Peter Lippolt

Intracoronary Bone Marrow Cell Transfer After Myocardial Infarction Eighteen Months’ Follow-Up Data From the Randomized, Controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) Trial

Background— Intracoronary transfer of autologous bone marrow cells (BMCs) may enhance recovery of left ventricular (LV) function in patients after acute myocardial infarction (AMI). However, clinical studies addressing the effects of BMCs after AMI have covered only limited time frames ranging from 3 to 6 months. The critical question of whether BMC transfer can have a sustained impact on LV function remains unanswered. Methods and Results– After percutaneous coronary intervention with stent implantation (PCI) of the infarct-related artery, 60 patients were randomized 1:1 to a control group with optimal postinfarction therapy and a BMC transfer group that also received an intracoronary BMC infusion 4.8±1.3 days after PCI. Cardiac MRI was performed 3.5±1.5 days, 6±1 months, and 18±6 months after PCI. BMC transfer was not associated with adverse clinical events. In the control group, mean global LV ejection fraction increased by 0.7 and 3.1 percentage points after 6 and 18 months, respectively. LV ejection fraction in the BMC transfer group increased by 6.7 and 5.9 percentage points. The difference in LVEF improvement between groups was significant after 6 months but not after 18 months (P=0.27). The speed of LV ejection fraction recovery over the course of 18 months was significantly higher in the BMC transfer group (P=0.001). Conclusions– In this study, a single dose of intracoronary BMCs did not provide long-term benefit on LV systolic function after AMI compared with a randomized control group; however, the study suggests an acceleration of LV ejection fraction recovery after AMI by BMC therapy.

Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial

AIMS We assessed whether a single intracoronary infusion of autologous bone marrow cells (BMCs) can have a sustained impact on left ventricular ejection fraction (LVEF) in patients after ST-elevation myocardial infarction (STEMI). In the BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) trial, 60 patients with STEMI and successful percutaneous coronary intervention were randomized to a control and a cell therapy group. As previously reported, BMC transfer led to an improvement of LVEF by 6.0% at 6 months (P = 0.003) and 2.8% at 18 months (P = 0.27). METHODS AND RESULTS Left ventricular ejection fraction and clinical status were re-assessed in all surviving patients after 61 +/- 11 months. Major adverse cardiac events occurred with similar frequency in both groups. When compared with baseline, LVEF assessed by magnetic resonance imaging at 61 months decreased by 3.3 +/- 9.5% in the control group and by 2.5 +/- 11.9% in the BMC group (P = 0.30). Patients with an infarct transmurality > median appeared to benefit from BMC transfer throughout the 61-month study period (P = 0.040). CONCLUSION A single intracoronary application of BMCs does not promote a sustained improvement of LVEF in STEMI patients with relatively preserved systolic function. It is conceivable that a subgroup of patients with more transmural infarcts may derive a sustained benefit from BMC therapy. However, this needs to be tested prospectively in a randomized trial.

Evaluation of left ventricular diastolic function by pulsed Doppler tissue imaging in mice.

BACKGROUND Diastolic left ventricular (LV) function is commonly characterized by transmitral flow pattern in human beings. Recently, Doppler tissue imaging (DTI) was introduced to evaluate diastolic function. The aim of our study was to validate DTI in the evaluation of diastolic function in mice. METHODS We measured indices of diastolic function using pulsed DTI, and transmitral Doppler and LV pressure and its maximal rate of decrease (LVdP/dt(min)), before and 4 weeks after aortic banding in C57BL/6 mice. RESULTS Peak early diastolic velocity and ratio of peak early-to-late filling velocities, both measured by DTI, were significantly reduced after banding, thereby indicating diastolic dysfunction. Diastolic dysfunction was confirmed by impaired LV dP/dt(min), decreased transmitral early filling velocity, and transmitral early-to-late filling velocity ratio using transmitral Doppler. CONCLUSION DTI detects diastolic dysfunction caused by chronic pressure overload in mice after aortic banding. DTI is suggested to be implemented as part of routine mouse echocardiography for evaluation of LV diastolic function.

Long-term effects of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: 5-year results from the randomized-controlled BOOST trial—an echocardiographic study

