Left ventricular dysfunction in patients with angina pectoris, normal epicardial coronary arteries, and abnormal vasodilator reserve

Thirty-three patients with chest pain despite angiographically normal coronary arteries underwent both coronary flow studies during pacing and resting and exercise gated blood pool scintigraphy. During atrial pacing after administration of ergonovine, those patients developing their typical chest pain demonstrated significantly lower great cardiac vein flow (97 +/- 31 vs 150 +/- 33 ml/min, p less than .001), higher coronary resistance (1.27 +/- 0.43 vs 0.77 +/- 0.18 mm Hg/ml/min, p less than .005), and less lactate consumption (30.5 +/- 22.0 vs 69.7 +/- 41.1 mM . ml/min, p less than .005) and a higher left ventricular end-diastolic pressure after pacing (20 +/- 4 vs 12 +/- 1, p less than .001) compared with those without pain and in the absence of significant luminal narrowing of the epicardial coronary arteries. The 26 patients with abnormal vasodilator reserve demonstrated reduced left ventricular ejection fraction during exercise (58 +/- 8%) compared with the seven patients with appropriate vasodilator reserve (66 +/- 4%, p less than .05) and with a group of 52 control patients of similar age and sex distribution and free of known heart disease (66 +/- 10%, p less than .001). In addition, 12 of the 26 patients with abnormal vasodilator reserve demonstrated exercise-induced regional wall motion abnormalities. Many of these patients also manifested impaired left ventricular diastolic filling at rest compared with the control subjects (peak filling rate 2.6 +/- 0.7 vs 3.2 +/- 0.7 end-diastolic volume/sec, p less than .005). Thus, patients with chest pain resulting from abnormal vasodilator reserve demonstrate abnormalities of left ventricular systolic and diastolic function suggestive of myocardial ischemia.     

Evaluation of coronary reserve in angina pectoris with angiographically normal coronary arteries

Coronary reserve was studied: 1) during rapid atrial pacing and then, 2) during dipyridamole infusion (0.6 mg/Kg/4 min) in 3 groups of subjects: 13 patients with angina pectoris and angiographically normal coronary arteries (ANC) with proven myocardial ischaemia during atrial pacing, 15 patients with coronary artery disease (COR) and 17 normal controls with normal coronary angiography and atrial pacing. Coronary sinus flow (QCS) was measured by thermodilution and myocardial metabolism studied by the coefficient of lactate extraction (K). At maximal pacing rates, K remained 15 p. 100 in the control group (average 24 +/- 7 p. 100) but was inversed in the ANC (-3 +/- 10 p. 100) and COR groups (-27 +/- 38 p. 100). The risk in QCS was low in the COR group (+60 +/- 33 p. 100) p less than 0.02, but significant in the ANC group (+104 +/- 57 p. 100) and normal controls (+107 +/- 41 p. 100). Coronary reserve, calculated as the percentage increase in QCS with dipryridamole, was found to be the same in the ANC group (+225 +/- 79 p. 100) as in normal subjects (+191 +/- 81 p. 100) but was low in the COR group (74 +/- 42 p. 100, p less than 0,001). Therefore, no reduction in coronary reserve was shown in patients with angina and normal coronary arteries whilst the myocardial ischaemia in coronary disease does seem to be related to an amputation of the coronary reserve.     

Thyrotoxicosis and lactate-producing angina pectoris with normal coronary arteries.

Three patients with thyrotoxicosis are described, in whom the presenting symptom was severe cardiac pain at rest or on effort and who were admitted to hospital with suspected or proven myocardial infarction. All patients were studied by selective coronary arteriography and left ventriculography after thyroid function tests which confirmed thyrotoxicosis. There was no demonstrable disease of the major coronary arteries in any of the patients, yet myocardial infarction and left ventricular aneurysm were shown to be present in 1, and there was definite electrocardiographic evidence of ischaemia in all 3. In addition, under stress the myocardium of all 3 patients produced lactate. It is recommended that thyrotoxicosis be seriously considered in the differential diagnosis of cardiac pain, particularly in younger women. The cause of the pain seems related to the cellular effects of thyrotoxicosis on the myocardium and current views of these effects are summarised. Of the 3 patients, 1 died suddenly 6 months after becoming euthyroid, indicating that the disease may not be as benign as expected. A guarded prognosis and continued medical follow-up are recommended when thyrotoxicosis presents with angina pectoris even when normal coronary arteries have been demonstrated.     

