Cor pulmonale

We have studied the hemodynamic and hormonal effects of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) in eight patients with cor pulmonale. Subjects were studied twice and were given a 20-min placebo infusion followed by either ANP or BNP (3 pmol/kg/min then 10 pmol/kg/ min for 20 min each). Responses were measured after placebo infusion and following low-dose then high-dose ANP or BNP. Placebo infusion had no significant effects on either study day. Low-dose ANP and BNP significantly reduced mean pulmonary artery pressure (MPAP) from baseline by 3.7 mm Hg (95% confidence interval [CI], 1.4 to 6.1) and 3.0 mm Hg (95% CI, 0.6 to 5.4), respectively. High-dose ANP and BNP further reduced MPAP from baseline by 7.1 mm Hg (95% CI, 4.8 to 9.4) and 7.1 mm Hg (95% CI,4.7 to 9.6), respectively. Effects on total pulmonary vascular resistance were similar. ANP and BNP had no confounding systemic hemodynamic effects. Plasma aldosterone was significantly suppressed from baseline by ANP: 156 pmol/L (95% CI, 93 to 220) after low dose, 275 pmol/L (95% CI, 207 to 343) after high dose; and by BNP: 92 pmol/L (95% CI, 30 to 153) after low dose, 159 pmol/L (95% CI, 98 to 220) after high dose. ANP and BNP produced dose-related pulmonary vasodilatation in patients with cor pulmonale, without worsening oxygen saturation or affecting systemic hemodynamics. ANP and BNP also exerted favorable neurohormonal effects by suppressing aldosterone. (CHEST 1996;110:1220-25)

Key words: atrial natriureric peptide; brain natriuretic peptide; cor pulmonale; pulmonary hypertension; renin-angiotensin system

Abbreviations: ANP=atrial natriuretic peptide; BNP=brain natriuretic peptide; CI=confidence interval; CO=cardiac output; CV=coefficient of variation; HR=heart rate; MAP=mean arterial pressure; MPAP=mean pulmonary artery pressure; NEP=neutral endopeptidase; PAT=pulmonary acceleration fume; PVR=pulmonary vascular resistance; RAAS=reninangiotensin-aldosterone system; SV=stroke volume; SVR=systemic vascular resistance

The natriuretic peptide system, especially atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), have been studied extensively as a possible mechanism for counterregulation of the he modynamic effects of circulatory pressure and volume overload." Both ANP and BNP have vasodilator activity mediated through a cyclic guanosine monophosphate-linked receptor on vascular smooth muscle cells.[2] In the systemic vasculature, ANP appears as potent a vasodilator as BNP in vitro[3] and in vivo.4 These peptides also directly suppress the renin-angiotensin-aldosterone system (RAAS) by inhibiting aldosterone biosynthesis, an effect which ANP may exert more than BNP.[4] In addition, the natriuretic actions of ANP and BNP are mediated by direct effects on the glomerulus[5] as well as by antagonizing the sodium-retaining effects of aldosterone. Although having similar actions, ANP appears to be released acutely in response to atrial stretching,[6] whereas BNP release may require a more sustained increase in ventricular afterload.[7] This differential pattern of release may be indicative of distinct roles in short- and long-term circulatory homeostasis.

These hemodynamic and hormonal effects of ANP and BNP may therefore be particularly relevant in pathophysiologic conditions in which there is abnormal vasoconstriction associated with activation of the reninangiotensin system. In the systemic circulation, these effects have been studied extensively in relation to congestive heart failure 8 where although plasma levels of both ANP and BNP are elevated,[9,10] their apparent beneficial effects have yet to be exploited as a therapeutic option.

In the pulmonary circulation, the effects of the natriuretic peptides have been less well examined, although this may be relevant in cor pulmonale where there is abnormal pulmonary vasoconstriction, activation of the RAAS,[11] and elevated ANP and BNP LEVELS.[12] In terms of pulmonary hemodynamic effects, ANP and BNP both have pulmonary vasorelaxant activity in normal humans in vivo,[13] but to date and to our knowledge, only ANP has been studied in cor pulmonale. Adnot et al[14] were the first to demonstrate that ANP lowered pulmonary vascular resistance (PVR) in patients with cor pulmonale secondary to hypoxemic COPD, an effect subsequently confirmed at lower doses by Rogers et al.[15] BNP, however, has not been studied in this respect, although it might be expected to have similar effects. In addition, the relative effects of ANP and BNP on the activity of the RAAS in cor pulmonale have not been documented.

We have therefore compared the effects of low- and high-dose infusion of ANP and BNP on pulmonary and systemic hemodynamics and on plasma aldosterone levels in patients with cor pulmonale.

