Postinfarction Heart Failure Research Articles

Treatment with the CC chemokine-binding protein Evasin-4 improves post-infarction myocardial injury and survival in mice

Chemokines trigger leukocyte trafficking and are implicated in cardiovascular disease pathophysiology. Chemokine-binding proteins, called "Evasins" have been shown to inhibit both CC and CXC chemokine-mediated bioactivities. Here, we investigated whether treatment with Evasin-3 (CXC chemokine inhibitor) and Evasin-4 (CC chemokine inhibitor) could influence post-infarction myocardial injury and remodelling. C57Bl/6 mice were submitted in vivo to left coronary artery permanent ligature and followed up for different times (up to 21 days). After coronary occlusion, three intraperitoneal injections of 10 μg Evasin-3, 1 μg Evasin-4 or equal volume of vehicle (PBS) were performed at 5 minutes, 24 hours (h) and 48 h after ischaemia onset. Both anti-chemokine treatments were associated with the beneficial reduction in infarct size as compared to controls. This effect was accompanied by a decrease in post-infarction myocardial leukocyte infiltration, reactive oxygen species release, and circulating levels of CXCL1 and CCL2. Treatment with Evasin-4 induced a more potent effect, abrogating the inflammation already at one day after ischaemia onset. At days 1 and 21 after ischaemia onset, both anti-chemokine treatments failed to significantly improve cardiac function, remodelling and scar formation. At 21-day follow-up, mouse survival was exclusively improved by Evasin-4 treatment when compared to control vehicle. In conclusion, we showed that the selective inhibition of CC chemokines (i.e. CCL5) with Evasin-4 reduced cardiac injury/inflammation and improved survival. Despite the inhibition of CXC chemokine bioactivities, Evasin-3 did not affect mouse survival. Therefore, early inhibition of CC chemokines might represent a promising therapeutic approach to reduce the development of post-infarction heart failure in mice.

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

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

Reversal of metabolic shift in post-infarct-remodelled hearts: possible novel therapeutic approach

This editorial refers to ‘Infarct-remodelled hearts with limited oxidative capacity boost fatty acid oxidation after conditioning against ischaemia/reperfusion injury’ by P.-H. Lou et al ., doi:10.1093/cvr/cvs323. With sophistication and improvement in coronary revascularization therapy, the chances of patients surviving acute myocardial infarction have been increasing. Though the procedure is life-saving, it also predisposes the patients to post-infarction ventricular remodelling and consequent heart failure. Since those patients usually have atherosclerotic lesions not only in the culprit vessel in the infarction but also in some part of the coronary artery, the likelihood of them having re-infarction is substantial. The mortality of patients with re-infarction has been reported to be more than twice as high as that by the first attack,1 probably due, at least in part, to disrupted intrinsic cardioprotective signalling in post-infarct-remodelled hearts.2 In addition to the change in intracellular signal transduction, it has been well established that a so-called metabolic shift takes place as cardiac hypertrophy and heart failure develop. In healthy hearts, oxidation of fatty acids (FAs) covers >70% of the cardiac energy need, with most of the remainder being accounted for by glucose oxidation.3 On the other hand, hearts change their substrate preference from FAs towards glucose as remodelling develops in response to diverse stresses.3 The oxidation of one molecule of FAs yields far more ATP (∼129 ATP in the case of palmitate) than glucose (∼36 ATP). Therefore, glucose oxidation can hardly compensate for the decrease in ATP synthesis when the oxidation of FAs …

The functional activity of inhibitory G protein (Gi) is not increased in failing heart ventricle

