Table 1

A summary of the key studies showing the role of serum biomarkers in valvular heart disease (VHD)

Biomarker	VHD	First author (Ref. #)	N	Year	Restricted to severe disease?	Study details
Natriuretic peptides	Pros	Readily available Large no. of studies Marker of severity and prognosis in AS, AR and MR			Cons	Poorly defined thresholds Significant overlap between groups Lacks specificity for VHD—can be elevated in other unrelated medical conditions
	AS	Gerber37	74	2003	No	NT-proBNP and BNP both associated with symptoms (AUC: 0.84 and 0.83, respectively)
	AS	Bergler-Klein42	130	2004	Yes	NT-proBNP and BNP both predicted the presence of symptoms as well as the risk of symptom onset or death among subjects with severe AS
	AS	Nessmith41	124	2005	No	BNP predicted presence of symptoms (AUC: 0.87); Optimal cut-off was 190 pg/mL
	AS	Monin40	107	2009	No	BNP independently predicted outcomes (cardiac death, hospitalisation for CHF or AVR)
	AS	Clavel39	1953	2014	Yes	BNP independently predicted long-term mortality even among asymptomatic subjects with at least moderate AS
	AS	Henri38	69	2016	No	Annual change in BNP levels predicted outcomes (symptoms, AVR or death)
	AR	Gerber47	40	2003	Yes	Natriuretic peptide (ANP, BNP and N-BNP) levels correspond with symptomatic status among patients with moderate to severe AR and preserved LV systolic function
	AR	Gabriel44	39	2007	Yes	Increased BNP level associated with increased severity of regurgitation and early LV dysfunction on exercise echo among asymptomatic or mildly symptomatic patients with moderate to severe AR with preserved LV systolic function
	AR	Weber46	60	2008	No	NT-proBNP linked to disease severity and functional status. It also predicted prognosis and clinical outcomes in patients with chronic AR and preserved LV systolic function
	AR	Pizarro45	294	2011	Yes	BNP independently predicted prognosis among asymptomatic patients with severe AR and preserved LV systolic function
	MR	Sutton48	49	2003	No	Natriuretic peptide (BNP, ANP and N-BNP) levels correspond with increasing severity of MR and symptomatic status (AUC 0.9, 0.89 and 0.89, respectively) even among patients with preserved LV function
	MR	Detaint50	124	2005	No	BNP was found to be an independent predictor of adverse events including death and heart failure
	MR	Pizarro49	269	2009	Yes	BNP was an independent predictor of adverse events including heart failure, LV dysfunction and death among patients with severe asymptomatic MR
	MR	Clavel52	1331	2016	No	BNP-ratio (ratio to upper limit of normal for age, sex and assay) was found to be an independent and incremental predictor of long-term mortality in patients with degenerative MR on medical therapy
	MS	Sharma54	44	2011	Yes	Raise serum BNP levels were associated with left atrial dilatation, raised pulmonary artery pressure, reduced mitral valve area and treadmill exercise capacity as well as being a marker of adverse events among patients with moderate to severe MS
	TR	Yoon55	39	2010	Yes	An elevated BNP level was determined by the LVEF and RVESVI, a baseline BNP level of >200 pg/mL predicted poor outcomes and increased mortality and morbidity among patients with isolated, severe TR undergoing corrective surgery
GDF-15 and ST2	Pros	markers of prognosis in AS undergoing AVR ST2 reflects symptom status, severity, diastolic function as well as being an independent predictor of cardiovascular events in AS			Cons	Limited available data for GDF-15 Available data only in AS
	AS	Lancellotti 69	86	2015	Yes	ST2 levels were related to symptomatic status, AS severity and diastolic dysfunction; furthermore, ST2 was identified as an independent predictor of cardiovascular events among patients with moderate to severe AS and preserved LV function
Combination of GDF-15, ST2 and NT-proBNP	AS	Lindman68	345	2015	Yes	Elevated baseline GDF-15, ST2 and NT-proBNP levels were associated with a higher postoperative mortality among patients with severe AS undergoing surgical or percutaneous valve replacement. Patients with elevation of all three biomarkers had a 10-fold higher 1-year and 2-year mortality than those with normal levels
