ABSTRACT
Cardiac complications are frequently found following a stroke in humans whose pathophysiological mechanism remains poorly understood. We used machine learning to analyse a large set of data from a metabolipidomic study assaying 630 metabolites in a rat stroke model to investigate metabolic changes affecting the heart within 72 h after a stroke. Twelve rats undergoing a stroke and 28 rats undergoing the sham procedure were investigated. A plasmatic signature consistent with the literature with notable lipid metabolism remodelling was identified. The post-stroke heart showed a discriminant metabolic signature, in comparison to the sham controls, involving increased collagen turnover, increased arginase activity with decreased nitric oxide synthase activity as well as an altered amino acid metabolism (including serine, asparagine, lysine and glycine). In conclusion, these results demonstrate that brain injury induces a metabolic remodelling in the heart potentially involved in the pathophysiology of stroke heart syndrome.
ABSTRACT
BACKGROUND: Inflammation is a key factor of myocardial damage in reperfused ST-segment-elevation myocardial infarction. We hypothesized that colchicine, a potent anti-inflammatory agent, may reduce infarct size (IS) and left ventricular (LV) remodeling at the acute phase of ST-segment-elevation myocardial infarction. METHODS: In this double-blind multicenter trial, we randomly assigned patients admitted for a first episode of ST-segment-elevation myocardial infarction referred for primary percutaneous coronary intervention to receive oral colchicine (2-mg loading dose followed by 0.5 mg twice a day) or matching placebo from admission to day 5. The primary efficacy outcome was IS determined by cardiac magnetic resonance imaging at 5 days. The relative LV end-diastolic volume change at 3 months and IS at 3 months assessed by cardiac magnetic resonance imaging were among the secondary outcomes. RESULTS: We enrolled 192 patients, 101 in the colchicine group and 91 in the control group. At 5 days, the gadolinium enhancement-defined IS did not differ between the colchicine and placebo groups with a mean of 26 interquartile range (IQR) [16-44] versus 28.4 IQR [14-40] g of LV mass, respectively (P=0.87). At 3 months follow-up, there was no significant difference in LV remodeling between the colchicine and placebo groups with a +2.4% (IQR, -8.3% to 11.1%) versus -1.1% (IQR, -8.0% to 9.9%) change in LV end-diastolic volume (P=0.49). Infarct size at 3 months was also not significantly different between the colchicine and placebo groups (17 IQR [10-28] versus 18 IQR [10-27] g of LV mass, respectively; P=0.92). The incidence of gastrointestinal adverse events during the treatment period was greater with colchicine than with placebo (34% versus 11%, respectively; P=0.0002). CONCLUSIONS: In this randomized, placebo-controlled trial, oral administration of high-dose colchicine at the time of reperfusion and for 5 days did not reduce IS assessed by cardiac magnetic resonance imaging. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03156816.
Subject(s)
Colchicine/therapeutic use , Myocardial Infarction/drug therapy , ST Elevation Myocardial Infarction/drug therapy , Ventricular Remodeling/drug effects , Acute Disease , Adult , Aged , Contrast Media/pharmacology , Female , Heart/drug effects , Hospitalization , Humans , Male , Middle Aged , Myocardium/pathology , Referral and ConsultationABSTRACT
AIMS: Periprocedural myocardial infarctions have been reported in the setting of planned percutaneous coronary intervention (PCI). We assessed the prevalence of nonculprit artery acute myocardial infarction (NCAMI) and its relationship with coronary artery characteristics, final infarct size, and 1-year adverse clinical outcomes in a population of anterior ST-elevated myocardial infarction (STEMI) patients. METHODS AND RESULTS: Late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) studies were performed within 7 days of admission in 129 anterior STEMI patients from the CIRCUS trial treated by primary PCI. Infarct in the noninfarct artery territory (circumflex, right coronary) was assessed on LGE-CMR and T2-weighted images. Eleven (8.5%) patients exhibited NCAMI. The only independent characteristic significantly associated with NCAMI was the presence of multiple complex coronary lesions (odds ratio = 12.9, 95% confidence interval [3.1-53.4]; p < 0.001). There was a significantly increased infarct size in NCAMI patients compared to patients without NCAMI (45.8 ± 20.4% of the left ventricle [LV] vs. 31.0 ± 15.1% of LV, respectively; p = 0.02), with lower LV ejection fraction (46 ± 10% vs. 34 ± 8%, respectively; p < 0.001). CONCLUSION: NCAMIs are present in 8.5% of anterior STEMI patients and are significantly associated with multiple complex coronary lesions without significant relationship to any revascularization procedural technique. NCAMI was associated with a greater infarct size and reduced LVEF but not worse clinical outcomes at 1 year.
