Aortic Stenosis: Predictive Value of Cardiac Biomarkers in Older Patients

  

    
Biomarkers
    
Source of release
    
Relation to pathophisiology process
    
Clinical features
  
  

    
BNPs
    
Cardiac myocites
    
Biomechanical stress, cardiac wall stretching
    
Prediction of all-cause and CV mortality,    sudden death, re-admission in the hospital due to CV reasons, prediction of    CV events after TAVI.
  
  

    
Cardiac specific troponins
    
Cardiac myocites
    
Myocardial injury
    
Prediction of CV events and mortality
  
  

    
miRNAs
    
Cardiac myocites
    
Biomechanical stress, fibrosis, inflammation
    
Progression of aortic stenosis, vascular    remodeling
  
  

    
GDF-15
    
Activated mononuclears, fibroblasts,    cardiomyocytes
    
Inflammation
    
Prediction of CV mortality, risk of HF and CV    events
  
  

    
sST2
    
Activated mononuclears, cardiomyocytes
    
Inflammation
    
Prediction of CV mortality, risk of HF and CV    events
  
  

    
Gal-3
    
Activated mononuclears, cardiomyocytes
    
Fibrosis, inflammation
    
Prediction of all-cause and CV mortality, risk    of HF and CV events
  
  

    
FGF-23
    
Activated mononuclears, fibroblasts
    
stimulating cardiac hypertrophy, promoting    cardiomyocyte growth and release of natriuretic peptides
    
Prediction of all-cause mortality, CV events,    and end-stage of CKD
  
  

    
Matricellular proteins
    
Activated mononuclears
    
Ectopic calcification
    
Prediction of CV events and probably CV    mortality
  
  

    
Abbreviations: BNP: Brain Natriuretic Peptides;    Microrna: Mirna; GDF-15: Growth Differentiation Factor-15; CV:    Cardiovascular; Gal-3: Galectin-3; FGF-23: Fibroblast Growth Factor-23; TAVI:    Transcatheter Aortic Valve Implantation; CKD: Chronic Kidney Disease; HF:    Heart Failure
      
 
  

Table 1:  Perspective cardiac biomarkers for risk stratification in aortic stenosis patients.

Brain natriuretic peptides

Natriuretic Peptides (NPs) are recognized as markers of biomechanical cardiac stress that are secreted resulting in stretching cardiac wall / volume overload and they have demonstrated high diagnostic and predictive value for Heart Failure (HF) [13]. Recent clinical studies have shown that Brain Natriuretic Peptide (BNP) and NT-proBNP levels are elevated in patients with aortic stenosis and decrease acutely after replacement of the stenotic valve including Transcatheter Aortic Valve Implantation (TAVI) [14]. Moreover, high pre-intervention serum BNP level independently predicted two-year cardiovascular outcomes after TAVI [14]. Indeed, authors reported that patients with high baseline BNP (higher tertile =591 pg/ml) had increased risk of all-cause mortality (adjusted hazard ratio 3.16, 95% confidence interval 1.84 to 5.42; p <0.001) and cardiovascular death at 2 years (adjusted hazard ratio 3.37, 95% confidence interval 1.78 to 6.39; p <0.001). Outcomes were most unfavorable in patients with persistently high BNP before and after intervention. Comparing the two biomarkers, NT-pro-BNP levels measured after TAVI showed the highest prognostic discrimination for 2-year mortality (area under the curve 0.75; p <0.01). Therefore, BNP and NT-proBNP levels have shown a correlation with outcomes in studies of aortic valve surgery [15]. Overall, in older patients with aortic stenosis beyond clinical presentation elevated plasma BNP is the strongest independent predictor of all-cause and cardiovascular mortality [16,17].

Signature of microRNAs

MicroRNA (miRNA) is short non-coding RNAs that play a pivotal role in posttranscriptional regulation of target cell function. It has been found that miRNA-21-5p has elevated in patients with aortic stenosis without presentation of presence of coexisting Coronary Artery Disease (CAD). In contrast, increased serum concentrations of miR-22-3p, miR-24-3p, miR-382-5p, and miR-451a were not detected. Despite miRNA-21-5p appear to be promised as biomarker of aortic stenosis, there are more evidences regarding clinically significance of miRNA signature refinement in prediction of aortic stenosis evolution [18].

