Biomarker for Cardiomyopathy-B-Type Natriuretic Peptide (Classification, Evaluation and Management of Cardiomyopathies) Part 1

Introduction

Cardiomyopathy is cardiac condition in which the normal muscular function of the myocardium has been altered by a variety of etiologies. Atherosclerotic coronary artery disease is the most common cause of cardiomyopathy in North America and Europe. Idiopathic cardiomyopathy is the second most common cause, although this may partially include undiagnosed etiologies such as viral infection, drug toxicity, and genetic factors. Other causes include endocrine diseases, collagen vascular diseases, metabolic disorders (hemochromatosis, amyloidosis, glycogen storage disease), neuromuscular disorders, and granulomatous diseases (sarcoidosis).

The cardiac malfunctions are variable, namely left ventricular (LV) systolic dysfunction, LV diastolic dysfunction, or both in accordance with etiologies and morphological findings (cardiac hypertrophy or dilatation). For example, hypertrophic cardiomyopathy initially has LV diastolic dysfunction, while amyloidosis that shows similar morphological change has LV systolic dysfunction. Ischemic or idiopathic cardiomyopathy with ventricular dilatation is represented by systolic dysfunction. Cardiac malfunctions are also altered on disease course. Initially, patients with cardiomyopathy may have asymptomatic LV systolic or diastolic dysfunction alone. However, adverse disease processes finally lead to both dysfunctions.

Imbalance between cardiac malfunctions and compensatory mechanisms worsens an outcome of cardiomyopathy. When abnormal LV filling pressure and volume is unable to be compensated by hemodynamic alterations such as the increases in heart rate and peripheral vascular tone by the accelerated vasoconstrictors including norepinephrine (NE), endothelin-1 (ET-1), and the renin-angiotensin-aldosterone (RAA), this imbalance precipitates decompensated heart failure (HF).

Early and simply identifying the decompensatory process is important therapeutic strategy in cardiomyopathy. Clinical utility of B-type natriuretic peptide (BNP) sensitively produced and secreted from heart in response to LV overload has been extended rapidly in patients with HF. At first, BNP emerged as a diagnostic marker for decompensated HF. Furthermore, BNP has been proved to predict a subsequent outcome in patients with HF. Recently, the efficiency of BNP-guided therapy in patients with HF has been demonstrated. In this topic, we discuss about clinical utility of BNP assessments in patients with cardiomyopathy.

B-type natriuretic peptide (BNP)

BNP is predominantly secreted from the overloaded LV as a 76 aminoacid N-terminal fragment and a 32 aminoacid active hormone, and synthesis and release of BNP are adversely and rapidly accelerated in conjunction with the degree of LV wall stretch (1-2). In addition to this primary regulation, BNP synthesis can be also upregulated by tachycardia, glucocorticoids, thyroid hormones, vasoactive peptides such as ET-1, angiotensin II, and NE, and inflammatory cytokines. On the other hand, BNP is clearance via the binding to a natriuretic peptide receptor (NPR)-C of three NPRs (NPR-A, -B, -C). BNP is also inactivated by neutral endopeptidase, a zinc metallopeptidase which is expressed on the surface of endothelial cells, smooth-muscle cells, cardiac myocytes, renal epithelium, and fibroblasts. BNP is included into compensatory mechanisms against HF. BNP promotes glomerular filtration and inhibits sodium reabsorption, resulting in natriuresis and diuresis. It reduces blood pressure through the relaxation of vascular smooth muscle and inhibits activations of not only central and peripheral sympathetic nerve systems but also cardiac sympathetic nervous system (3). Furthermore, it also inhibits the RAA system (4).

BNP as a diagnostic marker

BNP in heart failure

Plasma BNP levels have proven utility in the diagnostic evaluation of decompensated HF in patients with acute dyspnea (5-6). Particularly, BNP at a cutoff of 100 pg/ml could diagnose HF better than not only all other clinical parameters but also the clinical judgement by the emergency room physicians. However, BNP also has the diagostic limitation for HF. BNP is less accurate in detection of asymptomatic LV dysfunction than clinical parameters, because BNP has a close correlation with New York Heart Association (NYHA) functional class and patients with mild LV dysfunction often show normal range of BNP levels.