Subject(s)
Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction , Arteries , Humans , ST Elevation Myocardial Infarction/diagnostic imaging , ST Elevation Myocardial Infarction/surgeryABSTRACT
Inflammatory processes have been identified as key mediators of ischemia-reperfusion injury in ST-segment elevation myocardial infarction (STEMI). They add damage to the myocardium and are associated with clinical adverse events (heart failure and cardiovascular death) and poor myocardial recovery. Colchicine is a well-known alkaloid with potent anti-inflammatory properties. In a proof-of-concept phase II trial, colchicine has been associated with a significant 50% reduction of infarct size (assessed by creatine kinase levels) in comparison to placebo in acute STEMI patients referred for primary percutaneous coronary intervention (PPCI). The Colchicine in STEMI Patients Study (COVERT-MI) is an ongoing confirmative prospective, multicenter, randomized, double-blind trial testing whether a short course oral treatment with colchicine versus placebo decreases myocardial injury in patients presenting with STEMI referred for PPCI. Adult patients, with a first STEMI episode and an initial TIMI flow ≤1, referred for PPCI, will be randomized (n = 194) in a 1:1 ratio to receive an oral bolus of colchicine of 2 mg followed by 0.5 mg b.i.d. treatment during 5 days or matching placebo. The primary endpoint will be the reduction in infarct size as assessed by cardiac magnetic resonance at 5 ± 2 days between both groups. The main secondary endpoints will be tested between groups in hierarchical order with left ventricular ejection fraction at 5 days, microvascular obstruction presence at 5 days, and absolute adverse left ventricular remodeling between 5 days and 3 months. This academic study is being financed by a grant from the French Ministry of Health (PHRCN-16-0357). Results from this study will contribute to a better understanding of the complex pathophysiology underlying myocardial injury after STEMI. The present study describes the rationale, design, and methods of the trial.
Subject(s)
Myocardial Infarction , Percutaneous Coronary Intervention , Adult , Clinical Trials, Phase II as Topic , Colchicine , Humans , Magnetic Resonance Imaging , Multicenter Studies as Topic , Myocardial Infarction/drug therapy , Prospective Studies , Randomized Controlled Trials as Topic , Stroke Volume , Treatment Outcome , Ventricular Function, LeftABSTRACT
New treatments are needed to protect the myocardium against the detrimental effects of acute ischaemia/reperfusion (IR) injury following an acute myocardial infarction (AMI), in order to limit myocardial infarct (MI) size, preserve cardiac function and prevent the onset of heart failure (HF). Given the critical role of mitochondria in energy production for cardiac contractile function, prevention of mitochondrial dysfunction during acute myocardial IRI may provide novel cardioprotective strategies. In this regard, the mitochondrial fusion and fissions proteins, which regulate changes in mitochondrial morphology, are known to impact on mitochondrial quality control by modulating mitochondrial biogenesis, mitophagy and the mitochondrial unfolded protein response. In this article, we review how targeting these inter-related processes may provide novel treatment targets and new therapeutic strategies for reducing MI size, preventing the onset of HF following AMI.
Subject(s)
Cardiotonic Agents/pharmacology , Mitochondria, Heart/metabolism , Mitochondrial Dynamics , Mitochondrial Proteins/metabolism , Animals , Humans , Mitochondria, Heart/drug effects , Mitochondrial Dynamics/drug effects , Mitophagy/drug effects , Unfolded Protein Response/drug effectsABSTRACT
The actual protective mechanisms underlying cardioprotection with remote ischemic conditioning (RIC) remain unclear. Recent data suggest that RIC induces kynurenine (KYN) and kynurenic acid synthesis, two metabolites derived from tryptophan (TRP), yet a causal relation between TRP pathway and RIC remains to be established. We sought to study the impact of RIC on the levels of TRP and its main metabolites within tissues, and to assess whether blocking kynurenine (KYN) synthesis from TRP would inhibit RIC-induced cardioprotection. In rats exposed to 40-min coronary occlusion and 2-h reperfusion, infarct size was significantly smaller in RIC-treated animals (35.7 ± 3.0% vs. 46.5 ± 2.2%, p = 0.01). This protection was lost in rats that received 1-methyl-tryptophan (1-MT) pretreatment, an inhibitor of KYN synthesis from TRP (infarct size = 46.2 ± 5.0%). Levels of TRP and nine compounds spanning its metabolism through the serotonin and KYN pathways were measured by reversed-phase liquid chromatography-tandem mass spectrometry in the liver, heart, and limb skeletal muscle, either exposed or not to RIC. In the liver, RIC induced a significant increase in xanthurenic acid, nicotinic acid, and TRP. Likewise, RIC increased NAD-dependent deacetylase sirtuin activity in the liver. Pretreatment with 1-MT suppressed the RIC-induced increases in NAD-dependent deacetylase sirtuin activity. Altogether, these findings indicate that RIC mechanism is dependent on TRP-KYN pathway activation.
