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Both invasive and non-invasive parameters have been reported for assessment of the physiological status of the coronary circulation. Fractional flow reserve and coronary (or myocardial) flow reserve may be obtained by invasive or non-invasive means. These metrics of coronary stenosis severity have achieved wide clinical acceptance for guiding revascularization decisions and risk stratification. Other indices are obtained invasively (e.g., instantaneous wave-free ratio, iFR; hyperemic stenosis resistance) or non-invasively (e.g., PET absolute myocardial blood flow (mL/min/g)) and have been used for the same purposes. Both iFR, and whole-cycle distal coronary to aortic mean pressure (Pd/Pa) are measured under basal condition and used for assessment of hemodynamic stenosis severity as is index of basal stenosis resistance (BSR). These metrics typically are dichotomized at an empirically derived cut point into "normal" and "abnormal" categories for purposes of clinical decision making and data analysis. Once dichotomized the indices do not always point in the same direction and so confusion may arise. This review, therefore, will present basic principles relevant to understanding commonly employed metrics of the physiological status of the coronary circulation, potential strengths and weaknesses, and hopefully an improved appreciation of the clinical information provided by each.

This review focuses on clinical studies concerning assessment of coronary microvascular and conduit vessel function primarily in the context of acute and sub acute myocardial infarction (MI). The ability of quantitative PET measurements of myocardial blood flow (MBF) to delineate underlying pathophysiology and assist in clinical decision making in this setting is discussed. Likewise, considered are physiological metrics fractional flow reserve, coronary flow reserve, index of microvascular resistance (FFR, CFR, IMR) obtained from invasive studies performed in the cardiac catheterization laboratory, typically at the time of PCI for MI. The role both of invasive studies and cardiac magnetic resonance (CMR) imaging in assessing microvascular function, a key determinant of prognosis, is reviewed. The interface between quantitative PET MBF measurements and underlying pathophysiology, as demonstrated both by invasive and CMR methodology, is discussed in the context of optimal interpretation of the quantitative PET MBF exam and its potential clinical applications.

In the >40 years since planar myocardial imaging with(43)K-potassium was introduced into clinical research and management of patients with coronary artery disease (CAD), diagnosis and treatment have undergone profound scientific and technological changes. One such innovation is the current state-of-the-art hardware and software for positron emission tomography myocardial perfusion imaging, which has advanced it from a strictly research-oriented modality to a clinically valuable tool. This review traces the evolving role of quantitative positron emission tomography measurements of myocardial blood flow in the evaluation and management of patients with CAD. It presents methodology, currently or soon to be available, that offers a paradigm shift in CAD management. Heretofore, radionuclide myocardial perfusion imaging has been primarily qualitative or at best semiquantitative in nature, assessing regional perfusion in relative terms. Thus, unlike so many facets of modern cardiovascular practice and CAD management, which depend, for example, on absolute values of key parameters such as arterial and left ventricular pressures, serum lipoprotein, and other biomarker levels, the absolute levels of rest and maximal myocardial blood flow have yet to be incorporated into routine clinical practice even in most positron emission tomography centers where the potential to do so exists. Accordingly, this review focuses on potential value added for improving clinical CAD practice by measuring the absolute level of rest and maximal myocardial blood flow. Physiological principles and imaging fundamentals necessary to understand how positron emission tomography makes robust, quantitative measurements of myocardial blood flow possible are highlighted., (© 2016 American Heart Association, Inc.)

Considerable awareness has been raised of late of the need to reduce radiation exposure and control costs of x-ray and radionuclide imaging procedures. PET/CT cameras are now widely available and in conjunction with appropriate radionuclides and commercially available software make quantitative measurement of absolute MBF feasible for routine clinical practice. Quantitative measurement of absolute MBF under condition of coronary vasodilation permits independent assessment of the functional status of each of the three major coronary perfusion zones and so obviates the need for rest MBF determination in the great majority of cases. Coronary microvascular function also may be assessed in this same way. Thus, the stress-only protocol with quantitative PET measurement of MBF provides essential information required for clinical decision making related to need for catheterization and intervention for patients with known or suspected ischemic heart disease. Moreover, the single PET determination of maximal MBF in contrast to the usual rest/stress procedure addresses both safety and cost concerns. The present review focuses on: (1) quantitative PET measurements of myocardial blood flow for physiological assessment of the coronary circulation and (2) the value and potential limitations of performing stress only imaging in the clinical context.

Objectives: This study sought to determine the feasibility of performing a comprehensive cardiac computed tomographic (CT) examination incorporating stress and rest myocardial perfusion imaging together with coronary computed tomography angiography (CTA)., Background: Although cardiac CT can identify coronary stenosis, very little data exist on the ability to detect stress-induced myocardial perfusion defects in humans., Methods: Thirty-four patients who had a nuclear stress test and invasive angiography were included in the study. Dual-source computed tomography (DSCT) was performed as follows: 1) stress CT: contrast-enhanced scan during adenosine infusion; 2) rest CT: contrast-enhanced scan using prospective triggering; and 3) delayed scan: acquired 7 min after rest CT. Images for CTA, computed tomography perfusion (CTP), and single-photon emission computed tomography (SPECT) were each read by 2 independent blinded readers., Results: The DSCT protocol was successfully completed for 33 of 34 subjects (average age 61.4 +/- 10.7 years; 82% male; body mass index 30.4 +/- 5 kg/m(2)) with an average radiation dose of 12.7 mSv. On a per-vessel basis, CTP alone had a sensitivity of 79% and a specificity of 80% for the detection of stenosis > or =50%, whereas SPECT myocardial perfusion imaging had a sensitivity of 67% and a specificity of 83%. For the detection of vessels with > or =50% stenosis with a corresponding SPECT perfusion abnormality, CTP had a sensitivity of 93% and a specificity of 74%. The CTA during adenosine infusion had a per-vessel sensitivity of 96%, specificity of 73%, and negative predictive value of 98% for the detection of stenosis > or =70%., Conclusions: Adenosine stress CT can identify stress-induced myocardial perfusion defects with diagnostic accuracy comparable to SPECT, with similar radiation dose and with the advantage of providing information on coronary stenosis.