BNP in cardiomyopathy

BNP levels are raised in dilated, hypertrophic, and restrictive cardiomyopathies. Its increases seem to be different in accordance with cardiac malfunctions. BNP levels are generally higher in patients with systolic dysfunction than in those with isolated diastolic dysfunction, and highest in those with both dysfunctions (7). Furthermore, among patients with preserved LV systolic function, BNP correlates with the severity of diastolic dysfunction. BNP levels are raised in patients with impaired relaxation and especially highest in those with a restrictive filling pattern (8). BNP measurements may facilitate understanding the type and severity of cardiac malfunction on cardiomyopathy.

On the other hand, BNP measurement may be unavailable for distinguishing cardiomyopathies. Hypertrophic cardiomyopathy often shows extremely high levels of BNP, similarly to dilated cardiomyopathy (9). In addition, restrictive cardiomyopathy with systolic dysfunction also shows higher levels of BNP than that with diastolic dysfunction alone (8). However, several reports have demonstrated that BNP is able to distinguish constrictive pericarditis and restrictive cardiomyopathy, although these diseases overlap signs and symptoms of congestion (10). The level of BNP is elevated in patients with restriction, while level is nearly normal in those with constriction. The absence of cardiac stretch by constricting pericardium is thought to lead to lower BNP release.

BNP as a prognostic marker

Prognostic values of BNP have been identified in various heart diseases such as HF, cardiovascular diseases, and cardiomyopathy.

Heart failure

In patients with HF, higher levels of BNP have been implicated in increased risk of cardiovascular or all-cause mortality and readmission for decompensated HF. Furthermore, the cutoff points on the risk assessment curve are altered on time course after decompensated HF. In admitted patients for decompensated HF, the cutoff point of 800 pg/ml was associated with the increased risk of in-hospital mortality as shown by the ADHERE (Acute Decompensated Heart Failure National Registry) data (11). After the treatment, the predischarge cutoff point for the risk of readmission and mortality falls to about 500 pg/ ml (12). The cutoff point further declined to abut 200 pg/ml in clinically stable outpatients after decompensated HF (13). These obsevations suggested that the therapeutic strategies for HF including a safe hospital discharge and the prevention of readmission or cardiac event may be guided by BNP measurement.

Cardiovascular diseases

In disorders other than HF, BNP also has prognostic value. BNP level is able to identify patients at the high risk group of adverse cardiac remodelling from patients with post-myocardial infarction, independent of age, history of HF, and LV ejection fraction (LVEF) (14). Even in patients with unstable angina alone, increased levels of BNP were associated with an increased risk of death (15). In right ventricular dysfunction resulting from pulmonary hypertension, BNP also provides similar prognostic information. These observations have extended the potential role of BNP measurement to risk stratification of cardiovascular events in patients with and without HF.

Cardiac inflammatory diseases; acute myocarditis

Acute myocarditis is able to be mainly divided into two disease conditions on a basis of clinicopathologic profiles, namely fulminant and non-fulminant myocarditis (16-17). Briefly, fulminant myocarditis is represented by the distinct onset of cardiac symptoms within 2 weeks following flu-like symptoms accompanied by histologically proven active myocarditis according to Dallas criteria and severe circulatory failure requiring high-dose intravenous catecholamines use (>5.0 y) or mechanical circulatory assist devise, while non-fulminant myocarditis is by the indistinct onset of cardiac symptoms without those. Furthermore, these outcomes are distinguished by each unique clinical course (17). Non-fulminant myocarditis has been implicated in poorer long-term outcome than fulminant cases. A few patients with fulminant myocarditis lapsed into mortality from severely deteriorated circulatory collapse refractory to mechanical circulatory assist use or mechanical complications from its long-term use, including bleeding, infections, sepsis, and multiple organ failure. However, more than 80% of fulminant cases recover completely to an uncomplicated status, with cessation of myocardial inflammation and a generally favorable outcome, provided they are able to overcome poor cardiac condition successfully during acute phase (18). On the other hand, non-fulminant myocarditis without severe circulatory failure is likely to develop to chronic HF derived from dilated cardiomyopathy at chronic phase (16-17). Therefore, simple biomarkers to predict a requirement of mechanical assist devise use, outcome following its use, or the development to cardiomyopathy in patients with acute myocarditis have been sought.