Subject(s)
Ischemic Preconditioning, Myocardial , Kynurenine/metabolism , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/prevention & control , Myocardium/metabolism , Tryptophan/metabolism , Animals , Disease Models, Animal , Liver/metabolism , Male , Muscle, Skeletal/metabolism , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/metabolism , Myocardial Reperfusion Injury/pathology , Myocardium/pathology , Rats, WistarABSTRACT
Left ventricular remodeling (LVR) occurring after ST-segment elevation myocardial infarction (STEMI) is frequent and severe. We present a metabolomic approach as an attempt to reveal unknown biomarkers associated with post-STEMI LVR. Out of 192 consecutive patients with successfully revascularized STEMI, 32 presented LVR and were clinically matched with 32 no-LVR patients. They underwent cardiac magnetic resonance at baseline, three months and 12 months. Blood samples were collected during index hospitalization. Creatine kinase (CK) peak and inflammatory markers were higher for LVR patients compared to no-LVR patients (mean 3466 ± 2211 and 2394 ± 1615 UI/L respectively, p = 0.005 for CK peak; mean 35.9 ± 44.3 vs. 21.7 ± 30.4 mg/L respectively, p = 0.020 for C-reactive protein). Leukocyte and neutrophil counts were also higher for LVR patients (mean 12028 ± 2593/mL vs. 10346 ± 3626/mL respectively, p = 0.028 and mean 9035 ± 3036/mL vs. 7596 ± 3822/mL respectively, p < 0.001). For metabolomic analysis, sphingomyelin C20:2 and symmetrical dimethylarginine were higher for LVR patients, but did not reach significance after the correction for the alpha risk. The metabolomic approach did not discriminate patients with and without LVR. However, common parameters that focus on infarction severity, such as infarct size and inflammatory markers, differed between the groups.
Subject(s)
Arginine/analogs & derivatives , Biomarkers/metabolism , Metabolomics/methods , ST Elevation Myocardial Infarction/physiopathology , Sphingomyelins/metabolism , Aged , Arginine/metabolism , Creatine Kinase/blood , Female , Hospitalization , Humans , Leukocyte Count , Magnetic Resonance Imaging, Cine , Male , Middle Aged , Neutrophils/cytology , ST Elevation Myocardial Infarction/blood , ST Elevation Myocardial Infarction/metabolism , Ventricular Function, Left , Ventricular RemodelingABSTRACT
BACKGROUND: Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling. METHODS: In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume. RESULTS: A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval [CI], 0.78 to 1.39; P=0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups. CONCLUSIONS: In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.).