Growth differentiation factor-15

Growth Differentiation Factor-15 (GDF-15) is secreted cytokine belonging to the TGF-β super-family that highly expressed in states of inflammatory stress. GDF-15 may play a critical role in the atherosclerotic process in various vascular beds, starting from endothelial dysfunction and counting all stages of plaque development, as well as in ectopic calcification and aortic stenosis [19]. Elevated GDF-15 was found in older patients with asymptomatic and symptomatic moderate-to-severe aortic stenosis. Recent clinical study revealed that GDF-15was superior to NT-proBNP for TAVI risk stratification and provided additional prognostic information in aortic stenosis [20].

High-sensitivity soluble toll-like receptor-2

Soluble ST2 (sST2) is receptor for cytokine IL-33 that is upregulated in response to myocardial stress and exerts cardioprotective actions in the myocardium by reducing fibrosis, hypertrophy and enhancing survival. Recent clinical trials have shown that sST2 concentrations are strongly predictive of death, regardless of the cause and Left Ventricle (LV) ejection fraction, and contribute relevant information in addition to other prognosticators and biomarkers, as natriuretic peptides or cardiac troponins [21]. Current clinical guidelines have been recommended a measurement of sST2 as useful biomarker for death risk stratification and prognosis prediction in HF patients beyond other CV risk factors, NYHA functional class, LFEF, and renal function [22,23]. Elevated level of sST2 has defined in individuals with aortic stenosis irrespective etiology and coronary artery disease presentation [24]. Although both BNP and sST2 were associated with NYHA class but sST2 (>23 ng/mL, AUC = 0.68, p<0.01) was more accurate to identify asymptomatic patients or those who developed symptoms during follow-up. Furthermore, sST2 was independently related to left atrial index (p<0.0001) and aortic valve area (p = 0.004; model R2 = 0.32). Using multivariable analysis authors have found that peak aortic jet velocity (HR = 2.7, p = 0.007) and sST2 level (HR = 1.04, p = 0.03) were independent predictors of CV events and that sST2 levels have provided complementary information regarding symptomatic status, new onset HF symptoms and outcome in older aortic stenosis patients [24]. Lindman et al. [25] reported that three biomarkers, i.e. NT-proBNP, GDF15, and sST2, were elevated in older patients with aortic stenosis and closely associated with one-year mortality. Interestingly, the association between a greater number of elevated cardiac biomarkers and increased mortality after valve replacement was similar in the transcatheter and surgical aortic valve replacement populations. Authors concluded that the potential utility of multiple biomarkers to aid in risk stratification of older patients with aortic stenosis. Overall, sST2 is promised biomarker for risk stratification in older adults with aortic stenosis beyond traditional CV risk factors.

High sensitive cardiac specific troponins

Cardiac troponins are urgent biomarkers of myocardial injury and they are currently recommended to use for both diagnostic and prognostic purposes in acute coronary syndrome. The patterns of temporal change in highly-sensitivity troponin-T (hs-cTnT) may reflect a subclinical myocardial injury that is suitable for cardiomyopathy, heart failure and stable coronary artery disease. Therefore, mild elevated level of highly-sensitivity circulating cardiac troponins was found in untreated symptomatic aortic stenosis patients independently of traditional CV risk factors unless myocardial infarction. Moreover, high sensitive troponin T can be useful biomarkers to predict the occurrence of heart failure, atrial fibrillation, and death after aortic valve replacement surgery [26]. However, the predictive role of hs-cTnT in older adults with asymptomatic aortic stenosis is not clear yet.

