Persistent Coronary Vasomotor Tone During Myocardial Ischemia Occurs at the Capillary Level and May Involve Pericytes.

Background: There is persistent coronary vasomotor tone during myocardial ischemia, despite ongoing coronary arteriolar dilatation. The mechanism underlying this vasodilatory tone, which can be unmasked by coronary vasodilators, is unclear. We hypothesized that persistent microvascular resistance during myocardial ischemia occurs at the level of capillaries and may be caused by pericytes. Methods: We studied nine instrumented dogs where coronary blood flow and coronary driving pressure were reduced to half by placement of stenoses. Myocardial blood flow and myocardial blood volume were measured with myocardial contrast echocardiography before and during adenosine administration. In three animals, the heart was perfusion-fixed under these conditions for electron microscopic assessment of capillary and pericyte size. Results: During ischemia, myocardial blood volume decreased and myocardial vascular resistance remained unchanged. Adenosine administration reversed the decline in myocardial blood volume and decreased myocardial vascular resistance. Electron microscopy showed larger capillaries in ischemic beds receiving adenosine than ischemic beds not receiving adenosine. Pericytes in beds receiving adenosine also tended to be larger. Conclusion: Capillaries are the site of persistent vasomotor tone during myocardial ischemia; any other site of vascular regulation (arterioles or venules) cannot explain these myocardial contrast echocardiography findings, which are confirmed on post-mortem electron microscopic examination. The decrease in capillary size is likely caused by pericyte contraction in an attempt to maintain a constant capillary hydrostatic pressure. Adenosine relaxes pericytes, restores myocardial blood volume, reduces myocardial vascular resistance, and improves regional function during ischemia. These findings could have important therapeutic implications.

Plasma Oxylipins: A Potential Risk Assessment Tool in Atherosclerotic Coronary Artery Disease.

Background: While oxylipins have been linked to coronary artery disease (CAD), little is known about their diagnostic and prognostic potential. Objective: We tested whether plasma concentration of specific oxylipins may discriminate among number of diseased coronary arteries and predict median 5-year outcomes in symptomatic adults. Methods: Using a combination of high-performance liquid chromatography (HPLC) and quantitative tandem mass spectrometry, we conducted a targeted analysis of 39 oxylipins in plasma samples of 23 asymptomatic adults with low CAD risk and 74 symptomatic adults (≥70% stenosis), aged 38-87 from the Greater Portland, Oregon area. Concentrations of 22 oxylipins were above the lower limit of quantification in >98% of adults and were compared, individually and in groups based on precursors and biosynthetic pathways, in symptomatic adults to number of diseased coronary arteries [(1) n = 31; (2) n = 23; (3) n = 20], and outcomes during a median 5-year follow-up (no surgery: n = 7; coronary stent placement: n = 24; coronary artery bypass graft surgery: n = 26; death: n = 7). Results: Plasma levels of six quantified oxylipins decreased with the number of diseased arteries; a panel of five oxylipins diagnosed three diseased arteries with 100% sensitivity and 70% specificity. Concentrations of five oxylipins were lower and one oxylipin was higher with survival; a panel of two oxylipins predicted survival during follow-up with 86% sensitivity and 91% specificity. Conclusions: Quantification of plasma oxylipins may assist in CAD diagnosis and prognosis in combination with standard risk assessment tools.

Therapeutic Ultrasound Improves Myocardial Blood Flow and Reduces Infarct Size in a Canine Model of Coronary Microthromboembolism.