The coronary arteries and left ventricle in clinically isolated angina pectoris: a necropsy analysis.

Certain clinical and morphologic observations are described in 27 patients with severe isolated angina pectoris of either the stable (five patients) or the unstable form (22 patients). Twenty-four patients died during or shortly after cardiac operations designed to relieve angina pectoris and three died during cardiac catheterization. During life none had had clinical evidence of acute myocardial infarction or congestive cardiac failure. At necropsy, each had diffuse, extensive coronary atherosclerosis with severe luminal narrowing: the lumens of at least two, an average of three, of the four major epicardial coronary arteries were narrowed greater than 75% in cross-sectional area by old atherosclerotic plaques. Despite the severe coronary narrowing, there was little myocardial damage. Left ventricular scarring (excluding papillary muscle) was observed grossly in only 14 (52%) of the 27 patients and in each it involved only a small portion of myocardial wall. The left ventricular cavity was of normal size in all except two patients. The hearts were of normal weight in 15 (56%) patients, and the average increase above the upper range of normal for the other 12 hearts was 19%. Thus, clinically isolated, severe angina pectoris is associated with severe, diffuse luminal narrowing but relatively little myocardial damage.     

Angina pectoris due to possible vasospasm of small coronary arteries.

Recently, the presence of vasospasm in small coronary arteries is speculated in animals and humans. A 40-year-old female patient complained of chest pain at rest. Left ventriculogram showed normal wall motions. Left and right coronary arteries were also normal. After methylergometrine maleate was selectively administered to a right coronary artery, she complained of chest pain, and ST-segment elevation was detected in leads II, III, and aVF of ECG. Right coronary arteriography was performed immediately, but no coronary stenosis was found. The next day, methylergometrine maleate was again administered intravenously and the patient complained of chest pain, but no ischemic changes were observed in ECG. Thallium-201 myocardial scintigraphy followed immediately. Apical perfusion defect was detected in stress image. In the delayed image, it showed complete redistribution. Three days later, catheterization and scintigraphy were performed at the same time. When methylergometrine maleate was administered to the left coronary artery, she complained of chest pain within a few minutes of the injection; however, ECG remained unchanged. 201Tl myocardial scintigraphy was performed immediately. In the stress image, it showed apical perfusion defect as shown in the intravenous methylergometrine maleate injection study. It also showed complete redistribution in the delayed image. Apical perfusion defect can be attributed to myocardial ischemia of left coronary artery, which are too small to be detected by conventional coronary arteriography. Vasospasm in small coronary arteries may be involved in this phenomenon.     

Verapamil in effort-induced angina pectoris in patients with normal coronary arteries

Summary: Two patients with classical effort-induced angina pectoris associated with abnormal ST-segment depression on graded exercise testing and normal coronary arteriograms are described. Both patients deteriorated during treatment with propranolol, and became asymptomatic during treatment with verapamil with normal graded exercise tests. Verapamil may thus improve an inadequate vasodilatatory response of the coronary vascular bed to effort.     

