Negative Left Ventricular Remodeling Research Articles

Impact of Right Ventricular Pacing in Patients With TAVR Undergoing Permanent Pacemaker Implantation

BackgroundLong-term right ventricular pacing (VP) has been related to negative left ventricular remodeling and heart failure (HF), but there is a lack of evidence regarding the prognostic impact on transcatheter aortic valve replacement (TAVR) patients. ObjectivesThe aim of the PACE-TAVI registry is to evaluate the association of high percentage of VP with adverse outcomes in patients with pacemaker implantation after TAVR. MethodsPACE-TAVI is an international multicenter registry of all consecutive TAVR patients who underwent permanent pacemaker implantation for conduction disturbances in the first 30 days after the procedure. Patients were divided into 2 subgroups according to the percentage of VP (<40% vs ≥40%) at pacemaker interrogation. The primary endpoint was the composite of cardiovascular mortality or hospitalization for HF. ResultsA total of 377 patients were enrolled, 158 with VP <40% and 219 with VP ≥40%. After multivariable adjustment, VP ≥40% was associated with a higher incidence of the primary endpoint (HR: 2.76; 95% CI: 1.39-5.51; P = 0.004), first HF hospitalization (HR: 3.37; 95% CI: 1.50-7.54; P = 0.003), and cardiovascular death (HR: 3.77; 95% CI: 1.02-13.88; P = 0.04), while the incidence of all-cause death was not significantly different (HR: 2.17; 95% CI: 0.80-5.90; P = 0.13). Patients with VP ≥ 40% showed a higher New York Heart Association functional class both at 1 year (P = 0.009) and at last available follow-up (P = 0.04) and a nonsignificant reduction of left ventricular ejection fraction (P = 0.18) on 1-year echocardiography, while patients with VP <40% showed significant improvement (P = 0.009). ConclusionsIn TAVR patients undergoing permanent pacemaker implantation, a high percentage of right VP at follow-up is associated with an increased risk for cardiovascular death and HF hospitalization. These findings suggest the opportunity to minimize right VP through dedicated algorithms in post-TAVR patients without complete atrioventricular block and to evaluate a more physiological VP modality in patients with persistent complete atrioventricular block.

Systemic inflammation in the acute myocardial infarction can predict early negative left ventricular remodeling assessed by myocardial work analysis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): UEFISCDI Background. Left ventricular (LV) remodeling after acute myocardial infarction (AMI) is an important predictor of heart failure (HF). Systemic inflammatory response in the acute phase of AMI is of particular interest, while the relation to the remodeling process is still under debate. New imaging techniques derived from speckle tracking echocardiography (STE), such as myocardial work (MW), are attractive tools since they can detect myocardial remodeling before decrease of global LVEF. However, there is insufficient data regarding MW in AMI patients, and its relation to the inflammatory process. Methods. We assessed 57 patients (53 ± 9 years, 45 men, 64% smokers, 59% hypertensive, 54% with type 2 diabetes) with AMI, by clinical, 2D echo, and STE. Biomarkers panel was evaluated within the first 24 hours from admission: hsTpI and CRP. A second visit with clinical and echo assessment was performed at 6-8 weeks from the baseline visit. Exclusion criteria were unstable patients, non-sinus rhythm, significant valvular disease (&amp;gt;grade 2), other significant pathologies leading to decreased life expectancy, and low quality 2DE. At both visits, global longitudinal stain (GLS) and MW by 2DSTE were measured, on top of conventional echo parameters: global work index (GWI), global constructive work (GCW), global wasted work (GWW), global work efficiency (GWE) (Figure 1: upper panel - an example of a patient with increase of GWE from baseline to visit 2 ; lower panel - an example of a patient with decrease of the GWE from baseline to visit 2). Results. At baseline, myocardial necrosis by hsTpI significantly corelated with GLS (r = 0.44, p = 0.001) and MW (GWI: r=-0.44, p = 0.001; GCW: r=-0.40, p = 0.002), but not with LVEF. However, systemic inflammation by CRP did not correlate with LVEF or any of the STE parameters. Interestingly, systemic inflammation by CRP significantly correlated with changes of MW between the two visits: for GWE r=-0.53, p &amp;lt; 0.001; and for GWW r = 0.48, p &amp;lt; 0.001 (Figure 2). A CRP level &amp;gt;28 mg/l was able to predict decrease of GWE from baseline to visit 2. Conclusions. Magnitude of necrosis, expressed by hsTpI, corelates only with GLS and MW parameters, but not with LVEF. CRP level in the acute phase of AMI correlates with myocardial work changes, as an early marker of negative LV remodeling. Abstract Figure 1 Abstract Figure 2

