Carrie Geisberg

Cardiac Side Effects of Anticancer Treatments: New Mechanistic Insights

Damage to heart cells leading to heart failure is a known complication of well-established cancer therapies including anthracycline antibiotics and radiation therapy, and the cardiovascular complications of these therapies has been controlled in large part through dose limitations and modifications of delivery methods. Recent research into the cellular and molecular mechanisms for the cardiovascular effects of these therapies may lead to other cardioprotective strategies that improve effectiveness of cancer treatments. Newer cancer therapies that have been developed based upon specifically targeting oncogene signaling also have been associated with heart failure. Rapid development of a detailed understanding of how these agents cause cardiac dysfunction promises to improve outcomes in cancer patients, as well as stimulate concepts of cardiovascular homeostasis that will likely accelerate development of cardiovascular therapies.

Circulating Neuregulin-1β Levels Vary According to the Angiographic Severity of Coronary Artery Disease and Ischemia

BackgroundCoronary artery disease (CAD) is the leading killer in the United States. Patients with severe CAD and ischemia have worse prognosis. Therefore expansion of biomarker research, to identify at-risk individuals and explain the complex biology between cardiovascular growth factors and atherosclerosis is needed. Neuregulin-1&bgr; (NRG-1&bgr;) is a myocardial stress activated growth and survival factor released from endocardial and endothelial cells. NRG-1&bgr; is essential for cardiovascular development and a regulator of angiogenesis. We postulated that plasma and serum levels of NRG-1&bgr; would vary in relation to CAD severity and the presence of stress-induced ischemia. MethodsWe measured serum and plasma levels of NRG-1&bgr; and vascular endothelial growth factor (VEGF) in 60 patients undergoing cardiac catheterization. CAD severity was calculated from angiographic results using a modified Duke jeopardy score. ResultsSerum NRG-1&bgr; (sNRG-1&bgr;), plasma NRG-1&bgr; (pNRG-1&bgr;), serum VEGF, and plasma VEGF were detectable in the majority of patients. The pNRG-1&bgr; levels were approximately two-fold higher than sNRG-1&bgr;. Both sNRG-1&bgr; and pNRG-1&bgr; correlated inversely with CAD severity. pNRG-1&bgr; levels were statistically higher in patients with stress-induced ischemia denoted by a positive myocardial perfusion imaging study that correlated with angiographic findings (P=0.02). ConclusionBoth sNRG-1&bgr; and pNRG-1&bgr; correlated inversely with angiographic severity of CAD. pNRG-1&bgr; levels were two-fold higher than serum and were higher in patients with stress-induced ischemia. Therefore we conclude that plasma is the optimal source for the further exploration of the biological significance of NRG-1&bgr; as a biomarker of CAD severity and ischemia.

Neuregulin-1β regulation of embryonic endothelial progenitor cell survival

Endothelial progenitor cells (EPCs) are mobilized into the vascular space and home to damaged tissues, where they promote repair in part through a process of angiogenesis. Neuregulins (NRGs) are ligands in the epidermal growth factor family that signal through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3, and erbB4) and regulate endothelial cell biology, promoting angiogenesis. Stimuli such as ischemia and exercise that promote EPC mobilization also induce cleavage and release of transmembrane NRG from cardiac microvascular endothelial cells (CMECs). We hypothesized that NRG/erbB signaling may regulate EPC biology. Using an embryonic (e)EPC cell line that homes to and repairs injured myocardium, we were able to detect erbB2 and erbB3 transcripts. Identical receptor expression was found in EPCs isolated from rat bone marrow and human whole blood. NRG treatment of eEPCs induces phosphorylation of kinases including Akt, GSK-3β, and Erk1/2 and the nuclear accumulation and transcriptional activation of β-catenin. NRG does not induce eEPC proliferation or migration but does protect eEPCs against serum deprivation-induced apoptosis. These results suggest a role for tissue-derived NRG in the regulation of EPC survival.

EVALUATION OF CARDIAC FUNCTION IN SYMPTOMATIC HEART FAILURE PATIENTS IN A SINGLE INFUSION, PHASE 1, DOSE ESCALATION STUDY OF GLIAL GROWTH FACTOR 2

Glial Growth Factor 2 (GGF2) is a neuregulin peptide critical for myocardial function. GGF2 improves left ventricular function (LVF) in animal models of cardiac injury. We report echocardiographic findings in a first-in-man, double-blind, placebo controlled, escalating single dose study of

Risk Factors for Development of Heart Failure

Heart failure carries significant morbidity and mortality burden, with median survival from onset of symptoms been reported as low as 1.7 years among men and 3.2 years among women. It is the only major cardiovascular disease which is increasing in incidence and prevalence. There are several reasons for this including general aging of the population, improved outcomes from acute cardiovascular disease, and worsening risk factor profile in United States including increasing obesity and diabetes trends. Heart failure is also widely prevalent, with a reported prevalence of about 5 million people in the United States. A wide variety of demographic characteristics, life style factors, comorbidites, pharmacologic exposures, biochemical markers, echocardiographic parameters, and genetic markers have been linked to heart failure risk. Several risk factors such as increasing age, male gender, and prior MI are well established with respect to new onset heart failure chances whereas others risk factors such as many of the genetic markers are more recently discovered and need to undergo further evaluation to assess their association. This review article outlines the current state of the literature on risk factors for developing heart failure.