Beta-adrenergic receptor (βAR) inotropic effects are attenuated and muscarinic receptor-mediated inhibition thereof is enhanced in heart failure. We investigated if increased Gi activity contributes to attenuated βAR-inotropic effects and potentiates muscarinic accentuated antagonism in failing rat ventricle. Contractility was measured in ventricular strips and adenylyl cyclase (AC) activity in ventricular membranes from rats with post-infarction heart failure (HF) or Sham-operated controls (Sham). The maximal βAR-mediated inotropic effect of isoproterenol was reduced by ~70% and basal, βAR- & forskolin-stimulated AC activity was significantly lower in HF vs. Sham. Carbachol-evoked antagonism of the βAR-mediated inotropic response was complete only in HF despite a ~40% reduction in the ability of carbachol to inhibit βAR-stimulated AC. However, neither the relative efficacy (contractility decreased by ~46%) nor the potency of carbachol to inhibit the βAR inotropic response differed between Sham and HF ventricle. Pertussis toxin (PTX) inactivation of Gi did not increase the maximal βAR inotropic effect or the attenuated basal, βAR- & forskolin-stimulated AC activity in HF, but increased the potency of isoproterenol only in Sham (~0.5 log unit). In HF ventricle pretreated with PTX, simultaneous inhibition of phosphodiesterases 3,4 (PDE3,4) alone produced a larger inotropic response than isoproterenol in ventricle untreated with PTX (84% and 48% above basal respectively). In the absence of PTX, PDE3,4 inhibition evoked negligible inotropic effects in HF. These data are not consistent with the hypothesis that increased Gi activity contributes to the reduced βAR-mediated inotropic response and AC activity in failing ventricle. The data, however, support the hypothesis that Gi, through chronic receptor independent inhibition of AC, together with PDE3,4 activity, is necessary to maintain a low basal level of contractility.

Abstract 9711: Cardioprotection by Endogenous Cardiac Myocyte P2x4; Receptors in Pressure Overload and Ischemic Heart Failure

Despite progress in its therapy, heart failure is a leading cause of mortality and morbidity. In defining a biological role of the ligand-gated ion channel P2X4 receptor, we uncovered a protective role of this channel in heart failure. P2X4 gene was flanked by loxP sites bwteen exons 2 and 4. The second loxP site together with the Frt-PGKneo-Frt cassette was inserted in intron 1 in a direction opposite to P2X4 transcription. After targeting the ES cells, PGKneo was removed by breeding chimeric males with ROSA26-Flpe females to generate P2X4 flox/+ F1 pups. To create cardiac myocyte-specific knockout of P2X4 receptors, homozygous P2X4 floxed/floxed mice were bred with Tg mice (Myh6-cre/Esr1*, Jax stock no: 005650) containing a tamoxifen responsive Cre-estrogen receptor chimeric recombinase driven by the α-myosin heavy chain promoter. Knockout of P2X4 receptors (KO) was confirmed by lack of detectable P2X4 with immunoblotting and by lack of contractile response to the P2X agonist 2-methylthioATP. KO animals showed normal basal cardiac function but depressed contractile performance in both left coronary artery ligation and pressure overload models of heart failure by echocardiography and isolated working heart parameters. By contrast, cardiac myocyte-specific overexpression of the P2X4 receptor protected against pressure overload-induced and post-infarct heart failure. P2X4 receptors co-immunoprecipitated with nitric oxide synthase 3 (NOS3 or eNOS). Administration of eNOS inhibitor L-NIO blocked the salutary effect of cardiac P2X4 receptor overexpression in post-infarct heart failure as did eNOS knockout. The present study uncovered a protective role of endogenous cardiac myocyte P2X4 receptors in heart failure and demonstrated an important role of eNOS in mediating this protection.

Abstract 19698: Altered Dendritic Cell Network in Chronic Heart Failure - Implications for Chronic Inflammation

