Long-term Left Ventricular Remodeling Research Articles

Impact of DCM-Causing Genetic Background on Long-Term Response to Cardiac Resynchronization Therapy

BackgroundPatients with nonischemic dilated cardiomyopathy (DCM), severe left ventricular (LV) dysfunction, and complete left bundle branch block benefit from cardiac resynchronization therapy (CRT). However, a large heterogeneity of response to CRT is described. Several predictors of response to CRT have been identified, but the role of the underlying genetic background is still poorly explored. ObjectivesIn the present study, the authors sought to define differences in LV remodeling and outcome prediction after CRT when stratifying patients according to the presence or absence of DCM-causing genetic background. MethodsFrom our center, 74 patients with DCM subjected to CRT and available genetic testing were retrospectively enrolled. Carriers of causative monogenic variants in validated DCM-causing genes, and/or with documented family history of DCM, were classified as affected by genetically determined disease (GEN+DCM) (n = 25). Alternatively, by idiopathic dilated cardiomyopathy (idDCM) (n = 49). The primary outcome was long-term LV remodeling and prevalence of super response to CRT (evaluated at 24-48 months after CRT); the secondary outcome was heart failure–related death/heart transplant/LV assist device. ResultsGEN+DCM and idDCM patients were homogeneous at baseline with the exception of QRS duration, longer in idDCM. The median follow-up was 55 months. Long-term LV reverse remodeling and the prevalence of super response were significantly higher in the idDCM group (27% in idDCM vs 5% in GEN+DCM; P = 0.025). The heart failure–related death/heart transplant/LV assist device outcome occurred more frequently in patients with GEN+DCM (53% vs 24% in idDCM; P = 0.028). ConclusionsGenotyping contributes to the risk stratification of patients with DCM undergoing CRT implantation in terms of LV remodeling and outcomes.

Role of aldosterone in the mid- and long-term left ventricular remodelling after acute myocardial infarction: the REMI study.

Whether aldosterone levels after myocardial infarction (MI) are associated with medium and long-term left ventricular (LV) remodelling in the era of systematic use of renin-angiotensin system inhibitors is uncertain. We prospectively investigated the relationship between aldosterone levels and mid- and long-term LV remodelling in patients with acute MI. AND RESULTS: Plasma aldosterone was measured in 119 patients successfully treated by primary percutaneous coronary angioplasty for a first acute ST-elevated MI (STEMI) 2-4 days after the acute event. LV volumes were assessed by cardiac magnetic resonance (CMR) and transthoracic echocardiography (TTE) in the same timeframe and 6 months later. LV assessment was repeated by TTE 3-9 years after MI (N=80). The median aldosterone level at baseline was 23.1 [16.8; 33.1] pg/mL. Higher post-MI aldosterone concentration was significantly associated in multivariable model with more pronounced increase in LV end-diastolic volume index (TTE: β ± SE: 0.113 ± 0.046, P =0.015; CMR: β ± SE: 0.098 ± 0.040, P =0.015) and LV end-systolic volume index (TTE: β ± SE: 0.083 ± 0.030, P=0.008; CMR: β ± SE: 0.064 ± 0.032, P =0.048) at 6-month follow-up, regardless of the method of assessment. This result was consistent also in patient with a LV ejection fraction (LVEF) >40%. The association between baseline plasma aldosterone and adverse LV remodelling did not persist at the 3-9 years follow-up evaluation. Aldosterone concentration in the acute phase was associated with adverse LV remodelling in the mid-term, even in the subgroup of patients with LVEF >40%, suggesting a potential role of the mineralocorticoid system in post-MI adverse remodelling. Plasma aldosterone was no longer associated with LV remodelling in the long-term. (NCT01109225) This article is protected by copyright. All rights reserved.

Meta-Analysis of the Effects of Recombinant Human Brain Natriuretic Peptides on Left Ventricular Remodeling in Patients with Acute Myocardial Infarction.