MATERIALS AND METHODS

Subjects

Eight patients (5 men, 3 women) with clinically stable cor pulmonale secondary to hypoxemic COPD (mean age [+ or -] SEM; 74.1 [+ or -] 1.8 years) were included in the study after attending a screening visit to assess inclusion criteria and characterize the study population. All had spirometry reflecting COPD ([FEV.sub.1]/FVC <70%) and arterial hypoxemia while breathing air (Pa[O.sub.2] <8.0 kPa) and had a history of peripheral edema despite normal renal function (serum creatinine <120 [micro]mol/L) and normal serum albumin (>35 g/L). On echocardiogram, subjects were required to have normal left ventricular function and resting mean pulmonary arterial pressure (MPAP) greater than 25 mm Hg. In addition, all subjects had evidence of reversible, dynamic pulmonary vasoconstriction as assessed by a greater than 15% fall in MPAP while breathing 60% oxygen. Patients with systemic hypertension or atrial fibrillation were excluded.

All subjects were taking inhaled bronchodilators but not oral or inhaled steroids, and a constant dose of furosemide (median dose, 40 mg/d, range, 20 to 80 ma) for at least 2 weeks. Five patients used domiciliary oxygen for at least 15 h/d and medications were unchanged throughout the study period.

In this group of study patients, [FEV.sub.1] in liters was 0.67 [+ or -] 0.08 (range, 0.36 to 1.11), [FEV.sub.1] as percent of predicted was 30.1 [+ or -] 3.9 (range, 21 to 48), and [FEV.sub.1]/FVC ratio was 41 [+ or -] 4.1% (range, 30 to 65). Alveolar gas exchange as measured by carbon monoxide transfer factor (Dco) was impaired at 4.4 [+ or -] 1.5 mL/min/mm Hg (range, 1.54 to 8.5) while Pa[O.sub.2] on air was 6.70 [+ or -] 0.23 kPa (range, 5.56 to 7.32) and Pa[CO.sub.2] on air was 5.78 [+ or -] 0.46 kPa (range, 4.56 to 8.05). MPAP at screening was 34.4+/-1.6 mm Hg (range, 27 to 40) and decreased with 60% oxygen by 27.3 [+ or -] 5.0% (range, 18 to 48).

Study Protocol

All subjects gave informed written consent to the study protocol previously approved by the Tayside Committee for Medical Research Ethics.

Subjects were studied at the same time of day on two occasions at least 1 week apart. On each study day, IV cannulas were sited in each forearm for peptide infusion (left) and blood sampling (right). Subjects then remained semirecumbent throughout and were studied breathing room air. An initial rest period of at least 30 min was allowed to reach steady-state baseline hemodynamic parameters ([T.sub.0]). A 20-min placebo was then given ([T.sub.20]) before commencing an infusion of either human ANP or human BNP (Clinalfa Laufelfingen, Switzerland) at 3 pmoll/kg/min for 20 min ([T.sub.40]) then 10 pmol/kg/min for 20 min ([T.sub.60]) Active treatment infusions were given in random order and hemodynamic parameters were measured and blood samples taken at baseline ([T.sub.0]), after placebo infusion ([T.sub.20]), and after low- ([T.sub.40]) and high- ([T.sub.60]) dose ANP or BNP infusion.

Measurements

Oxygenation: Arterial blood oxygen saturation was continuously monitored by transcutaneous oximetry (CSI 503; Criticare Systems Inc; Waukesha, Wis).

Systemic Hemodynamics: Heart rate (HR) was recorded on an ECG trace, and rate over 1 min was averaged. Mean arterial blood pressure (MAP) was measured by semiautomatic sphygmomanometer (Vital Signs Monitor; Critikon; Tampa, Fla). Using pulsed-wave Doppler echocardiography (Vingmed SD50; Vingmed Sound; Horten, Norway), the aorhc systolic velocity integral was measured from aortic blood flow at the left subcostal positron by on-line computer-assisted determination having previously measured aortic cross-sectional area by M-mode echocardiography (Vingmed SD50).[16] On-line calculations of stroke volume (SV=systolic velocity integralxcross-sectional area) and cardiac output (CO) as the product of SV and HR could then be made.[16] Total systemic vascular resistance (SVR) was also calculated as follows: SVR=MAP/COx80 dynexsx[cm.sup.-5]. Reproducibility of the Doppler method was assessed in patients with cor pulmonale by repeated measurements after 30 min (short term) and after 1 week (long term). The shortterm coefficient of variability (CV) for determination of SV was 4.9% and for CO was 6.2%. Long-term CV for SV was 7.4% and for CO was 9.5%.

Pulmonary Hemodynamics: Pulmonary arterial flow was analyzed by pulsed-wave Doppler echocardiography (Vingmed SD50) from the subcostal positron to measure the pulmonary acceleration time (PAT), being time in milliseconds from the onset of pulmonary flow to peak velocity. A stable pulsed-wave Doppler signal over at least 1 min was recorded onto videotape and analyzed at the end of the study with the mean of 3 consistent waveforms at each time point used for the purpose of analysis. MPAP in mm Hg was then calculated as MPAP=90-(0.62xPAT) as described by Dabestani et al,[17] although the same method has also been used by a number of other workers.[18,19] Total PVR was also calculated as follows: PVR=MPAP/COx80 dynexsx[cm.sup.-5]. Reproductibility was assessed as before and short-term CV for measurement of PAT was 1.9% and for MPAP was 3.0% while long-term CV for PAT was 2.9% and for MPAP was 4.6%.

Laboratory Analyses: Samples for measurement of plasma aldosterone were collected into chilled lithium-heparin tubes and centrifuged at 4[degrees]C immediately. Separated plasma was stored at -20[degrees]C until assayed in duplicate at the end of the study. Assays were performed using a commercially available radioimmunoassay kit (Sorin Biomedica; Saluggia, Italy). The intra-assay CV for analysis was 8.3%. Plasma ANP and BNP were measured from venous blood collected in EDTA tubes containing 4,000 KIU aprotinin (Trasylol; Bayer; Newbury, UK) before centrifugation at 4[degrees]C and serum stored at -70[degrees]C. Assays were performed in duplicate at the end of the study after solid-phase plasma extraction with C18 cartridges, giving 86% extraction efficiency, using commercially available radioimmunoassay kits (Peninsula Laboratories Inc; Belmont, Calif., The intra-assay CV for assay of ANP was 8.0% and for BNP was 9.9%.

Data Analysis

All comparisons were made by multifactorial analysis of variance followed, where significant, by Duncan's multiple range testing.[20] A probability value of p<0.05 was considered to be significant. Data are presented as means and SEM, and where a significant difference between means is quoted, the 95% confidence interval (CI) for this difference is also given. Results are given in the text as change from baseline, while the figures depict absolute values.

RESULTS

Baseline oxygen saturation was similar on both study days (90.9 [+ or -] 0.9% vs 89.4 [+ or -] 1.5%) and was unchanged during placebo and during ANP or BNP infusion (89.4 [+ or -] 1.3% after high-dose ANP, 89.1 [+ or -] 1.7% after high-dose BNP). Plasma levels of ANP increased from 18.4 [+ or -] 2.3 pmol/L after placebo infusion to 37.5 [+ or -] 4.4 pmol/L following low-dose infusion and to 91.6 [+ or-] 18.3 pmol/L following high-dose infusion. Plasma levels of BNP after placebo (4.2 [+ or -] 0.3 pmol/L) were significantly lower than ANP levels at the same time point but increased significantly following low-dose infusion (21.2 [+ or -] 4.2 pmol/L) and high-dose infusion (54.7 [+ or -] 13.4 pmol/L) to molar concentrations statistically similar to the ANP levels achieved at equivalent infusion doses.

Pulmonary Hemodynamics

Baseline MPAP was similar on each study day and was not significantly affected by placebo infusion either before ANP or BNP infusion (Fig 1, top). Infusion of low-dose ANP significantly reduced MPAP by 3.7 [+ or -] 1.1 mm Hg from baseline (95% CI, 1.4, 6.1) while highdose ANP infusion caused a further significant reduction in MPAP by 7.1 [+ or -] 1.1 mm Hg from baseline (95% CI, 4.8 to 9.4) (Fig 1, top). BNP infusion had similar dose-related effects, reducing MPAP from baseline following low-dose infusion by 3.0 [+ or-] 1.1 mm Hg (95% CI, 0.6 to 5.4) and following high-dose BNP by 7.1 [+ or -] 1.6 mm Hg (95% CI, 4.7 to 9.6) (Fig 1, top). The effects of both doses of ANP and BNP were significantly different from placebo and in comparison with the fall in MPAP in response to 60% oxygen (27 [+ or -] 5%), infusion of ANP and BNP reduced MPAP by a maximum of 20 [+ or -] 3% and by 21 [+ or -] 5%, respectively.

