Our study is the first to compare the effects of rhBNP and dobutamine on ADHF patients with different plasma BNP levels. The results revealed that rhBNP was not superior to the traditional inotropic agent dobutamine at improving cardiac function in patients with extra-high BNP levels (>3000 pg/mL). On the contrary, rhBNP-treated patients tended to be more likely to experience hypotension than dobutamine-treated patients.
Dobutamine, a dopamine derivative, produces positive inotropic and chronotropic effects on myocardium mainly through stimulation of β1-receptors and by causing a reflex decrease in sympathetic tone
[1, 10, 11]. At low doses, dobutamine induces mild arterial vasodilatation, which augments stroke volume by reductions in afterload
, and has little influence on HR, blood pressure, and cardiovascular adverse events.
BNP, a natriuretic peptide, is produced and released from the ventricles in response to increased wall stretch and tension
. It binds to the A-type natriuretic peptide receptor that is present on the surface of vascular smooth muscle and endothelial cells
, resulting in activation of guanylate cyclase and the subsequent accumulation of intracellular cyclic GMP in target tissues
. Cyclic GMP, as a second messenger, mediates natriuretic, diuretic and smooth muscle relaxant effects, which lead to the therapeutic benefits of venous and arterial vasodilation and decreases in preload and afterload, resulting in increased cardiac output with improved dyspnea and systemic symptoms
In addition, BNP also serves as a physiological antagonist of the renin-angiotensin-aldosterone system and the sympathetic nervous system
. It inhibits renin-aldosterone secretion, suppresses the sympathetic nervous system, and antagonizes the action of antidiuretic hormone in inducing antidiuresis, antinatriuresis, and vasoconstriction, leading to a decrease in systemic vascular resistance and cardiac pre- and afterload
[4, 14, 15]. Thus, as a compensatory mechanism for heart failure, circulating BNP levels strongly correlate with the severity of heart failure
rhBNP has the same 32 amino acid sequence and biological activity as endogenous BNP, with a mean terminal elimination half-life of 18–20 min
[18, 19], which means that it is almost completely cleared at 3 h post infusion withdrawal (approximately 9–10 elimination half-lives). Several studies indicated that BNP changes during the first 5 days of hospitalization had a very high prognostic value in patients with heart failure
[20, 21]. Accordingly, we assayed the plasma BNP levels at day 5 after treatment to evaluate the efficacy of rhBNP and dobutamine. At this time, the exogenous rhBNP had been completely eliminated and did not interfere with the measurement of the endogenous BNP level, allowing accurate assessment of the therapeutic efficacy of the study drugs.
Numerous studies reported that BNP levels reflect heart failure severity
[16, 17, 22]. However, Law et al. found that extremely high BNP level ( > 3000pg/mL) did not correlate with heart failure severity when patients had complications such as neurological disorder, sepsis, or subarachnoid hemorrhage. The possible reasons might be that in these patients, an increase in sympathetic stimulation causes the hypothalamus to secrete excess vasopressin and BNP
[9, 23]. In our study, all patients with these confounders were excluded. Thus, BNP level might well reflect the status of heart function.
We found that rhBNP was more efficient than dobutamine at improving heart function in patients with BNP levels ≤3000 pg/mL. However, their efficacies were similar in patients with extra-high BNP levels. The difference might be explained by the following reasons. First, BNP exerts its biological activities through binding to the A-type natriuretic peptide receptor, which is present on the surface of vascular smooth muscle and endothelial cells
. When the compensatorily increased endogenous BNP is not sufficient to bind to all the free receptors, the introduced exogenous BNP (rhBNP) can fully activate the remaining free receptors, resulting in a marked improvement in heart function. However, when the circulating BNP increases to even greater levels, with subsequent full activation of their receptors, an insufficient number of free BNP receptors can be bound by exogenous BNP, meaning that the additional effects of exogenous BNP on decreasing cardiac pre- and afterload are inhibited. Second, patients with extremely high BNP levels might be resistant to the biological action of BNP. This phenomenon is characterized by extremely high circulating BNP levels in patients with congestive heart failure who have physical signs of fluid retention and vasoconstriction from poor biological activity of the BNP system
. A deficient response to BNP is attributed to inactivation of BNP by plasma and tissue proteases before they bind to their receptors, downregulation or desensitization of BNP-specific receptors, and mechanisms that counteract the biological effects of BNP at postreceptor level
. Third, patients with extremely high BNP levels usually suffer from more severe heart failure, accompanied by serious renal congestion and low renal blood flow
, which could inhibit the effects of rhBNP on renal vessel dilation, natriuresis, and diuresis, but would not affect the positive inotropic effects of dobutamine on myocardium. In this study, basal plasma creatinine was significantly higher in the extra-high BNP group, suggesting deterioration of renal function might be responsible for the low efficiency of rhBNP in patients with extremely high BNP. In addition, patients with more severe heart failure usually also have lower arterial pressure. The SBP level in the extra-high BNP group tended to be lower than in the high BNP group, although the difference was not significant (P = 0.079). Vasodilator drugs such as rhBNP might lead to more satisfactory clinical improvements in heart failure patients with high-normal blood pressure.
The blood pressure in the rhBNP subgroup was decreased after treatment (Table
6). One patient in the extra-high BNP group with low baseline blood pressure (96/64 mmHg) experienced symptomatic hypotension (84/50 mmHg) at 3 h after rhBNP infusion and had to withdraw from the study. Plasma creatinine remained unchanged in patients with plasma BNP ≤3000 pg/mL after treatment, but it tended to increase in patients with extra-high BNP levels after rhBNP treatment (Table
6). One male patient in the extra-high BNP group who received rhBNP had an increase in plasma creatinine from 165 μmol/L (1.9 mg/dl, baseline) to 243 μmol/L (2.7 mg/dl). These results indicate that rhBNP, as an antagonist of the renin-angiotensin-aldosterone system (RAAS), might impair renal function and induce azotemia in patients with severe heart failure whose renal function depends on RAAS. Dobutamine had no obvious effect on plasma creatinine.
The results of this study are limited by its open-label design and the relatively small number of patients in each subgroup. Moreover, the effects of rhBNP and dobutamine on hospital readmissions and long-term survival were not assessed. More information from a larger blinded study will be required to confirm the results of this study.