Pierre Chouraqui

Systemic Delivery of Bone Marrow–Derived Mesenchymal Stem Cells to the Infarcted Myocardium Feasibility, Cell Migration, and Body Distribution

Background—Systemic delivery of bone marrow–derived mesenchymal stem cells (BM-MSCs) is an attractive approach for myocardial repair. We aimed to test this strategy in a rat model after myocardial infarction (MI). Methods and Results—BM-MSCs were obtained from rat bone marrow, expanded in vitro to a purity of >50%, and labeled with 99mTc exametazime, fluorescent dye, LacZ marker gene, or bromodeoxyuridine. Rats were subjected to MI by transient coronary artery occlusion or to sham MI. 99mTc-labeled cells (4×106) were transfused into the left ventricular cavity of MI rats either at 2 or 10 to 14 days after MI and were compared with sham-MI rats or MI rats treated with intravenous infusion. Gamma camera imaging and isolated organ counting 4 hours after intravenous infusion revealed uptake of the 99mTc-labeled cells mainly in the lungs, with significantly smaller amounts in the liver, heart, and spleen. Delivery by left ventricular cavity infusion resulted in drastically lower lung uptake, better uptake in the heart, and specifically higher uptake in infarcted compared with sham-MI hearts. Histological examination at 1 week after infusion identified labeled cells either in the infarcted or border zone but not in remote viable myocardium or sham-MI hearts. Labeled cells were also identified in the lung, liver, spleen, and bone marrow. Conclusions—Systemic intravenous delivery of BM-MSCs to rats after MI, although feasible, is limited by entrapment of the donor cells in the lungs. Direct left ventricular cavity infusion enhances migration and colonization of the cells preferentially to the ischemic myocardium.

Significance of ST segment elevations in posterior chest leads (V7 to V9) in patients with acute inferior myocardial infarction: application for thrombolytic therapy.

OBJECTIVES This study was designed to examine whether ST segment elevation in posterior chest leads (V7 to V9) during acute inferior myocardial infarction (MI) identifies patients with a concomitant posterior infarction and whether these patients might benefit more from thrombolysis. BACKGROUND Because the posterior wall is faced by none of the 12 standard electrocardiographic (ECG) leads, the ECG diagnosis of posterior infarction is problematic and has often remained undiagnosed, especially in the acute phase. METHODS Eighty-seven patients with a first inferior infarction who were treated with recombinant tissue-type plasminogen activator were stratified according to the presence (Group A [46 patients]) or absence (Group B [41 patients]) of concomitant ST segment elevation in posterior chest leads V7 to V9. RESULTS Patients in Group A had a higher incidence of posterolateral wall motion abnormalities (p < 0.001) on radionuclide ventriculography, a larger infarct area (as evidenced by higher peak creatine kinase levels) (p < 0.02) and a lower left ventricular ejection fraction (LVEF) at hospital discharge (p < 0.008) than those in Group B. ST segment elevation in leads V7 to V9 was associated with a higher incidence of at least one of the following adverse clinical events: reinfarction, heart failure or death (p = 0.05). Although patency of the infarct-related artery (IRA) in Group A resulted in an improved LVEF at discharge (p < 0.012), LVEF was unchanged in Group B, regardless of the patency status of the IRA. CONCLUSIONS ST segment elevation in leads V7 to V9 identifies patients with a larger inferior MI because of concomitant posterolateral involvement. Such patients might benefit more from thrombolytic therapy.

The distinction between coronary and myocardial reperfusion after thrombolytic therapy by clinical markers of reperfusion.

OBJECTIVES We sought to examine the hypothesis that rapid resolution of ST-segment elevation in acute myocardial infarction (AMI) patients with early peak creatine kinase (CK) after thrombolytic therapy differentiates among patients with early recanalization between those with and those without adequate tissue (myocardial) reperfusion. BACKGROUND Early recanalization of the epicardial infarct-related artery (IRA) during AMI does not ensure adequate reperfusion on the myocardial level. While early peak CK after thrombolysis results from early and abrupt restoration of the coronary flow to the infarcted area, rapid ST-segment resolution, which is another clinical marker of successful reperfusion, reflects changes of the myocardial tissue itself. METHODS We compared the clinical and the angiographic results of 162 AMI patients with early peak CK (< or =12 h) after thrombolytic therapy with (group A) and without (group B) concomitant rapid resolution of ST-segment elevation. RESULTS Patients in groups A and B had similar patency rates of the IRA on angiography (anterior infarction: 93% vs. 93%; inferior infarction: 89% vs. 77%). Nevertheless, group A versus B patients had lower peak CK (anterior infarction: 1,083+/-585 IU/ml vs. 1,950+/-1,216, p < 0.01; and inferior infarction: 940+/-750 IU/ml vs. 1,350+/-820, p=0.18) and better left ventricular ejection fraction (anterior infarction: 49+/-8, vs. 44+/-8, p < 0.01; inferior infarction: 56+/-12 vs. 51+/-10, p=0.1). In a 2-year follow-up, group A as compared with group B patients had a lower rate of congestive heart failure (1% vs. 13%, p < 0.01) and mortality (2% vs. 13%, p < 0.01). CONCLUSIONS Among patients in whom reperfusion appears to have taken place using an early peak CK as a marker, the coexistence of rapid resolution of ST-segment elevation further differentiates among patients with an opened culprit artery between the ones with and without adequate myocardial reperfusion.

