Biomarkers in heart failure

Biomarkers for diagnosis, as guide to treatment, induvidual cut-off values, clinical usefullness

1. BY: Dr. Himanshu Rana Biomarkers in Heart Failure

2. Definition 1998 National Institutes of Health working group on biomarkers definitions defined a biomarker as – “a biological marker that is objectively measured and evaluated as an indicator of normal biological processes, pathological processes , or pharmacological responses to therapeutic interventions”. WHO – “any substance, structure, or process that can be measured in the body or its products and influences or predicts the incidence of outcome or disease”

3. ideal biomarker Tijsen et al. Easy to collect non-invasively, High degree of sensitivity and specificity, Cheap, Easily reproducible And rapid measurement system that assists in prompt clinical management

4. Why hf biomarker is needed? HF& COPD coexist in approx. 30% patients , making diagnosis confusing. The Breathing Not Properly (BNP) study reported clinical confusion in approx. half of cases presenting to emergency dept. with breathlessness need for better monitoring of patients receiving T/t for HF

5. BIOMARKERS IN HF Categorized according to primary pathophysiological mechanism , Myocyte Injury & Myocyte Stress Neurohormones Markers of Extracellular Matrix Remodeling Inflammatory Mediators & Markers of Oxidative Stress Other Biomarkers

6. 3

7. BIOMARKERS IN HF Biomarkers for Diagnosis BNP/NT proBNP /MR proANP /ST2/Galectin3/pro- adrenomedullin Biomarkers for Prognosis BNP/ NTproBNP /Troponin/MR proADM /ST2/Galectin3 Biomarkers as a Guide For Therapy NT- proBNP Newer Biomarkers ST2/ galectin 3/pro-ADM/micro RNA/ Procalcitonin /MMP/ interleukins and TNF-alpha ACC/AHA

8. MARKER OF MYOCYTE STRESS- NATRIURETIC PEPTIDES Most extensively studied and used Downregulate the sympathetic system, cause diuresis , decrease peripheral resistance and increase smooth muscle relaxation Atrial natriuretic peptide ( ANP) rapid clearance less consistent (not used routinely) Newer assays of mid-regional proANP ( MR- proANP ) MR- proANP is more stable>> reliable results

9. furin corin natriuretic peptidereceptor -C NEP & Kidney organs with high blood flow such as muscle, liver & kidney

10. Natriuretic peptides 120 min

11. Natriuretic peptides Biomarker for assessing prognosis of patients with heart failure – both in the acute & chronic heart failure the higher the BNP, the worse the prognosis , patients having almost a fivefold greater mortality between the highest and lowest tertiles the risk of readmission and death is high if the discharge BNP is not lower than the admission value

12. Natriuretic peptides Breathing Not Properly (BNP) Study first major trials studying the role of natriuretic peptides in the emergency for diagnosis of HF 1,586 patients presenting to the emergency with acute breathlessness clinically diagnosed HF had higher BNP levels compared to without heart failure ( mean 675 ± 450 pg /ml versus 110 ± 225 pg /ml; p=0.001) A cut-off BNP value of 100 pg /ml had sn = 90% and sp = 76%. In addition, BNP was more accurate (83%) than either the National Health and Nutrition Examination Survey criteria (67%) or the Framingham criteria (73 %)

13. Natriuretic peptides ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study NT- proBNP in the diagnosis of acutely decompensated heart had a high sensitivity for the diagnosis of heart failure International Collaborative Of NT- proBNP ( ICON) study examined NT- proBNP in 1256 acutely dyspnoeic patients. ADHF patients had higher NT- proBNP concentrations than those without heart failure (4,639 pg /ml versus 108 pg /ml; p<0.001) & symptom severity correlated with NT- proBNP concentrations investigators found the best approach for use of NT- proBNP was through use of age-stratified cut-off points

14. Natriuretic peptides MR- proANP was studied in the Biomarkers In Acute Heart Failure (BACH) study In those presenting to the emergency department with dyspnoea, a MR- proANP level > 120 pmol /l found to be noninferior to BNP at the 100 pg /ml cut point in the diagnosis of acute heart failure . More useful in obesity , old age, renal dysfunction or ‘grey zone ’ values, MR- proANP added value when used in combination with each biomarker. Thus it has been suggested that the addition of MR- proANP with other natriuretic peptides adds to diagnostic accuracy

