Eckart Fleck

Noninvasive Diagnosis of Ischemia-Induced Wall Motion Abnormalities With the Use of High-Dose Dobutamine Stress MRI: Comparison With Dobutamine Stress Echocardiography

BACKGROUND The analysis of wall motion abnormalities with dobutamine stress echocardiography (DSE) is an established method for the detection of myocardial ischemia. With ultrafast magnetic resonance tomography, identical stress protocols as used for echocardiography can be applied. METHODS AND RESULTS In 208 consecutive patients (147 men, 61 women) with suspected coronary artery disease, DSE with harmonic imaging and dobutamine stress magnetic resonance (DSMR) (1.5 T) were performed before cardiac catheterization. DSMR images were acquired during short breath-holds in 3 short-axis views and a 4- and a 2-chamber view (gradient echo technique). Patients were examined at rest and during a standard dobutamine-atropine scheme until submaximal heart rate was reached. Regional wall motion was assessed in a 16-segment model. Significant coronary heart disease was defined as >/=50% diameter stenosis. Eighteen patients could not be examined by DSMR (claustrophobia 11 and adipositas 6) and 18 patients by DSE (poor image quality). Four patients did not reach target heart rate. In 107 patients, coronary artery disease was found. With DSMR, sensitivity was increased from 74.3% to 86.2% and specificity from 69.8% to 85.7% (both P<0.05) compared with DSE. Analysis for women yielded similar results. CONCLUSIONS High-dose dobutamine magnetic resonance tomography can be performed with a standard dobutamine/atropine stress protocol. Detection of wall motion abnormalities by DSMR yields a significantly higher diagnostic accuracy in comparison to DSE.

Magnetic resonance perfusion measurements for the noninvasive detection of coronary artery disease

Background—With MRI, an index of myocardial perfusion reserve (MPRI) can be determined. We assessed the value of this technique for the noninvasive detection of coronary artery disease (CAD) in patients with suspected CAD. Methods and Results—Eighty-four patients referred for a primary diagnostic coronary angiography were examined with a 1.5 T MRI tomograph (Philips-ACS). For each heartbeat, 5 slices were acquired during the first pass of 0.025 mmol gadolinium-diethylenetriamine pentaacetic acid/kg body weight before and during adenosine vasodilation by using a turbo-gradient echo/echo-planar imaging-hybrid sequence. MPRI was determined from the alteration of the upslope of the myocardial signal intensity curves for 6 equiangular segments per slice. Receiver operating characteristics were performed for different criteria to differentiate ischemic and nonischemic segments. Prevalence of CAD was 51%. Best results were achieved when only the 3 inner slices were assessed and a threshold value of 1.1 was used for the second smallest value as a marker for significant CAD. This approach yielded a sensitivity of 88%, specificity of 90%, and accuracy of 89%. Conclusion—The determination of MPRI with MRI yields a high diagnostic accuracy in patients with suspected CAD.

Noninvasive Detection of Myocardial Ischemia From Perfusion Reserve Based on Cardiovascular Magnetic Resonance

BACKGROUND Myocardial perfusion reserve can be noninvasively assessed with cardiovascular MR. In this study, the diagnostic accuracy of this technique for the detection of significant coronary artery stenosis was evaluated. METHODS AND RESULTS In 15 patients with single-vessel coronary artery disease and 5 patients without significant coronary artery disease, the signal intensity-time curves of the first pass of a gadolinium-DTPA bolus injected through a central vein catheter were evaluated before and after dipyridamole infusion to validate the technique. A linear fit was used to determine the upslope, and a cutoff value for the differentiation between the myocardium supplied by stenotic and nonstenotic coronary arteries was defined. The diagnostic accuracy was then examined prospectively in 34 patients with coronary artery disease and was compared with coronary angiography. A significant difference in myocardial perfusion reserve between ischemic and normal myocardial segments (1.08+/-0.23 and 2.33+/-0.41; P<0.001) was found that resulted in a cutoff value of 1.5 (mean minus 2 SD of normal segments). In the prospective analysis, sensitivity, specificity, and diagnostic accuracy for the detection of coronary artery stenosis (> or =75%) were 90%, 83%, and 87%, respectively. Interobserver and intraobserver variabilities for the linear fit were low (r=0.96 and 0.99). CONCLUSIONS MR first-pass perfusion measurements yielded a high diagnostic accuracy for the detection of coronary artery disease. Myocardial perfusion reserve can be easily and reproducibly determined by a linear fit of the upslope of the signal intensity-time curves.

