Norepinephrine infusions in congestive heart failure

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of VT in this case. Recently, Waxman et al3 reported 9 patients with VT that could be terminated by a Valsalva maneuver. They postulated that the termination was due to an abrupt reduction of cardiac size. The VT in this patient is unique in that not only the termination, but also the initiation of the VT were closely related to LV size.

Norepinephrine Infusions in Congestive Heart Failure STEVEN R. GOLDSMITH, MD GARY S. FRANCIS, MD JAY N. COHN, MD Norepinephrine (NE) levels are frequently increased in patients with congestive heart failure (CHF).l12 The significance of high circulating NE levels in patients with CHF is unknown. To provide data concerning the effects of an increase in plasma NE on hemodynamic function and plasma renin activity in CHF, we measured these variables in responseto an infusion of exogenous NE in a group of 8 patients with CHF. Overall, the results do not suggest an important effect of circulating NE on either hemodynamic variables or plasma renin activity in CHF. Eight patients participated in these studies. All patients had chronic CHF (New York Heart Association Functional Class II or III) of at least several months’ duration but were in clinically stable condition at the time of study. Four had primary and 4 had ischemic cardiomyopathy. All had enlarged hearts on chest radiograph and decreased ejection fractions by either radionuclide scanning or echocardiography. All were receiving digitalis and diuretic therapy and some were taking vasodilators. None was taking al-blocking agents. All medications other than antiarrhythmic drugs were withheld on the day of study. After all patients gave informed consent, hemodynamic monitoring was instituted with the patient in the postabsorptive state. After at least 30 minutes of rest following placement of Swan-Ganz and arterial catheters, baseline hemodynamic measurements were made and repeated 15 minutes later. If these values were within 10% of one another they were accepted as basal, with averaged values used as control measurements. Blood was then drawn from the arterial catheter for determination of plasma NE and ienin activity. An infusion of Levophed@ (L-NE) was then begun into a peripheral vein at 0.1 pg/min and subsequently increased to 0.5 pg/min, and then to 1.0,1.5 and 2.5 pgcglmin. Each infusion rate was maintained for 20 minutes, with hemodynamic measurements made between the 10th and 20th From the Cardiovascular Division, University of Minnesota School of Medicine, Minneapolis, Minnesota. This study was supported by Grant HL22977-03 from the National Heart, Lung, and Blood Institute, Bethesda, Maryland, and by a research grant from the Veterans Administration, Washington, D.C. Manuscript received February 13, 1985; revised manuscript received May 10, 1985. Accepted May 13, 1985.

References 1. Peters M, Penner SL. Orthostatic ventricular tachycardia. Am Heart J 1946;32:645-652. 2. Waxman MB, Wald RW. Termination of ventricular tachycardia by an increase in cardiac vagal drive. Circulation 1977$56:3X-39 1. 3. Waxman MB, Wald RW, Finley JP, Bonet JF, Downar E, Sharma AD. Valsalva termination of venkicutar tachycardia. Circulation 1980;62:843-851. 4. Bevegard S, Holmgren A, Jonsson 6. Circulatory studies in well-trained athletes at rest and during heavy exercise, with special reference to stroke volume and influence to b&y position. Acta Physiol Stand 1963;57:26-50.

minute of each stage, and blood resampled for NE and renin just before increasing to the next level. At the conclusion of the 2.5uglmin infusion, blood was sampled a final time and the study concluded. Plasma for NE analysis was separated immediately by cold centrifugation, frozen and stored at -2O”Ffor later analysis by radioenzymatic assays; in our laboratory this has an interand intraassay coefficient of variation under 8%. Plasma renin activity was measured by radioimmunoassay with similar reliability in our laboratory. All data were analyzed using analysis of variance for repeated measures on the same elements. Baseline hemodynamic variables in those patients with CHF included a heart rate of 79 f 8.5 beatslmin, mean arterial pressure of 79 f 10 mm Hg, cardiac index of 2.5 f 0.56 liter/min/m2 and systemic vascular resistance of 1,272 f 311 dynes cmm5. Right atria1 pressure was 12 f 7 mm Hg and left ventricular filling pressure, estimate from either one pulmonary capillary wedge or pulmonary artery diastolic pressure, was 26 f 5 mm Hg. None of these variables changed significantly in response to the increase in plasma NE levels from 730 f 368 pglml (baseline) to 2,532 f 1,326pglml at the 2.5 pglmin level (Fig. 1). Plasma renin activity, 1.5 f 0.54 nglmllhour, also did not change during the infusion.

