Potent Antithrombotic Agents Research Articles

Synthesis of novel 3-carboxamide-benzocoumarin derivatives as orally active antithrombotic agents

In an effort to develop potent antithrombotic agents, a series of novel 3-carboxamide-benzocoumarin derivatives were synthesized and screened for their in vivo antithrombotic activity. Among 20 compounds tested, the compound 12b showed the most promising antithrombotic activity which was comparable with clinically used aspirin or warfarin, but, at variance with these standard drugs, 12b did not exhibit the increased bleeding time, suggesting its potential as a novel antithrombotic agent.

Relation Between Red Blood Cell Omega-3 Fatty Acid Index and Bleeding During Acute Myocardial Infarction

Omega-3 fatty acids have multiple cardiovascular benefits but may also inhibit platelet aggregation and increase bleeding risk. If this platelet inhibition is clinically meaningful, patients with the highest omega-3 indexes (red blood cell eicosapentaenoic acid plus docosahexaenoic acid), which reflect long-term omega-3 fatty acid intake, should be at the risk for bleeding. In this study, 1,523 patients from 24 United States centers who had their omega-3 indexes assessed at the time of acute myocardial infarction were studied. The rates of serious bleeding (Thrombolysis In Myocardial Infarction [TIMI] major or minor) and mild to moderate bleeding (TIMI minimal) were identified in patients with low (<4%), intermediate (4% to 8%), and high (>8%) omega-3 indices. There were no differences in bleeding across omega-3 index categories. After multivariate adjustment, there remained no association between the omega-3 index and either serious (per 2% increase, relative risk 1.03, 95% confidence interval 0.90 to 1.19) or mild to moderate bleeding (per 2% increase, relative risk 1.02, 95% confidence interval 0.85 to 1.23). In conclusion, no relation was found between the omega-3 index and bleeding in this large, multicenter cohort of patients with acute myocardial infarction, suggesting that concerns about bleeding should not preclude the use of omega-3 supplements or increased fish consumption when clinically indicated.

Nitric oxide regulates non-classical secretion of tissue transglutaminase

Nitric oxide (NO) is an endogenous second messenger which acts as a potent vasodilator, anti-inflammatory, anti-thrombotic, and pro-angiogenic agent in the vasculature. Recent studies revealed that the effects of NO on blood vessels are mediated in part by its ability to regulate protein trafficking machinery and vesicle-based exocytosis in vascular cells. Specifically, NO-dependent S-nitrosylation of N-ethylmaleimide sensitive factor (NSF), an ATPase that enables membrane fusion, was shown to inhibit exocytosis of vesicular secretory compartments such as endothelial Weibel-Palade bodies, platelet alpha granules, and cytolytic granules from activated lymphocytes. Tissue transglutaminase (tTG or TG2) is a multifunctional protein synthesized and secreted by various cell types in the vasculature, which is involved in multiple vascular diseases, including atherosclerosis, vascular calcification, and age-dependent aortic stiffening. Our recent findings indicate that tTG is delivered to the cell surface and the extracellular matrix (ECM) via a non-classical ER/Golgi-independent secretion pathway, which depends on the recycling endosomes and the NSF function. Here we report that NO attenuates the unconventional secretion of tTG in human aortic endothelial cells. NO-dependent down-regulation of extracellular tTG levels via inhibition of its secretion might be a part of general physiological mechanism which limits externalization of adhesive, pro-inflammatory and thrombogenic proteins in the vasculature.

Nitric oxide regulates non-classical secretion of tissue transglutaminase.

Nitric oxide (NO) is an endogenous second messenger which acts as a potent vasodilator, anti-inflammatory, anti-thrombotic and pro-angiogenic agent in the vasculature. Recent studies revealed that the effects of NO on blood vessels are mediated in part by its ability to regulate protein trafficking machinery and vesicle-based exocytosis in vascular cells. Specifically, NO-dependent S-nitrosylation of N-ethylmaleimide sensitive factor (NSF), an ATPase that enables membrane fusion, was shown to inhibit exocytosis of vesicular secretory compartments such as endothelial Weibel-Palade bodies, platelet alpha granules and cytolytic granules from activated lymphocytes. Tissue transglutaminase (tTG or TG2) is a multifunctional protein synthesized and secreted by various cell types in the vasculature, which is involved in multiple vascular diseases, including atherosclerosis, vascular calcification and age-dependent aortic stiffening. Our recent findings indicate that tTG is delivered to the cell surface and the extracellular matrix (ECM) via a non-classical ER/Golgi-independent secretion pathway, which depends on the recycling endosomes and the NSF function. Here we report that NO attenuates the unconventional secretion of tTG in human aortic endothelial cells. NO-dependent downregulation of extracellular tTG levels via inhibition of its secretion might be a part of general physiological mechanism which limits externalization of adhesive, pro-inflammatory and thrombogenic proteins in the vasculature.

