Anterior LV Wall Research Articles

Evaluation of Global Longitudinal Strain of Left Ventricle and Regional Longitudinal Strain in the Region of Left Ventricular Leads Predicts the Response to Cardiac Resynchronization Therapy in Patients with Ischemic Heart Failure

Myocardium viability in ischemic heart failure (HF) may affect the effect of cardiac resynchronization therapy (CRT). We hypothesized that longitudinal strain of 2D-STE, which reflects myocardium viability, can predict the response to CRT in patients with ischemic HF. 2D-STE was performed in 42 patients with HF, 1 week before and 1 year after CRT. GLS, RLS, and the LV synchrony index (SI), defined as the difference in timing to peak radial strain between LV anterior septal and posterior wall in LV short axis view, were calculated. A decrease in the LV end-systolic volume (LVESV) value of ≥ 15 % 1 year after CRT was defined as response to CRT. Twenty-nine patients responded to CRT (CRT-R group), while 13 patients did not respond and were assigned as CRT-NR group. Pre-CRT RLS and GLS were higher, while SI is lower, in CRT-R patients compared with CRT-NR group (p < 0.001). The ROC curve revealed that RLS of -11.5 % predicted response to CRT with sensitivity of 80.0 % and specificity of 77.9 % (AUC = 0.84, p < 0.001). Further, GLS of -13 % predicted response to CRT with sensitivity of 73.0 % and specificity of 73.4 % (AUC = 0.79, p < 0.001). In conclusion, LV dyssynchrony, GLS, and RLS calculated by 2D-STE can predict long-term response to CRT in patients with ischemic HF.

Inital experience of imaging cardiac sarcoidosis using hybrid PET-MR - a technologist's case study

Background Cardiac imaging has been identified as a potential use of hybrid PET-MRI. This new technology allows simultaneous Positron Emission Tomography (PET) and MR scanning to occur. This case study features a 34 year old male with known pulmonary sarcoidosis which was diagnosed in 2006 and initially treated with immunosuppressants. He presented with NYHA functional class 2 symptoms. ECHO showed asymmetrical LV anterior and lateral wall hypertrophy with a maximum wall thickness of 18mm in the basal and mid anterior and lateral wall. The patient was referred for a cardiac18F Fluorodeoxyglucose (FDG) PET-MR study to determine the cause of the hypertrophy. The possible differential diagnoses included hypertrophic cardiac myopathy with pulmonary sarcoidosis or cardiac sarcoidosis.

Novel Ultrafast Cardiac Dedicated SPECT-CT Enables Major Reductions in Patient Dose and Scan Time, While Synergistically Obtaining High Quality Diagnostic Images of Cardiac Anatomy and Function in a Single Scan Session

usingCSPAMM.Histological validationwasperformedby biopsy of the LV septal and free walls during AV surgery. Results: Sixty-three subjects (Severe AS, n= 25; Hypertension, n= 19; Healthy control, n= 19) were recruited. Subjects with HT and severe AS displayed higher Ve compared to healthy controls (p< 0.01). AS patients with elevated Ve also displayed increased levels of both interstitial and replacement fibrosis onhistology (Figs. A andB, respectively). Significant heterogeneity in fibrosis burden existed with LV anterior free wall fibrosis (Fig. C) significant lower when compared with the septum (p< 0.01, Fig. D). The Ve correlated with indices of reduced myocardial function including reduced circumferential strain (r=−0.69, p= 0.001), and radial strain (r=−0.59, p= 0.03). Conclusions:Multi-slice T1-mapping-derived Ve is significantly elevated in patients with AS and systemic hypertension and correlates well with histology and reduced myocardial performance. This technique is clinically practical and holds promise for the detection of IMF in pressure overload hypertrophy. Method: Comparison was made between the conventional state-of-the-art (Philips Precedence) SPECT-CT hybrid camera with the Discovery 570c SPECT-CT hybrid camera in 25 randomly selectedpatients fromeach camera (single day scan protocol). Diagnostic image quality was maintained while scan times and doses were compared for both rest and stress sestamibi myocardial perfusion images as well as for the CT component. Results: Effective doses for CT Philips CT (no ASIR) GE570c (with ASIR) CT for both calcium score and attenuation correction (AC) 0.86 ± 0.05mSv (mean±SD) 0.77 ± 0.09mSv (mean±SD) CT for AC only 0.74 ± 0.03mSv 0.18 ± 0.03mSv SPECT data Philips injected activity Philips effective dose Philips scan time GE570c injected activity GE570c effective dose GE570c scan time Rest 300MBq 2.70mSv 14min 100MBq 0.90mSv 10min Stress 900MBq 7.11mSv 7min 300MBq 2.37mSv 6min Conclusion: The GE Discovery 570c SPECT-CT with ASIR enablesmajor reductions in both radiation dose and scanning time while maintaining high image quality. An ultralow dose stress only (100MBq) SPECT-CT protocol including calcium score with an estimated total (SPECT plus CT) effective radiation dose of 1.6mSv is achievable. http://dx.doi.org/10.1016/j.hlc.2012.05.533 http://dx.doi.org/10.1016/j.hlc.2012.05.532

