Collagen Cross-Linking But Not Collagen Amount Associates With Elevated Filling Pressures in Hypertensive Patients With Stage C Heart Failure

Abstract

Abstract-We investigated whether the quality of myocardial collagen associates with elevated left-sided filling pressures in 38 hypertensive patients with stage C chronic heart failure. Filling pressures were assessed invasively measuring pulmonary capillary wedge pressure. Left ventricular chamber stiffness constant was calculated from the deceleration time of the early mitral filling wave. The fraction of myocardial volume occupied by total collagen tissue and collagen type I fibers was assessed histomorphologically. The degree of collagen cross-linking (CCL), which determines the formation of insoluble stiff collagen, was assessed by colorimetric and enzymatic procedures. Key Words: collagen Ⅲ filling pressures Ⅲ heart failure A rterial hypertension has been long considered as one of the most common etiologic conditions predisposing to heart failure (HF).1 Furthermore, a recent systematic review shows that HF development remains a major problem in treated hypertensive patients.2 It has been shown that myocardial fibrosis, a common finding in postmortem studies and endomyocardial biopsies of patients with hypertensive heart disease (HHD), 3 is associated with the increase of left ventricular (LV) chamber stiffness 4,5 and the development of clinically overt HF in these patients. 6,7 It has been proposed that the increase in LV stiffness can contribute to compromised diastolic function and elevate left-sided filling pressures (FPs) in hypertensive patients. 8 The definition of myocardial fibrosis is based on the quantification of an excess of collagen fiber deposition, as assessed by staining techniques. However, it must be considered that collagen-dependent LV chamber stiffness is influenced not only by the amount of collagen fibers but also by their qualitative properties (ie, the degree of collagen crosslinking [CCL] among collagen fibrils that determines the insolubility, stiffness, and resistance to degradation of the resulting fibers; the relative proportions of collagen types I and III fibers; and the diameter of the collagen fibers and their spatial alignment). 9 In fact, as demonstrated in different experimental models of pressure overload, although LV chamber stiffness is affected by changes in both collagen

Lysyl Oxidases Play a Causal Role in Vascular Remodeling in Clinical and Experimental Pulmonary Arterial Hypertension

“…23 More recent studies have underscored the importance of lysyl oxidase-mediated collagen cross-linking in heart failure, by demonstrating that elevated filling pressures in patients with hypertension with stage C chronic heart failure correlate not with total collagen but rather with the degree of collagen cross-linking in the myocardium. 24 The data we report here demonstrate that in the hypoxia model of PH, exposure of mice to hypoxia drives the increased cross-linking of collagen by the rapidly synthesized bifunctional collagen cross-links, dihydroxylysinonorleucine and hydroxylysinonorleucine. These cross-links are generated within hours and typically reflect newly synthesized collagen.…”

Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction

“…Myofibroblasts also express LOX, the collagen crosslinking enzyme. Increased expression of LOX enhances deposition of insoluble collagens that adversely affect cardiac contractility (23). Of note, LOX activation is increased during adverse cardiac remodeling and heart failure development (23).…”

Innate immune signaling induces expression and shedding of the heparan sulfate proteoglycan syndecan‐4 in cardiac fibroblasts and myocytes, affecting inflammation in the pressure‐overloaded heart

“…130 Collagen cross-linking is mediated by the enzyme lysyl oxidase (LOX), a molecule which has received recent attention in heart failure research. 116,131,132 Pressure overload is associated with a switch in collagen isoform expression, and these changes have been shown to relate to hypertrophic remodeling, heart failure and reverse remodeling. 133,134 In addition to the main structural collagens I and III, the non-fibrillar collagen VIII is differentially regulated in pressure-overloaded, failing hearts.…”