Previously, we related various variables to short-term outcome in patients with fulminant myocarditis (19). In-hospital mortality was extremely higher in patients with fulminant myocarditis than in non-fulminant cases. Especially, extremely increased levels of interleukin-10, a major anti-inflammatory cytokine in serum on admission were associated with short-term outcome including mechanical assist use and in-hospital mortality in patients with acute myocarditis (Figure 1), which might be explained by its inhibitory effect on viral elimination from host. A major pathogenic factor of acute myocarditis and subsequent cardiomyopathy is viral infection, especially coxsackievirus B3 (Table 1).

Virus	Type	Patient positive (%) Myocarditis	Dilated cardiomyopathy
Picornavirus	Coxackie A, B	5-50%	5-15%
	Echovirus	?	?
	Hepatitis A	?	?
	Hepatitis C	0-15%	0-10%
Orthomyxovirus	Influenza A, B	?	?
Paramyxovirus	RSV, Mumpus	?	<1%
Rubivirus/Toga	Rubella virus	?	<1%
virus
Rhabdo virus	Rabies virus	?	?
Arbovirus/Tahyna	Dengue, yellow	?	?
	fever virus
Retrovirus/Lenti	HIV	Variable	?
Herpes virus	Varicella-zoster	1-2%	1-2%
	Cytomegalovirus	1-15%	1-10%
	Epstein-Barr virus	1-3%	1-3%
	Human herpes virus 6	0-5%	0-5%
	herpes simplex virus	0-3%	?
Mastadenovirus	Adenovirus	5-20%	10-12%
Parvovirus	Parvo B 19 virus	10-30%	10-25%

Table 1. Virus-induced myocarditis or cardiomyopathy

Hoffmann et al also reported that IL-10 expression in human peripheral monocytes was strongly and persistently induced by coxsackievirus B3 infection in spite of only slight production of other pro-inflammatory cytokines such as TNF-a, IL-1 and IL-6 (20). It has been reported that the inhibition of natural killer (NK) cells results in increased virus titers in the heart through delayed virus clearance (21). IL-10 inhibits the production of IFN-y in NK cells, which has been demonstrated in association with susceptibility to Trypanosoma cruzi-induced myocarditis (22-23). In addition, it has been shown that IL-10 is transcribed in the myocardium parallel with viral replication in the acute and chronic stages of experimental Coxsackievirus B3 viral myocarditis (24-25). These findings imply that an extreme elevation of serum levels of IL-10, rather than TNF-a, on admission may reflect subsequent myocardial inflammation, which leads to the future deterioration of the disease, through delayed clearance of the virus. On the other hand, high levels of IL-10 may reflect a favorable long-term outcome in patients with acute myocarditis. Studies using experimental models have demonstrated a protective role of IL-10 in the development of acute myocarditis (26-27). This mechanism was explained by its suppressive effect against excessive and persistent immune response to viral infection or a subsequent autoimmune response leading to chronic myocardial injury. Cases with high level of IL-10 during acute phase may be not likely to develop to chronic myocarditis or cardiomyopathy. So far, almost studies with human myocarditis have been limited to a small number of patients. Further large number prospective studies are required to prove our idea. In our previous study, the association of BNP with outcome was examined, also. Its levels in plasma were significantly increased in fulminant cases than in non-fulminant cases. However, we could not confirm its prognostic utility. In such cases, BNP may simply reflect the existence of circulatory failure alone.

Serum levels of IL-10 were significantly increased in non-survivors than in survivors with fulminant myocarditis. IL-10 levels were significantly increased in not only patients with mechanical circulatory assist device on admission but also in those with it post admission, a few days after admission than in those without it throughout clinical course. IL: interleukin; FMC: fulminant myocarditis.

Fig. 1. Serum level of interleukin-10 in patients with acute myocarditis.

Cardiomyopathies

The HF is a major complication in cardiomyopathies such as dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and restrictive cardiomyopathy (RCM). BNP must be a useful prognostic predictor for cardiomyopathies.

