Markers of Focal and Diffuse Nonischemic Myocardial Fibrosis Are Associated With Adverse Cardiac Remodeling and Prognosis in Patients With Hypertension: The REMODEL Study

Abstract

Background: The prognostic significance of focal and diffuse myocardial fibrosis in patients with cardiovascular risk factors is unclear. Methods: REMODEL (Response of the Myocardium to Hypertrophic Conditions in the Adult Population) is an observational cohort of asymptomatic patients with essential hypertension. All participants underwent cardiovascular magnetic resonance to assess for myocardial fibrosis: nonischemic late gadolinium enhancement (LGE), native myocardial T1, postcontrast myocardial T1, extracellular volume fraction including/excluding LGE regions, interstitial volume (extracellular volume×myocardial volume), and interstitial/myocyte ratio. Primary outcome was a composite of first occurrence acute coronary syndrome, heart failure hospitalization, strokes, and cardiovascular mortality. Patients were recruited from February 2016 and followed until June 2021. Results: Of the 786 patients with hypertension (58±11 years; 39% women; systolic blood pressure, 130±14 mm Hg), 145 (18%) had nonischemic LGE. Patients with nonischemic LGE were more likely to be men, have diabetes, be current smokers, and have higher blood pressure ( P <0.05 for all). Compared with those without LGE, patients with nonischemic LGE had greater left ventricular mass (66±22 versus 49±9 g/m 2 ; P <0.001), worse multidirectional strain ( P <0.001 for all measures), and elevated circulating markers of myocardial wall stress and myocardial injury, adjusted for potential confounders. Twenty-four patients had primary outcome over 39 (30–50) months of follow-up. Of all the cardiovascular magnetic resonance markers of myocardial fibrosis assessed, only nonischemic LGE (hazard ratio, 6.69 [95% CI, 2.54–17.60]; P <0.001) and indexed interstitial volume (hazard ratio, 1.11 [95% CI, 1.04–1.19]; P =0.002) demonstrated independent association with primary outcome. Conclusions: In patients with hypertension, myocardial fibrosis on cardiovascular magnetic resonance is associated with adverse cardiac remodeling and outcomes.

Impact of Diabetes Mellitus on Myocardial Fibrosis in Patients with Hypertension: the REMODEL Study

“…Myocardial fibrosis is associated with worse outcomes in hypertensive patients (3), with and without DM ( Figure S2 in Online Supplemental Data ). There is increasing interest to target the myocardial interstitium to improve diagnosis, risk stratification and to discover novel therapies (22–24).…”

“…Myocardial fibrosis is a pathological hallmark of heart failure that can be assessed non-invasively with cardiovascular magnetic resonance (CMR) (1,2). In hypertensive heart disease, myocardial fibrosis from advanced left ventricular hypertrophy (LVH) eventually leads to cardiac decompensation and complications such as heart failure (3–5). Patients with hypertension and co-existing diabetes mellitus (HTN/DM) have worse cardiac function and higher mortality than those with hypertension only (HTN) (6,7).…”

Signaling Pathways and Potential Therapeutic Strategies in Cardiac Fibrosis

“…An indirect CMR technique, such as T1 mapping, allows a quantitative assessment of diffuse heart fibrosis by the determination of native T1, post-contrast T1, and extracellular cardiac volume (ECV). Measuring ECV has prognostic significance in non-ischemic myocardial fibrosis [ 98 , 99 , 100 , 101 ].…”

Time to reconsider the perception and management of hypertensive heart disease

“…In asymptomatic hypertensive patients, myocardial interstitial fibrosis on CMR imaging with non‐ischemic late gadolinium enhancement (LGE) was associated with greater LV mass, worse function, and elevated circulating levels of N‐terminal pro‐B type natriuretic peptide (NT‐proBNP) 14 . Importantly, non‐ischemic LGE was also associated with adverse outcomes, including first hospitalization for HF 14 . On the other hand, in individuals at risk for HF (including over 78% with chronic arterial hypertension), a circulating biomarker of myocardial interstitial fibrosis (i.e., serum C‐terminal type I collagen propeptide [PICP]) was associated with greater LV mass, worse LV diastolic function, and elevated levels of circulating NT‐proBNP 15 .…”

“…Two recent studies focused on imaging and circulating biomarkers of myocardial interstitial fibrosis may support this novel approach. In asymptomatic hypertensive patients, myocardial interstitial fibrosis on CMR imaging with non‐ischemic late gadolinium enhancement (LGE) was associated with greater LV mass, worse function, and elevated circulating levels of N‐terminal pro‐B type natriuretic peptide (NT‐proBNP) 14 . Importantly, non‐ischemic LGE was also associated with adverse outcomes, including first hospitalization for HF 14 .…”