Tachycardia-Induced Cardiomyopathy

Abstract Tachycardia-induced cardiomyopathy (TIC) is characterized by reversible left ventricular (LV) dysfunction caused by long-standing tachycardia. The diagnosis of TIC is challenging due to lack of guidelines and specific assessment tools. Advanced imaging and endomyocardial biopsy should be taken into consideration in the future as contributors in the diagnostic process. There are numerous unknowns to TIC, the most pressing being the lack of diagnostic and prognostic tools. The presence of persistent negative LV remodeling after the normalization of the LV ejection fraction with adequate treatment of the tachycardia gives us a glimpse into the complex pathophysiologic processes at play, as well as the disease prognosis.

Predictive Value of Apoptotic Factor M30 for Negative Left Ventricular Remodeling in Patients Undergoing Primary Percutaneous Coronary Intervention

Background: Left Ventricular Negative Remodeling (LVNR) following Primary Percutaneous Coronary Intervention (PPCI) is an important cause of LV systolic dysfunction due to Irreversible Myocardial Injury (IMI). Both necrosis and apoptosis contribute to IMI and LVNR. We assessed the role of specific apoptotic marker M30 in predicting LVNR in patients of anterior wall ST Elevation Myocardial Infarction (STEMI) undergoing PPCI within 12 hours of symptom onset. Methods: This prospective study was done on 100 consecutive patients of anterior wall STEMI (87 men and 13 women, mean age 52.15±12.08 years) meeting our inclusion and exclusion criteria. Blood sample for M30 was drawn at 24 hours after symptom onset, when it reaches peak level. Transthoracic echo was done in each patient at 24 hours after PPCI and at 6 months. LVNR was defined as ≥20% increase in LV end diastolic volume at 6 months after PPCI. Results: 44 patients (44%) developed LVNR at 6 months post PPCI. Diabetes mellitus (p=0.032), symptom onset to balloon time (p=0.059), CPK-MB (p=0.007) and M30 level (p=0.012) were independent predictors of LVNR. The cutoff value of M30 for predicting LVNR was 81.18u/ml with positive predictive value of 70.4% (AUC 85.3, p&lt;0.001). Conclusion: In patients of anterior wall STEMI undergoing PPCI, the apoptotic marker M30 is useful for early prediction of LVNR. This can assist in better risk stratification of patients after successful PPCI and identify the subgroup of patients who require more intensive medical follow up with antiremodeling drugs to attenuate the development of LVNR.

Injectable Myocardial Matrix Hydrogel Mitigates Negative Left Ventricular Remodeling in a Chronic Myocardial Infarction Model

A first-in-man clinical study on a myocardial-derived decellularized extracellular matrix hydrogel suggested the potential for efficacy in chronic myocardial infarction (MI) patients. However, little is understood about the mechanism of action in chronic MI. In this study, the authors investigated the efficacy and mechanism by which the myocardial matrix hydrogel can mitigate negative left ventricular (LV) remodeling in a rat chronic MI model. Assessment of cardiac function via magnetic resonance imaging demonstrated preservation of LV volumes and apical wall thickening. Differential gene expression analyses showed the matrix is able to prevent further negative LV remodeling in the chronic MI model through modulation of the immune response, down-regulation of pathways involved in heart failure progression and fibrosis, and up-regulation of genes important for cardiac muscle contraction.