Prognostic Value of Cardiac Magnetic Resonance Stress Tests Adenosine Stress Perfusion and Dobutamine Stress Wall Motion Imaging

Background— Adenosine stress magnetic resonance perfusion (MRP) and dobutamine stress magnetic resonance (DSMR) wall motion analyses are highly accurate for the detection of myocardial ischemia. However, knowledge about the prognostic value of stress MR examinations is limited. We sought to determine the value of MRP and DSMR, as assessed during a single-session examination, in predicting the outcome of patients with known or suspected coronary artery disease. Methods and Results— In 513 patients (with known or suspected coronary disease, prior coronary artery bypass graft, or percutaneous coronary intervention), a combined single-session magnetic resonance stress examination (MRP and DSMR) was performed at 1.5 T. For first-pass perfusion imaging, the standard adenosine stress imaging protocol (140 &mgr;g · kg−1 · min−1 for 6 minutes, 3-slice turbo field echo-echo-planar imaging or steady-state free precession sequence, 0.05 mmol/kg Gd-DTPA) was applied, and for DSMR, the standard high-dose dobutamine/atropine protocol (steady-state free-precession cine sequence) was applied. Stress testing was classified as pathological if at MRP ≥1 segment showed an inducible perfusion deficit >25% transmurality or if at DSMR ≥1 segment showed an inducible wall motion abnormality. During a median follow-up of 2.3 years (range, 0.06 to 4.55 years), 19 cardiac events occurred (4.1%; 9 cardiac deaths, 10 nonfatal myocardial infarctions). The 3-year event-free survival was 99.2% for patients with normal MRP and DSMR and 83.5% for those with abnormal MRP and DSMR. Univariate analysis showed ischemia identified by MRP and DSMR to be predictive of cardiac events (hazard ratio, 12.51; 95% confidence interval, 3.64 to 43.03; and hazard ratio, 5.42; 95% confidence interval, 2.18 to 13.50; P<0.001, respectively); other predictors were diabetes mellitus, known coronary artery disease, and the presence of resting wall motion abnormality. By multivariate analysis, ischemia on magnetic resonance stress testing (MRP or DSMR) was an independent predictor of cardiac events. In a stepwise multivariate model (Cox regression), an abnormal magnetic resonance stress test result had significant incremental value over clinical risk factors and resting wall motion abnormality (P<0.001). Conclusions— In patients with known or suspected coronary artery disease, myocardial ischemia detected by MRP and DSMR can be used to identify patients at high risk for subsequent cardiac death or nonfatal myocardial infarction. For patients with normal MRP and DSMR, the 3-year event-free survival was 99.2%. MR stress testing provides important incremental information over clinical risk factors and resting wall motion abnormalities.

Comparison of Dobutamine Stress Magnetic Resonance, Adenosine Stress Magnetic Resonance, and Adenosine Stress Magnetic Resonance Perfusion

Background—Dobutamine stress MR (DSMR) is highly accurate for the detection of inducible wall motion abnormalities (IWMAs). Adenosine has a more favorable safety profile and is well established for the assessment of myocardial perfusion. We evaluated the diagnostic value of IWMAs during dobutamine and adenosine stress MR and adenosine MR perfusion compared with invasive coronary angiography. Methods and Results—Seventy-nine consecutive patients (suspected or known coronary disease, no history of prior myocardial infarction) scheduled for cardiac catheterization underwent cardiac MR (1.5 T). After 4 minutes of adenosine infusion (140 &mgr;g · kg−1 · min−1 for 6 minutes), wall motion was assessed (steady-state free precession), and subsequently perfusion scans (3-slice turbo field echo-echo planar imaging; 0.05 mmol/kg Gd-BOPTA) were performed. After a 15-minute break, rest perfusion was imaged, followed by standard DSMR/atropine stress MR. Wall motion was classified as pathological if ≥1 segment showed IWMAs. The transmural extent of inducible perfusion deficits (<25%, 25% to 50%, 51% to 75%, and >75%) was used to grade segmental perfusion. Quantitative coronary angiography was performed with significant stenosis defined as >50% diameter stenosis. Fifty-three patients (67%) had coronary artery stenoses >50%; sensitivity and specificity for detection by dobutamine and adenosine stress and adenosine perfusion were 89% and 80%, 40% and 96%, and 91% and 62%, respectively. Adenosine IWMAs were seen only in segments with >75% transmural perfusion deficit. Conclusions—DSMR is superior to adenosine stress for the induction of IWMAs in patients with significant coronary artery disease. Visual assessment of adenosine stress perfusion is sensitive with a low specificity, whereas adenosine stress MR wall motion is highly specific because it identifies only patients with high-grade perfusion deficits. Thus, DSMR is the method of choice for current state-of-the-art treatment regimens to detect ischemia in patients with suspected or known coronary artery disease but no history of prior myocardial infarction.

