Elevated coronary vascular resistance in the presence of reduced resting blood flow distal to a severe coronary stenosis

Vascular reserve in underperfused myocardium has recently been described. This seemingly paradoxical observation conflicts with older concepts of the coronary circulation which hold that flow deficits do not develop until reserve is fully exhausted. To examine this phenomenon in greater detail in an animal model mimicking a fixed human coronary artery stenosis, we analysed the records of 25 carefully selected, sedated pigs all instrumented with a rigid intralumenal coronary stenosis (82% lumenal diameter reduction). Each animal satisfied the following criteria: 1) perfused myocardial mass beyond the stenosis was within a narrow weight range (16 to 24 g); and 2) post stenosis (distal) epicardial (Epi) and endocardial (endo) flows were less than or equal to 90% of respective flows in a region perfused by the non-stenosed circumflex (CX) coronary artery. Accordingly, distal flow was reduced compared to circumflex zone flow (p less than 0.01) in the Epi (173 +/- 51 to 113 +/- 32 ml . 100g-1 . min-1), Endo (146 +/- 39 to 116 +/- 27) and transmural (Tm) regions (164 +/- 45 to 124 +/- 31). Despite a flow deficit and constant severity of stenosis, distal zone Tm resistance (0.55 +/- 0.21 mmHg/ml . 100 g-1 . min-1) exceeded the minimum level achievable with intravenous infusion of adenosine (0.25 +/- 0.07) in a separate group of eight animals without a stenosis. Distal transmural resistance also varied over a five fold range (0.27 to 1.33) and in 20/25 animals exceeded the highest level (0.37) seen in non-stenosis animals during adenosine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absence of postprandial surge in coronary blood flow distal to significant stenosis: a possible mechanism of postprandial angina

OBJECTIVES: This study was designed to investigate a possible mechanism of postprandial angina. BACKGROUND: Postprandial angina has been recognized for more than two centuries; however, its mechanism is still controversial. The most widely accepted mechanism involves increased myocardial oxygen demand after food intake. Recently, the redistribution in coronary blood flow (CBF) was suggested as a possible mechanism. METHODS: Twenty young, healthy volunteer controls and 20 patients with significant stenosis in the left anterior descending (LAD) or left main coronary artery were enrolled in the study. Coronary blood flow was evaluated in the distal LAD by using transthoracic Doppler echocardiography before and 15, 30, 45, and 60 min after food intake. In the CBF curve, the time velocity integral of diastolic flow (Dtvi) and the product of Dtvi and heart rate (HR) were measured. In six patients, these measurements were repeated after successful coronary intervention. RESULTS: In the healthy volunteer controls, Dtvi and Dtvi x HR increased after food intake with a peak value at 15 min, which indicates the presence of postprandial surge in the CBF. Fasting values and peak values at 15 min were significantly different (Dtvi: 15.1 +/- 4.9 cm/s vs. 18.9 +/- 5.9 cm/s, p = 0.04, Dtvi x HR: 862.2 +/- 261.5 cm/min vs. 1,174.2 +/- 307.5, p = 0.002). In contrast with the controls, despite postprandial increase in double product (HR x blood pressure), Dtvi and Dtvi x HR in the patient group decreased after food intake, with a nadir value at 45 min. Fasting values and nadir values at 45 min were significantly different (Dtvi: 24.0 +/- 19.6 cm/s vs. 19.3 +/- 17.1 cm/s, p < 0.001, Dtvi x HR: 1,449.6 +/- 1,044.0 cm/min vs. 1,273.4 +/- 1,000.9 cm/min, p = 0.002). In six patients, the CBF pattern resumed the normal pattern of postprandial surge in the CBF after successful coronary intervention. CONCLUSIONS: Results of our study suggest that "steal phenomenon" may play a role in the mechanism of postprandial angina.     