Evidence for Mechanisms Underlying the Functional Benefits of a Myocardial Matrix Hydrogel for Post-MI Treatment

BackgroundThere is increasing need for better therapies to prevent the development of heart failure after myocardial infarction (MI). An injectable hydrogel derived from decellularized porcine ventricular myocardium has been shown to halt the post-infarction progression of negative left ventricular remodeling and decline in cardiac function in both small and large animal models. ObjectivesThis study sought to elucidate the tissue-level mechanisms underlying the therapeutic benefits of myocardial matrix injection. MethodsMyocardial matrix or saline was injected into infarcted myocardium 1 week after ischemia–reperfusion in Sprague–Dawley rats. Cardiac function was evaluated by magnetic resonance imaging and hemodynamic measurements at 5 weeks after injection. Whole transcriptome microarrays were performed on RNA isolated from the infarct at 3 days and 1 week after injection. Quantitative polymerase chain reaction and histologic quantification confirmed expression of key genes and their activation in altered pathways. ResultsPrincipal component analysis of the transcriptomes showed that samples collected from myocardial matrix-injected infarcts are distinct and cluster separately from saline-injected control subjects. Pathway analysis indicated that these differences are due to changes in several tissue processes that may contribute to improved cardiac healing after MI. Matrix-injected infarcted myocardium exhibits an altered inflammatory response, reduced cardiomyocyte apoptosis, enhanced infarct neovascularization, diminished cardiac hypertrophy and fibrosis, altered metabolic enzyme expression, increased cardiac transcription factor expression, and progenitor cell recruitment, along with improvements in global cardiac function and hemodynamics. ConclusionsThese results indicate that the myocardial matrix alters several key pathways after MI creating a pro-regenerative environment, further demonstrating its promise as a potential post-MI therapy.

Delivery of an engineered HGF fragment in an extracellular matrix-derived hydrogel prevents negative LV remodeling post-myocardial infarction

Hepatocyte growth factor (HGF) has been shown to have anti-fibrotic, pro-angiogenic, and cardioprotective effects; however, it is highly unstable and expensive to manufacture, hindering its clinical translation. Recently, a HGF fragment (HGF-f), an alternative c-MET agonist, was engineered to possess increased stability and recombinant expression yields. In this study, we assessed the potential of HGF-f, delivered in an extracellular matrix (ECM)-derived hydrogel, as a potential treatment for myocardial infarction (MI). HGF-f protected cardiomyocytes from serum-starvation and induced down-regulation of fibrotic markers in whole cardiac cell isolate compared to the untreated control. The ECM hydrogel prolonged release of HGF-f compared to collagen gels, and in vivo delivery of HGF-f from ECM hydrogels mitigated negative left ventricular (LV) remodeling, improved fractional area change (FAC), and increased arteriole density in a rat myocardial infarction model. These results indicate that HGF-f may be a viable alternative to using recombinant HGF, and that an ECM hydrogel can be employed to increase growth factor retention and efficacy.

Abstract 18840: Left Ventricular Enlargement Detected by Cardiac Magnetic Resonance Imaging Predicts Atrial Fibrillation Recurrence Following Pulmonary Vein Isolation