Objectives: This study tests the hypothesis that absolute measurement of adenosine (Ado)-stimulated myocardial blood flow (MBFado) is superior to measurement of relative tracer uptake for identification of hemodynamically significant coronary artery disease (CAD)., Background: Positron emission tomography measurement of absolute myocardial blood flow (MBF) ((13)N-ammonia) with Ado has the capability to more accurately assess hemodynamic severity of CAD than measurement of relative tracer content (TC) (nCi/ml) during Ado, which by definition depends on at least 1 normal zone to which others are compared., Methods: A total of 27 patients (20 male, 58 +/- 11 years, mean +/- SD) with known or suspected CAD and 21 normal subjects (13 male, 38 +/- 10 years) were studied. Parametric (K1) MBF images and TC sum images were analyzed. A stenosis > or =70% defined significant CAD. The receiver-operator characteristic curve (ROC) analysis area under the curve (AUC) compared MBF and TC results. Cut-point analysis for sensitivity, specificity, and accuracy showed the best MBF criteria for CAD as MBFado <1.85 ml/min/g and the best TC as <70% maximum. The myocardial blood flow reserve ratio (MBFR) (optimal <2.0x) also was studied., Results: The ROC analysis of PET parameters showed that MBFado was superior to <70% maximum uptake for CAD detection (n = 144 vessels; AUC 0.900 vs. 0.690, respectively, p < 0.0001) and was marginally greater than MBFR (0.856; p = 0.10). For CAD cut-point analysis, MBFado accuracy exceeded TC (0.84 vs. 0.72, respectively, p = 0.005), as did sensitivity (0.81 vs. 0.48, respectively; p = 0.001). Specificity of MBFado for CAD classification (0.85) was comparable to TC (0.82; p = NS). Sensitivity, specificity, and predictive accuracy for MBFR were 0.62, 0.85, and 0.79, respectively. The difference in specificity was not significant versus MBFado. However, MBFado was more sensitive than MBFR (p = 0.01). The difference in predictive accuracy was borderline (p = 0.06) in favor of MBFado., Conclusions: Measurement of Ado-stimulated absolute MBF is superior to relative measurement of myocardial tracer retention for identification of CAD and can be accomplished with a single MBFado measurement.

Regulating myocardial blood flow in health and disease is a complex, multifaceted process. The objective of this article is to outline for the practicing clinician a basic set of principles necessary for understanding important control mechanisms operative under normal physiologic conditions and in selected common disease states. Classical and newer insights into the process of myocardial blood flow regulation are reviewed. An improved understanding of these control mechanisms will enhance the clinician's ability to diagnose and treat abnormalities of the coronary circulation associated with such common clinical conditions as ischemic heart disease, diabetes, dyslipidemia, hypertension, and congestive heart failure.

Objectives: We tested the hypothesis, in patients with Friedreich's ataxia and no overt structural heart disease, that impairment of cardiac oxidative metabolism may be compensated for either by increased rest myocardial blood flow or more efficient oxygen consumption in performance of external work., Background: Friedreich's ataxia is characterized by a mutant frataxin gene, which causes mitochondrial iron overload and impaired energy production. Further, it is frequently associated with cardiomyopathy. Studies using magnetic resonance spectroscopy, however, suggest impaired cardiac energetics even in the absence of structural heart disease., Methods: Positron emission tomography measured rest myocardial blood flow (N-13-ammonia method) and myocardial oxygen consumption (11-C-acetate, Kmono) in Friedreich's ataxia patients (n=8; 31+/-5 years, mean+/-SD, four women) and healthy controls (n=8; 30+/-7 years, five women) matched for stroke work index and age. Stroke work index and power were determined by electrocardiogram gated positron emission tomography N-13-ammonia using modified Simpson's rule to compute left ventricular volumes., Results: Neither stroke work index nor rest myocardial blood flow differed significantly between the groups. Although myocardial oxygen consumption was lower in Friedreich's ataxia (P<0.001), Kmono/rest myocardial blood flow, an index of myocardial oxygen extraction, did not differ between the groups. Power/Kmono, an index of the efficiency of myocardial oxygen consumption, was greater in Friedreich's ataxia (P<0.04). Rest myocardial blood flow normalized to rate pressure product was lower in Friedreich's ataxia (P<0.05)., Conclusions: Prior to the onset of cardiomyopathy, selected patients with Friedreich's ataxia may compensate for impaired cardiac energetics through more efficient oxygen consumption rather than increased rest myocardial blood flow. The data illustrate a more general mechanism pertaining to metabolic regulation of myocardial blood flow and myocardial oxygen consumption.

Background: We tested the hypothesis that sildenafil increases myocardial dilator reserve in humans with ischemic heart disease., Methods: Positron emission tomography measured myocardial blood flow in 14 patients with ischemic heart disease. Patients were studied twice, in double-blind, placebo-control, cross-over design with sildenafil (or placebo) given approximately 2-3 h before measurements of hemodynamics and myocardial blood flow: at rest, with cold pressor stress and with adenosine. All myocardial segments of each patient with myocardial blood flow <1.65 ml/min per g with adenosine under placebo conditions were combined into one abnormal zone for that patient. Segments with myocardial blood flow >1.65 ml/min per g were averaged and combined into a normal zone for that patient., Results: At rest, rate pressure product (heart rate x systolic arterial pressure, mmHg/min) was comparable, as was abnormal zone myocardial blood flow (ml/min per g; 0.76+/-0.48 placebo versus 0.64+/-0.20 sildenafil, both P=NS; mean+/-SD). Both rate pressure product and myocardial blood flow increased (P<0.01) with cold pressor stress (11+/-3 K and 1.14+/-0.59 placebo versus 10+/-3 K and 1.21+/-0.62 sildenafil). However, sildenafil failed to improve the myocardial blood flow response to cold pressor stress in abnormal or normal zones. In contrast, abnormal zone myocardial blood flow reserve with adenosine and sildenafil (2.6+/-0.7) exceeded that with adenosine and placebo (2.0+/-1.3, P<0.04, paired sign test)., Conclusion: Sildenafil improves myocardial blood flow dilator response to adenosine in abnormal zones, possibly by augmenting nitric oxide-mediated increases in cGMP because adenosine response in part is nitric oxide dependent. Failure to improve myocardial blood flow response to cold pressor stress suggests that alpha-adrenergic constriction may offset enhanced nitric oxide effects. Clinically, the data suggest sildenafil may exert an anti-ischemic effect in patients with coronary artery disease.

