Chris Miller, BSc (Hons) MBChB (Hons) PhD MRCP
Interstitial heart disease
More than 25 years ago, Weber proposed the term “interstitial heart disease”, to reflect the fundamental role of the myocardial interstitium in cardiac disease (JACC 1989). Indeed myocardial extracellular matrix (ECM) expansion, primarily due to excess collagen, appears to be a common process following acute and chronic myocardial injury, and central to heart failure pathophysiology.
Fibroblasts are the most abundant cell in the myocardium and appear to function independently of myocytes. Their isolated activation leads to collagen accumulation and the development of heart failure.
ECM expansion distorts myocardial architecture and leads to mechanical dysfunction, impaired electrical conduction with increased vulnerability to arrhythmias and structural and functional abnormalities of the coronary microcirculation.
Importantly, ECM expansion, and its adverse effects, appear reversible. Indeed the collagen regression associated with inhibitors of the renin-angiotensin-aldosterone system (RAAS), medications that improve patient outcome in heart failure with reduced ejection fraction, is proposed to represent a key mechanism of their action. Significantly, RAAS inhibition may be most beneficial in patients with underlying ECM expansion.
Measuring myocardial ECM expansion
Many of the features of ECM expansion and fibrosis in the heart are common to those seen in other organs (cf. liver ‘cirrhosis’, ‘interstitial lung disease’). However, fibrosis of the myocardium has not gained the clinical prominence as that of other organs, at least in part because a robust method to quantify myocardial ECM expansion has been lacking.
Recently we, and a number of other groups, have demonstrated that cardiac magnetic resonance (CMR) imaging accurately and reproducibly quantifies the space the ECM occupies (Figure 1).
In keeping with the interstitial heart disease paradigm, ECM expansion measured using CMR, appears to be strongly and independently associated with death and with hospitalisation for heart failure.
CMR T1 maps before (A, D, G) and after contrast (B, E, F), which are used to calculate myocardial ECM volume, in a patient prior to undergoing heart transplantation. The corresponding macroscopic cuts through the same patient’s explanted heart after undergoing transplantation are shown in C, F and I.
We are developing a translational approach to myocardial fibrosis.
We are in the process of conducting clinical trials in humans of novel antifibrotic agents to determine if they lead to myocardial fibrosis regression, and if this in turn improves myocyte function.
We are characterising ECM expansion using CMR across a range of cardiovascular conditions in a large cohort study, and assessing its prognostic utility.
We are determining structural mechanisms responsible for the myocardial ECM expansion using electron microscopy and the molecular drivers using RNA sequencing and quantitative mass spectrometry.
Schelbert, E.B., Piehler, K.M., Zareba, K.M., Moon, J.C., Ugander, M., Messroghli, D.R., Valeti, U.S., Chang, C.C., Shroff, S.G., Diez, J., Miller, C.A., Schmitt, M., Kellman, P., Butler, J., Gheorghiade, M. and Wong, T.C. (2015) Myocardial fibrosis quantified by extracellular volume is associated with subsequent hospitalization for heart failure, death, or both across the spectrum of ejection fraction and heart failure stage. J Am Heart Assoc. 4, e002613. PubMed
Miller, C.A., Naish, J., Yonan, N., Williams, S.G., Shaw, S.M., Clark, D., Pearce, K., Stout, M., Potluri, R., Borg, A., Coutts, G., Chowdhary, S., McCann, G.P., Parker, G.J.M., Ray, S.G. and Schmitt, M. (2014) Multiparametric Cardiovascular Magnetic Resonance Assessment of Cardiac Allograft Vasculopathy. J Am Coll Cardiol. 63, 799-808. PubMed
Miller, C.A., Naish, J.H., Bishop, P., Coutts, G., Clark, D., Zhao, S., Ray, S.G., Yonan, N., Williams, S.G., Flett, A.S., Moon, J.C., Greiser, A., Parker, G.J. and Schmitt, M. (2013) Comprehensive validation of cardiovascular magnetic resonance techniques for the assessment of myocardial extracellular volume. Circ Cardiovasc Imaging. 6, 373-83. PubMed