Subsequent Left Ventricular Remodeling Research Articles

Acute sleep deprivation (ASD) and cardioprotection: Impact of ASD on oxytocin-mediated sympathetic nervous activation preceding myocardial infarction

IntroductionThis study explored how acute sleep deprivation (ASD) before myocardial ischemia influences oxytocin release from paraventricular (PVN) neurons and its correlation with sympathetic nervous system (SNS) activity post-acute sleep loss, impacting subsequent left ventricular (LV) remodeling following myocardial infarction (MI). MethodsThe study was conducted in two phases: induction of ASD, inducing MI, blood sampling, euthanizing animals and collecting their heart and brain for histological and gene expression evaluations. The animals in first and second phase were euthanized 24 h and 14 days after MI, respectively. ResultsPre-MI ASD, accompanied by increased serum epinephrine levels within 24 h of MI, upregulated oxytocin and cFos expression in the PVN. Also, pre-MI ASD resulted in decreased serum PAB levels 14 days post-MI (P < 0.001). While notable echocardiographic changes were seen in MI versus sham groups, ASD demonstrated protective effects. This was evidenced by reduced infarct size, elevated TIMP1, MMP2, and MMP9 in the LV of SD + MI animals versus MI alone (P < 0.05). Additionally, histological analysis showed reduced LV fibrosis in pre-MI ASD subjects (P < 0.05). ConclusionOur study supports the notion that activation of oxytocin neurons within the PVN subsequent to ASD interacts with autonomic centers in the central nervous system. This enhanced sympathetic outflow to the heart prior to MI triggers a preconditioning response, thereby mediating cardioprotection through decreased oxidative stress biomarkers and regulated extracellular matrix (ECM) turnover.

Insight into the Role of the PI3K/Akt Pathway in Ischemic Injury and Post-Infarct Left Ventricular Remodeling in Normal and Diabetic Heart.

Despite the significant decline in mortality, cardiovascular diseases are still the leading cause of death worldwide. Among them, myocardial infarction (MI) seems to be the most important. A further decline in the death rate may be achieved by the introduction of molecularly targeted drugs. It seems that the components of the PI3K/Akt signaling pathway are good candidates for this. The PI3K/Akt pathway plays a key role in the regulation of the growth and survival of cells, such as cardiomyocytes. In addition, it has been shown that the activation of the PI3K/Akt pathway results in the alleviation of the negative post-infarct changes in the myocardium and is impaired in the state of diabetes. In this article, the role of this pathway was described in each step of ischemia and subsequent left ventricular remodeling. In addition, we point out the most promising substances which need more investigation before introduction into clinical practice. Moreover, we present the impact of diabetes and widely used cardiac and antidiabetic drugs on the PI3K/Akt pathway and discuss the molecular mechanism of its effects on myocardial ischemia and left ventricular remodeling.

Acute Coronary Syndromes (ACS)-Unravelling Biology to Identify New Therapies-The Microcirculation as a Frontier for New Therapies in ACS.

In acute coronary syndrome (ACS) patients, restoring epicardial culprit vessel patency and flow with percutaneous coronary intervention or coronary artery bypass grafting has been the mainstay of treatment for decades. However, there is an emerging understanding of the crucial role of coronary microcirculation in predicting infarct burden and subsequent left ventricular remodelling, and the prognostic significance of coronary microvascular obstruction (MVO) in mortality and morbidity. This review will elucidate the multifaceted and interconnected pathophysiological processes which underpin MVO in ACS, and the various diagnostic modalities as well as challenges, with a particular focus on the invasive but specific and reproducible index of microcirculatory resistance (IMR). Unfortunately, a multitude of purported therapeutic strategies to address this unmet need in cardiovascular care, outlined in this review, have so far been disappointing with conflicting results and a lack of hard clinical end-point benefit. There are however a number of exciting and novel future prospects in this field that will be evaluated over the coming years in large adequately powered clinical trials, and this review will briefly appraise these.