30 Comparison of bivalirudin vs abciximab vs "unfractionated heparin only" for primary percutaneous coronary intervention in a high-volume centre

<h3>Introduction</h3> Primary percutaneous coronary intervention (PPCI) has been established as a standard therapy for ST elevation myocardial infarction (STEMI). In addition to thrombectomy and unfractionated heparin (UFH), thrombus burden in STEMI may require use of more potent antithrombotic agents. Bivalirudin is shown to be superior to abciximab in reducing the net adverse clinical events and major bleeding in STEMI in the HORIZONS-AMI trial (Stone <i>et al NEJM</i>, 2008). We aimed to carry out a “real world” comparison of different anti-thrombotic regimes in patients undergoing PPCI in our unit. <h3>Methods</h3> Our PPCI service started in September 2009 and we included all patients undergoing PPCI between September 2009 and September 2010. Prospectively entered data were obtained from our dedicated cardiac service database system (Philips CVIS). Mortality data were obtained from the summary care record (SCR) database. We used Fisher′s exact test to compare clinical outcomes between the groups. <h3>Results</h3> Of the 998 patients admitted with suspected STEMI to our unit during the study period, 776 (77.8%) underwent PPCI. After excluding patients who had both bivalirudin and abciximab during their procedure (n=15), we divided the others (n=761) into 3 groups according to the anti-thrombotic regime used (Grp 1- Abciximab+UFH, Grp 2- Bivairudin+UFH and Grp 3- “UFH only”). Patient demographics and procedural information are given in Abstract 30 table 1. Continuous data are presented as mean± SD. Clinical outcomes are shown in Abstract 30 table 2. In-hospital and 30-day mortality did not differ between patients who had bivalirudin vs abciximab (5.6% vs 3.8%, p=0.35 and 6.8% vs 5.2% p=0.53 respectively). Both acute and 30 day stent thrombosis rates were also similar in the two groups (0.6% vs none, p=0.3, 0.6% vs 0.9%, p=1.0 respectively). Even though the bleeding risk was higher in the abciximab group when compared with bivalirudin, this was not significant (5.8% vs 3.1%, p=0.27). There was also no difference in the outcomes between the bivalirudin and “UFH only” groups for mortality, stent thromboses (acute and 30-day) and major bleeding. The abciximab group had significantly higher major bleeding rates than the “UFH only” group (5.8% vs 2.4%, p=0.04); all other outcomes were similar. <h3>Conclusion</h3> These “real-world” data do not show any significant difference in the clinical outcome for patients who had bivalirudin or abciximab. There was no advantage seen with the more expensive agent (abciximab) in keeping with previous trial data. Therefore bivalirudin should be considered as a non-inferior alternative to abciximab. This would have considerable economic benefits in the present situation. The “UFH only” group had similar outcomes to both bivalirudin and abciximab, which suggests that this may be a viable alternative in its own right. However, our study is clearly limited by not being randomised and those patients treated with UFH alone may have been a lower risk group.

Bioanalytical method development and validation for simultaneous estimation of (R)- and (S)-isomers of S002-333: a potent novel anti-thrombotic agent using LC–MS/MS

A selective, sensitive, and high throughput liquid chromatography–tandem mass spectrometry (LC–MS/MS) method has been developed and validated for the chromatographic separation and quantitation of diastereomers of S002-333, a novel anti-thrombotic agent in rabbit plasma. Sample clean-up involved liquid–liquid extraction (LLE) of both the isomers and internal standard (β-carbolinamide) from 200 μl of rabbit plasma. Both the analytes were chromatographically separated on a Chiralcel OJ-RH column (150 × 4.6 mm, 5 μm particle size) using a gradient flow program comprising 0.1% formic acid, methanol, and acetonitrile as the mobile phase. The parent → product ion transitions (MRM) for both the isomers and IS were 386.4 → 214.2 m/z and 216.1 → 144.2 m/z, respectively, and were monitored on a triple quadrupole mass spectrometer, operating in positive ion mode. The MS/MS response was linear over the concentration range from 1.56 ng/ml to 400 ng/ml, with a lower limit of detection (LOD) 1.56 ng/ml. The intra- and inter-day precisions (% R.S.D.) between 3.96 and 13.80 for both analytes and the accuracies (% bias) were between −4.05 and 5.93. The validated method can be used in most or all stages of the screening and optimizing process for pharmacokinetic and toxicokinetics studies.

