significantly higher rate-pressure products than normal hearts. Compared with normal hearts, oxygen consumption was significantly lower in all hypertrophied hearts, especially untreated hypertrophied hearts. Also, before ischemia all normal or hypertrophied hearts (treated or untreated) began with comparable phosphorylation potentials (i.e., the supply of energy was not significantly different). Postischemic recovery was not related to energy supply-oxygen demand before onset of ischemia. Furthermore, it was not related to energy levels or intracellular pH during ischemia. For postischemic recovery, the rate-pressure product was 40 +/- 5% in the hypertrophied heart, 83 +/- 5% in the normal, 100 +/- 3% in the hypertrophied heart chronically treated with verapamil, and 82 +/- 5% in the hypertrophied heart acutely treated with verapamil. The degree of recovery was related to coronary flow both before and after ischemia. The latter is important for flushing deleterious metabolites and ions from the interstitial space as well as for delivery of oxygen and substrate to the myocardium.

Topics: Adenosine Triphosphate; Animals; Cardiomegaly; Coronary Circulation; Energy Metabolism; Magnetic Resonance Spectroscopy; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Oxygen Consumption; Phosphates; Phosphocreatine; Rats; Rats, Inbred Strains; Verapamil

Isolated buffer-perfused rat hearts with pressure-overload hypertrophy develop a greater decrease in left ventricular (LV) diastolic distensibility and a greater impairment in extent of LV relaxation in response to hypoxia than do normal hearts. Using 31P-NMR spectroscopy, we tested the hypothesis that the enhanced susceptibility of hypertrophied hearts to develop hypoxia-induced diastolic dysfunction is due to an accelerated rate of ATP and/or creatine phosphate depletion. Twelve minutes of hypoxia were imposed on isolated isovolumic (balloon-in-left-ventricle) buffer-perfused hearts from 14 rats with pressure-overload hypertrophy (LVH; LV/body wt ratio = 3.43 +/- 17) secondary to hypertension induced by uninephrectomy plus deoxycorticosterone and salt treatment and from 17 age-matched controls (LV/body wt ratio = 2.22 +/- 0.12, p less than 0.001). Coronary artery flow per gram left ventricle was matched in the LVH and control groups during baseline oxygenated conditions and held constant thereafter. Balloon volume was held constant throughout the experiment so that an increase in LV end-diastolic pressure during hypoxia represented a decrease in LV diastolic distensibility. LV systolic pressure was 165 +/- 9 mm Hg in the LVH group compared with 120 +/- 5 mm Hg in the controls during baseline aerobic perfusion (p less than 0.001). LV end-diastolic pressure rose significantly more in response to 12 minutes of hypoxia in the LVH group (12 +/- 1 to 44 +/- 10 mm Hg) than in the controls (12 +/- 1 to 20 +/- 3 mm Hg, p = 0.04). During baseline aerobic conditions, ATP content was the same in the LVH (17.1 +/- 0.5 mumol/g dry LV wt, n = 4) and control (18.8 +/- 0.6 mumol/g dry LV wt, n = 4, p = NS) groups. During hypoxia, ATP declined at the same rate in the LVH and control groups (3.2 +/- 0.5 versus 3.0 +/- 0.5%/min, p = NS) despite the greater rise in end-diastolic pressure in the LVH group. Creatine phosphate content during baseline aerobic perfusion was 14% lower in the LVH group compared with controls, but the rate of creatine phosphate depletion during 12 minutes of hypoxia was the same. During hypoxia, intracellular pH declined modestly and to the same degree in both groups. Thus, the greater susceptibility to hypoxia-induced diastolic dysfunction observed in isolated buffer-perfused hypertrophied rat hearts cannot be explained by an initially lower total ATP content or by an accelerated rate of decline of ATP or creatine phosphate.(ABSTRACT TRUNCATED AT

Topics: Adenosine Triphosphate; Animals; Cardiomegaly; Diastole; Energy Metabolism; Heart; Hypertension; Hypoxia; In Vitro Techniques; Magnetic Resonance Spectroscopy; Myocardial Contraction; Myocardium; Phosphates; Phosphocreatine; Rats; Rats, Inbred WKY; Systole

