André Uitterdijk

Quantification of myocardial blood flow by adenosine-stress CT perfusion imaging in pigs during various degrees of stenosis correlates well with coronary artery blood flow and fractional flow reserve

AIMS Only few preliminary experimental studies demonstrated the feasibility of adenosine stress CT myocardial perfusion imaging to calculate the absolute myocardial blood flow (MBF), thereby providing information whether a coronary stenosis is flow limiting. Therefore, the aim of our study was to determine whether adenosine stress myocardial perfusion imaging by Dual Source CT (DSCT) enables non-invasive quantification of regional MBF in an animal model with various degrees of coronary flow reduction. METHODS AND RESULTS In seven pigs, a coronary flow probe and an adjustable hydraulic occluder were placed around the left anterior descending coronary artery to monitor the distal coronary artery blood flow (CBF) while several degrees of coronary flow reduction were induced. CT perfusion (CT-MBF) was acquired during adenosine stress with no CBF reduction, an intermediate (15-39%) and a severe (40-95%) CBF reduction. Reference standards were CBF and fractional flow reserve measurements (FFR). FFR was simultaneously derived from distal coronary artery pressure and aortic pressure measurements. CT-MBF decreased progressively with increasing CBF reduction severity from 2.68 (2.31-2.81)mL/g/min (normal CBF) to 1.96 (1.83-2.33) mL/g/min (intermediate CBF-reduction) and to 1.55 (1.14-2.06)mL/g/min (severe CBF-reduction) (both P < 0.001). We observed very good correlations between CT-MBF and CBF (r = 0.85, P < 0.001) and CT-MBF and FFR (r = 0.85, P < 0.001). CONCLUSION Adenosine stress DSCT myocardial perfusion imaging allows quantification of regional MBF under various degrees of CBF reduction.

PCA-based groupwise image registration for quantitative MRI

Quantitative magnetic resonance imaging (qMRI) is a technique for estimating quantitative tissue properties, such as the T1 and T2 relaxation times, apparent diffusion coefficient (ADC), and various perfusion measures. This estimation is achieved by acquiring multiple images with different acquisition parameters (or at multiple time points after injection of a contrast agent) and by fitting a qMRI signal model to the image intensities. Image registration is often necessary to compensate for misalignments due to subject motion and/or geometric distortions caused by the acquisition. However, large differences in image appearance make accurate image registration challenging. In this work, we propose a groupwise image registration method for compensating misalignment in qMRI. The groupwise formulation of the method eliminates the requirement of choosing a reference image, thus avoiding a registration bias. The method minimizes a cost function that is based on principal component analysis (PCA), exploiting the fact that intensity changes in qMRI can be described by a low-dimensional signal model, but not requiring knowledge on the specific acquisition model. The method was evaluated on 4D CT data of the lungs, and both real and synthetic images of five different qMRI applications: T1 mapping in a porcine heart, combined T1 and T2 mapping in carotid arteries, ADC mapping in the abdomen, diffusion tensor mapping in the brain, and dynamic contrast-enhanced mapping in the abdomen. Each application is based on a different acquisition model. The method is compared to a mutual information-based pairwise registration method and four other state-of-the-art groupwise registration methods. Registration accuracy is evaluated in terms of the precision of the estimated qMRI parameters, overlap of segmented structures, distance between corresponding landmarks, and smoothness of the deformation. In all qMRI applications the proposed method performed better than or equally well as competing methods, while avoiding the need to choose a reference image. It is also shown that the results of the conventional pairwise approach do depend on the choice of this reference image. We therefore conclude that our groupwise registration method with a similarity measure based on PCA is the preferred technique for compensating misalignments in qMRI.