Introduction: Recurrence rates of atrial fibrillation (AF) following catheter ablation remain substantial. Studies on cardiac magnetic resonance imaging (cMRI) assessment of predictors of AF recurrence following pulmonary vein (PV) isolation have centered on left atrial volume and fibrosis. We sought to identify other anatomic predictors of recurrent AF following PV isolation by cMRI. Methods: Eighty-seven consecutive patients (72 [83%] male; age 61 ± 10 yrs) who underwent PV isolation for symptomatic AF (63% paroxysmal) and baseline cMRI were evaluated. Baseline left ventricular (LV) mass, LV end-diastolic and end-systolic volumes, LV size, LV ejection fraction, left atrial diameter and area, right atrial sizes, right ventricular size and function and presence of left common PV and right middle PV were assessed by cMRI. Recurrent AF (defined as AT/AF ≥ 30 seconds) during follow up was noted. Results: Over mean follow-up of 372 ± 109 days, a total of 30 (35%) patients had evidence of recurrent AF. Patients with LV enlargement (≥ mild) by cMRI had significantly reduced AF-free survival (53% vs. 73% at 1 year; p = 0.012) and patients with LV mass index ≥ 74.5 g/m 2 had significantly reduced AF-free survival (54% vs. 72% at 1 year; p = 0.031). There was no difference in AF-free survival among patients with and without left atrial, right atrial, and right ventricular enlargement. Patients with and without recurrent AF had similar right ventricular function and LV ejection fractions. In a multivariate analysis of cMRI parameters of cardiac anatomy, LV enlargement was the only significant independent predictor of recurrent AF (HR 2.78; 95% CI 1.26-6.11; p=0.011). Conclusion: Left ventricular enlargement assessed by cMRI is a significant independent predictor of recurrent AF following PV isolation. In addition to abnormal left atrial substrate, negative LV remodeling may also be an important marker of increased susceptibility to AF after ablation.

Engineering Biomaterials for Myocardial Regeneration and Repair

AbstractAugmentation of myocardial tissue regeneration processes in injured hearts represents a major challenge in cardiology as current therapeutic approaches do not regenerate the myocardial tissue. Herein, we describe three emerging biomaterial‐based strategies to treat heart injuries, as stand‐alone therapies or in combination with regeneration‐inducing signals and/or cells. One strategy relies on the injection of acellular biomaterials, at an early stage after myocardial infarction (MI); these materials replace the damaged extracellular matrix, maintain left ventricular (LV) thickness, and prevent the negative LV remodeling and progression to heart failure. This strategy is currently being investigated in advanced clinical trials using a novel alginate‐based biomaterial. The second strategy employs engineered biomaterials, spatially presenting multiple regeneration‐inducing factors, to promote myocardial tissue regeneration in chronic infarcted hearts. The recent attempts to understand the “natural capacity” of the myocardium to heal and the factors involved in these processes are promising to advance this therapy. The third strategy applies biomaterials to promote cardiac tissue engineering and create a pre‐vascularized cardiac patch to replace damaged or missing myocardial tissue. Collectively, this review emphasizes the increasing importance of biomaterials in cardiology, describes the engineering schemes used in their fabrication, and their implementation in various therapeutic strategies aimed at cardiac tissue regeneration and repair. It mainly highlights the contribution of our group in developing these strategies.

Mechanisms, Prevention and Treatment of Distal Embolization

Distal embolization (DE) can be either spontaneous or iatrogenic, occurring during percutaneous coronary intervention (PCI). The nature, composition and biochemical properties of embolized material differ according to the setting in which DE occurs: acute coronary syndromes (ACS) or stable coronary artery disease (CAD). DE occurrence is related to increased cardiac biomarkers, negative left ventricular remodeling and associated with a poor prognosis. Prevention and treatment of DE represent some of the most debated topics in interventional cardiology. This review paper is focused on mechanisms of DE and on the strategies for its prevention and treatment in both ACS and stable CAD.

Attenuation of cardiac vascular rhexis

We have previously identified a phenomenon that we called vascular rhexis (VR) after coronary occlusion in mice. To explore its potential pathogenetic impact on the destruction of vessels described, its potential universality, and its characterization as a scaffolding for evaluating amelioration, we studied Sprague-Dawley rats from which multiple blood samples and robust tissue samples can be obtained. Rats were subjected to nonsustained coronary occlusion for 15 min, 1 h, 90 min, 3 h, or 4 h, followed by reperfusion. Soluble fractions of left ventricular (LV) homogenates were obtained 48 h later and assayed by western blotting for quantification of α-smooth muscle actin, diminution of which has been immunohistochemically shown to reflect delineation of VR. The functional integrity of vessel walls was assessed 24 h after induction of ischemia for selected intervals, followed by reperfusion using fluorescein isothiocyanate-tagged albumin injected through the tail vein 2 h before harvesting tissue. Nonsustained coronary occlusion for 1 h initiated VR, evident 47 h after reperfusion; however, more brief ischemic insults did not. Loss of functional integrity was evident as judged from increases in extravasated fluorescein isothiocyanate-conjugated albumin in LV walls. Because VR occurs early and may be ameliorated by interventions that can be initiated soon after the onset of nonsustained ischemia before myocardial cell death is substantial, its amelioration is an attractive target for diminution of late negative LV remodeling associated with the 'no reflow' phenomenon to which it can contribute.

