By Michael H. Crawford, MD
SYNOPSIS: An international study of patients with moderate or asymptomatic severe aortic stenosis has demonstrated that increased amounts of left ventricular fibrosis, as measured by cardiac magnetic resonance imaging, is associated with worse outcomes.
SOURCE: Lee HJ, Singh A, Lim J, et al. Diffuse interstitial fibrosis of the myocardium predicts outcome in moderate and asymptomatic severe aortic stenosis. JACC Cardiovasc Imaging. 2024; Sep 10. doi: 10.1016/j.jcmg.2024.08.003. [Online ahead of print].
Patients with moderate aortic stenosis (AS) or asymptomatic severe AS are at higher risk of adverse events compared to those with milder degrees of AS. However, unless left ventricular (LV) dysfunction is detected, these patients are not recommended for intervention by current guidelines. Favorable long-term results of transcatheter aortic valve replacement (TAVR) have stimulated interest in identifying parameters in these patients that might help identify those who could benefit from TAVR. Increasing myocardial fibrosis is known to be associated with the progression of LV hypertrophy to LV failure. Thus, this international study of cardiac magnetic resonance (CMR) imaging for the detection of fibrosis in such patients is of interest.
The investigators hypothesized that diffuse interstitial fibrosis as detected by the relative extracellular volume fraction of the LV (ECV%) and the indexed absolute extracellular volume (iECV) or the amount of LV scar tissue represented by late gadolinium enhancement (%LGE) excluding subendocardial infarct-related scar would identify those at increased risk of adverse events.
The primary outcome was a composite of all-cause mortality and hospital admission for heart failure (HF). Clinical data were derived from the medical record, and TAVR decisions were made by the attending physician. Secondary outcomes included the incremental value of CMR fibrosis over other standard measures of AS severity and N-terminal pro-B-type natriuretic peptide (NT-proBNP).
The study included 457 patients: 176 with moderate AS and 281 with asymptomatic severe AS. Their mean age was 69 years and 67% were men. Low-gradient severe AS was present in 26% of subjects. The median ECV% was 27% and was not different between the moderate AS and severe AS patients, but iECV was higher in patients with severe AS because of their larger LV mass. LGE was present in 32%, but at minimal amounts.
During the median six-year follow-up, there were 83 events (mortality 67, HF 23). Compared to those without events, those with events had a higher ECV% (28% vs. 26%, P = 0.003). Also, ECV% was associated with clinical outcomes in a multivariable regression analysis of the whole population (hazard ratio [HR], 1.05; 95% confidence interval [CI], 1.02-1.10; P = 0.017) and the subgroup with low-gradient severe AS (HR, 1.05; 95% CI, 1.00-1.10; P = 0.03). iECV was not a significant predictor of outcomes, nor was the presence of LGE, but LGE% was associated with outcomes (HR, 1.08; 95% CI, 1.01-1.17; P = 0.034).
ECV% has significant incremental prognostic value when added to the standard parameters of AS severity, LV function, and comorbidities. The authors concluded that, in patients with moderate AS or asymptomatic severe AS, increased interstitial fibrosis detected by CMR is associated with worse outcomes.
Commentary
There is a growing realization that patients with moderate AS or severe AS without symptoms may have a similar prognosis to those with symptomatic severe AS and may warrant consideration for AVR. Other observational studies have shown that various parameters, such as NT-proBNP, LV hypertrophy, LV global longitudinal strain, diastolic LV function, and aortic valve calcium content by computed tomography scan, are predictive of outcomes in AS patients. Apparently, we now can add myocardial fibrosis as detected by CMR to the list, but not myocardial scar.
The problem with all these studies is that they do not establish a cut-off value for recommending AVR. A randomized controlled trial that assesses patient outcomes with or without AVR will be needed to establish any of these factors for decision-making in AS patients.
In this study, myocardial fibrosis was modestly but incrementally associated with outcomes when added to the standard measures of AS severity. Myocardial non-infarct scar was present in about one-third of patients but was minimal and not predictive of outcomes. This is good news, since myocardial fibrosis is potentially reversible whereas myocardial scar is not.
Fibrosis also is related to comorbidities such as hypertension and diabetes, but there were no differences in comorbidities among the patients by ECV% tertiles. Interestingly, fibrosis was not necessarily associated with AS severity in this population. So, it is not an AS surrogate, but an independent predictor across the moderate to severe AS range.
Strengths of this study include the international patient population, which enhances generalizability, and that the CMRs were read by a central core lab. There were weaknesses also. The sample size was small, which would impair subgroup analyses, but it is the largest study of its kind so far. The decision to undergo TAVR was made by the attending physician and not a standard protocol. Exercise testing to confirm symptoms was not routinely done.
The authors cautiously recommend that the health of the myocardium may be an important factor for decision-making in moderate to severe AS and that those with an ECV% > 29 by CMR should at least undergo closer surveillance.
Michael H. Crawford, MD, is a Professor of Medicine and Consulting Cardiologist, University of California Health, San Francisco.
An international study of patients with moderate or asymptomatic severe aortic stenosis has demonstrated that increased amounts of left ventricular fibrosis, as measured by cardiac magnetic resonance imaging, is associated with worse outcomes.
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