Abstract

Background

Although nesiritide is a potent vasodilator, studies using myocytes and isolated muscle strips have shown that recombinant B-type natriuretic peptide (BNP; nesiritide) decreases contractility. We sought to determine whether nesiritide decreases contractility in heart failure patients.

Methods and Results

Twenty-five heart failure patients underwent left heart catheterization (using a pressure-volume conductance catheter) and echocardiography at baseline and after a 2 mcg/kg bolus and 30-minute nesiritide infusion (0.01 mcg·kg·min). From invasive and noninvasive measurements, left ventricular (LV) systolic function indices were calculated, including ejection fraction, end-systolic elastance (E_es; single-beat invasive and noninvasive methods) and preload-recruitable stroke work (PRSW; noninvasive, single-beat method). The mean age was 60 ± 11 years, 48% were male, 56% had coronary disease, and 64% had hypertension. Although nesiritide did not change LV ejection fraction, it did decrease contractility on pressure-volume analysis. Noninvasive E_es decreased from 2.6 ± 1.6 to 2.0 ± 1.4 mm Hg/mL (P = .02). For those with reduced ejection fraction, E_es decreased by invasive (P = .006) and noninvasive (P = .02) methods. PRSW decreased from 76 ± 37 to 62 ± 28 g/cm² (P = .003). On tissue Doppler imaging, nesiritide reduced the systolic annular tissue velocity of the mitral annulus from 8.0 ± 1.9 to 6.9 ± 1.3 cm/s (P = .04).

Conclusions

Nesiritide infusion acutely decreases derived measures of contractility and systolic function in patients with chronic heart failure.

Recombinant B-type natriuretic peptide (BNP), otherwise known as nesiritide, is a potent vasodilator used to treat patients with acute decompensated heart failure.¹ Multiple studies have demonstrated that nesiritide can effectively reduce left ventricular filling pressures and systemic vascular resistance in a dose-dependent manner.^{[2] and [3]} However, conflicting reports have been published on the clinical effects of nesiritide on renal function and mortality,^{[4], [5], [6], [7], [8], [9], [10], [11], [12], [13] and [14]} suggesting that our knowledge of the cardiovascular effects of nesiritide is incomplete. Currently, nesiritide is thought to have vasodilatory and diuretic properties with no effect on left ventricular (LV) systolic function and contractility. However, in animal models, recombinant BNP appears to decrease contractility. In a study of rabbit myocytes, BNP decreased the percent shortening and maximal rate of shortening of myocytes, possibly from increases in cyclic GMP.¹⁵ In addition, BNP levels are inversely related to SERCA2a expression in isolated rabbit muscle strips and in humans, suggesting that high BNP levels may suppress SERCA2a and therefore may suppress contractility.¹⁶

Animal studies of other natriuretic peptides, including studies of atrial natriuretic peptide and C-type natriuretic peptide, have shown that the overall effects of natriuretic peptides on contractility may be varied based on type and concentration of the natriuretic peptide, and varying receptor activation.^{[17], [18], [19], [20], [21], [22] and [23]} The effect of atrial natriuretic peptide infusion on end-systolic pressure-volume relationships has been studied in humans and dogs, with conflicting results showing no inotropic effect,^{[24] and [25]} decreased contractility,²⁶ increased contractility,²⁷ and variable effect on contractility based on BNP levels (elevated BNP levels may blunt the positive inotropy of atrial natriuretic peptide).²⁸

Unlike atrial natriuretic peptide, the effect of BNP infusion on cardiac contractility has not been well studied. Based on evidence of a possible negative inotropic effect of nesiritide in animal models, we sought to determine whether nesiritide has any effect on cardiac contractility and systolic function in humans with heart failure.

Methods

We performed a prospective cohort study of 25 patients with symptomatic chronic heart failure (15 with low ejection fraction [<40%], 10 with normal ejection fraction [>50%]). Patients referred for nonurgent cardiac catheterization at the University of California, San Francisco, were recruited consecutively if they met the Framingham criteria for heart failure²⁹ and were willing to participate in the study. The protocol was approved by the University of California, San Francisco, Committee on Human Research, and all patients gave written informed consent before any study procedures.