Necroptosis mediated by impaired autophagy flux contributes to adverse ventricular remodeling after myocardial infarction

Loss of functional cardiomyocytes by cell death after myocardial infarction is most critical for the subsequent left ventricular remodeling, cardiac dysfunction and heart failure. Numerous studies have implicated that dysregulation of autophagy might contribute to cardiomyocyte death. However, the underlying mechanisms by which autophagy dysregulation-mediated cell death remains to be elusive. Herein, we showed that,in response to myocardial ischemic damage in vivo and in vitro, autophagy activity was increased quickly but followed by the process of impaired autophagic degradation as evidenced by the sustained higher level of beclin1 until 12 weeks after myocardial infarction, while, increased accumulation of LC3 and p62. The results from both tandem mRFP-GFP-LC3 adenovirus and lysosomal inhibitor chloroquine supported defective autophagy induction by ischemia injury. Importantly, we found that the impaired autophagy flux, induced not only pharmacologically by CQ but also genetically by beclin1 knockdown, upregulated the expression of RIP3 and aggravated OGD-induced necroptotic cardiomyocyte death and cardiac dysfunction. While, upregulation of autophagy by cardiac-specific beclin1 overexpression partially ameliorated cardiac dysfunction after MI. Furthermore, constitutive activation of necroptosis by forced cardiac-specific overexpression of RIP3 aggravated necrotic cardiomyocyte death, post-MI cardiac remodeling and cardiac dysfunction, but all of which could be ameliorated by inhibition of necroptosis by RIP3 knockdown. In conclusion, these results suggested that autophagy dysfunction-mediated necroptosis mechanistically contributed to loss of cardiomyocytes, adverse ventricular remodeling and progressive heart failure after myocardial Infarction. Inhibition of necroptosis might be the potential target for preventing post-infarction cardiac remodeling and heart failure.

Application of Hybrid Matrix Metalloproteinase-Targeted and Dynamic 201Tl Single-Photon Emission Computed Tomography/Computed Tomography Imaging for Evaluation of Early Post-Myocardial Infarction Remodeling.

The induction of matrix metalloproteinases (MMPs) and reduction in tissue inhibitors of MMPs (TIMPs) plays a role in ischemia/reperfusion (I/R) injury post-myocardial infarction (MI) and subsequent left ventricular remodeling. We developed a hybrid dual isotope single-photon emission computed tomography/computed tomography approach for noninvasive evaluation of regional myocardial MMP activation with 99mTc-RP805 and dynamic 201Tl for determination of myocardial blood flow, to quantify the effects of intracoronary delivery of recombinant TIMP-3 (rTIMP-3) on I/R injury. Studies were performed in control pigs (n=5) and pigs following 90-minute balloon occlusion-induced ischemia/reperfusion (I/R) of left anterior descending artery (n=9). Before reperfusion, pigs with I/R were randomly assigned to intracoronary infusion of rTIMP-3 (1.0 mg/kg; n=5) or saline (n=4). Three days post-I/R, dual isotope imaging was performed with 99mTc-RP805 and 201Tl along with contrast cineCT to assess left ventricular function. The ischemic to nonischemic ratio of 99mTc-RP805 was significantly increased following I/R in saline group (4.03±1.40), and this ratio was significantly reduced with rTIMP-3 treatment (2.22±0.57; P=0.03). This reduction in MMP activity in the MI-rTIMP-3 treatment group was associated with an improvement in relative MI region myocardial blood flow compared with the MI-saline group and improved myocardial strain in the MI region. We have established a novel hybrid single-photon emission computed tomography/computed tomography imaging approach for the quantitative assessment of regional MMP activation, myocardial blood flow, and cardiac function post-I/R that can be used to evaluate therapeutic interventions such as intracoronary delivery of rTIMP-3 for reduction of I/R injury in the early phases of post-MI remodeling.

ST-segment re-elevation following primary angioplasty in acute myocardial infarction with patent infarct-related artery: impact on left ventricular function recovery and remodeling.