15. Natriuretic peptides Kim and Januzzi have suggested cut-off points for different scenarios For BNP, ‘grey zone’ approach. A value of <100 pg /ml would exclude heart failure and >400 pg /ml would confirm heart failure . For those in the ‘grey zone’ of 100–400 pg /m l, further tests would be required. The sn & sp of NT- proBNP were identical to those of BNP if an NT- proBNP threshold of 900 pg /L was used, For NT proBNP , an age-stratified approach is suggested. AGE(in yrs ) CUT-OFF( pg /ml) (rule-in) <50 <450 50–75 <900 >75 <1,800

16. Natriuretic peptides cut-off values for BNP have been suggested based on BMI No correction is required for NT- proBNP based on BMI In patients with renal dysfunction, ( glomerular filtration rate <60 ml/min/1.73 m2), cut-off value of BNP 200 pg /ml or NT- proBNP of <1,200 pg /ml should be used. BMI CUT-OFF( pg /ml) <25 kg/m2 170 pg /ml 25–35 kg/m2 110 pg /ml >35 kg/m2 54 pg /ml Kim HN, Januzzi JL, Jr. Natriuretic peptide testing in heart failure . Circulation 2 011;123:2015–9 . https:// doi.org/10.1161/ CIRCULATIONAHA.110.979500 ; PMID: 21555724

17. Natriuretic peptides

18. guidelines Both ACC & ESC give measuring natriuretic peptides for the diagnosis of heart failure a class 1A recommendation. The European guidelines recommended I n non-acute setting cut-off values are 35 pg /ml for BNP and 125 pg /ml for NT- proBNP . In the acute setting, the cut-off values are 100 pg /ml for BNP and 300 pg /ml for NT- proBNP T he NPV are similar and high at 0.94–0.98 in both the acute and non-acute settings but the PPV are low. I t is suggested that use of natriuretic peptides are mainly for ruling out a diagnosis of HF rather than establishing it

19. TROPONINS O ften elevated in patients with HF Not specific for making a diagnosis Only represent myocardial injury and I ncreased in any condition that puts increased stress on the heart muscle

20. TROPONINS high baseline troponin corresponded to a worse prognosis with an OR of 2.5 for death within a year. Serial measurements during hospitalisation for acute HF can risk stratify patients for 90-day mortality and readmission. Another study showed that an elevated hsTn as well as a >20% increase in the value was associated with increased mortality. The prognostic value is enhanced when combined with natriuretic peptides

21. guidelines ACC recommend the use of natriuretic peptides & troponins for risk stratification & for determining prognosis in both acute and ambulatory patients with HF ESC mention the role of biomarkers in determining prognosis, but do not issue any specific recommendations

22. Neurohormones Plasma norepinephrine Even asymptomatic LV dysfunction patients have elevated levels When symptoms of HF appear, rise according to severity Measurement assays are cumbersome & costly.

23. Adrenomedullin (ADM) Amino acid peptide upregulated as a result of increased volume overload. Because of rapid clearance and short half-life (22 minutes), routine use is impractical. MR- proADM , the mid-regional segment of ADM’s precursor pre- proADM , released in equimolar concentrations as ADM inactivity and longer half-life, MR- proADM is a better surrogate marker. The BACH trial ADM appeared to predict 90-day mortality or rehospitalisation due to cardiovascular causes better than BNP/ proBNP

24. soluble suppression of tumourigenicity-2 (st-2) Shown to be associated with adverse outcomes in HF and predict mortality risk It is also known as interleukin-1 receptor-like 1, and is a member of the interleukin-1 receptor family. In the PRIDE study ST2 values >0.20 ng /ml had an increased risk of death at 1 year.

25. Studies Involving ST2

26. Markers of Extracellular Matrix Remodeling Measures of collagen fragments in the blood correlate with the intensity of remodeling like carboxy terminal telopeptide of type I collagen Matrix metalloproteinases ( mmps ) and Tissue inhibitors of MMP

27. Inflammatory Mediators and Markers of Oxidative Stress Tissue injury initiates inflammatory response in which Cytokines (and their receptors), Cell adhesion molecules, are released Mediators that have proved most IL (interleukin)-1, & IL-6 *. CRP (C-reactive protein) Tumor necrosis factor-α, GDF-15 (growth differentiation factor 15), member of TGF-β . ST2 (suppressor of tumorgenicity 2 ) Gal-3 (galectin-3), ABC study ( Health, Aging, and Body Composition ) * Strongest marker

28. Galectin-3 Secreted by macrophages, causes cardiac fibrosis by proliferation of fibroblasts. Also regulates inflammation, immunity & cancer, & can act as a surrogate marker of cardiac remodelling and the fibrosis. Not useful in diagnosis, but strong prognostic value. In PROVE-ITTIMI 22 study, higher galectin-3 levels correlated with the development of heart failure. Similarly , in the Coordinating Study Evaluating Outcomes Of Advising And Counselling In Heart Failure (COACH ) trial , higher levels increased the risk of death or rehospitalisation over 18 months. Its value also correlated with inflammatory markers such as CRP, VEGF and IL-6.

