Improvement In Global Ejection Fraction Research Articles

“B 2 or not B 2 ?”

The field of progenitor cell therapy appears to be poised to transform the management of many cardiovascular diseases. In particular, the use of bone marrow-derived mononuclear cells (BM-MNCs) and endothelial progenitor cells (EPCs) have shown indications of improved cardiac function post–myocardial infarction (MI), with a recent metaanalysis showing a highly significant mean improvement in global ejection fraction of 3% compared to control.1 The overall positive results from these early trials raise 2 important questions. The first is whether cell therapy really works, in other words, whether the results of these smaller trials, which generally enrolled less than 100 patients, will be reproducible in larger pivotal studies. A study currently being planned by Zeiher and colleagues (A.M. Zeiher, personal communication) will help answer this question. The second question is whether we can do better, either by selecting a more active subset of highly regenerative progenitor cells, or by enhancing progenitor cell activity before delivery. Several clinical studies exploring these strategies are already planned or underway, including our own ENACT-AMI (eNOS and Cell Therapy Đ Acute MI) trial. To inform further clinical studies, it is also critical to better understand progenitor cell biology, including the mechanisms by which they exert their function in vivo, as well as the genomic and proteomic interactions that underlie their survival, homing, and differentiation. In this issue of Circulation Research , Krankel et al2 demonstrate a novel pathway that may contribute importantly to EPC function and provide a potential marker of regenerative activity. They report that the kinin B2 receptor (B2R) was highly expressed by CD34+ and CD133+ MNCs, as well as in culture-selected “early growth” EPCs. Bradykinin (BK), a natural …

Pilot study to evaluate the safety and feasibility of intracoronary CD133+ and CD133− CD34+ cell therapy in patients with nonviable anterior myocardial infarction

The long-term effect of intracoronary infusion of progenitor cells in patients with chronic ischemic cardiomyopathy. Bone marrow stem-cell administration in patients with myocardial infarction improved myocardial performance and in some studies contributed to favorable left ventricular remodeling. We report on the results of a pilot, single center, controlled safety, and feasibility study, including 24 patients with old, nonviable anterior myocardial infarction. Twelve patients underwent intracoronary administration of selected CD133(+) and CD133(-)CD34(+) progenitor cells and 12 were followed up on medical therapy. Left ventricular volumes and ejection fraction, at rest and during low-dose dobutamine, and myocardial viability, using TL-201 reinjection scintigraphy, were analyzed at baseline and long-term follow-up. Patients in the treatment group experienced a sustained decrease in left ventricular end-diastolic and end-systolic resting volumes (P = 0.008 and P = 0.002, respectively), as well as an improvement in global ejection fraction at rest [from (27.2 +/- 6.8)% to (29.7 +/- 7.3)%, P = 0.016]. Segmental anterior and apical wall perfusion, during TL-201 reinjection, were similarly improved (P = 0.005 and P < 0.001, respectively). One patient developed restenosis at the cell delivery site and one progression of atherosclerosis. During 28.0 +/- 8.7 months of clinical follow-up, only one patient experienced deterioration of heart failure. In the control group, we observed stability in the perfusion defect and deterioration in end-diastolic and end-systolic volumes (P= 0.002 and P = 0.003, respectively) and a nonsignificant decrease in ejection fraction (P = 0.11). Intracoronary infusion of selected CD133(+) and CD133(-)CD34(+) progenitor cells to a previously infarcted and nonviable anterior wall is safe, and results in sustained improvement in segmental myocardial perfusion and in favorable left ventricular remodeling.

