Transcoronary transplantation of progenitor cells after myocardial infarction.

BACKGROUND: Pilot studies suggest that intracoronary transplantation of progenitor cells derived from bone marrow (BMC) or circulating blood (CPC) may improve left ventricular function after acute myocardial infarction. The effects of cell transplantation in patients with healed myocardial infarction are unknown. METHODS: After an initial pilot trial involving 17 patients, we randomly assigned, in a controlled crossover study, 75 patients with stable ischemic heart disease who had had a myocardial infarction at least 3 months previously to receive either no cell infusion (23 patients) or infusion of CPC (24 patients) or BMC (28 patients) into the patent coronary artery supplying the most dyskinetic left ventricular area. The patients in the control group were subsequently randomly assigned to receive CPC or BMC, and the patients who initially received BMC or CPC crossed over to receive CPC or BMC, respectively, at 3 months' follow-up. RESULTS: The absolute change in left ventricular ejection fraction was significantly greater among patients receiving BMC (+2.9 percentage points) than among those receiving CPC (-0.4 percentage point, P=0.003) or no infusion (-1.2 percentage points, P<0.001). The increase in global cardiac function was related to significantly enhanced regional contractility in the area targeted by intracoronary infusion of BMC. The crossover phase of the study revealed that intracoronary infusion of BMC was associated with a significant increase in global and regional left ventricular function, regardless of whether patients crossed over from control to BMC or from CPC to BMC. CONCLUSIONS: Intracoronary infusion of progenitor cells is safe and feasible in patients with healed myocardial infarction. Transplantation of BMC is associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months.

Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair.

BACKGROUND: The maintenance of endothelial integrity plays a critical role in preventing atherosclerotic disease progression. Endothelial progenitor cells (EPCs) were experimentally shown to incorporate into sites of neovascularization and home to sites of endothelial denudation. Circulating EPCs may thus provide an endogenous repair mechanism to counteract ongoing risk factor-induced endothelial injury and to replace dysfunctional endothelium. METHODS AND RESULTS: In 120 individuals (43 control subjects, 44 patients with stable coronary artery disease, and 33 patients with acute coronary syndromes), circulating EPCs were defined by the surface markers CD34+KDR+ and analyzed by flow cytometry. Cardiovascular events (cardiovascular death, unstable angina, myocardial infarction, PTCA, CABG, or ischemic stroke) served as outcome variables over a median follow-up period of 10 months. Patients suffering from cardiovascular events had significantly lower numbers of EPCs (P<0.05). Reduced numbers of EPCs were associated with a significantly higher incidence of cardiovascular events by Kaplan-Meier analysis (P=0.0009). By multivariate analysis, reduced EPC levels were a significant, independent predictor of poor prognosis, even after adjustment for traditional cardiovascular risk factors and disease activity (hazard ratio, 3.9; P<0.05). CONCLUSIONS: Reduced levels of circulating EPCs independently predict atherosclerotic disease progression, thus supporting an important role for endogenous vascular repair to modulate the clinical course of coronary artery disease.

Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial.

OBJECTIVES: The Transplantation of Progenitor Cells And Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI) trial investigates both safety, feasibility, and potential effects on parameters of myocardial function of intracoronary infusion of either circulating progenitor cells (CPC) or bone marrow-derived progenitor cells (BMC) in patients with acute myocardial infarction (AMI). BACKGROUND: In animal experiments, therapy with adult progenitor cells was shown to improve vascularization, left ventricular (LV) remodeling, and contractility after AMI. METHODS: A total of 59 patients with AMI were randomly assigned to receive either CPC (n = 30) or BMC (n = 29) into the infarct artery at 4.9 +/- 1.5 days after AMI. RESULTS: Intracoronary progenitor cell application did not incur any measurable ischemic myocardial damage, but one patient experienced distal embolization before cell therapy. During hospital follow-up, one patient in each cell group developed myocardial infarction; one of these patients died of cardiogenic shock. No further cardiovascular events, including ventricular arrhythmias or syncope, occurred during one-year follow-up. By quantitative LV angiography at four months, LV ejection fraction (EF) significantly increased (50 +/- 10% to 58 +/- 10%; p < 0.001), and end-systolic volumes significantly decreased (54 +/- 19 ml to 44 +/- 20 ml; p < 0.001), without differences between the two cell groups. Contrast-enhanced magnetic resonance imaging after one year revealed an increased EF (p < 0.001), reduced infarct size (p < 0.001), and absence of reactive hypertrophy, suggesting functional regeneration of the infarcted ventricles. CONCLUSIONS: Intracoronary infusion of progenitor cells (either BMC or CPC) is safe and feasible in patients after AMI successfully revascularized by stent implantation. Both the excellent safety profile and the observed favorable effects on LV remodeling, provide the rationale for larger randomized double-blind trials.