Objective Systematic evaluation of the efficacy of natriuretic recombination in human brain on disease myocardial infarction, left ventricular heart failure, and the efficacy and safety of long-term left ventricular remodeling. Methods Computerized search of CNKI, Wanfang database, Wipro Chinese Technology Publications (VIP) numerical database, Chinese Biomedical Literature Database (CBM), Medline Cochrane Library, clinical Trail.Gov clinical collection, and other documents. Randomized controlled trials (RCT) of recombinant human brain natriuretic peptide in the treatment of acute myocardial infarction from inception to December 2021 were searched. Based on the Jadad scale, inclusion-exclusion data for diseases were collected and elaborated by meta by RevMan 5.3 simulation software. In a total of 23 randomized controlled trials, 2 024 cases were used as the basic data, the control group was routinely treated for 1 012 cases, and 1 012 cases in the experimental group were also treated with natriuretic peptide in the recombinant human brain on the previous basis. Results In terms of overall efficacy, the experimental group was better than the control group, statistically significant (OR = 4.30, 95% CI (3.26, 5.67), P < 0.000 01), left ventricular ejection fraction in the experimental group than the control group (OR = 1.58, 95% CI (1.27, 1.90), P < 0.000 01). In terms of a myocardial strain in the left ventricle, the experimental group was superior to the control group. The difference was significant (OR = −0.91, 95% CI (-1.50, -0.33), P = 0.002). In terms of the cardiac output volume, the experimental group was superior to the control group (OR = 1.24, 95% CI (0.55, 1.94), P = 0.0005). Regarding brain natriuretic peptide precursors, the experimental group was superior to the control group (OR = −4.37, 95% CI (-6.21, -3.25), P < 0.00001). In terms of the heart rate, the experimental group was superior to the control group. Measurement of differential significance is as follows: OR = −13.70, 95% CI (-14.95, -12.46), P < 0.00001. In terms of contraction, the experimental group was superior to the comparison group (OR = −12.38, 95% CI (-17.98, -6.79), P < 0.00001). The experimental group outperformed the control group (OR = −7.42, 95% CI (-8.53, -6.30), P < 0.00001). In terms of bad influence, the measurement is as follows: OR = 0.95, 95% CI (0.29, 3.16), P = 0.94. Conclusion In patients with acute myocardial infarction and left ventricular remodeling, if treated with a heavy treatment of the group of cerebral natriuretic peptide mode, it can increase clinical treatment, improve the cardiac effect, inhibit ventricular remodeling, improve blood pressure and heart rhythm, and have greater clinical treatment and safety.

Infarct size and long-term left ventricular remodelling in acute myocardial infarction patients subjected to transcoronary delivery of progenitor cells.

Infarct size (IS) is a fundamental determinant of left-ventricular (LV) remodelling (end-systolic and end-diastolic volume change, ΔESV, ΔEDV) and adverse clinical outcomes after myocardial infarction (MI). Our prior work found that myocardial uptake of transcoronary-delivered progenitor cells is governed by IS. To evaluate the relationship between IS, stem cell uptake, and the magnitude of LV remodelling in patients receiving transcoronary administration of progenitor cells shortly after MI. Thirty-one subjects (age 36-69 years) with primary percutaneous coronary intervention (pPCI)-treated anterior ST-elevation MI (peak CK-MB 584 [181-962] U/l, median [range]) and sustained left ventricle ejection fraction (LVEF) ≤ 45% were studied. On day 10 (median) 4.3 × 106 (median) autologous CD34+ cells (50% labelled with 99mTc-extametazime) were administered via the infarct-related artery (left anterior descending). ΔESV, ΔEDV, and mid circumferential myocardial strain (mCS) were evaluated at 24 months. Infarct mass (cMRI) was 57 [11-112] g. Cell label myocardial uptake (whole-body γ-scans) was proportional to IS (r = 0.62), with a median 2.9% uptake in IS 1st tercile (≤ 45 g), 5.2% in 2nd (46-76 g), and 6.7% in 3rd (> 76 g) (p = 0.0006). Cell uptake in proportion to IS attenuated the IS-ΔESV (p = 0.41) and IS-ΔEDV (p = 0.09) relationship. At 24 months, mCS improved in IS 2nd tercile (p = 0.028) while it showed no significant change in smaller (p = 0.87) or larger infarcts (p = 0.58). This largest human study with labelled CD34+ cell transplantation shortly after MI suggests that cell uptake (proportional to IS) may attenuate the effect of IS on LV adverse remodelling. To boost this effect, further strategies should involve cell types and delivery techniques to maximize myocardial uptake.

Acute Microstructural Changes after ST-Segment Elevation Myocardial Infarction Assessed with Diffusion Tensor Imaging

Background Cardiac diffusion tensor imaging (cDTI) allows for in vivo characterization of myocardial microstructure. In cDTI, mean diffusivity and fractional anisotropy (FA)-markers of magnitude and anisotropy of diffusion of water molecules-are known to change after myocardial infarction. However, little is known about regional changes in helix angle (HA) and secondary eigenvector angle (E2A), which reflects orientations of laminar sheetlets, and their association with long-term recovery of left ventricular ejection fraction (LVEF). Purpose To assess serial changes in cDTI biomarkers in participants following ST-segment elevation myocardial infarction (STEMI) and to determine their associations with long-term left ventricular remodeling. Materials and Methods In this prospective study, 30 participants underwent cardiac MRI (3 T) after STEMI at 5 days and 3 months after reperfusion (National Institute of Health Research study no. 33963 and Research Ethics no. REC17/YH/0062). Spin-echo cDTI with second-order motion-compensation (approximate duration, 13 minutes; three sections; 18 noncollinear diffusion-weighted scans with b values of 100 sec/mm2 [three acquisitions], 200 sec/mm2 [three acquisitions], and 500 sec/mm2 [12 acquisitions]), functional images, and late gadolinium enhancement images were obtained. Multiple regression analysis was used to assess associations between acute cDTI parameters and 3-month LVEF. Results Acutely infarcted myocardium had reduced FA, E2A, and myocytes with right-handed orientation (RHM) on HA maps compared with remote myocardium (mean remote FA = 0.36 ± 0.02 [standard deviation], mean infarcted FA = 0.25 ± 0.03, P < .001; mean remote E2A = 55° ± 9, mean infarcted E2A = 49° ± 10, P < .001; mean remote RHM = 16% ± 6, mean infarcted RHM = 9% ± 5, P < .001). All three parameters (FA, E2A, and RHM) correlated with 3-month LVEF (r = 0.68, r = 0.59, and r = 0.53, respectively), with acute FA being independently predictive of 3-month LVEF (standardized β = 0.56, P = .008) after multivariable analysis adjusting for factors, including acute LVEF and infarct size. Conclusion After ST-segment elevation myocardial infarction, diffusion becomes more isotropic in acutely infarcted myocardium as reflected by decreased fractional anisotropy. Reductions in secondary eigenvector angle suggest that the myocardial sheetlets are unable to adopt their usual steep orientations in systole, whereas reductions in myocytes with right-handed orientation on helix angle maps are likely reflective of a loss of organization among subendocardial myocytes. Correlations between these parameters and 3-month left ventricular ejection fraction highlight the potential clinical use of cardiac diffusion tensor imaging after myocardial infarction in predicting long-term remodeling. © RSNA, 2021 Online supplemental material is available for this article.

