The current study demonstrates that circulating concentrations of the cardiac peptide BNP in our study population, free of HF (FHS criteria) or renal failure (serum creatine > 2.0 mg/dL), was predictive of increased mortality, thereby confirming earlier studies.4,5
Our studies further extend previous reports with 3 widely used assays for quantifying BNP, all of which predicted increased mortality. Whereas all 3 of the assays were predictive of mortality, the NT-proBNP and Biosite assays had a higher predictive value and remained significant even after the adjustment for both clinical phenotypes and echo-cardiographic abnormalities. We also provide important information on the cardiovascular clinical phenotype of those at greatest risk, as well as key structural and functional cardiac abnormalities as documented by in-depth echocardiographic examination. Thus, this investigation in adult humans in the general community provides new insights into BNP as a biomarker for cardiovascular disease and survival in subjects without HF of renal failure.
The cardiac hormone BNP is currently used in the diagnosis and prognosis of symptomatic HF.1–3,20–22
To date, both active BNP and the apparently nonbiologically active NT-proBNP fragment have emerged as potential biomarkers of preclinical asymptomatic left ventricular dysfunction.9,13,23–26
In this study, we confirm recent reports, which show that BNP may identify those at increased risk even in the absence of HF and with circulating concentrations well below the threshold for HF. We and others7,27,28
have speculated that the association between the natriuretic peptides and mortality may be because of increased filling pressures in the setting of diastolic dysfunction, which was not assessed in the previous large, population-based biomarker studies.4,5
In the current study, diastolic dysfunction was indeed more common among those with higher BNP levels. However, adjustment for diastolic function and other echocardiographic measurements was not found to alter the prognostic significance of the NT-proBNP or Biosite assays. This analysis, including diastolic dysfunction, further confirms the value of BNP as a biomarker for mortality beyond traditional clinical and echocardiographic risk factors. These findings may impact the clinical utility of these widely used assays to unmask individuals with increased risk of mortality during the study period of 7 years.
A significant aspect of our study was the use of 3 widely used assays for BNP to predict mortality in the general population. Importantly, we observed that all 3 of the assays possessed prognostic properties in predicting death. However, 1 assay emerged as more robust, as is illustrated in . Here, our models compared the relative predictive value for mortality among the 3 assays and suggested that NT-proBNP may be superior as a biomarker compared with the Biosite and Shionogi assays. Specifically, NT-proBNP adds significant predictive value to both the Shionogi and Biosite assays, whereas the predictive value of NT-proBNP is not improved with the addition of either the Shionogi or Biosite assays. This observation is also consistent with a recent report by Costello-Boerrigter et al9
of a superiority of NT-proBNP compared with Biosite BNP in this same cohort in detecting reduced ventricular systolic function. The superiority of NT-proBNP to BNP is likely secondary to the prolonged half-life of the nonbiologically active NT-proBNP that translates to relatively consistent intraday plasma levels. This is in contrast to the high intraday variability of the biologically active BNP. It is possible that the relationship between BNP and mortality during the study period may be stronger if intrasubject variation was minimized by the averaging of multiple plasma measurements.
In , we report among individuals without HF or renal failure that those with higher BNP levels had higher incidence of cardiovascular drug use. It is important to note that most drugs used to treat hypertension, including angiotensin-converting enzyme inhibitors,29
and angiotensin II receptor blockers,31
can reduce plasma BNP levels. Currently there is conflicting evidence regarding the effect of β-blockers on plasma BNP levels.32,33
The use of these drugs may have reduced both mortality and BNP over the 7 years of the study thereby potentially obscuring an even tighter association between BNP and mortality during the study period.
Our in-depth clinical and echocardiographic findings offer insight into the mechanism of modestly increased BNP in the adult general population. We report for the first time the phenotypic characteristics of individuals without HF or renal failure who are at increased risk for death during the study period as determined by their plasma BNP levels. In the current study, in the absence of HF and renal failure, there was an incremental and significant increase in the prevalence of traditional risk factors and echocardiographic abnormalities with increasing BNP values. Because our echocardiographic findings documented widespread structural changes in those with increasing BNP levels, it is tempting to speculate that the elevation of plasma BNP represents a plasma biomarker for asymptomatic cardiac abnormalities. Elevated BNP levels may, thus, represent a final common pathway for many cardiovascular pathologic disease states. Clearly, studies of myocardial structure and function in such populations free of HF are warranted together with careful assessment of myocardial secretion of BNP to better understand the underlying mechanism for enhanced plasma concentrations.
The strengths of our study include a large, well-characterized, community-based sample and thorough echocardiographic evaluation of cardiac function and structure. The use of 3 widely used BNP assays is also an important strength. There are several limitations to our study. The Olmsted County population is predominately white, and our results may not be generalized to nonwhites. Although we do confirm and report the predictive value of BNP for death, the mechanism of increased mortality was not defined. In addition, we report all-cause mortality, because of the number of specific-cause deaths was too few for statistical analysis. Finally, we do not assess any potential synergistic role of combining BNP with other biomarkers, such as C-reactive protein, which has been shown to enhance the predictive value of BNP for cardiovascular events in previous reports.26
However, we do assess the relative predictive value of 3 different assays.
The current study has clinical implications that deserve further investigation. Our studies and those of Wang et al4
suggest that a modest elevation of BNP predicts increased mortality during the study period, and the latter report would suggest that it also is predictive of future HF, stroke, and atrial fibrillation. Our echocardiographic and clinical data would suggest that the mechanism of the elevation may be structural abnormalities, such as LVH, diastolic dysfunction, and other myocardial abnormalities. It is important that future studies be directed at the use of BNP to detect people at risk and for populations in which BNP is modestly elevated but below HF and renal failure values. Such use of this cardiac hormone may prompt echocardiographic examination so as to detect structural changes in the heart and to identify clinical risk factors, both of which could be more aggressively treated. In addition, it will be important to then undertake human therapeutic studies to determine whether reduction of BNP in such a population results in improved outcomes and survival.
From a clinical perspective, the current findings may change the way we use NT-proBNP and BNP as biomarkers. It is common clinical practice to use these biomarkers in patients with HF to confirm diagnosis, assess prognosis, and guide therapy. Our findings go beyond HF and especially extend to the setting of general practice. Today, health care providers in the community assess cardiovascular risk factors and attempt to optimally control blood pressure, diabetes, and lipids so as to positively impact survival. Our studies suggest that the use of NT-proBNP or BNP could serve as a blood test to aid in identifying the “high-risk” subject with cardiovascular risk in the general population prompting more aggressive primary prevention. Such use of NT-proBNP or BNP in the general community might well prompt more use of echocardiography to look at underlying structural changes of the heart, which could also have an impact of the cost of care. Most importantly, if future studies clearly demonstrate that a reduction in NT-proBNP or BNP improves mortality in this type of general population, studies that clearly need to be done, then the use of NT-proBNP and BNP would evolve into established clinical practice in the care of the general population without HF.
In summary, we report the first study to compare NT-proBNP and BNP using 3 distinct assays in the same population-based cohort as a biomarker for mortality. Specifically, the NT-proBNP assay is most predictive of mortality even after adjustment for clinical phenotypes and echocardiographic abnormalities. Our findings further underscore that elevated NT-proBNP and BNP may also serve as biomarkers for underlying cardiac remodeling secondary to diverse cardiovascular disease entities. This study, thus, confirms the potential use of these peptides as biomarkers for future events and may enhance efforts at primary prevention.