Progression Of Cardiac Remodeling Research Articles

Equal stroke volumes, different costs: left ventricular 4D flow in normal and failing hearts

Summary Although total left ventricular (LV) stroke volume (SV) is equal in healthy subjects and heart failure patients with mild LV remodeling, the SV’s transventricular flow paths to ejection and diastolic energetics are different. These flow-specific markers of inefficiency of the failing heart are detectable prior to clinical decompensation, and might be predictors of progressive adverse cardiac remodeling. Background Heart failure is a common disorder with a dismal prognosis. Cardiac remodeling is a key component of heart failure that progresses from adaptive to maladaptive as the disease worsens, and is associated with increased risks of symptoms and mortality. In earlier stages of heart failure with adaptive remodeling, patients may remain clinically compensated and the failing heart’ sl eft ventricular (LV) stroke volume (SV) remains the same as in the normal heart. Recently, time-varying and complex three-dimensional flow patterns and energetics within the normal LV have been demonstrated. Based on such 4D flow-specific measures, we hypothesized that while the SV of normal and failing LVs may be equal, the SV’s diastolic kinetic energy (KE) and transventricular routes to ejection are different in the two states. Methods In ten patients with dilated cardiomyopathy (DCM) (6 females, 49±14 years [mean±SD]) and ten healthy subjects (4 female, 44±17 years), 4D phase-contrast CMR velocity data and morphological data were acquired at 1.5T (Philips Achieva). A previously validated method was used for the analysis: The LV endocardium was segmented from the morphological images at end-diastole (ED) and end-systole. Pathlines were emitted from the ED blood volume and traced forward and backward in time until end-systole, allowing separation of the Total SV into two flow components (figure 1): 1) Blood that enters and leaves the LV during the analyzed cardiac cycle (Direct SV), and 2) Blood that leaves but does not enter the LV during the analyzed cardiac cycle (Delayed SV). The KE was calculated over the cardiac cycle for these flow components based on the volume occupied by each pathline, its velocity, and blood density. Results The LV ED volume was larger and LV ejection fraction was smaller in DCM compared to healthy (179±33 vs 147±22 ml, p=0.021, and 42±5 vs 54±6 %, p<0.001, respectively). While the Total SV was equal in the two groups (77±19 vs 79±16 ml, p=0.8), the Direct SV represented a significantly smaller part of the Total SV in DCM compared to healthy (45±11 vs 69±5 %, p<0.001) (figure 2). At ED, the “KE of the Direct SV” / “KE of the Total SV”-ratio was lower in DCM compared to healthy (47±15 vs 76±7 %, p<0.001) (figure 2). Conclusions Although total LV stroke volume is equal in healthy subjects and in clinically compensated heart failure patients with mild LV remodeling, the diastolic routes through the LV and pre-systolic energetics of the SV are significantly different in the two states. Inefficient flow may augment the chronic stress on the failing heart’s reserve, promoting progressive maladaptive cardiac remodeling.

Agonist-Independent Constitutive Activity of Angiotensin II Receptor Promotes Cardiac Remodeling in Mice

The angiotensin II (Ang II) type 1 (AT(1)) receptor mainly mediates the physiological and pathological actions of Ang II, but recent studies have suggested that AT(1) receptor inherently shows spontaneous constitutive activity even in the absence of Ang II in culture cells. To elucidate the role of Ang II-independent AT(1) receptor activation in the pathogenesis of cardiac remodeling, we generated transgenic mice overexpressing AT(1) receptor under the control of α-myosin heavy chain promoter in angiotensinogen-knockout background (AT(1)Tg-AgtKO mice). In AT(1)Tg-AgtKO hearts, redistributions of the Gα(q11) subunit into cytosol and phosphorylation of extracellular signal-regulated kinases were significantly increased, compared with angiotensinogen-knockout mice hearts, suggesting that the AT(1) receptor is constitutively activated independent of Ang II. As a consequence, AT(1)Tg-AgtKO mice showed spontaneous systolic dysfunction and chamber dilatation, accompanied by severe interstitial fibrosis. Progression of cardiac remodeling in AT(1)Tg-AgtKO mice was prevented by treatment with candesartan, an inverse agonist for the AT(1) receptor, but not by its derivative candesartan-7H, deficient of inverse agonism attributed to a lack of the carboxyl group at the benzimidazole ring. Our results demonstrate that constitutive activity of the AT(1) receptor under basal conditions contributes to the cardiac remodeling even in the absence of Ang II, when the AT(1) receptor is upregulated in the heart.