Chronic right ventricular hypertrophy (RVH) has been shown to produce changes in left ventricular diastolic properties but minimal effects on left ventricular systolic function. We studied the effects of chronic pressure overload RVH on left ventricular systolic function before and after reversible hypothermic global ischemia. RVH was induced by pulmonary artery banding (PAB) in newborn piglets (5 to 7 days). At 2 months of age the PAB group (n = 6) and a control group (n = 8) were subjected to cardiac arrest on cardiopulmonary bypass with cold crystalloid cardioplegia (10 degrees C) for 2 hr and were reperfused for 1 hr. Left ventricular function was assessed by a conductance catheter in the left ventricle measuring the end-systolic pressure-volume relationship (Emax). Preischemic and postischemic Emax were the same in the control group (4.1 +/- 0.4 mm Hg/ml before vs 4.1 +/- 0.4 mm Hg/ml after ischemia), but significantly different in the PAB group (4.7 +/- 0.5 mm Hg/ml before vs 2.97 +/- 0.7 mm Hg/ml after ischemia, p less than .05). There also was a marked drop in ATP and phosphocreatine (CP) content in the PAB group during ischemia (ATP, 20 +/- 2 mmol/kg dry wt before vs 10 +/- 2 mmol/kg dry wt after ischemia, p less than .05; PC, 26 +/- 3 mmol/kg dry wt before vs 11 +/- 1 mmol/kg dry wt after ischemia, p less than .05). In the control group there was no change in ATP content and, although CP did drop by end-ischemia, there was complete recovery by 1 hr of reperfusion but minimal CP recovery in the PAB group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Cardiac Volume; Cardiomegaly; Chronic Disease; Coronary Circulation; Heart; Heart Arrest, Induced; Lactates; Lactic Acid; Myocardium; Organ Size; Phosphocreatine; Stroke Volume; Swine

Energy metabolism was assessed in dilated (congestive) and hypertrophic myopathic hearts from Syrian hamsters after isolated, working heart perfusion with palmitate and/or glucose as substrates. Hearts with these two types of cardiomyopathy were found to be distinctively different from control hearts, and also different from each other. Both cardiomyopathic groups had developed hypertrophy by 3 months but the dilated hearts had a decreased muscle mass by 6 months. In the hypertrophic hearts coronary flow rates per gram of non-collagen protein and, thus, oxygen delivery were markedly increased. With either substrate the hypertrophic hearts maintained more normal levels of adenosine triphosphate in contrast to the dilated hearts whose levels were approximately 50% lower than controls by 6 months of age despite similar heart rates and left ventricular systolic pressure development in all three groups. Lactate to pyruvate ratios in the diseased hearts were comparable to control values. Total coenzyme A levels were statistically lower in the dilated compared to the control group of hearts. Carnitine and its acyl esters, on the other hand, varied markedly with levels of total carnitine decreasing to 50% of control levels in both cardiomyopathic groups by 6 months. In spite of this, the mass action ratios for the carnitine acyl-CoA transferase enzyme complexes were not markedly altered in the control or myopathic hearts regardless of whether palmitate and/or glucose were the perfusate substrates. These results suggest that the decreased carnitine levels are not of sufficient magnitude at this stage in the disease to cause a decrease in cardiac function secondary to restricted energy production. Total carnitine levels were found to be increased in liver and serum of the cardiomyopathic hamsters but unchanged in skeletal muscle. Thus, the deficiency in myocardial carnitine would appear to be due to a specific myocardial problem and not due to a problem of synthesis or supply.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiomegaly; Carnitine; Coenzyme A; Coronary Circulation; Cricetinae; Diaphragm; Energy Metabolism; Glucose; Heart Failure; Heart Rate; Kidney; Lactates; Lactic Acid; Liver; Male; Mesocricetus; Palmitic Acid; Palmitic Acids; Phosphocreatine; Pyruvates; Pyruvic Acid

Isolated working hearts of 16 month old spontaneously hypertensive rats (SHR, n = 8) and age matched Wistar-Kyoto (WKY, n = 8) rats were exposed to 30 min global normothermic ischaemia followed by 60 min reperfusion. The hearts were routinely perfused at an afterload level of 13.3 kPa and a preload level of 1.0 kPa. The control values of left ventricular pressure, its maximal positive first derivative (dP1v/dtmax), coronary flow per gram heart tissue, and release of lactate and enzymes such as lactate dehydrogenase and aspartate aminotransferase were comparable in both groups. WKY rat hearts ejected almost twice as much perfusate per gram heart weight as the SHR hearts. In pressure-flow curves, obtained during the control period in SHR hearts, cardiac output was independent of changes in afterload, varying between 10.7 and 18.7 kPa. In contrast, in WKY rat hearts increases in afterload resulted in a progressive decrease in cardiac output. Reperfusion of the SHR hearts after 30 min of global normothermic ischaemia resulted in a poor recovery of cardiac output (13% of the control values) and dP1v/dtmax (32%) compared with the values in the WKY rat hearts (66% and 91% of the control values respectively). Reactive hyperaemia was prominent in the WKY rat hearts but completely absent in the SHR hearts. During one hour reperfusion, SHR hearts lost 3.5 times more lactate dehydrogenase and 2.5 times more aspartate aminotransferase than the WKY rat hearts. Pressure-flow curves, obtained during the reperfusion period, showed modest recovery of myocardial function of the WKY rat hearts at the lowest afterload level tested but completely depressed myocardial function of the SHR hearts at all afterload levels. Heart tissue contents of adenosine triphosphate and creatine phosphate after one hour of reperfusion were lower in the SHR than in the WKY rats, but compared with native values a comparable percentage decrease was seen in both groups of rats.