Abstract 9200: Targeted Delivery of Slow-Releasing Form of A Prostacyclin Analogue, ONO-1301®, Enhances Recruitment of Bone Marrow Derived Cell and Yields Functional Benefits in Acute Myocardial Infarction in Mice

Background: Prostacyclin is an endogenous factor having a variety of protective effects against ischemic pathologies. We have generated ONO-1301®, which is a synthetic prostacyclin analog characterized by chemically stable structure and enhances stromal cell derived factor-1 (SDF-1), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF) secretion. Here, we hypothesized that sustained delivery of ONO-1301® may induce therapeutic effects mediated by the recruited bone marrow derived cells into the injured myocardium in acute MI mouse. Methods and Results: ONO-1301® was conjugated with poly-DL-lactic-co-glycolic acid microsphere to generate a biodegradable controlled-release form. Either the atelocollagen-sheet with ONO-1301® microsphere eluted (ONO group; n=28) or ONO-1301® free microsphere eluted (control group; n=40) was implanted on the left ventricular anterior wall at 15 minutes following permanent LCA occlusion in C57BL6/N mice (male, 8-weeks old). ONO-1301® was still present in the plasma at 1 month (134±26 pg/ml; n=5). Expression levels of SDF-1, HGF, and VEGF in the infarct-border area were significantly elevated for 1 month in the ONO group. Recruitment of bone marrow cell induced by ONO-1301® was investigated using the acute-MI model in GFP-expressing bone marrow-transplanted chimera mice. Two months after LCA ligation followed by ONO-1301® treatment, there was a greater retention of the GFP+ cells in the infarct area. Some of the GFP+ cells were differentiated into the capillary components. In the ONO-1301® treated hearts, LV anterior wall thickness was significantly greater and infarct size was lower at 1 month. Cardiac performance was significantly greater in the ONO group (fractional area change: 24±1%; n=18) than the control group (20±1%; n=22; P=0.011), associated with greater 1 month survival in the ONO group (61±9 vs. 36±8%; P=0.052). Conclusions: Targeted delivery of the slow-releasing form of ONO-1301® possibly up-regulates protective factors, and recruits bone marrow cells into the infarct area, leading to the functional and survival benefits, indicating promising strategy to be translated into the clinical arena.

Speckle tracking analysis of the left ventricular anterior wall shows significantly decreased relative radial strain patterns in dystrophin deficient mice after 9 months of age

Background: Duchenne muscular dystrophy (DMD) is an inherited X-linked disorder with an incidence of 1 in 3,500 male births. Early treatment of DMD cardiomyopathy is under investigation and echocardiographic analysis of strain patterns may provide measures to better quantify early treatment outcomes.Methods: We compared cardiac function in 3, 9 and 12 month old dystrophin deficient mdx mice to wild type (C57BL10/J) using in vivo high frequency echocardiography (Vevo 770, VisualSonics, Inc., Toronto, CA) and 2D speckle tracking [Velocity Vector Imaging (VVI), Siemens Medical Solutions, Inc., Malvern, PA]. Mice were anesthetized with 1-2% inhaled isoflurane and images were obtained using a 30 MHz transducer in modified parasternal long and short axis views obtained at the level of the papillary muscles. Myocardial motion was analyzed using VVI in single-beat reconstructed images.Results: M-mode imaging showed significantly decreased shortening fraction in mdx mice compared to wild type at 12 months of age (SF% 26.6±3 vs. 32.2±2; p=0.002). Mdx mice showed significantly increased cardiac fibrosis at 12 months of age compared to controls (p<0.0001). Speckle tracking analysis of the left anterior mid ventricular wall segment showed significantly decreased relative radial strain in mdx mice at 9 and 12 months (4.5±1.3% vs. 8.4±0.7%; p=0.001). There were no significant differences in circumferential or longitudinal strain. Conclusion: Mdx mice show significantly decreased LV anterior mid wall radial strain with mild cardiomyopathy after 9 months of age compared to wild type. Speckle tracking analysis may provide novel outcome measures for preclinical cardiac drug treatment studies in DMD.