Although activation of Th1 inflammatory pathways is a hallmark of chronic heart failure (HF), underlying changes in immune effector cells are poorly understood. Dendritic cells (DCs) are orchestrators of T-cell polarization, and thereby can regulate Th1 and Th2 responses. We hypothesized that alterations in the local and systemic DC network, and tissue DC trafficking, underlie the pro-inflammatory state in HF. Post-infarction HF was studied in adult C57BL/6 mice 8 wks following left coronary ligation; sham operated mice served as controls. Pathological remodeling and HF were verified by echocardiography, hemodynamics, gravimetry and histology. Cardiac interstitial cells were isolated by collagenase digestion of the heart followed by density gradient centrifugation; standard isolation procedures were used to isolate splenic, BM, and PB cells. We characterized two major DC subsets using flow cytometry: 1) classical DCs (cDCs, CD11c+B220-) that initiate adaptive immune responses and enhance interferon production from T cells, and 2) plasmacytoid DCs (pDCs, CD11c+B220+) that upon proper stimulation can produce pro-inflammatory cytokines that polarize T cells to a Th1 phenotype or, alternatively, suppress adaptive immunity. Compared with sham-operated mice, HF mice exhibited significantly (p < 0.05) increased cDCs in PB (3.65±0.34 vs 1.36±0.27%), spleen (3.65±0.41 vs 2.35±0.22%), and heart (4.22±0.15 vs 3.1±0.40%), but no changes in BM. A major cDC subset, CD11c+B220-CD8+ cells, preferentially endocytose dying cells and stimulate Th1 CD4+ T cell responses. In HF mice, these cDCs significantly (p < 0.01) increased in PB (0.17±0.018 vs 0.053±0.017%) and spleen (0.35±0.035 vs 0.21±0.027%). Additionally, there were significant (p < 0.05) increases in pDCs in the heart (2.55±0.44 vs 0.60±0.30%), spleen (2.32±0.40 0.90±0.11%) and BM (1.30±0.10 vs 1.02±0.08%), but no changes observed in PB as compared with sham. Hence, we conclude that in HF, there are augmented cDCs and pDCs locally in the heart and selective alterations in the PB, spleen, and BM that together support the development of systemic Th1 responses. A better understanding of DC networks in HF can elucidate the mechanisms of pathological inflammation and lead to novel therapeutic approaches.

Isolation and Characterization of CD276+/HLA-E+ Human Subendocardial Mesenchymal Stem Cells from Chronic Heart Failure Patients: Analysis of Differentiative Potential and Immunomodulatory Markers Expression

Mesenchymal stem cells (MSCs) are virtually present in all postnatal organs as well as in perinatal tissues. MSCs can be differentiated toward several mature cytotypes and interestingly hold potentially relevant immunomodulatory features. Myocardial infarction results in severe tissue damage, cardiomyocyte loss, and eventually heart failure. Cellular cardiomyoplasty represents a promising approach for myocardial repair. Clinical trials using MSCs are underway for a number of heart diseases, even if their outcomes are hampered by low long-term improvements and the possible presence of complications related to cellular therapy administration. Therefore, elucidating the presence and role of MSCs that reside in the post-infarct human heart should provide essential alternatives for therapy. In the current article we show a novel method to reproducibly isolate and culture MSCs from the subendocardial zone of human left ventricle from patients undergoing heart transplant for post-infarct chronic heart failure (HSE-MSCs, human subendocardial mesenchymal stem cells). By using both immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR), we demonstrated that these cells do express key MSCs markers and do express heart-specific transcription factors in their undifferentiated state, while lacking strictly cardiomyocyte-specific proteins. Moreover, these cells do express immunomodulatory molecules that should disclose their further potential in immune modulation processes in the post-infarct microenvironment. Another novel datum of potentially relevant interest is the expression of cardiac myosin heavy chain at nucclear level in HSE-MSCs. Standard MSCs trilineage differentiation experiments were also performed. The present paper adds new data on the basic biological features of heart-resident MSCs that populate the organ following myocardial infarction. The use of heart-derived MSCs to promote in-organ repair or as a cellular source for cardiomyoplasty is a fascinating and challenging task, which deserves further research efforts.