Topics: Adenosine Triphosphate; Animals; Aspartate Aminotransferases; Cardiac Output; Cardiomegaly; Coronary Vessels; Heart; Hypertension; Ischemia; L-Lactate Dehydrogenase; Myocardium; Perfusion; Phosphocreatine; Rats; Rats, Inbred SHR; Rats, Inbred WKY

Asymmetric septal hypertrophy is considered by many to be pathologic but its presence in a number of states associated with left ventricular overload indicates that it may develop as an adaptive feature in the overloaded heart. This hypothesis implies that initially in these states a greater systolic stress and thus energy metabolism occurs in the ventricular septum than in the left ventricular free wall. It was previously demonstrated that in the early stages of ischemia regional differences in energy metabolism could be determined by comparisons of tissue high energy phosphate depletion and lactate accumulation. In the present study these measurements were made in an animal model of left ventricular overload. In open chest dogs aortic insufficiency was produced, which served to provide both volume overload to the left ventricle and regional myocardial ischemia. In addition to regional metabolite levels, measurements of regional blood flow were determined using radioactive microspheres. Tissue samples were taken from the left ventricle and interventricular septum, freeze clamped, divided transmurally into thirds and analyzed for creatine phosphate, adenosine triphosphate and lactate. Animals with myocardial ischemia after aortic insufficiency were classified into two groups: those in which ischemia was limited to the inner left ventricle and left side of the septum and those with more extensive ischemia transmurally. In the latter group, creatine phosphate depletion and lactate accumulation were greater in the septum, but myocardial blood flow was also more depressed in the septum than in the left ventricle. In the former group, where ischemia was more restricted, metabolite changes were also more severe in the left septum than in the inner left ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Aortic Valve Insufficiency; Blood Pressure; Cardiomegaly; Dogs; Energy Metabolism; Heart Septum; Lactates; Myocardium; Phosphocreatine

Uneven distribution of temperature and the persistence of electro-mechanical activity after aortic cross-clamping are 2 factors limiting the myocardial protection during cardioplegic arrest, especially in hypertrophied hearts which are known to be extremely vulnerable to ischemia. In the present study regional myocardial temperature (T) was continuously controlled, and the time until arrest occurred (delta t) was determined in 61 patients undergoing aortic valve replacement. In addition, the myocardial contents of high energy phosphates and lactate were assessed. Three different cardioplegic solutions were employed: In the first group we used Bretschneider solution (Br), in the second group St. Thomas' solution (St), and in the third group the so-called "Hamburg cardioplegia" (H). During cardiac arrest the regional myocardial temperature was adjusted to temperatures not exceeding 15 degrees C by intermittent infusions of cold cardioplegic solution. We found a positive correlation between left ventricular muscle mass (LVMM) and delta t. A negative correlation existed between LVMM and adenosine triphosphate (ATP) contents at the end of the ischemic period. The cooling characteristics and delta t were significantly longer and the cooling to 15 degrees C was less rapid when H was used. Adenosine-triphosphate contents were well preserved during ischemia in all 3 groups. We conclude that all 3 cardioplegic solutions tested protect the hypertrophied myocardium adequately if the regional myocardial temperature does not increase above 15 degrees C during cardiac arrest. Hearts with a higher LVMM showed a decreased myocardial ATP content at the end of the ischemic period. Therefore, the LVMM may limit myocardial protection.

Topics: Adenosine Triphosphate; Aortic Valve; Bicarbonates; Calcium Chloride; Cardiomegaly; Female; Glucose; Heart Arrest, Induced; Heart Valve Prosthesis; Humans; Intraoperative Care; Lactates; Lactic Acid; Magnesium; Male; Mannitol; Middle Aged; Monitoring, Physiologic; Myocardium; Phosphocreatine; Potassium Chloride; Procaine; Sodium Chloride

We have used 31P nuclear magnetic resonance (NMR) techniques to characterize bioenergetic changes in the Langendorff-perfused rat heart accompanying alterations in thyroid state. Cytosolic phosphocreatine and inorganic phosphate concentrations changed significantly in both the hypo- and hyperthyroid groups compared to controls; the calculated phosphorylation potential [( ATP]/[ADP][Pi]) increased by 60% in hypothyroidism and decreased by 60% in hyperthyroidism relative to the euthyroid value of 47 X 10(3) M-1. Creatine phosphokinase (CPK) and mitochondrial ATP synthase rates were measured in the intact tissue using a saturation-transfer NMR method. There were no significant differences in the measured fluxes through the CPK reaction among the three groups (4.24 +/- 1.00 mM X sec-1 for the euthyroid group). Although O2 consumption increased by 46% in hearts from hyperthyroid animals, no change in the measured mitochondrial ATP synthase flux was observed compared to the euthyroid flux of 1.05 +/- 0.11 mM X sec-1. These results suggest that the apparent in situ P/O ratio of mitochondria in hearts from hyperthyroid animals is reduced relative to that in euthyroid controls.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; ATP Synthetase Complexes; Cardiomegaly; Creatine Kinase; Energy Metabolism; Hyperthyroidism; Hypothyroidism; Magnetic Resonance Spectroscopy; Male; Multienzyme Complexes; Myocardium; Oxygen Consumption; Perfusion; Phosphates; Phosphocreatine; Phosphorus Isotopes; Phosphotransferases; Rats; Rats, Inbred Strains