Safety and Efficacy of an Injectable Extracellular Matrix Hydrogel for Treating Myocardial Infarction

New therapies are needed to prevent heart failure after myocardial infarction (MI). As experimental treatment strategies for MI approach translation, safety and efficacy must be established in relevant animal models that mimic the clinical situation. We have developed an injectable hydrogel derived from porcine myocardial extracellular matrix as a scaffold for cardiac repair after MI. We establish the safety and efficacy of this injectable biomaterial in large- and small-animal studies that simulate the clinical setting. Infarcted pigs were treated with percutaneous transendocardial injections of the myocardial matrix hydrogel 2 weeks after MI and evaluated after 3 months. Echocardiography indicated improvement in cardiac function, ventricular volumes, and global wall motion scores. Furthermore, a significantly larger zone of cardiac muscle was found at the endocardium in matrix-injected pigs compared to controls. In rats, we establish the safety of this biomaterial and explore the host response via direct injection into the left ventricular lumen and in an inflammation study, both of which support the biocompatibility of this material. Hemocompatibility studies with human blood indicate that exposure to the material at relevant concentrations does not affect clotting times or platelet activation. This work therefore provides a strong platform to move forward in clinical studies with this cardiac-specific biomaterial that can be delivered by catheter.

Predictive Value of Left Ventricular Remodeling by Area Strain Based on Three-Dimensional Wall-Motion Tracking After PCI in Patients with Recent NSTEMI

We aimed to explore whether a novel left ventricular performance index, area strain (AS), based on three-dimensional wall-motion tracking (3-D-WMT) done before and after percutaneous coronary intervention (PCI) could predict left ventricular (LV) remodeling in patients with recent non-ST elevation myocardial infarction (NSTEMI). Sixty-one patients (53.6 ± 8.8 years) with recent NSTEMI were enrolled. Coronary angiography and PCI were undertaken for reperfusion. Parameters of myocardial deformation (including LV end-diastolic volume, LV end-systolic volume, LV ejection fraction, LV global and regional peak area strain) were measured by 3-D-WMT before and 1 week after reperfusion therapy. Six months after reperfusion, LV negative remodeling was defined as lack of improvement in LV function, with increase in LV end-diastolic volume ≥15%. Patients were subdivided into remodeled group (n = 25) and non-remodeled group (n = 36) at follow-up. Patients with negative LV remodeling had significantly higher cardiac troponin I (cTnI) levels at baseline (21.21 ± 12.22 vs. 15.56 ± 8.91 ng/mL; p = 0.0357), higher B-type natriuretic peptide (BNP) level (247.56 ± 177.39 vs. 170.53 ± 97.89 pg/mL; p = 0.0336) and reduced global AS (−27.9 ± 4.6% vs. −31.9 ± 4.3%; p = 0.001) than those without remodeling. Global AS at baseline had a significantly close correlation with cTnI level 36 h after MI (r = 0.71, p < 0.001). Moreover, a weak relationship was found between LV global AS at baseline and BNP level 24 h after myocardial infarction (r = 0.423, p < 0.001). By multivariate logistic regression analysis, lack of improvement of global AS 1 week after PCI was found to be a powerful independent predictor of negative LV remodeling at follow-up (OR = 1.41, 95% CI 1.28–3.27, p = 0.003). In particular, a global AS ≤32% (absolute value) showed a sensitivity and a specificity of 86.1% and 68.0% in predicting negative LV remodeling. These data suggest that AS could be used to assess myocardial global and regional LV function with good feasibility and repeatability. Global AS 1 week after PCI is a good independent predictor of negative LV remodeling after 6-month follow-up.