Objectives: We investigated the acute effect of orally administered high-dose folic acid on coronary dilator function in humans., Background: Folic acid and its active metabolite, 5-methyltetrahydrofolate, increase endothelium-dependent vasodilation in human peripheral circulation. However, the acute effect on coronary circulation is not known., Methods: Fourteen patients with ischemic heart disease, age 62 +/- 12 years (mean +/- SD), were enrolled in a double-blind, placebo-controlled crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) were determined by positron emission tomography, and myocardial flow reserve was calculated. Each patient was studied after ingestion of placebo and after ingestion of 30 mg folic acid. Myocardial zones were prospectively defined physiologically as "normal" versus "abnormal" on the basis of MBF response to adenosine 140 microg/kg/min (normal = MBF >1.65 ml/min/g). Abnormal and normal zones were analyzed separately in a patient-based analysis., Results: Folate was associated with a reduction in mean arterial pressure (100 +/- 12 mm Hg vs. 96 +/- 11 mm Hg, placebo vs. folate, p < 0.03). Despite the fall in mean arterial pressure, folic acid significantly increased the MBF dose response to adenosine (p < 0.001 using analysis of variance) in abnormal zones, whereas MBF in normal zones did not change. In abnormal segments, folic acid increased peak MBF by 49% (1.45 +/- 0.59 ml/min/g vs. 2.16 +/- 1.01 ml/min/g, p < 0.02). Furthermore, folate increased dilator reserve by 83% in abnormal segments (0.77 +/- 0.59 vs. ml/min/g 1.41 +/- 1.08 ml/min/g, placebo vs. folate, p < 0.05), whereas dilator reserve in normal segments remained unchanged (2.00 +/- 0.61 ml/min/g vs. 2.12 +/- 0.69 ml/min/g, placebo vs. folate, p = NS)., Conclusions: The data demonstrate that high-dose oral folate acutely lowers blood pressure and enhances coronary dilation in patients with coronary artery disease.

Objective: This study tests the hypothesis that elevated levels of rest myocardial blood flow (MBF), indicative of inefficient aerobic metabolism, will be present in some patients with mitochondrial disorders but structurally normal hearts., Background: Regulation of MBF is a complex process closely linked to myocardial energy production. Aerobic metabolism in turn depends on normal mitochondrial function and so investigation of patients with mitochondrial disorders may provide important information regarding heritable mechanisms involved in regulation of myocardial flow., Methods: Rest and adenosine-stimulated MBF was measured by the positron emission tomography (PET) 13NH(3) technique in nine patients with mitochondrial disorders and compared with 15 age-matched control participants., Results: Basal heart rate (beats/min) and rate pressure product (mm Hg/min) were elevated in patients (76+/-13 and 9302+/-1910, mean+/-SD, respectively) compared with control participants (63+/-9 and 7411+/-1531, P<0.01 and P<0.05, respectively). However, rest and adenosine-stimulated MBF (ml/min per g) did not differ significantly between groups (patients, 1.13+/-0.52 and 4.17+/-0.84, respectively; control participants, 0.85+/-0.30 and 3.56+/-0.63, respectively). Normalization of rest MBF to rate pressure product, however, demonstrated three patients whose values exceeded that of all control participants (chi2=5.71, P<0.05, Fisher's exact test)., Conclusions: Elevated basal MBF, in some patients with mitochondrial disorders but structurally normal hearts, suggests the level of basal flow is responsive to efficiency of aerobic metabolism, which closely reflects mitochondrial function. Mitochondrial heteroplasmy with relative sparing of myocardial mitochondria may account for normal basal flow in others with these disorders.

Objectives: We sought to use positron emission tomography (PET) to test the hypothesis that hyperhomocysteinemia adversely effects coronary microvascular dilator function., Background: Hyperhomocysteinemia is associated with abnormal endothelium-dependent vasodilation in peripheral human arteries. However, its effect on the coronary circulation is not known., Methods: Eighteen healthy humans, age 24 to 56 years, were enrolled in a double-blind, crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) was determined by PET: after ingestion of placebo and after methionine-induced hyperhomocysteinemia. Further, brachial ultrasonography was used to assess flow-mediated vasodilation. Additionally, to assess the role of nitric oxide (NO) in adenosine-mediated vasodilation, the MBF response to adenosine was measured in the presence and absence of the NO synthase antagonist NG-monomethyl-l-arginine (l-NMMA) (0.3 mg/kg/min intravenously)., Results: Hyperhomocysteinemia resulted in a reduction in the MBF dose-response curve to adenosine (p < 0.05). This was most apparent with low dose adenosine, where MBF augmentation was significantly blunted during hyperhomocysteinemia (1.06 +/- 1.00 ml/min/g vs. 0.58 +/- 0.78 ml/min/g, placebo vs. methionine, p < 0.05). Similarly, flow-mediated brachial artery vasodilation was impaired during hyperhomocysteinemia (4.4 +/- 2.6% vs. 2.6 +/- 2.3%, placebo vs. methionine, p < 0.05). In a separate series of experiments, MBF during adenosine was reduced in the presence of l-NMMA (p < 0.05 analysis of variance). This was most apparent at the low dose of adenosine, where MBF response to adenosine was blunted in the presence of l-NMMA (2.08 +/- 1.34 ml/min/g vs. 1.48 +/- 1.32 ml/min/g, placebo vs. l-NMMA, p < 0.05)., Conclusion: The data, therefore, support the hypothesis that acute hyperhomocysteinemia impairs microvascular dilation in the human coronary circulation as a result of reduced NO bioavailability.

Objectives: We tested the hypothesis in patients (n = 24) with ischemic heart disease that chronic contractile dysfunction occurs in myocardial regions with true reduction in rest blood flow., Background: Whether viable myocardial regions with chronic contractile dysfunction have true reduction in rest myocardial blood flow is controversial., Methods: Positron emission tomography (PET) 13N-ammonia was used to measure myocardial blood flow in combination with 18F-fluorodeoxyglucose (18FDG) to assess myocardial viability. Viability also was assessed by dobutamine echo and recovery of function after coronary artery bypass grafting (CABG). Segments (n = 252) were selected based on PET measured reduced resting blood flow and rest asynergy on echo., Results: Regional myocardial viability was present in 20 of 23 patients by PET, 13 of 23 by dobutamine echo and 10 of 11 by postrevascularization criteria. Rest blood flow in normal regions was 1.14+/-0.52 ml/min/g and by definition exceeded (p < 0.005) that in both viable (0.48+/-0.15; n = 8 patients) and nonviable (0.45+/-0.14; n = 8 patients) regions (post-CABG criteria), which did not differ. Correction of rest myocardial blood flow in viable asynergic segments, only, for fibrosis and incomplete tracer recovery raised the level to 0.67+/-0.21 (p < 0.005 vs. normal). Finally, evidence of both stunning (rest asynergy with normal flow) and hibernation was present in 15 of 23 (65%) patients., Conclusions: Reduced rest blood flow in viable myocardial regions with chronic asynergy is common and cannot be accounted for by partial volume effect. Thus, hypotheses concerning physiologic mechanisms underlying chronic contractile dysfunction should consider the role played by chronic reduction of basal myocardial blood flow.