Comparison of epicardial coronary artery tone and reactivity in Prinzmetal's variant angina and chronic stable angina pectoris

It has been suggested that a generalized coronary vasomotion disorder is present in variant angina and that evaluation of baseline coronary artery tone may be useful for predicting the occurrence of coronary artery spasm. The vasomotor response of angiographically normal proximal and distal coronary artery segments was studied in 9 patients with atypical chest pain and normal coronary arteriograms (control group), 13 patients with active variant angina and 41 patients with chronic stable angina. Ergonovine (intravenous, 100 to 300 micrograms, or intracoronary, 8 to 20 micrograms, was administered to all 22 patients in the control and variant angina groups and to 11 of the 41 patients with chronic stable angina. All patients also received intracoronary isosorbide dinitrate (1 to 2 mg). Computerized coronary artery diameter measurement of angiographically normal segments was carried out before and after ergonovine and nitrate administration. Mean baseline intraluminal diameter of proximal and distal coronary segments was not significantly different in control patients and those with variant angina (nonspastic segments only) or coronary artery disease (proximal 2.89 +/- 0.15, 2.83 +/- 0.14 and 2.82 +/- 0.09 mm; distal 1.60 +/- 0.08, 1.63 +/- 0.07 and 1.62 +/- 0.06 mm, respectively). After ergonovine, proximal segments constricted by 10 +/- 2%, 15 +/- 3% and 11 +/- 4% and distal segments by 11 +/- 3%, 11 +/- 2% and 14 +/- 3% in control, variant angina and coronary artery disease groups, respectively (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Reactivity of canine isolated epicardial collateral coronary arteries. Relation to vessel structure

To study the relation between structure and vascular reactivity in mature coronary collateral arteries, we prepared 17 dogs with a casein occluder near the origin of the circumflex coronary artery. At least 24 weeks later, we examined the reactivity of surface collateral arteries (approximately 500 micron i.d.) to a range of constrictor and dilator agents and compared them with normal left anterior descending coronary arteries of similar size branching away from the collateral zone. Pairs of normal and collateral arteries 2 mm long were mounted in a double-vessel myograph for isometric force recording. Arteries were contracted by K+ (124 mM) or by cumulative addition of endothelin-1 (1-100 nM) or U46619 (1-300 nM), a thromboxane A2 mimetic drug. In each case, the collateral vessels contracted to approximately half the force generated by the normal arteries. When partially contracted by K+ (25-30 mM), the collateral vessels had a greater range of relaxation and similar sensitivity to acetylcholine, sodium nitroprusside, and cromakalim compared with normal arteries. Morphological and morphometric analyses revealed that the collateral arteries had thickened adventitia, thinner media, ruptured internal elastic laminae, and a thick neointima lined by endothelium. Theoretical calculations of luminal area were made for isotonic conditions in response to constrictor stimuli. Despite the poor contractility of the collateral arteries, the neointimal luminal encroachment further reduced the lumen to zero, an exaggerated response compared with normal arteries. Coronary collateral arteries are thus compromised flow conduits that may play a role in vasospastic angina.     

Effects of ketanserin on epicardial coronary arteries after coronary angioplasty in patients with stable angina

Previous studies have demonstrated the development of vasoconstrictionimmediately after percutanous coronary angioplasty (PTCA), distalto the dilated stenosis, presumably resulting from endothelialinjury. We have investigated the role of 5-HT₂ receptors inmediating vasomotor changes in proximal and distal coronarysegments and coronary stenoses, immediately after successfulPTCA in patients with chronic stable angina. We compared theeffects of the intracoronary infusion of 1 mg ketanserin (5-HT₂receptor antagonist) on proximal and distal coronary arterialsegments immediately after PTCA in both vessels subjected toPTCA and control vessels. Coronary diameters, before and afterangioplasty and after ketanserin administration, of proximaland distal segments and coronary stenoses were measured by computerizedquantitative coronary angiography (CAAS system) in 12 patients(10 male, two female; mean age 54 ±6 years) with stableangina subjected to PTCA. After coronary angioplasty, vasoconstrictionwas observed in the segment distal to the dilated stenosis butnot in the distal segments of control vessels ( – 0.12± 0.04 and – 0.02 ± 0.02 mm respectively,P<0.05). After ketanserin infusion significant dilatationwas found in the distal segments of both PTCA vessels and controlvessels, but the dilatation was greater in the PTCA vessels(P<0.05). No significant changes were found in the proximalsegments of either PTCA or control vessels, or at the PTCA site.In conclusion, the vasoconstriction distal to the site of PTCAis mediated, at least in part, via 5-HT₂ receptors.     

