Transmural metabolite distribution in regional myocardial ischemia as studied with <sup>31</sup>p NMR

Robitaille, Pierre‐Marie; Lew, Brian; Merkle, Hellmut; Sublett, E.; Lindstrom, Paul; From, Arthur H. L.; Garwood, Michael; Bache, Robert J.; Uğurbil, Kâmil

doi:10.1002/mrm.1910100110

Cited by 48 publications

(34 citation statements)

References 14 publications

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“…Under basal conditions, endocardial blood flow is thought to be slightly higher than or equal to the epicardial blood flow (10,21). Owing to a variety of factors, including greater wall stresses and intramyocardial pressure (7,8), and enhanced endocardial metabolism (9,10,22,23), subendocardial oxygen consumption is -1.5-fold greater than subepicardial oxygen consumption under normal conditions (5,6,10). Since tissue pressure during systole is so much greater in the subendocardium than in the subepicardium, endocardial coronary flow is largely restricted to diastole (7,8).…”

Section: Discussionmentioning

confidence: 99%

Transmural distribution of extracellular purines in isolated guinea pig heart.

Zhu¹,

Headrick²,

Berne³

1991

Proc. Natl. Acad. Sci. U.S.A.

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The purine adenosine appears to be involved in regulation of coronary vascular tone. Little is known concerning the levels and distribution of adenosine and related purines in the extracellular fluid of the heart. We have measured epicardial and endocardial levels of adenosine, inosine, hypoxanthine, AMP, and IMP in isolated constant flow perfused guinea pig hearts by using a recently developed technique with porous nylon sampling discs. Venous effluent purine levels were also measured. Concentrations of all purines measured, excluding IMP, were significantly higher in endocardial fluid samples than in epicardial fluid samples (P < 0.05). Conversely, IMP levels were significantly lower in endocardial than in epicardial samples. The magnitude of the endocardial/epicardial ratios for adenosine, inosine, hypoxanthine, AMP, and IMP were '12:1, 4:1, 5:1, 4:1, and 1:2, respectively. To assess cellular damage, lactate dehydrogenase activity was measured in all fluid samples and was not significantly different in endocardial and epicardial fluid. These data support the existence of significant transmural gradients for extracellular purine levels in crystalloid perfused guinea pig hearts. Transmural differences in vasoactive adenosine levels may be partially due to the greater endocardial oxygen consumption and metabolism and may be involved in maintaining relatively high subendocardial blood flows in the face of high intramyocardial pressures.Adenosine may be responsible for modulating myocardial blood flow in response to alterations in oxygen supply and demand (1). This hypothesis predicts a consistent relationship between extracellular adenosine levels and coronary vascular tone or blood flow. In examining this hypothesis, the process of myocardial adenosine formation has been intensively studied (1-4). Unfortunately, most indices of adenosine formation do not directly reflect interstitial adenosine levels-the adenosine pool in direct contact with extracellular receptors. Furthermore, these same indices only reflect global changes in adenosine levels and cannot detect regional differences in extracellular adenosine. The mammalian myocardium is a heterogeneous tissue and the subepicardial and subendocardial regions differ physically, metabolically, and functionally (5-10). Little information is available regarding spatial heterogeneities in extracellular metabolite levels. Interestingly, recent studies indicate that transmural differences exist in the distribution of adenosine-regulating enzymes (11) and it has been demonstrated that transmural gradients exist for intracellular adenosine during control perfusion and ischemia in vivo (12). Thus, it is possible that physiological messengers such as adenosine may be unevenly distributed throughout the myocardial interstitial space.Recently, different methods have been developed for sampling interstitial transudate on the epicardial surface of the myocardium (13)(14)(15)(16)(17)(18). In the present study, we measured epicardial and endocardial transudate concentrat...

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Section: Discussionmentioning

confidence: 99%

Transmural distribution of extracellular purines in isolated guinea pig heart.

Zhu¹,

Headrick²,

Berne³

1991

Proc. Natl. Acad. Sci. U.S.A.

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“…Creatine phosphate (PCr) levels fall rapidly, with a concomitant increase in inorganic phosphate and H + concentrations. If ischemia is severe or sufficiently prolonged, PCr is depleted, adenosine triphosphate (ATP) levels decrease, and acidosis worsens (1)(2)(3)(4). The magnitude of the decline in cardiac high-energy phosphates and intracellular pH directly indicates the severity of the imbalance of oxygen supply and demand in the myocardium, as well as the effectiveness of anti-ischemic interventions (1,5,6).…”

Section: Introductionmentioning

confidence: 99%

Preservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of hemoglobin–oxygen affinity