Microvascular dysfunction in angiographically normal or mildly diseased coronary arteries predicts adverse cardiovascular long-term outcome.

OBJECTIVE: To study the role of coronary flow reserve for the prediction of long-term cardiovascular event rate. DESIGN: Observational, longitudinal. SETTING: Single-center, coronary vasomotor testing at university hospital. PARTICIPANTS: One hundred and twenty patients with angiographically normal or minimally diseased coronary vessel. METHODS: Coronary flow reserve was assessed by intracoronary Doppler and quantitative coronary angiography. Cardiovascular events during follow-up (6.5+/-3 years, range 14-125 months) were defined as sudden death, myocardial infarction, unstable angina, ischemic stroke or the need for revascularization by percutaneous transluminal coronary angioplasty or coronary as well as peripheral bypass surgery. RESULTS: Reduced coronary flow reserve was significantly associated with a poor long-term outcome: cardiovascular events occurred in seven (18%) patients in the lowest tertile of coronary flow reserve compared with four patients in the middle tertile (10%) and two patients in the upper tertile (5%) (P=0.019 by Kaplan-Meier analysis). The multivariate Cox proportional hazard model revealed coronary flow reserve as an independent predictor of prognosis (P=0.017) in addition to angiographic evidence of atherosclerosis (P=0.047) and arterial hypertension (P=0.013). CONCLUSIONS: Coronary flow reserve in normal to mildly diseased arteries is an independent predictor of long-term prognosis of atherosclerosis within the next decade.

Transplantation of progenitor cells after reperfused acute myocardial infarction: evaluation of perfusion and myocardial viability with FDG-PET and thallium SPECT.

Clinical outcome after myocardial infarction depends on the extent of irreversibly damaged myocardium. Implantation of bone marrow-/circulating blood-derived progenitor cells has been shown to improve contractile cardiac function after myocardial infarction in both experimental and initial clinical studies. In the present study, first observations of the effect of local intracoronary progenitor cell infusion on the regeneration of infarcted cardiac tissue after acute myocardial infarction was evaluated by means of 18F-fluorodeoxyglucose positron emission tomography (PET) and 201Tl single-photon emission computed tomography (SPECT). Twenty-six patients underwent intracoronary infusion of bone marrow-derived (BMCs) (15 patients) or circulating blood-derived endothelial progenitor cells (EPCs) (11 patients) 4+/-2 days after acute myocardial infarction. Based on a left ventricular segmentation model (17 segments), mean signal intensities as a parameter of viability and perfusion in the infarct zone and non-infarct areas were calculated quantitatively by PET and SPECT at baseline and at 4 months of follow-up. Transplantation of progenitor cells was associated with a significant increase in the mean signal intensity (MSI) in the infarct zone from 54.5% (25th and 75th percentiles: 47.7%, 60.0%) to 58.0% (52.7%, 66.7%) on PET (P=0.013) and from 58.0% (49.5%, 63.0%) to 61.5% (52.5%, 70.2%) on SPECT (P=0.005). Global left ventricular ejection fraction (LVEF) increased from 53.5% (42.6%, 60.0%) to 58.0% (53.0%, 65.8%) (P<0.001). In the five patients without an increase in MSI on PET, LVEF changed from 60.0% (50.0%, 64.0%) to 72.0% (64.0%, 75.5%) at follow-up. PET and SPECT did not show any significant changes in MSI in the non-infarct areas [from 73% (68.5%, 76.2%) to 73% (69.7%, 78.0%) for PET and from 72.0% (66.5%, 77.6%) to 73.0% (67.5%, 78.2%) for SPECT]. There were no significant differences in myocardial viability and perfusion between BMC and EPC infusion. These preliminary results show that coronary stenting and transplantation of progenitor cells result in a significant increase in myocardial viability and perfusion. Therapeutic effects can be reliably measured by PET and SPECT.