Modulation of cardiac fibroblast function by thiazolidinediones with a focus on the role of LOX-1.

Cardiac fibroblasts play a pivotal role in cardiac remodeling. In response to various pro-fibrotic stimuli, such as pro-inflammatory cytokines, anoxia-reoxygenation and pressure overload as well as aging, cardiac fibroblasts undergo proliferation, migration and activation, leading to the accumulation of extracellular matrix components and increased thickness and stiffness of heart. The ligands for peroxisome proliferator-activated receptor γ, especially thiazolidinediones, modulate the function of cardiac fibroblasts and the progression of cardiac remodeling, especially under pathological conditions. Unfortunately these agents have not been found to be consistently beneficial in heart failure. Although the precise intracellular signaling pathways are not fully understood, existing evidence strongly supports the involvement of oxidative stress and related signaling pathways. Further, peroxisome proliferator-activated receptor γ and lectin-like oxidized low-density lipoprotein receptor-1 together play critical roles in thiazolidinediones-modulated cardiac fibroblast dysfunction.

Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats

Fetal hypoxia leads to progressive cardiac remodeling in rat offspring. The present study tested the hypothesis that maternal hypoxia results in reprogramming of matrix metalloproteinase (MMP) expression patterns and fibrillar collagen matrix in the developing heart. Pregnant rats were treated with normoxia or hypoxia (10.5% O(2)) from day 15 to 21 of gestation. Hearts were isolated from 21-day fetuses (E21) and postnatal day 7 pups (PD7). Maternal hypoxia caused a decrease in the body weight of both E21 and PD7. The heart-to-body weight ratio was increased in E21 but not in PD7. Left ventricular myocardium wall thickness and cardiomyocyte proliferation were significantly decreased in both fetal and neonatal hearts. Hypoxia had no effect on fibrillar collagen content in the fetal heart, but significantly increased the collagen content in the neonatal heart. Western blotting revealed that maternal hypoxia significantly increased collagen I, but not collagen III, levels in the neonatal heart. Maternal hypoxia decreased MMP-1 but increased MMP-13 and membrane type (MT)1-MMP in the fetal heart. In the neonatal heart, MMP-1 and MMP-13 were significantly increased. Active MMP-2 and MMP-9 levels and activities were not altered in either fetal or neonatal hearts. Hypoxia significantly increased tissue inhibitors of metalloproteinase (TIMP)-3 and TIMP-4 in both fetal and neonatal hearts. In contrast, TIMP-1 and TIMP-2 were not affected. The results demonstrate that in utero hypoxia reprograms the expression patterns of MMPs and TIMPs and causes cardiac tissue remodeling with the increased collagen deposition in the developing heart.

CGMP-PKG upregulates PGC1α and improves cardiac function in advanced cardiac hypertrophy independently of RGS2

Results Impaired mitochondrial respiration was observed in advanced stage dilative 9wk TAC hearts, associated with down-regulation of PGC1a, but not in 1-3 wk TAC hearts. Delayed sildenafil treatment (100mg/kg/day) initiated after hypertrophy establishment (1-3 wk TAC) inhibited progression of remodeling up to 9wks, which was associated with restored PGC1a expression and preserved mitochondrial function, but not with RGS2 activation. Mice lacking RGS2 develop exacerbated early hypertrophy (1wk TAC) which is unresponsive to sildenafil, whereas sildenafil treatment initiated after 1wk ameliorated long term (up to 7wk) progression of cardiac remodeling and function, with restored PGC1a expression and improved mitochondrial respiratory function. Importantly, similar findings were obtained in PKG1a leucine zipper knock-in animals, wherein RGS2-PKG interaction is disrupted. In rat neonatal cardiac myocytes (RNCM), 72hr exposure to phenylephrine (Gq agonist, 20μM) down-regulated PGC1a and impaired mitochondrial respiration, both of which were normalized by sildenafil co-treatment (1μM). Over-expression of PKG up-regulated PGC1a in RNCM, increasing mitochondrial respiration, whereas this was not observed when PGC1a was silenced.

