Thomas C. Smitherman

Conversion from chronic to acute coronary artery disease: Speculation regarding mechanisms

The factors that are primarily responsible for the conversion from chronic to acute coronary artery disease (CAD), including the development of unstable angina pectoris and acute myocardial infarction, remain uncertain. Some patients with angiographic evidence of extensive and severe coronary arterial stenoses anatomically do well with appropriate medical therapy, whereas others with similar or even anatomically less impressive coronary arterial stenoses have clinical manifestations of acute CAD. Improved insight into mechanisms responsible for the conversion of chronic CAD to acute CAD is essential for efforts directed at preventing acute myocardial infarction and sudden cardiac death. The purpose of this editorial is to emphasize recent developments in knowledge relating to alterations in prostaglandin production that may play a role in the development or perpetuation of acute CAD.

Submaximal exercise testing after unstable angina

Sixty-one consecutive men, mean age 56 years, who fulfilled criteria for unstable angina and who responded to medical therapy, underwent submaximal exercise testing prior to hospital discharge and at least 3 days after their last episode of angina. Forty-two patients were receiving propranolol at the time of exercise. Submaximal exercise was targeted to 120 beats/minute and strict criteria for the premature termination of each study were followed. Follow-up data were available on 55 patients post-discharge over a period of 6 to 36 weeks. No patient suffered recurrence of unstable angina or myocardial infarction due to the exercise test. Exercise was prematurely terminated by an ischemic response (chest pain and/or ST segment changes) in 34 patients (56%) and by leg fatigue in 13 patients (21%). Only five patients had exercise-induced ventricular ectopic activity, four of whom were not receiving propranolol. Nine patients achieved the target heart rate. Exercise-induced abnormal electrocardiographic changes predicted the postdischarge recurrence of episodes of unstable angina (p less than 0.05). Comparison of predischarge submaximal exercise data with postdischarge maximal exercise shows that recovery in cardiovascular function after unstable angina occurs soon after stabilization and prior to the submaximal test.

Serial myocardial scintigraphy after a single dose of Thallium-201 in men after acute myocardial infarction

Abstract Serial myocardial scintigraphy after a single dose of thallium-201 in the period immediately after myocardial infarction may demonstrate redistribution of thallium-201 into perfusion defects that were evident in the initial scan. This study tested the hypothesis that evaluation of this redistribution, available within hours of infarction, could provide a more accurate estimate of the eventual perfusion defect than a single thallium-201 Image obtained immediately after infarction. The study group comprised 14 patients with a diagnosis on admission of probable acute myocardial infarction. The patients received thallium-201 a mean of 1.3 hours after admission to the coronary care unit. Imaging began 10 minutes after the thallium injection and was repeated 4 to 8 hours later. Eight patients with acute myocardial infarction had a definite reduction in one or more perfusion defects on serial scintigraphy, possibly indicating reperfusion of transiently Ischemic zones. Two patients with acute infarction had an increase in perfusion defects in a second study performed 6 hours after the initial scintigram. In the interval between scans, one patient had a cardiac arrest with clinical evidence of infarct extension after successful resuscitation; the other sustained a lateral extension of the infarct. One patient with acute aortic dissection had normal scans on both studies. All three patients with unstable angina had an abnormal initial scan; on repeat scan, the thallium-201 defect was unchanged in one patient, increased in one and decreased in the third. In the patients with myocardial infarction, repeat thallium-201 scans corresponded more nearly than the initial scans to the extent of technetilum-99m stannous pyrophosphate uptake by the heart. These data suggest that serial myocardial imaging with thallium-201 immediately after myocardial infarction can overcome some of the limitations of a single thallium-201 scintigram and may be useful in delineating ischemic from infarcted myocardium in the postinfarction period.