Subject(s)
Cyclophilins/antagonists & inhibitors , Cyclosporine/administration & dosage , Enzyme Inhibitors/administration & dosage , Myocardial Infarction/drug therapy , Percutaneous Coronary Intervention , Ventricular Remodeling/drug effects , Aged , Combined Modality Therapy , Cyclosporine/adverse effects , Double-Blind Method , Electrocardiography , Enzyme Inhibitors/adverse effects , Female , Heart Failure/epidemiology , Humans , Injections, Intravenous , Kaplan-Meier Estimate , Male , Middle Aged , Mortality , Myocardial Infarction/therapyABSTRACT
Aims: Stress-induced right bundle-branch block morphology ventricular ectopy (SI-RBVE) may be caused by left ventricular myocardial anomalies. While frequent ventricular ectopy (FVE) has been linked to poor outcomes, the prognostic value of SI-RBVE has not been established. The study aims to determine whether SI-RBVE is associated with increased mortality. Methods and results: Three hundred forty-three patients with an intermediate to high probability of coronary artery disease were prospectively included. Patients were referred for a single-photon emission computed tomography and underwent a stress test according to standard protocols. Stress-induced right bundle-branch block morphology ventricular ectopy (VE) was defined as one or more induced premature beats with positive predominance in V1. Frequent VE was defined as the presence of seven or more ventricular premature beats per minute or any organized ventricular arrhythmia. During a mean follow-up of 4.5 ± 1.3 years, 59 deaths occurred. The death rate was higher in the SI-RBVE group (23.4% vs. 14.0%, P = 0.021). Age [odds ratio (OR) = 1.09 (95% CI: 1.06-1.13), P < 0.001] and peripheral artery disease [OR = 2.47 (95% CI: 1.35-4.50) P = 0.003] were independent factors of mortality, but single-photon emission computed tomography findings were not. There was an interaction between SI-RBVE and left ventricular ejection fraction (LVEF). In patients with LVEF > 50%, SI-RBVE was an incremental risk factor for mortality [OR = 2.83 (95% CI: 1.40-5.74), P = 0.004]. Stress-induced right bundle-branch block morphology VE patients also presented higher rates of known coronary artery disease, ischaemia, scar, and ST-segment changes. Frequent VE was not related to mortality. Conclusion: Stress-induced right bundle-branch block morphology VE is associated with an increased mortality in patients with preserved LVEF.
Subject(s)
Bundle-Branch Block/etiology , Coronary Artery Disease/diagnostic imaging , Exercise Test/adverse effects , Tomography, Emission-Computed, Single-Photon , Ventricular Premature Complexes/etiology , Aged , Bundle-Branch Block/diagnosis , Bundle-Branch Block/mortality , Bundle-Branch Block/physiopathology , Coronary Artery Disease/mortality , Coronary Artery Disease/physiopathology , Electrocardiography, Ambulatory , Female , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Risk Factors , Stroke Volume , Time Factors , Ventricular Function, Left , Ventricular Premature Complexes/diagnosis , Ventricular Premature Complexes/mortality , Ventricular Premature Complexes/physiopathologyABSTRACT
In recent years, the number of investigations based on nontargeted metabolomics has increased, although often without a thorough assessment of analytical strategies applied to acquire data. Following published guidelines for metabolomics experiments, we report a validated nontargeted metabolomics strategy with pipeline for unequivocal identification of metabolites using the MSMLS molecule library. We achieved an in-house database containing accurate m/z values, retention times, isotopic patterns, full MS, and MS/MS spectra. A UHPLC-HRMS Q-Exactive method was developed, and experimental variations were determined within and between 3 experimental days. The extraction efficiency as well as the accuracy, precision, repeatability, and linearity of the method were assessed, the method demonstrating good performances. The methodology was further blindly applied to plasma from remote ischemic pre-conditioning (RIPC) rats. Samples, previously analyzed by targeted metabolomics using completely different protocol, analytical strategy, and platform, were submitted to our analytical pipeline. A combination of multivariate and univariate statistical analyses was employed. Selection of putative biomarkers from OPLS-DA model and S-plot was combined to jack-knife confidence intervals, metabolites' VIP values, and univariate statistics. Only variables with strong model contribution and highly statistical reliability were selected as discriminated metabolites. Three biomarkers identified by the previous targeted metabolomics study were found in the current work, in addition to three novel metabolites, emphasizing the efficiency of the current methodology and its ability to identify new biomarkers of clinical interest, in a single sequence. The biomarkers were identified to level 1 according to the metabolomics standard initiative and confirmed by both RPLC and HILIC-HRMS.