Weiss¹,

Mejia²,

Kass³

et al. 1999

J. Clin. Invest.

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Conventional approaches for the treatment of myocardial ischemia increase coronary blood flow or reduce myocardial demand. To determine whether a rightward shift in the hemoglobin-oxygen saturation curve would reduce the metabolic and contractile effects of a myocardial oxygen-supply imbalance, we studied the impact of a potent synthetic allosteric modifier of hemoglobin-oxygen affinity, a 2- [4-[[(3,5-disubstituted anilino)carbonyl]methyl] phenoxy] -2-methylproprionic acid derivative (RSR13), during low-flow ischemia. Changes in myocardial high-energy phosphate levels and pH were studied by 31 P nuclear magnetic resonance (NMR) spectroscopy in 12 open-chest dogs randomized to receive RSR13 or vehicle control during a reversible reduction of left anterior descending (LAD) coronary artery blood flow. Changes in cardiac metabolites and regional ventricular function studied by pressure segment-length relations were also investigated in additional animals before and after RSR13 administration during low-flow LAD ischemia. The intravenous administration of RSR13 before ischemia resulted in a substantial increase in the mean hemoglobin p50 and attenuated the decline in cardiac creatine phosphate/adenosine triphosphate (PCr/ATP), percent PCr, and pH during ischemia without a change in regional myocardial blood flow, heart rate, or systolic blood pressure. RSR13 given after the onset of low-flow ischemia also improved cardiac PCr/ATP ratios and regional function as measured by fractional shortening and regional work. Thus, synthetic allosteric reduction in hemoglobin-oxygen affinity may be a new and important therapeutic strategy to ameliorate the metabolic and functional consequences of cardiac ischemia.

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“…Nineteen volunteers with a mean age of 24±2 years (range, [20][21][22][23][24][25][26][27][28][29] years) served as a control group. All volunteers were apparently healthy individuals with no signs of heart disease at rest and during exercise.…”

Section: Characteristics Of Volunteers and Patient Groupsmentioning

confidence: 99%

31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure.

et al. 1992

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BACKGROUND The purpose of this work was to further define the value of cardiac 31P magnetic resonance (MR) spectroscopy for patients with coronary artery disease and dilated cardiomyopathy. METHODS AND RESULTS Blood-corrected and T1-corrected 31P MR spectra of anteroseptal myocardium were obtained at rest using image-selected in vivo spectroscopy localization, a selected volume of 85 +/- 12 cm3, and a field strength of 1.5 T. Nineteen volunteers had a creatine phosphate (CP)/ATP ratio of 1.95 +/- 0.45 (mean +/- SD) and a PDE/ATP ratio of 1.06 +/- 0.53; in four patients with left anterior descending coronary artery (LAD) stenosis, six patients with chronic anterior wall infarction, and four patients with chronic posterior wall infarction, CP/ATP and phosphodiester (PDE)/ATP ratios did not differ from those in volunteers. Twenty-five measurements of 19 patients with dilated cardiomyopathy yielded a CP/ATP of 1.78 +/- 0.51 and a PDE/ATP of 0.98 +/- 0.56 (p = NS versus volunteers). When these patients were grouped according to the severity of heart failure, however, CP/ATP was 1.94 +/- 0.43 in mild (p = NS versus volunteers) and 1.44 +/- 0.52 in severe DCM (p < 0.05), respectively. No correlation was found between CP/ATP and left ventricular ejection fraction or fractional shortening, but correlation of CP/ATP with the New York Heart Association (NYHA) class was significant (r = 0.60, p < 0.005). Six patients with dilated cardiomyopathy were studied repeatedly before and after 12 +/- 6 weeks of drug treatment leading to clinical recompensation with improvement of the NYHA status by 0.8 +/- 0.3 classes. Concomitantly, CP/ATP increased from 1.51 +/- 0.32 to 2.15 +/- 0.27 (p < 0.01), whereas PDE/ATP did not change significantly. CONCLUSIONS Cardiac high-energy phosphate metabolism at rest is normal in LAD stenosis and chronic myocardial infarction in the absence of heart failure. The CP/ATP ratio has low specificity for the diagnosis of dilated cardiomyopathy. However, CP/ATP correlated with the clinical severity of heart failure and may improve during clinical recompensation.

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Transmural metabolite distribution in regional myocardial ischemia as studied with ³¹p NMR

Cited by 48 publications

References 14 publications

Transmural distribution of extracellular purines in isolated guinea pig heart.

Transmural distribution of extracellular purines in isolated guinea pig heart.

Preservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of hemoglobin–oxygen affinity

31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure.

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Transmural metabolite distribution in regional myocardial ischemia as studied with 31p NMR

Cited by 48 publications

References 14 publications

Transmural distribution of extracellular purines in isolated guinea pig heart.

Transmural distribution of extracellular purines in isolated guinea pig heart.

Preservation of canine myocardial high-energy phosphates during low-flow ischemia with modification of hemoglobin–oxygen affinity

31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure.

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Transmural metabolite distribution in regional myocardial ischemia as studied with ³¹p NMR