Pre-clinical data on involvement of mineralocorticoid receptor activation in healing and remodelling post-myocardial infarction

Myocardial infarction (MI) is one of the leading causes of death. Therapeutic strategies that target pathophysiological mechanisms of infarct healing and that improve cardiac remodeling after MI appear to be useful tools to prevent progressive myocardial dysfunction, heart failure and sudden death. Recent preclinical data highlight that activation of the mineralocorticoid receptor (MR) plays a pivotal role in post-infarct healing and remodelling. Immediate MR blockade after MI enhanced infarct neovascularization and reduced early myocardial dilatation and dysfunction. Moreover, cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure. This review summarizes new insights into the involvement of MR activation in wound healing and remodelling after myocardial infarction.

El aumento de la expresión del ARNm de la enzima convertidora de angiotensina I homóloga (ECA-2) inducido por atorvastatina se asocia a menor fibrosis e hipertrofia ventricular izquierda en un modelo de cardiomiopatía diabética

This study has investigated the effect of atorvastatin on the progression of cardiac remodelling and ACE- 2 expression in diabetic myocardium in rats. Diabetes was induced in Holtzman rats with an intraperitoneal injection of streptozotocin. The animals were divided into 3 groups: (1) normal control rats, (2) diabetic rats and (3) diabetic rats treated orally with atorvastatin (50 mg/kg/day). After eight weeks of treatment, the hearts were removed for morphometric studies, collagen content assay and genetic expressions of ACE and ACE2 mRNA. Myocardial hypertrophy index and collagen deposition were increased in diabetic rats, but not in the treated-diabetic rats, without producing changes in cholesterol levels. Myocardial ACE mRNA levels were increased while ACE2 mRNA levels were decreased in diabetic rats. Atorvastatin administration attenuated overexpression of ACE mRNA and overexpression of ACE-2 mRNA in diabetic rats. Our results indicate that atorvastatin, independently of its cholesterol-lowering capacity, lowers the ACE/ACE2 ratio to normal values and attenuates the development of adverse remodeling in the diabetic heart.

Cardiac remodeling caused by transgenic overexpression of a corn Rac gene

Rac1-GTPase activation plays a key role in the development and progression of cardiac remodeling. Therefore, we engineered a transgenic mouse model by overexpressing cDNA of a constitutively active form of Zea maize Rac gene (ZmRacD) specifically in the hearts of FVB/N mice. Echocardiography and MRI analyses showed cardiac hypertrophy in old transgenic mice, as evidenced by increased left ventricular (LV) mass and LV mass-to-body weight ratio, which are associated with relative ventricular chamber dilation and systolic dysfunction. LV hypertrophy in the hearts of old transgenic mice was further confirmed by an increased heart weight-to-body weight ratio and histopathology analysis. The cardiac remodeling in old transgenic mice was coupled with increased myocardial Rac-GTPase activity (372%) and ROS production (462%). There were also increases in α(1)-integrin (224%) and β(1)-integrin (240%) expression. This led to the activation of hypertrophic signaling pathways, e.g., ERK1/2 (295%) and JNK (223%). Pravastatin treatment led to inhibition of Rac-GTPase activity and integrin signaling. Interestingly, activation of ZmRacD expression with thyroxin led to cardiac dilation and systolic dysfunction in adult transgenic mice within 2 wk. In conclusion, this is the first study to show the conservation of Rho/Rac proteins between plant and animal kingdoms in vivo. Additionally, ZmRacD is a novel transgenic model that gradually develops a cardiac phenotype with aging. Furthermore, the shift from cardiac hypertrophy to dilated hearts via thyroxin treatment will provide us with an excellent system to study the temporal changes in cardiac signaling from adaptive to maladaptive hypertrophy and heart failure.