Subject(s)
Chromatography, High Pressure Liquid/methods , Ischemic Preconditioning, Myocardial , Mass Spectrometry/methods , Metabolomics , Animals , Biomarkers/blood , Biomarkers/metabolism , Databases, Factual , Humans , Limit of Detection , Male , Rats, Wistar , Reproducibility of ResultsABSTRACT
OBJECTIVE: Myogenic tone (MT) of resistance arteries ensures autoregulation of blood flow in organs and relies on the intrinsic property of smooth muscle to contract in response to stretch. Nucleotides released by mechanical strain on cells are responsible for pleiotropic vascular effects, including vasoconstriction. Here, we evaluated the contribution of extracellular nucleotides to MT. APPROACH AND RESULTS: We measured MT and the associated pathway in mouse mesenteric resistance arteries using arteriography for small arteries and molecular biology. Of the P2 receptors in mouse mesenteric resistance arteries, mRNA expression of P2X1 and P2Y6 was dominant. P2Y6 fully sustained UDP/UTP-induced contraction (abrogated in P2ry6(-/-) arteries). Preventing nucleotide hydrolysis with the ectonucleotidase inhibitor ARL67156 enhanced pressure-induced MT by 20%, whereas P2Y6 receptor blockade blunted MT in mouse mesenteric resistance arteries and human subcutaneous arteries. Despite normal hemodynamic parameters, P2ry6(-/-) mice were protected against MT elevation in myocardial infarction-induced heart failure. Although both P2Y6 and P2Y2 receptors contributed to calcium mobilization, P2Y6 activation was mandatory for RhoA-GTP binding, myosin light chain, P42-P44, and c-Jun N-terminal kinase phosphorylation in arterial smooth muscle cells. In accordance with the opening of a nucleotide conduit in pressurized arteries, MT was altered by hemichannel pharmacological inhibitors and impaired in Cx43(+/-) and P2rx7(-/-) mesenteric resistance arteries. CONCLUSIONS: Signaling through P2 nucleotide receptors contributes to MT. This mechanism encompasses the release of nucleotides coupled to specific autocrine/paracrine activation of the uracil nucleotide P2Y6 receptor and may contribute to impaired tissue perfusion in cardiovascular diseases.
Subject(s)
Arterioles/metabolism , Mesentery/blood supply , Receptors, Purinergic P2/metabolism , Vasoconstriction , Adenosine Triphosphatases/metabolism , Animals , Arterioles/drug effects , Arterioles/physiopathology , Blood Pressure , Calcium Signaling , Cells, Cultured , Connexin 43/deficiency , Connexin 43/genetics , Disease Models, Animal , Dose-Response Relationship, Drug , Genotype , Heart Failure/etiology , Heart Failure/metabolism , Heart Failure/physiopathology , Hydrolysis , Mechanotransduction, Cellular , Mice, Knockout , Mitogen-Activated Protein Kinases/metabolism , Muscle, Smooth, Vascular/metabolism , Myocardial Infarction/complications , Myocytes, Smooth Muscle/metabolism , Myosin Light Chains/metabolism , Phenotype , Phosphorylation , Purinergic P2X Receptor Agonists/pharmacology , Receptors, Purinergic P2/deficiency , Receptors, Purinergic P2/drug effects , Receptors, Purinergic P2/genetics , Receptors, Purinergic P2X7/deficiency , Receptors, Purinergic P2X7/genetics , Uridine Diphosphate/pharmacology , Vasoconstriction/drug effects , Vasoconstrictor Agents/pharmacology , rho GTP-Binding Proteins/metabolism , rhoA GTP-Binding ProteinABSTRACT
BACKGROUND: Both acute myocardial ischemia and reperfusion contribute to cardiomyocyte death in ST-elevation myocardial infarction (STEMI). The final infarct size is the principal determinant of subsequent clinical outcome in STEMI patients. In a proof-of-concept phase II trial, the administration of cyclosporine prior to primary percutaneous coronary intervention (PPCI) has been associated with a reduction of infarct size in STEMI patients. METHODS: CIRCUS is an international, prospective, multicenter, randomized, double-blinded, placebo-controlled trial. The study is designed to compare the efficacy and safety of cyclosporine versus placebo, in addition to revascularization by PPCI, in patients presenting with acute anterior myocardial infarction within 12 hours of symptoms onset and initial TIMI flow ≤1 in the culprit left anterior descending coronary artery. Patients are randomized in a 1:1 fashion to 2.5 mg/kg intravenous infusion of cyclosporine or matching placebo performed in the minutes preceding PCI. The primary efficacy end point of CIRCUS is a composite of 1-year all-cause mortality, rehospitalization for heart failure or heart failure worsening during initial hospitalization, and left ventricular adverse remodeling as determined by sequential transthoracic echochardiography. Secondary outcomes will be tested using a hierarchical sequence of left ventricular (LV) ejection fraction and absolute measurements of LV volumes. The composite of death and rehospitalization for heart failure or heart failure worsening during initial hospitalization will be further assessed at three years after the initial infarction. RESULTS: Recruitment lasted from April 2011 to February 2014. The CIRCUS trial has recruited 975 patients with acute anterior myocardial infarction. The 12-months results are expected to be available in 2015. CONCLUSIONS: The CIRCUS trial is testing the hypothesis that cyclosporine in addition to early revascularization with PPCI compared to placebo in patients with acute anterior myocardial infarction reduces the incidence of death, heart failure and adverse LV remodeling at one-year follow-up.
