Post Infarction Research Articles

Carotid body ablation improves survival, breathing disorders and autonomic control in heart failure rats

Sympathetic hyperactivity and breathing instability contribute to decompensation during chronic heart failure (CHF). Enhanced carotid body (CB) chemoreflex drive has been related to increased sympathetic outflow and breathing disorders in CHF. We hypothesized that ablation of CB afferents (CBA) improves cardiorespiratory function and survival in CHF. Selective CBA was performed on male Sprague‐Dawley rats after 16 weeks (wk) of coronary artery ligation (EF < 45%). Resting breathing and ventilatory responses to acute hypoxia (FiO2‐10%) were measured by plethysmography prior to and one wk after CBA/sham surgery. Heart rate (HRV) and systolic blood pressure variability (BPV) and spontaneous baroreflex gain (BG) were similarly determined at rest. Neuronal activation was assessed in the rostral ventrolateral medulla (RVLM) at the end of the study using Fra‐1 expression. CHF rats compared to sham exhibited elevated apnea incidence, hypoxic ventilatory responses, LF/HF HRV, LF‐BPV, and RVLM Fra‐1 expression and decreased BG. CBA in CHF rats decreased (pre‐ vs. post‐CBA, P < .05), LF/HF HRV (2.1±0.3 vs. 0.9±0.2), LF‐BPV (18.4±4.5 vs. 7.2±2.0 mmHg2), apnea frequency (16.8±1.8 vs. 10.6±0.6 events/h), RVLM Fra‐1 expression (1.5±0.1 vs. 0.9±0.1 a.u.), and increased BG (1.0±0.1 vs. 1.9±0.3 ms/mmHg) to levels comparable to sham rats. Mortality rate at 16 wk post infarct was elevated in CHF compared to sham (33% vs. 7%). CBA at 2 wk post infarct reduced the mortality rate in CHF rats at 16 wk to 15%. Our results show that CBA reduces hyperactivation of the RVLM and improves cardiorespiratory control and survival in CHF rats. Supported by NIH PO1‐HL62222.

Ventricular septal plication for post infarction anterior and anterior-septal aneurysm of the left ventricle

To determine the use of septal plication with Dor or Cooley procedure for post infarction anterior and anterior-septal aneurysm of the left ventricle. A total of 23 patients with post infarction anterior and anterior-septal aneurysm of the left ventricle underwent septal plication and Dor or Cooley procedure along with coronary artery bypass grafting concomitantly. Data of NYHA grading, left ventricular end diastolic volume index (LVEDVI), left ventricular end systolic volume index (LVESVI) and left ventricular ejection fraction (LVEF) were recorded before the surgery, before discharge and 3 months after the surgery. Compared with the preoperative data, the NYHA grading before the discharge and 3 months after the surgery improved from 3.21 ± 0.62 to 1.72 ± 0.31 and 1.57 ± 0.23(P<0.05); LVEDVI decreased from (102.31 ± 18.71) mL/m² to (62.11 ± 6.21) mL/m² and (54.63 ± 4.54) mL/m² (P<0.05); LVESVI decreased from (69.32 ± 17.48) mL/m² to (30.23 ± 3.25)mL/m² and (28.34 ± 3.12) mL/m²; while LVEF increased from (32.92 ± 8.12)% to (48.78 ± 4.51)% and (50.52 ± 4.68)% (P<0.05), respectively. Ventricular septal plication combined with Dor or Cooley procedure can remarkably improve the left heart function in patients with post infarction ventricular aneurysm.

MiRNA Overexpression Induces Cardiomyocyte Proliferation In Vivo

Many millions of muscle cells in the heart are lost following a heart attack (myocardial infarction), and replacing or regenerating these cells is of fundamental importance for the long-term recovery of heart function. Therefore, any strategy that induces proliferation of adult cardiomyocytes in the region damaged by ischemic injury is of great interest in regenerative medicine. A major hurdle for replenishing damaged myocardium is that adult mammalian cardiomyocytes, unlike those of zebrafish, have a very limited proliferative capacity.1,2 Indeed, a recent landmark study showed that the mouse heart loses the capacity to regenerate sufficient cells to recover from a myocardial infarction just a few days after birth.3 It is therefore very important to understand why the hearts of zebrafish and those of very young mice can completely regenerate after an infarction whereas those of the adult human heart cannot and instead form a scar that leads to compromised myocardial function. In a recent issue of Nature,4 Eulalio and colleagues shed some light on this issue by identifying a number of microRNA (miRNA) species that have the capacity to induce cardiomyocyte cell proliferation and improve heart function following myocardial infarction in rodents.