Repeated cell transplantation and adjunct renal denervation in ischemic heart failure: exploring modalities for improving cell therapy efficacy

Enthusiasm for cell therapy for myocardial injury has waned due to equivocal benefits in clinical trials. In an attempt to improve efficacy, we investigated repeated cell therapy and adjunct renal denervation (RDN) as strategies for augmenting cardioprotection with cardiosphere-derived cells (CDCs). We hypothesized that combining CDC post-conditioning with repeated CDC doses or delayed RDN therapy would result in superior function and remodeling. Wistar-Kyoto (WKY) rats or spontaneously hypertensive rats (SHR) were subjected to 45min of coronary artery ligation followed by reperfusion for 12-14weeks. In the first study arm, SHR were treated with CDCs (0.5 × 106 i.c.) or PBS 20min following reperfusion, or additionally treated with CDCs (1.0 × 106 i.v.) at 2, 4, and 8weeks. In the second arm, at 4weeks following myocardial infarction (MI), SHR received CDCs (0.5 × 106 i.c.) or CDCs + RDN. In the third arm, WKY rats were treated with i.c. CDCs administered 20min following reperfusion and RDN or a sham at 4weeks. Early i.c. + multiple i.v. dosing, but not single i.c. dosing, of CDCs improved long-term left ventricular (LV) function, but not remodeling. Delayed CDC + RDN therapy was not superior to single-dose delayed CDC therapy. Early CDC + delayed RDN therapy improved LV ejection fraction and remodeling compared to both CDCs alone and RDN alone. Given that both RDN and CDCs are currently in the clinic, our findings motivate further translation targeting a heart failure indication with combined approaches.

Abstract 113: Steering Fibroblast Phenotype to Promote Left Ventricular Scar Maturation and Function Post-MI

The prevalence for myocardial infarction (MI) in the US is ~7.9 million. Although current therapies have significantly improved survival rate, adverse left ventricular (LV) remodeling still occurs in nearly 40% of MI patients. The size, composition, and mechanical properties of the scar that forms post-MI determines patient outcomes. Scar formation is mostly driven by inflammatory factors and fibroblast differentiation into myofibroblast. Suppression of inflammation and fibrosis, however, have led to unexpected results, including infarct expansion and LV wall thinning. Recently our lab uncovered that extracellular matrix (ECM) degradation post-MI releases collagen derived fragments that are biologically active. Using a synthesized peptide mimetic of one such fragment - p1158/59 - we found that p1158/59 dynamically interacts with fibroblasts regulating cell migration and the type and amount of collagen deposited post-MI. We hypothesize that p1158/59 binds to fibroblasts to delay or prevent myofibroblast differentiation, which promotes scar stabilization by controlled secretion of ECM and scar maturation. Fibroblasts were isolated from mice LV and incubated with vehicle or p1158/59 in serum free media. Complete media (10% FBS) and TGFb were used as positive controls respectively for migration and myofibroblast activation. We assessed fibroblast phenotype and ECM secretion. Mice were treated with p1158/59 post-MI and mid- and long-term LV remodeling and function assessed. p1158/59 promoted fibroblast migration to levels similar to positive control. Surprisingly, this was not accompanied by increased alpha smooth muscle actin (i.e. myofibroblast activation). Mice treated with p1158/59 for 7 days (D7) post-MI presented less collagen deposition with decreased LV dilation compared to controls. At D14 post-MI, p1158/59 repressed expression of pro-angiogenic factors and promoted fiber alignment and cellular apoptosis, which resulted in improved cardiac function, providing proof-of-concept that p1158/59 reduces adverse LV remodeling. These data suggest that p1158/59 modulates scar formation and remodeling post-MI by delaying or partially inhibiting fibroblast phenotype transition and promoting scar stabilization and maturation.