MRI manifestations of persistent microvascular obstruction and acute left ventricular remodeling in an experimental reperfused myocardial infarction.

To investigate varied manifestations of persistent microvascular obstruction (PMO) and acute left ventricular (LV) remodeling in an experimental reperfused myocardial infarction (MI) using MRI. In eleven Yorkshire pigs an acute MI was produced through a 90-minute balloon occlusion of the middle left anterior descending coronary artery, followed by reperfusion. All animals underwent MRI examinations on a 1.5T system including a SSFP functional study, first pass myocardial perfusion (FPMP), T1 preparation Look-Locker and delayed contrast-enhanced MRI (DE-MRI). Imaging was performed immediately post-intervention (day 0) and at days 7-9. In four animals a repeat MRI examination was performed at day 2 as well. Upon study completion, animals underwent histological analysis including infarct assessment with triphenyltetrazolium chloride (TTC). Following reperfusion, Thrombolysis In Myocardial Infarction (TIMI) Flow grade 3 was achieved in all animals, demonstrated by repeat angiography following balloon deflation (day 0). Various MR appearances of PMO were noticed including predominance in the subendocardial region, a central core within the infarcted tissue and also multiple separate clusters. In ten of eleven animals PMO was demonstrated as a persistent hypo-enhanced area in FPMP and DE-MRI, and identified as bright regions in later T1 difference images. In one animal PMO was identified only at day 2. At day 7-9 PMO could be identified on early DE-MRI at 5-15 minutes post Gd injection but not on late DE-MRI and T1 difference images after 45-60 minutes post-contrast. A larger volume of PMO and MI at day 2 was noted in comparison to data from day 0 but the difference was not statistically significant. An increased end-diastolic LV volume (EDV) without changes in end-systolic LV volume (ESV) and LV mass at end-diastolic phase (LVM) was observed at day 7-9 in comparison to data from day 0. There was good correlation between the relative extent of persistent MO in the infarcted myocardium (% MO/MI) and EDV at day 7-9 (r=0.83, n=10, P=0.003). MI was confirmed in all animals by TTC staining and/or histology. A variable MR appearance of persistent microvascular obstruction is observed during a short time course MRI study of reperfused acute MI. Acute negative LV remodeling was closely related to the relative extent of persistent microvascular obstruction within the infarct myocardium.

Modulators of induction of plasminogen activator inhibitor type-1 in HepG2 cells by transforming growth factor-β

An increased expression of plasminogen activator inhibitor type-1 (PAI-1) has been implicated in accelerating atherogenesis and coronary artery disease in patients with type 2 diabetes. Transforming growth factor (TGF)-β increases its expression. An increased PAI-1 appears to predispose also to augmented fibrosis potentially contributing to negative left ventricular remodeling and heart failure after myocardial infarction. Diabetes is well known to induce oxidative stress. To elucidate molecular mechanisms underlying an increased PAI-1 production, the effects of TGF-β and oxidative stress implicated as agonists of PAI-1 synthesis were characterized with the use of human liver-derived HepG2 cells. PAI-1 mRNA was assayed by real-time PCR, and PAI-1 protein was assayed by western blotting. PAI-1 promoter (-825 -+42 bp) activity was assessed with the luciferase assay. The role of the 3'-untranslated region was delineated with the use of luciferase constructs containing the 3'-untranslated region. Oxidative stress was measured after loading carboxy-2,7-dichlorodihydrofluorescein into cells. TGF-β increased oxidative stress, which was accompanied by increases in NADPH oxidase 3 mRNA and membrane translocation of Rac proteins. TGF-β-inducible increases in the PAI-1 promoter activity involved Smad-binding elements and a nuclear factor-κB-binding site. TGF-β did not increase the activity of the PAI-1 mRNA 3'-untranslated region. TGF-β-inducible PAI-1 expression was attenuated by simvastatin and curcumin, a natural polyphenol. TGF-β can increase the expression of PAI-1 through multiple mechanisms involving Smad and nuclear factor-κB pathways and oxidative stress. As both oxidative stress and PAI-1 production were reduced by simvastatin and curcumin, modulation of oxidative stress and PAI-1 production are attractive targets for pharmacotherapy of cardiovascular disorders associated with an increased PAI-1 including type 2 diabetes and its associated consequences including accelerated coronary artery disease and an increased fibrosis that may exacerbate adverse left ventricular remodeling after myocardial infarction.