An 8 month old girl presented with undiagnosed non-anatomic congenital cardiomyopathy with massive cardiomegaly on chest X-ray film. Her older sibling had died suddenly at 6 months of age from what appeared to be a similar abnormality. Utilizing phosphorus-31 nuclear magnetic resonance (P-31 NMR) surface coil spectroscopy, a metabolic disorder was demonstrated in both her myocardium and skeletal muscle, revealing a phosphocreatine (PCr) to inorganic phosphate (Pi) ratio of half of that for a normal control infant. Manipulation of serum substrate availability indicated that medium chain triglycerides alone did not improve myocardial metabolism, but that intravenous glucose or oral carbohydrate loading raised the myocardial PCr/Pi ratio from 1.0 +/- 0.05 to 1.8 +/- 0.1 (p less than 0.01) without significantly affecting the PCr/Pi value of her resting skeletal muscle. This study demonstrates the feasibility of using P-31 nuclear magnetic resonance to evaluate the biochemistry of the human myocardium in vivo and to diagnose a metabolic abnormality. Phosphorus-31 nuclear magnetic resonance can thus be used to optimize therapy for human disease.

Topics: Cardiomegaly; Cardiomyopathy, Hypertrophic; Female; Humans; Infant; Magnetic Resonance Spectroscopy; Muscles; Myocardium; Phosphates; Phosphocreatine; Phosphorus; Time Factors

Rates of protein synthesis and degradation were measured in hearts from normal and thyroxine-injected rats that were perfused as working preparations with Krebs-Henseleit bicarbonate buffer containing 400 microU insulin/ml, 2 mM lactate, 10 mM glucose, and normal plasma concentrations of amino acids. Hearts were perfused after four daily injections (1 microgram/g body wt) of thyroxine. Protein synthesis was 24% greater in hypertrophying hearts compared with controls; ribosomal RNA content increased 25%. In addition, the proportion of total RNA in free ribosomal subunits in hypertrophying hearts was unchanged from perfused hearts of control rats and from unperfused normal hearts. These results indicated that increased protein synthetic machinery as monitored by content of ribosomes, rather than more efficient initiation or elongation of peptide chains, accounted for the faster rate of protein synthesis in hypertrophying hearts. Rates of protein degradation were the same in hearts from thyroxine-injected and control animals. When rates of ribosome production were measured in vitro at various times after a single injection of thyroxine in vivo, faster ribosome synthesis was detected within 8 h; no change in the rate of total protein synthesis occurred after a single injection of thyroxine. These studies indicated that accelerated ribosome formation was an early and quantitatively important factor in cardiac hypertrophy.

Topics: Adenine Nucleotides; Amino Acids; Animals; Cardiomegaly; Creatine; Female; Insulin; Perfusion; Phosphocreatine; Rats; Rats, Inbred Strains; Ribosomal Proteins; Ribosomes; RNA, Ribosomal; Stimulation, Chemical; Thyroxine; Time Factors