The Activation of (Pro)renin Receptor Plays an Important Role on the Development of Insulin Resistance in Experimental Post-infarct Heart Failure

The Activation of (Pro)renin Receptor Plays an Important Role on the Development of Insulin Resistance in Experimental Post-infarct Heart Failure

The Cardiac Ventricular 5-HT4 Receptor Is Functional in Late Foetal Development and Is Reactivated in Heart Failure

A positive inotropic responsiveness to serotonin, mediated by 5-HT4 and 5-HT2A receptors, appears in the ventricle of rats with post-infarction congestive heart failure (HF) and pressure overload-induced hypertrophy. A hallmark of HF is a transition towards a foetal genotype which correlates with loss of cardiac functions. Thus, we wanted to investigate whether the foetal and neonatal cardiac ventricle displays serotonin responsiveness. Wistar rat hearts were collected day 3 and 1 before expected birth (days -3 and -1), as well as day 1, 3, 5 and 113 (age matched with Sham and HF) after birth. Hearts from post-infarction HF and sham-operated animals (Sham) were also collected. Heart tissue was examined for mRNA expression of 5-HT4, 5-HT2A and 5-HT2B serotonin receptors, 5-HT transporter, atrial natriuretic peptide (ANP) and myosin heavy chain (MHC)-α and MHC-β (real-time quantitative RT-PCR) as well as 5-HT-receptor-mediated increase in contractile function ex vivo (electrical field stimulation of ventricular strips from foetal and neonatal rats and left ventricular papillary muscle from adult rats in organ bath). Both 5-HT4 mRNA expression and functional responses were highest at day -3 and decreased gradually to day 5, with a further decrease to adult levels. In HF, receptor mRNA levels and functional responses reappeared, but to lower levels than in the foetal ventricle. The 5-HT2A and 5-HT2B receptor mRNA levels increased to a maximum immediately after birth, but of these, only the 5-HT2A receptor mediated a positive inotropic response. We suggest that the 5-HT4 receptor is a representative of a foetal cardiac gene program, functional in late foetal development and reactivated in heart failure.

The role of aldosterone receptor antagonists in the management of heart failure: An update

The aldosterone receptor antagonists (ARAs) spironolactone (Aldactone) and eplerenone (Inspra) have become part of standard medical therapy for heart failure, having shown clinical efficacy in randomized trials in patients with advanced symptomatic systolic heart failure, postinfarction heart failure with cardiac dysfunction, and systolic heart failure with mild symptoms. The benefits include a lower rate of death. Yet to be answered is whether the two drugs are clinically equivalent; another question is whether they may benefit everyone with symptomatic heart failure, including diastolic heart failure.

Elevated Levels of the Mediator of Catabolic Bone Remodeling RANKL in the Bone Marrow Environment Link Chronic Heart Failure with Osteoporosis

Chronic heart failure (CHF) is associated with a 4-fold increased risk for osteoporotic fractures. Therefore, we sought to identify the pathophysiological link between chronic heart failure and catabolic bone remodeling. In a total cohort of 153 subjects (123 patients with CHF, 30 patients with coronary artery disease and preserved cardiac function) as well as mice with heart failure, bone marrow (BM) plasma levels of the catabolic receptor activator of NF-κB ligand (RANKL), and its antagonist, osteoprotegerin were measured. The osteoclast inducing activity of BM plasma was tested in cell culture. BM plasma levels of RANKL and of the ratio RANKL/osteoprotegerin were significantly elevated in patients with CHF. On multivariate regression analysis, parameters of severity and duration of heart failure were independent determinants of elevated BM plasma RANKL levels. BM plasma levels of RANKL were directly correlated with the systemic marker of bone turnover C-telopeptide of type 1 collagen (r=0.6; P<0.001). Alterations in BM plasma levels of RANKL/osteoprotegerin were confirmed in a mouse model of postinfarction heart failure. Stimulation of human mesenchymal cells with BM plasma obtained from CHF patients increased the formation of osteoclasts, and this effect was blocked by the RANKL inhibition. CHF is associated with a profound and selective elevation of the bone resorption stimulating RANKL within the BM microenvironment. These data for the first time disclose a direct pathophysiological pathway linking CHF with catabolic bone remodeling associated with an increased osteoporotic fracture risk. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT 00289822, NCT 00284713, NCT 00326989, NCT 00962364.

