1. Date of download: 5/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: Cirrhotic Cardiomyopathy J Am Coll Cardiol. 2010;56(7):539-549. doi:10.1016/j.jacc.2009.12.075 Clinical Basis of Blunted Cardiac Response In the setting of liver cirrhosis and portal hypertension, a wide spectrum of factors, such as volume expansion and hyperdynamic circulation, contribute to electrophysiological abnormalities, diastolic dysfunction, and systolic dysfunction. Cardiomyocyte plasma membrane abnormalities, cytokines, growth factors, and autonomic impairment are also implied in this process. With advanced liver disease, these factors can lead to cardiac failure. ATPase = adenosine triphosphatase; CO = cardiac output. Figure Legend:

2. Date of download: 5/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: Cirrhotic Cardiomyopathy J Am Coll Cardiol. 2010;56(7):539-549. doi:10.1016/j.jacc.2009.12.075 Clinical View on Relationship Between Clinical and Instrumental Abnormalities and Cardiac Function Progressive deterioration of cardiac function in cirrhosis may be recognized by means of clinical, electrocardiographic (ECG), and echocardiographic abnormalities whose severity is predictive of contemporary seriousness of heart failure. CO = cardiac output. Figure Legend:

3. Date of download: 5/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: Cirrhotic Cardiomyopathy J Am Coll Cardiol. 2010;56(7):539-549. doi:10.1016/j.jacc.2009.12.075 Molecular Basis of Blunted Cardiac Response Gap-junction linked cardiomyocytes in which plasma membrane, myosin-actin cross-bridge, and sarcoplasmic reticulum are clearly depicted. This picture elucidates the following cardiomyocyte abnormalities: 1) reduced cholesterol plasma membrane content and alteration in cholesterol-to-phospholipid molar ratio; 2) downregulation of myocardial β-adrenoceptor density and a dysfunction of adrenergic intracellular signaling by G protein, adenylyl cyclase, and cyclic adenosine monophosphate (cAMP); 3) alteration of muscarinic receptors (in particular, receptor M2 inhibits adenylyl cyclase, and receptors M1 and M3 are linked to intracellular signaling pathways, including phospholipase C); and 4) the density of K + channels is reduced, probably because of plasma membrane alterations. The receptor function is stimulated by calcitonin gene-related peptide and adenosine, while noradrenaline, 5- hydroxytryptamine, neuropeptide Y, angiotensin II, and endothelin-1 show inhibitory action. ATP = adenosine triphosphate; RyR2 = ryanodine receptor Ca 2+ release channels. Figure Legend:

4. Date of download: 5/29/2016 Copyright © The American College of Cardiology. All rights reserved. From: Cirrhotic Cardiomyopathy J Am Coll Cardiol. 2010;56(7):539-549. doi:10.1016/j.jacc.2009.12.075 Molecular Basis of Blunted Cardiac Response Gap-junction linked cardiomyocytes in which plasma membrane, myosin-actin cross-bridge, and sarcoplasmic reticulum are clearly depicted. This picture elucidates the following cardiomyocyte abnormalities: 1) L-type voltage-gated Ca 2+ channels contribute to the Ca 2+ influx across the cell during depolarization; the dysfunction of cardiomyocyte β-adrenoceptor is implied in inhibition of ryanodine receptor Ca 2+ release channels (RyR2) by a Ca 2+ /calmodulin pathway leading to reduction of intracellular Ca 2+ concentration; 2) increased levels of carbon monoxide (CO) stimulate guanylyl cyclase in cirrhosis; this process leads to hyperexpression of cyclic guanosine monophosphate (cGMP) that inhibits Ca 2+ release by sarcoplasmic reticulum; 3) cannabinoids receptor 1 (CB1) inhibition of β-adrenoceptor function has been reported; and 4) the increased circulating levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1-β stimulate inducible nitric oxide synthase (iNOS), leading to nitric oxide (NO) production; the NO induces apoptosis and inhibits RyR2, reducing Ca 2+ current. Figure Legend: