Review: Predicting Cardiac Remodeling in Heart Failure with Reduced Ejection Fraction
- Strain echocardiography is relatively independent of left ventricular volume and shape and is more sensitive than conventional echocardiography for tracking systolic dysfunction
- 3-D echocardiography and 3-D speckle tracking echocardiography may be additive to traditional echocardiography for identifying which patients are likely to respond to cardiac resynchronization therapy
- Natriuretic peptides such as B-type natriuretic peptide (BNP) and N-terminal B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin and soluble ST-2 are promising circulating biomarkers of cardiac remodeling
- Better understanding of these biomarkers may eventually allow cardiologists to tailor the aggressiveness of treatment and follow-up
Cardiac remodeling is initially adaptive, but a pivotal process in the development and progression of heart failure. Remodeling is typically accompanied by increasingly worse cardiac function and poor clinical outcomes.
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On the other hand, reversal of remodeling is often associated with improved symptoms, better quality of life and lower risk of hospitalization or death.
Therefore, remodeling is a potential target for therapy in heart failure with reduced ejection fraction (HFrEF), and reliable tools are needed to detect it preclinically and to monitor it. Hanna Gaggin, MD, MPH, clinical investigator and cardiologist, James L. Januzzi, Jr, MD, director of the Dennis and Marilyn Barry Fellowship in Cardiology Research at Massachusetts General Hospital, and colleagues review promising methods for predicting and assessing left ventricular (LV) remodeling in patients with HFrEF in JACC: Heart Failure.
Standard serial echocardiography is the gold standard for assessing left ventricular ejection fraction (LVEF). Reduction of LV end-systolic volume (LVESV) is the most commonly used echocardiographic measurement of reverse remodeling because it integrates both geometric and functional information.
Strain echocardiography is relatively independent of LV volume and shape and is more sensitive than conventional echocardiography for tracking systolic dysfunction. However, it is limited by inter-reader variability.
3-D echocardiography and 3-D speckle tracking echocardiography can rapidly quantify global LV dyssynchrony. Data obtained from these imaging modalities have proven additive to traditional echocardiography for identifying which patients are likely to respond well to cardiac resynchronization therapy (CRT) and have reverse remodeling after CRT. However, availability of 3-D imaging may be limited and more evidence is needed before it can be routinely recommended.
Cardiac Magnetic Resonance
Compared with echocardiography, cardiac magnetic resonance has better resolution, higher reproducibility and independence from available acoustic windows. It can provide valuable information about the presence and pattern of scar tissues or myocardial fibrosis in the form of late gadolinium enhancement. The extent of late gadolinium enhancement is inversely related to the likelihood of reverse remodeling.
Wall stress from volume overloaded state or abnormal LV chamber size, volume and systolic and diastolic function can affect concentrations of natriuretic peptides. Thus, there is an association between serially measured natriuretic peptide concentrations and LV remodeling.
In the PROTECT trial, as published in JACC, Dr. Januzzi and colleagues found that patients with a greater reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentrations showed greater improvements in LVEF, indexed LVESV and LV end-diastolic volume. In the GUIDE-IT trial, as seen in JACC: Heart Failure, they demonstrated that the degree of NT-proBNP reduction was proportional to the reduction in LV volume and improvement in LVEF.
High-sensitivity troponin assays quantify the severity of ongoing cardiomyocyte damage. In a study of patients with various causes of HF and LVEF ≤40%, also found in JACC: Heart Failure, Dr. Januzzi and others determined that patients with low concentrations of high-sensitivity troponin T had the highest frequency of reverse remodeling during follow-up. They have reported similar associations for high-sensitivity troponin I assays in the Journal of Cardiovascular Translational Research.
Soluble suppression of tumorigenesis-2 (sST2) is a promising biomarker of cardiac remodeling because sST2 is released by cardiomyocytes and fibroblasts under stress and blunts the antifibrotic effects of interleukin-33. In a multicenter study of outpatients with HFrEF, reported in International Journal of Cardiology, a lower sST2 concentration was an independent predictor of reverse remodeling when considered together with clinical variables.
Serial echocardiography has been used to monitor LV remodeling for many years, but little guidance is available about the optimal interval for repeated examinations or how to predict worsening of LV geometry or function. The use of circulating biomarkers or novel imaging modalities may allow cardiologists to adopt a more tailored approach to patient care.
For example, based on the results of the GUIDE-IT trial, the reviewers say that patients with persistently low concentrations of natriuretic peptides (e.g., BNP <100 ng/L or NT-proBNP <1,000 ng/L) have a low risk of adverse remodeling and a generally favorable prognosis. Therefore, it may be possible to defer repeated imaging.
In contrast, patients with persistently elevated or rising natriuretic peptides are at higher risk of further LV dilation or LVEF decline, so more aggressive follow-up and treatment may be indicated. Stable or falling values of these biomarkers suggest a higher likelihood of reverse remodeling, particularly after the initiation and titration of HF therapies or initiation of CRT.
Toward the Future
There is an unmet need to develop and rigorously test novel biomarkers and imaging modalities in order to better predict reverse remodeling. Researchers are working to establish which remodeling parameters should be routinely used and the best way to define remodeling; what determines clinically significant changes in LV remodeling indexes; and whether other measurements are important, such as LV strain, left atrial volumes or diastolic filling parameters.
A better understanding may allow LV remodeling to be used as an endpoint in clinical trials, which could speed the development of new HF therapies compared with focusing on clinical events such as mortality.
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