Richard Tang

Determination of location, size, and transmurality of chronic myocardial infarction without exogenous contrast media by using cardiac magnetic resonance imaging at 3 T.

Background—Late-gadolinium–enhanced (LGE) cardiac MRI (CMR) is a powerful method for characterizing myocardial infarction (MI), but the requisite gadolinium infusion is estimated to be contraindicated in ≈20% of patients with MI because of end-stage chronic kidney disease. The purpose of this study is to investigate whether T1 CMR obtained without contrast agents at 3 T could be an alternative to LGE CMR for characterizing chronic MIs using a canine model of MI. Methods and Results—Canines (n=29) underwent CMR at 7 days (acute MI [AMI]) and 4 months (chronic MI [CMI]) after MI. Infarct location, size, and transmurality measured by using native T1 maps and LGE images at 1.5 T and 3 T were compared. Resolution of edema between AMI and CMI was examined with T2 maps. T1 maps overestimated infarct size and transmurality relative to LGE images in AMI (P=0.016 and P=0.007, respectively), which was not observed in CMI (P=0.49 and P=0.81, respectively) at 3 T. T1 maps underestimated infarct size and transmurality relative to LGE images in AMI and CMI (P<0.001) at 1.5 T. Relative to the remote territories, T1 of the infarcted myocardium was increased in CMI and AMI (P<0.05), and T2 of the infarcted myocardium was increased in AMI (P<0.001) but not in CMI (P>0.20) at both field strengths. Histology showed extensive replacement fibrosis within the CMI territories. CMI detection sensitivity and specificity of T1 CMR at 3 T were 95% and 97%, respectively. Conclusions—Native T1 maps at 3 T can determine the location, size, and transmurality of CMI with high diagnostic accuracy. Patient studies are necessary for clinical translation.

Persistent Microvascular Obstruction After Myocardial Infarction Culminates in the Confluence of Ferric Iron Oxide Crystals, Proinflammatory Burden, and Adverse Remodeling.

Background—Emerging evidence indicates that persistent microvascular obstruction (PMO) is more predictive of major adverse cardiovascular events than myocardial infarct (MI) size. But it remains unclear how PMO, a phenomenon limited to the acute/subacute period of MI, drives adverse remodeling in chronic MI setting. We hypothesized that PMO resolves into chronic iron crystals within MI territories, which in turn are proinflammatory and favor adverse remodeling post-MI. Methods and Results—Canines (n=40) were studied with cardiac magnetic resonance imaging to characterize the spatiotemporal relationships among PMO, iron deposition, infarct resorption, and left ventricular remodeling between day 7 (acute) and week 8 (chronic) post-MI. Histology was used to assess iron deposition and to examine relationships between iron content with macrophage infiltration, proinflammatory cytokine synthesis, and matrix metalloproteinase activation. Atomic resolution transmission electron microscopy was used to determine iron crystallinity, and energy-dispersive X-ray spectroscopy was used to identify the chemical composition of the iron composite. PMO with or without reperfusion hemorrhage led to chronic iron deposition, and the extent of this deposition was strongly related to PMO volume (r>0.8). Iron deposits were found within macrophages as aggregates of nanocrystals (≈2.5 nm diameter) in the ferric state. Extent of iron deposits was strongly correlated with proinflammatory burden, collagen-degrading enzyme activity, infarct resorption, and adverse structural remodeling (r>0.5). Conclusions—Crystallized iron deposition from PMO is directly related to proinflammatory burden, infarct resorption, and adverse left ventricular remodeling in the chronic phase of MI in canines. Therapeutic strategies to combat adverse remodeling could potentially benefit from taking into account the chronic iron-driven inflammatory process.

Assessment of Myocardial Reactivity to Controlled Hypercapnia with Free-breathing T2-prepared Cardiac Blood Oxygen Level–Dependent MR Imaging