Comparison of cyclic RGD peptides for αvβ3 integrin detection in a rat model of myocardial infarction

BackgroundExpression of αvβ3 integrin is increased after myocardial infarction as part of the repair process. Increased expression of αvβ3 has been shown by molecular imaging with 18F-galacto-RGD in a rat model. The 68Ga-labelled RGD compounds 68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 have high specificity and affinity, and may therefore serve as alternatives of 18F-galacto-RGD for integrin imaging.MethodsLeft coronary artery ligation was performed in rats. After 1 week, rats were imaged with [13N]NH3, followed by 18F-galacto-RGD, 68Ga-NODAGA-RGD or 68Ga-TRAP(RGD)3 using a dedicated animal PET/CT device. Rats were killed, and the activity in tissues was measured by gamma counting. The heart was sectioned for autoradiography and histology. Immunohistochemistry was performed on consecutive sections using CD31 for the endothelial cells and CD61 for β3 expression (as part of the αvβ3 receptor).ResultsIn vivo imaging showed focal RGD uptake in the hypoperfused area of infarcted myocardium as defined with [13N]NH3 scan. In autoradiography images, augmented uptake of all RGD tracers was observed within the infarct area as verified by the HE staining. The tracer uptake ratios (infarct vs. remote) were 4.7 ± 0.8 for 18F-galacto-RGD, 5.2 ± 0.8 for 68Ga-NODAGA-RGD, and 4.1 ± 0.7 for 68Ga-TRAP(RGD)3. The 68Ga-NODAGA-RGD ratio was higher compared to 68Ga-TRAP(RGD)3 (p = 0.04), but neither of the 68Ga tracers differed from 18F-galacto-RGD (p > 0.05). The area of augmented 68Ga-RGD uptake was associated with β3 integrin expression (CD61).Conclusion68Ga-NODAGA-RGD and 68Ga-TRAP(RGD)3 uptake was equally increased in the infarct area at 1 week post infarction as 18F-galacto-RGD. These results show the potential of 68Ga-labelled RGD peptides to monitor integrin expression as a part of myocardial repair and angiogenesis after ischaemic injury in vivo.

Microvascular obstruction is associated with greater infarct heterogeneity

Methods 21 patients post primary percutaneous coronary intervention for acute ST elevation myocardial infarction were prospectively enrolled and each had 3 MRI scans on a 1.5T GE Signa Excite scanner at 48 hours, 3 weeks and 6 months post infarction. A T1-weighted IR-GRE sequence was used for late gadolinium enhancement assessment of infarcted myocardium. Core infarct size (CIS) and gray zone (GZ) volumes were quantified using the full width at half-maximum technique and were expressed in grams. Repeated Measures Analysis of Variance was used to assess for changes in CIS and GZ evolution over the three time frames. Data is presented as means ± standard deviation at the 48 hour, 3 week and 6 month time frames respectively.

Postinfarction Ventricular Septal Rupture – A Rare Complication Remains Challenge for Cardiac Surgical Team

The incidence of post infarction ventricular septal rupture (PIVSR) is decreasing in the last years due to aggressive treatment of myocardial infarction with early percutaneous coronary interventions. As a consequence patients with PIVSR are referred to surgery more often with significant heart failure. The aim of this retrospective study was to assess the influence of these on the operative results and to identify the risk factors of operative mortality. A retrospective analysis of prospectively collected data of patients with the PIVSR admitted to our center from November 2004 to February 2012 was performed. Variables were analyzed using two-dimensional correspondence analysis. There were 25 patients (12 males and 13 females) with mean age 70.2 years (47-82) operated on; 17 (68%) presented with anterior and 8 (32%) with posterior PIVSR. Eighteen patients (72%) had acute heart failure, 13 (52%) presented with cardiogenic shock. Before surgery, intraaortic balloon pump (IABP) had 20 (80%) patients; in 4 (16%) a ventricular assist device was used, either Extracorporeal Membrane Oxygenation (ECMO) or centrifugal pumps as biventricular assist. Operative mortality was 40% (10 pts.). Four patients (12%) had small non-significant recurrent shunt on postoperative echocardiography. Although majority of patients with PIVSR have significant heart failure prior to surgery the operative mortality remains comparable to older studies. Predictors of perioperative death were concomitant surgical reconstruction of the left ventricle, renal impairment before operation, male gender, history of coronary artery disease, PIVSR location posterior, and shock at surgery.