The myocardial protective effects of crystalloid, blood, and Fluosol-DA-20% cardioplegia were compared by subjecting hypertrophied pig hearts to 3 hours of hypothermic (10 degrees to 15 degrees C), hyperkalemic (20 mEq/L) cardioplegic arrest and 1 hour of normothermic reperfusion. Left ventricular hypertrophy was created in piglets by banding of the ascending aorta, with increase of the left ventricular weight-body weight ratio from 3.01 +/- 0.2 gm/kg (control adult pigs) to 5.50 +/- 0.2 gm/kg (p less than 0.001). An in vivo isolated heart preparation was established in 39 grown banded pigs, which were divided into three groups to receive aerated crystalloid (oxygen tension 141 +/- 4 mm Hg), oxygenated blood (oxygen tension 584 +/- 41 mm Hg), or oxygenated Fluosol-DA-20% (oxygen tension 586 +/- 25 mm Hg) cardioplegic solutions. The use of crystalloid cardioplegia was associated with the following: a low cardioplegia-coronary sinus oxygen content difference (0.6 +/- 0.1 vol%), progressive depletion of myocardial creatine phosphate and adenosine triphosphate during cardioplegic arrest, minimal recovery of developed pressure (16% +/- 8%) and its first derivative (12% +/- 7%), and marked structural deterioration during reperfusion. Enhanced oxygen uptake during cardioplegic infusions was observed with blood cardioplegia (5.0 +/- 0.3 vol%), along with excellent preservation of high-energy phosphate stores and significantly improved postischemic left ventricular performance (developed pressure, 54% +/- 4%; first derivative of left ventricular pressure, 50% +/- 5%). The best results were obtained with Fluosol-DA-20% cardioplegia. This produced a high cardioplegia-coronary sinus oxygen content difference (5.8 +/- 0.1 vol%), effectively sustained myocardial creatine phosphate and adenosine triphosphate concentrations during the extended interval of arrest, and ensured the greatest hemodynamic recovery (developed pressure, 81% +/- 6%, first derivative of left ventricular pressure, 80% +/- 10%) and the least adverse morphologic alterations during reperfusion. It is concluded that oxygenated Fluosol-DA-20% cardioplegia is superior to oxygenated blood and especially aerated crystalloid cardioplegia in protecting the hypertrophied pig myocardium during prolonged aortic clamping.

Topics: Adenosine Triphosphate; Animals; Aorta; Blood; Body Water; Cardiomegaly; Constriction; Crystalloid Solutions; Drug Combinations; Fluorocarbons; Heart Arrest, Induced; Heart Ventricles; Hemodynamics; Hydroxyethyl Starch Derivatives; Isotonic Solutions; Microscopy, Electron; Myocardium; Oxygen Consumption; Phosphocreatine; Plasma Substitutes; Swine

Oxfenicine (S-4-hydroxyphenylglycine) is a cardioselective inhibitor of long-chain fatty acid oxidation. In anesthetized dogs, oxfenicine (3.3 mg/kg, i.v.) increased myocardial blood flow by 33% under normal conditions and by 71% during isoprenaline infusion, but produced no other hemodynamic changes. Similar results were obtained with two other inhibitors of fatty acid oxidation, 2-bromopalmitate and 2-tetradecylglycidate. Chronic administration of oxfenicine to dogs for 1 year produced dose-related, nonpathological increases in relative heart weight (up to 85% at 750 mg/kg per day). Smaller effects (up to 30% at 900 mg/kg per day) were observed in a similar study in rats. Cardiac hypertrophy has previously been reported in rodents treated with 2-tetradecylglycidate. Moreover, cardiomegaly is frequently observed in cases of carnitine deficiency. We therefore suggest that coronary hyperemia and cardiac hypertrophy following either inhibition of fatty acid oxidation or an increase in cardiac work load may be adaptive changes triggered by a common mechanism-namely, a fall in cytosolic phosphorylation potential. In support of this, oxfenicine decreased the phosphocreatine/creatine ratio in rat hearts perfused in the presence of oleate. These findings suggest the possibility that metabolic abnormalities may provide the key to many idiopathic cardiomyopathies of uncertain origin.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Cardiomegaly; Coronary Circulation; Creatine; Cytosol; Dogs; Fatty Acids; Glycine; Hemodynamics; Isoproterenol; Organ Size; Oxidation-Reduction; Oxygen Consumption; Palmitates; Phosphocreatine; Phosphorylation

Tissue contents of intermediates of fatty acid metabolism were determined in isolated volume-overloaded rat hearts, 3 months after creation of an aorto-caval fistula. In the absence of any modification of blood carnitine, tissue levels of total carnitine were reduced by 33% in overloaded hearts compared to normal hearts. Total tissue CoA was unchanged. Fifteen minutes of whole-heart ischemia (i.e. a 50% reduction in coronary flow) did not increase levels of long-chain acyl esters of CoA and carnitine of the overloaded myocardium, in the presence of glucose as the only exogenous substrate. This was associated with lower than normal levels of long-chain acyl carnitine under normoxic conditions. The addition of exogenous palmitate (1.5 mM) resulted in an ischemia-induced accumulation of long-chain acyl-CoA and acyl carnitine in the overloaded heart although to a smaller extent than in the normal heart under similar perfusion conditions.