Tissue velocity imaging during dobutamine stimulation for assessment of myocardial viability: Segmental analysis in patients after myocardial infarction

Background Dobutamine stress echocardiography (DSE) is an established method for the detection of viable myocardium, but evaluation of this method is subjective. Tissue velocity Imaging (TVI) allows quantitative analysis of regional myocardial wall motion by assessment of systolic myocardial velocities. The aim of this study was to evaluate the diagnostic value of DSE and TVI for detection of viable myocardium. Methods In 56 patients (58 ± 12 years) with previous myocardial infarction (130 ± 42 days, mean ejection fraction 42 ± 15%) low-dose DSE was combined with analysis of peak systolic myocardial velocities ( V peak) by TVI for assessment of myocardial viability. As reference served a follow-up echocardiography after successful revascularization (mean 91 ± 3 days). Results Of a total of 896 segments 200 showed abnormal wall motion (31 mildly hypokinetic, 50 severely hypokinetic, 115 akinetic, 4 dyskinetic). In 125 of these 200 segments regional improvement of regional wall motion was observed (62.5% viable). An increase of V peak > 1 cm/s during dobutamine stimulation allowed the identification of viable myocardium with a sensitivity of 82% and a specificity 82% (DSE: 77% and 80%). By receiver operating characteristic (ROC) curve analysis, a cut-off value of 1.0 cm/s was the best parameter to differ viable from nonviable myocardium (area under the curve 0.85; p < 0.01; 95% CI 0.79 to 0.90). Improvement of global ejection fraction after revascularization (47 ± 13%, p = 0.11) corresponded with three TVI viable segments with a sensitivity of 92% and a specificity of 89% ( p = 0.012). Conclusions TVI allows the identification of viable myocardium during dobutamine stimulation and enables a quantitative interpretation of DSE.

Usefulness of Real-Time Myocardial Perfusion Imaging to Evaluate Tissue Level Reperfusion in Patients With Non–ST-Elevation Myocardial Infarction

Microvascular integrity is a prequisite for functional recovery in patients who have myocardial infarction after recanalization of the infarct-related coronary artery. In this study, we investigated whether impaired myocardial perfusion is present in patients who have non-ST-elevation myocardial infarction and whether the extent and time course of myocardial tissue reperfusion as assessed by myocardial contrast echocardiography (MCE) are related to functional recovery. Consecutive patients (n = 32) who presented with a first non-ST-elevation myocardial infarction were included in our study. MCE was performed on admission, 1 to 4 hours after angioplasty, and at 24 hours, 4 days, and 4 weeks of follow-up. Contrast images were analyzed visually and quantitatively. Myocardial blood flow was estimated by calculating the product of peak signal intensity and the slope of signal intensity increase. Improvement of wall motion on follow-up echocardiograms after 4 weeks served as a reference for functional recovery of impaired left ventricular function. Of 496 segments available for analysis, 128 (26%) were initially dysfunctional and 96 (75%) recovered at 4 weeks of follow-up. Myocardial tissue reperfusion occurred gradually, expanding over the first 24 hours after percutaneous coronary intervention (myocardial blood flow of 0.4 +/- 0.3 initially, 0.6 +/- 0.4 at 24 hours, and 1.6 +/- 0.7 dB/s at 4 weeks of follow-up, p <0.001). Extent of tissue reperfusion was closely related to grade of improvement of global ejection fraction (r2 = 0.76, p <0.001). MCE predicted functional recovery with a sensitivity of 81%, a specificity of 88%, and accuracy of 83% on a segmental level. Thus, impaired microvascular integrity is suggested by MCE in patients who present with non-ST-elevation myocardial infarction. Improvement of regional tissue perfusion after revascularization is closely related to functional recovery. This information may aid risk stratification and allow monitoring of the effectiveness of reperfusion therapy in these patients.

Effect of reperfusion on ventricular mass, topography, and function during healing of anterior infarction.