Assessing Safety of CABG in the Era Post Primary PCI, an Outcome Analysis of STEMI Population

Background: Primary PCI (PPCI) has replaced thrombolysis as the treatment of choice for STEMI. The effect of this change on outcomes of patients referred for subsequent CABG is unknown. Methods: All STEMI patients having thrombolysis or PPCI between 2000 and 2010 were identified. Of these, patients subsequently referred for isolated first time CABG form the cohort for this study. Results: 83 of 2476 (3.4%) patients from the PPCI cohort (median follow-up [FU] 3 years [range 6 m - 7.8 y]) and 49 of 528 (9.2%) from the thrombolysis cohort (median FU 9 y [range 1.5 - 10 y] were referred for subsequent CABG. In this referred group, initial reperfusion success (as defined) was: PPCI = 86%, lysis = 84%, p = 0.69. Surgical waiters with prior PPCI had less post infarct angina (1.2% vs. 25%, p 0.01) and late re-infarction (6% vs. 20%, p = 0.034) prior to surgery. Timing of CABG was: 6 m (PPCI 82%, lysis 73%), 6 m-1 y (PPCI 8.4%, lysis: 9%), >1 y (PPCI 9.6%, lysis 18%).Other than an increased prevalence of diabetes in the thrombolysis group, there were no differences in demographic details or risk profile. There were no post-operative deaths, MIs or CVAs. There were no significant differences in post-op AF (28% vs. 22% p = 0.5), respiratory failure (8% vs. 18%, p = 0.08), renal failure (5% vs. 6%, p = 0.5) or re-openings (0% vs. 6%, p = 0.8). Mortality at 3 years was 2.4% in the PPCI cohort and 4% in the thrombolysis cohort. Overall mortality during follow-up for the PPCI group was 3.6% (n = 3) (median FU 3 years), and for the lysis group was 24.5% (n = 12) (median FU 9 years). Conclusions: In patients awaiting CABG after STEMI, PPCI reduces the risk of post-infarct angina and re-infarction prior to surgery, but early surgical results were equally favorable in both groups. Additional follow-up is needed in the PPCI cohort to determine whether there are any significantly different longer-term outcomes.

Resveratrol Reverses Remodeling in Hearts with Large, Old Myocardial Infarctions through Enhanced Autophagy-Activating AMP Kinase Pathway

We investigated the effect of resveratrol, a popular natural polyphenolic compound with antioxidant and proautophagic actions, on postinfarction heart failure. Myocardial infarction was induced in mice by left coronary artery ligation. Four weeks postinfarction, when heart failure was established, the surviving mice were started on 2-week treatments with one of the following: vehicle, low- or high-dose resveratrol (5 or 50 mg/kg/day, respectively), chloroquine (an autophagy inhibitor), or high-dose resveratrol plus chloroquine. High-dose resveratrol partially reversed left ventricular dilation (reverse remodeling) and significantly improved cardiac function. Autophagy was augmented in those hearts, as indicated by up-regulation of myocardial microtubule-associated protein-1 light chain 3-II, ATP content, and autophagic vacuoles. The activities of AMP-activated protein kinase and silent information regulator-1 were enhanced in hearts treated with resveratrol, whereas Akt activity and manganese superoxide dismutase expression were unchanged, and the activities of mammalian target of rapamycin and p70 S6 kinase were suppressed. Chloroquine elicited opposite results, including exacerbation of cardiac remodeling associated with a reduction in autophagic activity. When resveratrol and chloroquine were administered together, the effects offset one another. In vitro, compound C (AMP-activated protein kinase inhibitor) suppressed resveratrol-induced autophagy in cardiomyocytes, but did not affect the events evoked by chloroquine. In conclusion, resveratrol is a beneficial pharmacological tool that augments autophagy to bring about reverse remodeling in the postinfarction heart.

