Citations

Checkerboard bactericidal studies were performed with two strains each of Streptococcus mitis, S. salivarius , and S. sanguis , and the results were analyzed by the use of isobolograms. Synergy between penicillin and streptomycin or gentamicin was demonstrated with four strains, representing two of S. salivarius , one of S. sanguis , and one of S. mitis ; the remainder were either too susceptible or too resistant to be analyzed. Clindamycin with streptomycin or gentamicin acted synergistically with three strains, representing two of S. sanguis and one of S. salivarius ; the remainder were either too susceptible or too resistant to be analyzed.

Potential changes attending excitation of the atrioventricular node, the common bundle, the bundle branches, and initial ramifications of the conducting tissue in the subendocardium of the bovine heart beating in situ have been recorded from unipolar exploring electrodes. Correlations between the form of nodal deflection and the location in the node of the electrode tip have been established. From right bundle branch and subendocardial action potentials, data were derived indicating a rate of transmission through the right branch of 2.02 M/sec. Certain observations on the effects of acute injury and severe hypoxia are recorded. The character of nodal deflections attending retrograde excitation is reviewed. In studies on canine hearts beating in situ , electrograms have been made from the regions in which the atrioventricular node, the common bundle, and bundle branches are believed to lie. Deflections comparable to those recorded in bovine experiments were encountered and, by analogy with those bovine studies, certain morphologic correlations postulated. In general, canine nodal deflections are smaller than their bovine counterparts and lack the variety of form ascribed to potential changes in the several portions of the bovine node. In canine studies, deflections of atrial, atrionodal, and nodal type coexisted in recordings from a single needle electrode suggesting a degree of proximity between the sources of these potential changes not encountered in bovine experiments.

Background —Use of mortality as an end point in randomized trials of reperfusion therapy requires increasingly large sample sizes to test advances compared with existing therapy, which is already highly effective. There has been a growing interest in infarct size measurements by 99m Tc-sestamibi SPECT (single photon emission computed tomographic) imaging as a surrogate end point. Methods and Results —We reviewed the reports published in English regarding infarct size measurements by 99m Tc-sestamibi. Four separate lines of published evidence support the validity of SPECT imaging with 99m Tc-sestamibi for determination of infarct size. This end point has been used in a total of 7 randomized trials—1 single center and 6 multicenter. The end point compares favorably with left ventricular function and infarct size measurements with the use of other radiopharmaceuticals. The most important limitation of this approach is the absence thus far of a randomized trial that has shown a corresponding decrease in mortality in association with a therapy that reduces infarct size. Conclusions —SPECT imaging with 99m Tc-sestamibi is the best available measurement tool for infarct size. It has already served as an end point in early pilot studies to evaluate potential efficacy and in dose-ranging studies. It has the potential to serve as a surrogate end point to uncover advantages of new therapies that may be equivalent to existing therapies with respect to early mortality.

Background —Quantitative measures of myocardial perfusion defect severity from acute 99m Tc-sestamibi tomographic images (nadir) have correlated closely with collateral and residual antegrade blood flow during acute myocardial infarction. The purpose of this study was to determine whether a viability threshold could be identified from this measure in patients with acute myocardial infarction treated in a homogeneous manner with successful reperfusion therapy. Methods and Results —The study group consisted of 61 patients with acute myocardial infarction with a risk area of >6% LV treated with primary angioplasty between 120 and 240 minutes after symptom onset. All patients were injected with 20 to 30 mCi of 99m Tc-sestamibi before primary angioplasty and imaged after the procedure. Acute myocardium at risk (MAR) and subsequent infarct size (IS) were quantified by a threshold program. Severity (nadir) from the acute image was the lowest ratio of minimal/maximum counts from 5 short-axis slices. Infarct location was anterior in 22 and inferior in 39 patients. MAR was 33±15% LV and IS was 13±15% LV: 23 patients had no infarction despite MAR similar to those with infarction. Receiver-operator characteristic curve analysis identified a nadir value of 0.26 as providing the best separation of patients with and without infarction (sensitivity, 74%; specificity, 74%). This nadir threshold varied by infarct location: anterior defect, 0.21; inferior defect, 0.31. The sensitivity and specificity for absent infarction for these values were anterior, 69% and 67%, and inferior, 88% and 84%, respectively. Conclusions —In a time frame in which the presence of residual blood flow is important, the severity of the acute 99m Tc-sestamibi defect can be used to predict whether infarction will develop despite successful reperfusion.