Details of coronary stenosis morphology influence its hemodynamic severity and distal flow reserve

Differences in coronary flow reserve with anatomically similar coronary artery stenoses have been attributed to 1) nonstandard physiologic conditions, 2) inadequacies of measurements of coronary artery stenosis dimension and/or coronary blood flow, and 3) inadequate hyperemic stimulus. Our study tested the hypothesis that details of coronary artery stenosis geometry, which may or may not be apparent on coronary angiograms, also may contribute importantly to such differences. A simple and complex coronary artery stenosis, each of which reduced vessel cross-sectional area by 84%, was introduced in random order into the left anterior descending coronary artery of nine closed-chest, sedated swine. The simple stenosis had a single lumen while the complex stenosis had five small lumena whose combined area equaled that of the single lumen stenosis. Measurements of hemodynamics and regional myocardial blood flow (microspheres) were made at control and after 10 minutes of adenosine infused at 400 micrograms/min and then at 800 micrograms/min distal to each stenosis. Both heart rate and aortic mean pressure were controlled and thus did not change versus initial baseline (129 +/- 4 minutes and 120 +/- 10 mm Hg, mean +/- SD, respectively) during the study. Baseline total flow (ml/sec) distal to the stenosis was similar at each control (1.05 +/- 0.35 vs. 0.92 +/- 0.34, simple versus complex, respectively; p = NS). At maximal adenosine, total flow with the simple stenosis was 3.44 +/- 0.92 versus 2.77 +/- 0.51 for complex (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Inotropic reserve and histological appearance of hibernating myocardium in conscious pigs with ameroid-induced coronary stenosis

Inotropic reserve, demonstrated with administration of sympathomimetic amines, is characteristic of hibernating myocardium. The goal of this study was to determine whether inotropic reserve was present following chronic coronary artery constriction in the pig, which is one potential model of hibernating myocardium. The effects of isoproterenol were examined in five conscious pigs 21±2.1 days after ameroid implantation on the left circumflex coronary artery on measurements of left ventricular (LV) pressure, LV dP/dt, and regional wall thickening in the ameroid-dependent zone (posterior wall) and contralateral non-ischemic zone (anterior wall). Isoproterenol, 0.1 g/kg/min, increased LV dP/dt by 96±11%, heart rate by 43±13 beats/min, and normalized systolic wall thickening, slightly, but not significantly more in the ameroid-dependent zone (+1.57±0.31 mm) than in the contralateral non-ischemic zone (+1.04±031 mm), although the baseline wall thickening was reduced significantly in the ameroid-dependent zone. This occurred at a time when baseline myocardial blood flow was preserved and myocardial perfusion in the ameroid-dependent zone was derived in part from the native coronary circulation and also through collateral channels. Two weeks later histological evidence of lesions characteristics of hibernating myocardium, i.e., myofibrolysis and increased glycogen deposition, were observed. Thus, these histological changes and the confluence of chronically depressed regional function and residual inotropic reserve in the conscious pig with chronic ameroid-induced coronary constriction support this model for further study of hibernating myocardium.Supported in part by USPHS grants HL 33065, 33107 and 38070     

Tachycardia induced reduction in coronary blood flow distal to a stenosis

Clinical and experimental data indicate that some coronary stenoses can rapidly change shape thereby influencing the hemodynamic severity of the stenosis. In 7 closed chest dogs, we examined the effects of distal coronary arteriolar vasomotor tone and myocardial oxygen demands on a coronary stenosis created by partial intraluminal occlusion, using a small balloon catheter. Myocardial blood flow (ml/g per min) was measured with 15-microns radioactive microspheres. Stenotic resistance was calculated as the mean pressure gradient across the stenosis divided by the mean blood flow through the stenosis. The mean pressure gradient was calculated as the ascending aortic pressure minus the left anterior descending coronary artery pressure distal to the stenosis. Coronary arteriolar vasodilation induced by pacing (170 beats/min) increased stenotic resistance (1.64 +/- 0.27 to 26.48 +/- 13.77 mmHg/ml per min, P less than 0.05) and decreased myocardial blood flow (endocardial 0.42 +/- 0.04 to 0.17 +/- 0.04, P less than 0.05, midcardial 0.35 +/- 0.03 to 0.13 +/- 0.04, P less than 0.05; epicardial 0.22 +/- 0.05 to 0.15 +/- 0.05). Five dogs fibrillated within 10 min of continuous tachycardia and partial arterial occlusion. The change in arteriolar vasomotor tone and decreased aortic pressure induced by pacing altered the severity of the stenosis and resulted in a reduction of blood flow to the myocardium.     