Fibroblast growth factor-23

Fibroblast Growth Factor-23 (FGF-23) is phosphate-regulating 251-amino-acid protein secreted by osteocytes and regulates mineral metabolism and inflammatory response [27]. FGF-23 increases urinary phosphorus excretion by decreasing phosphorus re-absorption in the proximal tubule of nephron and inhibits 1.25-dihydroxyvitamin D synthesis, resulting in decreased dietary phosphorus absorption from the gastrointestinal tract. Therefore, biological role of FGF-23 affects a secretion of parathyroid hormone [28,29]. The exactly mechanisms leading to increased FGF-23 are not fully investigated. There are evidences that hypoxia and ischemia through unknown mechanisms may induce FGF-23 over production. It is suggested that FGF- 23 may effect on target cells directly and through FGF-23-related effects. In animal models FGF-23 directly stimulated left ventricular hypertrophy by activating hypertrophic gene programs, promoting cardiomyocyte growth, and stimulating the release of natriuretic peptides [30,31]. FGF-23 also inhibits 1.25-dihydroxy vitamin D via effects on CYP27B1 and CYP24A1 enzymes, stimulates the reninangiotensin system via binding with Klotho, which is a key cofactor for FGF-23 [29]. Although elevated intact FGF-23 was found in aortic stenosis patients with heart failure, the role of this biomarker in risk stratification of the patients is not fully understood. Probably, FGF- 23 could help to stratify the older adults with aortic stenosis beyond classical CV risk factors and individualize the medical care.

Galectin-3

Galectin-3 is a soluble beta galactoside-binding lectin produced by activated macrophages which binds and activates the fibroblasts [32]. The main biological role of galectin-3, as reported, is modulation of biological recognition processes, regulation of fibroblast proliferation and matrix synthesis that lead to fibrosis and extracellular remodeling. Results of recent studies have reported that galectin-3 is a biomarker that mediates an important link between inflammation and fibrosis, which play a pivotal role in CV remodeling [33]. The pathogenetic role of galectin-3 in the several setting of pressure overload, neuro-endocrine activation, hypertension, coronary artery disease / myocardial infarction, atrial fibrillation, and HF has strongly established [34-36].

Galectin-3 has emerged a predictive value for the onset of HF in apparently healthy patients and has been found being surrogate marker of a worse prognosis, mortality and re-admission in HF [22,23]. The results of the sub-study of COACH (The Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure) trial have shown that only galectin-3 was significantly associated with the absence of CV events at 180 days in patients with HF at low risk for death or HF re-hospitalization [37]. Therefore, authors indicated that this biomarker demonstrated an incremental value when added to the clinical risk model without NT-proBNP [37]. Overall, galectin-3 is obviously powerful prognosticator of death and re-hospitalization in HF patients at discharge from the hospital and in generally population individuals at higher risk of HF development.

Matricellular proteins

Matricellular proteins belong to family of multifunctional growth factors that are main components of the extracellular matrix which regulate bone developing, vascular remodeling, and tissue regeneration [38]. Although matricellular proteins (osteopontin, osteoprotegrin, osteonectin, thrombospondin) are surrogate biomarkers of vascular calcification and endothelia dysfunction in coronary artery disease, diabetes, obesity, atherosclerosis, dyslipidemia [39-41], the predictive role of these biomarkers in persons with aortic stenosis are still not understood because evidences are limited [42]. It has suggested that over production of matricellular proteins in aortic stenosis and CV diseases may consider as response to prevent vascular calcification [42]. However, the interrelation between CV mortality and circulating level of matricellular proteins in aortic stenosis in older adults is needed to be established.