BACKGROUND: Therapeutic ultrasound (TUS) has been used to lyse infarct-related coronary artery thrombus. There has been no study examining the effect of TUS specifically on myocardial microthromboemboli seen in acute myocardial infarction and acute coronary syndromes. The aim of this study was to test the hypothesis that TUS improves myocardial blood flow (MBF) and reduces infarct size (IS) in this situation by dissolving myocardial microthrombi. METHODS: An open-chest canine model of myocardial microthromboembolism was created by disrupting a thrombus in the left anterior descending coronary artery, and 1.05- and 0.25-MHz TUS (n = 7 each) delivered epicardially for 30 min was compared with control (n = 6). MBF and IS (as a percentage of left anterior descending coronary artery perfusion bed size) were measured 60 min after treatment. In addition, immunohistochemistry was performed to assess microthrombi, and histopathology was performed to define inflammation. RESULTS: Transmural, epicardial, and endocardial myocardial blood volume and MBF (measured using myocardial contrast echocardiography) and percentage wall thickening were significantly higher 60 min after receiving TUS compared with control. The ratio of IS to left anterior descending coronary artery perfusion bed size was significantly smaller (P = .03) in the 1.05-MHz TUS group (0.14 ± 0.04) compared with the control (0.31 ± 0.06, P = .04) and 0.25-MHz (0.36 ± 0.08) groups. MBF versus percentage wall thickening exhibited a linear relation (r = 0.65) in the control and 1.05-MHz TUS groups but not in the 0.25-MHz TUS group (r = 0.29). The presence of myocardial microemboli in vessels >10 µm in diameter was significantly reduced in the 1.05-MHz TUS group compared with the other two groups. The distribution and intensity of inflammation was higher in the 0.25-MHz TUS group compared with the other groups. CONCLUSIONS: TUS at 1.05 MHz is effective in restoring myocardial blood volume and MBF, thus reducing IS by clearing the microcirculation of microthrombi. IS reduction is not seen at 0.25 MHz, despite improvement in MBF, which may be related to the increased inflammation noted at this frequency. Because both acute myocardial infarction and acute coronary syndromes are associated with microthromboembolism, these results suggest that TUS could have a potential adjunctive role in the treatment of both conditions.

Ranolazine may exert its beneficial effects by increasing myocardial adenosine levels.

We hypothesized that ranolazine-induced adenosine release is responsible for its beneficial effects in ischemic heart disease. Sixteen open-chest anesthetized dogs with noncritical coronary stenosis were studied at rest, during dobutamine stress, and during dobutamine stress with ranolazine. Six additional dogs without stenosis were studied only at rest. Regional myocardial function and perfusion were assessed. Coronary venous blood was drawn. Murine endothelial cells and cardiomyocytes were incubated with ranolazine and adenosine metabolic enzyme inhibitors, and adenosine levels were measured. Cardiomyocytes were also exposed to dobutamine and dobutamine with ranolazine. Modeling was employed to determine whether ranolazine can bind to an enzyme that alters adenosine stores. Ranolazine was associated with increased adenosine levels in the absence (21.7 ± 3.0 vs. 9.4 ± 2.1 ng/mL, P < 0.05) and presence of ischemia (43.1 ± 13.2 vs. 23.4 ± 5.3 ng/mL, P < 0.05). Left ventricular end-systolic wall stress decreased (49.85 ± 4.68 vs. 57.42 ± 3.73 dyn/cm2, P < 0.05) and endocardial-to-epicardial myocardial blood flow ratio tended to normalize (0.89 ± 0.08 vs. 0.76 ± 0.10, P = nonsignificant). Adenosine levels increased in cardiac endothelial cells and cardiomyocytes when incubated with ranolazine that was reversed when cytosolic-5'-nucleotidase (cN-II) was inhibited. Point mutation of cN-II aborted an increase in its specific activity by ranolazine. Similarly, adenosine levels did not increase when cardiomyocytes were incubated with dobutamine. Modeling demonstrated plausible binding of ranolazine to cN-II with a docking energy of -11.7 kcal/mol. We conclude that the anti-adrenergic and cardioprotective effects of ranolazine-induced increase in tissue adenosine levels, likely mediated by increasing cN-II activity, may contribute to its beneficial effects in ischemic heart disease.NEW & NOTEWORTHY Ranolazine is a drug used for treatment of angina pectoris in patients with ischemic heart disease. We discovered a novel mechanism by which this drug may exhibit its beneficial effects. It increases coronary venous levels of adenosine both at rest and during dobutamine-induced myocardial ischemia. Ranolazine also increases adenosine levels in endothelial cells and cardiomyocytes in vitro, by principally increasing activity of the enzyme cytosolic-5'-nucleotidase. Adenosine has well-known myocardial protective and anti-adrenergic properties that may explain, in part, ranolazine's beneficial effect in ischemic heart disease.

Therapeutic Ultrasound Increases Myocardial Blood Flow in Ischemic Myocardium and Cardiac Endothelial Cells: Results of In Vivo and In Vitro Experiments.