Gene transfer as a strategy to achieve permanent cardioprotection II: rAAV-mediated gene therapy with heme oxygenase-1 limits infarct size 1 year later without adverse functional consequences

Extensive evidence indicates that heme oxygenase-1 (HO-1) exerts potent cytoprotective effects in response to stress. Previous studies have shown that gene therapy with HO-1 protects against myocardial ischemia/reperfusion injury for up to 8weeks after gene transfer. However, the long-term effects of HO-1 gene therapy on myocardial ischemic injury and function are unknown. To address this issue, we created a recombinant adeno-associated viral vector carrying the HO-1 gene (rAAV/HO-1) that enables long-lasting transgene expression. Mice received injections in the anterior LV wall of rAAV/LacZ (LacZ group) or rAAV/HO-1 (HO-1 group); 1year later, they were subjected to a 30-min coronary occlusion (O) and 4h of reperfusion (R). Cardiac HO-1 gene expression was confirmed at 1month and 1year after gene transfer by immunoblotting and immunohistochemistry analyses. In the HO-1 group, infarct size (% of risk region) was dramatically reduced at 1year after gene transfer (11.2±2.1%, n=12, vs. 44.7±3.6%, n=8, in the LacZ group; P<0.05). The infarct-sparing effects of HO-1 gene therapy at 1year were as powerful as those observed 24h after ischemic PC (six 4-min O/4-min R cycles) (15.0±1.7%, n=10). There were no appreciable changes in LV fractional shortening, LV ejection fraction, or LV end-diastolic or end-systolic diameter at 1year after HO-1 gene transfer as compared to the age-matched controls or with the LacZ group. Histology showed no inflammation in the myocardium 1year after rAAV/HO-1-mediated gene transfer. These results demonstrate, for the first time, that rAAV-mediated HO-1 gene transfer confers long-term (1year), possibly permanent, cardioprotection without adverse functional consequences, providing proof of principle for the concept of achieving prophylactic cardioprotection (i.e., "immunization against infarction").

Gene transfer as a strategy to achieve permanent cardioprotection I: rAAV-mediated gene therapy with inducible nitric oxide synthase limits infarct size 1 year later without adverse functional consequences

The ultimate goal of prophylactic gene therapy is to confer permanent protection against ischemia. Although gene therapy with inducible nitric oxide synthase (iNOS) is known to protect against myocardial infarction at 3days and up to 2months, the long-term effects on myocardial ischemic injury and function are unknown. To address this issue, we created a recombinant adeno-associated viral vector carrying the iNOS gene (rAAV/iNOS), which enables long-lasting transgene expression. The ability of rAAV/iNOS to direct the expression of functional iNOS protein was confirmed in COS-7 cells before in vivo gene transfer. Mice received injections in the anterior LV wall of rAAV/LacZ or rAAV/iNOS; 1year later, they underwent a 30-min coronary occlusion (O) and 4h of reperfusion (R). iNOS gene transfer resulted in elevated iNOS protein expression (+3-fold vs. the LacZ group, n=6; P<0.05) and iNOS activity (+4.4-fold vs. the LacZ group, n=6; P<0.05) 1year later. Infarct size (% of risk region) was dramatically reduced at 1year after iNOS gene transfer (13.5±2.2%, n=12, vs. 41.7±2.9%, n=10, in the LacZ group; P<0.05). The infarct-sparing effect of iNOS gene therapy at 1year was as powerful as that observed 24h after ischemic preconditioning (six 4-min O/4-min R cycles) (19.3±2.3%, n=11; P<0.05). Importantly, compared with the LacZ group (n=11), iNOS gene transfer (n=10) had no effect on LV dimensions or function for up to 1year (at 1year: FS 34.5±2.0 vs. 34.6±2.6%, EF 57.0±2.0 vs. 59.7±2.9%, LVEDD 4.3±0.1 vs. 4.2±0.2mm, LVESD 2.8±0.1 vs. 2.9±0.2mm) (echocardiography). These data demonstrate, for the first time, that rAAV-mediated iNOS gene transfer affords long-term, probably permanent (1year), cardioprotection without adverse functional consequences, providing a strong rationale for further preclinical testing of prophylactic gene therapy.