PURPOSEnTo examine whether controlled and tolerable levels of hypercapnia may be an alternative to adenosine, a routinely used coronary vasodilator, in healthy human subjects and animals.nnnMATERIALS AND METHODSnHuman studies were approved by the institutional review board and were HIPAA compliant. Eighteen subjects had end-tidal partial pressure of carbon dioxide (PetCO2) increased by 10 mm Hg, and myocardial perfusion was monitored with myocardial blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging. Animal studies were approved by the institutional animal care and use committee. Anesthetized canines with (n = 7) and without (n = 7) induced stenosis of the left anterior descending artery (LAD) underwent vasodilator challenges with hypercapnia and adenosine. LAD coronary blood flow velocity and free-breathing myocardial BOLD MR responses were measured at each intervention. Appropriate statistical tests were performed to evaluate measured quantitative changes in all parameters of interest in response to changes in partial pressure of carbon dioxide.nnnRESULTSnChanges in myocardial BOLD MR signal were equivalent to reported changes with adenosine (11.2% ± 10.6 [hypercapnia, 10 mm Hg] vs 12% ± 12.3 [adenosine]; P = .75). In intact canines, there was a sigmoidal relationship between BOLD MR response and PetCO2 with most of the response occurring over a 10 mm Hg span. BOLD MR (17% ± 14 [hypercapnia] vs 14% ± 24 [adenosine]; P = .80) and coronary blood flow velocity (21% ± 16 [hypercapnia] vs 26% ± 27 [adenosine]; P > .99) responses were similar to that of adenosine infusion. BOLD MR signal changes in canines with LAD stenosis during hypercapnia and adenosine infusion were not different (1% ± 4 [hypercapnia] vs 6% ± 4 [adenosine]; P = .12).nnnCONCLUSIONnFree-breathing T2-prepared myocardial BOLD MR imaging showed that hypercapnia of 10 mm Hg may provide a cardiac hyperemic stimulus similar to adenosine.

Contrast-free T1 mapping at 3T can characterize chronic myocardial infarctions with high diagnostic accuracy

Background Characterizing myocardial infarctions (MIs) on the basis of LGE CMR requires gadolinium infusion, which poses limitations in certain patient populations and imaging workflow. We hypothesized that T1 differences between MI and remote territories at 3T would enable reliable characterization of chronic MI. Methods Canines (n = 29) underwent CMR at 7 days (acute) and 4 months (chronic) following reperfused MIs at 3T (n = 19) and 1.5T (n = 10). Contrast-free T1 maps (MOLLI; 8 TIs with 2 inversion blocks of 3+5 images; minimum TI = 110 ms; ΔTI = 80 ms; TR/TE = 2.2/1.1 ms) and LGE images (IR-prepared FLASH; TI optimized to null remote myocardium; TR/TE = 3.5/1.75 ms) were acquired. MI location, size and transmurality were determined using Mean+5SD criterion relative to remote myocardium. T2 maps (T2-prepared SSFP; T2 preparation times = 0, 24 and 55 ms; TR/TE = 2.8/1.4 ms) were acquired to compare acute and chronic MIs. Commonly used imaging parameters were slice thickness = 6 mm and spatial resolution = 1.3 × 1.3 mm 2. Histological validation was sought to confirm the presence of replacement fibrosis within the chronic infarct zones. Results Contrast-free T1 maps and LGE images of a representative mid-ventricular slice, along with AHA 17-segment bulls-eye plots depicting the MI size and transmurality acquired from a canine scanned imaged 4 months post-MI at 3T are shown in Figure 1. Bland-Altman plots, linear regression plots and receiver-operating characteristic curve comparing T1 maps and LGE images for measuring infarct volume (IV, %LV) and transmurality (IT) in the chronic phase at 3T are also shown. At 3T, T1 maps and LGE images were not different for measuring IV (5.6 ± 3.7% vs. 5.5 ± 3.7%; p = 0.61) and IT (44 ± 15% vs. 46 ± 15%; p = 0.81) in the chronic phase, but were significantly different in the acute phase (IS: 13.3 ± 8.4% vs. 11.6 ± 6.8%, p = 0.007 and IT: 64 ± 19% vs. 56 ± 17%, p = 0.007). At 1.5T, IV and IT were significantly underestimated by T1 maps relative to LGE images during acute (IS: 9.4 ± 5.6% vs. 15.5 ± 9.4%, p < 0.001 and IT: 59 ± 5% vs. 76 ± 6%, p < 0.001) and chronic phases (IS: 2.1 ± 1.2% vs. 4.8 ± 1.8%, p < 0.001 and IT: 47 ± 7% vs. 66 ± 9%, p < 0.001). At 3T and 1.5T, T1 values of the MI remained elevated in both acute (3T: p < 0.001; 1.5T: p < 0.001) and chronic phases (3T: p < 0.001; 1.5T: p = 0.037) compared to remote myocardium (Table 1). At both 3T and 1.5T, relative to the remote myocardium, T2 values of the MI were elevated in the acute phase (p < 0.001 for both cases), but were not different in the chronic phase (3T: p = 0.19, 1.5T: p = 0.55). Ex-vivo TTC and Elastinmodified Masson’s Trichrome (EMT) stainings (Figure 1) confirmed extensive replacement fibrosis within the MI territories at 4 months post MI. Sensitivity and specificity of contrast-free T1 maps at 3T for detecting chronic MIs were 95% and 97%, respectively. Conclusions Contrast-free T1 maps at 3T can determine the location, size and transmurality of chronic MIs with high diagnostic accuracy.