DIRECT CORONARY VASODILATION INDUCED BY INTRACORONARY VASOACTIVE INTESTINAL PEPTIDE

Summary: Vasoactive intestinal peptide (VIP) is a neurotransmitter that has been identified in epicardial coronary arteries. To evaluate the direct effect of VIP on coronary hemodynamics and blood flow, graded doses of VIP (0.01, 0.03, 0.10, and 0.30 μg/min) were infused into the left coronary artery of 7 patients at the time of diagnostic cardiac catheterization for chest pain syndromes. None of the patients had coronary stenoses >50% during subsequent angiography. Coronary sinus VIP concentrations increased during each infusion (22 ± 28 pg/ml at baseline to 109 ± 22 pg/ml at 0.30 μg/min; p < 0.05), but arterial VIP was elevated (39 ± 29 pg/ml) only at the maximal dose of 0.30 μg/min. During all dosages of VIP, heart rate, right atrial and left ventricular end-diastolic pressure, and the heart rate × blood pressure product did not change. Moreover, neither mean aortic pressure nor left ventricular peak + dP/dt changed significantly at doses <0.30 μg/min; at 0.30 μg/min, mean aortic pressure decreased (97 ± 15 to 90 ± 15 mm Hg; p < 0.05) and LV peak + dP/dt increased (1,621 ± 230 to 1,801 ± 226 mm Hg/s; p < 0.05). Compared to baseline, the arterial-coronary sinus O2 content difference and myocardial O2 extraction diminished progressively at the 0.03, 0.10, and 0.30 μg/min doses of VIP (118 ± 12 ml O2/L vs. 94 ± 15, 70 ± 9, and 61 ± 26 ml O2/L, respectively, and 0.64 ± 0.05 vs. 0.53 ± 0.10, 0.38 ± 0.06, and 0.34 ± 0.15, respectively). In the absence of hemodynamic alterations indicating a substantial variation in myocardial oxygen demand, these changes imply an increase in coronary blood flow and confirm that VIP has a direct effect on the coronary vasculature. These data support the concept that VIP may have a physiological role in the regulation of coronary resistance in man.

Reverse redistribution of thallium-201 detected by SPECT imaging after dipyridamole in angina pectoris

Reverse redistribution refers to a thallium-201 perfusion defect that develops or becomes more evident on delayed imaging compared with the initial image immediately after stress. To determine the diagnostic importance of reverse redistribution after intravenous dipyridamole, thallium-201 single photon emission computed tomography and quantitative coronary arteriography were performed in 90 men with angina pectoris. Of the 250 myocardial segments analyzed, reverse redistribution was present in 17 (7%). Minimal coronary cross-sectional area in proximal vessel segments was less than or equal to 2.0 mm2 more often in regions with transient perfusion abnormalities than in regions with reverse redistribution (66 vs 29%, p less than 0.05). Compared with regions exhibiting transient perfusion abnormalities, regions with reverse redistribution had larger proximal arterial diameters (1.9 +/- 1.1 vs 1.3 +/- 1.1 mm, p less than 0.001) and cross-sectional areas (3.9 +/- 3.1 vs 2.2 +/- 2.6 mm2, p less than 0.001). Coronary artery dimensions and relative stenosis severity did not differ between those regions with normal perfusion and those with reverse redistribution. Reverse redistribution detected by thallium-201 single photon emission computed tomographic imaging after dipyridamole is uncommon, appears to occur as frequently in normal subjects as in patients undergoing coronary arteriography and does not indicate the presence of severe coronary artery disease.

Comparison of dipyridamole-Doppler echocardiography to thallium-201 imaging and quantitative coronary arteriography in the assessment of coronary artery disease

This study was undertaken to determine whether Doppler measurements of systolic aortic and diastolic mitral blood flow velocities could reliably detect the presence of reversible myocardial perfusion defects during intravenous dipyridamole-thallium-201 imaging. In addition, the ability of dipyridamole-Doppler echocardiography to predict the presence of significant coronary artery disease (CAD) was evaluated. Baseline and post-dipyridamole Doppler studies were performed in 10 normal control subjects and 23 patients with CAD. Aortic peak velocity and acceleration increased from baseline to post-dipyridamole in normal subjects by 0.07 +/- 0.07 m/s (p = 0.016) and 2.1 +/- 2.0 m/s2 (p = 0.009), respectively. The ratio of early to late peak transmitral velocities decreased slightly in normal subjects, by 0.18 +/- 0.72 (difference not significant), whereas the ratio of early to late transmitral velocity-time integrals increased by 0.07 +/- 0.93 (difference not significant). The response of aortic velocity and acceleration to intravenous dipyridamole was not significantly different between normal subjects, patients without reversible thallium-201 perfusion defects and patients with reversible thallium-201 perfusion defects. Furthermore, only 3 of 14 subjects with reversible thallium-201 perfusion defects had abnormal (greater than 2 standard deviations from the mean) responses of aortic velocity or acceleration to intravenous dipyridamole. No patient had an abnormal response of the early to late mitral peak velocity ratio. In addition, the response of Doppler aortic and mitral indexes to intravenous dipyridamole was not able to identify the presence of significant CAD as assessed by quantitative coronary arteriography.(ABSTRACT TRUNCATED AT 250 WORDS)

Dissociation of myosin light chains and decreased myosin ATPase activity with acidification of synthetic myosin filaments: possible clues to the fate of myosin in myocardial ischemia and infarction.