E0662 Evaluation of the whole and regional myocardial function of left ventricle in dogs with congestive heart failure induced by fast right ventricular pacing

ObjectiveUse the Doppler and strain rate imaging (SRI) to evaluate the systolic and diastolic function of the whole and regional ventricular myocardial in congestive heart failure dog models induced by...

Effects of electric stimulations applied during absolute refractory period on cardiac function of rabbits with heart failure

The effects of electric currents applied during absolute refractory period (ARP) on the cardiac function of rabbits with heart failure due to myocardial infarction (MI), and the safety of this method were investigated. Thirty rabbits were randomly assigned equally to 3 groups: sham-operated group, LV-anterior wall cardiac contractility modulation (LV-CCM) group, and septum-CCM (S-CCM) group. A thoracotomy was performed on all the rabbits. Electric pulses were delivered during the ARP on the anterior wall of left ventricle in CCM group and in the septum in S-CCM group, respectively. The left ventricular systolic pressure (LVSP) and maximum positive left ventricular pressure change (+dp/dt(max)), heart rates, ventricular tachycardia, ventricular fibrillation were observed. It was found that, as compared with the baseline, LVSP, and +dp/dtmax were significantly increased, on average, by 15.2% and 19.5% in LV-CCM group (P<0.05), and by 8.5% and 10.8% in S-CCM group (P<0.05). LVEDP was significantly decreased and -dp/dt(max) increased both in LV-CCM group and S-CCM group (P<0.05). CCM had no effect on heart rate and induced no arrhythmia in short time. It is concluded that electric currents delivered during the ARP could significantly enhance the contractility of myocardium safely, suggesting that CCM stimulation is a novel potent method for contractility modulation.

Efficacy of intracoronary administration of a short-acting β-blocker landiolol during reperfusion in pigs

Although β-blockers are used to prevent myocardial ischemia/reperfusion injury, the risk of heart failure has limited β-blocker therapy in patients with acute myocardial infarction. This study evaluated efficacy of intracoronary administration of the short-acting β-blocker, landiolol, during reperfusion in pigs with acute myocardial ischemia. In the non-ischemic model landiolol administered into the left anterior descending coronary artery (LAD) inhibited in a dose-dependent fashion segmental wall thickening (SWT) in the anterior LV wall without altering SWT in the posterior LV wall and without prolonged depression of global LV function except for the highest dose. In the ischemic model with 60 min LAD occlusion followed by reperfusion the medium dose landiolol administered into the LAD 1 min before and for 10 min during reperfusion inhibited initial recovery of SWT in the anterior LV wall but improved SWT in this region and global LV function late after reperfusion. Ultrastructural studies showed inhibition of sub-sarcolemmal bleb formation by treatment with landiolol 10 min after reperfusion associated with the inhibition of CK-MB release and the reduction of infarct size. There was no significant difference in CK-MB release and infarct size between landiolol treatment for 10 min and 180 min during reperfusion. Selective and brief intracoronary administration of landiolol during reperfusion enhances myocardial salvage without causing deterioration of global LV function.

Abstract 1614: Inducible Nitric Oxide Synthase Upregulates Heme Oxygenase-1 (HO-1) in Myocardium by Enhancing Nrf2 Phosphorylation and Binding to the HO-1 Promoter