Abstract 18934: Inhibition of Wnt6 by Sfrp2 Regulates CPC Differentiation by Differential Modulation of Canonical and Non Canonical Wnt Pathways

Introduction: We have previously shown that in vivo administration of Sfrp2, an inhibitor of canonical Wnt signaling, into injured myocardium enhanced cardiac regeneration. In vitro, Sfrp2 selectively bound to Wnt6 expressed in cardiac progenitor cells (CPCs) and induced cell cycle arrest and cardiac differentiation. Here, we explore the role of Wnt6 inhibition by Sfrp2 in modulating Wnt pathways and regulation of CPC proliferation and differentiation. We also employ lineage tracing to investigate the contribution of CPCs to the in vivo effects of Sfrp2. Methods: Sca1+ CPCs were established and treated with recombinant Sfrp2 or Wnt6. Wnt pathway activation was measured by Western blotting. Proliferation was assessed by BrdU. Differentiation was documented by Nkx2.5 and Gata4 staining. Recombinant Sfrp2 protein was injected in Sca1-eGFP mice after ischemia/reperfusion injury. Co-staining of GFP with cardiac markers was assessed by confocal microscopy. Cardiac function was evaluated by echocardiography. Results: Treatment with Wnt6 increased canonical Wnt signaling and induced a 3.9 ± 0.9 fold increase in CPC proliferation. Simultaneous addition of Sfrp2 abolished the effects of Wnt6. Sfrp2 treatment alone inhibited canonical and activated non canonical Wnt signaling through β-catenin and JNK, respectively. JNK inhibitor SP600125 repressed Sfrp2 induced differentiation. To further explore the dual role of Sfrp2 in regulating Wnt signaling, CPCs modified to express constitutive active β-catenin (CA-CPCs) were treated with Sfrp2 and found to be resistant to both cell cycle arrest and differentiation. Interestingly, Sfrp2 treatment of CA-CPCs did not result in JNK activation suggesting Sfrp2 regulates JNK indirectly. Preliminary in vivo data indicate that exogenous Sfrp2 increased CPC differentiation and restored fractional shortening and contractility 2 months post infarction. Conclusion: Inhibition of Wnt6 by Sfrp2 differentially regulates canonical and non canonical Wnt pathways in CPCs, permitting further lineage commitment towards cardiomyocytes. Along with its cytoprotective and antifibrotic effects, Sfrp2 enhances cardiac regeneration in vivo thus highlighting its value as a potential therapeutic agent for cardiac disease.

Abstract 9633: Human Blood and Cardiac Stem Cells Synergize to Enhance Cardiac Repair When Co-transplanted Into Ischemic Myocardium

Blood-derived circulatory angiogenic cells (CACs) and resident cardiac stem cells (CSCs) have both been shown to improve cardiac function after myocardial infarction (MI). However, whether one cell type is superior has long been an area of speculation with no head-to-head trial. In this study, we compared the effect of human CACs and CSCs, alone or in combination, on myocardial function in an immunodeficient mouse model of MI. Methods and Results- CACs and CSCs were cultured from left atrial appendages and blood samples obtained from patients undergoing clinically-indicated heart surgery. In hypoxic culture conditions designed to mirror ischemic myocardium, protein arrays demonstrated that CACs expressed a broader cytokine profile than CSCs (36 vs. 5, respectively; p&lt;0.05) with 3 cytokines in common. Co-culture of CACs and CSCs further enhanced the production of stromal cell derived factor-1α and vascular endothelial growth factor (p&lt;0.05). Conditioned media promoted equivalent vascular networks and endothelial progenitors recruitment with superior effects using co-cultured conditioned media (p&lt;0.05 vs. single cell cultures). Intramyocardial injection of CACs or CSCs alone improved left ventricular ejection fraction (LVEF) when injected one week after MI (p&lt;0.05 vs. vehicle (PBS) or normal human dermal fibroblasts (NHDF); Figure). Co-transplantation of CACs and CSCs together improved LVEF to a greater extent than either stem cell therapy alone (p&lt;0.05 vs. CAC or CSC injection alone). Conclusions- CACs and CSCs provide unique paracrine repertoires with equivalent effects on angiogenesis, stem cell migration and myocardial repair. Combination therapy with both cell types synergistically improves post infarct myocardial function greater than either therapy alone. This synergy is likely mediated by the complimentary paracrine signatures that promote revascularization and the growth of new myocardium.

