Progression of myocardial fibrosis in hypertrophic cardiomyopathy: mechanisms and clinical implications

Abstract

Aims: Myocardial fibrosis as detected by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is a powerful prognostic marker in hypertrophic cardiomyopathy (HCM) and may be progressive. The precise mechanisms underlying fibrosis progression are unclear. We sought to assess the extent of LGE progression in HCM and explore potential causal mechanisms and clinical implications.

Methods and results: Seventy-two HCM patients had two CMR (CMR1-CMR2) at an interval of 5.7 ± 2.8 years with annual clinical follow-up for 6.3 ± 3.6 years from CMR1. A combined endpoint of heart failure progression, cardiac hospitalization, and new onset ventricular tachycardia was assessed. Cine and LGE imaging were performed to assess left ventricular (LV) mass, function, and fibrosis on serial CMR. Stress perfusion imaging and cardiac energetics were undertaken in 38 patients on baseline CMR (CMR1). LGE mass increased from median 4.98 g [interquartile range (IQR) 0.97-13.48 g] to 6.30 g (IQR 1.38-17.51 g) from CMR1 to CMR2. Substantial LGE progression (ΔLGE ≥ 4.75 g) occurred in 26% of patients. LGE increment was significantly higher in those with impaired myocardial perfusion reserve (<MPRI 1.40) and energetics (phosphocreatine/adenosine triphosphate <1.44) on baseline CMR (P ≤ 0.01 for both). Substantial LGE progression was associated with LV thinning, increased cavity size and reduced systolic function, and conferred a five-fold increased risk of subsequent clinical events (hazard ratio 5.04, 95% confidence interval 1.85-13.79; P = 0.002).

Conclusion: Myocardial fibrosis is progressive in some HCM patients. Impaired energetics and perfusion abnormalities are possible mechanistic drivers of the fibrotic process. Fibrosis progression is associated with adverse cardiac remodelling and predicts an increased risk of subsequent clinical events in HCM.

Figure 1

A flowchart of hypertrophic cardiomyopathy (HCM) patients through the study. CMR, cardiovascular magnetic resonance imaging; ICD, implantable cardioverter defibrillator; LGE, late gadolinium imaging; ³¹P, Phosphorus-31 spectroscopy; T, Tesla. *CMR2 was at 1.5T or 3T (see Supplementary data online).

Figure 2

Comparison of (A) LGE mass and (B) relative LGE mass from CMR1 to CMR2 (***P < 0.0001, error bars represent SD). (C) a representative case of fibrosis progression in HCM (blue arrows indicate new regions of fibrosis).

Figure 3

LGE/fibrosis progression (red arrow indicated LGE progression) results in a reduction in wall thickness (WT-) (A, B, C), increase in LV end-diastolic volume (A, B) and impairment in myocardial contractility (D, E) (WT0/- stable or increasing wall thickness; GLS, global longitudinal strain, **P < 0.01, error bars represent standard deviation, *P < 0.05).

Figure 4

LGE mass increases from CMR1-CMR2 in HCM patients with (A) impaired myocardial energetics and (B) impaired myocardial perfusion reserve index at baseline CMR. (C) Myocardial energetics and (D) perfusion reserve index are impaired in those with substantial LGE progression. (MPRI, myocardial perfusion reserve index; PCr/ATP, phosphocreatine to adenosine triphosphate ratio; **P < 0.01, *P < 0.05, ΔLGE ≥ 4.75 g LGE progression of ≥4.75 g or substantial LGE increment, error bars represent standard deviation).

Figure 5

Kaplan–Meier curves depict the freedom from clinical events in HCM patients with LGE increment ≥4.75 g or less (A) and in those with LGE on CMR1 ≥ 15% of LV mass or less (B) (error bars represent 95% confidence intervals).