Previous studies have shown that iNOS gene transfer leads to elevated expression of HO-1, which in turn protects against ischemic injury. However, the mechanism of this effect is unknown. Recently, Nrf2 has emerged as a key transcription factor in response to stress. Thus, we hypothesized that the upregulation of HO-1 by iNOS gene therapy involves an Nrf2-mediated pathway. Mice received injections in anterior LV wall of Av3/LacZ or Av3/iNOS; 3 days later, they were subjected to a 30-min coronary occlusion and 4 h of reperfusion. At 24 h after iNOS gene transfer (confirmed by iNOS immunoblotting), phosphorylated Nrf2 increased significantly in the myocardial nuclear fraction (+ 220% vs. LacZ group, n=6, P&lt;0.05; Fig ); chromatin Nrf2-immunoprecipitation (Nrf2-ChIP) analysis in vivo showed that Nrf2 was specifically recruited to the HO-1 gene promoter (+ 4.7-fold vs. LacZ group, n=4, P&lt;0.05; Fig ). At 3 days after iNOS gene transfer, myocardial HO-1 protein expression increased markedly (+ 2.6-fold vs. LacZ group, n=6, P&lt;0.05; Fig ), but HO-2 did not change (n=3). The infarct-sparing effects of iNOS gene therapy were completely abrogated by disruption of Nrf2 (Nrf2−/−) (62.8±2.1% in Nrf2−/−+Av3/iNOS group, n=5, vs. 15.3±4.3% in WT+Av3/iNOS group, n=7; Fig ). We conclude that iNOS upregulates HO-1 by enhancing Nrf2 phosphorylation and binding to the HO-1 promoter; and targeted disruption of the Nrf2 gene completely abrogates cardioprotection after iNOS gene transfer. These results provide unequivocal molecular genetic evidence for a necessary role of Nrf2 in the protection afforded by iNOS. Thus, activation of Nrf2 is a key molecular event that links iNOS to HO-1.

Abstract 5423: rAAV-Mediated Gene Therapy with Inducible Nitric Oxide Synthase (iNOS) Affords Permanent Cardioprotection (1 Year) without Adverse Functional Consequences

The ultimate goal of prophylactic gene therapy is to confer permanent protection against ischemia. Although gene therapy with iNOS is known to protect against myocardial infarction at 3 days and up to 2 months, the long-term effects of iNOS gene therapy on myocardial ischemic injury and function are unknown. To address this issue, we created a recombinant adeno-associated viral vector carrying the iNOS gene (rAAV/iNOS) which enables long-lasting transgene expression. Mice received injections in anterior LV wall of rAAV/LacZ or rAAV/iNOS; 1 year later, they underwent a 30-min coronary occlusion (O) and 4 h of reperfusion (R). iNOS gene transfer resulted in elevated iNOS protein expression (+ 2.9-fold vs. LacZ group, n=6, P&lt;0.05; Fig ) and iNOS activity (+ 3.3-fold vs. LacZ group, n=4, P&lt;0.05) 1 year later. Infarct size (% of risk region) was dramatically reduced at 1 year after iNOS gene transfer (13.5+/−2.2%, n=12, vs. 42.9+/−2.6%, n=12, in LacZ group; Fig ). The infarct-sparing effects of iNOS gene therapy at 1 year were as powerful as those observed 24 h after ischemic PC (six 4-min O/4-min R cycles) (16.3+/−2.3%, n=8; Fig ). Importantly, compared with the LacZ group (n=11), iNOS gene transfer (n=10) had no effect on LV dimensions or function for up to 1 year (at 1 year: LVEDD 4.4+/−0.1 vs. 4.2+/−0.2 mm; LVESD 2.9+/−0.1 vs. 2.9+/−0.2 mm; FS 34+/−1.8 vs. 32+/−2.6%; EF 56+/−2.3 vs. 60+/−2.9%) (echocardiography). These data demonstrate, for the first time, that rAAV-mediated iNOS gene transfer affords long-term, probably permanent (1 year) cardioprotection without adverse functional consequences, providing a strong rationale for further preclinical testing of prophylactic gene therapy.

Magnetresonanztomografie bei kardialer Amyloidose - Morphologie, Funktion und late enhancement

Since limited data is available using MR imaging in cardiac amyloidosis, the purpose of our study was to evaluate morphological and functional differences of the heart using cardiac MRI. 19 consecutive patients (14 males, 5 females, mean age 59 +/- 6 years) with histologically proven cardiac amyloidosis were evaluated with MRI at 1.5 T. Results were compared with data of 10 healthy, age-matched control subjects (5 males, 5 females, mean age 60 +/- 6 years). Functional and morphological data including late enhancement (LE) was acquired. Compared to the control group, patients with cardiac amyloidosis had thickened atrial walls and dilated atriums. Both ventricles and the interventricular septum were thickened. The LV hypertrophy was focal in 11 / 19 (58 %) and global in 4 / 19 (21 %) of patients. A myocardial edema occurred in 2 / 19 patients with cardiac amyloidosis (11 %). An edema of the myocardium was visible in 2 / 19 (11 %) of patients. The LV ejection fraction was statistically significantly decreased. The prevalence of LE was 74 % (14 / 19 of patients). LE was detected predominantly in the LV anterior wall and in the interventricular septum. Within the segments LE was located predominantly in a subendocardial location. Between patients with and without LE no statistically significant differences of functional and morphological results were able to be established. There are three major outcomes of our assessment: 1. The LV hypertrophy is focal in the majority of patients with cardiac amyloidosis. 2. No statistically significant differences can be established in regard to the functional and morphological features between patients with and without LE. 3. Myocardial edema is a possible feature in cardiac amyloidosis.