Chronic Manifestation of Post-Reperfusion Intramyocardial Hemorrhage as Regional Iron Deposition: A Cardiovascular MR Study with Ex-vivo Validation

Background— Intramyocardial hemorrhage frequently accompanies large reperfused myocardial infarctions. However, its influence on the makeup and the ensuing effect on the infarcted tissue during the chronic phase remain unexplored. Methods and Results— Patients (n=15; 3 women), recruited after successful percutaneous coronary intervention for first segment–elevation myocardial infarction, underwent cardiovascular magnetic resonance imaging on day 3 and month 6 after percutaneous coronary intervention. Patients with hemorrhagic (Hemo+) infarctions, as determined by T2* cardiovascular magnetic resonance on day 3 (n=11), showed persistent T2* losses colocalized with scar tissue on the follow-up scans, suggesting chronic iron deposition. T2* values of Hemo+ territories were significantly higher than nonhemorrhagic (Hemo−) and remote territories (P<0.001); however, T2* values of nonhemorrhagic (Hemo−) and remote territories were not different (P=0.51). Canines (n=20) subjected to ischemia-reperfusion injury (n=14) underwent cardiovascular magnetic resonance on days 3 and 56 after ischemia-reperfusion injury. Similarly, sham-operated animals (Shams; n=3) were imaged using cardiovascular magnetic resonance at similar time points. Subsequently, hearts were explanted and imaged ex vivo, and samples of Hemo+, Hemo−, remote, and Sham myocardium were isolated and stained. The extent of iron deposition ([Fe]) within each sample was measured using mass spectrometry. Hemo+ infarcts showed significant T2* losses compared with the other (control) groups (P<0.001), and Perls stain confirmed localized iron deposition. Mean [Fe] of Hemo+ was nearly an order of magnitude greater than that of the control groups (P<0.001), but no significant differences were observed among the control groups. A strong linear relationship was observed between log(T2*) and −log([Fe]); R 2=0.7 and P<0.001. The monoclonal antibody Mac387 stains, along with Perls stains, showed preferential localization of newly recruited macrophages at the site of chronic iron deposition. Conclusions— Hemorrhagic myocardial infarction can lead to iron depositions within the infarct zones, which can be a source of prolonged inflammatory burden in the chronic phase of myocardial infarction.Background— Intramyocardial hemorrhage frequently accompanies large reperfused myocardial infarctions. However, its influence on the makeup and the ensuing effect on the infarcted tissue during the chronic phase remain unexplored.nnMethods and Results— Patients (n=15; 3 women), recruited after successful percutaneous coronary intervention for first segment–elevation myocardial infarction, underwent cardiovascular magnetic resonance imaging on day 3 and month 6 after percutaneous coronary intervention. Patients with hemorrhagic (Hemo+) infarctions, as determined by T2* cardiovascular magnetic resonance on day 3 (n=11), showed persistent T2* losses colocalized with scar tissue on the follow-up scans, suggesting chronic iron deposition. T2* values of Hemo+ territories were significantly higher than nonhemorrhagic (Hemo−) and remote territories ( P <0.001); however, T2* values of nonhemorrhagic (Hemo−) and remote territories were not different ( P =0.51). Canines (n=20) subjected to ischemia-reperfusion injury (n=14) underwent cardiovascular magnetic resonance on days 3 and 56 after ischemia-reperfusion injury. Similarly, sham-operated animals (Shams; n=3) were imaged using cardiovascular magnetic resonance at similar time points. Subsequently, hearts were explanted and imaged ex vivo, and samples of Hemo+, Hemo−, remote, and Sham myocardium were isolated and stained. The extent of iron deposition ([Fe]) within each sample was measured using mass spectrometry. Hemo+ infarcts showed significant T2* losses compared with the other (control) groups ( P <0.001), and Perls stain confirmed localized iron deposition. Mean [Fe] of Hemo+ was nearly an order of magnitude greater than that of the control groups ( P <0.001), but no significant differences were observed among the control groups. A strong linear relationship was observed between log(T2*) and −log([Fe]); R 2=0.7 and P <0.001. The monoclonal antibody Mac387 stains, along with Perls stains, showed preferential localization of newly recruited macrophages at the site of chronic iron deposition.nnConclusions— Hemorrhagic myocardial infarction can lead to iron depositions within the infarct zones, which can be a source of prolonged inflammatory burden in the chronic phase of myocardial infarction.