Topics: Acyl Coenzyme A; Adenosine Triphosphate; Animals; Cardiomegaly; Carnitine; Coenzyme A; Coronary Disease; Energy Metabolism; Fatty Acids; Female; Heart Failure; Myocardium; Phosphocreatine; Rats; Rats, Inbred Strains

In order to perform intracardiac repair safely during aortic cross clamping, we designed this study to evaluate the protective effect of coenzyme Q10 (CoQ10) on hypertrophied ischemic myocardium from the aspect of energy metabolism. Six to nine months preceding the study, aortic bandings were carried out on 14 puppies to produce left ventricular hypertrophy (LVH). These dogs with LVH were then subjected to total cardiopulmonary bypass and were evenly divided into control and CoQ10-treated groups (10 mg/kg of intravenous administration plus 1 mg/kg per hr of intracoronary injection). Myocardial ischemia was induced by aortic cross clamping for 2 hr under moderate systemic hypothermia. The results indicated that the administration of CoQ10 had a protective effect on hypertrophied ischemic myocardium, since depletion of high-energy phosphate (HEP) was uniformly prevented, and accumulation of lactate was simultaneously decreased during the 2 hr of aortic cross clamping. On the other hand, there were marked exhaustion of HEP and rapid increase in lactate following the 2 hr of ischemia in the control group, these being much more predominant in the subendocardial layer.

Topics: Adenosine Triphosphate; Animals; Aorta; Cardiomegaly; Dogs; Energy Metabolism; Lactates; Ligation; Phosphocreatine; Ubiquinone

Studies in animal models of myocardial ischemia and left ventricular hypertrophy have demonstrated a number of derangements in purine and pyrimidine nucleotide content of myocardium that are postulated to play a role in the pathogenesis of muscle dysfunction in these disorders. The present study examined myocardium of patients with coronary artery disease, left ventricular hypertrophy, or neither of these two abnormalities, to determine whether derangements in purine and pyrimidine nucleotide metabolism occur in humans. In patients with coronary artery disease, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was reduced and ranged between 60% and 86% of the amount found in the epicardium. In patients without coronary artery disease or ventricular hypertrophy, endocardial content of these nucleotides was equal to or greater than that of epicardium. Endocardial and epicardial content of inosine was increased in patients with coronary artery disease, and after vein bypass grafting inosine content fell to the levels observed in myocardium of patients with normal coronary arteries. In patients with left ventricular hypertrophy, endocardial content of ATP, GTP, UTP, CTP, and creatine phosphate was also reduced and ranged between 64% and 88% of the epicardial content. In contrast to results obtained in patients without left ventricular hypertrophy, epicardial content of GTP, UTP, and CTP was increased by 131%, 123%, and 132% in hypertrophied myocardium. Thus the changes noted in myocardial nucleotide content in patients are similar to those noted in animal models of occlusive coronary disease and ventricular hypertrophy. These results suggest that the pathophysiological abnormalities in nucleotide metabolism noted in animal models also occur in human myocardium.

Topics: Adenine Nucleotides; Cardiomegaly; Coronary Disease; Guanosine Triphosphate; Humans; Myocardium; NAD; Nucleotides; Phosphocreatine; Pyrimidine Nucleotides

It is frequently stated that hypertrophied ventricles tolerate ischemia less well than nonhypertrophied ventricles. The authors' earlier studies in a rat supravalvular aortic stenosis model and canine valvular aortic stenosis model, both with concentric left ventricular hypertrophy, disclosed accelerated rates of ischemic contracture and diminished basal myocardial high energy phosphate stores. These studies have been extended to ten patients with severe left ventricular hypertrophy caused by valvular aortic stenosis and normal coronary arteries. ATP (endocardial and epicardial) from transmural left ventricular biopsies taken at operation before aorta cross-clamping, and frozen immediately in liquid nitrogen, were compared with similar biopsies from patients with nonhypertrophied myocardium supplied by normal coronary arteries. The subendocardial high energy phosphate levels in the nonhypertrophied myocardium was greater than high energy phosphate levels in the subepicardium of nonhypertrophied ventricles (ATP-micromoles/gram-protein, epi = 36.8 +/- 3.3, endo = 37.7 +/- 3.3) (p = NS). However, in the hypertrophied myocardium the subendocardium consistently showed significantly depressed high-energy phosphate levels when compared with subepicardial levels (ATP-hypertrophied myocardium, epi = 31.5 +/- 1.6, endo = 25.9 +/- 1.7) (p less than 0.05). This uniform depression of ATP stores, greatest in the subendocardium, in left ventricular hypertrophy suggests a common biologic mechanism for the enhanced sensitivity to ischemia. Of importance for patients may be the prior observation in rats that repletion of ATP( stores before ischemia eliminates the accelerated rate to ischemic contracture. Diminished subendocardial ATP stores appear to be an intrinsic property of severely hypertrophied myocardium and probably contribute to its enhanced sensitivity to ischemia.