ChemInform Abstract: Synthesis and Pharmacological Evaluation of 4,4a,5,6-Tetrahydro-2H-thieno(2,3-h)cinnolin-3-ones Bioisosters of Antihypertensive and Antithrombotic Benzo(h)cinnolinones.

Abstract The 8-acetylamino-4,4a,5,6-tetrahydro-2H-thieno[2,3-h]cinnolin-3-one (2b) has been synthesized and tested for its pharmacological profile in comparison with the bioisoster 8-acetylamino-4,4a,5,6-tetrahydrobenzo(h)cinnolin-3(2H)one (1b), which we reported to be a potent antihypertensive and antithrombotic agent. The new compound retained antithrombotic properties which were higher than those of acetylsalycilic acid but without significant antihypertensive activity. Conformational analysis performed by molecular mechanic calculations suggests that the lack of activity could be due to a different orientation of the acetylamino group in the 2 compounds. In addition, the unsubstituted term 2a was found to be comparable to ASA as an antithrombotic agent.

The Thromboxane/Endoperoxide Receptor (TP): The Common Villain

The stimulation of thromboxane/endoperoxide receptors (TP) elicits diverse physiological/pathophysiological reactions, including platelet aggregation and contraction of vascular smooth muscle. Furthermore, the activation of endothelial TP promotes the expression of adhesion molecules and favors adhesion and infiltration of monocytes/macrophages. In various cardiovascular diseases, endothelial dysfunction is predominantly the result of the release of endothelium-derived contracting factors that counteract the vasodilator effect of nitric oxide produced by the endothelial nitric oxide synthase. Endothelium-dependent contractions involve the activation of cyclooxygenases, the production of reactive oxygen species along with that of endothelium-derived contracting factors, which diffuse toward the vascular smooth muscle cells and activate their TP. TP antagonists curtail the endothelial dysfunction in diseases such as hypertension and diabetes, are potent antithrombotic agents, and reduce vascular inflammation. Therefore, TP antagonists, because of this triple activity, may have a unique potential for the treatment of cardiovascular disorders.

Vasoconstrictor prostanoids

In cardiovascular diseases and during aging, endothelial dysfunction is due in part to the release of endothelium-derived contracting factors that counteract the vasodilator effect of the nitric oxide. Endothelium-dependent contractions involve the activation of endothelial cyclooxygenases and the release of various prostanoids, which activate thromboxane prostanoid (TP) receptors of the underlying vascular smooth muscle. The stimulation of TP receptors elicits not only the contraction and the proliferation of vascular smooth muscle cells but also diverse physiological/pathophysiological reactions, including platelet aggregation and activation of endothelial inflammatory responses. TP receptor antagonists curtail endothelial dysfunction in diseases such as hypertension and diabetes, are potent antithrombotic agents, and prevent vascular inflammation.

Platelet function testing and risk of bleeding complications

Antiplatelet therapy has a key role in preventing atherothrombotic events in patients with coronary artery disease, particularly in those undergoing revascularisation procedures. However, this may occur at the expense of an increase risk of bleeding. Therefore, the balance between thrombotic and bleeding events is critical in order to achieve optimal outcomes. Since there is a broad variability in individual response profiles to antiplatelet therapy, these outcomes (thrombosis vs. bleeding) may depend on the level of platelet inhibition achieved in a given subject. Platelet function assays have emerged as a useful tool for its potential to determine patients at a higher risk of ischaemic and bleeding complications. The present manuscript will review the available evidence associating platelet function testing with adverse clinical outcomes, in particular bleeding, and their potential applications in lieu of novel and more potent antithrombotic agents that will be introduced into clinical practice in the near future.

Pharmacological Characterization and Structure Activity Relationship of FXI Antisense Oligonucleotides in Cynomolgus Monkeys.

