Reduced force generating capacity in myocytes from chronically ischemic, hibernating myocardium.

The contractile dysfunction of the hibernating myocardium in situ results from local environmental factors, but also from intrinsic cellular remodelling that may determine reversibility. Previous studies have suggested defects in myofilament Ca2+ responsiveness. We prepared single myocytes from control (CTRL, n(pigs)=7) and from hibernating myocardium (HIB, n(pigs)=8), removed the membranes and measured isometric force development during direct activation of the myofilaments. One- and 2-dimensional polyacrylamide gel electrophoresis and specific phosphoprotein immunoblotting were performed on tissue homogenates from matched samples. Cellular ultrastructure was evaluated using electron microscopy. Normalized for cross-sectional area, passive force was not different but maximal isometric force was significantly reduced in myocytes from HIB (11.6+/-1.5 kN/m2 versus 18.7+/-1.6 kN/m2 in CTRL, P<0.05). Ca2+ sensitivity and steepness of the normalized force-pCa relationship were not different, and neither was the rate of force redevelopment (K(tr)). No alterations were observed in isoform expression, phosphorylation or degradation of specific myofibrillar proteins. However, in HIB samples the total protein volume density was decreased by 23% (P<0.05). Histology showed glycogen accumulation and electron microscopy confirmed a reduction in myofilament density from 69.9+/-1.9% in CTRL to 57.1+/-0.9% of cell volume in HIB (P<0.05). In conclusion, decreased potential for force development in the hibernating myocardium is related to a reduction of myofibrillar protein per cell volume unit with replacement by glycogen and mitochondria. These changes may contribute to slow functional recovery on revascularization.

Local paclitaxel delivery after coronary stenting in an experimental animal model.

The goal of this study was to test the safety and efficacy of local paclitaxel delivery via a newly designed application catheter in an experimental animal study. Drug-eluting stents reduce restenosis in comparison to bare-metal stents. The drug-eluting polymer, however, may exert potential thrombogenic and inflammatory effects. A catheter-based local paclitaxel delivery offers further advantages, particularly a homogenous drug transfer into the vessel wall and a pharmacotherapy of the stent edges. In 30 pigs, both bare-metal stent (3.0 x 13 mm) implantation and balloon angioplasty were performed. Ten pigs received subsequent local delivery of paclitaxel-solution via a newly designed catheter (Genie, ACROSTAK corp., Switzerland), 10 animals served as a sham group and received vehicle (0.9% NaCl solution) and 10 animals were used as a control group. All animals were treated with aspirin and clopidogrel to prevent stent thrombosis. After final angiography the vessels were excised 42 days after intervention and prepared for histological and histomorphometric analysis. All coronary arteries showed complete endothelialization 42 days following treatment. Paclitaxel treatment led to a marked reduction of neointimal proliferation either post stent implantation (neointimal area: 1.04 +/- 0.10 mm(2) vs. 2.37 +/- 0.23 mm(2), p < 0.001) or post balloon dilatation (neontimal area: 0.35 +/- 0.14 mm(2), vs. 0.68 +/- 0.24 mm(2), p < 0.01). There were no significant angiographic or histomorphometric differences between the control and the sham group. In both paclitaxel groups neither angiographic edge phenomena nor a significant histomorphometric inflammatory response were found in the treated vessel segments. In conclusion, the local application of paclitaxel via the Genie catheter is safe and effective to significantly reduce the proliferative response post-stent implantation or balloon dilatation in an experimental animal model.

Mechanisms of postsystolic thickening in ischemic myocardium: mathematical modelling and comparison with experimental ischemic substrates.