Acute reperfusion intramyocardial hemorrhage leads to regional chronic iron deposition in the heart

Background Intramyocardial hemorrhage commonly occurs in large reperfused myocardial infarctions. However, its long-term fate remains unexplored. We hypothesized that acute reperfusion intramyocardial hemorrhage leads to chronic iron deposition. Methods Fifteen patients (mean age = 58±8 years; 3 women), who underwent successful angioplasty for first STEMI, were recruited following informed consent. Cardiovascular Magnetic Resonance (CMR) imaging (1.5T) was performed on day 3 and month 6 post-angioplasty. 2D T2* maps (6 TEs = 2.6-13.7 ms; ΔTE=2.2ms) and Late Gadolinium Enhancement (LGE) images of the entire left ventricle (LV) were acquired. Threshold-based image analysis was performed to identify remote, hemorrhagic (Hemo+) and non-hemorrhagic (Hemo-) myocardium. Fourteen canines, subjected to ischemia-reperfusion (I-R) injury (3 hours of LAD occlusion followed by reperfusion), underwent CMR (1.5T) on days 3 and 56 post-I-R injury. Three sham-operated animals (Shams) were also studied using CMR at similar time points. 2D T2* maps (6 TEs = 3.4-18.4 ms; ΔTE=3.0ms) and LGE images of the entire LV were acquired. Threshold-based image analysis was performed to identify remote, Hemo+ and Hemo- myocardium. Subsequently, animals were euthanized (day 56), hearts were excised and imaged ex-vivo. Sections of Hemo +, Hemo-, remote and Sham myocardium were isolated and histology was performed. The concentration of iron ([Fe]) within each type of tissue was measured using mass spectrometry.

CMR-based assessment of myocardial edema in the setting of ischemia and reperfusion

Background Cardiovascular Magnetic Resonance (CMR) based assessments of area-at-risk and salvageable myocardium on the basis of myocardial edema in the setting of acute coronary syndrome is of significant clinical interest. However, their dependence on the choice of acquisition method and time to imaging has not been studied. In this study, we investigated the temporal evolution of myocardial edema during ischemia and reperfusion phases using both T2 maps and T2-STIR images. Methods Canines (n=10), subjected to I-R injury, underwent CMR (1.5T) before ischemia (baseline), during ischemia and on days 2, 5, and 7 post-reperfusion. T2-preapred SSFP (T2-preparation durations = 0, 24 and 55 ms; TR/TE =