IntroductionSpontaneous recanalization of the infarct-related artery (IRA) in ST-segment elevation myocardial infarction (STEMI) before primary angioplasty (PCI) improves clinical outcomes.AimTo investigate the impact of ST-segment re-elevation (reSTE) following PCI in patent IRA on left ventricular (LV) function recovery and remodeling.Material and methodsOf 155 STEMI patients with patent IRA, 19 (12.3%) patients with TIMI-2 (T2Res) and 85 (54.8%) with TIMI-3 (T3Res) had further STE resolution following PCI, 20 (12.9%) with TIMI-3 did not require PCI (T3noPCI) and 31 (20.0%) with TIMI-2/3 had reSTE of ≥ 1 mm following PCI as compared with pre-PCI recordings (T23reSTE). LV ejection fraction (LVEF, %) and LV end-diastolic and end-systolic volume indexes (LVEDVI, LVESVI, ml/m2) were measured by echocardiography 2 days and 6 months following PCI.ResultsIn 6-month observation the improvement of LVEF in T3Res (by 3.9 ±5.1%) and in T3noPCI (by 5.7 ±6.1%) patients was higher as compared with T23reSTE (0.2 ±7.0%, p < 0.05 versus both). LVEDVI increased in T23reSTE patients by 6.6 ±12.6 ml/m2, but decreased in T3Res by 3.8 ±9.7 ml/m2 and in T3noPCI by 2.4 ±6.2 ml/m2 (for both p < 0.05 vs. T23reSTE). LVESVI increased in T23reSTE patients (by 3.8 ±10.8 ml/m2), did not change in T2Res (by 0.1 ±9.0 ml/m2), but decreased in T3Res (by 4.2 ±7.2 ml/m2, p < 0.05 vs. T23reSTE) and in T3noPCI patients (by 4.7 ±7.7 ml/m2, p < 0.05 vs. T23reSTE). ReSTE was an independent predictor of LVEF, LVEDVI and LVESVI changes (p < 0.001 for all).ConclusionsReSTE following PCI in a patent IRA is associated with a lack of improvement of LV contractility and subsequent LV remodeling.

Plasma Circulating Extracellular RNAs in Left Ventricular Remodeling Post-Myocardial Infarction

Despite substantial declines in mortality following myocardial infarction (MI), subsequent left ventricular remodeling (LVRm) remains a significant long-term complication. Extracellular small non-coding RNAs (exRNAs) have been associated with cardiac inflammation and fibrosis and we hypothesized that they are associated with post-MI LVRm phenotypes. RNA sequencing of exRNAs was performed on plasma samples from patients with “beneficial” (decrease LVESVI ≥ 20%, n = 11) and “adverse” (increase LVESVI ≥ 15%, n = 11) LVRm. Selected differentially expressed exRNAs were validated by RT-qPCR (n = 331) and analyzed for their association with LVRm determined by cardiac MRI. Principal components of exRNAs were associated with LVRm phenotypes post-MI; specifically, LV mass, LV ejection fraction, LV end systolic volume index, and fibrosis. We then investigated the temporal regulation and cellular origin of exRNAs in murine and cell models and found that: 1) plasma and tissue miRNA expression was temporally regulated; 2) the majority of the miRNAs were increased acutely in tissue and at sub-acute or chronic time-points in plasma; 3) miRNA expression was cell-specific; and 4) cardiomyocytes release a subset of the identified miRNAs packaged in exosomes into culture media in response to hypoxia/reoxygenation. In conclusion, we find that plasma exRNAs are temporally regulated and are associated with measures of post-MI LVRm.

Inflammation following acute myocardial infarction: Multiple players, dynamic roles, and novel therapeutic opportunities.

Acute myocardial infarction (AMI) and the heart failure that often follows, are major causes of death and disability worldwide. As such, new therapies are required to limit myocardial infarct (MI) size, prevent adverse left ventricular (LV) remodeling, and reduce the onset of heart failure following AMI. The inflammatory response to AMI, plays a critical role in determining MI size, and a persistent pro-inflammatory reaction can contribute to adverse post-MI LV remodeling, making inflammation an important therapeutic target for improving outcomes following AMI. In this article, we provide an overview of the multiple players (and their dynamic roles) involved in the complex inflammatory response to AMI and subsequent LV remodeling, and highlight future opportunities for targeting inflammation as a therapeutic strategy for limiting MI size, preventing adverse LV remodeling, and reducing heart failure in AMI patients.

Myocardial Inflammation Predicts Remodeling and Neuroinflammation After Myocardial Infarction

BackgroundThe local inflammatory tissue response after acute myocardial infarction (MI) determines subsequent healing. Systemic interaction may induce neuroinflammation as a precursor to neurodegeneration. ObjectivesThis study sought to assess the influence of MI on cardiac and brain inflammation using noninvasive positron emission tomography (PET) of the heart-brain axis. MethodsAfter coronary artery ligation or sham surgery, mice (n = 49) underwent serial whole-body PET imaging of the mitochondrial translocator protein (TSPO) as a marker of activated macrophages and microglia. Patients after acute MI (n = 3) were also compared to healthy controls (n = 9). ResultsInfarct mice exhibited elevated myocardial TSPO signal at 1 week versus sham (percent injected dose per gram: 8.0 ± 1.6 vs. 4.8 ± 0.9; p < 0.001), localized to activated CD68+ inflammatory cells in the infarct. Early TSPO signal predicted subsequent left ventricular remodeling at 8 weeks (rpartial = −0.687; p = 0.001). In parallel, brain TSPO signal was elevated at 1 week (1.7 ± 0.2 vs. 1.4 ± 0.2 for sham; p = 0.017), localized to activated microglia. After interval decline at 4 weeks, progressive heart failure precipitated a second wave of neuroinflammation (1.8 ± 0.2; p = 0.005). TSPO was concurrently up-regulated in remote cardiomyocytes at 8 weeks (8.8 ± 1.7, p < 0.001) without inflammatory cell infiltration, suggesting mitochondrial impairment. Angiotensin-converting enzyme inhibitor treatment lowered acute inflammation in the heart (p = 0.003) and brain (p = 0.06) and improved late cardiac function (p = 0.05). Patients also demonstrated elevation of cardiac TSPO signal in the infarct territory, paralleled by neuroinflammation versus controls. ConclusionsThe brain is susceptible to acute MI and chronic heart failure. Immune activation may interconnect heart and brain dysfunction, a finding that provides a foundation for strategies to improve heart and brain outcomes.

Left ventricular torsion assessed by two‐dimensional echocardiography speckle tracking as a predictor of left ventricular remodeling and short‐term outcome following primary percutaneous coronary intervention for acute myocardial infarction: A single‐center experience

Left ventricular (LV) torsion is a novel method to assess systolic LV function. This study aimed at exploring the utility of 2D speckle tracking-based assessment of left ventricular torsion in patients with acute myocardial infarction (AMI) undertaking primary percutaneous intervention (pPCI) in predicting left ventricular remodeling. The study included 115 patients (mean±SD, age 52.2±9.67, males 84.3%) who underwent pPCI for AMI. Echocardiographic assessment of LV torsion by two-dimensional speckle tracking was performed early after the index pPCI. Patients underwent repeat echocardiography at 6months to detect remodeling. LV torsion in the acute setting was significantly lower in those who demonstrated LV remodeling at follow-up compared to those without remodeling (7.56±1.95 vs 15.16±4.65; P<.005). Multivariate analysis identified peak CK & CK-MB elevation (β=-0.767 and -0.725; P<.001), SWMA index (β=-0.843; P<.001), and Simpson's derived LV ejection fraction (LVEF; β=0.802; P<.001) as independent predictors of baseline LV torsion. It also identified peak LV torsion (β: 0.27; 95% CI: 0.15-0.5, P=.001) and SWMA index (β:1.07, 95% CI: 1.03-1.12, P=.005) as independent predictors of LV remodeling. Baseline Killip's grades II and higher (β: 48.6; 95% CI 5.5-428, P<.001) and diabetes mellitus (β: 29.7; 95% CI 1.1-763, P<.05) were independent predictors of mortality. Left ventricular torsion in acute MI setting is impaired and predicts subsequent LV remodeling at 6-month follow-up.

The Prognostic Impact of the Evolution of RV Function in Idiopathic DCM

ObjectivesIn this study, the authors analyzed the prognostic role of right ventricular systolic function (RVF) longitudinal trends in a large cohort of patients affected by dilated cardiomyopathy (DCM). BackgroundRVF is a known prognostic predictor in DCM; however, whether RVF changes over time to better predict the long-term disease progression has not been investigated. MethodsFrom 1993 to 2008, we analyzed 512 patients with DCM (46 years of age [36 to 55 years of age], left ventricular ejection fraction 32% [25% to 41%]) with a potential follow-up of ≥72 months and available data at baseline and at least 1 pre-specified follow-up evaluation (i.e., 6, 24, 48, or 72 months). RV dysfunction was defined as RV fractional area change <35% at 2-dimensional echocardiography. The primary outcome measure was a composite of death or heart transplantation. ResultsAt enrollment, 103 (20%) patients had RV dysfunction. During follow-up, 89 of them (86%, 17% of the overall cohort) normalized RVF at a median time of 6 months, whereas 38 of the remaining 409 patients with normal baseline RVF (9%; 7% of the overall population) exhibited a new-onset RV dysfunction (median time: 36 months). RVF normalization was significantly associated with subsequent left ventricular reverse remodeling that was observed at a median time of 24 months (odds ratio: 2.49; 95% confidence interval [CI]: 1.17 to 5.3; p = 0.018). At baseline multivariate analysis, RV dysfunction was independently associated with the primary outcome measure (hazard ratio: 1.71; 95% CI: 1.02 to 2.85; p = 0.0413). At time-dependent model, RVF revaluation over time maintained an independent predictive value (hazard ratio: 2.83; 95% CI: 1.57 to 5.11; p = 0.0006). ConclusionsPatients with DCM frequently present RV dysfunction at first evaluation. However, a complete RVF recovery is largely observed early after optimization of medical therapy and predates subsequent left ventricular reverse remodeling. Systematic revaluation of patients including RVF throughout regular follow-up conferred additive long-term prognostic value to the baseline evaluation.

Associations between scar characteristics by cardiac magnetic resonance and changes in left ventricular ejection fraction in primary prevention defibrillator recipients

Left ventricular ejection fraction (LVEF) improves over time in 25%-40% of patients with cardiomyopathy with primary prevention implantable cardioverter-defibrillator (ICD). The determinants of LVEF improvement, however, are not well characterized. We sought to examine the associations of clinical risk factors and cardiac imaging markers with changes in LVEF after ICD implantation. We conducted a retrospective analysis of cardiac magnetic resonance images in 202 patients who underwent primary prevention ICD implantation to quantify the amount of heterogeneous myocardial tissue (gray zone), dense core, and total scar. LVEF was reassessed at least once after ICD implantation. Over a mean follow-up of 3 years, LVEF decreased in 43 (21.3%), improved in 88 (43.6%), and was unchanged in 71 (35.1%) of the patients. Baseline LVEF and myocardial scar characteristics were the strongest determinants of LVEF trajectory with high scar burden and increasing lack of myocardial viability associated with a greater decline in LVEF. There was a trend toward an association between both changes in LVEF and scar extent with subsequent appropriate ICD shock. Changes in LVEF were also strongly associated with heart failure hospitalizations. Scar burden and characteristics were strong determinants, independent of baseline LVEF and other traditional cardiovascular risk factors, of changes in LVEF. Both worsened LVEF and high scar extent were associated with a trend toward increased risk of appropriate shock. These findings suggest that baseline cardiac magnetic resonance imaging of the myocardial substrate may provide important prognostic information on subsequent left ventricular remodeling and adverse events.

Clinical significance of endomyocardial biopsy in conjunction with cardiac magnetic resonance imaging to predict left ventricular reverse remodeling in idiopathic dilated cardiomyopathy.

Endomyocardial biopsy (EMB) and cardiac magnetic resonance (CMR) are useful modalities to study the characteristics of myocardial tissue. However, the prognostic impact of both diagnostic tools to predict subsequent left ventricular reverse remodeling (LVRR) has not been well elucidated. A total of 187 consecutive patients with idiopathic dilated cardiomyopathy (IDCM) who were treated by optimal pharmacotherapy (OPT) and underwent EMB of the LV wall were investigated. The myocardial specimens were semiquantitatively evaluated measuring cardiomyocyte degeneration (CD), interstitial fibrosis (IF), and hypertrophy. In addition, late gadolinium enhancement (LGE)-CMR was performed in 78 (48%) patients. Seventy-eight (48%) patients developed LVRR, defined as a ≥10% increase in LV ejection fraction with a ≥10% decrease in indexed LV end-diastolic dimension at 12months after OPT. Multivariate regression analysis revealed that CD (P=0.003), but not IF (P=0.320), was an independent predictor of LVRR. In the patients with not only EMB but also CMR, the CD score and LGE area were independent predictors of LVRR (odds ratios/P values 0.268/0.010, 0.855/<0.001, respectively). The patients with mild CD and negative LGE had a better achievement rate of LVRR than those with severe CD and positive LGE (74 vs. 19%). A combination of CD score on EMB and LGE-CMR is useful to predict subsequent LVRR in IDCM patients.

Heart disease: recruitment of MEF2 activity by β-blockers wards off cardiomyocyte death.

Heart disease: recruitment of MEF2 activity by β-blockers wards off cardiomyocyte death.