Subject(s)
Cyclosporine/adverse effects , Cyclosporine/therapeutic use , Myocardial Infarction/surgery , Percutaneous Coronary Intervention , Biomarkers/blood , Coronary Angiography , Double-Blind Method , Echocardiography , Electrocardiography , Female , Humans , Male , Myocardial Infarction/physiopathology , Prospective Studies , Time Factors , Treatment OutcomeABSTRACT
Remote ischemic conditioning (RIC) represents an innovative cardioprotective method that has been investigated in numerous clinical studies providing miscellaneous results. This systematic review and meta-analysis sought to assess RIC-induced effects on myocardial injury biomarkers and clinical outcomes in clinical situations at risk of myocardial ischemia/reperfusion damage. PubMed and Cochrane databases were searched for randomized clinical trials testing any RIC protocol versus a control in a situation or procedure at risk of cardiac ischemia/reperfusion damage, including coronary angioplasty and cardiac or major vascular surgery. Data were collected from publications reporting biological markers of myocardial injury or clinical events, including major adverse cardiovascular and cerebral events (MACCE), all-cause mortality, myocardial infarction incidence, and repeat revascularization. Standardized mean difference (SMD) (continuous outcomes) and odds ratios (OR) (dichotomous outcomes) were compared between groups. Heterogeneity was investigated by means of meta-analysis regression. A total of 53 articles (44 studies) were identified by the search, with 5,317 patients included in the systematic meta-analysis. RIC significantly reduced troponin area under curve (AUC) (SMD -0.27, 95% confidence interval (CI): [-0.36, -0.18]; p < 0.01) and troponin peak (SMD: -0.22, 95% CI: [-0.30, -0.15]; p < 0.01). The same reduction was observed with creatine kinase MB (CK-MB) AUC and peak. Long-term MACCE and all-cause mortality were significantly lower in the RIC group (OR: 0.42, 95% CI [0.28, 0.64]; p < 0.01 vs. OR: 0.27, 95% CI [0.13, 0.58]; p < 0.01, respectively), as was myocardial infarction incidence (OR: 0.54, 95% CI [0.40, 0.73]; p < 0.01). We observed no difference regarding repeat revascularization. RIC appears to be an effective method for reducing ischemia/reperfusion myocardial injury, and our findings suggest that it may reduce long-term clinical events.
Subject(s)
Ischemic Postconditioning/methods , Ischemic Preconditioning, Myocardial/methods , Myocardial Reperfusion Injury/prevention & control , Humans , Randomized Controlled Trials as TopicABSTRACT
In 1993, Przyklenk and colleagues made the intriguing experimental observation that 'brief ischemia in one vascular bed also protects remote, virgin myocardium from subsequent sustained coronary artery occlusion' and that this effect'... may be mediated by factor(s) activated, produced, or transported throughout the heart during brief ischemia/reperfusion'. This seminal study laid the foundation for the discovery of 'remote ischemic conditioning' (RIC), a phenomenon in which the heart is protected from the detrimental effects of acute ischemia/reperfusion injury (IRI), by applying cycles of brief ischemia and reperfusion to an organ or tissue remote from the heart. The concept of RIC quickly evolved to extend beyond the heart, encompassing inter-organ protection against acute IRI. The crucial discovery that the protective RIC stimulus could be applied non-invasively, by simply inflating and deflating a blood pressure cuff placed on the upper arm to induce cycles of brief ischemia and reperfusion, has facilitated the translation of RIC into the clinical setting. Despite intensive investigation over the last 20 years, the underlying mechanisms continue to elude researchers. In the 8th Biennial Hatter Cardiovascular Institute Workshop, recent developments in the field of RIC were discussed with a focus on new insights into the underlying mechanisms, the diversity of non-cardiac protection, new clinical applications, and large outcome studies. The scientific advances made in this field of research highlight the journey that RIC has made from being an intriguing experimental observation to a clinical application with patient benefit.