Role for MicroRNA-21 in Atrial Profibrillatory Fibrotic Remodeling Associated With Experimental Postinfarction Heart Failure

Atrial tissue fibrosis is often an important component of the atrial fibrillation (AF) substrate. Small noncoding microRNAs are important mediators in many cardiac remodeling paradigms. MicroRNA-21 (miR-21) has been suggested to be important in ventricular fibrotic remodeling by downregulating Sprouty-1, a protein that suppresses fibroblast proliferation. The present study examined the potential role of miR-21 in the atrial AF substrate resulting from experimental heart failure after myocardial infarction (MI). Large MIs (based on echocardiographic left ventricular wall motion score index) were created by left anterior descending coronary artery ligation in rats. Changes induced by MI versus sham controls were first characterized with echocardiography, histology, biochemistry, and in vivo electrophysiology. Additional MI rats were then randomized to receive anti-miR-21 (KD21) or scrambled control sequence (Scr21) injections into the left atrial myocardium. Progressive left ventricular enlargement, hypocontractility, left atrial dilation, fibrosis, refractoriness prolongation, and AF promotion occurred in MI rats versus sham controls. Atrial tissues of MI rats showed upregulation of miR-21, along with dysregulation of the target genes Sprouty-1, collagen-1, and collagen-3. KD21 treatment reduced atrial miR-21 expression levels in MI rats to values in sham rats, decreased AF duration from 417 (69-1595; median [Q1-Q3]) seconds to 3 (2-16) seconds (8 weeks after MI; P<0.05), and reduced atrial fibrous tissue content from 14.4 ± 1.8% (mean ± SEM) to 4.9 ± 1.2% (8 weeks after MI; P<0.05) versus Scr21 controls. MI-induced heart failure leads to AF-promoting atrial remodeling in rats. Atrial miR-21 knockdown suppresses atrial fibrosis and AF promotion, implicating miR-21 as an important signaling molecule for the AF substrate and pointing to miR-21 as a potential target for molecular interventions designed to prevent AF.

Predictive value of advanced glycation end products for the development of post-infarction heart failure: a preliminary report

BackgroundSince post-infarction heart failure (HF) determines a great morbidity and mortality, and given the physiopathology implications of advanced glycation end products (AGE) in the genesis of myocardial dysfunction, it was intended to analyze the prognostic value of these molecules in order to predict post-infarction HF development.MethodsA prospective clinical study in patients after first acute coronary syndrome was conducted. The follow-up period was consisted in 1 year. In 194 patients consecutively admitted in the coronary unit for myocardial infarct fluorescent AGE levels were measured. The association between glycaemic parameters and the development of post-infarction HF were analyzed in those patients. Finally, we identified the variables with independent predictor value by performing a multivariate analysis of Hazard ratio for Cox regression.ResultsEleven out of 194 patients (5.6%) developed HF during follow-up (median: 1.0 years [0.8 - 1.5 years]). Even though basal glucose, fructosamine and glycated haemoglobin were significant predictive factors in the univariate analysis, after being adjusted by confounding variables and AGE they lost their statistical signification. Only AGE (Hazard Ratio 1.016, IC 95%: 1.006-1.026; p<0,001), together with NT-proBNP and the infarct extension were predictors for post-infarction HF development, where AGE levels over the median value 5-fold increased the risk of HF development during follow-up.ConclusionsAGE are an independent marker of post-infarction HF development risk.

Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases.

Interleukin-1 (IL-1) is a highly active pro-inflammatory cytokine that lowers pain thresholds and damages tissues. Monotherapy blocking IL-1 activity in autoinflammatory syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function. This approach can therefore be effective in treating common conditions such as post-infarction heart failure, and trials targeting a broad spectrum of new indications are underway. So far, three IL-1-targeted agents have been approved: the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept and the neutralizing monoclonal anti-IL-1β antibody canakinumab. In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α antibody are in clinical trials.

