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Acute myocardial infarction is caused by sudden coronary artery occlusion. Persistent ischemia results in necrosis of the myocardial tissue supplied by the occluded vessel. It has recently been shown that the final size of the infarct is a major predictor of future clinical events, and is, therefore, used as a surrogate outcome in clinical trials. Moreover, it has become clear that the duration of ischemia in the main determinant of the success of myocardial salvage (i.e. of non-necrotic at-risk myocardium). In addition to minimizing the time between symptom onset and reperfusion, there is considerable interest in finding therapies that can further limit the size of the infarction (i.e. cardioprotective therapies) and they are the focus of numerous clinical studies. Oral β-blockade within the first few hours of an AMI is a class-IA indication in clinical practice guidelines. However, early intravenous β-blockade, even before coronary artery reperfusion, is not routinely recommended. Preclinical research has demonstrated that the selectiveβ1-blocker metoprolol is able to reduce the infarct size only when administered before coronary artery reperfusion, which indicates that its cardioprotective properties are secondary to its ability to reduce reperfusion injury. In addition, retrospective studies of AMI suggest that starting intravenous β-blockade early has clinical benefits (i.e. lower mortality and better recovery of left ventricular contractility) in patients without contraindications. Our general hypothesis is that early administration of metoprolol (i.e. intravenously before reperfusion) results in smaller infarcts than administering the drug orally after reperfusion. The Effect of METOprolol in CARDioproteCtioN during an acute myocardial InfarCtion (METOCARD-CNIC) trial will test this hypothesis in patients with ST-segment elevation AMI., (Copyright © 2011 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

Worldwide, the leading causes of death are ischemic heart disease and stroke. Moreover, patients with several risk factors or a history of ischemic heart disease are at a high risk of coronary event recurrence. There is evidence that primary cardiovascular disease prevention programs are effective when applied to the general population. However, therapeutic strategies designed to control several risk factors simultaneously in patients without evidence of cardiovascular disease are expensive and difficult to implement. In contrast, combination drug therapy is commonly used for secondary cardiovascular prevention and its beneficial effects on morbidity and mortality have been clearly demonstrated. Nevertheless, the actual impact of this approach is less than might be expected, partly because of poor adherence to drug regimens and the high cost of treatment in low- and middle-income countries. In patients who have had an acute myocardial infarction, the complexity of the regimen is inversely correlated ith compliance and is, in most cases, the reason for treatment discontinuation. Moreover, globally the ast majority of cardiovascular events take place in developing countries with limited health resources here access to treatment is poor. The development of fixed-dose combinations of drugs (i.e. polypills) designed for the treatment of myocardial infarction patients could help overcome these limitations, improve compliance and facilitate the distribution of and access to treatment in developing countries. We have begun a large clinical trial in five countries to investigate the beneficial effects of treatment using a polypill (i.e. aspirin, an angiotensin-converting enzyme inhibitor and a statin) on ischemic heart disease recurrence. The results of this study could provide the basis for a new therapeutic approach to the management of not only cardiovascular disease but also diabetes and stroke., (Copyright © 2011 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

The development of drug-eluting stents has raised great hopes that percutaneous coronary intervention has a potential role in the revascularization of patients with three-vessel disease and left main coronary artery disease. However, recent results from the SYNTAX clinical trial have shown that, compared with drug-eluting stents, bypass surgery is associated with a lower restenosis rate and a reduced incidence of major cardiovascular events. This study used an index that quantifies the severity of coronary artery disease on the basis of a number of anatomical criteria of lesion complexity (i.e. the SYNTAX score). The study results indicate that the higher the index (i.e. the more complex the lesion), the greater the benefits of surgery. Other recent studies (e.g. PROSPECT and FAME) have used imaging to investigate the natural history of acute coronary syndrome, or the role of functional parameters in identifying vulnerable plaque that can lead to complications during follow-up. The sum of the evidence available shows that therapeutic approaches to complex disease should take into account both the anatomical and structural characteristics of lesions, as well as functional parameters, and that high-resolution imaging techniques are essential for establishing both an individual's risk profile and the potential benefits of treatment. In diabetic patients with multivessel disease, the results of the FREEDOM study (currently ongoing) could be crucial for incorporating this new knowledge into practice and for defining the optimum management for this group of high-risk patients.