Predictors of Left Ventricular Remodeling After Myocardial Infarction in Patients With a Patent Infarct Related Coronary Artery After Percutaneous Coronary Intervention (from the Post-Myocardial Infarction Remodeling Prevention Therapy [PRomPT] Trial)

Left ventricular (LV) remodeling after myocardial infarction (MI) is a strong predictor of heart failure and mortality. The predictors of long-term remodeling after MI have been incompletely studied. We therefore examined the correlates of LV remodeling in patients with large ST-segment elevation myocardial infarction and a patent infarct artery after percutaneous 2coronary intervention (PCI) from the randomized Post-Myocardial Infarction Remodeling Prevention Therapy trial. Peri-infarct pacing had a neutral effect on long-term remodeling in patients with large first MI. The present analysis includes 109 patients in whom an open artery was restored after PCI, and in whom LV end-diastolic volume (LVEDV) at baseline and 18 months was assessed by transthoracic echocardiography. Multivariable models were fit to identify the independent predictors of LVEDV at baseline and 18 months. By multivariable analysis, male sex (p = 0.004) and anterior MI location (p = 0.03) were independently associated with baseline LVEDV. The following variables were independent predictors of increased LVEDV at 18 months: younger age (p = 0.01), male sex (p = 0.03), peak creatine phosphokinase (p = 0.03), shorter time from MI to baseline transthoracic echocardiography (p = 0.04), baseline LVEDV (p < 0.0001), and lack of statin use (p = 0.03). In conclusion, patients with large MI and an open infarct artery after PCI, anterior MI location, and male sex were associated with greater baseline LVEDV, but MI location was not associated with 18-month LVEDV. In contrast, younger age, peak creatine phosphokinase, male sex, baseline LVEDV, and lack of statin use were associated with long-term LV remodeling.

Pre-revascularization coronary wedge pressure as marker of adverse long-term left ventricular remodelling in patients with acute ST-segment elevation myocardial infarction

The aim of this study was to investigate the relationship between coronary wedge pressure (CWP), measured as a marker of pre-procedural microvascular obstruction, and left ventricular remodelling in high-risk ST-segment elevation myocardial infarction (STEMI) patients. Pre-revascularization CWP was measured in 25 patients with high-risk anterior STEMI. Left ventricular volumes and ejection fraction were echocardiographically measured at discharge and at follow-up. A 20% increase in left ventricular volumes was used to define remodelling. Patients with CWP ≤ 38 mmHg were characterized by late ventricular remodelling. Patients with CWP > 38 mmHg developed a progressive remodelling process which was associated with a significant 60 months increase in left ventricular volumes (P = 0.01 for end-systolic volume and 0.03 for end-diastolic volume) and a significant decrease in left ventricular ejection fraction (P = 0.05). A significant increase in both left ventricular end-systolic (P = 0.009) and end-diastolic volume (P = 0.02) from baseline to 60 months follow-up was recorded in patients with extracted thrombus length ≥2 mm. Pre-revascularization elevated CWP was associated with increased left ventricular volumes and decreased ejection fraction at long-term follow-up. CWP was a predictor of severe left ventricular enlargement, besides extracted thrombus quantity.

Evaluation on the impact of spontaneous reperfusion on cardiac muscle of acute myocardial infarction by three-dimensional speckle tracking imaging.

To explore the effect of spontaneous reperfusion (SR) on three-dimensional myocardial strain in patients with acute anterior myocardial infarction by three-dimensional speckle tracking imaging (3D-STI) technology. Patients diagnosed with acute anterior myocardial infarction during 2013 to 2016 were consecutively selected and divided into SR group and non-spontaneous reperfusion (Non-SR) group based on whether there was SR. Patients in both groups received direct percutaneous coronary intervention (PCI) in time window. Baseline information, patency rates of culprit vessel, durations of operation, intraoperative non-reflow phenomenon ratios, and thrombolysis in myocardial infarction (TIMI) blood flows after reperfusion of patients in each group were recorded. Hospital stays of patients were compared between the two groups. Before discharge, left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDd) were measured. Global longitudinal strain (GLS), global radial strain (GRS), and global circumferential strain (GCS) of left ventricular (LV) were also detected by 3D-STI, so as to assess movement situations of ventricular wall and cardiac muscle in occlusive blood vessel distribution area. LVEF, LVEDd and various 3D-STI parameters were reexamined and compared one year after discharge. There were no significant differences between the Non-SR group and the SR group regarding the patency rate of culprit vessel, duration of operation, intraoperative non-reflow phenomenon ratio, TIMI blood flow after reperfusion, and LVEDd (p>0.05). Both LVEF before discharge and LV three-dimensional strain indexes of the SR group, were clearly higher than those of the Non-SR group (p<0.05). After one-year follow-up, the SR group had a remarkably lower LVEDd than the Non-SR group (p<0.05). LVEF of the SR group was overtly higher than that of the Non-SR group (p<0.05). LV three-dimensional strain indexes were also distinctly higher in the SR group than in the Non-SR group (p<0.05). There were good correlations between GLS, GRS, GCS and LVEF (r values were -0.620, -0.674 and 0.723, respectively). SR can improve nosocomial and long-term LV remodeling in patients with acute anterior myocardial infarction, and 3D-STI is able to assess ventricular remodeling after myocardial infarction.