BACKGROUND: Therapeutic ultrasound can reduce infarct size in a model of coronary thrombosis even when sonothrombolysis is ineffective. The aim of this study was to test the hypothesis that ultrasound-induced cardioprotection is mediated by molecules released from the vascular endothelium that increase myocardial blood flow (MBF) and also have direct tissue-salvaging effects. METHODS: In vivo and in vitro experiments were performed using a 1.05-MHz transducer. For the in vivo experiments 10 control and 10 ultrasound-treated dogs undergoing occlusion of the left anterior descending coronary artery were studied. MBF was measured using myocardial contrast echocardiography. For the in vitro experiments, primary mouse cardiac endothelial cells were exposed to ultrasound at baseline or following oxygen-glucose deprivation and endothelial nitric oxide synthase phosphorylation as well as adenosine and the eicosanoids epoxyeicosatrienoic acids, dihydroxyeicosatrienoic acids, and hydroxyl-eicosatetraenoic acids were measured. RESULTS: In vivo, ultrasound treatment caused higher MBF (20 ± 10 vs 10 ± 8, P = .03) and higher wall thickening (3 ± 3% vs 1 ± 0.4%, P = .01) in the collateral-derived border zone compared with control. Epicardial MBF in the left anterior descending coronary artery bed also tended to be higher (17 ± 17 vs 5 ± 4, P = .05) in ultrasound-treated versus control animals; however, endocardial MBF in this region was similar to that in controls (13 ± 14 vs 14 ± 7). In vitro, phosphorylated endothelial nitric oxide synthase and adenosine increased (by 129 ± 11% and 286 ± 63%, respectively, P < .01) with ultrasound compared with unstimulated cells. Similar results were obtained with epoxyeicosatrienoic acids. After oxygen-glucose deprivation, phosphorylated endothelial nitric oxide synthase decreased and was restored with application of ultrasound. Similar changes were noted with epoxyeicosatrienoic acids. Cell viability decreased with oxygen-glucose deprivation and returned to near baseline with ultrasound. CONCLUSIONS: Ultrasound increases MBF in ischemic tissue in vivo. This effect is likely mediated by the release of a plethora of coronary vasodilators during ultrasound treatment that also have direct tissue-salvaging effects. Therapeutic ultrasound, therefore, has potential for treatment of acute and chronic myocardial ischemia independent of its effect on thrombolysis.

High molecular weight chitosan derivative polymeric micelles encapsulating superparamagnetic iron oxide for tumor-targeted magnetic resonance imaging.

Magnetic resonance imaging (MRI) contrast agents based on chitosan derivatives have great potential for diagnosing diseases. However, stable tumor-targeted MRI contrast agents using micelles prepared from high molecular weight chitosan derivatives are seldom reported. In this study, we developed a novel tumor-targeted MRI vehicle via superparamagnetic iron oxide nanoparticles (SPIONs) encapsulated in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan (FAPLCS) micelles. The tumor-targeting ability of FAPLCS/SPIONs was demonstrated in vitro and in vivo. The results of dynamic light scattering experiments showed that the micelles had a relatively narrow size distribution (136.60±3.90 nm) and excellent stability. FAPLCS/SPIONs showed low cytotoxicity and excellent biocompatibility in cellular toxicity tests. Both in vitro and in vivo studies demonstrated that FAPLCS/SPIONs bound specifically to folate receptor-positive HeLa cells, and that FAPLCS/SPIONs accumulated predominantly in established HeLa-derived tumors in mice. The signal intensities of T2-weighted images in established HeLa-derived tumors were reduced dramatically after intravenous micelle administration. Our study indicates that FAPLCS/SPION micelles can potentially serve as safe and effective MRI contrast agents for detecting tumors that overexpress folate receptors.

Anti-inflammatory and pro-angiogenic effects of beta blockers in a canine model of chronic ischemic cardiomyopathy: comparison between carvedilol and metoprolol.