Multidetector-row cardiac CT: diagnostic value of calcium scoring and CT coronary angiography in patients with symptomatic, but atypical, chest pain.

The aim of this study was to investigate the accuracy of multidetector-row cardiac CT (MDCT), calcium scoring (Ca-Sc), and MDCT coronary angiography (MD CTA) in the assessment of coronary atherosclerosis. Thirty-eight patients underwent invasive coronary angiography (CA) and MDCT (collimation 4x1 mm, pitch 1.5 mm, TI 500 ms, 120 kV, 300 mAs, and retrospective ECG-gating). Calcium scoring was calculated for the total coronary artery territory and for RCA, LCA, and LCX separately. The MD CTA served to assess the degree and the localization of stenoses. All findings were compared to invasive coronary angiography. Approximately 68.4% (390 of 570) of all coronary segments could be visualized by MDCT. Correlation coefficient for MD CTA and CA amounted to r=0.58, showing distinct differences for the individual segments. Proximal segments generally showed better correlation (range 0.81-0.77) than medial segments (range 0.91-0.20), distal segments (range 0.55-0.04), or side branches (range 0.76-0.00). Patients with hemodynamically relevant (>75%) stenoses were detected by MD CTA with 72.2% sensitivity (13 of 18) and 100% specificity (20 of 20). For Ca-Sc sensitivity ranged between 94.7% (17 of 18) and 66.7% (12 of 18), specificity between 20% (4 of 20) and 80% (16 of 20) respectively, depending on the prevailing cutoff value. Combination of both methods led to 83.3% sensitivity (15 of 18) and 100% specificity (20 of 20), reaching no level of significance as compared with Ca-Sc (p=0.73) or MD CTA (p=0.23) alone. Calcium scoring as a single method showed highest sensitivity in the detection of coronary atherosclerosis but at the expense of low specificity. In patients with no or moderate calcifications, combination with MD CTA helped to distinctly increase specificity and NPV.

Effects of cardiovascular risk factors on coronary artery remodeling in patients with mild atherosclerosis.

BACKGROUND: Vascular remodeling counteracts luminal encroachment during the progression of coronary artery disease (CAD) and modulates the manifestation of hemodynamically significant lesions. However, the role of cardiovascular risk factors for coronary remodeling has not been fully clarified. METHODS: Therefore, we investigated the role of local plaque burden and systemic risk factors on coronary vascular remodeling in 25 patients (49 segments) with angiographically normal or minimally diseased coronary arteries by intravascular ultrasound. In an additional 12 patients without coronary atherosclerosis, physiological vessel tapering was determined and used to calculate the extent of remodeling in diseased segments. RESULTS: An increase in local plaque burden was directly correlated with positive vascular remodeling (r = 0.54, P<0.001). However, cardiovascular risk factors like hypertension (P<0.001) and hypercholesterolemia (P = 0.03) were associated with reduced positive or even negative remodeling. Moreover, the total number of classical cardiovascular risk factors was a strong predictor for reduced positive remodeling (P for trend <0.001). In contrast, coronary flow reserve, a measure of shear stress imposed on the vessel wall, positively correlated with compensatory enlargement (r = 0.44, P = 0.002). By multivariate analysis, plaque burden (P = 0.001), hypertension (P = 0.001) and coronary flow reserve (P = 0.018) proved to be independent determinants of vascular remodeling of epicardial coronary arteries. CONCLUSIONS: Cardiovascular risk factors impair compensatory arterial enlargement and even predispose to shrinkage of epicardial arteries during the initial stage of atherosclerosis. Reduced positive vascular remodeling might contribute to the clinical manifestation of CAD by facilitating the development of flow-limiting stenoses in patients at risk.

Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI).