Objective: To test the hypothesis that, in humans with ischemic heart disease, nifedipine is a primary dilator of the coronary circulation and in general exerts a net positive effect on the balance of myocardial oxygen supply and demand., Methods: Positron-emission tomography with [13N]-ammonia was used to measure myocardial blood flow in patients at rest, and during infusion of adenosine and ingestion of nifedipine (10 mg capsule, a bite-and-chew technique). Myocardial segments were defined physiologically on the basis of blood flow to adenosine as being normal or having mild, moderate, or severe impairment of dilator reserve. Myocardial systolic function was assessed under comparable physiologic conditions using gated single-photon-emission computed tomography radionuclide ventriculography., Results: Our study population consisted of 13 male patients and one female patient. Ingestion of nifedipine increased heart rate (from 63 +/- 11 to 80 +/- 16 beats/min, P < 0.001) and, as intended, lowered systolic arterial pressure (from 148 +/- 20 to 123 +/- 14 mmHg, P < 0.001) but had no effect on heart rate-pressure product (which changed from 9283 +/- 1576 to 9942 +/- 2162 mmHg/min). Myocardial blood flow in patients at rest in segments with mild, moderate, and severe reductions of dilator capacity (0.63 +/- 0.20, 0.67 +/- 0.25, and 0.58 +/- 0.27 ml/min per g, respectively) was less (P < 0.01) than normal (0.91 +/- 0.29 ml/min per g). Nevertheless, flow of blood was increased versus that at rest (P < 0.01) by infusion of adenosine (to 1.78 +/- 0.13, 1.29 +/- 0.16, and 0.75 +/- 0.22 ml/min per g) and ingestion of nifedipine (to 1.17 +/- 0.51, 1.06 +/- 0.36, 0.85 +/- 0.42 ml/min per g) in segments with mild, moderate, and severe reduction of dilator capacity as well as in normal segments (to 3.18 +/- 0.85 ml/min per g with adenosine and 1.68 +/- 0.65 ml/min per g with nifedipine). Global left ventricular systolic function remained unchanged versus baseline (ejection fraction 0.74 +/- 0.09) with nifedipine (0.76 +/- 0.10). Regional contraction expressed in normalized amplitude units also remained unchanged versus baseline in response to nifedipine., Conclusion: Nifedipine increases myocardial blood flow in humans with ischemic heart disease in normal segments as well as in segments with mild, moderate, and severe reductions of dilator capacity, albeit to a lesser extent with increasing impairment of dilator capacity. Both global and regional left ventricular contractile function also are not adversely affected by nifedipine. These improvements in myocardial blood flow in face of no change or a decrease in myocardial demand for oxygen reflect an overall favorable effect on the balance between the supply of and demand for myocardial oxygen.

This study tests the hypothesis that myocardial blood flow and coronary microvascular dilator capacity vary as a function of time after orthotopic heart transplantation in humans. Positron emission tomography measurements of myocardial blood flow were obtained at rest and during adenosine in 24 patients between 1 and 86 months after heart transplantation. At the time of the study all patients were clinically well and had angiographically normal epicardial coronary artery vessels. Patients were divided into 3 groups based on time from transplant to positron emission tomography measurement of myocardial blood flow: group 1 to 12 months (n = 9); group 13 to 34 months (n = 8); and group > or = 37 months (n = 7). Basal myocardial blood flow in group 1 to 12 months (1.86+/-1.01 ml/min/g) exceeded (p <0.05) that of group 13 to 34 months (1.17+/-0.73) and group > or = 37 months (0.98+/-0.34). In group 13 to 34 months, basal myocardial blood flow and maximal dilator capacity (minimal coronary vascular resistance with adenosine 36+/-12 mm Hg/ml/min/g) were comparable to that of normal volunteers (1.01+/-0.20 and 37+/-, respectively). In group > or = 37 months, maximal flow response to adenosine was reduced (2.54+/-1.25 vs 3.16+/-0.52, respectively, p = 0.06). Maximal dilator capacity in group > or = 37 months (60+/-34) was impaired versus group 1 to 12 months (36+/-10) and group 13 to 34 months (36+/-12; both p <0.05) as well as normals (37+/-9, p <0.05). During the first year after cardiac transplantation basal myocardial blood flow is elevated out of proportion to external determinants of myocardial oxygen demand, but maximal dilator capacity of the coronary microcirculation is normal. Between 1 and 3 years both basal myocardial blood flow and microvascular function tend to normalize. After 3 years, although basal myocardial blood flow is normal, microvascular dilator capacity is impaired.

Background: We tested the hypothesis that correction of hyperlipidemia improves coronary vasodilator response and maximal perfusion in myocardial regions having substantial impairment of pretreatment vasodilator capacity., Methods and Results: Measurements of myocardial blood flow were made with PET [13N]ammonia in 12 patients with ischemic heart disease (11 men; age, 65+/-8 years [mean+/-SD]) at rest and during adenosine at 70 and then 140 microg . kg-1 . min-1 for 5 minutes each before and approximately 4 months after simvastatin treatment (40 mg daily). Simvastatin reduced LDL (171+/-13 before versus 99+/-18 mg/dL after simvastatin, P<0.001) and increased HDL (39+/-8 versus 45+/-9 mg/dL, P<0.05). Myocardial segments were classified on the basis of pretreatment blood flow response to 140 microg . kg-1 . min-1 adenosine as normal (flow >/=2 mL . min-1 . g-1) or abnormal (flow <2 mL . min-1 . g-1). In normal segments, baseline myocardial blood flow (0.95+/-0.32) increased (P<0.001) at both low- (1.62+/-0.81) and high- (2.63+/-0.41) dose adenosine and was unchanged both at rest and with adenosine after simvastatin. In abnormal segments, myocardial blood flow at rest (0. 73+/-0.19) increased at low- (1.06+/-0.59, P<0.02) and high- (1. 29+/-0.33, P<0.01) dose adenosine. After simvastatin, myocardial blood flow increased more compared with pretreatment at both low- (1. 37+/-0.66, P<0.05 versus pretreatment) and high- (1.89+/-0.79, P<0. 01 versus pretreatment) dose adenosine., Conclusions: Short-term lipid-lowering therapy increases stenotic segment maximal myocardial blood flow by approximately 45%. The mechanism involves enhanced, flow-mediated dilation of stenotic epicardial conduit vessels and may account at least in part for the efficacy of lipid lowering in secondary prevention trials and in reducing ischemic episodes in ambulatory patients.