There is controversy regarding the superiority of carvedilol (C) over metoprolol (M) in congestive heart failure. We hypothesized that C is superior to M in chronic ischemic cardiomyopathy because of its better anti-inflammatory and pro-angiogenic effects. In order to test our hypothesis we used a chronic canine model of multivessel ischemic cardiomyopathy where myocardial microcatheters were placed from which interstitial fluid was collected over time to measure leukocyte count and cytokine levels. After development of left ventricular dysfunction, the animals were randomized into four groups: sham (n = 7), placebo (n = 8), M (n = 11), and C (n = 10), and followed for 3 months after treatment initiation. Tissue was examined for immunohistochemistry, oxidative stress, and capillary density. At 3 months both rest and stress wall thickening were better in C compared to the other groups. At the end of 3 months of treatment end-systolic wall stress also decreased the most in C. Similarly resting myocardial blood flow (MBF) improved the most in C as did the stress endocardial/epicardial MBF. Myocardial interstitial fluid showed greater attenuation of leukocytosis with C compared to M, which was associated with less fibrosis and oxidative stress. C also had higher IL-10 level and capillary density. In conclusion, in a chronic canine model of multivessel ischemic cardiomyopathy we found 3 months of C treatment resulted in better resting global and regional function as well as better regional function at stress compared to M. These changes were associated with higher myocardial levels of the anti-inflammatory cytokine IL-10 and less myocardial oxidative stress, leukocytosis, and fibrosis. Capillary density and MBF were almost normalized. Thus in the doses used in this study, C appears to be superior to M in a chronic canine model of ischemic cardiomyopathy from beneficial effects on inflammation and angiogenesis. Further studies are required for comparing additional doses of these drugs.

ACCF/SCAI/AATS/AHA/ASE/ASNC/HFSA/HRS/SCCM/SCCT/SCMR/STS 2012 appropriate use criteria for diagnostic catheterization: American College of Cardiology Foundation Appropriate Use Criteria Task Force Society for Cardiovascular Angiography and Interventions American Association for Thoracic Surgery American Heart Association, American Society of Echocardiography American Society of Nuclear Cardiology Heart Failure Society of America Heart Rhythm Society, Society of Critical Care Medicine Society of Cardiovascular Computed Tomography Society for Cardiovascular Magnetic Resonance Society of Thoracic Surgeons.

The American College of Cardiology Foundation, in collaboration with the Society for Cardiovascular Angiography and Interventions and key specialty and subspecialty societies, conducted a review of common clinical scenarios where diagnostic catheterization is frequently considered. The indications (clinical scenarios) were derived from common applications or anticipated uses, as well as from current clinical practice guidelines and results of studies examining the implementation of noninvasive imaging appropriate use criteria. The 166 indications in this document were developed by a diverse writing group and scored by a separate independent technical panel on a scale of 1 to 9, to designate appropriate use (median 7 to 9), uncertain use (median 4 to 6), and inappropriate use (median 1 to 3). Diagnostic catheterization may include several different procedure components. The indications developed focused primarily on 2 aspects of diagnostic catheterization. Many indications focused on the performance of coronary angiography for the detection of coronary artery disease with other procedure components (e.g., hemodynamic measurements, ventriculography) at the discretion of the operator. The majority of the remaining indications focused on hemodynamic measurements to evaluate valvular heart disease, pulmonary hypertension, cardiomyopathy, and other conditions, with the use of coronary angiography at the discretion of the operator. Seventy-five indications were rated as appropriate, 49 were rated as uncertain, and 42 were rated as inappropriate. The appropriate use criteria for diagnostic catheterization have the potential to impact physician decision making, healthcare delivery, and reimbursement policy. Furthermore, recognition of uncertain clinical scenarios facilitates identification of areas that would benefit from future research. © 2012 Wiley Periodicals, Inc.

Detection of coronary stenosis with myocardial contrast echocardiography using regadenoson, a selective adenosine A2A receptor agonist.

