Search

Patients with heart failure have impaired baroreflex control of the peripheral circulation with attenuated vasoconstrictor response during orthostatic stress. The aim of this study was to test if this impaired baroreflex control not only affects the arterial, but also the capillary bed. Blood flow and capillary filtration were measured in the forearm (plethysmography) in 7 normal subjects and 7 patients with mild congestive heart failure (New York Heart Association functional class II). Measurements were done with the subjects supine and during head-up tilt at 45 [degrees]. While supine, forearm vascular resistance and capillary filtration coefficient did not differ significantly between the groups. In the control subjects, tilt decreased capillary filtration coefficient by 14 [+ or -] 3% (p Orthostatic stress in congestive heart failure is accompanied by attenuation of the normal peripheral vasoconstrictor response.[1-5] Studies in both animal models of heart failure and in patients with heart failure have suggested that abnormal vascular response to orthostatic stress can be attributed to impairment of both arterial and cardiopulmonary baroreflexes.[3-11] Most of these earlier studies have focused on the effects of this impaired reflex control on the arteriolar bed. However, the role of this impaired reflex control on the peripheral capillary bed has not been investigated. Accordingly, we hypothesized that attenuation of the peripheral vasoconstrictor response to orthostatic stress in heart failure might be associated with an increase of water filtration in the capillary bed -- a potential mechanism for formation of peripheral edema in patients with heart failure. To test this hypothesis we measured forearm transcapillary water filtration in patients with congestive heart failure and in normal control subjects in the supine position and during 45 [degrees] head-up tilt. METHODS Subjects: We studied 7 patients (6 men and 1 woman, aged 44 to 62 years) with mild heart failure (New York Heart Association functional class II, ejection fraction 25 [+ or -] 3%, mean [+ or -] SEM). Patient with severe heart failure were excluded to allow comparison of baseline hemodynamics with those obtained from the control subjects.[12] All medicine, except digoxin and diuretic drugs, were discontinued 2 weeks before the study. The cause of heart failure was coronary artery disease, diagnosed by cardiac catheterization. No patient had myocardial infarction [is greater than or equal to] 12 weeks before the study. All patients were in sinus rhythm and had normal electrolytes. Seven healthy subjects (6 men and 1 woman, aged 32 to 50 years) served as control subjects. Informed consent was obtained from all subjects and the protocol was approved by the ethical committee in Copenhagen County, Denmark. Hemodynamic measurements: Forearm blood flow was measured using venous occlusion plethysmography (mercury-in-Silastic strain gauge).[13] The forearm was elevated 10 cm above the level of the right atrium to collapse the veins and the strain gauge was positioned on the greatest circumference of the forearm. The blood flow, expressed as ml/min [.] 100 g was measured every 15 seconds. Heart rate was obtained from an electrocardiogram. Arterial pressure was measured every 30 seconds by an automated sphygmomanometer (Dinamap, Criticon, Tampa, Florida). Mean arterial pressure was calculated as diastolic pressure plus 1/3 of pulse pressure. Forearm vascular resistance, expressed in units (U), was calculated as mean arterial pressure divided by blood flow. Capillary filtration rate was measured 10 minutes after the last flow measurement according to earlier descriptions of the method.[14,15] Briefly, the venous occlusion cuff was inflated for 10 minutes and the increase in forearm circumference was recorded. The increase in venous pressure causes an increase in tissue volume, consisting of an initial rapid phase followed by a slow phase. The initial phase (3 to 4 minutes) reflects pooling of blood in the vessels, whereas the subsequent slower increase in tissue volume is due to interstitial fluid accumulation produced by transcapillary water filtration.[16] Venous pressure was measured from a forearm vein catheter positioned in close proximity to the strain gauge and monitored by a Statham P23DB pressure transducer (Spectramed, Oxnard, California). The capillary filtration coefficient, expressed in ml/min . mm Hg . 100 g, was calculated from the linear slope obtained 5 minutes after the occlusion cuff was inflated, divided by the mean capillary pressure, taken to be 80% of the venous pressure.