LB.03.01] LONG TERM CARDIAC STRUCTURE CORRELATES WITH ADVERSE PERINATAL COMPLICATIONS IN YOUNG ADULTS BORN PRETERM

Objective: Studies support a direct causal association between preterm birth and increased risk of cardiovascular diseases. Increased left and right ventricular mass and impaired systolic and diastolic function have been reported in young adults born preterm. Deleterious neonatal complications associated with preterm birth could significantly impact myocardial tissue. We assessed cardiac structure and function in young adults born extremely preterm (EPT) versus term and examined the impact of neonatal bronchopulmnonary dysplasia (BPD). Design and method: Eighty-five EPT (gestational age < 29 weeks) were recruited along with term-born controls matched for age, sex and socio-economic status. Birth data including neonatal parameters (gestational age, birth weight, BPD indicated by 36 weeks postnatal oxygen use) was collected. Ambulatory blood pressure (Spacelabs) and echocardiographic measurements (Phillips)were taken. Comparisons were performed using ANOVA or Student's t-test. Results: EPT presented with increased systolic (119 ± 9 vs 116 ± 8 mmHg, P < 0.05) and diastolic (68 ± 5 vs 66 ± 6 mmHg, P < 0.05) blood pressures. EPT exhibited reduced septal thickness (6.8 ± 0.8 vs 7.1 ± 1.1 mm, P < 0.05), left ventricular (LV) internal dimension (46 ± 4 vs 48 ± 5 mm, P < 0.05), LV end-diastolic (98 ± 20 vs 106 ± 24 ml/m2, P < 0.05) and end-systolic (36 ± 9 vs 40 ± 11 ml, P < 0.01) volumes, right ventricular internal dimension (22 ± 3 vs 24 ± 4 mm, P < 0.05), and LV mass (104 ± 27 vs 115 ± 30 g, P < 0.05), but similar LV mass index and volume indexes. EPT exhibited increased LV myocardial performance index (0.41 ± 0.04 vs 0.39 ± 0.04, P < 0.01), reduced mitral lateral e’ (17.6 ± 2.8 vs 19.1 ± 2.6 cm/s, P < 0.01), mitral s’ (10.7 ± 2.3 vs 11.6 ± 2.3 cm/s, P < 0.01), tricuspid E’ (15.8 ± 2.7 vs 16.8 ± 2.1 cm/s, P < 0.05), and tricuspid S’ (13.1 ± 2.0 vs 14.0 ± 2.0 cm/s, P < 0.01) waves, and a trend in reduced mitral E wave (81 ± 14 vs 85 ± 15 cm/s, P = 0.09). EPT with neonatal BPD exhibited greater reduction in septal thickness (6.5 ± 0.8 mm, P < 0.05 vs terms and EPT without BPD), LV internal dimension (45 ± 4 mm, P < 0.05 vs terms), LV Mass (98 ± 22 g, P < 0.05 vs terms), and trend in reduced LV mass index (59 ± 10 g, P = 0.13 vs terms using T-test). Conclusions: EPT exhibit cardiac structural and functional alterations compared to term-born individuals. Neonatal BPD in EPT is a key contributor to long-term left ventricular remodeling.

Long-term left ventricular remodelling after revascularisation for ST-segment elevation myocardial infarction as assessed by cardiac magnetic resonance imaging

ObjectiveLeft ventricular remodelling following a ST-segment elevated myocardial infarction (STEMI) is an adaptive response to maintain the cardiac output despite myocardial tissue loss. Limited studies have evaluated long term ventricular...

Integrative network analysis reveals time-dependent molecular events underlying left ventricular remodeling in post-myocardial infarction patients

To elucidate the time-resolved molecular events underlying the LV remodeling (LVR) process, we developed a large-scale network model that integrates the 24 molecular variables (plasma proteins and non-coding RNAs) collected in the REVE-2 study at four time points (baseline, 1month, 3months and 1year) after MI. The REVE-2 network model was built by extending the set of REVE-2 variables with their mechanistic context based on known molecular interactions (1310 nodes and 8639 edges). Changes in the molecular variables between the group of patients with high LVR (>20%) and low LVR (<20%) were used to identify active network modules within the clusters associated with progression of LVR, enabling assessment of time-resolved molecular changes. Although the majority of molecular changes occur at the baseline, two network modules specifically show an increasing number of active molecules throughout the post-MI follow up: one involved in muscle filament sliding, containing the major troponin forms and tropomyosin proteins, and the other associated with extracellular matrix disassembly, including matrix metalloproteinases, tissue inhibitors of metalloproteinases and laminin proteins. For the first time, integrative network analysis of molecular variables collected in REVE-2 patients with known molecular interactions allows insight into time-dependent mechanisms associated with LVR following MI, linking specific processes with LV structure alteration. In addition, the REVE-2 network model provides a shortlist of prioritized putative novel biomarker candidates for detection of LVR after MI event associated with a high risk of heart failure and is a valuable resource for further hypothesis generation.

Neutrophil extracellular traps in ischemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy.