Limitation of Infarct Size and No-Reflow by Intracoronary Adenosine Depends Critically on Dose and Duration

OBJECTIVES In the absence of effective clinical pharmacotherapy for prevention of reperfusion-mediated injury, this study re-evaluated the effects of intracoronary adenosine on infarct size and no-reflow in a porcine model of acute myocardial infarction using clinical bolus and experimental high-dose infusion regimens. BACKGROUND Despite the clear cardioprotective effects of adenosine, when administered prior to ischemia, studies on cardioprotection by adenosine when administered at reperfusion have yielded contradictory results in both pre-clinical and clinical settings. METHODS Swine (54 ± 1 kg) were subjected to a 45-min mid-left anterior descending artery occlusion followed by 2 h of reperfusion. In protocol A, an intracoronary bolus of 3 mg adenosine injected over 1 min (n = 5) or saline (n = 10) was administered at reperfusion. In protocol B, an intracoronary infusion of 50 μg/kg/min adenosine (n = 15) or saline (n = 21) was administered starting 5 min prior to reperfusion and continued throughout the 2-h reperfusion period. RESULTS In protocol A, area-at-risk, infarct size, and no-reflow were similar between groups. In protocol B, risk zones were similar, but administration of adenosine resulted in significant reductions in infarct size from 59 ± 3% of the area-at-risk in control swine to 46 ± 4% (p = 0.02), and no-reflow from 49 ± 6% of the infarct area to 26 ± 6% (p = 0.03). CONCLUSIONS During reperfusion, intracoronary adenosine can limit infarct size and no-reflow in a porcine model of acute myocardial infarction. However, protection was only observed when adenosine was administered via prolonged high-dose infusion, and not via short-acting bolus injection. These findings warrant reconsideration of adenosine as an adjuvant therapy during early reperfusion.

Serial measurement of hFABP and high-sensitivity troponin I post-PCI in STEMI: How fast and accurate can myocardial infarct size and no-reflow be predicted?

The objective of this study was to compare heart-specific fatty acid binding protein (hFABP) and high-sensitivity troponin I (hsTnI) via serial measurements to identify early time points to accurately quantify infarct size and no-reflow in a preclinical swine model of ST-elevated myocardial infarction (STEMI). Myocardial necrosis, usually confirmed by hsTnI or TnT, takes several hours of ischemia before plasma levels rise in the absence of reperfusion. We evaluated the fast marker hFABP compared with hsTnI to estimate infarct size and no-reflow upon reperfused (2 h occlusion) and nonreperfused (8 h occlusion) STEMI in swine. In STEMI (n = 4) and STEMI + reperfusion (n = 8) induced in swine, serial blood samples were taken for hFABP and hsTnI and compared with triphenyl tetrazolium chloride and thioflavin-S staining for infarct size and no-reflow at the time of euthanasia. hFABP increased faster than hsTnI upon occlusion (82 ± 29 vs. 180 ± 73 min, P < 0.05) and increased immediately upon reperfusion while hsTnI release was delayed 16 ± 3 min (P < 0.05). Peak hFABP and hsTnI reperfusion values were reached at 30 ± 5 and 139 ± 21 min, respectively (P < 0.05). Infarct size (containing 84 ± 0.6% no-reflow) correlated well with area under the curve for hFABP (r(2) = 0.92) but less for hsTnI (r(2) = 0.53). At 50 and 60 min reperfusion, hFABP correlated best with infarct size (r(2) = 0.94 and 0.93) and no-reflow (r(2) = 0.96 and 0.94) and showed high sensitivity for myocardial necrosis (2.3 ± 0.6 and 0.4 ± 0.6 g). hFABP rises faster and correlates better with infarct size and no-reflow than hsTnI in STEMI + reperfusion when measured early after reperfusion. The highest sensitivity detecting myocardial necrosis, 0.4 ± 0.6 g at 60 min postreperfusion, provides an accurate and early measurement of infarct size and no-reflow.

UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine

Modulation of Wnt/Frizzled signaling with UM206 reduced infarct expansion and prevented heart failure development in mice, an effect that was accompanied by increased myofibroblast presence in the infarct, suggesting that Wnt/Frizzled signaling has a key role in cardiac remodeling following myocardial infarction (MI). This study investigated the effects of modulation of Wnt/Frizzled signaling with UM206 in a swine model of reperfused MI. For this purpose, seven swine with MI were treated with continuous infusion of UM206 for 5 weeks. Six control swine were treated with vehicle. Another eight swine were sham-operated. Cardiac function was determined by echo in awake swine. Infarct mass was estimated at baseline by heart-specific fatty acid-binding protein ELISA and at follow-up using planimetry. Components of Wnt/Frizzled signaling, myofibroblast presence, and extracellular matrix were measured at follow-up with qPCR and/or histology. Results show that UM206 treatment resulted in a significant decrease in infarct mass compared with baseline (−41±10%), whereas infarct mass remained stable in the Control-MI group (+3±17%). Progressive dilation of the left ventricle occurred in the Control-MI group between 3 and 5 weeks after MI, while adverse remodeling was halted in the UM206-treated group. mRNA expression for Frizzled-4 and the Frizzled co-receptor LRP5 was increased in UM206-treated swine as compared with Control-MI swine. Myofibroblast presence was significantly lower in infarcted tissue of the UM206-treated animals (1.53±0.43% vs 3.38±0.61%) at 5 weeks follow-up. This study demonstrates that UM206 treatment attenuates adverse remodeling in a swine model of reperfused MI, indicating that Wnt/Frizzled signaling is a promising target to improve infarct healing and limit post-MI remodeling.

Evolution of reperfusion post-infarction ventricular remodeling: New MRI insights

BACKGROUND Our current understanding is that left ventricular (LV) remodeling after acute myocardial infarction (AMI) is caused by expansion of the infarcted myocardium with thinning of the wall and eccentric hypertrophy of the remote myocardium. To study the geometric changes in the remodeling process after reperfused AMI we used cardiac magnetic resonance imaging (CMR). METHODS Nine juvenile swine underwent a 120-min occlusion of the left circumflex coronary artery followed by reperfusion. CMR was performed at 3 and 36 days post-infarction. Global and regional LV remodeling was assessed including geometric changes of infarcted and remote myocardium; infarct longitudinal length (mm), mean circumferential length (mm), total infarct surface (mm(2)), end-diastolic wall thickness (EDWT) (mm) and transmural extent of infarction (TEI). RESULTS From 3 days to 36 days post-infarction end-diastolic volume increased by 43% (p<0.01). Infarct mass decreased by 36% (p<0.01), mainly by reduction of EDWT with 26%, while mean infarct circumferential length and longitudinal infarct length did not change. Remote myocardial mass increased by 23%, which was the result of an increase in its circumferential length from 95 ± 10 mm to 113 ± 11 mm (p<0.01), with no change in its EDWT. In contrast, EDWT in the infarct, peri-infarct and border zone decreased. CONCLUSIONS Contrary to the widely held view the present, using CMR measurements, shows that post-infarction remodeling was not associated with expansion of the infarcted myocardium. These findings suggest that eccentric hypertrophy of the remote myocardium, but not expansion of the infarct region, is responsible for left ventricular dilatation after AMI.

VEGF165A microsphere therapy for myocardial infarction suppresses acute cytokine release and increases microvascular density but does not improve cardiac function

Angiogenesis induced by growth factor-releasing microspheres can be an off-the-shelf and immediate alternative to stem cell therapy for acute myocardial infarction (AMI), independent of stem cell yield and comorbidity-induced dysfunction. Reliable and prolonged local delivery of intact proteins such as VEGF is, however, notoriously difficult. Our objective was to create a platform for local angiogenesis in human-sized hearts, using polyethylene-glycol/polybutylene-terephthalate (PEG-PBT) microsphere-based VEGF165A delivery. PEG-PBT microspheres were biocompatible, distribution was size dependent, and a regimen of 10 × 10(6) 15-μm microspheres at 0.5 × 10(6)/min did not induce cardiac necrosis. Efficacy, studied in a porcine model of AMI with reperfusion rather than chronic ischemia used for most reported VEGF studies, shows that microspheres were retained for at least 35 days. Acute VEGF165A release attenuated early cytokine release upon reperfusion and produced a dose-dependent increase in microvascular density at 5 wk following AMI. However, it did not improve major variables for global cardiac function, left ventricular dimensions, infarct size, or scar composition (collagen and myocyte content). Taken together, controlled VEGF165A delivery is safe, attenuates early cytokine release, and leads to a dose-dependent increase in microvascular density in the infarct zone but does not translate into changes in global or regional cardiac function and scar composition.