BACKGROUND: Experimental studies suggest that transplantation of blood-derived or bone marrow-derived progenitor cells beneficially affects postinfarction remodeling. The safety and feasibility of autologous progenitor cell transplantation in patients with ischemic heart disease is unknown. METHODS AND RESULTS: We randomly allocated 20 patients with reperfused acute myocardial infarction (AMI) to receive intracoronary infusion of either bone marrow-derived (n=9) or circulating blood-derived progenitor cells (n=11) into the infarct artery 4.3+/-1.5 days after AMI. Transplantation of progenitor cells was associated with a significant increase in global left ventricular ejection fraction from 51.6+/-9.6% to 60.1+/-8.6% (P=0.003), improved regional wall motion in the infarct zone (-1.5+/-0.2 to -0.5+/-0.7 SD/chord; P<0.001), and profoundly reduced end-systolic left ventricular volumes (56.1+/-20 mL to 42.2+/-15.1 mL; P=0.01) at 4-month follow-up. In contrast, in a nonrandomized matched reference group, left ventricular ejection fraction only slightly increased from 51+/-10% to 53.5+/-7.9%, and end-systolic volumes remained unchanged. Echocardiography revealed a profound enhancement of regional contractile function (wall motion score index 1.4+/-0.2 at baseline versus 1.19+/-0.2 at follow-up; P<0.001). At 4 months, coronary blood flow reserve was significantly (P<0.001) increased in the infarct artery. Quantitative F-18-fluorodeoxyglucose-positron emission tomography analysis revealed a significant (P<0.01) increase in myocardial viability in the infarct zone. There were no differences for any measured parameter between blood-derived or bone marrow-derived progenitor cells. No signs of an inflammatory response or malignant arrhythmias were observed. CONCLUSIONS: In patients with AMI, intracoronary infusion of autologous progenitor cells appears to be feasible and safe and may beneficially affect postinfarction remodeling processes.

Heart-rate-adapted image reconstruction in multidetector-row cardiac CT: influence of physiological and technical prerequisite on image quality.

The purpose of this study was to develop strategies for optimal image reconstruction in multidetector-row cardiac CT and to discuss the results in the context of individual heart rate, cardiac physiology, and technical prerequisite. Sixty-four patients underwent multidetector-row cardiac CT. Depending on the heart rate either a single-segmental reconstruction (SSR) or an adaptive two-segmental reconstruction (ASR) was applied. Image reconstruction was done either antegrade (a) or retrograde (r) in relation to the R-peak. Reconstruction of all data sets was performed at multiple time points within the t-wave/p-wave interval, differing from each other by 50 ms. In addition, each reconstruction was assigned to one of six reconstruction intervals (A-F), each corresponding to a specific event in the cardiac cycle. While no significant time points were found for absolute values, the following interval/reconstruction technique combinations provided significant better image quality: F/r at HR <60 bpm for all coronary segments ( p65 bpm for all segments ( p

Benefits of immediate initiation of statin therapy following successful coronary stent implantation in patients with stable and unstable angina pectoris and Q-wave acute myocardial infarction.

Statin therapy reduces clinical events in patients with stable coronary artery disease. Recent data indicate that the beneficial effects of statin therapy may also extend to patients experiencing an acute ischemic coronary event. However, the potential role of statins to further modify clinical outcome in patients undergoing coronary stent implantation has not been addressed. Therefore, we investigated whether the initiation of statin therapy immediately after successful coronary stent implantation improves short-term clinical outcome in 704 patients (335 patients with stable angina pectoris [AP], 224 patients with unstable AP, and 145 patients with Q-wave acute myocardial infarction [AMI]). Compared with the lowest risk group (patients with stable AP receiving statin therapy), patients with unstable AP (RR 6.9, 95% confidence interval [CI] 1.5 to 31, p = 0.004) and patients with Q-wave AMI (RR 7.6, 95% CI 1.5 to 37, p = 0.004) experienced an increased risk for the occurrence of the primary combined end point of cardiac death and AMI. Importantly, initiation of statin therapy abrogated the increased risk in patients with unstable AP to the level of patients with stable AP receiving statin therapy (RR 1.5, 95% CI 0.2 to 11, p = 0.7). In contrast, statin therapy did not affect the RR in patients with Q-wave AMI during 6-month follow-up (RR 7.9, 95% CI 1.6 to 39 vs RR 7.6, 95% CI 1.5 to 37, p = NS). The beneficial effects of statin therapy after successful coronary stent implantation in unstable AP were most prominent during the first 4 weeks after the ischemic episode. Statins appear to contribute to the rapid transformation of unstable coronary artery disease into a stable condition with a very low event rate over the forthcoming 6 months in patients with unstable AP undergoing successful coronary stent implantation.