AIMS: Regadenoson is comparable to adenosine in pharmacologic radionuclide stress tests but has not been studied with stress myocardial contrast echocardiography. This study assessed the haemodynamic profile and ability of regadenoson, a novel selective A(2A) receptor agonist, to detect coronary artery stenosis during myocardial contrast echocardiography. METHODS AND RESULTS: Myocardial contrast echocardiography was performed to measure myocardial blood volume, myocardial blood flow velocity, and total regional myocardial blood flow before and after administration of regadenoson (5 µg kg(-1), 10 s bolus) in 10 open-chest dogs with mild-to-moderate coronary stenosis that was not flow limiting at rest. Regadenoson decreased blood pressure but did not change heart rate. It increased coronary blood flow significantly (P < 0.05) for 30 min, which was attenuated in proportion to coronary stenosis severity. Whereas myocardial blood volume maximally increased by 0.5-0.75-fold in the control region, it did not change in the region supplied by the non-flow limiting stenosis. Perfusion defects were visually and quantitatively detectable for as long as 10 min after administration of regadenoson. No arrhythmias were noted with regadenoson either prior to or during myocardial contrast echocardiography. CONCLUSION: Regadenoson can be used as a vasodilator stress agent with myocardial contrast echocardiography to detect the presence of physiologically significant coronary stenosis. The optimum time for image acquisition was 3-10 min after drug administration.

[Assessment of direct effects of dobutamine on coronary microcirculation with myocardial contrast echocardiography: comparison with adenosine].

OBJECTIVE: To evaluate the direct effects of dobutamine as compared to adenosine on the coronary microcirculation in both normal and stenotic segments using myocardial contrast echocardiography (MCE). METHODS: Left anterior descending (LAD) coronary artery stenosis, which was not flow limiting at rest, was established in 9 dogs. At the baseline and during intracoronary infusion of dobutamine (2 mg.kg(-1).min(-1)) and adenosine (5 mg.kg(-1).min(-1)), the radiolabeled microsphere (RM)-derived myocardial blood flow (MBF) were determined, and the double product (DP) and myocardial vascular resistance (MVR) were calculated. MCE was performed to determine the myocardial blood volume (MBV, represented by A) and microbubble velocity (beta). RESULTS: As compared to the baseline level, the MBF increased and MVR decreased significantly in both the normal and abnormal beds during infusion of both drugs (P<0.05). In the normal bed, adenosine had no effect on MBV, the decrease in MVR was the result of decreased arteriolar (plus venular) resistance, and the increase in MBF was predominately due to the increase in b (deltabeta/ deltaA=13.6). Dobutamine caused a 28% increase in MBV, responsible for 32% of the decrease in the total MVR, but the increase in MBF arose mainly from the increase in b (deltabeta/deltaA=5.9). In the abnormal bed, both the drugs caused a similar increase in MBF entirely by increasing b, and 14% and 15% of the increases in capillary resistance were associated with the capillary derecruitment during administration of dobutamine and adenosine, respectively. CONCLUSION: The direct effects of intracoronary dobutamine infusion on the coronary microcirculation are similar to that of adenosine, and the increase in MBF occurs mostly as the result of increased myocardial blood velocity.

[Nitroglycerine promotes myocardial oxygen metabolism and regional cardiac function in vivo].

OBJECTIVE: To investigate the effects of nitroglycerine (NTG) on myocardial oxygen metabolism and regional cardiac function in canine hearts with a stable systemic hemodynamics in situ. METHODS: Eight anesthetized open-chest dogs with flow-limited left anterior descending branch of the coronary artery or left circumflex artery (LCx) stenosis were studied. The percentage of ventricular wall thickening (%WT) was measured with quantitative two-dimensional echocardiography (2DE), myocardial blood flow (MBF) with radiolabeled microspheres and tissue oxygen pressure (tPO(2).) with oxygen-dependent quenching of phosphorescence. 2DE was performed and radiolabeled microspheres and Pd-porphyrin injected in the dogs at rest during intracoronary infusion of 0.3-0.6 mg x kg(-1) x min(-1) of NTG. Myocardial oxygen consumption (MVO(2), ml x min(-1) x 100 g(-1)) was calculated as the multiplication product between the arterio-venous oxygen content difference and MBF, and myocardial O(2) delivery as the product between arterial oxygen content and MBF. RESULTS: As compared with the baseline, NTG increased %WT and MBF significantly in both normal and ischemic beds (P<0.05). There was a significant increase in MVO(2) during NTG infusion in the ischemic bed (P<0.05) in comparison with that measured at rest. NTG, however, significantly increased the ability of myocardial O(2) delivery in both normal and ischemic beds (P<0.05), therefore tPO(2) was still higher in the ischemic bed during NTG infusion than that at rest (P<0.05). The percentage increment in tPO(2) was significantly greater in the ischemic bed than percentage MBF increment. CONCLUSIONS: NTG enhances myocardial oxygen concentration in normal and ischemic myocardium and may increase oxygen release to the ischemic myocardium in vivo. NTG may have a positive inotropic effect on regional cardiac function. In addition to direct effect on vascular tone, NTG plays important roles in the cardiovascular system by modulating myocardial oxygen metabolism and contractile function.