Evaluation of an attenuation correction method for thallium-201 myocardial perfusion tomographic imaging of patients with low likelihood of coronary artery disease

BackgroundImage artifacts caused by nonuniform photon attenuation are a source of error in interpretation of images during myocardial perfusion single photon emission computed tomography (SPECT). A newly introduced attenuation correction method was evaluated for improvement in image homogeneity during 201Tl SPECT. The method was assessed with a cardiac phantom and in examinations of 42 patients (29 men) with a low likelihood of coronary disease.Methods and ResultsSimultaneous transmission-emission SPECT was performed with a moving collimated 153Gd line source synchronized with a moving electronic acquisition window for transmission imaging and a novel variable-width electronic exclusion window for emission imaging designed to avoid transmission-to-emission cross talk. The resulting uncorrected and corrected polar maps were analyzed visually and divided into 31 segments for quantitative analysis. Visual analysis of the color-coded mean polar maps showed clear improvement in homogeneity after correction among the phantom, male patients, female patients, and 42 patients combined at stress and redistribution. The male and female mean polar maps showed very little differences in regional count distribution after correction. Quantitative analysis of the mean polar maps showed the following mean segmental counts (%SD) before and after attenuation correction: phantom 88 (9) to 90 (7.5), P=.00005; men at stress 83 (10) to 88 (6), P=.0007, and at redistribution 84 (8) to 88 (6), P=.01; women at stress 86 (7) to 90 (5), P=.0002, and at redistribution 87 (5) to 88 (7), P=.3; patients combined at stress 84 (8) to 88 (6), P =.0004, and at redistribution 85(7) to 87 (7), P=.03. Inferior/anterior count ratio for men at stress increased after correction from 0.82 to 0.99 and septal/lateral count ratio from 0.94 to 1.02. Inferior/anterior count ratio for men at redistribution increased from 0.86 to 1.06 and septal/lateral count ratio from 0.97 to 1.04. Inferior/anterior count ratio for women at stress increased from 0.95 to 1.03 and septal/lateral count ratio from 0.93 to 1.00. Inferior/anterior count ratio for women at redistribution increased from 1.04 to 1.10, and septal/lateral count ratio decreased from 1.02 to 1.00.ConclusionImprovement in image homogeneity was demonstrated with this attenuation correction method with a cardiac phantom and for patients with low likelihood of coronary artery disease. The slight relative increase in inferior wall counts at redistribution was most likely caused by scatter from the relatively higher liver activity compared with the situation during stress and emphasizes the need for scatter correction. The close similarity in count distribution for the mean male and female polar maps supports use of a sex-independent normal database for quantitative analysis. The reduced variation in corrected images from patient to patient implies increased accuracy for detection of myocardial defects.

Imaging of Aortic Atherosclerotic Lesions by 125I-LDL, 125I-Oxidized-LDL, 125I-HDL and 125I-BSA

Objective: The aim of the present study was to compare the accumulation of ¹²⁵I-labeled low-density lipoproteins (LDL), oxidized LDL (oxLDL), HDL and BSA in advanced atherosclerotic lesions of apoE-deficient mice. Methods:¹²⁵I-lipoproteins or ¹²⁵I-BSA were injected into the tail vein of apoE-deficient mice. Blood clearance of ¹²⁵I-lipoproteins and ¹²⁵I-BSA and their accumulation in atherosclerotic lesions were assayed. Results: Blood clearance of ¹²⁵I-LDL and ¹²⁵I-HDL was moderate, and approximately 30% of the injected lipoproteins were present in plasma 24 h following injection. oxLDL was removed much faster from plasma, and less than 10% of ¹²⁵I-oxLDL was present in the circulation 30 min after ¹²⁵I-oxLDL injection. The clearance of ¹²⁵I-BSA from the circulation was slower than the lipoprotein clearance. The highest accumulation of LDL, oxLDL, HDL and BSA was detected in atherosclerotic lesions in the aortic arch and abdominal aorta, while lower accumulation was detected in the less atherosclerotic descending thoracic aorta. Conclusion: Our findings demonstrate that both ¹²⁵I-HDL and ¹²⁵I-BSA as well as ¹²⁵I-LDL are accumulated in atherosclerotic plaques and that they can be used for the detection of atherosclerotic lesions.

