Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Abstract-The early and long-term effects of coronary artery ligation on the plasma and left ventricular angiotensinconverting enzyme (ACE and ACE2) activities, ACE and ACE2 mRNA levels, circulating angiotensin (Ang) levels [Ang I, Ang-(1-7), Ang-(1-9), and Ang II], and cardiac function were evaluated 1 and 8 weeks after experimental myocardial infarction in adult Sprague Dawley rats. Sham-operated rats were used as controls. Coronary artery ligation caused myocardial infarction, hypertrophy, and dysfunction 8 weeks after surgery. At week 1, circulating Ang II and Ang-(1-9) levels as well as left ventricular and plasma ACE and ACE2 activities increased in myocardial-infarcted rats as compared with controls. At 8 weeks post-myocardial infarction, circulating ACE activity, ACE mRNA levels, and Ang II levels remained higher, but plasma and left ventricular ACE2 activities and mRNA levels and circulating levels of Ang-(1-9) were lower than in controls. No changes in plasma Ang-(1-7) levels were observed at any time. Enalapril prevented cardiac hypertrophy and dysfunction as well as the changes in left ventricular ACE, left ventricular and plasmatic ACE2, and circulating levels of Ang II and Ang-(1-9) after 8 weeks postinfarction. Thus, the decrease in ACE2 expression and activity and circulating Ang-(1-9) levels in late ventricular dysfunction post-myocardial infarction were prevented with enalapril. These findings suggest that in this second arm of the renin-angiotensin system, ACE2 may act through Ang-(1-9), rather than Ang-(1-7), as a counterregulator of the first arm, where ACE catalyzes the formation of Ang II. Key Words: angiotensin-converting enzyme Ⅲ myocardial infarction Ⅲ renin-angiotensin system Ⅲ remodeling Ⅲ cardiac function T he renin-angiotensin system (RAS) is a more complex system than originally thought. A new angiotensin-converting enzyme (ACE), ACE2, has been recently identified as a homologue of ACE. 1 ACE2 is also a metalloprotease consisting of 805 amino acids with a considerable degree of homology to ACE (40% identity and 61% similarity). 2,3 ACE2 contains a single zinc-binding domain and is a carboxypeptidase, unlike somatic ACE, which contains 2 zinc-binding domains and is a dipeptidyl carboxypeptidase. 2 Both ACE2 and ACE are bound to the plasma membrane and must be cleaved to release the soluble enzyme. 2 Their cellular and tissue distributions are also different, in that ACE is expressed in the endothelium throughout the vasculature, whereas ACE2 is distributed to most tissues, including to the heart and kidney. 3 Analyses in vitro have shown that ACE2 cleaves angiotensin (Ang) I to Ang-(1-9), which is then cleaved by ACE to Ang-(1-7). However, ACE2 also cleaves Ang II to form Ang-(1-7). Because Ang-(1-7) is a potent vasodepressor peptide, its actions could counterbalance the vasopressor effect of Ang II. 4,5 ACE2 does not act on bradykinins and its activity is not inhibited by ACE inhibitors. 2 Although a significant activation of the RAS system occurs after myocardial infarction, 6 -10 ...

Heart failure (HF) data in Latin America (LA) were reviewed to guide health service planning in the prevention and treatment of HF. The HF epidemiology and the adequacy of relevant health service provision related to HF in LA are not well delineated. A systematic search of the electronic databases and the World Health Organization website was undertaken for HF in LA. LA countries have reduced gross income and lower total expenditure on health per capita. LA is a heterogeneous region with HF risk factors of developed and nondeveloped countries, including lower risk of raised blood glucose levels, obesity, tobacco, and aging, whereas systemic hypertension (SH), rheumatic fever, and Chagas' disease (C'D) are higher in LA. Main etiologies of HF in LA are idiopathic dilated cardiomyopathy (from 1.3% to 37%), C'D (from 1.3% to 21%), ischemic (from 68% to 17%), SH (from 14% to 76%), valvular (from 3% to 22%), and alcohol related (from 1.1% to 8%). The prognosis of C'D HF is worse than for other etiologies. Chronic HF is the cause of death in 6.3% of cases. Decompensated HF is the main cause of cardiovascular hospitalization. The prevalence of systolic HF varies from 64% to 69%. LA is under the awful paradox of having the HF risk factors and HF epidemiology of developed countries with the added factors of SH, C'D, and rheumatic fever. Overall, in the scenario of lower total expenditure on health per capita and lower gross national income per capita, new strategies are essential for prevention and treatment of HF in LA.