Emerging evidence suggests a potential role of neutrophil extracellular traps (NETs) in linking sterile inflammation and thrombosis. We hypothesized that NETs would be induced during myocardial ischemia-reperfusion (I/R), and NET-mediated microthrombosis may contribute to myocardial "no-reflow". Male Wistar rats were randomly divided into I/R control, DNase (DNase I, 20 μg/rat), recombinant tissue-type plasminogen activator (rt-PA, 420 μg/rat), DNase + rt-PA, and sham control groups after 45-min myocardial ischemia. In situ NET formation, the anatomic "no re-flow" area, and infarct size were evaluated immediately after 3 h of reperfusion. Long-term left ventricular (LV) functional and histological analyses were performed 45 days after operation. Compared with the I/R controls, the DNase + rt-PA group exhibited reduced NET density [8.38 ± 1.98 vs. 26.86 ± 3.07 (per 200 × field), P < 0.001] and "no-flow" area (15.22 ± 0.06 vs. 34.6 ± 0.05%, P < 0.05) in the ischemic region, as well as reduced infarct size (38.39 ± 0.05 vs. 71.00 ± 0.03%, P < 0.001). Additionally, compared with the I/R controls, DNase + rt-PA treatment significantly ameliorated I/R injury-induced LV remodeling (LV ejection fraction: 64.22 ± 3.37 vs. 33.81 ± 2.98%, P < 0.05; LV maximal slope of the LV systolic pressure increment: 3,785 ± 216 vs. 2,596 ± 299 mmHg/s, P < 0.05). The beneficial effect was not observed in rats treated with DNase I or rt-PA alone. Our study provides evidence for the existence of NETs in I/R-challenged myocardium and confirms the long-term benefit of a novel DNase-based reperfusion strategy (DNase I + rt-PA), which might be a promising option for the treatment of myocardial I/R injury and coronary no-reflow.

Abstract 351: Nonlinear Dynamics in Long-Term Left Ventricular Remodeling in Chagas Heart Disease and Adverse Outcomes: SEARCH-Rio Substudy

Introduction: Left ventricular (LV) remodeling in Chagas heart disease (CHD) depends on the severity of the initial insult and may have clinical implication. SEARCH-Rio study investigated nonlinear dynamics in long-term LV remodeling in CHD. Methods: Fifty stable outpatients with CHD were enrolled and followed at scheduled visits. Cardiac death (sudden, arrhythmic or heart failure) was ascertained by review of medical records. LV dimension was assessed by echocardiogram, and mass estimated by Devereux. Subjects were distributed in four equally spaced groups according to initial mass. Intra-group standard deviation (SD) was calculated throughout follow-up. A plot of LV mass (corrected to initial value) vs recurrences during follow-up assessed non-linear relationship. Lyapunov exponent (LE) assessed LV mass dynamics during follow-up. Results: Median follow-up was 95 months; 10 subjects died. LV mass groups were [mean; Figure 1]: I-110g, II-140g, III-170g, IV-200g. No inter-group SD differences at baseline were observed (p=NS; table inset). At end of follow-up, intra-group SD increased roughly proportional to initial mean LV mass (Figure 1; p=0.01). A logistic parabolic-shaped equation was fit to corrected LV mass data in the plot (r²=0.98) and alpha coefficient was 3.9 (p&lt;0.01; Figure 2). In groups, median LE was: I: 0.22; II: 0.17; III: 0.22; IV: 0.15. Median LE was 0.7 for survivors and -0.45 for nonsurvivors. LE cutoff at 0.26 yielded 100% sensitivity and 88% specificity for cardiac death (AUC=0.89; p&lt;0.01). Conclusion: In CHD, LV remodeling exhibits complex nonlinear dynamics. LV remodeling dynamics has prognostic implication in this population.

Long-Term Left Ventricular Remodelling in Rat Model of Nonreperfused Myocardial Infarction: Sequential MR Imaging Using a 3T Clinical Scanner

Purpose. To evaluate whether 3T clinical MRI with a small-animal coil and gradient-echo (GE) sequence could be used to characterize long-term left ventricular remodelling (LVR) following nonreperfused myocardial infarction (MI) using semi-automatic segmentation software (SASS) in a rat model. Materials and Methods. 5 healthy rats were used to validate left ventricular mass (LVM) measured by MRI with postmortem values. 5 sham and 7 infarcted rats were scanned at 2 and 4 weeks after surgery to allow for functional and structural analysis of the heart. Measurements included ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), and LVM. Changes in different regions of the heart were quantified using wall thickness analyses. Results. LVM validation in healthy rats demonstrated high correlation between MR and postmortem values. Functional assessment at 4 weeks after MI revealed considerable reduction in EF, increases in ESV, EDV, and LVM, and contractile dysfunction in infarcted and noninfarcted regions. Conclusion. Clinical 3T MRI with a small animal coil and GE sequence generated images in a rat heart with adequate signal-to-noise ratio (SNR) for successful semiautomatic segmentation to accurately and rapidly evaluate long-term LVR after MI.