Abstract 3364: Serial MRI Assessment of Macrophage Activity in the Murine Heart after Myocardial Infarction using Gadolinium-labeled Liposomes as a Positive Contrast Agent

Introduction: Macrophage activity in the heart after myocardial infarction (MI) has previously been assessed by iron-particle cardiac magnetic resonance (CMR) that produces negative contrast. We hypothesized that a new multimodal, liposomal agent with both Gd-DTPA and fluorescent DiI dye could be used for positive contrast macrophage tracking. Methods: Multimodal liposomes (ML) were prepared with Gd-DTPA-bis-stearylamide and DiI then filtered to ∼0.3 μm size. Nine C57Bl/6 mice were subjected to 1h coronary occlusion followed by up to 7d of reperfusion. ML volumes of 50μl were injected IV on Day 2 post-MI for monocyte/macrophage phagocytosis. Mice were studied by CMR 2–4h after Day 2 injection and daily until Day 7 post-MI. CMR included inversion-recovery (IR) to image ML followed by IP infusion of Gd-DTPA and more IR to image the entire infarct (IF). After final imaging, hearts were removed for Mac2 immunostaining &amp; fluorescence microscopy. Results: Day 2 IR CMR 2–4h after ML injection revealed strong signal enhancement in the spleen with none in the heart. In all mice from Day 3–7, ML signal enhancement marked the LV anterior wall in IF regions (Fig A ). The ML contrast peaked at Day 5 and decreased by Day 7 post-MI (Fig B ). In mice euthanized at Days 4 &amp; 7, ML-enhanced regions corresponded well with regions containing macrophages as labeled by anti-Mac2 (Fig C ) and DiI (Fig D ) Conclusions: ML can assess the accumulation of macrophages in the heart until at least Day 7 post-MI. The Gd tag provides specific positive contrast and the fluorescent tag expedites histological confirmation. This improves over iron-based agents that preclude complementary CMR imaging in regions containing iron.

Myocardial Functional and Textural Findings of the Right and Left Ventricles and Their Association with Cellular Adhesion Molecules in Behçet's Disease

This study was designed to assess whether ultrasonic reflectivity, evaluated by integrated backscatter analysis was associated with the severity of inflammation and diastolic dysfunction of the left (LV) and right ventricles (RV) in Behçet's disease (BD). The study consisted of 20 patients with BD and 18 healthy controls. The expression of CD11b and CD63 on the surface of granulocytes and monocytes were measured by flow cytometry. RV and LV diastolic functions were assessed by tricuspid and mitral annular tissue Doppler recordings, respectively. Backscatter cyclic variation (CV) and maximal intensity (IB) were measured in RV lateral wall, interventricular septum, and posterior LV wall from parasternal long-axis view, apex from apical four-chamber view, anterior, inferior, and lateral LV walls from parasternal short axis view. The mean fluorescence intensity (MFI) of CD11b on granulocytes and CD63 on monocytes in BD patients was higher than those of controls. Patients with BD had smaller mitral and tricuspid annular early diastolic wave velocities and early/late diastolic wave velocity ratios (E/A) than controls. MFI of CD11b and CD63 was inversely correlated with tricuspid and mitral annular E/A in BD patients. CV of RV and global CV of LV were found to be diminished in BD patients than controls. CV of RV and global CV of LV showed a direct correlation with tricuspid and mitral annular E/A ratio, respectively. There is an association between the levels of cellular adhesion molecules, deterioration of diastolic function, and altered myocardial ultrasonic reflectivity in BD.