Background: This study tests the hypothesis in humans with ischemic heart disease that myocardial blood flow response to dobutamine is linearly correlated with blood flow response to adenosine., Methods and Results: PET with [13N]ammonia was used to measure myocardial blood flow at rest and during adenosine and dobutamine at the maximally tolerated dose. Myocardial segments were defined physiologically on the basis of blood flow response to adenosine: normal, > or = 2 mL x min(-1) x g(-1); abnormal, < 2 mL x min(-1) x g(-1); and "steal," decline versus baseline > or = 0.15 mL x min(-1) x g(-1). The patient population consisted of 11 men and 2 women. Dobutamine increased heart rate (79+/-22 to 115+/-28 bpm) and rate-pressure product (9748+/-2862 to 15,157+/-3433 mm Hg/min) significantly (both P<.01). Myocardial blood flow at rest in abnormal segments (0.50+/-0.23 mL x min(-1) x g(-1)) was reduced (P<.001) versus normal (0.90+/-0.45) and steal (0.92+/-0.60). Nevertheless, in abnormal segments, blood flow increased versus rest (P<.001) with dobutamine (0.83+/-0.43) and adenosine (0.90+/-0.49). In steal segments, myocardial blood flow declined versus baseline (P<.001) with dobutamine (0.68+/-0.46) and adenosine (0.50+/-0.45). In normal segments, myocardial blood flow increased (P<.001) with dobutamine (2.16+/-0.99) and adenosine (3.10+/-0.90). Over the range of flows, the correlation between adenosine and dobutamine was good (r=.78, P<.0001). Although flow with dobutamine in normal segments correlated with rate-pressure product (r=.81, P<.05), the slope of the line was 2.7+/-0.8 (P<.02), and normalized blood flow (3.3+/-2.5 x rest) exceeded normalized rate-pressure product (1.9+/-0.8 x rest; P<.05)., Conclusions: In humans with ischemic heart disease, myocardial blood flow responses to dobutamine and adenosine are linearly correlated over a wide range. The hyperemic response to dobutamine is in excess of that predicted by rate-pressure product and reflects the unmeasured inotropic, oxygen-wasting, and beta2-agonist effects of the drug. Dobutamine induces coronary steal with a frequency approaching that of adenosine.

Objectives: To test the hypotheses: that acute administration of 17 beta-estradiol dilates normal coronary microvessels in vivo; that coronary microvascular responses to acute estrogen stimulation exhibit sexual dimorphism; and that nitric oxide has a role in mediating these effects., Methods: Measurements of hemodynamics, coronary flow velocity (Doppler), myocardial blood flow (microspheres) and oxygen consumption were made in closed-chest swine: group 1 consisted of castrated juvenile males, groups 2 and 3 of estrogen pretreated, castrated juvenile males, and group 4 of sexually mature females. 17 beta-Estradiol (2, 20 or 200 ng/kg) was given by intracoronary injection and data obtained 20-30 min later; additional measurements were made 1 h after the 200 ng/kg dose. The effect of L-NG-monomethylarginine (L-NMMA) on 17 beta-estradiol responses was also tested. Tissue and blood concentrations of 17 beta-estradiol, and concentrations of estrogen receptor in myocardium and coronary vessels were obtained., Results: In estrogen-naive castrated males, 17 beta-estradiol had no effect on coronary flow velocity or myocardial blood flow, but 1 h after the 200 ng/kg dose there was an increase in diastolic coronary resistance compared with baseline (48 +/- 20 versus 41 +/- 17 mmHg/mkHz; P < 0.05). Estrogen pretreated castrated males also showed no change in myocardial blood flow after 17 beta-estradiol, but coronary flow velocity decreased (P < 0.05) compared with baseline 1 h after the 200 ng/kg dose (from 1.69 +/- 0.61 to 1.41 +/- 0.42 kHz) and diastolic coronary resistance increased significantly (P < 0.01) compared with control at this time (51 +/- 15 compared with 39 +/- 14 mmHg/mkHz). In sexually mature females, 17 beta-estradiol had no effect on myocardial blood flow but did cause a significant (P < 0.05) decrease in diastolic coronary vascular resistance compared with baseline (51 +/- 9 mmHg/mkHz) at both the 20 ng/kg and the 200 ng/kg doses (both 43 +/- 11 mmHg/mkHz). Coronary flow velocity also increased (P < 0.06) compared with baseline (1.34 +/- 0.26 mmHg/mkHz) after the 200 ng/kg dose (1.69 +/- 0.61 mmHg/mkHz). L-NMMA had no effect on flow responses to 17 beta-estradiol in any group. Classical estrogen receptors were not present in myocardium or coronary arteries from male or female swine., Conclusions: These results demonstrate that 17 beta-estradiol exerts a mild constrictor effect on the coronary microvessels of normal castrated, juvenile males whether estrogen-naive or estrogen-pretreated. In contrast, sexually mature normal females exhibit mild dilatation of the coronary microcirculation in response to acute estrogen stimulation. Nitric oxide does not appear to have a role in mediating the dilator response in females, and classical estrogen receptors are not involved. A direct membrane effect of the hormone (perhaps via alteration in potassium conductance) seems likely, and demonstrates sexual dimorphism.

Background: We tested the hypotheses that prolonged, demand-induced myocardial ischemia plateaus and that on relief of stress, myocardial function remains depressed, with proportionate reductions in blood flow and oxygen consumption indicative of hibernation., Methods and Results: Closed-chest swine (n = 20) were prepared with an 80% coronary stenosis. Hemodynamics, myocardial blood flow, oxygen, and lactate metabolism were measured in group 1 (n = 9) (1) at baseline, (2) at 10 and 30 minutes of atrial pacing plus intravenous norepinephrine infusion, and (3) in 5 of 9 (group 1a) at approximately 50 minutes after stress. Group 1a had ischemia assessed with 99mTc-labeled BMS 181321. In group 2 (n = 11), myocardial function was determined with radionuclide ventriculography (n = 8), and myocardial necrosis was looked for with trichlorotetrazolium chloride staining (n = 7), histology (n = 10), and myocardial creatine kinase concentration (n = 4). Baseline stenotic-zone endocardial blood flow was reduced versus the normal zone (0.94 +/- 0.33 versus 1.38 +/- 0.27 mL.min-1.g-1, mean +/- SD; P < .05), whereas epicardial flows were comparable (1.15 +/- 0.36 versus 1.16 +/- 0.26 mL.min-1.g-1). Stenotic-zone endocardial flow was unchanged versus baseline at 10 and 30 minutes of stress, whereas epicardial flow increased (1.62 +/- 0.53 mL.min-1.g-1 at 10 minutes and 1.44 +/- 0.51 mL.min-1.g-1 at 30 minutes, both P < .05). Myocardial oxygen consumption increased versus baseline (10.8 +/- 2.9 mL.min-1.100 g-1) at 10 and 30 minutes of stress (14.9 +/- 5.2 and 13.9 +/- 4.5 mL.min-1.100 g-1, both P < .05). After stress, stenotic-zone blood flow and oxygen consumption were reduced approximately 30% (P < .01) versus baseline. In group 2, stenotic-zone contraction with stress declined versus baseline and remained depressed throughout recovery. Histological and biochemical evidence of myocardial necrosis was absent in group 2., Conclusions: Myocardial ischemia induced by a sustained increase in oxygen demand may not progress to necrosis but may instead plateau. After relief of stress, myocardial function remains depressed, with a proportionate reduction in blood flow and oxygen consumption consistent with myocardial hibernation.