Dilated cardiomyopathy

Recently, we reported prognostic utility of BNP in clinically stable 83 outpatients with nonischemic DCM after decompensated HF (13). They were in a clinically stable status during at least 6 months after hospital discharge at relatively low BNP level, namely mean BNP level of about 200 pg/ml. This implied that pre-discharge BNP level may predict a post-discharge outcome in nonischemic DCM, as reported in general decompensated HF patients (12). Additionally, in this observation, the prognostic value of post-discharge BNP level was identified. Especially, among various predictors, levels at 6 months after hospital discharge showed the closest relation to the high risk of readmission for decompensated HF and mortality (Table 2). This association was explained by adverse cardiac remodeling. Persistently high levels of BNP during 6 months were related to poor improvement on cardiac remodeling (Figure 2).

	Below vs. above median values
Variable	median level	HR	95% CI	P value
Univariate analysis
Age	56	1.1895	0.74311.9246	0.47
Sex (Female)		1.0347	0.58862.0433	0.89
Hypertension		1.4902	0.89122.2819	0.18
Atrial fibrillation		1.2965	0.88852.0973	0.301
Ventricular tachycardia		1.2026	0.61322.1693	0.57
Beta-blocker use		1.6691	0.90562.5641	0.06
Diuretic use		1.3551	0.80862.1936	0.24
Echocardiographic parameters
Left ventricular end-diastolic dimension at discharge	6.4 cm	0.8356	0.51891.3516	0.48
Left ventricular ejection fraction at discharge	30%	1.1629	0.71891.8729	0.54
Left atrial diastolic dimension at discharge	4.5 cm	1.3054	0.81062.1164	0.28
Left ventricular end-diastolic dimension at 6 months	6.0 cm	1.3866	0.83832.3598	0.22
Left ventricular ejection fraction at 6 months	36%	1.5019	0.92092.4641	0.11
Left atrial diastolic dimension at 6 months	4.25 cm	2.0003	1.24363.2233	0.0046
BNP measurements
Plasma BNP level at discharge	180 pg/ml	1.2642	0.80511.9888	0.31
Plasma BNP level at 3 months	134 pg/ml	1.5097	0.94132.4212	0.09
Plasma BNP level at 6 months	174 pg/ml	2.2679	1.43363.5863	0.0005
Percentage change in BNP level between discharge and 3	-20.5%	1.4204	0.8863-	0.14
months			2.2765
Percentage change in BNP level between discharge and 6 months	-11.5%	2.0127	1.27293.1757	0.0026
Multivariate analysis
Plasma BNP level at 6 months	174 pg/ml	1.8427	1.11273.0426	0.0181
Percentage change in BNP level between discharge and 6 months	-11.5%	1.6538	0.99912.7214	0.051
Left atrial diastolic dimension at 6 months	4.25 cm	1.5678	0.94862.5904	0.0792

NYHA: New York Heart Association functional class; HR: hazard ratio; CI: confidence interval; BNP: B-type natriuretic peptide (Nishii M, et al. J Am Coll Cardiol. 2008;51:2329-2335)

Table 2. Univariate and multivariate Cox analyses of the incidence of death or readmission for heart failure.

Hypertrophic cardiomyopathy

Several reports have demonstrated that BNP levels reflect the severity of symptoms and HF in HCM (28-29). Additionally, high level of BNP has been related to cardiac events including silent myocardial ischemia (30), admission for HF, and mortality (31). On the other hand, our previous observation was unable to confirm these values, because even patients with high levels of BNP were in a clinically stable status. In HCM, BNP expression, however, is thought to occur as a response to not only hemodynamic changes resulting from diastolic dysfunction and obstruction but also histological changes such as myocardial fiber disarray, hypertrophy of myocytes, and fibrosis (32). Thus, even in clinically stable patients with HCM, extremely high levels may indicate a poor long-term outcome. Further studies are required to elucidate its prognostic value in HCM.

Restrictive cardiomyopathy

There is no report regarding prognostic value of BNP in RCM. However, when RCM had a further increase of LV end-diastolic pressure (LVEDP) or systolic dysfunction, BNP level would be more increased (7). BNP measurement may predict the occurrence of decompensated HF, although its value remains uncertain in RCM.