[17] Both intra- and extravascular colloid pressure were assumed to be unchanged.[18] Protocol: Subjects were placed in the supine position on a tilt table. The room temperature was 24 [degrees] C Thirty minutes elapsed between the experimental setup and data collection. Measurements were performed in the supine position, and repeated after 10 minutes in the 45 [degrees] head-up tilted position. Upper rather than lower extremities were used to examine orthostatic changes in capillary filtration to avoid the confounding effects of hydrostatic pressure changes. Statistical analysis: The Wilcoxon test was used for paired comparisons and the Mann-Whitney test for nonpaired comparisons. The level of significance was chosen as 0.05. Values are given as mean [+ or -] SEM. RESULTS Normal subjects and patients with heart failure: An original record illustrating the increase in the forearm volume in response to increased venous pressure is shown in Figure 1. Supine mean arterial pressure, forearm blood flow, forearm vascular resistance and capillary filtration did not significantly differ between the 2 groups (Table I). [TABULAR DATA I OMITTED] Perturbation of baroreceptors: The peripheral vascular responses to tilt are shown in Figures 2 and 3. In normal subjects vascular resistance increased from 24 [+ or -] 5 to 45 [+ or -] 9 U (p DISCUSSION The principal new finding in this study is that orthostatic stress in patients with mild heart failure increases the forearm capillary filtration coefficient, in contrast to the decrease seen in control subjects. Our data confirm and extend previous studies[1-5]; we confirmed that patients with heart failure have an attenuation of the normal orthostatic-induced vasoconstrictor response, and extend this observation by showing that the normal orthostatic-induced decrease in capillary filtration is replaced by an increase in capillary filtration. We suggest a reflexogenic, i.e., nonhumoral, explanation for the accumulation of excess water in peripheral tissues, typical for the patients with heart failure. Potential mechanisms for orthostatic-induced increased capillary filtration coefficient in patients with heart failure: We can only speculate on the underlying mechanism(s) for the observed orthostatic-induced increase in capillary filtration in patients with heart failure. Our control subjects were younger than our patients; however, the fact that the peripheral hemodynamic responses were qualitatively, not quantitatively, different, makes it unlikely that our data can be explained by age. It is more likely that our data potentially can be ascribed to structural changes of the capillary wall, hormonal factors, or reflex mechanism(s) regulating the precapillary sphincters. First, structural changes of the capillary wall in patients with heart failure[19,20] seems an unlikely explanation, since supine values of capillary filtration were lowest in the patients. Second, it is well established that heart failure is associated with changes in plasma hormones.[21] In this respect angiotensin and atrial natriuretic peptide are the 2 most likely candidates[22-26] to influence the capillary filtration. Angiotensin constricts both precapillary arterioles and postcapillary venules,[23] whereas the natriuretic peptide causes increases in both blood flow[26] and in capillary filtration.[27] However, studies in patients with mild heart failure have reported normal values of angiotensin, both at baseline and in response to orthostatic stress[24,25]; although the supine plasma level of atrial natriuretic peptide is known to be elevated in heart failure,[26] this peptide concentration decreases, not increases, during tilt.[28] During measurements of capillary filtration, the increase in venous pressure evokes the venoarteriolar reflex,[29] known to decrease filtration.[30] However, this reflex cannot explain the tilt-induced differences in capillary filtration, because the reflex retains normal function in patients with heart failure.[31] Head-up tilt of 45 [degrees] unloads both arterial and cardiopulmonary baroreceptors,[32-35] which in patients with heart failure is associated with attenuation of the normal reflex vasoconstriction.[1-4,31] Thus, a more likely mechanism for the tilt-induced increase in capillary filtration in patients with heart failure seems to be abnormal reflex control of peripheral circulation. There are several lines of evidence to support this. First, animal studies have demonstrated that capillary filtration is under cardiovascular reflex control.