In the setting of regional ischemia, the "at-risk" myocardium exhibits a flow-related reduction in systolic thickening with a concomitant development of abnormal thickening after aortic valve closure (postsystolic thickening [PST]). With the introduction of high time-resolution ultrasonic-based strain/strain-rate imaging, this short lived phenomenon can be measured accurately in the clinical setting. The mechanisms underlying this ischemia-related PST are poorly understood and both active and passive etiologies have been proposed. This study aims at elucidating the potential mechanisms behind PST in the intact heart. A theoretical model, describing active force development, elasticity and segment interaction has been developed to simulate radial deformation during systole and iso-volumetric relaxation. Simulation results have been compared with experimental deformation curves obtained from postero-basal segments of a pig model undergoing varying controlled ischemic challenges. Three forms of regional ischemia could be simulated by varying the model parameters of the ischemic segments: (i) chronic regional hypo-perfusion (reduced and prolonged active force development; preserved elasticity); (ii) acute short-lived ischemia-temporary vessel occlusion (no active force development; preserved elasticity); and (iii) chronic myocardial infarction (no active force development; decreased elasticity). For all ischemic substrates, the simulated curves closely correlate to the deformation measured in the corresponding porcine models without the need for active force development during the occurrence of PST. This suggests that segment interaction is the key determinant in the development of PST. Thus, in all instances, at the time of its manifestation, ischemia-related PST could be explained in a unified way as a passive phenomenon that was the result of elastic segment interaction. Its occurrence originates from the end-systolic inhomogeneous state where neighboring segments have a different wall thickness. The occurrence of these differences at end-systole depends on the presence of regional differences within the ventricle in the magnitude and duration of the developed contraction force during the first part of systole, the elasticity of the ischemic segment and the left-ventricular pressure.

Defining the transmurality of a chronic myocardial infarction by ultrasonic strain-rate imaging: implications for identifying intramural viability: an experimental study.

BACKGROUND: In a correlative functional/histopathologic study, we investigated the regional deformation characteristics of both chronic nontransmural and transmural infarctions before and after a dobutamine challenge. METHODS AND RESULTS: After stenosing copper-coated stent implantation to produce circumflex artery endothelial proliferation, 18 pigs were followed up for 5 weeks. Posteuthanasia histology showed 10 to have a nontransmural and 8 a transmural infarction. Eight nonstented animals served as controls. Regional radial function was monitored by measuring ultrasound-derived peak systolic strain rates (SR(SYS)) and systolic strains (epsilon(SYS)) (1) before stent implantation and (2) at 5 weeks, at baseline (bs) and during an incremental dobutamine infusion. In controls, dobutamine induced a linear increase in SR(SYS) (dobutamine: bs, 4.8+/-0.4 s(-1); 20 microg x kg(-1) x min(-1), 9.9+/-0.7 s(-1); P<0.0001) and an initial increase of epsilon(SYS) at low dose (bs, 58+/-5%; at 5 microg x kg(-1) x min(-1), 78+/-6%; P<0.05) but a subsequent decrease during higher infusion rates. In the nontransmural group, bs SR(SYS) and epsilon(SYS) were significantly lower than prestent values (SR(SYS), 2.9+/-0.5 s(-1) and epsilon(SYS), 32+/-6%, P<0.05 versus prestent). During dobutamine infusion, SR(SYS) increased slightly at 5 microg x kg(-1) x min(-1) (4.7+/-0.6 s(-1), P<0.05) but fell during higher infusion rates, whereas epsilon(SYS) showed no change. For nontransmural infarctions, transmural scar extension correlated closely with epsilon(SYS) at bs (r=0.88). For transmural infarctions, SR(SYS) at bs was significantly reduced and epsilon(SYS) was almost not measurable (SR(SYS), 1.8+/-0.3 s(-1); epsilon(SYS), 3+/-4%). Both deformation parameters showed no further change during the incremental dobutamine infusion. CONCLUSIONS: Ultrasonic deformation values could clearly differentiate chronic nontransmural from transmural myocardial infarction. The transmural extension of the scar could be defined by the regional deformation response.

Quantification of regional right and left ventricular function by ultrasonic strain rate and strain indexes after surgical repair of tetralogy of Fallot.