Background —The appropriate management of patients with intermediate-risk Duke treadmill scores is not established. The purpose of this study was to determine the long-term risk of subsequent cardiovascular events in patients with an intermediate-risk treadmill score who do not have myocardial perfusion defects on radionuclide imaging. Methods and Results —The existing databases of the nuclear cardiology laboratories of 4 academic institutions were searched retrospectively. A total of 4649 patients were identified who had intermediate-risk Duke treadmill scores (−10 to 4), normal or near-normal exercise single photon-emission computed tomographic myocardial perfusion images using either thallium-201 or technetium-99m sestamibi, and no previous coronary revascularization. Follow-up was 95% complete. Cardiovascular survival was 99.8% at 1 year, 99.0% at 5 years, and 98.5% at 7 years. Cardiac survival free of myocardial infarction was similarly high at 96.6% at 7 years. Cardiac survival free of myocardial infarction or revascularization was 87.1% at 7 years. Near-normal scans and cardiac enlargement were independent predictors of time to cardiac death. Seven-year cardiac survival was still high at 97.0% in the 357 patients with near-normal scans and normal cardiac size and somewhat lower, at 89.0%, in the 167 patients with cardiac enlargement. Conclusions —Patients with an intermediate-risk treadmill score but with normal or near-normal exercise myocardial perfusion images and normal cardiac sizes are at low risk for subsequent cardiac death and can be safely managed medically until their symptoms warrant revascularization. The appropriate management of patients with cardiac enlargement will remain a matter of clinical judgment.

Background —The prognostic value of tomographic myocardial perfusion imaging with dipyridamole or adenosine in patients with left bundle-branch block has not been established. Methods and Results —The study group consisted of 245 patients with left bundle-branch block who underwent tomographic (single photon emission tomography) myocardial perfusion imaging with thallium-201 (n=173) or technetium-99m sestamibi (n=72) and either dipyridamole (n=153) or adenosine (n=92) stress. Patients were prospectively classified into two groups. Patients were classified as “high risk” if they had (1) a large severe fixed defect (n=28), (2) a large reversible defect (n=36), or (3) cardiac enlargement and either increased pulmonary uptake (thallium) or a decreased resting ejection fraction (sestamibi) (n=20). The remaining 161 patients (66% of the study group) were at “low risk.” Follow-up was 99% complete at 3±1.4 years. Three-year overall survival was 57% in the high-risk group compared with 87% in the low-risk group ( P <.0001). Survival free of cardiac death/nonfatal myocardial infarction/cardiac transplantation was 55% in the high-risk group and 93% in the low-risk group ( P <.0001). The presence of a high-risk scan had significant incremental prognostic value after adjustment for age, sex, diabetes, and previous myocardial infarction ( P <.0001). Patients with a low-risk scan had an overall survival that was not significantly different from that of a US age-matched population ( P =.86). Conclusions —Tomographic myocardial perfusion imaging with adenosine or dipyridamole stress provides important prognostic information in patients with left bundle-branch block, which is incremental to clinical assessment.

Background Coronary endothelial dysfunction may occur in patients with minimally obstructive coronary artery disease and angina, and potentially may cause myocardial ischemia. Methods and Results Coronary endothelium-dependent vasodilation was examined in patients with angina and <50% coronary artery diameter (CAD) stenosis by selectively infusing acetylcholine (10 −6 mol/L to 10 −4 mol/L) into the left anterior descending coronary artery (LAD). Percent change in CAD (%ΔCAD) was measured by quantitative coronary angiography, and percent change in coronary blood flow (%ΔCBF) was calculated using intracoronary flow Doppler. Coronary endothelium-independent vasodilation was examined using intracoronary adenosine and nitroglycerin. 99m Tc sestamibi was injected intravenously just prior to the infusion of the highest dose of acetylcholine. Patients were divided blindly into three groups: Perfusion defects in non-LAD territory (group 1, n=6), no perfusion defects (group 2, n=7), and perfusion defects in the LAD territory (group 3, n=7). All patients had intact endothelium-independent vasodilation. In group 1, perfusion defects outside the LAD territory reflected an increase in %ΔCAD and %ΔCBF by 24±5% and 241±46% in the LAD. In group 2, %ΔCAD decreased by 26±5%, but %ΔCBF increased by 54±17%. In group 3, perfusion defects were within the LAD territory, reflecting a decrease in %ΔCAD and %ΔCBF by 35±5% and 51±14%, respectively. Conclusions This study demonstrates that coronary endothelial dysfunction in humans may be temporally associated with myocardial perfusion defects and supports a role for the coronary epicardial and microcirculation endothelium in regulating myocardial perfusion. Myocardial ischemia may occur in humans with impaired endothelium-dependent coronary flow reserve of the coronary epicardial and microcirculation.