[36,37] This was supported by direct evidence showing sympathetic innervation of precapillary sphincters ('terminal arterioles') that dilated in response to baroreceptor stimulation.[38] Second, other studies have shown a [Beta]-adrenergic vasodilator reflex in cats that mainly affects microcirculation and increases capillary filtration.[39,40] This [Beta]-adrenergic reflex has also been shown to control capillary filtration during other challenges to the circulation, e.g., hemorrhagic shock.[41,42] In line with these findings, a study in patients with heart failure has suggested that the attenuated vasoconstrictor response to tilt also is mediated by a [Beta]-adrenergic reflex mechanism.[31] Although the tilt-induced changes in capillary filtration were small, the directional changes were consistent from one subject to the other, producing a robust directionally opposite pattern of capillary filtration response to orthostatic stress in the 2 groups. Acknowledgment: We are grateful to P. Fritz Hansen, MD, PhD, for his continued support and review of our work, and to Richard A. Cooley, Ronald G. Victor, MD, and Paul A. Grayburn, MD, for their helpful comments and critical reading of this manuscript. [1] Brigden W, Sharpey-Schafer EP. Postural change in peripheral blood flow in cases with left heart failure. Clin Sci 1950;9:93-100. [2] Levine TB, Francis GS, Goldsmith SR, Cohn JN. The neurohumoral and hemodynamic responses to orthostatic tilt in patients with congestive heart failure. Circulation 1983;67:1070-1078. [3] Goldsmith SR, Francis GS, Levine TB, Cohn JN. Regional blood flow response to orthostasis in patients with congestive heart failure. J Am Coll Cardiol 1983;1: 1391-1395. [4] Ferguson DW, Abboud FM, Mark AL. Selective impairment of baroreflex-mediated vasoconstrictor responses in patients with ventricular dysfunction. Circulation 1984;69:451-460. [5] Eckberg DL, Drabinsky M, Braunwald E. Defective cardiac parasympathetic control in patients with heart disease. N Engl J Med 1971;285:877-883. [6] Ferguson DW, Berg WJ, Roach PJ, Oren RM, Mark AL. Effects of heart failure on baroreflex control of sympathetic neural activity. Am J Cardiol 1992;69: 523-531. [7] Higgins CB, Vatner SF, Eckberg DL, Braunwald E. Alternations in the baroreceptor reflex in conscious dogs with heart failure. J Clin Invest 1972;51:715-724. [8] Greenberg TT, Richmond WH, Stocking RA, Gupta PD, Meehan JP, Henry JP. Impaired atrial receptor responses in dogs with heart failure due to tricuspid insufficiency and pulmonary artery stenosis. Circ Res 1973;32:424-433. [9] Vatner SF, Buettcher DH, Heyndrickx GR, McRitchie RJ. Reduced baroreflex sensitivity with volume loading in conscious dogs. Circ Res 1975;37:236-242. [10] Zucker IH, Earle AM, Gilmore JP. The mechanism of adaptation of left atrial stretch receptors in dogs with chronic congestive failure. J Clin Invest 1977;60: 323-331. [11] Abboud FM, Thames MD. Interaction of cardiovascular reflexes in circulatory control. In: Sheperd JT, Abboud FM, eds. Handbook of Physiology. The Cardiovascular System III. Bethesda, MD: American Physiological Society, 1983: 675-753. [12] Myers HA, Honig CR. Influence of initial resistance on magnitude of responses to vasomotor stimuli. Am J Physiol 1969;215:1429-1436. [13] Greenfield ADM, Whitney RJ, Mowbray JF. Methods for the investigation of peripheral blood flow. Br Med Bull 1963;19:101-109. [14] Michel CC. Fluid movements through capillary walls. In: Sheperd JT, Abboud FM, eds. Handbook of Physiology. The Cardiovascular System VI. Bethesda, MD: American Physiology Society, 1983:375-409. [15] Katz MA. Capillary filtration measurements by strain gauge. I. Analysis of methods. Am J Physiol 1977;232:H354-H360. [16] Sejrsen P, Henriksen O, Paaske WP, Nielsen SL. Duration of increase in vascular volume during stasis. Acta Physiol Scand 1981;111:293-298. [17] Pappenheimer JR, Soto-Rivera A. Effective osmotic pressure of the plasma proteins and other quantities associated with the capillary circulation in the hindlimbs of cats and dogs. Am J Physiol 1948;152:471-491. [18] Dittrich HC, Peck WW, Slutsky RA. Sustained venous occlusion plethysmography: Effects on protein osmotic pressure, intravascular volume, and capillary filtration. Am Heart J 1984;108:548-553. [19] Longhurst J, Capone RJ, Zelis R. Evaluation of skeletal muscle capillary basement membrane thickness in congestive heart failure. Chest 1975;67:195-198. [20] Hesse B, Parving HH, Lund-Jacobsen H, Noer I. Transcapillar escape rate of albumin and right atrial pressure in chronic congestive heart failure before and after treatment. Circ Res 1976;39:358-362. [21] Anand IS, Ferrari R, Kalra GS, Wahi PL, Poole-Wilson A, Harris PC. Edema of cardiac origin: studies of body water and sodium, renal function hemodynamic indexes, and plasma hormones in untreated congestive cardiac failure. Circulation 1989;80:299-305. [22] Dzau VJ, Colucci WS, Hollenberg NK, Williams GH. Relation of the reninangiotensin-aldosterone system to clinical state in congestive heart failure. Circulation 1981;63:645-657. [23] Garrison JC, Peach MJ. Cardiovascular drugs. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. The pharmacological Basis of Therapeutics. New York: Pergamon Press, 1990;749-756. [24] Bayliss J, Norell M, Canepa-Anson R, Sutton G, Poole-Wilson P. Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics. Br Heart J 1987;57:17-22. [25] Kubo SH, Clark M, Laragh JH, Borer JS, Cody RJ. Identification of normal neurohumoral activity in mild congestive heart failure and stimulating effect of upright position and diuretics. Am J Cardiol 1987;60:1322-1328. [26] Cody RJ, Atlas SA, Laragh JH, Kubo SH, Covit AB, Ryman KS, Shaknovich A, Pondolfino K, Clark M, Camargo JF, Scarborough RM, Lewicki JA. Atrial natriuretic factor in normals and heart failure patients: plasma levels and renal, hormonal, and hemodynamic responses to peptide infusion. J Clin Invest 1986;78: 1362-1374. [27] Groban L, Cowley AW, Ebert TJ. Atrial natriuretic peptide augments forearm capillary filtration in humans. Am J Physiol 1990;259:H258-H263. [28] Rouleau JL, Bichet D, Kortas C. Atrial natriuretic peptide in congestive heart failure: postural changes and reset with chronic captopril therapy. Am Heart J 1988;115:1060-1067. [29] Henriksen O, Sejrsen P. Local reflex in microcirculation in human skeletal muscle. Acta Physiol Scand 1977;99:19-26. [30] Henriksen O, Sejrsen P, Paaske WP, Eickhoff JH. Effect on chronic sympathetic denervation upon the transcapillary filtration rate induced by venous stasis. Acta Physiol Scand 1983;117:171-176. [31] Kassis E, Jacobsen TN, Mogensen F, Amtorp O. Sympathetic reflex control of skeletal muscle blood flow in patients with congestive heart failure: evidence for [Beta]-adrenergic circulatory control. Circulation 1986;74:929-938. [32] Mark AL, Mancia G. Cardiac baroreflexes in humans. In: Sheperd JT, Abboud FM, eds. Handbook of Physiology. The Cardiovascular System III. Bethesda, MD: American Physiology Society, 1983:795-813. [33] Zoller RO, Mark AL, Abboud FM, Schmid PG, Heistad DD. The role of low pressure baroreceptors in reflex vasoconstrictor responses in man. J Clin Invest 1972;51:2967-2972. [34] Abboud FM, Eckberg DL, Johannsen UJ, Mark AL. Carotid and cardiopulmonary baroreceptor control of splanchnic and forearm vascular resistance during venous pooling in man. J Physiol (Lond) 1979;286:173-184. [35] Jacobsen TN, Morgan B, Jost C, Hansen J, Cooley R, Victor RG. Sympathetic activation during orthostatic stress is caused by mainly by arterial, not cardiac, baroreflexes (abstr). Circulation 1992;86(suppl I):I-776. [36] Cobbold A, Folkow B, Kjellmer I, Mellander S. Nervous and local chemical control of pre-capillary sphincters in skeletal muscle as measured by changes in filtration coefficient. Acta Physiol Scand 1963;57:180-192. [37] Oberg B. Effects of cardiovascular reflexes on net capillary fluid transfer. Acta Physiol Scand 1964;62(suppl 229):1-98. [38] Hebert MT, Marshall JM. Direct observations of the effects of baroreceptor stimulation on skeletal muscle circulation of the art. J Physiol (Lond) 1988;400:45-59. [39] Lundvall J, Hillman J, Gustafsson D. [Beta]-adrenergic dilator effects in consecutive vascular sections of skeletal muscle. Am J Physiol 1982;243:H819-H829. [40] Lundvall J, Jarhult J. Beta-Adrenergic dilator component of the sympathetic vascular response in skeletal muscle: influence on the micro-circulation and on transcapillary exchange. Acta Physiol Scand 1976;96:180-192. [41] Hillmann J. Beta-adrenergic control of transcapillary fluid absorption and plasma volume in haemorrhage. Acta Physiol Scand 1983(suppl 516):1-62. [42] Gustafsson D, Lundvall J. [Beta]2-adrenergic vascular control in hemorrhage and its influence on cardiac performance. Am J Physiol 1984;246:H351-H359. Tage N. Jacobsen, MD, Eli Kassis, MD PhD, and Ole Amtorp, MD PhD From the Department of Cardiology, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark. This study was supported by the Danish Heart Foundation. Dr. Jacobsen is the recipient of N.I.H. Fogarty International Fellowship 1991-1992.