All subjects underwent comprehensive transthoracic echocardiography including tissue Doppler imaging (Acuson Sequoia, Siemens, Malvern, PA) immediately before cardiac catheterization. Echocardiographic contrast (Optison, Amersham, Little Chalfont, UK; 0.3 to 0.5 mL injected into a peripheral vein) was administered when required to improve endocardial border detection. Next, patients underwent left-heart catheterization with a pressure-volume conductance catheter (CD Leycom, Zoetermeer, Netherlands) and right-heart catheterization with a pulmonary artery catheter. All invasive hemodynamic measurements were made at baseline and after 2 mcg/kg bolus and 30-minute infusion (0.01 mcg·kg·min) of nesiritide (Scios, Mountain View, CA). Immediately after invasive measurements were made, comprehensive echocardiography was repeated and completed within 30 minutes of the post-nesiritide invasive measurements. Nesiritide infusion was continued until the echocardiogram was completed.

ConductNT software version 3.13 (CD Leycom, Zoetermeer, Netherlands) was used for offline construction of pressure-volume loops. For analysis, 7 artifact-free beats where averaged. We measured the following LV parameters of contractility and systolic function: single-beat invasive (P_max method)³⁰ and noninvasive end-systolic elastance³¹; single-beat preload recruitable stroke work³²; cardiac output (measured by the thermodilution method with a pulmonary artery catheter); ejection fraction (measured on echocardiography using the biplane method of discs for determination of ventricular end-diastolic and end-systolic volumes)³³; and systolic tissue velocity, measured by pulse wave tissue Doppler imaging at the lateral mitral annulus.³⁴ Because end-systolic elastance (the slope of the end-systolic pressure volume relationship) cannot be evaluated without consideration of V_o (volume at the zero pressure-intercept of the end-systolic pressure volume relationship) and changes in end-systolic pressure and volume,³⁵ ESV₁₂₀ was calculated. ESV₁₂₀ is defined as the end-systolic volume at an idealized end-systolic pressure of 120 mm Hg, and was calculated for each patient by first solving for b in the following equation for the end-systolic pressure volume relationship:

('Eq.)After the constant b was calculated, we were able to solve for V₁₂₀ in Eq. 1: V₁₂₀ = (120 mm Hg – b)/E_es. Systolic wall stress was calculated as [0.334(P(LVID))]/[PWT(1+PWT/LVID)], where P = aortic systolic pressure, LVID = end-systolic minor axis dimension, and PWT = end-systolic posterior wall thickness.³⁶

Data are presented as mean values and standard deviations for continuous variables. Baseline differences in demographic, clinical, laboratory, and hemodynamic data, comparing heart failure patients with reduced and preserved ejection fraction were analyzed using unpaired t-tests (or nonparametric equivalent) for continuous variables, and chi-squared (or Fisher exact) tests for categorical variables. Within-patient changes from baseline values to measurements obtained after nesiritide infusion were assessed using paired t-tests. Two-tailed P values < .05 were considered significant. Given the possibility that nesiritide-induced reductions in preload could have an effect on indices of systolic function, we performed Spearman correlation analyses to determine whether nesiritide-induced changes in contractility parameters were correlated with changes in preload. Finally, we performed additional analyses to determine whether there were differences between patients with and without a significant decrease in contractility with nesiritide infusion (defined as decrease in E_es > 5%). All statistical analyses were performed using Stata version 9.2 (Stata Corporation, College Station, TX).

Results

The mean age of the cohort was 60 ± 11 years, 48% were male, 56% had coronary artery disease, and 64% had hypertension.Table 1 lists the characteristics of the total cohort as well as the subgroups of patients with preserved (n = 10) and reduced (n = 15) LV ejection fraction. Patients in the 2 heart failure subgroups were similar except for a higher proportion of patients with hypertension in the preserved ejection fraction group (10/10 [100%] versus 6/15 [40%]; P = .002). Patients with heart failure and preserved ejection fraction were also more likely to be female, and were more likely to have diabetes and chronic kidney disease, although the difference between the 2 heart failure groups did not reach statistical significance. Medication use was similar between the 2 heart failure groups except for more calcium channel blocker use in the preserved ejection fraction group and more aldosterone blocker use in the reduced ejection fraction group.