Defining Heart Failure End Points in ST-Segment Elevation Myocardial Infarction Trials

Mortality rates for patients with acute myocardial infarction (MI) continue to decline as evidence-based therapies are implemented on a broader scale, invasive management and revascularization are more widely used, and reperfusion times for patients with acute ST-segment elevation myocardial infarction (STEMI) are shortened.1,2 Recent data from the Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines (ACTION Registry-GWTG) in the United States demonstrated that, by 2009, risk-adjusted in-hospital mortality had decreased to 5.5% among STEMI patients treated in routine practice.3 In addition, mortality rates through and beyond 1 year among STEMI patients treated with primary percutaneous coronary intervention (PCI) enrolled in recent clinical trials have declined by 3% to 6%.4,5 Yet, improvements in survival demonstrated with STEMI patients may be tempered by the consequent morbidity of postinfarction heart failure (HF), which, unfortunately remains a common clinical event.6 Acute STEMI is an independent predictor of HF at admission, and the development of HF among STEMI patients is associated with a much higher long-term mortality rate compared with patients who do not develop HF.7 Because mortality rates for STEMI patients have declined and reinfarction rates have been shown to be low with the widespread use of primary PCI, attention has shifted toward reducing postinfarction HF because this outcome is thought to reflect the downstream impact of acute therapies for STEMI. There are multiple convergent trends that could contribute to the rising prevalence of HF after STEMI, including an aging population and a decrease in sudden cardiac death because of defibrillator therapy. Fortunately, though, HF hospitalizations are declining nationwide,8 partially because of a declining risk of postinfarction HF.9,10 Given that ischemic heart disease is the most common cause of HF,11 the relationship of improvements in upstream treatment …

Secretogranin II; a protein increased in the myocardium and circulation in heart failure with cardioprotective properties.

BackgroundSeveral beneficial effects have been demonstrated for secretogranin II (SgII) in non-cardiac tissue. As cardiac production of chromogranin A and B, two related proteins, is increased in heart failure (HF), we hypothesized that SgII could play a role in cardiovascular pathophysiology.Methodology/Principal FindingsSgII production was characterized in a post-myocardial infarction heart failure (HF) mouse model, functional properties explored in experimental models, and circulating levels measured in mice and patients with stable HF of moderate severity. SgII mRNA levels were 10.5 fold upregulated in the left ventricle (LV) of animals with myocardial infarction and HF (p<0.001 vs. sham-operated animals). SgII protein levels were also increased in the LV, but not in other organs investigated. SgII was produced in several cell types in the myocardium and cardiomyocyte synthesis of SgII was potently induced by transforming growth factor-β and norepinephrine stimulation in vitro. Processing of SgII to shorter peptides was enhanced in the failing myocardium due to increased levels of the proteases PC1/3 and PC2 and circulating SgII levels were increased in mice with HF. Examining a pathophysiological role of SgII in the initial phase of post-infarction HF, the SgII fragment secretoneurin reduced myocardial ischemia-reperfusion injury and cardiomyocyte apoptosis by 30% and rapidly increased cardiomyocyte Erk1/2 and Stat3 phosphorylation. SgII levels were also higher in patients with stable, chronic HF compared to age- and gender-matched control subjects: median 0.16 (Q1–3 0.14–0.18) vs. 0.12 (0.10–0.14) nmol/L, p<0.001.ConclusionsWe demonstrate increased myocardial SgII production and processing in the LV in animals with myocardial infarction and HF, which could be beneficial as the SgII fragment secretoneurin protects from ischemia-reperfusion injury and cardiomyocyte apoptosis. Circulating SgII levels are also increased in patients with chronic, stable HF and may represent a new cardiac biomarker.

Eplerenone Survival Benefits in Heart Failure Patients Post-Myocardial Infarction

Reduced left ventricular ejection fraction (≤40%) and/or signs of clinical heart failure after acute myocardial infarction (AMI) are associated with a relatively high incidence of mortality and hospitalization for heart failure. The potential of eplerenone to impact on mortality and morbidity of post-infarction heart failure patients was the subject of the EPHESUS trial ( E plerenone P ost-Acute Myocardial Infarction H eart Failure E fficacy and Su rvival S tudy). That trial concluded that eplerenone reduced total mortality by 31%, cardiovascular mortality by 32% and sudden cardiac death by 37% within 30 days of randomization after AMI. Risk reduction in mortality with eplerenone seemed to occur as early as 10 days after randomization and continued through the end of the study. In conclusion, eplerenone improves survival in heart failure patients post-AMI.

