REVIEW ARTICLE

JIACM 2010; 11(4): 282-6

Biochemical Markers in Congestive Heart Failure Nagina Agarwal*, SC Sharma**

Introduction

diabetes, hypertention, oestrogen intake, obesity8.

There is growing interest in the field of biomarkers in cardiovascular diseases. In 2001, NIH working group standardised the definition of biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biological or pathological processes or pharmacological response to a therapeutic intervention. It may be a biochemical substance from a biosample or a recording (blood pressure, electrocardiogram, holter) or an imaging test (echocardiogram/CT). It is an indicator of disease trait (risk factor), disease state (preclinical/clinical) or disease rate (progression)1.

NF is proinflammatory cytokine produced in nucleated cells of heart and leads to myocyte apoptosis/necrosis accelerating CHF. In 1990, Levine et al observed that TNF is increased in CHF9. TNF and IL-6 predict development of heart failure in asymptomatic elderly patients10 .

This article focuses on the biochemical markers in congestive heart failure (CHF). CHF is a the result of a complex interplay of genetic, neurohormonal, inflammatory, and biochemical changes in cardiac myocytes, interstitium, or both, associated with release of various biochemical markers like cytokines, neurohormones, enzymes, etc., which can be estimated in blood.

Fas (Apo-1) is a member of TNF family which mediates apoptosis. In heart failure, there is an increase in the soluble form of Fas13. It helps in screening asymptomatic patients at risk of heart failure and risk stratification. Inhibition of soluble Fas decreases post infarct ventricular remodelling and improves survival14.

1. Markers of inflammation: C-reative protein (CRP), tumour necrosis factor alpha α ), interleukin-1, 6 (IL), Fas (APO-1) (TNFα CRP is a circulating pentraxin produced in the liver and smooth muscle cells of atherosclerotic arteries2. It plays a role in immune response3, atherogenesis, and plaque vulnerability4. It was first detected in 1954 in CHF by a crude assay. Later on, highly sensitive assays were developed. In the Framingham Heart Study, it was found that CRP helps in identifying asymptomatic patients at risk for CHF5. It correlates with severity of CHF; severe the CHF, higher is the CRP 6. On multivariate analysis, it is an independent predictor of adverse outcome in CHF7. It also serves as a therapeutic target. But it lacks specificity as it is increased in acute and chronic infections, cigarette smoking, acute coronary syndrome, active inflammation,

ST-2 is a member of IL-1 receptor family which binds to IL-33. It is induced and released by stretched myocytes. It is increased in severe heart failure. Increase in ST-2 during two week period in heart failure is independent predictor of subsequent death or need for cardiac transplant11, 12.

Pentoxiphylline and intravenous immunoglobulin decrease plasma levels of CRP and Fas in ischaemic and dilated cardiomyopathy and improve left ventricular function15.

2. Marker of oxidative stress In CHF, there is increased oxidative stress because of generation of reactive oxygen molecules and decrease in endogenous antioxidants which is responsible for endothelial dysfunction and progression of heart failure. Although there is no direct marker of oxidative stress which can be measured in blood, but indirect markers like plasma oxidized LDL, malondialdehyde, myeloperoxidase and isoprostane can be measured16. However, there use is limited to research studies. Myeloperoxidase and isoprostane correlate directly with severity of CHF and are independent predictors of death from heart failure17. A simple and readily available indirect biomarker of

* Specialist and Assistant Professor, ** Consultant and Professor, Department of Medicine, PGIMER and Dr. Ram Manohar Lohia Hospital, Baba Kharak Singh Marg, New Delhi - 110 001.

oxidative stress is serum uric acid resulting from increased xanthine oxidase activity. It correlates with impaired haemodynamics and predicts adverse prognosis in heart failure18, 19.

also increases in HT, septic shock, preeclampsia which are often associated with increased RAAS activity 28 . Midregional fragment of adrenomedullin which is more stable than adrenomedullin is easier to measure.

3. Markers of breakdown

Brain natriuretic peptide (BNP), a neurohormone released from ventricular myocytes in response to myocytes stress as a prohormone is cleaved into N-terminal (NT) pro-BNP and BNP. It causes vasodilation, diuresis, and natriuresis and decreases activity of SNS and RAAS. It helps in screening patients at risk of development of heart failure, e.g., diabetics and asymptomatic coronary artery disease29, 30 . It helps in deciding whether heart failure is the cause of dyspnoea in the emergency department. In breathing not properly study by Maisel et al, BNP less than 100 pg/ ml made diagnosis of heartfailure unlikely, and BNP more than 400 pg/ml made diagnosis of heart failure likely31. In another study by Silver et al, BNP less than 100 pg/ml has 90% negative predictive value for heart failure and BNP more than 500 pg/ml has 90% positive predictive value for heart failure32.

extra-cellular

matrix

In CHF, there is increase in extra-cellular matrix breakdown because of decrease in tissue inhibitor of metalloproteinases leading to increased collagen, ventricular dilatation, and remodelling. Cocaine et al found procollagen III to be independent predictor of adverse outcome in CHF20. In RALES study, an aldosterone inhibitor spironolactone decreased myocardial collagen synthesis21, and post-infarct left ventricular remodelling, thereby suggesting its therapeutic role in CHF22.