Public health predictions indicate that the prevalence of cardiovascular disease will reach epidemic levels throughout the world in coming years, principally because of increasing obesity and diabetes in the general population. Numerous studies have confirmed that diabetes will affect morbidity and mortality in patients with complex multivessel disease. The magnitude of the public health problem and the enormous economic costs associated with the treatment and hospitalization of these patients make it essential that clinical studies designed to elucidate the pathophysiological mechanisms underlying the development of clinical atherosclerosis from its subclinical form are carried out, with the aim of identifying treatment that can lead to disease regression. Moreover, it is important that evidence from patient registries, and not only from large clinical studies, is interpreted correctly, so that the most effective therapies can be implemented. Registries are not subject to the same patient inclusion biases as studies and they contain information that is not included in clinical studies. Recent evidence from patient registries indicates that the physician's judgment is a predictive variable for a successful clinical outcome. In addition, clinical studies confirm that medical treatment, when it is well monitored and implemented aggressively, can provide similar benefits to surgery. Using the knowledge that has been gained over the last few decades, we have designed a study, named FREEDOM, that will enable us to use high-resolution imaging to reliably and reproducibly correlate plaque characteristics, including the level of inflammation and the so-called <>, with the effectiveness of medical treatment aimed at promoting endogenous defense mechanisms. In this way, we hope to be able to influence atherosclerotic disease in high-risk groups from its early silent phase onwards, to slow its spread, and to alter its clinical epidemiology.

Pulmonary hypertension is a very serious condition, with 10-year survival rates under 10%. Despite this, knowledge of the pathophysiological mechanisms underlying its development and progression has been seriously limited by a lack of appropriate tools for studying the condition. The introduction of new noninvasive high-resolution imaging techniques, such as magnetic resonance imaging, could provide a promising new approach to the investigation of not only the anatomical, but also the functional and molecular, features of pulmonary hypertension. As has happened with atherosclerotic disease in recent years, high-resolution imaging, combined with other imaging techniques such as computed tomography (CT) and positron-emission tomography, could provide useful data on morphological and physiological factors of fundamental importance to understanding unresolved issues concerning the etiology, diagnosis, and treatment of patients with pulmonary arterial hypertension. Moreover, the application of molecular techniques is leading to the development of a new discipline, molecular imaging, that will enable patients to be studied from a biological perspective and which could uncover mechanisms of great clinical relevance in experimental models. The key to the treatment of pulmonary arterial disease could be discovered by studying these mechanisms. For example, knowledge of the pathways involved in the development of endothelial dysfunction or in endothelial repair associated with bone marrow-derived cells--a common feature of a number of cardiovascular conditions--could lead to treatments that are able to stimulate endothelial replacement with circulating progenitor cells in patients with pulmonary arterial hypertension of whatever etiology.

Surgical valve replacement is the treatment of choice in patients with severe valvular heart disease. However, published data clearly show that long-term survival is seriously compromised in those with a low inotropic reserve. In addition, a growing number of patients (estimated to be around 15% of those with aortic stenosis) present in such a poor and deteriorating clinical condition that they cannot be accepted for surgery because it involves a very high risk of death. Percutaneous balloon valvuloplasty is a less aggressive alternative which offers a form of palliative treatment that can increase the patient's life expectancy and bring about immediate hemodynamic and clinical improvement. It is in this context that the possibility of carrying out percutaneous valve replacement has become available as a novel therapeutic option since Cribier first reported using the procedure to treat a patient with severe aortic stenosis. Since this first operation, both the techniques employed and the material composition of the prosthesis have undergone substantial development. However, significant problems have been encountered in evaluating the safety and efficacy of percutaneous valve replacement. These, to a great extent, stem from the risks associated with treating elderly patients who have high morbidity and mortality. In the United States, one clinical study was even suspended because two of the first four patients undergoing treatment died. In contrast, studies carried out in other countries, although they have involved only a few patients, have produced more promising results. Moreover, because the cause of death in these series was frequently due to factors that were independent of good valvular function, the future of the technique is generally thought to be positive. Nevertheless, the results obtained with percutaneous mitral valve replacement have been poor. In conclusion, the technique of percutaneous valve replacement, although still undergoing development, is becoming established as a viable alternative for treating inoperable valve disease, at least in aortic valves.