Prognostic value of intracoronary flow velocity and diameter stenosis in assessing the short- and long-term outcomes of coronary balloon angioplasty - The DEBATE study (Doppler Endpoints Balloon Angioplasty Trial Europe)

BACKGROUND The aim of this prospective, multicenter study was the identification of Doppler flow velocity measurements predictive of clinical outcome of patients undergoing single-vessel balloon angioplasty with no previous Q-wave myocardial infarction. METHODS AND RESULTS In 297 patients, a Doppler guidewire was used to measure basal and maximal hyperemic flow velocities proximal and distal to the stenosis before and after angioplasty. In 225 patients with an angiographically successful percutaneous transluminal coronary angioplasty (PTCA), postprocedural distal coronary flow reserve (CFR) and percent diameter stenosis (DS%) were correlated with symptoms and/or ischemia at 1 and 6 months, with the need for target lesion revascularization, and with angiographic restenosis (defined as DS > or = 50% at follow-up). Logistic regression and receiver operator characteristic curve analyses were applied to determine the prognostic cutoff value of CFR and DS separately and in combination. Optimal cutoff criteria for predictors of these clinical events were DS, 35%; CFR, 2.5. A distal CFR after angioplasty > 2.5 with a residual DS < or = 35% identified lesions with a low incidence of recurrence of symptoms at 1 month (10% versus 19%, P=.149) and at 6 months (23% versus 47%, P=.005), a low need for reintervention (16% versus 34%, P=.024), and a low restenosis rate (16% versus 41%, P=.002) compared with patients who did not meet these criteria. CONCLUSIONS Measurements of distal CFR after PTCA, in combination with DS%, have a predictive value, albeit modest for the short- and long-term outcomes after PTCA, and thus may be used to identify patients who will or will not benefit from additional therapy such as stent implantation.

Magnetic Resonance Low-Dose Dobutamine Test Is Superior to Scar Quantification for the Prediction of Functional Recovery

Background—Low-dose dobutamine challenge (DSMR) by MRI was compared with delayed enhancement imaging with Gd-DTPA (SCAR) as a predictor of improvement of wall motion after revascularization (RECOVERY). Methods and Results—In 29 patients with coronary artery disease (68±7 years of age, 2 women, 32±8% ejection fraction), wall motion was evaluated semiquantitatively by MRI before and 3 months after revascularization. SCAR and DSMR were performed before revascularization. The transmural extent of scar was assessed semiquantitatively. Binary prediction of RECOVERY was performed by logistic regression in 288 segments with wall motion abnormalities at rest. Receiver operating characteristic–area under curve (AUC) statistics were used to compare different models. Low-dose DSMR (AUC 0.838) was superior to SCAR (AUC 0.728) in predicting RECOVERY. SCAR did not improve accuracy of prediction by DSMR. Subgroup analysis showed superiority of DSMR for 1% to 74% transmural extent of infarction. Conclusions—Low-dose DSMR is superior to SCAR in predicting RECOVERY. This advantage is largest in segments with a delayed enhancement of 1% to 74%.

Mitogen-Activated Protein Kinase Activation Is Involved in Platelet-Derived Growth Factor-Directed Migration by Vascular Smooth Muscle Cells

Migration of vascular smooth muscle cells (VSMCs) is a crucial response to vascular injury resulting in neointima formation and atherosclerosis. Platelet-derived growth factor (PDGF-BB) functions as a potent chemoattractant for VSMCs and enhances these pathologies in the vasculature. However, little is known about the intracellular pathways that mediate VSMC migration. In the present study, we investigated the role of mitogen-activated protein kinase (MAPK) activation in this function, since PDGF-BB as well as other growth factors activate this pathway. Using an in-gel kinase assay, we observed that PD 98059 an inhibitor of MEK that activates MAP kinase, inhibited PDGF-BB-induced activation of ERK-1 and ERK-2 in cultured rat aortic smooth muscle cells in a concentration-dependent manner. In contrast, PDGF-mediated activation of intracellular calcium release was not affected by PD 98059. The chemotactic response of both rat aortic smooth muscle cells (RASMCs) and human umbilical vein smooth muscle cells (HUSMCs) toward PDGF-BB (10 ng/mL) was significantly reduced by PD 98059 (10 mumol/L) to 41.7 +/- 7.1% in RASMCs (P < .01) and to 47.2 +/- 5.3% in HUSMCs (P < .01). Similar inhibition was seen at 30 mumol/L, less at 1 mumol/L. To further confirm the specificity of these results implicating the MAPK pathway, an antisense oligodeoxynucleotide (ODN) directed against the initiation translation site of rat ERK-1 and ERK-2 mRNA was used to suppress MAP kinase synthesis and function in rat VSMCs. Liposomal transfection with 0.4 mumol/L antisense ODN reduced ERK-1 and ERK-2 protein by 65% (P < .01) after 48 hours. The chemotactic response to PDGF-BB (10 ng/mL) was reduced by 75% (P < .01) in rat VSMCs transfected with the same antisense ODN concentration. Sense and scrambled control ODNs (0.4 mumol/L) did not affect ERK-1 and ERK-2 protein concentrations or chemotaxis of VSMCs induced by PDGF-BB. These experiments provide the first evidence that activation of MAPK is a critical event in PDGF-mediated signal transduction regulating VSMC migration.