These observations indicate that exogenous infusions of L-NE, which produce plasma levels comparable to those found during maximal exercise,5 do not cause significant hemodynamic effects in patients with CHF. Silverberg et al6 and Izzo (7) showed that in normal subjects, 2-fold or greater increases in plasma NE levels do raise blood pressure and reduce heart rate. Since with comparable or greater absolute and relative increases in plasma NE over baseline in heart failure we saw no hemodynamic changes, our data suggest a blunted peripheral vascular response to circulating NE in this condition with the lack of reflex bradycardia as a consequence. A blunted blood pressure response to infused NE could be ,a consequence of “down regulation” of oiadrenergic receptors exposed to the chronically high levels of NE found in patients with CHF.122 Such down regulation has recently been demonstrated in vascular smooth muscle.8 Alternatively, the blunted response could be due to changes in number or sensitivity of peripheral as-adrenergic receptors, because they also may influence peripheral vascular resistance and may be more responsive to circulating as opposed to neuronally released NE.g Platelet 012 receptors are decreased in CHF,1° although we have no direct information concerning the postsynaptic cy2 receptor. Overall, down regulation of a! receptors would not be surprising in,

November

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CI (l/min/m2) FIGURE 1. Response of plasma norepinephrine (PNE), plasma renin activity (PRA), heart rate (HR), mean arterial pressure (MAP), cardiac index (Cl), systemic vascular resistance (SVR) and left ventricular filling pressure (LVFP) to exogenous norepinephrine infusions in patients with congestive heart failure (n = 8). Values are expressed as f standard error of the mean. NS = not significant; RAP = right atrial pressure.

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patients with CHF in view of the well documented down regulation of p receptors in this condition.i1J2 The lack of hemodynamic effects during an exogenous NE infusion does not necessarily bear on the effects of endogenously released NE in patients either in the basal state or during stress. Plasma NE measured during endogenous stress represents only a small fraction of total NE released, because most is either taken up into the presynaptic nerve terminal or immediately metabolized in the synaptic cleft.i3 Hence, a given plasma level of NE produced by endogenous stress represents a much higher total NE response than that produced by an infusion. Nonetheless, these,data do show that circulating NE itself, at the levels produced here, does not have a marked circulatory effect in patients with CHF. Any contribution of plasma NE as a circulating hormone to the vasoconstriction produced by a stimulus such as exercise is therefore likely to be minimal. The fact that vasoconstriction in nonexercising muscle beds does occur during exercise in patients with CHF,14 strongly militates against another possible explanation for the current results-that NE-induced vasoconstriction is maximal or near-maximal in the basal state and therefore not amenable to further change by exogenously increased levels of circulating NE. Also in opposition to this interpretation is the observation that patients with CHF can respond in normal or even exaggerated fashion to infusion of another vasoconstrictor such as vasopressin.15 There was also no change in plasma renin activity during the infusions. Because plasma renin levels were essentially normal in this group of stable patients, it is unlikely that excessive baseline stimulation would account for the lack of response to the infused NE. Also, because there were no significant hemodynamic effe&s, a reflexly mediated decrease in renin activity probably did not offset any direct stimulation. Again, because synaptic cleft NE levels may be much higher than those in the plasma, circulating plasma NE levels in the range produced here may not be adequate to stimulate renin

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release by adrenergic mechanisms. However, as with the lack of vasoconstrictor response, an alternative possibility is down regulation of the renal ,8 receptors responsible for mediating sympathetically induced renin release. This interpretation is buttressed by Izzo’s study in normal subjects7 in whom small changes in NE were associated with clear increases in plasma renin activity. In summary, infusions of L-NE, which produced plasma NE levels of approximately 2,500 pg/ml, were without significant effects on either hemodynamic variables or renin activity in 8 patients with CHF. Although the role of endogenous sympathetic stimulation on hemodynamic variables and renin release is not resolved, the results do suggest a lack of any important effect on these variables from plasma levels of NE per se, and may point to altered peripheral adrenergic receptor activity in patients with this disease. Acknowledgmenti We thank Susan Ziesche, Dennis Lura and Terry Cameron for their technical help in performing the studies; Ada Simon for performing thk tiorepinephrine and renin determinations; Darryl Erlien for help with the statistics and graphics, and Belinda Anderson for preparing the manuscript.