Abstract 192: Defibrillation Strategy with Postshock Synchronized Pacing in Excitable Gaps

Introduction: It was previously demonstrated that ventricular fibrillation (VF) can be synchronized with a novel spatiotemporal excitable gap pacing (SyncP) technique using low-energy pacing pulses that causes pace termination of VF. Therefore, we hypothesize that a spatiotemporally controlled (STCD) defibrillation strategy using defibrillation shocks followed by SyncP may be effective in defibrillation efficacy improvement. Methods and Results: We explored the STCD effects in 10 isolated rabbit hearts (n=10) with optical mapping of the anterior wall in LV. Optical recording guided real-time detection and stimulation of spatiotemporal excitable gaps was performed. SyncP was shown to cause wavefront synchronization as indicated by a decreased number of phase singularity points (p&lt;0.0001) and reduced spatial dispersion of VF cycle length (p&lt;0.01). After a defibrillation shock delivery, an isoelectrical window (IW) was present and the duration of the IW was a function of the shock strength. When the reference site detected the earliest activation (early site) of the reinitiated VF during IW, a 5-mA electric stimulus was delivered from the pacing electrode to depolarize the excitable gap, creating a functional block to stop VF propagation or change the propagation timing/pattern for VF termination. The location of the early site varied, however, about 80% arose from the right side of LV anterior wall close to apex, with the arrangement of the defibrillation anode electrode in the RV and cathode against the posterior wall. For 90% of the episodes where the reference site accurately detected the early site location, the SyncP pacing electrode successfully administered pacing in the excitable gap after low-energy shock delivery. VF was demonstrated to be successfully terminated by the STCD defibrillation with low-energy shock and pacing in the excitable gaps to cause functional block for reinitiated VF propagation in heart tissues. Conclusion: We implemented the concept of post-shock synchronized pacing in excitable gaps by a real-time feedback mechanism. Further optimization of this technique may prove effective in improving the defibrillation efficacy by synchronized VF activation.

Pacing-Induced Dys-Synchrony Preconditions Rabbit Myocardium Against Ischemia/Reperfusion Injury

Because increased mechanical load induces preconditioning (PC) and dys-synchrony increases loading in late-activated regions, we investigated whether dys-synchrony induced by ventricular pacing (VP) at normal heart rate leads to cardioprotection. Isolated working rabbit hearts were subjected to 35 minutes of global ischemia and 2 hours of reperfusion. Seven hearts underwent VP PC (3 periods of 5 minutes VP at the posterior left ventricular [LV] wall), 7 hearts underwent ischemic preconditioning (IPC) (3 periods of 5 minutes of global ischemia), and 9 hearts served as control (C). LV pressure and sonomicrometry were used to assess global hemodynamics and segment work (SW) and end-diastolic segment length (EDSL) in anterior and posterior LV myocardium. Myocardial release of lactate and expression of proBNP mRNA were determined to gain insight in molecular processes involved in VP PC (*P<0.05). Infarct size (triphenyl tetrazolium chloride staining) was 18.3+/-13.0% in group C, and was uniformly reduced in the VP PC and IPC groups (1.8+/-0.8%*, and 3.5+/-3.1%*, respectively; and not significant between VP PC and IPC). LV posterior wall pacing (VP PC group) increased EDSL (by 6.3+/-5.8%*) and SW (to 335+/-207%*) in the LV anterior wall, whereas posterior wall SW decreased to negative values (-23+/-63%*). LV pacing did not significantly change lactate release and coronary flow but significantly increased proBNP mRNA expression in both anterior and posterior myocardium as compared with controls. Intermittent dys-synchrony is equally cardioprotective as "classical" IPC. Stretch-mediated signaling is a more likely trigger for VP PC than ischemia. VP PC is potentially applicable in cardiac surgery.

Comparison of channelized hotelling and human observers in determining optimum OS-EM reconstruction parameters for myocardial SPECT

The performance of the Channelized Hotelling Observer (CHO) was compared to that of human observers for determining optimum parameters for the iterative OS-EM image reconstruction method for the task of defect detection in myocardial SPECT images. The optimum parameters were those that maximized defect detectability in the SPECT images. Low noise, parallel SPECT projection data, with and without an anterior, inferior or lateral LV wall defect, were simulated using the Monte Carlo method. Poisson noise was added to generate noisy realizations. Data were reconstructed using OS-EM at 1 & 4 subsets/iteration and at 1, 3, 5, 7 & 9 iterations. Images were converted to 2D short-axis slices with integer pixel values. The CHO used 3 radially-symmetric, 2D channels, with varying levels of internal observer noise. For each parameter setting, 600 defect-present and 600 defect-absent image vectors were used to calculate the detectability index (dA). The human observers rated the likelihood that a defect was present in a specified location. For each parameter setting, the AUC was estimated from 48 defect-present and 48 defect-absent images. The combined human observer results showed the optimum parameter setting could be in the range 5-36 updates ([number of subsets]/iteration /spl times/ number of iterations). The CHO results showed the optimum parameter setting to be 4-5 updates. The performance of the CHO was much more sensitive to the reconstruction parameter setting than was that of the human observers. The rankings of the CHO detectability values did not change with varying levels of internal noise.