Serum Uric Acid for Risk Stratification of Patients with Coronary Artery Disease

Objectives: In patients with coronary artery disease (CAD), elevated serum uric acid (SUA) levels may predict worse cardiovascular outcomes. It is known that SUA levels are influenced by renal function. We aimed to assess the predictive value of SUA while taking into account patients’ renal function. Methods: The primary end point (PEP) risk, including fatal or nonfatal myocardial infarction (MI) or sudden death, was assessed by SUA quintiles before and after adjustment for the estimated glomerular filtration rate (eGFR) in 2,796 nondiabetic CAD patients enrolled in the Bezafibrate Infarction Prevention study. Results: The PEP risk increased from the lowest (11.8%) to highest SUA quintile (18.0%), p < 0.005, respectively. After adjustment for age, sex, smoking, prior MI, metabolic syndrome variables, NYHA classes II–IV, heart rate and treatment with bezafibrate, diuretics, angiotensin-converting enzyme inhibitors, β-blockers, calcium channel blockers and antiplatelets, the highest SUA quintile exhibited the highest PEP risk [hazard ratio (HR): 1.47 (95% CI: 1.06–2.04)]. Patients in the highest – compared with those in the lowest – quintiles continued to demonstrate an increased PEP risk [HR: 1.46 (95% CI: 1.04–2.06)], even after additional adjustment for the eGFR. Conclusion: In nondiabetic patients with CAD, elevated SUA levels are associated with an increased risk of cardiac events, independent of renal function.

Usefulness of Routine Use of Multidetector Coronary Computed Tomography in the “Fast Track” Evaluation of Patients With Acute Chest Pain

Recently published American Heart Association/American College of Cardiology guidelines suggest that multidetector computed tomography (MDCT) may be appropriate for investigating acute chest pain (ACP). Only a few small studies have evaluated the use of MDCT in ACP, where it was not part of routine investigation. We sought to evaluate the routine use of MDCT in a large cohort of patients presenting with ACP in a real-world setting. We studied 785 consecutive patients with ACP who underwent evaluation by MDCT or myocardial perfusion scintigraphy after an observation period of > or = 12 hours. Patients with findings suggestive of significant coronary artery disease (CAD) were referred to coronary angiography. Forty-two patients were hospitalized due to evidence of myocardial ischemia and 44 patients were discharged after the observation period. Of the remaining 699 patients, 340 underwent MDCT and 359 myocardial perfusion scintigraphy. In 22 patients (7%) multidetector computed tomogram showed significant CAD and in 32 (9%) patients myocardial perfusion scintigram showed significant ischemia. Significant CAD was confirmed by coronary angiography in 65% and 60%, respectively. Multidetector computed tomogram was nondiagnostic in 31 patients (9%). Extracardiac findings that might be related to ACP and/or necessitated further investigation were demonstrated by multidetector computed tomogram in 71 patients (21%). During 3-month follow-up, 1 patient (0.3%) with negative multidetector computed tomographic and 9 (3%) with negative myocardial perfusion scintigraphic findings developed an acute coronary syndrome or died. Rehospitalization, due to recurrent chest pain, occurred in 9 patients (3.3%) and 21 patients (7.2%), respectively. In conclusion, MDCT could be an appropriate alternative to traditional noninvasive techniques for investigating ACP.

Assessment of peripheral artery tonometry in the detection of treadmill exercise-induced myocardial ischemia ☆

OBJECTIVES We sought to assess the added diagnostic value of peripheral artery tonometric (PAT) measurements, based on finger pulsatile arterial volume changes, to standard 12-lead stress electrocardiography (ECG), for detecting exercise-induced myocardial ischemia, using single-photon emission computed tomography (SPECT) as the standard of comparison in a double-blinded, multicenter protocol. METHODS An automated algorithm for identifying myocardial ischemia from PAT was derived from 345 training cases. The PAT outcome was combined with the ECG result (ischemic, nonischemic, or equivocal), giving a PAT-enhanced value. A threshold of normality was determined to optimize agreement with the SPECT results in the training sample. The PAT-enhanced analysis was then validated in 616 subjects, only two of whom had technically unacceptable PAT studies. RESULTS In the validation cohort, receiver operating characteristic curve analysis of the PAT-enhanced diagnosis yielded an area under the curve of 0.72, a sensitivity of 63.5%, compared with 44.7% for ECG alone (p < 0.0001), and a specificity of 67.8% common to both ECG and PAT-enhanced diagnoses. Similar results were found in the training sample. Although over 10% of validation subjects had equivocal ECG results, with the aid of PAT, it was possible to provide diagnostic information for all but one subject. CONCLUSIONS Peripheral artery tonometry may be useful for improving the diagnosis of exercise-induced myocardial ischemia by both enhancing the sensitivity without impairing the specificity and increasing the percentage of definitive test results.

Human umbilical cord blood cells: a new alternative for myocardial repair?

Cell therapy for myocardial disease is a rapidly progressive field. However, present strategies of cell transplantation into the infarcted myocardium have limitations from practical points of view. One of the biggest challenges is to achieve a sufficient number of suitable cells. Umbilical cord blood (UCB), an unlimited source of stem/progenitor cells that could be used for transplantation into the injured heart, is readily available. The aim of our review is to describe the potential and prospect of UCB as a new supplier of cells for myocardial repair. The use of UCB stem cells might be of importance to elderly and sick people in whom the availability of autologous stem cells is limited.

Limited clinical value of exercise stress test for the screening of coronary artery disease in young, asymptomatic adult men

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