Tachycardia‐Induced Matrix Metalloproteinases Activation Associated with Collagen Type III Cardiac Fibrosis and Heart Failure in Swine

Abstract

Cardiovascular disease remains the most common cause of death in the developed world, with heart failure (HF) increasing in prevalence. In the HF disease state, the left ventricle (LV) manifests a robust plasticity response called remodeling. Cardiac remodeling is a dynamic process that can lead to myocardial fibrosis, which is associated with an increased risk of sudden cardiac death. The extracellular matrix (ECM) is a dynamic support structure that is remodeled following cardiac injury and HF. All of the ECM constituents are vulnerable to the diverse stresses on the heart. Within the ECM, matrix metalloproteinases (MMPs), a key family of proteolytic enzymes, alter the interactions between different structural and metabolically active interstitial molecules and play a major role in the structure and function of the ECM.After obtaining Institutional Animal Care and Use Committee (IACUC) approval, Yorkshire swine (N=10) were paced for 3 to 5 weeks with implanted devices at 200 beats per minute. Prior to termination, all 10 paced swine had left ventricular shortening fraction <16%. Ten additional healthy swine served as controls.The results demonstrated differences between control and HF animals consistent with the HF state. Early biomarkers of HF extracellular‐signal regulated kinase 1 and 2 (ERK1/2) (32%), galectin‐3 (25%), Membrane Type 1 MMP (MMP‐14) (68%) and Tissue Inhibitor of Metallo‐Proteinase‐1 (TIMP‐1) (45%) were elevated (by the percentages shown) in the HF animals (p≤0.05) compared to controls. Oxidative stress may have a key role in the transition from compensated hypertrophy to heart failure. In this study, elevated expression of key transcription factors NFκ‐B p65 (39%) and NRF‐2 (62%) (p≤0.05) was seen in HF animals, which is consistent with elevated ROS and inflammation in the myocardium, thus supporting the idea that oxidative stress may have an adverse effect on the heart.Fluorescent staining of left ventricular myocardial tissue sections demonstrated an increase in all collagens of HF animals relative to controls. The overall increase in ECM fibrosis in HF was clearly demonstrated on Masson’s trichrome histology, including the changes in the ratios of structural collagens in the heart. The control tissue shows a small percentage of collagen, whereas HF tissue shows visible increases in Types I, III and VI collagens. Furthermore, the HF tissue also demonstrated a shifting of the Type I/Type III ratio, with Type III, a more elastic collagen, becoming more preponderant and thus allowing for the structural and functional changes consistent with typical HF. Additional exploration into the mechanisms of cardiac remodeling, may lead to treatments to prevent adverse ECM changes and slow the progression of adverse remodeling and ultimately reduce the risk of progression to lethal HF.Support or Funding InformationUniformed Services University Early Career Scientist Award, USU Grant # R089354417