Transmyocardial revascularization ameliorates ischemia by attenuating paradoxical catecholamine-induced vasoconstriction.

BACKGROUND: The mechanism by which transmyocardial revascularization (TMR) offers clinical benefit is controversial. We hypothesized that TMR ameliorates ischemia by reversing paradoxical catecholamine-induced vasoconstriction. METHODS AND RESULTS: Chronic ischemic cardiomyopathy was created in 11 dogs by placing ameroid constrictors on the proximal coronary arteries and their major branches. Six weeks later, 35 channels were created percutaneously in the left circumflex artery region, with the left anterior descending artery region serving as control. At rest, wall thickening and myocardial blood flow did not change in the treated region, whereas they deteriorated in the control bed. Contractile and myocardial blood flow reserve increased in the treated region but deteriorated in the control region. There was diminished iodine 123 metaiodobenzylguanidine uptake and a significant reduction in noradrenergic nerves in the treated region compared with the control region, with a corresponding reduction in tissue tyrosine hydroxylase activity. CONCLUSIONS: We conclude that the absence of a catecholamine-induced reduction in MBF reserve and contractile reserve in the TMR-treated region with associated evidence of neuronal injury indicates that the relief of exercise-induced ischemia after TMR most likely results from reversal of paradoxical catecholamine-induced vasoconstriction. These findings may have implications in selecting patients who would benefit from TMR.

Effects of nitroglycerin on erythrocyte rheology and oxygen unloading: novel role of S-nitrosohemoglobin in relieving myocardial ischemia.

BACKGROUND: We hypothesized that nitroglycerin improves O2 delivery to ischemic tissue by altering erythrocyte rheology and O2 unloading through an increase in bioactive nitric oxide (NO) content. METHODS AND RESULTS: Twelve dogs with resting flow-reducing single-vessel stenosis were studied at rest and during intracoronary infusion of nitroglycerin (0.3 to 0.6 microg.kg(-1).min(-1)). Half the dogs also had occlusion of the remote coronary artery to remove any collateral effects. Systemic and coronary hemodynamics, myocardial blood flow (MBF), whole blood viscosity (WBeta), erythrocyte charge (EC) and mobility (EM), regional myocardial O2 delivery and consumption, and tissue O2 pressure (Po2) were measured. No changes in systemic hemodynamics were seen with nitroglycerin. Despite flow-limiting stenosis, MBF increased significantly in the central 25% of the ischemic bed, which was associated with an approximately 19% decrease in WBeta. There was a good correlation (r=0.87) between the two. The decrease in WBeta was associated with a decrease in EC and an increase in EM (r=0.83). The nitroglycerin-induced increase in tissue Po2 was disproportionate to the increase in MBF, indicating enhanced O2 unloading. Erythrocyte S-nitrosothiol content (reflecting mainly S-nitrosohemoglobin) was significantly higher for blood exposed in vitro to 0.1 micromol/L nitroglycerin or the NO donor SNAP, as compared with control (18.9+/-8.8 and 10.5+/-6.5 versus 2.6+/-0.5x10(-5), P<0.05). CONCLUSIONS: The augmented MBF in the ischemic microcirculation during nitroglycerin administration occurs in tandem with increased erythrocyte S-nitrosothiol content, EM, and O2 unloading. These additional microvascular mechanisms may contribute to the powerful antiischemic effects of nitroglycerin, especially during low-flow states.

A1-receptor blockade: a novel approach for assessing myocardial viability in chronic ischemic cardiomyopathy.