Vasomotor responses of coronary stenoses to acetylcholine and their relation to serum lipid levels in stable angina pectoris

The effects of acetylcholine administration on coronary stenoses in relation to serum lipids level were evaluated in 18 patients (15 men, 3 women) with coronary artery disease and stable angina. Intracoronary acetylcholine was infused in concentrations 10⁻⁷, 10^−6, 10⁻⁵ M, followed by intracoronary bolus administration of isosorbide dinitrate. Computerized angiography was used to assess the changes in the diameter of stenoses and of proximal and distal segments. During acetylcholine infusion, at concentrations between 10⁻⁷ to 10 ⁻⁵M, there was a significant (p <0.01) dose-dependent constriction of proximal and distal segments and of stenoses reversed by isosorbide dinitrate. There was no correlation between the serum total cholesterol level and the responses of proximal and distal segments to acetylcholine or nitrate. A correlation (p <0.05) was found between the serum total cholesterol level and the response of stenoses to acetylcholine, but there was no correlation with the response to isosorbide dinitrate. In conclusion, in patients with stable angina current serum total cholesterol level correlates with the vasomotor response of coronary stenoses to intracoronary acetylcholine. These findings are consistent with a direct effect of cholesterol, increasing basal coronary vasomotor tone and increasing the stimulated vasoconstrictor response of stenoses.     

Inhibition of nitric oxide synthesis in human epicardial coronary arteries and stenoses in relation to serum lipid level

Administration of N(G)-monomethyl-L-arginine (LNMMA), an inhibitor of nitric oxide synthase, causes a reduction in epicardial coronary artery and stenosis diameter in patients with coronary artery disease, indicating that these diseased vessels produce nitric oxide. Elevations of low density lipoprotein cholesterol impair human endothelium-dependent relaxation. The relationship between serum lipid level and nitric oxide production by normal and atheromatous human epicardial coronary arteries in vivo is unknown. The effects of an intracoronary infusion of LNMMA (8 and 16 micromol/min) followed by intracoronary administration of 250 mcg nitroglycerin on non-stenotic proximal and distal coronary segments and coronary stenoses were studied in 11 patients with coronary artery disease and in 19 patients with 'normal arteriograms'. Coronary luminal diameter was measured by computerized quantitative angiography. In patients with cholesterol level> or = 220 mg/dl, no significant response to LNMMA was observed in the proximal segments in either those with 'normal angiograms' or those with coronary disease. In patients with cholesterol <220 mg/dl significant constriction (P<0.01) was observed in the proximal segments of patients with 'normal coronary angiograms' at both 8 and 16 micromol doses, but occurred only at the 16 micromol/min dose (P<0.01) in those with coronary disease. In conclusion the difference in vasomotor response to LNMMA in relation to cholesterol level is localised to the proximal coronary segments, and the response does not correlate with cholesterol or triglyceride level. This is therefore more likely to be an indirect effect of elevated cholesterol, e.g. undetected atheroma, than a direct effect on nitric oxide synthesis.     

Disabling angina pectoris with normal coronary arteries in patients undergoing long-term hemodialysis

Reports of patients undergoing long-term hemodialysis presenting with angina pectoris have usually shown severe coronary atherosclerosis. we studied a series of nine patients undergoing regular maintenance dialysis referred for incapacitating angina. Of them, four had strictly normal coronary angiograms.The patients with normal angiograms were all females who were significantly younger (p < 0.05) and had more severe hypertension and higher left ventricular wall stress than patients showing coronary artery lesions.Anemia and increased myocardial oxygen consumption due to high blood pressure may explain the syndrome of angina pectoris in the presence of long-term dialysis in patients with normal coronary arteries. The prevalence of this association cannot be ascertained unless prospective studies are conducted. However, our data suggest that it might not be an uncommon finding.     