AIMS We have recently observed that intracoronary autologous bone marrow cell (BMC)-transfer improves parameters of diastolic function in patients after acute myocardial infarction at 6 and 18 months. There is no clinical study addressing the long-term effect of BMC transfer on diastolic function. Therefore, we conducted a 5-year follow-up of the BOOST trial to evaluate a sustained benefit on echocardiographic parameters on diastolic function. METHODS AND RESULTS After successful primary percutaneous coronary intervention (PCI) for acute ST-elevation MI, patients were randomized to a control (n = 28) or BMC transfer group (n = 28). Echocardiography was performed at 4.5 +/- 1.5 days after PCI, at 6, 18, and 60 months. Diastolic function was determined by measuring transmitral flow velocities (E/A ratio), diastolic myocardial velocities (E(a)/A(a) ratio), isovolumic relaxation time (IVRT), and deceleration time (DT). All analyses were performed in a blinded fashion. There was an overall treatment effect of BMC transfer on E/A (0.25 +/- 0.10; 95% CI 0.05-0.44; P = 0.01). E/A ratio was significantly lower at 6 (Control 0.90 +/- 0.07; BMC 1.23 +/- 0.14; P = 0.03) and 18 months (Control 0.87+/-0.04; BMC 1.13 +/- 0.09; P = 0.01) in the control group, whereas E/A ratio was not different at 60 months between both groups (Control 0.90 +/- 0.06; BMC 1.05 +/- 0.07; P = 0.12). We found no overall effect of BMC transfer on E(a)/A(a) ratio (0.21 +/- 0.14; 95% CI -0.03 to 0.46; P = 0.09), DT (-12 +/- 11 ms; 95% CI -21 to 28; P = 0.75), IVRT -6 +/- 7 ms; 95% CI -9 to 19; P = 0.43), and E/E(a) ratio (0.58 +/- 0.88; 95% CI -1.18 to 2.34; P = 0.51). CONCLUSION Intracoronary autologous BMC transfer provides an overall treatment effect on echocardiographic parameters of diastolic function in patients after AMI. However, this effect is basically related to an early improvement of parameters of diastolic function without a sustained effect on long-term follow-up.

Progression of coronary artery disease is dependent on anatomic location and diameter

OBJECTIVES This study represents the first prospective, quantitative analysis of the association of progression of coronary atherosclerosis with anatomic site and diameter. BACKGROUND The progressive course of coronary artery disease has been documented in many angiographic follow-up trials. METHODS The data of 348 patients with coronary artery disease from the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT) were reviewed. Standardized coronary angiograms were taken 3 years apart and were analyzed quantitatively. The coronary tree was subdivided into 25 segments. The progression of 1,063 preexisting coronary stenoses and the appearance of 247 newly formed stenoses was assessed in relation to the mean diameter of segments (< 2 mm, 2 to 3 mm, > 3 mm) and to their position in the coronary tree (proximal, mid, distal) and in the three major coronary arteries. RESULTS Decreases in the minimal diameter of preexisting stenoses were largest in segments that were > 3 mm in diameter (mean +/- SD 0.23 +/- 0.5 mm vs. 0.10 +/- 0.4 mm and 0.02 +/- 0.3 mm, p < 0.001), in a proximal position (0.14 +/- 0.5 mm vs. 0.09 +/- 0.4 mm and 0.06 +/- 0.3 mm, p = 0.081) and in the right coronary artery (0.14 +/- 0.4 mm vs. 0.07 +/- 0.4 mm and 0.07 +/- 0.3 mm, p < 0.01). Changes in percent diameter stenosis of preexisting stenoses were lowest in segments that were < 2 mm in diameter and in a distal position (p = NS). The number of new stenoses/segment was lowest in segments that were < 2 mm in diameter (44 of 1,756 vs. 139 of 1,967 and 64 of 1,125, p < 0.001) and in a distal position (77 of 2,370 vs. 84 of 1,193 and 86 of 1,285, p < 0.001) and was highest in segments of the right coronary artery (100 of 1,546 vs. 66 of 1,496 and 72 of 1,492, p = 0.044). CONCLUSIONS Progression of coronary artery disease occurs most frequently in coronary segments that are > 2 mm in diameter, in a proximal or midartery position and in the right coronary artery.

Influence of radiographic contrast agents on quantitative coronary angiography

PurposeQuantitative angiographic studies on the vasomotility of epicardial coronary arteries are gaining increasing relevance. We investigated whether radiographic contrast agents might influence coronary vasomotor tone and thereby the results of such studies.MethodsCoronary angiograms were taken in 12 patients with coronary artery disease at intervals of 5, 3, 2, and 1 min with the low-osmolar, nonionic contrast agent iopamidol 300, and were repeated at identical intervals with the high-osmolar, ionic agent diatrizoate 76%.ResultsQuantitative cine film analysis demonstrated no significant diameter changes in angiographically normal and stenotic coronary arteries with iopamidol. With diatrizoate, however, normal segments were dilated 2%±2% (p<0.01) after 2 min and 10%±3% after the 1 min interval (p<0.001). Stenoses showed no uniform responses to diatrizoate.ConclusionLow-osmolar, nonionic contrast agents should be preferred for quantitative angiographic studies on epicardial coronary vasomotility. When using ionic contrast agents, injection intervals of at least 3 min are required.