The quantification of regional myocardial function in tetralogy of Fallot (TOF) by conventional M-mode and 2-dimensional echocardiography is difficult because of the complex right ventricular (RV) and altered left ventricular (LV) geometry. In 30 asymptomatic postoperative TOF patients (aged 4 to 16 years) with a low pressure in the right ventricle and with varying degrees of pulmonary regurgitation and in 30 aged-matched healthy children, the ultrasonic-derived regional deformation parameters peak systolic strain rate (SR) and systolic strain (epsilon) were acquired from ventricles and compared. In TOF RV free walls, SR, and epsilon were reduced in the basal, mid-, and apical segments and averaged -1.5 +/- 0.6 second(-1) for SR and -22 +/- 8% for epsilon, respectively (p <0.001 vs normals). Peak systolic SR of the basal RV free wall correlated significantly with the QRS duration of the electrocardiogram (r = 0.81, p <0.0001). Abnormalities in RV deformation were more marked in patients with transannular patches versus infundibular patches. In the septum there was a homogeneous reduction in SR and epsilon in the basal, mid-, and apical segments. These averaged -1.4 +/- 0.3 second(-1) for SR and -19 +/- 4% for epsilon, respectively (p <0.01 vs normals). Longitudinal SR and epsilon values of the 3 LV lateral wall segments (averaged SR = -1.6 +/- 0.4 second(-1), averaged epsilon = -20 +/- 5%; p <0.05 vs normals), and radial SR and epsilon of the LV posterior wall (SR = 3.3 +/- 0.9 second(-1); epsilon = 51 +/- 14%; p <0.05 vs normals) were significantly reduced. Thus, abnormalities in regional RV and LV systolic myocardial function in asymptomatic postoperative TOF patients were quantified by the deformation parameters SR and epsilon. RV deformation abnormalities are associated with electrical depolarization abnormalities.

The sequential changes in myocardial thickness and thickening which occur during acute transmural infarction, infarct reperfusion and the resultant expression of reperfusion injury.

AIM: Successful primary PTCA (with TIMI 3 reflow) in patients with acute transmural infarction has been observed to result in an immediate abnormal increase in wall thickness associated with persisting abnormal post-systolic thickening. To understand the sequential changes in regional deformation during: (i) the development of acute transmural infarction, (ii) upon TIMI grade 3 infarct reperfusion and (iii) during the subsequent expression of reperfusion injury the following correlative experimental study was performed in a pure animal model in which there was no distal dispersion of thrombotic material causing either no reflow or secondary microvascular obstruction. METHODS: In 10 closed-chest pigs, a 90 min PTCA circumflex occlusion was used to induce a transmural infarction. This was followed by 60 min of TIMI 3 infarct reperfusion. M-mode ultrasound data from the "at risk" posterior wall infarct segment and from a control remote non-ischemic septal segment were acquired at standardized time intervals. Changes in regional deformation (end-diastolic (EDWT), end-systolic (ESWT) and post-systolic (PSWT) wall thickness, end-systolic strain (epsilonES) and post-systolic strain (epsilonps)) were measured. RESULTS: In this pure animal model of acute transmural infarction/infarct reperfusion (with no pre-existing intra-luminal thrombus), the induced changes in wall thickness and thickening were complex. During prolonged occlusion, after an initial acute fall in ESWT, there was no further change in systolic deformation to indicate the progression of ischaemia to infarction. Both transmurally infarcted and reperfused-infarcted myocardium retained post-systolic thickening indicating that this parameter, taken in isolation, is not a consistent marker of segmental viability and, in this regard, should be interpreted only in combination with other indices of segmental function. The most striking abnormality induced by reperfusion was an immediate increase in EDWT which then increased logarithmically over a 60 min period as reperfusion injury was further expressed. PS did not change significantly during reperfusion. Histology confirmed the wall thickness changes on reperfusion to be due to massive extra-cellular oedema. CONCLUSIONS: The identification of an acute increase in regional wall thickness in a reperfused infarct zone by cardiac ultrasound following primary PTCA might be used in patients to both identify successful infarct reperfusion and to monitor the presence, extent and resolution of the oedema associated with reperfusion injury.