Background: We hypothesized that the response of a myocardial segment to maximal dobutamine reflects not only maximal blood flow but also tethering, metabolic, and beta-blocker status., Methods and Results: Patients with stable ischemic heart disease (n = 27) had positron emission tomographic measurement of blood flow at rest and with adenosine, and echocardiography at rest and with dobutamine. Positron emission tomographic measurement of [18F]fluorodeoxyglucose myocardial distribution also was made. Adenosine blood flow in segments that contracted normally at peak dobutamine was similar to that of segments that became hypokinetic (1.06 +/- 0.72 versus 1.02 +/- 0.77 mL.g-1.min-1). Segments that became akinetic failed to augment blood flow (0.68 +/- 0.30 mL.g-1.min-1). Fluorodeoxyglucose-blood flow mismatch was more common in segments with abnormal wall motion at peak dobutamine (24 of 59, 41%) versus those that contracted normally (63 of 269, 23%; chi 2, 7.40; P < .01). In patients off beta-blockers, segments that contracted normally at peak dobutamine increased blood flow with adenosine (0.70 +/- 0.31 to 0.86 +/- 0.46 mL.g-1.min-1; P < .05), whereas those that became abnormal did not (0.63 +/- 0.24 to 0.65 +/- 0.19 mL.g-1.min-1; P = NS). Segments of patients on beta-blockers that contracted normally at peak dobutamine increased blood flow with adenosine (0.78 +/- 0.31 to 1.10 +/- 0.70 mL.g-1.min-1; P < .05), as did segments that became abnormal (0.74 +/- 0.34 to 1.06 +/- 0.82 mL.g-1.min-1; P = NS). However, segments adjacent to ones with abnormal wall motion at rest had higher frequency of abnormal response at peak dobutamine in groups on (48% versus 16%; chi 2, 14.1; P < .001) and off (51% versus 21%; chi 2, 10.9; P < .01) beta-blockers., Conclusions: Augmented contraction at maximal dobutamine depends not only on increased myocardial blood flow but also on tethering, metabolic, and beta-blocker status. Furthermore, impaired flow reserve does not preclude a normal response to maximal dobutamine, since blood flow need not increase greatly to meet demand.

Unlabelled: The purpose of this study was to test the hypothesis that 99mTc-teboroxime retention within the heart depends at least in part on the presence of viable myocytes., Methods: We used a porcine model of acute myocardial infarction with reperfusion and compared the myocardial uptake of labeled microspheres at 1 hr of reperfusion with that of 99mTc-teboroxime. Eleven domestic swine had measurements of hemodynamics and regional myocardial blood flow (microspheres) at baseline, at 10 and 50 min of left anterior descending (LAD) coronary artery occlusion and at 10 and 60 min of LAD reperfusion. Technetium-99m-teboroxime was injected intravenously at 60 min of reperfusion and the animal was killed 5-7 min later. The heart was then perfused with triphenyl tetrazolium chloride to identify infarcted and jeopardized myocardium in the occlusion zone and with Evans blue dye to mark normally perfused myocardium. After imaging, tissue sections were digested and colored microspheres were extracted and counted to determine myocardial blood flow., Results: After coronary occlusion, infarct zone (MIZ) to normal zone (NZ) blood flow ratios declined from 0.95 +/- 0.27 (pre-occlusion) to 0.18 +/- 0.15 at 10 min and 0.25 +/- 0.35 at 50 min of occlusion (both p < 0.05). The MIZ:NZ count ratio at 60 min of reperfusion was less than the MIZ:NZ blood flow ratio in every animal and over the entire range of flow ratios (0.55-3.64)., Conclusion: Technetium-99m-teboroxime requires viable myocytes for retention within the heart and is not exclusively a tracer of myocardial blood flow when imaged 5-7 min after injection. Additional in vivo imaging studies are required to determine the extent to which reduced retention of the tracer by reperfused but nonviable myocardium influences the appearance of clinical scans.

Objectives: This study tested the hypothesis that nonviable myocardium can be identified by quantitative measurements of regional myocardial blood flow obtained using positron emission tomography in conjunction with a mathematical model of nitrogen-13 (N-13) ammonia tracer kinetics., Background: Under steady state basal conditions there is a minimal level of blood flow required to sustain myocardial viability. Therefore, the hypothesis predicts that regions with flow below a certain threshold are likely to be composed primarily of scar., Methods: Studies were conducted in 26 patients with chronic myocardial infarction. Positron emission tomographic measurements of basal regional myocardial blood flow (N-13 ammonia) and fluorine-18 (F-18) fluorodeoxyglucose uptake were made and correlated with information about coronary anatomy and regional wall motion to assess myocardial viability., Results: In patients with chronic myocardial infarction, normal zone blood flow (0.81 +/- 0.32 ml/min per g [mean +/- SD]) was greater (p < 0.02) than that of border zones (0.59 +/- 0.29 ml/min per g), which in turn exceeded (p < 0.001) that of infarct zone flow (0.27 +/- 0.17 ml/min per g). Good correlation was noted between relative F-18 fluorodeoxyglucose uptake and relative regional myocardial blood flow in all zones (r = 0.63, p < 0.001). Mismatch between blood flow and F-18 fluorodeoxyglucose uptake, with a single exception, was not observed in any segment with blood flow < 0.25 ml/min per g. All dyskinetic segments (n = 5) also had blood flow < 0.25 ml/min per g. In contrast, 43 of 45 myocardial segments (23 patients) with normal contraction or only mild hypokinesia had flow > or = 0.39 ml/min per g (average flow 0.78 +/- 0.35 ml/min per g)., Conclusions: In patients with chronic myocardial infarction, myocardial viability is unlikely when basal regional myocardial blood flow is < 0.25 ml/min per g. Average basal flow in segments with normal or nearly normal wall motion is 0.78 +/- 0.35 ml/min per g. Thus, positron emission tomographic measurement of regional myocardial blood flow is helpful in identifying nonviable myocardium in these patients.