Concept of an antiatherosclerotic efficacy of calcium entry blockers

Animal experiments suggest an inhibitory effect of calcium entry blockers on arterial calcinosis and the formation of atherosclerotic plaques. Experiments with isolated tissues suggest various mechanisms for an antiatherosclerotic effect of calcium entry blockers.INTACT, the International Nifedipine Trial on Antiatherosclerotic Therapy, is the first study investigating, with a prospective, placebo-controlled, randomized, double-blind design, the influence of a calcium entry blocker (nifedipine 80 mg/day) on the progression of coronary atherosclerosis in patients with proven coronary artery disease. Study endpoints were changes of established coronary stenoses (diameter reduction ≥ 20%), as well as the formation of new stenoses as documented by coronary angiography. Standardized coronary angiograms were taken before and after a treatment period of 3 years. The angiograms were quantitatively analyzed with the computer-assisted edge detection system CHAS. Of the 425 patients included in the study, 282 patients (134 on nifedipine and 148 on placebo) revealed no protocol violations. In the inclusion angiograms of these patients, 893 coronary stenoses were detected which were not significantly influenced in their development by nifedipine. However, 196 entirely new coronary lesions, 185 stenoses and 11 occlusions, were found in the follow-up angiograms. There were 78 lesions in 54 patients (40%) on nifedipine (0.58 new lesions/patient) and 118 lesions in 73 patients (49%; n.s.) on placebo (0.8 new lesions/patient; p = 0.031).In two other studies on the inhibiting effect of dihydropyridine calcium entry blockers on the progression of coronary artery disease in man defining angiographic endpoints, the drugs were also shown to reduce the number of newly formed significant coronary lesions. If further trials in man confirm a protective role of calcium entry blockers against the formation of atherosclerotic coronary lesions, a new strategy in the prevention of coronary artery disease has to be considered.

Acute Effects of Celiprolol on Angiographically Normal and Stenotic Coronary Arteries

Unselective and β_1-selective beta-blockers may induce vasoconstriction of normal and stenotic epicardial coronary arteries. To analyze the influence of the vasodilatory beta-blocker celiprolol on coronary vasomotility, 0.4 mg celiprolol/kg were intravenously infused over 4 minutes in 13 patients with coronary artery disease. Coronary angiograms were taken before (control) and at 4, 6, 8, 10, 15, and 20 minutes after the onset of infusion and 4 minutes after final sublingual administration of 0.4 mg nitroglycerin. Quantitative analysis of cinefilms demonstrated no significant diameter changes in angiographically normal coronary segments and stenoses. The vasodilatory capacity of normal segments (18 ± 12%; p ` 0.001) and stenoses (17 ± 14%; p ` 0.01) was proven by nitroglycerin. Systolic blood pressure, heart rate, and pulmonary wedge pressure revealed no significant changes with celiprolol. Thus, celiprolol exerts no vasoconstricting effects on angiographically normal and stenotic coronary arteries.

Association between coronary occlusions and myocardial infarcts

The number of angiographically documented coronary occlusions and the incidence of Q-wave myocardial infarcts were retrospectively compared in 348 patients with moderate coronary artery disease from the INTACT study (International Nifedipine Trial on Antiatherosclerotic Therapy). In only 68 out of 118 infarcts (58%) an occlusion of the respective coronary artery was found, suggesting a spontaneous recanalization rate of 42%. On the other hand, only 68 out of 150 coronary occlusions (45%) had resulted in a Q-wave infarct. Considering the high spontaneous recanalization rate of the occlusions, it seemed possible that roughly only every fourth coronary occlusion might result in a myocardial infarct. This hypothesis was confirmed in the prospective 3 years follow-up of the identical patients during which 41 new occlusions developed causing only 10 myocardial infarcts (24%). These findings might contribute to explain the relatively low incidence of clinically apparent coronary heart disease in the general population despite a high prevalence of coronary artery disease.

Quantitative angiographic follow-up studies on the development of coronary artery disease: which coronary segments should be analyzed? Experience from INTACT

Angiographic follow-up studies on the evolution of coronary artery disease are of increasing relevance. It has still to be evaluated which coronary segments are predominantly involved in the process of atherosclerosis and, thus, should be preferably included in the analysis. Therefore, the correlation of progression and regression of coronary disease with the diameter and location (proximal, mid or distal) of coronary segments was investigated from the data of the INTACT-study, in which 25 different coronary segments were defined including anatomic variants of rather distal segments. In 348 patients with coronary artery disease, standardized coronary angiograms were repeated within 3 years and were quantitatively analyzed (CAAS). In 1063 coronary stenoses (% diameter stenosis > 20%) compared from both angiograms, progression and regression were not influenced by diameter nor location of arterial segments. In the follow-up angiograms, the number of new lesions (stenoses and occlusions) per coronary segment differed with regard to segment diameter (> 3 mm: 64/1125 (6%); 2–3 mm: 139/1967 (7%);<2 mm: 44/1756 (2%); p<0.001) and location of segments (proximal: 86/1285 (7%); mid: 84/1193 (7%); distal: 77/2370 (3%); p<0.001). Out of 77 distal new lesions, only 25 (32%) were found in segments<2 mm in diameter.Since the absolute number of new lesions was high in distal coronary segments, but low in segments with diameters<2 mm, angiographic follow-up studies should analyze coronary segments at any location, but may neglect segments with diameters smaller than 2 mm.