The effect of reperfusion performed 2 h after left anterior descending coronary artery occlusion on in vivo changes (echocardiograms) in ventricular mass, topography, and function during postinfarction healing over 6 wk and postmortem topography (planimetry) and collagen (hydroxyproline) content at 6 wk were measured in dogs randomized to reperfusion (n = 12) and no reperfusion (n = 12). Compared with no reperfusion over the 6 wk, reperfusion resulted in less increase in systolic and diastolic volumes, less increase in ventricular mass, less infarct wall thinning, and mild improvement in global ejection fraction without any change in regional asynergy. Although reperfusion decreased the infarct collagen content at 6 wk, it reduced the in vivo expansion of the endocardial surface area; the elongation, diastolic bulge, echogenicity, and systolic thinning of the infarct zone; and the global shape index and aneurysm frequency. Thus reperfusion after 2 h attenuates regional and global dilation and produces less increase in mass during postinfarct healing than no reperfusion, so that the improvement in global systolic function cannot be attributed to global hypertrophy.

Prospective Evaluation of Viable Myocardium by Quantitative Dipyridamole-Thallium-201 Scintigraphy and Radionuclide Ventriculography

Improvement of myocardial function is a major goal of coronary revascularization. Considerable interest remains in the preoperative identification of viable myocardium. We examined 26 consecutive patients with left ventricular dysfunction undergoing coronary artery bypass grafting. Serial dipyridamole-thallium imaging and radionuclide ventriculography was performed preoperatively and postoperatively. The relationship between preoperative and postoperative thallium perfusion and segmental wall motion was analyzed. The mean preoperative ejection fraction was 32 +/- 9 (21 to 51%) and increased to 41 +/- 12 (17 to 67%) postoperatively (p > 0.01). Seventy-seven percent of patients improved their global ejection fraction postoperatively by > 5%. Thallium perfusion improved postoperatively in 84% of reversible defects vs 63% of partially reversible defects and 35% of fixed defects. Segments with either reversible or partially reversible thallium defects showed an improved postoperative wall motion in 71% and 68%, respectively. Postoperative wall motion improved in 43% of fixed defects. Overall, 67% of hypokinetic segments showed improved postoperative wall motion while only 29% of akinetic or dyskinetic segments improved postoperatively. Preoperative thallium redistribution coupled with preserved wall motion was predictive of improvement in wall motion was predictive of improvement in wall motion postoperatively and indirectly indicates myocardial viability. However, 43% of fixed defects also showed improved postoperative wall motion. A significant improvement in global ejection fraction was found and could be predicted by a linear regression analysis utilizing clinical and thallium parameters.

Accelerated plasminogen activator dose regimens for coronary thrombolysis

To determine the clinical profile and efficacy of accelerated recombinant tissue-type plasminogen activator (rt-PA) dose regimens, five different strategies of thrombolytic therapy in a total of 232 patients were systematically evaluated in the setting of acute myocardial infarction. The fifth strategy involved a combination of accelerated rt-PA and intravenous urokinase (regimen E). A weight-adjusted dose of 1.25 mg/kg body weight of tissue plasminogen activator over 90 min (regimen C) yielded the highest coronary patency rate (83%) at acute angiography. The associated in-hospital reocclusion rate for this regimen was low (4%). An exaggerated (60-min) dosage regimen yielded an inferior coronary patency rate (63%). Combination therapy (regimen E) was associated with a 72% patency rate and 3% reocclusion rate. Marginal improvement in global ejection fraction and regional wall function was demonstrated with all strategies by predischarge catheterization. Bleeding complications were most common at the periaccess site and were not different from those in previous experiences reported with conventional 3-h dosing regimens. Measurements of baseline, 30-min and 3-h levels of tissue plasminogen activator, fibrinogen and fibrin(ogen) degradation products were obtained. At 3 h, fibrinogen levels of less than 1 g/liter were demonstrated with combination therapy (regimen E) as well as with regimen C. Major clinical outcomes including death, reocclusion and reinfarction also showed a tendency to be less common with regimen C. Therefore, although accelerated dose regimens of rt-PA do not reliably yield acute coronary patency rates greater than 85%, an acute coronary patency rate of approximately 85% can be approached.(ABSTRACT TRUNCATED AT 250 WORDS)

Nuclear magnetic resonance and radionuclide angiographic assessment of acute myocardial infarction in a randomized trial of intravenous streptokinase