The effects of maternal hypoxia on the heart development in fetal and neonatal rats

Fetal hypoxia leads to progressive cardiac remodeling in the rat offspring. Our objective is to determine the effects of hypoxia on heart remodeling in fetus and neonates. Pregnant rats were treated with normoxia or hypoxia (10.5% O2) from day 15 to 21 of gestation. Hearts were isolated from 21‐day fetuses (E21) and 7‐day‐old pups (PD7). The fibrillar collagen was examined by scanning electron microscopy (SEM). The expression of matrix metalloproteinases (MMP) 1, 2, 9 &amp; 13, tissue inhibitors of metalloproteinases (TIMP) 1, 2, 3 and collagen 1 &amp; 3 in the heart was measured by Western blots. Maternal hypoxia caused a significant decrease in the body weight of the pups at both E21 and PD7. The heart weight was decreased at PD7, but not in E21. SEM indicated less amount of fibrillar collagen at E21 but greater amount of collagen at PD7 in the heart of hypoxic pups, as compared with those of control animals. Myocardium wall thickness was decreased by hypoxia in both E21 and PD7. Hypoxia also reduced collagen‐1 and MMP‐1 in fetuses, while increased collagen‐1 and MMP‐1 in neonates. MMP‐13 was enhanced in fetuses but reduced in neonates, while TIMP‐3 level was increased in both developmental stages. There was no change in MMP‐2 &amp; 9, TIMP‐1 &amp; 2 and collagen‐3. Maternal hypoxia results in differential remodeling of fibrillar collagen in fetal and neonatal hearts, which may be mediated by the altered expression patterns of MMPs and TIMPs.

Inflammation and Apoptosis in the Myocardium in rats following Myocardial Infarction

Following myocardial infarction (MI) a variety of mechanisms contribute to progressive cardiac remodelling and dysfunction. The objective of this study is to assess changes in inflammation and apoptosis in the myocardium of the left ventricle (LV) after MI. Rats were subjected to left anterior descending coronary artery occlusion, and studied 10 days, 4 weeks and 16 weeks after surgery. MI size was ~40% of LV. LVEDP increased to ~15mmHg. TNF-α, IL-6, IL-1β and IL-10 showed no significant changes in the non-infarcted LV. Macrophages were not found in the non-infarcted LV in either MI or sham rats. Apoptosis was absent in sham rats. Macrophage Immunohistochemistry: (macrophages/field 515x1158 μm) Peri-Infarcted Infarct 10 days MI n=7 127±16 144±12 4 weeks MI n=13 13±2.5 53±4.7 16 weeks MI n=10 2±0.6 28±5.7 Apoptotic Index: (% TUNEL stained cardiac nuclei in 2x2mm field) Non-Infarcted Peri-Infarcted Infarct 10 days MI n=6 0.5±0.3 1.3±0.7 2.6±0.5 4 weeks MI n=3 0±0 0±0 0±0 16 weeks MI n=2 0.6±0.6 0±0 0±0 After MI there is a rapid increase in macrophages and TUNEL staining in the infarct and peri-infarcted myocardium which both decrease over subsequent weeks. There is no inflammation in the non-infarcted myocardium up to 16 weeks post MI. Funding for this project provided by the Canadian Institutes of Health Research.

