Comparative 13C and 31P NMR assessment of altered metabolism during graded reductions in coronary flow in intact rat hearts.

13C NMR spectroscopy may offer a unique ability to characterize the metabolic response to graded reduction in coronary flow since it allows repeated, nondestructive identification of products of intermediary metabolism in the same heart. The sensitivity of 13C parameters of glucose metabolism was compared with changes in levels of phosphocreatine, ATP, and pH as determined by 31P NMR in the intact, beating rat heart model during graded reductions in coronary flow. Experiments were performed during 60 min of perfusion with [1-13C]glucose (5 mM) at normal flow (15 ml/min) and at the reduced flow rates of 5 and 2 ml/min. During flow at 5 ml/min, isovolumic developed pressure fell to 51 +/- 4% of control. Although phosphocreatine, ATP, and pH were not changed, [3-13C]lactate was increased (1.46 +/- 0.12 mumol/g of wet weight vs. 0.63 +/- 0.08 during normal flow). In addition, the time to 50% maximum enrichment of [2-13C]glutamate was prolonged (17 +/- 1 min vs. 9 +/- 1 min during normal flow), indicating that glucose-supported flux through the tricarboxylic acid (TCA) cycle was decreased. The relative anaplerotic contribution to citrate synthase-supported TCA flux was increased from 6% to 35%. These 13C metabolic changes could not be reproduced by reduced [1-13C]glucose delivery in the absence of ischemia, although similar reduced TCA flux indices were reproduced in additional hearts when workload was reduced by low calcium (0.7 mM) perfusion. Therefore, the information provided by 13C NMR spectroscopy can be a more sensitive indicator of flow-induced alterations in cardiac metabolism than that provided by the much more commonly used 31P NMR technique.

A phosphorus-31 nuclear magnetic resonance study of the metabolic, contractile, and ionic consequences of induced calcium alterations in the isovolumic rat heart.

Isolated adult rat hearts perfused in an isovolumic mode were used to study the effects of sodium-potassium pump inhibition and sodium-calcium exchange alterations on the tissue content of adenosine triphosphate, phosphocreatine, inorganic phosphate, and intracellular pH, all measured by phosphorus-31 nuclear magnetic resonance spectroscopy. Rates of oxygen consumption, contractile function, and the cell contents of calcium, sodium, and potassium also were determined. The inhibition of sodium-potassium adenosine triphosphatase, either by the reduction in perfusate potassium from 5.9 to 1 millimolar or less, or by the addition of 10(-4) molar ouabain, transiently increased systolic pressure. This was followed by a decrease in systolic pressure, an increase in diastolic pressure, and eventual inexcitability. This contractile profile was accompanied by a persistent increase in oxygen consumption, a monotonic decline in cellular adenosine triphosphate and phosphocreatine content, the development of marked intracellular acidosis, a gain in cell sodium and calcium content, and a reduction in cell potassium. Quite similar metabolic changes were also observed when cell calcium was increased after a reduction in perfusate sodium. These metabolic and contractile effects could be prevented or reversed by decreasing perfusate calcium. The results emphasize the profound role of calcium in modulating cell oxygen consumption, energy balance, pH, excitability, and force production. These data are discussed in light of changes in the myocardial energy supply/demand balance, as well as from the viewpoint of the known competition between mechanisms for mitochondrial calcium transport vs. high-energy phosphate production.

Variables predictive of successful medical therapy in patients with unstable angina: selection by multivariate analysis from clinical, electrocardiographic, and angiographic evaluations.

