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STATE-OF-THE-ART PAPER

Molecular Mechanisms in Heart Failure

Focus on Cardiac Hypertrophy, Inflammation, Angiogenesis, and Apoptosis

Departments of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.

Manuscript received December 8, 2005; revised manuscript received May 25, 2006, accepted June 6, 2006.

^_* Reprint requests and correspondence: Dr. Helmut Drexler, Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Carl-Neuberg Strasse 1, 30625 Hannover, Germany. (Email: drexler.helmut{at}mh-hannover.de).

Heart failure is a final common pathway in cardiovascular disease, as a result of sustained pressure overload (i.e., hypertension), myocardial ischemia or infarction, volume overload (i.e., mitral regurgitation), or inherited and acquired cardiomyopathies. Heart failure is a major health care burden, and despite significant therapeutic advances, morbidity and mortality in heart failure remain unacceptably high. Therefore, novel insights into pathophysiology and molecular mechanisms of heart failure are required to develop novel therapeutic approaches. In this review we highlight several advances in the understanding of molecular pathways involved in cardiac hypertrophy, inflammatory signaling (i.e., tumor necrosis factor-, interleukin-6), and oxidant stress that may play a key role in altering transcriptional regulatory networks regulating adaptation or maladaptation, and consequently, the transition to overt heart failure. In this respect we focus on paracrine mechanisms (vascular endothelial growth factor, CCN1) and intracellular signaling (interleukin-6–glycoprotein 130–signal transducer and activator of transcription-3). In addition, we highlight the impact of current treatment options on these molecular pathways and their potential impact on progression of heart failure.

Abbreviations and Acronyms   Akt = protein kinase B   ERK = extracellular signal-regulated kinases   gp130 = glycoprotein 130   GSK = glycogen synthase kinase   IL-6 = interleukin-6   JAK = Janus kinase   LIF = leukemia inhibitory factor   LV = left ventricle/ventricular   MHC = myosin heavy chain   MLP = muscle limb protein   NF-kappaB = nuclear factor kappaB   NO = nitric oxide   PI3-K = phosphatidylinositol 3-kinase   ROS = reactive oxygen species   STAT3 = signal transducer and activator of transcription   TNF- = tumor necrosis factor-   VEGF = vascular endothelial growth factor

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