PVR was also similar at baseline on each study day and did not change significantly during placebo infusion prior to either ANP or BNP infusion (Fig 1, center). ANP infusion at low dose reduced PVR from baseline by 47 [+ or -] 18 dynexsx[cm.sup.-5] (95% CI, 7 to 87) and at high dose by 98 [+ or -] 32 dynexsx[cm.sup.-5] (95% CI,61 to 136) (Fig 1, center). The effects of BNP were similar where low-dose infusion reduced PVR from baseline by 61 [+ or -] 26 dynexsx[cm.sup.-5] (95% CI,25 to 97) and at high dose by 128 [+ or -] 30 dynexsx[cm.sup.-5] (95% CI, 92 to 163) (Fig 1, center). The effects of both doses of ANP and BNP were significantly different from placebo.

There were no significant differences between the effects of ANP and BNP on MPAP or PVR at either dose level.

Systemic Hemodynamics

Baseline conditions were similar on both study days for all of the systemic hemodynamic parameters measured (Table 1). Infusion of placebo did not affect any of these parameters while low- and high-dose ANP or BNP had no significant systemic hemodynamic effects (Table 1).

[TABULAR DATA 1 OMITTED]

Plasma Aldosterone

Mean plasma aldosterone levels were elevated at baseline on both study days (laboratory reference range <415 pmol/L). During placebo infusion, there was a nonsignificant fall in aldosterone levels on both study days; ANP day -78 [+ or -] 23 pmol/L from baseline, BNP day -48 [+ or -] 30 pmol/L from baseline (Fig 1, bottom). Both doses of ANP significantly lowered aldosterone levels compared with baseline or placebo with a significant difference between the two doses of ANP: change from baseline at low dose was 156 [+ or -] 48 pmol/L (95% CI, 93 to 220) and at high dose was 275 [+ or -] 57 pmol/L (95% CI, 207 to 343) (Fig 1, bottom). BNP had weaker effects where although low-dose infusion reduced plasma aldosterone levels significantly from baseline by 92 [+ or -] 36 pmol/L (95% CI, 30 to 153), this was not significantly different from the effect of placebo. High-dose BNP, however, did significantly reduce aldosterone levels from baseline in comparison with placebo, by 159 [+ or -] 55 pmol/L (95% CI, 98 to 220) (Fig 1, bottom). The decrease in plasma aldosterone levels following high-dose ANP infusion was significantly greater than that observed following high-dose BNP, although no differences between ANP and BNP were observed at the lower dose.

DISCUSSION

In the present study, we have demonstrated for the first time (to our knowledge) that BNP, like ANP, has pulmonary vasorelaxant activity in patients with cor pulmonale and that both these peptides exert favorable suppressive effects on the RAAS in terms of aldoster one levels in these patients. We have also shown that ANP and BNP have pulmonary vasodilator efficacy approaching that observed with the same method in response to 60% oxygen. Although a number of studies have demonstrated the vasorelaxant properties of ANP and BNP in human pulmonary vessels in vitro[3] and in vivo,[13] only ANP has been studied in this respect in cor pulmonale. Our study is unique, therefore, in that we have compared the hemodynamic activity of the two known cardiac natriuretic peptides, ANP and BNP, as well as being the first to document their actions on the RAAS in cor pulmonale. We are therefore able to discuss the physiologic roles of ANP and BNP as counterregulatory hormones in cor pulmonale in terms of both their hemodynamic and their hormonal properties.

Direct comparison with previous studies, however, is difficult, as even at the same infusion rate (10 pmol/ kg/min), we achieved higher plasma ANP levels and greater pulmonary vasodilatation than was observed in the study of Rogers et al.[15] This may be because we have used pharmaceutical-grade peptides rather than filtered chemical grade compound which have the attendant risks of peptide loss during the filtration process and during storage in a solution that may be less than stable. It is also possible that the patients we selected had greater capacity for vasodilatation as we specifically excluded subjects who did not have demonstrable pulmonary vascular reactivity to short-term oxygen therapy. We believe that it is important that those included had at least some dynamic component to their pulmonary hypertension, a situation analagous to studying bronchodilator therapy where the degree of airway reversibility is established before assessing the impact of therapy.

In terms of methodologic differences, the results obtained by invasive methods are very similar to our own both in the nature and magnitude of the observed changes in response to ANP infusion.[14,15] Thus, we believe that the Doppler method employed is applicable as a quantitative and highly reproducible measure of pulmonary hemodynamic changes in this setting. Indeed, these methods have been shown previously to accurately measure changes in pulmonary artery pressure in response to hypoxemia[18] as well as to give measurements that correlate well with invasive measurement across a wide range of pulmonary artery pressures.[17,19]

Thus, although there are differences in the magnitude of change in some of the parameters, it is interesting to note some concordant findings. As has been observed previously,[15] there were no significant systemic hemodynamic changes during ANP infusion in our study. This phenomenon of relative pulmonary selectivity may be important in terms of therapeutic potential, where the efficacy of many vasodilator substances in the pulmonary vasculature is limited by intolerable systemic hemodynamic upset. An additional concern when using vasodilator drugs in hypoxemic patients is the possibility of worsening hypoxemia through an increase in ventilation/perfusion mismatching.[21] It is therefore reassuring to note in previous studies that oxygen saturation was not adversely affected by ANP infusion,[15] which was also the case for both ANP and BNP in the present study. Some workers have noted that ANP actually improves oxygenation during acute hypoxia,[22] further enhancing the possibility of finding a therapeutic niche.

In the present study, ANP and BNP appeared equipotent in terms of ability to reduce pulmonary vascular tone, in contrast to our previous findings in normal volunteers where BNP appeared to have greater pulmonary vasorelaxant activity than ANP.[13] This may indicate that both ANP and BNP have a counterregulatory role in cor pulmonale. ANP is released acutely in response to atrial stretching[6] and would appear in teleologic terms to be ideally suited to attenuating acute increases in right ventricular eg, in response to hypoxemia.[23] BNP synthesis by ventricular myocytes, however, is only stimulated after a more prolonged increase in right ventricular afterload[7,24] and may therefore be more important than ANP as a regulator in the longer term. The finding that both these peptides can still produce significant pulmonary vasodilatation in cor pulmonale indicates that it is important to consider BNP and ANP when discussing possible therapeutic strategies.

Although RAAS suppression by ANP in cor pulmonale has been noted previously,[14] the hormonal effects of BNP are unknown. ANP and BNP were similar in hemodynamic efficacy, but ANP was significantly more effective in terms of lowering plasma aldosterone levels. We have previously observed this pattern in the aldosterone response to angiotensin II in normal subjects, where on a molar basis, ANP had significantly greater hormonal effects than BNP.[4] As both ANP and BNP are equipotent agonists of the type A natriuretic peptide receptor,[2] these effects are difficult to explain. The additional effects of ANP on the type C receptor[25] or a further uncharacterized receptor subtype in the adrenal gland may be responsible.

In any case, both the natriuretic peptides studied had beneficial effects on plasma aldosterone levels. This property may be important in attenuating the overactivity of the RAAS observed in cor pulmonale.[26] By lowering plasma aldosterone levels, ANP and BNP may act to prevent excessive salt and water retention, which may well be important as a precipitating or exacerbating factor in acute exacerbations of cor pulmonale.[27] The RAAS also has significant trophic effects on vascular and cardiac muscle,[28] a process that is also directly inhibited by ANP.[29] Whether lowering plasma aldosterone levels to the extent seen in the present study is sufficient to inhibit these mitogenic effects is unknown but may be important in arresting the cardiopulmonary remodeling that characterizes this condition.[30]

As these hemodynamic and hormonal effects of ANP and BNP appear beneficial, it is worth considering the potential of the natriuretic peptides as therapeutic agents. ANP and BNP are not orally active and must therefore be given IV which, although possible in the short term (eg, during acute exacerbations), is inconvenient. For this reason, much interest has centered on the neutral endopeptidase (NEP) inhibitors that inhibit the metabolism of the natriuretic peptides. Although animal studies have shown attenuation of cardiopulmonary remodeling during hypoxia,[31] no studies using NEP inhibitors in patients with cor pulmonale have been carried out (to our knowledge). It would also appear that some of the NEP inhibitors have less of an effect on BNP than on ANP.[32] In view of the present findings, it would be important to use an agent that increased both ANP and BNP levels like candoxatril,[33] although some workers claim that NEP inhibitors may be effective at receptor level without affecting plasma natriuretic peptide levels.

Thus, in considering the therapeutic implications from our study, we believe that it is important to consider the roles of both ANP and BNP. These roles appear to differ not only in their time scale but also in their relative effects on hemodynamic and hormonal parameters in these patients. Further studies should now assess the long-term effects of manipulating the natriuretic peptides in cor pulmonale and clarify their potential role in a condition where current best treatment remains unsatisfactory.[34] Although supplemental oxygen therapy does reduce mortality in these patients, this treatment is expensive, onerous, and does not alter the underlying disease process. Whether the natriuretic peptides would achieve further pulmonary vasodilatation during oxygen therapy and whether this would impact on morbidity or mortality are two important questions that should now be addressed.

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(*) From the Department of Clinical Pharmacology, University of Dundee, ScotEand. ([dagger]) Currently at Department of Cardiology, Aberdeen Royal Infirmary Foresterhlll Aberdeen, Scotland. Manuscript received January 18, 1996; revision accepted May 2.

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