Subject(s)
Ischemic Preconditioning, Myocardial , Acute Kidney Injury/prevention & control , Aldehyde Dehydrogenase/physiology , Aldehyde Dehydrogenase, Mitochondrial , Humans , Myocardial Reperfusion Injury/prevention & control , Reperfusion Injury/prevention & control , Signal Transduction , Ventricular Function, LeftABSTRACT
BACKGROUND: Benefit of ß-blockers (BB) and angiotensin-converting-enzyme inhibitors (ACEI) on mortality following acute myocardial infarction (MI) is well demonstrated. This study assessed the impact of BB and ACEI doses administered following ST-elevation MI on mortality and outcome up to 1 year. METHODSâANDâRESULTS: The French prospective observational cohort "RIMA" included 1,461 MI patients. Dosing of BB and ACEI given at 24 h and at time of discharge was assessed as follows: no treatment; <50% of target dose; or ≥50% of target dose. For in-hospital mortality, after MI, the use of BB in the first 24 h, but not ACEI, was associated with significantly lower event rate on multivariate analysis (OR, 5.78; 95% CI: 2.62-12.76, P<0.001). In contrast at 1 year, use of higher doses of ACEI, but not BB, was associated with significantly lower CV mortality, readmission for heart failure and the composite of CV mortality and readmission for heart failure (HR, 2.65; 95% CI: 1.32-5.31, P=0.006 for absence of ACEI at discharge). CONCLUSIONS: Prescription of BB in the first 24 h was independently associated with a lower in-hospital mortality following MI. There appeared to be a significant dose effect on outcome with regard to <50% vs. ≥50% of target dose, which requires confirmation in further large-scale clinical studies.
Subject(s)
Adrenergic beta-Antagonists/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Heart Failure , Myocardial Infarction , Registries , Aged , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Heart Failure/drug therapy , Heart Failure/mortality , Hospital Mortality , Humans , Male , Middle Aged , Myocardial Infarction/drug therapy , Myocardial Infarction/mortality , Retrospective Studies , Survival RateABSTRACT
BACKGROUND: Erythropoiesis-stimulating agents (ESAs) have been investigated in small studies in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Erythropoiesis-stimulating agents did not show a clear effect on left ventricular function or clinical outcome, but some studies suggested an increased risk of thromboembolic events. METHODS: A systematic literature search in MEDLINE was performed, until December 2012. We included randomized clinical trials investigating the effect of ESAs in STEMI patients undergoing primary PCI, with ≥30 days of follow-up. The primary end point was a composite of all-cause mortality, myocardial infarction, and stent thrombosis after PCI. Secondary end point was all-cause mortality. RESULTS: Individual patient data were obtained from 10 of 11 trials, including 97.3% (1,242/1,277) of all patients randomized to control (n = 600) or to ESAs (n = 642). Baseline characteristics were well balanced between the treatment allocations. Mean follow-up time was 248 (±131) days. The primary end point occurred in 3.5% (20/577) in the control group and in 2.1% (13/610) in the ESA group (hazard ratio for ESAs, 0.63; 95% CI [0.31-1.27]; P = .20). Mortality occurred in 13 (2.3%) in the control group and 5 (0.8%) in the ESA group (hazard ratio for ESAs, 0.38; 95% CI [0.13-1.06]; P = .06). CONCLUSIONS: Erythropoiesis-stimulating agent administration does not result in an increased risk of adverse cardiac events in STEMI patients undergoing primary PCI. Results of ongoing studies may provide further insight to the potential beneficial clinical effects of ESAs in STEMI patients.
Subject(s)
Hematinics/pharmacology , Humans , Myocardial Infarction/mortality , Percutaneous Coronary Intervention , Risk Assessment , Thromboembolism/epidemiology , Ventricular Function, Left/drug effectsABSTRACT
Local ischemic postconditioning (IPost) and remote ischemic perconditioning (RIPer) are promising cardioprotective therapies in ST-elevation myocardial infarction (STEMI). We aimed: (1) to investigate whether RIPer initiated at the catheterization laboratory would reduce infarct size, as measured using serum creatine kinase-MB isoenzyme (CK-MB) release as a surrogate marker; (2) to assess if the combination of RIPer and IPost would provide an additional reduction. Patients (n = 151) were randomly allocated to one of the following groups: (1) control group, percutaneous transluminal coronary angioplasty (PTCA) alone; (2) RIPer group, PTCA combined with RIPer, consisting of three cycles of 5-min inflation and 5-min deflation of an upper-arm blood-pressure cuff initiated before reperfusion; (3) RIPer+IPost group, PTCA combined with RIPer and IPost, consisting of four cycles of 1-min inflation and 1-min deflation of the angioplasty balloon. The CK-MB area under the curve (AUC) over 72 h was reduced in RIPer, and RIPer+IPost groups, by 31 and 29 %, respectively, compared to the Control group; however, CK-MB AUC differences between the three groups were not statistically significant (p = 0.06). Peak CK-MB, CK-MB AUC to area at risk (AAR) ratio, and peak CK-MB level to AAR ratio were all significantly reduced in the RIPer and RIPer+IPost groups, compared to the Control group. On the contrary, none of these parameters was significantly different between RIPer+IPost and RIPer groups. To conclude, starting RIPer therapy immediately prior to revascularization was shown to reduce infarct size in STEMI patients, yet combining this therapy with an IPost strategy did not lead to further decrease in infarct size.