Diminished myocardial function can be seen in chronic coronary stenosis (CS) even in the presence of normal resting myocardial blood flow. We hypothesized that adenosine contributes to myocardial depression in this setting, predominantly through activation of the A(1) adenosine receptor. To test this hypothesis we used aminophylline, a nonselective adenosine receptor antagonist, and 8-cyclopentyl 1,3 dipropylxanthine, a selective A(1) adenosine receptor antagonist, in a canine model of chronic CS. Chronic CS was produced by placement of ameroid constrictors on the left anterior descending and left circumflex coronary arteries in 17 adult mongrel dogs, which resulted in severe left ventricular dysfunction 6 weeks later. Eight dogs without ameroid placement were used as controls (C). Closed-chest echocardiographic short-axis images at the low midpapillary level, hemodynamics, and radiolabeled microsphere-derived myocardial blood flow were obtained before and immediately after injection of either 5 mg/kg(-1) of aminophylline (7 left ventricular dysfunction and 4 C dogs) or 1 mg/kg(-1) of 8-cyclopentyl 1,3-dipropylxanthine (10 left ventricular dysfunction and 4 C dogs). Both 8-cyclopentyl 1,3-dipropylxanthine and aminophylline had no effect in C animals but resulted in a significant transient increase in regional percent wall thickening (P <.05) with a concomitant decrease in end-systolic wall stress (P <.05) in CS animals. There was no change in transmural myocardial blood flow or systemic hemodynamics to explain these results. Thus, adenosine plays a significant role in myocardial dysfunction in chronic ischemia by activation of the A(1) receptor. Aminophylline or a selective A(1) adenosine receptor antagonist can be used to detect viable myocardium and may be safer than dobutamine in severe chronic ischemic heart disease.

Direct effects of dobutamine on the coronary microcirculation: comparison with adenosine using myocardial contrast echocardiography.

The direct effects of dobutamine on capillary blood volume (VOL) and blood flow velocity (VEL) are not known. We hypothesized that these would be more similar to that of adenosine because of its effects on the beta(2) receptors on the coronary circulation. A total of 9 open-chest anesthetized dogs were studied after placement of 2 noncritical stenoses at rest and during separate intracoronary administrations of 5 microg/kg(-1)/min(-1) of adenosine and 2 microg/kg(-1)/min(-1) of dobutamine. VOL and VEL were measured using myocardial contrast echocardiography, wall thickening with 2-dimensional echocardiography, and myocardial blood flow (MBF) with radiolabeled microspheres. Dobutamine increased the rate-pressure product significantly, whereas adenosine had no effect on the rate-pressure product. In the normal myocardium, adenosine had no effect on VOL and increases in MBF were all a result of increases in VEL. Dobutamine also caused mostly an increase in VEL and only a 30% increase in VOL indicating modest capillary recruitment. In the bed with stenosis both drugs attenuated increase in MBF by the same amount, which was associated with an attenuation in the increase in VEL secondary to a 15% increase in capillary resistance because of capillary derecruitment. The MBF-wall thickening relation was described for both drugs by the same function: y = 1 - exp(x) with wall thickening being significantly higher for dobutamine compared with adenosine for each level of MBF. We conclude that the increase in MBF in the normal myocardium with intracoronary dobutamine occurs mostly from an increase in VEL rather than from an increase in VOL. In the bed with a noncritical stenosis, the increases in MBF and VEL are similar for both drugs. Similar to intracoronary adenosine, intracoronary dobutamine also caused capillary derecruitment distal to a noncritical coronary stenosis.

Relation between myocardial oxygen consumption and myocardial blood volume: a study using myocardial contrast echocardiography.

Myocardial blood volume (MBV) is the volume of blood residing in myocardial vessels, 90% of which is in capillaries. MBV can be measured in vivo using myocardial contrast echocardiography (MCE). It has been shown that when increases in coronary blood flow (CBF) are not associated with increase in myocardial oxygen consumption (MVO(2)), MBV does not increase. We hypothesized that MBV would increase when increases in CBF are associated with an increase in MVO(2). The atrioventricular node was ablated in 18 dogs and dual-chamber pacing was instituted. In group 1 dogs (n = 9), heart rate was altered from 50 to 150 bpm(-1) in increments of 20 bpm(-1) in random order. In group 2 dogs (n = 9), heart rate was kept constant, and dobutamine was infused at doses of 5, 10, 20, 30, and 40 microg/kg(-1)/min(-1). During each intervention, hemodynamic parameters and MVO(2) were measured, and MCE was performed. MVO(2) increased more (P <.01) with inotropic compared with chronotropic stimulation, resulting in a parallel increase in CBF. MBV fraction and MCE-derived myocardial blood flow increased significantly with increases in MVO(2) (P <.05 and P <.001, respectively) when dobutamine was infused, but remained unchanged when heart rate alone was increased. We conclude that when MVO(2) is increased substantially, the resulting increase in CBF and MCE-derived myocardial blood flow is mediated, in part, by an increase in MBV. Thus, capillary recruitment plays an important role in the physiologic regulation of CBF. Lack of increase in MBV during dobutamine stress may indicate the presence of coronary stenosis or microvascular disease.