Abstract The effect of mild acidification of synthetic (reconstituted) myosin filaments was studied in order to gain insight into some of the possible effects of ischemia-induced intracellular acidosis on the structure and function of myosin following myocardial infarction and myocardial ischemia. Degradation products of myosin that are soluble (at physiologic ionic strength and pH) would be of potential diagnostic value for myocardial infarction. Acidification of rabbit skeletal synthetic myosin filaments led to a pH dependent partial dissociation of the heaviest (LC 1 ) and lightest (LC 3 ) of the 3 light chains. Dissociation was detected from pH 5.0 to 6.5 and was maximal at pH 6.0, at which 30% of LC 1 was dissociated. Acidification of canine cardiac synthetic myosin filaments led to partial dissociation of both light chains; but more LC 1 than LC 2 was dissociated. Light chains reassociated with heavy chains upon return of the pH to 7. Light chains of myosin have recently been reported to appear in the peripheral blood after myocardial infarction but the small amount of free light chains in the heart is insufficient to account for the amount that appears in the blood. Acid-mediated dissociation of light chains in vitro suggests that circulating light chains after myocardial infarction may arise as a result of the intracellular acidosis of ischemic myocytes. The mechanisms responsible for the acidification-induced decrease in myofibrillar actomyosin adenosine triphosphatase (ATPase) activity are unclear. One possibility is that the decreased myofibrillar ATPase activity is due in part to an acid-induced decrease of the myosin ATPase of the myofibril irrespective of the effect of acid on the troponin-tropomyosin regulatory system. This possible mechanism is supported by the observations that acidification of rabbit skeletal and human and canine cardiac synthetic myosin filaments resulted in a reduction of ATPase activity (measured at pH 7.5) of the redissolved myosin which was progressive with greater acidification. The reduction in ATPase activity occurred whether the return of the myosin to pH 7.5 was accomplished in the presence or absence of dissociated light chains.Abstract The effect of mild acidification of synthetic (reconstituted) myosin filaments was studied in order to gain insight into some of the possible effects of ischemia-induced intracellular acidosis on the structure and function of myosin following myocardial infarction and myocardial ischemia. Degradation products of myosin that are soluble (at physiologic ionic strength and pH) would be of potential diagnostic value for myocardial infarction. Acidification of rabbit skeletal synthetic myosin filaments led to a pH dependent partial dissociation of the heaviest (LC 1 ) and lightest (LC 3 ) of the 3 light chains. Dissociation was detected from pH 5.0 to 6.5 and was maximal at pH 6.0, at which 30% of LC 1 was dissociated. Acidification of canine cardiac synthetic myosin filaments led to partial dissociation of both light chains; but more LC 1 than LC 2 was dissociated. Light chains reassociated with heavy chains upon return of the pH to 7. Light chains of myosin have recently been reported to appear in the peripheral blood after myocardial infarction but the small amount of free light chains in the heart is insufficient to account for the amount that appears in the blood. Acid-mediated dissociation of light chains in vitro suggests that circulating light chains after myocardial infarction may arise as a result of the intracellular acidosis of ischemic myocytes. The mechanisms responsible for the acidification-induced decrease in myofibrillar actomyosin adenosine triphosphatase (ATPase) activity are unclear. One possibility is that the decreased myofibrillar ATPase activity is due in part to an acid-induced decrease of the myosin ATPase of the myofibril irrespective of the effect of acid on the troponin-tropomyosin regulatory system. This possible mechanism is supported by the observations that acidification of rabbit skeletal and human and canine cardiac synthetic myosin filaments resulted in a reduction of ATPase activity (measured at pH 7.5) of the redissolved myosin which was progressive with greater acidification. The reduction in ATPase activity occurred whether the return of the myosin to pH 7.5 was accomplished in the presence or absence of dissociated light chains.