Subject(s)
Ischemic Postconditioning/methods , Myocardial Infarction/therapy , Myocardial Reperfusion Injury/therapy , Percutaneous Coronary Intervention/methods , Aged , Aged, 80 and over , Algorithms , Biomarkers/blood , Cardiotonic Agents , Creatine Kinase, MB Form/blood , Electrocardiography , Female , Humans , Male , Middle Aged , Myocardial Infarction/diagnosis , Prospective Studies , Treatment OutcomeABSTRACT
INTRODUCTION: There are little data about patients with cardiogenic shock (CS) who survive the early phase of acute myocardial infarction (AMI). The aim of this study was to assess long-term (5-year) mortality among early survivors of AMI, according to the presence of CS at the acute stage. METHODS: We analyzed 5-year follow-up data from the French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI) 2005 registry, a nationwide French survey including consecutive patients admitted for ST or non-ST-elevation AMI at the end of 2005 in 223 institutions. RESULTS: Of 3670 patients enrolled, shock occurred in 224 (6.1%), and 3411 survived beyond 30 days or hospital discharge, including 99 (2.9%) with shock. Early survivors with CS had a more severe clinical profile, more frequent concomitant in-hospital complications, and were less often managed invasively than those without CS. CONCLUSIONS: In patients surviving the early phase of AMI, CS at the initial stage carries an increased risk of death up to one year after the acute event. Beyond one year, however, mortality is similar to that of patients without shock. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00673036, Registered May 5, 2008.
Subject(s)
Myocardial Infarction/diagnosis , Myocardial Infarction/mortality , Registries , Shock, Cardiogenic/diagnosis , Shock, Cardiogenic/mortality , Aged , Aged, 80 and over , Female , Follow-Up Studies , France/epidemiology , Humans , Male , Middle Aged , Survival Rate/trends , Time Factors , Treatment OutcomeABSTRACT
OBJECTIVE: In the COVERT-MI randomised placebo-controlled trial, oral administration of high-dose colchicine at the time of reperfusion and for 5 days in acute ST-elevated myocardial infarction did not reduce infarct size but was associated with a significant increase in left ventricular thrombus (LVT) in comparison to placebo. We aimed to assess the 1-year clinical outcomes of the study population. METHODS: This study is a follow-up analysis of the COVERT-MI study on prespecified secondary clinical endpoints at 1 year. The primary endpoint of this study was a composite of major adverse cardiovascular events (MACEs), including all-cause death, acute coronary syndromes, heart failure events, ischaemic strokes, sustained ventricular arrhythmias and acute kidney injury at 1-year follow-up. The quality of life (QOL) and the drug therapy prescription were also assessed. RESULTS: At 1 year, 192 patients (101 patients in the colchicine group, 91 in the placebo group) were followed up. Seventy-six (39.6%) MACEs were reported in the study population. There was no significant difference regarding the number of MACEs between groups: 36 (35.6%) in the colchicine group and 40 (44.1%) in the placebo group (p=0.3). There were no differences in the occurrence of ischaemic strokes between the colchicine group and the control group (3 (3%) vs 2 (2.2%), respectively, p=0.99). There was a trend towards fewer heart failure events in the colchicine group compared with the placebo group (12 (11.9%) vs 18 (19.8%), p=0.20). There was no significant difference in QOL scores at 1 year (75.8±15.7 vs 72.7±16.2 respectively, p=0.18). CONCLUSIONS: There was no significant difference between the colchicine and placebo groups at 1 year regarding MACEs, especially concerning deaths or ischaemic strokes. No excess of ischaemic adverse events was observed despite the initial increase in LVT in the colchicine group. TRIAL REGISTRATION NUMBER: NCT0315681.