Editorials
Activin A ― A Potentially Useful Biomarker of Diastolic Dysfunction ―
2019 Volume 83 Issue 7 Pages 1443-1445
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2019 Volume 83 Issue 7 Pages 1443-1445
Diastolic dysfunction plays a major role in advancing heart failure (HF) in both patients with reduced or preserved ejection fraction (HFrEF and HFpEF, respectively).1 In daily practice diastolic function is evaluated using echocardiography,2 but none of the single echocardiographic indexes can perfectly stratify the level of diastolic function; hence, the current algorithm3 for evaluating diastolic function inevitably has become complicated. By contrast, evaluation of a biomarker, once established and generally performed, is an easy and helpful tool. Currently, the most frequently used biomarkers for diagnosing and stratifying HF are B-type natriuretic peptide (BNP) and N-terminal (NT)-pro BNP. Because end-diastolic wall stress highly correlates with the BNP level in both HFrEF and HFpEF,4 BNP and NT-pro BNP levels reflect well myocardial stress and stretch. However, in general, myocardial stress and stretch levels and BNP and NT-pro BNP levels in HFpEF do not severely increase, unlike in HFrEF,4 even with similar HF symptoms.
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Inflammation and fibrosis are important factors in advanced diastolic dysfunction. Activin A, a member of the transforming growth factor-β (TGF-β) superfamily and multifunctional cytokines,5 may play a role in inflammation.6 It has been investigated in many cardiovascular diseases such as HF7 (Figure 1), myocardial infarction,8 hypertension,9 and pulmonary hypertension10 (Figure 2). It is interesting that the opposite effect of activin A levels on the inflammatory response can be observed depending on the situation. In contrast to the anti-inflammatory effects of activin A in peripheral blood mononuclear cells from patients with coronary artery disease, activin A markedly enhances the release of inflammatory cytokines in peripheral blood mononuclear cells from healthy controls.6
Serum activin A levels in healthy control subjects (n=20) and patients with heart failure in NYHA functional classes II (n=20), III (n=38), and IV (n=28). (Reprinted with permission from Yndestad et al.7)
(A,B) Serum activin A levels in patients with pulmonary hypertension (PH) classified as idiopathic (IPAH; n=15), with associated pulmonary arterial hypertension (APAH; n=18) or chronic thromboembolic PH (CTEPH; n=14) and in sex- and age-matched control subjects (n=14). Blood samples were collected from the pulmonary (A) or femoral artery (B). Values are mean±SE. *P<0.05, **P<0.01, and ***P<0.001, compared with the control subjects. (C,D) Kaplan-Meier curves show the cumulative incidence of death during the observation period according to the dichotomized activin A levels (higher or lower than the median level) at baseline in venous blood (pulmonary artery) (C) and arterial blood (femoral artery) (D). (Reprinted and modified with permission from Yndestad et al.10)
The relationship between the activin A level and diastolic dysfunction remains to be clarified. Postpartum activin A levels have been recently demonstrated to correlate with an increasing left ventricular mass index (LVMI) and mean arterial pressure and decreasing early mitral annular velocities (e′).11 In this issue of the Journal, Tsai et al12 focus on the relationship between diastolic dysfunction and activin A in adult patients with stable angina and preserved EF. They found that subjects with elevated circulating activin A levels showed echocardiographic diastolic dysfunction such as a significantly elevated LVMI, left atrial dimension, and right ventricular systolic pressure. Furthermore, the prevalence rates of HFpEF and development of HF in 3 consecutive years were significantly higher in the group with high activin A, indicating the usefulness of the activin A level as a prognostic marker.
Given these attractive results, the utility of this interesting marker deserves further large-scale prospective study. Several directions can be considered. First, the high activin A level group also had elevated C-reactive protein (CRP) and NT-pro BNP levels. Significant correlations were found between activin A and CRP (R=0.380) and between activin A and NT-pro BNP (R=0.525). An important next step would be to test if a combination of those other markers with activin A would provide better stratification of the patients and improved prognostic ability. Second, it would be valuable to extend the study subjects and investigate the usefulness of activin A as a diagnostic and prognostic marker in HFpEF patients without angina. Imbalance between activin A and follistatin, an antagonist of activin A,13 could also be considered. Third, the present study used a single-point measurement of activin A level in each patient. It would be clinically important to investigate whether serial changes in activin A expression parallel the changes in diastolic dysfunction or HF severity in response to therapy.
Recently, the technological development of proteomics has allowed unbiased searches, which may lead to a novel finding of unexpectedly useful biomarkers of HF.14 Nevertheless, an approach to investigating a target substance based on the basic and clinical evidence of related situations, as performed in this study by Tsai et al,12 remains important for identifying and establishing new biomarkers. In any approach, establishing novel, inexpensive biomarkers that can better stratify HF severity and provide a higher prognostic value than does the BNP or NT-pro BNP level has high clinical importance in this field.
The author has no financial relationships relevant to this article to disclose.
The author has no conflicts of interest relevant to this article to disclose.
None declared.