Abstract 2101Poster Board II-78The absence of abnormal bleeding associated with congenital deficiencies of the intrinsic coagulation pathway factor, FXI, suggests that this pathway is not important for normal blood coagulation in vivo. However, recent work in mice and higher species demonstrates that the intrinsic pathway is an important contributor to pathologic intravascular thrombosis, suggesting that targeting this pathway may yield effective antithrombotic agents with high safety.We have previously demonstrated that second generation antisense oligonucleotides (ASOs) targeting the intrinsic pathway member FXI were potent antithrombotic agents and that this activity was achieved in several mouse models of thrombosis without any increase in bleeding risk (Zhang et al. ASH 2008).Here we characterize the pharmacological activity, chemical SAR and safety profile of FXI antisense oligonucleotides administered subcutaneously in Cynomologus monkeys. Our first monkey study was designed to address the PK/PD kinetics of FXI ASOs from a single chemical series (20 mers, 5-10-5 MOE Gapmers). Two dose escalation regimes were evaluated (1) 5mg/kg (3wks), 10mg/kg (3 wks) followed by 25 mg/kg (6wks) and (2) 5mg/kg (3wks) followed by 10mg/kg (9 wks). The subsequent study was designed to evaluate chemical SAR around the active ASOs identified in the study 1. FXI antisense oligonucleotides FXI-AS1, FXI-AS2 demonstrated dose and time dependent pharmacologic activity, including, decreased FXI mRNA in liver (up to 90%), decreased FXI protein levels and FXI activity measured in plasma, with a maximal inhibition of >80% observed at 25mg/kg on both schedules, prolonged activated partial thromboplastin times (aPTT), maximal aPTT ratio of 2.O, but no change in prothrombin time (PT) as expected. Similar to previous studies in mouse the anticoagulant activity observed from FXI depletion in monkeys was not associated with increased bleeding risk as assessed in a skin bleeding time test. Additionally, FXI ASOs had no deleterious effects on organ weights, platelets, or on measures of liver and kidney function. The second study confirmed the effects of FXI-AS1 and FXI-AS2 and demonstrated that shorter ASOs with decreased gap size were equally potent.These results further support the development of FXI ASOs as human therapeutics for the treatment of coagulation related disorders with the potential for improved safety profiles. Disclosures:MacLeod:Isis Pharmaceuticals: Employment. Crosby:Isis Pharmaceuticals, Inc.: Employment. Zhao:Isis Pharmaceuticals, Inc.: Employment. Gao:Isis Pharmaceuticals, Inc.: Employment. May:Isis Pharmaceuticals, Inc.: Employment. Zhang:Isis Pharmaceuticals, Inc.: Consultancy. Lowenberg:Isis Pharmaceuticals, Inc.: Consultancy. Levi:Isis Pharmaceuticals, Inc.: Consultancy. Monia:Isis Pharmaceuticals, Inc.: Employment.

ChemInform Abstract: Aeruginosin Analogues and Other Compounds with Rigid Bicyclic Structure as Potential Antithrombotic Agents

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Cangrelor (ARC69931MX) produces global inhibition of human platelet function by increasing cAMP levels through a Gi‐independent mechanism.

The recent use of antagonists against the P2Y1 and P2Y12 ADP receptors has significantly contributed to the characterization of ADP signaling in human platelets. Specifically, the results have suggested that while P2Y1 activation can initiate platelet aggregation, P2Y12 signaling accounts for the bulk of the ADP‐mediated effects. On this basis, efforts have focused on the development of a new class of P2Y12 antagonists (separate from clopidogrel and ticlopidine) as potential antithrombotic agents. The present work examined the molecular mechanisms by which one such adenosine‐based P2Y12 antagonist, i.e., Cangrelor (ARC69931MX), inhibits human platelet activation. It was found that the ability of ARC69931MX to block aggregation was associated with significant increases in platelet cAMP levels. It was also found that this elevation of cAMP did not require Gi signaling or even P2Y12 receptors, but was mediated through a separate G protein‐coupled pathway, presumably involving Gs. However, additional experiments revealed that ARC69931MX does not increase cAMP through activation of known platelet Gs‐coupled receptors, i.e., A2a, IP, DP or EP2. Collectively, these findings provide evidence that ARC69931MX interacts with an unidentified platelet G protein‐coupled receptor that stimulates substantial cAMP elevation and significant inhibition of platelet function through a P2Y12‐independent mechanism.