29. Neutrophil gelatinase -associated lipocalin Neutrophil gelatinase -associated lipocalin is expressed by neutrophils and epithelial cells. Marker of renal injury. Also raised in heart failure, even when the reductions in renal function or minimal. Studies such as Optimal Trial In Myocardial Infarction With The Angiotensin II Antagonist Losartan (OPTIMAAL ) & NGAL Evaluation Along With B-type Natriuretic Peptide (BNP) In Acutely Decompensated Heart Failure (GALLANT ) have demonstrated a role diagnosis & prognostication in patients with HF

30. microRNA ( mi RNA ) These are differentially expressed in the failing heart miR423-5p, miR320a and miR22, have been shown to be increased in HF recent meta-analysis suggested that miR423-5p offered the best potential as a biomarker in HF.

31. PREVEND study (Prevention of Vascular and Renal End Stage Disease ), a total of 13 biomarkers were evaluated for their value in the prediction of new-onset HF on top of a clinical base model. Again , the overall additive value of biomarkers was small

32. as a Guide For Therapy Early studies were promising . In the Systolic Heart Failure Treatment Supported By BNP (STARS-BNP) trial , & the Pro-BNP Outpatient Tailored CHF Therapy (PROTECT) trial showed a benefit for patients who had BNP/NT- proBNP -guided therapy for HF.

33. as a Guide For Therapy The NT- proBNP –Assisted Treatment To Lessen Serial Cardiac Readmissions and Death (BATTLESCARRED) trial randomised 364 HF patients to natriuretic-peptide-guided therapy , clinical-guided therapy or usual care. NT- proBNP guided management was associated with improved mortality compared with usual care only in patients aged <75 years .

34. as a Guide For Therapy The Trial of Intensified versus Standard Medical Therapy In Elderly Patients With Congestive Heart Failure (TIME-CHF) No benefit either in terms of QOL or CV outcomes with intensive NT- proBNP guided management. Similarly , the Can Pro-Brain-Natriuretic Peptide Guided Therapy Of Chronic Heart Failure Improve Heart Failure Morbidity And Mortality? (PRIMA) study also failed to show any benefit with NT- proBNP guided therapy

35. as a Guide For Therapy A recent Cochrane review concluded that low-quality evidence to suggest that NT- proBNP guided therapy could lead to reduction in HF admissions, but there was uncertainty regarding the effect of NT- proBNP guided therapy on mortality & all cause admission and QOL

36. guidelines The ACC recommend the use of BNP or NT-pro BNP to achieve optimal dosing for GDMT in select euvolaemic patients (in the outpatient setting) who are followed up in a well structured HF management programme. Class IIa (level of evidence B) However , they suggest that using serial natriuretic peptide monitoring during therapy does not help in reducing hospitalisation or mortality in either the ambulatory outpatient setting or in the acute decompensated setting. The ESC do not advocate the use of natriuretic peptides in monitoring the progress of patients being treated for heart failure , stating there is insufficient data to recommend it

37. Heart Failure with Preserved Ejection Fraction ( HFP r EF ) All the biomarkers as in HF with reduced EF are also increased in HFPrEF . COACH study, higher levels of galectin-3 were associated with higher rates of rehospitalisation & death in HFpEF but not HFrEF patients Insulin growth factor–binding protein-7 MMP-2, MMP-8, tissue inhibitor of MMP-4, & procollagen -III N-terminal peptide

38. Areas of research Metabolomic profiling (study of the by products of metabolism) and transcriptomics (the study of complete sets of RNA transcripts produced by the genome) are another two areas that are undergoing extensive research in the field of heart failure

39. Take home message… Natriuretic peptides are the most commonly used biomarker and help in the diagnosis & prognostication in HF Should be more aptly to used as rule out test for confusing clinical scenarios rather than diagnostic tests for HF. Serial monitoring is not recommended for guiding treatment, however 3 time approach seems reasonable, i.e. on admission, on discharge and on out-patient follow up. Many new biomarkers currently under investigation however , on their own, none of them are specific for HF & none are recommended for routine clinical use at present