The coagulation cascade leads, via thrombin activation, to the formation of fibrin (from its precursor fibrinogen) and platelet thrombus. Several drugs are able to interfere with some of the enzymatic factors involved in thrombin activation, but thrombin inhibitors (heparin, hirudin and hirulog [bivalirudin]) are of particular interest because they disrupt the coagulation cascade by acting upon one of its final steps. Among the thrombin inhibitors, oral antithrombins (ximelagatran) appear to hold great promise for the control of thrombogenicity in a number of clinical contexts. Oral antithrombins do not require the participation of cofactors to exert their action, and in contrast to thrombin inhibitors administered parenterally, they bind specifically to the active site of thrombin without interfering with other portions of the molecule. Their specificity makes these drugs safe and obviates the need to monitor coagulability. Moreover, they show a low rate of interaction with other drugs or with foods, and the response to fixed doses is predictable. A number of clinical studies have investigated antithrombins for prophylaxis prior to orthopedic surgery, in the prevention of cerebrovascular accidents associated with atrial fibrillation, and in the control of coronary artery disease. These studies have shown that antithrombins are superior to other habitually used treatment options. Surprisingly, their use in long-term studies has not been associated with an increased rate of bleeding events. Their interesting molecular characteristics and considerable therapeutic efficacy and safety suggest that oral antithrombins will in the near future become a valuable therapeutic option.

Recent advances in basic science have linked some systemic risk factors to endothelial dysfunction which gives rise to atherosclerotic disease and triggers the progression of thrombotic complications. Superficial erosion of the stenotic plaque can be observed in one-third of acute coronary syndromes (ACS). In these cases the presence of classic risk factors such as diabetes mellitus, hypercholesterolemia and smoking favor a state of "vulnerable blood" or high risk. Increased thrombogenicity can exacerbate thrombus formation and is able to trigger an ACS. The vessel endothelium regulates contractile, mitogenic and thrombotic activities of the vessel wall. Risk factors impair both homeostasis and hemostasis of the vessel wall and promote inflammatory signals. Platelet and monocyte activation favors the expression of tissue factor (TF), thus triggering the coagulation cascade with thrombin generation and clot formation. Increased blood thrombogenicity linked to classic risk factors may be associated with circulating TF levels which are much higher than those observed in healthy subjects without risk factors. These observations not only emphasize the usefulness of aggressive management of risk factors but open a new avenue for future studies to devise therapeutic strategies to treat ACS by inhibiting TF expression.

The history of rapamycin dates from 1965, when it was isolated from a microorganism in soil and its antibiotic properties were confirmed. Since its discovery, many scientific papers have demonstrated its antifungal and immunosuppressive properties. Our team pioneered in the study of the mechanism of action of rapamycin, motivated by its enormous promise as a therapeutic agent in atherosclerotic disease. We reported how it can inhibit the proliferation and migration of smooth muscle cells after a mechanical aggression, and demonstrated that this effect is mediated by p27 activation by rapamycin. The participation of p27, a key cyclin in the modulation of cell replication, in rapamycin's molecular signaling also spurred expectations in the field of oncological research because it involves a non-redundant system of regulation of the cell cycle susceptible to mutatio. The interesting characteristics of this active principle suggested that it would be worthwhile to investigate its protective effect in an experimental porcine model of angioplasty. Rapamycin showed that it can notably reduce vascular wall thickening, thus helping to preserve patency after angioplasty. Shortly after this study, the use of rapamycin-coated stents designed to release the active principle into the area of the atherosclerotic lesion was accompanied by an effective preservation of the arterial lumen in experimental models. It also produced a highly significant reduction in the rate of post-stent restenosis in various clinical studies in humans. However, the potential of this type of stent in diabetic patients is still unknown and we are on the point of beginning a large clinical trial (the FREEDOM study) to investigate its impact on the management of diabetic patients. Experimental and clinical evidence indicates that the development of oral agents capable of modifying the progression of atherosclerotic disease by acting on molecular targets involved in the control of the cell cycle will be a challenge in the coming years.