Oxygen utilization and coronary vascular reserve in the ischemic myocardium following acute coronary occlusion in the dog.

Oxygen extraction ratio (OER), oxygen consumption, heat production index, and flow (measured both as venous outflow and heat clearance) were measured in an area of myocardium to be rendered ischemic by acute occlusion of the anterior descending coronary artery. Prior to occlusion a linear relation was established between heat clearance and venous outflow. Heat production index and OER also showed a relationship, but its precise mathematical nature is not yet clear. Acute artery occlusion produced a rise in OER (from 58.4 to 84.4%) and a fall in both venous outflow (30.7%) and heat clearance (35.4%); heat production index fell over 1 hr by 57.3% and thereafter remained unchanged. Oxygen consumption changes were variable but mainly showed a reduction. In the unstressed anaesthetized dog, OER was not maximal but with acute ligation rose markedly, in isolated instances to 100%. It is suggested that increase in OER might be an important component of coronary vascular reserve, that it might in part, at least, be mediated by diversion of blood from relatively non-nutritional channels to channels in which, especially under conditions of cardiac stress, extraction of oxygen can be maximum.     

Functional and structural adaptations of coronary microvessels distal to a chronic coronary artery stenosis

Distal to a chronic coronary artery stenosis, structural remodeling of the microvasculature occurs. The microvascular functional changes distal to the stenosis have not been studied in detail. We tested the hypothesis that microvascular structural remodeling is accompanied by altered regulation of coronary vasomotor tone with increased responsiveness to endothelin-1. Vasomotor tone was studied in coronary microvessels from healthy control swine and from swine 3 to 4 months after implantation of an occluder that causes a progressive coronary narrowing, resulting in regional left ventricular dysfunction and blunted myocardial vasodilator reserve. Arterioles (approximately 200-microm passive inner diameter at 60 mm Hg) were isolated from regions perfused by the stenotic left anterior descending and normal left circumflex coronary arteries and studied in vitro. Passive pressure-diameter curves demonstrated reduced distensibility of subendocardial left anterior descending compared with subendocardial left circumflex or control arterioles, suggestive of structural remodeling. Myogenic responses were blunted in subendocardial left anterior descending compared with left circumflex arterioles, reflecting altered smooth muscle function. However, vasodilator responses to nitroprusside and bradykinin were not different in the endocardium, suggesting preserved endothelium and smooth muscle responsiveness. Finally, vasoconstrictor responses to endothelin-1 were enhanced in left anterior descending arterioles compared with left circumflex or control arterioles. Regional myocardial vascular conductance responses to bradykinin and endothelin in vivo confirmed the in vitro observations. In conclusion, inward remodeling of coronary microvessels distal to a stenosis is accompanied by exaggerated vasoconstrictor responses to endothelin-1. These structural and functional alterations may aggravate flow abnormalities distal to a chronic coronary artery stenosis.     