Dobutamine versus dipyridamole for inducing reversible perfusion defects in chronic multivessel coronary artery stenosis.

OBJECTIVES: We hypothesized that, although the effects of dipyridamole and dobutamine on myocardial blood volume (MBV) and mean microbubble velocity (VEL) are different, the magnitude of perfusion deficit during both forms of stress is the same because both drugs unmask abnormal myocardial blood flow (MBF) reserve. BACKGROUND: Both dipyridamole and dobutamine are used clinically as pharmacologic stress agents to induce reversible perfusion defects in patients with chronic coronary artery disease (CAD), but the basis for doing so for dobutamine is not clear. METHODS: Eleven chronically instrumented closed-chest dogs with multivessel coronary stenosis were studied. Hemodynamics, radiolabeled microsphere-derived MBF, and myocardial contrast echocardiography (MCE)-derived myocardial perfusion were measured at rest, after dipyridamole infusion (0.56 mg x kg(-1)), and at peak dobutamine dose (either 30 or 40 microg x kg(-1) x min(-1)). Abnormal beds were defined as those demonstrating an MBF reserve <3 with dipyridamole. RESULTS: In the presence of either drug, MBV increased more in the normal bed than in the abnormal bed, but the increase was higher in both beds with dobutamine than with dipyridamole. The slope of the relationship between MBF reserve and MBV reserve was greater during dobutamine than dipyridamole (p < 0.05). The converse was true for VEL reserve (p < 0.05). Consequently, the relationship between the ratios of either variable, or the product of the two, between the abnormal bed and normal bed was similar for both drugs. CONCLUSIONS: Although the effects of dipyridamole and dobutamine on MBV and VEL are different, both are equally effective in detecting physiologically relevant coronary stenoses on MCE. Both can therefore be used interchangeably with myocardial perfusion imaging for the detection of CAD.

Perfusion versus function: the ischemic cascade in demand ischemia: implications of single-vessel versus multivessel stenosis.

BACKGROUND: We hypothesized that during demand ischemia, abnormal perfusion will precede abnormal function, the spatial extent of perfusion abnormality will be greater than that of functional abnormality, and the spatiotemporal disparity between abnormal perfusion and abnormal function will be more marked in the presence of single-vessel stenosis (SVS) versus multivessel stenosis (MVS). METHODS AND RESULTS: Nine dogs each underwent either SVS or MVS placement. These noncritical stenoses were classified as mild, moderate, or severe on the basis of the transstenotic pressure gradient (10 to 14, 15 to 20, or >20 mm Hg). Dobutamine was infused starting at 10 and reaching 40 microg/kg(-1) x min(-1). Wall thickening (WT) and myocardial perfusion (myocardial contrast echocardiography) were assessed at each stage. Resting perfusion and function were normal in all dogs. In SVS, abnormal perfusion (delayed rate of microbubble replenishment) was seen at the lowest dose of dobutamine irrespective of the stenosis severity, whereas WT abnormality was seen only at high doses of dobutamine and was influenced by the stenosis severity. The spatial extent of abnormal perfusion exceeded that of WT abnormality at all but the highest dobutamine dose. This spatiotemporal discordance between abnormal perfusion and function was significantly less in MVS, where it was possible to identify separate regions with abnormal function at lower doses of dobutamine. CONCLUSIONS: These data support the occurrence of the ischemic cascade during demand ischemia. They also explain the higher sensitivity of abnormal perfusion compared with abnormal function for the detection of coronary stenosis as well as the higher sensitivity of dobutamine echocardiography for MVS compared with SVS.