Although unstable angina can be initially controlled with medical therapy in most patients, there is a high incidence of subsequent death, myocardial infarction, or need for coronary bypass surgery to control symptoms. Identification at the time of presentation of the patient likely to do poorly on continued medical therapy would be useful in advising consideration of surgical therapy. Since coronary arterial spasm may have a significant role in the pathophysiology of unstable angina in some patients, the recently developed calcium channel antagonists may therefore be of particular benefit in the medical therapy of unstable angina. One hundred thirty-eight patients were entered into a randomized double-blind study of the efficacy of adding nifedipine to conventional treatment of unstable angina (nitrates and beta-blockers) and were followed for 18 months. Of these patients, 104 underwent coronary arteriography. A multivariate Cox's hazard function analysis was applied to variables selected from the history, electrocardiographic (ECG) changes during chest pain, and from scintigraphic and coronary arteriographic data to determine those variables most predictive of response to medical therapy. The percentage of the left ventricular myocardium supplied by vessels with 70% or greater luminal stenosis was the most significant variable in influencing failure of medical therapy defined as sudden death, myocardial infarction, or need for bypass surgery. Whether or not the patient received nifedipine was the second most powerful variable, with the use of nifedipine reducing by half the relative risk of failing medical therapy. These were followed by cigarette smoking and presence of global ST segment changes during ischemia. After 18 months the nifedipine group had fewer patients failing medical therapy (p = .02), with fewer patients undergoing coronary bypass surgery (p less than .01). However, nifedipine did not appear to have a preventive effect against myocardial infarction or death. Kaplan-Meier actuarial curves confirmed that medical therapy was significantly less successful in the presence of increasing numbers of significantly stenotic vessels (p = .03). However, nifedipine provided a significant beneficial effect in patients with two or more stenotic vessels (p less than .01) and in whom 50% or more of the myocardium was supplied by vessels with 70% or greater stenosis (p = .01). Thus, although patients with advanced obstructive coronary disease have the greatest likelihood of unfavorable outcomes, the addition of nifedipine is of significant benefit.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute nifedipine withdrawal: consequences of preoperative and late cessation of therapy in patients with prior unstable angina.

Reports of acute ischemic events after withdrawal of calcium antagonist therapy in outpatients and during bypass surgery in patients with prior angina at rest prompted the examination of the effect of nifedipine withdrawal in 81 patients who had completed a prospective, double-blind randomized trial of nifedipine versus placebo for rest angina. Thirty-nine patients underwent bypass surgery for uncontrolled angina or left main coronary artery disease. No significant difference between patients withdrawn from nifedipine or placebo was seen in the incidence of perioperative myocardial infarction, hypotension requiring intraaortic balloon counterpulsation, vasopressor or vasodilator requirements or incidence of significant arrhythmias. An additional 42 patients had completed 2 years on a protocol consisting of nitrates and propranolol in addition to nifedipine or placebo. During a mean of 66 hours of continuous monitoring after withdrawal of nifedipine or placebo, heart rate and blood pressure were unchanged. A worsening of previously present angina at rest occurred in five patients who had continued to experience rest angina before drug withdrawal, four of whom were withdrawn from nifedipine. No patient with class I to III angina experienced new onset of rest angina during drug withdrawal. No patient experienced myocardial infarction. There was no significant difference between patients withdrawn from nifedipine or placebo in the duration or frequency of ischemic ST changes on continuous electrocardiographic monitoring, or in duration or positive results of serial exercise treadmill testing. Thus, no early adverse effects of acute nifedipine withdrawal were found in patients with prior rest angina at the time of bypass surgery or in stable patients receiving long-term medical therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Nifedipine in unstable angina: a double-blind, randomized trial.

We assessed the efficacy of adding nifedipine to the conventional treatment of unstable angina in 138 patients in a prospective, double-blind, randomized, placebo-controlled trial. There was no difference between the two groups in the dose of conventional antianginal medication or in age, prior myocardial infarction, ejection fraction, or other risk factors. Failure of medical treatment (defined as sudden death, myocardial infarction, or bypass surgery within four months) occurred in 43 of 70 patients given placebo and in 30 of 68 given nifedipine. Kaplan-Meier survival-curve analysis of the number and time dependence of treatment failures demonstrated a benefit of nifedipine over placebo (P = 0.03). The benefit was particularly marked in patients with ST-segment elevation during angina (P = 0.02). Side effects (transient hypotension or diarrhea) required withdrawal of the drug from four patients given nifedipine and from one given placebo. We conclude that the addition of nifedipine to conventional therapy is safe and effective in unstable angina.