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Cardiomegaly; Dogs; Endocardium; Humans; Myocardium; Pericardium; Phosphocreatine

Using a canine model of subcoronary valvular aortic stenosis, we determined myocardial blood flow, high-energy phosphate content, and mitochondrial function in eight hearts with chronic left ventricular hypertrophy. Fourteen normal hearts were used for control data. Myocardial blood flow was determined by injection of tracer microspheres. During cardiopulmonary bypass, left ventricular transmural biopsy specimens were taken for metabolic analyses. Subepicardial and subendocardial content of adenosine triphosphate (ATP) and creatine phosphate (CP) were assayed. Respiratory control indices for isolated mitochondria were measured by use of NAD-linked and FAD-linked substrates. Endocardial blood flow, subendocardial high-energy phosphate content, and respiratory control indices for NAD-linked substrate in the hearts with chronic left ventricular hypertrophy were significantly lower than the normal values. These data provide insight into the metabolic and myocardial blood flow abnormalities occurring in cardiac hypertrophy and provide a framework for understanding the altered response of hypertrophied hearts to ischemia.

Topics: Adenosine Triphosphate; Animals; Aortic Valve Stenosis; Cardiomegaly; Coronary Circulation; Dogs; Mitochondria, Heart; Oxygen Consumption; Phosphocreatine

The increased susceptibility of hearts with chronic left ventricular hypertrophy (CLVH) to damage during ischemia has been suggested but not documented. The purpose of this study was to isolate ischemic events in hearts with CLVH from reperfusion events. Using physiological and biochemical parameters, we compared the rate and extent of myocardial injury during ischemic contracture between eight canine hearts with CLVH induced by subcoronary valvular aortic stenosis and 14 normal canine hearts. Preischemic myocardial blood flow was determined by injection of tracer microspheres. During cardiopulmonary bypass, each heart was instrumented with a left ventricular balloon and made globally ischemic. At control, contracture initiation, and contracture completion left ventricular transmural biopsy specimens were assayed for subepicardial and subendocardial adenosine triphosphate (ATP) and creatine phosphate (CP). Mitochondrial respiratory control indices for NAD-linked and FAD-linked substrates were measured. Preischemic endocardial blood flow in hearts with CLVH was significantly lower than in normal hearts. At control, subendocardial ATP and CP and the respiratory control index for NAD-linked substrate were significantly lower in hearts with CLVH than in normal hearts. Hearts with CLVH reached contracture initiation significantly sooner than normal hearts. All hearts demonstrated significant decreases in high-energy phosphate content and mitochondrial function during ischemia. Reperfusion injury notwithstanding, we concluded that hearts wih CLVH are more susceptible to ischemic injury than are normal hearts, perhaps related to lower endocardial blood flow, lower subendocardial high-energy phosphate stores, and depressed mitochondrial function prior to ischemia.

Topics: Adenosine Triphosphate; Animals; Aortic Valve Stenosis; Cardiomegaly; Coronary Circulation; Dogs; Ischemia; Mitochondria, Heart; Myocardial Contraction; Oxygen Consumption; Phosphocreatine

Topics: Adenosine Triphosphate; Animals; Cardiomegaly; Creatine; Female; Heart Ventricles; Myocardium; Phosphocreatine; Rats; Time Factors

Using experimental models of various disease states, the ability of the isolated perfused working rat heart to withstand and recover from a period of severe ischemia was investigated. The results revealed that the coexistence of a diabetic state, obesity, or left ventricular hypertrophy increased the susceptibility of the hearts to ischemic damage and reduced the rate or the extent of postischemic recovery. In contrast, hearts obtained from moderately hypertensive rats exhibited a greater resistance to, and a superior recovery from, ischemia than did hearts obtained from normotensive controls.

Topics: Adenosine Triphosphate; Animals; Cardiac Output; Cardiomegaly; Coronary Circulation; Coronary Disease; Diabetes Mellitus, Experimental; Disease Models, Animal; Electrolytes; Heart Arrest, Induced; Hypertension; Male; Myocardial Contraction; Myocardium; Obesity; Phosphocreatine; Procaine; Rats; Triglycerides

An attempt was made to determine the effect of hypothermic potassium cardioplegia (35 mEq of potassium chloride) on the hypertrophic ventricle. Puppies with induced left ventricular hypertrophy were divided into four groups and studied after one hour on global ischemia. Myocardial adenosine triphosphate (ATP) was best preserved in the hypothermically perfused groups and correlated well with measurements of coronary sinus creatine phosphokinase (CPK). In Groups 1 and 2 (anoxic arrest at 37 degrees C and KC1 perfusion at 37 degrees C), CPK at 30 minutes of reperfusion was 1,031 and 198 IU, respectively, compared to 35 IU in Group 3 (KC1 perfusion at 4 degrees C) and 44 IU in Group 4 (Ringer's lactate at 4 degrees C). Myocardial injury was milder in Groups 3 and 4 regardless of whether potassium chloride was added. It is apparent that hypothermic perfusion of a hypertrophic ventricle was the major factor in myocardial preservation, as determined by myocardial ATP and coronary sinus CPK.