Tissue acidosis: role in sustained arteriolar dilatation distal to a coronary stenosis

This study tested the hypothesis that myocardial tissue acidosis is responsible for maintenance of reduced arteriolar tone distal to a severe coronary arterial stenosis. Domestic swine (n = 10) were instrumented with a coronary arterial stenosis that reduced vessel diameter 80%. Measurements of hemodynamic indexes were made 1) before stenosis, 2) at 5, 20, and 60 minutes after stenosis placement, and 3) after each of three, 20-minute NaOH infusions (0.05 M, 0.1 M, and 0.5 M) distal to the stenosis (group 1). Intracellular pH at the end of 30 minutes of 0.5 M NaOH infusion distal to the stenosis was measured in a second group (n = 6) of swine (group 2). After stenosis placement in group 1, endocardial blood flow declined significantly, and evidence of regional acidosis (increased coronary venous Pco2 and decreased coronary venous pH) and ischemia (lactate production) developed. One hour later, evidence of acidosis persisted, though to a lesser extent. Myocardial oxygen and lactate metabolism exhibited similar patterns. Infusion of 0.5 M NaOH (0.38 ml/min) reduced (p less than 0.01) distal zone epicardial blood flow but did not change endocardial flow. Regional myocardial oxygen extraction (75 +/- 8%, mean +/- SD) and consumption (8.2 +/- 2.3 ml/min/100 g) also declined significantly (p less than 0.01) in response to 0.5 M NaOH infusion compared with 60 minutes after stenosis (86 +/- 4 and 12.4 +/- 2.8 ml/min/100 g respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

New protocol to detect coronary spastic angina without fixed stenosis

A new combined test, accelerated exercise following mild hyperventilation (HV), was examined to determine whether it is effective at detecting a positive response in patients with pharmacologically-induced coronary vasospasm and near normal coronary arteries. Fifty-eight consecutive patients who underwent both triple non-invasive spasm provocation tests and diagnostic coronary angiography were enrolled. They all had pharmacologically-induced coronary vasospasms and no significant organic stenosis. In these patients, an HV test was performed first, followed by a treadmill exercise test (TET), and finally the new combined test under no medication within 3 days. Of the 58 patients, positive responses were observed in 9 patients to the HV, in 15 to the TET, and in 35 to the newly combined test. The remaining 21 patients had negative responses although the triple sequential tests were perfomed. Thus, the sensitivities of the HV test, TET, and newly combined test were 16% (9/58), 26% (15/58), and 63% (35/56), respectively. Forty-six subjects with near normal coronary arteries and no ACh-provoked spasm served as controls. None of these subjects had positive responses to any of these three tests, and thus their specificity was all 100%. No serious or irreversible complications were seen in this study. We recommend this newly-combined protocol for the induction of coronary artery spasm in patients with vasospastic angina pectoris and without significant stenosis as a diagnostic tool.     

Evidence for decreased coronary flow reserve in viable postischemic myocardium

To try to unravel the complexity and heterogeneity of the "no-reflow" phenomenon and its underlying mechanisms, we studied tissue perfusion in reperfused heart muscle by using tracer microspheres in an anesthetized dog model of 90-minute coronary occlusion followed by reperfusion for 2 1/2 hours, 24 hours, or 1 week. Regional myocardial blood flow was determined both in basal flow conditions and during reactive hyperemia. The effect of intracoronary adenosine administration was examined, and the ultrastructure of postischemic myocardium was analyzed. In viable reperfused tissue (as delineated by triphenyltetrazolium chloride staining), reflow in basal conditions is unimpaired. Coronary flow reserve (as approximated by peak reactive hyperemic flow) is intact at the start of reperfusion, decreases by more than half after 2 1/2 hours, and recovers completely within 1 week. This impairment of coronary reserve can be relieved by intracoronary adenosine administration. On ultrastructural examination, the capillaries are patent. On the other hand, in irreversibly damaged myocardium, both the basal reflow impairment and the decrease in coronary flow reserve are severe and permanent. Coronary flow reserve is already decreased at the start of reperfusion, and the pharmacological intervention has no beneficial effect. Ultrastructurally, extracellular and intracellular edema invariably are present, whereas the vascular endothelium is damaged and the capillaries are packed with red blood cells. We conclude that the no-reflow phenomenon (i.e., mechanical obstruction to blood flow) is limited to infarcted tissue. In viable myocardium, however, coronary flow reserve is transiently diminished, probably because of washout and subsequent insufficient availability of the chemical mediator adenosine after breakdown and slow recovery of the precursor ATP pool.     