Adeno-Associated Virus-Mediated Transduction of VEGF165 Improves Cardiac Tissue Viability and Functional Recovery After Permanent Coronary Occlusion in Conscious Dogs

We have previously shown that VEGF165 gene delivery into ischemic skeletal muscle exerts not only proangiogenic, but also remarkable antiapoptotic and proregenerative activity. The aim of this study was to determine whether recombinant adeno-associated virus (rAAV)-mediated gene delivery of VEGF165 into cardiac muscle, during acute myocardial infarction, exerts a protective effect to promote long-term functional recovery. Acute infarction of the anterior LV wall was induced in 12 chronically instrumented dogs by permanent occlusion of the LAD coronary artery. Four hours after occlusion, rAAV-VEGF165 or rAAV-LacZ (n=6 each; 5x10(12) viral particles per animal) was directly injected with an echo-guided needle into the dysfunctional cardiac wall. LV and arterial pressure, dP/dtmax, and ejection fraction were not significantly different between the two groups over time. In contrast, in the infarcted region, at four weeks after infarction, fractional shortening was 75+/-18% and -3+/-15% of baseline and length-pressure area was 54+/-15% and 0.8+/-15% of baseline in VEGF165 versus LacZ, respectively (P<0.05). Histological analysis of the border regions showed a marked increase in the number of alpha-SMA-positive arterioles (68+/-2.8 versus 100+/-3.8 vessels per microscopic field in LacZ and VEGF165 group, respectively; P<0.05). In both groups, the receptor VEGFR-2 was diffusely expressed on the surviving cardiomyocytes and, consistently, myocardial viability was significantly improved in the VEGF165-treated group, with several troponin T-expressing cardiomyocytes displaying nuclear positivity for the proliferation marker PCNA. Altogether, our results indicate that VEGF165 gene delivery exerts a marked beneficial action by enhancing both arteriologenesis and cardiomyocyte viability in infarcted myocardium.

Bone marrow-derived myocyte-like cells and regulation of repair-related cytokines after bone marrow cell transplantation

Whether bone marrow cells injected following acute myocardial infarction (MI) transdifferentiate into cardiomyocytes remains controversial, and how these cells affect repair-related cytokines is not known. Autologous bone marrow-derived mononuclear cells (BM-MNCs) labeled with DiI, 1,1'-dioctadecyl-1 to 3,3,3',3'-tetramethylindocarbocyanine perchlorate, or saline were intravenously injected into rabbits 5 h following a 30-min ischemia and reperfusion protocol, and cardiac function and the general pathology of the infarcted heart were followed up 1 and 3 months post-MI. To search for regenerated myocardium, electron microscopy as well as confocal microscopy were performed in the infarcted myocardium 7 days post-MI. Expression levels of repair-related cytokines were evaluated by immunohistochemistry and Western blotting. Improvements in cardiac function and reductions in infarct size were observed in the BM-MNC group 1 month and 3 months post-MI. Using electron microscopy 7 days after infarction, clusters of very immature (fetal) and relatively mature cardiomyocytes undergoing differentiation were identified in the infarcted anterior LV wall in the BM-MNC group, though their numbers were small. These cells contained many small and dense DiI particles (a BM-MNC marker), indicating that cardiomyocytes had regenerated from the injected BM-MNCs. The expression of both transforming growth factor-beta, which stimulates collagen synthesis and matrix metalloproteinase-1, a collagenase, were both down-regulated 7 days and 1 month post-MI in the BM-MNC group. Stromal cell-derived factor-1, which is known to recruit BM-MNCs into target tissues, was overexpressed in the infarcted areas of BM-MNC hearts 7 days post-MI. Intravenous transplantation of BM-MNCs leads to the development of BM-MNC-derived myocyte-like cells and regulates the expression of repair-related cytokines that facilitate repair following myocardial infarction.