The renin-angiotensin system (RAS) is a key component of cardiovascular physiology and homeostasis due to its influence on the regulation of electrolyte balance, blood pressure, vascular tone and cardiovascular remodeling. Deregulation of this system contributes significantly to the pathophysiology of cardiovascular and renal diseases. Numerous studies have generated new perspectives about a noncanonical and protective RAS pathway that counteracts the proliferative and hypertensive effects of the classical angiotensin-converting enzyme (ACE)/angiotensin (Ang) II/angiotensin type 1 receptor (AT1R) axis. The key components of this pathway are ACE2 and its products, Ang-(1-7) and Ang-(1-9). These two vasoactive peptides act through the Mas receptor (MasR) and AT2R, respectively. The ACE2/Ang-(1-7)/MasR and ACE2/Ang-(1-9)/AT2R axes have opposite effects to those of the ACE/Ang II/AT1R axis, such as decreased proliferation and cardiovascular remodeling, increased production of nitric oxide and vasodilation. A novel peptide from the noncanonical pathway, alamandine, was recently identified in rats, mice and humans. This heptapeptide is generated by catalytic action of ACE2 on Ang A or through a decarboxylation reaction on Ang-(1-7). Alamandine produces the same effects as Ang-(1-7), such as vasodilation and prevention of fibrosis, by interacting with Mas-related GPCR, member D (MrgD). In this article, we review the key roles of ACE2 and the vasoactive peptides Ang-(1-7), Ang-(1-9) and alamandine as counter-regulators of the ACE-Ang II axis as well as the biological properties that allow them to regulate blood pressure and cardiovascular and renal remodeling.

Eukaryotic cells contain a variety of subcellular organelles, each of which performs unique tasks. Thus follows that in order to coordinate these different intracellular functions, a highly dynamic system of communication must exist between the various compartments. Direct endoplasmic reticulum (ER)-mitochondria communication is facilitated by the physical interaction of their membranes in dedicated structural domains known as mitochondria-associated membranes (MAMs), which facilitate calcium (Ca(2+)) and lipid transfer between organelles and also act as platforms for signaling. Numerous studies have demonstrated the importance of MAM in ensuring correct function of both organelles, and recently MAMs have been implicated in the genesis of various human diseases. Here, we review the salient structural features of interorganellar communication via MAM and discuss the most common experimental techniques employed to assess functionality of these domains. Finally, we will highlight the contribution of MAM to a variety of cellular functions and consider the potential role of MAM in the genesis of metabolic diseases. In doing so, the importance for cell functions of maintaining appropriate communication between ER and mitochondria will be emphasized.

Cardiovascular diseases are the leading cause of death worldwide. Despite preventive efforts, early detection of atherosclerosis, the common pathophysiological mechanism underlying cardiovascular diseases remains elusive, and overt coronary artery disease or myocardial infarction is often the first clinical manifestation. Nanoparticles represent a novel strategy for prevention, diagnosis, and treatment of atherosclerosis, and new multifunctional nanoparticles with combined diagnostic and therapeutic capacities hold the promise for theranostic approaches to this disease. This review focuses on the development of nanosystems for therapy and diagnosis of subclinical atherosclerosis, coronary artery disease, and myocardial infarction and the evolution of nanosystems as theranostic tools. We also discuss the use of nanoparticles in noninvasive imaging, targeted drug delivery, photothermal therapies together with the challenges faced by nanosystems during clinical translation.

The HFS provides an accurate method for PAP assessment in the intermediate follow-up of HF patients.

Type 2 diabetes mellitus (T2DM) is a highly prevalent disease worldwide. Cardiovascular disorders generated as a consequence of T2DM are a major cause of death related to this disease. Diabetic cardiomyopathy (DCM) is characterized by the morphological, functional and metabolic changes in the heart produced as a complication of T2DM. This cardiac disorder is characterized by constant high blood glucose and lipids levels which eventually generate oxidative stress, defective calcium handling, altered mitochondrial function, inflammation and fibrosis. In this context, insulin is of paramount importance for cardiac contractility, growth and metabolism and therefore, an impaired insulin signaling plays a critical role in the DCM development. However, the exact pathophysiological mechanisms leading to DCM are still a matter of study. Despite the numerous questions raised in the study of DCM, there have also been important findings, such as the role of micro-RNAs (miRNAs), which can not only have the potential of being important biomarkers, but also therapeutic targets. Furthermore, exosomes also arise as an interesting variable to consider, since they represent an important inter-cellular communication mechanism and therefore, they may explain many aspects of the pathophysiology of DCM and their study may lead to the development of therapeutic agents capable of improving insulin signaling. In addition, adenosine and adenosine receptors (ARs) may also play an important role in DCM. Moreover, the possible cross-talk between insulin and ARs may provide new strategies to reverse its defective signaling in the diabetic heart. This review focuses on DCM, the role of insulin in this pathology and the discussion of new molecular insights which may help to understand its underlying mechanisms and generate possible new therapeutic strategies.