Increased infarct wall thickness by a bio-inert material is insufficient to prevent negative left ventricular remodeling after myocardial infarction.

BackgroundSeveral injectable materials have been shown to preserve or improve cardiac function as well as prevent or slow left ventricular (LV) remodeling post-myocardial infarction (MI). However, it is unclear as to whether it is the structural support or the bioactivity of these polymers that lead to beneficial effects. Herein, we examine how passive structural enhancement of the LV wall by an increase in wall thickness affects cardiac function post-MI using a bio-inert, non-degradable synthetic polymer in an effort to better understand the mechanisms by which injectable materials affect LV remodeling.Methods and ResultsPoly(ethylene glycol) (PEG) gels of storage modulus G′ = 0.5±0.1 kPa were injected and polymerized in situ one week after total occlusion of the left coronary artery in female Sprague Dawley rats. The animals were imaged using magnetic resonance imaging (MRI) at 7±1 day(s) post-MI as a baseline and again post-injection 49±4 days after MI. Infarct wall thickness was statistically increased in PEG gel injected vs. control animals (p<0.01). However, animals in the polymer and control groups showed decreases in cardiac function in terms of end diastolic volume, end systolic volume and ejection fraction compared to baseline (p<0.01). The cellular response to injection was also similar in both groups.ConclusionThe results of this study demonstrate that passive structural reinforcement alone was insufficient to prevent post-MI remodeling, suggesting that bioactivity and/or cell infiltration due to degradation of injectable materials are likely playing a key role in the preservation of cardiac function, thus providing a deeper understanding of the influencing properties of biomaterials necessary to prevent post-MI negative remodeling.

Vascular rhexis in mice subjected to non-sustained myocardial ischemia and its therapeutic implications

We previously described the death of vascular cells (vascular rhexis) following persistent coronary occlusion. The present study was designed to determine whether non-sustained ischemia can initiate vascular rhexis and if so, whether relatively brief ischemic insults are sufficient. C57BL6 mice were subjected to coronary ligation for 15 min or 3 h followed by reperfusion. Soluble fractions of left ventricular (LV) homogenates were obtained 48 h after the onset of transitory coronary occlusion. They were assayed by Western blotting for quantification of alpha smooth muscle actin (α-SMA) and smooth muscle myosin heavy chain (SM-MHC) that we have shown reflect vascular rhexis delineated immunohistochemically. Non-sustained coronary occlusion for 3 h initiated vascular rhexis evident 45 h after reperfusion, but not earlier, as judged from Western blotting of α-SMA and SM-MHC. The number of small- and medium-sized vessels in the previously ischemic zones was reduced at 45 h after reperfusion as well. Thus, vascular rhexis occurs after ischemia as brief as 3 h but evolves slowly and is not evident for 45 h. The delayed disintegration of the vasculature makes it likely that it can be ameliorated by interventions initiated after non-sustained ischemia, rendering it an attractive target for diminution of phenomena such as late negative LV remodeling, and 'no reflow.'

Global longitudinal speckle-tracking strain is predictive of left ventricular remodeling after coronary angioplasty in patients with recent non-st elevation myocardial infarction