Non-rigid Groupwise Image Registration for Motion Compensation in Quantitative MRI

Quantitative magnetic resonance imaging (qMRI) aims to extract quantitative parameters representing tissue properties from a series of images by modeling the image acquisition process. This requires the images to be spatially aligned but, due to patient motion, anatomical structures in the consecutive images may be misaligned. In this work, we propose a groupwise non-rigid image registration method for motion compensation in qMRI. The method minimizes a dissimilarity measure based on principal component analysis (PCA), exploiting the fact that intensity changes can be described by a low-dimensional acquisition model. Using an unbiased groupwise formulation of the registration problem, there is no need to choose a reference image as in conventional pairwise approaches. The method was evaluated on three applications: modified Look-Locker inversion recovery T 1 mapping in a porcine myocardium, black-blood variable flip-angle T 1 mapping in the carotid artery region, and apparent diffusion coefficient (ADC) mapping in the abdomen. The method was compared to a conventional pairwise alignment that uses a mutual information similarity measure. Registration accuracy was evaluated by computing precision of the estimated parameters of the qMRI model. The results show that the proposed method performs equally well or better than an optimized pairwise approach and is therefore a suitable motion compensation method for a wide variety of qMRI applications.

Transition from post‐capillary pulmonary hypertension to combined pre‐ and post‐capillary pulmonary hypertension in swine: a key role for endothelin

Passive, isolated post‐capillary pulmonary hypertension (PH) secondary to left heart disease may progress to combined pre‐ and post‐capillary or ‘active’ PH This ‘activation’ of post‐capillary PH significantly increases morbidity and mortality, and is still incompletely understood. In this study, pulmonary vein banding gradually produced post‐capillary PH with structural and functional microvascular remodelling in swine. Ten weeks after banding, the pulmonary endothelin pathway was upregulated, likely contributing to pre‐capillary aspects in the initially isolated post‐capillary PH. Inhibition of the endothelin pathway could potentially stop the progression of early stage post‐capillary PH.

Pulmonary vasodilation by phosphodiesterase 5 inhibition is enhanced and nitric oxide independent in early pulmonary hypertension after myocardial infarction

Myocardial infarction (MI) may result in pulmonary hypertension (PH). Inhibition of phosphodiesterase 5 (PDE5), the enzyme responsible for the breakdown of cGMP in vascular smooth muscle, has become part of the contemporary therapeutic armamentarium for pulmonary arterial hypertension and may also be beneficial for PH secondary to MI. Nitric oxide (NO) is an important activator of cGMP synthesis and can be enhanced in early PH and decreased in severe PH. In the present study, we investigated if PDE5 inhibition ameliorates pulmonary hemodynamics in swine with PH secondary to MI and whether NO is essential. The PDE5 inhibitor EMD360527 was administered in awake, chronically instrumented swine with or without MI. At rest, PDE5 inhibition produced pulmonary vasodilation as evidenced by a decrease in pulmonary vascular resistance, which was more pronounced in MI ( n = 5) compared with normal swine ( n = 10, P ≤ 0.01) and was accompanied by an increase in stroke volume in MI swine. Both pulmonary vasodilation and increased stroke volume were maintained during exercise, suggesting that this therapy may improve exercise capacity in patients with PH secondary to MI. Interestingly, prior inhibition of NO significantly enhanced ( P ≤ 0.01) pulmonary vasodilation by PDE5 inhibition in both normal ( n = 8) and MI swine ( n = 5, P ≤ 0.05 vs. normal). This suggests that the increased vasodilator responses to PDE5 inhibition after MI were not due to an increase in NO-induced cGMP production. These observations indicate that PDE5 inhibition represents an interesting pharmacotherapeutic approach in early PH after a recent MI to prevent overt PH. NEW & NOTEWORTHY This research article is the first to describe that pulmonary vasodilation to phosphodiesterase 5 inhibition is enhanced and nitric oxide independent in resting and exercising swine with pulmonary hypertension as a result of myocardial infarction. This suggests that phosphodiesterase 5 inhibition can normalize pulmonary hemodynamics in postcapillary pulmonary hypertension after a recent myocardial infarction and may improve exercise capacity.