Are users of sulphonylureas at the time of an acute coronary syndrome at risk of poorer outcomes?

Aims: Adenosine triphosphate sensitive potassium (K(ATP)) channel activity is cardioprotective during ischaemia. One of the purported mechanisms for sulphonylurea adverse effects is through inhibition of these channels. The purpose of this study is to examine whether patients using K(ATP) channel inhibitors at the time of an acute coronary syndrome are at greater risk of death or heart failure (HF) than those not exposed.

PI3K inhibitors as novel cancer therapies: implications for cardiovascular medicine.

Background: The phosphatidylinositol 3-kinase (PI3K) signaling cascade has fundamental roles in cell growth, survival, and motility; and increased PI3K activity is an important and common contributor to tumorigenesis and cancer progression. This pathway also has a significant role in physiologic hypertrophy, myocardial contractility, and metabolism in the heart and is a central determinant of pathologic remodeling in the cardiovascular system.

Methods And Results: PI3K inhibitors are a promising class of anticancer drugs, although systemic inhibition of the PI3K pathway demands careful attention to possible adverse side effects of inhibiting these ubiquitously expressed proteins.

Loss of p47phox subunit enhances susceptibility to biomechanical stress and heart failure because of dysregulation of cortactin and actin filaments.

Rationale: The classic phagocyte nicotinamide adenine dinucleotide phosphate oxidase (gp91(phox) or Nox2) is expressed in the heart. Nox2 activation requires membrane translocation of the p47(phox) subunit and is linked to heart failure. We hypothesized that loss of p47(phox) subunit will result in decreased reactive oxygen species production and resistance to heart failure.

S4153R is a gain-of-function mutation in the cardiac Ca(2+) release channel ryanodine receptor associated with catecholaminergic polymorphic ventricular tachycardia and paroxysmal atrial fibrillation.

Mutations in ryanodine receptor 2 (RYR2) gene can cause catecholaminergic polymorphic ventricular tachycardia (CPVT). The novel RYR2-S4153R mutation has been implicated as a cause of CPVT and atrial fibrillation. The mutation has been functionally characterized via store-overload-induced Ca(2+) release (SOICR) and tritium-labelled ryanodine ([(3)H]ryanodine) binding assays.

ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4.

The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (ANG II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an ANG II-induced hypertrophy model.

Cyclophosphamide-Induced Cardiomyopathy: A Case Report, Review, and Recommendations for Management.

Cyclophosphamide is increasingly used to treat various types of cancers and autoimmune conditions. Higher doses of this drug may produce significant cardiac toxicity, including fatal hemorrhagic myocarditis. In this review, we present a case of cyclophosphamide-induced cardiomyopathy requiring mechanical circulatory support.

Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload.

Aims: Development of heart failure is known to be associated with changes in energy substrate metabolism. Information on the changes in energy substrate metabolism that occur in heart failure is limited and results vary depending on the methods employed. Our aim is to characterize the changes in energy substrate metabolism associated with pressure overload and ischaemia-reperfusion (I/R) injury.

Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia.

Background: Bronchopulmonary dysplasia (BPD) remains a main complication of extreme prematurity and currently lacks efficient treatment. Rat bone marrow-derived mesenchymal stem cells (MSC) prevent lung injury in an oxygen-induced model of BPD. Human cord is an advantageous source of stem cells that is especially appealing for the treatment of neonatal diseases.

Loss of Timp3 gene leads to abdominal aortic aneurysm formation in response to angiotensin II.

Aortic aneurysm is dilation of the aorta primarily due to degradation of the aortic wall extracellular matrix (ECM). Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs), the proteases that degrade the ECM. Timp3 is the only ECM-bound Timp, and its levels are altered in the aorta from patients with abdominal aortic aneurysm (AAA).

Enhanced recovery from ischemia-reperfusion injury in PI3Kα dominant negative hearts: investigating the role of alternate PI3K isoforms, increased glucose oxidation and MAPK signaling.

Classical ischemia-reperfusion (IR) preconditioning relies on phosphatidylinositol 3-kinase (PI3K) for protective signaling. Surprisingly, inhibition of PI3Kα activity using a dominant negative (DN) strategy protected the murine heart from IR injury. It has been proposed that increased signaling through PI3Kγ may contribute to the improved recovery of PI3KαDN hearts following IR.

Effects of hypoxia-induced intrauterine growth restriction on cardiac siderosis and oxidative stress.

We have previously shown that adult rat offspring born intrauterine growth restricted (IUGR) as a result of a prenatal hypoxic insult exhibit several cardiovascular characteristics that are compatible with common manifestations of chronic iron toxicity. As hypoxia is one of the major regulators of iron absorption and metabolism, we hypothesized that hypoxia-induced IUGR offspring will have long-term changes in their ability to regulate iron metabolism leading to myocardial iron deposition and induction of myocardial oxidative stress. Pregnant Sprague Dawley rats were randomized to control (n = 8) or maternal hypoxia (11.

Loss of TIMP3 selectively exacerbates diabetic nephropathy.

Diabetic nephropathy is the most common cause of end-stage renal disease. Polymorphism in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene, and the ECM-bound inhibitor of matrix metalloproteinases (MMPs), has been linked to diabetic nephropathy in humans. To elucidate the mechanism, we generated double mutant mice in which the TIMP3 gene was deleted in the genetic diabetic Akita mouse background.

Angiotensin-converting enzyme 2 antagonizes angiotensin II-induced pressor response and NADPH oxidase activation in Wistar-Kyoto rats and spontaneously hypertensive rats.

Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase capable of metabolizing angiotensin II (Ang II) into angiotensin-(1-7) [Ang-(1-7)], has emerged as a potential therapeutic target. We hypothesized that ACE2 is a negative regulator of Ang II-mediated pathological effects in vivo. In Wistar-Kyoto (WKY) rats, Ang II infusion (0.

Agonist-induced hypertrophy and diastolic dysfunction are associated with selective reduction in glucose oxidation: a metabolic contribution to heart failure with normal ejection fraction.

Background: Activation of the renin-angiotensin and sympathetic nervous systems may alter the cardiac energy substrate preference, thereby contributing to the progression of heart failure with normal ejection fraction. We assessed the qualitative and quantitative effects of angiotensin II (Ang II) and the α-adrenergic agonist, phenylephrine (PE), on cardiac energy metabolism in experimental models of hypertrophy and diastolic dysfunction and the role of the Ang II type 1 receptor.

Methods And Results: Ang II (1.

Targeting the ACE2 and Apelin Pathways Are Novel Therapies for Heart Failure: Opportunities and Challenges.

Angiotensin-converting enzyme 2 (ACE2)/Ang II/Ang 1-7 and the apelin/APJ are two important peptide systems which exert diverse effects on the cardiovascular system. ACE2 is a key negative regulator of the renin-angiotensin system (RAS) where it metabolizes angiotensin (Ang) II into Ang 1-7, an endogenous antagonist of Ang II. Both the prolonged activation of RAS and the loss of ACE2 can be detrimental as they lead to functional deterioration of the heart and progression of cardiac, renal, and vascular diseases.

Deletion of p47phox attenuates the progression of diabetic nephropathy and reduces the severity of diabetes in the Akita mouse.

Aims/hypothesis: Reactive oxygen species (ROS) contribute to diabetes-induced glomerular injury and endoplasmic reticulum (ER) stress-induced beta cell dysfunction, but the source of ROS has not been fully elucidated. Our aim was to determine whether p47(phox)-dependent activation of NADPH oxidase is responsible for hyperglycaemia-induced glomerular injury in the Akita mouse, a model of type 1 diabetes mellitus resulting from ER stress-induced beta cell dysfunction.

Methods: We examined the effect of deleting p47 (phox) (also known as Ncf1), the gene for the NADPH oxidase subunit, on diabetic nephropathy in the Akita mouse (Ins2 (WT/C96Y)) by studying four groups of mice: (1) non-diabetic mice (Ins2 (WT/WT)/p47 (phox+/+)); (2) non-diabetic p47 (phox)-null mice (Ins2 (WT/WT)/p47 (phox-/-)); (3) diabetic mice: (Ins2 (WT/C96Y)/p47 (phox+/+)); and (4) diabetic p47 (phox)-null mice (Ins2 (WT/C96Y)/p47 (phox-/-)).

The use of ω-3 poly-unsaturated fatty acids in heart failure: a preferential role in patients with diabetes.

Purpose: To review the evidence for a beneficial effect of ω-3 PUFAs in heart failure (HF) and its co-morbidities, their possible preferential effect in diabetes and the potential mechanism for their benefit.

Methods: We summarize the clinical studies which investigated the use of ω-3 PUFAs in patients with HF with an emphasis on diabetes. We briefly summarize the evidence for an effect of ω-3 PUFAs in patients with coronary artery disease (CAD), atrial fibrillation (AF) and ventricular arrhythmias.

Role of PI3Kα and sarcolemmal ATP-sensitive potassium channels in epoxyeicosatrienoic acid mediated cardioprotection.

Aims: Epoxyeicosatrienoic acids (EETs) are cytochrome P450 epoxygenase metabolites of arachidonic acid that have known cardioprotective properties. While the mechanism(s) remains unknown, evidence suggests that phosphoinositide 3-kinase (PI3K) and sarcolemmal ATP-sensitive potassium channels (pmK(ATP)) are important. However the role of specific PI3K isoforms and corresponding intracellular mechanisms remains unknown.

Cardioprotective effects mediated by angiotensin II type 1 receptor blockade and enhancing angiotensin 1-7 in experimental heart failure in angiotensin-converting enzyme 2-null mice.

Loss of angiotensin (Ang)-converting enzyme 2 (ACE2) and inability to metabolize Ang II to Ang 1-7 perpetuate the actions of Ang II after biomechanical stress and exacerbate early adverse myocardial remodeling. Ang receptor blockers are known to antagonize the effect of Ang II by blocking Ang II type 1 receptor (AT(1)R) and also by upregulating the ACE2 expression. We directly compare the benefits of AT(1)R blockade versus enhancing Ang 1-7 action in pressure-overload-induced heart failure in ACE2 knockout mice.

Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: a critical role of the angiotensin II/AT1 receptor axis.

Rationale: Diabetic cardiovascular complications are reaching epidemic proportions. Angiotensin-converting enzyme-2 (ACE2) is a negative regulator of the renin-angiotensin system. We hypothesize that loss of ACE2 exacerbates cardiovascular complications induced by diabetes.

Angiotensin converting enzyme 2 abrogates bleomycin-induced lung injury.

Despite substantial progress, mortality and morbidity of the acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI), remain unacceptably high. There is no effective treatment for ARDS/ALI. The renin-angiotensin system (RAS) through Angiotensin-converting enzyme (ACE)-generated Angiotensin II contributes to lung injury.