Soluble Epoxide Hydrolase Inhibitors and Heart Failure

Cardiovascular disease remains one of the leading causes of death in the Western societies. Heart failure (HF) is due primarily to progressive myocardial dysfunction accompanied by myocardial remodeling. Once HF develops, the condition is, in most cases, irreversible and is associated with a very high mortality rate. Soluble epoxide hydrolase (sEH) is an enzyme that catalyzes the hydrolysis of epoxyeicosatrienoic acids (EETs), which are lipid mediators derived from arachidonic acid through the cytochrome P450 epoxygenase pathway. EETs have been shown to have vasodilatory, antiinflammatory, and cardioprotective effects. When EETs are hydrolyzed by sEH to corresponding dihydroxyeicosatrienoic acids, their cardioprotective activities become less pronounced. In line with the recent genetic study that has identified sEH as a susceptibility gene for HF, the sEH enzyme has received considerable attention as an attractive therapeutic target for cardiovascular diseases. Indeed, sEH inhibition has been demonstrated to have antihypertensive and antiinflammatory actions, presumably due to the increased bioavailability of endogenous EETs and other epoxylipids, and several potent sEH inhibitors have been developed and tested in animal models of cardiovascular disease including hypertension, cardiac hypertrophy, and ischemia/reperfusion injury. sEH inhibitor treatment has been shown to effectively prevent pressure overload- and angiotensin II-induced cardiac hypertrophy and reverse the pre-established cardiac hypertrophy caused by chronic pressure overload. Application of sEH inhibitors in several cardiac ischemia/reperfusion injury models reduced infarct size and prevented the progressive cardiac remodeling. Moreover, the use of sEH inhibitors prevented the development of electrical remodeling and ventricular arrhythmias associated with cardiac hypertrophy and ischemia/reperfusion injury. The data published to date support the notion that sEH inhibitors may represent a promising therapeutic approach for combating detrimental cardiac remodeling and HF.

Hybrid approach of ventricular assist device and autologous bone marrow stem cells implantation in end-stage ischemic heart failure enhances myocardial reperfusion

We challenge the hypothesis of enhanced myocardial reperfusion after implanting a left ventricular assist device together with bone marrow mononuclear stem cells in patients with end-stage ischemic cardiomyopathy. Irreversible myocardial loss observed in ischemic cardiomyopathy leads to progressive cardiac remodelling and dysfunction through a complex neurohormonal cascade. New generation assist devices promote myocardial recovery only in patients with dilated or peripartum cardiomyopathy. In the setting of diffuse myocardial ischemia not amenable to revascularization, native myocardial recovery has not been observed after implantation of an assist device as destination therapy. The hybrid approach of implanting autologous bone marrow stem cells during assist device implantation may eventually improve native cardiac function, which may be associated with a better prognosis eventually ameliorating the need for subsequent heart transplantation. The aforementioned hypothesis has to be tested with well-designed prospective multicentre studies.

Deletion of Cardiomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling After Myocardial Infarction

Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR(MLCCre)) that were generated with a conditional MR allele (MR(flox)) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter. Control (MR(flox/flox), MR(flox/wt)) and MR(MLCCre) mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MR(MLCCre) mice. Chronically infarcted MR(MLCCre) mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O(2)(·-) production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR(MLCCre) mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-κB and reduced apoptosis early after myocardial infarction. Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression.

Activation of SUR2B/Kir6.1 Subtype of Adenosine Triphosphate-sensitive Potassium Channel Improves Pressure Overload-induced Cardiac Remodeling via Protecting Endothelial Function

We sought to explore new strategies targeting SUR2B/Kir6.1, a subtype of adenosine triphosphate (ATP)-sensitive potassium channels (KATP), against pressure overload-induced heart failure. The effects of natakalim, a SUR2B/Kir6.1 selective channel opener, on progression of cardiac remodeling were investigated. Pressure overload-induced heart failure was induced in Wistar rats by abdominal aortic banding. The effects of natakalim (1, 3, and 9 mg·kg⁻¹·d⁻¹ for 10 weeks) on myocardial hypertrophy and heart failure, cardiac histology, vasoactive compounds, and gene expression were assessed. Ten weeks after the onset of pressure overload, natakalim treatment potently inhibited cardiac hypertrophy and prevented heart failure. Natakalim remarkably inhibited the changes of left ventricular hemodynamic parameters and reversed the increase of heart mass index, left ventricular weight index, and lung weight index. Histological examination demonstrated that there was no significant hypertrophy or fibrosis in pressure-overloaded hearts of natakalim-treated rats. Ultrastructural examination of hearts revealed well-organized myofibrils with mitochondria grouped along the periphery of longitudinally oriented fibers in rats from the natakalim group. The content of serum nitric oxide and plasma prostacyclin was increased, whereas that of plasma endothelin-1 and cardiac tissue hydroxyproline and atrial and B-type natriuretic peptide messenger RNA was downregulated in natakalim-treated rats. Natakalim at 0.01-100 µM had no effects on isolated working hearts derived from Wistar rats; however, natakalim had endothelium-dependent vasodilatory effects on the isolated tail artery helical strips precontracted with norepinephrine. These results indicate that natakalim reduces heart failure caused by pressure overloading by activating the SUR2B/Kir6.1 KATP channel subtype and protecting against endothelial dysfunction.

