Plasma heparin cofactor II activity is inversely associated with left atrial volume and diastolic dysfunction in humans with cardiovascular risk factors

Abstract

Thrombin has a crucial role in cardiac remodeling through protease-activated receptor-1 activation in cardiac fibroblasts and cardiomyocytes. As heparin cofactor II (HCII) inhibits the action of tissue thrombin in the cardiovascular system, it is possible that HCII counteracts the development of cardiac remodeling. We investigated the relationships between plasma HCII activity and surrogate markers of cardiac geometry, including left atrial volume index (LAVI), relative wall thickness (RWT) and left ventricular mass index, and deceleration time (DcT) and the ratio of peak E velocity to early diastolic mitral annulus velocity (E/e' ratio) as surrogate markers of left ventricular diastolic dysfunction measured using echocardiography in 304 Japanese elderly individuals without systolic heart failure (169 men and 135 women; mean age: 65.4±11.8 years). Mean plasma HCII activity in all participants was 95.8±17.0% and there was no difference between the mean plasma HCII activities in males and females. Multiple regression analysis revealed that there were significant inverse relationships between plasma HCII activity and LAVI (coefficient: À0.2302, Po0.001), between HCII activity and RWT (coefficient: À0.0007, Po0.05), between HCII activity and DcT (coefficient: À0.5189, Po0.05) and between HCII activity and E/e' ratio (coefficient: À0.0558, Po0.01). Plasma HCII activity was independently and inversely associated with the development of cardiac remodeling, including cardiac concentric change, left atrial enlargement and left ventricular diastolic dysfunction. These findings suggest that cardiac tissue thrombin inactivation by HCII is a novel therapeutic target for cardiac remodeling and atherosclerosis.

Heparin Cofactor II, a Serine Protease Inhibitor, Promotes Angiogenesis via Activation of the AMP-activated Protein Kinase-Endothelial Nitric-oxide Synthase Signaling Pathway

“…In experimental animal studies, we and Vicente et al revealed that HCII-deficient mice showed more prominent intimal hyperplasia after vascular injury than did in wild-type (WT) littermates (11,12). In addition, plasma HCII activity is inversely associated with acceleration of human and murine cardiac remodeling including atrial enlargement and left ventricular concentric alteration (13,14). These findings revealed that HCII plays a protective role in the development of vascular remodeling and cardiac remodeling in humans and mice.…”

“…We have shown pathophysiological roles of HCII action such as protective effects against cardiovascular remodeling (8,9,(12)(13)(14)16). In addition, Huang et al showed that plasma HCII activity is positively correlated with flow-mediated vasodilatation, a marker of endothelial function, suggesting that HCII increases NO bioavailability in humans (40).…”

Plasma heparin cofactor II activity is inversely associated with albuminuria and its annual deterioration in patients with diabetes

“…The thrombin-PAR system promotes CVDs and insulin resistance, and HCII is an endogenous mammalian thrombin inhibitor; therefore, we hypothesized that HCII prevents CVDs and preserves insulin sensitivity. Indeed, we previously reported that low plasma HCII activity was associated with the development of atherosclerosis, cardiac remodeling, and hyperglycemia with insulin resistance in humans 13,14,16,18,21 . Moreover, we generated heterozygous HCII-deficient mice by a gene-targeting method and demonstrated that the HCII-deficient mice manifested exaggerated cardiovascular remodeling and enhanced insulin resistance with increased gluconeogenesis 15,[19][20][21] .…”

“…HCII is synthesized by hepatocytes and secreted into the bloodstream at a concentration of approximately 1.0 lmol/ L, and upon activation by binding to dermatan sulfate proteoglycans, it specifically inhibits thrombin activities in various tissue matrices 12 . We and others have shown that HCII prevents the development of cardiovascular diseases (CVDs) [13][14][15][16][17][18][19][20] and ameliorates insulin resistance 21 by attenuating thrombinmediated PAR activation.…”

Plasma Heparin Cofactor II Activity Is Inversely Associated with Hepatic Fibrosis of Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus

“…We generated heterozygous HCII-deficient mice and demonstrated that the mutant mice manifested exaggerated cardiovascular remodeling 22,[36][37][38] and enhanced insulin resistance with increased gluconeogenesis 26) . In addition, we previously found that cuff injury and HFD feeding prominently augmented MCP-1 gene expression in arterial walls and in epidydimal fat of heterozygous HCII-deficient mice, respectively 22,26) .…”