366 Abrogation of S100B Expression in S100A1 Deficient Mice Improves Survival Post Myocardial Infarction

Post-myocardial infarction (MI) ventricular remodeling involves ventricular dilation, hypertrophy of non-infarcted myocardium, myocyte apoptosis, the induction of S100B and the downregulation of S100A1. Whereas S100A1 deficiency results in cardiac functional impairment and high early mortality post-MI, abrogation of S100B preserves cardiac function in the setting of augmented hypertrophy post-MI. To assess the consequences of S100B expression in S100A1 knock out (KO) mice, wild-type (WT), S100A1 KO, S100B KO and S100A1-B KO 6-8 week-old mice were subjected to 35 days after left anterior descending coronary artery ligation with similar age-matched sham-operated controls. S100A1-B KO mice demonstrated better survival as compared to S100A1 KO and WT mice (79.5% vs. 28.6% vs. 69.7 % respectively, p<0.05), comparable to S100B KO mice (82.6%). Most of the deaths in S100A1 KO mice occurred 3-6 days following MI. Acute hemodynamic monitoring post-MI demonstrated that the S100A1 KO animals died of rapidly of progressive pump failure. At day 2 post-MI, S100A1 KO mice demonstrated S100B expression, increased left ventricular dilatation by echocardiography, less collagen I and III mRNAs within the infarct area, an increase in MMP-9 expression and apoptosis (as assessed by Caspase-3 activity and TUNEL staining) in the infarct border zone of versus WT. Among survivors at day 35, post mortem examination indicated that the WT and KO groups of infarcted mice mounted a hypertrophic response that was augmented in the S100B KO and S100A1-B KO groups (WT 3.95±0.21; S100A1 KO 4.05±0.13; S100B KO 4.39±0.18; S100A1-B KO 4.71±0.21 mg/g Body Weight, p<0.05 S100A1-B KO vs. S100A1 KO). The augmented hypertrophic response in the S100B KO and S100A1-B KO groups was associated with less apoptosis (as assessed by Caspase-3 activity) compared to the WT and S100A1 KO mice (WT 52.5±5.4; S100A1-KO 58.6±6.9; S100B KO 41.6±3.7; S100A1-B KO-43.8±3.5 µmol/mL, p<0.05 S100A1-B KO vs. S100A1 KO). The post infarct left ventricular end diastolic pressure was lower in S100A1-B KO and S100B KO mice compared to WT and S100A KO mice (S100A1-B KO 6.1±0.4 vs. S100A1KO 12.1±1.9 mmHg, p<0.05). Our results suggest that the abrogation of S100B expression in S100A1-B KO mice augmented hypertrophy, decreased apoptosis, preserved extracellular matrix proteins and was beneficial to the preservation of cardiac function and survival within this time frame.

Abstract 105: The Therapeutic Efficacy of Embryonic Stem Cell-Derived Exosomes for Postinfarction Myocardial Repair and Regeneration

Although embryonic stem cells (ESCs) hold great promise for regeneration of the heart post myocardial infarction (MI) due to their pluripotent potential, it is this same potential that poses risk for the formation of teratomas. Lately there have been reports that exosomes, 30-100nm membrane bound vesicles, are not simply used by the cell to exocytose unwanted material, but contain intact protein, mRNA, and miRNA important for intercellular communication. Here we hypothesize that ESC derived exosomes can be used to exploit an already established mechanism to shuttle ESC content intercellularly in a cell free system for physiological and anatomical repair of the myocardium following acute myocardial infarction. To test our hypothesis exosomes were isolated by ultracentrifugation from equal numbers of murine ESCs or primary embryonic fibroblasts (MEFs). ESC exosomes had intact pluripotent transcripts similar to their parent cells in contrast the MEF exosomes. Using a double blinded acute myocardial infarction model, immediately after permanent ligation of the coronary artery, mice were injected with saline, ESC exosomes, or MEF exosomes at 3 locations in the border-zone of the left ventricle (LV). To assess the functional recovery of the LV, echocardiographical analysis was performed at Day 7, 14, and 28 following the AMI. Mice were sacrificed at D28 for histological assessments. LV fractional shortening, ejection fraction, and end systolic diameter measurements demonstrate that mice treated with ESC exosomes have improved LV function compared to mice treated with control MEF exosomes or saline alone (P&lt;.05 for all functional parameters). Mice treated with ESC exosomes show less infarct size and apoptosis, greater capillary density, and greater cycling of both cardiomyocytes and ckit+ stem cells. Taken together, these data demonstrate a novel cell free system in which ESC exosomes can exploit regenerative capabilities of ESCs while bypassing the risk of teratoma formation and hold great promise for cardiovascular regenerative medicine.

Atrial Fibrillation in Acute Coronary Syndrome.

Atrial fibrillation (AF) is a common cardiac arrhythmia occurring in an estimated 2.7 to 6.1 million people in the United States. The risk factors for the development of AF are very similar to those for developing coronary artery disease, and AF is often associated with acute coronary syndrome (ACS) and acute myocardial infarction (MI). Overall, AF complicates approximately 10% of acute infarcts and the incidence rate is comparable between the thrombolytic and percutaneous coronary intervention (PCI) eras. Prior to widespread use of thrombolysis, the incidence of AF during acute MI was as high as 18%. Moreover, AF is a marker for increased long term mortality post infarct. Over the past 20 years, the relative mortality risk for patients with AF post MI has remained around 2.5 times that for patients without AF. The treatment of AF in the setting of MI and ACS is similar to without; however there is often an increased urgency to limiting rapid heart rates which may exacerbate acute ischemia. Cardioversion and IV amiodarone may be utilized more liberally in this setting than otherwise. Anticoagulation is usually required both for the treatment of MI and possible PCI, as well as for cerebral vascular accident prevention from AF-induced thromboembolism. Often patients require triple-therapy for optimal treatment of both conditions, and special considerations for bleeding risk must be analyzed.

Early and late results of entire septal patch technique for post infarction ventricular septal rupture

Surgical results for post-infarction ventricular septal rupture (VSR) remain poor, even today. The aim of this study was the establishment and clinical evaluation of a simple, standardized septal patch technique for this disease. From 1999 to 2011, 16 consecutive patients with a mean age of 73.1±10.1 (range 55-89) underwent emergency repair of VSR following anterior myocardial infarction. Entire septal patch technique, in which a large pericardial patch is fixed reciprocally between transmural sutures placed in the posterior free wall adjacent to the ventricular septum and anterior left ventriculotomy closing sutures, thus almost entirely covering the septal wall, was used in all cases. Mean interval between the onset of septal rupture and surgery was 1.3±0.6(range 1-3)days. Eight patients presented cardiogenic shock and 14 patients underwent preoperative intra-aortic balloon pumping. Average operation, cardiopulmonary bypass, and aortic clamp time were 233±71(145-360), 128±51(82-240), and 46±15(29-76)min, respectively. Coronary artery bypass grafting was performed concomitantly in five cases. Average intra-operative blood loss was 340±184(123-740)g. Thirty-day mortality was 0%, and in-hospital mortality was 13.3% (2/16). Significant residual shunt occurred in one patient. All hospital survivors were followed up with a mean period of 44.5±40(5-131)months. Five-year survival of all operated patients was 69±14%. Entire septal patch technique proved to be an easily reproducible method for anterior VSR that demonstrated stable early and late results.

Prostaglandin E2 in Remote Control of Myocardial Remodeling

Prostaglandin E2 in Remote Control of Myocardial Remodeling

125 Monocyte subpopulation counts and functional characteristics predict adverse clinical events post ST elevation myocardial infarction

BackgroundMonocytes are implicated in the initiation of the atherosclerotic plaque through to plaque instability and rupture during presentation with an acute coronary syndrome (ACS). Little is known about the predictive...

Cell Therapy Limits Myofibroblast Differentiation and Structural Cardiac Remodeling

Background— Experimental cell therapy attenuates maladaptive cardiac remodeling and improves heart function. Paracrine mechanisms have been proposed. The effect of cell therapy on post infarction cardiac fibroblast and extracellular matrix (ECM) regulation was examined. Methods and Results— Vascular smooth muscle cells (VSMC) were injected into the border zone of subacute infarcted syngeneic Fischer rat hearts and compared with medium-injected controls. Twelve weeks post injection, cell-treated hearts showed preserved ECM content and attenuated structural chamber remodeling. Myofibroblast activation (α-smooth muscle actin expression) was decreased significantly, while basic fibroblast growth factor (bFGF) expression, a known inhibitor of transforming growth factor β-1–induced fibroblast differentiation, was increased. Matrix metalloproteinase-2 expression and activation by gelatin zymography was unchanged between groups, while its endogenous inhibitor, tissue inhibitors of matrix metalloproteinase (TIMP)-2, showed both increased expression and enhanced inhibitory capacity in cell-treated hearts. To define paracrine mechanisms, in vitro effects of VSMC conditioned media on myofibroblast activation were assessed by 3-D collagen gel contraction assay. VSMC conditioned media significantly inhibited collagen contraction, while a specific bFGF inhibitor abolished this paracrine response. TIMP-2 induced collagen contraction, but the effect was suppressed in the presence of bFGF. Conclusions— Extracellular matrix dysregulation post myocardial infarction is improved by cell therapy. These data suggest that cell transplantation attenuates myofibroblast activation and subsequent maladaptive structural chamber remodeling through paracrine mechanisms involving bFGF and TIMP-2.