4. Markers of neurohormonal activation In CHF, there is increased activity of sympathetic nervous system (SNS) and renin angiotensin aldosterone system (RAAS) resulting in release of norepinephrine (NE), angiotensin II, aldosterone, antidiuretic hormone, and endothelin in circulation. NE is independent predictor of mortality in CHF23. But being highly unstable, it cannot be measured and results cannot be reproduced in blood. ADH causes dilutional hyponatraemia, fluid accumulation and systemic vasoconstriction in CHF. It predicts poor clinical outcome in CHF and blockade of vasopressin-2 receptor relieves acute symptoms of CHF, but does not alter the natural history of CHF24. Endothelin-1 is a neurohormone produced by vascular endothelium as big endothelin. It converts in active form Endothelin-1 in circulation and is responsible for vascular smooth muscle contraction and proliferation, ventricular and vessel fibrosis25 in CHF. It correlates with pulmonary artery pressure, disease severity and mortality26. But trials involving endothelin-1 receptor antagonists failed to show any benefit25. Adrenomedullin is also a prohormone produced and secreted by vascular endothelial cells. It is a vasodilator, inhibits smooth muscle proliferation and migration, and decreases oxidative stress27. It prevents organ damage by improving haemodynamics in CHF and HT. Besides CHF, it

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NTpro BNP more than 400 ng/l for patients less than 50 years of age and more than 900 ng/l patients more than 50 years of age is sensitive and specific for heart failure while value less than 300 ng/l makes diagnosis of heart failure unlikely with negative predictive value of 99%33. Factors affecting natriuretic peptide levels include age34, sex, body habitus30, renal function, thyroid function, anaemia, prior history of heart failure, rhythm abnormalities, underlying aetiology of heart failure, diastolic dysfunction, mitral regurgitation, right ventricular dysfunction, recurrent heart surgery34. Levels increase after long-term treatment with angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and spironolactone 35-37. Nesiritide increases BNP but not NTpro BNP38. The levels may not increase initially in acute pulmonary oedema and acute mitral regurgitation32. Both BNP and NTpro BNP have prognostic value in heart failure. Those with higher values on admission do worse and those whose values decrease after treatment fare better39. Adhere trial done in 48,629 patients of acute decompensated heart failure found linear correlation between BNP levels and in hospital mortality 40 .

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Bettencourt et al observed that failure of BNP to decline during hospitalisation predicts death/re-hospitalisation, and discharge levels less than 250 pg/ml predict eventfree survival39. Out of BNP and NTpro BNP, NTpro-BNP is superior to BNP in predicting hospitalisation and death in heart failure in two studies41, 42. If in hospital BNP is more than 600 pg/ml, it implicates that the patient requires intensive treatment (Logeart et al)43. BNP has half-life of 20 minutes, and NTpro BNP has a half-life of 2 hours but values do not decrease as rapidly as in response to treatment as is expected from half life which suggests that body takes its own time to auto regulate44. When considering serial values, a change of approximately 85% for increase and 46% for decrease is the minimum requirement for it to be significant45. In Valsartan heart failure trial where prognostic values of various neurohormones was determined in 4,300 patients of heart failure, it was found that the most powerful predictor of mortality and hospitalisation was BNP followed by big endothelin, norepinephrine, endothelin, PRA, and aldosterone46. 5. Markers of myocyte injury – troponin I, T, myosin light chain-1 (MLC-1), heart fatty acid binding protein (hFABP), creatine kinase (CK-MB) These are released as a result of stress, injury secondary to increased inflammation, oxidative stress and neurohormonal activation. Horwhich et al observed that troponin-I was more than 0.04 ng/ml in approximately half of the 240 patients with advanced chronic heart failure heart failure without ischaemia and after adjusting for other variables, troponin-I was found to be independent predictor of death47. In chronic heart failure, troponin-T value more than 0.02 ng/ml was associated with hazard ratio of more than 4 for death48. Latini et al has developed a highly sensitive assay for troponin-T by which 92% patients with chronic heart failure have increased myocyte injury like troponin-T and also associated with increase risk of death49. While with standard assay, it is detectable only in 10% of patients with chronic heart failure. Other markers MLC-1, hFABP and CK-MB also increase in heart failure and are accurate predictors of death and hospitalisation for heart failure50.

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Summary In this article, various biomarkers have been discussed but none satisfies all the criteria of an ideal biomarker. However, BNP has scored over others in prognostic, diagnostic, and therapeutic values and has also a found place in the guidelines for the diagnosis of congestive heart failure 5. But this also needs to be carefully interpreted in the presence of clinical settings and various confounding factors as discussed above. A multimarker approach is better for risk stratification. There are other future biomarkers underway, e.g., chromogranin A, galactin-3, osteoprotegrin, adiponectin, GDF-15 which may open up a new paradigm in the diagnosis and management of CHF, superceding the presently available biomarkers.

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