PPAR gamma-ligands inhibit migration mediated by multiple chemoattractants in vascular smooth muscle cells.

The purpose of this study was to determine the effect of the peroxisome proliferator-activated receptor gamma-(PPAR gamma) ligands troglitazone (TRO), rosiglitazone (RSG), and 15-deoxy-delta prostaglandin J2 (15d-PGJ2) on vascular smooth muscle cell (VSMC) migration directed by multiple chemoattractants. Involvement of mitogen-activated protein kinase (MAPK) in migration also was examined, because TRO was previously shown to inhibit nuclear events stimulated by this pathway during mitogenic signaling in VSMCs. Migration of rat aortic VSMCs was induced 5.4-fold by PDGF, 4.6-fold by thrombin, and 2.3-fold by insulin-like growth factor I (IGF-I; all values of p < 0.05). The PPAR gamma ligands 15d-PGJ2, RSG, or TRO all inhibited VSMC migration with the following order of potency: 15d-PGJ2 > RSG > TRO. Inhibition of MAPK signaling with PD98059 completely blocked PDGF-, thrombin-, and IGF-I-induced migration. All chemoattractants induced MAPK activation. PPAR gamma ligands did not inhibit MAPK activation, suggesting a nuclear effect of these ligands downstream of MAPK. The importance of nuclear events was confirmed because actinomycin D also blocked migration. We conclude that PPAR gamma ligands are potent inhibitors of VSMC migration pathways, dependent on MAPK and nuclear events. PPAR gamma ligands act downstream of the cytoplasmic activation of MAPK and appear to exert their effects in the nucleus. Because VSMC migration plays an important role in the formation of atherosclerotic lesions and restenosis, PPAR gamma ligands like TRO and RSG, which ameliorate insulin resistance in humans, also may protect the vasculature from diabetes-enhanced injury.

Regulation, Chamber Localization, and Subtype Distribution of Angiotensin II Receptors in Human Hearts

BACKGROUND To assess the chamber localization, subtype distribution, and regulation of human myocardial angiotensin II receptors in heart failure, we determined the binding of angiotensin II, Sar1Ile8-angiotensin II, and the subtype-specific antagonists Dup 753 (AT1-specific) and PD 123319 (AT2-specific) in atria from patients with normal (left ventricular ejection fraction > 55%) or moderately impaired (left ventricular ejection fraction 30% to 55%) cardiac function and in atria and ventricles from explanted end-stage failing hearts. Sarcolemmal and combined fractions, the latter including internalized receptors, were studied. In addition, AT1 mRNA content was analyzed by polymerase chain reaction after reverse transcription. METHODS AND RESULTS The number of angiotensin II binding sites (Bmax) in sarcolemmal fractions was significantly reduced in explanted end-stage failing hearts in comparison with control subjects and moderate heart failure (Bmax 3.9 +/- 0.8 versus 11.2 +/- 1.7 and 9.6 +/- 0.8 fmol/mg protein, respectively). A comparable 65% reduction in receptor numbers was found in combined fractions from end-stage failing hearts, indicating that the loss of binding sites was not due to their internalization. The dissociation constants were comparable in sarcolemmal and combined fractions and in nonfailing and failing hearts, ranging from 0.5 +/- 0.2 to 1.2 +/- 0.5 nmol/L. In nonfailing hearts, 69 +/- 4% of binding sites were blocked by the subtype-2-specific inhibitor PD 123319 and were therefore classified as AT2; 33 +/- 5% were blocked by the subtype-1-specific inhibitor DUP 753 and thus classified as subtype 1. In explanted hearts, comparable ratios of 66 +/- 5% AT2 sites and 34 +/- 5% AT1 sites were found. AT1 cDNA amplification signals by polymerase chain reaction were reduced to about one third of the level in control subjects in end-stage failing hearts. CONCLUSIONS Angiotensin II receptors in human myocardium are present in relatively low numbers, and AT2 is the predominant subtype. A significant loss of angiotensin II receptors occurs in end stage but not in moderate heart failure. The loss of receptors affects both subtypes to a comparable degree. The data suggest that the decrease in receptor density is due to a decrease in steady-state mRNA abundance.