Coronary artery disease, heart failure, and cardiac natriuretic peptides in the middle.

An experienced cardiologist recently reminded me that most heart failure patients have a medical history of arteriosclerosis and coronary artery disease (CAD) (Figure 1). With or without myocardial infarction, the ventricular myocardium becomes hypoxic during increased workload, which, in turn, strangulates cardiac performance and initiates pathological remodelling of the myocardium. In the course of reduced left ventricular systolic function, the endocrine heart compensates with increased production and secretion of natriuretic hormones, that is, the cardiac natriuretic peptides. In fact, the association between cardiac disease and increased concentrations of natriuretic peptides was reported more than 20 years ago. Since then, numerous clinical studies have established that the plasma concentrations of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) reflect left ventricular systolic function and accordingly are helpful markers in heart failure diagnostics. However, the most feasible clinical application today seems to be as rule-out markers, which means that low plasma concentrations efficiently can exclude left ventricular systolic dysfunction. In contrast, the relatively low diagnostic specificity in heart failure diagnosis suggests that also other pathophysiological stimuli besides left ventricular systolic dysfunction can trigger increased production and secretion of natriuretic peptides from the cardiac myocytes. In the last decade, there has been an increasing focus on the association between ischaemic heart disease and the cardiac natriuretic peptides. Several studies have shown that the plasma concentrations of pro-BNP-derived peptides (both the N-terminal pro-BNP fragment and the C-terminal BNP-32 hormone) are increased in patients presenting with acute myocardial infarction with or without ST-elevation. Notably, increased concentrations are associated with later development of heart failure and death, which clearly provides critical information for identifying highand low-risk patients. Most of the information so far comes from clinical studies on hospital patients with symptoms or signs of CAD. De Sutter et al. take one step back and examine men at work. In this case–control study, they are able to show that the plasma concentration of N-terminal pro-BNP (sometimes abbreviated as NT-pro-BNP or N-BNP) provides predictive information on later development of coronary events defined as myocardial infarction, unstable angina, or coronary revascularization. Moreover, this prognostic information was established after a relatively short follow-up period. The work therefore seems to support the conception that measurement of cardiac natriuretic peptides may provide new information on CAD risk assessment. In support of this, a recent study from Kragelund et al. assessed the long-term prognostic value of N-terminal pro-BNP measurement in connection to coronary angiography in symptomatic, stable CAD patients. This study disclosed that N-terminal pro-BNP measurement is a marker of long-term mortality and provides prognostic information beyond that of conventional risk factors and the degree of left ventricular dysfunction. Other reports seem to point in the same direction (for reviews, see Costello-Boerrigter and Burnett and Struthers and Davies). Some speculation on what increased concentrations of cardiac natriuretic peptides actually reflect in a biological context seems appropriate. Although it is sometimes stated that the endocrine heart responds to ‘cardiac strain’, this is not a clear and well-defined pathophysiological mechanism. Cardiac strain neither has a uniform treatment strategy. Rather, the likely pathophysiological stimuli should be narrowed down to preferably measurable entities. For instance, some experimental data suggest that the BNP gene expression, in fact, is stimulated directly by myocardial hypoxia, which could well explain most of the new clinical results. In simple terms, that would mean that plasma concentrations of cardiac natriuretic peptides reflect the ischaemic burden, which in itself is predictive of later clinical outcome. We recently established that the myocardial BNP gene expression can be stimulated both in vivo and in vitro by reduced oxygen delivery. Others have shown that the related ANP gene promoter is directly activated by the hypoxia inducible transcription