Progressive nature of heart failure and systems biology

&lt;p&gt;The progressive nature of heart failure (HF) is the predominant cause for the clinical course that the HF syndrome is taking. Systems biology methodology is of the utmost importance to explain and comprehend the build-in mechanisms of clinical adverse progression. Various heart diseases produce myocardial damage with subsequent left ventricular remodeling which is the principal underlying pathophysiological mechanism for the clinical progression of HF. The self-organized positive feedback stabilization mechanisms of left ventricular remodeling, adrenergic stimulation and activation of the renin-angiotensin-aldosterone system and natriuretic peptide systems, are hierarchical adaptive processes. These adaptive processes are responsible for further left ventricular remodeling with subsequent clinical deterioration and for the emergence of clinical phenotypes. These mechanisms are counteracted with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and β-blockers in an attempt to improve the adverse clinical phenomena of HF progression in a new but clinically worse stabilization level. In this review our intention is to underline the progressive nature of the HF syndrome and to demonstrate the significance of ventricular remodeling and the role of self-organized positive feedback adaptive processes.&lt;/p&gt;

Admission NTproBNP levels better predict subsequent left ventricular remodelling than infarct size and salvage index assessed by cardiac magnetic resonance

Admission NTproBNP levels better predict subsequent left ventricular remodelling than infarct size and salvage index assessed by cardiac magnetic resonance

013 RELATION OF MATRIX METALLOPROTEINASES AND THEIR TISSUE INHIBITORS TO LEFT VENTRICULAR REMODELLING FOLLOWING FIRST ST-ELEVATION MYOCARDIAL INFARCTION

<h3>Introduction</h3> Adverse Left ventricular (LV) remodelling with increase in LV volumes and reduction in ejection fraction (EF) can occur following ST-elevation myocardial infarction (STEMI) and confers worse prognosis. LV remodelling is mediated in part by degradation of the extra-cellular matrix, through the activity of Matrix Metalloproteinase (MMP) enzymes and their intrinsic inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs). We examined the relationships of NTproBNP, MMP and TIMP biomarkers measured at index admission with infarct characteristics, and relations to subsequent changes in LV volumes and mass. <h3>Methods</h3> Seventy-five patients with first STEMI presenting between January and December 2010 were prospectively enrolled. Pre-discharge serum samples were collected (median 45 h, IQR 40 h) before analysis via in-house chemiluminescent assay. Patients underwent Cardiac Magnetic Resonance (CMR) examination (1.5 T Seimens Avanto) during admission (median day 2, IQR 2 days) incorporating volume assessment (cine-SSFP) with further follow-up volume assessment at 4 months (median 120 days, IQR 8 days) completed in 67 patients. Percentage LV remodelling was determined by the following index for changes in end-systolic and end-diastolic volumes and masses: (Volume at 4 months−Volume at STEMI)÷Volume at STEMI×100% Patient demographics are shown in table&nbsp;1. Where required, data was log transformed to normalise distribution. Biomarkers were correlated to volume and mass changes using Pearson9s correlation to compare continuous variables and Spearman9s rank correlation to compare non-parametric data. Correlations with p&lt;0.1 were entered into multivariate linear regression model to predict subsequent remodelling. <h3>Results</h3> TIMP-4 levels sampled at the time of STEMI correlated with a relative change in LV end-systolic volume index (LVESVI) (R=0.315, p=0.009). Microvascular obstruction (MVO) and intra-myocardial haemorrhage (IMH) also correlated with LVESVI. There were no biomarker correlates with a relative change in LV End-diastolic volume index (LVEDVI). Percentage MVO and IMH positively correlated with LVEDVI. EF at 4 months correlated significantly with MMP3 (R=−0.346, p=0.004), NTproBNP (R=−0.450, p&lt;0.001), time to reperfusion, Infarct size, MVO, IMH, and myocardial salvage index (MSI). There were no significant biomarker correlates with LV mass index. On univariate linear regression analysis, TIMP4 was an independent predictor of relative change in LVESVI (R=0.294, t=2.483, p=0.016). TIMP4 remained the only significant predictor of ESVI change on multivariate linear regression analysis incorporating IS%, MVO%, IMH% (R-0.390, TIMP4 t=2.131, p=0.037). NTproBNP remained the only independent predictor of EF at 4 months on multivariate linear regression (R=0.738, t=2.162, p=0.036). NTproBNP was also the only significant predictor of Infarct size at STEMI (R=0.733, t=4.852, p&lt;0.001). <h3>Conclusions/implications</h3> TIMP4 is an independent predictor of a change in LVESVI in patients with STEMI. Early TIMP4 measurement might select patients at risk of subsequent LV remodelling. NTproBNP is an independent predictor of EF% and IS%.