Galectin-3	Pros	Marker of prognosis in AS Potential biotarget to delay AV calcification			Cons	Limited data Only AS assessed
	AS	Sádaba74	77	2016	Yes	Galectin-3 overexpressed in aortic valve tissue and in vitro blockade of Galectin-3 among vascular interstitial cells extracted from AV obtained from patients with severe AS undergoing AVR surgery lead to a delay in valve calcification.
Troponins	Pros	Readily available Various large studies Marker of prognosis in AS, MR			Cons	Not specific for VHD—can be elevated in other conditions Limited evidence of utility outside AS
	AS	Røsjø85	57	2011	Yes	hs-TnT levels were universally detectable, LV mass and systolic function were independent determinants of hs-TnT levels and high hs-TnT levels were associated with a poor prognosis among patients with moderate to severe AS
	AS	Frank86	107	2013	Yes	hsTnT was found to be superior to NT-proBNP in predicting survival and hsTnT alongside preprocedural AR were identified as the independent predictors of survival among patients with severe AS undergoing TAVI
	AS	Chin87	253	2014	No	Plasma TnI concentrations detectable in 98% of subjects and were increased when compared with age-matched and sex-matched healthy volunteers. TnI concentrations were found to be associated with advanced LV hypertrophy and replacement fibrosis as well as AVR or cardiovascular death among patients with AS
	AS	Shah88	242	2014	No	ECG LVH with strain was identified as a marker of midwall myocardial fibrosis, and it was also associated with increased myocardial injury, impaired LV function and was found to be an independent predictor of cardiovascular death or AVR among patients with AS
(Troponins and MR-proANP)	MR	Wöhrle51	34	2015	Yes	MR-proANP and hsTnT were strong predictors of cardiovascular death and rehospitalisation for HF among patients with severe MR undergoing percutaneous repair for MR (MitraClip procedure)
miRNA	Pros	Several small studies Can help in understanding pathophysiology of VHD Potential biotarget in myocardial reverse remodelling			cons	Expensive, lengthy processing Lack of standardised protocols Reproducibility is affected by confounding factors Higher technical expertise needed for sample processing
	AS	García82	74	2013	Yes	Preoperative plasma levels of miR-133a were found to predict the regression potential of LV hypertrophy post-AVR among patients with severe AS undergoing AVR AUC 0.89, p value <0.001
	AS	Villar81	107	2013	Yes	Myocardial and circulating levels of miR-21 were higher and correlated directly with the transvalvular gradients among patients with severe AS when compared with controls
	AS	Beaumont78	38	2014	Yes	miR-122 was found to be downregulated in endomyocardial biopsies taken from 28 patients using necropsies of 10 subjects as controls, possibly leading to myocardial fibrosis through TGF-β1 upregulation among subjects with severe AS
	AS	Derda79	120	2015	Yes	miR-29a levels were found to be increased in patients with hypertrophic obstructive cardiomyopathy, while miR-29c were found to be increased in patients with AS (awaiting TAVI) in a study involving patients with AS and hypertrophic cardiomyopathy

ANP, atrial natriuretic peptide; AR, aortic regurgitation; AS, aortic stenosis; AUC, area under the curve; AV, aortic valve; AVR, aortic valve replacement; BNP, B-type natriuretic peptide; CHF, congestive heart failure; GDF-15, growth differentiation factor-15; hsTnT, high-sensitivity troponin T; LV, left ventricular; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; miRNA, microRNA; MR, mitral regurgitation; MR-proANP, midregional proatrial natriuretic peptide; MS, mitral stenosis; N-BNP, N-terminal B-type natriuretic peptide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; RVESVi, right ventricular end-systolic volume index; TAVI, transcatheter aortic valve intervention; TGF, transforming growth factor; TnI, troponin I; TnT, troponin T; TR, tricuspid regurgitation.