Disruption of the epigenetic regulator locus in hematopoietic cells phenocopies the profibrotic attributes of Y chromosome loss in heart failure.

Heart failure affects millions of people worldwide, with men exhibiting a higher incidence than women. Our previous work has shown that mosaic loss of the Y chromosome (LOY) in leukocytes is causally associated with an increased risk for heart failure. Here, we show that LOY macrophages from the failing hearts of humans with dilated cardiomyopathy exhibit widespread changes in gene expression that correlate with cardiac fibroblast activation.

Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction.

Background: Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model.

Mosaic Loss of Y Chromosome in White Blood Cells: Its Impact on Men's Health.

We present a brief introduction of loss of Y chromosome (LOY) in blood and describe the known risk factors for this condition. We then overview the associations between LOY and age-related disease traits. Finally, we discuss murine models and the potential mechanisms by which LOY contributes to disease.

Clonal hematopoiesis: the nonhereditary genetics of age-associated cardiovascular disease.

Purpose Of Review: Somatic mutations, described as noninherited changes in DNA that arise and are passed on to descendant cells, are well known to cause cancers; however, it is increasingly appreciated that the propagation of somatic mutations within a tissue may have a role in causing nonneoplastic disorders and abnormalities in elderly individuals. The nonmalignant clonal expansion of somatic mutations in the hematopoietic system is termed clonal hematopoiesis. This review will briefly discuss how this condition has been linked to various age-related diseases outside the hematopoietic system.

Retrospective analysis of somatic mutations and clonal hematopoiesis in astronauts.

With planned deep space and commercial spaceflights, gaps remain to address health risks in astronauts. Multiple studies have shown associations between clonal expansion of hematopoietic cells with hematopoietic malignancies and cardiometabolic disease. This expansion of clones in the absence of overt hematopoietic disorders is termed clonal hematopoiesis (CH) of indeterminate potential (CHIP).

Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality.

Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor β1-neutralizing antibody ameliorated cardiac dysfunction in mLOY mice.

Integrilin, Intervention, and the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy Trial.

Eptifibatide (Integrelin, Corr Therapeutics, South San Francisco, CA) is a cyclic heptapeptide competitive inhibitor of the platelet glycoprotein (GP) IIb/IIIa receptor that has a short half-life. The results of the initial dose-finding and phase III trials are reviewed and the ongoing Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial are described.

Timing of and risk factors for myocardial ischemic events after percutaneous coronary intervention (IMPACT-II). Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis.

We studied both the time course and risk factors for adverse clinical events after percutaneous coronary intervention (PCI). Such information is critical to clinical decision-making, but scant quantitative data exist to describe the time course of these adverse outcomes. Patients enrolled in the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II (IMPACT-II) trial were analyzed.

Clinical risk factors for ischemic complications after percutaneous coronary interventions: results from the EPIC trial. The EPIC Investigators.

Background: Most analyses of complications after percutaneous coronary intervention have been limited to angiographic predictors of abrupt closure. We sought to determine the relation between baseline clinical and angiographic characteristics and clinical ischemic events and whether treatment with the platelet glycoprotein IIb/IIIa receptor antagonist c7E3 reduced ischemic events differentially in patients with distinct lesion morphologic characteristics. In the EPIC trial, a bolus and infusion of c7E3 decreased the 30-day incidence of death, myocardial infarction, and need for revascularization by 35% in 2099 high-risk patients.

Cardiopulmonary resuscitation: historical perspective to recent investigations.

There are at least 300,000 cardiac arrests annually in the United States. Cardiopulmonary resuscitation (CPR) effectively restores hemodynamic stability, return of spontaneous circulation (ROSC), in 40% to 60% of arrests. Prolonged survival is significantly lower because of underlying illness and the postresuscitation syndrome, specifically central nervous system injury and left ventricular stunning after resuscitation.

Randomised trial of magnesium in in-hospital cardiac arrest. Duke Internal Medicine Housestaff.

Background: The apparent benefit of magnesium in acute myocardial infarction, and the persistently poor outcome after cardiac arrest, have led to use of magnesium in cardiopulmonary resuscitation. Because few data on its use in cardiac arrest were available, we undertook a randomised placebo-controlled trial (MAGIC trial).

Methods: Patients treated for cardiac arrest by the Duke Hospital code team were randomly assigned intravenous magnesium (2 g [8 mmoles] bolus, followed by 8 g [32 mmoles] over 24 h; 76 patients) or placebo (80 patients).

Clostridium septicum abscess in hepatic metastases: successful medical management.

Clostridium septicum bacteremia is frequently associated with hematologic and colonic malignancies and neutropenia. It frequently produces 'metastatic' gangrene with excessive mortality. Standard therapy usually includes surgical debridement and antibiotics.

Hyperrenin-hyperaldosterone-dependent malignant hypertension in polyarteritis nodosa.

We have described a patient, subsequently found to have polyarteritis, whose renin activity was 60 times normal, a level associated with malignant hypertension and severe renal artery stenosis. The severe hypertension and its resistance to multiple medications in the face of a dramatic response to low-dose enalapril imply the renin-angiotensin system was the primary pathophysiologic mechanism. We believe renin activity should be measured in hypertensive patients with polyarteritis.