1. Thomas

JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978:41:233-243. 2. Levine TB, Franci; GS, Goldsmith SR, Simon A, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol 1982;49:1659-1665. 3. Passon PG, Peuler JD. A simplified radiometric assay for noreplnephrine and epinephrine. Anal Blochem 1973;51:618-631. 4. Sealey JE, Gerten-Elenes J, Laragh JH. The renin system: variations in men T;;,sured by radioimmunoassay or bioassay. Kldncy Int 1972;1:2405. Francis GS, Goldsmiyh SR, Ziesche SM, Cohn JN. Response of plasma norepinephrine and epinephrine to dynamic exercise in patients with congestive heart failure. Am J Cardiol 1982;49:1152-1156. 6. Silverberg AB, Shah SD, Haymond MW, Cryer B. Norepinephrine hormone and neurotransmitter in man. Am J Physiol-1978;234:E252-E256. 1. lzzo J. Cardiovascular hormonal effects of circulating norepinephrlne. Hypertension 1983;5:787-789. 8. Colucci WS! Gimbrone MA, Alexander WA. Regulation of the post-synaptic a-adrenerglc receptor in rat mesenteric artery. Effects of chemical sympathectomy and epinephrine treatment. Cird Res 1961;48:104-111.

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PA, Timmermans

PB. Cardiovascular alpha-2 receptors. J 1983:15:717-733. 10. Weiss RJ, Tobes M, Wertz CE, Smith CB. Platelet’alpha-2 adrenoreceptors in chronic congestive heart failure. Am J Cardiol 1983;52:101-105. 11. Colucci WS, Alexander RW, Williams GD. Decreased lymphocyte beta receptor density in’patients with heart failure and tolerance to the beta adrenergic agonist pirbuteral. N Engl J Med 1981;305:185-,190. 12. Bristow MR, Ginsburg R, Minobe WB. Decreased catecholamine sensitivity and bets adrenergic receptor density in failing human hearts. N Engl J Med Mol Cell Cardiol

Upright Paradoxicgl posterior Wall Movement iri Mitral Valve Prolapse JACK KRAFCHEK, MD MARY SHAW, RDMS JOSEPH KISSLO, MD

Upright exercise 2-dimensional echocardiography (2-D echo) is being used frequently to evaluate patients with suspected coronary artery disease (C!AD).l As with other techniques, this diagnosis is suggested when segmental wall motion abnormalities appear with exercise. We have noted the spontaneous development of high posterior wall’motion abnormalities during casual upright From the Department of Medicine, Division of Cardiology, Duke University Medical Center, Durham, North Carolina 2771O.,This study was Supported in part by Grants HL-12715, CA-37586.and HL-07063 from the U.S. Public Health Service, Bethesda, Maryland: Manuscript received February.28 1985;,revised manuscript received April 19, 1985, accepted April 23, 1985.

1982;307:205-211.

13. Esler M. Assessment

of sympathetic nervous function in humans from plasma kinetics. Clin Sci 1982;62:247-254. 14. Zelis R. Nellis S. Conahursl J, Lee G. Mason D. Abnormalities in regional circulations accompanying congestive heart failure. Prog Cardiova& Dis 1975;18:181-199. noradrenallne

15. Goldsmith

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vasopressin in patients 1984;7O:suppl ll:ll-192.

AW, Cohn JN. Hemodynamic

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2-D echo that were not present in the study during supine rest. These abnormalities appeared to be more obvious in patients with known or suspected mitral valve prolapse (MVP). This study documents the prevalence of a postural phenomenon in patients with MVP. Forty-six subjects were studied and were separated into 2 groups on the basis of the absence or presence of MVP by 2-D echo. MVP by 2-D echo was defined as systolic movement of 1 or both of the mitral valve leaflets into the left atrium and breaking the plane of the mitral valve anulus.2 The non-MVPgroup consisted of 19 normal volunteers, aged 20 to 48 years (mean 33). The MVPgroup consisted of 27 persons, aged 22 to 45 years (mean 30), with definite auscultatory and 2-D echocardiographic evidence for MVP (15 with clicks alone and 12 with clicks and late systolic murmurs). No person had historical, physical or electrocardiographic evidence for CAD or any other form of heart disease and, except for findings of MVP, the 2-D echocardiographic results were normal. Except for 3 subjects with MVP who were receiving diuretic drugs, the study population was free from medication. Complete 2-D echocardiographic examinations in all standard views were performed with the patient in the re-

FIGURE 1. Composite long-axis recumbent views in diastole (R-D) and systole (R-S) as well as standing diastole (S-D) and systole (S-S) from a patient in group II, with more extensive changes during standing systole (open arrows, panel S-S). Black arrows indicate position of posterior mitral anu: Ms. Ao = aortic root; DAo = descending aorta; LA = left atrium; LV = left ventricle.