Detecting Myocardial Ischemia at Rest with Cardiac Phase-Resolved BOLD CMR

Noninvasive imaging approaches that can rapidly assess an ongoing ischemia can be of great value in managing patients with clinically significant coronary artery disease. Although a number of imaging approaches exist for the identification of myocardial territories supplied by stenotic coronary arteries, generally all available imaging methods require provocative stress and/or exogenous contrast media. The most desirable imaging approach is one that can non-invasively and rapidly identify ischemic territories prior to the onset of tissue specific changes (development of edema or necrosis) and can permit the assessment of functional/volumetric status while minimizing patient discomfort. n nPrevious studies have shown that ongoing ischemia may be detected with CMR (Cardiac Magnetic Resonance) on the basis of stress perfusion and changes in functional indices. More recently, it has been shown that myocardial edema may be utilized as a marker of ongoing ischemia using animal models 1 and patients 2. While the edema approach eliminates the need for provocative stress, both approaches require separate acquisitions for accurate assessment of functional indices. In this work, we propose and test a new CMR approach for a rapid assessment of myocardial ischemia. The proposed method is based on cardiac phase-resolved steady-state free precession (SSFP) magnetic resonance (MR) signal changes originating primarily from alterations in oxygenation (%HbO2) and secondarily from changes in regional myocardial blood volume (MBV) in the myocardial territory supplied by a stenotic artery. Since the proposed approach can generate functional and tissue specific indices in one acquisition, the proposed approach can provide opportunities to rapidly determine the presence and territory of myocardial ischemia. n nIt is known that (a) MBV is a function of cardiac phase, increasing during diastole and decreasing during systole 3,4; and (b) MBV directly determines the oxygen extraction by cardiomyocytes 5. Thus, MBV and %HbO2 are expected to be different between systole and diastole. Hence, under normal (healthy) conditions, one expects the MBV and oxygen extraction to be maximal during diastole, and minimal in systole. In addition to these effects, as MBV increases, each unit volume of ventricle, i.e., each voxel in a myocardial image, contains a slightly higher proportion of blood, and a correspondingly smaller proportion of myocardial tissue 6. Thus, even at a stable level of %HbO2, the number of deoxygenated hemoglobin molecules within a voxel increases as MBV increases. Moreover, a number of studies have also shown that with increasing grade of coronary stenosis, MBV in the myocardial territory supplied by a stenotic artery increases in systole 7–9. Thus based on these studies, the relative MBV and %HbO2 changes between systole and diastole are expected to be different between myocardial territories supplied by healthy and stenotic coronary arteries. n nCardiac phase-resolved BOLD SSFP CMR might provide a unique opportunity to capture these physiological changes and hence assess ongoing ischemia. It is known that T1 of myocardium is dependent on blood volume 10 and that T2 is dependent on blood oxygenation saturation 11. Since BOLD SSFP signals are approximately T2/T1 weighted 12,13, it may be possible to capture the changes in MBV 4 (via T1) and %HbO2 14 (via T2) in one acquisition. In particular, since coronary artery stenosis leads to an increased systolic MBV that is expected to be accompanied by decreases in %HbO2 (due to increased oxygen extraction), we hypothesized that the BOLD SSFP method can be used to detect the presence of coronary stenosis even at rest (i.e. without pharmacological stress). Under conditions of coronary stenosis, the physiological changes in basal MBV and %HbO2 are expected to work synergistically to enhance the SSFP-based detection capacity of myocardial territories supplied by stenotic arteries. In this work, we test these hypotheses using a canine animal model of severe coronary artery stenosis and computer/numerical simulations. In particular, we examine whether the systolic to diastolic myocardial SSFP signal intensity ratio (S/D) is greater than 1 in health and is diminished during ischemia. In addition, we investigate the effects of acute coronary occlusion on ejection fraction, wall thickening, and myocardial edema.Background— Fast noninvasive identification of ischemic territories at rest (before tissue-specific changes) and assessment of functional status can be valuable in the management of severe coronary artery disease. This study investigated the use of cardiac phase–resolved blood oxygen level–dependent (CP-BOLD) cardiovascular magnetic resonance in detecting myocardial ischemia at rest secondary to severe coronary artery stenosis. Methods and Results— CP-BOLD, standard cine, and T2-weighted images were acquired in canines (n=11) at baseline and within 20 minutes of ischemia induction (severe left anterior descending stenosis) at rest. After 3 hours of ischemia, left anterior descending stenosis was removed, and T2-weighted and late-gadolinium-enhancement images were acquired. From standard cine and CP-BOLD images, end-systolic and end-diastolic myocardium was segmented. Affected and remote sections of the myocardium were identified from postreperfusion late-gadolinium-enhancement images. Systolic-to-diastolic ratio (S/D), quotient of mean end-systolic and end-diastolic signal intensities (on CP-BOLD and standard cine), was computed for affected and remote segments at baseline and ischemia. Ejection fraction and segmental wall thickening were derived from CP-BOLD images at baseline and ischemia. On CP-BOLD images, S/D was >1 (remote and affected territories) at baseline; S/D was diminished only in affected territories during ischemia, and the findings were statistically significant (ANOVA, post hoc P<0.01). The dependence of S/D on ischemia was not observed in standard cine images. Computer simulations confirmed the experimental findings. Receiver-operating characteristic analysis showed that S/D identifies affected regions with performance (area under the curve, 0.87) similar to ejection fraction (area under the curve, 0.89) and segmental wall thickening (area under the curve, 0.75). Conclusions— Preclinical studies and computer simulations showed that CP-BOLD cardiovascular magnetic resonance could be useful in detecting myocardial ischemia at rest. Patient studies are needed for clinical translation.