Isointegral body surface maps and left ventricular hypertrophy in post-infarction heart failure patients

Ventricular remodeling causes left ventricular hypertrophy (LVH) in myocardial infarction patients. We hypothesized that LVH can be evaluated using isointegral body surface maps. Thirty-two patients with post-infarction stable chronic heart failure underwent a 64-electrode body surface mapping (isointegral QRS, QRST, ST and STT maps) and 2-D echocardiography. LVH was present in 16 of them (50%) according to 2D-echocardiography. Isointegral maxima increased and the minima were more negative in patients with LVH, and the differences were statistically significant for: isointegral QRS maxima (35±16 versus 60±21 mV.ms, p=0.0085) and minima (25±15 versus 69±14 mV.ms, p=0.0067), isointegral maxima and minima in the second third of the QRS complex, isointegral QRST minima and isointegral ST minima (5±2 versus 10±4 mV.ms, p=0.0026). Isointegral multipolar maps prevalence was increased in patients with LVH (75% versus 50%). Isointegral QRS and QRST maxima correlated best with the left ventricular mass (r=0.73 and 0.81). Body surface mapping is a useful method for the evaluation of patients with left ventricular hypertrophy in post-infarction heart failure. The most sensitive parameters are: isointegral QRS maxima and minima, especially in the second third of the QRS complex, isointegral QRST maps (minima, maxima and multipolarity) and isointegral ST minima.

Direct Renin Inhibition Exerts an Anti-hypertrophic Effect Associated with Improved Mitochondrial Function in Post-infarction Heart Failure in Diabetic Rats

Background: In addition to hypertension control, direct renin inhibition has been shown to exert direct beneficial effects on the heart in post-infarction cardiac remodeling. This study elucidates the possible contribution of mitochondria to the anti-hypertrophic effects of the direct renin inhibitor aliskiren in post-infarction heart failure complicated with diabetes in rats. Methods: Diabetes was induced in male Sprague-Dawley rats by a single injection of streptozotocin (IP, 65 mg/kg body weight). After 7 days, the animals were randomly assigned to 4 groups: sham, heart failure, sham+aliskiren, and heart failure+aliskiren. Post-infarction HF was induced by coronary artery ligation for 4 weeks. Results: showed that heart failure reduced ejection fraction and cardiac output by 41% (P<0.01) and 42% (P<0.05), respectively, compared to sham-operated hearts. Cardiac dysfunction was associated with suppressed state 3 respiration rates and respiratory control index in mitochondria, and increased mitochondrial permeability transition pore (PTP) opening. In addition, heart failure reduced expression of the major mitochondrial sirtuin, SIRT3 and increased acetylation of cyclophilin D, a regulatory component of the PTP. Aliskiren significantly improved cardiac function and abrogated mitochondrial perturbations. Conclusion: Our results demonstrate that aliskiren attenuates post-infarction remodeling which is associated with its beneficial effects on mitochondria.

Normal training response in skeletal muscle of post-infarction heart failure patients

Congestive heart failure (CHF) patients experience reduced muscle fatigue resistance and exercise capacity. The aim of this study was to assess whether skeletal muscle in CHF patients has a normal training response compared to healthy subjects. We compared the effect of one-legged knee extensor (1-KE) endurance training in CHF patients (n=10), patients with coronary artery disease (CAD, n=9) and healthy subjects (n=13). The training response was evaluated by comparing trained leg and control leg after the training period. The fall in peak torque during 75 maximal 1-KE isokinetic contractions revealed that CHF patients were less fatigue resistant than healthy subjects in the control leg, but not in the trained leg. Peak power and peak oxygen uptake during dynamic 1-KE exercise was ~10–16% higher in trained leg than control leg. This training response was not significant different between groups. Muscle biopsies of vastus lateralis showed that fibre type composition was not different between trained leg and control leg. Capillary density was 6.5% higher in trained leg than control leg when all groups were pooled. In conclusion, the more fatigable skeletal muscle of CHF patients responds equally to endurance training compared to skeletal muscle of CAD patients and healthy subjects.