Mineralocorticoid receptors, corticosteroids and the heart: where do we stand?

Mineralocorticoid receptors, corticosteroids and the heart: where do we stand?

Brain renin–angiotensin–aldosterone system and ventricular remodeling after myocardial infarct: a reviewThis article is one of a selection of papers published in a special issue on Advances in Cardiovascular Research.

After a myocardial infarct (MI), a variety of mechanisms contribute to progressive cardiac remodeling and dysfunction. Progressive activation of central sympathoexcitatory pathways appears to depend on a neuromodulatory pathway, involving local production of aldosterone and release of endogenous ouabain-like compounds ('ouabain') possibly from magnocellular neurons in the supraoptic and paraventricular nuclei. 'Ouabain' may lower the membrane potential of neurons and thereby enhance activity of angiotensinergic pathways. These central pathways appear to coordinate progressive activation of several peripheral mechanisms such as sympathetic tone and circulating and cardiac renin-angiotensin-aldosterone system (RAAS). Central blockade of aldosterone production, mineralocorticoid receptors, 'ouabain' activity, or AT1 receptors similarly prevents activation of these peripheral mechanisms. Cardiac remodeling after MI involves progressive left ventricular dilation, fibrosis, and decrease in contractile performance. Central blockade of this neuromodulatory pathway causes a marked attenuation of the remodeling and dysfunction, presumably by inhibiting increases in (cardiac) sympathetic activity and RAAS. At the cellular level, these systems may contribute to the cardiac remodeling by activating proinflammatory cytokines and cardiac myocyte apoptosis. New therapeutic approaches, specifically preventing activation of this brain neuromodulatory pathway, may lead to more optimal and specific approaches to the prevention of heart failure after MI.

The accelerated post‐infarction progression of cardiac remodelling is associated with genetic changes in an untreated streptozotocin‐induced diabetic rat model

The mechanism by which diabetes mellitus exacerbates myocardial injury and the incidence of heart failure after acute myocardial infarction (AMI), remains unclear. We studied the severity of cardiac dysfunction and time-dependent gene expression in a hyperglycaemic rat model with AMI. The diabetic model was produced by injection of streptozotocin in Sprague-Dawley rats. Ten weeks after induction of diabetes, AMI was induced by ligation of the left anterior descending coronary artery. Cardiac function and left ventricular (LV) dimensions were evaluated using two-dimensional echocardiography. Structural changes were assessed by histological examination. Gene expression profile was documented by using affymetrix genechip U230 2.0 array and real time-PCR. During 56 days post-AMI, lower survival rates, worse LV function, more severe fibrosis, and larger LV diameters were identified in diabetic rats compared with non-diabetic rats. A total 1221 genes involved in processes, such as glucose metabolism, fatty acid metabolism, extracellular matrix, and apoptosis, were found to be differentially expressed between diabetic and non-diabetic rats, of these 770 were up-regulated and 451 down-regulated. Up-regulation of the genes was found 1-2 weeks earlier in diabetic rats than in non-diabetic rats. The present data suggest that hyperglycaemia up-regulates remodelling-related genes, which may be responsible for the worse outcomes in diabetics than in non-diabetics after AMI.