Topics: Adenosine Triphosphate; Animals; Cardiomegaly; Creatine Kinase; Disease Models, Animal; Dogs; Electrocardiography; Glycogen; Heart Arrest, Induced; Hypothermia, Induced; Lactates; Myocardial Contraction; Myocardium; Organ Size; Perfusion; Phosphocreatine; Potassium Chloride

Topics: Adenosine Triphosphate; Adult; Aortic Valve Insufficiency; Aortic Valve Stenosis; Cardiomegaly; Cyclic AMP; DNA; Fatty Acids, Nonesterified; Humans; Lactates; Middle Aged; Myocardium; Phosphocreatine; RNA

Topics: Adenosine Triphosphate; Animals; Blood Volume; Cardiomegaly; Coronary Circulation; Dogs; Muscle Tonus; Myocardial Contraction; Myocardium; Oxygen Consumption; Perfusion; Phosphocreatine; Physical Exertion

A single subcutaneous dose (1 mg/kg) of isoproterenol (ISO) increases the net calcium-45 uptake into the ventricular myocardium of normal rats by a factor of 3 to 4 within 6 hr. When the same dose of ISO was administered to rats previously treated with 1 mg ISO/kg per day for 1--3 weeks, this rise in labeled Ca-uptake was greatly reduced. Consequently the stimulatory effect of ISO on the Ca-dependent high-energy phosphate consumption was considerably diminished. Furthermore the chronic application of ISO produced a hypertrophy of both ventricles. When this treatment was discontinued for 7 days the ventricular weights returned to normal, whereas the restriction of beta-adrenergic reactivity persisted for more than 3 weeks. The results indicate that the decrease in responsiveness to beta-adrenergic agents is not due to the hypertrophy itself but must be considered to be an independent phenomenon-possibly resulting from adaptation to chronic beta-adrenergic overstimulation.

Topics: Adenosine Triphosphate; Animals; Biological Transport, Active; Calcium; Cardiomegaly; Heart; Isoproterenol; Male; Phosphocreatine; Rats; Time Factors

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Antimetabolites; Body Weight; Carbon Dioxide; Cardiomegaly; Electrocardiography; Heart; Heart Rate; Hydrogen-Ion Concentration; Lactates; Male; Myocardium; Organ Size; Phosphocreatine; Pyridinium Compounds; Pyrimidines; Pyruvates; Rats; Thiamine; Thiamine Deficiency; Thiazoles

Topics: Adenosine Triphosphate; Altitude; Animals; Body Weight; Cardiomegaly; Disease Models, Animal; Heart Ventricles; Hypoxia; Organ Size; Phosphocreatine; Rats; Time Factors

Topics: Aging; Aortic Coarctation; Atrophy; Cardiomegaly; Cell Count; Cell Membrane; Cell Physiological Phenomena; Hemodynamics; Hypertrophy; Membrane Potentials; Muscles; Myocardium; Organ Size; Phosphocreatine; Protein Biosynthesis

Topics: Adenosine Triphosphate; Animals; Body Weight; Carbon Isotopes; Cardiomegaly; Female; Glycine; Leucine; Muscle Proteins; Organ Size; Phosphocreatine; Rats

Topics: Adrenal Cortex Hormones; Cardiomegaly; Cardiomyopathies; Dermatomyositis; Diagnosis, Differential; Electrocardiography; Female; Humans; Middle Aged; Mitral Valve Insufficiency; Phosphocreatine; Tachycardia

Topics: Adenosine Triphosphate; Animals; Calcium; Calcium Isotopes; Cardiomegaly; Heart; Isoproterenol; Phosphocreatine; Rats

Topics: Adaptation, Physiological; Adenine Nucleotides; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Aortic Valve Insufficiency; Biopsy; Cardiomegaly; Glycogen; Heart Failure; Heart Ventricles; Lactates; Muscle Proteins; Myocardium; Phosphocreatine; Rabbits

Topics: Adenine Nucleotides; Animals; Asphyxia; Cardiomegaly; Cricetinae; Disease Models, Animal; Energy Metabolism; Heart Failure; Mesocricetus; Phosphocreatine; Rats

Topics: Adenosine Triphosphate; Cardiomegaly; Heart; Heart Failure; Humans; Phosphocreatine

Topics: Animals; Calcium; Cardiomegaly; Cats; Chromatography, Paper; Guinea Pigs; Heart Failure; Humans; Hypoxia; Myocardium; Phosphates; Phosphocreatine; Rats

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Biochemical Phenomena; Biochemistry; Cardiomegaly; Chromatography; Coenzymes; Creatine; Creatinine; Cytosine Nucleotides; Dogs; Flavin-Adenine Dinucleotide; Guanine Nucleotides; Heart Failure; Metabolism; Myocardium; NAD; Nucleotides; Phosphates; Phosphocreatine; Pulmonary Valve Stenosis; Purines; Pyrimidine Nucleotides; Research; Uracil Nucleotides

Topics: Cardiomegaly; Coenzymes; Creatine; Creatinine; Hypertrophy; Phosphocreatine