AimsTo test whether two-dimensional longitudinal strain (2DSE) performed after revascularization by percutaneous coronary intervention (PCI) could predict left ventricular (LV) remodeling in patients with recent non-ST elevation myocardial infarction (NSTEMI). MethodsIn 70 patients (62.7±8.7years) with recent NSTEMI (between 72hours and 14days), undergoing coronary angiography for recurrent angina, myocardial deformation parameters were measured by 2DSE before and 24hours after reperfusion therapy. Strain in all LV segments was averaged to obtain a global value (Global longitudinal Strain – GLS). Infarct size was estimated by clinical parameters and cardiac markers. After 6months from intervention, LV negative remodeling was defined as lack of improvement of LV function, with increase in LV end-diastolic volume of greater than or equal than 15%. ResultsAt follow-up, patients were subdivided into remodeled (n=32) and non-remodeled (n=38) groups. Patients with negative LV remodeling had significantly lower baseline LV ejection fraction (44.8±6.9 vs. 48.7±5.5 %; p<0.05), higher peak troponin I (p<0.001) and reduced GLS (- 10.6±6.1 vs - 17.6±6.7 % p<0.001) than those without LV remodeling. GLS showed a close correlation with peak troponin I after PCI (r=0.64, P<0.0001) and LV WMSI (r=0.42, p<0.01). By multivariable analysis, diabetes mellitus (P<0.005), peak of Troponin I after PCI (P<0.0005), GLS at baseline (OR: 4.3; p<0.0001), and lack of improvement of GLS soon after PCI (OR: 1.45, P<0.01) were powerful independent predictors of negative LV remodelling at follow-up. In particular, a GLS≤12 % showed a sensitivity and a specificity respectively of 84.8% and 87.8% to predict negative LV remodelling at follow-up. Conclusionsin patients with recent NSTEMI, longitudinal LV global and regional speckle-tracking strain measurements are powerful independent predictors of LV remodeling after reperfusion therapy.

Invited Commentary

The Gorman research group [1] has extended their laboratory investigation into the complex relationship of ischemic myocardial injury, left ventricular (LV) remodeling, and functional mitral regurgitation (FMR). They have previously demonstrated in experimental models that ongoing negative LV remodeling will continue to occur in the presence of severe ischemic injury, even if the FMR is pretreated or prevented by restrictive annuloplasty performed at the time of ischemic insult. In the current report, restrictive mitral annuloplasty performed 8 weeks after large ischemic injury and myocardial infarction did not alter the ongoing process of LV dilation and negative remodeling, despite successful elimination of FMR.

Vascular rhexis: loss of integrity of coronary vasculature in mice subjected to myocardial infarction

We previously observed gross hemorrhage in plasminogen activator inhibitor type-1 (PAI-1) knockout (PKO) mice with induced myocardial infarction (MI). We hypothesized that it reflected degradation of vessels - a phenomenon we termed vascular rhexis. Accordingly, in the present study we characterized vascular rhexis in C57BL6 mice. MI was induced in 10- to 12-week-old mice by coronary artery ligation for 24, 48, 72 or 96 h. Hemorrhage was quantified by non-cross-reacting enzyme-linked immunosorbent assay of left ventricular (LV) hemoglobin corrected for myoglobin. Degradation of vasculature was quantified by the appearance of alpha smooth muscle actin (alphaSMA) in low salt soluble fractions of LV homogenates (Western blotting) and by immunohistochemistry (residual alphaSMA). Co-staining for CD31 (endothelial cells) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) (a marker of cell death) was used to identify capillary rhexis. PKO mice (n = 9) had marked hemorrhage in infarct zones (432 +/- 27 standard error of mean microL blood/g). Hemorrhage was evident in C57BL6 mice as well (n = 6): 51 +/- 8 microL/g LV 96 h after coronary occlusion compared with 10 +/- 5 microL /g, n = 13 in normal LVs. Residual intact vasculature was reduced 48 h after infarction. Thus, an average of 16 +/- 1.6 small- and medium-sized vessels (n = 5 hearts) were seen compared with 84 +/- 4.8 in normal LVs (n = 3, P < or = 0.05). An approximately three-fold increase in soluble alphaSMA 48 h after MI (2.68 +/- 0.28, n = 6) was seen relative to that in normal LVs defined as 1.0 +/- 0.04, n = 10, P < or = 0.05. Capillary degradation was evident as well, as judged from CD31 and TUNEL co-localization. Vascular rhexis occurs within 48 h after the onset of MI. It may contribute to the early no-reflow phenomenon and to late negative LV remodeling.