BackgroundNumerous studies have demonstrated the ability of angiotensin II (Ang II) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors to inhibit intimal hyperplasia after balloon dilatation of noncoronary arteries in small-animal models, suggesting an important role for Ang II in the response to injury. Although ACE inhibitors have not been similarly effective in nonhuman coronary models or in human restenosis trials, questions remain regarding the efficacy of ACE inhibitors against tissue ACE and the contributions of ACE-independent pathways of Ang II generation. Unlike ACE inhibitors, Ang II receptor antagonists have the potential to inhibit responses to Ang II independent of its biosynthetic origin.Methods and ResultsIn separate studies, three Ang II receptor antagonists, including AT1-selective (L-158,809), balanced AT1/AT2(L-163,082), and AT2-selective (L-164,282) agents, were evaluated for their ability to inhibit vascular intimal thickening in a porcine coronary artery model of vascular injury. Preliminary studies in a rat carotid artery model revealed that constant infusion of L-158,809 (0.3 or 1.0 mg·kg−1·d−1) reduced the neointimal cross-sectional area by up to 37% measured 14 days after balloon dilatation. In the porcine studies, animals were treated with vehicle or test compound beginning 2 days before and extending 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of commercially available angioplasty balloons with placement of coiled metallic stents. Infusion of L-158,809 (1 mg·kg−1·d−1), L-163,082 (1 mg·kg−1·d−1), or L-164,282 (1.5 mg·kg−1·d−1) in the study animals yielded plasma drug levels sufficient either to chronically block or, for L-164,282, to spare pressor responses to exogenous Ang II. Neither L-158,809, L-163,082, nor L-164,282 had statistically significant effects (P=.12,P=.75, andP=.48, respectively, compared with vehicle-treated controls) on neointimal thickness (normalized for degree of injury) measured by morphometric analysis at day 28 after angioplasty.ConclusionsThese findings indicate that chronic blockade of Ang II receptors by either site-selective or balanced AT1/AT2antagonists is insufficient to inhibit intimal hyperplasia after experimental coronary vascular injury in the pig. The results further suggest that, unlike in the rat carotid artery, Ang II is not a major mediator of intimal thickening in the pig coronary artery.

Background 99m Tc sestamibi is a recently developed radioisotope that has been used to measure myocardium at risk and infarct size. The relation between these measurements and subsequent patient outcome has not yet been demonstrated. Methods and Results Two hundred seventy-four consecutive patients with acute myocardial infarction underwent tomographic 99m Tc sestamibi imaging on arrival at the hospital (to measure myocardium at risk before reperfusion therapy) and at hospital discharge (to measure the amount of salvaged myocardium and final infarct size). Defect size on the sestamibi images was quantified using a threshold value of 60% of peak counts from the circumferential count profile curves generated for five representative slices of the left ventricle. Patients were followed after hospital discharge to evaluate the association between final infarct size and subsequent mortality. The median defect size measured was 27% of the left ventricle at presentation to the hospital (range, 0% to 77%) and was 12% of the left ventricle at hospital discharge (range, 0% to 68%). Almost one half of the patients had a final infarct size of ≤10%. The median amount of myocardium salvaged was 9% (range, −31% to 75%). During a median duration of follow-up of 12 months, there were 10 deaths (7 cardiac and 3 noncardiac) and 1 resuscitated out-of-hospital cardiac arrest. There was a significant association between infarct size and overall mortality (χ 2 =8.66, P =.003) and cardiac mortality (χ 2 =11.89, P <.001). Two-year mortality was 7% for patients whose infarct size was ≥12% versus 0% for patients whose infarct size was <12%. There also was a significant association between myocardium at risk and cardiac mortality (χ 2 =6.87, P =.009). There was no association between myocardium at risk and overall mortality or between amount of myocardium salvaged and either overall mortality or cardiac mortality. Conclusions Larger infarct size measured by 99m Tc sestamibi imaging after acute myocardial infarction is associated with increased mortality risk during short-term follow-up.

Background —Left ventricular ejection fraction (LVEF) is a recognized determinant of survival in patients with coronary artery disease. In major trials comparing surgical and percutaneous revascularization approaches, the long-term effect of the coronary revascularization strategy on LVEF has not been reported. Methods and Results —In the NHLBI-sponsored Bypass and Angioplasty Revascularization Investigation (BARI) randomized trial comparing angioplasty and bypass surgery as initial treatment strategies, 1220 (75%) of the 1617 surviving randomized patients had their EF measured by radionuclide ventriculography 5 years after study entry. For the total study group, the 5-year EF in the CABG group (n=623) was 55.8±12.3, compared with 55.7±12.7 in PTCA group (n=597, P =0.82). There was no significant difference in measured EF between the CABG group and the PTCA group within multiple subgroups determined by the presence or absence of diabetes, 3-vessel disease, complete revascularization, or prior myocardial infarction. In a multiple linear regression model developed to predict 5-year EF, treatment assignment to PTCA or CABG was not significant ( P =0.95). If an EF of 0 was imputed for patients who were dead and missing EF data, however, there was a higher EF in the CABG group ( P =0.0018) among diabetic patients only. Conclusions —In the BARI randomized trial, initial treatment assignment to angioplasty was not associated with any difference in long-term ventricular function compared with initial treatment assignment to surgery. These results apply, however, only to patients who were alive at 5 years.