Influence of Myocardial Hemorrhage on Staging of Reperfused Myocardial Infarctions With T2 Cardiac Magnetic Resonance Imaging: Insights Into the Dependence on Infarction Type With Ex Vivo Validation

OBJECTIVES This study sought to determine whether T2 cardiac magnetic resonance (CMR) can stage both hemorrhagic and nonhemorrhagic myocardial infarctions (MIs). BACKGROUND CMR-based staging of MI with or without contrast agents relies on the resolution of T2 elevations in the chronic phase, but whether this approach can be used to stage both hemorrhagic and nonhemorrhagic MIs is unclear. METHODS Hemorrhagic (n = 15) and nonhemorrhagic (n = 9) MIs were created in dogs. Multiparametric noncontrast mapping (T1, T2, and T2*) and late gadolinium enhancement (LGE) were performed at 1.5- and 3.0-T at 5 days (acute) and 8 weeks (chronic) post-MI. CMR relaxation values and LGE intensities of hemorrhagic, peri-hemorrhagic, nonhemorrhagic, and remote territories were measured. Histopathology was performed to elucidate CMR findings. RESULTS T2 of nonhemorrhagic MIs was significantly elevated in the acute phase relative to remote territories (1.5-T: 39.8 ± 12.8%; 3.0-T: 27.9 ± 16.5%; p < 0.0001 for both) but resolved to remote values by week 8 (1.5-T: −0.0 ± 3.2%; p = 0.678; 3.0-T: −0.5 ± 5.9%; p = 0.601). In hemorrhagic MI, T2 of hemorrhage core was significantly elevated in the acute phase (1.5-T: 17.7 ± 10.0%; 3.0-T: 8.6 ± 8.2%; p < 0.0001 for both) but decreased below remote values by week 8 (1.5-T: −8.2 ± 3.9%; 3.0-T: −5.6 ± 6.0%; p < 0.0001 for both). In contrast, T2 of the periphery of hemorrhage within the MI zone was significantly elevated in the acute phase relative to remote territories (1.5-T: 35.0 ± 16.1%; 3.0-T: 24.2 ± 10.4%; p < 0.0001 for both) and remained elevated at 8 weeks post-MI (1.5-T: 8.6 ± 5.1%; 3.0-T: 6.0 ± 3.3%; p < 0.0001 for both). The observed elevation of T2 in the peri-hemorrhagic zone of MIs and the absence of T2 elevation in nonhemorrhagic MIs were consistent with ongoing or absence of histological evidence of inflammation, respectively. CONCLUSIONS Hemorrhagic MIs are associated with persisting myocardial inflammation and edema, which can confound staging of hemorrhagic MIs when T2 elevations alone are used to discriminate between acute and chronic MI. Moreover, given the poor prognosis in patients with hemorrhagic MI, CMR evidence for myocardial hemorrhage with persistent edema may evolve as a risk marker in patients after acute MI.

Arterial CO2 as a Potent Coronary Vasodilator: A Preclinical PET/MR Validation Study with Implications for Cardiac Stress Testing

Myocardial blood flow (MBF) is the critical determinant of cardiac function. However, its response to increases in partial pressure of arterial CO2 (PaCO2), particularly with respect to adenosine, is not well characterized because of challenges in blood gas control and limited availability of validated approaches to ascertain MBF in vivo. Methods: By prospectively and independently controlling PaCO2 and combining it with 13N-ammonia PET measurements, we investigated whether a physiologically tolerable hypercapnic stimulus (∼25 mm Hg increase in PaCO2) can increase MBF to that observed with adenosine in 3 groups of canines: without coronary stenosis, subjected to non–flow-limiting coronary stenosis, and after preadministration of caffeine. The extent of effect on MBF due to hypercapnia was compared with adenosine. Results: In the absence of stenosis, mean MBF under hypercapnia was 2.1 ± 0.9 mL/min/g and adenosine was 2.2 ± 1.1 mL/min/g; these were significantly higher than at rest (0.9 ± 0.5 mL/min/g, P < 0.05) and were not different from each other (P = 0.30). Under left-anterior descending coronary stenosis, MBF increased in response to hypercapnia and adenosine (P < 0.05, all territories), but the effect was significantly lower than in the left-anterior descending coronary territory (with hypercapnia and adenosine; both P < 0.05). Mean perfusion defect volumes measured with adenosine and hypercapnia were significantly correlated (R = 0.85) and were not different (P = 0.12). After preadministration of caffeine, a known inhibitor of adenosine, resting MBF decreased; and hypercapnia increased MBF but not adenosine (P < 0.05). Conclusion: Arterial blood CO2 tension when increased by 25 mm Hg can induce MBF to the same level as a standard dose of adenosine. Prospectively targeted arterial CO2 has the capability to evolve as an alternative to current pharmacologic vasodilators used for cardiac stress testing.