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

Raman, Betty 
Ariga, Rina 
Spartera, Marco 
Sivalokanathan, Sanjay 
Chan, Kenneth 

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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.

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Cardiomyopathy, Hypertrophic, Contrast Media, Disease Progression, Female, Fibrosis, Gadolinium DTPA, Humans, Magnetic Resonance Imaging, Cine, Male, Meglumine, Middle Aged, Myocardium, Organometallic Compounds, Prognosis, Retrospective Studies, Risk Factors
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Eur Heart J Cardiovasc Imaging
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Oxford University Press (OUP)
Wellcome Trust (Unknown)
Wellcome Trust (098436/Z/12/B)
This study was funded by the National Institute of Health Research (NIHR) Oxford Biomedical Research Centre and the British Heart Foundation. BR, MM, MS were funded by National Institute of Health Research Oxford Biomedical Research Centre. RA was funded by a British Heart Foundation Clinical Research Training Fellowship grant (RA: 098436/Z/12/Z). K.C was supported by an NIHR academic clinical fellowship. CTR is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society [098436/Z/12/B].SEP acknowledges support from the NIHR Barts Biomedical Research Centre. MJD is supported by the Wellcome Trust (WT098519MA). AJL is supported by the British Heart Foundation (FS/18/3/33292). EOO acknowledges support from Cancer Research UK. SN and HW acknowledge support from the Oxford British Heart Foundation Center of Research Excellence. CMK, SN and HW are supported by U.S. NIH Grant/Contract (U01HL117006-01A1).