Cardiac dose response relationship for intravenously infused glucagon in normal intact dogs and men

Abstract The mechanism of glucagons cardiac effects is not well understood. As the cardiac dose response to glucagon in intact animals has not been elucidated, this was determined in normal men and dogs. In man, heart rate, blood pressure, systolic time intervals and echocardiographic indices of ventricular wall motion were determined. Plasma glucagon levels (PGL) were measured by radioimmunoassay. Men received 3 glucagon infusions of 10 −10 to 10 −8 moles/minute followed by a bolus of 0.5 mg. or 1.0 mg. Small but significant changes were observed in ejection fraction and left ventricular posterior wall displacement at the 10 −9 moles/minute infusion rate (mean PGL 1.9 ng./ml.), a PGL close to that of some pathophysiologic states such as burns, ketoacidosis, and acute myocardial infarction, while cardiac output, heart rate, and other indices of cardiac performance were significantly changed only at the 10 −8 moles/minute and bolus injections. Some indices, notably stroke volume, were unchanged. In dogs, left ventricular (LV) pressure, LV pressure derivative (LV dPdt), and aortic flow were measured with implanted LV solid state pressure transducers and electromagnetic flow probes. Dogs received six infusions from 2.7 × 10 −11 to 2.7 × 10 −8 moles/minute followed by a bolus of 2 mg. In dogs, significant changes occurred in LV dPdt at 2.7 × 10 −9 moles/minute (mean PGL 31.5 ng./ml.) and in heart rate at 2.7 × 10 −8 moles/minute only. It appears that substantial hemodynamic effects do not appear in man or dogs until PGL 10 to 100 times those seen in pathophysiologic states are achieved. Thus, it seems unlikely that glucagon contributes substantially to the hyperdynamic circulatory conditions observed in these states. Significant hemodynamic response to glucagon was noted in normal men, however, at a PGL less than that achieved by usual pharmacologic doses of glucagon and this lower PGL was not associated with the gastrointestinal symptoms commonly observed clinically.

Myocardial Infarction in Men in the Third Decade of Life

Excerpt Myocardial infarction is uncommon in the fourth decade and rare in the third decade of life. Our recent experience with several patients in the third decade of life led us to search for all...

Acute thyrotoxicosis in the rabbit: changes in cardiac myosin, contractility, and ultrastructure.

Abstract Alterations in the activity of cardiac myosin ATPase are known to develop during hyperthyroidism. We have characterized some of the changes in the biochemical and structural properties of myosin from rabbits made severely hyperthyroid by injection of 1-thyroxine (200–250 μg/kg per day), and compared the development of these changes to development of abnormalities of cardiac contractility and ultrastructure. Ca 2+ -adenosine triphosphatase (ATPase) activity of thyrotoxic rabbit cardiac myosin was enhanced 1.9–2.4 times that of normal and had a greater alkali stability. Similar enhancement of cardiac myosin Mg 2+ -ATPase was found. The enhancement was specific to cardiac myosin and was not due to cachexia alone. K + (EDTA)-ATPase of cardiac muscle was unaltered as were the α-helical content and the number and electrophoretic mobility of the light subunits. Myosin prepared from a mix of myocardium from normal and thyroxine-treated animals had Ca 2+ -ATPase activity intermediate to that of the normal and thyrotoxic rabbit myosins, consistent with the hypothesis that the enhanced enzymatic activity was due to a molecular change rather than the presence of activators in hearts of thyrotoxic animals or inhibitors in control animal hearts. A decrease in developed tension and maximum rate of tension development was found in papillary muscles from severely thyrotoxic rabbits (a change opposite to that which would be expected from enhanced myosin ATPase activity alone). Simultaneously, striking alterations of myofibrillar organization developed in the hearts of thyrotoxic animals as observed by electron microscopy of fixed sections, including disorganized deployment of thin filaments, as well as areas of muscle necrosis and repair. Thus, in this experimental model, severe hyperthyroidism is accompanied by major alterations in cardiac myosin that should tend to enhance contractility, but also by toxic changes that may damage the tissue directly and/or render it more susceptible to injury in vitro and thereby reduce its contractility. Experimentally induced thyrotoxicosis in rabbits may serve as a useful model for studying thyroid-induced cardiomyopathy.