Cardioprotection of Insulin-Like Growth Factor-1 During Reperfusion Therapy

In the setting of acute myocardial infarction, reperfusion of ischemic myocardium carried out early after coronary occlusion can salvage reversibly injured, viable myocardium. Although still controversial, however, reperfusion itself may cause a population of reversibly injured cells to die, a phenomenon termed lethal reperfusion injury .1 A variety of pharmacological agents have been studied to limit ischemia/reperfusion injury as an adjunct to current reperfusion, and some beneficial effects have been demonstrated in experimental animal research, but their clinical applications have not been achieved.2–4 Article see p 327 Among the various agents claimed to have cardioprotective effects is insulin-like growth factor-1 (IGF-1), which is a hormone produced primarily by the liver. Its molecular structure is similar to that of insulin. IGF-1 plays an important role in cellular survival and growth by binding to its specific receptor (IGF1R), which is present on many cell types, including cardiac cells. Activation of IGF1R, a receptor tyrosine kinase, has been demonstrated to attenuate both apoptotic and necrotic cell death induced by ischemia/reperfusion injury through stimulating both the intracellular phosphoinositide 3-kinase/protein kinase B signaling pathway and extracellular signal-regulated kinase 1/2 signaling cascades.5 Buerke at al6 administered IGF-I 1 hour before ischemia in a murine model of 20 minutes of myocardial ischemia followed by 24 hours of reperfusion. IGF-I preserved ischemic/reperfused myocardium through inhibition of polymorphonuclear leukocyte-induced cardiac necrosis and inhibition of reperfusion-induced apoptosis of cardiac myocytes. Davani et al7 subjected isolated murine hearts to 20 minutes of global ischemia followed by 2 hours of reperfusion with either modified Kreb's solution alone or …

Relationship between infarct size and severity measured by gated SPECT and long-term left ventricular remodelling after acute myocardial infarction

After acute myocardial infarction (AMI), left ventricular (LV) remodelling may occur despite successful reperfusion. This study aimed to investigate by gated single photon emission computed tomography (SPECT) the long-term evolution of myocardial perfusion and LV function after AMI and to identify the predictors of LV remodelling. Sixty-eight AMI patients successfully treated by primary percutaneous coronary intervention underwent (99m)Tc-sestamibi gated SPECT at 1 month (baseline) and over 6-month follow-up after the acute event. LV remodelling was defined as 20% increase in LV end-diastolic volume at follow-up. At baseline, patients with remodelling (n = 14) showed larger (infarct size 29.3 ± 7.8%) and more transmural (infarct severity 0.28 ± 0.10) infarctions, and reduced LV ejection fraction (35.4 ± 5.6%), but similar LV volume indexes, compared to patients without remodelling (n = 54) (infarct size 20.8 ± 14.4%, p < 0.05, infarct severity 0.40 ± 0.11, p < 0.001, ejection fraction 44.5 ± 9.2, p < 0.001). At stepwise multivariate regression analysis, infarct severity showed the best predictive value for predicting LV remodelling (F = 5.54, p < 0.05). Using the thresholds identified by receiver-operating characteristic curve analysis, infarct size and severity detected patients with remodelling with 75% accuracy and 95% negative predictive value. Infarct resorption (defined as the defect size difference between follow-up and baseline) was comparable between patients with (-4.4 ± 8.4%) and without remodelling (-6.8 ± 9.4%) (p = NS). Perfusion parameters assessed by gated SPECT in the subacute phase after successfully treated AMI correlate with changes in functional parameters at long-term follow-up. Infarct severity is more effective than infarct size, but both are helpful for predicting LV remodelling.

Time course of infarct healing and left ventricular remodelling in patients with reperfused ST segment elevation myocardial infarction using comprehensive magnetic resonance imaging

To describe the time course of myocardial infarct (MI) healing and left ventricular (LV) remodelling and to assess factors predicting LV remodelling using cardiac MRI. In 58 successfully reperfused MI patients, MRI was performed at baseline, 4 months (4M), and 1 year (1Y) post MI RESULTS: Infarct size decreased between baseline and 4M (p < 0.001), but not at 1Y; i.e. 18 ± 11%, 12 ± 8%, 11 ± 6% of LV mass respectively; this was associated with LV mass reduction. Infarct and adjacent wall thinning was found at 4M, whereas significant remote wall thinning was measured at 1Y. LV end-diastolic and end-systolic volumes significantly increased at 1Y, p < 0.05 at 1Y vs. baseline and vs. 4M; this was associated with increased LV sphericity index. No regional or global LV functional improvement was found at follow-up. Baseline infarct size was the strongest predictor of adverse LV remodelling. Infarct healing, with shrinkage of infarcted myocardium and wall thinning, occurs early post-MI as reflected by loss in LV mass and adjacent myocardial remodelling. Longer follow-up demonstrates ongoing remote myocardial and ventricular remodelling. Infarct size at baseline predicts long-term LV remodelling and represents an important parameter for tailoring future post-MI pharmacological therapies designed to prevent heart failure.