Aeruginosin Analogs and Other Compounds with Rigid Bicyclic Structure as Potential Antithrombotic Agents

Direct inhibition of blood coagulation factors such as thrombin, factor VIIa, and factor Xa has shown great promise for treating thrombosis disorders. Inhibitors of these serine proteases have been designed, synthesized, and evaluated. Small molecule thrombin inhibitors typically contain P(1)-P(2)-P(3) components targeting the active binding site. Structure optimizations on the P(1) position and the P(3) position have been done extensively, but the P(2) position has not been as thoroughly studied as the other positions. Thrombin inhibitors with a rigid bicyclic P(2) unit are interesting compounds with a more defined conformation. Aeruginosins are a family of naturally occurring small molecules that exhibit serine protease inhibition activities; their structures are typically tetrapeptides with an unusual bicyclic amino acid core structure occupying the P(2) position. About 21 compounds sharing the same core structure have been isolated and identified so far, and their analogs have also been synthesized. In this review, the Structure Activity Relationship (SAR) of these compounds against thrombin and other serine proteases and their potential as antithrombotic agents will be discussed. The binding modes to thrombin and other factors of the coagulation cascade and the preparation of the aeruginosin core structure will be summarized. Besides the aeruginosin family, the SAR of other small molecule serine protease inhibitors with a rigid bicyclic P(2) unit will also be covered.

The Role of New Antiplatelet Agents in Percutaneous Coronary Intervention

While the current armamentarium of antithrombotic agents used in the setting of percutaneous coronary intervention (PCI) has led to decreased mortality, re-infarction and recurrent ischaemia rates, there are also increasing rates of major bleeding events with the use of more potent antithrombotic agents. Major bleeding associated with PCI leads to significantly increased mortality. Additionally, adequate rates of antiplatelet activity are not reached in large proportions of patients receiving clopidogrel due to interactions with its hepatic metabolism. As a result, current research has focused on creating antiplatelet agents that bypass hepatic metabolism, such as prasugrel and ticagrelor, as well as on decreasing major bleeding risks in patients undergoing PCI. Large trials such as ACUITY and HORIZONS have demonstrated that the direct thrombin inhibitor bivalirudin is able to adequately anticoagulate patients undergoing urgent PCI while also significantly decreasing adverse bleeding events. Additionally, novel reversible anticoagulants and factor Xa inhibitors are being examined as agents that may reduce bleeding risk in this patient population.

Influence of molecular weight of chemically sulfated citrus pectin fractions on their antithrombotic and bleeding effects

Evaluated were the anticoagulant and antithrombotic activities, and bleeding effect of two chemically sulfated polysaccharides, obtained from citric pectin, with different average molar masses. Both low-molecular-weight (Pec-LWS, 3,600 g/mol) and high-molecular-weight sulfated pectins (Pec-HWS, 12,000 g/mol) had essentially the same structure, consisting of a (1-->4)-linked alpha-D-GalpA chain with almost all its HO-2 and HO-3 groups substituted by sulfate. Both polysaccharides had anticoagulant activity in vitro, although Pec-HWS was a more potent antithrombotic agent in vivo, giving rise to total inhibition of venous thrombosis at a dose of 3.5 mg/kg body weight. Surprisingly, in contrast with heparin, Pec-HWS and Pec-LWS are able to directly inhibit alpha-thrombin and factor Xa by a mechanism independent of antithrombin (AT) and/or heparin co-factor II (HCII). Moreover, Pec-HWS provided a lower risk of bleeding than heparin at a dose of 100% effectiveness against venous thrombosis, indicating it to be a promising antithrombotic agent.

Transfusion associated microchimerism: a heretofore little recognized complication following transfusion

Potent antiplatelet and antithrombotic agents have significantly reduced mortality in the setting of acute coronary syndromes and percutaneous coronary intervention. However these agents are associated with increased bleeding which is in turn associated with adverse clinical outcomes. In many centers, transfusion is often used to correct for blood loss. Blood transfusion in the setting of acute coronary syndrome has been associated with adverse clinical outcomes including increased mortality. Transfusion associated microchimerism (TA-MC) is a newly recognized complication of blood transfusion. There is engraftment of the donor's hematopoietic stem cells in patients who then develop microchimerism. This article discusses the association of bleeding/blood transfusion with adverse outcomes and the potential role of TA-MC in clinical outcomes.