We tested the hypothesis that chronic reduction in perfusion pressure and flow in the coronary circulation induces a state of myocardial "hibernation" characterized not only by a steady-state reduction in myocardial O2 consumption (MVO2) but also by evidence of persistent dilator reserve of the distal vasculature. Biochemical and morphological changes in the coronary vasculature were also assessed. Experiments were conducted in swine with an extraluminal coronary stenosis placed 4-32 wk before study. Stenosis reduced lumen diameter by approximately 80% at the time of final experimentation. Baseline, regional myocardial blood flow distal to the stenosis in both endocardial and epicardial layers was reduced vs. that of the normal zone. Vasodilator reserve persisted in both endocardial and epicardial layers of the stenosis zone. Flow increased in each layer in response to adenosine plus phenylephrine and failed to decline despite a marked reduction in perfusion pressure in response to adenosine alone. Regional MVO2 at baseline was reduced vs. historical controls without coronary stenosis. Protein synthesis rate in coronary vessels of the stenosis zone was reduced vs. that of the normal zone. Morphological responses of stenosis zone vessel walls were heterogeneous. Smaller microvessels exhibited mild hypertrophy of their walls, whereas walls of larger microvessels tended to atrophy. Thus chronic reduction in perfusion pressure and flow induces a state of myocardial hibernation characterized by a steady-state reduction in MVO2 in association with persistent dilator capacity. Biochemical and morphological changes occur in microvessel walls and may contribute to observed physiological responses.

This study tested the hypothesis that anterior interventricular vein effluent of domestic swine is composed primarily of blood draining the perfusion territory of the left anterior descending coronary artery. As a corollary, the extent to which circumflex and right coronary inflow contributes to anterior interventricular vein outflow also was determined. Experiments were conducted in vitro with buffer-perfused swine hearts in which anterior interventricular vein flow was measured under various combinations of left anterior descending and circumflex coronary perfusion. Studies also were performed in vivo in different groups of intact swine with normal, stenosed, and occluded left anterior descending coronary artery. The results of the study confirm the hypothesis and demonstrate under a variety of conditions that at least 90% of anterior interventricular vein effluent is derived from blood originating from myocardium perfused by the left anterior descending coronary artery.

This study tested the hypothesis that 5-HT may impair coronary flow regulation by inappropriately increasing arteriolar tone in the coronary circulation. Ten closed chest, domestic swine were studied both in the presence and in the absence of a severe artificial intraluminal coronary stenosis. A 5-French micromanometer catheter with fluid lumen was placed in the left anterior descending coronary artery and used to record pressure and infuse 5-HT (40 and 100 micrograms/min) into the coronary circulation. For the stenosis phase of the protocol the catheter was embedded in the artificial stenosis. Hemodynamics, regional myocardial blood flow (microsphere technique), coronary vascular resistance, lactate consumption, and oxygen metabolism were measured at control and at 5 min of each 5-HT dose. In the absence of coronary artery stenosis (i.e., full vasodilatory reserve), there was no change in regional myocardial blood flow or coronary vascular resistance during 5-HT infusion. In the presence of a severe coronary stenosis (i.e., limited vasodilator reserve) 5-HT produced a significant (P less than 0.05) decrease versus control in the distal left anterior descending: circumflex zone endocardial blood flow ratio (0.63 +/- 0.19, mean +/- 1 SD, to 0.55 +/- 0.15) and a significant (P less than 0.05) increase versus control in endocardial (50.6 +/- 16.6 to 61.2 +/- 19.8 mm Hg/ml/min/g) and transmural (49.9 +/- 9.5 to 57.2 +/- 12.8) coronary vascular resistance. Thus, 5-HT does not impair coronary flow regulation when full vasodilatory reserve is present. When coronary vasodilatory reserve is impaired by the presence of a severe proximal stenosis, 5-HT causes modest impairment of endocardial flow regulation.

This study examined the role of adenosine in regulating coronary arteriolar tone under basal conditions in the normal coronary circulation. Measurements of hemodynamics and flow (microspheres) were made in eight closed-chest, sedated pigs at 1) control and 2) after 10 min of infusion of adenosine deaminase (ADA, 10 U X kg-1 X min-1) into the left anterior descending (LAD) coronary artery. Heart rate was held constant by atrial pacing. Transmural flow in the distal LAD zone did not change versus control (1.81 +/- 0.36) with ADA (1.78 +/- 0.46). However, in comparison with control the distal LAD:circumflex zone transmural flow ratio (0.96 +/- 0.04) declined (P less than 0.01) during ADA infusion (0.93 +/- 0.04). Similarly, the distal LAD:circumflex zone transmural flow resistance ratio increased significantly (P less than 0.01) versus control (1.04 +/- 0.05) in response to intracoronary ADA infusion (1.08 +/- 0.04). Regional myocardial oxygen consumption in the distal LAD zone did not change versus control (16.9 +/- 3.3 3.3 ml X min-1 X 100 g-1) during ADA (16.9 +/- 4.5). Additional studies in 15 open-chest swine given intracoronary infusion of ADA demonstrated that 1) the enzyme penetrates the interstitial fluid (ISF) and 2) attains ISF levels which are adequate to reduce basal adenosine concentration 10 fold even if substantial increase in adenosine production occurs in response to ADA. Thus, since destruction of adenosine by ADA caused only very modest relative reduction in regional flow, it is likely that the nucleoside plays only a limited role in regulation of arteriolar tone under basal conditions in the normal coronary circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

To test the hypothesis that endogenous prostacyclin is required to maintain reduced arteriolar tone distal to a severe coronary arterial stenosis under basal conditions and during challenge with a vasoconstrictor eicosanoid such as thromboxane A2 10 closed chest, domestic swine were prepared with an artificial stenosis, which reduced the luminal diameter of the left anterior descending coronary artery by 80%. Haemodynamic variables, regional myocardial blood flow (microsphere method), and lactate metabolism were measured at control (1); after infusion of U46619 (thromboxane A2 mimetic) distal to the stenosis at 1 microgram.min-1 for 10 min and 5 micrograms.min-1 for 10 min; at control (2); after indomethacin infusion distal to the stenosis; and after repeat infusion of U46619. At the end of the study the animal hearts were removed and their coronary vessels harvested for in vitro determination of prostacyclin (PGI2) production. Regional myocardial blood flow in all layers of the heart distal to the stenosis did not change compared with control during the initial 1 microgram.min-1 dose of U46619 but was reduced significantly after the 5 micrograms.min-1 dose (approximately 20% vs control). Distal zone flow (all layers) returned to baseline at control (2) and remained unchanged after indomethacin infusion. Although distal zone flows were reduced significantly in response to the second 5 micrograms.min-1 dose, the reduction in each layer after indomethacin was comparable to that observed with the 5 micrograms.min-1 dose before indomethacin infusion. Finally, the in vitro production of PGI2 by coronary vessels was considerably impaired by indomethacin infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