Limitations of previous studies

Recent studies have shown that older adults acutely hospitalized are at risk of disability and mortality [43]. Although presence of significant abnormalities in transthoracic two-D echocardiography is closely associated with mortality in symptomatic aortic stenosis individuals, asymptomatic older adults with aortic stenosis that is represented in 16% of all geriatric individuals might require other approaches including another method of visualization and / biomarker strategy assay [44]. However, there are not evidence exists that gait speed is optimal to test in older adults with aortic stenosis, whereas two-D echocardiography is the primary imaging modality that is used in clinical practice to assess the aortic valve morphology, the severity of aortic valve disease, and its repercussions on left ventricular function and aortic circulation [45]. Three-D echocardiography, dobutamine stress echocardiography and, more recently, aortic valve calcium scoring by multidetector computed tomography have been shown to be useful to confirm stenosis severity in the challenging subsets of patients with low-flow, low-gradient of aortic stenosis, despite interpretation of obtained results in older adults with aortic stenosis and multiple comorbidities might be limited. Conventional pre- and perioperative surgical risk scores lack accuracy in risk stratification of older adults undergoing TAVI. Indeed, advanced age is a leading barrier to surgical intervention in elderly patients. Based on previous evidence, the peri-operative TAVI mortality rate which is found to increase with age from 1.3% in patients = 70 years old, to about 5% at age 80-85 years, and 10% in patients = 90 years old [46]. Practically, it has been deemed that age is not definitely predictor of poor clinical outcomes of TAVI, and those patients usually enjoy the same survival rates within their age and gender matched population [47]. Indeed, relative survival rates excluding early deaths after 5, 10 and 15 years within aortic valve replacement were 94.6%, 84.7% and 74.9%, respectively [47]. In this context, more exactly assay of the risk of asymptomatic and symptomatic older adults with aortic stenosis is required. Current data support hypothesis regarding use of hemodynamic parameters as sensitive predictors in symptomatic patients. Probably, using of cardiac biomarkers might extend our knowledge about CV risk in asymptomatic persons, whereas asymptomatic older patients are at higher CV risk and require rather cardiac functional status determining to enroll them in the group for further aortic valve replacement procedure. On the other hand, in older adults with aortic stenosis adding new biomarkers could increase the discriminative value of contemporary non-invasive hemodynamic characteristics to predict CV complications before non-cardiac surgery and performing of aortic valve replacement within long-term period. Indeed, the rationale for obtaining a preoperative and / or postoperative biomarker levels might have the utility when having a baseline Echo / Doppler parameters and functional cardiac status are abnormal, but there were not enough data to clinical decision making. Here one cannot discuss about pretreatment in this patient population, while the perspective of cardiac biomarkers utility might be determined in future. The next limitation of cardiac biomarker implementation is being low value care for older adults that might reduce the so-called clinical utility. It has suggested that the cardiac biomarkers are to be used in the specific contexts in high-income countries. This assumption requires more investigations using headto- head comparison biomarkers with echo / Doppler parameters, as well as patient clinical status. Overall, cardiac biomarker release signifying myocardial injury post-TAVI is common, yet its clinical impact within large TAVI cohort older persons receiving differing types of valve and procedural approaches is unknown.

Directions for further studies

Current clinical recommendations have reported that imaging modalities are essential for the staging and management of aortic valve disease in older adults. Because there are a large body of evidence regarding elevated brain natriuretic peptide levels as predictive biomarkers in symptomatic aortic stenosis older adults after TAVI, one might resume that serial measurements of BNPs and other markers of biomechanical stress, inflammation, cardiac injury, could be useful for risk stratification of the older adults enrolled for TAVI. Moreover, cardiac biomarkers may probably have utility in risk stratification of asymptomatic individuals with aortic stenosis when closely corresponding between two-dimensional and Doppler echocardiographic parameters and clinical outcomes are absent. Other modalities such as biomarkers for the assessment of myocardial fibrosis, cardiac injury or inflammation might be promising to predict aortic stenosis progression and related outcomes in older individuals, but further research is necessary before implementation of these modalities into clinical practice.

Conclusion

Two-dimensional and Doppler echocardiography’s remain to be key tool for the evaluation and monitoring of aortic stenosis. Although there is no consensus on the prognostic value, sensitivity, and specificity of biomarkers to stratify older patients with aortic stenosis at risk, BNP / NT-proBNP, galectin-3, sST2 appear to be promising predictors of C death and clinical outcomes in this population. Whether combined biomarker approach might have an impact on clinical decision-making for risk stratification in aortic stenosis older adults is still not understood and requires further investigations.

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