Twenty patients on conventional therapy for severe congestive heart failure (CHF) were randomly assigned to adjunctive treatment with felodipine (n = 10) or placebo (n = 10) and followed over a 6-month period. Baseline clinical, hemodynamic, angiographic, and neu-rohumoral estimates of CHF were comparable in the two treatment groups. These estimates remained virtually unchanged at 6 months in patients on placebo therapy, but circulating noradrenaline levels were further augmented. In patients on felodipine therapy, substantial reductions in left ventricular end-systolic pressure, mean arterial pressure, and systemic vascular resistance were observed at 6 months. This afterload reduction led to a preferential increment in the stroke volume (36) which increased cardiac output (30), whereas heart rate tended to decrease. The improved hemodynamics during felodipine treatment were paralleled by marked improvements in the angiographic left ventricular ejection fraction and regional segmental wall motion score. The enhanced contractile state of the left ventricle was accompanied by significant reductions in the augmented plasma levels of catecholamines, and the patient clinical status improved. The 6-month mortality rate in the 20 patients was 40 and indicated a closer relation to baseline noradrenaline plasma levels than to hemodynamic or angiographic estimates of CHF. Despite the limited number of patients, the long-term clinical efficacy of felodipine is thus evidenced in patients with CHF and is related to sustained arteriolar dilatation and improved neurohumoral profile by this vasoselective calcium antagonist.

1. Central and local regulation of forearm subcutaneous vascular resistance (FSVR) during postural changes were studied in congestive heart failure (CHF). Blood flow was measured by the local 133Xe-washout technique. Nine patients with severe CHF (baseline angiographic ejection fraction, 23 ± 2%, mean ± sem; cardiac index, 2.2 ± 0.2 litres min−1 m−2; increased left ventricular pressures and dimensions) were compared with seven control subjects who had normal cardiac performance. 2. Baseline FSVR and plasma concentrations of noradrenaline and adrenaline were substantially higher in patients with CHF than control subjects. However, the patients, like control subjects, increased FSVR by 46 ± 3% in response to increase in local venous transmural pressure and disclosed a normal response to decrease in forearm perfusion pressure. Both responses to changes in vascular transmural pressure were preserved after either proximal nervous blockade or local β-receptor blockade. 3. Central sympathetic stimulation was induced with use of 45° upright tilt. Control subjects developed vasoconstriction (FSVR increased by 59 ± 5%), which was completely abolished after proximal nerve blockade. Patients with CHF developed vasodilatation (FSVR decreased by 24 ± 8%), which was not only abolished but reversed after proximal nerve blockade (FSVR increased by 22 ± 7%), probably owing to the increased humoral vasoconstrictor activity. The paradoxical vasodilator response to central sympathetic stimulation in these patients was reversed after local β-receptor blockade (FSVR increased by 19 ± 9%). 4. The local vasoconstrictor reflex responsiveness and intrinsic vascular reactivity were not affected by the augmented baseline sympathetic vasoconstrictor activity in patients with CHF. Central sympathetic stimulation seems to elicit a β-adrenergic reflex effect intended to improve perfusion of the subcutaneous tissue in these patients.