Cardiac-Selective Expression of Extracellular Superoxide Dismutase After Systemic Injection of Adeno-Associated Virus 9 Protects the Heart Against Post–Myocardial Infarction Left Ventricular Remodeling

Cardiac magnetic resonance imaging has not been used previously to document the attenuation of left ventricular (LV) remodeling after systemic gene delivery. We hypothesized that targeted expression of extracellular superoxide dismutase (EcSOD) via the cardiac troponin-T promoter would protect the mouse heart against both myocardial infarction (MI) and subsequent LV remodeling. Using reporter genes, we first compared the specificity, time course, magnitude, and distribution of gene expression from adeno-associated virus (AAV) 1, 2, 6, 8, and 9 after intravenous injection. The troponin-T promoter restricted gene expression largely to the heart for all AAV serotypes tested. AAV1, 6, 8, and 9 provided early-onset gene expression that approached steady-state levels within 2 weeks. Gene expression was highest with AAV9, which required only 3.15×10(11) viral genomes per mouse to achieve an 84% transduction rate. AAV9-mediated, cardiac-selective gene expression elevated EcSOD enzyme activity in heart by 5.6-fold (P=0.015), which helped protect the heart against both acute MI and subsequent LV remodeling. In acute MI, infarct size in EcSOD-treated mice was reduced by 40% compared with controls (P=0.035). In addition, we found that cardiac-selective expression of EcSOD increased myocardial capillary fractional area and decreased neutrophil infiltration after MI. In a separate study of LV remodeling, after a 60-minute coronary occlusion, cardiac magnetic resonance imaging revealed that LV volumes at days 7 and 28 post-MI were significantly lower in the EcSOD group compared with controls. Cardiac-selective expression of EcSOD from the cardiac troponin-T promoter after systemic administration of AAV9 provides significant protection against both acute MI and LV remodeling.

Living Without Creatine

Rationale: Creatine is thought to be involved in the spatial and temporal buffering of ATP in energetic organs such as heart and skeletal muscle. Creatine depletion affects force generation during maximal stimulation, while reduced levels of myocardial creatine are a hallmark of the failing heart, leading to the widely held view that creatine is important at high workloads and under conditions of pathological stress. Objective: We therefore hypothesised that the consequences of creatine-deficiency in mice would be impaired running capacity, and exacerbation of heart failure following myocardial infarction. Methods and Results: Surprisingly, mice with whole-body creatine deficiency due to knockout of the biosynthetic enzyme (guanidinoacetate N-methyltransferase [GAMT]) voluntarily ran just as fast and as far as controls (&gt;10 km/night) and performed the same level of work when tested to exhaustion on a treadmill. Furthermore, survival following myocardial infarction was not altered, nor was subsequent left ventricular (LV) remodelling and development of chronic heart failure exacerbated, as measured by 3D-echocardiography and invasive hemodynamics. These findings could not be accounted for by compensatory adaptations, with no differences detected between WT and GAMT −/− proteomes. Alternative phosphotransfer mechanisms were explored; adenylate kinase activity was unaltered, and although GAMT −/− hearts accumulated the creatine precursor guanidinoacetate, this had negligible energy-transfer activity, while mitochondria retained near normal function. Conclusions: Creatine-deficient mice show unaltered maximal exercise capacity and response to chronic myocardial infarction, and no obvious metabolic adaptations. Our results question the paradigm that creatine is essential for high workload and chronic stress responses in heart and skeletal muscle.

ASSOCIATION BETWEEN GLOBAL LEFT VENTRICULAR LONGITUDINAL STRAIN AND LEFT VENTRICULAR REMODELING AFTER STEMI

Myocardial infarct size is a major determinant of subsequent left ventricular (LV) remodeling after ST-segment elevation myocardial infarction (STEMI). Global longitudinal strain (GLS) has been proposed as a novel marker of infarct size. We aimed to assess whether baseline LV GLS is associated with