To test the hypothesis that adenosine is required to mediate the sustained increase in myocardial flow evoked by isoproterenol haemodynamic indices, myocardial blood flow (microspheres), and regional myocardial oxygen consumption were measured in eight closed chest, sedated pigs at control, after isoproterenol (6.9(2.8) ng X kg-1 X min-1 (mean (SD)) infused into the left anterior descending coronary artery, repeat control, and after a simultaneous infusion of the same dose of isoproterenol and adenosine deaminase (10 U X kg-1 X min-1). Data were acquired at one and 10 minutes after each infusion and compared with control measurements. Heart rate was held constant by atrial pacing. Peak left ventricular dP/dt (mm Hg X s-1) increased significantly (control 2190(32) mean (SD)) at both one (2900(302)) and 10 minutes (3010(391)) of isoproterenol infusion alone. At one minute of simultaneous infusion there was no change (control 1970(447)) in left ventricular dP/dt (2290(521)), although dP/dt was significantly increased at 10 minutes of simultaneous infusion (2790(483)). Transmural flow (ml X min-1 X g-1) increased significantly (control 1.49(0.46)) in the distal left anterior descending zone at one (1.94(0.48)) and 10 minutes (2.07(0.27)) of isoproterenol infusion alone. In contrast, flow failed to increase (control 1.65(0.27)) during the first minute of simultaneous infusion (1.73(0.38)), although it did increase significantly by 10 minutes (1.91(0.21). Finally, although myocardial oxygen consumption (ml X min-1 X 100 g-1) increased significantly (control 16.4(4.7)) at both one (20.1(4.7)) and 10 minutes (19.4(3.6)) of isoproterenol infusion alone, it failed to increase (control 18.2(3.8)) at one (19.3(4.6)) and 10 minutes (19.1(3.8)) of simultaneous infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

This study tested the hypothesis that intrinsic negative inotropic effects of a drug used to induce coronary vasodilation distal to a severe coronary arterial stenosis may influence the extent of redistribution of transmural flow and its metabolic consequences. To test this hypothesis, studies were conducted in eight closed-chest, sedated swine with severe (82% reduction in luminal diameter) coronary arterial stenoses. Measurement of hemodynamic parameters, regional myocardial blood flow (microsphere technique), lactate metabolism, and oxygen consumption were made (1) under control conditions, (2) after 10 min of intracoronary infusion of a vasodilator distal to the stenosis, and (3) under repeat control conditions. Each animal received both intracoronary adenosine (400 micrograms/min) and nifedipine (50 micrograms/min). The order of drug infusion was chosen at random and a control period separated administration of each. In response to nifedipine there was no significant change in the group mean (+/- SD) value of endocardial flow (1.21 +/- 0.34 to 1.29 +/- 0.61 ml/min X g-1) distal to the stenosis. In contrast, epicardial flow increased in comparison with control in response to nifedipine (1.30 +/- 0.58 to 1.79 +/- 0.74 ml/min X g-1; p less than .05). Regional myocardial oxygen consumption (MVO2) declined in comparison with control in response to nifedipine (14.0 +/- 4.2 to 11.1 +/- 5.0 ml/min X 100 g-1; p less than .05). Regional lactate extraction did not change in comparison with control during infusion of nifedipine (18.2 +/- 22.4 vs 11.7 +/- 16.8). In response to adenosine, endocardial blood flow distal to the stenosis declined in comparison with control (1.25 +/- 0.53 to 1.07 +/- 0.38 ml/min X g-1; p less than .05), while epicardial flow increased (1.31 +/- 0.55 to 2.26 +/- 0.59 ml/min X g-1; p less than .01). Regional MVO2 also tended to decline in comparison with control in response to adenosine (13.4 +/- 4.9 to 11.7 +/- 2.9 ml/min X 100 g-1) and was significantly (p less than .05) reduced in comparison with postintervention control (14.6 +/- 4.2 ml/min X 100 g-1). In contrast to nifedipine, adenosine caused a significant decline in regional lactate extraction in comparison with control (12.7 +/- 23.2% to -40.6 +/- 55.0%; p less than .01). Thus, administration of nifedipine, a negative inotropic agent, resulted in (1) a decline in regional MVO2, (2) increased epicardial blood flow with variable effects on endocardial flow distal to the stenosis, and (3) no evidence of de novo or worsening ischemia, even in animals in which endocardial flow decreased.(ABSTRACT TRUNCATED AT 400 WORDS)

Limited data are available concerning the effects of mild-to-moderate, sustained reductions of coronary blood flow on myocardial aerobic metabolism. This study tested the hypothesis that a sustained flow reduction distal to a severe coronary artery stenosis may be well tolerated (after the initial insult is passed) because of gradual improvement in the balance between myocardial oxygen supply and demand. Studies were performed in eight sedated, closed-chest domestic swine that were instrumented with an artificial coronary arterial stenosis (80% diameter reduction). Hemodynamics, regional myocardial blood flow and oxygen, lactate, acid, and base metabolism were measured before stenosis and at 5, 20, 60, 120, and 180 minutes after stenosis insertion. Regional myocardial function (ultrasonic length sensors) was measured serially during 2 hours in three additional swine. After stenosis placement, endocardial and transmural flows declined (p less than 0.05) compared with flows before stenosis (from 1.54 +/- 0.37 to 0.73 +/- 0.24 ml/min/g [mean +/- SD] and from 1.44 +/- 0.31 to 1.19 +/- 0.25 ml/min/g, respectively). Thereafter, flows remained unchanged for the duration of the study. Similarly, prestenosis heart rate (135 +/- 7 beats/min), aortic mean pressure (113 +/- 17 mm Hg), and tension time index (27.1 +/- 3.6 mm Hg.sec) remained constant for the duration of the study. In contrast, regional coronary venous pH declined (p less than 0.05) compared with prestenosis levels (7.35 +/- 0.02) 5 minutes after stenosis (7.28 +/- 0.04), but it returned to prestenosis levels during the next hour. Regional coronary venous PCO2 exhibited a similar pattern (i.e., acute increase during poststenosis with gradual return to prestenosis levels).(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether a reduction in myocardial oxygen demand or an increase in coronary blood flow or both are responsible for the salutory effect of intraaortic balloon counterpulsation (IABP) in relieving medically refractory angina, we assessed these variables in six patients in whom IABP was required for relief of myocardial ischemia. IABP decreased the rate-pressure product and aortic end-diastolic pressure, and the peak systolic aortic pressure and regional myocardial oxygen consumption declined in all but one patient. Peak and mean aortic diastolic pressures increased. Changes in regional coronary blood flow paralleled changes in peak systolic aortic pressure (r = 0.92, p less than 0.007). Thus, relief of angina during IABP could not be ascribed to an increase in regional coronary blood flow. Reduction of myocardial oxygen consumption is the most likely mechanism by which IABP relieves myocardial ischemia in patients with unstable angina pectoris.

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)