ASYMPTOMATIC LEFT VENTRICULAR DIASTOLIC DYSFUNCTION AND RISK OF DEATH IN THE COMMUNITY

LV to untwist in diastole is dependent on systolic twist. We hypothesise that patients with heart failure and normal ejection fraction (HFNEF) have reduced LV untwist to facilitate rapid early diastolic filling particularly during exercise thus symptoms of exertional dyspnoea. Methods: 34 clinically diagnosed HFNEF patients with proven cardiac limitation (72± 7 years, 23 females, LVEF 60± 7%, VO2max 17.9± 3.0ml/(min kg)) and 23 agematched healthy controls (70± 8 years, 15 females, LVEF 63± 8%, VO2max 30.9± 4.6ml/(min kg)) were recruited. Rest and submaximal supine exercise echocardiography were performed to comparable heart rate and blood pressure. Apical rotation and untwist were studied by speckle tracking. The mitral flow propagation velocity (Vp) was derived from colour M-mode Doppler. Results: LV apical systolic rotation and early diastolic untwist are significantly less at rest and on exercise in patients. Vp at rest is comparable between the two groups. However, the increase in Vp on exercise is significantly less in patients hence Vp is significantly lower than controls. LV early untwist correlates significantly with the increase in Vp (r= 0.43, p= 0.005) and VO2max (r= 0.526, p= 0.007). Exercise Vp also correlates with VO2max (r= 0.347, p= 0.03). Patients Controls p-Value Rotation rest (◦) 10.7 ± 4.1 13.9 ± 3.2 0.002 Rotation exercise (◦) 13.5 ± 4.8 17.6 ± 4.0 0.006 Untwist rest (◦) 24.3 ± 9.4 30.9 ± 9.7 0.013 Untwist exercise (◦) 22.1 ± 8.9 29.5 ± 7.8 0.008 Vp rest (m/s) 40.2 ± 10.8 39.8 ± 7.3 0.875 Vp exercise (m/s) 52.6 ± 12.0 62.4 ± 13.8 0.012 Conclusion: LV rotation and untwist mechanics are impaired in HFNEF. This is associated with reduced LV suction in early diastole and reduced exercise tolerance. The efficiency of LV rotation and untwist is crucial to aid rapid early diastolic filling particularly on exercise when heart rate is increased and diastole shortens. doi:10.1016/j.hlc.2009.03.042 Tuesday Young Investigators ASYMPTOMATIC LEFT VENTRICULAR DIASTOLIC DYSFUNCTION AND RISK OF DEATH IN THE COMMUNITY Walter Abhayaratna, Katrina Hayes, Christine O’Reilly, Satoru Sakuragi, Niels Becker Australian National University, Canberra, ACT, Australia Background: There is limited information regarding the risk of death in asymptomatic individuals with left ventricular (LV) diastolic dysfunction (LVDD) and ejection fraction (EF) >50%. In this population-based study, we assessed mortality rates of subjects with LVDD without a history or clinical evidence of congestive heart failure. Methods and results:Weassessed diastolic function using comprehensive Doppler echocardiography in 1275 Canberra Heart Study participants (mean age 69 years; 50% men). Diastolic dysfunction was classified as mild or advanced (with elevated LV filling pressure). Prevalence rates of mild and advanced preclinical LVDD were 26% and 7.5% in women, respectively; and 24% and 6.9% in men, respectively. During a mean follow-up of 4.8 years, there were 61 deaths in preclinical subjects with EF> 50%. Death rates among individuals with normal LV diastolic function and mild LVDD were similar (0.8 vs. 1.1 per 100 person-years, respectively; p= 0.24). However, the rate of death among those with advanced LVDD (3.0 per 100 person-years)was higherwhen compared to subjectswith normal diastolic function and mild LVDD (p< 0.01 for both). After adjustment for age, sex, EF and cardiovascular risk factors, preclinical advanced LVDDwas associated with an increased mortality risk (adjusted Hazards Ratio 2.2, CI 1.1–4.2). Conclusion: Community-based adults with preclinical LVDD are at increased risk of death only when the condition is advanced and is associatedwith increased LVfilling pressures. doi:10.1016/j.hlc.2009.03.043 LEFT VENTRICULAR DYSSYNCHRONY EARLY AFTER NON-ST ELEVATION MYOCARDIAL INFARCTION INDEPENDENTLY PREDICTED LONG-TERM LEFT VENTRICULAR REMODELLING A. Ng, J. Vidiac, D.Y. Leung Liverpool Hospital, Sydney, NSW, Australia We evaluated the prognostic significance of LV dyssynchrony early after non-ST elevation myocardial infarction (NSTEMI). Methods: LV dyssynchrony was measured as standard deviation of times to 12 regional peak Smvelocities (SDTs) in 100 NSTEMI patients (age 60.0± 11.8 years, 71 men) prior to angiography, at 6 and 12 months. Significant dyssynchrony was defined as SDTs≥ 32.6ms. Results: LV end-diastolic volume (EDV) index decreased with time (47.1± 14.2mL/m2 vs. 46.4± 13.6mL/m2 vs. 43.1± 12.8mL/m2, p< 0.001) and was independently predicted by lower number of diseased vessels (p= 0.001) and revascularization (p= 0.041). LV end-systolic volume (ESV)