Sixty-six patients presenting with their first evolving transmural acute myocardial infarction (AMI) were randomized to receive either streptokinase (n = 41) or placebo therapies (n = 25) within 6 hours of the onset of chest pain. These patients then underwent supine rest, exercise and after-nitroglycerin radionuclide angiography 3 weeks after AMI. Nuclear magnetic resonance (NMR) imaging was performed at 3 weeks as a more direct estimate of AMI size. Although peak creatine kinase values were comparably elevated between groups (2,367 ± 1,486 IU/liter for streptokinase vs 2,637 ± 1,305 IU/liter for placebo), there was a significant reduction in NMR-measured AMI size in the streptokinase group (3 ± 2% of left ventricular volume vs 10 ± 4% in the placebo group, p < 0.05). This occurred despite comparable resting (54 ± 11 vs 47 ± 10% and exercise (53 ± 12 vs 49 ± 11%) global ejection fractions. However, following nitroglycerin, there was an improvement in global ejection fraction in the streptokinase-treated group that was not observed with placebo (61 ± 13 vs 48 ± 10%, p < 0.05). A similar pattern was also observed with regional functional analysis. Thus, streptokinase therapy leads to a significant reduction in NMR-measured AMI size and to a greater degree of reversible left ventricular dysfunction.

Early reperfusion therapy improves left ventricular function after acute inferior myocardial infarction associated with right coronary artery disease

Quantitative global and regional ventriculographic analysis was performed acutely and 1 week later in 46 patients undergoing reperfusion procedures within 6 hours of acute inferior myocardial infarction due to right coronary artery disease. While serial improvement in global left ventricular ejection fraction was not demonstrated for the group, infarct zone regional wall motion did improve (−2.7 ± 0.9 vs −2.3 ± 1.4 SD/chord, p < 0.007). Serial improvement in global ejection fraction was demonstrated in the subgroup of patients treated within 2 hours of symptom onset (55 ± 10 vs 62 ± 10%; n = 5; p < 0.03). Infarct zone regional wall motion improved serially only in the subgroup of patients treated within 3 hours of symptom onset (−2.4 ± 1.1 vs −1.3 ± 1.7 SD/chord; n = 11; p < 0.007). Patients with initially patent arteries had a higher ejection fraction on follow-up catheterization than did those with initially occluded vessels (61 ± 11 vs 55 ± 7%; p < 0.02), and patients with patent arteries at follow-up had a higher ejection fraction than did those whose arteries were occluded (60 ± 9 vs 48 ± 4%; p < 0.0001). We conclude that significant improvement in global and reglonal left ventricular function in patients with inferior myocardial infarction is possible when reperfusion therapy is begun early or when arterial patency is achieved.

Intracoronary thrombolytic therapy in acute myocardial infarction: A prospective, randomized, controlled trial

A prospective, randomized trial was designed to assess the efficacy of intracoronary thrombolytic therapy with streptokinase (STK) in acute myocardial infarction. Sixty-four patients with acute myocardial infarction were randomized within 6 hours of onset of symptoms to 1 of 3 groups. Sixteen patients were treated by conventional means (control group). Nineteen patients underwent coronary arteriography and received corticosteroids and intracoronary and intravenous nitroglycerin (NTG group). Twenty-nine patients received management identical to that of the NTG group, with the addition of intracoronary STK therapy (STK group). Recanalization was demonstrated in 21 of 29 patients (72%) in the STK group. Global and regional ejection fraction (EF) was determined by radionuclide ventriculography before any intervention and 7 to 10 days later. No significant improvement in global EF was achieved in the control and NTG groups. In STK patients as a group, global EF did not increase significantly; however, in patients recanalized with STK, EF improved from 42 ± 17% to 49 ± 16% (p − 0.023). All groups showed wide variability of response. Improvement in global EF of more than 5% was noted in 44% of patients recanalized with STK. When subgrouped on the basis of initial global EF of 45% or less or more than 45%, only patients recanalized with STK with an initial EF of 45% or less had an improved global EF (from 30 ± 10% to 42 ± 10%, p = 0.015). Regional EF of all involved infarct regions was improved only in the STK group (from 34 ± 19% to 42 ± 23%, p = 0.027) and STK-recanalized subgroup (from 33 ±18% to 45 ± 24%, p = 0.003). When only the most involved infarct regions were analyzed, control, NTG and STK groups improved, with patients recanalized with STK showing the greatest degree of improvement. Thus, this trial demonstrates a beneficial effect of thrombolytic therapy in global and, more strikingly, in regional function in patients in whom recanalization with STK is successful, with predominant benefit in those with initially depressed left ventricular function.