Diameter changes of epicardial coronary arteries and coronary stenoses after intracoronary application of SIN 1, a molsidomine metabolite

The vasodilating effects of intracoronary injections of 0.4 mg SIN 1, the active metabolite of molsidomine, on epicardial coronary arteries and coronary stenoses were evaluated in 14 patients with coronary artery disease in a double-blind randomized fashion versus placebo. 9 additional patients with well-definable coronary stenoses received 0.4 mg SIN 1 as well. Diameter changes of nonstenotic coronary arteries in proximal, medial and distal coronary segments as well as changes of the residual luminal diameters within coronary stenoses were determined before (K), immediately after (M1) and 10 minutes after (M2) intracoronary application of SIN 1; in addition, aortic pressure and heart rate were monitored continuously. Aortic pressure and heart rate did not change after SIN 1 or placebo. After SIN 1, the diameter of nonstenotic coronary arteries increased in proximal segments by + 9% (M1) and + 11.7% (M2), in medial segments by + 17.6% (M1) and + 17.6% (M2), in distal segments by + 26.4% (M1) and + 28.8% (M2). Within coronary stenoses, the residual luminal diameters showed a mean increase by 31.5% (M1) and 48.3% (M2). Placebo did not alter coronary diameters significantly. SIN 1 effectively dilates nonstenotic and especially stenotic epicardial coronary arteries, as it is already known for nitrates and calcium-channel blockers. By intracoronary injections, the direct effects on coronary vessels can be detected without interference with systemic effects. The increase in residual luminal diameters within dynamic coronary stenoses after SIN 1 is most likely an important antianginal mechanism also for molsidomine.     

Histologic evidence for small-vessel coronary artery disease in patients with angina pectoris and patent large coronary arteries

We studied six patients who suffered from angina pectoris but had angiographically patent major coronary arteries. Two of the patients suffered also from congestive heart failure. Three patients had supraventricular tachyarrhythmias. Three patients had conduction disturbances. During coronary angiography the patients had significantly reduced flow velocity of angiographic contrast medium compared with that in a control group. Echocardiographic and Doppler flow studies showed a tendency for symmetrical thickening of the left ventricular wall, enlargement of the right ventricle, and reduced compliance of both ventricles. Right ventricular endomyocardial biopsy revealed pathologic small coronary arteries with fibromuscular hyperplasia, hypertrophy of the media, myointimal proliferation, and endothelial degeneration. Capillaries had swollen endothelial cells encroaching on the lumen. Myocardial hypertrophy, lipofuscin deposition, and patchy fibrosis were also observed. These cases show that small-vessel coronary artery disease can cause classic angina pectoris. The diagnosis can be suspected when the coronary angiogram shows large patent arteries with slow flow of the angiographic contrast medium and it can be confirmed by endomyocardial biopsy.     

Morphologic comparison of frequency and types of acute lesions in the major epicardial coronary arteries in unstable angina pectoris, sudden coronary death and acute myocardial infarction

The frequency and type of acute lesions in the four major (right, left main, left anterior descending, left circumflex) epicardial coronary arteries were examined at necropsy in 14 patients with unstable angina pectoris, 21 patients with sudden coronary death and 32 patients with a fatal first acute myocardial infarction. None of the 67 patients had a grossly visible left ventricular scar (healed myocardial infarct) and only the group with acute myocardial infarction had left ventricular myocardial necrosis. Although the frequency of intraluminal thrombus was similar in patients with unstable angina (29%) and sudden death (29%) and significantly lower than in those with acute infarction (69%) (p = 0.02), the thrombus in the patients with unstable angina and sudden death consisted almost entirely of platelets and was nonocclusive, whereas the thrombus in the group with acute infarction consisted almost entirely of fibrin and was occlusive. The frequency of plaque rupture was insignificantly different in the groups with unstable angina (36%) and sudden death (19%), and was significantly lower than in the group with acute infarction (75%) (p = 0.02). The frequency of plaque hemorrhage was insignificantly different in the groups with unstable angina (64%) and sudden death (38%) and was significantly lower than in the group with acute infarction (90%) (p = 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)