Beneficial effects of soluble epoxide hydrolase inhibitors in myocardial infarction model: Insight gained using metabolomic approaches

Myocardial infarction (MI) leading to myocardial cell loss represents one of the common causes leading to cardiac failure. We have previously demonstrated the beneficial effects of several potent soluble epoxide hydrolase (sEH) inhibitors in cardiac hypertrophy. sEH catalizes the conversion of epoxyeicosatrienoic acids (EETs) to form the corresponding dihydroxyeicosatrienoic acids (DHETs). EETs are products of cytochrome P450 epoxygenases that have vasodilatory properties. Additionally, EETs inhibit the activation of nuclear factor (NF)-κB-mediated gene transcription. Motivated by the potential to uncover a new class of therapeutic agents for cardiovascular diseases which can be effectively used in clinical setting, we directly tested the biological effects of sEH inhibitors (sEHIs) on the progression of cardiac remodeling using a clinically relevant murine model of MI. We demonstrated that sEHIs were highly effective in the prevention of progressive cardiac remodeling post MI. Using metabolomic profiling of the inflammatory lipid mediators, we documented a significant decrease in EETs/DHETs ratio in MI model predicting a heightened inflammatory state. Treatment with sEHIs resulted in a change in the pattern of lipid mediators from one of inflammation towards resolution. Moreover, the oxylipin profiling showed a striking parallel to the changes in inflammatory cytokines in this model. Our study provides evidence for a possible new therapeutic strategy to improve cardiac function post MI.

Time-dependent changes of myocardial and systemic oxidative stress are dissociated after myocardial infarction

Reactive oxygen species (ROS) is increased in myocardium after myocardial infarction (MI), which may play a causal role in cardiac remodelling. However, there is scant direct and longitudinal evidence that systemic oxidative stress is enhanced accompanying an increase of ROS in myocardium. The authors conducted a comprehensive investigation of ROS markers by simultaneously sampling urine, blood and myocardium and in vivo ESR for the heart at different stages of post-MI cardiac remodelling in mouse with permanent occlusion of left coronary artery. Systemic oxidative markers increased at early days after MI and were normalized later. In contrast, TBARS and 4-hexanoyl-Lys staining were increased in non-infarct myocardium at day 28. The enhancement of ESR signal decay of methoxycarbonyl-PROXYL measured at the chest was associated with the progression of left ventricle dilatation and dysfunction. This study provided the direct evidence that redox alteration and production of ROS occurred in myocardium during the progression of cardiac remodelling and failure; however, ROS marker levels in blood and urine do not reflect the production of ROS from failing myocardium.

Biological Pacemaker Engineered by Nonviral Gene Transfer in a Mouse Model of Complete Atrioventricular Block

We hypothesized that a nonviral gene delivery of the hyperpolarization-activated HCN2 channel combined with the beta(2)-adrenergic receptor (ADRB2) would generate a functional pacemaker in a mouse model of complete atrioventricular block (CAVB) induced by radiofrequency ablation of the His bundle. Plasmids encoding HCN2 and ADRB2 mixed with tetronic 304, a poloxamine block copolymer, were injected in the left ventricular free wall (HCN2-ADRB2 mice). Sham mice received a noncoding plasmid. CAVB was induced 5 days later. Ventricular escape rhythms in HCN2-ADRB2 mice were significantly faster than in sham mice at day 15 after ablation and later. In HCN2-ADRB2 mice, QRS complexes were larger than in sham mice and characterized by abnormal axes. Immunostaining of GFP-HCN2 fusion protein showed an expression of HCN2 channel in left ventricular myocardium for at least 45 days after injection. In the mouse, CAVB induces progressive hypertrophy and heart failure leading to 50% mortality after 110 days. HCN2-ADRB2 mice survived 3 weeks longer than sham mice. Finally, beta-adrenergic input increased ventricular escape rhythms significantly more in HCN2-ADRB2 mice than in sham mice. In conclusion, nonviral gene transfer can produce a functional cardiac biological pacemaker regulated by sympathetic input, which improves life expectancy in a mouse model of CAVB.