Return of left ventricular function after reperfusion in patients with myocardial infarction: importance of subtotal stenoses or intact collaterals.

To determine whether subsequent improvement in left ventricular ejection fraction can be predicted from preintervention coronary arteriograms, we divided 63 patients with acute myocardial infarction into two groups based on findings at emergency coronary arteriography at a mean of 7 hr after onset of symptoms: (1) a "no-flow" group with an occluded infarct-related artery and no easily visible collaterals (n = 36) and (2) a "limited-flow" group with either subtotal stenosis or total occlusion of the infarct-related vessel with intact collaterals (n = 27). Of the 63 patients, 61 underwent emergency procedures to establish reperfusion. At follow-up angiography (contrast or radionuclide) performed 12 +/- 7 days after infarction, global ejection fraction had increased significantly in patients with limited flow to the infarct zone and "successful" early reperfusion intervention due primarily to a significant increase in the regional ejection fraction in the infarct zone. Global ejection fraction fell significantly between baseline and follow-up in patients with no flow to the infarct zone and "unsuccessful" early reperfusion intervention due primarily to a fall in the regional ejection fraction of the noninfarct zone. Global and regional ejection fractions did not change significantly in patients with no flow to the infarct zone and successful early reperfusion or in patients with limited flow to the infarct zone and unsuccessful early reperfusion intervention. The elapsed time before reperfusion did not relate significantly to the change in either regional or global ejection fraction. However, the magnitude of improvement in both global and regional ejection fraction at follow-up was greater among patients with anterior infarcts than among those with inferior infarcts, possibly because baseline ejection fraction was lower in patients with anterior infarcts. These data indicate that among patients with acute myocardial infarction undergoing emergency coronary arteriography at a mean of 7 hr after onset of symptoms, improvement in global ejection fraction is unlikely to occur even after a successful early reperfusion intervention in the absence of preserved flow to the infarct area. However, among patients with subtotally occluded infarct-related arteries or significant collateral blood flow to the infarct zone, subsequent improvement in global and regional ejection fraction in the zone of myocardial infarction frequently occurs. Improvement in both global and regional ejection fraction may be more readily demonstrated in patients initially having more severe depression of these parameters.

The effect of recanalization of the occluded coronary artery in acute myocardial infarction on left ventricular function.

In 20 patients with acute myocardial infarction a left ventriculogram was obtained within 6 h after the onset of chest pain and again during a follow-up study, 2–3 weeks later. In 17 patients the infarct-related vessel (IR V) could be recanalized with selective intracoronary infusion of a thrombolytic agent and was still patent during the second study. In three other cases the IR V was already patent during the first angiogram and remained so at the time of the follow-up study. The ejection fraction of these 20 patients increased from 52 to 56% (P < 0.02). In eight other patients the infarct-related artery could not be recanalized or was reoccluded at the time of the control study. The ejection fraction of these patients with unsuccessful recanalization decreased from 49 to 37% (P<0.001). Analysis of regional function in eight patients with anterior infarction and seven patients with inferior infarction, all with a successful recanalization and persistent patency of the infarct-related vessels, suggests that improvement of global ejection fraction is only partially due to improvement of regional pump function in the reperfused ‘infarct zone’ but may also be caused by enhancement of regional function in other wall regions or by changes in afterload.