Diastolic coronary vascular reserve: a new index to detect changes in the coronary microcirculation in hypertrophic cardiomyopathy

OBJECTIVES: The present study introduces a modification of the diastolic coronary conductance concept that maintains its sensitive properties to detect changes in the coronary microcirculation in human hypertrophy. BACKGROUND: Decrements of coronary flow in hypertrophy have been explained by changes in the coronary microcirculation. No measure is available to detect these changes. METHODS: Doppler velocity catheters were introduced into the left anterior descending artery (LAD) and left circumflex coronary artery (LCx) of patients with obstructive hypertrophic cardiomyopathy (HCM) (n = 11) and into the LAD of cardiac transplant recipients (n = 9). The diastolic coronary conductance was measured at rest and after maximal hyperemia induced by a bolus injection of adenosine. Diastolic coronary vasodilator reserve (DCVR) was calculated as the hyperemic diastolic coronary conductance, divided by the coronary conductance during resting conditions. RESULTS: Left ventricular outflow tract gradient in the HCM group (83 +/- 31 mm Hg) was significantly higher (p < 0.05). Septal wall thickness was significantly increased (p < 0.05), while wall thickness was unchanged in the posterior wall of the HCM group. The coronary flow reserve was significantly decreased in the HCM-LCx region (to 64 +/- 7% of control) and in the HCM-LAD regions (to 57 +/- 7% of control). The DCVR was only decreased in the HCM-LAD (to 46 +/- 3% of control) and not in the HCM-LCx group (86 +/- 6%, p > 0.05). Esmolol did affect the pressure gradient and systolic shortening, but did not affect the maximal diastolic conductance. CONCLUSIONS: The DCVR, in contrast with the coronary flow reserve, is decreased in those regions that display a disturbance in the microcirculation and may, therefore, offer a new way to study coronary adaptations in patients with hypertrophy.     

Evolution of regional ischemia distal to a proximal coronary stenosis: Self-propagation of ischemia

The temporal evolution of myocardial ischemia was studied in open chest dogs at constant preload, afterload and heart rate. In one group of animals, a variable circumflex arterial stenosis was used to maintain constant distal circumflex arterial hypotension (40 to 50 mm Hg). During a 3 hour period of stenosis, flow in the subendocardial fourth of the ischemic ventricular wall decreased from 0.22 to 0.09 ml/g per min (P < 0.02), whereas subepicardial flow was not significantly changed. Local vascular resistance, therefore, doubled in the most ischemic area of myocardium. In a second group of animals in which proximal coronary stenosis was held constant and pressure varied, an ischemia-mediated increase in local vascular resistance was also demonstrated. In addition, a reciprocal relation was observed between changes in flow in the left anterior descending coronary region and changes in collateral flow to the region of the circumflex artery. A coronary steal mechanism and an ischemiamediated resistance increase may be two means by which ischemia is self-propagating.     

Fractional flow reserve in a patient with intermediate coronary stenosis and hypertrophic cardiomyopathy

We discuss the case of a 61-year-old male patient with hypertrophic cardiomyopathy and chest pain on exertion. Coronary angiography and intravascular ultrasound revealed an intermediate stenosis in the proximal site of the left anterior descending artery, while Tc-99m myocardial scintigraphy revealed exercise-induced myocardial ischemia in the anteroseptal wall and apical portion. Flow velocity-derived coronary flow reserve (CFR) and pressure-derived fractional flow reserve (FFRmyo) were both low (1.1 and 0.59), suggesting that the stenosis was functionally significant. Directional coronary atherectomy greatly improved the FFRmyo (0.99), the scintigraphic findings, and anginal pain but did not improve the CFR (1.2). FFRmyo was useful in assessing the functional significance of an equivocal coronary stenosis and its interventional resolution.