116 Matrix metalloproteinase inhibition attenuates reperfusion injury, independently of and additive to mitochondrial permeability transition pore inhibition

While matrix-metalloproteinase (MMP) inhibitors appear to protect against myocardial ischaemia/reperfusion injury, the mechanisms are poorly understood. We hypothesised that cardioprotection resultant from MMP inhibition is independent of mitochondrial permeability transition...

Hybrid closure of postinfarction ventricular septal rupture enlargement after transcathether closure with Amplatzer occluder

Ventricular septal rupture (VSR) is nowadays a rare complication of myocardial infarction (MI), but with a mortality rate still very high. Urgent surgical correction is recommended, although in specific cases percutaneous closure of a post-infarct VSR is a therapeutic option or a bridge to surgical correction. We report a case of an 80-year-old woman, with a subacute anterior MI with an antero-septal VSR. Rapid clinical deterioration in a high-surgical-risk patient led us to attempt percutaneous VSR closure at day 8 post MI. A 16-mm Amplatzer post-infarction (PI) muscular VSD closed the defect with intra-cardiac echocardiography guidance, that allowed conscious sedation. Clinical and haemodynamic improvement was immediate. Unfortunately, a small orifice distal to the device persisted, which enlarged to 8 mm over the following days, with a Qp/Qs shunt of 1.9. At day 17 post MI, the VSR was surgically closed by suturing the Amplatzer device to the septum. A residual shunt was evident, but with no progression, being the patient discharged in NYHA class I. Percutaneous closure of a post-MI VSR as a bridge to surgery is a therapeutic option in patients with high surgical risk, allowing haemodynamic stabilization and thus gaining time for a further surgical intervention if needed, improving these patients grim prognosis. Intra-cardiac echocardiography for monitoring the percutaneous procedure instead of a transoesophageal approach, as well as the surgical technique, make this case unique.

OP-209 THE EFFECT OF INCREMENTAL ENDURANCE EXERCISE TRAINING ON LEFT VENTRICULAR MECHANICS

Objective: A 35-years-old male patient presented with post anterior myocardial infarction angina. Coronary angiography revealed tight ostio-proximal stenosis of the left anterior descending (LAD) coronary artery, plus bilateral coronary artery fistulas, one originating from the proximal segment of LAD and the other from the proximal segment of circumflex coronary artery. Both fistulas form a network of vessels draining into the pulmonary artery trunk. Successful surgical management was undertaken. Methods: A 35-years-old male patient presented with post anterior myocardial infarction angina. Coronary angiography revealed tight ostio-proximal stenosis of the left anterior descending (LAD) coronary artery, plus bilateral coronary artery fistulas, one originating from the proximal segment of LAD and the other from the proximal segment of circumflex coronary artery. Both fistulas form a network of vessels draining into the pulmonary artery trunk. Successful surgical management was undertaken. Results: A 35-years-old male patient presented with post anterior myocardial infarction angina. Coronary angiography revealed tight ostio-proximal stenosis of the left anterior descending (LAD) coronary artery, plus bilateral coronary artery fistulas, one originating from the proximal segment of LAD and the other from the proximal segment of circumflex coronary artery. Both fistulas form a network of vessels draining into the pulmonary artery trunk. Successful surgical management was undertaken. Conclusions: A 35-years-old male patient presented with post anterior myocardial infarction angina. Coronary angiography revealed tight ostio-proximal stenosis of the left anterior descending (LAD) coronary artery, plus bilateral coronary artery fistulas, one originating from the proximal segment of LAD and the other from the proximal segment of circumflex coronary artery. Both fistulas form a network of vessels draining into the pulmonary artery trunk. Successful surgical management was undertaken.