A randomized trial comparing eptifibatide vs. placebo in patients with diffuse coronary artery disease undergoing drug-eluting stent implantation: design of the INtegrilin plus STenting to Avoid myocardial Necrosis Trial

Despite the availability of several potent antithrombotic agents, the optimal antiplatelet regimen in elective patients undergoing complex percutaneous coronary interventions is still debated. Aim of the INtegrilin plus STenting to Avoid myocardial Necrosis Trial will be to assess the safety and efficacy of routine usage of the glycoprotein IIb/IIIa inhibitor eptifibatide in patients already treated with aspirin and clopidogrel and undergoing implantation of at least two drug-eluting stents in the same lesion, thus identifying a clinically stable but anatomically complex patient subset. This will be a single-blind, placebo-controlled multicenter randomized trial. Patients with stable coronary artery disease, who are undergoing percutaneous coronary intervention by means of implantation of greater than 33 mm of drug-eluting stents (e.g. with two 23-mm drug-eluting stents or one 32-mm and one 12-mm drug-eluting stent), will be randomized, after administration of aspirin and clopidogrel (600 mg loading dose recommended), to eptifibatide and unfractioned heparin according to the ESPRIT protocol or placebo and unfractioned heparin. Blood draws for creatine kinase-MB mass, total creatine kinase, and cardiac troponin levels will be taken at baseline, 6 and 12 h postprocedurally. Patients will be followed for clinical events by direct visit or phone contact up to 6 months. The primary endpoint of the study will be the rate of abnormal values of creatine kinase-MB mass after percutaneous coronary intervention. Secondary endpoints will be the composite of cardiac death, nonfatal myocardial infarction, urgent target vessel revascularization, and thrombotic bailout glycoprotein IIb/IIIa inhibitor therapy within 180 days, and in-hospital, 1-month and 6-month major adverse cardiovascular events, defined as the composite of cardiac death, nonfatal myocardial infarction or urgent target vessel revascularization. The INtegrilin plus STenting to Avoid myocardial Necrosis Trial study will test for the first time the beneficial impact of routine glycoprotein IIb/IIIa inhibition on top of dual oral antiplatelet treatment in clinically stable yet anatomically complex patients undergoing drug-eluting stents implantation. Results of this single-blind randomized trial will provide important insights to improve the management strategy of patients and outcomes in the current drug-eluting stents era.

Peptides and pseudopeptides incorporating D‐Phe–Pro–Arg and Arg–Gly–Asp lead sequences as potential antithrombotic agents

Peptide leads D-Phe-Pro-Arg for thrombin inhibition and Arg-Gly-Asp for antagonistic activity on fibrinogen receptor were combined in one molecule in order to produce compounds capable of acting both as thrombin inhibitors and as fibrinogen receptor antagonists. Peptide conjugate 7 possessing both leads joined by a tetraglycine linker as well as tripeptides and peptidomimetics with highly overlapped D-Phe-Pro-Arg and Arg-Gly-Asp pharmacophore groups were prepared. Conjugate 7 was found to possess antagonistic activity on fibrinogen receptor, but was unexpectedly inactive as thrombin inhibitor. Compound 9 comprising of highly integrated D-Phe-Pro-Arg and Arg-Gly-Asp pharmacophore groups was found to possess a moderate but well balanced thrombin inhibitory and fibrinogen receptor antagonistic activity.

Stunning, Hibernation, and Assessment of Myocardial Viability

The last 3 decades have witnessed an unprecedented improvement in the outcome of patients with acute coronary syndromes. The widespread use of thrombolytic therapy and percutaneous coronary interventions, in association with increasingly potent antithrombotic agents, has contributed to significant reductions in mortality and morbidity in these patients. Although overall survival has improved, a downside of this success has been the greater number of patients with residual left ventricular (LV) dysfunction undergoing progressive LV remodeling and congestive heart failure. This problem is compounded by the rising age of our population and the higher prevalence of comorbidities such as diabetes mellitus that confer an increased risk of coronary artery disease (CAD) and congestive heart failure. Patients with CAD represent by far the most numerous cohort among those with congestive heart failure, and their treatment remains a partial success.1 Typically, these patients have multivessel disease, increased LV volumes, and variable degrees of regional and/or global systolic dysfunction, although more cases of isolated diastolic dysfunction have been reported recently.2–4 In these patients, coronary revascularization may lead to symptomatic and prognostic improvement, and these clinical benefits are accompanied by evidence of reverse LV remodeling. In this context, the concept of myocardial viability was developed and a number of different techniques have been used to demonstrate the presence of viable tissue before coronary revascularization. The aim of this review article is to summarize our current understanding of the concept of myocardial viability and its clinical implications in patients with CAD and chronic LV dysfunction. Throughout this review, we use the term viability to describe dysfunctional myocardium subtended by diseased coronary arteries with limited or absent scarring that therefore has the potential for functional recovery. Viability is a prospective definition, but it does not imply evidence of functional recovery after interventions. The term hibernation, which …